Issue in Honor of Prof.

Nikolai Zefirov

ARKIVOC 2005 (iv) 49-87

Recent developments in guanylating agents

Alan R. Katritzky*, and Boris V. Rogovoy Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, P. O. Box 177200, Gainesville, FL 32611-7200 Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854 E-mail: [email protected] Dedicated to Professor Nikolai Zefirov on the occasion of his 70th birthday (received 26 Oct 04; accepted 08 Jan 05; published on the web 05 Jan 05) Abstract Guanidines are important molecules with a wide range of interesting properties. In this overview we summarize recent advances in the development of guanylating reagents which we define as compounds forming a guanidine structure by a chemical transformation. We cover important classes of guanylating agents developed in the last two decades and representative examples are reported. Keywords: Guanidine, guanidines, guanylating agent, guanylation, synthesis, preparation

Contents
1. Introduction 2. Reagents for the Preparation of Guanidines 2.1. Thioureas 2.2. Isothioureas 2.3. Carbodiimides and Cyanamides 2.4. Pyrazole-1-carboximidamides 2.5. Triflyl guanidines 2.6. Aminoiminomethane sulfonic and -sulfinic acids 2.7. Benzotriazole and Imidazole-containing Reagents 3. Conclusions 4. References

1. Introduction
Guanidines possess great biochemical and pharmaceutical importance. Guanidine itself is a strong base (pKa of conjugated acid is 12.5) as are substituted guanidines.1a Guanidine was first prepared by Strecker in 1861 by oxidizing guanine. The biological role, chemical and biochemical properties of natural and synthetic guanidine derivatives have been outlined.1b The

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natural amino acid, L-arginine 1, is often found at active (or catalytic) sites in proteins and enzymes; it is critical for the normal function of living organisms.2
NH H2N N H 1 COOH NH2

Many natural guanidines have been isolated and tested for biological activity. The isolation, structural identification and synthesis of naturally occurring guanidines have been reviewed by Berlinck.3a-d The isolation and synthesis of guanidine metabolites from Ptilocaulis spiculifer has also been summarized.3e Isolation of guanidine compounds as metabolites provides leads for the prevention of metabolic disorders and helps the prognosis of cancer, cardiovascular diseases, diabetes etc.3f Recent examples of synthetic, biologically-active guanidines include antimicrobial activity,4a,b thrombin inhibitors,5 Na+/H+ exchanger (NHE) inhibitors,6a,b transport for the delivery of anti-cancer agents,7a,b anti-influenza agents.7d Figure 1 shows a few examples of superpotent sweeteners with the guanidine core structure;8a which have attracted a great deal of recent interest.8b-e

NC NC N H N CN N H CH2O2H NC N H N CN N H CO2H

H N N

H N CN

H N CO

NC CO2CH3 N H

SO2 N H CO2H

CO2H 40,000 x sucrose

900 x sucrose

7,000 x sucrose

45,000 x sucrose

NC N H

NC N N H CO2H N H

N N H CO2H

NC N H

N N H CO2H

30,000 x sucrose

170,000 x sucrose

200,000 x sucrose

Figure 1. Superpotent guanidine sweeteners. Guanidines are also known as useful basic catalysts.1a,9 Several reports describe the synthesis of chiral guanidines and their use in asymmetric synthesis.10a-c An excellent review of preparative methods for guanidines was prepared by Anslyn et al.,11a and others have emphasized solid phase synthesis.11b,c Their wide importance has prompted the investigation of new approaches to guanidine derivatives. In this overview we summarize recent advances in the development of guanylating reagents (i.e. compounds which form the guanidine structure by a chemical transformation) for guanidine synthesis. Functionalizations of pre-existing guanidine cores, e.g., by alkylation, arylation or acylation are not covered. We do not attempt to catalog exhaustively the enormous

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range of synthetic guanidine derivatives, but limit our review to reports describing the discovery of guanylating reagents, and investigations of reaction conditions (time, temperature, catalysis etc.) undertaken to improve the yields of guanidines. Reports of the preparation of guanidine compounds by previously developed methods (such as the synthesis of guanidine natural products and oligomers) are also outside the scope of this report.

2. Reagents for the preparation of guanidines

2.1. Thioureas Thioureas are common reagents for the synthesis of guanidines. Usually the conversion of a thiourea into a guanidine requires initial activation. However, in many cases the characterization, isolation or even definition of active intermediates is not described. Scheme 1 presents the conversion of thioureas 2 into guanidines 4 in a suitable solvent (THF, acetonitrile, or chloroform) containing copper sulphate silica gel in the presence of tertiary amines.12 The formation of the intermediate carbodiimide 3 (non-isolable under these conditions) proceeds quickly and the overall reaction time is short (Table 1). The presence of a tertiary amine, e.g., triethylamine, accelerates the desulfurization. The procedure allows the preparation a very wide range of di-, tri- and tetra-substituted guanidines.
S R1 N H 2 N H R1 CuSO4, SiO2 TEA, THF, rt N R2R3NH rt, stirring R1 R2 N H N R3 N 4 R1

C 3

R1

Scheme 1 Table 1. One pot desulfurization of thioureas and reaction with an amine by the procedure of Scheme 1 Entry 1 2 3 4 5 6 7 8 9 10 11 R1 Ph Ph Ph Ph Ph Ph o-Tolyl Ph o-Tolyl C6H11 n-Bu R2 CH3 CH3 C6H11 C2H5 PhCH2 n-Bu C2H4OH H H H H R3 H CH3 H C2H5 H H H H H H H Reaction time, min 50 55 50 50 50 45 55 50 50 60 50 Yield, % 78 75 85 90 80 75 75 90 85 86 80

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Electron withdrawing substituents in the thiourea fragment also accelerate the reaction. Many recent synthetic approaches utilize protected thioureas, containing electron withdrawing protecting groups which can be removed by standard methods. Thus, di-Boc protected thiourea 5 is converted into guanidines 7 by amines in the presence of 1-methyl-2-chloropyridinium iodide13 6 (Mukaiyamas reagent, Scheme 2, Table 2) as follows: (i) primary and unhindered secondary amines are guanylated in high (>80%) yield using a slight excess of reagent in anhydrous DMF (entries 1-4); (ii) for hindered or unreactive amines, methylene chloride provides a substantial increase in yield (entries 7 and 8) over reactions run in DMF (entries 5 and 7). The effect of solvent on yield probably results from the instability of the carbodiimide intermediates. When nucleophilic attack by an amine is slow, competitive decomposition of the carbodiimide occurs. In methylene chloride, the reactions are heterogeneous owing to sparing solubility of the di-Boc protected thiourea; it is believed that this results in slower production of the di-Boc carbodiimide and consequently, more efficient consumption of the thioureum by less reactive amines. The guanylation of resin-bound amines under these conditions was also examined.

S Boc N H 5 N H Boc + R1R2NH

Cl N CH3 I 6

R1 Boc N

R2 N H Boc

Scheme 2 Table 2. Preparation of guanidines from thioureas promoted by Mukaiyamas reagent (Scheme 2) Entry 1 2 3 4 R1R2NH PhCH2NH2 Diallylamine Piperidine
Ph H2N CO2Me

Solvent DMF DMF DMF DMF

Product yield, % 91 86 57 85

5 6 7 8 9

Diisopropylamine Diisopropylamine Aniline Aniline 4-Nitropyrazole

DMF CH2Cl2 DMF CH2Cl2 DMF

21 71 34 92 43

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Ethoxycarbonyl substituted thioureas 8 are prepared using the corresponding isothiocyanate (Scheme 3). Guanidines 9 are prepared by displacement of sulfur in the presence of ethyl-3aminopropyl carbodiimide hydrochloride (EDCI)14 in 48 h without the formation of any major side products. The guanidines obtained via EDCI coupling (Table 3) were easily purified by flash chromatography. Deprotection can be achieved by the treatment with Me3SiBr.
O SCN O Me + Ph NH2 CH2Cl2 2 h, 98 % Ph N H 8 S N H O O Et R1NH2, EDCI Et3N, CH2Cl2 Ph R1 NH O O Et

N N H 9

Scheme 3 Table 3. One pot preparation of guanidines by EDCI desulfurization and reaction of with amines (of Scheme 3) Entry 1 2 3 4 5 R1NH2 Benzylamine 4-Aminobenzylamine 4-Nitrobenzylamine 4-Methoxybenzylamine 2,4-Dimethoxybenzylamine Yield, % 80 83 88 85 78 Entry 6 7 8 9 R1NH2 2-Methylbenzylamine Aniline i-Propylamine t-Butylamine Yield, % 80 87 85 83

Amines can be converted into guanidines 11 by the reaction di-Boc thiourea 515 in the presence of mercuric chloride or copper(II) chloride in the presence of triethylamine (Scheme 4). The influence of the desulphurizing agent is shown in Table 4.
S Boc N H N H Boc
1 2

R1 Boc N H

R R NH HgCl2 or CuCl2 Et3N, DMF

R2 Boc

N 11

Scheme 4

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Table 4. Preparation of guanidines in the presence of copper or mercuric salts (see Scheme 4) Entry 1 Amine
CO2Bn N H
Me Me N H N

Metal Salt HgCl2 CuCl2 HgCl2

Conditions 0 oC, 20 min 0 oC, 0.5 h, rt, 0.5 h 60 oC, 2 h

Yield, % 90 62 87

3 4

CF3CH2NH2
Cl NH2

HgCl2 None HgCl2 HgCl2 none HgCl2

rt, 1 h 60 oC, 4 h rt, 2 h rt, 20 h 60 oC, 6 h 0 oC, 0.5 h

89 0 78 92 0 90

((CH3)2CH)2NH

N-Boc-N'-alkyl or aryl thioureas 12 reacted smoothly with an aryl or alkyl amine in the presence of HgCl216a (Scheme 5). The N- boc-N',N"-disubstituted guanidine products 13 are easily deprotected, as shown in Scheme 5, providing an efficient route to N,N'-disubstituted guanidines14, which compares favorably with other methods (Table 5). For an adaptation to solid phase synthesis see ref 16b.
S R N H 12 N H Boc Boc R R NH Et3N, HgCl2 DMF, rt
1 2

N N R1 13 R2 30% TFA-DCM 3h, rt R

H N H

N N R1 14 R2

N H

Scheme 5 Table 5. Synthesis of protected guanidines in the presence of HgCl2 (see Scheme 5) Entry 1 2 3 4 5 6 7 8
a

X Boc Boc Boc CH3CO PhCO PhCH2CO Ts CN

R Cyclohexyl Cyclohexyl 4-Nitrophenyl Cyclohexyl Cyclohexyl Cyclohexyl Cyclohexyl Cyclohexyl

R1R2NH 2-Tetrahydroisoquinoline Aniline 4-Methoxyaniline 2-Tetrahydroisoquinoline 2-Tetrahydroisoquinoline 2-Tetrahydroisoquinoline 2-Tetrahydroisoquinoline 2-Tetrahydroisoquinoline

Yield, % 63 70 85 75 75 67 83(41a) 61a

Overall yield for the two steps: formation of thiourea and in situ conversion into a guanidine derivative.
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Carbamoyl isothiocyanates 15 possess several advantages for the preparation of thioureas17 (Scheme 6, Table 6): These reagents provide a protecting group throughout the synthesis, facilitating purification, and they show increased reactivity over alkyl isothiocyanates, forming thioureas even with hindered amines. A second amine can be coupled to the carbamoyl thiourea 16 using EDCI, forming 1,3-disubstituted and 1,1,3-trisubstituted guanidines 17 through either a stepwise or one-pot synthesis. To gauge the steric and electronic limitations of this procedure, amines of varying reactivity (A-G) were investigated for their ability to form protected thiourea and guanidine; yields for reactions of ethoxycarbonyl isothiocyanate are shown in Table 6. This procedure is general for other carbamoyl isothiocyanates (ethyl carbamate, benzyl carbamate (Cbz), 2,2,2-trichloro-1,1-dimethylethyl carbamate, fluorenylmethyl carbamate (Fmoc), and phenyl carbamate) which allows synthetic flexibility in the deprotection.
O R
1

O 15

Amine A-G

O R1 O 16 N H

S C

Amine A-G NR2R3 R1 O

NR2R3 C NR4R5 N

17

NH2 A Me

Me Me NH2 Me B

Me NH O C OMe O2N Me N H D

Me Me

NH2 E F

NH2 G

NH2

Scheme 6 Table 6. Synthesis of protected thioures 16 and guanidines 17 (see Scheme 6) Amine % Yield of thiourea 16 A 99 B 99 C 99 D 99 E 92 F 77 G 72 A 99 99 0 0 99 96 85 B 99 74 0 0 87 99 76 % Yield of guanidine 17 C D E F 95 76 92 82 59 55 99 99 0 0 0 0 0 0 0 0 99 81 95 97 61 84 98 67 99 42 35 34 G 85 65 0 0 34 39 0

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N-Hydroxyguanidines 19 were prepared from 1-benzyloxy-3-Cbz-thiourea 1818 (Scheme 7, Table 7). The Cbz strategy was chosen because cleavage of the Cbz and benzyl groups could be accomplished simultaneously. The solvent of choice was DMF; mercuric chloride provided efficient desulphurization.
S Cbz N H 18 N H OBn R1R2NH HgCl2, Et3N DMF Cbz R1 N H N R2 N 19 OBn

Scheme 7 Table 7. Synthesis of hydroxyguanidines in the presence of HgCl2 (see Scheme 7) Entry Amine Reaction time, h Yield, % 1 Benzyl amine 7 47 2 2-Aminocarbonylaziridine 9 34 3 Aniline 7.5 54 4 Diisopropylamine 9 34 5 3-Hydroxypropylamine 7 35 6 Aminoadamantane 10.5 67 The desulphurization of a thiourea to a carbodiimide and subsequent reaction with an amine was applied to solid phase synthesis.19 The thiourea 20 was treated with an amine (5 equiv.) at 50C in CHCl3 in the presence of DIC (diisopropylcarbodiimide) (5 equiv.) and DIEA (5 equiv.) to give the resin bound guanidine 21. The disubstituted guanidine 22 was then cleaved under mild Rink resin cleavage conditions (25% TFA/CH2Cl2 at room temperature) (Scheme 8, Table 8).
S N H 20 NHR1 DIC, DIEA CHCl3, 50 oC 2d R2R3NH R2 N H 21 N R3 NR1 TFA/DCM R2 H2N 22 N R3 NR1

Scheme 8

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Table 8. Conversion of thioureas to guanidines on solid phase (of Scheme 8) Entry 1 2

N H

Product
NH N H N

Yield, % 71 77 70 95

Purity 70 54 56 86 91 75 90 85 95 83 83 83

NH N H

3
N H

NH N

4
N H

NH N

5
N H

NH N H

98 89 87
N

6
N H

NH N

7 8 9 10 11 12
Cl
O 2N

O2N N H

NH N

NH N H N H

95 96 100

O2N N H
Cl N H NH

NH N

NH N H N H

99 88

Cl N H

NH N

The approach of Scheme 9 combines the advantages of traditional solution phase chemistry with the application of polymeric reagents.20 The desired compounds are obtained in a high throughput manner without additional purification, and in satisfactory purity. No base is required.
S BocHN 5 + R R NH
1 2

NHBoc H N

N N C

23 NH2 NH2 24 BocN

NR1R2 NHBoc 25

Scheme 9

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The use of TFA-cleavable Pbf-group protection/activation is an advantageous alternative for the synthesis of guanidines21a (Scheme 10). Primary or secondary amines, including tertbutylamine and diisopropylamine, in the presence of Mukaiyamas reagent, give guanidines 27 in high yields at room temperature and in 12-18 h. The high efficiency of Mukaiyamas reagent in promoting the guanidinylating reaction contrasts with its role in sulfamoylthiourea based systems. The transformation also succeeds with EDCI in place of Mukaiyamas reagent. No heavy metal salt or excessive heating was needed.
Mukaiyama reagent NHR 26
1

S Pbf HN

NR2R3 NR 27
1

Me Pbf = Me Me O Me O S Me O

Mukaiyama's reagent

DIEA HN THF/DMF Pbf

N Cl Me I

Scheme 10 Solid phase strategy for the preparation of guanidines 30 has also applied triphenylphosphine dichloride as a desulphurizing agent.21b The immobilised thiourea 28 was treated with triphenylphosphine dichloride freshly prepared from triphenylphosphine with hexachloroethane in THF. The use of base proved to be detrimental.
O O H 1N R S 28 29 R2R3NH O O R
1N

NR R

2 3

NR R NR R
4 5

2 3

PPh3/C2Cl6 R4R5NH O HO R1

NR2R3 NR4R5

30

Scheme 11 The preparation of N,N'-disubstituted acylguanidines from primary amides 31, isothiocyanates 32 and amines 21b has utilized three alternative one pot procedures: HgCl2, EDCI and Mukaiyamas reagent; each showed comparable yields of guanidines.
O R 31 NH2 R1NCS 32 NaH/DMF O S 33 A = HgCl2 B = EDCI, DMAP, Et3N C = 2-Chloro-1-methylpyridinium Iodide Na N H N R2NH2 A or B or C

R1

N O HN 34

H N R2

R1

Scheme 12 2.2. Isothioureas As well as thioureas, isothioureas, particularly S-methylisothioureas, are well developed as guanylating agents due to their easy preparation and availability.

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Guanidines have been successfully prepared from N-arylsulfonyl S-methylisothioureas.22 The Mtr-reagent 35 (Mtr is 4-methoxy-2,3,6-trimethylphenylsulfonyl) reacted with piperidine or aniline in the presence of triethylamine and Hg(ClO4)2 in refluxing THF (or toluene) to produce mono Mtr-protected guanidines 36 in moderate to good yields (Schemes 13, Table 10). Higher yields were obtained when the reactions were carried out in refluxing THF in the presence of triethylamine and mercuric perchlorate.
Me Me NH2O H3C S S Me Me O + R1R2NH R1 Me Me NH O N R2 N H S O 36 Me Me O

N O 35

Scheme 13 Table 10. Synthesis of Mtr-protected guanidines 36 (of Scheme 13) Entry 1 2 3 4 5 6 7 8
O O NHBoc O O NH2

R1R2NH
NH

Conditions HgCl2 (1.1 eq.), THF, HgCl2 (1.1 eq.), Et3N (2 eq.), toluene, Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), toluene, AgClO4 (1.1 eq.), Et3N (2 eq.), toluene, Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), THF, HgCl2 (1.1 eq.), Et3N (2 eq.), toluene, Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), toluene, HgCl2 (1.1 eq.), Et3N (1.5 eq.), THF, AgClO4 (1.1 eq.), Et3N (2 eq.), toluene, Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), THF,

Yield, % 42 37 62 46 80 >20 47 51

NH

NH

NH

NH NH2

NH2

NHBoc NH2

71

10

O O

NHBoc NH2

93

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Reagents 35 and 37 (Schemes 13,14) were evaluated with several substrates to determine optimal conditions (Tables 10, 11). The reagents were reacted with Boc-Lys-OMe.HC1 and Bocp-aminophenylalanine-OMe. The protected lysine ester (Table 11, Entries 1-3) has a primary aliphatic amine side chain but appears to react with 35 and 37 less readily and in lower yield, than the other substrates. The Boc-p-aminophenylalanine-OMe substrate reacts efficiently with both reagents in high yield to produce the target guanylated amino acids (Entry 4). These results indicate that arylsulfonyl isothioureas react with the less nucleophilic electron deficient amines more readily than the more basic primary aliphatic amines.
Me Me NH O H3C S S N H O Me 37 O Me Me Me + R1R2NH R1 Me NH O S N N O R2 H 38 O Me Me Me

Scheme 14 Table 11. Synthesis of Pbf-protected guanidines 36 by procedure of Scheme 14 Entry 1

Me O O
NHBoc Me O O NH2

R1R2NH
NHBoc NH2

Conditions Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), toluene, , 16 h

Yield, % 24

Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), THF, , 48 h

35

3
Me O O

NHBoc NH2 NHBoc NH2

Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), THF, , 60 h

41

Me O O

Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), THF, , 60 h

93

CF3CH2-

Hg(ClO4)2 (1.1 eq.), Et3N (2 eq.), neat, , 16 h

72

The relatively easy activation of thioureas 39 as thiazetidines 40 provides tri- and tetrasubstituted guanidines 41 23 (Scheme 15, Table 12) in good to excellent yields.
S R1 N H N H R2 CH2I2 Et3N S N N R2 R3R4NH R1 R3 N N R4 N H R2

39

40

41

Scheme 15

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Table 12. Synthesis of polysubstituted guanidines via thiazetidine derivatives 40 (of Scheme 15) Entry 1 2 3 4 5 6 7 8 9 R1 2,4-Cl2-C6H3-CO 2,4-Cl2-C6H3-CO 2,4-Cl2-C6H3-CO 2,4-Cl2-C6H3-CO 2,4-Cl2-C6H3-CO 2,4-Cl2-C6H3-CO 4-CH3-C6H4-CO 4-CH3-C6H4-CO 4-CH3-C6H4-CO R2 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 4-Cl-C6H4 Ph Ph Ph R3 PhCH2 CH3 n-C3H7 i-C3H7 CH3 (EtO)2CHCH2 CH3 (CH2)5 (CH2)2O(CH2)2 R4 H H H H CH3 H CH3 Yield,% 92 68 90 89 80 58 99 76 88

Reactions of S-methylisothioureas 42 24 with various cyclic amines in refluxing tert-butyl alcohol gave almost a hundred salts of guanidine (Table 13, See Supplemental Materials) in fair to good yields (Scheme 16), accommodating phenyl substituents ranging from strongly electron withdrawing to strongly electron donating, as well as those with bulky substituents in the orthoposition. Either the isothiourea or the amine should be in the form of a soluble salt to achieve the satisfactory reaction rates.
H3C H2N S NR3 R1R2NH NR1R2 H2N NR3

t-BuOH or CH3CN

42

43

Scheme 16 Mild and efficient promotion by mercuric chloride converts di-Cbz-isothioureas 44 into protected guanidines 4525 (Scheme 17, Table 14). Free and Cbz-protected guanidinoacids 47 were prepared similarly (Scheme 18, Table 15) from 44 and 46 by in situ carboxyl protection with trimethylsilyl chloride at the first stage of the reaction.26 Simple crystallization after work up provided pure materials. The utility of generating a protected guanidine was established further by converting Gly-Gly to -(bisbenzyloxycarbonyl)guanidinoacetylglycine.
NCbz Me CbzHN S 44 RNH2 HgCl2, Et3N, DMF rt NCbz R CbzHN N H 45

Scheme 17

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Table 14. Synthesis of Cbz-substituted guanidines in the presence of HgCl2 (of Scheme 17) Entry RNH2 Yield, % 1 Ethyl 3-aminobutyrate hydrochloride 92 2 Benzylamine 75 3 4-Bromoaniline 83 4 m-Nitroaniline 58 5 3-Amino-4chlorobenzoic acid 56 6 3-Aminoacetophenone 89 7 3-Aminobenzyl alcohol 92
NHCbz NCbz Me CbzHN S 44 NH2.HCl + CbzHN 46 (CH2)n COOH Method A or B HN NCbz

(CH2)n CbzHN 47 COOH

Scheme 18 Table 15. Synthesis of Cbz-substituted guanidines in the presence of HgCl2 (of Scheme 18) Entry 1 2 3 4 5 6a 6b 7 8 9 10 Amino acid N-Cbz-L-Orn.HCl N-Cbz-L-Lys.HCl H2NCH2COOH (S)PhCH2CH(NH2)COOH H2N(CH2)2COOH H2N(CH2)3COOH H2N(CH2)3COOH.HCl H2N(CH2)4COOH H2N(CH2)5COOH HCl.p-NH2CH2C6H4COOH Gly-Gly Method A A B B B B A B B A B Molar ratio Yield, % Amino acid/reagent 1:1.25 87 1:1.1 62 1.2:1 97 1.2:1 84 1.2:1 92 1.2:1 92 1.2:1 92 1.2:1 91 1.2:1 80 1.2:1 97 1.2:1 69

Guanidinoureas 49 and 50 were obtained by condensation of N-Cbz-ureido-N`-Cbz-Smethylisothiourea 48 27 with amines in the presence of triethyl amine in DMF at 20 oC (Scheme 19. Table 16). In the reaction with butylamine, a triazinedione by-product 52 formed, but all the other cases gave exclusively guanidine compounds.

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R2NH

+ CbzHN

O N H 48

Me NCbz

Et3N DMF CbzHN

H2 (60 psi) 20% Pd(OH)2/C H2N

R N 50

R NH2

N NCbz H 49

NHCbz n-BuNH2 + CbzHN O N H 48 S Me Et3N O HN N H 48% 51 Bu + NCbz Bu O DMF NCbz CbzHN N N O

N H 44% 52

Scheme 19 Table 16. Synthesis of guanylureas 50 Entry Amine Yield of protected product, % Yield of final product, % 1 Piperidine 81 96 2 Morpholine 75 97 3 c-Hexylamine 99 93 4 n-Butylamine 48 99 A library of acylguanidinoureas has been reported.28a Isothioureas 53 were carbamoylated by a resin bound reagent, then acylated. Susequent aminolysis of the thiomethyl group in the presence of mercuric chloride led to 54 which were cleaved to give the guanidine library (Scheme 20, Table 17).
O O R1 H N O 53 H N R3R4NH O HgCl2, Et3N DMF R
1

N SH O

H N

H N

R2

O 3 N 4O R R 54

Scheme 20

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Table 17. Solid phase synthesis of guanylureas 54 (of Scheme 20) Entry R1 1 H 2 CH3 3 i-Butyl 4 H 5 H 6 H 7 H 8 i-Butyl 9 i-Butyl 10 i-Butyl 11 Benzyl 12 Benzyl 13 Benzyl 14 4-Aminobutyl 15 4-Aminobutyl R2 PhCH:CH c-Hexyl PhCH2 Ph c-Propyl 2-NO2C6H4 2-CH3OC6H4 PhOCH2 3-BrC6H4 4-pyridyl c-Hexyl 2-NO2C6H4 c-Propyl PhOCH2 4-CH3OC6H4CH2 R3 R4 Benzyl H Benzyl H 2-Benzothiazolyl H n-Butyl H 2-CH3OC6H4CH2 H i-Propyl i-Propyl -(CH2)4Benzyl H Benzyl H -(CH2)4Benzyl H -(CH2)4Benzyl H Benzyl H 2-CF3C6H4 H Yield,% 55 49 83 91 86 76 47 85 76 59 93 57 93 92 53 Purity 72-95 72-95 72-95 85 95 90 95 95 88 95 57 97 99 92 94

Another solid support approach for acyl guanidine synthesis utilizes resin bound Smethylthioureas 55.28b Displacements of the methylthio group with ammonia, primary or secondary amines and aniline all proceeded cleanly at room temperature to give 56 which we than cleaved to 57.
1. R1COOH O O 55 H N S NH PyAOP, DIEA NMP Me 2. R R NH, NMP
2 3

O O

H N N

R2 N

R3 R1

25% TFA DCM R1

O N 57

NH2 N R3 R2

56

Scheme 21 Commercially available di-Boc-S-methylisothiourea 58 reacted with amines in the presence of mercuric chloride at 0-20 oC affording, after simple work up, the guanylated products 59 in goods yields29 (Scheme 22). The results, summarized in Table 18, illustrate the broad application of the reagent. Since the synthesis is equally successful with aliphatic and aromatic amines. Sterically hindered amines react well as do anilines with electron donating groups. Electron deficient anilines react slowly to afford the guanylated product in acceptable yields.

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Me BocHN

S NBoc

R1R2NH HgCl2, Et3N DMF, 0 oC

R1 BocHN

NBoc

58

59

Scheme 22 Table 18. Preparation of guanidines 59 Entry 1 2 3 4 5 6 7 R1 i-Pr Ph 3-HOCH2C6H4 3-NO2C6H4 4-HOC6H4 2-NO2-4-HOC6H4 o-Phenylenediamine R2 i-Pr H H H H H H, H Yield, % 77 89 89 68 87 87 80

Guanidinoglycosides 61 were prepared by the intramolecular cyclization of -amino NFmoc-protected acyl isothioureas 60 (Scheme 23). A catalytic amount of DBU (0.7% equiv) is optimal for converting these isothioureas into guanidinoglycosides (35-66%) within an hour.
R1 R2 AcO OAc DBU/THF HN Me S N O R3 NHFmoc rt, 1 h R1 R2 AcO OAc

AcO 60

AcO 61

HN HN

R3

Scheme 23 S-Linked isothioureas 64 were formed via bis-electrophilic chlorothioformimines 63, as key intermediates.31 Dithiocarbamates were prepared from amines, carbon disulfide and benzyl chloride. Benzyl chloride was chosen for this study because it mimics the Merrifield resin. The dithiocarbamates 62 are quantitatively converted into the corresponding chlorothioformimines 63 by treatment at 60 C with phosgene in toluene for 12 h. The first amine converts chlorothioformimines 63 into the isothiourea 64 without double addition. The second substitution to give 65 was effected at 100 C, with an excess of a third amine, optimally in toluene. The reported reaction sequence is well adapted for SPS since it allows, in a four-step process, the addition of three primary amines under reaction conditions compatible with a wide variety of functional groups (Scheme 24). Moreover since the reaction conditions are suitable for automation and high-throughput synthesis, it appears possible to prepare large libraries of guanidines by this traceless linker strategy.

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CS2, R1NH2 Cl Merrifield Resin THF, rt 12 h S

S N H R1 COCl2, PhH 60 C, 12 h
o

Cl S N 63 R1

62

R2NH2 60 oC, 12 h R2 R3 N H 65 R3NH2 N H R1 PhH, 100 oC, 60 h R2 S 64

N N H R
1

Scheme 24 S-Linked isothioureas 66 as a masked guanidine scaffold allow the parallel synthesis of mono and dialkylated guanidines in high yield and purity32 (Scheme 25, Table 19). This procedure allows a high level of diversity using parallel array or combinatorial synthesis. The initial Mitsunobu step allows the use of either primary or secondary alcohols to generate 67 with the first point of diversity. Subsequent treatment of the resin bound N-alkyl isothioureas 67 with ammonia or primary amines liberates traceless guanidines 68 with a second point of diversity.
NBoc S R1OH S 67 NBoc NBoc R1 R2NH2 DMF 80 oC R
2

NHBoc PPh3, DIAD THF 66

NBoc TFA/CH2Cl2 NH R2 R1 R1 N N N N H H H Boc 68 69

Scheme 25 Table 19. Traceless solid phase synthesis of guanidines via S-linked isothioureas (of Scheme 25) Entry R1OH R2NH2 Purity of DiBoc, % 95 95 95 95 100 90 86 * * * * * Yield of DiBoc, % 88 100 88 95 95 85 85 90 92 92 96 0

1 PhCH2OH NH3 2 PhOCH2CH2OH NH3 3 BocNH(CH2)3OH NH3 4 PhCHC(CH3)CH2OH NH3 5 (CH3)2CCHCH2OH NH3 6 (CH3)2CHCH2C(CH3)OH NH3 7 (CH3)2CCH(CH2)2C(CH3)OH NH3 8 PhOCH2CH2OH PhCH2NH2 9 PhOCH2CH2OH c-propylamine 10 PhOCH2CH2OH (CH3)2CH(CH2)2NH2 11 PhOCH2CH2OH BocNH(CH2)3NH2 12 PhOCH2CH2OH 2-MeOC6H4NH2 * - Purity of compound was not determined.

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Another combinatorial synthesis of guanidines utilizes resin bound thiourea 70, which after conversion into the isothiourea 71 by treatment with iodomethane, reacted with primary or secondary amines to give polymer supported guanidines 72. Cleavage provided access to a variety of guanidines 7333 (Scheme 26, Table 20).
O HN n NH NHFmoc 20% piperidine/DMF CH3I/DMF O HN n 71 NH S HN
1 2

R R NH DMSO, 70 oC

S n = 0, 1 70 O HN n 72 NH HN R1 N R2 95 : 5 TFA/H2O H2N

O n 73 NH HN R1 N R2

Scheme 26 Table 20. Synthesis of guanidines via resin-bound isothioureas (of Scheme 26) Entry 1 2 3 4 5 6 7 8 9 10 n 0 0 0 0 0 1 1 1 1 1 R1R2NH Morpholine Piperidine N-Methyl-N-phenethylamine 4-Methoxyphenethylamine n-Butylamine Morpholine Piperidine N-Methyl-N-phenethylamine 4-Methoxyphenethylamine n-Butylamine Purity, % 73 80 82 40 44 88 92 89 79 82 Yield, % 77 89 73 64 64 95 95 93 72 83

Cyanoguanidines 76 were obtained in high yields by the reaction of substituted isothioureas 75 with cyanamide34 in boiling butanol in the presence of 1,4-diazabicyclo[2.2.2]octane (Scheme 27, Table 21).
S R1 N H 74 N H R2 CH3I acetone Me R1 N H 75 S N NH2CN R2 1,4-diazabicyclo- R1 N [2,2,2]octane H BuOH, relux N CN N H 76 R2

Scheme 27

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Table 21. Synthesis of cyanoguanidines 76 in the presence of 1,4-diazabicyclo[2.2.2]octane (see Scheme 27) Entry 1 2 3 4 5 6 7 8 9 10 11 12 R1 Ph Ph Ph Ph c-Hexyl c-Hexyl c-Hexyl Bn Bn Bn Bu Bu R2 Ph Me Allyl c-Hexyl Me Allyl c-Hexyl Ph Me c-Hexyl Ph c-Hexyl Yield, % 68 70 77 77 73 76 73 67 73 69 74 70

Readily available dithiobiuret 77 and amines in refluxing isopropanol35 provide a convenient method for the preparation of mono N-substituted guanylthioureas 79 in moderate to very good yields (Scheme 28, Table 22).
S H2N N H 77 S NH2 CH3I (excess) THF, rt Me H2N S N 78 S NH2 R1NH2 i-PrOH reflux R1 H2N NH N 79 S NH2

Scheme 28 Table 22. Synthesis of guanylthioutreas from dithiobiuret 78 by method of Scheme 28 Entry 1 2 3 4 5 R1 Ethyl c-Pr n-Pentyl n-Hexyl 2-(Ethoxy)ethyl Yield, % 34 57 68 75 73 Entry R1 Yield, % 6 2-(Acetylamino)ethyl 56 7 2-(t-Boc-amino)ethyl 75 8 Benzyl 75 9 3-Pyridylmethyl 58 10 Phenyl 28

2.3. Carbodiimides and cyanamides N-Aryliminophosphoranes 80 were converted into N1,N2,N3-triarylguanidines 83 in good yields by reaction with isocyanates 81 followed by treatment of the intermediate N1,N2diarylcarbodiimides 82 with aromatic amines in the presence of TBAF.36 The presence of one equiv of TBAF is essential and the reaction takes place at room temperature within 10 min to

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give the desired guanidine (Scheme 29). As the commercially available THF solution of TBAF containes ca. 5 wt% water, it was pretreated with anhydrous MgSO4.
Ar3NH2 TBAF THF rt Ar3 Ar1 N H 83 N N H Ar2

Ar

N PPh3 + Ar2-NCO 80 81

THF rt

Ar1 N C N Ar2 82

Scheme 29 Table 23. Synthesis of carbodiimides 82 and guanidines 83 (Scheme 29) Entry 1 2 3 4 5 6 Ar1 2-BrC6H4 4-CH3C6H4 2-BrC6H4 4-CH3C6H4 C6H5 2-pyridyl Ar2 4-CH3C6H4 2-BrC6H4 4-CH3C6H4 2-BrC6H4 2-BrC6H4 4-CH3C6H4 Ar3 4-CH3C6H4 4-CH3OC6H4 4-ClC6H4 4-NO2C6H4 4-NO2C6H4 2-pyridyl Yield, % 73 80 75 67 52 18

Guanidinoacetic acids were prepared as outlined in Scheme 30 on solid support via treatment of anchored amines with intermediate solution-generated carbodiimides 85.37 This particular protocol is extremely practical. Conversion of thioureas 84 to carbodiimides 85 on treatment with Mukaiyamas reagent (2-chloro-1-methypyridinium iodide) is almost instantaneous at room temperature though brief sonication was desirable to accelerate solubilization of the reagent. The carbodiimides are very nonpolar and are generally isolated by extraction into hexanes and filtration through a short silica plug using the same solvent. Reaction times for addition of the carbodiimides 85 to Wang-supported glycine or alanine 86 varied, but the transformation was conveniently monitored via the ninhydrin test.
O R1NCS + R2NH2 R1 N H S N H 84 R2 N I Cl R1 Wang N C N R2 85 O 86 NH2 n O 87 O

H N n

NHR2 NR1

Scheme 30 Another approach via carbodiimides involves their preparation on solid support followed by the reaction with amines to furnish resin bound guanidines38 (Scheme 31). The sequence commenced with coupling of the p-bromomethyl benzoic acid to a primary amine of a Rinkextended macrocrown. The p-bromomethylbenzamide obtained underwent nucleophilic

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displacement with azide to afford the -azido-p-toluamide 88. Treatment with triphenylphosphine and phenyl isothiocyanate provided the carbodiimide 89, presumably via an in situ Staudinger reaction, to generate the intermediate iminophosphorane and subsequent azaWittig coupling with the isothiocyanate. Reaction of the carbodiimide with N-phenylpiperazine yielded a polymer-bound guanidine 90, which was cleaved with TFA/H20 (95:5) to afford 91.
O HN Rink 88 N HN Ph DMSO 16 h, 60 oC O TFA/DCM N 90 H2N R1 HN C N N N 91 Ph R NCS N3 PPh3/THF 4 h, 25 oC
1

O HN Rink

R1

N C N

89 R1 = Ph 1 R = i-Pr

O HN Rink

HN C N N

R1

Ph

Scheme 31 Cyanamides serve as suitable starting materials for the preparation of guanidines: a recent example describes the formation of 92 in situ and immediate reaction with excess of amine39 to yield 93 (Scheme 32, Table 24).
NH2 NH2 R BrCN Ether 0 C - rt 92 For Entry 1, R-Ar = For R and R see Table
1 o 1

H N R

R CN

H N EtOH or Toluene, Reflux R

H N NH 93 R1

Scheme 32

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Table 24. Synthesis of diarylguanidines 93 by method of Scheme 32 Entry R R1 Yield, %b Entry R R1 Yield, %b 1 See Scheme s-C4H9 50 9 n-C6H13 n-C6H13 68 2 CH3 CH3 20 10 C6H5 C6H5 8 3 C2H5 C2H5 38 11 OC6H5 OC6H5 38 4 i-C3H7 i-C3H7 27 12 SC6H5 SC6H5 14 5 s-C4H9 s-C4H9 32 13 OCH2C6H5 t-C4H9 53 6 t-C4H9 t-C4H9 40 14 OCH2C6H5 n-C4H9 44 7 n-C4H9 n-C4H9 20 15 n-OC4H9 (CH2)4-OH 67 8 n-OC4H9 n-OC4H9 27 16 (CH2)4-OH (CH2)4-OH 79

2.4. Pyrazole-1-carboximidamides Pyrazole-1-carboximidamides 94 are now frequently used for the preparation of guanidines 95. The reaction of 2,4-dimethylpyrazole-1-carboximidamide with amines was considered in 1953 as abnormal because the initial desire was to substitute an NH2 group in analogy to ureas and related compounds40a (Scheme 33). The guanidines prepared are listed in Table 25. For related work see references 40b,c.
Me N N Me 94 NH . HNO3 NH2 RNH2 NH. HNO3 R
1

Neat, reflux, (Method A) H2O, reflux (method B)

N R2

NH2 95

For Entry 7: R =

NH

Scheme 33 Table 25. Synthesis of guanidines from 2,4-dimethylpyrazole-1-carboximidamide nitrate (Scheme 33) Entry 1 2 3 4 5 6 7 8 R1 PhCONH PhCH2 -(CH2)2O(CH2)2PhCH2CH2 -(CH2)5-(CH2)4See Scheme 4-CH3C6H4SO2NH R2 H H H Method B B A B B A B B Yield, % 66 63 50 75 68 92 67 16

H H

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A recent investigation showed that the presence of electron withdrawing groups in the pyrazole ring and/or on one or both of the carboximidamide nitrogens can be advantageous for the yield of guanidines and allow milder reaction conditions. Thus, di-Boc-4-nitropyrazole-1carboximidamide 96 has been used for the preparation of protected guanidines 97 41 (Scheme 34). A 4-nitro group in the pyrazole ring facilitates the reaction and gives higher yields (Table 26)
X N BocN 96 N NHBoc X=H X = NO2 R1R2NH DMF, 25 C
o

NBoc BocHN 97 NR1R2

Scheme 34 Table 26. Synthesis of guanidines from di-Boc-4-nitropyrazole-1- carboximidamide 97 (Scheme 34) Entry 1 2 3 4 R1R2NH Benzylamine Piperidine Aniline Diisopropylamine X = H, Yield, % 80 70 11 <5 X = NO2, Yield, % 94 82 78 64

The use of N-Boc-N-tosylpyrazole-1-carboximidamide 100 is very efficient for the preparation of guanidines 101 and for coupling to peptides42 (Scheme 34). This reagent was also used for coupling with peptides in solution and on solid supports.
NH H2N 98 N N Boc2O DIEA CH2Cl2 H2N 99 O NH2 MeO NH2 NBoc N N TsCl NaH/THF BocHN NTs N 100 N R1R2NH BocHN NTs NR1R2 101 NH2

Me

NH2

NH2 Me

Me NH2 Me NH O2N

NH2

Scheme 34

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The reactions of a variety of amines with di-Boc-pyrazole-1-carboximidamide 102 have also been examined43 (Scheme 35, Table 27). In adidition to the guanylation of simple amines, several amino acids were converted into guanidino acids. Amino acids have a low solubility in many organic solvents, but reaction can be achieved in water, or aqueous acetonitrile to give satisfactory results.
BocN N N 102 BocHN N H BocHN N NBoc NBoc NHBoc + R1R2NH CH3CN, 25-80 oC 1-20 h, 40 - 98% BocN R1 N NHBoc R2

103

Structure for Entry 11

Scheme 35 Table 27. Synthesis of guanidines from di-Boc-pyrazole-1-carboximidamide (Scheme 35) Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 R1 Bu t-Bu c-Hex Bn Allyl Ph 4-MeOC6H4 4-NO2C6H4 R2 H H H H H H H H Yield, % 90 93 96 91 98 71 71 5 92 86 67 71 38 70 76 73 57 70 89

-(CH2)5-(CH2)2O(CH2)2-(CH2)2CH(CH2NH2)(CH2)2Gly H -Ala H 3-Aminobutyric acid H 6-Aminocaproic acid H Pro Fmoc-Lys H Cbz-Orn H -Ala-OMe H

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Pyrazole-1-carboximidamide connected to a solid support by an oxycarbonyl linker 104 can be acylated to 105 and thus becomes a potent reagent for the generation of guanidines 106 on solid supports44 (Scheme 36) by utilizing electronically diverse acylating agents and amines. Guanidine derivatives from nitroanilines were obtained in good yields for a range of acylated derivatives of pyrazole-1-carboximidamide.
LiHMDS/THF O O N H 104 NH N N R COCl 0-5 C
o 1

O O O N H 105 N N R1 N O R2R3NH O N H 106 N

O R1 NR2R3

TFA/DCM O N H2N R1 NR2R3 107

Scheme 36

2.5. Triflyl guanidines Triflyl guanidines, first reported in 1998, are becoming popular reagents for the preparation of guanidines.45 Di-Boc-triflylguanidine 110 and di Cbz-triflylguanidine 113 are efficiently converted by various primary amines into guanidines 111, 114.45-47 (Schemes 37, 38, Tables 28, 29).
Cl H2N 108 NH2 NH2 (Boc)2O, NaOH 58% BocHN NH NHBoc 109 Tf2O 88% BocHN 110 NTf NHBoc R1R2NH CH2Cl2 BocHN 111 NBoc NR1R2

Scheme 37

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Table 28. Synthesis of guanidines from di-Boc-triflylguanidine 110 (Scheme 37) Entry 1 2 3 4 5 6 7 8
BocHN O H N

R1R2NH Benzylamine Cyclohexylamine t-Butylamine 4-Pyrrolidine Aniline

FmocHN COOH (CH2)3 NH2 H N

Conditions Yield, % Ref. CH2Cl2, 0.5 h, rt 100 45 CH2Cl2, 1.0 h, rt 99 45 CH2Cl2, 8.0 h, reflux 75 45 CH2Cl2, 2.0 h, rt 96 45 CH2Cl2, 24 h, rt 89 45 82 45 CH2Cl2, 4 h, rt CH2Cl2, 4 h, rt CH2Cl2, 4 h, rt
CO2Et

Cl H3N

CO2Me

85 88

45 45

O N H

NH2 (CH2)3 H N O

9 10 11 12 13 14

CH3(CH2)4NH2 Piperidine Morpholine Piperazine Monoethanolamine

NH2 HO HO R3 R2 R1 O NH2 O O O OH NH2 NH2 OH

CH2Cl2, 1 h, rt CHCl3, 20 h, rt CH2Cl2, 2 h, rt H2O, Dioxane CH3CN

98 85 86 100 100 22-49

45 45 45 45 45 46

15 16
Ph HO
Ph MeO Ph MeO Ph

CH2Cl2
NH2

42 21

47 47

CH2Cl2
NH2

17

CH2Cl2
NH2

38

47

18

CH2Cl2
NH2
OH

39

47

19
N H

CH2Cl2

42

47

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Cl H2N

NH2 NH2 108

CbzCl, NaOH 83% CbzHN

NH

1. NaH 2. Tf2O 75% CbzHN

NTf NHCbz

R1R2NH CH2Cl2 CbzHN

NCbz NR1R2 114

NHCbz

112

113

Scheme 38 Table 29. Synthesis of guanidines from di-Cbz-triflylguanidine 113 (Scheme 38) Entry 1 2 3 R1R2NH Benzylamine Aniline
FmocHN COOH (CH2)3 NH2

Conditions CH2Cl2, 1.0 h, rt CH2Cl2, 1 h, rt CH2Cl2, 4 h, rt

Yield, % 94 98 85

Primary and secondary amines were also converted into guanidines 116 by triflylguanidines 11548 (Scheme 39, Table 30).
NTf PGHN NHPG R1R2NH PGN NR1R2 NHPG

115

116

Scheme 39 Table 30. Conversion of secondary amines into guanidines by di-protected triflylguanidine 115 (Scheme 39) Entry 1 2 3 4 PG Boc Boc Boc Cbz
O O

R1
O O N

R2 H H
AcHN

Yield, % 100 88 49

95

2.6. Aminoiminomethane-sulfonic and -sulfinic acids Aminoiminosulfonic and -sulfinic acids, prepared by the oxidation of thioureas, are useful reagents for the synthesis of guanidines.
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Marianoff and coworkers described a practical two-step procedure based on thioureas 117 oxidized with H2O2.49 A high yield of pure sulfonic acid 118 was obtained rapidly in a short reaction time when the reaction was run as a slurry in water. The rate of reaction was dependent on the concentration of catalyst (Na2MoO4) employed. In general, the sulfonic acid derivatives are stable at room temperature and are the preferred intermediates. The oxidation products were isolated by filtration and air-dried for use in the displacement reaction (Scheme 40, Table 31). The second step of the sequence, displacement of the oxidized sulfur with amine nucleophiles, to give 119 was carried out under mild conditions (Scheme 40). Yields of the displacement reactions are reported in Table 32.
S R
1

H2O2, Na2MoO4.2H2O NH2 NaCl, H2O R1 N

SO3H NH2

R2R3NH 20 oC, 1 h R1

R2 N

R3

N H

117

118

NH2 119

Scheme 40 Table 31. Oxidation of thioureas 117 to sulfonic acid 118 Entry 1 2 3 4 R1 Ph n-Pr 2-CH3C6H4 4-FC6H4 Yield, % 86 56 83 76

Table 32. Synthesis of guanidines 119 from thiourea derived sulfonic acid 118. Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 R1 Ph Ph Ph Ph Ph n-Pr Ph Ph Ph Ph n-Pr n-Pr Ph Ph R2 t-Butyl i-Butyl sec-Butyl Ph 4-CH3OC6H4 sec-Butyl c-Hexyl 4-ClC6H4 2-CH3-4-CH3OC6H4 4-NO2C6H4 i-Butyl n-Butyl -(CH2)4-(CH2)2O(CH2)2R3 H H H H H H H H H H H H Yield, % 99 56 50 99 77 62 72 50 51 84 23 60 73 79

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Similar investigation on the use of aminoiminomethansulfonic acids 121 has been described for the conversion of amino acids into a guanidino acids 122 50 (Scheme 41, Table 33). This method is advantageous for the preparation of di- and tri-substituted guanidine acids due to their synthesis from isothiouronium compounds.
S R1 N H 120 N H R2 H2O2/CH3COOH R
1

SO3H R2 N N H 121

Amino Acid K2CO3/H2O 25 C

o

HN R
1

R N H

COOH R2

122

Scheme 41 Table 33. Synthesis of guanidines 122 via oxidized thioureas 121 Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Amino Acid 3-Aminopropanoic Acid DL-Alanine p-Aminobenzoic Acid 4-Aminobutanoic Acid 5-Aminopentanoic Acid Glycine L-Iisoleucine L-Leucine DL-Methionine L-Phenylalanine L-Proline DL-Serine DL-Valine 3-Aminopropanoic Acid p-Aminobenzoic Acid 4-Aminobutanoic Acid Glycine L-Leucine 3-Aminopropanoic Acid p-Aminobenzoic Acid Glycine R1 H H H H H H H H H H H H H H H H H H Ph Ph Ph R2 H H H H H H H H H H H H H Ph Ph Ph Ph Ph Ph Ph Ph Yield, % 75 5 80 50 55 80 5 -a 60 45 -a 50 55 70 65 0 85 0 25 25 35

Continued optimization of the protocol for guanidine preparation led to use of the oxidized product without isolation51 (Scheme 42). Oxidizing agents are compared in Table 32 and the oxidation rate for aliphatic derivatives was improved by addition of a catalytic amount of triethyl amine. The guanidines 124 were obtained by treatment with amines in water with short reaction times, excellent conversion, and simple isolation. However, trisubstituted thioureas resisted the oxidation.

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S R N H N H R

Oxidant DMF/H2O

SOxH R R N N H

R1R2NH

R1 R N

R2 N H R

120

123 x = 2 and/or 3

124

Scheme 42 Table 34. Synthesis of guanidines 124 via nonisolatable intermediate oxidized thioureas 123 Entry 1 2 3 4 5 6 7 8 9 R Ph o-Tolyl C6H11 Ph Ph Ph Ph Ph Ph R1 R2 NaIO4 Yield, % 76 80 72 75 84 68 76 75 60 NaClO2 Yield, % 80 76 67 72 81 65 80 72 55

H H H H H H -(CH2)2O(CH2)2H C6H11 H Benzyl Et Et H Et C6H11 C6H11

In a recent, one-pot procedure, quaternary ammonium permanganate in the presence of amine showed advantages over other oxidizing agents for thioureas 12052 (Scheme 43, Table 33). Table 35. Synthesis of guanidines from oxidation of thioureas by quaternary ammonium permanganate (Scheme 43) Entry 1 2 3 4 5 6 7 8 9 10 R1 Ph Ph Ph Ph Ph o-Tolyl Ph Ph Ph 2,6-Diethylphenyl R2 R3 c-C6H11 H Ethyl Ethyl H H Benzyl H n-Bu H H H c-C6H11 c-C6H11 i-Propyl i-Propyl -(CH2)2O(CH2)2-(CH2)2O(CH2)2Yield, % 92 95 90 87 86 82 82 78 89 95

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S R1 N H N H 120 R1

THF/PhCH2N+(C2H5)3MnO45 - 10 C, 30 min
o

R1

SOxH R1 N N H 125

R2R3NH R1

R2 N H

R3 N R1

126

Scheme 43 2.7. Benzotriazole and imidazole-activated reagents Benzotriazole-1-carboxamidinium tosylate 12953 prepared from benzotriazole 128 with cyanamide 127 in refluxing 1,4-dioxane in the presence of p-TsOH, is an efficient general reagent for the synthesis of mono and disubstituted guanidines 130. Reactions are conveniently carried out using equimolar amine in (i) DMF-diisopropylethylamine at room temperature, (ii) acetonitrile or (iii) the absence of solvent. Product isolation is facile as the precipitated guanidine can be filtered from the ether soluble benzotriazole by-poduct when DMF is used. The product precipitates during the reaction, while in the absence of solvent product can be isolated chromatographically. Under mild conditions, benzotriazole-1-carboxamidinium tosylate gives guanidines in moderate to good yields and offers advantages over previous procedures (Scheme 44, Table 36).
H2N 127 N + N N N H H NH2+ * TsON 2 1 R R N H2N N N 1,4-dioxane 1,4-dioxane reflux reflux 77% 129 TsOH
NH2+ * TsO 2 R H2N N R1 130

128

Scheme 44 Table 36. Synthesis of guanidines from benzotriazole-1-carboxamidinium tosylate Entry 1 2 3 4 5 6 7 8

O

Amine
Me2NH

Guanidine
NH2+ Me2N
NH2+ N

TsO

Yield, % 69 84
TsO-

NH2
TsONH2

NH

MeO

OMe

NH2
N H

NH2+

68 55 68 86 71 67

NH2

C4H9NH2
C4H9HN

NH2+
NH2+ N H

TsONH2
TsO-

NH2
NH

NH2

NH2+ N O

TsO-

NH2

NH2+

NH

TsONH2

C6H13NH2
C6H13HN

NH2+

TsONH2

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Modification of benzotriazole-1-carboxamidine by introducing electron withdrawing groups, Boc on both nitrogens of the amidine moiety and nitro or chloro group in benzotriazole to give 131, enhanced the ability of the benzotriazole moiety as a leaving group54 (Scheme 45).
BocN X N N N NHBoc

X=H X = Cl X = NO2

131

Scheme 45 Di(benzotriazolyl)carboximidamide 132 has been developed as a new guanylating agent, for the synthesis of tri- 136 and tetra-substituted guanidines 135.55 The sequential condensation of two amines with di(benzotriazolyl)carboximidamide is insensitive to electronic and steric effects allowing the use of a wide variety of amines and guanidines as free bases. The products were obtained in high yields under neutral and mild conditions using an easy purification protocol (Scheme 46, Tables 37, 38).
H N NH R
2

NH Bt
1

NH
1

R
2

Bt

Bt 132

+ Bt

Bt 132'

THF rt H N

N R2 133

R1

R2=H

NH2 Bt1 N 134 R1

BrCN, NaOH 65 % 2 N N N H Bt1 = benzotriazol-1-yl Bt = benzotriazol-2-yl

2

R4 NH

THF NH2 R
3

N R2

N R4

R1 R =H
3

N R2 136

N R4

135

Scheme 46 Table 37. Preparation of benzotriazole-1-carboximidamides 133 (of Scheme 46) Entry 1 2 3 4 5 6 R2 C6H5 n-C5H11 CH2C6H5 -(CH2)4-(CH2)2O(CH2)2CH(CH3)2 CH(CH3)2 R1 H H H Yield, (%) 80 74 68 71 68 68

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Table 38. Preparation of guanidines 135 (of Scheme 46) Entry 1 2 3 4 5 6 7 R1 R2 R3 C6H5 4-CH3C6H4 C6H5CH2 C6H5 C6H5 4-CH3OC6H4 4-CH3OC6H4 R4 H H H CH3 H H H Reaction time (h) 10 12 12 18 12 17 15 Yield (%) 64 74 71 85 68 60 48

-(CH2)2O(CH2)2-(CH2)2O(CH2)2-(CH2)2O(CH2)2-(CH2)2O(CH2)2-(CH2)4-(CH2)4CH(CH3)2 CH(CH3)2

Analogous to the di(benzotriazolyl)carboximidamide reagent 132, di(imidazol-1yl)carboximidamide 138 was later synthesized by treatment of cyanogens bromide with imidazole.56 Reagent 138 can also be converted into substituted guanidines 141 by sequential displacement of imidazole moieties with amines. Further, through its N-cyano derivative 139 it provides an access to substituted cyanoguanidines 143 (Scheme 47, Table 38).
CN N NH BrCN N N CN 137 NH imidazole N 138 N N N BrCN N N 139 N N N

NH R 2R 1N 141 NR3R4 R 2R 1N 140

NH N N R 2R 1N 143

CN NR3R4 R 2R 1N 142

CN N N

Scheme 47

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Table 39. Preparation of Guanidines 141 and cyanoguanidines 143 (of Scheme 47) No 1 Imidazol-1-yl carboximidamide
NH
N

Guanidine
NH N

Yield, % 53 76 81 51 64

N N
N NH N

NH N N H

NH N N H

2
N

NH N N
N

NH N
NH N

70

NH N N H NH N N H
NH N H N H
NH N H N H

3
N H

NH N N

74 90
NH

4
N H

NH N N
N N
N H

85

N H

5
N

CN N N

CN N

82

CN N N N H

70

CN N N N H
N N CN N H

NO2

N N

CN N N

42

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Benzotriazolylcarboximidoyl chlorides 145 (stable, odorless and convenient to handle) also allow the preparation of unsymmetrical guanidines57 (Scheme 48).
N N N Cl 144 R1NC 2a-f CHCl3 Bt1,2 NR1 Cl 145 NR1 R 5R 4N NR2R3 147

R2R3NH Bt1,2

NR1 NR1R2 146

R4R5NH

Scheme 48

3. Conclusions
We have attempted to summarize recent advances in guanidine synthesis from the point of view of guanylating agents.

Supplementary information is available 4. References

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8. (a) Tinti, J.-M.; Nofre, C. Design of Sweeteners In Sweeteners: Discovery, Molecular Design and Chemoreseption, Walters, D. E.; Orthoefer, F. T.; DuBois, G. E. Eds.; ACS: Washington, D.C. 1991; pp 88-112. (b) Glaser, D. P. Appl. Chem. 2002, 74, 1153. (c) Katritzky, A. R.; Petrukhin, R.; Perumal, S.; Karelson, M.; Prakash, I.; Desai, N. Croat. Chem. Acta 2002, 75, 475. (d) Nagarajan, S.; Kellogg, M. S.; DuBois, G. E.; Hellekant, G. J. Med. Chem. 1996, 39, 4167. (e) Droupadi, P. R.; Linthicum, D. S. Int. J. Biochem. Cell. Biol. 1995, 27, 351. 9. Costa, M.; Chiusoli, G. P.; Taffurelli, D.; Dalmonego, G. J. Chem. Soc., Perkin Trans. 1 1998, 1541. 10. (a) Ishikawa, T.; Isobe, T. Chem. Eur. J. 2002, 8, 553. (b) McManus, J. C.; Genski, T.; Carey, J. S.; Taylor, R. J. K. Synlett 2003, 369. (c) McManus, J. C.; Carey, J. S.; Taylor, R. J. K. Synlett 2003, 365. 11. (a) Manimala, J. C.; Anslyn, E. V. Eur. J. Org. Chem. 2002, 3909. (b) Solid Phase synthesis of Guanidines, Burgess, K.; Chen, J. In Solid Phase Organic Synthesis, Burgess, K. Ed.; John Wiley & Sons, Inc.: New York, 2000, pp 1-23. (c) Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E. V. Tetrahedron 1998, 54, 15063. 12. Ramadas, K.; Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841. 13. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540. 14. Manimala, J. C.; Anslyn, E. V. Tetrahedron Lett. 2002, 43, 565. 15. Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677. 16. (a) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997, 53, 5291. (b) Dahmen, S.; Brse, S. Org. Lett. 2000, 2, 3563. 17. Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65, 1566. 18. Jirgensons, A.; Kums, I.; Kauss, V.; Kalvins, I. Synth. Commun. 1997, 27, 315. 19. Li, M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2001, 42, 2273. 20. Guisado, O.; Martinez, S.; Pastor, J. Tetrahedron Lett. 2002, 43, 7105. 21. (a) Kilburn, J. P. Lau, J.; Jones, R. C. F. Tetrahedron 2002, 58, 1739. (b) Zhang, J.; Shi, Y.; Stein, P.; Atwal, K.; Li, C. Tetrahedron Lett. 2002, 43, 57. 22. Kent, D. R.; Cody, W. L.; Doherty, A. M. Tetrahedron Lett. 1996, 37, 8711. 23. Okajima, N.; Okada, Y. J. Het. Chem. 1991, 28, 177. 24. Rasmussen, C. R.; Villani Jr., F. J.; Reynolds, B. E.; Plampin, J. N.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Constanzo, M. J.; Howse Jr., R. M.; Molinari, A. J. Synthesis 1988, 460. 25. Chandrakumar, N. S. Synth. Commun. 1996, 26, 2613. 26. Lal, B.; Gangopadhyay, A. K. Tetrahedron Lett. 1996, 37, 2483 27. Yuan, C.; Williams, R. M. Tetrahedron Lett. 1996, 37, 1945. 28. (a) Lin, P.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9789. (b) Dodd, D. S.; Zhao, Y. Tetrahedron Lett. 2001, 42, 1259. 29. Guo, Z.-X.; Cammidge, A. N.; Horwell, D. C. Synth. Commun. 2000, 30, 2933. 30. Lin, P.; Heng, S. H. C.; Sim, M. M. Synthesis 2003, 255. 31. Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C. Chem. Eur. J. 2000, 6, 4016. 32. Dodd, D. S.; Wallace, O. W. Tetrahedron Lett. 1998, 39, 5701. 33. Kearney, P. C.; Fernandez, M.; Flygare, J. A. Tetrahedron Lett. 1998, 39, 2663.

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34. Novak, L.; Hanania, M.; Kovacs, P.; Kovacs, C. E.; Kolonits, P.; Szantay, C. Synth. Commun. 1999, 29, 1757. 35. Reiter, L. A.; Brighty, K. E.; Bryant, R. A.; Goldsmith, M. E. Synth. Commun. 1996, 26, 1423. 36. Molina, P.; Aller, E.; Larenzo, A. Synlett 2003, 714. 37. Chen, J.; Pattarawarapan, M.; Zhang, A. J.; Burgess, K. J. Comb. Chem. 2000, 2, 276. 38. Drewry, D. H.; Gerritz, S. W.; Linn, J. A. Tetrahedron Lett. 1997, 38, 3377. 39. Reddy, N. L.; Fan, W.; Magar, S. S.; Perlman, M. E.; Yost, E.; Zhang, L.; Berlove, D.; Fischer, J. B.; Burke-Howie, K.; Wolcott, T.; Durant, G. J. J. Med. Chem. 1998, 41, 3298. 40. (a) Scott, F. L.; ODonovan, D. G.; Reilly, J. J. Am. Chem. Soc. 1953, 75, 4053. (b) Brederec, H.; Effenberger, F.; Hajek, M. Chem. Ber 1965, 98, 3178. (c) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org. Chem. 1992, 57, 2497. 41. Yong, Y. F.; Kowalski, J. A.; Thoen, J. C.; Lipton, M. A. Tetrahedron Lett. 1999, 40, 53. 42. Zhang, Y.; Kennan, A. J. Org. Lett. 2001, 3, 2341. 43. Drake, B.; Patek, M.; Lebl, M. Synthesis 1994, 579. 44. Ghosh, A. K.; Hol, W. G.; Fan, E. J. Org. Chem. 2001, 66, 2161. 45. Feichtinger, K.; Zapf, C.; Singh, H. L.; Goodman, M. J. Org. Chem. 1998, 63, 3804. 46. Feichtinger, K.; Singh, H. L.; Mattews, K.; Goodman, M. J. Org. Chem. 1998, 63, 8432 47. (a) Hui, Y.; Ptak, R.; Paulman, R.; Pallasch, M.; Chang, C.-W. T. Tetrahedron Lett. 2002, 43, 9255. (b) Sun, C.-M.; Shey, J.-Y. J. Comb. Chem. 1999, 1, 361. 48. Baker, T. J.; Goodman, M. Synthesis 1999, 1423. 49. Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills, J. E. J. Org. Chem. 1986, 51, 1882. 50. Miller, A. E.; Bischoff, J. J. Synthesis 1996, 777. 51. Ramadas, K.; Janarthanan, N.; Pritha, R. Synlett 1997, 1053. 52. Srinivasan, N.; Ramadas, K. Tetrahedron Lett. 2001, 42, 343. 53. Katritzky, A. R.; Parris, R. L.; Allin, S. M.; Steel, P.J. Synth. Commun. 1995, 25, 1173. 54. Musiol, H.-J.; Moroder, L. Org. Lett. 2001, 3, 3859. 55. Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.; Vvedensky, V. J. Org. Chem. 2000, 65, 8080. 56. Wu, Y.-Q.; Hamilton, S. K.; Wilkinson, D. E.; Hamilton, G. S. J. Org. Chem. 2002, 67, 7553. 57. Katritzky, A. R.; Rogovoy, B.; Klein, C.; Insuasty, H.; Vvedensky, V.; Insuasty, B. J. Org. Chem. 2001, 66, 2854.

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Biographical sketch
Alan Katritzky has taught, researched, consulted and published on heterocyclic chemistry, synthetic methods, and QSPR, first in the UK and since 1980 at the University of Florida where he is Kenan Professor of Chemistry and Director of the Center for Heterocyclic Compounds.

Dr. Rogovoy was born January 18th, 1973. He received his MS degree in 1995 in Chemical Engineering at Ukrainian State University for Chemical Engineering, Dnepropetrovsk, Ukraine and PhD degree in 2002 at the University of Tartu, Tartu, Estonia. In 1998 Dr. Rogovoy joined the Center for Heterocyclic Compounds at the University of Florida. In 2003 he joined the Department of Pharmaceutical Chemistry in School of Pharmacy in Rutgers University where he was involved in a development of prodrug systems for the site-specific release and activation of anticancer drugs and improvement of therapeutic effectiveness of anticancer agents with reduced systemic toxicity. In November of 2004, Dr. Rogovoy obtained a position of Senior Research Scientist at ChemDiv Inc, San Diego, CA. His research interests include heterocyclic synthesis, combinatorial synthesis in solution and solid support, development of efficient synthetic approaches.

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