pubs.acs.

org/joc

Synthesis of Monoacylated Derivatives of trans-Cyclohexanediamine is widely exploited as a source

1,2- Cyclohexanediamine. Evaluation of their of chirality in many organic chemistry processes,5 and numer-
ous derived bifunctional catalysts have been prepared. Many
Catalytic Activity in the Preparation of of these organocatalysts combine the presence of the chiral
Wieland-Miescher Ketone† primary amine group with another functionality (thiourea, urea,
sulfonamide, etc.), so selective monoacylation is desired.6


Angel L. Fuentes de Arriba,‡ David G. Seisdedos,‡ Monoacylation of cyclohexanediamine can be achieved

)
on,‡ Victoria Alc

Luis Sim
azar,§ C
esar Raposo, and following the procedure of Kim et al.,4 protecting both amines
Joaquı́n R. Mor
an*,‡ as their benzyloxycarbonyl derivatives, followed by reaction
‡
Organic Chemistry Department, Plaza de los Caı´dos 1-5, with Boc2O and hydrogenolysis. Here, we develop an alter-
Universidad de Salamanca, Salamanca 37008, Spain, native procedure for monoacylation based on the reactivity
§
Industrial Chemistry and Environmental Engineering of urea 1 (Scheme 1).
Department, Jos
e Guti

errez Abascal 2, Universidad SCHEME 1. Preparation of Ureas Starting from (R,R)-Cyclo-
Polit

ecnica de Madrid, Madrid 28006, Spain, and hexanediamine
)

Mass Spectrometry Service, Plaza de los Caı´dos, 1-5,

Universidad de Salamanca, Salamanca 37008, Spain

[email protected]
Received September 1, 2010

Cyclic urea 1 can be obtained when cyclohexanediamine is

reacted with the gaseous and toxic carbonyl sulfide.7 A simple
and high-yield alternative synthesis is based on the use of
diphenylcarbonate, which can also be employed when the
Ureas, carbamoyl derivatives, amides, and sulfonamides starting material is the straightforwardly obtained enantio-
can be easily prepared from the strained (R,R)-cylohexane- pure (R,R)-cyclohexanediamine tartrate salt.8
diamine urea (1) in high yield, leaving a free amino group Owing to the trans-fused rings, under acidic conditions
that shows good catalytic activity in intramolecular aldol urea 1 shows suitable reactivity with nucleophiles.9 Thus,
condensations. The preparation of Wieland-Miescher aromatic amines can open the urea 1 ring in the presence of
ketone has been studied with these catalysts. methanesulfonic acid to afford the corresponding aminoureas
2-6 after basic workup (Scheme 1). The reaction seems to
be general for all anilines, including electron-poor (3 and 4)
Although the formation of amide bonds by reaction of amines
(5) (a) Xue, F.; Zhang, S.; Duan, W.; Wang, W. Adv. Synth. Catal. 2008,
with acid chlorides is a common procedure in organic syn- 350, 2194. (b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int.
thesis, high-yield monoacylation of symmetrical diamines Ed. 2006, 45, 6366. (c) Uehara, H.; Barbas, C. F., III. Angew. Chem., Int. Ed.
may be, in some cases, a difficult process. Several hypotheses 2009, 48, 9848. (d) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451.
(e) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Chem. Pharm.
have been proposed to explain these findings, such as an Bull. 2004, 52, 477. (f) Rasappan, R.; Reiser, O. Eur. J. Org. Chem. 2009,
inefficient mixture of reagents or intramolecular catalysis by 1305. (g) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem. 2008, 285, 1. (h) Luo, S.;
the first-formed amide group.1 However, monoacylation has Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074.
(i) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan, W.;
been shown to be possible by working with low reactivity Wang, W. Org. Lett. 2009, 11, 2864. (j) Wang, J.; Wang, X.; Ge, Z.; Cheng,
compounds like esters,2 by employing aggregation effects,3 T.; Li, R. Chem. Commun. 2010, 1751. (k) Ma, H.; Liu, K.; Zhang, F.- G.;
Zhu, C.- L.; Nie, J.; Ma, J.- A. J. Org. Chem. 2010, 75, 1402. (l) Huang, H.;
or by making use of steric hindrance.4 Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (m) Liu, K.; Cui, H.-F.;
Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923. (n) He, T.;
Gu, Q.; Wu, X.-Y. Tetrahedron 2010, 66, 3195.
†
Dedicated to Professor Carmen N
ajera on the occasion of her 60th birthday. (6) Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431.
(1) Jacobson, A. R.; Makris, A. N.; Sayre, L. M. J. Org. Chem. 1987, 52, (7) Davies, S. G.; Mortlock, A. A. Tetrahedron 1993, 49, 4419.
2592. (8) Schanz, H.-J.; Linseis, M. A.; Gilheany, D. G. Tetrahedron: Asymmetry
(2) Tang, W.; Fang, S. Tetrahedron Lett. 2008, 49, 6003. 2003, 14, 2763.
(3) Mu~niz, F. M.; Sim
on, L.; S
aez, S.; Raposo, C.; Mor
an, J. R. Tetra- (9) Hutchby, M.; Houlden, C. E.; Ford, J. G.; Tyler, S. N. G.; Gagn
e,
hedron Lett. 2008, 49, 790. M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int. Ed.
(4) Kim, Y. K.; Lee, S. J.; Ahn, K. H. J. Org. Chem. 2000, 65, 7807. 2009, 48, 8721.

DOI: 10.1021/jo101723v Published on Web 11/08/2010 J. Org. Chem. 2010, 75, 8303–8306 8303
r 2010 American Chemical Society
JOC Note Fuentes de Arriba et al.

SCHEME 2. Monoprotection of Cyclohexanediamine as SCHEME 4. One-Pot Synthesis of Carbamate 9 and Preparation

Carbamoyl (Carbamothioyl) Derivatives of Amides and Sulfonamides

SCHEME 3. Transformation of the Carbamoyl Derivatives

into Sulfonamides

and electron-rich systems (5) and hindered amines (6). Ring SCHEME 5. Preparation of Catalyst 18
opening can also be carried out without methanesulfonic acid
when the hydrochloride salt of the aromatic amine is employed.
In this case, the reaction also works well and the isolation
of the corresponding ureas may be easily accomplished by
precipitation upon addition of a proper solvent to the reac-
tion medium (see the Supporting Information). By contrast,
aliphatic amines failed to produce the desired ring opening
under the above conditions.
Monoamides and sulfonamides are other target compounds
whose synthesis is achieved through the monocarbamoyl
derivatives (see Schemes 3 and 4). Hence, the first step in monocarbamoylated compound 9. This compound is highly
the synthesis comprises the reaction of urea 1 with alcohols water-soluble as its methanesulfonate salt but readily crystallizes
yielding the monocarbamates (Scheme 2). Compound 7 was as the hydroiodide. Tosylation or benzoylation, for example,
obtained by reacting the cyclic urea 1 with MeOH/HCl, can be carried out in chloroform in the presence of triethylamine
and the carbamoyl derivatives 8 and 9 were prepared by to yield compounds 15 and 16. Hydrolysis of the phenylcar-
treatment with the corresponding alcohols and MeSO3H. bamoyl group can be readily achieved under mild basic condi-
Under the same conditions, dodecanethiol afforded the mono- tions to yield the sulfonamide 13 and the amide 17 (Scheme 4).
carbamothioyl derivative 10. The “oxyanion hole” properties of isophthalic derivatives11
Preparation of sulfonamides 11 and 12 was carried out in two inspired us to prepare compound 18, which incorporates an
steps, starting from the related carbamoyl derivatives. For the extra amide functionality. This cyclohexanediamine derivative
obtention of sulfonamides, compounds 7 and 8, respectively, is obtained starting from the isophthalic acid monobutyl amide,12
were reacted with tosyl chloride. These sulfonamides may be according to the synthetic procedure depicted in Scheme 5
deprotected yielding the primary amine 13 (Scheme 3). Depro- (see the Supporting Information).
tection can be carried out under basic conditions, nucleophilic Chiral amines derived from diaminocyclohexane have proved
displacement in the case of the methyl group,10 or hydrogeno- to be efficient organocatalysts for the aldol reaction.13 Due to
lysis for the benzyl group. Additionally, the tosyl derivative 11
was converted to the corresponding methylamine 14 through
(11) (a) Dixon, R. P.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1992,
reduction of the carbamoyl group with LiAlH4. 114, 365. (b) Gale, P. A. Coord. Chem. Rev. 2003, 240, 191. (c) Mu~ niz, F. M.;
The one-pot synthesis of the monocarbamate 9 starting Montero, V. A.; Fuentes de Arriba, A. L.; Sim
on, L.; Raposo, C.; Mor
an,
from the cyclohexanediamine tartrate salt offers an attrac- J. R. Tetrahedron Lett. 2008, 49, 5050.
(12) Oliva, A. I.; Sim
on, L.; Mu~ niz, F. M.; Sanz, F.; Mor
an, J. R.
tive possibility to achieve the monoprotected compounds Tetrahedron 2004, 60, 3755.
(Scheme 4). Since urea 1 can be obtained from diphenyl carbo- (13) (a) Raj, M.; Parashari, G. S.; Singh, V. K. Adv. Synth. Catal. 2009,
nate, generating two phenol equivalents in situ, the addition of 351, 1284. (b) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130,
17666. (c) Luo, S.; Xu, H.; Chen, L.; Cheng, J.-P. Org. Lett. 2008, 10, 1775.
methanesulfonic acid led to ring opening, directly affording the (d) Luo, S. Z.; Xu, H.; Li, J. Y.; Zhang, L.; Cheng, J. P. J. Am. Chem. Soc.
2007, 129, 3074. (e) Mei, K.; Zhang, S.; He, S.; Li, P.; Jin, M.; Xue, F.; Luo,
G.; Zhang, H.; Song, L.; Duan, W.; Wang, W. Tetrahedron Lett. 2008, 49,
(10) Elsinger, F.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1960, 2681. (f) Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu, X.; Feng, X.;
43, 113. Su, Z.; Hu, C. J. Am. Chem. Soc. 2008, 130, 5654.

8304 J. Org. Chem. Vol. 75, No. 23, 2010

Fuentes de Arriba et al.
JOC Note
TABLE 1. Preparation of the Wieland-Miescher Ketone in CDCl3 the preparation of the Hajos-Wiechert ketone; however, in
(1.0 M) with 10 mol % of Catalyst at 20 °C this case, the reaction was much slower (only 20% conver-
sion to the ketone after 94 h and 81% ee), which limits its use
for preparative purposes.
In summary, an alternative approach to the synthesis
of monofunctionalized 1,2-cyclohexanediamines has been
described, starting from the readily available (R,R)-cyclo-
entry catalyst conversiona (%) yieldb (%) time (h) eec (%) hexanediamine urea and taking advantage of the reactivity
1 2d
95 76 22 85 provided by the trans ring junction. In addition, we have
2 3 94 82 30 89 explored the possibilities of these compounds as catalysts in
3 4 81 63 117 75 the intramolecular aldol condensation yielding the Wieland-
4 8 76 59 117 65 Miescher ketone, with the best results being obtained for ureas
5 13 3 n.d. 161 61
6 14 24 n.d. 161 -11
and amides, reaching up to 95% ee.
7 17 94 77 44 91
8 18d 100 85 16 95 Experimental Section
a 1
Determined by integration of the corresponding signals in the H (3aR,7aR)-Hexahydro-1H-benzo[d]imidazol-2(3H)-one (1).
NMR spectra. bIsolated yield after silica gel chromatography. cDeter-
mined by chiral HPLC (Daicel Chiralpak IC column). d2.0 M concen-
Enantiopure (R,R)-cyclohexanediamine tartrate salt was readily
tration of the ketone, 10 mol % catalyst. Higher concentrations of the obtained starting from the racemic trans-cyclohexane-1,2-diamine
ketone yielded reduced enantioselectivities. and L-tartaric acid.8 This tartrate salt (40.0 g, 150.8 mmol) and
KOH (17.0 g, 303.6 mmol) were dissolved in H2O (30 mL) to
generate the free diamine. The reaction mixture was heated until all
our interest in this reaction,14 we decided to explore the ability of of the solid was dissolved. Then, 2-propanol (100 mL) was added,
these compounds in the preparation of the Wieland-Miescher and the solution was stirred and cooled (ice bath) to yield a
ketone.15 Ureas 2-4 are good organocatalysts for this reaction, potassium tartrate precipitate. To complete the precipitation and
showing high enantioselectivities (Table 1, entries 1-3). The remove the water, powdered sodium sulfate (40.0 g) was added and
catalytic activity of the carbamoyl derivative 8 was also eval- the precipitate was filtered off. The solid was washed with more
uated (entry 4, Table 1), but enantioselectivity was reduced in 2-propanol (220 mL), diphenyl carbonate (35.0 g, 163 mmol) was
added to the filtrate, and the mixture was refluxed for 30 min. Steam
comparison with that obtained with the urea compounds. distillation and water evaporation allowed us to obtain a crude urea
Considering enantioselectivity, sulfonamide 13 proved to which could be further purified by recrystallization from EtOH/
be a similar catalyst to the carbamoyl derivative 8 (entries 4 H2O (1:1) to yield 18.8 g (90% yield) of a compound with the same
and 5, Table 1), although the conversion rate was consider- physical properties as those described in the literature.16
ably reduced. To test the influence of a secondary amine in General Procedure for the Preparation of Monoureas (2-6)
the conversion and enantioselectivity, we prepared the sulfon- with Methanesulfonic Acid (Procedure A). To a mixture of the
amide 14 with a methylamino group (entry 6, Table 1). This urea 1 (2.2 mmol) and the aromatic amine (2.2 mmol) in diglyme
catalyst showed the lowest enantioselectivity with the opposite (2 mL) was added methanesulfonic acid (0.15 mL) was added,
enantiomer as the major product. and the reaction mixture was heated at 120 °C for ∼1 h with
When amide 17 was used, enantioselectivity was increased stirring under argon atmosphere. After the mixture was cooled to
room temperature, H2O (10 mL) and Na2CO3 (2.0 g, 19 mmol)
up to 91% ee (entry 7, Table 1). The isophthalic derivative 18, were added, and a crystalline solid precipitated that was filtered to
which resembles the oxyanion hole geometry, gave the best afford the desired compound. If the urea did not crystallize
enantioselectivity (95% ee) with a complete conversion with- spontaneously, diethyl ether (2 mL) was added to assist the precipi-
in 16 h (entry 8, Table 1). This catalyst has also been tested in tation. This procedure has been carried out on a 2-15 mmol scale.
(1R,2R)-1,2-Diaminocyclohexane 3,5-bis(trifluoromethyl) phenyl-

L.; Sim

(14) (a) Fuentes de Arriba, A. on, L.; Raposo, C.; Alc
azar, V.; urea (3). Urea 1 (2.0 g, 14.2 mmol), 3,5-bis(trifluoromethyl)aniline
Mor
an, J. R. Tetrahedron 2009, 65, 4841. (b) Fuentes de Arriba, A.
L.; (3.4 g, 14.8 mmol), and methanesulfonic acid (1 mL) were dissolved
Sim
on, L.; Raposo, C.; Alc
azar, V.; Sanz, F.; Mu~ niz, F. M.; Mor
an, J. R. in diglyme (2 mL), and the mixture was heated at 120 °C for 30 min.
Org. Biomol. Chem. 2010, 8, 2979. Then, H2O (30 mL) and Na2CO3 (7 g, 66 mmol) were added. The
(15) (a) Almasi, D.; Alonso, D. A.; Balaguer, A.-N.; N
ajera, C. Adv.
Synth. Catal. 2009, 351, 1123. (b) Almasi, D.; Alonso, D. A.; N
ajera, C. Adv. product was extracted with ethyl acetate (2  20 mL), and the
Synth. Catal. 2008, 350, 2467. (c) Bradshaw, B.; Etxebarrı́a-Jardi, G.; solvent was evaporated. The crude residue was purified by recrys-
Bonjoch, J.; Vi
ozquez, S. F.; Guillena, G.; N
ajera, C. Adv. Synth. Catal. tallization from ether-hexane at 0 °C to afford 3.5 g (66% yield)
2009, 351, 2482. (d) Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thomson, of compound 3, whose properties are in agreement with those
J. E. Chem. Commun. 2005, 3802. (e) Lacoste, E.; Vaique, E.; Berlande, M.;
Pianet, I.; Vincent, J.-M.; Landais, Y. Eur. J. Org. Chem. 2007, 167. (f) He, L. published.5e
Hecheng Huaxue (Chin. J. Synth. Chem.) 2007, 15, 231. (g) Akahane, Y.; General Procedure for the Preparation of Monoureas (2-6)
Inage, N.; Nagamine, T.; Inomata, K.; Endo, Y. Heterocycles 2007, 74, 637. Starting from the Hydrochloride Salts of the Amines (Procedure B).
(h) Akahane, Y.; Inomata, K.; Endo, Y. Heterocycles 2009, 77, 1065. Urea 1 (3.5 mmol) and the amine hydrochloride (3.5 mmol) were
(i) D’Elia, V.; Zwicknagl, H.; Reiser, O. J. Org. Chem. 2008, 73, 3262.
(j) Guillena, G.; Hita, M. d. C.; N
ajera, C.; Vi
ozquez, S. F. J. Org. Chem. heated in diglyme (2 mL) at 120 °C. After the mixture was heated
2008, 73, 5933. (k) Kanger, T.; Kriis, K.; Laars, M.; Kailas, T.; Muurisepp, for ∼1 h, a solid precipitated from the reaction medium. NMR
1
A.-M.; Pehk, T.; Lopp, M. J. Org. Chem. 2007, 72, 5168. (l) Davies, S. G.; H analysis of an aliquot confirmed that the reaction had finished.
Russell, A. J.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E. Org. Biomol. The mixture was cooled to room temperature, and diethyl ether
Chem. 2007, 5, 3190. (m) Guillena, G.; N
ajera, C.; Vi
ozquez, S. F. Synlett
2008, 19, 3031. (n) Kriis, K.; Kanger, T.; Laars, M.; Kailas, T.; Muurisepp, (10 mL) was added. The solid was filtered and dried under vacuum
A.-M.; Pehk, T.; Lopp, M. Synlett 2006, 11, 1699. (o) Nozawa, M.; Akita, T.; (0.1 mmHg) heating at 90 °C to remove completely the traces of
Hoshi, T.; Suzuki, T.; Hagiwara, H. Synlett 2007, 4, 661. (p) Zhang, X.-M.; diglyme, affording the monoureas as their hydrochloride salts.
Wang, M.; Tu, Y.-Q.; Fan, C.-A.; Jiang, Y.-J.; Zhang, S.-Y.; Zhang, F.-M. This procedure has been carried out on a 1-5 mmol scale.
Synlett 2008, 18, 2831. (q) Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.;
Pascard, C. Tetrahedron 1984, 40, 1031. (r) Bui, T.; Barbas, C. F. Tetrahedron
Lett. 2000, 41, 6951. (16) Davies, S. G.; Mortlock, A. A. Tetrahedron 1993, 49, 4419.

J. Org. Chem. Vol. 75, No. 23, 2010 8305

JOC Note Fuentes de Arriba et al.

(1R,2R)-1,2-Diaminocyclohexane Phenylurea (2). Urea 1 (495 mg, was added, and the phenol was extracted with ethyl acetate
3.5 mmol) and aniline hydrochloride (460 mg, 3.5 mmol) were (2  30 mL). To the aqueous layer, cooled to 0 °C, was added KI
heated in diglyme (2 mL) at 120 °C. After the mixture was heated (7.0 g, 42 mmol), and a precipitate of the hydroiodide salt of
for ∼1 h, a solid precipitated from the reaction medium. 1H NMR compound 9 (12 g, 87% yield) was obtained: mp 187-189 °C;
analysis of an aliquot confirmed that the reaction had finished. The [R]20D -6.33 (c 0.6, CH3OH); 1H NMR (200 MHz, CDCl3/
mixture was cooled to room temperature, and diethyl ether (10 mL) CD3OD) δ 7.22-7.15 (2H, m), 7.06-6.97 (3H, m), 3.38 (1H, m),
was added. The solid was filtered and dried under vacuum 3.03 (1H, m), 1.94-1.84 (2H, m), 1.65-1.55 (2H, m), 1.30-1.16
(0.1 mmHg) heating at 90 °C to remove completely the traces of (4H, m); 13C NMR (50 MHz, CDCl3/CD3OD) δ 155.9 (C), 150.9
diglyme. The urea 2 as its hydrochloride salt (621 mg, 66%) was (C), 129.3 (CH), 125.6 (CH), 121.8 (CH), 54.6 (CH), 53.1 (CH),
obtained. Spectral and physical data of the free amine (liberated 31.7 (CH2), 29.9 (CH2), 24.4 (CH2), 23.7 (CH2); IR (film) 3565,
with aqueous KOH (3.3 mL, 6 mM) and extracted with diethyl 3318, 1729, 1599, 1462 cm-1. Anal. Calcd for C13H19IN2O2: C,
ether) were in agreement with those published.17 43.11; H, 5.29; N, 7.73. Found: C, 42.89; H, 5.38; N, 7.83.
Phenyl (1R,2R)-2-Aminocyclohexylcarbamate 9. Initially, (R,R)-
cyclohexane-1,2-diamine tartrate salt (10.02 g, 37.9 mmol) was Acknowledgment. This work was supported by the Spanish
reacted under the same conditions described for the preparation of Direcci

on General de Investigaci
on, Ciencia y Tecnologı́a
urea 1. After the mixture was refluxed with diphenyl carbonate (DGICYT) (CTQ-2008-01771/BQU), and the UE (European
(8.11 g, 37.9 mmol) in 2-propanol, the solvent was evaporated
Reintegration Grant PERG04-GA-2008-239244). A.L.F.A.
under reduced pressure, and the crude residue was dried through
azeotropic destillation with benzene (100 mL). To this mixture of thanks the Ministerio de Educaci

on y Ciencia for a FPU Grant
phenol and the urea 1 was added 1 equiv of methanesulfonic acid and Ang
elica del Castillo for working with us.
(2.5 mL), and the reaction was heated at 110 °C with stirring for 1 h
under Ar atmosphere. Then the solution was cooled, water (30 mL) Supporting Information Available: Synthesis of catalysts,
characterization data (including 1H and 13C spectra of the new
(17) Bied, C.; Moreau, J. J. E.; Wong Chi Man, M. Tetrahedron: compounds), and HPLC chromatograms. This material is avail-
Asymmetry 2001, 12, 329. able free of charge via the Internet at http://pubs.acs.org.

8306 J. Org. Chem. Vol. 75, No. 23, 2010