Solvent-free synthesis of α-amino nitrile-derived ureas

Article abstract of DOI:10.1021/ol303452r

An efficient and environmentally friendly methodology for the solvent-free synthesis of α-amino nitrile derived ureas from α-amino acid based amino nitriles has been developed. At room temperature no epimerization was observed in the resulting ureas, but

Full text of DOI:10.1021/ol303452r

ORGANIC
LETTERS
2013
Vol. 15, No. 3
632–635
Solvent-Free Synthesis of r‑Amino
Nitrile-Derived Ureas
ꢀ
Pilar Ventosa-Andres, Juan A. Gonzalez-Vera, M. Teresa Garcıa-Lopez, and
ꢀ
ꢀ
´
Rosario Herranz*
´ ꢀ
Instituto de Quımica Medica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
rosario@iqm.csic.es
Received December 17, 2012
ABSTRACT
An efficient and environmentally friendly methodology for the solvent-free synthesis of R-amino nitrile derived ureas from R-amino acid based
amino nitriles has been developed. At room temperature no epimerization was observed in the resulting ureas, but under microwave heating,
epimerization occurred at the chiral center bearing the cyano group.
R-Amino nitriles are versatile intermediates for the
synthesis of multiple building blocks.1 In particular,
R-amino acid derived amino nitriles have shown high
potential for molecular diversity generation.2 Thus, we
have shown their utility in the synthesis of pseudopeptides3
and diverse chiral heterocyclic compounds.4
Among R-amino nitrile derivatives, N-acyl-amino-
nitriles have proven to be important molecules for the
search of inhibitors of therapeutically important peptidases,5
such as dipeptidyl peptidase IV,6 prolyl oligopeptidases,7
and cysteine cathepsins.8 More concretely, several R-amino
nitrile derived ureas have been patented as inhibitors of
cholesteryl ester transfer protein9 and diverse enzymes,10
agents for neurological disorders,11 pesticides,12 or
fungicides.13 On the other hand, R-amino nitrile derived
ureas are intermediates in the synthesis of diverse phar-
macologically active hydantoin derivatives from R-amino
nitriles,14 although these intermediates have not been
isolated and characterized. Therefore, the development
of simple and versatile methods for the synthesis and
identification of N-(cyanomethyl)ureas is an important
goal in synthetic organic chemistry, in particular, envi-
ronmentally friendly solvent-free procedures.
(1) (a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359–373.
(b) Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947–6983.
In the context of a medicinal chemistry project focused on
the search for modulators of proteinÀprotein interactions,
ꢀ
ꢀ
(2) Gonzalez-Vera, J. A.; Garcıa-Lopez, M. T.; Herranz, R. Mini-
´
Rev. Org. Chem. 2008, 5, 209–221.
ꢀ
ꢀ
(3) (a) Herranz, R.; Suarez-Gea, M. L.; Vinuesa, S.; Garcıa-Lopez,
´
ꢀ
M. T. J. Org. Chem. 1993, 58, 5186–5191. (b) Herrero, S.; Suarez-Gea,
ꢀ
M. L.; Gonzalez-Muniz, R.; Garcı
S.; Barber, A.; Fortuno, A.; Del Rı
~
ꢀ
´
a-Lopez, M. T.; Herranz, R.; Ballaz,
€
(8) (a) Frizler, M.; Stirnberg, M.; Sisay, M. T.; Gutschow, M. Curr.
~
´
o, J. Bioorg. Med. Chem. Lett. 1997, 7,
Top. Med. Chem. 2010, 10, 294–322. (b) Wijkmans, J.; Gossen, J. Expert.
Opin. Ther. Pat. 2011, 21, 1611–29.
855–860.
ꢀ
´
a-Lopez, M. T.; Latorre, M.; Cenarruzabeitia,
(4) (a) Herrero, S.; Garcı
E.; Del Rıo, J.; Herranz, R. J. Org. Chem. 2002, 67, 3866–3873. (b)
Herrero, S.; Garcı
68, 4582–4585. (c) Herrero, S.; Salgado, A.; Garcı
Herranz, R. Tetrahedron Lett. 2002, 43, 4899–4902. (d) Gonzalez-
Vera, J. A.; Garcı
3660–3666. (e) Gonzalez-Vera, J. A.; Garcı
R. Org. Lett. 2004, 6, 2641–2644.
(9) Salvati, M. E.; Finlay, H.; Harikrishnan, L. S.; Jiang, J.; Johnson,
J. A.; Kamau, M. G.; Lawrence, R. M.; Miller, M. M.; Qiao, J. X.;
Wang, T. C.; Wang, Y.; Yang, W. WO2007062314A2, 2007.
(10) (a) Matsuno, K.; Ueno, K.; Iwata, Y.; Matsumoto, Y.; Nakanishi,
S.; Tasaki, K.; Kusaka, H.; Nomoto, Y.; Ogawa, A. US20040180925A1,
2004. (b) Bloomfield, G. C.; Bruce, I.; Hayler, J. F.; Leblanc, C.; Le, G. D. M.;
McCarthy, C. WO2005021519A2, 2005.
´
ꢀ
a-Lopez, M. T.; Herranz, R. J. Org. Chem. 2003,
´
ꢀ
a-Lopez, M. T.;
´
ꢀ
ꢀ
´
a-Lopez, M. T.; Herranz, R. J. Org. Chem. 2005, 70,
ꢀ
ꢀ
a-Lopez, M. T.; Herranz,
´
(5) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C.
J. Med. Chem. 2010, 53, 7902–7917.
(11) Ross, D. T.; Sauer, H.; Hamilton, G. S.; Steiner, J. P.
WO2000009106A2, 2000.
(6) (a) Weber, A. E. J. Med. Chem. 2004, 47, 4135–4141. (b) Pei, Z.
Curr. Opin. Drug Discovery Dev. 2008, 11, 512–32.
(7) Lawandi, J.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L.; Moitessier,
N. J. Med. Chem. 2010, 53, 3423–38.
(12) Pazenok, S.; Krautstrunk, G.; Lantzsch, R. WO2005035508A2,
2005.
(13) Schulze, W.; Klepel, M.; Jumar, A.; Lehmann, H.; Braemer, B.
DD232636A1, 1986.
r
10.1021/ol303452r
Published on Web 01/15/2013
2013 American Chemical Society

we required the basic amino acid derived N-(cyanomethyl)-
ureas of general formula A (Scheme 1), which were
expected to be easily accessible from the corresponding
R-amino nitriles B, by reaction with isocyanates. These
R-amino nitriles B were previously obtained by a mod-
ified Strecker synthesis as epimeric mixtures in the carbon
bearing the cyano group, which were chromatographi-
cally resolved.15
Scheme 2. Synthesis of the N-(Cyanomethyl)ureas 2a from the
R-Amino nitrile (S)-1a as Indicated in Table 1
Scheme 1
Table 1. Influence of Reaction Conditions on the Synthesis of
the N-(Cyanomethyl)ureas 2a
(cyanomethyl)urea
amino nitrile
no.
entry
solvent t (°C)
THF
t
no
(%)a
1
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(R)-1a
0
3 d
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(RS)-2a
(RS)-2a
86
0
2
CH2Cl2 rt
rt
5 d
3
À
48 h
98
0
98c
98c
4b
5b
6b
CH2Cl2 80 2 h
À
80 2 h
80 2 h
À
a Isolated yield. b Microwave irradiation. c [(R)/(S)] epimer ratio ≈ 1:1.
The reaction of the R-amino nitrile (S)-1a (Scheme 2)
with 2 equiv of phenyl isocyanate was used for setting
up the methodology. Initially, the synthesis of the
N-(cyanomethyl)urea (S)-2a was explored in parallel in
two different solvents, in CH2Cl2 at room temperature and
in THF at 0 °C, under described reaction conditions.14a,16
When the reaction was carried out in THF, 86% of urea
(S)-2awasisolatedafter3 daysofreaction. However, inthe
case of the reaction in CH2Cl2, after 5 days, the starting
amino nitrile (S)-1a remained unaltered, but after 3 addi-
tional days, when the solvent had accidentally evaporated,
the TLC and HPLC analysis of the crude reaction mixture
showed the presence of 60% of (S)-2a. This result induced
us to study the reaction under solvent-free conditions.
These involved the mixture and homogenization of re-
agents with a minimum amount of dry CH2Cl2, followed
by evaporation of the solvent under argon. As shown in
Table 1, under these conditions, a 98% yield of the desired
urea (S)-2a was obtained after 48 h.
Next, with the aim of decreasing the reaction time, the
reaction was carried out under heating at 80 °C by micro-
wave irradiation. When this heating was applied using
CH2Cl2 as solvent, the starting amino nitrile (S)-1a was
recovered unaltered after 2 h (Table 1, entry 4). However,
when microwave (MW) heating was applied to the solvent-
free reaction mixture, a 98% yield of the epimeric mixture
of ureas (RS)-2a was obtained. A similar result was
obtained when the starting amino nitrile was the epimer
(R)-1a (Table 1, entry 6). In both cases, the HPLC analysis
of the crude reaction mixture showed the presence of
the two epimeric ureas (R)- and (S)-2a with tR = 27.7
and 27.5 min, respectively, in an ∼1:1 ratio and traces of
the corresponding starting amino nitrile (R)- or (S)-1a at
23.28 or 23.89 min. These data indicated epimerization in
the (cyanomethyl)urea at the carbon bearing the cyano
group, which had not occurred in the starting amino
nitriles (R)- and (S)-1a. These results were confirmed in
the 1H NMR analysis of the crude reaction products. As
shown in Scheme 3, the higher propensity of N-(cyano-
methyl)ureas to epimerize, with respect to the correspond-
ing R-amino nitrile, could be explained by the elec-
tron attracting effect of the ureido group, which would
increase the acidity of the proton in the position R to the
cyano group, facilitating the formation of the tautomeric
ketimine species 3a, which would revert to give the epi-
meric mixture of N-(cyanomethyl)ureas (RS)-2a. Both
pure isolated epimers (R)- and (S)-2a epimerized by heat-
ing at 80 °C under MW irradiation, although this epimer-
ization was slower in (S)-2a than in (R)-2a (180 vs 120 min
for complete epimerization). However, under similar
(14) (a) Rowbottom, M. W.; Vickers, T. D.; Tamiya, J.; Zhang, M.;
Dyck, B.; Grey, J.; Schwarz, D.; Heise, C. E.; Hedrick, M.; Wen, J.;
Tang, H.; Wang, H.; Fisher, A.; Aparicio, A.; Saunders, J.; Goodfellow,
V. S. Bioorg. Med. Chem. Lett. 2007, 17, 2171–2178. (b) Coburn, C. A.;
Egbertson, M. S.; Graham, S. L.; McGaughey, G. B.; Stauffer, S. R.;
Rajapakse, H. A.; Nantermet, P. G.; Stachel, S. R.; Yang, W.; Lu, W.;
Fahr, B. WO2007011833A2, 2007. (c) Coburn, C. A.; Egbertson, M. S.;
Graham, S. L.; McGaughey, G. B.; Stauffer, S. R.; Yang, W.; Lu, W.; Fahr, B.
WO2007011810A1, 2007. (d) Jung, M. E.; Ouk, S.; Yoo, D.; Sawyers, C. L.;
Chen, C.; Tran, C.; Wongvipat, J. J. Med. Chem. 2010, 53, 2779–2796. (e)
Sacchetti, A.; Silvani, A.; Gatti, F. G.; Lesma, G.; Pilati, T.; Trucchi, B.
Org. Biomol. Chem. 2011, 9, 5515–5522.
ꢀ
ꢀ
(15) Ventosa-Andres, P.; Garcı
´
a-Lopez, M. T.; Herranz, R. Tetra-
hedron: Asymmetry 2012, 23, 1198–1205.
ꢀ
ꢀ
a-Lopez, M. T.; Gonzalez-
Muniz, R.; Cenarruzabeitia, E.; Latorre, M.; Del Rıo, J.; Herranz, R.
ꢀ
(16) Bartolome-Nebreda, J. M.; Garcı
´
~
´
J. Med. Chem. 2001, 44, 4196–206.
Org. Lett., Vol. 15, No. 3, 2013
633

Scheme 3. Proposed Mechanism of Epimerization of N-(Cyanomethyl)ureas
conditions, the starting amino nitriles (R)- and (S)-1a were
recovered without epimerization. In relation to these
results, two recent reports, on the enzymatic resolution
of R-amino nitriles, reported the complete racemization of
R-acylamino nitriles at 40 °C, while no racemization at all was
observed in their respective R-amino nitriles.17After chroma-
tographic resolution of the epimeric mixtures (RS)-2a, each
of the resulting epimers showed the same optical rotation
as (R)-2a and (S)-2a obtained under epimerization-free
conditions. This result indicated that epimerization had
taken place at the carbon bearing the cyano group and not
at the carbon bearing the N-benzyl carboxamide group, as
in that case the epimerization compounds would be en-
antiomers of (R)-2a and (S)-2a with the same optical
rotation value, but opposite sign.
the synthesisof ureas2aÀdand 4À6aasshowninScheme 4
and Table 2. When, due to problems of resolution, the
starting R-amino nitrile was an epimeric mixture, to opti-
mize the reaction time, the synthesis was carried out under
MW irradiation.
The methodology was also applied to the methyl ester
R-amino nitriles (R)- and (S)-7a,b, derived from ornithine
(a) and lysine (b) (Scheme 5). In these cases, the HPLC-MS
analyses of the crude reaction mixtures indicated that the
Table 2. Synthesis of N-(Cyanomethyl)ureas 2aÀd from
R-Amino Nitriles 1aÀd
R-amino nitrile
(cyanomethyl)urea
In view of the results shown in Table 1, we considered
thatthebestconditionsforthe epimerization-freesynthesis
of N-(cyanomethyl)ureas from R-amino nitriles would
include the solvent-free reaction with 2 equiv of isocyanate
at room temperature. These conditions were applied for
entry
no.
methoda
no.
R2
(%)b
1
(R)-1a
B
B
C
B
B
C
B
B
C
B
C
C
C
C
(R)-2a
(S)-2a
Ph
Ph
96
86
95
95
93
97
94
93
90
91
96
95
92
97
2
(S)-1a
3
(RS)-1ac
(R)-1a
(RS)-2a Ph
4
(R)-4a
(S)-4a
Bn
Bn
5
(S)-1a
6
(RS)-1ac
(R)-1a
(RS)-4a Bn
7
(R)-5a
(S)-5a
4-MeO-Ph-(CH2)2
4-MeO-Ph-(CH2)2
8
(S)-1a
Scheme 4
9
(RS)-1ac
(S)-1a
(RS)-5a 4-MeO-Ph-(CH2)2
(S)-6a 4-F-Ph-(CH2)2
10
11
12
13
14
(RS)-1ac
(RS)-1bd
(RS)-1cc
(RS)-1dc
(RS)-6a 4-F-Ph-(CH2)2
(RS)-2b Ph
(RS)-2c Ph
(RS)-2d Ph
a Method B: Solvent-free, rt, 2À3 days. Method C: MW 80 °C,
2À3 h. b Isolated yield. c [(R)/(S)] epimer ratio = 1:1. d [(R)/(S)] epimer
ratio = 1:3.
Scheme 5
634
Org. Lett., Vol. 15, No. 3, 2013

reactions were significantly slower and, after 7 days,
they showed 75% conversion to give 43% of the re-
spective N-(cyanomethyl)urea (R)- and (S)-8a,b along
with 33% of the corresponding hydantoin derivative
(R)- and (S)-9a,b. However, when the reactions were
carried out under MW irradiation at 80 °C, after 2 h,
the HPLC-MS analyses of the crude reaction mixtures
showed the formation of a 90% yield of ureas (R)- and
(S)-8a,b and traces of the corresponding hydantoin.
After silica gel column chromatography, the ureas
cyclized completely to the respective hydantoin deriva-
tives (R)- and (S)-9a,b, which were isolated free of
epimerization in 70À78% yield.
amino acid based chiral highly functionalized N-(cyano-
methyl)ureas with a high potential for the generation of
molecular diversity in drug discovery. Although the syn-
thesis can be activated by MW heating, precautions must
be taken as it can induce epimerization at the chiral center
bearing the cyano group.
Acknowledgment. This work was supported by the
ꢀ
Spanish Ministerio de Ciencia e Innovacion Grant
SAF2009-09323. P.V.-A. held an FPI fellowship from
ꢀ
the Ministerio de Ciencia e Innovacion.
In conclusion, we have developed an environmentally
friendly solvent-free methodology for the synthesis of
Supporting Information Available. Detailed experimen-
tal procedures and full characterization for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
€
(17) (a) Vongvilai, P.; Ramstrom, O. J. Am. Chem. Soc. 2009, 131,
14419–14425. (b) Vongvilai, P.; Linder, M.; Sakulsombat, M.; Svedendahl
€
Humble, M.; Berglund, P.; Brinck, T.; Ramstrom, O. Angew. Chem., Int.
Ed. 2011, 50, 6592–6595.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
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