Unexpected formation of O-methoxycarbonyl cyanohydrin showing potential as a protective group of ketones

Article abstract of DOI:10.1055/s-1999-2859

A one-step procedure using methyl cyanoformate and a secondary alkylamine was reported to efficiently transform ketones into O- methoxycarbonyl cyanohydrins. This functional group shows interesting potential in protecting group chemistry.

Full text of DOI:10.1055/s-1999-2859

LETTER
1423
Unexpected formation of O-methoxycarbonyl cyanohydrin showing potential
as a protective group of ketones
Donald Poirier,* David Berthiaume, Roch P. Boivin
Medicinal Chemistry Division, Laboratory of Molecular Endocrinology, Laval University Medical Research Center,
2705 Laurier Boulevard, Quebec, G1V 4G2, Canada
Fax 418-654-2761; E-mail: donald.poirier@crchul.ulaval.ca
Received 27 June 1999
was also important since no protection occurred with dial-
Abstract: A one-step procedure using methyl cyanoformate and a
lylamine and diphenylamine (entries 7 and 8). On the con-
secondary alkylamine was reported to efficiently transform ketones
trary, dialkylamines were very efficient giving 84, 83, and
into O-methoxycarbonyl cyanohydrins. This functional group
97% of 2 for diisopropylamine, N-isopropyl-cyclohexy-
lamine, and N-t-butyl-ethylamine, respectively, (entries 3,
9, and 10).
shows interesting potential in protecting group chemistry.
Key words: protective group, ketone, cyanohydrin, carbonate
The protection and deprotection of a carbonyl group is a Table 1 Formation of O-methoxycarbonyl cyanohydrin derivative 2
from steroid ketone 1: effect of reaction time and amine type
widely used process in multi-step organic synthesis.
Among the range of protective groups developed for car-
NCCOOCH3 (10 eq)
Amine (20 eq)
bonyl groups in the past,1 four O-substituted cyanohydrin
derivatives (acetyl,2,3 silyls,4-7 ethoxyethyl,8 and
tetrahydropyranyl9) have been reported. During the
course of our studies of the synthesis of C16-steroid deriv-
atives as inhibitors of 17b-hydroxysteroid dehydrogena-
se,10-12 we found that O-methoxycarbonyl cyanohydrin 2
can be easily obtained from a C17-steroid ketone 1
(Scheme 1). This observation prompted us to perform ad-
ditional experi-ments to optimize the conditions of forma-
tion and to define the scope of this new protective group
of the cyanohydrin family.
R1
R2
R1
R2
CN
O
THF, rt, 16-18 h
OCOOCH3
3
4
OCOOCH3
CN
O
NCCOOCH3 (10 eq)
Amine (20 eq)
THF, RT
CH3O
CH3O
2
1
K2CO3 (1%) in MeOH/H2O (3:1)
RT, 4 h, qt yield
Scheme 1
The steroid ketone 1 was selected for the first part of our
study (Table 1). Preliminary results suggested to use an
excess of methyl cyanoformate (10 equiv) and diisoprop-
ylamine (20 equiv) to facilitate the completion of the for-
mation of O-methoxycarbonyl cyanohydrin 2. The pres-
ence of an amine was deemed crucial since no reaction
was observed without diisopropylamine after 72 h (entry
1). As reported in entries 2-4, the yield of 2 (44, 84, and
100%) increased with the time of reaction (4, 8, and 24 h,
respectively). We then retained the intermediate time of 8
h to determine the most appropriate amine. Clearly, a pri-
mary amine (entry 5) was not suitable for protection,
while a tertiary amine (entry 6) was less efficient than a
secondary amine (entry 3). The type of secondary amine
(a) See general procedure in Note 13 and characterization of 2 in Note
14. (b) Starting ketone 1 was the only other compound observed. The
yield of 2 was determined by H NMR integration of CH3-18 (0.91
1
and 0.96 ppm for 1 and 2, respectively).
After establishing the standard conditions for the forma-
tion of O-methoxycarbonyl cyanohydrin 2,13 we studied
the ability of different types of ketones to be protected and
we determined the isolated yields (Table 2). Diisopropy-
lamine (DIPA) and N-t-butyl-ethylamine (TBEA) were
selected for our assays. In both cases, similar results were
Synlett 1999, No. 9, 1423–1425 ISSN 0936-5214 © Thieme Stuttgart · New York

1424
D. Poirier et al.
LETTER
.
obtained (entries 1, 2 and 4, 5). Under standard condi- ity in presence of Lewis acids (AlCl3, BBr3, BF3 OEt2) and
tions, cyclic and aliphatic ketones (entries 1-7) reacted oxidants (NaClO4, CrO3, KMnO4).
very well with high isolated yields (85-98%). However,
for the strained ketone, cyclooctanone, the yield dropped
to 55-65% in spite of the fact that only one product was
observed on TLC (entries 4 and 5).
As exemplified in Scheme 1, the ketone 1 can be easily re-
stored from 2 in a quantitative yield by treatment with
15
K2CO3 (1%) in MeOH/H2O. Since these conditions are
known to hydrolyze carbonate groups,16 the methoxy-car-
bonyloxy moiety of 2 was hydrolyzed before eliminating
the cyanide through formation of the carbonyl group.
Table 2 Isolated yields for the formation of O-methoxy carbonyl cy-
anohydrin derivative 4.
In conclusion, high yeilds of a new protective group of ke-
tones was generated through an efficient one-step proce-
dure at room temperature using methylcyanoformate and
a secondary alkylamine. This O-methoxycarbonyl cyano-
hydrin group is more stable under acid conditions than its
known analogs (O-silyl, O-tetrahydropyranyl, and O-ket-
al). It is thus a valuable addition to the family of cyanohy-
drin protective group of ketones. Work is now under
progress to establish the generality of the method regard-
ing other ketones, aldehydes, and to reduce the amount of
reagent. These results will be reported in due time in a full
paper.
Acknowledgement
The authors would like to thank the Medical Research Council of
Canada (MRC) and the Fonds de la Recherche en Santé du Québec
(FRSQ) for their financial support. We are grateful to the Laborato-
ry of Molecular Endocrinology for providing the chemical facilities.
Helpful discussions with Martin Tremblay and Richard Labrecque
were also greatly appreciated.
References and Notes
(1) Greene, T. W.; Wuts, P. G. M. In Protective groups in organic
synthesis, 2nd ed.; Wiley-Interscience: New York, 1991; pp
175-223.
(2) Klimstra, P. D.; Colton, F. B. Steroids 1967, 10, 411.
(3) Hiyama, T.; Oishi, H.; Saimoto, H. Tetrahedron Lett. 1985,
26, 2459.
(a) DIPA: diisopropylamine; TBEA: N-t-butyl-ethylamine. (b) After
work up (Note 13) and silica-gel chromatography. Compounds exhi-
bited satisfactory IR, NMR and MS data (c) 17b-t-butyldimethylsily-
loxy-5a-androstan-3-one. (d) 17b-t-butyldimethylsilyloxy-5a-an-
drost-4-en-3-one.
(4) Evans, D. A.; Hoffman, J. M.; Truesdale, L. K. J. Am. Chem.
Soc. 1973, 95, 5822.
(5) Evans, D. A.; Wong, R. Y. J. Org. Chem. 1977, 42, 350.
(6) Duboudin, F.; Cazeau, Ph.; Moulines, F.; Laporte, O.
Synthesis 1982, 212.
(7) Rawal, V. H.; Rao, J. A.; Cava, M. P. Tetrahedron Lett. 1985,
26, 4275.
(8) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1971, 93, 5286.
(9) deRuggieri, P.; Ferrari, C. J. Am. Chem. Soc. 1959, 81, 5725.
(10) Tremblay, M. R.; Poirier, D. J. Steroid Biochem. Molec. Biol.
1998, 66, 179.
(11) Tremblay, M. R.; Auger, S.; Poirier, D. Synth. Commun. 1995,
25, 2483.
The reactivity of two conjugated ketones was also studied,
and only 15% and 25% of cyanohydrin derivative 4 was
obtained respectively with an aromatic ketone such as 5-
methoxy-1-tetralone (entry 8) or an a,b-unsaturated cy-
clohexanone derivative such as 17b-TBDMS-testosterone
(entry 9). In both cases, the starting ketone was the only
other compound detected. As demonstrated with the two
tetralone derivatives (entries 7 and 8), conjugated ketones
were found to be less reactive than unconjugated ones,
suggesting the nucleophilic nature of the reactive cyano
species.
(12) Sam, K. M.; Boivin, R. P.; Tremblay, S.; Auger, S.; Poirier, D.
Drug Design Discovery 1998, 15, 157.
(13) General Procedure for synthesis of 2 and 4: Amine (20
mmol) and methyl cyanoformate (10 mmol) were added to a
solution of carbonyl derivative 1 or 3 (1 mmol) in THF (10
mL). After stirring at r.t. for the appropriate time (Table 1: 4-
72 h or Table 2: 16-18 h), H2O was added and the mixture
extracted with Et2O. The organic phase was washed with HCl
(10%), dried over MgSO4, and concentrated under vacuum.
The residue was analyzed by 1H NMR without (Table 1) or
with (Table 2) a purification by silica gel column
chromatography.
The stability of O-substituted cyanohydrin derivatives de-
pends on the cyano group and the O-R counter part. Until
now, the nature of the R group was considered to be the
cause of high sensitivity to acid conditions.1 Interestingly,
the O-methoxycarbonyl cyanohydrin derivative 2 resists
cleavage under acid conditions (AcOH, TfOH, TsOH, and
aqueous HCl). Preliminary results also show good stabil-
Synlett 1999, No. 9, 1423–1425 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Unexpected formation of O-methoxycarbonyl cyanohydrin
1425
(14) 17a-Cyano-3-methoxy-17b-methoxycarbonyloxy-estra-
1,3,5 (10)-triene (2): White solid; IR (KBr) n 1754 (C=O,
carbonate), 2372 very weak (C∫N, nitrile); 1H NMR (300
MHz, CDCl3) d 0.96 (s, CH3-18), 3.78 (s, CH3O-Ar), 3.85 (s,
CH3OCO), 6.64 (d, J = 2.6 Hz, CH-4), 6.73 (dd, J1 = 2.6 Hz
and J2 = 8.6 Hz, CH-2), 7.20 (d, J = 8.6 Hz, CH-1); 13C NMR
(75 MHz, CDCl3) d 12.85 (C18), 23.08 (C15), 25.98 (C11),
27.07 (C7), 29.53 (C6), 33.58, 35.56, 38.84 (C8), 43.02 (C9),
48.09 (C13), 48.47 (C14), 55.13 (CH3O), 55.31 (CH3O),
84.98 (C17), 111.55 (C2), 113.78 (C4), 118.40 (CN), 126.27
(C1), 131.61 (C10), 137.56 (C5), 153.86 (OCOO), 157.56
(C3); MS m/z 370 [M+H]+, 387 [M+NH4]+.
(15) Procedure for cleavage of protective group: A solution of
K2CO3 (1%) in MeOH:H2O (3:1) (10 mL) was added to a
solution of O-methoxycarbonyl cyanohydrin 2 (0.27 mmol) in
MeOH (10 mL). After 4 h at room temperature, water was
added, and 3-methyl-O-estrone (one spot on TLC) was
extracted with EtOAc.
Poirier, D.; Labrie, C; Mérand, Y.; Labrie, F. J. Steroid
Biochem. Molec. Biol.s 1991, 38, 759.
Article Identifier:
1437-2096,E;1999,0,09,1423,1425,ftx,en;S01499ST.pdf
Synlett 1999, No. 9, 1423–1425 ISSN 0936-5214 © Thieme Stuttgart · New York