Synthesis of cyanoacetyl oxazolidinones

Article abstract of DOI:10.1055/s-0031-1291123

Carefully controlled displacement of chiral chloroacetyl imides with cyanide afforded previously unreported cyanoacetimides in good overall yield. Knoevenagel condensation of the cyanoacetimides to furnish acrylonitriles was also demonstrated. Georg Thiem

Full text of DOI:10.1055/s-0031-1291123

PAPER
▌1993
paper
Synthesis of Cyanoacetyl Oxazolidinones
Synthesis of Cyanoacetyl Oxazolidinones
Kaitlyn M. Weeber, Jacob B. Schwarz*
Genentech, Inc., 1 DNA Way, S. San Francisco, CA 94080, USA
Fax +1(650)7424943; E-mail: schwarz.jacob@gene.com
Received: 22.03.2012; Accepted after revision: 16.04.2012
Our initial attempt to fashion the cyanoacetyl oxazolidi-
none 1 involved coupling of the NH-oxazolidinone to cy-
anoacetic acid by traditional methods (acid chloride8 or
mixed anhydride9), but none of these attempts led to us-
able quantities of the desired product. It was noted that the
corresponding chloroacetimides 3 were readily available
from chloroacetyl chloride, and we envisioned that simple
displacement of 3 by cyanide ion should afford 1. Howev-
er, when 3a (R1 = Me, R2 = Ph) was exposed to an excess
of potassium cyanide in DMF at ambient temperature,
conversion to the desired product was accompanied by
what appeared to be a by-product 4a corresponding to at-
tack by product 1a onto starting material (Scheme 2). The
‘dimeric’ product 4a was formed as a nearly 1:1 mixture
Abstract: Carefully controlled displacement of chiral chloroacetyl
imides with cyanide afforded previously unreported cyanoaceti-
mides in good overall yield. Knoevenagel condensation of the cya-
noacetimides to furnish acrylonitriles was also demonstrated.
Key words: oxazolidinone, Knoevenagel, cyanoacetic, chloroace-
tic, tetrabutylammonium cyanide
FSC231, an α,β-unsaturated cyanoimide, was recently re-
ported as a micromolar inhibitor of protein interacting
with Cα-kinase 1 (PICK1), a potential therapeutic inter-
vention point for stroke, pain, and addiction (Scheme 1).1,2
Oxazolidinones of type 2 strongly resemble FSC231, and
reportedly undergo coupling with N,N- or N,O-ketene
acetals to generate densely functionalized bicyclic lac-
tams.3 As part of a continuing interest4,5 in exploring the
utility of cyanoacetic acid derivatives, oxazolidinones of
type 1 were targeted as a way of accessing such structures
for synthetic and medicinal chemistry applications. To our
surprise, these seemingly simple reagents had not been re-
ported to date.6,7 Indeed, we found that the preparation of
1
of diastereomers by H NMR analysis (55:45). Unfortu-
nately, the undesired by-product 4a was inseparable from
1a by simple chromatography (HPLC was used to isolate
4a for characterization). Hence, we sought to minimize
formation of dimer 4 in the displacement process.
O
O
O
O
KCN (5 equiv)
DMF, r.t.
NC
cyanoimides 1 was not straightforward, which prompted
us to disclose our efforts in this area.
Cl
N
O
N
O
Ph
Ph
Xc
O
O
1a
Cl
3a
FSC231
PICK1 Ki = 9.6 μM
refs. 1, 2
NC
Ar
O
N
O
H
O
O
NC
O
constraint
Ph
N
O
O
1a
+
N
O
O
O
O
O
Ph
NC
N
Y
NC
ref. 3
N
(1a/4a 3:1)
4a
X
Ar
Ar
R2
R1
Scheme 2 Competitive formation of undesired by-product 4
O
2
X = NH, O
Y = OEt, Me, Ar
As no conversion of 3 to 1 was detected below –15 °C, we
reasoned that maintaining the KCN/DMF reaction at
around 0 °C should slow the facile dimerization process.
Gratifyingly, this proved to be the case. By LC/MS no
conversion to the desired nitrile was observed until the
temperature reached ca. –15 °C, at which point decent
conversion to 1 could be effected if the temperature was
maintained between –10 and 0 °C for 3 hours (Table 1,
Method A). Although formation of by-product 4 was min-
imized at lower temperatures, the acyl imide moiety of 1
was prone to hydrolysis under these reaction conditions
resulting in formation of a significant quantity of free NH-
oxazolidinone. The chiral auxiliary by-product was easily
ArCHO
O
O
NC
N
O
R2
R1
1
Scheme 1 Utility of unsaturated cyanoimides as receptor ligands and
synthetic intermediates
SYNTHESIS 2012, 44, 1993–1996
Advanced online publication: 25.05.2012
DOI: 10.1055/s-0031-1291123; Art ID: SS-2012-M0301-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1994
K. M. Weeber, J. B. Schwarz
PAPER
removed from 1 by chromatography, but unfortunately
this decomposition pathway substantially diminished the
yield and hence the utility of the process.
Table 2 Formation of Knoevenagel Adducts 2
O
O
NC
CHO
1a,b
N
O
NH4OAc, AcOH
Table 1 Formation of Cyanoimides 1
R1
R2
Cl
CHCl3, 80 °C
O
O
O
O
method
A or B
Cl
Cl
Cl
NC
N
O
N
O
Cl
2a–b
R1
3a–d
R2
R1
1a–d
R2
Entry
R1
R2
Product
Yield (%)a
Entry
R1
R2
Product
Methoda Yield (%)b
1
2
Me
Bn
Ph
H
2a
2b
31
53
1
2
3
4
5
6
7
8
Me
Me
Bn
Bn
Ph
Ph
H
1a
1a
1b
1b
1c
1c
1d
1d
A
B
A
B
A
B
A
B
19
57
27
59
24
53
18
57
a Isolated yield.
tion of a dimeric product 4, which was difficult to exclude
chromatographically. Optimization of the reaction in-
volved use of n-Bu4CN as the cyanide source, which al-
lowed for smooth conversion in a shorter time frame, and
translated to much improved yields. Knoevenagel con-
densation of cyanoimides 1 under modified dehydrative
conditions furnished α,β-unsaturated cyanoimides 2, rep-
resenting constrained analogues of previously reported
PICK1 inhibitors.
H
i-Prc
i-Prc
Ph
H
H
H
Ph
H
a Reaction conditions: Method A: KCN, DMF, 0 °C, 3 h. Method B:
Bu4NCN, CH2Cl2, 0 °C, 30 min.
b Isolated yield.
Optical rotations were measured at r.t. and 589 nm using an SPISC
WZZ-2S polarimeter. Melting points were determined using a DSC
Q100 instrument. IR spectra were collected using a Thermo Scien-
tific Nicolet 380 FT-IR spectrophotometer. HRMS were recorded
on a Waters LCT Primer XE spectrometer. Bruker instruments (300
and 400 MHz) were used for NMR characterization.
c The S-isomer was used.
Successful optimization of the displacement reaction was
based upon the literature conversion of a chloroacetic pi-
perazine amide to the corresponding nitrile using tetrabu-
tylammonium cyanide.10 Toward this end, exposure of
chloroimide 3b to a slight excess (1.2 equiv) of tetrabutyl-
ammonium cyanide in CH2Cl2 at 0 °C led to clean, albeit
partial conversion of 3b to product. Increasing the reagent
stoichiometry to two equivalents of cyanide allowed for
complete conversion of 3b at 0 °C, and significantly im-
proved the yield (Table 1, method B). That the conversion
was also fast at 0 °C relative to the KCN/DMF conditions
(30 min vs 3 h) also served to obviate competing hydroly-
sis of the product. In all cases, the optimized conditions
led to at least a doubling of isolated yield compared to
method A.11
Cyanide Displacement of Chloroacetyl Oxazolidinones 3; (S)-3-
(4-Isopropyl-2-oxooxazolidin-3-yl)-3-oxopropanenitrile (1c);
Typical Procedures
Method A: To a solution of (S)-3-(2-chloroacetyl)-4-isopropyloxa-
zolidin-2-one (3c;13 0.35 g, 1.7 mmol) in DMF (5 mL) at –30 °C was
added KCN (0.57 g, 8.5 mmol) in one portion. The mixture was al-
lowed to warm slowly to –10 °C over 20 min, then maintained be-
tween 0 and –10 °C for 3.5 h. The reaction was quenched at 0 °C by
addition of H2O (10 mL), then EtOAc (10 mL). The mixture was
warmed directly to r.t. and partitioned between EtOAc and H2O
(1:1, 40 mL). The phases were separated, the organic phase was
washed with brine (20 mL), dried (Na2SO4), and concentrated onto
silica gel. Silica gel chromatography (Combiflash, 12 g cartridge,
flow rate 30 mL/min, gradient 0–100% EtOAc in heptane over 15
min) afforded 81 mg (24%) of 1c as a colorless solid; mp 79.5 °C;
[α]D23 +107 (c 1.3, CHCl3).
Next, the effect the Knoevenagel reaction on the chiral cy-
anoimide templates was examined. Utilizing a modifica-
tion of a previously reported azeotropic dehydration
procedure,12 the condensation of 1a and 1b proceeded
with 3,4-dichlorobenzaldehyde, the relevant substrate for
PICK1 inhibitor analogues (Table 2). Importantly, if the
condensation reaction was not distilled to dryness (i.e., a
reflux condenser was employed) only starting material 1
was obtained.
IR (KBr): 2259 cm–1.
1H NMR (CDCl3): δ = 4.47 (m, 1 H), 4.36 (t, J = 8.7 Hz, 1 H), 4.29
(dd, J = 9.2, 3.2 Hz, 1 H), 4.14 (m, 2 H), 2.43 (m, 1 H), 0.95 (d, J =
7.0 Hz, 3 H), 0.90 (d, J = 6.9 Hz, 3 H).
13C NMR (CDCl3): δ = 161.8, 153.7, 112.9, 64.1, 58.8, 28.2, 27.3,
17.8, 14.6.
HRMS: m/z calcd for C9H12N2O3: 197.0926; found: 197.1342.
Method B: To a solution of 3c (0.16 g, 0.76 mmol) in CH2Cl2 (5 mL)
at 0 °C was added a solution of n-Bu4NCN (0.43 g, 1.53 mmol) in
CH2Cl2 (3 mL) quickly dropwise. The solution was stirred for 30
min at 0 °C, then quenched at 0 °C by addition of EtOAc and H2O
(1:1, 20 mL). The mixture was poured into EtOAc (20 mL) and the
phases were separated. The organic phase was washed with brine
In summary, we have described the first synthesis of un-
substituted chiral cyanoacetimides 1 bearing an oxazolid-
inone moiety. Cyanide displacement of 3 with KCN was
performed at a controlled temperature to obviate forma-
Synthesis 2012, 44, 1993–1996
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Cyanoacetyl Oxazolidinones
1995
(20 mL), dried (Na2SO4), and concentrated onto silica gel for silica
gel chromatography (Combiflash, 12 g cartridge, flow rate 30
mL/min, gradient 0–100% EtOAc in heptane over 15 min) to afford
80 mg (53%) of 1c as a colorless solid.
pale yellow oil, which on trituration with Et2O provided a pale yel-
low solid; mp 125 °C; [α]D23 –61.3 (c 1.3, CHCl3).
IR (KBr): 2227 cm–1.
1H NMR (CDCl3): δ = 7.97 (d, J = 2.0 Hz, 1 H), 7.86 (dd, J = 8.4,
2.0 Hz, 1 H), 7.67 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.40–7.28 (m,
3 H), 7.22 (d, J = 7.1 Hz, 2 H), 4.76 (m, 1 H), 4.36 (t, J = 8.5 Hz, 1
H), 4.26 (dd, J = 9.1, 5.3 Hz, 1 H), 3.42 (dd, J = 13.5, 3.7 Hz, 1 H),
2.90 (dd, J = 13.5, 9.2 Hz, 1 H).
13C NMR (CDCl3): δ = 162.9, 152.8, 150.3, 137.4, 134.4, 133.8,
132.4, 131.5, 131.3, 129.4, 129.2, 129.2, 127.7, 114.2, 108.5, 67.3,
55.9, 37.4.
3-[(4R,5S)-4-Methyl-2-oxo-5-phenyloxazolidin-3-yl]-3-oxopro-
panenitrile (1a)
Prepared from (4R,5S)-3-(2-chloroacetyl)-4-methyl-5-phenyloxa-
zolidin-2-one (3a)14 using method B to yield 0.12 g (57%) as a col-
orless solid; mp 174 °C; [α]D23 +11.0 (c 1.1, DMSO).
IR (KBr): 2261 cm–1.
1H NMR (DMSO-d6): δ = 7.42 (m, 5 H), 5.87 (d, J = 7.6 Hz, 1 H),
4.84 (m, 1 H), 4.43 (q, J = 19.8 Hz, 2 H), 0.78 (d, J = 6.6 Hz, 3 H).
Anal. Calcd for C20H14Cl2N2O3: C, 59.87; H, 3.52; N, 6.98. Found:
C, 59.76; H, 3.32; N, 6.88.
13C NMR (CDCl3): δ = 161.6, 152.7, 132.4, 129.2, 128.9, 125.6,
112.8, 79.8, 55.3, 27.4, 14.4.
(E)-3-(3,4-Ddichlorophenyl)-2-[(4R,5S)-4-methyl-2-oxo-5-
phenyloxazolidine-3-carbonyl]acrylonitrile (2a)
Prepared from 1a to yield 26 mg (31%) as a colorless solid; mp 144
°C; [α]D23 +73.5 (c 1.4, CHCl3).
HRMS: m/z calcd for C13H12N2O3 + Na: 267.0746; found:
267.0751.
(R)-3-[4-Benzyl-2-oxooxazolidin-3-yl]-3-oxopropanenitrile (1b)
Prepared from (R)-4-benzyl-3-(2-chloroacetyl)oxazolidin-2-one
(3b)6 using method B to yield 0.14 g (59%) as a colorless solid; mp
140 °C; [α]D23 –61.8 (c 1.0, CHCl3).
IR (KBr): 2216 cm–1.
1H NMR (DMSO-d6): δ = 7.98 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H),
7.71 (s, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.43 (m, 3 H), 7.32 (d, J =
7.4 Hz, 2 H), 5.79 (d, J = 7.4 Hz, 1 H), 4.79 (pent, J = 6.7 Hz, 1 H),
1.04 (d, J = 6.5 Hz, 3 H).
13C NMR (CDCl3): δ = 162.7, 152.5, 150.2, 137.3, 133.8, 132.9,
132.4, 131.5, 131.3, 129.3, 129.1, 128.9, 126.0, 114.3, 108.7, 80.2,
56.1, 14.4.
IR (KBr): 2266 cm–1.
1H NMR (CDCl3): δ = 7.33 (m, 3 H), 7.20 (d, J = 7.0 Hz, 2 H), 4.72
(m, 1 H), 4.28 (m, 1 H), 4.14 (m, 1 H), 3.34 (dd, J = 13.5, 3.2 Hz, 1
H), 2.83 (dd, J = 13.5, 9.5 Hz, 1 H).
13C NMR (CDCl3): δ = 161.9, 153.1, 134.4, 129.4, 129.2, 127.8,
112.8, 66.9, 55.4, 37.6, 27.3.
Anal. Calcd for C20H14Cl2N2O3: C, 59.87; H, 3.52; N, 6.98. Found:
C, 59.71; H, 3.26; N, 6.92.
HRMS: m/z calcd for C13H12N2O3: 245.0926; found: 245.1380.
(R)-3-Oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)propanenitrile
(1d)
Acknowledgment
Prepared from (R)-3-(2-chloroacetyl)-4-phenyloxazolidin-2-one
(3d)15 using method B, modified using a chromatography gradient
of 0–20% EtOAc in CH2Cl2 to yield 0.11 g (57%) as a colorless sol-
id, mp 206 °C; [α]D23 –152 (c 1.0, DMSO).
The authors wish to thank Baiwei Lin, Deven Wang, and WuXi
AppTec, Co. for assisting with compound characterization, and
Bryan Chan for critical review of the manuscript.
IR (KBr): 2261 cm–1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of 1H and 13C NMR spectra of compounds 1a, 1b, 1c, 1d,
1H NMR (DMSO-d6): δ = 7.36 (m, 5 H), 5.48 (dd, J = 8.7, 3.8 Hz,
1 H), 4.77 (t, J = 8.8 Hz, 1 H), 4.56 (d, J = 19.9 Hz, 1 H), 4.38 (d,
J = 19.9 Hz, 1 H), 4.23 (dd, J = 8.9, 3.9 Hz, 1 H).
2a, 2b, and 4a.SnoIufproig
m
iotSrat
nugIiofop
r
t
13C NMR (DMSO-d6): δ = 163.0, 153.4, 139.0, 128.8, 128.2, 125.9,
114.9, 70.7, 57.1, 27.4.
References
HRMS: m/z calcd for C12H10N2O3: 231.0770; found: 231.0753.
(1) Thorsen, T. S.; Madsen, K. L.; Rebola, N.; Rathje, M.;
Anggono, V.; Bach, A.; Moreira, I. S.; Stuhr-Hansen, N.;
Dyhring, T.; Peters, D.; Beuming, T.; Huganir, R.;
Weinstein, H.; Mulle, C.; Stromgaard, K.; Ronn, L. C. B.;
Gether, U. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 413.
(2) Bach, A.; Stuhr-Hansen, N.; Thorsen, T. S.; Bork, N.;
Moreira, I. S.; Frydenvang, K.; Padrah, S.; Christensen, S.
B.; Madsen, K. L.; Weinstein, H.; Gether, U.; Strømgaard,
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Chinese Patent CN 2008-10233712, 2, 2008; Chem. Abstr.
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experimentals for preparing compounds of type 2 were
provided.
(4) Schwarz, J. B.; Gibbons, S. E.; Graham, S. R.; Colbry, N. L.;
Guzzo, P. R.; Le, V.-D.; Vartanian, M. G.; Kinsora, J. J.;
Lotarski, S. M.; Li, Z.; Dickerson, M. R.; Su, T.-Z.; Weber,
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4-[(4R,5S)-4-Methyl-2-oxo-5-phenyloxazolidin-3-yl]-2-
[(4R,5S)-4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl]-4-
oxobutanenitrile (4a)
Obtained from HPLC purification of 1a, prepared using method A,
to yield 40 mg (4%) as a 55:45 mixture of diastereomers.
1H NMR (CDCl3): δ = 7.43 (m, 10 H), 5.93 (m, 2 H), 5.21 (m, 1 H),
4.88 (m, 2 H), 3.63 (m, 2 H), 0.77 (m, 6 H).
HRMS: m/z calcd for C25H23N3O6 + Na: 484.1485; found:
484.1519.
Knoevenagel Condensation of 3,4-Dichlorobenzaldehyde with
1; (R,E)-2-(4-Benzyl-2-oxooxazolidine-3-carbonyl)-3-(3,4-di-
chlorophenyl)acrylonitrile (2b); Typical Procedure
To a mixture of 3,4-dichlorobenzaldehyde (43 mg, 0.25 mmol), 1b
(72 mg, 0.29 mmol), and NH4OAc (39 mg, 0.49 mmol) in CHCl3 (5
mL) was added glacial AcOH (2 drops), and the reaction mixture
was heated at 80 °C overnight resulting in complete evaporation of
solvent. The residue was cooled, dissolved in CH2Cl2 (10 mL), and
concentrated onto silica gel. Silica gel chromatography (Combifla-
sh, 12 g silica cartridge, flow rate 30 mL/min, gradient 0–100%
EtOAc in heptane over 15 min) afforded 52 mg (53%) of 2b as a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1993–1996

1996
K. M. Weeber, J. B. Schwarz
PAPER
(11) In entry 8, a modified chromatography eluent system
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J. Org. Chem. 1996, 61, 8750.
(EtOAc–CH2Cl2) was utilized owing to reduced solubility of
product 1d, see the experimental section.
(7) SmI2-promoted rearrangement of isocyanides of the type
reported in ref. 3 to nitriles similar to 1 have been reported:
Kang, H.-Y.; Pae, A. N.; Cho, Y. S.; Koh, H. Y.; Chung, B.
Y. Chem. Commun. 1997, 821.
(12) Abu-Bakr, S. M.; El-Shehry, M. F.; El-Telbani, E. M.;
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(10) Katz, H. E.; Schilling, M. L. J. Org. Chem. 1989, 111, 7554.
Synthesis 2012, 44, 1993–1996
© Georg Thieme Verlag Stuttgart · New York