Mild and efficient DBU-catalyzed amidation of cyanoacetates

Article abstract of DOI:10.1021/ol900435t

A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.

Full text of DOI:10.1021/ol900435t

ORGANIC
LETTERS
2009
Vol. 11, No. 9
2003-2006
Mild and Efficient DBU-Catalyzed
Amidation of Cyanoacetates†
Kristin E. Price, Claude Larrive´e-Aboussafy, Brett M. Lillie,
Robert W. McLaughlin, Jason Mustakis, Kevin W. Hettenbach, Joel M. Hawkins,
and Rajappa Vaidyanathan*
Chemical Research and DeVelopment, Pfizer, Inc., Eastern Point Road,
Groton, Connecticut 06340
rajappa.Vaidyanathan@pfizer.com
Received March 2, 2009
ABSTRACT
A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates
the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a
compound under development for the treatment of autoimmune diseases.
The formation of amide bonds is one of the most common
reactions in organic synthesis.1 Generally, amides are formed
either by direct coupling of an amine with a carboxylic acid
that is activated in situ2,3 or in a two-step process involving
activation of the carboxylic acid followed by reaction of the
activated intermediate with an amine.4-6 Although many
amidation strategies have been developed, none of these are
universally applicable across substrate classes. While inves-
tigating the synthesis of cyanoacetamides, we found that most
of the known amidation methods were not ideal for our pur-
poses (vide infra). Our subsequent studies have resulted in an
effective protocol for the direct formation of cyanoacetamides
from commercially available alkyl cyanoacetates. This method
is mild and provides high yields with minimal waste.
such as rheumatoid arthritis and psoriasis, as well as the
prevention of transplant rejection.7 The final bond-forming
step in the synthesis of 1 is the installation of the cyanoacetyl
moiety to afford free base 2 (Figure 1). The amidation had
The cyanoacetamide of particular interest to us, CP-
690,550-10 (1), is a potent immunosuppressant currently
under development for the treatment of autoimmune diseases,
Figure 1. Structures of CP-690,550-10 (1) and the corresponding
free base (2).
† This paper is dedicated to Prof. K. K. Balasubramanian (formerly of
IIT, Madras) on the occasion of his 70th birthday.
previously been executed in two steps via activation of
cyanoacetic acid with pivaloyl chloride and subsequent
reaction with piperidine 3 in CH2Cl2 (Scheme 1). This
(1) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–
10852.
(2) Ormerod, D.; Willemsens, B.; Mermans, R.; Langens, J.; Winderickx,
G.; Kalindjian, S. B.; Buck, I. M.; McDonald, I. M. Org. Process Res.
(5) Vaidyanathan, R.; Kalthod, V. G.; Ngo, D. P.; Manley, J. M.;
Lapekas, S. P. J. Org. Chem. 2004, 69, 2565–2568.
(6) Chen, J.; Corbin, S. P.; Holman, N. J. Org. Process Res. DeV. 2005,
9, 185–187.
DeV. 2005, 9, 499–507
.
(3) Tang, P. Org. Synth. 2005, 81, 262–272
.
(4) Ager, D. J.; Babler, S.; Erickson, R. A.; Froen, D. E.; Kittleson, J.;
Pantaleone, D. P.; Prakash, I.; Zhi, B. Org. Process Res. DeV. 2004, 8,
(7) Wilcox, G. E.; Koecher, C.; Vries, T.; Flanagan, M. E.; Munchhof,
J. WO 2002/096909 A1, 2002.
72–85
.
10.1021/ol900435t CCC: $40.75
Published on Web 04/02/2009
 2009 American Chemical Society

Scheme 1
.
Synthesis of 1 via Activation of Cyanoacetic Acid
Scheme 2. Synthesis of 1 via Direct Amidation
We envisioned that amine 3 could be converted to
cyanoacetamide 2by direct treatment with an alkyl cyanoac-
etate in the presence of added base. The reaction of 3 with
ethyl cyanoacetate (4) was examined at 55 °C with various
bases in 1-butanol.17 In this screen, 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) afforded 26% conversion after 30 min
while other bases provided only 1-6% conversion.18,19 After
18 h at 55 °C, all reactions showed some decomposition.
When the base screen was repeated at room temperature to
minimize decomposition, the DBU-promoted reaction was
method provided 1 in 67% yield, which was adequate to meet
early clinical demands.8
As we moved toward a long-term synthetic solution for
the manufacture of 1, several factors were considered. (1)
A single-step process would be preferred over a two-step
activation-amidation sequence, both for process efficiency
and to avoid decomposition of the activated cyanoacetic
acid.9 (2) Halogenated solvents should be avoided to reduce
environmental impact.10 (3) This is the final step in the
synthesis of an active pharmaceutical ingredient, so mild
conditions are needed to limit the formation of byproducts.
One of the most efficient and atom-economical options
for the formation of an amide is the reaction of an amine
with a simple ester. Alkyl cyanoacetates have been converted
to simple cyanoacetamides in moderate to high yield under
solvent-free conditions,11,12 with microwave irradiation,13 or
at high temperatures.14,15 Amidation has also been ac-
complished using lithium amides derived from primary and
secondary amines at low temperatures.16 However, none of
these protocols seemed attractive for the large-scale manu-
facture of 1.
Table 1. Reaction of Amines with Ethyl Cyanoacetate in the
Presence and Absence of DBUa
All reactions were run at 20 °C unless otherwise specified. a t1/2 is the
time required for the amidation to reach 50% conversion by HPLC or GC.
b Isolated, purified yield. See the Supporting Information for full procedures.
c Reaction run at 40 °C. d 64% conversion at 15 min. e 62% conversion at
10 min. f 36% conversion at 360 min. g No product visible on GC traces.
Figure 2. Profiles of the reaction between amine 3 and ethyl
cyanoacetate (4) in 5 mL of 1-BuOH per gram of 3 with 1.0 equiv
of various tertiary amines.
2004
Org. Lett., Vol. 11, No. 9, 2009

Figure 3. Comparison of reaction between 5 and various alkyl cyanoacetates (R ) Me, Et, i-Pr, t-Bu) with and without DBU.
still much faster than those using other bases20 and led to
high conversion (Figure 2).
synthesize multikilogram quantities of 1 in 90% yield after
salt formation (Scheme 2).
After further refinement, this step was streamlined to effect
clean conversion of 3 to 2 within 12 h using only 0.5 equiv
of DBU at 40 °C.21 The new process was used to successfully
In an effort to explore the generality of this method, several
primary and secondary amines were treated with 4 under
the above conditions (0.5 equiv of DBU, 2.0 equiv of ester)
on a 2-10 g scale (Table 1). For these reactions, 2-meth-
yltetrahydrofuran22 was used as the solvent in order to
simplify workup and product isolation.23 The addition of
DBU led to dramatic rate enhancement as evidenced by t1/2
values and furnished the amides in high yield.
(8) Ruggeri, S. G.; Hawkins, J. M.; Makowski, T. M.; Rutherford, J. L.;
Urban, F. J. WO 2007/012953 A2, 2007.
(9) In our experience, some activated forms of cyanoacetic acid, such
as the acyl imidazole, decomposed readily to unidentifiable products.
(10) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.;
Johnson, T. A.; Kleine, H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.;
Stefaniak, M. Green Chem. 2008, 10, 31–36.
A series of alkyl cyanoacetates was treated with 4-ben-
zylpiperidine (5) in order to understand the effect of the alkyl
group on the reaction rate (Figure 3). In all cases, DBU was
found to accelerate the amide formation. The relative rates
of the reactions were dependent on the steric bulk of the
ester. As the size of the alkyl group was increased, the
difference in rates between the catalyzed and uncatalyzed
reactions became more pronounced. In the extreme case of
the tert-butyl ester, the background reaction was almost
(11) Demin, P.; Rounova, O.; Grunberger, T.; Cimpean, L.; Sharfe, N.;
Roifman, C. M. Bioorg. Med. Chem. 2004, 12, 3019–3026.
(12) Eddings, D.; Barnes, C.; Gerasimchuk, N.; Durham, P.; Do-
masevich, K. Inorg. Chem. 2004, 43, 3894–3909.
(13) Zradni, F. Z.; Hamelin, J.; Derdour, A. Synth. Commun. 2002, 32,
3525–3531.
(14) Osdene, T. S.; Santilli, A. A.; McCardle, L. E.; Rosenthale, M. E.
J. Med. Chem. 1967, 10, 165–167.
(15) Chew, W.; Papamichelakis, M.; Wang, Y. US App. 2005159446,
2005.
(16) Bhawal, B. M.; Khanapure, S. P.; Biehl, E. R. Synth. Commun.
1990, 20, 3235–3243.
(17) 1-Butanol was chosen because 1 could be directly crystallized and
isolated from this solvent.
(18) This screen was run in the Conjure Flow System, Accendo
Corporation, Tucson, AZ.
(19) 1,5-Diazabicyclo[4.3.0]nonane (DBN) was subsequently compared
to DBU in the reaction of 5 with 4 and gave virtually identical rate
enhancement.
(20) The use of potassium tert-butoxide (t-BuOK) for the synthesis of
cyanoacetamides under microwave conditions is known (see ref 13);
however, it led to low conversions in our case at 23 °C in 1-BuOH.
(21) DBU accelerates the reaction of amine 5 and ethyl cyanoacetate
(4) at lower loadings as well. The profiles for reactions run at 0.1-0.5
equiv of DBU are compared in the Supporting Information.
(22) Ripin, D. H. B.; Vetelino, M. Synlett 2003, 2353.
(23) A solvent screen on the conversion of 3 to 2 indicated that the
DBU-promoted reaction worked well in most solvents slowing down only
in polar aprotic solvents (NMP, DMSO). See the Supporting Information
for further details.
Org. Lett., Vol. 11, No. 9, 2009
2005

nonexistent and even the DBU reaction was too slow at 40 °C
to be synthetically useful.
shown that DBU accelerates the Baylis-Hillman reaction
relative to 1,4-diazabicyclo[2.2.2]octane (DABCO) and
DMAP.26 This behavior has been attributed to the higher
carbon basicity27 of DBU.28 Thus, the nucleophilic catalysis
pathway seems consistent with literature precedent and our
own observations.29
In conclusion, we have developed a mild, high-yielding
protocol for the direct amidation of alkyl cyanoacetates using
DBU. These conditions obviate the need for preactivation
of cyanoacetic acid prior to the amidation, thereby eliminat-
ing the associated waste. The byproduct from this reaction
is a simple alcohol. Further work aimed at exploring the
scope and elucidating the mechanistic aspects of this reaction
is ongoing in our laboratory,30 and the results will be com-
municated in due course.
The fact that catalytic DBU provides significant accelera-
tion compared to other amine bases (Figure 2) and t-BuOK20
suggests that DBU is not simply acting as a base. While a
number of pathways may be postulated to explain the effect
of DBU, one of the most plausible is a nucleophilic (Lewis
base) catalysis mechanism, wherein DBU displaces the
alkoxy moiety and activates the carbonyl for attack by the
amine (Scheme 3).
Scheme 3. Proposed Catalytic Cycle
Acknowledgment. We thank the following Pfizer col-
leagues: Nathan Ide, Ste´phane Caron, and Sally Gut Ruggeri
for helpful suggestions and discussions, Kevin Doyle for
prompt analytical support, and Brian Marquez for NMR
support.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900435T
While DBU has traditionally been considered a non-
nucleophilic base, there have been a few reports on its use
as a nucleophilic catalyst in recent literature.24 For instance,
DBU was found to catalyze reactions of dimethyl carbonate
with carboxylic acids to form esters, and a nucleophilic
catalysis pathway was proposed to explain the results.25 In
this case, 4-dimethylaminopyridine (DMAP), a more com-
monly employed nucleophilic catalyst, was less effective at
accelerating the reaction than DBU. Aggarwal et al. have
(26) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311–2312.
(27) Hine, J.; Weimar, R. D. J. Am. Chem. Soc. 1965, 87, 3387–3396.
(28) Baidya, M.; Mayr, H. Chem. Commun. 2008, 1792–1794.
(29) It is conceivable that the rate enhancement is due to the direct
formation of a ketene from ethyl cyanoacetate and DBU. However, in the
reaction of ethyl cyanoacetate with hydroxide, pre-equilibrium formation
of the enolate is unproductive due to the poor leaving ability of ethoxide,
and hydrolysis proceeds by a BAc2 mechanism rather than an E1cB (ketene)
mechanism:Holmquist, B.; Bruice, T. C. J. Am. Chem. Soc. 1969, 91, 3003–
3009. Further work aimed at clarifying the mechanism is ongoing.
(30) Although the amidation of diethyl malonate with 5 was slow, the
addition of DBU led to a 12-fold increase in reaction rate (t1/2 ) 16 h with
0.5 equiv of DBU in 2-MeTHF at 40 °C). Significant rate enhancements
have been observed in the amidation of acyl imidazoles as well. Larrive´e-
Aboussafy, C.; Price, K. E.; Hawkins, J. M.; Vaidyanathan, R. Manuscript
in preparation.
(24) Zhang, W.; Shi, M. Org. Biomol. Chem. 2006, 4, 1671–1674.
(25) (a) Shieh, W. C.; Dell, S.; Repic, O. J. Org. Chem. 2002, 67, 2188–
2191. (b) Shieh, W. C.; Dell, S. J. US 6515167, 2003.
2006
Org. Lett., Vol. 11, No. 9, 2009