Chemoselective Reduction of α-Cyano Carbonyl Compounds: Application to the Preparation of Heterocycles

Article abstract of DOI:10.1021/acs.orglett.6b03285

β-Aminoacrylates are reactive intermediates that are useful building blocks in synthesis. General methods for their preparation typically afford α and β disubstitution patterns or β only. Molecules with only α-substituents (β-hydrogen) are much less well-known. A chemoselective reductive tautomerization of α-cyanoacetates, using DIBAL-H, has been developed to access these valuable synthons. α,β-Unsaturated cyanoacetates and α-cyanoketones can, also, be selectively reduced via this methodology. A series of heterocycles were prepared using these β-enamino carbonyl compounds.

Full text of DOI:10.1021/acs.orglett.6b03285

Letter
pubs.acs.org/OrgLett
Chemoselective Reduction of α‑Cyano Carbonyl Compounds:
Application to the Preparation of Heterocycles
Scott R. Pollack* and Jeffrey T. Kuethe
Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: β-Aminoacrylates are reactive intermediates that are useful building blocks in synthesis. General methods for their
preparation typically afford α and β disubstitution patterns or β only. Molecules with only α-substituents (β-hydrogen) are much
less well-known. A chemoselective reductive tautomerization of α-cyanoacetates, using DIBAL-H, has been developed to access
these valuable synthons. α,β-Unsaturated cyanoacetates and α-cyanoketones can, also, be selectively reduced via this
methodology. A series of heterocycles were prepared using these β-enamino carbonyl compounds.
hydrazines, may add in a conjugate manner to the double bond
(with loss of the original β-amine) followed by attack of the
distal hydrazine nitrogen at the carbonyl to generate pyrazoles
(2a; Z, X = N).1 The β-amine can be derivatized (e.g., by
acylation) and then cyclize onto the ester to form heterocycles
such as pyrimidines (2b; Y = CO; X, Z = N).2 Finally, the
enamine may react to form heterocycles (2c) without ester
participation.3 In addition, these substrates are also useful,
directly or via N-acyl derivatives, in the synthesis of β-amino
acids (3).4 Those reactions, among others, show that β-
enaminoesters are valuable synthons, and consequently, new
methods for their generation are important synthetic tools.
Numerous methods have been reported for the synthesis of
β-aminoacrylates (see Figure 1). Most of these generate
acrylates with a β-carbon substitution (1, R2 ≠ H; 4,5 5,6 6,7
78). Far fewer reactions produce substrates with a β-hydrogen.
Those that are known are limited in scope and either proceed
through reactive intermediates, which are typically formed in
moderate yields from esters (8),9 or work only with substrates
containing an active α-methylene group (9).10 A more general
methodology to make β-unsubstituted (1; R2 = H) analogues
would therefore be of use. Herein, we describe the develop-
ment of such a reaction.
β-Aminoacrylates (1, Figure 1), a class of masked β-dicarbonyl
compounds, are reactive intermediates that are useful synthetic
building blocks. The conjugation of enamine and ester gives
functionality that can participate in bond-forming reactions via
a number of different pathways. These substrates have found
their greatest utility in the construction of heterocycles for
which there are three general routes. Nucleophiles, such as
While engaged in efforts supporting a drug discovery
program, we made an unexpected observation. We had an
interest in developing a selective partial reduction of a common
program intermediate (10, Scheme 1). In our attempts to make
either the α-formyl ester or α-formylnitrile, we subjected the
cyanoester to a variety of reducing agents and conditions (e.g.,
LiALH4, NaBH4, LiBH4, Red-AL, H2, etc.) In all but one case,
we either observed selective reduction of the ester (to alcohol)
Received: November 1, 2016
Figure 1. β-Aminoacrylates: preparation and uses.
© XXXX American Chemical Society
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a,b
Scheme 1. Chemoselective Nitrile Reduction
Table 1. Scope of Heterocycles from Cyanoesters
or nitrile (to amine)11 or a complex mixture due to partial or
over-reduction of both groups. However, treatment of
cyanoester 10 with DIBAL-H (3 equiv) in THF at 0 °C
followed by warming to ambient temperature gave a single
1
product. H NMR (in CDCl3) showed the ester remained, the
α-proton disappeared, and a new downfield proton formed (δ
6.66, triplet; 10.75 Hz). In addition, the mass of the isolated
product was 1 amu lower than the formyl ester. The data were
consistent with the formation of β-aminoacrylate 11. Acylation
of the product gave amide 12, wherein the alkene proton was a
doublet (δ 7.39, 11.1 Hz) and confirmed the unusual result.
a
b
Methyl ester. P1 N-substitution: R2 = H, except for 35, where R2 =
1
The olefin geometry of both compounds was found (via H
Ph.
NMR NOE) to be exclusively Z. While the reduction did not
result in either of the intended targets, this chemoselective
reductive-tautomerization was nonetheless interesting and
worth further investigation.
hydrolyzed. The aminoacrylates are reasonably stable on cold
storage but are prone to tautomerization under acidic
conditions, including silica gel, or on standing at rt for
extended periods (>1−2 weeks). In all cases, the olefin
geometry favored the Z isomer, but the ratio is dependent on
structure and reaction workup conditions. Z:E selectivity
typically ranges from 5:1 to >60:1. 1H NMR readily
distinguishes the isomers.15 Most intermediates are oils for
which complete solvent removal is difficult. Consequently, they
are used directly in subsequent steps without further
purification.
A series of pyrazoles and pyrimidines were smoothly
generated by heating the acrylate intermediates with hydrazine
or benzamidine in alcohol solvents for 24 or 48 h, respectively.
Most of the products could be cleanly isolated via precipitation
on addition of the reaction to water or aqueous pH 7 buffer.
The yields over the two steps were generally good to excellent.
The poor yield of compound 28 appears to be the result of
reaction of the Boc group with hydrazine as condensation with
benzamidine provides much better conversion (see compound
65).
In a manner similar to that for the chemoselective reduction
of α-cyanoacetates, it was found that α-cyanoketones can be
reduced to β-aminoenones and converted to heterocycles under
the same conditions (see Scheme 2). Unlike the previous case,
where no ester reduction was seen, ketone reduction can be
competitive. The best substrates tend to be acetophenone
derivatives. In order to understand the cause of the loss of
chemoselectivity in the reduction reaction, we undertook an
examination of the reaction mechanism.
The reduction of an α-cyanoacetate to β-aminoacrylate, such
as 11, is not totally without precedent and has been described
for a series of purine-derived α,β-unsaturated α-cyanoacetates
under hydrogenolytic conditions.12 The isolation of β-amino-
acrylates was likely substrate dependent as α-cyanoacetates are
normally converted to β-aminoesters under those conditions.
In exploring the generality of the reaction, we subjected a
simplified substrate (13) to the same conditions as cyanoester
10. The reaction did not produce the expected enamine.
Instead, a complex mixture, due to over-reduction of both the
nitrile and ester, resulted. The key difference between
cyanoesters 10 and 13 is the lack of a basic tertiary amine.
Repeating the reaction in the presence of triethylamine (1.1
equiv) produced the expected enamine cleanly, as a mixture of
isomers (14 and 15), in a 7:1 ratio favoring the Z isomer.13 The
reaction can be effected with other tertiary amines (e.g., N-
methylmorpholine, N-ethylpiperidine, etc.), but triethylamine
was used throughout due to its higher volatility and, hence, ease
of removal.
To examine the scope of the reaction, a series of α-
cyanoacetates were reduced by addition of DIBAL-H to a
solution of substrate in THF at 0 °C in the presence of
triethylamine (see Table 1). An excess (2.5−3.0 equiv) of
DIBAL-H was typically employed to ensure the reaction was
driven to completion. After addition, cooling was removed and
the reaction was stirred at ambient temperature for 30−60 min
before the reaction was quenched by the method of Fieser.14
Enamine formation is generally quantitative. Lower yields may
result if aluminum salts formed during the reaction are not fully
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peaks (1678 and 1645 cm−1) are seen which correspond to the
regenerated ester and the conjugated enamine (24d).
Liberation of hydrogen gas was confirmed through use of a
colorimetric gas detection tube.17 Based on those results, it
seemed likely that the base might function catalytically. In fact,
the reduction of compound 18 (analogue of 13) with 20 mol %
of Et3N under the usual conditions resulted in complete
conversion to the expected β-aminoacrylate. In addition, it
seemed plausible that it might be possible to form the metal
enolate through a conjugate reduction process.
Scheme 2. Cyanoketone Reduction/Heterocycle Formation
Gratifyingly, it was found that treatment of α,β-unsaturated
α-cyanoacetates with DIBAL-H (in the absence of amine)
results in the formation of the same β-aminoacrylates generated
from α-cyanoacetates containing an α-proton. Table 2 shows
that many of the same substrates undergo conjugate reduction
followed by reductive-tautomerization of the nitrile.
ReactIR16 (Figure 2) was used to explore the reduction
mechanism. During the addition of DIBAL-H a gas is evolved.
a
Table 2. Conjugate Reduction Chemistry
Figure 2. ReactIR of saturated cyanoester reduction (24).
We suspect the base, which is necessary for chemoselectivity,
promotes formation of the ester tautomer (24a), which then
reacts with DIBAL-H to give metal enolate 24b and liberate
hydrogen (Scheme 3). The protected ester is essential for the
chemoselective reductive-tautomerization of the nitrile.
Scheme 3. Proposed Reductive Rearrangement Mechanism
a
P1 N-substitution: R2 = H, except for 64, where R2 = Ph.
Conversion to pyrazoles and pyrimdines was achieved under
the same conditions used for the conversion of products from
the reduction of the saturated cyanoacetates. The overall yields
are as good or better than the saturated cyanoacetates. As an
added benefit, the ability to use the unsaturated cyanoacetates
may save a step as they are often precursors to the saturated
compounds.
Since the in situ protection/reduction is very fast under the
reaction conditions, it was necessary to examine it at a lower
temperature (−78 °C). One equivalent of DIBAL-H was
quickly added with the ester disappearing almost immediately.
This confirmed the in situ protection (24b). Warming to 0 °C
followed by immediate addition of an additional 1.5−2 equiv of
DIBAL-H (then stirred at ambient for 35 min) generates the
imine salt (24c; 1609 cm−1). Upon quenching, two new IR
In addition to the increased efficiency of using the
unsaturated cyanoacetate, it was observed that these β-
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aminoacrylates were exclusively formed as the Z-isomer. None
of the E isomer was detected by H NMR. We speculate
stereocontrol during enolate formation occurs via a conjugate
olefin reduction with concomitant transfer of aluminum to the
enolate oxygen (see Scheme 4). This would require a syn-
ACKNOWLEDGMENTS
■
1
We thank Dr. Yi Ning Ji Chen (Merck, Process Chemistry) for
assistance in acquiring ReactIR data, Drs. Peter Dormer and
Melissa Mengfen Lin (Merck, Process Chemistry) for support
in acquiring NMR spectra, and Dr. Paul Bulger (Merck, Process
Chemistry) for useful discussions and review of this manuscript.
Scheme 4. Unsaturated Cyanoester Reduction Mechanism
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conjugated enamines that are produced can be efficiently
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current methods. Finally, we are actively engaged in expanding
the synthetic utility of the intermediate β-aminoacrylates via
their conversion to different classes of compounds.
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(14) The method of Fieser for quenching reactions using DIBAL-H
is as follows: Cool the reaction in an ice/water bath and slowly add, in
succession, 0.04X mL of water, 0.04X mL of 15 wt % aq NaOH
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ASSOCIATED CONTENT
* Supporting Information
■
(16) For information on the use and applications of ReactIR, see:
http://www.mt.com/gb/en/home/products/L1_AutochemProducts/
ReactIR.tabs.documents.html.
(17) Gastec detector tube No. 30. For a review and instruction in use
of colorimetric gas detection tubes, see: Gastec Handbook: Environ-
mental Analysis Technology, 15th ed.; Gastec Corp.: Ayase City, 2014.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03285.
Experimental details, characterization of new com-
1
pounds, and H and 13C spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: scott_pollack2@merck.com.
ORCID
Scott R. Pollack: 0000-0001-8292-2989
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.6b03285
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