One-pot synthesis of 4-substituted 3-amino-2-cyanothiophenes involving O-ethyl thioformate

Article abstract of DOI:10.1021/ol500895t

An efficient one-pot synthesis of 4-substituted 3-amino-2-cyanothiophenes is described. Treatment of 2-alkyl or aryl substituted acetonitrile sequentially with 2.1 equiv of LDA, 1.1 equiv of O-ethyl thioformate, and 1.2 equiv of 2-chloroacetonitrile affor

Full text of DOI:10.1021/ol500895t

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of 4‑Substituted 3‑Amino-2-cyanothiophenes
Involving O‑Ethyl Thioformate
Haiming Zhang,*,† Mark S. Bednarz, Ngiap-Kie Lim, Gonzalo Hernandez, and Wenxue Wu*
Chemical Development, Lexicon Pharmaceuticals, Inc., 350 Carter Road, Princeton, New Jersey 08540, United States
S
* Supporting Information
ABSTRACT: An efficient one-pot synthesis of 4-substituted 3-
amino-2-cyanothiophenes is described. Treatment of 2-alkyl or aryl
substituted acetonitrile sequentially with 2.1 equiv of LDA, 1.1 equiv
of O-ethyl thioformate, and 1.2 equiv of 2-chloroacetonitrile afforded
the thiophenes in moderate to good yields. The thiophene core can
be readily incorporated into more elaborate pharmaceutically
relevant structures as demonstrated by converting 3-amino-2-cyano-4-phenylthiophene (1g) to various functionalized
thieno[3,2-d]pyrimidines in only two steps.
he utilities of substituted 2- or 3-aminothiophenes have
been demonstrated in an array of applications in
Scheme 1. Synthesis of 4-Substituted 3-Amino-2-
cyanothiophenes 1
T
pharmaceuticals, dyes, and agrochemicals.1 The synthesis of
2-aminothiophenes can be accomplished by well-established
Gewald reactions2 involving multicomponent condensation of a
ketone, an activated nitrile, and elemental sulfur.1a,c Alter-
natively, 2-aminothiophene can be accessed via a stepwise
approach employing a Knoevenagel condensation,3 followed by
a base-promoted sulfuration and cyclization.1a,c In contrast, the
synthesis of 3-aminothiophenes is rather challenging and
underdeveloped.1b,c The synthetic routes to 3-aminothiophenes
primarily involve the modified Fiesselmann thiophene
synthesis,1d,e,4a the Gommper reaction,1f and reaction of β-
halogenated or oxygenated acrylonitriles with mercaptans
containing an activated methylene group.4b−e
Scheme 2. Proposed Synthesis of 1 Using O-Ethyl
Thioformate
Our recent project needs required us to develop an efficient
synthesis of 4-substituted 3-amino-2-cyanothiophenes (1).
Literature searches showed that the only available synthesis of
4-substituted 3-amino-2-cyanothiophenes (1) involved the
generation of a vinyl mesylate intermediate 3 from nitrile 2,
followed by treatment with S-acetylmercaptoacetonitrile in the
presence of a base and heat to complete the cyclization
(Scheme 1A).5 This chemistry, however, suffers from a very
limited scope, the use of an expensive reagent S-acetyl-
mercaptoacetonitrile, and the requirement of a multistep
synthesis. Therefore, a more practical and efficient synthesis
was highly desirable.
Herein, we wish to report a one-pot synthesis of 4-
substituted 3-amino-2-cyanothiophenes (1) from 2-alkyl or
aryl substituted acetonitrile (2) by sequential treatment with
LDA, O-ethyl thioformate,6 and 2-chloroacetonitrile (Scheme
1B).
It has been reported in the literature that treatment of
substituted acetonitriles with a strong base and then ethyl
formate generates a vinyl oxide species which can be readily
quenched with an electrophile to produce oxygenated
acrylonitriles (Scheme 2A).5,7 We envisioned that substituting
ethyl formate with O-ethyl thioformate (4) should produce a
Received: March 25, 2014
Published: April 18, 2014
© 2014 American Chemical Society
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Letter
vinyl thiolate intermediate 5, which should react with 2-
chloroacetonitrile to give intermediate 6. In the presence of a
base, compound 6 should cyclize to furnish the desired 4-
substituted 3-amino-2-cyanothiophenes (1) (Scheme 2B).
It is noteworthy that O-ethyl thioformate (4) has been used
to generate thioformamides which are synthetically useful
intermediates for the synthesis of various heterocycles,8
thioamides,9 iminyl sulfides,10 enamines,11 and amines.12
However, it was only recently, as reported by Borths, that the
preparation of O-ethyl thioformate became readily achievable at
a large scale and in high yield.6a
To our great delight, when 2-alkyl or aryl substituted
acetonitriles (2) were sequentially treated at −40 °C with LDA
(2.1 equiv), O-ethyl thioformate (4, 1.1 equiv), and 2-
chloroacetonitrile (1.2 equiv), the desired thiophene product
1 was indeed produced (Table 1).13
As shown in Table 1, simple alkyl-substituted acetonitriles
produced moderate to good yields of the desired thiophenes
(entries 1−3). The yield of the isopropyl substituted thiophene
1b was relatively low, presumably due to the extra steric
hindrance that the isopropyl group introduced. Acetonitriles
substituted with an electron-withdrawing group, for example
3,3,3-trifluoropropanenitrile (2d) and malonitrile (2e), as well
as simple acetonitrile (2f), unfortunately, did not afford any
desired thiophene products (entries 4−6). Instead, formation
of dark-colored gummy residues was observed in each of these
three reactions, which indicates possible polymerization of
intermediates 5 due to either their electron-deficient nature (for
2d and 2e) or the lack of steric hindrance (for 2f). 2-Aryl
substituted acetonitriles, on the other hand, underwent the
thiophene formation smoothly, generating the desired products
in good yields. For example, benzyl cyanide (2g) readily
afforded the desired 3-amino-2-cyano-4-phenylthiophene (1g)
in 70% yield (entry 7). 2-Aryl acetonitrile with either an
electron-donating group (4-MeO, 2h) or an electron-with-
drawing group (4-F, 2i), as well as a heterocycle (2-thiophenyl)
substituted acetonitrile (2j), also uneventfully produced the
desired thiophene products in 73−76% yields (entries 8−10).
Gratifyingly, tert-butyl 2-chloroacetate reacts similarly to
chloroacetonitrile to give the desired thiophene ester 1k in
good yield (65%) (entry 11). Thus, we believe this chemistry
could be readily extended and provide an alternative to the
synthesis of a wide spectrum of 4-subsituted 3-aminothiophene-
2-carboxylates.4b−e
Table 1. One-Pot Synthesis of 3-Amino-2-cyanothiophenes
a
1
We propose that the mechanism for this process, illustrated
using benzyl cyanide (2g) as a representative example, involves
the deprotonation of nitrile 2g, followed by a Claisen-like
nucleophilic addition of the resulting anion to O-ethyl
thioformate (4) to generate thiolate 7 when 1 equiv of LDA
was employed. The second equivalent of LDA then promotes
an elimination reaction of thiolate 7 to afford an ethoxide and
thiolate 5a. Upon treatment with 2-chloroacetonitrile, thiolate
5a is readily converted to a mixture of isomeric vinyl thiolates
(6a and 6b). An ethoxide anion promotes not only the
isomerization of E-thiolate 6b to Z-thiolate 6a but also the
facile cyclization of Z-thiolate 6a to the cyclized intermediate 9,
which quickly undergoes tautomerization to form the desired
thiophene 1g (Scheme 3).
Scheme 3. Proposed Mechanism
a
All reactions were carried out at 1.00 g scale of the nitrile except for
b
c
2a (0.50 g). The yield is based on the isolated HCl salt. 1.2 equiv of
tert-butyl 2-chloroacetate was employed.
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Under our reaction conditions, we were unable to observe
the formation of intermediates 6a and 6b, presumably because
the isomerization of 6b to 6a and the cyclization of 6a to
thiophene 1g are too rapid to monitor on the experimental
time scale. To confirm the formation of thiolates 6a and 6b,
benzyl cyanide (2g) was treated with 2.1 equiv of LDA and 1.1
equiv of O-ethyl thioformate (4) to generate intermediate 5a,
which was neutralized with 2.1 equiv of HCl in dioxane. 2-
Chloroacetonitrile was then charged into the reaction mixture.
Sonogashira17 reactions to generate the desired coupling
products in moderate yields (Table 2, entries 4−5).
a
Table 2. Functionalization of Thieno[3,2-d]pyrimidine 11
1
Gratifyingly, we were able to isolate an 8:1 mixture (by H
NMR) of thiolates 6a:6b in 77% yield (eq 1). The mixture was
then treated with 1 equiv of EtOLi (prepared from n-BuLi and
EtOH) at −40 °C to afford thiophene 1g in 93% yield (eq 2).
The reaction kinetics clearly showed that, in the presence of 1
equiv of base EtOLi, the conversion of Z-isomer 6a to
thiophene 1g is essentially instantaneous (<5 min) while the
transformation of E-isomer 6b to 6a/1g is somewhat slower
(ca. 1% remaining at 30 min based on HPLC analysis, Figure 1)
at −40 °C.
a
All reactions were performed using 0.50 mmol of 11. Conditions: (A)
4.0 equiv of morpholine in THF at 20 °C. (B) 1.2 equiv of p-cresol, 2.0
equiv of K2CO3 in THF/DMF at 60 °C. (C) 1.2 equiv of n-C12H23SH,
2.0 equiv of K2CO3 in MeOH at 20 °C. (D) 10 mol % Pd(OAc)2, 20
mol % PPh3, 2.5 equiv of c-PrB(OH)2, 3.0 equiv of K2CO3 in PhMe/
H2O (4:1) at 90 °C. (E) 2 mol % PdCl2(PPh3)2, 4 mol % CuI, 2.4
b
equiv of PhCCH in Et3N at 80 °C. 38% of 11 was recovered.
Figure 1. EtOLi promoted thiophene 1g formation from 6a/6b.
In conclusion, we have developed an efficient one-pot
synthesis of 4-substituted 3-amino-2-cyanothiophenes in
moderate to good yields by treating 2-alkyl or aryl substituted
acetonitrile with LDA, followed by O-ethyl thioformate and
then 2-chloroacetonitrile. The synthetic utility of the resulting
thiophenes was demonstrated by converting 3-amino-2-cyano-
4-phenylthiophene (1g) to the corresponding 4-chlorothieno-
[3,2-d]pyrimidine 11 which then undergoes nucleophilic
aromatic substitution with amine, phenol, or thiol nucleophiles
or palladium-catalyzed cross-coupling reactions to generate
structurally diverse thieno[3,2-d]pyrimidines in moderate to
excellent yields.
To demonstrate the synthetic utility of 4-substituted 3-
amino-2-cyanothiophenes (1), thiophene 1g was smoothly
converted to 4-chloro[3,2-d]thienopyrimidine 11 in 98% yield
under Vilsmeier−Haack conditions (Scheme 4).14 Compound
11 then can react with nitrogen, oxygen, or sulfur nucleophiles
via SNAr reactions to afford the desired substituted thieno[3,2-
d]pyrimidines15 in excellent yields (Table 2, entries 1−3). It
can also undergo palladium-catalyzed Suzuki−Miyaura16 or
Scheme 4. Synthetic Utility of Thiophene 1g
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental information, copies of H and 13C NMR
1
of new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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(11) Ireland, R. E.; Brown, F. R. J. Org. Chem. 1980, 45, 1868−1880.
(12) (a) Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780−781.
(b) Murai, T.; Ui, K.; Narengerile. J. Org. Chem. 2009, 74, 5703−5706.
(13) Reactions employing weaker bases, such as MOt-Bu and
MHMDS (M = Li, Na, K), generated inferior results possibly due to
incomplete deprotonation of the nitrile. Reactions using dimethyl-
thioformamide as the electrophile did not produce any desired
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zhang.haiming@gene.com.
*E-mail: wwu@lexpharma.com.
Present Address
†Small Molecule Process Chemistry, Genentech, Inc., 1 DNA
Way, South San Francisco, CA 94080.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Mr. Leonard Hargiss for
collecting HRMS data as well as Drs. Matt Zhao and Lauren
Sirois (all from Lexicon Pharmaceuticals) for proofreading the
manuscript.
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1975, 16, 4467−4470. (b) Chinchilla, R.; Naj
́
era, C. Chem. Rev. 2007,
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