A One-Step, Atom Economical Synthesis of Thieno[2,3-d]pyrimidin-4-amine Derivatives by a Four-Component Reaction

Article abstract of DOI:10.1002/ejoc.201900414

A Na₂HPO₄-catalyzed four-component reaction between a ketone, malononitrile, S₈ and formamide has been realized for the first time. This reaction provides a concise approach to thieno[2,3-d]pyrimidin-4-amines, previously r

Full text of DOI:10.1002/ejoc.201900414

A Journal of
Accepted Article
Title: A one-step, atom economical synthesis of thieno[2,3-
d]pyrimidin-4-amine derivatives via a four-component reaction
Authors: Taoda Shi, Christopher J. Zerio, Jared Sivinski, Andrew J.
Ambrose, Kohlson T Moore, Thomas M Buckley, Lynn K
Kaneko, Mae Zhang, Donna D. Zhang, and Eli Chapman
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900414
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10.1002/ejoc.201900414
European Journal of Organic Chemistry
COMMUNICATION
A one-step, atom economical synthesis of thieno[2,3-d]pyrimidin-
4-amine derivatives via a four-component reaction
Taoda Shi,[a] Christopher J. Zerio,[a] Jared Sivinski,[a] Andrew J. Ambrose,[a] Kohlson T. Moore,[a]
Thomas Buckley,[a] Lynn Kaneko,[a] Mae Zhang,[a] Donna D. Zhang,[a] and Eli Chapman*[a]
Dedication
Abstract: A Na2HPO4-catalyzed four-component reaction between a
ketone, malononitrile, S8 and formamide has been realized for the first
time. This reaction provides a concise approach to thieno[2,3-
d]pyrimidin-4-amines, previously requiring 5 steps. The utility of this
reaction was validated by preparing a multi-targeted kinase inhibitor
and an inhibitor of the NRF2 pathway with excellent atom- and step-
economy.
has been interested in facile syntheses of these molecules.
Currently, the reported synthesis of TPAs requires 5 steps
starting with malononitrile and acetyltrimethylsilane (Scheme 1,
top).[4] To develop
a general, straightforward method of
synthesizing TPAs, we designed a one-step synthesis using a
four-component reaction between ketones, malononitrile, S8 and
formamide based on the Gewald reaction (Scheme 1, bottom).[5]
Introduction
Thieno[2,3-d]pyrimidin-4-amines (TPAs) have been discovered to
possess many important bioactivities, including inhibition of hepatitis
C virus (HCV) replication[1], inhibition of kinases,[2] modulation of
the NRF2 anti-oxidant response pathway,[3]and inhibition of
human farnesyl pyrophosphate synthase (hFPPS)[4] (Figure 1).
Notably, GDC-0941 is currently being evaluated as an
anticancer agent in a phase II clinical trial,[2a] while GDC-0980
and SNS-314 are both being tested as anticancer agents in
phase I clinical trials[2b],[2c]. In light of the biological and
pharmaceutical value of TPAs, the organic synthesis community
Scheme 1. The previously reported route of TPA synthesis and the presently
reported route.
This design is expected to improve atom economy, [6] step economy,[7]
structural diversity[8] and ease of purification.
Results and Discussion
To test our proposed atom-economical thieno[2,3-d]pyrimidin-4-
amine synthesis, we started with 1 equivalent of acetophenone
(
1a), 1.5 equivalents of malononitrile (
2
), 1.1 equivalents of S8
(3
) and 12 equivalents of formamide (4). We were surprised to
find that by simply heating the reaction to 170°C, even in the
absence of a catalyst, we could isolate the desired product 5a in
34% yield (Table 1, Entry 1). Next, we evaluated a panel of
potential catalysts including L-proline/Et2NH, Na2CO3, Na2HPO4,
K2CO3, and K3PO4 (Table 1, Entries 2-6), and found Na2HPO4 as
the optimal catalyst giving 5a in 85% yield (Table 1, Entry 4).
Compared to other catalysts tested, Na2HPO4 is the only one that
could function as both a base and an acid, which is a possible
reason for its superior catalytic effects. Using Na2HPO4 as the
catalyst, we next explored solvent effects (Table 1, Entries 7-10).
Water, tert-butanol, sec-butanol, and isopropanol all caused a
decrease in the yield of 5a. This result indicated that the reactant
Figure 1. Bioactive molecules bearing a thieno[2,3-d]pyrimidin-4-amine
core.
[a] Dr. T. Shi, C. J. Zerio, Dr. J. Sivinski, A. J. Ambrose, K. T.
Moore, T. Buckley, L. Kaneko, M. Zhang, Prof. D. D. Zhang, and
Prof. E. Chapman
Department of Pharmacology and Toxicology, College of Pharmacy,
University of Arizona, 1703 East Mabel Street, P.O. Box 210207,
Tucson, AZ 85721, United States
Email: chapman@pharmacy.arizona.edu
www.pharmacy.arizona.edu/directory/profile/eli-chapman-phd
formamide, 4, is also an excellent solvent for the reaction. Next,
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201900414
European Journal of Organic Chemistry
COMMUNICATION
in order to optimize the efficiency of the reaction, we explored
15[b], [c]
16[b]
Na2HPO4
12
-
200
96
the minimum amount of
11-13). With 4 eq. of
when we investigated the substrate scope with 4 eq. of
found many of the substrates gave a poor yield in these
conditions. When the amount of dropped to 2 eq., the yield of
5a decreased from 86% to 75%, and was further reduced to 62%
if 1.5 eq. of was used. Therefore, 12 eq. of gives the highest
4
that could be used (Table 1, Entries 4,
, the yield of 5a was slightly lower, but
, we
4
PPh3
12
-
200
55
4
[a] 1.0 eq. ketone (1a), 1.5 eq. malononitrile (2), 1.1 eq. S8 (3), 12.0 eq.
formamide (4), and 20 mol% catalyst were used for 6 hours. [b] 0.5 hour. [c] 10
mol% Ph3P added. [d] Isolated yields.
4
After optimizing conditions, a set of aromatic moieties at the R1
position were evaluated. Electron-withdrawing groups (EWG)
gave an 81% average yield (Scheme 2, 5b and 5c). Para-halide
substituents gave an 85% average yield (Scheme 2, 5d- 5g).
Meta- and ortho-F substituents gave 85% and 82% yields,
respectively. Electron-donating groups (EDG) offered desired
4
4
yield and, importantly, the greatest substrate scope. We next
explored time and temperature and found the yield increased to
91% and the reaction time could be decreased from 6 hours to
0.5 hour by increasing the temperature to 200°C (Table 1, Entry
14). Further, in the presence of 10 mol% triphenylphosphine as
an additive, the yield of 5a further increased to 96% (Table 1,
Entry 15). But with Ph3P and no Na2HPO4, the yield dropped to
55% (Table 1, Entry 16). The presence of Ph3P possibly prevents
products in 77% average yield (Scheme 2, 5j-5m). The structure
of 5l was unambiguously assigned by X-ray crystallography
(Figure 2; CCDC 1904050). Heterocyclic groups including
furanyl and thiophenyl generated 5n and 5o in 62% and 65%
yields,
respectively.
the dimerization of 5a [9]
. Overall, we chose 20 mol% Na2HPO4 as
catalyst, 10 mol% Ph3P, and 200°C for 0.5 h, as the standard
conditions for a survey of the substrate scope.
Table 1. Optimization of conditions of a four-component reaction between
acetophenone 1a, malononitrile 2, S8 3, and formamide 4.[a]
%
Yield[d]
Entry
Catalyst
Eq. of 4
Solvent
T/°C
1
2
None
L-proline/Et2NH
Na2CO3
12
12
12
12
12
12
12
12
12
12
4
-
170
170
170
170
170
170
170
170
170
170
170
170
170
200
34
Scheme 2. Substrate scope of a four-component reaction of ketones 1,
malononitrile 2, S8 3, and formamide 4.
-
61
35
85
52
45
10
45
41
32
84
75
62
91
3
-
4
Na2HPO4
K2CO3
-
5
-
Figure 2. ORTEP diagram of 5I with atomic labeling scheme. Thermal ellipsoids
at a 50 % probability level are shown. CCDC 1904050.
6
K3PO4
-
7
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
H2O
Next, we set R1 = Phenyl, and looked at the effect of changing
the R2 group. Both phenyl and methyl groups had excellent
compatibility in the reaction, providing 5p and 5q with 97% and
91% yields, respectively. Finally, an alkyl group at both R1 and
R2 was tested, producing 5r in 87% yield. Generally, the reaction
has broad ketone substrate scope.
8
t-BuOH
9
s-BuOH
10
11
12
13
14[b]
i-PrOH
Scalability of an organic reaction is one of the important features
when it is used by medicinal chemists and chemical process
scientists.[10] We were able to scale-up the reaction to 50 mmol,
furnishing 9 grams of product 5a in 79% yield after a simple work-
up and recrystallization (Scheme 3).
-
-
-
-
2
1.5
12
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10.1002/ejoc.201900414
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Scheme 3. Scalable four-component reaction of acetophenone 1a,
malononitrile 2, S8 3 and formamide 4.
The practicality of the reaction was demonstrated by the rapid
synthesis of the NRF2 regulator AEM1 and the multi-target
kinase inhibitor (MTKI; Scheme 4). AEM1 could be obtained via
a conventional N-alkylation of 5c with 74% overall yield in two
steps from the readily available 1c. This is the first disclosure of
the synthesis of AEM1. MTKI was synthesized with a 49% overall
yield in 2 steps from the inexpensive para-nitro starting material,
1i. The quick access to intermediate 5i via the four-component
reaction of 1i, 2, 3, and 4 makes this route an attractive
alternative to the preparation the MTKI.
Scheme 5. Proposed mechanism of the Na2HPO4-catalyzed four-component
reaction of ketone, malononitrile, S8 and formamide
In conclusion, we have developed a four-component reaction
between ketones, malononitrile, S8 and formamide, to prepare
TPAs in 62-97% yield. This reaction provides a facile synthesis
of high value intermediates with excellent atom economy, short
reaction times, high structural diversity, and facile purification. In
addition, the reaction could be scaled up to a multi-gram scale
that did not require chromatography for purification. To
demonstrate the general applicability of our four-component
reaction, the reaction was applied to prepare the NRF2 regulator
AEM2 and MTKI in two steps with high overall yields. In the
future, the invention of this reaction is expected to accelerate the
synthesis of TPA-based molecules for both drug discovery
efforts and process chemistry.
Scheme 4. Total synthesis of AEM2 and MTKI using a Na2HPO4-catalyzed four-
component reaction of ketones (1c or 1i), malononitrile (2), S8 (3) and
formamide (4).
Experimental Section
General procedure for the preparation of compounds 5a-r. To a 10
mL reaction vial, was added 1.0 mmol (1.0 eq.) ketone (1a-r), 1.5 mmol
(1.5 eq.) malononitrile (2), 1.1 mmol (1.1 eq.) S8 (3), 12 mmol (12.0 eq.)
formamide (4), 20 mol% Na2HPO4, and 10 mol% PPh3. The mixture was
heated to 200°C in a sand bath for 0.5 hour. 1 was confirmed to be
consumed by TLC analysis. Then 2 mL of water was poured into the
reaction mixture after it cooled to 22°C. The resulting mixture was
extracted with ethyl acetate (EtOAc) 3 times (5 mL EtOAc per extraction).
The organic layers were combined and washed with 15 mL water.
Subsequently, the organic layer was dried with anhydrous magnesium
sulfate. The crude product was obtained after removing the EtOAc with
vacuum rotation. Further purification was performed with flash column
chromatography to afford products 5a-r as solids.
Finally, we propose a possible mechanism of the four-
component reaction of ketones, malononitrile, S8 and formamide
(Scheme 5). The reaction is initiated by Na2HPO4 extracting the
proton of
of activated
product of a Knoevenagel reaction[11]
the elimination of with the help of Na2HPO4. Subsequently,
Na2HPO4 activated opens the S8 ring through nucleophilic
attack to yield intermediate . Intermediate undergoes
intramolecular addition to the cyano group to form . Then
Na2HPO4-promoted aromatization of leads to the formation of
Gewald reaction product E [12]
Condensation of and produces
intermediate which undergoes intramolecular addition to the
cyano group to give Finally, the Na2HPO4-catalyzed
gives the product
2
. Then the ketone is subjected to nucleophilic attack
, leading to the formation of intermediate . The
, is generated through
2
A
,
B
A
B
C
C
D
D
.
E
4
F
Acknowledgements
G
.
tautomerization of
G
5.
This work was supported by NIH grant ES023758 to E.C. and
D.D.Z.
Conclusion
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Keywords: atom economy• multi-component reaction•
thieno[2,3-d]pyrimidin-4-amines • structural diversity
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Taoda Shi, Christopher J. Zerio, Jared
Sivinski, Andrew J. Ambrose, Kohlson
Taylor Moore, Thomas Buckley, Lynn
Kaneko, Mae Zhang, Donna D. Zhang,
and Eli Chapman*
Page No. – Page No.
Improving atom economy in the
synthesis of Thieno[2,3-d]pyrimidin-
4-amine derivatives via
a
four-
component reaction with ketones,
malononitrile, S8 and formamide
Concise synthesis of thieno[2,3-d]pyrimidin-4-amines with improved atom economy, increased step economy, enhanced structural diversity
and simplified purification has been realized.
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