Transition Metal-Free Synthesis of 3-Alkynylpyrrole-2-carboxylates via Michael Addition/Intramolecular Cyclodehydration

Article abstract of DOI:10.1002/adsc.201501073

A transition metal-free and efficient method for the synthesis of 3-alkynylpyrrole-2-carboxylates from diynones and glycine esters or 2-aminoacetophenone hydrochloride has been developed. This transformation provides a large range of substituted pyrroles in good to excellent yields with the elimination of water as the only by-product. The detailed mechanistic studies elucidated that this transformation involves a Michael addition/intramolecular cyclodehydration process. (Figure presented.) .

Full text of DOI:10.1002/adsc.201501073

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DOI: 10.1002/adsc.201501073
Transition Metal-Free Synthesis of 3-Alkynylpyrrole-2-carboxy-
lates via Michael Addition/Intramolecular Cyclodehydration
Qing-hu Teng,+a Yan-li Xu,+b Ying Liang,c,* Heng-shan Wang,a Ying-chun Wang,a
and Ying-ming Pana,*
a
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China),
School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, Peopleꢀs Republic of
China
Fax: (+86)-773-580-3930; e-mail: panym@mailbox.gxnu.edu.cn
College of Pharmacy, Guilin Medical University, Guilin 541004, Peopleꢀs Republic of China
School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin 541004, Peopleꢀs Republic
b
c
of China
Fax: (+86)-773-219-1683; e-mail: liangyi0774@guet.edu.cn
+
These authors contributed equally to this work.
Received: November 24, 2015; Revised: March 20, 2016; Published online: June 2, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501073.
Abstract: A transition metal-free and efficient
method for the synthesis of 3-alkynylpyrrole-2-car-
boxylates from diynones and glycine esters or 2-
aminoacetophenone hydrochloride has been devel-
oped. This transformation provides a large range of
substituted pyrroles in good to excellent yields with
the elimination of water as the only by-product.
The detailed mechanistic studies elucidated that
this transformation involves a Michael addition/in-
tramolecular cyclodehydration process.
[Scheme 1 Eq, (1)].[3d,e,4f,5] A more recent strategy for
the construction of 3-alkynylpyrrole-2-carboxylates is
the Cu(II)-promoted ortho-alkynylation of pyrroles
with terminal alkynes [Scheme 1 Eq. (2)].[6] However,
these reported methods primarily rely on the incorpo-
ration of alkynyl groups into pyrrole substrates. Thus,
the direct assembly of polysubstituted pyrroles from
simple and readily available starting materials re-
mains a challenging and attractive research topic. Re-
cently, Park and co-workers have reported that poly-
substituted pyrroles can be formed by rhodium-cata-
lyzed tandem rearrangements of a-diazo oxime ethers
[Scheme 1 (Eq. (3)].[7] Although this improvement is
a useful complement to the current approaches, the
method suffers from several additional drawbacks,
such as expensive catalysts and multi-step synthesis of
precursors.
Keywords: 3-alkynylpyrrole-2-carboxylates; 2-ami-
noacetophenones; diynones; glycine esters
Pyrroles are among the most prevalent and important
Diynones, symmetrical molecules with multiple re-
heterocycles in natural products, modern pharmaceut- action sites, are highly nucleophilic acceptors to con-
icals, and materials science.[1,2] In particular, 3-alkynyl- struct diverse types of attractive cyclization prod-
pyrrole-2-carboxylates have been used for the prepa- ucts.[8] To the best of our knowledge, there have been
ration of polyfunctional pyrrole and indole derivatives no reports of the preparation of 3-alkynylpyrrole-2-
with distinct structures and properties.[3] They also carboxylates from diynones and glycine esters or 2-
play significant roles in designing macrocycles that aminoacetophenone hydrochloride. As part of our
possess a wide variety of biological activities.[4] continuing efforts in the development of efficient
Indeed, the applications of pyrroles continue to drive methods for the preparation of N-heterocycles,[9]
the interest in the development of new approaches to herein we report a transition metal-free synthesis of
the preparation of 3-alkynylpyrrole-2-carboxylates. 3-alkynylpyrrole-2-carboxylates from diynones and
Among them, the most commonly used method is the glycine esters or 2-aminoacetophenone hydrochloride
well-known Sonogashira coupling reaction of halogen- via a Michael addition/intramolecular cyclodehydra-
ated pyrroles with terminal alkynes in the presence of tion process.
a palladium catalyst and a copper source (cocatalyst)
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Table 1. Optimization of the reaction conditions.[a]
Entry
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
KHCO3
K2CO3
Na2CO3
Cs2CO3
t-BuOK
NaOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
CH3OH
CH3CN
DMF
85
80
78
30
60
55
32
43
trace
trace
trace
25
trace
trace
40
48
46
0
20
KOH
CH3ONa
NH3·H2O
(HOCH2CH2)3N
DMAP
Et3N
KHCO3
–
K2CO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
9
10
11
12
13[c]
14[d]
15[e]
16[f]
17[g]
18[h]
19[h]
20[h]
21[i]
0
59
[a]
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), base
(1 equiv.), KOAc (0.5 mmol), solvent (2 mL), 2 h, 1208C.
Isolated yields (based on 1a).
Using KHCO3 (2 equiv.), without KOAc.
Using KOAc (2 equiv.).
Using K2CO3 (2 equiv.), without KOAc.
Using KHCO3 (0.5 equiv.).
Using KHCO3 (0.5 equiv.), KOAc (0.5 equiv.).
The reaction was carried out in a sealed tube.
At 808C.
Scheme 1. Approaches to polysubstituted pyrroles.
[b]
[c]
[d]
[e]
[f]
The reaction of 1,5-diphenylpenta-1,4-diyn-3-one 1a
with ethyl glycinate hydrochloride 2a was chosen as
a model system for the optimization studies (Table 1).
Initially, the reaction was carried out in the presence
of KHCO3 (1 equiv.) and KOAc (1 equiv.) in DMF at
1208C for 2 h, affording the desired product 3aa in
85% yield (Table 1, entry 1). The investigation of vari-
[g]
[h]
[i]
ous bases [K2CO3, Na2CO3, Cs2CO3, t-BuOK, NaOH, entry 1 vs. entries 18–20). A decrease in the tempera-
KOH, CH3ONa, NH3·H2O, (HOCH2CH2)3N, DMAP, ture from 1208C to 808C resulted in the desired prod-
Et3N] revealed that inorganic bases were more effec- uct in lower yields (Table 1, entry 1 vs. entry 21).
tive than organic amine bases and that KHCO3 was Therefore, the optimal conditions for this transforma-
optimal (Table 1, entries 1–12). The control experi- tion are KHCO3 (1 equiv.) and KOAc (1 equiv.) in
ments indicated that a combination of KHCO3 and DMF at 1208C for 2 h.
KOAc was indispensable in this reaction (Table 1, en-
With the optimal conditions in hand, we next exten-
tries 13 and 14). When a stronger base, K2CO3, was sively evaluated the substrate scope and functional
used alone, the reaction afforded the desired product group tolerance of this reaction (Table 2). Gratifying-
in low yield (Table 1, entry 15). Further experiments ly, the desired products were obtained in excellent
demonstrated that a decrease in the loading amount yields from the reactions of diynone substrates with
of either KHCO3 or KOAc reduced the yield of 3aa various substitutes. This reaction is relatively tolerant
significantly (Table 1, entries 16 and 17). Moreover, of both electron-withdrawing and electron-donating
a solvent screening study indicated that DMF was the groups on the phenyl ring. Specifically, diynones fea-
most suitable solvent for this transformation (Table 1, turing electron-donating groups on the phenyl ring
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Table 2. Synthesis of 3-alkynylpyrrole-2-carboxylates.[a,b]
[a]
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), KHCO3 (1 equiv.), KOAc (1 equiv.), DMF (2 mL), at 1208C, 2 h.
Isolated yields (based on 1).
[b]
typically provided higher yields of the pyrroles than
Having investigated the reaction substrate scope
those bearing electron-withdrawing groups (3aa–3ga and functional group tolerance, we next examined the
vs. 3ha). Recrystallization of 3ha in a mixture of cycloaddition selectivity of diynones with asymmetri-
hexane and CH2Cl2 resulted in single crystals, the mo-
lecular structure of which was further confirmed by
Table 3. Synthesis of pyrrole derivatives.[a,b]
X-ray crystallographic analysis.[10] To our delight, the
diynone 1g possessing an electron-donating group at
the meta-position of phenyl ring (R1 =R2 =3-Me-
C6H4) reacted readily to afford the desired product
3ga in 86% yield. This reaction is also compatible
with aliphatic diynones, furnishing the desired product
in good yields (3ia and 3ja). In addition, 67–89%
yields of the corresponding products (3ab–3bc) were
obtained when R2 was t-BuO-, 4-F-C6H4, 4-Br-C6H4,
or 4-MeO-C6H4. Unfortunately, when R2 was a chain
structure, such as ethyl 5-amino-4-oxopentanoate and
ethyl 2-(2-aminoacetamido)acetate, the reaction failed
to yield the desired products under the typical reac-
tion conditions.
Furthermore, it was also found that this reaction
was applicable to aryldiynones. As expected, the reac-
tion of aryldiynones with ethyl glycinate hydrochlo-
ride (2a) afforded the corresponding pyrroles 3ma–
3qa in good yields under the standard conditions
(Table 3).
[a]
Reaction conditions:
KHCO3 (1 equiv.), KOAc (1 equiv.), DMF (2 mL), at
1208C, 2 h.
1
(0.5 mmol), 2a (0.6 mmol),
[b]
Isolated yields (based on 1).
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Scheme 2. Competition experiments.
cal structures, in which two different substituents are active intermediate 9 under the basic conditions. Sub-
attached to the two sides of the alkynyl groups. The sequently, an intramolecular cyclodehydration reac-
intramolecular competition experiments employing tion of 9 resulted in the formation of the desired
asymmetrical diynones 1k, 1l and 1s predominantly product 3aa.[12]
yielded isomers 3ka, 4la and 3sa, respectively
In conclusion, we have developed a simple, cost-ef-
(Scheme 2), which can be rationalized as the diynones fective, and transition metal-free cascade reaction for
featuring electron-donating groups on the phenyl ring the synthesis of 3-alkynylpyrrole-2-carboxylates. This
provided higher yields of the pyrroles than those transformation features easy accessibility of starting
bearing electron-withdrawing groups did. In contrast,
1-phenylpenta-1,4-diyn-3-one (1r) did not yield the
expected pyrrole products under the typical reaction
conditions.
To elucidate the reaction mechanism of diynones
with glycine esters, we performed some control ex-
periments and present the results in Scheme 3. The
reaction of 1,5-diphenylpenta-1,4-diyn-3-one 1a with
ethyl glycinate hydrochloride 2a in the presence of
1 equiv. KOAc in toluene at 1108C afforded the prod-
uct 8aa in 90% isolated yield. Subsequently, 8aa un-
derwent an intramolecular cyclodehydration reaction
to provide 3aa in 91% yield under the standard condi-
tions.
On the basis of above results, a plausible mecha-
nism is proposed in Scheme 4. At first, the Michael
addition of 2a onto 1a generated the a,b-enaminone
intermediate 8aa,[11] which converted in situ into a re- Scheme 3. Control experiments.
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stirred at 1108C for 2 h. The reaction was monitored period-
ically by TLC. Upon completion, the solvent was removed
under vacuum. The residue was purified by flash column
chromatography to afford 8aa (90%).
Supporting Information
General experimental procedures, spectral data, NMR spec-
tra, high-resolution mass spectra for all compounds, and the
X-ray crystal structure of 3ha are provided in the Supporting
Information.
Acknowledgements
We thank Ministry of Education of China (IRT1225), the Na-
tional Natural Science Foundation of China (21362002,
41465009 and 81260472), Guangxi Natural Science Founda-
tion of China (2014GXNSFDA118007), State Key Laborato-
ry for the Chemistry and Molecular Engineering of Medicinal
Resources (CMEMR2014A02 and CMEMR2012A20), and
Bagui Scholar Program for financial support.
Scheme 4. Plausible mechanism.
materials, relatively wide functional group tolerance,
and a broad range of substrates, thus enabling the for-
mation of 3-alkynylpyrrole-2-carboxylates that cannot
be accessed effectively by other means. Moreover, the
simple experimental manipulation makes this process
an excellent alternative to the preparation of 3-alky-
nylpyrrole-2-carboxylates under air. Further studies
on the applications of 3-alkynylpyrrole-2-carboxylates
in drug discovery are currently ongoing in our labora-
tory.
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