Catalyst-Free Domino Reaction of 1-Acryloyl-1-N-arylcarbamylcyclopropanes with Amines: One-Pot Approach to 2,3,6,7-Tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones

Article abstract of DOI:10.1002/adsc.201500251

A facile one-pot, catalyst-free reaction has been developed for the synthesis of 2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones from readily available 1-acryloyl-1-N-arylcarbamylcyclopropanes and amines using a domino ring-opening/cyclization/aza-addition sequence.

Full text of DOI:10.1002/adsc.201500251

FULL PAPERS
DOI: 10.1002/adsc.201500251
Catalyst-Free Domino Reaction of 1-Acryloyl-1-N-arylcarbamyl-
cyclopropanes with Amines: One-Pot Approach to 2,3,6,7-Tetra-
hydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones
Zhiguo Zhang,a,* Feisong Zhang,a Huanhuan Wang,a Hao Wu,a Xinyu Duan,a
Qingfeng Liu,a Tongxin Liu,a and Guisheng Zhanga,*
a
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of
Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang, Henan 453007, Peopleꢀs Republic of China
E-mail: zhangzg@htu.edu.cn or zgs6668@yahoo.com
Received: March 12, 2015; Revised: May 17, 2015; Published online: August 13, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500251.
Abstract: A facile one-pot, catalyst-free reaction has Keywords: catalyst-free conditions; domino reac-
been developed for the synthesis of 2,3,6,7-tetrahy- tions; doubly activated cyclopropane; ring-opening;
dro-1H-pyrrolo[3,2-c]pyridin-4(5H)-ones from readi- 2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-
ly available 1-acryloyl-1-N-arylcarbamylcyclopro- ones
panes and amines using a domino ring-opening/cycli-
zation/aza-addition sequence.
Introduction
compounds require multistep procedures to generate
the pyrrole and pyridine rings individually, which can
Pyrrolo[3,2-c]pyridinone derivatives possess a wide have an adverse impact on their overall efficiency and
variety of interesting biological activities, and com- practicality. In 2004, Xi et al.[9] reported the develop-
pounds belonging to this class have been reported to ment of a multi-component domino reaction for the
behave as CK1g inhibitors,[1] NAMPT inhibitors,[2] preparation of pyrrolo[3,2-c]pyridines, which involved
PLK1 inhibitors,[3] Cdc7 kinase inhibitors,[4] ATP-com- the reaction of Si-tethered diynes with three different
petitive MK2 inhibitors,[5] DP receptor antagonists[6] organonitriles in the presence of a zirconocene spe-
and CB2 agonists[7] (Figure 1). Pyrrolo[3,2-c]pyridi- cies. In this process, the pyrrolo[3,2-c]pyridine prod-
none derivatives are generally prepared from pre- ucts were formed by the cleavage of one of the three
formed pyrroles or pyridines.[6,8] However, most of the C N triple bonds and two Si C bonds. Despite these
methods currently available for the synthesis of these advances, the development of a one-pot approach for
the construction of pyrrolo[3,2-c]pyridines in an envi-
ꢀ
À
ronmentally benign and economically viable manner
with broad substrate scope remains largely unrealized.
Herein, we report the results of our recent efforts to-
wards the development of a novel one-pot approach
for the synthesis of 2,3,6,7-tetrahydro-1H-pyrrolo[3,2-
c]pyridin-4(5H)-one derivatives via a domino ring-
opening/cyclization/aza-addition reaction sequence in-
volving doubly activated cyclopropanes and amines
without the need for a catalyst or additives.
Donor–acceptor (D–A) cyclopropanes possess an
inherent strain energy (27.5 kcalmolÀ1) that allows
them to react as 1,3-dipolar synthons. These com-
pounds are particularly suitable for synthetic applica-
tions because of the electronic effects of their sub-
stituents, which not only activate the cyclopropanes to
Figure 1. Representative pyrrolo[3,2-c]pyridinones possess-
ing bioactivities.
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the second route used 1-carbamoyl-1-dimethylami-
noalkenoylcyclopropanes as the starting materials and
ammonium acetate (NH4OAc) as the ammonia
source (Scheme 2).[11e] In 2007, our group established
an approach for the divergent construction of g-imi-
nolactones, dihydroquinolin-2-ones and g-lactams
using three different types of Lewis acid. Notably, all
three of these products started from b-hydroxyme-
Scheme 1. The synthesis of pyrroles using doubly activated
cyclopropanes.
ring-opening reactions but also provide versatile func- thylcyclopropanylamides, which were themselves de-
tional groups in the resulting products.[10] Further- rived from 1-acryloyl-1-N-arylcarbamylcyclopropanes
more, the cyclopropane moieties of doubly activated via a reduction reaction in the presence of NaBH4.[13]
cyclopropanes are more electrophilic than the corre- Based on a combination of research from the litera-
sponding singularly activated systems because of the ture[11c–e,12a–h] and our related research towards the
electron-withdrawing effects of the two acceptors.[11] synthesis of nitrogen-containing compounds from
The results of several studies published in the litera- doubly activated cyclopropane precursors,[11a,12h,14] it
ture have demonstrated that doubly activated 1-alke- was envisioned that novel N,N-bicyclic 1H-pyrro-
noyl-1-carbamoylcyclopropane derivatives are an im- lo[3,2-c]pyridin-4(5H)-one derivatives 3 could be pre-
portant class of cyclopropanes, which play an impor- pared from the reaction of doubly activated cyclopro-
tant role in the construction of pyrroles[12] and N,O-bi- panes 1 with amines 2 (Scheme 2).
cyclic dihydrofuro[3,2-c]pyridine skeletons (Scheme 1
and Scheme 2). In 2011, Liang et al.[11b] reported the
development of an efficient new route for the con- Results and Discussion
struction of furo[3,2-c]pyridinone skeletons from
readily available 1-cinnamoylcyclopropanecarbox- With this in mind, 1-cinnamoyl-1-N-(2-methoxyphe-
amides in a single step. Using 1-cinnamoylcycloprop- nyl)carbamylcyclopropane (1a) was selected as
anecarboxamides generated in situ from the reaction a model substrate and reacted with aniline (2a) to op-
of 1-acetylcyclopropanecarboxamides with aldehydes, timize the reaction conditions, and the key results of
the same group successfully extended this methodolo- these optimization experiments are summarized in
gy to achieve the construction of multi-substituted Table 1. Two different bases, including NaOH and
furo[3,2-c]-pyridinones via a multi-component domino pyridine, were initially evaluated for the reaction of
reaction (Scheme 2).[11c] Dongꢀs group developed two 1a (1.0 mmol) with 2a (1.2 mmol). The results of these
new routes for the synthesis of substituted dihydro- experiments revealed that both bases failed to afford
furo[3,2-c]pyridines, which were reported in 2011 and a high yield of the desired compound 3a when the re-
2012. The first of these routes involved the Vilsmeier- action was conducted in an alcohol solvent in a sealed
type reaction of 1-aminoalkenoyl-1-carbamoylcyclo- tube at reflux, although they did allow for a significant
propanes in the presence of Tf2O in DMF,[11d] whereas reduction in the reaction time, and the simultaneous
Scheme 2. The synthesis of dihydrofuro[3,2-c]pyridines using doubly activated cyclopropanes.
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Catalyst-Free Domino Reaction of 1-Acryloyl-1-N-arylcarbamylcyclopropanes
Table 1. Survey of the reaction conditions.[a]
Entry
Base (equiv)
Solvent
Temperature [8C]
Time [days]
Yield [%][b]
1
NaOH (0.01)
NaOH (0.1)
NaOH (0.1)
pyridine (0.1)
–
–
–
–
EtOH
EtOH
MeOH
EtOH
EtOH
EtOH
i-PrOH
glycol
reflux
reflux
reflux
reflux
reflux
reflux
reflux
110
1.5
0.75
0.2
0.7
3.5
5
58
34
14
46
89
89
83
58
2
3[c]
4
5
6[d]
7
3.5
0.8
8
[a]
Unless otherwise indicated, all of these reactions were carried out with 1a (1.0 mmol) and 2a (1.2 mmol) in solvent
(3.0 mL) in a sealed tube.
Isolated yield.
26% 1a was recovered.
Reaction was performed under an N2 atmosphere.
[b]
[c]
[d]
formation of a complex black mixture (Table 1, en- its impact on the outcome on this domino reaction. The
tries 1–4 vs. 5).[15] However, the yield of 3a was in- results of these experiments revealed that the electronic
creased significantly to 89% when a mixture of 1a nature (i.e., electron-donating or electron-withdrawing)
and 2a was heated at reflux for 3.5 days in EtOH and the position (i.e., ortho-, meta- or para-position) of
(3 mL) in a sealed tube (Table 1, entry 5). Further in- the substituents (e.g., OMe, Cl and CO2Et) on the
creasing the reaction time, however, did not lead to phenyl ring had very little impact on the yields of the
further increase in the yield of 3a, even when the re- corresponding products 3a–h (80–94%). It is noteworthy
action was carried out under an atmosphere of nitro- that 1i (R2 =benzyl group) reacted smoothly to give the
gen to prevent the oxidation of the amine (Table 1, desired compound 3i in 60% yield. Unfortunately, how-
entry 6). Several other alcohol solvents, including iso- ever, it was not possible to synthesize starting material
propyl alcohol and glycol were also tested in the reac- 2j or any of its analogues (such as R2 =methyl, isopro-
tion, but performed much less effectively than EtOH pyl and cyclohexyl) because of limitations posed by the
(Table 1, entries 7 and 8). It is well known that Lewis existing synthetic methods.[18] For this reason, it was not
acids can be beneficial for the ring-opening reaction possible to assess the universal applicability of this ap-
of D–A cyclopropanes.[10a,e,11a,16] With this in mind, proach with this type of compound. These scoping ex-
several Lewis acids, including anhydrous FeCl3, periments showed that a variety of aryl groups could be
FeCl3·6H2O, anhydrous SnCl4, SnCl4·5H2O, ZnCl2, tolerated at the R1 position of the cyclopropane starting
BF3·Et2O and TiCl4, were evaluated in terms of their material, with the corresponding products 3k–s being
ability to catalyze the current reaction. The results of isolated in 64–90% yields, regardless of the electronic
these screening experiments revealed that the addi- nature and the position of the substituents on the
tion of a Lewis acid had an adverse impact on the phenyl ring. Changes to the nature of the amine 2 (R3)
yield of 3a, with almost all of these reactions resulting were also well tolerated, with 4-methoxyaniline and
in formation of a complex mixture.[17]
ethyl 4-aminobenzoate both reacting smoothly to give
The optimal conditions for this transformation were the corresponding products 3t and 3u in 70% yield, re-
finally identified as heating a mixture of 1 (1.0 mmol) spectively. It is noteworthy, however, that the reaction
and 2 (1.2 mmol) in EtOH at reflux in a sealed tube time required by the former of these two anilines was
(Table 1, entry 5). With the optimized conditions in much shorter than that required by the latter. Interest-
hand, we proceeded to explore the scope and limitations ingly, the reaction afforded 3v in 80% yield after 2 days
of this reaction using a range of doubly activated cyclo- when benzylamine was employed as the amine in the
propanes 1 and substituted aniline derivatives 2. The re- reaction. However, the use of aliphatic amines, such as
sults of these experiments are summarized in Table 2.
tert-butylamine and cyclohexylamine resulted in much
The influence of the R2 substituent on the amide of lower yields of the desired fused cyclic compounds 3w
the cyclopropane substrate 1 was evaluated in terms of and 3x in 17% and 34% yields, respectively.
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Table 2. Evaluation of the reaction scope.[a,b]
3a: 3.5 d, 89%
3b: 2 d, 83%
3c: 3 d, 94%
3d: 3 d, 91%
3e: 2 d, 91%
3f: 2 d, 80%
3g: 3 d, 90%
3h: 1.5 d, 93%
3i: 2.5 d, 60%[c]
3k: 5 d, 84%
3l: 4 d, 90%
3m: 5.5 d, 87%
3n: 6 d, 84%
3o: 3 d, 81%
3p: 6.5 d, 75%
3q: 2.5 d, 85%[d]
3r: 2 d, 64%[e]
3s: 5 d, 89%
3t: 2 d, 70%
3u: 9 d, 70%[f]
3v: 2 d, 80%
3w: 4 d, 17%[c]
3x: 2.5 d, 34%[c]
[a]
Unless otherwise indicated, all of these reactions were carried out with 1 (1.0 mmol) and 2 (1.2 mmol) in EtOH (3.0 mL)
at reflux.
Isolated yield.
[b]
[c]
[d]
Formed as part of a complex mixture.
The reaction was performed with the methyl formate substitute 1q, with R=Et or Me in the final product 3q, and the
ratio of the two compounds was approximately 2:1, as determined by 1H NMR.
22% 1r was recovered and the yield of 3r could not be increased by prolonging the reaction time.
26% 1u was recovered and the yield of 3u could not be increased by prolonging the reaction time.
[e]
[f]
A controlled experiment was conducted to get sired compound 5a was not isolated following the
a deeper understanding of the mechanism of this quenching of the reaction, and that compound 4a was
domino reaction. Compound 4a was reacted with ani- recovered instead in 97% yield (Scheme 3). Taken to-
line under the standard reaction conditions for 3 days. gether with the results of similar studies from the lit-
The results of this experiment revealed that the de- erature, this result allowed us to propose a possible
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Catalyst-Free Domino Reaction of 1-Acryloyl-1-N-arylcarbamylcyclopropanes
Scheme 3. A controlled experiment.
Scheme 4. Proposed mechanism.
mechanism for the current reaction, which is shown in (4.0 mL) at room temperature was added aniline (2a)
Scheme 4.[11c–e,12a] According to this mechanism, amine
(0.109 mL, 1.2 mmol) in a sealed tube at reflux. Then the
mixture was well stirred under reflux for 3.5 days (the whole
process was closely monitored by TLC). After cooling off,
the mixture was added water (5.0 mL), and the aqueous
phase was extracted with ethyl acetate (20 mL”3). The
combined organic layer was dried over sodium sulfate. The
solvent was evaporated, and the residue was purified by
a short flash silica gel column chromatography (eluent:
ethyl acetate/petroleum ether=4/5) to give 5-(2-methoxy-
2 would initially attack the doubly activated cyclopro-
pane 1 to generate the quaternary ammonium ana-
logue A, which would undergo a cyclization reaction
through intermediate B to give the multi-substituted
dihydropyrrole D.[12a] Finally, pyrrole D would give
the 1H-pyrrolo[3,2-c]pyridin-4(5H)-one 3 via an intra-
molecular aza-addition reaction.[19]
phenyl)-1,6-diphenyl-2,3,6,7-tetrahydro-1H-pyrrolo[3,2-
c]pyridin-4(5H)-one (3a) as yellow solid; yield: 352.6 mg
(89%).
Conclusions
In summary, a facile and efficient, one-pot, catalyst-
free domino reaction has been developed for the syn-
thesis of 2,3,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-
Acknowledgements
4(5H)-one derivatives from doubly activated cyclo-
propanes and amines. This domino procedure involves
a contiguous bond cleavage/formation process. Fur-
thermore, this protocol uses readily available starting
materials, has a broad substrate scope and provides
good to excellent yields of the desired products with
dense and flexible substitution patterns. The products
themselves could be used as important building
blocks for the synthesis of complex products.[20]
We thank the NSFC (21172056, 21272057 and 21372065),
PCSIRT (IRT1061), China Postdoctoral Science Foundation
funded
project
(2012M521397,
2013T60701
and
2013M530339), the Program of Foundation and Frontier
Technology Research of Henan Province (122300410296),
and Innovation Scientists and Technicians Troop Construc-
tion Projects of Henan Province (134200510016).
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[17] Please see the Supporting Information for more details.
[18] The starting materials with alkyl substituents (such as
R1 =methyl, isopropyl and cyclohexyl, etc. or R2 =
alkyl) could not be converted to the corresponding con-
densation products 2, which is the limitation of the
method for the preparation of starting materials.
[19] H. Stamm, V. Gailius, Chem. Ber. 1981, 114, 3599–3608.
[20] E. Bisagni, M. Legraverend, J. M. Lhoste, J. Org.
Chem. 1982, 47, 1500–1503.
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Adv. Synth. Catal. 2015, 357, 2681 – 2686