Synthesis of C3-alkenylated 2,3,4-trisubstituted pyrrole derivatives through cyclization of methylene isocyanides and ene-yne-ketones

Article abstract of DOI:10.1039/d0nj05253a

A mild, transition-metal-free and facile C3-alkenylated 2,3,4-trisubstituted pyrrole cyclization of methylene isocyanides with ene-yne-ketones in moderate to good yields was explored. The E-alkenylated products were isolated in moderate to exclusive selec

Full text of DOI:10.1039/d0nj05253a

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Synthesis of C3-alkenylated 2,3,4-trisubstituted
pyrrole derivatives through cyclization of
methylene isocyanides and ene–yne–ketones†
Cite this: New J. Chem., 2021,
45, 1834
Shasha Li,‡a Gongruixue Zeng,‡b Xiaoqi Xing,b Zhiheng Yang,a Feiyun Ma,a Boxia Li,a
Weiyan Cheng, *a Jiankang Zhang*b and Ruoyu He*c
Received 26th October 2020,
Accepted 20th December 2020
A mild, transition-metal-free and facile C3-alkenylated 2,3,4-trisubstituted pyrrole cyclization of methylene
isocyanides with ene–yne–ketones in moderate to good yields was explored. The E-alkenylated products
were isolated in moderate to exclusive selectivity in most cases. The investigated compounds in this work
are expected to open up for use as potential medicinal agents or precursors for post-modification.
DOI: 10.1039/d0nj05253a
rsc.li/njc
aldehydes employed as alkenylating agents, Samrat et al. presented
Introduction
an alkenylation strategy with sulfone used as a starting precursor.11
Multi-substituted pyrroles have been exploited as important Additionally, Joydev et al. exploited a site-selective alkenylation of
drugs or drug candidates, which are also present in diverse (NH)-pyrroles with an electron-withdrawing group, which also
bioactive natural products.1–7 Among various functional groups required expensive palladium as an oxidative reagent.10 To avoid
introduced into pyrroles, incorporation of the alkenyl group the negative effects caused by the active pyrrole, cycloaddition
opens new opportunities for diversification of the scaffold to approaches for forming a pyrrole ring together with a vinyl
develop functionalized molecules with additional therapeutic substitution would be an efficient alternative option. Cyclization
potential.8–12 Alkenylated pyrrole-containing biologically active of active methylene isocyanides with diverse synthons yielding
drug like compounds have been well developed including poly-substituted pyrroles has been performed.27,30–36 Therefore,
multitarget tyrosine kinase inhibitor sunitinib and histone considering the synthetic utility of methylene isocyanides for
deacetylase inhibitor domatinostat (Fig. 1).13–21
constructing pyrroles and with our continuing effort in the synthesis
Several approaches to obtain C-alkenylpyrroles have been of this five-membered heterocyclic ring, we herein describe a simple
reported including traditional methods the Wittig reaction and protocol providing 3-alkenylated 2,3,4-trisubstituted pyrroles via
Knoevenagel condensation using aldehyde functionalized pyrroles [3+2] cyclization of methylene isocyanides with ene–yne–ketones
as starting materials.10,11,22–29 Recently, the described methods are under basic conditions (Fig. 2).
mainly focused on direct alkenylation on the pyrrole ring (Fig. 2).
Because of the instability of pyrroles in acidic and oxidative
environments, alkenylation was mainly achieved on NH-protected
Results and discussion
pyrrole. Gaunt and colleagues reported a palladium-catalyzed
oxidative alkenylation of N-triisopropylsilyl (TIPS) protected pyrrole
with an activated alkene.8 Notably, to explore more convenient
methods, direct alkenylation on NH-free pyrrole was recently
developed. Through a one-pot two-fold alkenylation strategy with
We commenced our investigation by exploring the reaction of
3-(3-phenylprop-2-yn-1-ylidene)pentane-2,4-dione (1a) with ethyl
isocyanoacetate (2a) (Table 1). A base proved to be an essential
influence factor for entry into alkenylated pyrroles. No reaction
was observed in initial attempts with various attempted bases
(entries 1–7), while product 3a could only be obtained in 35%
a Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University,
Zhengzhou 450052, Henan, China. E-mail: fccchengwy@zzu.edu.cn
b School of Medicine, Zhejiang University City College, Hangzhou 310015,
Zhejiang, China. E-mail: zjk0125@yeah.net
c Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital,
Hangzhou 310023, Zhejiang, China. E-mail: heruoyu_hry@hotmail.com
† Electronic supplementary information (ESI) available. CCDC 2035580 and
2035586. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/d0nj05253a
Fig. 1 Drugs or candidates with an alkenylated pyrrole.
‡ These authors contributed equally.
1834 | New J. Chem., 2021, 45, 1834--1837
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influence on the yield (entries 18 and 19). To check the effect
of the temperature on the outcome, we next conducted the
reaction at various temperatures (entries 20 and 21). The yield
got diminished at 0 1C, which was mainly attributed to the
slower reaction velocity, while the yield was desirable at 50 1C
with a shorter reaction period. However, with these optimized
conditions changed, the E/Z selectivity of product 3a remained
the same.
With the optimized conditions in hand, we intended to
investigate the scope of this method with respect to various
ene–yne–ketones (Scheme 1). While the dione substrate with an
unsubstituted phenyl ring (1a) gave 3a in good yield, both
electron-withdrawing and -donating groups in the ortho, para
and meta positions on the phenyl group could be tolerated,
furnishing the corresponding target compounds (3a–3l) in
favorable yields. Besides, by replacing the phenyl group with
a naphthyl group, 3m could also be obtained in good yield.
Various electron-withdrawing R1 groups were also suitable
reaction partners and provided products 3n–3p in 62–84%
yields. It is noteworthy that although no obvious regularity of
the E/Z selectivity for the product was observed, the (E)-isomer
was considered to be the preferential conformation, and only in
a few cases was the (E)-isomer of the products isolated exclu-
sively (3c, 3f, 3g, 3h, and 3i).
Fig. 2 Construction of alkenylated pyrroles.
yield with almost no stereoselectivity (1: 1 E/Z ratio) in the
presence of DBU with MeCN as a solvent (entry 8). Subsequently,
the screening of diverse solvents showed DCM to be the most
suitable one, furnishing product 3a in 63% yield, while no
product was observed with MeOH as a solvent (entries 9–14).
Increasing the equivalency of 2a to 1.5-fold did improve the yield
to 68% (entry 15), while no obvious improvement was observed
when further raised to 2- and 5-fold (entries 16 and 17). Similarly,
alteration of the equivalency of DBU also had little positive
In order to check the endurance of various active methylene
isocyanides, we next evaluated several isocyanoacetates with
different ester moieties under the reaction parameters
Table 1 Optimization of the reaction conditionsa
Entry
Base
Solvent
Temp. (1C)
Yieldb/(%)
1
2
3
4
5
6
7
8
NaOH
K2CO3
NaOAc
EtONa
Et3N
DIPEA
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
MeOH
Dioxane
DMF
DCE
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
0
0
0
o5
0
0
0
35
52
0
57
31
45
63
68
65
64
55
53
35
60
9
10
11
12
13
14
15c
16d
17e
18 f
19 g
20h
21i
DBU
50
a
Reaction conditions unless otherwise specified: 0.5 mmol of 1a,
b
Scheme 1 Scope of the ene–yne–ketones. Reaction conditions unless
otherwise specified: 0.5 mmol of 1a, 0.75 mmol of 2a, 1.5 equiv. DBU, 2 mL
of solvent, r.t., 1 h, air. Isolated yield.
0.55 mmol of 2a, 1.5 equiv. base, 2 mL of solvent, r.t., 1 h, air. Isolated
yield. 0.75 mmol of 2a. 1 mmol of 2a. 2.5 mmol of 2a. 2 equiv.
DBU. 5 equiv. DBU. Reacted for 3 h. Reacted for 0.5 h.
c
d
e
f
g
h
i
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Conclusions
In conclusion, we have developed a valuable and wide-in-scope
protocol for the synthesis of trisubstituted C3 alkenylated
pyrroles via DBU mediated [3+2] cyclization of isocyanoacetates
to ene–yne–ketone derivatives. The facile process occurs at
room temperature and is transition-metal-free. We anticipate
that this strategy would be helpful for searching for more
complex molecules containing alkenylated pyrrole, which
may have potential for further post-synthetic modifications or
medicinal applications.
Scheme 2 Scope of the methylene isocyanides. Reaction conditions
unless otherwise specified: 0.5 mmol of 1a, 0.75 mmol of 2a, 1.5 equiv.
DBU, 2 mL of solvent, r.t., 1 h, air. Isolated yield.
Conflicts of interest
There are no conflicts to declare.
(Scheme 2). Notably, different isocyanoacetates generated the
corresponding products (3q–3t) in moderate to good yields.
However, the E/Z selectivity for the isopropyl isocyanoacetate
generated product (3r) was opposite to the other products, in
which the (Z)-isomer of 3r was more preferable with an E/Z ratio
of 1 : 15, and the irregularity of the selectivity needs to be
further evaluated.
On the basis of the observations, a plausible mechanism is
proposed as illustrated in Scheme 3. Firstly, active methylene
isocyanide was deprotonated by DBU to generate 2a0, which
reacted with 1a to obtain intermediate I. Subsequently, intra-
molecular cyclization followed by protonation gave III. Then,
deacetylation with the assistance of water afforded IV, which
upon interconversion formed VI. Finally, in the presence of
DBU, a 1,3-H shift took place in intermediate VI leading to the
allene intermediate VII, which would further go through a
tautomerism process to obtain the final product 3a.
Acknowledgements
The authors are grateful for the support of the National Natural
Science Foundation of China (81703417, 81803432).
References
1 B. Diaz de Grenu, P. Iglesias Hernandez, M. Espona,
D. Quinonero, M. E. Light, T. Torroba, R. Perez-Tomas
and R. Quesada, Chem. – Eur. J., 2011, 17, 14074–14083.
2 G. Poce, S. Consalvi, G. Venditti, S. Alfonso, N. Desideri,
R. Fernandez-Menendez, R. H. Bates, L. Ballell, D. B. Aguirre,
J. Rullas, A. De Logo, M. Gardner, T. R. Ioerger, E. J. Rubin
and M. Biava, ACS Med. Chem. Lett., 2019, 10, 1423–1429.
3 S.-G. Zhang, C.-G. Liang, Y.-Q. Sun, P. Teng, J.-Q. Wang and
W.-H. Zhang, Mol. Diversity, 2019, 23, 915–925.
4 I. Gulcin, B. Trofimov, R. Kaya, P. Taslimi, L. Sobenina,
E. Schmidt, O. Petrova, S. Malysheva, N. Gusarova,
V. Farzaliyev, A. Sujayev, S. Alwasel and C. T. Supuran,
Bioorg. Chem., 2020, 103, 104171.
5 P. Olszewska, D. Cal, P. Zagorski and E. Mikiciuk-Olasik,
Eur. J. Pharmacol., 2020, 871, 172943.
6 G. A. Vitale, M. Sciarretta, F. P. Esposito, G. G. January,
M. Giaccio, B. Bunk, C. Sproeer, F. Bajerski, D. Power,
C. Festa, M. C. Monti, M. V. D’Auria and D. de Pascale,
J. Nat. Prod., 2020, 83, 1495–1504.
7 X. Yin, K. Ma, Y. Dong and M. Dai, Org. Lett., 2020, 22,
5001–5004.
8 E. M. Beck, N. P. Grimster, R. Hatley and M. J. Gaunt, J. Am.
Chem. Soc., 2006, 128, 2528–2529.
9 J.-H. Duan, R.-J. Mi, J. Sun and M.-D. Zhou, Org. Chem.
Front., 2018, 5, 162–165.
10 J. K. Laha, R. A. Bhimpuria and G. B. Mule, ChemCatChem,
2017, 9, 1092–1096.
11 S. Sahu, A. Roy, M. Gorai, S. Guria and M. S. Maji, Eur. J. Org.
Chem., 2019, 6396–6400.
12 J. Sakurada and T. Satoh, Tetrahedron, 2007, 63, 3806–3817.
13 C. J. Matheson, K. A. Casalvieri, D. S. Backos, M. Minhajuddin,
C. T. Jordan and P. Reigan, Eur. J. Med. Chem., 2020,
197, 112316.
Scheme 3 Plausible reaction mechanism.
1836 | New J. Chem., 2021, 45, 1834--1837
This journal is ©The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021

View Article Online
Paper
NJC
14 H. K. Mahmoud, T. A. Farghaly, H. G. Abdulwahab, N. T. Al- 24 N. Karousis, J. Liebscher and G. Varvounis, Synthesis, 2006,
Qurashi and M. R. Shaaban, Eur. J. Med. Chem., 2020,
208, 112752.
1494–1498.
25 G. Jones, H. M. Gilow and J. Low, J. Org. Chem., 1979, 44,
15 C. Karnthaler-Benbakka, B. Koblmueller, M. Mathuber,
2949–2951.
K. Holste, W. Berger, P. Heffeter, C. R. Kowol and 26 V. K. Outlaw and C. A. Townsend, Org. Lett., 2014, 16, 6334–6337.
B. K. Keppler, Chem. Biodiversity, 2019, 16, e1800520.
16 J. Kaur, B. Kaur and P. Singh, Bioorg. Med. Chem. Lett., 2018,
28, 129–133.
17 T.-H. Yang, C.-I. Lee, W.-H. Huang and A.-R. Lee, Molecules,
2017, 22, 913.
18 J. Zhang, W. Shen, X. Li, Y. Chai, S. Li, K. Lv, H. Guo and
M. Liu, Molecules, 2016, 21, 1674.
19 S. Shah, C. Lee, H. Choi, J. Gautam, H. Jang, G. J. Kim,
27 J. Moskal and A. M. Vanleusen, J. Org. Chem., 1986, 51,
4131–4139.
28 L. M. Hodges, M. L. Spera, M. W. Moody and W. D. Harman,
J. Am. Chem. Soc., 1996, 118, 7117–7127.
29 H. T. Kim, W. Lee, E. Kim and J. M. Joo, Chem. – Asian J.,
2018, 13, 2418–2422.
30 A. Aitha, N. Payili, S. R. Rekula, S. Yennam and
J. S. Anireddy, ChemistrySelect, 2017, 2, 7246–7250.
Y.-J. Lee, C. L. Chaudhary, S. W. Park, T.-G. Nam, J.-A. Kim 31 F. Qiu, J. Wu, Y. Zhang, M. Hu, F. Yu, G. Zhang and Y. Yu,
and B.-S. Jeong, Org. Biomol. Chem., 2016, 14,
4829–4841.
20 X. Peng, G. Liao, P. Sun, Z. Yu and J. Chen, Curr. Top. Med.
Chem., 2019, 19, 1005–1040.
Lett. Org. Chem., 2012, 9, 305–308.
32 W. Chen, J. Shao, Z. Li, M. A. Giulianotti and Y. Yu,
Can. J. Chem., 2012, 90, 214–221.
33 O. V. Larionov and A. de Meijere, Angew. Chem., Int. Ed.,
2005, 44, 5664–5667.
21 S. W. Henning, R. Doblhofer, H. Kohlhof, R. Jankowsky,
T. Maier, T. Beckers, M. Schmidt and B. Hentsch, 34 N. D. Smith, D. H. Huang and N. D. P. Cosford, Org. Lett.,
EJC Suppl., 2010, 8, 61. 2002, 4, 3537–3539.
22 R. Settambolo, R. Lazzaroni, T. Messeri, M. Mazzetti and 35 D. Vanleusen, E. Vanechten and A. M. Vanleusen, J. Org.
P. Salvadori, J. Org. Chem., 1993, 58, 7899–7902. Chem., 1992, 57, 2245–2249.
23 R. Settambolo, M. Mariani and A. Caiazzo, J. Org. Chem., 36 D. Vanleusen, E. Flentge and A. M. Vanleusen, Tetrahedron,
1998, 63, 10022–10026. 1991, 47, 4639–4644.
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