Regioselective Synthesis of Pyrroles from Alkyne-Isocyanide Click Reactions: An Angle Strain-Induced Bond Migration Approach

Article abstract of DOI:10.1002/adsc.201601017

The direct regioselective synthesis of highly functionalized pyrroles with two different electron-withdrawing groups has been developed using an angle strain-induced 1,2-shift of an electron-withdrawing group in 2H-pyrroles. The preferential migration aptitude of an electron-withdrawing group over alkyl and aryl groups is believed to be the result of the orbital overlap between the internal alkene and the electron-withdrawing group. The newly developed regioselective synthesis of pyrroles features a wide substrate scope, simple reaction set-up, and high yields (60–82%), capturing the essence of alkyne-isocyanide “click” reactions. (Figure presented.).

Full text of DOI:10.1002/adsc.201601017

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DOI: 10.1002/adsc.201601017
Regioselective Synthesis of Pyrroles from Alkyne-Isocyanide
Click Reactions: An Angle Strain-Induced Bond Migration
Approach
Jimil George,a Hun Young Kim,a,* and Kyungsoo Oha,*
a
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul
06974, Republic of Korea
Fax : (+82) 2-816-7338; e-mail: hunykim@cau.ac.kr or kyungsoooh@cau.ac.kr
Received: September 13, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601017.
Abstract: The direct regioselective synthesis of
highly functionalized pyrroles with two different
electron-withdrawing groups has been developed
using an angle strain-induced 1,2-shift of an elec-
tron-withdrawing group in 2H-pyrroles. The prefer-
ential migration aptitude of an electron-withdraw-
ing group over alkyl and aryl groups is believed to
be the result of the orbital overlap between the in-
ternal alkene and the electron-withdrawing group.
The newly developed regioselective synthesis of
pyrroles features a wide substrate scope, simple re-
action set-up, and high yields (60–82%), capturing
the essence of alkyne-isocyanide “click” reactions.
The cycloaddition reaction between alkynes and
isocyanides fulfils the requirements of “click chemis-
try” that are high yielding, wide in scope, stereospecif-
ic, and simple to perform.[5] The pioneering works of
Yamamoto[6] and de Meijere[7] in 2005 opened up the
copper-catalyzed alkyne-isocyanide [3+2] cycloaddi-
tion reactions, where the phosphine-catalyzed reac-
tion provided the regiodivergent synthesis of highly
substituted pyrroles (Scheme 1a). In 2013, the groups
of Bi[8] and Lei[9] independently reported the silver-
catalyzed alkyne-isocyanide [3+2] cycloaddition reac-
tions, expanding the alkyne substrate scope to termi-
nal alkynes.[10] Mechanistically, whereas the cationic
phosphonium and the anionic carbanion intermediate
species were postulated for the Lewis basic phosphine
catalysts,[6] the formation of C-metallated isocyanides
has been proposed by a recent experimental and the-
Keywords: alkynes; angle strain; click reaction; iso-
cyanides; pyrroles
Pyrroles constitute one of the most widely sought
after heterocyclic compounds in medicinal and mate-
rial chemistry.[1] Numerous synthetic methods for pyr-
roles have been developed over a century with an aim
to provide structural diversity, high reaction efficien-
cy, and controlled regioselectivity.[2] Thus, the objec-
tives of ideal pyrrole synthesis may require the use of
basic chemicals to directly assemble multi-substituted
pyrroles in the presence of catalysts.[3] In this vein, the
transition metal-catalyzed migratory cycloisomeriza-
tion reactions of propargylic imines via a pinacol-type
1,2-alkyl (preferentially aryl) shift realize the highly
selective assembly of diversely substituted pyrroles.[4]
However, the use of elaborately designed propargylic
imines limits the full synthetic potential of migratory
approaches to pyrroles. Consequently, the identifica-
tion of new migration precursors to pyrroles from
basic chemicals is an attractive area of research.
Scheme 1. Alkyne-isocyanide “click” reactions and angle
strain-induced bond migration to substituted pyrroles.
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Table 1. Optimization of the 1,2-ester shift.[a]
oretical study.[11] To capitalize on the full synthetic
benefit of “click chemistry” that features in the
alkyne-isocyanide [3+2] cycloaddition reactions, we
envisioned an angle strain-induced bond migration of
2,2-disubstituted-2H-pyrroles to the regioselective
synthesis of pyrroles (Scheme 1b). While the 1,2-shift
of sulfur groups in 2H-thienopyrroles has been postu-
lated during the photochemical conversion of 3-azido-
2-vinylthiophenes,[12] the 1,2-shift of an ester group in
2H-pyrroles has been only observed either as a side-
product from the [3+2] cycloaddition of azomethine
ylides and activated alkynes[13] or the acid-promoted
elimination of 2,5-dihydropyrroles.[14] Herein, we
report a facile and operationally simple synthetic
access to 2,2-disubstituted-2H-pyrroles and a subse-
quent angle strain-induced 1,2-migration of an elec-
tron-withdrawing group (EWG) in 2H-pyrroles to fur-
nish highly functionalized pyrroles. Importantly, the
current approach provides the one-pot regioselective
synthesis of 2,3,4-substituted pyrroles with two differ-
ent EWGs at the 3- and 4-carbon atoms.
Motivated by the synthetic potential of high bond
strain associated with 2,2-disubstituted-2H-pyrroles,[15]
we evaluated the use of Brçnsted and Lewis base cat-
alysts in the alkyne-isocyanide [3+2] cycloaddition re-
action (Table 1). Upon mixing a-substituted isocya-
nide 1a and but-3-yn-2-one 2a in the presence of a cat-
alytic amount of Brçnsted base, Et3N, the formation
of 2H-pyrrole 3a was observed at ambient tempera-
ture in 6 h. Gratifyingly, a longer reaction time slowly
converted 2H-pyrrole 3a to pyrrole 4a via a selective
methyl ester migration from C-2 to C-3 atom
(entry 1). The structure of pyrrole 4a was unambigu-
ously confirmed by X-ray crystallographic analysis.[16]
Other bases were screened to improve the reaction
efficiency, however while the use of DABCO led to
the formation of 3a in 40% yield (entry 2), no desired
product was obtained in the reactions using either
DBU or DMAP (entries 3 and 4). Interestingly, the
reaction in the presence of DMAP exclusively provid-
ed an acylic conjugate addition product 5a that was
En- Cat.
try (mol%)
Sol-
vent
T
[8C]
t
Yield
[h] [%][b]
1
2
3
4
5
6
7
8
Et3N (10)
DABCO (10)
DBU (10)
DMAP (10)
Ph3P (10)
Ph3P (10)
Ph3P (10)
Ph3P (10)
Ph3P (10)
Ph3P (10)
Ph3P (10)
Cy3P (10)
Ph3P (5)
THF
THF
THF
THF
THF
23
23
23
23
23
24
24
24
24
24
24
24
24
24
35
40
0
0[c]
70
20
25
0
PhCH3 23
CH2Cl2 23
CH3CN 23
[d]
9
–
23
<2
0
10
11
12
13
14
15
THF
THF
THF
THF
THF
THF
23!66 12/3
23!66 12/3 71
23!66 12/3 75
23!66 12/3 73
23!66 12/3 81
23!66 12/3 76
Ph3P (2)
Ph3P (1)
16[e] Ph3P (10), CuOAc (5) THF
66
66
66
1
3
12
86
75
0
17
18
Ph3P (5), CuOAc (5) THF
CuOAc (10) THF
[a]
Reaction conditions: 1 (0.2 mmol) and 2 (0.22 mmol) in
solvents (0.10M) under argon.
Isolated yield of products after column chromatography.
Michael product 5a in 56%.
DMF or DMSO.
[b]
[c]
[d]
[e]
CuOTf (84%), CuCl (76%), CuCl2 (80%), and Cu(OTf)2
(82%).
inert to the bond migration, thus signifying the cyclic was deleteriously affected by the presence of Lewis
structure of 2H-pyrrole 3a for the ester migration. base, PPh3. Thus, the catalyst loading was investigated
The employment of Lewis base, PPh3, prompted an (entries 13–15), and the optimal use of 2 mol% PPh3
enhanced reaction conversion to 70% in 36 h was established (entry 14). In addition to the sole use
(entry 5), and the optimal reaction solvent was identi- of Lewis base as catalyst, we also discovered the syn-
fied as THF (entries 6–9). Since the formation of pyr- ergistic role of copper Lewis acids (entries 16 and 17).
role 4a from 2H-pyrrole 3a was a thermal process,[17] Thus, an addition of copper Lewis acids drastically re-
the reaction temperature was increased to refluxing duced the reaction time to 1 h at reflux THF, yielding
THF temperature after the consumption of both start- 4a in 86% yield (entry 16). A slight excess of Lewis
ing materials 1a and 2a. The use of PBu3 did not pro- base, PPh3, was necessary, possibly due to the Lewis
mote the alkyne-isocyanide cycloaddition reaction acid-base interaction between PPh3 and copper salt
(entry 10), whereas the use of PPh3 or PCy3 provided (entry 17). The control experiment confirmed the in-
comparable yields of 4a under elevated reaction tem- ability of copper Lewis acid in promoting the alkyne-
perature in 3 h (entries 11 and 12). The amount of isocyanide [3+2] cycloaddition reaction (entry 18).
catalyst loading turned out to be quite important
The optimized alkyne-isocyanide [3+2] cycloaddi-
since the formation of pyrrole 4a from 2H-pyrrole 3a tion conditions were further scrutinized using other
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Table 2. Scope of alkynes in the alkyne-isocyanide “click” reaction.
[a]
Reactions in 1,4-dioxane at 1008C.
alkynes (Table 2). The selective methyl ester migra- ethyl-substituted 2H-pyrroles (3x and 3y) were inert
tion from C-2 to C-3 atom of 2H-pyrrole was general, to our 1,2-migration reaction conditions, however, the
thus the sterically and electronically varied alkyl and reaction of an isopropyl-substituted 2H-pyrrole
aryl moiety of alkynones did not influence the out- smoothly provided the desired pyrrole (4z) in 84%
come of the reaction, providing good to excellent yield. The steric change in the ester moiety to tert-
yields of pyrroles (4a–4n).[18] The reaction was also butyl ester effected the 1,2-migration of the tert-butyl
applicable to other functionalized alkynes (4o–4r), ester moiety, providing pyrroles (4za and 4zb) with
tolerating ester (4o), thioester (4p), sulfonyl group much improved reaction rates (4a in 1 h at 668C vs.
(4q), and phosphonate group (4r). One noteworthy 4zb in 0.5 h at 668C). The use of substituted isocya-
aspect of the current bond migration strategy is the nides with other electron-withdrawing groups such as
facile introduction of two different EWGs to pyr- sulfonate (4zc) and phosphonate (4zd) could be also
roles.[19]
The scope and limitation of the stereospecific 1,2- sis.
migration of an electron-withdrawing group (EWG)
tolerated in the current stereospecific pyrrole synthe-
Based on our experimental observations on the 1,2-
was further explored using diversely substituted iso- migration of electron-withdrawing groups, it is reason-
cyanides 1 (Table 3). The electronic effect of aryl sub- able to assume two different mechanistic pathways of
stituent revealed that the 1,2-migration of a methyl 2H-pyrroles (Figure 1). When the sp3-carbon of 2H-
ester moiety was facilitated in the presence of an elec- pyrrole is substituted with an electron-withdrawing
tron-withdrawing substituent, thus the 4-MeC6H4 group and a hydrogen, the preferential reaction path-
group required 5 h heating for full migration (4s) way involves 1,5-hydrogen shift to provide pyrroles
whereas the 1,2-migration with 4-FC6H4 group was with two EWGs at the 2- and 4-carbon atoms (Fig-
complete in 1 h at 668C (4u). Isocyanides with alkyl ure 1a).[6–9] The replacement of hydrogen at the sp3-
groups also underwent the desired 1,2-migration to carbon of 2H-pyrrole with smaller substituents such
give pyrroles (4v–4w), albeit in a longer reaction time as a methyl group provides the inert structure of 2H-
than the aryl cases. The steric requirement of the 1,2- pyrrole with a smaller bond angle for MeO2C–C–CH3
migration was also investigated. Thus, the methyl- or that is free from the bond migration. The fact that
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Table 3. Scope of isocyanides in the alkyne-isocyanide
“click” reaction.
over alkyl and aryl groups could be explained by the
possible orbital overlap between the pC bond of the
=
C
internal alkene and the p*C bond of the electron-
=
O
withdrawing group.[20]
In summary, we have developed the highly regiose-
lective synthesis of pyrroles with two different elec-
tron-withdrawing groups at C-3 and C-4 atoms. Cap-
turing the full synthetic benefits of click chemistry in
the alkyne-isocyanide [3+2] cycloaddition reaction,
the newly developed angle strain-induced bond mi-
gration strategy should provide a simple and stereo-
specific synthetic route to diversely substituted pyr-
roles. While more studies are needed for the theoreti-
cal origin of 1,2-bond migration, our experimental
data strongly suggest the highly predictable migration
aptitude for electron-withdrawing groups over alkyl
and aryl groups. This unique bond migration strategy
should be applicable to other heterocycles with high
selectivity, and our current research efforts are direct-
ed to expanding the chemistry to other heteroaromat-
ic systems.
Experimental Section
General Procedure for Synthesis of Substitued
Pyrrole Derivatives
[a]
A dry flask was charged with isocyanide (1, 0.20 mmol) and
alkyne (2, 0.22 mmol) under argon. To this flask dry THF
(2.0 mL) was added followed by CuOAc (1.23 mg,
0.01 mmol, 5 mol%) and triphenylphosphine (5.25 mg,
0.02 mmol, 10 mol%) at ambient temperature. After stirring
at this temperature for 15 min, the reaction mixture was
slowly warmed to 668C. Then the solution was allowed to
stir at reflux until the reaction was completed by TLC (1–
15 h). The reaction mixture was allowed to cool to room
temperature and the solvent was removed on a rotary evap-
orator. The residue was purified by column chromatography
on silica gel to afford desired products.
Reactions in 1,4-dioxane at 1008C.
Methyl 4-acetyl-2-phenyl-2H-pyrrole-2-carboxylate (3a):
Prepared by the reaction of the corresponding isocyanide
and alkynone in THF at ambient temperature for 30 min;
1
yield: 74%: pale yellow oil. H NMR (CDCl3, 600 MHz): d
=8.59 (s, 1H), 8.23 (s, 1H), 7.55–7.52 (m, 2H), 7.41–7.33 (m,
3H), 3.76 (s, 3H), 2.46 (s, 3H); 13C NMR (CDCl3,
150 MHz): d=193.2, 167.9, 164.4, 159,5, 140.4, 134.5, 128.9,
128.8, 127.0, 93.1, 53.5, 27.7; IR (neat): n=3088, 2954, 1747,
1681, 1613, 1433, 1228, 1023 cmꢀ1; HR-MS (ESI): m/z=
244.0963, calcd. for C14H14NO3 [M+H]+: 244.0968. Note: this
compound will convert to pyrrole 4a on stirring of the reac-
tion mixture for a longer time (36 h) or by refluxing (2 h) in
THF.
Methyl 4-acetyl-2-phenyl-1H-pyrrole-3-carboxylate (4a):
Yield: 86%; pale yellow solid; mp 137–1398C. 1H NMR
(CDCl3, 600 MHz): d=8.58 (s, 1H), 7.34–7.32 (m, 2H),
7.31–7.28 (m, 3H), 7.05 (d, J=3.0 Hz, 1H), 3.84 (s, 3H),
2.34 (s, 3H); 13C NMR (CDCl3, 150 MHz): d=193.0, 168.4,
133.9, 130.4, 128.8, 128.2, 126.8, 125.7, 124.3, 112.5, 52.5,
Figure 1. Proposed mechanism for angle strain-induced
bond migration of an electron-withdrawing group.
acyclic conjugate addition product 5a did not undergo
1,2-bond migration illustrates the critical need of
a cyclic structure of the 2H-pyrrole for the 1,2-shift of
EWGs. In contrast, when the sp3-carbon of 2H-pyr-
role possesses a substituent other than hydrogen and
smaller groups, the angle strain of MeO2C–C(sp3)–R
increases, thus resulting in the 1,2-bond migration of
an electron-withdrawing group (Figure 1b). The pre-
dominant migration of electron-withdrawing groups 27.4; IR (neat): n=3260, 1717, 1653, 1540, 1290, 1275, 1170,
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1044 cmꢀ1
;
HR-MS (ESI): m/z=244.0963, calcd. for
[9] M. Gao, C. He, H. Chen, R. Bai, B. Cheng, A. Lei,
C14H14NO3 [M+H]+: 244.0968.
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Org. Lett. 2011, 13, 340–343.
Acknowledgements
This work was supported by the National Research Founda-
tion of Korea (NRF) grants funded by the Korea govern-
ment (MSIP) (NRF-2015R1A5A1008958 and NRF-
2015R1C1A2A01053504).
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6 Regioselective Synthesis of Pyrroles from Alkyne-
Isocyanide Click Reactions: An Angle Strain-Induced Bond
Migration Approach
Adv. Synth. Catal. 2016, 358, 1 – 6
Jimil George, Hun Young Kim,* Kyungsoo Oh*
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