Synthesis of Pyrroles through Rhodium(III)-Catalyzed Reactions of Allylamines and Alkenes

Article abstract of DOI:10.1021/acs.orglett.5b01811

Pyrrole derivatives are generated in reactions of allylamines with alkenes that are promoted by a Rh(III) catalyst in the presence of AgOAc. This process, which involves chelation assisted C-H bond activation and N-annulation, is applied to a three step synthesis of Zomepirac.

Full text of DOI:10.1021/acs.orglett.5b01811

Letter
pubs.acs.org/OrgLett
Synthesis of Pyrroles through Rhodium(III)-Catalyzed Reactions of
Allylamines and Alkenes
†
†
Dong-Su Kim, Yong-Sik Seo, and Chul-Ho Jun*
Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea
*
S Supporting Information
ABSTRACT: Pyrrole derivatives are generated in reactions of
allylamines with alkenes that are promoted by a Rh(III) catalyst in
the presence of AgOAc. This process, which involves chelation assisted
C−H bond activation and N-annulation, is applied to a three step
synthesis of Zomepirac.
uch attention has been given recently to transition metal
catalyzed reactions that are applicable to the synthesis of
(entry 6) and an optimized yield is obtained when 2 equiv of 4a
M
are used (entries 1−5).
heterocyclic compounds such as isoquinolines, pyridines,
Among other oxidants, Cu(OAc) (4b, 77%) and CuSO (4c,
2
4
1
isocumarins, isoquinolones, and isoindoles. Among these
40%) display lower activity than does AgOAc, and CuCl (4d),
2
heterocycles, pyrrole derivatives are notable because of their
wide use in constructing various natural products and bioactive
K S O (4e), OXONE (4f), and benzoquinone (4g) do not have
2
2
8
any activity (entries 7−12). In addition, the results show that
Rh(I) complex 3c does not promote the reaction and that the use
of the cationic Rh(III) complex 3b does not lead to an improved
yield of the pyrrole forming reaction (entries 13−14). Finally, of
2
molecules. In this regard, several transition-metal catalyzed
3
processes, which produce pyrroles that employ enamines,
enamides, and oximes, have been developed.
4
5
6
Recently, we described a method for the facile synthesis of
pyridines from allylamines and internal alkynes that utilizes
the various solvents tested, CH CN was found to be the best one
3
for this process (entries 1, 15−19).
7
Rh(III) and Cu(II), eq 1. This process can be employed to
The allylamine and alkene scope of the pyrrole forming
process was explored. As can be seen by viewing the results
displayed in Table 2, reaction of 1a with alkenes 2a−2e under
optimized reaction conditions produces the corresponding
pyrroles 5a−5e in good to moderate yields (entries 1−5). Steric
bulkiness of the alkoxy group in acrylic esters, as in n-butyl
9
acrylate (2b) and tert-butyl acrylate (2c), does not affect the
efficiency of the process (entries 2−3). Reactions of nitrogen
containing alkenes such as acrylonitrile (2d) and N,N-dimethyl
acrylamide (2e) form the respective pyrroles 5d and 5e in 34 and
5
9% yield, which are lower than reactions of acrylic esters
(
entries 4−5). Additionally, nonelectron withdrawing group
substituted alkenes such as styrene, 1-hexene, 1-(vinyloxy)-
butane, and (allyloxy)benzene do not participate in this pyrrole
forming process. The reaction is also very sensitive for steric
hindrance of substituent on alkene. Methyl-substituted acrylates
prepare multiply-substituted pyridines from simple allylamine
derivatives. During the course of these studies, we observed that
electron-withdrawing group substituted alkenes participate in
modified Rh(III) and Ag(I) promoted reactions with allylamines
to form highly substituted pyrroles, eq 2. Below, we describe the
results of an effort that has led to the development of the new
method for facile synthesis of pyrrole derivatives and its
application to the preparation of the bioactive compound,
10
at alpha or beta position did not give any product.
To obtain insight of the reactivity of N-phenethylallylamines 1
containing different allyl substituents, reactions with 1b, 1c, 1d,
and 1e were explored (entries 6−9). Reaction of 1b with 2a was
found to take place to give pyrrole 5f in 15% yield, while that of
1c with 2a occurs in 75% yield to form 5g. However, reactions of
8
Zomepirac.
3
-methyl-substituted N-phenethylallylamine 1d and N-phene-
N-Phenethyl-N-2-phenyl-1-prop-2-enyl amine (1a) was chos-
en as a model allylamine substrate to explore the new process and
to uncover optimized reaction conditions (Table 1). Reaction of
thylallylamine (1e) with 2a do not take place. The results suggest
that the position of the substituent in the allylamine is an
important factor governing the efficiency of the process.
1a with ethyl acrylate (2a) was carried out in the presence of
[
Cp*RhCl ] (3a, 5 mol %) and AgOAc (4a, 2 equiv) at 80 °C
2
2
for 6 h. This process produces pyrrole 5a in 86% yield (entry 1).
Notably, the reaction does not take place in the absence of 4a
Received: June 24, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01811
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Rh(III) Catalyzed Pyrrole
Synthesis Method
Table 2. Secondary Allylamine and Alkene Substrate Scope of
Pyrrole Synthesis Method
a
a
yield
b
entry
1
metal
oxidant
solvent
(%)
[Cp*RhCl ] (3a)
AgOAc (4a,
CH CN
86
46
59
42
14
2
2
3
2
.0 equiv)
2.5 equiv)
1.5 equiv)
1.0 equiv)
0.5 equiv)
2
3
4
5
3a
3a
3a
3a
4a
(
CH CN
3
4a
(
CH CN
3
4a
(
CH CN
3
4a
(
CH CN
3
6
7
3a
3a
CH CN
0
3
Cu(OAc)2
4b)
CH CN
77
3
(
8
9
3a
3a
3a
3a
3a
CuSO (4c)
CH CN
40
0
4
3
CuCl (4d)
CH CN
2
3
1
1
1
1
0
1
2
3
K S O (4e)
CH CN
0
2
2
8
3
OXONE (4f) CH CN
0
3
BQ(4g)
CH CN
0
3
[Cp*Rh(MeCN) SbFe]
(
4a
CH CN
68
3
2
3
3b)
14
15
16
17
18
19
(Ph P) RhCl (3c)
4a
4a
4a
4a
4a
4a
CH CN
0
3
3
3
3a
3a
3a
3a
3a
t-BuOH
DMF
36
53
42
63
18
AcOH
ClCH CH Cl
2
2
o-xylene
a
Unless otherwise noted, reactions were carried out with 1a (0.2
mmol), 2a (0.4 mmol), 3 (5 mol %), and 4 (0.4 mmol) in 0.1 mL of
b
solvent at 80 °C. All yields are isolated yields.
Specifically, it appears that allylamines containing a 2-substituent
react with highest efficiencies. Interestingly, reaction of the 2,3-
disubstituted analogue 1f leads to formation of corresponding
pyrrole 5j in 29% yield (entry 10). Finally, the N-phenyl-
allylamine 1h participates in a lower yielding reaction with 2a
than does its N-n-butyl analogue (entries 12−13).
Based on the above result, it is possible to propose the
mechanism depicted in Scheme 1 for the reaction of 1a with 2a.
In this pathway, chelation assisted cleavages of allylic C−H bond
and N−H bond in allylamine takes place initially to form five-
membered rhodacycle 6a. Carbometalation of 6a with ethyl
acrylate (2a) gives seven-membered rhodacyclic complex 7a,
which undergoes β-H elimination to generate 8a. Intramolecular
Michael type reaction of 8a leads to formation of complex 9a,
which upon β-H elimination followed by olefin isomerization of
1
1
the resulting 10a affords pyrrole 5a along with Rh(III)-H .
2
9
a
Reduction of 2a with Rh(III)-H gives the Rh(I) species, which
2
Unless otherwise noted, reactions were carried out with 1 (0.2
is oxidized by AgOAc (4a) to regenerate the active Rh(III)
catalyst.
Next, reactions of primary allylamine with various alkenes were
examined. The results (Table 3) show that reaction of 2-
methylallylamine (1j) with ethyl acrylate (2a) in the presence of
mmol), 2 (0.4 mmol), 3a (5 mol %), and 4a (0.4 mmol) in 0.1 mL of
b
c
CH CN at 80 °C. All yields are isolated yields. 91% of the 1,4-
3
d
addition product is formed. 65% of the 1,4-addition product is
formed.
3
a and 4a at 80 °C for 6 h generates ethyl 3-(2-(2-ethoxy-2-
oxoethyl)-4-methyl-1H-pyrrol-1-yl)propanoate (5n) in 77%
yield (entry 1). Moreover, reactions of 1j with n-butyl 2b and
t-butyl acrylate (2c) give the corresponding pyrroles 5o and 5p in
66% and 63% respective yields. However, reaction of 1j with
acrylonitrile (2d) results in only low yielding (8%) formation of
the pyrrole 5q (entry 4).
B
DOI: 10.1021/acs.orglett.5b01811
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
12
Scheme 1. Proposed Mechanism of the Pyrrole Forming
Reaction
The HCl salt of α,α-dimethylallylamine 1l was utilized in the
reaction to gain further mechanistic insight. Specifically, 1l was
found to react with 2a using the standard catalytic system in the
presence of NaHCO to give 3-pyrroline 10a in 24% yield
3
(
Scheme 2). Pyrroline 10a is formed in this process by reductive
Scheme 2. Reaction of α,α-Dimethylallyl Ammonium
Chloride
13
elimination of intermediate Rh complex 9b. Note that the
presence of gem-dimethyl substitution in 9b prevents olefin
isomerization. This result confirms that the reaction in Scheme 1
takes place through intermediate 9a.
Table 3. Primary Allylamine Scope of the Pyrrole Forming
Reaction
a
The reaction of 1-phenylallylamine 1m, which has both
14
benzylamine and allylamine groups (Scheme 3), was explored.
Scheme 3. Comparison of Reactivity of Allylic and Benzylic
a
C−H Bonds
a
Reaction is carried out with 1m (0.2 mmol), 2a (0.4 mmol), 3a (5
mol %), and 4a (0.4 mmol) in 0.1 mL of CH CN at 80 °C.
3
We observed that reaction of 1m with 2a in the presence of 3a
and 4a leads to exclusive formation of ethyl 2-(1-phenethyl-5-
phenyl-1H-pyrrol-2-yl)acetate (5r) in 54% yield without any
a
2
Unless otherwise noted, reactions were carried out with 1j (0.2
formation of isoindole 11a. This result shows that the sp -vinyl
2
mmol), 2 (0.4 mmol), 3a (5 mol %), and 4a (0.4 mmol) in 0.1 mL of
CH CN at 80 °C. All yields are isolated yields.
C−H bond is more reactive than sp -aromatic C−H bond in this
b
3
process.
The applicability of Rh(III) catalyzed pyrrole forming method
was demonstrated by its use in the total synthesis of the
Zomepirac (5u), which has been shown to have antipyretic
activity (Scheme 4). In the first step of the three-step route,
reaction of N-2-dimethylprop-2-en-1-aminium chloride (1n)
In reactions of the primary allylamine 1j, N-alkylated pyrroles
are produced exclusively. To gain information about the origin of
these products, two separate reactions were performed, eq 3.
with 2a in the presence of 3a, 4a, and NaHCO at 80 °C for 12 h
3
produces pyrrole 5s in 51% yield. Reaction of 5s with 4-
chlorobenzoyl chloride in the presence of DBN (15 mol %) in
toluene at 115 °C for 4 h then generates ethyl 2-(5-(4-
chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl)acetate (5t) in 30%
isolated yield. Finally, hydrolysis of 5t gives Zomepirac (5u) in
66% yield.
In the effort described above, we developed a new procedure
for the synthesis of multiply-substituted pyrroles from allyl-
amines and alkenes. The process, promoted by a combination of
15
Reaction of 2-methylallylamine (1j) with ethyl acrylate (2a) in
the absence of 3a and 4a at 80 °C for 6 h was found to produce
ethyl 3-((2-methylallyl)amino)propanoate (1k) in 49% yield.
Furthermore, reaction of secondary allylamine 1k with 2a in the
presence of 3a and 4a produces pyrrole 5n in 63% yield.
C
DOI: 10.1021/acs.orglett.5b01811
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Morris, J. C.; Phillips, A. J. Nat. Prod. Rep. 2008, 25, 95. (e) Fan, H.;
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(
5
(
̈
(
̈
2
(
2
(
(
́
́
dez, J. C. Chem. Soc. Rev.
2
4
(
1
Rh(III) and Ag(I), takes place through Rh(III) promoted vinyl
C−H bond activation of the allylamine substrate followed by
carbometalation of the alkene. Reactive substrates are limited to
secondary amine with allyl groups and alkenes possessing
electron-withdrawing groups. Finally, the utility of this method
was demonstrated by its application to the three-step total
synthesis of bioactive Zomepirac.
K.; Park, J.-W.; Jun, C.-H. Chem. - Eur. J. 2014, 20, 323. (c) Kim, D.-S.;
Park, J.-W.; Jun, C.-H. Adv. Synth. Catal. 2013, 355, 2667. (d) Sim, Y.-K.;
Lee, H.; Park, J.-W.; Kim, D.-S.; Jun, C.-H. Chem. Commun. 2012, 48,
1
(
1787.
8) Morley, P. A.; Borgden, R. N.; Carmine, A. A.; Heel, R. C.; Speight,
T. M.; Avery, G. S. Drugs 1982, 23, 250.
9) Due to volatility of ethyl propionate, the reaction was carried out
(
with butyl acrylate (Table 2, entry 2), and 45% G.C. yield of butyl
propionate was obtained.
(10) The reaction of 1a with methyl but-2-enoate (2f) or methyl
ASSOCIATED CONTENT
Supporting Information
■
*
S
methacrylate (2g) in the standard reaction condition did not take place.
1
13
Compound characterization data, H and C NMR spectra. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01811.
AUTHOR INFORMATION
Corresponding Author
■
*
(
11) Gabriele, B.; Salerno, G.; Fazio, A.; Veltri, L. Adv. Synth. Catal.
2
006, 348, 2212.
E-mail: junch@yonsei.ac.kr.
Author Contributions
(12) The primary amine is readily generated in situ from the HCl salt 1l
by addition of NaHCO3.
(
complex 9a in Scheme 1 through β-hydride elimination, while gem-
dimethyl substitution in complex 9b prevents formation of pyrrole by
olefin isomerization. As a result, direct reductive elimination in complex
13) Stable aromatic pyrrole can be generated from intermediate
†
These authors are equally contributed to this work.
Notes
The authors declare no competing financial interest.
9
(
b occurs.
14) Recently, it was reported that the reaction of α,α-dimethyl
ACKNOWLEDGMENTS
This study was supported by a grant from the National Research
Foundation of Korea (NRF) (2011-0016830).
■
benzylamine with butyl acrylate in the presence of Rh(III)/Cu(II)
system results in formation of butyl 2-(3,3-dimethylisoindolin-1-yl)
acetate. In this system, only aryl C−H bonds can be activated by Rh(III).
For an example of this work, see: Suzuki, C.; Morimoto, K.; Hirano, K.;
Satoh, T.; Miura, M. Adv. Synth. Catal. 2014, 356, 1521.
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DOI: 10.1021/acs.orglett.5b01811
Org. Lett. XXXX, XXX, XXX−XXX