Base-Mediated Direct Transformation of N-Propargylamines into 2,3,5-Trisubstituted 1 H-Pyrroles

Article abstract of DOI:10.1021/acs.orglett.8b03112

An efficient and base-mediated intramolecular cyclization of N-propargylamines for the synthesis of structurally diversified pyrroles in high yield has been described. The developed methodology is broadly applicable and is tolerated by a variety of functional groups. Key intermediates of natural product discoipyrrole C as well as HMG-CoA-reductase inhibitor have been successfully synthesized using developed chemistry. The proposed mechanism was supported by control experiments.

Full text of DOI:10.1021/acs.orglett.8b03112

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Base-Mediated Direct Transformation of N‑Propargylamines into
2,3,5-Trisubstituted 1H‑Pyrroles
Pawan K. Mishra, Shalini Verma, Manoj Kumar, and Akhilesh K. Verma*
Department of Chemistry, University of Delhi, Delhi 110007, India
S
* Supporting Information
ABSTRACT: An efficient and base-mediated intramolecular cyclization of N-propargylamines for the synthesis of structurally
diversified pyrroles in high yield has been described. The developed methodology is broadly applicable and is tolerated by a
variety of functional groups. Key intermediates of natural product discoipyrrole C as well as HMG-CoA-reductase inhibitor have
been successfully synthesized using developed chemistry. The proposed mechanism was supported by control experiments.
Trost and co-workers.13 Later, Wan and co-workers14 reported
yrroles are ubiquitous heterocyclic motifs present in various
the synthesis of tetrasubstituted pyrroles by the reaction of N-
Pnatural products and a wide range of pharmaceutically
active molecules (Figure 1).1,2 In addition, pyrrole core having
propargylamines with imines (Scheme 1a). In 2015, Castago-
templates also exhibit anti-tumor, anti-HIV, and anti-hyper-
glycemic activities.3 Furthermore, they are broadly used in
Scheme 1. Novel Approaches to Synthesis of Pyrroles
materials chemistry.4
Figure 1. Representative biologically active pyrrole scaffolds.
Several traditional syntheses of the pyrroles in the literature
was reported as Paal−Knorr5a,b and Hantzsch6 reactions. In the
nolo’s group15 reported the synthesis of 1,2,3-trisubstituted
past decades, several methods have been documented for the
synthesis of pyrroles such as metal-catalyzed reactions,7
pyrroles from propargylamines via enyne cross-metathesis using
multicomponent reactions,8 and base-catalyzed reactions.9
the Grubbs II catalyst (Scheme 1b). More recently, Shen’s
group16 has explored the synthetic utility of N-propargylamines
However, the use of expensive metal catalysts, prolonged
for the synthesis of substituted furans through the base-catalyzed
reaction time, and limited substrate scope restricted their
[3 + 2] cycloaddition to aldehydes. The direct transformations
application for industrial purposes. Thus, the development of
of N-propargylamines into pyrroles without a coupling partner
have not been much explored. Keeping these challenges in mind
sustainable and transition-metal-free approaches for the syn-
thesis of multisubstituted pyrroles is of vital importance.
and continuation of our ongoing research on base-mediated
N-Propargylamines are key precursors for the construction of
reactions17 and N-heterocyclic synthesis,18 herein, we have
demonstrated a base-mediated direct transformation of N-
propargylamine into 2,3,5-trisubstituted 1H-pyrroles under
transition-metal-free conditions (Scheme 1c).
various heterocyclic compounds and natural products.10 Among
them, synthesis of pyrroles from N-proparagylamine11 has
gained significant attention in recent years. Bremner and co-
worker12 have reported the synthesis of pyrroles from N-
propargylamines with aldehydes. In 2011, synthesis of pyrroles
by a Pd(II)-catalyzed cascade reaction of N-propargylamines
and alkynes through 5-endo-dig cyclization was demonstrated by
Received: September 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
We have initiated our investigation with N-benzyl-1,3-
diphenylprop-2-yn-1-amine 1a as our model substrate. The
reaction of 1a with potassium hydroxide (1.2 equiv) in DMSO at
25 °C only led to none or a trace amount of pyrrole 3a (Table 1,
Scheme 2. Scope of Aryl/Heteroaryl/Alkyl Aldehydes
a b
,
Table 1. Optimization of Reaction Conditions
b
entry
base
solvent
t (h)
temp (°C)
yield of 3a (%)
1
2
3
4
5
6
7
8
KOH
KOH
KOH
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
12
12
12
1
1
1
1
1
1
1
1
1
1
1
1
2
8
25
60
80
trace
50
65
75
25
74
25
30
20
n.r.
53
45
30
20
55
35
n.r.
n.r.
n.r.
n.r.
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
c
KOH
KOH
d
KOH
KOH
KOH
KOH
CsOH
NaOH
LiOH
KtOBu
K3PO4
DBU
DABCO
K2CO3
Cs2CO3
NMP
DMA
9
10
11
12
13
14
15
16
17
18
19
20
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
a
Reactions were performed using 0.5 mmol of 1a−q and KOH (1.2
b
c
equiv) in 2.0 mL of DMSO. Isolated yield. Using 1.0 mmol of 1a.
The substrates 1i and 1j having trifluoromethyl (−CF3) and
fluoro (−F) groups at the para position afforded the
corresponding pyrroles 3i and 3j in 65−70% yields.
Halogenated substrate 1k was well tolerated to afford the
cyclized product 3k in 75% yield. Substrates 1l−n bearing a
heterocyclic substituent as an R1 group such as 2-indolyl (1l), 2-
thienyl (1m), and 2-furyl (1n) provided the desired products
3l−n in 72−78% yields. Notably, when unactivated N-
proparagylamines 1o−q were employed as the substrate,
pyrroles 3o−q were obtained in good yields.
In order to gain insight into the above results (Scheme 2), we
explored differently substituted R1, R2, and R3 in the N-
propargylamine moiety (Scheme 3). The propargylamine 1r
with the electron-withdrawing group (R1) and an electron-
releasing group (R2) provided the pyrrole 4a in 68% yield. The
12
12
2
a
Reactions were performed using 0.5 mmol of 1a and base (1.2
b
c
equiv) in 2.0 mL of solvent. Isolated yield. KOH (20 mol %).
d
Under N2 atmosphere. n.r. = no reaction. DMSO = dimethyl
sulfoxide, DMF = dimethylformamide, DMA = dimethylacetamide.
entry 1). The increase in temperature of the reaction improved
the yield of the product 3a (entries 2 and 3). The product 3a was
obtained in 75% yield at 120 °C (entry 4). The results of entries
2−4 clearly suggest that temperature has a significant role in the
reaction. The catalytic amount of base was found to be
inefficient for the formation of pyrrole 3a (entry 5). No
significant change in the yield of the product 3a was observed on
performing the reaction of 1a under an inert atmosphere (entry
6). On switching to polar solvents such as DMF, NMP or DMA
could not improve the yield of the desired product 3a (entries
7−9). The desired product was not formed when the reaction
was performed in toluene as solvent (entry 10). Other bases
such as CsOH, NaOH, LiOH, KtOBu, K3PO4, and DBU were
found inferior for the reaction (entries 11−16), whereas
DABCO, K2CO3, and Cs2CO3 failed to provide the desired
product (entries 17−19). In the absence of a base, no product
was formed (entry 20).
Scheme 3. Scope of Aryl/Heteroaryl/Alkyl-Substituted
Pyrroles
Under the optimized conditions, we explored the scope of the
base-mediated transformation of various substituted N-prop-
argylamines to pyrroles (Scheme 2). The reaction was first
explored by the variation of R1 on the N-propargylamine 1. The
substrate 1a−d having electronically neutral aryl groups (such as
Ph, biphenyl, naphthyl, and 4-ethylphenyl) as an R1 gave the
cyclized products 3a−d in 75−81% yields. Substrates 1e−h with
electron-rich substituents as R1 group provided 2,3,5-trisub-
stituted pyrroles 3e−h in good to excellent yields (79−85%).
a
Reactions were performed using 0.5 mmol of 1r−z and KOH (1.2
b
equiv) in 2.0 mL of DMSO. Isolated yield.
B
DOI: 10.1021/acs.orglett.8b03112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electron-rich propargylamine substrates 1s (R1 and R2 = p-
OMe−C6H4) and 1t (R1 = p-Bu−C6H4 and R2 = p-OMe−
C6H4) are viable substrates and gave the desired products 4b
and 4c in 78 and 88% yields, respectively. Substrate 1u also
underwent the desired reaction to gave the desired product 4d in
good yield. Interestingly, 3-phenyl-2,5-di(thiophen-2-yl)-1H-
pyrrole 4e and 3-phenyl-2,5-di(furan-2-yl)-1H-pyrrole 4f were
obtained in 85 and 83% yields, respectively, when R1 and R2
were heterocyclic groups such as thiophene (1v) and furan
(1w). The synthesis of 2,3,5-trisubstituted (−NH) pyrroles
having an identical substituent such as R1 = R2 = R3 = p-Me−
C6H4 (4g) and R1 = R2 = R3 = p-OMe−C6H4 (4h) were attained
successfully under the standard reaction conditions. The bulky
tert-butyl substituent at the para position of alkyne (R3) was
successful in providing the desired product 4i in 84% yield.
The scope of this reaction was further extended toward the
synthesis of 2,4,5-trisubstituted pyridines, utilizing substrate 1
having R3 as arylethylamine (Scheme 4). The reaction of N-(3,4-
The developed strategy provides a simple synthetic route with
short reaction time and good yield compared with other
reported protocols for the synthesis of these key intermediates
(Scheme 5b).19,20
Finally, a one-pot, sequential A3 coupling of aldehyde, amine,
and alkyne using CuBr/toluene as a catalyst has been utilized to
generate the N-propargylamine22 1a, which further underwent
cyclization in the presence of KOH−DMSO at 120 °C to
provide 2,3,5-trisubstituted (NH) pyrroles 3a in moderate yield
(Scheme 6). The one-pot methodology of the synthesized
heterocycles is likely to be of high synthetic utility.
Scheme 6. Sequential One-Pot Synthesis of 3a
a b
,
Scheme 4. Synthesis of 2,4,5-Trisubstituted Pyridines
To gain insight into the mechanism, we have performed two
sets of control experiments: (i) to find the role of solvent and (ii)
to find the role of the benzylamine group. When we performed
the reaction of 1a in KOH−DMSO-d6, 80% deuterium
incorporation in the desired product 8a was observed. This
result suggests that the incoming proton originates from solvent
(Scheme 7a, i). Further, to ascertain the role of a benzyl group,
a
Reactions were performed using 0.5 mmol of 1aa−bb and KOH (2.0
b
equiv) in 2.0 mL of DMSO. Isolated yield.
Scheme 7
dimethoxyphenethyl)-1,3-diphenyl prop-2-yn-1-amine 2a in the
presence of the strongly basic KOH−DMSO system provided
the desired product 5a in 50% yield. The substrates 2b with the
electron-releasing group effectively provided the cyclized
product 5b in moderate yield (Scheme 4, see the Supporting
Information).
To demonstrate the synthetic utility of the reaction’s
products, 2,3,5-triaryl-1H-pyrrole 3a was easily converted to
the bromo-substituted pyrroles 6a in 65% yield which on Suzuki
coupling reaction provided tetraphenyl-1H-pyrrole 6b in 90%
yield (Scheme 5a).
To illustrate the application of our developed chemistry, the
key intermediate 7a of natural product discoipyrrole C and 7b of
HMG-CoA-reductase inhibitor were obtained in good yields.
Scheme 5. Synthetic Application
the reaction of 1ac with a propyl group was carried out under
standard reaction conditions which did not furnish the desired
product (Scheme 7a, ii). This observation suggests that the
presence of a benzylic substituent R2 is necessary for the
reaction.
On the basis of the previous reports13,17,21 and with the
support of control experiments (Scheme 7b), we have proposed
a plausible mechanism for the formation of 2,3,5-trisubstituted
pyrroles. The mechanism is initiated by the base-assisted
deprotonation of N-propargylamine 1, forming a species P
which undergoes allene formation to Q. From Q, two possible
C
DOI: 10.1021/acs.orglett.8b03112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03112.
■
S
Data and spectral copies of 1H and 13C NMR and HRMS
for target compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: averma@acbr.du.ac.in.
ORCID
Akhilesh K. Verma: 0000-0001-7626-5003
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research work was supported by DST (SERB), CSIR
02(0264)/16/EMR-II, and University of Delhi. S.V., M.K., and
P.K.M. are thankful to CSIR and UGC for fellowships,
respectively.
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DOI: 10.1021/acs.orglett.8b03112
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