Synthesis of tetrasubstituted pyrroles from terminal alkynes and imines

Article abstract of DOI:10.1021/ol401369d

Tetrasubstituted pyrroles can be obtained via the reaction of terminal alkynes and imines using ⁿBuLi as the base in one step with high chemoselectivity (method 1). Alternatively, the intermediate propargylamines can also react with imines to afford tetrasubstituted pyrroles when using LiHMDS as the base (method 2), which provides a complementary method to construct the pyrroles with different substituents.

Full text of DOI:10.1021/ol401369d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Tetrasubstituted Pyrroles
from Terminal Alkynes and Imines
Yancheng Hu, Chunxiang Wang, Dongping Wang, Fan Wu, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, China
bswan@dicp.ac.cn
Received May 15, 2013
ABSTRACT
n
Tetrasubstituted pyrroles can be obtained via the reaction of terminal alkynes and imines using BuLi as the base in one step with high
chemoselectivity (method 1). Alternatively, the intermediate propargylamines can also react with imines to afford tetrasubstituted pyrroles when
using LiHMDS as the base (method 2), which provides a complementary method to construct the pyrroles with different substituents.
Pyrroles are not only key structural units in numerous
biologically active compounds but also important building
blocks in material chemistry.1 Consequently, their syn-
thetic methods have gained much attention and a lot of
amazing progress has been achieved in the past decades.2
Generally, the construction of the pyrrole ring involves a
multistep process from preformed intermediates, such as
theclassical Knorr, PaalꢀKnorr, and Hantzschreactions.3
Recently, some more efficient and benign approaches,
including using new building blocks4 as well as transition
metal catalyzed5 and multicomponent reactions,1b,6 have
been developed to access multifunctionalized pyrroles.
Recently, we have reported the cyclization of 3-aza-1,5-
enynes into pyrroles via sulfonyl migration.4a As a con-
tinuation of our interest in the synthesis of other 3-aza-1,5-
enynes, we found that the addition of phenyl acetylene 1a
to N-phenyl imine 2a failed to provide the desired propar-
gylamine (Scheme 1, eq 1). In contrast, tetrasubstituted
pyrrole 3a was obtained unexpectedly as the main product
(Scheme 1, eq 2). Considering that terminal alkynes are
commercially available and imines can be easily prepared
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r
10.1021/ol401369d
XXXX American Chemical Society

from aldehydes and amines, herein, we reported the first one-
step synthesis of tetrasubstituted pyrroles from readily avail-
able terminal alkynes and imines with high chemoselectivity.
Scheme 3. Control Experiments To Probe the Possible Pathway
Scheme 1. New Approach for the Synthesis of Pyrroles
Scheme 4. Proposed Mechanism
Scheme 2. Synthesis of Tetrasubstituted Pyrrolesa
conditions.7 We were delighted to find that tetraphenyl
pyrrole 3a was obtained in an acceptable yield when the
reaction was conducted in a 1:2 molar ratio (1a/2a) in the
presence of nBuLi. With this result in hand, the reaction of
terminal alkynes 1 with imines 2 was then examined, as
shown in Scheme 2. Treatment of phenylacetylene with
various aromatic imines 2 afforded the corresponding
pyrroles 3 in moderate to excellent isolated yields. Imines
2 with both electron-withdrawing and -donating substitu-
ents in R2 were well tolerated for this process (3bꢀ3e,
62ꢀ80%). In addition, an aryl group (R2) bearing steri-
cally demanding substituent iPr was suitable for the reac-
tion and furnished the product as 3c in 91% yield.
However, when an alkyl substituent was used in R2, no
desired product was observed. To our delight, furanyl and
thiophenyl-derived imines underwent this reaction as well
and gave the pyrroles 3f and 3g in 48% and 59% yield,
respectively. Remarkably, 2-naphthaldimine was also tol-
erated, and the desired product 3h was afforded in 82%
yield. It is noteworthy that this reaction proceeded smoothly
only when group R3 was an aryl substituent (3iꢀ3k).
a 0.625 mmol of 1, 1.25 mmol of 2, 0.625 mmol of nBuLi, 4 mL of
THF, ꢀ78 °C for 1 h, rt for 10 h.
Initially, phenylacetylene 1aand N-phenyl imine 2a were
selected as the model substrates to optimize the reaction
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(7) For the screening of the reaction conditions, please see Support-
ing Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Substrate Scope for the Synthesis of Pyrrolesa
a 0.25 mmol of 2, 0.5 mmol of 4, 0.5 mmol of LiHMDS, 0.6 mmol of PMDTA, 4 mL of THF, ꢀ78 °C for 1 h, rt for 10 h. b Isolated yield.
For terminal alkynes, group R1 had a slight impact on the
reaction; both aryl and alkyl groups provided satisfactory
yields for the corresponding pyrroles (3lꢀ3p, 73ꢀ93%).
In view of the fact that two of the substituents in the
pyrrole product were from the imine moieties, we sus-
pected that the propargylamine intermediate was possibly
first generated in the reaction. To confirm this hypothesis,
we synthesized propargylamine 4a according to the re-
ported method.8 Fortunately, the same desired product 3a
was indeed observed as we anticipated under the same
reaction conditions, albeit with a lower yield (Scheme 3,
eq 1). Besides, when propargylamine 4e was employed to
react with imine 2a, the pyrrole 3a was found to be the only
product(Scheme3, eq2). Nopyrrole3mwasdetected. This
result indicated that the nitrogen atom of the pyrrole
originated exclusively from imine 2a instead of propargy-
lamine 4e.
On the basis of these observations, a plausible mechan-
ism was suggested as depicted in Scheme 4. Terminal
alkyne 1 and imine 2 were first transformed into the
intermediate 5 through an addition reaction, which subse-
quently underwent a 1,2-anion shift to afford propargyl-
lithium reagent 6. We considered that the intermediate
propargyllithium 6 was converted to the allenyllithium 7
by equilibrium.9 Then allenyllithium 7 reacted with an-
other molecule of imine 2 to form a new intermediate 8,
(8) (a) Li, C. J.; Wei, C. M. Chem. Commun. 2002, 268. For recent
reviews on the synthesis of propargylamines, see: (b) Li, C. J. Acc. Chem.
Res. 2010, 43, 581. (c) Peshkov, V. A.; Pereshivko, O. P.; Van der
Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790.
(9) For the equilibria between allenylꢀpropargyllithium reagents,
see: Reich, H. J. J. Org. Chem. 2012, 77, 5471.
Org. Lett., Vol. XX, No. XX, XXXX
C

followed by the intramolecular ring closure which resulted
in the formation of the cyclized intermediate 9. Protona-
tionwith5 gaveintermediate10. Finally, the elimination of
aniline from 10 produced the desired product 3.
effects and the position of the substituents (Table 1, entries
2ꢀ7). Notably, 2-naphthaldimine 2w was also suitable for
this process and the corresponding product 3w was ob-
tained in 86% yield (entry 8). In addition, the scope of
propargylamines 4 was also investigated. The results sug-
gested that both aryl and heterocyclic R4 substitutions
were well tolerated in the reaction (Table 1, entries 9ꢀ11).
In accordance with the previous observations, the reac-
tion only proceeded smoothly to afford the same desired
pyrrole product in good yield when group R5 was an aryl
substituent.
In summary, we have developed an efficient and general
protocol for the synthesis of tetrasubstituted pyrroles in
just one step from terminal alkynes and imines. Moreover,
the direct deprotonation of the preformed propargyla-
mines with imines can be used as a complementary access
to afford pyrroles. These two approaches may find appli-
cations in the synthesis of various, more complex struc-
tures. Further studies to elucidate the reaction mechanism
in detail are underway.
From the proposed mechanism, it is easy to find that the
pyrroles generated from propargylamines 4 and imines 2
had different groups on the C1 and C4 positions adjacent
to the nitrogen atom. Therefore, the reaction of propargy-
lamine 4 and imine 2 may provide a complementary
method to obtain tetrasubstituted pyrroles with different
substituents.10 However, the control experiment (Scheme 3,
eq 1) revealed that the current reaction conditions were not
optimal for the reaction of 4 and 2. As a consequence,
propargylamine 4a and imine 2a were selected as the model
substrates to optimize the reaction conditions.7 To our
delight, when sterically hindered organolithium reagent
bis(trimethylsilyl)amide (LiHMDS) was chosen as the
base and N,N,N0,N00,N00-pentamethyldiethylenetriamine
(PMDTA) as the additive, the desired pyrrole 3a could
be afforded in an acceptable yield (Table 1, entry 1).
We further explored the substrate scope of the reaction
under the optimized conditions, and the results are shown
in Table 1. The scope of groups R2 and R4 were mainly
explored owing to its advantages over the previous ap-
proach. For imines 2, this reaction tolerated various sub-
stituents on the aromatic ring, regardless of the electronic
Acknowledgment. We are grateful for the National
Natural Science Foundation of China (21172218).
Supporting Information Available. General experimen-
1
tal procedures, H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) The reaction of propargyl silyl ethers with imines has been reported
to synthesize multisubstituted pyrroles; for details, please see ref 6o.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX