Visible Light Initiated Hantzsch Synthesis of 2,5-Diaryl-Substituted Pyrroles at Ambient Conditions

Article abstract of DOI:10.1021/acs.orglett.6b01059

Irradiation of a mixture of enamines and α-bromo ketones, with a catalytic amount of Ir(ppy)₃ by visible light (Λ= 450 nm), enables the production of various 2,5-diaryl-substituted pyrroles in good to excellent yields. The key intermediates in

Full text of DOI:10.1021/acs.orglett.6b01059

Letter
pubs.acs.org/OrgLett
Visible Light Initiated Hantzsch Synthesis of 2,5-Diaryl-Substituted
Pyrroles at Ambient Conditions
Tao Lei, Wen-Qiang Liu, Jian Li, Mao-Yong Huang, Bing Yang, Qing-Yuan Meng, Bin Chen,
Chen-Ho Tung, and Li-Zhu Wu*
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry &
University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100190, P. R. China
S
* Supporting Information
ABSTRACT: Irradiation of a mixture of enamines and α-bromo
ketones, with a catalytic amount of Ir(ppy)3 by visible light (λ = 450
nm), enables the production of various 2,5-diaryl-substituted pyrroles in
good to excellent yields. The key intermediates in this reaction have
been identified as alkyl radicals, generated from single-electron transfer
from the photoexcited Ir(ppy)3* to α-bromo ketones, which
subsequently react with a broad range of enamines to undergo the Hantzsch reaction rapidly at ambient conditions.
yrrole, first isolated in 1857 from the products of bone
ketones, followed by dehydration condensation (Scheme 1).
High temperature, strong organic base, or Lewis acid has always
been required.
P
pyrolysis, is found in a broad range of natural products and
biologically active compounds.1 The best known natural
pyrroles are the heme derivatives and chlorophyll, which
contain four pyrrole groups jointed by methyne bridges (Figure
1). As one of the most important simple heterocycles, pyrrole is
Scheme 1. Hantzsch Reaction
Here, a facile and efficient approach to polysubstituted
pyrroles in a one-pot reaction is reported. This unique
Hantzsch reaction is initiated by visible light. Owing to the
inherent green and mild character of light, visible light catalysis
has recently become an attractive strategy for organic
synthesis.6 By using Ru(II), Ir(III), and Pt(II) complexes and
organic dyes as photosensitizers, a variety of organic trans-
formations including reductive reaction,7 oxidative addition,8
and cross-coupling reaction9 have been accomplished. Herein,
we use Ir(ppy)3 as a photosensitizer to initiate the Hantzsch
reaction. In contrast to the conventional route reported in the
literature, the α-bromo ketones are expected to be converted to
alkyl radicals via single-electron transfer from the photo-
sensitizer Ir(ppy)3. Then the radical intermediates would react
with the double bond of enamines to construct the five-
Figure 1. Natural products and biologically active compounds
containing the pyrrole structure.
also common structural fragment of marine origin, like
lamellarin A. The architectural complexity and functional
importance2 of these compounds have rendered them popular
synthetic targets. Developing methods for the fast and
experimentally simple preparation of this typical five-membered
ring structure has been of importance in the field of organic
synthesis.3
Early in 1890, Hantzsch reported the synthesis of pyrrole4 by
an equimolecular mixture of chloroacetone and acetoacetic
ester under reflux in concentrated aqueous ammonia. However,
further development of the so-called Hantzsch pyrrole synthesis
has lagged far behind that of other classical name reactions5
until recently.3 Traditionally, the Hantzsch reactions involve an
SN2 nucleophilic substitution between enamine and α-bromo
Received: April 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01059
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Organic Letters
Letter
membered ring through dehydration condensation, as shown in
Scheme 1. The successful application of this strategy for the
Hantzsch synthesis of pyrrole derivatives is described as follows.
Initially, to explore the above transformation, we employed
(Z)-ethyl 3-phenyl-3-(phenylamino)acrylate (1a) and 2-
bromo-1-phenylethanone (2a) as substrates, with 2 mol % of
Ir(ppy)3 as the photosensitizer (Scheme 2). To our delight, the
identical conditions, however, the absorption spectra of a
mixture of Ir(ppy)3 and 1a or 2a were simply the sum of the
individual components (Figure S1), indicative of the interaction
of the substrates with Ir(ppy)3 in its excited state. The
shortened lifetime of Ir(ppy)3 from 1340 to 17 ns for 2a and
454 ns for 1a suggested further that the interaction of Ir(ppy)3*
with 1a is much weaker than that of 2a, as reflected in the
luminescence quenching constant ket of 7.07 × 107 s−1 M−1 for
1a and 1.56 × 109 s−1 M−1 for 2a, respectively. In addition,
when triethylamine (TEA) was added into the system, little
change could be detected in both luminescent intensity and
lifetime of Ir(ppy)3. Therefore, the interaction of photoexcited
Ir(ppy)3* with 2a is the strongest among them with an order of
association ability 2a ≫ 1a ≫ TEA.
Scheme 2. Visible Light Initiated Hantzsch Reaction
Combining the electrochemical and spectroscopic studies, we
examined the possibility of the photoinduced electron transfer
from Ir(ppy)3 to 2a initiating the Hantzsch reaction (Figure
S3). The redox potentials EIV/III and EIII/II of Ir(ppy)3 were
determined to be 0.72 V vs SCE and −2.3 V vs SCE,
respectively. Together with the excited state energy E00 of
Ir(ppy)3 that was read from the cross point of the absorption
and luminescence spectra at 485 nm being 2.56 eV, we
obtained the redox potential of the excited Ir(ppy)3* (EIV/III* =
EIV/III − E00 = −1.84 V vs SCE, EIII*/II = EIII/II + E00 = 0.26 V vs
SCE). According to the determined redox potentials of 1a
(Eox= 0.90 V vs SCE, Ered = −2.0 V vs SCE), 2a (Eox > 1.6 V vs
SCE, Ered = −1.2 V vs SCE), the free energy change (ΔG)
calculated by using the Rehm−Weller equation10 revealed that
the electron transfer from Ir(ppy)3* to 2a is thermodynamically
feasible but not for Ir(ppy)3* to 1a. In this situation, the
luminescence quenching experiment of Ir(ppy)3 by 1a might be
a result of energy transfer from the excited Ir(ppy)3* to 1a
(Figure 2b). Indeed, 1a prefers existing in Z form because of
the hydrogen bond effect. Upon irradiation by blue LEDs for 5
designed pyrrole 3a was obtained in a yield of 92% after
irradiation of the mixture containing 1a, 2a, and Ir(ppy)3 in
DMSO for 2 h (Table S1, entry 1). Moreover, when
triethyamine (TEA) was added into the reaction solution, the
yield of pyrrole 3a was dramatically promoted to 99% (Table
S1, entry 2). When 2 equiv of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added into the solution, the
yield of pyrrole 3a was decreased from 99% to 29%, implying
some radicals were involved in the reaction system (Scheme 2).
The selective removal of light, photosensitizer Ir(ppy)3,
enamines 1a, or α-bromo ketone 2a showed that each of
them was necessary for the successful Hantzsch reaction
between 1a and 2a (Table S1, entries 3−4).
1
min, the signal of 1a in E form was detected by H NMR
(Figure S4), indicating the photoisomerization of 1a taking
place. Taken together, we believe the photoinduced electron
transtfer from Ir(ppy)3 to 2a dominated the reaction pathway.
In view of the above experimental results, a possible
mechanistic rationale of the transformation is outlined in
Scheme 3. Upon excitation of Ir(ppy)3 at 450 nm, single-
electron-transfer oxidation of Ir(ppy)3* by 2a takes place to
To understand the primary process of the reaction, we
examined the interaction between photosensitizer Ir(ppy)3 and
the reaction substrates 1a and 2a, respectively. Figure 2 shows
+
generate Ir(ppy)3 and reduced 2a, which is subsequently
debrominated to yield alkyl radical A. The generated radical A
Scheme 3. Proposed Mechanism
Figure 2. (a) Absorption spectra of Ir(ppy)3, 1a, 2a: [Ir(ppy)3] = 0.1
mM, [1a] = 0.1 mM, [2a] = 0.1 mM. (b) Luminescence spectra of
Ir(ppy)3 in the absence and presence of 1a and 2a: [Ir(ppy)3] = 0.5
mM, [1a] = 0.5 mM, [2a] = 0.5 mM.
the absorption and luminescence spectra of Ir(ppy)3 in the
absence and presence of 1a and 2a. Ir(ppy)3 displayed a broad
visible light absorption ranging from 400 to 500 nm. Excitation
of the absorption resulted in intense luminescence at 530 nm
with a lifetime of 1340 ns in degassed DMSO solution at room
temperature, which was readily quenched by 1a and 2a (Figure
2) following the Stern−Volmer kinetics (Figure S2). Under
B
DOI: 10.1021/acs.orglett.6b01059
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Letter
reacts with enamine 1a to form the intermediate B, and then B
is further oxidized by Ir(ppy)3 to afford imine C and
4, 3m). Instead of the ethyl ester in enamines 1a−m, methyl
ester in 1n, amide in 1o, and carboxide in 1p were also suitable
for this transformation (3n−p). To our surprise, the species
with an amide group in R3 could convert into the desired
product (3o) in 93% yield.
On the other hand, good to excellent yields for both 2-
bromo-1-p-tolylethanone 2q and 2-bromo-1-(naphthalen-2-
yl)ethanone 2s were achieved (Scheme 5, 3q, 3s), even for
+
simultaneously to regenerate Ir(ppy)3. Dehydration of C
leads to the formation of target product 3a. Here, TEA helps
with the regeneration of Ir(ppy)3 photosensitezer and
debromination of 2a.
With an understanding of the mechanism in hand, we
explored the generality of this visible light initiated reaction on
the scope of enamines. When electron-donating and electron-
withdrawing groups were introduced at different positions of
the phenyl in enamines 1, the desired 2,5-diaryl-substituted
pyrrole products 3 could be obtained smoothly (Scheme 4, 3a−
a
Scheme 5. Scope of α-Bromo Ketones
a
Scheme 4. Scope of Enamines
a
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Ir(ppy)3 (2 mol
%), TEA (35 mol %), DMSO (2 mL), in Ar, under blue LED
irradiation at room temperature for 2 h.
2-bromo-1-(4-nitrophenyl)ethanone 2r, which had a strong
electron-withdrawing group and enabled production of 3r in
32% yield. When 2-bromo-2,3-dihydro-1H-inden-1-one was
used, a condensed ring could be obtained (Scheme 5, 3t).
In conclusion, we have developed the Hantzsch reaction in a
green and efficient manner for the synthesis of 2,5-diaryl-
substituted pyrroles. Compared with the traditional Hantsch
reaction, this system is initiated by visible light to yield alkyl
radicals from Ir(ppy)3 photosensitizer and α-bromo ketones,
which subsequently react with enamine to realize radical
addition over a short reaction time (2 h) at room temperature.
This photocatalytic method is a practical tool for the synthesis
of five-membered ring structure, pyrroles, in good to excellent
yields. Such an approach enriches the Hantzsch reaction and
represents a milder, greener, and more efficient process for the
organic transformation.
a
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01059.
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Ir(ppy)3 (2 mol
■
S
%), TEA (35 mol %), DMSO (2 mL), in the Ar under blue LED
irradiation at room temperature for 2 h.
j). For (E)-ethyl 3-phenyl-3-(phenylamino)acrylates, having
methyl-substituted phenyl, the steric hindrance seemed not to
affect the reaction, giving rise to 3b−d in relative yields of 90%,
85%, and 91% (Scheme 4, 3b−d). Other substrates bearing
methoxyl, fluoro, and chloro also showed good performance
(Scheme 4, 3e−g), but irradiation of bromo-substituted
enamine 1h under identical conditions resulted in a relatively
lower yield than that of fluoro- and chloro-substituted enamines
(Scheme 4, 3h). When the group on the nitrogen of 1 was α-
naphthyl or benzyl, the reactions with 1a afforded the products
3i and 3j in yields of 80% and 54%, respectively. The
substituent R2 next to nitrogen of 1 was then studied. The
electron-donating groups were found to have a higher activity
than electron-withdrawing groups (Scheme 4, 3k−m). Even the
nitro-substituted 1m was tolerable for this conversion (Scheme
Experimental procedures, methods, and product charac-
terization (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lzwu@mail.ipc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Ministry of
Science and Technology of China (2013CB834804 and
2013CB834505), the National Natural Science Foundation of
C
DOI: 10.1021/acs.orglett.6b01059
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