Selective synthesis of pyrrolo[1,2-a] azepines or 4,6-dicarbonyl indoles via tandem reactions of alkynones with pyrrole derivatives

Article abstract of DOI:10.1039/c7ob01516j

Novel methodologies for the selective synthesis of pyrrolo[1,2-a]azepines or 4,6-dicarbonyl indoles starting from pyrrole derivatives and alkynones are described. When reactions were carried out with 1,2,4-trisubstituted N-propargyl pyrroles using a ZnI₂ catalyst, pyrrolo[1,2-a]azepines were obtained. Whereas 4,6-dicarbonyl indoles were produced selectively with 1,2-disubstituted pyrroles in the presence of silica gel. The reaction outcomes depend on the substituent pattern of the substrates and the nature of the catalysts chosen. Control reactions suggested that the formation of a conjugated enamine intermediate was crucial for both the processes. With easily accessible starting materials, inexpensive catalysts and an easy-to-handle procedure, this reaction has the potential to become a general protocol for the synthesis of pyrrolo[1,2-a]azepines or indoles.

Full text of DOI:10.1039/c7ob01516j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Selective synthesis of pyrrolo[1,2‐a]azepines or 4,6‐dicarbonyl
indoles via tandem reactions of alkynones with pyrrole
derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Yulei Zhao, Yang Yuan, Murong Xu, Zhong Zheng, Runhua Zhang and Yanzhong Li*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Novel methodologies for the selective synthesis of pyrrolo[1,2‐ methods with few steps are scarce. In 2009, Renaud and co‐
a]azepines or 4,6‐dicarbonyl indoles starting from pyrrole workers developed an excellent intramolecular Schmidt
derivatives and alkynones are described. When reactions were reaction starting from primary azidoalcohols to construct the
4
carried out with 1,2,4‐trisubstituted N‐propargyl pyrroles using a pyrrolo[1,2‐a]azepine structure (Scheme 1, a). In 2016, Opatz
ZnI catalyst, pyrrolo[1,2‐a]azepines were obtained. Whereas 4,6‐ synthesized pyrrolo[1,2‐a]azepines from easily accessible 3,4‐
2
dicarbonyl indoles were produced selectively with 1,2‐ dihydro‐2H‐pyrrole‐2‐carbonitriles in a one‐pot procedure
5
disubstituted pyrroles in the presence of silica gel. The reaction (Scheme 1, b). On the other hand, common synthetic
6
outcomes depend on the substituent pattern of the substrates methods to indoles mainly include classical approaches,
7
8
and the nature of the catalysts chosen. Control reactions transition metal‐catalyzed C‐H activations, et al. These
suggested that the formation of conjugated enamine intermediate approaches usually involve the pyrrole ring construction from
was crucial for both two processes. With easily accessible starting functionalized benzene precursors. Nevertheless, methods
materials, inexpensive catalysts and easy‐to‐handle procedure, featuring the construction of a benzene ring from pyrrole
this reaction has the potential to become a general protocol for derivatives were insufficient and mainly focused on precious
9
10
the synthesis of pyrrolo[1,2‐a]azepines or indoles.
metal catalysis, multimetal catalysis
or multi‐step
1
1
approaches. In 2014, Katukojvala and co‐workers reported an
excellent synthesis of indoles via rhodium(II) catalyzed [4+2]
Pyrrolo[1,2‐a]azepine structure is a core skeleton in many
1
natural
Didehydrotuberostemonine,
or
bioactive
products,
such
as
1
b
1c
2
009, by Renaud's group
Didehydroprotostemonine
and NS5B inhibitors. Substituted indoles are also key
structural subunits and widely present in many biologically
active structures. For example, Gonadotropin Releasing
Hormone (GnRH), a decapeptide which is produced in the
hypothalamus, and Vallesiachotamine, exhibiting cytotoxicity
against HL‐60 and SK‐BR‐3 cells. However, the synthetic
methods to pyrrolo[1,2‐a]azepine derivatives mainly
1d
Ph
1
) NaH (2.0 eq.), Tf2O (1.0 eq.)
78 oC - RT, DCM
H
-
HO
Ph
2) DIBALH (2.4 eq.), 0 o
N
N3
(trans/cis: 83/17)
C
2
77%, dr 95/5
2
a
2016, by Opatz's group
R
R
2b
) LDA (1.2 eq.), -78 oC - RT
1
+
Cl
Br
Ph
N
CN
2) LDA (1.2 eq.), -78 oC - RT
N
Ph
(1.2 eq.)
R = Ph, 55%
R = 4-NCPh, 53%
3
concentrate on multi‐step approaches and highly effective
2014, by Katukojvala's group
R3
N
R5
R2
R1
Rh2(OAc)4 (1 mol%)
CH2Cl2, RT or reflux
R4
R4
+
O
N
R3
R2
N2
R5
R1
O
2
015, by Lei and Itami's group
Pd(OAc)2 (10 mol%)
Cu(OAc)2 (20 mol%)
AgOCOCF3 (4.0 eq.)
R2
O
+
R2
N
R1
toluene (1.0 mL)
DMSO (50 uL)
Figure 1 Representative natural and bioactive products
R2
N
R1
1
00 oC, 14 h, air
O
R3
R1'
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of
Chemistry and Molecular Engineering, East China Normal University, 500
Dongchuan Road, Shanghai 200241, China. E‐mail: yzli@chem.ecnu.edu.cn
R4
O
R1
O
R2
N
R2
N
R2
R5
O
O
N
R4
0.25 mol%)
PhMe, 110 oC, air
R1
R1
(
R2
N
†Electronic supplementary information (ESI) available: Experimental details,
R3
PhMe, 60 oC, air
R5
spectroscopic characterization of all new compounds. CCDC 1527955‐1527957.
For ESI and crystallographic data in CIF or other electronic format See Scheme 1 Synthesis of pyrrolo[1,2‐a]azepines and indoles
DOI: 10.1039/x0xx00000x
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Journal Name
9
a
benzannulation of pyrroles (Scheme 1, c). In 2013, Lei and ineffective for the formation of 4a (entries 7‐10). When the
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DOI: 10.1039/C7OB01516J
Itami’s group developed a Pd‐Cu‐Ag trimetallic system that amount of ZnCl was reduced to 0.25 equiv, a longer reaction
2
allowed the conversion of indoles into carbazoles using time was required (entry 11 vs 4). Changing substrate
10
electron‐deficient alkenes as two‐carbon units (Scheme 1, d).
concentration from 0.1 M to 0.05 M or 0.17 M did not achieve
The development of effective low‐cost novel methods to better results (entries 12, 13). Nitrogen atmosphere had no
synthesize pyrrolo[1,2‐a]azepine or indole derivatives is highly significant effect for the reaction outcome (entry 14).
desirable.
Interestingly, strong anion effects were observed (entries 15‐
We have disclosed protocols for the selective synthesis of 17). Zn(OTf) was nearly ineffective for the formation of 4a
2
12
hetero‐ or carbocyclic structures using enamines. Pyrroles (entry 17). Whereas the best result was achieved using 0.25
are special cyclic enamines. As part of our ongoing efforts to equiv of ZnI (entry 16, 90%, 5 h). A lower yield (68%) was
2
enamine chemistry, we envision that it might be possible to obtained with 0.1 equiv of ZnI (entry 18). Without catalyst, no
2
prepare pyrrole ring‐fused cyclic products via intermolecular reaction occurred (entry 19).
tandem reaction starting from pyrrole derivatives. Herein, we
report the cascade reactions of pyrrole derivatives with
alkynones for the selective synthesis of pyrrolo[1,2‐a]azepines
or 4,6‐dicarbonyl indoles catalyzed by ZnI or in the presence
2
of silica gel (Scheme 1, e).
a
Table 1 Optimization of the reaction conditions
With the optimized reaction conditions established, the
scope of this reaction was investigated (Figure 2). Substituent
groups were varied to investigate their steric and electronic
1
influences. For substituents R , electron‐poor aryl groups gave
better yields than electron‐rich ones (4b‐e: 87‐95% vs 4f‐h: 71‐
8
3%). The structure of 4b was confirmed by X‐ray
1
4
t
crystallographic analysis. 2‐Furyl, sterically hindered p‐ BuPh,
‐naphthyl and 2‐naphthyl groups (4i‐l) were tolerable in the
1
N‐propargyl pyrrole derivatives were useful precursors for
reaction, offering the desired pyrrolo[1,2‐a]azepines in good to
excellent yields (81‐94%). However, when R = 2‐pyridyl group,
1
3
intramolecular cyclizations. We started the investigation with
,2,4‐trisubstituted 1‐(but‐2‐yn‐1‐yl)‐2,4‐diphenyl‐1H‐pyrrole
1a) and 1.0 equiv of 1‐phenylprop‐2‐yn‐1‐one (2a) in the
presence of 50 mol % of ZnCl in various solvent at 110 °C
1
1
(
no reaction occurred. Alkyl group such as n‐hexyl was
compatible in the reaction and 4m was generated in 83% yield.
2
2
For R , alkyl substituent such as n‐Bu was suitable to generated
(
Table 1, entries 1‐6). Toluene (PhMe) was found to be optimal
solvent to obtain the desired pyrrolo[1,2‐a]azepine (4a) (entry
, 81%). When 1,4‐dioxane was used as the solvent, only a
2
3
4o in 76% yield. When R = R = Me, the desired product 4n
could also be obtained in a moderate yield. In addition,
4
electron‐poor aryl groups required longer reaction time than
conjugate addition product 3a was produced (entry 1, 90%).
Other Lewis acids such as FeCl , AlCl , CoCl , and BF ∙Et O were
2
2
electron‐rich ones (4p, R = p‐OMePh, 3 h, 85%; 4q, R = p‐ClPh,
7
3
3
2
3
2
4
h, 83%). For R , not only alkyl substituent, but also aryl
2
| J. Name., 2012, 00, 1‐3
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substituent (such as, p‐MePh) was suitable, offering 4s with a without a substituent on C‐4 site of N‐propargyl pyrroles, a
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4
DOI: 10.1039/C7OB01516J
moderate yield. However, when R was p‐ClPh, the reaction possible Diels‐Alder process (to generate
6
) was preferential
was messy (4r). Only conjugate addition occurred with rather than the nucleophilic attack of conjugated enamine to
4
electron‐donating p‐OMePh (4t). When R = H, 4u and alkyne moiety (to furnish
indolizine 4u’ were obtained in a total yield of 65% with a ratio 4 site of the pyrrole ring, after the conjugate addition to
4). Whereas with a substituent on C‐
of 1:1.4.
alkynone, N‐propargyl pyrroles 1 was hard to act as diene unit
for the Diels‐Alder reaction because of steric effect.
With this unexpected discovery, we thought it might open
a door for us to find a novel indole synthetic method with
simple substituted pyrrole and low‐cost catalyst. To improve
the yield of
and temperature, were screened (see Supporting Information,
Table S1). We found the best result to synthesize was to use
mild acidic silica gel in combination with toluene as the
6, reaction parameters, such as catalysts, solvents
6
1
6
1
7
18
Scheme 2. Mechanistic investigations
solvent. Structural identifications of 6a and 7a were carried
out by X‐ray crystallography.
To probe the reaction mechanism, the reaction of 1a and
o
2
a
was carried out with 0.25 equiv of ZnI
2
at 50 C, offering a
conjugate addition product 3a in 94% yield (Scheme 2, a).
o
Treatment of 3a with ZnI at 110 C furnished 4a in 92% yield
2
(Scheme 2, b), suggesting 3a a possible intermediate.
R
O
Cl
O
Me
O
O
O
O
O
O
Ph
Ph
N
Ph
Ph
N
N
N
R
4
d, 74% (13/1) Cl
, R = F, 3 d, 71% (11/1)
4 d, 80% (13/1)
4 d, 74% (11/1)
Me
,
R = Br, 4 d, 73% (12/1)
O
O
Ph
O
O
5
O
O
O
O
5
Ph
N
Ph
Ph
N
Ph
Ph
N
N
Br
5
d, 67% (9/1)
4 d, 81% (11/1)
4 d, 27%
6 d, 69% (11/1)
O
O
O
Ph
Ph
Ph
O
Ph
O
O
O
O
O
Ph
Ph
Ph
N
Ph
N
Ph
N
Ph MeO
Scheme 3 Proposed reaction mechanism and catalytic cycle
N
Ph
Br
4
d, 63% (>20/1)
Based on the experimental results and reported works
catalyzed by Zn(II) , we proposed a plausible reaction
6 d, 74% (10/1)
6 d, 69% (13/1)
Ph
6 d, 71% (12/1)
1
5
O
O
Cl
O
Ph
F
O
O
O
Ph
O
mechanism (Scheme 3). Firstly, 2a is activated with ZnI by
O
2
N
N
Ph
Ph
forming the coordination complex 2a’. Then, the conjugate
Me
Cl
Ph
N
N
addition via the nucleophilic attack of C‐5 of 1a to 2a’
,
4
d, 70% (17/1)
5 d, 76% (9/1)
4 d, 58%
4 d, 54%
F
furnishes 1a’. Protonolysis of 1a’ provides 3a. Subsequently,
endo‐cyclization occurs via a nucleophilic attack of conjugated
Synthesis of dicarbonyl indoles. Unless otherwise noted, the reactions were carried
out using 300 mg silica gel in PhMe at 60 oC . Isolated yield of
+
. The ratio of was
determined by 1H NMR analysis of the crude reaction mixture. Yield of
.
see SI.
enamine to alkyne moiety (3a
proceeds to furnish 4a
‐3a’). Finally, elimination of Zn(II)
.
We next examined the substrate scope for accessing
diversely substituted dicarbonyl indoles (Figure 3). For
1
substituents R , with electron‐withdrawing groups on phenyl
ring, such as p‐F, p‐Cl, p‐Br, the corresponding products (6a
‐c)
could be obtained in 71‐74% yields with good selectivity (11:1‐
t
1
3:1). Phenyl, p‐MePh, sterically hindered p‐ BuPh and
Scheme 4 Unexpected formation of 4,6‐dicarbonyl indole
naphthyl groups were tolerable for the reaction, offering the
desired products with good yields and selectivities (6d‐g).
Nevertheless, nearly no reaction occurred with p‐MeOPh. Alkyl
substituent such as n‐hexyl resulted in a lower reactivity,
furnishing the 6h in 27% yield. Then, different substituted
pyrroles were examined. The reaction proceeded smoothly
Moreover, when the reaction of 1,2‐disubstituted 1‐(but‐2‐
yn‐1‐yl)‐2‐phenyl‐1H‐pyrrole (1d) with 2a was carried out
under optimized reaction conditions (Table 1, entry 16), no
pyrrolo[1,2‐a]azepine was detected. A conjugate addition
product 5’ (32%) and 4,6‐dicarbonyl indole 6’ (18%) were
obtained instead (Scheme 4). These results implied that
5
with benzylic R , affording corresponding indoles with good
2
yields (6i‐6l: 69‐74%, 10:1‐13:1). For substituents R , alkyl
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substituent was also tolerable to offer 6m in 63% yield with an obtained via ZnI
Journal Name
catalyzed tandem conjugate addition/endo‐
2
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excellent selectivity (>20:1). In addition, electron‐donating cyclization reaction. Silica gel promoteDdOIt:a1n0.d10e3m9/Cc7oOnBj0u1g5a16teJ
substituent offered better selectivity than electron‐ addition/Diels‐Alder/oxidation reaction produced 4,6‐
withdrawing substituent (6n vs 6o, 17:1 vs 9:1). Interestingly, dicarbonyl indoles. Mechanistic investigations suggest that
two different alkynones could be incorporated selectively into conjugated enamines are key intermediates for both two
the final indole molecule step by step. Firstly, treatment of 5a processes. These procedures are compatible in air and provide
and 2a (1:1) at room temperature for about 24 hours good chemo‐ or regioselectivity. Further investigation of the
generated an intermediate. Then, another alkynone, namely 1‐ synthetic application of these processes are underway
(
4‐fluorophenyl)prop‐2‐yn‐1‐one (2c) was added to furnish p‐ currently.
fluorobenzoyl and benzoyl substituted 6p in 58% yield. We thank the National Natural Science Foundation of China
Similarly, indole 6q with different benzoyl groups was also (grant no. 21272074) and the Program for Changjiang Scholars
obtained in 54% yield. Nevertheless, when ethyl propiolate and Innovative Research Team in University (PCSIRT) for
was used instead of alkynone to react with 5a, no desired financial support.
pyrrole was detected possibly due to its relative lower
electrophilicity. In addition, the reactions of 2b with other
heterocycls, such as 2‐ethylfuran, 1‐methylindole and 2‐
Notes and references
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In order to clarify the reaction mechanism, controlled
experiments were carried out with 5a and 2b (Scheme 5).
When the reaction was performed at room temperature, 5a’
was obtained in 88% yield (Scheme 5, a). 5a’ could be
transformed to 6a and 7a in 71% yield with a ratio of 13:1
9
McGowan, K. Amssoms, S. Last, B. Devogelaere, M. Rouan, L.
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012, 51, 4637.!
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Scheme 5, b). These results implied that 5a’ was a possible 2. (a) T. F. Walsh, R. B. Toupence, F. Ujjainwalla, J. R. Young, M.
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2
3
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Chin. J. Org. Chem., 2015, 35, 2275.
Scheme 5. Mechanistic investigations
A plausible mechanism with model substrates 5a and 2a is
speculated on the basis of our experimental results (Scheme 6).
For major process, 2a was firstly activated by silica gel. Then,
nucleophilic attack of 5a to 2a furnished the conjugate
addition product. Then, regioselective Diels‐Alder reaction
occurred due to steric effects to give 4,6‐dicarbonyl indoline
8
. For selected recent reviews, see: (a) M. Platon, R. Amardeil, L.
Djakovitch, J.‐C. Hierso, Chem. Soc. Rev., 2012, 41, 3929; (b)
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5
1
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9
6
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a’. Finally, oxidation of 6a’ afforded 6a. For minor process,
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1
Scheme 6. Proposed reaction mechanism
In conclusion, we have developed novel methodologies for
selective synthesis of pyrrolo[1,2‐a]azepines or 4,6‐dicarbonyl
indoles starting from substituted pyrroles and alkynones in the
presence of low‐cost catalysts. Pyrrolo[1,2‐a]azepines were
1
1
4. CCDC 1527955 (4b)
5. (a) T. Sugiishi, H. Nakamura, J. Am. Chem. Soc., 2012, 134
,
2504; (b) S. Yamazaki, S. Morikawa, K. Miyazaki, M.
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Mikata, Org. Lett., 2009, 11, 2796; (c) P. Aschwanden, D. E.
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DOI: 10.1039/C7OB01516J
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7. CCDC 1527956 (6a
8. CCDC 1527957 (7a
)
)
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