A cascade reaction of pyrrole-2-carbaldehyde substituted Morita-Baylis-Hillman adducts in the presence of tetrabutylammonium hydroxide or acetate to construct aza-heterocycles

Article abstract of DOI:10.1039/c2cc31358h

The phase-transfer catalyst promoted intramolecular transformation of pyrrole-2-carbaldehyde substituted Morita-Baylis-Hillman adducts has been disclosed, providing an efficient way to construct pyrrolo[1,2-a]azepin-7(6H)- one skeletons in moderate to goo

Full text of DOI:10.1039/c2cc31358h

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COMMUNICATION
A cascade reaction of pyrrole-2-carbaldehyde substituted
Morita–Baylis–Hillman adducts in the presence of tetrabutylammonium
hydroxide or acetate to construct aza-heterocyclesw
Long Huanga and Min Shi*ab
Received 23rd February 2012, Accepted 14th March 2012
DOI: 10.1039/c2cc31358h
The phase-transfer catalyst promoted intramolecular transformation
of pyrrole-2-carbaldehyde substituted Morita–Baylis–Hillman adducts
has been disclosed, providing an efficient way to construct
pyrrolo[1,2-a]azepin-7(6H)-one skeletons in moderate to good
yields (up to 92%) under mild conditions.
Scheme 1 Reaction mode.
Highly efficient construction of cyclic skeletons is one of the most
important themes in organic synthesis. The structurally diverse
yields with excellent ee values in the presence of multifunctional
Cinchona alkaloids.6h Herein, we wish to report that pyrrole-
2-carbaldehyde substituted Morita–Baylis–Hillman adducts could
and biologically interesting N-bridgehead pyrrole skeletons are
well-represented and widely distributed in nature. For example,
their structures can be often found in natural products such as
Stemona alkaloids,1 ant venom/frog alkaloids,2 and Cephalotaxus
be isomerized to pyrrolo[1,2-a]azepin-7(6H)-one skeletons in the
alkaloids,3 exhibiting a broad range of biological activities. Their
presence of phase-transfer catalyst (PTC) (Scheme 1, eqn (2)). To
the best of our knowledge, this is the first example on the direct
complex architectures provide the impetus for the development of
C–N bond cleavage with a new C–N bond forming sequence
catalyzed by a PTC, giving a seven-membered N-bridged pyrrole
skeleton.
new synthetic methodologies. Therefore, it is not surprising that
much attention has been paid to developing creative strategies for
the construction of such bridged pyrrole skeletons and the
development of a more general and efficient strategy to afford
We first investigated reaction conditions for the intra-
molecular transformation of pyrrole-2-carbaldehyde substituted
such azabicyclic skeletons remains important and continues to
MBH adduct 1a, and the results are summarized in Table 1.
Carrying out the reaction in the presence of 0.2 equiv. of PTC
attract interest from the organic synthesis community.
In the past decade, the Morita–Baylis–Hillman (MBH) reaction
catalyst such as tetrabutylammonium acetate in DMSO at 80 1C
gave 2a in 19% yield with >20 : 1 E/Z ratio (Table 1, entry 1).
Tetrabutylammonium bromide, Bu4NHSO4, and C16H33Me3NBr
(CTAB) did not promote the reaction (entries 2–4). Organic
and inorganic bases themselves did not promote this reaction
either (entries 5–7). Tetrabutylammonium fluoride could
promote this reaction at ambient temperature, affording 2a in
37% yield (entry 8). A more basic PTC catalyst tetrabutyl-
ammonium hydroxide provided 2a in 52% yield with >20 : 1
E/Z ratio within shorter reaction time and using 1.0 equiv. of
tetrabutylammonium hydroxide decreased the yield of 2a
(entry 9). Upon screening the reaction conditions using tetra-
butylammonium hydroxide (20 mol%) as the catalyst together
with several inorganic bases (20 mol%), we realized that
tetrabutylammonium hydroxide combined with sodium ethoxide
could furnish 2a in 60% yield with >20 : 1 E/Z ratio in DMSO at
ambient temperature (entries 10–14). Next, we studied the solvent
effects under this condition and found that tetrahydrofuran
(THF) turned out to be the best solvent, giving 2a in 78% yield
with >20 : 1 E/Z ratio after 1 h (entries 15–19). The examination
of catalyst and base loadings revealed that the reaction outcome
was affected significantly by the catalyst and base loadings
has attracted great attention because it leads to the formation of
densely functionalized products in a catalytic and atom-economic
way.4 The carbon–carbon double bond in the Morita–Baylis–
Hillman adducts and their acetates could be easily isomerized
under various conditions to give different products, such as
cinnamyl alcohols and cinnamyl acetates (Scheme 1, eqn (1)).5
Recently we and others have developed several highly asymmetric
allylic alkylation reactions of Morita–Baylis–Hillman (MBH)
carbonates or acetates with diverse nucleophiles.6 For example, we
have reported that the asymmetric substitution of O-Boc-protected
Morita–Baylis–Hillman adducts with 1H-pyrrole-2-carbonitrile
provided the desired N-allylic alkylation products in high
a Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
and 130 MeiLong Road, Shanghai 200237, P. R. China
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China.
E-mail: mshi@mail.sioc.ac.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data of new compounds. CCDC
834094. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2cc31358h
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4501–4503 4501

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Table 1 Screening of reaction conditions
Table 2 Substrate scope and limitations
Base
(equiv.)
Yieldb
Solvent t/h (%) E/Z ratioc
Entrya Cat.
Entrya
Ar
R
t/h
Yieldb (%)
E/Z ratioc
1d
2d
3d
4d
5d
6d
7d
8
Bu4NOAc
—
—
—
—
—
—
—
—
—
DMSO 48 19
>20 : 1
—
—
—
—
—
—
>20 : 1
>20 : 1
1
2
3
4
5
6
7
8
4-FC6H4, 1b
4-CF3C6H4, 1c
2,3-Cl2C6H3, 1d
4-BrC6H4, 1e
3-BrC6H4, 1f
2-BrC6H4, 1g
3-NO2C6H4, 1h
C6H5, 1i
4-MeC6H4, 1j
3-OMeC6H4, 1k
2-OMeC6H4, 1l
2-Furyl, 1m
H
H
H
H
H
H
H
H
H
H
H
H
4
5
2
3
4
4
5
5
5
3
5
5
3
6
6
3
2b, 52
2c, 40
2d, 67
2e, 55
2f, 61
2g, 61
2h, 36
2i, 74
2j, 92
2k, 64
2l, 78
2m, 83
2n, 83
2o, 55
2p, 37
2q, 73
>20 : 1
12 : 1
>20 : 1
>20 : 1
16 : 1
Bu4NBr
Bu4NHSO4
CTAB
DABCO
K2CO3
Et3N
DMSO 48
DMSO 48
DMSO 48
DMSO 48
DMSO 48
DMSO 48
—
—
—
—
—
—
>20 : 1
8 : 1
Bu4NF
Bu4NOH
DMSO 48 37
DMSO 10 52
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
15 : 1
9
9
(2)e (28)e (>20 : 1)e
10
11
12
13
14
15
16
10
11
12
13
14
15
16
17
18
19
20
21
22f
23g
24
Bu4NOH K2CO3 (0.2)
Bu4NOH NaOAc (0.2)
Bu4NOH NaOEt (0.2)
DMSO 24 52
DMSO 18 48
DMSO 60
7 : 1
>20 : 1
>20 : 1
16 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
15 : 1
>20 : 1
>20 : 1
>20 : 1
10 : 1
10 : 1
>20 : 1
2
2-Thienyl, 1n
4-ClC6H4, 1o
4-ClC6H4, 1p
4-ClC6H4, 1q
H
Bu4NOH LiOHꢀH2O (0.2) DMSO 20 30
CN
Ac
tBu
Bu4NOH NaOtBu (0.2)
Bu4NOH NaOEt (0.2)
Bu4NOH NaOEt (0.2)
Bu4NOH NaOEt (0.2)
Bu4NOH NaOEt (0.2)
Bu4NOH NaOEt (0.2)
Bu4NOH NaOEt (0.5)
Bu4NOH NaOEt (1.0)
Bu4NOH NaOEt (0.2)
Bu4NOH NaOEt (0.5)
Me4NOH NaOEt (0.2)
DMSO 18 30
DMF 56
11 : 1
17 : 1
8
Acetone 24 37
DCM 24 30
Toluene 48 37
a
Unless otherwise specified, all reactions were carried out using 1
(0.1 mmol, 1.0 equiv.) and NaOEt (0.05 mmol, 0.5 equiv.) in THF (1 mL)
b
c
with 20 mol% Bu4NOH at room temperature. Isolated yields. E/Z
ratios were determined by 1H NMR spectroscopic data of crude products.
THF
THF
THF
THF
THF
THF
1
2
78
82
24 59
8
2
70
41
(E/Z ratio > 20 : 1) of product 2j were obtained for pyrrole-2-
carbaldehyde substituted MBH adduct 1j bearing a 4-Me
group on the aromatic ring. Furthermore, MBH adducts 1m
and 1n having heteroaromatic groups were also suitable
substrates in this reaction, affording the corresponding
products 2m and 2n in good yields (up to 83%) along with
E/Z ratios >20 : 1 (entries 12 and 13). We next attempted to
use the other pyrrole-2-carbaldehyde derivative substituted
MBH adducts in this reaction. These reactions also proceeded
smoothly to give the desired products 2o–2q in modest to good
yields (37–73% yields) with high stereoselectivities under the
standard conditions (entries 14–16). The starting materials of
pyrrole-2-carbaldehyde substituted Morita–Baylis–Hillman adducts
derived from pyridinecarboxaldehydes are not available at the
present stage.
1.5 74
a
Unless otherwise specified, all reactions were carried out using 1a
(0.1 mmol, 1.0 equiv.) and base in solvent (1 mL) with 20 mol% catalyst
b
c
at room temperature. Isolated yields. E/Z ratios were determined by
1H NMR spectroscopic data of crude products. Reaction was carried
d
e
f
out at 80 1C. 1 equiv. of cat. was used. 10 mol% of cat. was used.
g
Reaction was carried out at 50 1C.
(entries 20–22). For example, 0.2 equiv. of tetrabutylammonium
hydroxide (PTC catalyst) combined with 0.5 equiv. of sodium
ethoxide was the most efficient catalytic system, affording 2a in
82% yield. Raising the reaction temperature did not favor the
formation of 2a (entry 23). It might be noted that tetramethyl-
ammonium hydroxide could also promote this reaction efficiently
(Table 1, entry 24). The structure of 2a has been unambiguously
determined by X-ray diffraction and the ORTEP drawing along
with CIF data are presented in the ESIw (CCDC 834094).
With the optimized reaction conditions (0.2 equiv. of Bu4NOH
and 0.5 equiv. of NaOEt in THF) in hand, we next examined the
substrate scope. The results are shown in Table 2. Most of the
reactions using pyrrole-2-carbaldehyde substituted MBH adducts
1 proceeded smoothly to give the corresponding products 2 in
moderate to good yields along with good to excellent E/Z ratios.
It is worth noting that, in general, substrates bearing electron-
donating groups (entries 8–11) on their aromatic rings provide
better results than substrates bearing electron-withdrawing
groups, presumably due to the electronic property (entries 1–7).
For instance, pyrrole-2-carbaldehyde substituted MBH
adduct 1h with a 3-NO2 group on the aromatic ring gave the
corresponding product 2h in 36% yield and 8 : 1 E/Z ratio,
while higher yield (up to 92%) and excellent stereoselectivity
Recently, Kim and co-workers synthesized tetracyclic indole
derivatives via the palladium-mediated intramolecular Heck
reaction from indole-containing MBH adducts.7 Thus we
attempted to use 1r–1t as substrates to conduct intramolecular
Heck reaction with PTC as a base. Gratifyingly, we found that
the reactions proceeded smoothly under the conditions of
0.2 equiv. of Pd(OAc)2, 0.2 equiv. of JohnPhos and 1.5 equiv.
of tetrabutylammonium acetate in DMF at 100 1C, producing
seven or eight-membered aza-heterocycles 2r–2t in good yields
(up to 93%, Scheme 2). It should be noted that, in the case of
MBH adduct 1t, the eight-membered product 2t was formed in
60% yield, rendering that the formation of a seven-membered
ring is impossible in this case and aryl–aryl cross-coupling
reaction takes place (Scheme 2). Product 2s has hepatitis C
virus (HCV) NS5B polymerase inhibitory activity.
A plausible mechanism for this PTC-promoted reaction is
proposed in Scheme 3. MBH adduct 1 first affords intermediate
c
4502 Chem. Commun., 2012, 48, 4501–4503
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Notes and references
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Scheme 3 A possible mechanism for the PTC-promoted reaction.
A through an SN20 reaction process along with the elimination
of pyrrole anions in the presence of tetrabutylammonium
hydroxide, which undergoes a Michael type addition reaction
to give intermediate B. The subsequent intramolecular aldol
reaction of intermediate B along with the elimination of water
affords the desired product 2. In fact, we have isolated trace of
pyrrole-2-carbaldehyde in some cases during the workup
stage, suggesting the formation of pyrrole anions (see ESIw).
In conclusion, we have developed an efficient PTC-promoted
cascade reaction of pyrrole-2-carbaldehyde substituted Morita–
Baylis–Hillman adducts, leading to pyrrolo[1,2-a]azepin-7(6H)-
one skeletons in moderate to good yields. This cascade reaction
proceeds with high stereoselectivity through a C–N bond
cleavage along with a new C–N bond formation as well as an
intramolecular aldol reaction. Further exploration of other
cascade reactions using PTC as a promoter with MBH adducts
to construct heterocycles is ongoing.
We thank the Shanghai Municipal Committee of Science
and Technology (11JC1402600), National Basic Research
Program of China (973)-2010CB833302, the Fundamental
Research Funds for the Central Universities and the National
Natural Science Foundation of China for financial support
(21072206, 20872162, 20672127, 20732008, 21121062 and
20702013).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4501–4503 4503