Intermolecular dearomatization reaction of pyrroles promoted by silica gel

Article abstract of DOI:10.1002/adsc.201401150

An efficient synthesis of polysubstituted 2H-pyrrole derivatives via a silica gel-promoted intermolecular dearomative Michael addition of pyrroles with α,β-unsaturated ketones has been developed. This transformation features environmentally benign promoter, high efficiency, wide substrate scope and mild reaction conditions.

Full text of DOI:10.1002/adsc.201401150

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DOI: 10.1002/adsc.201401150
Very Important Publication
Intermolecular Dearomatization Reaction of Pyrroles Promoted
by Silica Gel
Yong Zhou,a,b Chun-Xiang Zhuo,b Qing Gu,b and Shu-Li Youa,b,*
a
School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, Peopleꢀs
Republic of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, Peopleꢀs Republic of China
E-mail: slyou@mail.sioc.ac.cn
Received: December 9, 2014; Revised: January 18, 2015; Published online: March 13, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201401150.
Abstract: An efficient synthesis of polysubstituted
2H-pyrrole derivatives via a silica gel-promoted in-
termolecular dearomative Michael addition of pyr-
roles with a,b-unsaturated ketones has been devel-
oped. This transformation features environmentally
benign promoter, high efficiency, wide substrate
scope and mild reaction conditions.
tization reaction,[6] we envisioned that a dearomatiza-
tion reaction of pyrroles might be achieved under
metal-free conditions by the choice of proper electro-
philes and catalyst or promoter (Scheme 1, bottom).
Herein, we report an intermolecular dearomative Mi-
chael addition of pyrroles with a,b-unsaturated ke-
tones promoted by silica gel for the synthesis of poly-
substituted 2H-pyrroles.
Keywords: alkylation; dearomatization; Michael ad-
dition; pyrroles; silica gel
At the beginning, we chose 2,3,4-trimethylpyrrole
(1b) and 1-phenyl-2-propen-1-one (2a) as the model
substrates to test the dearomatization reaction. In the
presence of TsOH·H2O (10 mol%), the Friedel–Crafts
type[7] dearomatization reaction proceeded smoothly
in DCM to afford 2H-pyrrole 3ba along with 4ba in
Pyrrole moieties are widely found in numerous bio- less than 40% yield after 10 h (Table 1, entry 1). To
logically active natural products and pharmaceutical
agents. Moreover, they are also useful intermediates
in organic synthesis. Therefore extensive efforts have
been directed at the synthesis and transformation of
pyrroles and their derivatives.[1] In the meantime, the
dearomatization of aromatic compounds has achieved
great progress.[2] Among the substrates, pyrrole and
its derivatives can undergo the dearomatization reac-
tion to deliver complex molecules. For instance, in
2007, an elegant [4+3]cyclization of pyrrole with 2-
(siloxy)vinyldiazoacetate catalyzed by adamantyl gly-
cine-derived Rh2(S-PTAD)4 was reported by Davies
and co-workers, offering a promising access to optical-
ly active tropanes.[3] Later, the groups of Kuwano and
Zhou and Fan reported asymmetric hydrogenative
dearomatizations of pyrrole derivatives by chiral Ru
and Pd catalysts, respectively.[4,5] Recently, we de-
scribed a Pd-catalyzed intermolecular allylic dearoma-
tization reaction of pyrroles, providing various chiral
polysubstituted 2H-pyrroles in excellent enantioselec-
tivity and regioselectivity (Scheme 1, top).[6e] To the
best of our knowledge, however, there are limited ex-
amples of metal-free dearomatization reactions of
pyrroles. With our continuing interest in the dearoma- roles.
Scheme 1. Intermolecular dearomatization reactions of pyr-
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Yong Zhou et al.
Table 1. Investigation of the reaction conditions.[a]
Entry
Catalyst
Solvent
Time
Yield[b] [%]
3/4[b]
1
2
3
4
5
6
7
8
TsOH·H2O (10 mol%)
TsOH·H2O (10 mol%)
silica gel I (50 mg)[c]
silica gel II (50 mg)[d]
slica gel III (50 mg)[e]
silica gel II (50 mg)[f]
silica gel I (30 mg)
silica gel I (10 mg)
none
silica gel I (50 mg)
silica gel I (50 mg)
silica gel I (50 mg)
silica gel I (50 mg)
silica gel I (50 mg)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
Et2O
10 h
16 h
<40
>95
>95
>95
>95
>95
89
74
trace
90
–
83/17
88/12
88/12
86/14
88/12
87/13
87/13
–
85/15
83/17
81/19
86/14
85/15
10 min
10 min
10 min
20 min
10 min
10 min
60 min
10 min
10 min
10 min
10 min
10 min
9
10
11
12
13
14
85
46
84
>95
THF
CH3CN
hexane
[a]
Reaction conditions: 0.3 mmol of 1b, 0.45 mmol of 2a in 2.0 mL of solvent at room temperature.
Determined by H NMR.
Supplied by Silicycle, Quebec city, Canada (230–400 mesh).
Supplied by Jiangyou silicone Co., Ltd., Yantai, Shangdong province (100–200 mesh).
Supplied by Jiangyou silicone Co., Ltd., Yantai, Shangdong province (300–400 mesh).
Pretreated with Et3N.
[b]
[c]
[d]
[e]
[f]
1
our delight, the yield of product 3ba and 4ba can be tion to afford the desired product in good yields and
further enhanced to 95% after 16 h in a ratio of 85:15 regioselectivity except for THF, in which only 46%
(Table 1, entry 2). Interestingly, we found that the yield was obtained (Table 1, entries 10–14). DCM was
silica gel alone could promote this reaction and dis- found to be the optimal solvent (>95% yield,
play high efficiency. In the presence of silica gel I Table 1, entry 3). Thus the optimized conditions were
(50 mg), this intermolecular reaction (0.3 mmol scale) obtained as follows: 50 mg silica gel (0.3 mmol sub-
proceeded to completion in 10 min (Table 1, entry 3). strate scale), 1.5 equivalents of 2 in DCM at room
As silica gel is inexpensive, readily available and non- temperature.
toxic, such a reaction is an environmentally benign
Under the optimized reaction conditions, the sub-
and highly desirable process.[8] Encouraged by this strate scope was then examined. Firstly, various pyr-
preliminary result, we investigated various silica gels role derivatives 1 were tested. The results are sum-
and other reaction parameters. The results are sum- marized in Scheme 2. When symmetrical 2,5-dime-
marized in Table 1. We found that silica gels from dif- thylpyrrole (1a) was used, the dearomatization pro-
ferent suppliers with varying sizes all efficiently pro- cess proceeded well, giving the desired product 3aa in
moted this reaction, resulting in nearly the same yield 76% yield (Scheme 2, 3aa). When the methyl group
and regioselectivity (Table 1, entries 3–5). A silica gel at the C-3 position was replaced by n-butyl (1c), cy-
pretreated with Et3N gave identical results although clopropyl (1d) or n-pentyl (1e), the dearomatization
a slightly longer reaction time was required (Table 1, reaction also occurred smoothly, affording the dearo-
entry 6). Notably, only a trace amount of the desired matization products in excellent yields and good re-
product was detected in the absence of silica gel, gioselectivity (Scheme 2, 95–99% yields). In addition,
which ruled out the background reaction (Table 1, 2,3-dimethyl-5-phenylpyrrole (1f) was also a suitable
entry 9). Next, we further examined the solvent ef- substrate in this reaction, dearomative product was
fects. A variety of solvents such as toluene, Et2O, obtained in 99% yield with 95/5 regioselectivity in
CH3CN and hexane could be employed in the reac- favour of 3fa (Scheme 2). Notably, the reaction
2
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Intermolecular Dearomatization Reaction of Pyrroles
occurs preferentially at that position of the pyrroles
where the HOMO of the molecule distributes most
significantly.[6f] Moreover, when substrate 1g bearing
2,3,4,5-tetramethyl groups was employed, the desired
product was obtained in 51% yield (Scheme 2, 3ga).
The structures of the major regioisomers (3ba, 3da
and 3fa) were further confirmed unambiguously by
2D-NOESY analysis.[9]
In addition, the reactions of various enones 2 with
2,3,5-trimethylpyrrole were also investigated. As seen
from the results in Scheme 3, enones 2 bearing either
an electron-donating group (4-Me, 4-MeO, 3-MeO, 2-
Me) or electron-withdrawing group (4-F, 4-Cl, 4-Br, 2-
Br) on the phenyl ring were well tolerated, and the
corresponding products were obtained in good to ex-
cellent yields and regioselectivity (Scheme 3, 3bb–3bi,
60–99% yields). It is worth noting that the reaction
conditions are also compatible for both a naphthyle-
none (2j) and an aliphatic enone (2k) (Scheme 3,
96% and 66% yields, respectively). Unfortunately, the
reaction of 2,5-dimethylpyrrole (1a) with an a,b-dis-
ubstituted enone such as chalcone only gave a trace
amount of product under the optimized reaction con-
ditions.
In summary, we have developed a highly efficient
synthesis of polysubstituted 2H-pyrrole derivatives via
silica gel-promoted intermolecular dearomative addi-
tion of pyrroles and a,b-unsaturated enones. With
commercially available silica gel, the dearomatized
products were obtained with up to 99% yield under
mild reaction conditions. Further studies on the enan-
Scheme 2. Reaction substrate scope: pyrroles. Reaction con-
ditions: silica gel (50 mg), 1 (0.3 mmol) and 2a (0.45 mmol)
in DCM (2.0 mL) at room temperature for 20 min. Isolated
yields of 3 and 4 were reported. The ratio of 3/4 was deter-
1
mined by H NMR analysis of the crude reaction mixture.
Scheme 3. Reaction substrate scope: enones. Reaction conditions: silica gel (50 mg), 1b (0.3 mmol) and 2 (0.45 mmol) in
DCM (2.0 mL) at room temperature for 20 min. Isolated yields of 3 and 4 are reported. The ratio of 3/4 was determined by
1H NMR analysis of the crude reaction mixture.
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Yong Zhou et al.
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tioselective control and new metal-free dearomatiza-
tion reactions are currently underway in our laborato-
ry.
Experimental Section
General Procedure for the Intermolecular
Dearomatization Reaction of Pyrroles Promoted by
Silica Gel
A flame-dried Schlenk tube was cooled to room tempera-
ture. To a solution of substituted pyrrole 1 (0.30 mmol,
1.0 equiv.) in dichloromethane (2 mL) in this tube was
added enone 2 (0.45 mmol, 1.5 equiv.), then silica gel
(50 mg, 0.17 gmmolÀ1) was added in one portion. The reac-
tion mixture was stirred at room temperature. After the re-
action was complete, the mixture was purified by silica gel
column chromatography (PE/acetone=3/1–1/1) to afford
the desired product.
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Acknowledgements
We thank the National Basic Research Program of China
(973 Program 2015CB856600) and National Natural Science
Foundation of China (21272253, 21332009, 21361140373,
21421091) for generous financial support.
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[9] For details, see the Supporting Information.
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6 Intermolecular Dearomatization Reaction of Pyrroles
Promoted by Silica Gel
Adv. Synth. Catal. 2015, 357, 1 – 6
Yong Zhou, Chun-Xiang Zhuo, Qing Gu, Shu-Li You*
6
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These are not the final page numbers!