Cycloadditions with Bromo-Substituted Morita-Baylis-Hillman Adducts of Isatins and N-(ortho-Chloromethyl)aryl Amides

Article abstract of DOI:10.1021/acs.orglett.5b02279

Efficient construction of a challenging aza-spirocycloheptane oxindole scaffold is reported through an unprecedented [4 + 3] cycloaddition reaction with bromo-substituted Morita-Baylis-Hillman adducts of isatins and N-(ortho-chloromethyl)aryl amides. Both reactive intermediates, the allylic phosphonium ylides and aza-o-quinone methides, were in situ generated, chemoselectively facilitated by a Lewis base and Bronsted base, respectively.

Full text of DOI:10.1021/acs.orglett.5b02279

Letter
pubs.acs.org/OrgLett
[4 + 3] Cycloadditions with Bromo-Substituted Morita−Baylis−
Hillman Adducts of Isatins and N‑(ortho-Chloromethyl)aryl Amides
Gu Zhan,† Ming-Lin Shi,† Qing He,† Wei Du,† and Ying-Chun Chen*,†,‡
†Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, and
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
‡College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: Efficient construction of a challenging aza-
spirocycloheptane oxindole scaffold is reported through an
unprecedented [4 + 3] cycloaddition reaction with bromo-
substituted Morita−Baylis−Hillman adducts of isatins and N-
(ortho-chloromethyl)aryl amides. Both reactive intermediates,
the allylic phosphonium ylides and aza-o-quinone methides,
were in situ generated, chemoselectively facilitated by a Lewis
base and Brønsted base, respectively.
transformations with MBH derivatives via Lewis base
catalysis,13 we wondered whether a novel [4 + 3] cycloaddition
reaction could be accomplished between allylic ylides and aza-
oQMs, as outlined in Scheme 1. However, this unprecedented
he [4 + 3] cycloaddition reaction has emerged as one of
Tthe most powerful strategies for the construction of seven-
membered carbo- and heterocycles.1 In recent years, impressive
progress has been made and diverse 3C dienophiles have been
utilized in [4 + 3] cycloaddition reactions besides classical
allylic cations.2 For example, the Chiu group reported silyl
triflate-catalyzed [4 + 3] cycloadditions using epoxy enolsilanes
as dienophiles.3 Breslow intermediates generated from enals
and an N-heterocyclic carbene (NHC) catalyst were success-
fully applied as the dienophiles by Ye and Glorius.4 In addition,
azomethine imines, azomethine yildes, nitrones, cyclopropanes,
and metal vinylcarbenes were also shown to act as partners in
[4 + 3] cycloadditions with different dienes, further enriching
the structural diversity of the products.5
Scheme 1. Proposed [4 + 3] Cycloadditions of in situ
Generated Allylic Ylides and Aza-o-quinone Methides
On the other hand, the Morita−Baylis−Hillman (MBH)
derivatives could react with a Lewis base, generating
zwitterionic allylic phosphonium, ammonium, or sulfonium
ylides after deprotonation.6 Such intermediates could serve as
nucleophilic 3C synthons, and fruitful [3 + 2]7 and [3 + 3]8
cycloaddition reactions have subsequently been developed. In
contrast, their application in more challenging [4 + 3]
cycloadditions has received much less attention, probably
because it is difficult to find suitable electrophilic diene
components.9
Aza-o-quinone methides (aza-oQMs), first introduced by
Corey and Steinhagen through the base-mediated elimination
of N-(ortho-chloromethyl)aryl amides, have been applied as
useful synthons in [4 + 2] cycloaddition reactions.10 Later, Xiao
and co-workers developed the formal [4 + 1] cycloadditions of
sulfur ylides and aza-oQMs.11 In Scheidt’s work, dihydroqui-
nolones and 2-aryl indoles were synthesized through [4 + 1]
and [4 + 2] cycloaddition reactions, by combining aza-oQMs
with acyl anion and enolate equivalents, respectively, via NHC
catalysis.12 In our continuing efforts to expand the synthetic
protocol might be very challenging, as both reactants must be
in situ generated from multifunctional starting materials, and
subtle conditions would be necessary to control the formation
of the intermediates and the following cycloaddition process.
Consequently, MBH carbonate 1 derived from N-methyl
isatin, which has been successfully applied in tertiary amine-
catalyzed [3 + 2] cycloadditions,13a,e was initially selected in a
reaction with ethyl [2-(ortho-chloromethyl)phenyl]-carbamate
3a, in order to construct an aza-spirocycloheptane oxindole
skeleton that might be useful in medicinal chemsitry.14
Unfortunately, complex reactions were generally observed,
when either DABCO or PPh3 was employed as the Lewis base
catalyst in combination with Cs2CO3 or other Brønsted bases.
The desired [4 + 3] cycloadduct could not be detected in the
Received: August 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02279
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Letter
mixture. After extensive screenings, a γ-regioselective [4 + 3]
cycloaddition product 4a was obtained in 62% yield at 50 °C
after 12 h, by using the bromo-substituted MBH adduct15 2a
and precursor 3a as the starting materials in the presence of
stoichiometric Ph3P and excess Cs2CO3. The addition of 4 Å
molecule sieves was beneficial for the reaction (Table 1, entry
With the optimized reaction conditions in hand, substrate
scope and limitations for [4 + 3] cycloadditions were examined
in PhCF3 in the presence of stoichiometric (4-FC6H4)3P and
excess Cs2CO3. At first, different bromo-substituted MBH
adducts 2 were investigated in reactions with ethyl [2-
(chloromethyl)phenyl]-carbamate 3a. As summarized in
Scheme 2, the bromo-substituted MBH adducts 1 with diverse
a
Table 1. Screening Conditions of [4 + 3] Cycloaddition
a b
,
Scheme 2. Scope of Bromo-substituted MBH Adducts 2
b
entry
phosphine
Ph3P
solvent
PG
yield/%
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Boc
4a, 62
−
−
2
HMPT
3
nBu3P
4
(2-furyl)3P
Cy3P
−
5
4a, 55
4a, 68
4a, 38
4a, 60
4a, 73
4a, 60
4a, 56
4a, 43
4a, 80
4b, 70
−
6
MePh2P
7
(2-MeC6H4)3P
(4-MeC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
(4-FC6H4)3P
8
9
10
11
12
13
14
15
CHCl3
THF
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
Ts
c
16
CO2Et
CO2Et
CO2Et
4a, 74
4a, 79
4a, 54
d
17
e
18
a
Unless noted otherwise, reactions were performed with 2a (0.1
mmol), 3 (0.25 mmol), phosphine (0.1 mmol), Cs2CO3 (1.0 mmol),
b
and 4 Å MS (80 mg) in solvent (2.0 mL) at 50 °C for 12 h. Isolated
yield. At 40 °C. At 60 °C. 0.05 mmol of (4-FC6H4)3P was used.
a
c
d
e
Reactions were performed with 2 (0.1 mmol), 3a (0.25 mmol), (4-
FC6H4)3P (0.1 mmol), Cs2CO3 (1.0 mmol), and 4 Å MS (80 mg) in
PhCF3 (2.0 mL) at 50 °C for 12 h. Isolated yield.
b
1). It should be noted that such a [4 + 3] cycloaddition still did
not occur by using DABCO or DMAP as the promoter.
Subsequently, an array of tertiary phosphine substances were
explored (entries 2−9). While hexamethyl phosphoryamide
(HMPT), nBu3P, and tri(2-furyl) phosphine failed to produce
the expected product (entries 2−4), the other phosphine
compounds exhibited comparable activity, and better results
were achieved with (4-FC6H4)3P (entry 9). In addition, solvent
effects were further investigated (entries 10−13), and the yield
was improved to 80% in PhCF3 (entry 13). On the other hand,
the N-protecting group of aza-oQM precursor was examined.
An inferior yield was obtained by using N-Boc precursor 3b
(entry 14). Nevertheless, the N-Ts group was not suitable and
the expected [4 + 3] cycloadduct was formed in a very low yield
due to the dimerization of 3c via N-alkylation reaction (entry
15). Moreover, the yields were slightly diminished at lower or
higher temperature (entries 16 and 17). It was found that the
reaction could smoothly proceed with 50 mol % of (4-
FC6H4)3P, albeit in a modest yield (entry 18). Finally, a
diversity of chiral phosphines were explored in order to induce
the chirality into the product; unfortunately, complex or side
reactions were generally observed, and the desired cycloadduct
4a could not be successfully isolated.16 Therefore, the
asymmetric [4 + 3] version still remains to be explored.
electron-donating or -withdrawing groups on the aryl ring could
smoothly afford the aza-spirocycloheptane oxindole products
4c−4h in moderate to good yields. In general, substrates with
electron-donating groups exhibited higher reactivity than those
with electron-withdrawing groups, probably because the latter
substituents would lower the nucleophilicity of the allylic
phosphonium ylides. In addition, a moderate yield for product
4i was obtained by using the bromo-substituted MBH adduct
with an N-benzyl group. It should be noted that the bromo-
substituted MBH adducts from aryl aldehydes and methyl
acrylate failed to participate in this type of [4 + 3] cycloaddition
reaction under the same conditions.
Subsequently, a series of ethyl [2-(chloromethyl)phenyl]-
carbamates 3 bearing different substituents were explored in
reactions with the bromo-substituted MBH adduct 2a. As
summarized in Table 2, good tolerance for diverse electron-
donating or -withdrawing groups at different positions on the
phenyl ring was observed. A spectrum of aza-spirocycloheptane
oxindoles 4j−4t were generally produced in modest yields
(Table 2, entries 1−11). Moreover, as outlined in Scheme 3, an
ethyl [3-(chloromethyl)naphthalen-2-yl]carbamate 3o could
also be successfully used. The corresponding [4 + 3]
cycloaddition 4u was obtained in a good yield, which showed
B
DOI: 10.1021/acs.orglett.5b02279
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Letter
a
BF3·OEt2, giving tetrahydrospiro[benzo[b]azepine-4,3′-indo-
line] 6 in a high yield and with good diastereoselectivity.
In summary, we have developed a challenging and efficient
method for rapid construction of aza-spirocycloheptane
oxindole frameworks through a new [4 + 3] cycloaddition
reaction between N-(ortho-chloromethyl)aryl amides and
bromo-substituted MBH adducts derived from isatins, employ-
ing tertiary phosphine and Cs2CO3 as the promoters. This
process relies on the in situ generation of allylic phosphonium
ylides facilitated by a Lewis base and Brønsted base, and aza-o-
quinone methides via Brønsted base mediated elimination.
Moreover, the cycloadduct could be further transformed to
tetrahydrospiro[benzo[b]azepine-4,3′-indoline] architecture
through simple deprotection and reduction under mild
conditions. Currently, more attempts to develop an asymmetric
[4 + 3] cycloaddition process are under investigation in this
laboratory.
Table 2. Scope of 2-(Chloromethyl)phenyl-carbamates 3
b
entry
R (3)
4
yield/%
1
5-F (3d)
4j
66
45
62
71
63
60
64
68
56
73
53
2
3-Cl (3e)
4-Cl (3f)
4k
4l
3
4
5-Cl (3g)
4-Br (3h)
5-CF3 (3i)
3-Me (3j)
4-Me (3k)
6-Me (3l)
4-MeO (3m)
5,6-Me2 (3n)
4m
4n
4o
4p
4q
4r
5
6
7
8
9
10
11
4s
ASSOCIATED CONTENT
* Supporting Information
■
4t
S
a
Reactions were performed with 2a (0.1 mmol), 3 (0.25 mmol), (4-
FC6H4)3P (0.1 mmol), Cs2CO3 (1.0 mmol) and 4 Å MS (80 mg) in
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02279.
b
PhCF3 (2.0 mL) at 50 °C for 12 h. Isolated yield.
Scheme 3. Reaction of Ethyl [3-(Chloromethyl)naphthalen-
2-yl]-carbamate 3o
Complete experimental procedures and characterization
of new products; NMR spectra (PDF)
Crystallographic data for cycloadduct 4a (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ycchen@scu.edu.cn.
Notes
that the precursor of aza-diene was not limited to N-(ortho-
chloromethyl)phenyl amides.
The authors declare no competing financial interest.
As illustrated in Scheme 4, the structure of [4 + 3]
cycloaddition product 4a was unambiguously identified by X-
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the NSFC
(21122056, 21321061, and 21572135) and Program for
Changjiang Scholars and Innovative Research Team in
University (IRT13031).
Scheme 4. Transformations of Product 4a
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