Cycloaddition of in Situ Formed Azaoxyallyl Cations with 2-Alkenylindoles: An Approach to Tetrahydro-β-carbolinones

Article abstract of DOI:10.1021/acs.orglett.7b00914

A novel [3 + 3] cycloaddition between in situ formed azaoxyallyl cations and 2-alkenylindoles has been developed. This concise method allows the efficient construction of a series of tetrahydro-β-carbolinones in good yields under mild conditions. Gram-sca

Full text of DOI:10.1021/acs.orglett.7b00914

Letter
pubs.acs.org/OrgLett
[3 + 3] Cycloaddition of in Situ Formed Azaoxyallyl Cations with
2‑Alkenylindoles: An Approach to Tetrahydro-β-carbolinones
Kaifan Zhang,† Xiaoying Xu,† Jiuan Zheng,† Hequan Yao,† Yue Huang,*,‡ and Aijun Lin*,†
†State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
‡Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: A novel [3 + 3] cycloaddition between in situ
formed azaoxyallyl cations and 2-alkenylindoles has been
developed. This concise method allows the efficient con-
struction of a series of tetrahydro-β-carbolinones in good
yields under mild conditions. Gram-scale experiments and
further derivatization of tetrahydro-β-carbolinones highlighted
the potential utility of our method.
etrahydro-β-carbolinone structural motifs have been
identified as high-profile skeletons in a wide range of
Scheme 1. Methods for the Synthesis of Tetrahydro-β-
carbolinones
T
indole alkaloids with potent antitumor activity,1 such as
cladoniamides F and G and ophiorrhisides A and B (Figure
1). On account of their prominent bioactivities and medicinal
Figure 1. Selected examples of natural products and bioactive
compounds containing a tetrahydro-β-carbolinone framework.
value, the exploration of efficient methods to build such
frameworks has attracted widespread research interest.2
Representative methods include the three-component Ugi
reaction (Scheme 1a),3 zinc-catalyzed intramolecular alkyne
oxidation/C−H functionalization (Scheme 1b),4 and gold-
catalyzed intramolecular hydro-heteroarylation of acrylamides
(Scheme 1c).5 Although the previous approaches were of
interest in achieving tetrahydro-β-carbolinones, multistep
processes, metal catalysts, extra oxidants, and/or restricted
substrate scopes remained to be addressed for these methods to
be generally applicable. Accordingly, the development of
efficient methods with easily acquired materials under mild
conditions is still highly desirable.
which to develop new nitrogen heterocycles.7 Recently, we
realized a [3 + 2] cycloaddition reaction between azaoxyallyl
cations and aldehydes, leading to the synthesis of oxazolidin-4-
ones in excellent yields.8 In view of our continuous interest in
constructing functional indoles,9 herein we report our results
on the synthesis of tetrahydro-β-carbolinones through [3 + 3]
cycloaddition between in situ formed azaoxyallyl cations and 2-
alkenylindoles10 under metal-free conditions (Scheme 1d).
We commenced our feasibility studies with dimethyl 2-((1-
methyl-1H-indol-2-yl)methylene)malonate (1a) and N-(benz-
yloxy)-2-bromo-2-methylpropanamide (2a) as the pilot sub-
Since the seminal discovery of cycloaddition involving in situ
formed azaoxyallyl cations from α-halohydroxamates reported
by Jeffrey,6 azaoxyallyl cations represented ideal synthons on
Received: March 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00914
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
strates. Impressively, the strong hydrogen-bond-donating and
sterically bulky solvent hexafluoroisopropanol (HFIP) was
effective in achieving the reaction, providing the lactamization
product 3aa in 50% yield (Table 1, entry 5), while 2,2,2-
Scheme 2. Substrate Scope of 2-Alkenylindoles
a
Table 1. Optimization of Reaction Conditions
b,c
entry
base
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOH
TFE
12
12
12
12
3
nr
nr
TFP
CH3CN
DCM
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
nr
nr
50
33
39
28
18
66
69
77
84
86
nr
3
Et3N
3
KHCO3
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
3
3
d
10
3
e
11
3
f
12
3
g
13
3
h
14
3
15
3
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), base (2.0 equiv)
b
c
in solvent (1.0 mL) for 3 h at room temperature. Isolated yields. nr
d
e
= no reaction. 1.2 equiv of 2a was used. 1.5 equiv of 2a was used.
f
g
h
2.0 equiv of 2a was used. 3.0 equiv of Na2CO3 was used. 4.0 equiv
of Na2CO3 was used.
trifuoroethanol (TFE), 2,2,3,3-tetrafluoropropanol (TFP),
CH3CN, and DCM rendered no conversion (Table 1, entries
1−4). Other bases including inorganic and organic bases such
as NaOH, Et3N, KHCO3, and Cs2CO3 failed to enhance the
yields (Table 1, entries 6−9). Increasing the loading amount of
2a and Na2CO3 could lead to the improvement of 3aa (Table
1, entries 10−13). The optimal reaction conditions were
obtained when 2.0 equiv of 2a and 4.0 equiv of Na2CO3 were
employed with the complete conversion of 1a (Table 1, entry
14). No desired product was detected without base (Table 1,
entry 15).
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Na2CO3 (0.8
b
mmol) in HFIP (1.0 mL) for 3 h at room temperature. Isolated
yields. 2a (0.6 mmol), Na2CO3 (1.2 mmol). TFA (1.4 mmol) was
added until 2-alkenylindoles were completely consumed and then
stirred at room temperature for another 3 h. 2a (0.3 mmol), Na2CO3
c
d
e
(0.6 mmol).
With the optimized reaction conditions established, the
substrate scope of the reaction with respect to the 2-
alkenylindole moiety was examined, and the results are
summarized in Scheme 2. The reactions were well compatible
with 2-alkenylindoles bearing methyl and methoxyl groups at
the C-5 position, affording 3ba and 3ca in 94% and 87% yields.
When an indole framework bearing a chloro substituent at the
C-5 position was used, 3da was obtained in 41% yield with
iminolactonization product 4da (42% yield) under standard
conditions. The yield of 3da could be further improved to 76%
by treatment with trifluoroacetic acid (TFA) as an additive after
the complete conversion of 1d (see the SI for details). Steric
hindrance retarded the reaction and 3ha was achieved in
moderate yield with a methyl group at the C-4 position. 2-
Alkenylindoles 1 with various N-substituents, such as ethyl,
allyl, and benzyl groups, underwent smooth reactions to
provide 3ka−ma in 72−91% yields under the optimized
conditions. Satisfactorily, switching the Michael acceptors from
diester groups to monoester groups, 3na−pa could be realized
in 90−95% yields. X-ray crystallography of 3pa unambiguously
determined its configuration as shown in Figure 2.11 Replacing
the monoester group with ketone carbonyl groups resulted the
cycloaddition of 1q and 1r in 91% and 96% yields. The reaction
could also endure nitro and cyano groups, which are valuable
and versatile precursors to an array of functional compounds,
leading to 3sa and 3ta in 63% and 94% yield, respectively.
Figure 2. X-ray structure of product 3pa. Hydrogen atoms are omitted
for clarity.
B
DOI: 10.1021/acs.orglett.7b00914
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Organic Letters
Letter
After checking the generality of 2-alkenylindoles 1, we then
switched our attention to the reactivity of α-halohydroxamates
2, and the results are summarized in Scheme 3. Substrates with
Scheme 4. Further Study on [3 + 3] Cycloaddition Reaction
between in Situ Formed Azaoxyallyl Cations and 2-
Alkenylindoles
a,b
Scheme 3. Substrate Scope of α-Halohydroxamates
involved.7a,8b,12c To further understand the mechanistic details
of this [3 + 3] cycloaddition reaction, a control experiment was
carried out (Scheme 5a). When the iminolactonization
cycloadduct 4da was treated with 2.0 equiv TFA, lactamization
cycloadduct 3da could be achieved in 73% yield.
Scheme 5. Mechanism Study
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Na2CO3 (0.8
b
mmol) in HFIP (1.0 mL) for 3 h at room temperature. Isolated
yields. TFA (1.0 mmol) was added until 2-alkenylindoles was
c
completely consumed and stirred at room temperature for another 3 h.
d
e
f
dr = Diastereoisomeric ratio. X = Cl, 2 (0.3 mmol), Na2CO3 (0.6
g
h
mmol). 60 °C. K2CO3 (0.6 mmol) as base.
various protecting groups on the nitrogen atom such as
methoxy, ethoxy, isopropoxy, tert-butoxy, and allyloxy groups
behaved well, furnishing 3ab−af in 63−91% yields. Cyclohexyl-
substituted hydroxamate 2g performed smoothly in the
reaction to give 3ag in 83% yield. When α-halohydroxamates
bearing a monoaryl group were tested, 3nh−nj were prepared
in 54−57% yields (dr >20:1). The relative configuration of 3nj
was determined by single-crystal X-ray analysis (see the SI for
details).11 Additionally, α-halohydroxamates 2 with a mono-
alkyl group delivered 3qk in 79% (dr = 2.3:1) and 3ql in 91%
(dr = 3.0:1) yields at elevated temperature.
In order to showcase the robustness and practicality of this
cycloaddition reaction, we carried out gram-scale experiments.
As illustrated in Scheme 4a, 3na and 3pa could be isolated in
1.13 g (90%) and 1.27 g (85%) yields under the optimized
conditions. Cleavage of the N−O bond of 3pa could be readily
achieved through refluxing with Mo(CO)6 in a MeCN/H2O
mixture solvent, and N-unprotected tetrahydro-β-carbolinone
5pa was obtained in 94% yield (Scheme 4b). The nitro group
of cycloadduct 3sa could be converted to a primary amine in
the presence of sodium borohydride and nickel catalyst. The
tert-butoxycarbonyl (Boc) group protected product 6sa was
obtained in 67% yield through a two-step route (Scheme 4c).10a
Since both lactamization products and iminolactonization
products could be detected in some reaction processes, we
speculated that an O-addition pathway was likely to
On the basis of the above control experiment and previous
reports,6−8,12 a plausible mechanism was proposed as shown in
Scheme 5b. Under weakly basic conditions, α-halohydroxamate
2a in situ generates azaoxyallyl cation A. The ensuing
cycloaddition of 2-alkenylindole 1 and azaoxyallyl cation A
could occur through two possible pathways. In pathway a, the
nitrogen atom as nucleophile delivers the N-cyclization product
3. In pathway b, O-addition to the Michael acceptors produces
intermediate 4. Eventually, the generated O-alkylated inter-
mediate 4 could rearrange to form tetrahydro-β-carbolinone 3.
As observed in our experiments, some O-cyclization product,
such as 4da, is stable enough to be isolated under standard
conditions. Treatment of such reactions with TFA could
C
DOI: 10.1021/acs.orglett.7b00914
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Jeffrey, C. S. Synthesis 2013, 45, 1825. (c) Barnes, K. L.; Koster, A. K.;
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accelerate the conversion of O-cyclization product 4 to N-
cyclization product 3.
In summary, we have realized a novel [3 + 3] cycloaddition
reaction between in situ formed azaoxyallyl cations and 2-
alkenylindoles. This procedure provided an efficient route to
synthesize tetrahydro-β-carbolinones in good yields under mild
reaction conditions, exhibiting good functional group tolerance
and gram-scale ability. Underlining the utility of our reaction,
the product could be further converted to some functional
molecules with potential bioactivity. Further applications of this
methodology to the construction of natural products and
pharmaceutical molecules are currently underway in our
laboratory.
(8) (a) Zhang, K.; Yang, C.; Yao, H.; Lin, A. Org. Lett. 2016, 18,
4618. For similar works, see: (b) Acharya, A.; Montes, K.; Jeffrey, C.
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Org. Chem. Front. 2017, 4, 91.
ASSOCIATED CONTENT
* Supporting Information
■
S
(9) For selected examples on the synthesis of indoles and indolines in
our group, see: (a) Zhao, L.; Li, Z.; Chang, L.; Xu, J.; Yao, H.; Wu, X.
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(11) Crystallographic data for 3pa and 3nj have been deposited with
the Cambridge Crystallographic Data Centre as deposition nos.
CCDC 1539525 and 1546162. Detailed information can be found in
the Supporting Information.
(12) For selected examples employing oxyallyl cations, see: (a) Tang,
Q.; Chen, X.; Tiwari, B.; Chi, Y. R. Org. Lett. 2012, 14, 1922.
(b) Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C. Chem. Sci.
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136, 6288. (d) Liu, C.; Oblak, E. Z.; Vander Wal, M. N.; Dilger, A. K.;
Almstead, D. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138,
2134. For selected examples employing diazaoxyallyl cations, see:
(e) Jeffrey, C. S.; Anumandla, D.; Carson, C. R. Org. Lett. 2012, 14,
5764. (f) Anumandla, D.; Littlefield, R.; Jeffrey, C. S. Org. Lett. 2014,
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2016, 18, 476.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00914.
1H and 13C NMR spectra for all new compounds (PDF)
X-ray crystallographic data for 3pa (CIF)
X-ray crystallographic data for 3nj (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yhuang@cpu.edu.cn.
*E-mail: ajlin@cpu.edu.cn.
ORCID
Hequan Yao: 0000-0003-4865-820X
Aijun Lin: 0000-0001-5786-4537
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232), the Natural Science
Foundation of Jiangsu Province (BK20140655), and the
Foundation of State Key Laboratory of Natural Medicines
(ZZYQ201605) is gratefully acknowledged.
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DOI: 10.1021/acs.orglett.7b00914
Org. Lett. XXXX, XXX, XXX−XXX