Direct C-H Allylation of N-Acyl/Sulfonyl Tetrahydroisoquinolines and Analogues

Article abstract of DOI:10.1021/acs.orglett.5b03042

A highly efficient direct C-H allylation reaction at the α position of N-acyl/sulfonyl tetrahydroisoquinolines under mild conditions was developed. The reaction was also suitable for allylation of other protected nitrogen-containing heterocycles. Several

Full text of DOI:10.1021/acs.orglett.5b03042

Letter
pubs.acs.org/OrgLett
Direct C−H Allylation of N‑Acyl/Sulfonyl Tetrahydroisoquinolines
and Analogues
Changcun Yan, Yuxiu Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300071, People’s Republic of China
*
S Supporting Information
ABSTRACT: A highly efficient direct C−H allylation reaction at
the α position of N-acyl/sulfonyl tetrahydroisoquinolines under
mild conditions was developed. The reaction was also suitable for
allylation of other protected nitrogen-containing heterocycles.
Several interesting transformations of the products into valuable
synthetic intermediates are featured with the successful total
synthesis of (±)-crispine A.
he direct transformation of C−H bonds into useful
Scheme 1. Various Transformations of the Allyl Group
T
functional groups, called C−H functionalization, is a
fascinating synthetic strategy for the construction of new
chemical bonds (especially C−C bonds) from an atom- and
1
3
step-economic point of view. Oxidative C −H functionaliza-
tion of nitrogen-containing heterocycles such as tetrahydro-
isoquinolines (THIQs), which are common structural motifs in
sp
2
3
alkaloids, has achieved impressive progress in the past decade;
however, the scope is limited to highly reactive N-aryl
substituted substrates, which limits the synthetic utility because
4
of the difficulty in removing the N-aryl group. Thus,
3
sp
functionalization of the adjacent C −H bond to readily
removable acyl moieties has attracted the attention of organic
5
chemists, and several examples have been disclosed. However,
the nucleophile scope is limited, likely owing to the
decomposition of unstable N-acyliminium ions in the reaction
5
h
5
conditions. The addition of a stabilizer such as alcohol can
silane (Scheme 2). We used N-Cbz THIQ (1a) and
5h,i
lead to a troublesome operation. Using a nucleophile that
can be easily manipulated to access various functional groups
after the C−C bond formation instead would increase the
possibility of solving the problem.
allyltrimethylsilane as the substrates to optimize the reaction
Scheme 2. Mechanism of the Allylation Reaction
The allyl moiety is an exceptionally versatile functional
group, offering a wealth of opportunities for further
6
−14
functionalizations (Scheme 1).
Traditionally, the SN2
reaction was used to realize the α-allylation of N-acyl THIQs,
15
which required strong bases and a limited substrate scope. In
001, an electrochemical method was developed by the Yoshida
group, in which a specific device was needed, thereby limiting
its academic and industrial applications. Despite this progress,
the development of a mild and efficient method for direct α-C−
H allylation of N-acyl THIQs is still in high demand. Herein,
we report our recent effort on the direct C−H allylation of N-
acyl tetrahydroisoquinolines with allyltrimethylsilane and
further derivatization of the product to representative natural
compounds.
2
conditions (Table 1). Initially, 2,2,6,6-tetramethylpiperidine-1-
+
−
16
oxoammonium tetrafluoroborate (T BF ) was used which had
4
been reported to be an excellent oxidant to oxidize 1a to N-
5h,i
acyliminium.
Fortunately, when CH CN was used as the
3
solvent, the reaction was complete within 2 h and gave the
expected 2a in a yield of 97% (entry 1). Triphenylcarbenium
tetrafluoroborate resulted in a lower yield of 77% (entry 2).
The commonly used oxidant 1,2-dichloro-4,5-dicyanobenzo-
Based on our and others’ previous work, we believed that the
N-acyliminium species could be generated after α-oxidation,
which would undergo nucleophilic addition by allyltrimethyl-
Received: October 20, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03042
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
,
b
Table 1. Optimization of Reaction Conditions
Scheme 3. Reaction Scope with Different N-Acyl THIQs
b
entry
solvent
oxidant
time (h)
yield (%)
+
−
1
2
3
4
5
6
7
8
9
CH CN
T BF
2
2
97
77
92
<5
<5
96
94
93
62
<5
63
<5
96
87
3
4
CH CN
Ph CBF
3
3
4
CH CN
DDQ
24
24
24
12
2
3
CH CN
CAN
3
CH CN
Na S O
8
3
2
2
+
−
−
−
−
−
−
−
−
CHCl3
T BF
4
4
4
4
4
4
4
+
CH Cl2
T BF
2
+
ClCH CH Cl
T BF
2
2
2
+
DMF
T BF
2
+
10
11
12
1
1
DMSO
THF
T BF
24
24
24
2
c
+
T BF
+
CH OH
T BF
3
d
+
3
CH CN
T BF
3
4
−
d
,
e
+
4
CH CN
T BF
2
3
4
a
Reaction conditions: 1a (0.4 mmol, 1 equiv), oxidant (1.5 equiv),
allyltrimethylsilane (1.5 equiv) in solvent (4 mL) at rt under Ar unless
b
c
otherwise noted. Isolated yield; NR, no reaction. 16% of 1a was
recovered. T BF (1 equiv), allyltrimethylsilane (1.2 equiv). Under
d
+
−
e
4
air atmosphere.
quinone (DDQ) could also give a high yield of 92%, but with a
longer reaction time of 24 h (entry 3). However, only a trace
amount of product was obtained when ceric ammonium nitrate
(
CAN) and Na S O were used (entries 4 and 5). Therefore,
2
2
8
+
−
we used T BF4 as the appropriate oxidant for further solvent
screening. Chloralkanes such as CHCl , CH Cl , and
3
2
2
ClCH CH Cl as solvents also gave good yields (entries 6−8).
2
2
+
−
However, due to the poor solubility of T BF , a longer
4
reaction time was needed when CHCl was used (entry 6).
3
Other commonly used solvents such as DMF, DMSO, THF,
a
+
−
Reaction conditions: 1a (0.4 mmol, 1 equiv), T BF4 (1 equiv),
and CH OH resulted in lower yields or no reaction (entries 9−
3
allyltrimethylsilane (1.2 equiv) in solvent (4 mL) at rt under Ar unless
otherwise noted. Isolated yield.
+
−
1
2). Because T BF can dissolve in CH CN excellently, we
b
4
3
think that the quantity of the oxidant can be lowered. An
experiment indicated that the yield was not significantly
+
−
affected when 1.0 equiv of T BF
and 1.2 equiv of
substrates were more stable than the N-acyliminium
intermediates of the former ones. Many functional groups
such as a double bond, cyclopropyl, and halogen at the acyl
moiety were well tolerated, and corresponding products (2j−l)
were obtained in good yields. To explore the regioselectivity of
the reaction, we used N,N-dimethyl carboxamide (1m) as the
substrate and found that the reaction gave 2m as the only
product in 77% yield; no N-methyl allylation product was
detected. This result indicated that the C−H allylation
proceeded selectively at the benzyl of the N-acyl THIQs.
Both the allylic N-sulfonyl THIQs 2n and 2o were obtained in
good yields. We also investigated various substituents on the
benzene ring of the THIQs. THIQs with electron-donating
methoxy groups (1p and 1q), an electron-withdrawing nitro
group (1r), and a halogen (1s) all underwent the reaction with
good yields. Notably, enlarging the scale of the reaction
resulted in a similar yield (see 2p).
4
allyltrimethylsilane were used (entry 13). The reaction can
also proceed smoothly under an air atmosphere but with a
slightly lower yield (entry 14). By this time, we obtained the
optimization conditions without using any transition metal.
With the optimized conditions in hand, we then investigated
the scope of N-acyl/sulfonyl THIQs of the reaction (Scheme
3
). A variety of carbamates of THIQ were examined. The
reactions of benzyl carbamate (1a), methyl carbamate (1b),
and ethyl carbamate (1c) all gave corresponding products (2a−
c) in high yields. The allylic tert-butyl carbamate (2d) was
obtained with a lower yield of 81%, maybe because of the high
steric hindrance. The reaction of phenyl carbamate (1e) also
gave a very high yield. A different result was obtained from the
reaction of amide substrates when compared to the reaction of
carbamate substrates. Acetamide (1f) and n-hexanamide (1g)
(which has a long alkyl chain) underwent direct C−H allylation
to afford the expected products in lower yields than sterically
bulky benzamide (1h) and pivaloylamide (1i). This phenom-
enon can be explained by the stability of the N-acyliminium
intermediates. The N-acyliminium intermediates of the latter
The direct C−H allylation of other carbobenzoxy (Cbz)
protected nitrogen-containing heterocycles were studied next
(Figure 1). For Cbz protected tetrahydro-β-carboline, a
moderate yield of 43% was obtained (see 3). Cbz-protected
B
DOI: 10.1021/acs.orglett.5b03042
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Organic Letters
Letter
Scheme 4. Transformation of the Products and Total
Synthesis of (± )-Crispine A
Figure 1. Reaction scope with other nitrogen-containing heterocycles.
+
−
Reaction conditions: 1a (0.4 mmol, 1 equiv), T BF (1 equiv),
4
allyltrimethylsilane (1.2 equiv) in solvent (4 mL) at rt under Ar unless
+
−
otherwise noted. Isolated yields provided. In the case of 5, T BF4 (2.5
equiv) and allyltrimethylsilane (2.5 equiv) were used.
isoindoline was also tolerated and gave a 44% yield under
standard conditions with a trace amount of diallylic product 5.
When 2.5 equiv of oxidant and allyltrimethylsilane were used, 5
was formed as the only product. We also investigated 1,2,5,6-
tetrahydropyridine which is an important synthon in natural
product synthesis. The reaction proceeded smoothly to give a
good yield. 4-Phenyl-substituted tetrahydropyridine could also
be converted with a higher yield of 88%. Unfortunately, with
piperidine as the substrate, the desired product 8 was not
detected, probably because N-acyliminium could not be
generated due to the higher energy of the C−H bond.
Similarly, linear amine derivatives such as Cbz-protected
benzylic amine and Cbz-protected N-methyl benzylic amine
were proven to be not tolerated.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03042.
The utility of our reaction was further demonstrated. The
Cbz group of 2a could be easily removed under acidic
conditions (Scheme 4, reaction 1). Deprotection and double-
bond reduction could be realized in good yield by one step
involving catalytic hydrogenation (Scheme 4, reaction 2). N-
Acyl products are also very important organic synthetic
intermediates. For example, 2j could be converted to a tricyclic
Detailed experimental procedures and characterization
data of relevant compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangqm@nankai.edu.cn; wang98@263.net.
17
product 11 which is a core scaffold of a number of alkaloids
Notes
via a ring closure metathesis reaction (Scheme 4, reaction 3).
Eventually, we applied our method to the synthesis of
The authors declare no competing financial interest.
8
a
(
±)-crispine A (13) adopting a three-step sequence viz.
ACKNOWLEDGMENTS
■
hydroboration−oxidation, tosylation, and N-deprotection−
cyclization in an overall 71% yield. In addition, compound 12
could serve as an advanced intermediate for the synthesis of
We are grateful to the National Natural Science Foundation of
China (21132003, 21421062, 21372131), the Specialized
Research Fund for the Doctoral Program of Higher Education
8f
crispine C and crispine E after simple synthetic elaboration.
(
20130031110017), and the “111” Project of Ministry of
In conclusion, we report a highly efficient direct C−H
allylation reaction at the α position of N-acyl/sulfonyl THIQs
and analogues that proceeded under mild conditions. The
products of the reaction are suitable for various further
modifications, and the methodology has been successfully
exploited in the synthesis of (±)-crispine A. Further synthetic
exploration toward the enantioselective variant of this strategy
is currently under active investigation and will be reported in
due course.
Education of China (B06005) for generous financial support
for our programs.
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