Intramolecular Imidoylative Heck Reaction: Synthesis of Cyclic Ketoimines from Functionalized Isocyanide

Article abstract of DOI:10.1021/acs.orglett.6b01174

Efficient access to five- to seven-membered cyclic ketoimines, through palladium-catalyzed intramolecular imidoylative Heck reaction of alkene-containing isocyanides, has been developed. Consecutive isocyanide and alkene insertion into aryl or alkyl Pd(II) intermediates takes place in this process. No byproduct derived from monoinsertion or reversed sequence is detected.

Full text of DOI:10.1021/acs.orglett.6b01174

Letter
pubs.acs.org/OrgLett
Intramolecular Imidoylative Heck Reaction: Synthesis of Cyclic
Ketoimines from Functionalized Isocyanide
Jian Wang, Shi Tang, and Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190
Kaiyuan Avenue, Guangzhou 510530, China
S
* Supporting Information
ABSTRACT: Efficient access to five- to seven-membered
cyclic ketoimines, through palladium-catalyzed intramolecular
imidoylative Heck reaction of alkene-containing isocyanides,
has been developed. Consecutive isocyanide and alkene
insertion into aryl or alkyl Pd(II) intermediates takes place
in this process. No byproduct derived from monoinsertion or
reversed sequence is detected.
zepines, a class of seven-membered N-heterocycles, are
ubiquitous in many bioactive synthetic compounds as well
as natural products (Scheme 1). For example, mozavaptan is a
In recent years, nonfunctionalized isocyanides have been
extensively studied in palladium-catalyzed imidoylation reac-
tions to synthesize acyclic imine derivatives.7,8 To access to
cyclic products using nonfunctionalized isocyanides, a nucleo-
philic group is usually preinstalled in a precursor of imidoyl
Pd(II) intermediate, formed either from oxidative addition or
C−H bond activation followed by isocyanide insertion.9 For
example, 4-aminoquinazolines were efficiently accessed from N-
(2-bromoaryl)amidines9a or N-arylamidines9b through palla-
dium-catalyzed imidoylative cyclization and tautomerization,
developed by Maes and our group, respectively. Besides, cyclic
guanidine and related heterocycles could be synthesized by Pd-
catalyzed oxidative imidoylative coupling using substrates
containing two nucleophilic heteroatoms.10 In these non-
functionalized isocyanide approaches, isocyanide is used as a C1
synthon, and only the terminal carbon of isocyanide is
contributed to the ring construction. On the other hand, by
using the so-called functionalized isocyanide strategy, multiple
atoms including the isocyanide nitrogen could be introduced to
the ring.11 Therefore, the diversity of isocyanide could be fully
used, demonstrating the advantage of isocyanide over carbon
monoxide CO in relevant carbonylation reactions. By applying
this approach, indole derivatives,11a,b camptothecin ana-
logues,11c multisubstituted oxazoles,12 and phenanthridines13
were efficiently prepared (Scheme 2).
A
Scheme 1. Representative Molecules Containing the Azepine
Moiety
drug used in Japan for the treatment of paraneoplastic
syndrome of inappropriate secretion of antidiuretic hormone.1
Eslicarbazepine acetate is an efficient drug used for the
treatment of adjunctive therapy for partial onset of seizures.2
Deoxyharringtonine, isolated from the Cephalotaxus genus, is
an important antileukemia alkaloid exhibiting acute toxicity
toward P388 and L1210 leukemia cells.3 Spiroimine-containing
alkaloid (+)-pinnatoxin A is a toxic amphoteric macrocycle
isolated from the Okinawan bivalve Pinna muricata.4a Tradi-
tional preparation of such azepine derivatives was mainly based
on ring-expansion reactions,5a Beckman rearrangements,5b and
other multistep sequences.5c,d However, a general and efficient
method for the construction of azepine derivatives remains an
attractive synthetic task.6
Concerning the size of the rings formed, the synthesis of
seven-membered N-heterocycles through Pd-catalyzed imidoy-
lation of functionalized isocyanide was unprecedented (Scheme
2). Herein, we developed efficient access to seven-membered
cyclic ketoimines starting from alkene-containing isocyanides.
In this imidoylative Heck process, isocyanide and alkene
underwent insertion to Pd(II) intermediate sequentially,
affording 6-methylene-3,4,5,6-tetrahydro-2H-azepines exclu-
sively. In addition, by altering the length between the isocyano
Received: April 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01174
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Pd-Catalyzed Functionalized Isocyanide Strategy
Table 1. Optimization of the Reaction Conditions
for the Synthesis of N-Heterocycles
b
entry
solvent
base (1.2 equiv)
temp (°C)
yield (%)
c
1
toluene
toluene
toluene
toluene
toluene
DMSO
dioxane
CH3CN
toluene
toluene
toluene
toluene
Na2CO3
K2CO3
Cs2CO3
CsOPiv
Et3N
80
80
80
80
80
80
80
80
80
80
70
100
18
18
30
70
25
70
33
40
c
2
c
3
c
4
c
5
c
6
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
c
7
c
8
c
,
e
f
9
81 (79)
c
c
,
g
f
10
11
12
56
f
45
d
,
e
f
85 (82)
a
Reaction conditions: 1a (0.2 mmol), 2 (0.30 mmol), Pd(OAc)2 (0.02
mmol, 10 mol %), PPh3 (0.04 mmol, 20 mol %), base (0.24 mmol),
Ar. A solution of 1a in solvent (1 mL) was added slowly within 1 h.
b
NMR yield with 1-iodo-4-methoxybenzene as an internal standard.
c
d
e
X = I. X = Br. A solution of 1a in toluene (1 mL) was added via a
f
g
syringe pump within 1 h. Isolated yield. 5 mol % of Pd(OAc)2 and 10
mol % of PPh3.
Azepines 3a and 3d were also accessed in 82% and 92% yields,
respectively, using corresponding aryl bromides at 100 °C.
Sterically hindered 1-iodonaphthalene afforded the product 3m
in lower yield (59%). Heteroaryl halides could also participate
in the reaction smoothly, generating 3n−q in comparable
yields. A symmetrical bis-azepine 3r was obtained in 76% yield
using 1,4-diiodobenzene as the coupling partner. When N-(2-
iodophenyl)-N-methylmethacrylamide was applied in the
reaction, a cascade process involving alkene, isocyanide, and
alkene insertion took place sequentially to give a methylene-
tethered oxindole−azepine pair 3s in 61% yield. When alkenyl
and alkynyl bromides were carried out in the reaction, no
corresponding products were generated. It is notable that gram-
scale preparation of 3f (1.37 g) was accessible in 70% yield.
Then, the scope of isocyanide was studied in reactions with
iodobenzene under the standard conditions (Scheme 4). Other
α-alkylated methyl 2-isocyanohept-6-enoates were tested, and
the corresponding azepines (4a−c) were obtained in excellent
yields. Substrate containing two alkenyl groups reacted
smoothly to give 4d, with the other alkenyl group unreacted,
in 83% yield. Other electron-withdrawing groups such as
phosphate were well tolerated in the reaction (4e). In addition
to azepines, six- and five-membered cyclic imines were obtained
as well by shortening the alkenyl carbon chain (4f,g). It is
worth of mentioning that α-unsubstituted ethyl 2-isocyanopent-
4-enoate also survived the reaction, generating 4-methylene-
3,4-dihydro-2H-pyrrole derivative 4h in 72% yield. Internal
alkene underwent the insertion reaction smoothly, generating
trisubstituted exocyclic alkene 4i in 97% yield. Unfortunately,
eight-membered and larger sized cyclic imines could not be
synthesized by extending the distance between the isocyano
and alkenyl groups under the same reaction conditions.
and alkenyl moieties, five- and six-membered cyclic imines
could also be obtained.
The reaction conditions were screened with ethyl 2-isobutyl-
2-isocyanohept-6-enoate 1a and iodobenzene as model
substrates. However, a reaction of premixed reactants under
normal Heck conditions (Pd(OAc)2, PPh3, Na2CO3 in toluene)
yielded only a messy mixture. When a solution of isocyanide 1a
in toluene was introduced to the reaction mixture slowly, the
desired product, ethyl 2-isobutyl-6-methylene-7-phenyl-3,4,5,6-
tetrahydro-2H-azepine-2-carboxylate 3a, was formed in 18%
NMR yield (entry 1, Table 1). Screening of bases revealed that
CsOPiv was the base of choice for this imidoylative Heck
reaction, and 3a could be obtained in 70% yield (entries 2−5).
The reaction was equally efficient in DMSO, but less efficient in
dioxane or CH3CN (entries 6−8). The yield of 3a was
increased to 81% when a solution of 1a in 1 mL of toluene was
added via a syringe pump during 1 h (entry 9). The yield
decreased to 45% at 70 °C (entry 10) and 56% with 5 mol % of
Pd(OAc)2 and 10 mol % of PPh3 (entry 11). When using
bromobenzene as the arylating reagent, the same product 3a
was generated in 85% yield at elevated temperature (100 °C,
entry 12). (For more details, see Supporting Information.)
With the optimized conditions in hand, the substrate scope
of electrophiles was investigated first (Scheme 3). Substituents
such as OMe, Ph, Cl, Br, CO2Me, COMe, CN, NO2, and CHO
on aryl iodide were well tolerated in reactions with ethyl 2-
isobutyl-2-isocyanohept-6-enoate 1a, generating the corre-
sponding products in good to excellent yields (3a−l). When
1-chloro-2-iodobenzene was used as the substrate, the reaction
was messy and a only trace product was detected by LC−MS,
indicating that the reaction was sensitive to steric hindrance.
Similar to the reported imidoylation reactions, the current
imidoylative Heck reaction is likely initiated by oxidative
addition of aryl halide to Pd(0), as shown in Scheme 5.5
B
DOI: 10.1021/acs.orglett.6b01174
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Substrate Scope of Aryl Halides
Scheme 4. Substrate Scope of Isocyanides
a
Reaction conditions: 1 (0.2 mmol), PhI (0.30 mmol), Pd(OAc)2
(0.02 mmol, 10 mol %), PPh3 (0.04 mmol, 20 mol %), CsOPiv (0.24
mmol), 80 °C, Ar. A solution of 1 in toluene (1 mL) was added to the
reaction mixture via a syringe pump within 1 h. Isolated yields were
b
c
given. dr = 2.6:1. THF as solvent.
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1a (0.2 mmol), 2 (0.30 mmol), Pd(OAc)2 (0.02
mmol, 10 mol %), PPh3 (0.04 mmol, 20 mol %), CsOPiv (0.24 mmol),
80 °C (X = I) or 100 °C (X = Br), Ar. 1a in toluene (1 mL) was added
to the reaction mixture (in 1 mL of toluene) via a syringe pump within
b
1 h. Isolated yields were given. 1a (0.2 mmol), 1,4-diiodobenzene
(0.1 mmol).
Migratory isocyanide insertion to intermediate II affords
imidoyl Pd(II) intermediate III. The following intramolecular
alkene insertion and β-hydride elimination via IV yields the
final product and regenerates Pd(0) to complete the catalytic
cycle.
In conclusion, we have developed an efficient and practical
method for the synthesis of imine-containing azepines via
palladium-catalyzed imidoylative Heck reaction. Seven-mem-
bered heterocycles were first synthesized using the function-
alized isocyanide under palladium catalysis. The reaction
proceeds through consecutive isocyanide and alkene insertion
into aryl or alkyl Pd(II) intermediates, and no byproduct
derived from monoinsertion or reversed sequence is detected.
A broad range of substrates are applicable to the reaction in
good to excellent yields. These five- to seven-membered cyclic
imine products bearing an exocyclic methylene group may serve
C
DOI: 10.1021/acs.orglett.6b01174
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01174.
■
S
General experimental procedures and characterization
data of the compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhu_qiang@gibh.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Science Foundation
of China (21272233, 21472190, and 21573095).
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Giofre, S. V.; Gabriele, B. J. Org. Chem. 2014, 79, 3506.
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DOI: 10.1021/acs.orglett.6b01174
Org. Lett. XXXX, XXX, XXX−XXX