Efficient and regioselective 9-endo cyclization of α-carbamoyl radicals

Article abstract of DOI:10.1021/ol201180g

With the promotion of Lewis acid BF₃?OEt₂, various N-(hex-5-enyl)-2-iodoalkanamides underwent efficient and regioselective 9-endo iodine-atom-transfer radical cyclization reactions at room temperature. The cyclized products were readily converted to the corresponding azonan-2-ones by reduction with Bu₃SnH or to hexahydroindolizin-3(5H)-ones by treatment with aqueous Na₂CO₃ in a one-pot, two-stage manner.

Full text of DOI:10.1021/ol201180g

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3434–3437
Efficient and Regioselective 9-Endo
Cyclization of R-Carbamoyl Radicals
Liyan Song, Kun Liu, and Chaozhong Li*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
P. R. China
clig@mail.sioc.ac.cn
Received May 4, 2011
ABSTRACT
With the promotion of Lewis acid BF3•OEt2, various N-(hex-5-enyl)-2-iodoalkanamides underwent efficient and regioselective 9-endo iodine-atom-
transfer radical cyclization reactions at room temperature. The cyclized products were readily converted to the corresponding azonan-2-ones by
reduction with Bu3SnH or to hexahydroindolizin-3(5H)-ones by treatment with aqueous Na2CO3 in a one-pot, two-stage manner.
Azonan-2-ones, along with their reduction product
azonanes, are structural motifs in a number of biologically
active natural products such as rhazinilam-type indole
alkaloids1 and Lycopodium alkaloids.2 They are also ver-
satile intermediates in organic synthesis. However, the
efficient and general synthesis of nine-membered lactams
is still a challenging task. They are often prepared by
indirect methods such as ring expansion reactions3 or
Claisen rearrangement4 of heterocyclic enamines. The
direct construction of the nine-membered ring via Beck-
mann rearrangement5 or the dehydration of ω-amino
acids6 suffers from the low chemoselectivity or limited
scope of application. The recently developed ring-closing
metathesis7 requires the use of expensive and air-sensitive
metal complexes. Herein we report that the 9-endo cycliza-
tion of R-carbamoyl radicals provides an efficient and
convenient entry to various substituted azonan-2-ones.
Radical cyclizations have gained increasing popularity
in organic synthesis in the past decades.8 However, most
studies were centered on the 5-exo or 6-exo cyclizations,
while other types of cyclization9 such as 9-endo cyclization
were much less investigated. Nevertheless, scattered exam-
ples could be found in the literature on the 9-endo cycliza-
tions of aryl,10 vinyl,11 alkyl,12 and R-ester radicals.13 On
the other hand, the 9-endo cyclization of R-carbamoyl
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r
10.1021/ol201180g
Published on Web 06/07/2011
2011 American Chemical Society

radicals remains unexplored. Owing to our interest in the
reactivity of R-carbamoyl radicals,14 we set out to explore
this possibility.
Scheme 2. Iodine-Atom-Transfer Reactions of Iodoacetamides
Scheme 1. Reactions of Bromoacetamides with Bu3SnH/AIBN
7a and 9a were employed for this purpose. The direct
cyclization of 7a under the catalysis of BEt3/O2 or
(Bu3Sn)2/hv proceeded sluggishly. However, we were de-
lighted to find that the cyclization was significantly accel-
eratedbyLewisacidBF3•OEt2.17,18 Whensubstrate7awas
treated with (Bu3Sn)2 (30 mol %) and BF3•OEt2 (300 mol
%) inCH2Cl2 atrtunder sunlamp irradiation, the expected
azonanone 8a was obtained in 91% yield (Scheme 2). No
products derived from the 8-exo cyclization could be
detected. The reaction was very clean except that a slow
decomposition of 8a was observed during the workup
procedure. Substrate 9a also underwent cyclization
smoothly under the above conditions. However, the cy-
clized product 10a was very unstable. It underwent fast
decomposition during the purification step, and hexahy-
droindolizinone 11a was detected, which could be gener-
ated via intramolecular nucleophilic substitution. Indeed,
when the crude product 10a, without purification, was
directly treated with an aqueous Na2CO3 solution, the
bicyclic product 11a was isolated in 46% yield based on the
substrate 9a. To improve the yield of 11a, we switched the
solvent from CH2Cl2 to CH3CN. The radical cyclization in
CH3CN proceeded nicely as well under the promotion of
BF3•OEt2. After the same workup with Na2CO3, 11a was
secured in 64% yield. Presumably the intermediate10a was
more stable in CH3CN than in CH2Cl2.
Thus, a number of iodoamide substrates were subjected
to the above radical cyclization conditions in either
CH2Cl2 or CH3CN followed by workup with aqueous
Na2CO3. The results are listed in Table 1. In all cases the
expected indolizinones were obtained in good to excellent
yields. With benzo-fused substrates 7bÀ7g, the corre-
sponding tricyclic products 12bÀ12g were obtained as
mixtures of two stereoisomers. The configurations of the
two stereoisomers of 12b were unambiguously determined
by the coupling constants of related protons and by 2D
NOESY experiments (see the Supporting Information).
2-Bromo-N-(hex-5-enyl)acetamide (1) was initially used
as the substrate. The slow addition (with the aid of a
syringe pump) of the benzene solution of Bu3SnH and
AIBN into 1 in benzene (0.03 M) at reflux yielded only a
trace amount of the expected cyclizationÀreduction pro-
duct 2a, the major product being the direct reduction
product 3 (Scheme 1). Similarly, the reaction of benzo-
fused amide 4 with Bu3SnH/AIBN gave the cyclized
product 5 in only 36% yield while the direct reduction
product 6 was obtained in 63% yield.
We then turned to examine the corresponding iodine-
atom-transfer cyclization reactions.15,16 Iodoacetamides
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Org. Lett., Vol. 13, No. 13, 2011
3435

the two stereoisomers occurred under the reaction condi-
tions. For substrates 9aÀ9d without a benzo-fused substi-
tuent, the product yields were lower presumably due to the
partial decomposition of the azonanone intermediates.
While substrate 9b with an R-carbonyl substituent gave
the mixture of two stereoisomers in 1:1 ratio, substrate 9d
having a phenyl group R to the nitrogen afforded the
product 11d with a high stereoselectivity. The reason for
this difference is not clear at this moment.
Table 1. Synthesis of Indolizinones
In light of the above results and in order to obtain stable
azonanone products, we designed the following experi-
ment (eq 1). After the BF3•OEt2-promoted cyclization of
9a was complete (as indicated by TLC), Bu3SnH (2 equiv)
and BEt3 (0.5 equiv) were added into the reaction mixture
to reduce the iodo-containing intermediate 10a. Azona-
none 2a was thus obtained in 57% yield in a one-pot, two-
stage manner. It is worth mentioning that the direct
treatment of 9a with Bu3SnH/AIBN in benzene at reflux
yielded the direct reduction product 3 only.
The above cyclizationÀreduction sequence was thus
applied to a number of unsaturated iodoamides, and the
results are summarized in Table 2. The reactions were
highly regioselective, and no products derived from 8-exo
cyclization could be detected. These results parallel closely
with those in Table 1.
Scheme 3. Stereoselective 9-Endo Cyclization
a Reaction conditions: (1) iodoamide (0.3 mmol), (Bu3Sn)2 (0.09
mmol), BF3•OEt2 (0.9 mmol), solvent (10 mL), rt, hv, 2 h, then (2)
saturated aqueous Na2CO3 (10 mL), rt, 5 h. b Isolated yield based on the
d
corresponding iodoamide. c Determined by 1H NMR (400 MHz).
Solvent: CH2Cl2. e Solvent: CH3CN.
Interestingly, the substituents R R to the carbonyl group
showed a remarkable influence on the product stereose-
lectivity. The ratio of trans to cis isomers increases when
the size of R increases. These ratios might reflect the
stereoselectivity of 9-endo radical cyclization if we assume
that the intramolecular nucleophilic substitution is an SN2
process. Indeed, prior to the basic workup, the reaction of 7b
afforded the iodo-substituted azonanone (analogous to 8a)
as the mixture of two stereoisomers in a 3:1 ratio determined
by the crude 1H NMR, consistent with the trans/cis ratio of
12b (entry 2, Table 1). Note that the ratio did not change
with reaction time, implying that no equilibrium between
Encouraged by the above excellent regioselectivity of
cyclization, we moved one step further to study the reac-
tion of iodoamide 13 with two methyl substituents, one R
to the amide carbonyl and the other R to the nitrogen
(Scheme 3). The cyclization was carried out in CH2Cl2.
After the reduction with Bu3SnH, the product 14 was
isolated in 61% yield as a single isomer, whose configura-
tion was finally determined to be 3,9-cis by the X-ray
diffraction experiment. This example indicates that the
9-endo cyclization can be highly stereoselective.
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Org. Lett., Vol. 13, No. 13, 2011

Table 2. Synthesis of Azonan-2-ones
Scheme 4. Calculated (B3LYP/6-31G*) Activation Free
Energies
lower than that for the corresponding 8-exo cyclization,
consistent with the experimental observations. Moreover,
the activation energy for 9-endo cyclization via the Z-con-
formational TS (11.2 kcal/mol) is lower than the energy
barrier (13.5 kcal/mol) for the Z toE interconversion of the
substrate radical. The activation energy for cyclization is
expected tobefurther loweredinthe presenceof Lewisacid
BF3•OEt2.14a Therefore, it is more likely that the 9-endo
cyclization proceeds via the Z-conformational TS.
In conclusion, the above experiments in combination
with theoretical calculations have clearly demonstrated
that the 9-endo cyclization of R-carbamoyl radicals is an
efficient and highly regioselective process. The cyclization
can be significantly promoted by BF3•OEt2. The iodine-
atom-transfer cyclization followed by reduction with
Bu3SnH allows the convenient generation of various sub-
stituted nine-membered lactams. Furthermore, the 9-endo
iodine-atom-transfer cyclization products can be effec-
tively converted to the corresponding bicyclic indolizi-
nones by the simple workup with Na2CO3, which should
be an important application in organic synthesis.
a Reaction conditions: (1) iodoamide (0.3 mmol), (Bu3Sn)2 (0.09
mmol), BF3•OEt2 (0.9 mmol), solvent (10 mL), rt, hv, 2 h, then (2)
Bu3SnH (0.6 mmol), BEt3 (0.15 mmol), rt, dark, 2 h. b Isolated yields
based on the corresponding iodoamides. c Solvent: CH2Cl2. d Solvent:
CH3CN.
Acknowledgment. This project was supported by the
National Natural Science Foundation of China (Grant
Nos. 20832006 and 21072211) and by the National Basic
Research Program of China (Grant No. 2010CB833206).
To gain further insight into the reactivity of R-carba-
moyl radicals in 9-endo cyclization, we performed the
density functional calculations on radical 7R derived from
substrate 7a. The activation free energies calculated at the
B3LYP/6-31G* level are listed in Scheme 4. The cyclization
may proceed via two possible pathways, the E-conforma-
tional transition states (TSs) or the Z-conformational TSs.
In both cases the activation energy for 9-endo cyclization is
Supporting Information Available. Full experimental
1
procedures, compound characterizations, copies of H
and 13C NMR spectra, DFT calculation results, and
crystallographic data in CIF format. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 13, 2011
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