Efficient regio- And stereoselective formation of azocan-2-ones via 8-endo cyclization of α-carbamoyl radicals

Article abstract of DOI:10.1021/ja9082649

The iodine-atom-transfer 8-endo cyclization of α-carbamoyl radicals was investigated experimentally and theoretically. With the aid of Mg(CIO ₄)₂ and a bis(oxazoline) ligand, N- ethoxycarbonylsubstituted N-(pent-4-enyl)-2-iodoalkanamides underwent 8-endo cyclization leading to the formation of only the corresponding 3,5-trans-substituted azocan-2-ones in excellent yields. Similarly, the BF ₃·OEt₂/H₂O-promoted reactions of N-ethoxycarbonyl-N-(2-allylaryl)-2-iodoalkanamides afforded exclusively the benzazocanone products with a 3,5-cis configuration in high yields. The bidentate chelation of substrate radicals not only significantly improved the efficiency of cyclization but also resulted in the change of stereochemistry of azocanone products from 3,8-iransto 3,8-cis. Theoretical calculations at the UB3LYP/6-31G* level revealed that the cyclization of N-carbonyl- substituted α-carbamoyl radicals occurs via the E-conformational transition states without the presence of a Lewis acid. On the other hand, the cyclization proceeds via the Z-conformational transition states when the substrates form the bidentate chelation with a Lewis acid. In both cases, the 8-endo cyclization is always fundamentally preferred over the corresponding 7-exo cyclization. The complexed radicals having the more rigid conformations also allow the better stereochemical control in the iodine-atom-abstraction step. To further understand the reactivity of a-carbamoyl radicals, the competition between the 8-endo and 5-exo cyclization was also studied. The results demonstrated that the 8-endo cyclization is of comparable rate to the corresponding 5-exo cyclization for a-carbamoyl radicals with fixed Z-conformational transition states. As a comparison, the 8-endo mode is fundamentally preferred over the 5-exo mode in the cyclization of NH-amide substrates because the latter requires the Z-conformational transition states, whereas the former proceeds via the more stable E-conformational transition states.

Full text of DOI:10.1021/ja9082649

Published on Web 02/01/2010
Efficient Regio- and Stereoselective Formation of
Azocan-2-ones via 8-Endo Cyclization of r-Carbamoyl
Radicals
Xinqiang Fang, 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
Received October 5, 2009; E-mail: clig@mail.sioc.ac.cn
Abstract: The iodine-atom-transfer 8-endo cyclization of R-carbamoyl radicals was investigated experi-
mentally and theoretically. With the aid of Mg(ClO4)2 and a bis(oxazoline) ligand, N-ethoxycarbonyl-
substituted N-(pent-4-enyl)-2-iodoalkanamides underwent 8-endo cyclization leading to the formation of
only the corresponding 3,5-trans-substituted azocan-2-ones in excellent yields. Similarly, the BF3 ·OEt2/
H2O-promoted reactions of N-ethoxycarbonyl-N-(2-allylaryl)-2-iodoalkanamides afforded exclusively the
benzazocanone products with a 3,5-cis configuration in high yields. The bidentate chelation of substrate
radicals not only significantly improved the efficiency of cyclization but also resulted in the change of
stereochemistry of azocanone products from 3,8-trans to 3,8-cis. Theoretical calculations at the UB3LYP/
6-31G* level revealed that the cyclization of N-carbonyl-substituted R-carbamoyl radicals occurs via the
E-conformational transition states without the presence of a Lewis acid. On the other hand, the cyclization
proceeds via the Z-conformational transition states when the substrates form the bidentate chelation with
a Lewis acid. In both cases, the 8-endo cyclization is always fundamentally preferred over the corresponding
7-exo cyclization. The complexed radicals having the more rigid conformations also allow the better
stereochemical control in the iodine-atom-abstraction step. To further understand the reactivity of
R-carbamoyl radicals, the competition between the 8-endo and 5-exo cyclization was also studied. The
results demonstrated that the 8-endo cyclization is of comparable rate to the corresponding 5-exo cyclization
for R-carbamoyl radicals with fixed Z-conformational transition states. As a comparison, the 8-endo mode
is fundamentally preferred over the 5-exo mode in the cyclization of NH-amide substrates because the
latter requires the Z-conformational transition states, whereas the former proceeds via the more stable
E-conformational transition states.
Introduction
of 7-octenyl radical is preferred over the corresponding 7-exo
cyclization.2 The 8-endo cyclizations of various types of
The addition of carbon-centered radicals to CdC bonds has
been firmly established as an indispensable tool for carbon-
carbon bond formations.1 The intramolecular version, in par-
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with unique chemo-, regio-, and stereoselectivities. This radical
cyclization strategy has found wide application in the synthesis
of complex natural products and medicinal agents.
Among various modes of radical cyclization, 5-exo and 6-exo
cyclizations are perhaps the most extensively studied types of
reactions. As a comparison, 7-exo and 8-endo radical cycliza-
tions have received much less attention. Theoretical calculations
by Beckwith and Schiesser predicted that the 8-endo cyclization
radicals,3-15 including alkyl,3 aryl,4 acyl,5 ketyl,6 and even
amidyl radicals,7 were later implemented with variable efficien-
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2274 J. AM. CHEM. SOC. 2010, 132, 2274–2283
10.1021/ja9082649  2010 American Chemical Society

Formation of Azocan-2-ones
A R T I C L E S
cyclization of R-ester radicals,8-12 especially those leading to
the synthesis of heptanolactones.9-12 Literature reports revealed
that the 8-endo cyclization is fundamentally preferred over the
corresponding 7-exo cyclization for R-ester radicals. The pres-
ence of Lewis acids such as BF3 ·OEt2 significantly accelerated
the cyclization, providing a highly efficient entry to heptano-
lactones.12 More importantly, Lee and co-workers discovered
that the 8-endo mode was even preferred over the 5-exo mode
in the cyclization of (R-alkoxycarbonyl)methyl radicals.11 This
was analyzed by the fact that the 5-exo cyclization requires the
E-conformational (s-cis) transition states (TS), whereas the
8-endo cyclization can proceed via the more stable Z-confor-
mational (s-trans) TS. Nevertheless, the weakness of these
8-endo cyclization reactions was also obvious in that poor
stereoselectivity was typically observed.12
Scheme 1
(Scheme 1), in which they observed that the regioselectivity
depended strongly on the types of radical precursors.13 For
example, the dichloroamides 1 (X ) Y ) Cl) gave exclusive
7-exo cyclization product 2, whereas the bisthiophenylamide 1
(X ) Y ) PhS) generated the corresponding 8-endo cyclization
product 3.13 Similar results were also obtained in the N-benzyl
analogues of 1 as reported by Murphy et al.9g The iodine-atom-
transfer radical cyclization reactions of N-(4-pentenyl)-2-io-
doalkanamides such as 4 were later investigated by us (Scheme
2).14 The reactions were carried out at much milder conditions
(room temperature) with the promotion of BF3 ·OEt2. An
excellent regioselectivity in favor of 8-endo cyclization was
observed. However, the yields of azocanones (such as 5) were
only moderate, and lactones such as 7 were also generated as
the side products. This phenomenon was then analyzed by our
density functional calculations, which showed that the 8-endo
cyclization could proceed via both the Z- and the E-conforma-
tional TS and that the cyclized product 6 via the Z-conforma-
tional TS underwent decomposition to give 7. As a comparison,
the atom-transfer cyclization of N-(2-allylphenyl)-2-iodoalkana-
mides had a high efficiency but a very poor regioselectivity.
For example, the cyclization of iodide 8 afforded the mixture
of benzazepinone 9 and benzazocinone 10 in about a 2:3 ratio.
A clear understanding and efficient control of the reactivity
of R-carbamoyl radicals are thus required in order to develop
the halogen-atom-transfer 8-endo R-carbamoyl radical cycliza-
tion into a useful synthetic methodology. Specifically, (1) the
difference between the Z-conformational TS and the E-confor-
mational TS in terms of the efficiency and regioselectivity of
cyclization has to be understood; (2) effective control over the
TS conformations is necessary to direct the cyclization to
proceed as planned; (3) the substituent effect on the cyclization
has to be examined on the basis of which highly stereoselective
reactions might be developed; and finally, (4) to make the 8-endo
cyclization of more synthetic value, it is highly desirable that a
high degree of stereochemical control over the halogen-atom-
abstraction step could be achieved, although poor stereoselec-
tivity is typically observed in endo-type halogen-atom-
abstractions.12
The examples of successful regioselective 8-endo cyclization
of R-ester radicals certainly encouraged the development of
8-endo cyclization of R-carbamoyl radicals because of the
structural similarity between these two types of radicals.16
However, only a few examples could be found in the literature
on the 7-exo versus 8-endo cyclization of R-carbamoyl radicals,
which showed a behavior dramatically different from that of
R-ester radicals.13-15,9g Ikeda and co-workers reported the
reactions of haloamides 1 with the initiation of Bu3SnH/AIBN
(6) (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1994, 59, 3186. (b)
Monovich, L. G.; Huerou, Y. L.; Ronn, M.; Molander, G. A. J. Am.
Chem. Soc. 2000, 122, 52. (c) Molander, G. A.; George, K. M.;
Monovich, L. G. J. Org. Chem. 2003, 68, 9533. (d) Saadi, J.; Reissig,
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Lett. 1988, 29, 5209. (b) Snider, B. B.; Merritt, J. E. Tetrahedron
1991, 47, 8663. (c) Ali, A.; Harrowven, D. C.; Pattenden, G.
Tetrahedron Lett. 1992, 33, 2851. (d) Begley, M. J.; Pattenden, G.;
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Udding, J. H.; Giesselink, J. P. M.; Hiemstra, H.; Speckamp, W. N.
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2009, 11, 2285.
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J. Tetrahedron Lett. 1992, 33, 5141. (b) Pirrung, F. O. H.; Hiemstra,
H.; Kaptein, B.; Sobrino, M. E. M.; Petra, D. G. I.; Schoemaker, H. E.;
Speckamp, W. N. Synlett 1993, 739. (c) Pirrung, F. O. H.; Hiemstra,
H.; Speckamp, W. N.; Kaptein, B.; Schoemaker, H. E. Tetrahedron
1994, 50, 12415. (d) Pirrung, F. O. H.; Hiemstra, H.; Speckamp, W. N.;
Kaptein, B.; Shoemaker, H. E. Synthesis 1995, 458. (e) De Campo,
F.; Lastecoueres, D.; Verlhac, J.-B. Chem. Commun. 1998, 2117. (f)
De Campo, F.; Lastecoueres, D.; Verlhac, J.-B. J. Chem. Soc., Perkin
Trans. 1 2000, 575. (g) Lang, S.; Corr, M.; Muir, N.; Khan, T. A.;
Schonebeck, F.; Murphy, J. A.; Payne, A. H.; Williams, A. C.
Tetrahedron Lett. 2005, 46, 4027. (h) Ram, R. N.; Tittal, R. K.; Upreti,
S. Tetrahedron Lett. 2007, 48, 7994. (i) Bull, J. A.; Hutchings, M. G.;
Quayle, P. Angew. Chem., Int. Ed. 2007, 46, 1869. (j) Bull, J. A.;
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1352.
Scheme 2
(10) Russell, G. A.; Li, C. Tetrahedron Lett. 1996, 37, 2557.
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10981. (b) Lee, E.; Yoon, C. H. Tetrahedron Lett. 1996, 37, 5929. (c)
Lee, E.; Yoon, C. H.; Lee, T. H.; Kim, S. Y.; Ha, T. J.; Sung, Y.-s.;
Park, S.-H.; Lee, S. J. Am. Chem. Soc. 1998, 120, 7469.
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Trans. 1 1991, 353. (b) Ikeda, M.; Obata, K.-i.; Oka, J.-i.; Ishibashi,
H.; Sato, T. Heterocycles 1997, 44, 203.
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2006, 47, 8259.
(16) Although no 8-endo cyclization has been reported for R-keto radicals,
the endo-selectivity was generally observed in their cyclization
reactions. For selected examples, see: (a) Clive, D. L. J.; Cheshire,
D. R. J. Chem. Soc., Chem. Commun. 1987, 1520. (b) Curran, D. P.;
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9
J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010 2275

A R T I C L E S
Fang et al.
Azocan-2-ones, along with their reduction products azocanes,
are important structural motifs in many biologically active
natural products and medicinal agents such as shearinines C
and H-J17 and manzamine alkaloids.18 They are also versatile
intermediates in a number of areas ranging from organic
synthesis to polymer chemistry. However, the efficient and
general synthesis of eight-membered lactams is still a challeng-
ing task.19 For example, the dehydration of ω-amino acids often
gives low yields of azocanones.20 The Beckmann rearrangement
of ketoximes suffers from harsh reaction conditions and poor
chemoselectivity.21 The recently developed ring-closing me-
tathesis requires the use of expensive and air-sensitive transition
metal complexes.22 The importance of azocanones urged us to
study the reactivity of R-carbamoyl radicals in detail. In this
paper, we report the experimental results and theoretical basis
on the regio- and stereocontrol of this 8-endo cyclization.
10 min afforded a mixture of cyclized products 12a (23%) and
13a (27%), whose structures were unambiguously established
by their X-ray diffraction experiments. The irradiation of 11a
by sunlamp in the presence of (Bu3Sn)216b,25 (40 mol %) resulted
in a much slower reaction (rt, 12 h). However, the outcome
was almost identical (24% yield of 12a and 27% yield of 13a).
No corresponding 7-exo cyclization products could be detected.
In a similar fashion, the reactions of substrates 11b-11f bearing
different alkyl groups at the R-position were also examined with
BEt3/O2 as the initiator, and the results are summarized in Table
1. In all cases the 8-endo cyclization products were isolated in
moderate yields, while no 7-exo products could be observed.
All products 12 and 13 have the 3,8-trans configuration. The
ratio of 12 to 13 increases with the increasing bulkiness of the
R group.
Results
N-Acyloxazolidinone 11a was first designed as the model
substrate for the 8-endo cyclization. It could be anticipated that
11a would exist exclusively in the E-conformation to avoid the
steric interaction between the olefinic chain and the iodoethyl
moiety in its Z-conformation (eq 1). On the other hand, the
Z-conformation would predominate if the bidentate chelation
between a Lewis acid and the two carbonyl groups in 11a could
be effectively formed. Such a concept23 has been widely applied
in a variety of stereoselective organic transformations, including
asymmetric radical reactions developed by Sibi.24 In our case
it would allow us to direct the 8-endo radical cyclization to
proceed via either the fixed Z- or the fixed E-conformational
TS.
The cyclization of substrate 11a in the presence of a Lewis
acid26 was then examined (Table 2). With 1 equiv of Yb(OTf)3
as the additive, the reaction of 11a with BEt3/O2 yielded the
mixture of 12a, 13a and the third product 14a, all in low yields
(entry 1, Table 2). The structure of 14a was also unambiguously
determined by X-ray diffraction experiment. Note that com-
pound 14a has the 3,8-cis configuration, implying that it could
be generated via a different TS, which will be further discussed
later. Changing the Lewis acid to Zn(OTf)2 or Mg(OTf)2 did
not show any improvement (entries 2 and 3, Table 2). We then
turned to trifluoroborane etherate for help.12,14,27 Initially the
commercially available BF3 ·OEt2 was directly used without
further purification. With the presence of 4 equiv of such kind
of BF3 ·OEt2, the reaction of 11a gave 14a in 31% yield, while
only trace amounts of 12a and 13a could be detected (entry 5,
Table 2). When BEt3/O2 was switched to (Bu3Sn)2/hν, the yield
of 14a was increased to 53% (entry 6, Table 2). However, the
reaction was hard to repeat when freshly distilled BF3 ·OEt2 was
used (entry 7, Table 2). Such a phenomenon had previously
been observed by us in the oligomerization of R-carbonyl
radicals.28 With the assumption that the aged BF3 ·OEt2 might
be contaminated by moisture, we deliberately added water into
the reaction system. To our delight, when 4 equiv of freshly
distilled BF3 ·OEt2 and 0.2 equiv of water were used as the
additives, the reaction of 11a proceeded smoothly, leading to the
exclusive formation of 14a in 70% yield (entry 11, Table 2).29
The optimized conditions (entry 11, Table 2) were then
applied to the reactions of other substrates 11b-11g. We were
pleased to find that, in all cases, the corresponding 8-endo
cyclization products 14 were achieved in high yields with
The cyclization of substrate 11a without the presence of a
Lewis acid was carried out. The treatment of 11a with BEt3
(20 mol %)/O2 in CH2Cl2 (0.03 M) at room temperature (rt) for
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2276 J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010

Formation of Azocan-2-ones
A R T I C L E S
Table 1. BEt3/O2-Initiated Radical Cyclization of Oxazolidinones 11
Table 3. BF3 ·OEt2/H2O-Promoted Cyclization of Oxazolidinones 11
entrya
substrate
R
product (yield, %)b
entrya
R
product
yield (%)b
1
2
3
4
5
6
11a
11b
11c
11d
11e
11f
Me
Et
Bu
C6H13
i-Pr
t-Bu
12a (23)
13a (27)
13b (13)
13c (10)
13d (10)
13e (trace)
13f (trace)
1
2
3
4
5
6
7
Me
Et
Bu
C6H13
i-Pr
t-Bu
H
14a
14b
14c
14d
14e
14f
70
82
84
80
83
87
73
12b (31)
12c (35)
12d (36)
12e (45)
12f (42)
14g
a Reaction conditions: 11 (0.3 mmol), BEt3 (0.06 mmol), CH2Cl2 (10
mL), rt, 10 min. b Isolated yield based on 11.
a Reaction conditions: 11 (0.3 mmol), (Bu3Sn)2 (0.09 mmol),
BF3 ·OEt2 (0.12 mmol), H2O (0.06 mmol), CH2Cl2 (10 mL), rt, hν, 1 h.
b Isolated yield based on 11.
Table 2. Effect of Lewis Acids on Product Distribution of the
Cyclization of 11a
excess (ee), afforded the cyclized product 14a with a 94% ee,
indicating that the absolute configuration of C-8 was nicely
retained.
The above reactions dealt with N-acyloxazolidinone substrates
that have relatively rigid conformations. To gain further
understanding on the behavior of 8-endo cyclization of R-car-
bamoyl radicals, we set out to study the cyclization of N-
ethoxycarbonyl-substituted substrate 15a, which is structurally
similar to oxazolidinone 11a but conformationally more flexible.
The direct treatment of 15a with BEt3/O2 in CH2Cl2 at rt yielded
the eight-membered lactam 16a in 56% yield as the mixture of
two stereoisomers in about 2:1 ratio. The above optimized
conditions (BF3 ·OEt2/H2O, (Bu3Sn)2, hν) were then applied to
the reaction of 15a. To our disappointment, no improvement
could be achieved either on the product yield or on the
stereoselectivity. This prompted us to reoptimize the reaction
conditions under Lewis acid catalysis (Table 4). The presence
of Yb(OTf)3 or Zn(OTf)2 showed no effect (entries 3 and
4, Table 4), presumably because of their poor solubility in
CH2Cl2.30 To increase the solubility, a ligand was introduced.
Two types of ligands of wide applications, pyridine-2,6-
bis(oxazoline) L131 and bis(oxazoline) L2,32 were chosen. After
the screening of a few combinations (entries 5-10, Table 4),
we were pleased to find that, with the aid of 1.5 equiv of
Mg(ClO4)2 and 1.5 equiv of L2, the reaction of 15a afforded
the 8-endo cyclization product 16a in 92% yield with the trans/
cis ratio of about 8 to 1 (entry 10, Table 4). The trans
configuration of the major isomer was determined by the
relevant proton coupling constants as well as 2D NMR
experiments (see Supporting Information for details). The ee
of the trans-isomer was measured to be 9%. Nevertheless, we
continued to use the chiral ligand L2 in the control of
stereoselectivity because of its easy availability.33,34 Lowering
the amounts of Mg(ClO4)2/L2 or the reaction temperature
resulted in the decrease of both the product yield and the
stereoselectivity (entries 11 and 12, Table 4). The reaction
had a better performance in CH2Cl2 than in toluene (entry
13, Table 4).
yield (%)b
entrya
conditions
12a
13a 14a
1
2
3
4
BEt3 (20 mol %)/O2, Yb(OTf)3 (100 mol %), 1 h 10
BEt3 (20 mol %)/O2, Zn(OTf)2 (100 mol %), 2 h 12
BEt3 (20 mol %)/O2, Mg(OTf)2 (100 mol %), 5 h 11
11
18
8
0
13
12
13
BEt3 (20 mol %)/O2, BF3 ·OEt2 (aged, 200
12
23
mol %), 1 h
5
6
7
8
9
BEt3 (20 mol %)/O2, BF3 ·OEt2 (aged, 400
mol %), 1 h
(Bu3Sn)2 (30 mol %), BF3 ·OEt2 (aged, 400
trace trace 31
0
trace 53
trace 21
mol %), hν, 1 h
(Bu3Sn)2 (30 mol %), BF3 ·OEt2 (freshly distilled, 0
400 mol %), hν, 1 h
(Bu3Sn)2 (30 mol %), BF3 ·OEt2 (freshly distilled, 0
400 mol %), H2O (400 mol %), hν, 1 h
(Bu3Sn)2 (30 mol %), BF3 ·OEt2 (freshly distilled, 0
400 mol %), H2O (200 mol %), hν, 1 h
0
0
0
0
58
60
67
70
10 (Bu3Sn)2 (30 mol %), BF3 ·OEt2 (freshly distilled, 0
400 mol %), H2O (40 mol %), hν, 1 h
11 (Bu3Sn)2 (30 mol %), BF3 ·OEt2 (freshly distilled, 0
400 mol %), H2O (20 mol %), hν, 1 h
a Reaction conditions: 11a (0.3 mmol), CH2Cl2 (10 mL), additives, rt.
b Isolated yield based on 11a.
excellent regio- and stereoselectivity (Table 3). More impor-
tantly, the product configuration was changed from 3,8-trans
to 3,8-cis. The presence of BF3 ·OEt2/H2O significantly increased
the efficiency and stereoselectivity of cyclization presumably
by stabilizing the Z-rotamers of the substrates via complexation
(vide infra). It should be mentioned that the substrates were
prepared from racemic serine (see the Supporting Information
for details). The optically pure L-serine was also utilized for
the synthesis of 11a in order to examine the diastereoselectivity
of cyclization. The reaction of 11a, thus prepared from the
corresponding oxazolidinone intermediate in a 95% enantiomeric
(29) Without the use of BEt3/O2 or (Bu3Sn)2/hν, the cyclization did not
proceed at all, even at refluxing temperature for a prolonged time,
indicating that the reaction could not be an ionic process. Furthermore,
the attempted ionic iodocarbocyclization with the deiodinated deriva-
tive of 11a as the substrate failed to give any carbocyclization product
under various conditions tested (NaHCO3/I2, LDA/I2, BuLi/NIS, or
tBuOCl/I2). For examples of ionic iodocarbocyclization, see: (a)
Kitagawa, O.; Inoue, T.; Hirano, K.; Taguchi, T. J. Org. Chem. 1993,
58, 3106. (b) Kitagawa, O.; Inoue, T.; Taguchi, T. Tetrahedron Lett.
1992, 33, 2167.
(30) For a similar discussion, see: Dakternieks, D.; Perchyonok, V. T.;
Schiesser, C. H. Tetrahedron: Asymmetry 2003, 14, 3057.
(31) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. ReV. 2003, 103, 3119.
(32) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asym-
metry 1998, 9, 1. (b) Jorgensen, K. A.; Johannsen, M.; Yao, S.;
Audrain, H.; Thornauge, J. Acc. Chem. Res. 1999, 32, 605.
9
J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010 2277

A R T I C L E S
Fang et al.
Table 4. Optimization of Reaction Conditions for Amide 15a
Table 5. 8-Endo Cyclization of N-Ethoxycarbonyl-Substituted
Iodoamides 15
entrya
14
R
product
yield (%)b
1
2
3
4
5
6
15a
15b
15c
15d
15e
15f
Me
Et
Bu
C6H13
i-Pr
t-Bu
16ac
92
87
80
83
79
77
trans-16bd
trans-16cd
trans-16dd
trans-16ed
trans-16fd
entrya
LA (mol %)
ligand (mol %)
yield (%)b
trans:cisc
1
2
3
4
5
6
7
8
none
none
none
none
none
56
39
55
53
52
85
f
66:34
50:50
66:34
66:34
73:27
76:24
a Reaction conditions: 15 (0.3 mmol), Mg(ClO4)2 (0.45 mmol), L2
(0.45 mmol), BEt3 (0.09 mmol), O2 (5 mL), CH2Cl2 (10 mL), rt, 1 h.
b Isolated yield based on 15. c Trans:cis ) 89:11. d The cis isomer was
BF3 ·OEt2 (400)
Yb(OTf)3 (100)
Zn(OTf)2 (100)
Yb(OTf)3 (100)
Yb(OTf)3 (300)
Cu(OTf)2 (300)
Cu(OTf)2 (300)
Mg(ClO4)2 (300)
Mg(ClO4)2 (150)
Mg(ClO4)2 (30)
Mg(ClO4)2 (150)
Mg(ClO4)2 (150)
Mg(ClO4)2 (200)
1
not observed by H NMR (300 MHz).
L1 (100)
L1 (300)
L1 (300)
L2 (300)
L2 (300)
L2 (150)
L2 (30)
L2 (150)
L2 (150)
L1 (200)
reoptimized conditions. The bromine-atom-transfer radical cy-
clization product 18 was achieved in a good efficiency (eq 2).35
However, the stereoselectivity dropped to 2:1. This implies that
the fast trapping of the cyclized radicals is necessary in order
to achieve high stereoselectivity, which will be further analyzed
later in the theoretical calculation section.
f
9
69
92
48
74
65
38
88:12
89:11
50:50
84:16
74:26
81:19
10
11
12d
13e
14
a Reaction conditions: 15a (0.3 mmol), BEt3 (0.09 mmol), LA/ligand,
CH2Cl2 (10 mL), O2 (5 mL), rt, 1 h. b Isolated yield based on 15a.
c Determined by 1H NMR (300 MHz). d The reaction was run at 0 °C.
e Toluene was used as the solvent. f A complex mixture was generated
from which no pure product 16a could be isolated.
The reoptimized conditions (entry 10, Table 4) were then
applied to the cyclization reactions of 15b-15f, and the results
are summarized in Table 5. We were delighted to find that, in
all the cases, the 8-endo cyclization products were obtained in
high yields, while no corresponding 7-exo cyclization products
could be detected. The increase of the bulkiness of the R group
in 15 further increased the stereoselectivty (trans:cis > 20:1).
Compared to the cyclization of NH-amide 4 (Scheme 2),14 the
efficiency of lactam formation was dramatically increased by
the introduction of the N-ethoxycarbonyl group. It is worth
mentioning that the reoptimized conditions also allowed the
cyclization of oxazolidinone 11a to proceed smoothly to give
the expected product 14a in 72% yield, implying that BF3 ·OEt2/
H2O had a role similar to that of Mg(ClO4)2/L2.
The successful results in Tables 3 and 5 urged us to
investigate the cyclization of N-aryl-substituted substrates
analogous to 8. Iodoamide 19a as the N-ethoxycarbonyl-
substituted derivative of 8 was then synthesized as the model
substrate. The direct treatment of 19a with BEt3/O2 in CH2Cl2
at rt gave the 8-endo cyclization product 20a in 60% as the 1:9
mixture of trans- and cis-isomers, the latter being the major
isomer. With the use of Mg(ClO4)2/L2 as the Lewis acid, 20a
was obtained in 74% yield with a ratio of cis/trans over 10:1.
When the combination of BF3 ·OEt2 and H2O as indicated in
Table 3 was employed, 20a was achieved in 80% yield as a
single stereoisomer, whose structure was also confirmed by its
X-ray diffraction experiment. Thus, without further optimization
of reaction conditions, a number of N-arylamides 19b-19f were
prepared and subjected to treatment with BEt3/O2 under the
promotion of BF3 ·OEt2/H2O (Table 6). The corresponding
benzazocanones 20 were obtained exclusively in high yields.
In sharp contrast to the cyclization of NH-amide 8 (Scheme
2),14 excellent regio- and stereoselectivity were now observed.
Also note that the products 20 have the 3,5-cis configuration
rather than the opposite in lactams 14 and 16.
It should be pointed out that halogen-atom-transfer radical
cyclization in an endo mode usually has a poor stereoselectiv-
ity.12 To learn more on this, compound 17 as the bromo-
analogue of 15a was prepared and subjected to the above
(33) For selected examples of enantioselective intermolecular radical
reactions, see: (a) Sibi, M. P.; Yang, Y.-H.; Lee, S. Org. Lett. 2008,
10, 5349. (b) Hein, J. E.; Zimmerman, M. P.; Sibi, M. P.; Hultin,
P. G. Org. Lett. 2005, 7, 2755. (c) Sibi, M. P.; Petrovic, G.;
Zimmerman, J. J. Am. Chem. Soc. 2005, 127, 2390. (d) Sibi, M. P.;
Rheault, T. R.; Chandramouli, S. V.; Jasperse, C. P. J. Am. Chem.
Soc. 2002, 124, 2924. (e) Sibi, M. P.; Chen, J. J. Am. Chem. Soc.
2001, 123, 9472. (f) Sibi, M. P.; Ji, J.; Wu, J. H.; Gurtler, S.; Porter,
N. A. J. Am. Chem. Soc. 1996, 118, 9200.
Encouraged by the above excellent control of stereoselectivity,
we moved one step further to study the chemistry of iodoamide
21a with two methyl substituents, one R to the amide carbonyl
and the other R to the nitrogen. The optimized conditions (BEt3/
O2, Mg(ClO4)2/L2) for the cyclization of substrates 15 were
directly applied to the reaction of 21a, yielding the cyclized
products (83% yield) as the mixture of two isomers in about a
(34) Successful examples of enantioselective radical cyclization reactions
are rare and deal solely with the 5-exo mode of cyclization. See: (a)
Miyabe, H.; Asada, R.; Takemoto, Y. Angew. Chem., Int. Ed. 2006,
45, 5863. (b) Yang, D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-
K. J. Am. Chem. Soc. 2001, 123, 8612. (c) Yang, D.; Gu, S.; Yan,
Y.-L.; Zhao, H.-W.; Zhu, N.-Y. Angew. Chem., Int. Ed. 2002, 41,
3014. (d) Yang, D.; Zheng, B.-F.; Gao, Q.; Gu, S.; Zhu, N.-Y. Angew.
Chem., Int. Ed. 2006, 45, 255.
(35) For selected bromine-atom-transfer radical reactions, see: (a) Mero,
C. L.; Porter, N. A. J. Am. Chem. Soc. 1999, 121, 5155. (b) Yorimitsu,
H.; Shinokubo, H.; Matsubara, S.; Oshima, K.; Omoto, K.; Fujimoto,
H. J. Org. Chem. 2001, 66, 7776.
9
2278 J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010

Formation of Azocan-2-ones
A R T I C L E S
Table 8. Competition between 8-Endo and 5-Exo Cyclizations
Table 6. 8-Endo Cyclization of N-Arylamides 19
entrya
19
R
G
product
yield (%)b
product/yield (%)b
1
2
3
4
5
6
19a
19b
19c
19d
19e
19f
Me
Et
t-Bu
Me
Me
Me
H
H
H
6-Me
6-OMe
4-Cl
cis-20a
cis-20b
cis-20c
cis-20d
cis-20e
cis-20f
80
77
73
72
69
79
entrya
R
8-endo
5-exoc
28
1
2
3
Me
Et
i-Pr
27a (43)
27b (28)
27c (trace)
38
45
66
28a (21)
28b (31)
28c (50)
a Reaction conditions: (1) 26 (0.3 mmol), Mg(ClO4)2 (0.45 mmol),
L2 (0.45 mmol), BEt3 (0.09 mmol), O2 (5 mL), CH2Cl2 (10 mL), rt, 4 h;
(2) Bu3SnH (0.6 mmol), BEt3 (0.6 mmol), O2 (3 × 10 mL), C6H6 (5
mL), rt, 10 min. b Isolated yield based on 26. c The combined yield of
pyrrolidinones.
a Reaction conditions: 19 (0.3 mmol), BF3 ·OEt2 (0.12 mmol), H2O
(0.06 mmol), BEt3 (0.09 mmol), O2 (5 mL), CH2Cl2 (10 mL), rt, 1 h.
b Isolated yield based on 19.
Table 7. Cyclization-Reduction of Iodoamides 21
generality of this stereoselectivity in the 8-endo cyclization of
R-carbamoyl radicals with bidentate chelation.
The bidentate chelation played a crucial role in the above
8-endo cyclization. The regio- and stereoselectivity of cycliza-
tion were dramatically increased. In the meantime, the efficiency
of cyclization was also significantly improved. Such a strategy
could also be extended to the control of other modes of
cyclization of R-carbamoyl radicals. As an example, the 5-exo
cyclization36 of N-ethoxycarbonyl-substituted iodoamides 24a-
24c under the above optimized conditions with Mg(ClO4)2/L2
led to the exclusive formation of 25a-25c as single stereoiso-
mers in almost quantitative yields (eq 3). Compared to literature
reports,36 a much better control of stereoselectivity was achieved
under milder conditions.
entrya
21
R
G
23
yield (%)b
1
2
3
4
5
6
21a
21b
21c
21d
21e
21f
Me
Et
Bu
i-Pr
Bu
i-Pr
Me
Me
Me
Me
Et
23a
23b
23c
23d
23e
23f
77
76
80
74
79
74
C5H11
Both the 5-exo and the 8-endo cyclization of N-ethoxycar-
bonyl-substituted R-carbamoyl radicals exhibited a high ef-
ficiency. This aroused our interest in the direct competition
between these two modes of cyclization. Substrates 26a-26c
were thus synthesized for this purpose. The cyclization-reduction
sequence outlined in Table 7 was carried out for 26a-26c, and
the results are depicted in Table 8. Both azocanones and
pyrrolidinones were obtained. The 8-endo cyclization products
27 were isolated as single stereoisomers. The 5-exo cyclization
product pyrrolidinones consisted of at least three isomers with
28 as the major isomers as indicated by LC-MS analysis.
Compounds 28a-c were then isolated by preparative HPLC,
and their stereochemistry was readily determined by the relevant
proton coupling constants (see Supporting Information for
details). Both the combined yields of pyrrolidinones and the
isolated yields of 28a-c were listed in Table 8. In the reaction
of 26a, azocanone 27a was achieved in 43% yield while the
combined yield of pyrrolidinones was only 38%, indicating that
the 8-endo cyclization was even slightly preferred over the
corresponding 5-exo cyclization. With the increase of bulkiness
a Reaction conditions: (1) 21 (0.3 mmol), Mg(ClO4)2 (0.45 mmol),
L2 (0.45 mmol), BEt3 (0.09 mmol), O2 (5 mL), CH2Cl2 (10 mL), rt, 4 h;
(2) Bu3SnH (0.6 mmol), BEt3 (0.6 mmol), O2 (3 × 10 mL), C6H6 (5
mL), rt, 10 min. b Isolated yield based on 21.
1:1 ratio. The two isomers were not only inseparable by column
chromatography on silica gel but also not very stable. To
characterize, the crude products were reduced by excess (2
equiv) Bu3SnH/BEt3 in benzene at rt. The reduced product 23a
was thus isolated as a single stereoisomer in 77% yield based
on the starting material 21a. The stereochemistry of 23a was
clearly determined by its NOESY experiments, which showed
a strong NOE between the two protons at C-3 and C-8 positions.
This indicated that the iodine-atom-transfer cyclization products
in the first step were 22a. Although the stereochemical control
in the I-abstraction was poor, the excellent control of the 3,8-
cis stereochemistry was achieved in the 8-endo cyclization.
To test the generality of this stereoselective 8-endo cycliza-
tion, the above two-step sequence was extended to the reactions
of radical precursors 21b-21f (Table 7). In all cases the
corresponding products 23b-23f were generated in high yields
as single stereoisomers. Note that the same 3,8-cis configuration
was also observed in the cyclized products 14, indicating the
(36) For selected examples, see: (a) Ikeda, M.; Teranishi, H.; Nozaki, K.;
Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1998, 1691. (b) Cao, L.;
Li, C. Tetrahedron Lett. 2008, 49, 7380.
9
J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010 2279

A R T I C L E S
Fang et al.
Scheme 3
at UBHandHLYP/6-31G* level were also performed to confirm
the relative accuracy of the UB3LYP method.40
of the R group in 26, the yield of 8-endo cyclization product
decreased. Based on this trend, it could be anticipated that the
8-endo cyclization would predominate if the R group in 26 was
H. Unfortunately, our various attempts to synthesize this
substrate all failed; only deiodinated compound could be
isolated. This phenomenon might be analyzed by the instability
of 26 (R ) H) due to the possible intramolecular nucleophilic
substitution.
The cyclization of radical R-11 derived from substrate 11a
was first computed. The calculated activation energies and the
corresponding computed TS structures at UB3LYP/6-31G* level
are shown in Figure 1. The calculations at UBHandHLYP/6-
31G* level were also performed, which showed an excellent
consistency with the UB3LYP method (see Supporting Informa-
tion for details). The 8-endo cyclization may proceed via two
possible pathways, the E-conformational TS (TS-11-8E) or the
Z-conformational TS (TS-11-8Z1 or TS-11-Z2). Similarly, the
7-exo cyclization also has two possible routes, via TS-11-7E
or TS-11-7Z. Of all the five structures, TS-11-8E is at least 6
kcal/mol lower in energy than any other structure. This strongly
suggests that only the 8-endo cyclization via the E-conforma-
tional TS is possible for R-11. The product configuration via
TS-11-8E is 3,8-trans, consistent with the experimental obser-
vations in Table 1. The relatively high activation energy (13
kcal/mol) also accounts for the moderate efficiency of cycliza-
tion of 11 in the absence of a Lewis acid.
As a comparison, the radical cyclization of amide 29 without
N-ethoxycarbonyl-substitution was also carried out (Scheme 3).
With the promotion of BF3 ·OEt2,14 the BEt3/O2-initiated reaction
of 29 proceeded smoothly at rt. We were pleased to find that
the 8-endo cyclization product 30 was achieved exclusively
while no corresponding 5-exo cyclization product could be
detected. Compound 30 existed as the mixture of two stereoi-
1
somers in about 1:1 ratio determined by H NMR. It was then
reduced with Bu3SnH/BEt3 to azocanone 31 (55% yield based
on the starting substrate 29) and unambiguously characterized.
Calculations and Discussion
The above results have clearly demonstrated that efficient and
stereoselective formation of azocanones can be achieved via
the cyclization of R-carbamoyl radicals. The difference between
R-carbamoyl radicals and R-ester radicals in 8-endo cyclization
is also evident. While both processes are efficient and highly
regioselective, the cyclization of R-ester radicals suffers from
the poor stereoselectivity. On the other hand, an excellent control
of stereoselectivity could be achieved in the cyclization of
R-carbamoyl radicals. Furthermore, the Lewis acid chelation
not only significantly improves the efficiency and stereoselec-
tivity of cyclization, but also changes the product stereochem-
istry from 3,8-trans to 3,8-cis. To gain more insight into the
unique reactivity of N-(4-pentenyl)-substituted R-carbamoyl
radicals, we turn to density functional calculations for help,
which have been demonstrated to be a fairly accurate tool in
the study of radical reactions.37 All calculations were carried
out with the Gaussian 03 program38 using the B3LYP functional
and the 6-31G* basis sets for all the elements (including Mg39).
The transition state structures and energies were fully optimized.
Once convergence is reached, the harmonic vibration frequencies
were calculated at this point to confirm the geometry obtained
to be a true first-order saddle point. The zero-point vibrational
energy and thermal corrections were also obtained at the
UB3LYP/6-31G* level, from which the activation free energies
(∆Gq) of cyclization were calculated. In some cases, calculations
With the presence of a Lewis acid able to form bidentate
chelation with the radical precursor, it is expected that only the
Z-conformational TS are involved in the cyclization. As either
TS-11-8Z1 or TS-11-8Z2 is at least 3 kcal/mol lower in energy
than TS-11-7Z, the 8-endo cyclization should be overwhelm-
ingly predominant, if we assume that the Lewis acid lowers
the activation energies in approximately the same extent. Both
TS-11-8Z1 and TS-11-8Z2 lead to the cyclized product in the
3,8-cis configuration, consistent with the experimental observa-
tions in Table 2. Thus, the E-conformational TSs generate
lactams 12 and 13, while the Z-conformational TSs produce
lactams 14. Since BF3 ·OEt2/H2O is not a good model for
theoretical calculations, we will discuss the effect of Lewis acids
later with Mg(ClO4)2/L2 as the model.
The preference of 8-endo cyclization of R-11, with or without
the promotion of Lewis acids, can also be analyzed on the basis
ofthecomputedTSstructures(Figure1).TheC(3)-N(2)-C(1)-C(8)
dihedral angle, which is 178° in the starting radical R-11, is
147° in TS-11-8E but 123° in TS-11-7E. The severe confor-
mational distortion of the amide plane in the latter case reveals
that the N-pentenyl chain is too short for 7-exo cyclization via
the E-conformation. With regard to the Z-conformers, there is
not much difference in the C(3)-N(2)-C(1)-C(8) dihedral
angles. However, TS-11-7Z exists in a boat-boat-like confor-
mation (the amide boat and the C(5)-C(6)-C(7)-C(8) boat)
with a N(1)-C(8)-C(7)-C(6) dihedral angle of 41°. This
(37) For review articles on the use of calculations in radical reactions, see:
(a) Eksterowicz, J. E.; Houk, K. N. Chem. ReV. 1993, 93, 2439. (b)
Schiesser, C. H.; Skidmore, M. A. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001;
Vol. 1, p 337.
(38) Frisch, M. J. Gaussian 03, reVision C.02; Gaussian Inc.: Wallingford,
CT, 2004. See Supporting Information for the full reference.
(39) For selected examples, see: (a) Ruan, C.; Rodgers, M. T. J. Am. Chem.
Soc. 2009, 131, 10918. (b) Kannappan, B.; Gready, J. E. J. Am. Chem.
Soc. 2008, 130, 15063.
(40) For selected examples, see: (a) Kyne, S. H.; Schiesser, C. H.;
Matsubara, H. J. Org. Chem. 2008, 73, 427. (b) Schiesser, C. H.;
Matsubara, H.; Ritsner, I.; Wille, U. Chem. Commun. 2006, 1067. (c)
Matsubara, H.; Falzon, C. T.; Ryu, I.; Schiesser, C. H. Org. Biomol.
Chem. 2006, 4, 1920. (d) Lingwood, M.; Hammond, J. R.; Hrovat,
D. A.; Mayer, J. M.; Borden, W. T. J. Chem. Theory Comput. 2006,
2, 740. (e) Morihovitis, T.; Schiesser, C. H.; Skidmore, M. A. J. Chem.
Soc., Perkin Trans. 2 1999, 2041.
9
2280 J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010

Formation of Azocan-2-ones
A R T I C L E S
Figure 1. Computed (UB3LYP/6-31G*) 8-endo versus 7-exo cyclization of R-11.
Table 9. Calculated (UB3LYP/6-31G*) Activation Free Energies of
7-Exo versus 8-Endo Cyclization
activation free energy by about 12 kcal/mol in each of the three
pathways, indicating that the regioselectivity pattern is not
affected by the presence of a Lewis acid. The 8-endo cyclization
now has the activation energy of ∼7 kcal/mol. The dramatic
decrease of activation energy makes the cyclization a highly
efficient process, consistent with the experimental results in
Table 5. Furthermore, the 3,8-cis stereochemistry of azocanones
23a-f (Table 7) can also be well explained on the basis of the
computed transition structures.
∆Gq (kcal/mol)
radical
8-endo (E)
8-endo (Z)
7-exo (E)
7-exo (Z)
R-15
R-15 L
14.2
19.3a (19.9)b
7.1a (7.3)b
23.2
23.0
11.4
a Boat-boat conformational TS. b Boat-chair conformational TS.
causes the structure rather congested as evidenced by the very
short distance between the C-3 proton and the C-5 proton (2.306
Å). Although TS-11-8Z1 also has the boat-boat-like conforma-
tion, the N(1)-C(8)-C(7)-C(6) dihedral angle is much larger
(53°) and the distance between the C-3 proton and the C-5 (or
C-6) proton is 3.224 Å (or 2.778 Å). On the other hand, TS-
11-8Z2 possesses the boat-chair-like conformation with a
N(1)-C(8)-C(7)-C(6) dihedral angle of 71°. Thus, when the
cyclization proceeds via the E-conformational TS, the N-
pentenyl chain is again too short for 7-exo cyclization if
compared to 8-endo cyclization. Therefore, whether the starting
radical is fixed in the Z-conformation or in the E-conformation,
the 7-exo cyclization always suffers from more structural
distortion than the corresponding 8-endo cyclization, thus
illustrating that the 8-endo mode is fundamentally preferred over
the 7-exo mode.
The calculations on the cyclization of radical R-15 derived
from substrate 15a were then performed. The calculated ac-
tivation free energies are also listed in Table 9. The activation
energy pattern in the cyclization of R-15 closely parallels to
that in the cyclization of R-11. Meanwhile, the TS structures
are also very similar to those in the cyclization of R-11 (see
Supporting Information for details).Thus, without the promotion
of a Lewis acid, 8-endo cyclization should prevail, consistent
with the experimental results (entry 1, Table 4).
We then turn to the stereochemistry of the iodine abstraction.
As mentioned above, the cyclization of radical R-11 should
proceed via E-conformational TS without the presence of a
Lewis acid. The subsequent fast I-abstraction of the cyclized
radical P-12/13 would give predominantly the corresponding
products 12a with the 3,5-cis configuration. However, the
product azocanones 12 and 13 all exist exclusively in the
Z-conformations both in solid states and in a solution (see
Supporting Information for details). This means that P-12/13
in E-conformations have to rotate to Z-conformations. The
rotational barrier41 is computed at the UB3LYP/6-31G* level
to be 10.0 and 14.1 kcal/mol for P-12/13 derived from 11a (R
) Me) and 11f (R ) t-Bu), respectively. In the meantime, the
cyclized radicals undergo I-abstraction with the rate constant
of 106-107 M-1 s-1.42 These two competing processes resulted
in the poor stereoselectivity in the reaction of 11a. On the other
hand, a very good stereoselectivity in the reaction of 11f was
observed because the rotation was much slower. This analysis is
in excellent agreement with the experimental results in Table 1.
In the presence of a chelating agent, the 8-endo cyclization
proceeds via Z-conformational TS. As indicated above, two
possible TS are involved, the boat-boat conformational TS and
the boat-chair one. The fast trapping of the cyclized radicals
via the boat-boat TS of slightly lower energy would lead to
the 3,5-cis stereoselectivity, inconsistent with the experimental
results in Tables 3 and 5. To understand the 3,5-trans stereo-
chemistry of azocanones 14 and 16, the cyclized radicals derived
from R-15 and R-15L were computed. As shown in Figure 2,
Next, the reactivity of the complexed radical R-15L, derived
from the reaction of 15a under the promotion of Mg(ClO4)2/
L2, was computed. To reduce the otherwise enormous amount
of time required for calculations, the ligand L2 was replaced
by its simpler analogue without the two isopropyl-substitution,
namely, 2,2′-(propane-2,2-diyl)bis(4,5-dihydrooxazole). The
calculated activation free energies are included in Table 9. It
can be clearly seen that the Lewis acid chelation lowers the
(41) For a review on the rotational barriers of amide bonds, see: Stewart,
W. E.; Siddall, T. H., III Chem. ReV. 1970, 70, 517.
(42) Curran, D. P.; Bosch, E.; Kaplan, J.; Newcomb, M. J. Org. Chem.
1989, 54, 1826.
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J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010 2281

A R T I C L E S
Fang et al.
Figure 2. Computed (UB3LYP/6-31G*) structures of product radicals in the 8-endo cyclization of R-15 and R-15-MgL.
Table 10. Calculated (UB3LYP/6-31G*) Activation Free Energies
of 5-Exo versus 8-Endo Cyclization
Figure 3. X-ray crystal structures of 14a and cis-20a.
the cyclized radical via the reaction of R-15 has two
stable conformations, P-15-1 of boat-boat conformation and
P-15-2 of boat-chair conformation. P-15-1 is only 0.1 kcal/
mol higher in energy than P-15-2 at the UB3LYP/6-31G* level.
Similarly, the cyclized radical via the reaction of R-15L has
also two stable conformations, P-15L-1 of boat-boat conforma-
tion and P-15L-2 of boat-chair conformation. However,
P-15L-1 is 1.1 kcal/mol higher in energy than P-15L-2 at the
UB3LYP/6-31G* level. Thus, the fast trapping of P-15L-1 leads
to the 3,5-trans configuration in the final products.43 The energy
difference between P-15L-1 and P-15L-2 is in excellent
agreement with the experimental observation in 16a (trans/cis
) 8:1). It is interesting to see that the Lewis acid chelation
enlarges the energy difference between the two conformations.
Such a differentiation by Lewis acid complexation can also be
observed in the computation of product radicals derived from
the reaction of N-arylamide 19a (see Supporting Information
for details). For example, in the reaction of 19a with the 7,8-
benzo-fused substitution, the boat-boat conformation is com-
puted to be 1.1 kcal/mol lower in energy than the corresponding
boat-chair conformation for the complexed product radical, thus
leading to the 3,5-cis stereochemistry in the product 20a. The
relative stability of the two conformations is thus vulnerable to
substituents. It is worth mentioning that, in the solid state,
azocanone 14a has the boat-chair conformation and benzazo-
canone cis-20a has the boat-boat conformation (Figure 3),
consistent with the above theoretical analysis. When the iodine
is replaced by a bromine atom, the stereoselectivity becomes
poor as indicated in eq 2. This might be attributed to the much
lower rate of Br-abstraction (103-104 M-1 s-1) compared to
I-abstraction (106-107 M-1 s-1).42
∆Gq (kcal/mol)
entry
radical
8-endo
5-exo
1
2
3
4
R-26L (R ) H)
R-26L (R ) Me)
R-26L (R ) t-Bu)
R-29
1.4
6.9, 6.5
9.5
4.6
6.1
6.1
10.9 (Z)a, 10.9 (E)b
10.6
a Z-Conformational TS. b E-Conformational TS.
radical R-29 were taken as the models, and the calculated
activation energies are summarized in Table 10. Again, two
possible TS are computed for the 8-endo cyclization of R-26L
(R ) Me). However, the TS of 8-endo cyclization of R-26L
(R ) H or t-Bu) are in boat-boat conformations, while the
corresponding boat-chair conformations are about 2 kcal/
mol higher in energy. We are delighted to find that the 8-endo
mode of cyclization is overwhelmingly predominant over the
corresponding 5-exo mode for radical R-26L (R ) H). The
fundamental preference of 8-endo cyclization can be ratio-
nalized on the basis of the transition structures. The C(3)-
C(2)-N(1)-C(8) dihedral angel, which is expected to be 0°
in the ideal case, is computed to be 2.5° in the TS of 8-endo
cyclization but 31.6° in the TS of 5-exo cyclization. Thus,
the 5-exo cyclization requires the severe conformational
distortion in order for the R-carbamoyl radical to add to the
double bond. On the other hand, the N-(4-pentenyl) chain is
long enough to allow the addition in the 8-endo mode to
proceed while maintaining the planarity of the amide moiety.
For radicals R-26L (R ) Me or t-Bu), the activation energies
are increased for both pathways. However, the 5-exo cy-
clization is insensitive to the size of the R group, while the
8-endo cyclization slows down when the size of R increases.
This different trend can also be rationalized on the basis of
the TS structures in which the vinyl and the R groups point
to the same direction in the TS of 8-endo cyclization but to
different directions in the TS of 5-exo cyclization. Therefore,
with the increasing bulkiness of the R group, the preferred
mode of cyclization is reversed from 8-endo to 5-exo. This
The competition between 5-exo and 8-endo cyclization was
also computed at the UB3LYP/6-31G* level. The complexed
radicals R-26L (R ) H, Me, or t-Bu) and the uncomplexed
(43) The I-abstraction process was irreversible under the experimental
conditions (Table 5). This was evidenced by the observation that the
cis/trans ratio of product 16a did not change when 16a (cis/trans )
1:1) was subjected to the treatment of BEt3/O2 under the experimental
conditions shown in Table 5.
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2282 J. AM. CHEM. SOC. VOL. 132, NO. 7, 2010

Formation of Azocan-2-ones
A R T I C L E S
calculated trend is in excellent qualitative agreement with
our experimental results in Table 8.
the two processes are of comparable rates, and both products
are generated.
For the cyclization of radical R-29, the activation energy
of 8-endo cyclization is computed to be 10.9 kcal/mol via
either a Z- or E-conformational TS, which is close to that of
5-exo cyclization. If the cyclization proceeded via E-
conformational TS, we would expect that 5-exo cyclization
product was also formed. The only observation of 8-endo
cyclization product 30 illustrates that the cyclization takes
place via Z-conformational TS only. Curran has clearly
demonstrated that, once the rate of radical cyclization far
exceeds that of amide bond rotation, the starting rotamer ratio
of an amide radical precursor can have a significant impact
on the radical cyclization.44 As the amide substrate exists
exclusively in Z-conformations and the rotation barrier of
the amide bond in the substrate radical (18.8 kcal/mol at
UB3LYP/6-31G* level) is much higher than the activation
energy of 8-endo cyclization, only the 8-endo cyclization via
Z-conformational TS is possible under the experimental
conditions, while the 5-exo cyclization is unlikely to happen
because of its requirement of E-conformational TS.
Conclusion
The results reported herein provide a basis for understanding
the unique reactivity of R-carbamoyl radicals in 8-endo cy-
clization. The cyclization can proceed via either a Z- or an
E-conformational TS. In both cases, the 8-endo cyclization is
fundamentally preferred over the corresponding 7-exo cycliza-
tion. The introduction of an N-ester group to the radical
precursors, together with the promotion of a Lewis acid, not
only significantly improves the efficiency of iodine-atom-transfer
radical cyclization but also pushes the R-carbamoyl radicals to
cyclize via fixed Z-conformation TS, resulting in a high degree
of stereochemical control. The competition experiments illustrate
that the 8-endo cyclization is of comparable rates to the 5-exo
cyclizationevenwhenthesubstratesareinZ-(s-cis)conformations.
The calculations offer a quantitative view on the mechanism
of 8-endo cyclization of R-carbamoyl radicals, which will
certainly allow more controlled and predictable applications of
this important class of 8-endo cyclization of haloamides. The
mechanistic study along with the conformational analyses also
shed light on other modes of cyclization of R-carbamoyl radicals.
Furthermore, the quantitative assessment on the effect of Lewis
acids can be extrapolated to other types of radical reactions as
well.
Finally, the above discussion also helps to clarify the
mechanism of cyclization of N-(4-pentenyl)iodoacetamide 4
depicted in Scheme 2. The activation free energies for 8-endo
cyclization (rather than relative energy difference in our
previous report14) are computed to be 13.0 kcal/mol via the
Z-conformational TS and 13.2 kcal/mol via the E-conforma-
tional TS. Both activation energies are lower than the rotation
barrier of the amide bond.41 Moreover, the presence of Lewis
acid BF3 · OEt2 should further lower the activation energies.
Thus, it is unlikely that both pathways occur for 8-endo
cyclization at the same time in the reaction of amide 4 under
mild conditions as previously proposed.14 It is more likely
that the cyclization proceeds via the Z-conformational TS
only. The cyclized product 6 with a Z-conformation may
undergo either the amide bond rotation (to give the stable
azocanone 5 in an E-conformation) or the intramolecular
nucleophilic substitution (to give the lactone 7). Presumably
Acknowledgment. This project was supported by the National
Natural Science Foundation of China (Grant Nos. 20672136,
20702060, and 20832006), by the National Basic Research Program
of China (Grant No. 2010CB833206), and by the Shanghai
Municipal Committee of Science and Technology (Grant No.
07XD14038). We thank Shana Zhu of the Shanghai Institute of
Organic Chemistry for double-checking some of the experimental
data. This paper is dedicated to Prof. You-Cheng Liu, a pioneer in
physical organic chemistry in China, on the occasion of his 90th
birthday.
Supporting Information Available: Full experimental proce-
dures, compound characterizations, copies of 1H and 13C NMR
spectra of all substrates and products, DFT calculation data,
crystallographic data in CIF format, and complete ref 38. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(44) (a) Curran, D. P.; Tamine, J. J. Org. Chem. 1991, 56, 2746. (b) Curran,
D. P.; DeMello, N. C. J. Chem. Soc., Chem. Commun. 1993, 1314.
(c) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem.
Soc. 1994, 116, 3131. (d) Curran, D. P.; Liu, H. T. J. Chem. Soc.,
Perkin Trans. 1 1994, 1377. (e) Curran, D. P.; Guthrie, D. B.; Geib,
S. J. J. Am. Chem. Soc. 2008, 130, 8437.
JA9082649
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