Selective approach toward multifunctionalized lactams by lewis acid promoted PhSe group transfer radical cyclization

Article abstract of DOI:10.1021/jo100139u

We have developed a regiospecific and highly stereoselective strategy for constructing the five-/six-membered monocyclic and bicyclic nitrogen heterocycle skeletons using PhSe group transfer radical cyclization of α-phenylseleno amido esters promoted by a Lewis acid (e.g., Yb(OTf)₃) under UV irradiation. We obtained 5-/6-exo-trig mode cyclization products for the N-allyl/homoallyl substrates, whereas the enamide substrate gave 5-endo-trig ring closure.

Full text of DOI:10.1021/jo100139u

pubs.acs.org/joc
Selective Approach toward Multifunctionalized Lactams by Lewis Acid
Promoted PhSe Group Transfer Radical Cyclization
Jin-Di Yu,† Wei Ding,† Gao-Yan Lian,† Ke-Sheng Song,‡ Dan-Wei Zhang,*,† Xiang Gao,†
and Dan Yang*,†,‡
†Department of Chemistry, Fudan University, Shanghai 200433, China, and ‡Department of Chemistry,
The University of Hong Kong, Pokfulam Road, Hong Kong, China
yangdan@hku.hk; zhangdw@fudan.edu.cn
Received January 30, 2010
We have developed a regiospecific and highly stereoselective strategy for constructing the five-/six-
membered monocyclic and bicyclic nitrogen heterocycle skeletons using PhSe group transfer radical
cyclization of R-phenylseleno amido esters promoted by a Lewis acid (e.g., Yb(OTf)3) under UV
irradiation. We obtained 5-/6-exo-trig mode cyclization products for the N-allyl/homoallyl sub-
strates, whereas the enamide substrate gave 5-endo-trig ring closure.
Introduction
alized pyrrolidines/pyrrolidinones, the key intermediates, have
deservedly attracted much attention in research.5
Multifunctionalized five- and six-membered nitrogen hetero-
cyclic skeletons are common in biologically active natural
products and pharmaceutically relevant molecules.1 In particu-
lar, 4-alkyl-2-pyrrolidinones, 4-alkylpyrrolidine-3-carboxylic
acids, and 4-alkyl-2-pyrrolidinone-3-carboxylic acids form the
core structures of many biologically significant compounds, for
example, the antiepileptic drug brivaracetam (BRV),2 the phos-
phodiesterase (PDE4) inhibitor rolipram,3 and the endothelin
antagonist ABT-627 (atrasentan).4 Therefore, efficient and
selective methods for the construction of highly function-
Radical cyclization method is a general strategy used for
building up cyclic compounds.6 Atom or group transfer
radical cyclization reactions, which involve the transfer of
(1) (a) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355. (b) Masse, C.
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40, 2224. (i) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 695. (j) Bowman,
W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc., Perkin Trans. 1 2002, 2747.
(k) Rheault, T. R.; Sibi, M. P. Synthesis 2003, 803. (l) Ishibashi, H. Chem. Record
2006, 6, 23. (m) Majumdar, K. C.; Basu, P. K.; Chattopadhyay, S. K. Tetrahedron
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3232 J. Org. Chem. 2010, 75, 3232–3239
Published on Web 04/21/2010
DOI: 10.1021/jo100139u
r
2010 American Chemical Society

Yu et al.
JOCArticle
SCHEME 1. Synthesis of Cyclization Precursor 1a
TABLE 1. Effect of Lewis Acids on the PhSe Group Transfer Radical
Cyclization of 1a
a halogen atom (X = I, Br, or Cl) or an aryl chalcogen group
(X = SePh, or TePh) from one carbon center to another with
concomitant C-C bond formation, are particularly effective
for cyclic skeleton construction.7 This approach is popular in
organic synthesis since the halogen atom or chalcogen group
retained in the product readily allows further functionaliza-
tion.8 In previous studies, we have demonstrated the possi-
bility of enantioselective synthesis of carbocycles by bromo
atom or PhSe group transfer radical cyclization of unsatu-
rated β-keto esters catalyzed by chiral Lewis acids.9 Very
recently, we reported a photoinduced PhSe group transfer
radical cyclization of N-alkenyl β-keto amides and its appli-
cation in the formal synthesis of (()-isocynometrine.10 We
report herein regiospecific and stereoselective synthesis of
highly functionalized γ- and δ-lactams by exploiting Lewis
acid promoted PhSe group transfer radical cyclization with
amido esters as precursors.
Lewis acid
(equiv)
initiating
condition solvent
time
(h)
yield (%)a of
entry
2a (trans/cis)b
1
2
3
Yb(OTf)3 (1)
Et2O
16
16
2
2
6
2
2
4
5
hν
hν
hν
hν
hν
hν
hν
hν
hν
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
64c (8.1:1)
85 (7.5:1)
71 (6.8:1)
71e (7.5:1)
83 (7.3:1)
76 (8.0:1)
<5
Yb(OTf)3 (1)
Yb(OTf)3 (0.3)
Yb(OTf)3 (0.3)
Sc(OTf)3 (1)
Sm(OTf)3 (1)
Cu(OTf)2 (1)
Mg(ClO4)2 (1)
Mg(ClO4)2 (1)
4
5d
6
7
8
9
10
<5
68 (11.3:1)
5
Results and Discussion
aIsolated yield. bThe ratio of trans/cis isomers was determined by the
crude 1H NMR analysis of 3a. cIncluding 8% oxidative elimination
product 3a. dReaction at -45 °C. eIncluding 10% oxidative elimination
product 3a.
Screening of Reaction Conditions. A PhSe group transfer
radical cyclization precursor, amido ester 1a, was synthe-
sized as shown in Scheme 1. Since the steric bulkiness of
substituents on the nitrogen atom of the tertiary amides
significantly affects the cyclization efficiency,10,11 bulky tert-
butyl group was selected as the substituent on the nitrogen
atom of the substrates. On one hand, the tert-butyl group
locks the substrate in a conformation prone to cyclization;
on the other hand, it can be readily removed by treatment
with Lewis acid Sc(OTf)3,12 which is advantageous in synth-
eses of various substituted heterocycles.
The results of the cyclization of the amido ester substrate
1a under various reaction conditions are summarized in
Table 1. Without UV irradiation, no reaction occurred even
in the presence of 1 equiv of Lewis acid Yb(OTf)3 after 16 h
(entry 1). However, when the substrate was irradiated by UV
light in the absence of Yb(OTf)3, a 64% total yield of cyclized
products, including 5-exo product 2a (56%) and oxidative
elimination product 3a (8%), was obtained (entry 2). These
results suggest that the photoinduced PhSe group transfer
cyclization of R-phenylseleno amido ester proceeds via a
(7) (a) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140.
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47, 3051.
1
radical pathway. The H NMR analysis of the oxidative
elimination product 3a revealed that the dominant isomer of
5-exo product 2a had a trans relationship of the 3-ester group
and 4-alkyl group. In the presence of 1 equiv of Yb(OTf)3,
cyclized product 2a could be obtained in 85% yield by
initiating the radical reaction through UV irradiation, and
the reaction time was shortened to 2 h (entry 3). When the
amount of Lewis acid was reduced to 0.3 equiv, 71% yield
was achieved (entry 4). This clearly indicates that Lewis acids
may play an important role in accelerating the radical
cyclization. However, the ratio of trans/cis isomers of 2a
remained at close range from 6.8 to 8.1 (entries 2-4),
regardless of the addition of Lewis acid. This indicates that
Lewis acid affects little if any on the stereoselectivity of the
cyclization step. We also tried to increase the stereoselectivity
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TABLE 2. Lewis Acid-promoted PhSe Group Transfer Radical Cycli-
the homoallyl substrate 1e, the allyl type substrates 1f-g
containing a double bond being part of the carbocycles, and
enamine compound 1h) were prepared15 and subjected to the
above optimized cyclization conditions.
zations of Compounds 1b-ea
N-Allyl and Homoallyl Type Substrates 1b-e. Similar to
compound 1a, compounds 1b-d are N-allyl-type substrates
but have different substitution patterns on the CdC double
bond. By subjecting 1b-d to the optimized condition for the
PhSe group transfer radical cyclization, high yields of 5-exo-
cyclization from 85 to 95% were achieved (Table 2, entries
1-3). Excellent stereoselectivities were observed for the
cyclization of 1b and 1d; however, the ratio of trans/cis
isomers was 2.2:1 for 1c. As for the N-homoallyl-type sub-
strate 1e, 6-exo product 2e was produced in 83% yield as a
single stereoisomer (Table 2, entry 4). The structures of the
cyclization products 2b-e were determined by NMR experi-
ments and were further confirmed by the structural analysis
of 3b, 3c, 3e (the reductive dephenylselenation products of
2b, 2c, 2e, respectively), and 3d (the oxidative elimination
product of 2d).15
The above results have revealed some interesting features
which aid our understanding of the factors governing the
outcome of the PhSe group transfer radical cyclization
reactions of interest.
First of all, the above radical cyclization reactions are
promoted by Lewis acid Yb(OTf)3, similar to our previous
report on PhSe group transfer radical cyclization of β-keto
amides.16 The 1,3-dicarbonyl groups of the amido ester
substrates can chelate to strong Lewis acid like Yb(OTf)3
in a bidentate fashion, which makes the R-radical intermedi-
ates generated from the cleavage of C-Se bond by photolysis
even more electrophilic. As a result, the ring-closure step is
accelerated through the addition of more electron-deficient
R-radicals toward unactivated olefins. In addition, the PhSe
group transfer step may also be accelerated in the presence of
Lewis acid.16 Therefore, the chelation of the β-dicarbonyl
moiety of amido ester substrates to strong Lewis acids results
in the rate acceleration for the cylization reactions. Con-
venient structural modifications of the multiple functiona-
lized cyclization products render this method applicable to
the synthesis of N-heterocyclic natural products. For exam-
ple, the methoxycarbonyl group of the cyclization products
can be removed to afford β-substituted γ-lactams following a
literature procedure.17
Second, the cyclization reactions of amido esters 1a-e are
exclusively in exo-mode, which is independent of CdC
double bond substitution patterns. However, in our previous
studies, endo-cyclization products were obtained for the
cyclization of β-keto amides I, analogous of the amido ester
1b, under UV irradiation in the presence of Lewis acids
(eq 1).18 This difference may be attributed to distinct pro-
ducts formed from the two classes of substrates. N-Hetero-
cycles were produced by Lewis acid-promoted PhSe
group transfer radical cyclization of amido ester substrates,
aUnless otherwise indicated, reaction time was 2 h. bIsolated yield.
cDetermined by 1H NMR analysis of 2. dReaction time was 1.5 h.
of the cyclization by lowering down the reaction tempera-
ture. Substrate 1a was irradiated for 6 h at -45 °C by UV
light in the presence of 0.3 equiv of Yb(OTf)3. A mixture of
5-exo product 2a and oxidative elimination product 3a was
obtained in 71% combined yield, but the trans/cis ratio of 2a
(7.5:1) was not significantly increased compared with the
result at room temperature (entry 5 vs entry 4). Other Lewis
acids have also been screened (entries 6-10). In the presence
of 1 equiv of Sc(OTf)3 and Sm(OTf)3 (two kinds of strong
Lewis acids13), 83% and 76% yields were achieved, respec-
tively, with the ratios of trans/cis isomers being 7.3:1 and
8.0:1, respectively (entries 6 and 7). However, in the presence
of Cu(OTf)2, a weaker Lewis acid, low conversion was
observed (entry 8). In the case of Mg(ClO4)2, the solvents
used seemed to have a key impact on the reaction outcomes.
Specifically, no cyclized product was obtained in Et2O
(entry 9), whereas 68% yield and a higher trans/cis ratio
(11.3:1) were achieved in CH2Cl2, with the reaction time
being extended to 5 h (entry 10).6f,14 Here, the solvent effect
may be accounted for by the fact that Mg(ClO4)2 dissolves
much better in CH2Cl2 than in Et2O.
Then various types of N-alkenyl R-phenylseleno amido
ester substrates (including the allyl-type substrates 1b-d,
(13) (a) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem.
Rev. 2002, 102, 2227. (b) Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Chem.
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(15) For details, see the Supporting Information.
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Eur. J. 2009, 15, 4224.
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ꢀ
formations by magnesium-based Lewis acids, see: (a) Guerin, B.; Ogilvie, W.
W.; Guindon, Y. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; and references cited therein. (b) Dakterniuks, D.;
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while carbocycles were obtained from the β-keto amide
substrates.
(TS2) would be much favored over TS1 because of less steric
interaction, resulting in a cyclization product having a trans
configuration between 3-ester group and 4-alkyl group of
2-pyrrolidinones under kinetic control condition.
In contrast, for substrate 1c, the R3 is a methyl group and
the R1 and R2 are both protons. Both the methyl group (R3)
and the methylene group (dCR1R2) are sterically hindered
to a similar extent with respect to the ester group. As a result,
TS1 and TS2 would be similar in energy and poor stereo-
selectivity is expected under kinetic control.
While it is not obvious whether the radical cyclization of
1a-d proceeded through kinetic or thermodynamic control,
we have carried out density function calculations on the
thermodynamic stabilities of possible cyclization products
for radical reactions of compounds 1b, 1c, and 6, a model
compound of I, using the Gaussian 03 program (eqs 2 and 3).25
The regioselectivity (5-exo vs 6-endo) of the cyclization of
δ-unsaturated carbon-centered radicals have been well in-
vestigated in literature by theoretical calculations as well as
experimental studies.19-24 Julia reported that the regioselec-
tivity of δ-unsaturated alkyl radicals forming either five- or
six-membered carbocycles from the same precursor can
be controlled by kinetic or thermodynamic factors.20 Cycli-
zation of 3-aza-5-hexenyl and 3-aza-5-methyl-5-hexenyl
radicals revealed that 5-exo mode is preferred over 6-endo
one.21,22 Beckwith and Houk attributed the fact that the
3-aza systems, with a large group on nitrogen atom, produce
exclusively exo product, regardless of substituents of the
double bond, to the increased stereoelectronic effect due to
the shorter C-N bonds with respect to C-C bonds.20 The
same outcome (5-exo cyclization) was observed in Ueno-
Stork reactions which employ 3-oxa-5-hexenyl radical as the
substrate.23 Renaud reported that a highly stereoselective
Ueno-Stork reaction was observed in which the acetal
center was the unique stereogenic element, and δ-unsatu-
rated carbon-centered radicals, either unactivated or stabilized
by electron-withdrawing carbonyl groups, provided 5-exo
mode cyclization.24 Our observed 5-exo cyclization of N-allyl-
type substrates 1a-d seemed consistent with the above exam-
ples of constructing heterocycles by radical cyclizations.
SCHEME 2. Stereoselectivities of Radical Cyclization of 1a-d
Third, in terms of stereoselectivity, the PhSe group trans-
fer radical cyclization of substrates 1a-e gave trans products
as the major stereoisomers. In particular, high to excellent
stereoselectivities were obtained for the PhSe group transfer
radical cyclization of substrates 1a-b and 1d-e. A plausible
explanation for the stereoselectivity of PhSe group transfer
radical cyclization (5-exo mode closure, for example) is
depicted in Scheme 2. For the substrates (1a-b and 1d) with
R3 group being hydrogen atom (Scheme 2), transition state 2
All of the cyclization products were full optimized
by B3LYP/6-31G(d) method without any restriction.
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Gaussian, Inc.: Pittsburgh, PA, 2003.
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(20) Julia, M. Acc. Chem. Res. 1971, 4, 386 and references cited therein.
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FIGURE 1. Calculated structures (trans/cis-2b and trans/cis-5b) and relative energies (kcal/mol) in Et2O and in vacuum (in parentheses).
FIGURE 2. Calculated structures (trans/cis-2c and trans/cis-5c) and relative energies (kcal/mol) in Et2O and in vacuum (in parentheses).
And harmonic vibration frequency calculations were also
performed to ensure each structure being a minimum by using
B3LYP/6-31G(d) method. Solvent effect in Et2O and CH2Cl2
was evaluated by PCM model.26 The relative free energies were
calculated on the basis of the B3LYP/6-31G(d) energies with
the thermal, entropy, and solvent energy corrections (eq 4).
ΔG ¼ ΔEðB3LYPÞ þ enthalpy corrections - TΔS
ð4Þ
The calculation results (Figures 1-3) support our experi-
mental data. The relative energies shown in Figure 1 reveal
that the 5-exo cyclization products trans/cis-2b are much
more stable than the 6-endo ones (trans/cis-5b) in Et2O as
well as in a vacuum, and trans-2b is more favorable than
cis-2b. The same trend is found for the cyclization products
2c and 5c (Figure 2). But for the cyclization of model 6, the
6-endo products (trans/cis-8) are more stable than 5-exo
products (trans/cis-7) in both CH2Cl2 and a vacuum, and
cis-8 is more stable than trans-8 due to the favorable diequa-
torial orientation of the two substituents on the cyclohexane
skeleton. Therefore, we conclude that the trans-5-exo mode
for the cyclization of 1a-d to form lactams is both kinetically
and thermodynamically preferred, whereas for the cycliza-
tion of compound I to form a carbocycle, the cis-6-endo
product is preferred under thermodynamic control.
FIGURE 3. Calculated structures (trans/cis-7 and trans/cis-8) and
relative energies (kcal/mol) in CH2Cl2 and in vacuum (in
parentheses).
piperidine ring fused to other rings in a variety of ways are
core skeletons of many alkaloids and therapeutic agents.
Bicyclic nitrogen heterocycles are important building blocks
for their synthesis. Some key intermediates of the synthesis of
(þ)-coccinine,27a pancracine,27b and a PGD2 receptor anta-
gonist27c as well as the bicyclic nitrogen heterocycle nature
product lepadin27d are shown in Figure 4.
To construct bicyclic nitrogen heterocycles, we prepared
the N-allyl-type substrates 1f and 1g, with the double bond
being part of the ring, as precursors for PhSe group transfer
radical cyclization. By subjecting compounds 1f and 1g to the
above cyclization conditions, bicyclic nitrogen heterocycles
N-Allyl-Type Substrates 1f and 1g with a Double Bond as
Part of the Carbocycle. The structures of pyrrolidine or
(26) (a) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107,
3032. (b) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem. Phys. Lett.
1998, 286, 253. (c) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151.
(d) Cossi, M.; Scalmani, G..; Rega, N.; Barone, V. J. Chem. Phys. 2002, 117,
43.
(27) (a) Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37,
1724. (b) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662. (c) Campos,
K. R.; Journet, M.; Lee, S.; Grabowski, E. J. J.; Tillyer, R. D. J. Org. Chem.
2005, 70, 268. (d) Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2000, 2,
2955.
3236 J. Org. Chem. Vol. 75, No. 10, 2010

Yu et al.
SCHEME 3. Construction of Bicyclic Nitrogen Heterocycles via PhSe Group Transfer Radical Cyclization of 1f and 1g
JOCArticle
were obtained in high yields with excellent stereoselecti-
vities (Scheme 3). Four stereocenters were established in
one single step.
of 3g,15 the reductive dephenylselenation product of 2g.
Compound 3g has a cis-fused bicyclic structure, and its ester
group is cis to the bridgehead protons.
Enamide-Type Substrate 1h. The radical cyclization of
enamides usually proceeds in 4-exo mode.28 When the
enamide substrate 1h was subjected to the above PhSe group
transfer radical cyclization conditions, a 3,5-trans-substi-
tuted 5-endo mode cyclization product 2h was obtained
exclusively in 65% yield (Scheme 4). 2D NMR analysis
revealed that the ring closure of substrate 1h proceeded via
5-endo-trig mode cyclization, and the 3-ester group was trans
to the 5-PhSe group.
SCHEME 4. PhSe Group Transfer Radical Cyclization of
Enamide 1h
SCHEME 5. Plausible Mechanism of PhSe Group Transfer
Radical Cyclization of Enamide 1h
FIGURE 4. Examples of natural products and pharmaceutically
relevant molecules.
A plausible mechanism for the cyclization of 1h is shown in
Scheme 5. The 5-endo-trig mode of radical cyclization is
generally considered a “disfavored” process according to
the Baldwin-Beckwith rules.19,21a However, recently repo-
rted theoretical studies suggest that the 5-endo-trig mode
of cyclization is strongly favored over the 4-exo cyclization
not only thermodynamically but also kinetically in the
absence of steric or conformational effects.29 For the
R-radical generated from substrate 1h, the steric effect
between tert-butyl group on the nitrogen atom and the
isopropyl substituent would hinder the 4-exo cyclization
(Scheme 5). Therefore, the 5-endo mode cyclization is pre-
ferred. Furthermore, the trans stereochemistry of the 3-ester
FIGURE 5. NOE correlations of compound 2f.
The stereochemistry of compound 2f was determined by
2D-NOESY spectroscopy. Strong NOE was observed bet-
ween two bridgehead protons Ha and Hb, as well as Hc and
Hd, while weak NOEs are observed for the pairs of Hb/Hc
and Hb/Hd (Figure 5). This NOE pattern indicates that the
two five-membered rings are cis-fused.15 The ester group is
syn to the bridgehead protons and the PhSe group radical is
captured from the convex face. The stereochemistry of
product 2g was confirmed by X-ray crystallographic analysis
(28) (a) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 6, 695 and
references cited therein. (b) D'Annibale, A.; Nanni, D.; Trogolo, C.; Umani, F.
Org. Lett. 2000, 2, 401. (c) Edmonds, D. J.; Muir, K. W.; Procter, D. J. J. Org.
Chem. 2003, 68, 3190. (d) Clark, A. J.; Battle, G. M.; Bridge, A. Tetrahedron
Lett. 2001, 42, 4409.
(29) Chatgilialoglu, C.; Ferreri, C.; Guerra, M.; Timokhin, V.; Froudakis,
G.; Gimisis, T. J. Am. Chem. Soc. 2002, 124, 10765.
J. Org. Chem. Vol. 75, No. 10, 2010 3237

Yu et al.
JOCArticle
group and the 5-PhSe group is favored to avoid the steric
clash between them.
0.7 ꢀ 1H), 3.28 (d, J = 9.6 Hz, 0.7 ꢀ 1H), 3.25 (s, 0.7 ꢀ 1H),
3.15-3.08 (m, 0.3 ꢀ 1H þ 2H), 3.03 (d, J = 12.4 Hz, 0.3 ꢀ 1H),
1.34 (s, 0.3 ꢀ 9H), 1.28 (s, 0.3 ꢀ 3H and 0.7 ꢀ 9H), 1.13 (s, 0.7 ꢀ
3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 169.5, 169.4, 169.3,
133.2, 133.1, 130.6, 130.5, 129.4, 129.3, 127.5, 127.4, 61.9, 60.9,
56.3, 55.2, 54.5(2), 52.3, 52.1, 40.7, 40.4, 35.6, 27.5(2), 26.2, 21.0;
IR (neat) 2970, 1737, 1691 cm-1; LRMS for C18H25NO3Se (EI,
20 eV) m/z 383 (Mþ, 98), 226 (100), 212 (28); HRMS (EI) for
C18H25NO3Se (Mþ) calcd 383.1000, found 383.1006.
Methyl trans-1-tert-butyl-2-oxo-4-(2-(phenylseleno)propan-2-
yl)pyrrolidine-3-carboxylate (2d): yellow oil, 95% yield; ana-
lytical TLC (silica gel 60), 50% EtOAc in n-hexane, Rf = 0.53;
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.8 Hz, 2H),
7.41-7.29 (m, 3H), 3.76 (s, 3H), 3.60 (t, J = 9.3 Hz, 1H), 3.57
(d, J = 8.3 Hz, 1H), 3.39 (dd, J = 9.8, 7.3 Hz, 1H), 2.88-2.82
(m, 1H), 1.40 (s, 9H), 1.35 (s, 3H), 1.27 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 171.3, 169.0, 138.4, 129.1, 129.0, 126.5, 54.9,
53.5, 52.7, 48.4, 47.0, 45.7, 28.4, 27.7, 27.0; IR (neat) 2963, 1741,
1689 cm-1; LRMS for C19H27NO3Se (EI, 20 eV) m/z 397 (Mþ,
7), 240 (75), 184 (100); HRMS (EI) for C19H27NO3Se (Mþ) calcd
397.1156, found 397.1172.
Conclusion
In conclusion, Lewis acid-promoted PhSe group transfer
radical cyclization represents an efficient, regiospecific, and
stereoselective strategy for the formation of highly functio-
nalized monocyclic and bicyclic nitrogen heterocyles, which
constitute important core structures of many biologically
interesting natural products and therapeutic agents. The
method is highly flexible and encompasses a broad substrate
scope. Given its mild reaction conditions and high yields and
selectivities, this synthetic approach to lactams and ring-
fused nitrogen heterocyles possesses clear intrinsic advan-
tages. Future efforts will be steered toward developing
methods for enantioselective radical cyclization.
Experimental Section
Methyl trans-1-tert-butyl-2-oxo-4-(phenylselenomethyl)piper-
idine-3-carboxylate (2e): yellow oil, 83% yield; analytical TLC
(silica gel 60), 50% EtOAc in n-hexane, Rf = 0.44; H NMR
A 320 nm, 125W high-pressure mercury lamp was used as the
UV source. The reactions were carried out in Pyrex glass flasks.
General Procedure for the Group Transfer Radical Cycliza-
tion. Methyl trans-1-tert-Butyl-2-oxo-4-(1-phenylselenoethyl)-
pyrrolidine-3-carboxylate (2a). To a stirred solution of Yb(OTf)3
(386 mg, 0.62 mmol) in Et2O (10 mL) was added a solution of 1a
(238 mg, 0.62 mmol) in Et2O (20 mL) at -78 °C. The system was
deoxygenated with N2 for 0.5 h at -78 °C and then irradiated
with a UV lamp at room temperature. After 2 h, the reaction
mixture was diluted with Et2O and washed with water. The
organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated. The crude product was purified by column chro-
matography to give 2a (203 mg, 85%) as a light yellow oil.
Analytical TLC (silica gel 60): 50% EtOAc in n-hexane, Rf =
1
(400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.29-7.25 (m, 3H),
3.71 (s, 3H), 3.42 (dt, J = 11.9, 4.7 Hz, 1H), 3.27 (d, J = 10.6 Hz,
1H), 3.27-3.21 (m, 1H), 3.05 (dd, J = 12.8, 4.1 Hz, 1H), 2.69
(dd, J = 12.7, 8.3 Hz, 1H), 2.43-2.34 (m, 1H), 2.16 (dq, J =
13.4, 4.2 Hz, 1H), 1.54-1.46 (m, 1H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 171.1, 166.4, 132.6, 130.1, 129.3, 127.2,
58.0, 57.7, 52.4, 42.9, 36.4, 32.5, 28.4, 28.2; IR (neat) 2955, 1740,
1644 cm-1; LRMS for C18H25NO3Se (EI, 20 eV) m/z 384 (Mþ þ
1, 9), 383 (Mþ, 46), 226 (64), 170 (100); HRMS (EI) for
C18H25NO3Se (Mþ) calcd 383.1000, found 383.0992.
Methyl cis-1-tert-butyl-2-oxo-cis-4-(phenylseleno)octahydro-
cyclopenta[b]pyrrole-cis-3-carboxylate (2f): yellow oil, 81% yield;
analytical TLC (silica gel 60), 50% EtOAc in n-hexane, Rf = 0.33;
1H NMR (400 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.31-7.26 (m,
3H), 4.33 (td, J = 8.0, 5.0 Hz, 1H), 3.69 (s, 3H), 3.50-3.46 (m,
1H), 3.20 (d, J = 6.9 Hz, 1H), 3.03 (ddd, J = 8.0, 6.9, 4.1 Hz, 1H),
2.31-2.15 (m, 2H), 1.79-1.65 (m, 2H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 170.4, 168.4, 134.8, 129.3, 128.6, 128.0, 61.6,
55.9, 55.2, 52.7, 47.2, 46.3, 34.4, 32.0, 28.2; IR (neat) 2961, 1740,
1685, 1578 cm-1; LRMS for C19H25NO3Se (EI, 20 eV) m/z 395
(Mþ, 58), 150 (100); HRMS (EI) for C19H25NO3Se (Mþ) calcd
395.1000, found 395.0999.
Methyl cis-1-tert-butyl-2-oxo-cis-4-(phenylseleno)octahydro-
1H-indole-cis-3-carboxylate (2g): yellow oil, 84% yield; analy-
tical TLC (silica gel 60), 50% EtOAc in n-hexane, Rf = 0.29; 1H
NMR (400 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.31-7.27 (m,
3H), 3.95 (dt, J = 11.5, 6.0 Hz, 1H), 3.72-3.67 (m, 4H), 3.43 (d,
J = 12.8 Hz, 1H), 2.99 (dd, J = 12.8, 6.4 Hz, 1H), 2.20-2.16 (m,
1H), 1.91-1.86 (m, 1H), 1.83-1.75 (m, 1H), 1.72-1.57 (m, 2H),
1.41 (s, 9H), 1.24-1.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
169.7, 168.5, 133.9, 129.6, 129.3, 127.7, 54.9, 53.8, 52.7, 52.6,
42.9, 41.6, 31.6, 28.3, 26.1, 19.5; IR (neat) 2974, 1744, 1675
cm-1; LRMS for C20H27NO3Se (EI, 20 eV) m/z 410 (Mþ þ 1, 6),
409 (Mþ, 36), 252 (27), 164 (100), 157 (6); HRMS (EI) for
C20H27NO3Se (Mþ) calcd 409.1156, found 409.1157.
Methyl trans-1-tert-butyl-4,4-dimethyl-2-oxo-5-(phenylseleno)-
pyrrolidine-3-carboxylate (2h): yellow oil, 65% yield; analytical
TLC (silica gel 60), 50% EtOAc in n-hexane, Rf = 0.57; 1H NMR
(500 MHz, CDCl3) δ 7.57-7.54 (m, 2H), 7.31-7.29 (m, 3H), 4.86
(s, 1H), 3.74 (s, 3H), 3.50 (s, 1H), 1.58 (s, 9H), 1.27 (s, 3H), 1.20 (s,
3H), 13C NMR (100 MHz, CDCl3) δ 169.2, 168.5, 134.4, 129.8,
129.6, 128.0, 76.4, 57.8, 55.9, 52.1, 44.5, 27.6, 25.2, 24.1; IR (neat)
2971, 1753, 1701 cm-1; LRMS for C18H25NO3Se (EI, 20 eV) m/z
226 (C12H20NO3, Mþ - SePh, 58), 170 (100); HRMS (EI) for
1
0.51; H NMR (400 MHz, CDCl3) (diastereomer ratio 7/3) δ
7.57-7.54 (m, 2H), 7.34-7.27 (m, 3H), 3.79 (s, 0.3 ꢀ 3H), 3.74
(s, 0.7 ꢀ 3H), 3.69 (dd, J = 9.8, 8.5 Hz, 0.7 ꢀ 1H), 3.60 (dd, J =
10.4, 8.7 Hz, 0.3 ꢀ 1H), 3.39 (d, J = 8.2 Hz, 0.3 ꢀ 1H), 3.38 (d,
J = 8.7 Hz, 0.7 ꢀ 1H), 3.29-3.14 (m, 2H), 2.97-2.84 (m, 1H),
1.41 (d, J = 6.7 Hz, 3H), 1.38 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.5, 168.9, 135.3, 135.2, 129.2, 128.1, 128.0, 55.4,
55.2, 54.84, 54.80, 52.7, 52.6, 49.1, 47.7, 43.1, 42.3, 41.6, 40.8,
27.6, 20.4, 19.4; IR (neat) 2970, 1741, 1689 cm-1; LRMS for
C18H25NO3Se (EI, 20 eV) m/z 384 (Mþ þ 1, 6), 383 (Mþ, 51), 170
(88), 138 (100); HRMS (EI) for C18H25NO3Se (Mþ) calcd
383.1000, found 383.1000.
Methyl 1-tert-butyl-2-oxo-4-(phenylselenomethyl)pyrrolidine-
3-carboxylate (2b): yellow oil, 85% yield; analytical TLC (silica
gel 60), 50% EtOAc in n-hexane, Rf = 0.33; H NMR (400
1
MHz, CDCl3) (diastereomer ratio 13.4/1) δ 7.52-7.50 (m, 2H),
7.30-7.26 (m, 3H), 3.76 (s, 0.93 ꢀ 3H), 3.72 (s, 0.07 ꢀ 3H), 3.66
(dd, J = 9.9, 7.6 Hz, 0.93 ꢀ 1H), 3.58 (dd, J = 9.2, 7.8 Hz, 0.07 ꢀ
1H), 3.41 (d, J = 8.7 Hz, 0.07 ꢀ 1H), 3.33 (t, J = 9.2 Hz, 0.07 ꢀ
1H), 3.27 (d, J = 8.0 Hz, 0.93 ꢀ 1H), 3.11 (dd, J = 9.9, 6.7 Hz,
0.93 ꢀ 1H), 3.07-3.02 (m, 1H), 2.95-2.87 (m, 2H), 1.37 (s,
0.07 ꢀ 9H), 1.36 (s, 0.93 ꢀ 9H); 13C NMR (100 MHz, CDCl3) δ
170.0, 168.8, 133.4, 133.2, 129.4, 129.2, 127.7, 127.6, 56.6, 54.9,
54.8, 52.7, 52.3, 50.7, 49.8, 36.1, 35.9, 31.0, 27.6; IR (neat) 2972,
1740, 1689, 740, 692 cm-1; LRMS for C17H23NO3Se (EI, 20 eV)
m/z 369 (Mþ, 100), 212 (95); HRMS (EI) for C17H23NO3Se
(Mþ) calcd 369.0843, found 369.0855.
Methyl 1-tert-butyl-4-methyl-2-oxo-4-(phenylselenomethyl)-
pyrrolidine-3-carboxylate (2c): yellow oil, 95% yield; analytical
TLC (silica gel 60), 50% EtOAc in n-hexane, Rf = 0.51; H
1
NMR (400 MHz, CDCl3) (diastereomer ratio 2.2:1) δ 7.55-
7.50 (m, 2H), 7.29-7.25 (m, 3H), 3.71 (s, 0.7 ꢀ 3H), 3.68 (s,
0.3 ꢀ 3H), 3.50 (d, J = 9.6 Hz, 0.3 ꢀ 1H), 3.41 (d, J = 10.1 Hz,
3238 J. Org. Chem. Vol. 75, No. 10, 2010

Yu et al.
JOCArticle
C18H25NO3Se calcd 226.1443 (C12H20NO3, Mþ - SePh), found
226.1446.
Methyl 1-tert-butyl-4,4-dimethyl-2-oxopyrrolidine-3-carboxy-
late (3c): yellow oil, 87% yield; analytical TLC (silica gel 60),
50% EtOAc in n-hexane, Rf = 0.45; 1H NMR (400 MHz,
CDCl3) δ 3.72 (s, 3H), 3.38 (d, J = 9.3 Hz, 1H), 3.11 (d, J =
9.3 Hz, 1H), 2.99 (s, 1H), 1.41 (s, 9H), 1.21 (s, 3H), 1.07 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.3, 169.8, 62.1, 57.9, 54.2,
General Procedure for the Oxidative Elimination of the Phe-
nylseleno Group. Methyl trans-1-tert-Butyl-2-oxo-4-vinylpyrro-
lidine-3-carboxylate (3a). H2O2 (0.12 mL, 1.06 mmol, 30 wt % in
H2O) was added to a solution of 2a (223 mg, 0.58 mmol) in THF
(25 mL) at 0 °C. The solution was then stirred overnight at room
temperature. After removal of the solvent, the mixture was
diluted with CH2Cl2 (30 mL), washed with water and brine,
dried over anhydrous Na2SO4, and concentrated. The crude
residue was purified by flash column chromatography to pro-
vide 3a (121 mg, 92%) as colorless oil: analytical TLC (silica gel
60), 50% EtOAc in n-hexane, Rf = 0.52; 1H NMR (400 MHz,
CDCl3) (diastereomer ratio 9:1) δ 5.76 (ddd, J = 17.1, 10.3, 6.8
Hz, 1H), 5.18 (d, J = 17.1 Hz, 1H), 5.12 (d, J = 10.3 Hz, 1H),
3.78 (s, 0.9 ꢀ 3H), 3.70 (s, 0.1 ꢀ 3H), 3.66 (dd, J = 9.5, 7.6 Hz,
0.9 ꢀ 1H), 3.53 (d, J = 8.8 Hz, 0.1 ꢀ 2H), 3.42 (d, J = 8.8 Hz,
0.1 ꢀ 1H), 3.31-3.27 (m, 0.9 ꢀ 2H), 3.18-3.12 (m, 1H), 1.42 (s,
0.1 ꢀ 9H), 1.40 (s, 0.89 ꢀ 9H); 13C NMR (100 MHz, CDCl3) δ
170.0, 169.1, 136.4, 134.0, 118.6, 117.3, 55.8, 55.4, 54.7, 54.6,
52.6, 52.0, 49.6, 49.1, 40.1, 39.7, 27.6; IR (neat) 2975, 1743, 1691
cm-1; LRMS for C12H19NO3 (EI, 20 eV) m/z 226 (Mþ þ 1, 6),
225 (Mþ, 44), 210 (100); HRMS (EI) for C12H19NO3 (Mþ) calcd
225.1365, found 225.1364.
51.9, 35.7, 28.7, 27.6, 22.6; IR (neat) 2964, 1739, 1690 cm-1
;
LRMS for C12H21NO3 (EI, 20 eV) m/z 227 (Mþ, 57), 212 (100),
170 (3); HRMS (EI) for C12H21NO3 (Mþ) calcd 227.1521, found
227.1530.
Methyl trans-1-tert-butyl-4-methyl-2-oxopiperidine-3-carboxy-
late (3e): yellow oil, 81% yield; analytical TLC (silica gel 60),
50% EtOAc in n-hexane, Rf = 0.40; 1H NMR (400 MHz, CDCl3)
δ 3.74 (s, 3H), 3.45-3.38 (m, 1H), 3.26 (td, J = 11.6, 4.4 Hz, 1H),
2.98 (d, J = 11.0 Hz, 1H), 2.21-2.15 (m, 1H), 1.89 (dq, J = 13.7,
3.9 Hz, 1H), 1.46-1.35 (m, 10H), 0.97 (d, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 171.7, 167.0, 59.6, 57.8, 52.2, 43.2,
31.0, 30.8, 28.1, 20.1; IR (neat) 2958, 1743, 1643 cm-1; LRMS for
C12H21NO3 (EI, 20 eV) m/z 228 (Mþ þ 1, 15), 227 (Mþ, 100), 212
(87); HRMS (EI) for C12H21NO3 (Mþ) calcd 227.1521, found
227.1549.
Methyl cis-1-tert-butyl-2-oxooctahydrocyclopenta[b]pyrrole-
cis-3-carboxylate (3f): yellow oil, 60% yield; analytical TLC
(silica gel 60), 50% EtOAc in n-hexane, Rf = 0.33; H NMR
1
Methyl trans-1-tert-butyl-2-oxo-4-(prop-1-en-2-yl)pyrrolidine-
3-carboxylate (3d): yellow oil, 92% yield; analytical TLC (silica
gel 60), 50% EtOAc in n-hexane, Rf = 0.51; 1H NMR (400 MHz,
CDCl3) δ 4.85 (s, 1H), 4.82 (s, 1H), 3.79 (s, 3H), 3.67 (t, J = 8.8
Hz, 1H), 3.40 (d, J = 9.6 Hz, 1H), 3.29 (q, J = 8.8 Hz, 1H), 3.20 (t,
J = 8.8 Hz, 1H), 1.74 (s, 3H), 1.41 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.5, 169.3, 142.8, 112.2, 54.8, 54.6, 52.6, 48.4, 42.5,
27.7, 20.4; IR (neat) 2972, 1743, 1691 cm-1; LRMS for
C13H21NO3 (EI, 20 eV) m/z 241 (Mþ þ 2, 51), 226 (100), 198
(48); HRMS (EI) for C13H21NO3 (Mþ) calcd 239.1521, found
239.1522.
(400 MHz, CDCl3) δ 4.18 (td, J = 7.8, 4.1 Hz, 1H), 3.77 (s, 3H),
3.19 (d, J = 6.9 Hz, 1H), 3.03 (qd, J = 7.8, 3.6 Hz, 1H),
1.92-1.50 (m, 6H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.5, 169.3, 62.4, 56.7, 54.9, 52.6, 40.0, 35.3, 31.9, 28.2, 24.6; IR
(neat) 2960, 1741, 1683 cm-1; LRMS for C13H21NO3 (EI, 20 eV)
m/z 239 (Mþ, 48), 224 (100); HRMS (EI) for C13H21NO3 (Mþ)
calcd 239.1521, found 239.1524.
Methyl cis-1-tert-butyl-2-oxo-octahydro-1H-indole-cis-3-car-
boxylate (3g): yellow oil, 81% yield; analytical TLC (silica gel
60), 50% EtOAc in n-hexane, Rf = 0.44; 1H NMR (400 MHz,
CDCl3) δ 3.79 (s, 3H), 3.65-3.59 (m, 1H), 3.46 (d, J = 13.3 Hz,
1H), 2.82-2.76 (m, 1H), 2.14-2.10 (m, 1H), 1.76-1.72 (m, 2H),
1.60-1.56 (m, 2H), 1.41 (s, 9H), 1.30-1.11 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.7, 169.6, 56.4, 54.6, 52.5, 51.6, 37.3,
General Procedure for the Reductive Dephenylselenation.
Methyl trans-1-tert-Butyl-4-methyl-2- oxopyrrolidine-3-carboxy-
late (3b). To a stirred solution of 2b (111 mg, 0.30 mmol) in dry
benzene (10 mL) was added Bu3SnH (0.16 mL, 0.60 mmol) at
room temperature. Et3B (1 M n-hexane solution, 0.29 mL, 0.29
mmol) and oxygen gas (7 mL) were added via syringe. The
reaction was complete 3.5 h later. After removal of benzene, the
residue was diluted with Et2O. DBU (48 μL, 0.32 mmol) was
added followed by I2/Et2O solution until the light yellow color
persisted. The precipitate was filtered off, and the filtrate was
concentrated. The crude product was purified by column chro-
matography to give 3b (53 mg, 82%) as a white solid: mp 65-
66 °C; analytical TLC (silica gel 60), 50% EtOAc in n-hexane,
Rf = 0.30; 1H NMR (400 MHz, CDCl3) (diastereomer ratio 95/5)
δ 3.78 (s, 0.95 ꢀ 3H), 3.72 (s, 0.05 ꢀ 3H), 3.65 (dd, J = 9.3, 7.8Hz,
0.95 ꢀ 1H), 3.52 (dd, J = 9.3, 7.3 Hz, 0.05 ꢀ 1H), 3.34 (d,
J = 9.3 Hz, 0.05 ꢀ 1H), 3.23 (t, J = 9.1 Hz, 0.05 ꢀ 1H), 3.03 (d,
J = 8.3 Hz, 0.95 ꢀ 1H), 2.97 (dd, J = 9.3, 7.8 Hz, 0.95 ꢀ 1H),
2.74-2.63 (m, 1H), 1.41 (s, 0.05 ꢀ 9H), 1.39(s, 0.95ꢀ 9H), 1.13 (d,
J =6.8 Hz, 0.95 ꢀ 3H), 1.05 (d, J=6.8Hz, 0.05ꢀ 3H); 13CNMR
(100 MHz, CDCl3) (major diastereomer) δ 170.6, 169.7, 58.1,
31.8, 28.3, 25.4, 23.2, 20.4; IR (neat) 2945, 1740, 1688 cm-1
;
LRMS for C14H23NO3 (EI, 20 eV) m/z 254 (Mþ þ 1, 9), 253
(Mþ, 63), 238 (100), 196 (7); HRMS (EI) for C14H23NO3 (Mþ)
calcd 253.1678, found 253.1681.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (Project No. 20229201),
the Research Grants Council of Hong Kong (Project No. HKU
7121/02P), Fudan University, and the Science and Technology
Commission of Shanghai Municipality (STCSM). D.-W.Z.
thanks Fudan University for the conferment of the Century
Star Award. We thank Jing-Mei Wang for X-ray analysis of
compound 3g.
Supporting Information Available: Synthetic schemes and
characterization data of compounds 1a-h, NMR spectra of
compounds 1a-h, 2a-h, 3a-g, and 4a-h, and crystallographic
data of compound 3g. Theoretical calculation details of 2b/c, 5b/
c, 7, and 8. This material is available free of charge via the
Internet at http://pubs.acs.org.
54.5, 52.5, 51.4, 30.9, 27.7, 18.3; IR (neat) 2926, 1742, 1690 cm-1
;
LRMS for C11H19NO3 (EI, 20 eV) m/z 213 (Mþ, 62), 198 (100);
HRMS (EI) for C11H19NO3 (Mþ) calcd 213.1365, found
213.1371.
J. Org. Chem. Vol. 75, No. 10, 2010 3239