Pyrrolidine and piperidine formation via copper(II) carboxylate-promoted intramolecular carboamination of unactivated olefins: Diastereoselectivity and mechanism

Article abstract of DOI:10.1021/jo070321u

(Chemical Equation Presented) An expanded substrate scope and in-depth analysis of the reaction mechanism of the copper(II) carboxylate-promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic γ- and δ-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring.

Full text of DOI:10.1021/jo070321u

Pyrrolidine and Piperidine Formation via Copper(II)
Carboxylate-Promoted Intramolecular Carboamination of
Unactivated Olefins: Diastereoselectivity and Mechanism
Eric S. Sherman, Peter H. Fuller, Dhanalakshmi Kasi, and Sherry R. Chemler*
Department of Chemistry, The UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260
schemler@buffalo.edu
ReceiVed February 15, 2007
An expanded substrate scope and in-depth analysis of the reaction mechanism of the copper(II) carboxylate-
promoted intramolecular carboamination of unactivated alkenes is described. This method provides access
to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic γ- and δ-alkenyl
N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also
underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than
those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond
formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II)
carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of
microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted
pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed
in the context of the observed reactivity and in comparison to analogous reactions promoted by other
reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via
intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary
carbon radical to an aromatic ring.
Introduction
may prove especially useful in the concise synthesis of nitrogen
heterocycles for natural product synthesis and drug discovery
endeavors.11,14,15,26-32 Herein is reported an expansion of the
substrate scope of the copper(II)-promoted intramolecular car-
Nitrogen heterocycles make up a significant proportion of
biologically active small organic molecules. Recently developed
methods for the synthesis of nitrogen heterocycles by transition
metal facilitated intramolecular amine additions onto unactivated
alkenes have expanded the repertoire of tools available to the
medicinal chemist.1-25 Methods that provide for concise build-
up of functionality by installing two rings in a single operation
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10.1021/jo070321u CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/12/2007
3896
J. Org. Chem. 2007, 72, 3896-3905

Formation of Pyrrolidine and Piperidine
boamination of unactivated alkenes,11 a transformation that
installs two new rings from acyclic N-substituted amines.
We recently reported that copper(II) acetate promotes the
oxidative cyclization of N-arylsulfonyl-2-allylanilines 1 (eqs 1
and 2).11 In these reactions, aryl sulfonamides with electron
donating groups proved most reactive: 4-methyl, methoxy,
chloro and bromoaryl sulfonamides reacted efficiently albeit the
bromide was removed under the reaction conditions (eqs 1 and
2). 4-Nitro and 4-trifluoromethyl arylsulfonamides displayed
TABLE 1. Reaction Conditions: Carboxylate, Solvent,
Temperaturea
entry
R
solvent
DMF
temp, time
yield (%)d
1
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OPiv
EH
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 24 h
120 °C,b 0.5 h
120 °C,c 0.5 h
160 °C,b 0.5 h
160 °C,c 0.5 h
69
2
3
4
5
6
7
CH3CN
i-PrOH
t-amyl-OH
EtOAc
toluene
DMA
73
16e
33
24e
51e
37
8
DMF
69
64
69
9
DMF
10
11
12
13
14
15
ND
ND
ND
ND
ND
ND
DMF
toluene
DMF
DMF
DMF
71
29e
27e
63
DMF
64
a All reactions were run with 3 equiv of copper(II) carboxylate, 1 equiv
of Cs2CO3 at 0.1 M 1a concentration. b Oil bath heating, pressure tube.
c Microwave heating. d Amount isolated after flash chromatography on SiO2.
e Remainder of the material is starting 1a. In entry 3 another cyclization
product (net aminoetherification, incorporation of i-PrOH in the product)
was also formed in 21% yield (see the Supporting Information). Ac )
COCH3, Piv ) COC(CH3)3, neodecanoate (ND) ) OCO(CH2)5C(CH3)3,
ethylhexanoate (EH) ) OCOCH(C2H5)C4H9.
product over the para adduct (eq 2). This surprising ortho
preference (the more sterically hindered site) indicated that C-C
bond formation may occur via addition of a carbon radical to
the aromatic ring [intermolecular additions of radicals to
aromatics have shown a slight preference (ca. 2:1) for the ortho
adduct].34,35
significantly lower reactivity (eq 1). (Similar electronic effects
have been observed in Bro¨nsted acid catalyzed intramolecular
hydroamination reactions.33) Meta-substituted aryl sulfonamides
demonstrated a preference (ca. 2:1) for the ortho addition
Results and Discussion
To further expand the utility of this method, several copper-
(II) carboxylate salts, solvents, and reaction heating methods
were examined. Our former optimized reaction conditions for
the carboamination reaction of 1a (R ) Me) required DMF or
CH3CN solvent at 120 °C for 24 h (Table 1, entries 1 and 2).
The need for polar solvents and additives (added DMSO
increased the yield with some substrates) was attributed to the
poor solubility of Cu(OAc)2 in organic solvents. We therefore
examined the reaction further by using more polar solvents with
Cu(OAc)2 and more organic soluble copper carboxylates with
nonpolar solvents, respectively. The reaction did proceed in both
i-PrOH and tert-amyl alcohol (Table 1, entries 4 and 5) although
in the former case a substantial amount of another product was
obtained (net aminoetherification, see the Supporting Informa-
tion) while in the latter case a more efficient, albeit not optimal
carboamination process occurred. Several copper(II) carboxy-
lates were also compared. We found that while the use of Cu-
(12) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R.
Organometallics 2004, 23, 5618-5621.
(13) Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett. 2004, 45, 1785-1788.
(14) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005,
127, 11250-11251.
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Soc. 2005, 127, 14586-14587.
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127, 7690-7691.
(17) Donohoe, T. J.; Chughtai, M. J.; Klauber, D. J.; Griffin, D.;
Campbell, A. D. J. Am. Chem. Soc. 2006, 128, 2514-2515.
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2004, 6, 2583-2585.
(19) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906-13907.
(20) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605-
3608.
(21) Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61 (26), 6447-
6459.
(22) Hiroya, K.; Itoh, S.; Sakamoto, T. Tetrahedron 2005, 61, 10958-
10964.
(23) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543-17594.
(24) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303-5305.
(25) Donohoe, T. J.; Churchill, G. H.; Wheelhouse, K. M. P.; Glossop,
P. A. Angew. Chem., Int. Ed. 2006, 45, 8025-8028.
(26) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006,
128, 2893-2901.
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Chem. Soc. 2006, 128, 3130-3131.
(28) Molander, G. A.; Pack, S. K. Tetrahedron 2003, 59, 10581-10591.
(29) Sharp, L. A.; Zard, S. Z. Org. Lett. 2006, 8, 831-834.
(30) Banwell, M. G.; Lupton, D. W. Heterocycles 2006, 68 (1), 71-92.
(31) Senboku, H.; Kajizuka, Y.; Hasegawa, H.; Fujita, H.; Suginome,
H.; Orito, K.; Tokuda, M. Tetrahedron 1999, 55, 6465-6474.
(32) Hasegawa, H.; Senboku, H.; Kajizuka, Y.; Orito, K.; Tokuda, M.
Tetrahedron 2003, 59, 827-832.
(33) Yin, Y.; Zhao, G. Heterocycles 2006, 68 (1), 23-31.
(34) Ito, R.; Migita, T.; Morikawa, N.; Simamura, O. Tetrahedron 1965,
21, 955-961.
(35) Pryor, W. A.; Davis, W. H.; Gleaton, J. H. J. Org. Chem. 1975, 40,
2099-2102.
J. Org. Chem, Vol. 72, No. 10, 2007 3897

Sherman et al.
TABLE 2. Expanded Sulfonamide Substrate Scopea
1
a Reaction conditions: 3 equiv of Cu(ND)2, 1 equiv of Cs2CO3, DMF (0.08-0.1 M), temp, time. b Selectivity determined by analysis of the crude H
NMR spectrum, and by the amount of isolated adducts. c Yield refers to the amount of product isolated by chromatography on silica gel. d Reaction run with
Cu(OAc)2 instead of Cu(ND)2. CA ) carboamination product, HA ) hydroamination product, ND ) neodecanoate.
SCHEME 1. Mechanism for Formation of the Carboamination and Hydroamination Adducts
(OAc)2 in toluene did promote oxidative cyclization (51% yield
+ remaining starting material, entry 6, Table 1), the more
organic soluble copper(II) neodecanoate [Cu(ND)2] provided a
more efficient reaction (71% yield, entry 11, Table 1). Copper-
(II) neodecanoate also provided a more efficient reaction with
more entropically challenging substrates (Table 2, vide infra).
Copper(II) pivalate and copper(II) 2-ethylhexanoate also pro-
vided efficient reaction in DMF (entries 8 and 9) and under
these conditions are comparable to Cu(ND)2 and Cu(OAc)2. On
the basis of these examples, the relative steric demand of the
3898 J. Org. Chem., Vol. 72, No. 10, 2007

Formation of Pyrrolidine and Piperidine
carboxylate alkyl chain does not affect the reactivity of the
carboxylate salt in these reactions.
4-enyl sulfonamide 16 produced 1:1 diastereomeric mixtures
of carboamination and hydroamination products, 17 and 18,
respectively (entries 5 and 6, ratio of 17:18 ) 3.5:1 in an oil
bath at 210 °C). In the case of substrate 19, with a methylcy-
clohexyl group at the allylic position, a 3:1 mixture of 2,3-
trans:2,3-cis diastereomers of carboamination and also 3:1 2,3-
trans:2,3-cis hydroamination adducts, 20 and 21, were formed
(ratio of carboamination:hydroamination ) 2:1). Cyclization
reactions of substrates with allylic substitution under several
other reaction conditions also favor the formation of the anti
adduct, presumably due to reaction via a chairlike transition
state that favors placement of the allylic alkyl substituent in a
pseudoequatorial position.13,20 The need for high temperature
in the copper(II) carboxylate-promoted cyclization may account
for the modest level of asymmetric induction observed.
The carboamination adducts derived from styrenyl substrates
22 and 27 were obtained in modest yield upon heating at 200-
210 °C (entries 8 and 11). These substrates are challenging due
to the ground state resonance stabilization that is lost in the
cyclization transition state. Few intramolecular carboamination
protocols have been reported with styrenyl substrates.28 Forma-
tion of six-membered rings is also possible via the copper(II)-
promoted carboamination protocol (entries 9-11, Table 2).
The products formed in these oxidative cyclization reactions
are consistent with a mechanism that involves formation of a
radical intermediate (e.g., 29) that may either perform intramo-
lecular addition onto the neighboring aromatic ring or abstraction
of a proton from the reaction medium (Scheme 1). In the case
of endo cyclization adduct 10, the secondary radical undergoes
Cu(II)-facilitated elimination to form an alkene.38,39
Increasing the reaction temperature decreased the time
required for product formation. As judged by the crude 1H NMR
spectra, at 160 °C the reaction was complete after 0.5 h (63%
isolated yield of 2) while only a 29% yield of 2 was obtained
at 120 °C for 0.5 h [using Cu(ND)2 in DMF], the remaining
material being unreacted starting material (compare entries 12
and 14). At these reaction scales with substrate 1a (ca. 30 mg
of 1a, 1 mL of solvent) we did not find a notable difference in
reactivity between microwave and oil bath heating (compare
entry 12 to 13 and entry 14 to 15). This may be due in part to
the fact that both reactions are run in sealed tubes, thus, in both
cases, the reaction solutions are subject to superheating and also
the transfer of heat due to surface area heating is not a significant
problem with small-scale reactions.36
Effect of the Nitrogen Substituent. Although arylsulfona-
mides are superior substrates for this reaction (lower reaction
temperatures required, higher yield), the N-benzoyl-2-allylaniline
6 also provides the oxidative cyclization product 7 (eq 3, ND
) neodecanoate). Formation of fused carbon/nitrogen ring
systems allows entry into a broader range of nitrogen hetero-
cycles and further examination of the copper carboxylate-
promoted reactions with such substrates is warranted.
The mechanism was further probed by using the carboami-
nation reaction of deuterioalkene 14-D (eq 4). The partial
conversion of 14-D provides a 1:1 mixture of diastereomers
15-D, indicating the presence of an sp2-hybridized carbon
intermediate, likely a primary radical. The remaining deuterio-
alkene was recovered with complete retention of stereochem-
istry, indicating that the carbon radical intermediate does not
revert back to the alkene.
Effect of Chain Length and Substitution. In an effort to
expand the substrate scope of the copper(II) carboxylate-
promoted carboamination reaction of sulfonamides as well as
gain more insight into the reaction mechanism, the oxidative
cyclizations of a number of substrates were explored, including
arylsulfonamides derived from aliphatic amines, substrates with
different olefin substitution patterns, and substrates containing
chiral centers (Table 2). Both microwave and oil bath heating
methods were used. Both five-membered-ring pyrrolidines and
six-membered-ring piperidines can be formed through this
oxidative cyclization protocol. All of the substrates examined
in this reaction give exclusively the exo cylization adduct except
for the 1,1-disubstituted olefin 8, which gave a ca. 1:1 mixture
of the exo carboamination adduct 9 and the endo oxidative
amination adduct 10 (Table 2, entry 1).
Sulfonamides 11, 14, 16, and 19, derived from primary
aliphatic amines (entries 2-7), undergo cyclization efficiently
although the gem-dimethyl-substituted substrate 14 demonstrated
the highest reactivity.37 The more organic soluble Cu(ND)2 had
a significant effect on the reaction yields with less reactive
substrates (compare entries 2 and 3, Table 2). The formation of
hydroamination minor products was also observed with some
substrates and the carboamination to hydroamination ratio is
presumably a function of the relative rates of radical addition
to the aromatic ring vs hydrogen atom abstraction from the
reaction medium (vide infra). Reaction of the 2-phenyl-pent-
When an unambiguous primary radical was generated from
the primary bromide 31 (AIBN, HSnBu3, PhH, reflux), a mixture
of carboamination adducts 4 and 5 (ortho:para ) 2.7:1) and
hydroamination adduct 32 was obtained (eq 5). The fact that
the carboamination products were obtained in the same ortho:
para ratio (2.7:1) as observed in the copper(II)-promoted reaction
(see eq 2) is compelling evidence that a similar intermediate, a
primary carbon radical, is involved in the C-C bond formation.
No ipso (1,5-addition) substitution of the radical onto the
aromatic ring was observed. Mixtures of ipso (1,5) addition
products and direct (1,6) addition products along with the direct
reduction products have previously been observed in the
intramolecular radical reactions of N-arylsulfonyl-2-halometh-
(36) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717-727.
(38) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351-360.
(37) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080.
(39) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. ReV. 1994, 94, 519-
564.
J. Org. Chem, Vol. 72, No. 10, 2007 3899

Sherman et al.
TABLE 3. 1,2-Disubstituted (Internal) Olefin Substrates
a Remainder of the mass was recovered starting material. b A 5:1 E:Z
mixture of olefin isomers of 36 was used. c Isolated yield. ND )
neodecanoate.
ylpiperidines (AIBN, HSnBu3, PhH, reflux), and in many
instances, the ipso product predominates.40-44 It has previously
been observed, however, that the propensity for direct addition
versus ipso substitution in the intramolecular addition reactions
of carbon radicals to aromatic rings is highly dependent on the
structure of the substrate.42,44,45
SCHEME 2. Mechanism of Oxidative Cyclization of
Substrates with Internal Olefins
In an additional experiment, we have trapped the copper(II)
carboxylate-promoted carboamination reaction intermediate
derived from sulfonamide 1 with TEMPO (2,2,6,6-tetrameth-
ylpiperidine-N-oxyl), a classical carbon radical trap (eq 6).46
of the radical to the aromatic ring in cases when the carbon
radical is secondary rather than primary (Scheme 2). Copper-
(II)-promoted oxidative elimination reactions of carbon radicals
have been previously invoked by Kochi; the elimination is not
thought to occur via a carbocation intermediate unless a stable
carbocation can be formed.47
To aid in our mechanism investigation as well as further
explore the scope of the carboamination reaction, we examined
the oxidative cyclization of several R-substituted γ-alkenyl
sulfonamides 39 for the synthesis of 2,5-disubstituted pyrro-
lidines (Table 4).48 Sulfonamides 39 can be efficiently synthe-
sized in enantiomerically enriched form via ring opening
addition of substituted tosylaziridines with allylmagnesium
bromide.49 We found that cis-2,5-disubstituted pyrrolidines 40
can be formed with very high diastereoselectivity (>20:1) and
in 31-51% yield in the copper(II)-promoted oxidative cycliza-
tion of substrates 39 using either oil bath heating (sealed tube,
170-200 °C, 72 h) or microwave irradiation (210 °C, 3 h).
Heating in an oil bath at 200 °C for 3 h gave only slightly lower
conversion (entry 3). The net hydroamination adducts 41 are
formed in these reactions as well (15-28%) and are formed
with high 2,5-cis selectivity (>20:1) in all cases examined. The
products emerge as ca. 2:1 mixtures of carboamination and
hydroamination adducts, 40 and 41, respectively. A series of
high boiling solvents [toluene, trifluorotoluene, tert-butyltoluene,
N,N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidinone
(DMI), and 1-methyl-2-pyrrolidinone (NMP)] and different
reaction concentrations (0.01 and 0.5 M in DMF, reactions in
Table 4 were run at 0.1 M substrate concentration) were tried
with substrate 39b in an attempt to improve the carboamination
product yield; unfortunately no improved conditions have yet
been identified.
No reaction occurred under the same conditions but in the
absence of Cu(OAc)2. It should be noted that carbon radicals
do react rapidly with copper(II) salts to form organocopper(III)
intermediates.38 This process might be reversible for primary
carbon radicals under our reaction conditions. Although we
cannot rule out the possibility that some of the reactions
discussed above might take place via such an organocopper
species, we believe the carbon radical mechanism is the simplest
explanation and most consistent with the observed results (vide
supra, eqs 5 and 6). Previously, organocopper(III) species have
been shown to undergo oxidative elimination or reductive
elimination reactions.38
Substrates with internal disubstituted olefins require higher
temperature conditions in the copper(II) carboxylate-promoted
oxidative cyclization than their terminal olefin counterparts
(Table 3). The reactions are also less efficient and the cyclization
cascade concludes in elimination rather than radical addition
to the aromatic ring of the sulfonamide (e.g., compare entry 4
in Table 2 to entries 2 and 3 in Table 3).
The reactivity pattern of the internal olefin substrates indicates
that (1) the rate of the initial nitrogen addition to the alkene is
retarded by substitution on the terminal carbon and (2) oxidation
of the resulting carbon radical to the olefin is faster than addition
(40) Kohler, J. J.; Speckamp, W. N. Tetrahedron Lett. 1977, 7, 631-
634.
(41) Speckamp, W. N.; Kohler, J. J. Chem. Commun. 1978, 166-167.
(42) Kohler, J. J.; Speckamp, W. N. Tetrahedron Lett. 1977, 7, 635-
638.
(43) Loven, R.; Speckamp, W. N. Tetrahedron Lett. 1972, 1567-1570.
(44) da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.
Tetrahedron Lett. 1997, 38, 137-140.
(45) Bonfand, E.; Motherwell, W. B.; Pennell, A. M. K.; Uddin, M. K.;
Ujjainwalla, F. Heterocycles 1997, 46, 523-534.
(46) Root, K. S.; Hill, C. L.; Lawrence, L. M.; Whitesides, G. M. J.
Am. Chem. Soc. 1989, 111, 5405-5412.
When substrate 39b was treated first with NaH (1.2 equiv)
and then with Cu(ND)2 (1.2 equiv) and subsequently heated,
the reaction proceeded efficiently and gave similar results as
when Cs2CO3 was used as base (compare entry 4 to 6). This
(47) Kochi, J. K.; Bacha, J. D. J. Org. Chem. 1968, 33, 2746-2754.
(48) Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927-
964.
(49) Akiyama, T.; Ishida, Y.; Kagoshima, H. Tetrahedron Lett. 1999,
40, 4219-4222.
3900 J. Org. Chem., Vol. 72, No. 10, 2007

Formation of Pyrrolidine and Piperidine
TABLE 4. Diastereoseletive Formation of 2,5-cis-Pyrrolidinesa
yield (%)c
yield (%)c
entry
substrate
method, temp, time
40
41
1
2
3
4
5
6
7
8
39a, R1 ) i-Pr, R2 ) Me
oil bath, 190 °C, 72 h
210 °C (µW), 3 h
49
51
40
49
51
33
34
31
48
48
49
49
50
47
25
28
19
23
23
24
15
17
15
15
20
19
22
21
39a
39a
oil bath, 200 °C, 3 h
oil bath, 190 °C, 72 h
210 °C (µW), 3 h
39b, R1 ) i-Pr, R2 ) OMe
39b
39b
oil bath, 190 °C, 72 hb
oil bath, 170 °C, 72 h
210 °C (µW), 3 h
39c, R1 ) t-Bu, R2 ) Me
39c
9
39d, R1 ) Me, R2 ) Me
oil bath, 200 °C, 72 h
210 °C (µW), 3 h
oil bath, 200 °C, 72 h
210 °C (µW), 3 h
oil bath, 200 °C, 72 h
210 °C (µW), 3 h
10
11
12
13
14
39d
39e, R1 ) i-PrCH2, R2 ) Me
39e
39f, R1 ) Bn, R2 ) Me
39f
a Sulfonamides 39 were dissolved in DMF (0.1 M) and treated with Cs2CO3 (1 equiv) and Cu(ND)2 (3 equiv) and were heated in the indicated manner
at the indicated temperature and time. b Reaction run with NaH as base instead of Cs2CO3: sulfamide 39b in DMF was treated with NaH (1.2 equiv) at 23
°C for 0.5 h, then Cu(ND)2 (1.2 equiv) in DMF was added, the solution was stirred for 0.5 h, then the reaction was heated at 190 °C for 72 h. c Yields refer
1
to isolated products; diastereomeric ratios (>20:1) were determined by analysis of the crude H NMR and by isolated yields. ND ) neodecanoate.
SCHEME 3. Possible Mechanisms for cis-Pyrrolidine Formation
indicates that a R2N-CuL intermediate can productively convert
to the observed products (vide infra).
especially when compared to the stereochemical trends observed
when other reagents are used to promote pyrrolidine formation
(vide infra).
Analysis of the C-N Bond Formation Mechanism. The
level and direction of diastereoselectivity in the 2,5-disubstituted
pyrrolidine formation (Table 4) provides insight into the initial
steps of the reaction mechanism. Three mechanistic scenarios
that lead to the carbon radical intermediate 43 were considered
(Scheme 3): (1) trans aminocupration, generating an unstable
organocopper(II) species50,51 that homolyzes to the carbon
radical and Cu(I); (2) syn aminocupration, generating an unstable
organocopper(II) species that homolyzes to the carbon radical
and Cu(I); and (3) Cu(II) oxidation of the nitrogen to the
nitrogen radical, followed by cyclization onto the olefin.
The predominance for the formation of the cis pyrrolidine
diastereomer can provide insight into the reaction mechanism,
Consideration of a Nitrogen Radical Pathway. Pyrrolidines
can be formed via cyclization of a nitrogen radical onto an
olefin. Nitrogen radicals are usually formed via the homolytic
cleavage of nitrogen-heteroatom bonds.23,52,53 For example,
amine, amidyl, and sulfamidyl radicals have been generated by
treatment of (1) xanthates (N-(O-ethyl thiocarbonylsulfanyl)-
amides) with lauroyl peroxide and heat,54 (2) O-acyl hydroxamic
55
acids with Bu3SnH and AIBN,55-57 or Cu(OTf)2 (3) N-X
(52) Neale, R. S. Synthesis 1971, 1, 1-15.
(53) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337-422.
(54) Gagosz, F.; Moutrille, C.; Zard, S. Z. Org. Lett. 2002, 4, 2707-
2709.
(55) Clark, A. J.; Filik, R. P.; Peacock, J. L.; Thomas, G. H. Synlett
1999, 441-443.
(56) Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-Sire, B.; Schiana, A.-
M.; Zard, S. Z. Tetrahedron 1995, 51 (23), 6517-6528.
(57) Clark, A. J.; Deeth, R. J.; Samuel, C. J.; Wongtap, H. Synlett 1999,
4, 444-446.
(50) Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M.
AdVanced Inorganic Chemistry, 6th ed.; John Wiley & Sons: New York,
1999.
(51) Chmielewski, P. J.; Latos-Grazynski, L.; Schmidt, I. Inorg. Chem.
2000, 39, 5475-5482.
J. Org. Chem, Vol. 72, No. 10, 2007 3901

Sherman et al.
(X ) Cl, Br, or I) with Et3B, light, or a transition metal
catalyst,52,58-65 and (4) N-acyltriazines with heat.66 Typical
products of nitrogen radical cyclizations onto olefins include
net carboamination, hydroamination, and atom transfer (eqs 7
and 8).55,66 Typically, terminal, internal and trisubstituted olefins
provide amine and amidyl radical cyclization adducts.54,63
coordinated nitrogen radical that promotes an organized addition
to the alkene is also unlikely given the poor diastereoselectivity
observed when CuCl/CuCl2 was used to promote the radical
reaction of chlorosulfonamide 46 (eq 10).
The oxidation of an amide or sulfonamide to the correspond-
ing nitrogen radical by the agency of a copper salt is, in fact,
unprecedented. (It should be noted, however, that the oxidation
of aliphatic amines to nitriles, imines, and aldehydes by copper
salts has been reported, and these reactions have been postulated
Clark has reported studies regarding the stereoselectivity of
an amidyl radical cyclization where the substrate contained a
stereocenter R to the amine.57 He found that the trans pyrrolidine
product is favored (dr ) 3.3:1) (eq 9, remainder of isolated
material is uncyclized amide resulting from reduction of the
N-O bond).57 Similar nitrogen radical reactions performed by
Senboku and Tokuda involve homolysis of N-Cl substrates with
AIBN and Bu3SnH and provide the 2,5-trans pyrrolidines as
the major diastereomeric products.31,32
to occur through both radical and two-electron processes.68-70
)
The oxidation of N-aryl amides with o-iodoxybenzoic acid (IBX)
has, however, been reported, and the derived radicals undergo
intramolecular cyclization onto variously substituted olefins.71
Amides derived from aliphatic amines (non-aniline) are reported
to be unreactive under these conditions.71 In our hands,
subjection of N-arylsulfonyl-o-allylaniline 1a to these reaction
1
conditions resulted in no reaction by crude H NMR analysis.
In comparison to the IBX-promoted reaction, it is also note-
worthy that the arylsulfonamides derived from aliphatic amines
are not significantly less reactive than arylsulfonamides derived
from anilines in the copper(II) carboxylate-promoted oxidative
cyclization. This fact also argues against the formation of a
nitrogen radical. In addition, the lower reactivity of the internal
olefins [substrate 36 (Table 3) is less reactive than substrate 14
(Table 2)] indicates that steric hindrance at the terminal carbon
impedes reactivity in the copper(II) carboxylate-promoted
reactions; by comparison, amidyl radical reactions are not
impeded by substitution on the terminal alkene carbon (e.g., eq
8).72 Transition metal-mediated additions of nitrogens to alkenes
often suffer lower reactivity with internal alkenes.4,73 We
therefore conclude that the reactivity pattern observed in the
copper(II) carboxylate-promoted carboaminations is most con-
sistent with a reaction mechanism that requires addition of [Cu]
to the terminal alkene carbon.
We further examined the stereoselectivity of a nitrogen radical
reaction with a sulfonamide substrate. In our hands, of a number
of methods attempted, the N-chlorosulfonamide 46 proved to
be the most facile nitrogen radical precursor to synthesize.
Hence, 46 was obtained uneventfully by treatment of the
sulfonamide with NaH followed by N-chlorination with NCS.64
The N-chlorosulfonamide was subjected to two conditions
reported to induce nitrogen radical cyclization reactions.59,63,64
Treatment of 46 with Et3B led to a 64:36 cis:trans mixture of
chloromethylpyrrolidines 47 in 73% combined yield. When
CuCl/CuCl2 was used as the radical initiator,59,63,67 a 44:56 cis:
trans mixture of 47 was obtained. Both reactions are relatively
unselective (dr ) <2:1). On the basis of these comparisons, it
is unlikely that the highly diastereoselective copper(II) car-
boxylate-promoted oxidative cyclization proceeds via a nitrogen
radical. A mechanism involving a copper(I)- or copper(II)-
Consideration of a Trans Aminocupration Mechanism.
Intramolecular cyclization of amines onto olefins to form
pyrrolidines can be promoted by metallic electrophiles such as
mercury(II) and palladium as well as halogens and analogous
electrophilic reagents.5,74,75 Elegant work by Harding and co-
workers established that the trans-pyrrolidine is the kinetic
(58) Daoust, B.; Lessard, J. Tetrahedron 1999, 55, 3495-3514.
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1989, 30 (11), 1327-1330.
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3902 J. Org. Chem., Vol. 72, No. 10, 2007

Formation of Pyrrolidine and Piperidine
product in the mercury(II)-promoted cyclization of N-Cbz
γ-unsaturated amine (eq 11).76 The proposed mechanism
reactions described herein, suggestive of similar diastereocontrol
elements in the two reactions.80
It is also noteworthy that lanthanide-catalyzed hydroamina-
tions of primary amines are routinely trans selective operations
and are thought to occur via a syn addition mechanism (eq
14).4,73 Conversely, cationic titanocene and zirconocene cata-
lyzed hydroaminations of secondary amines favor formation of
the 2,5-cis pyrrolidines (eq 15).81 Hydroamination reactions of
secondary amines catalyzed by n-BuLi also afford 2,5-cis
pyrrolidines.82 Clearly, the nitrogen substituent (H vs Me, Ar,
or Ts) significantly affects the diastereoselectivity of such
reactions (vide infra).
involves a chairlike tranisition state and a trans-aminomercu-
ration of the olefin.77 As proposed by Harding, the substituents
adopt pseudoequatorial positions on the chairlike transition state.
No evidence has been proposed to refute this mechanism. When
sulfonamide 39a was treated under modified78 mercuration-
demercuration conditions, an 8:1 diastereomeric mixture favor-
ing the trans hydroamination adduct trans-41a was obtained in
56% yield (eq 12). That the trans rather than cis adduct
substantially predominates in this kinetically controlled reaction
is a strong indication that the cis-selective copper(II) carboxylate
oxidative cyclization reaction does not proceed by the same
mechanism as the mercury(II) acetate reaction.
Other Pyrrolidine Formation Methods. In addition to the
methods described above, the Bro¨nsted acid-catalyzed cycliza-
tion of γ-alkenyl sulfonamide 39e provided a mixture of
hydroamination products, pyrrolidines trans-41e and cis-41e,
where the trans 2,5-pyrrolidine was slightly favored (eq 16).33,83
The direction of diastereoselectivity and level of stereocontrol
in this reaction indicates that the mechanism of the copper(II)
carboxylate reactions is not controlled by analogous factors.
Consideration of a Syn Aminocupration Mechanism. A
mechanism for the copper(II) carboxylate-promoted carboami-
nation reaction that involves the intermediacy of a copper-
coordinated nitrogen (cf. 44, Scheme 3) is supported by the fact
that when such an intermediate is generated at room temperature
by deprotonation of the sulfonamide 39a at 23 °C with NaH
followed by treatment with 1 equiv of Cu(ND)2 at 23 °C for
0.5 h, upon heating, it forms the oxidative cyclization products
cis-40b and cis-41b (Table 4, entry 6). That internal olefins
(Table 3) are less reactive than terminal olefins in this reaction
also supports the hypothesis that a copper-carbon bond is
formed in the rate-determining step.
Transition State Analysis for Copper(II) Carboxylate-
Promoted Carboaminations. Syn addition transition state
models that rationalize the observed diastereoselectivity of the
copper(II) carboxylate-promoted carboamination reactions of
substrates with stereocenters R to the amine are illustrated in
Figure 1. The copper(II) is assumed to be tetracoordinate in
these transition states. The top two transition states, A and B,
are chairlike, where A leads to the 2,5-cis-disubstituted pyrro-
lidine and B leads to the 2,5-trans-disubstituted pyrrolidine. The
boatlike transition state C also leads to the 2,5-cis pyrrolidine
while the boatlike transition state D leads to the 2,5-trans
In addition, palladium-catalyzed carboamination reactions that
are thought to occur via syn aminopalladation favor formation
of cis-2,5-disubstituted pyrrolidines.20,21,79 As reported by Wolfe
and co-workers, N-Aryl, N-Boc, and N-acyl substrates all
provide the cis-2,5-disubstituted pyrrolidine as the major adduct
(eq 13). Examination of the reaction of cyclic disubstituted
olefins led Wolfe to conclude that a syn insertion of the nitrogen
and palladium into the olefin is operative in these reactions.20
The nitrogen substitution pattern and cis pyrrolidine selectivity
in this reaction is most analogous to the copper(II)-promoted
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2840.
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2005, 347, 1614-1620.
(82) Fujita, H.; Tokuda, M.; Nitta, M.; Suginome, H. Tetrahedron Lett.
1992, 33, 6359-6362.
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J. Org. Chem, Vol. 72, No. 10, 2007 3903

Sherman et al.
FIGURE 1. Competing syn addition transitions states that lead to the cis- and trans-pyrrolidines.
pyrrolidine. Both the chair and boat transition states A and C
that lead to the cis pyrrolidine orient the SO2Ar group trans to
the R substituent, R. Both the chair and boat transition states B
and D that lead to the trans pyrrolidine orient the SO2Ar group
syn with respect to substituent R. It appears that the steric
interaction between these two groups is the dominant sterecon-
trol element. Chairlike transition state models of other intramo-
lecular additions of amines to unactivated olefins are typically
favored over the boatlike transition states.4,57,77,81
Reductive Removal of Sulfur Dioxide. The use of sulfona-
mides and sultams as biologically active agents for medicinal
chemistry purposes as well as herbicides is well established.84
It is hoped that the methods described in this report for the direct
synthesis of sultams from acyclic γ- and δ-alkenyl sulfonamides
will prove useful for the synthesis of novel sultam small
molecule scaffolds for medicinal chemistry endeavors. Should
the free amine be desired, the SO2 unit may be directly excised
under dissolving metal conditions (Li, NH3) (eq 17).85
anism of these reactions is often complicated by the dual polar,
organometallic, and redox properties of copper and it is often
difficult to differentiate between radical and polar reaction
mechanisms. We have reported the first copper-promoted
addition of unfunctionalized nitrogens to unactivated alkenes
forming a new sp3 stereocenter.11,14 As described herein, we
have found these reactions to be highly diastereoselective in a
number of cases and useful for the synthesis of a range of five-
and six-membered nitrogen heterocycles, We have provided
evidence for a syn aminocupration pathway for the formation
of the N-C bond. A copper-facilitated N-C bond-forming
process is required for asymmetric induction controlled by chiral
ligands on copper(II) to be envisioned. We have also provided
evidence for a carbon radical intermediate that can undergo
either intramolecular addition to aryl rings or hydrogen abstrac-
(88) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
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(92) Taylor, J. G.; Whittall, N.; Hii, K. K. M. Org. Lett. 2006, 8, 3561-
3564.
Additionally, methods for the use of sultams directly in Ni-
(acac)2-catalyzed cross-coupling reactions with Grignard re-
agents have been reported and provide a method for subsequent
C-C bond formation.86
(93) Rovis, T.; Evans, D. A. Prog. Inorg. Chem. 2001, 50, 1-150.
(94) Wang, Q.; Chan, T. R.; Hilgraf, R.; Folkin, V. V.; Sharpless, K.
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Conclusion
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The low cost of copper and the wide range of valuable
transformations enabled by this metal continue to stimulate
significant research effort in the discovery, development, and
refinement of copper-facilitated chemistry.22,38,87-104 The mech-
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3904 J. Org. Chem., Vol. 72, No. 10, 2007

Formation of Pyrrolidine and Piperidine
tion from the reaction medium. We have also observed oxidative
amination with internal alkene substrates. Thus far we have
demonstrated that both net intramolecular carboamination and
diamination of unactivated alkenes can be efficiently facilitated
by copper(II) carboxylates.11,14 This chemistry should also be
amenable to the addition of other functional groups to alkenes
via either radical or copper-facilitated mechanisms, and studies
along those lines, as well as additional mechanistic studies and
exploration of asymmetric catalysis methods, will be reported
in due course.
1.90 (m, 2 H), 1.76 (m, 1 H), 0.93 (d, J ) 7.0 Hz, 3 H), 0.88 (d,
J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 142.8, 136.3,
135.8, 130.0, 128.7, 124.3, 62.5, 60.8, 36.7, 32.9, 32.6, 29.6, 21.9,
20.4, 16.5; IR (neat, thin film) υ 2962, 1698, 1465, 1323, 11578,-
1094, 909 cm-1; HRMS (EI) calcd for C15H21O2NSNa [M + Na]+
302.1185, found 302.1192.
The relative stereochemistry of the hydroamination product 41a
was determined by X-ray crystallography.
Experimental Section
X-ray Structure of (2S,5S)-N-Tosyl-2-isopropyl-5-methylpyr-
Representative Synthesis of R-Substituted N-Tosyl-4-pente-
nylamines (Substrates in Table 4): (S)-N-Tosyl-1-isopropyl-4-
pentenylamine (39a). Magnesium metal (254 mg, 10.5 mmol, 5
equiv) was placed in a 25 mL 2-necked flask equipped with a reflux
condenser and magnetic stirring bar, then suspended in 10 mL of
Et2O under Ar(g). Freshly distilled allyl bromide (1.24 g, 0.89 mL,
10.5 mmol, 5 equiv) was added dropwise at rt. The mixture was
stirred for 2 h (until the magnesium was consumed). (S)-2-
Isopropyl-N-tosylaziridine105 (500 mg, 2.1 mmol, 1 equiv) was
dissolved in 5 mL of Et2O under Ar(g) and added dropwise. The
mixture was stirred for an additional 16 h. The reaction was
quenched with saturated NH4Cl(aq) (15 mL), and extracted with
ethyl acetate (2 × 10 mL). The crude oil was purified by flash
chromatography on SiO2 (20% EtOAc in hexanes) to give 428 mg
of (S)-N-tosyl-1-isopropyl-4-pentenylamine (39a) in a 73% yield
as a white solid. Data for 39a: mp 49-51 °C, [R]20D -8.6 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J ) 8.0 Hz, 2 H),
7.28 (d, J ) 8.4 Hz, 2 H), 5.64 (m, 1 H), 4.85-4.95 (m, 2 H), 4.26
(d, J ) 9.2 Hz, 1 H), 3.12 (m, 1 H), 2.41 (s, 3 H), 1.85-1.95 (m,
2 H), 1.73 (m, 1 H), 1.48 (m, 1 H), 1.30 (m, 1 H), 0.78 (d, J ) 3.6
Hz, 3 H), 0.76 (d, J ) 2.8 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
δ 143.2, 138.9, 138.3, 130.0, 127.6, 115.5, 59.3, 31.6, 31.5, 30.3,
22.0, 18.7, 18.1; IR (neat, thin film) υ 2961, 1641, 1599, 1429,
1323, 1156, 1094 cm-1; HRMS (EI) calcd for C15H23O2NS [M]+
281.1444, found 281.1447.
Representative Procedure (Table 4) for Carboamination
Reactions in a Microwave: (3S,10aS)-3-Isopropyl-8-methyl-2,3,-
10,10a-tetrahydro-1H-pyrrolo[1,2-b]1,2benzothiazine 5,5-Dioxide
(40a) and (2S,5S)-N-Tosyl-2-isopropyl-5-methylpyrrolidine (41a).
(S)-N-Tosyl-1-isopropyl-4-pentenylamine 39a (35.1 mg, 0.125
mmol) in a microwave vial equipped with a magnetic stir bar was
treated with copper(II) neodecanoate (60% by wt in toluene, 152
mg, 0.275 mmol, 3 equiv) and Cs2CO3 (40.7 mg, 0.125 mmol, 1
equiv) and dissolved in DMF (1.3 mL) under Ar(g). The vial was
sealed and the reaction mixture was heated at 210 °C for 1.5 h in
a microwave. After cooling to rt, it was heated again at 210 °C for
1.5 h in a microwave. The mixture was cooled to rt, diluted with
Et2O, and washed with saturated EDTANa2(aq). The organic layer
was dried over Na2SO4 and filtered, and the solvents were removed
in vacuo. The mixture was purified by flash chromatography on
SiO2 (10-30% EtOAc in hexanes gradient) providing (S,S)-N-tosyl-
2-isopropyl-5-methylpyrrolidine 41a (9.8 mg, 0.0351 mmol) in 28%
yield (Rf 0.5 in 10% EtOAc in hexanes) and (S,S)-3-isopropyl-8-
methyl-2,3,10,10a-tetrahydro-1H-pyrrolo[1,2-b]1,2benzothiazine 5,5-
dioxide 40a (17.8 mg, 0.0639 mmol) in 51% yield (Rf 0.3 in 10%
EtOAc in hexanes).
rolidine (41a). Data for 41a: mp 83-86 °C, [R]20D +130.0 (c 0.28,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J ) 8.1 Hz, 2 H),
7.30 (d, J ) 7.8 Hz, 2 H), 3.65 (m, 1 H), 3.40 (m, 1 H), 2.42 (s,
3 H), 2.10 (m, 1 H), 1.30-1.65 (m, 4 H), 1.29 (d, J ) 6.6 Hz, 3
H), 0.98 (d, J ) 7.2 Hz, 3 H), 0.92 (d, J ) 6.9 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 143.0, 135.2, 129.5, 127.6, 67.4, 57.3, 31.9,
31.5, 25.3, 23.1, 21.5, 20.0, 17.3; IR (neat, thin film) υ 2962, 1734,
1592, 1459, 1341, 1153, 1096, 1014 cm-1; HRMS (ESI) calcd for
C15H24O2NS [M + H]+ 282.1522, found 282.1524.
Representative Procedure for Carboamination in an Oil Bath
(Table 4). (S)-N-Tosyl-1-isopropyl-4-pentenylamine 39a (92.6 mg,
0.330 mmol) was treated with copper(II) neodecanoate (60% by
wt in toluene, 402 mg, 0.990 mmol, 3 equiv), and cesium carbonate
(108 mg, 0.330 mmol, 1 equiv) in DMF (3.3 mL) under Ar(g) in
a pressure tube equipped with a magnetic stir bar. The tube was
capped and the mixture was heated at 190 °C for 72 h. Workup
and chromatography as described above provided the carboami-
nation adduct 40a (45.2 mg, 0.162 mmol) in 49% yield, and the
hydroamination adduct 41a (23.2 mg, 0.083 mmol) in 25% yield.
Acknowledgment. The authors thank Dr. Cara L. Nygren
[CCDC 614781 (trans-17) and CCDC 296132 (41a)] and Dr.
Marc Messerschmidt [CCDC 628996 (trans-20)] for X-ray
crystallographic analysis. The authors thank Prof. Dennis Curran
and Dr. Maria Manzoni for helpful discussions. The authors
thank Mr. Thomas Zabawa and Mr. Thomas Hayes for their
efforts in the synthesis of substrates 14-D and 22, respectively.
The authors gratefully acknowledge the financial support of the
NIH (NIGMS 1RO1-GM07838301) and the donors of the
Petroleum Research Fund (PRF 40968-G1).
The relative stereochemistry of the carboamination product 40a
was determined by a 1D NOE experiment that showed a signal
between Ha and Hb.
Data for 40a: mp 85-88 °C; [R]20D +198.9 (c 1.2, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 7.77 (d, J ) 8.5 Hz, 1 H), 7.19 (d, J
) 8.0 Hz, 1 H), 7.02 (s, 1 H), 4.11 (m, 1 H), 3.94 (m, 1 H), 2.88-
3.09 (m, 2 H), 2.36 (s, 3 H), 2.24 (m, 1 H), 2.19 (m, 1 H), 1.86-
Supporting Information Available: Procedures and charac-
terization data and NMR spectra for all new products and X-ray
data in the form of CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
(105) Berry, M. B.; Craig, D. Synlett 1992, 41.
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