Copper(II)-catalyzed enantioselective intramolecular carboamination of alkenes

Article abstract of DOI:10.1021/ja0762240

The enantioselective oxidative cyclizations of γ-alkenyl arylsulfonamides and a δ-alkenyl arylsulfonamide for the synthesis of nitrogen heterocycles are presented. The reactions are catalyzed by chiral copper(II) complexes, and MnO₂ is used as

Full text of DOI:10.1021/ja0762240

Published on Web 10/05/2007
Copper(II)-Catalyzed Enantioselective Intramolecular Carboamination of
Alkenes
Wei Zeng and Sherry R. Chemler*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York, Buffalo, New York 14260
Received August 17, 2007; E-mail: schemler@buffalo.edu
Scheme 1. Copper(II)-Promoted Carboamination and Mechanism
The transition-metal-mediated intramolecular carboamination of
alkenes is a direct method for complex nitrogen heterocycle
synthesis. A number of research groups have investigated this
transformation in recent years.1 The catalytic asymmetric carboami-
nation of alkenes is an obvious challenge for these reactions and
has been realized rarely.1d Herein is described a novel copper(II)-
catalyzed asymmetric carboamination reaction that involves in-
tramolecular addition of arylsulfonamides across terminal alkenes
to provide chiral sultams. Sultams and sulfonamides are common
components of biologically active small molecules.2
The copper-facilitated synthesis of heterocycles via addition of
heteroatoms to alkenes and alkynes is an important area in organic
synthesis.3 We have recently reported the first copper(II)-facilitated
intramolecular carboamination of alkenes, a net oxidative cyclization
process (Scheme 1).1c,f In depth mechanistic studies led us to
conclude that the stereochemistry-determining C-N bond-forming
step occurred via syn aminocupration of the alkene (cf. 3 f 5 via
4, Scheme 1).1f If the copper salt is involved in the stereochemistry-
determining step, chiral ligands on copper could allow for a
stereocontrolled synthesis of the product. In the proposed C-N
bond-forming transition state 4, the substrate occupies two coor-
dination sites on a tetracoordinate copper(II),4 leaving two coordina-
tion sites available for a bidentate ligand (Scheme 1). Inspired by
this analysis, we initiated a search for an appropriate oxidant for
copper turnover and ligand for asymmetric induction. Herein is
reported the first catalytic as well as catalytic asymmetric variant
of this copper(II)-facilitated carboamination reaction.
In the search for conditions catalytic in copper, we screened a
number of oxidants [O2, PhI(OAc)2, oxone, Me3NO, MnO2], with
and without ligands in different solvents for the conversion of 1a
to 2a with a catalytic amount (0.2 equiv) of copper(II) ethylhex-
anoate. The highest conversions were obtained with MnO2 (3 equiv)
as oxidant in trifluorotoluene in the presence of ligands (Table 1).
Under the optimized conditions but in the absence of copper(II),
no reaction occurs. In toluene, a mixture of carboamination and
hydroamination products 2a and 7 was observed (Table 1, entries
3 and 4). We hypothesized the hydroamination product 7 is formed
via carbon radical (e.g., 6) capture of a hydrogen atom from solvent.
Gratifyingly, changing the solvent to trifluorotoluene substantially
decreased formation of the hydroamination adduct (Table 1, entries
5, 6, and 8). The carboamination reactions stoichiometric in copper-
(II) (cf. Scheme 1) start out blue [due to copper(II)] and terminate
as orange-brown heterogeneous mixtures, indicating formation of
copper(0), possibly from disproportionation of copper(I) to copper-
(II) and copper(0). Reoxidation of copper(0) under the mildly basic
reaction conditions used in these reactions is challenging. We
hypothesized that ligands would stabilize copper(I) and copper(II)
in preference to copper(0).3 Addition of diethylsalicylamide 8 (0.2
and 0.8 equiv) increased the reaction yields, likely due to improved
copper turnover (Table 1, compare entries 1 and 2 with 3-6).5 We
changed the copper(II) source to Cu(OTf)2 to achieve better ligand
Table 1. Dependence on Solvent and Liganda
ligand
yieldb of 2
yieldb of 7
entry
R
solvent
(equiv)
(%)
(%)
1
2
3
4
5
6
7
8
EH
EH
EH
EH
EH
OTf
OTf
OTf
PhCH3
PhCF3
PhCH3
PhCH3
PhCF3
PhCF3
PhCH3
PhCF3
-
<5
7
trace
trace
7
-
8 (0.2)
8 (0.8)
8 (0.8)
8 (0.8)
9 (0.2)
9 (0.2)
41
63
75
29
59
60
17
<5
<5
12
<5
a Reaction conditions: substrate 1a was dissolved in solvent (0.1 M)
and treated with K2CO3 (1 equiv), MnO2 (3 equiv), CuR2 (0.2 equiv), and
the specified amount of ligand and stirred in a sealed tube at 120 °C for 24
h. b Yields refer to amount of compound isolated after chromatography on
SiO2. Remainder of material was always unreacted starting 1a. EH )
2-ethylhexanoate.
chelation (entries 6-8). The bipyridine ligand 9 (0.2 equiv) gave
more efficient conversion when Cu(OTf)2 was used (compare entry
6 to 8).
We screened chiral ligands 10-13 by precomplexing Cu(OTf)2
(0.2 equiv) with ligand (0.2 equiv) followed by addition of substrate
1a, K2CO3 (1 equiv), and MnO2 (3 equiv) and heating in a sealed
tube for 24 h in PhCF3 (Table 2).
We quickly found that 2,2-bis[(4R)-4-phenyl-2-oxazolin-2-yl]-
propane (11a) gave the highest asymmetric induction, providing
carboamination adduct 2a in 85% isolated yield and 92% ee (Table
2, entry 5). We were unable to reduce the catalyst loading below
0.2 equiv without adversely affecting the product yield (Table 2,
entries 10 and 11). Lowering the reaction temperature to 110 °C
provided the product in slightly lower yield (72%) and 94% ee
9
12948
J. AM. CHEM. SOC. 2007, 129, 12948-12949
10.1021/ja0762240 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Transition-State Model and Removal of SO2
Table 2. Chiral Ligand Screeninga
equiv of
ligand
yieldb
(%)
entry
Cu(OTf)2
(equiv)
%eec
ERc
1
2
3
4
5
6
7
8
9
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.15
0.05
0.2
(R,R)-10a (0.2)
(S,S)-10b (0.2)
(S,S)-10c (0.2)
(S,S)-11a (0.2)
(R,R)-11a (0.2)
(S,S)-11b (0.2)
(R,R)-11c (0.2)
(R,S)-12 (0.2)
(R,R)-13 (0.2)
(R,R)-11a (0.15)
(R,R)-11a (0.05)
(R,R)-11a (0.2)
54
53
73
75
85
50
55
<5
18
64
34
72
24
14
28
86
92
24
82
-
62:38
43:57
36:64
7:93
96:4
38:62
91:9
-
80-94% ee.6 The 2-sulfamido thiophene substrate 14 reacted very
sluggishly but with good enantioselectivity. N-Tosyl-2-allylaniline
16 reacted efficiently but with low (46%) enantioselectivity, and
N-tosyl-2-allylbenzylamine 18 reacted sluggishly and in moderate
yield and enantioselectivity to provide tetrahydroisoquinoline 19
(entry 12).
X-ray crystal structures of sultams 2g and 15 indicate the S
configuration. The other carboamination adducts in Table 3 are
assigned the S stereochemistry by analogy. Sultam 2i was converted
to the known 2(S)-benzylpyrrolidine 20,7 an intermediate used in
the synthesis of a potent calcium-sensing receptor antagonist,8 by
reductive removal of SO2 (Scheme 2). Pyrrolidine (S)-20 is thus
available by this method in three steps from commercially available
starting materials (see Supporting Information for complete details).
The observed stereochemistry is consistent with transition state
A (Scheme 2), where the substrate’s N-substituent is on the face
opposite of the oxazoline phenyl substituent it is cis to about the
distorted square planar copper center.4
4
48:52
96:4
-
10
11
12d
92
-
94
97:3
a Reaction conditions: Cu(OTf)2 and ligand were combined, dissolved
in PhCF3 (0.1 M w/r to 1a) and heated at 50 °C for 1 h. Substrate 1a,
MnO2 (3 equiv), and K2CO3 (1 equiv) were added, and the reaction tube
was sealed and heated at 120 °C for 24 h unless otherwise noted. b Yield
refers to amount of isolated 2a after purification by flash chromatography
on SiO2. c Enantiomeric excess and ratios (ER) were determined by chiral
HPLC analysis (Chiralcel OD-H). d Reaction was run at 110 °C.
Table 3. Scope of Enantioselective Carboamination with
(R,R)-11aa
The method reported herein provides access to enantiomerically
enriched nitrogen heterocycles. Applications of this reaction toward
the synthesis of bioactive compounds are underway. This method
will also inspire the development of other copper(II)-catalyzed
enantioselective amination reactions.
Acknowledgment. The financial support of the NIH/NIGMS
RO1 GM078383 is gratefully acknowledged. Dr. Shao-Liang Zheng
(SUNY, Buffalo X-ray crystallography facility) is gratefully
acknowledged for obtaining crystal structures of 2g and 15.
Supporting Information Available: Experimental procedures,
compound characterization data, X-ray structures with determination
of absolute configuration, and HPLC traces with determination of
enantiomeric excess. This material is available free of charge via the
Internet at http://pubs.acs.org.
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a Reaction conditions: Cu(OTf)2 (0.2 equiv) and (R,R)-11a (0.2 equiv)
were combined and treated with PhCF3 (0.1 M w/r to substrate) and heated
at 50 °C for 1 h. Substrate (1 equiv), MnO2 (3 equiv), and K2CO3 (1 equiv)
were added, and the reaction tube was sealed and heated at 120 °C for 24
h unless otherwise noted. All reactions were run at least two times to ensure
reproducibility. b Yields refer to amount isolated after purification by flash
chromatography on SiO2. c Enantiomeric excess and ratios were determined
by chiral HPLC analysis (Chiralcel OD-H or AD-RH). d Reactions were
run for 96 h.
(Table 2, entry 12). Ligands 12 and 13 rendered the copper(II)
complex less reactive (entries 8 and 9).
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The generality of the reaction was examined as shown in Table
3. γ-Alkenyl arylsulfonamides 1 cyclized in 45-85% yield and
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