Copper(II) acetate promoted intramolecular diamination of unactivated olefins

Article abstract of DOI:10.1021/ja053335v

A concise method for the synthesis of cyclic sulfamides and vicinal diamines is presented. This method is enabled by Cu(OAc)₂ and demonstrates a new transformation for this metal. Both five- and six-membered vicinal diamine-containing heterocyc

Full text of DOI:10.1021/ja053335v

Published on Web 07/26/2005
Copper(II) Acetate Promoted Intramolecular Diamination of
Unactivated Olefins
Thomas P. Zabawa, Dhanalakshmi Kasi, and Sherry R. Chemler*
Department of Chemistry, 618 Natural Sciences Complex, UniVersity at Buffalo, State UniVersity of New York,
Buffalo, New York 14260
Received May 22, 2005; E-mail: schemler@buffalo.edu
Scheme 1
Nitrogen heterocycles containing the vicinal diamine unit are
ubiquitous in biologically active small molecules and are also
common ligands for inorganic as well as organic catalysts.1 An
intramolecular alkene diamination offers a direct method for the
Table 1. Olefin Diamination Reaction Optimizationa
synthesis of cyclic vicinal diamines. Herein is presented the first
intramolecular diamination of unactivated olefins. This method is
general for the formation of both five- and six-membered hetero-
cycles, and substrate-based asymmetric induction has been achieved.
The direct diamination of olefins is an important method for the
synthesis of 1,2-diamines1 and is analogous to the highly useful
olefin dihydroxylation reaction.2 Current methods for the intermo-
lecular olefin diamination are primarily limited to the use of
stoichiometric amounts of late transition metal salts, which are both
expensive and toxic.3 A PdII-catalyzed intermolecular diamination
has been reported recently; however, this method is limited to
conjugated diene substrates.3h We sought a solution to this problem
using an inexpensive alternative to bring about the diamination of
isolated alkenes.
We envisioned the diamination would occur optimally via an
intramolecular strategy, where the two nitrogen nucleophiles are
tethered (Scheme 1). In this reaction design, a transition metal must
activate the olefin toward nucleophilic attack by the first nitrogen,
then become displaced by the second nitrogen nucleophile (a net
Mn+2 f Mn reduction). An intramolecular aminocarbonation
reaction recently discovered in ours labs indicated that copper(II)
could perform such oxidative cyclization chemistry.4
Gratifyingly, we found that Cu(OAc)2 is an excellent promoter
for the intramolecular diamination of olefins using sulfamide
substrates, such as 1a (Table 1). Treatment of N-(2-allylphenyl)-
N′-benzyl sulfamide 1a with Cu(OAc)2 (1.2 equiv) in the presence
of K2CO3 at elevated temperature (90 °C) provided the desired
diamination adduct 2a in up to 92% yield. We screened several
solvents, bases, and copper(II) salts in order to define the reaction
parameters. We found the polar solvent DMF to be superior to THF
and CH3CN, and added DMSO increased the reaction yield in DMF,
possibly due to increased Cu(OAc)2 solubility (entries 1-4). These
reactions were conducted in pressure tubes, and stirring was
controlled so as to keep the copper salt in solution. The sulfamide
functional group proved to be a significantly superior dinitrogen
source compared to the urea 1b, possibly indicating a sensitivity
to the electron density or coordinating ability of nitrogen (compare
entries 4 and 5). Use of base (2 equiv) was also necessary for
optimal conversion (compare entry 7 to entry 4, Table 1), and K2-
CO3 proved slightly superior to Cs2CO3.
entry
tether
Cun (equiv)
base (2 equiv)
solventb
% yieldc
1
2
3
4
5
6
7
8
9
X ) SO2
X ) SO2
X ) SO2
X ) SO2
Cu(OAc)2 (1.2) K2CO3
Cu(OAc)2 (1.2) K2CO3
Cu(OAc)2 (1.2) K2CO3
Cu(OAc)2 (1.2) K2CO3
THF
CH3CN
DMF
43
38
78
DMF/DMSO 92
DMF/DMSO no rxn
DMF/DMSO 84
DMF/DMSO 34
DMF/DMSO no rxn
DMF/DMSO no rxn
DMF/DMSO 22
DMF/DMSO 54
X ) CdO Cu(OAc)2 (1.2) K2CO3
X ) SO2
X ) SO2
X ) SO2
X ) SO2
Cu(OAc)2 (1.2) Cs2CO3
Cu(OAc)2 (1.2) none
Cu(OTf)2 (1.2) K2CO3
CuF2 (1.2)
CuOAc (1.0)
CuOAc (3.0)
K2CO3
K2CO3
K2CO2
10 X ) SO2
11 X ) SO2
a Pressure tube, Ar atmosphere, dry solvent. b When DMSO was included,
10 equiv was used. c Remainder of material is recovered substrate 1.
shown previously to provide aminohalogenation rather than diami-
nation products.4 Treatment of sulfamide 1a with CuOAc (3.0
equiv) under argon atmosphere (to prevent air oxidation of CuI)
provided 54% of the cyclized product 2a, while the reaction of 1a
with 1 equiv of CuOAc gave only 22% of 2a. The partial conversion
can be explained by the disproportionation of CuOAc to Cu(OAc)2
and Cu0, thus enabling the oxidative cyclization.5 This oxidative
cyclization requires a stoichiometric amount (1-3 equiv) of Cu-
(OAc)2 for optimal conversion. Copper(II) acetate is inexpensive
and relatively nontoxic. Cross-coupling and oxidation methods
mediated by stoichiometric and, in some cases, catalytic CuII are
of recognized importance in organic synthesis.4,6
With the optimized reaction conditions in hand, a variety of
substrates were surveyed to explore the scope of the reaction (Table
2). The intramolecular diamination reaction occurred with complete
regioselectivity (exo vs endo cyclization) in all cases, generating
the smaller ring size. Both five- and six-membered rings can be
formed efficiently. These substrates required 1-3 equiv of Cu-
(OAc)2 and a temperature range of 90-120 °C for optimal
conversion. The geminal disubstituted aliphatic amine 3 underwent
conversion to cyclic sulfamide 4 in 73% yield. The styrenyl
substrate 5 provided the benzylic diamine 6 in 56% yield. Geminal
olefin substitution is also tolerated. The 1,1-disubstituted olefin 7
provided the tertiary amine 8 upon cyclization in 57% yield. The
allylic alcohol substrate 9 provided the diamination product 10 with
>20:1 diastereoselectivity (71% yield). This example also illustrates
The nature of the ligands and the oxidation state of copper
profoundly affect the reaction outcome. Copper(II) acetate was
infinitely superior to Cu(OTf)2 and CuF2 as no diamination product
was observed in the crude 1H NMR spectra of the latter two
reactions (entries 8 and 9, Table 1). Other copper(II) halide salts
(CuBr2, CuCl2) were not further investigated as they have been
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10.1021/ja053335v CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Intramolecular Diamination of Olefinsa
Scheme 2
sulfamide nitrogen to Cu(OAc)2, providing intermediate 17. Migra-
tory insertion would then form the new sp3 N-C bond, giving 18.4,7
The organocopper species 18 may undergo ligand exchange with
the remaining nitrogen, followed by reductive elimination, providing
sulfamide 2a. Yet another mechanistic scenario would involve
homolysis of the carbon-copper bond of 18 followed by copper-
(II)-promoted oxidative coupling for N-C bond formation.
The method communicated herein expands the olefin diamination
concept to include an intramolecular process and new copper(II)
chemistry, thereby yielding a number of cyclic diamines. The cyclic
sulfamide adducts are valuable entities to medicinal chemistry and
material science,8 and the free diamine is easily liberated using
LiAlH4. Further expansion of the substrate scope and mechanism
studies are underway.
Acknowledgment. This research was supported by the Uni-
versity at Buffalo, SUNY and the donors of the Petroleum Research
Fund (PRF 40968-G1).
Supporting Information Available: Procedures and characteriza-
tion data for all new products. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reaction conditions: 3 equiv of Cu(OAc)2, 2 equiv of K2CO3, DMF
(0.08-0.1 M), DMSO (10 equiv), 90 °C, 48 h. b Selectivity determined by
analysis of the crude 1H NMR spectrum and by amount of the isolated
adducts. c Yield refers to amount of product isolated by chromatography
on silica gel. d Reaction was conducted at 120 °C.
References
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Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
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Chem., Int. Ed. 1998, 37, 2580.
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can survive the mild diamination reaction conditions.
The isoquinoline 12 was formed in 83% yield upon cyclization
of the 2-allylbenzylamine sulfamide 11. Cyclization of the branched
benzylic sulfamide 13 led to a 1.2:1 mixture of diastereomeric
isoquinolines 14 and 15, albeit only in 34% yield. Reaction of
substrate 13 is both entropically and sterically challenging, and side
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NHSO2-) under the reaction conditions.
The trans-methyl-1,2-disubstituted olefin derivative of 3 (R )
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provide the diamination products; primarily starting compounds with
and without the sulfamide group were obtained. Clearly, steric
hindrance on the terminal position of the olefin affects the reactivity
of the substrate.
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The free diamine can be obtained by reduction of the sulfamide
with LiAlH4 (cf. 2a f 16, 93% yield).
A working hypothesis for the diamination mechanism is proposed
in Scheme 2. The reaction is likely initiated by coordination of the
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