Direct amination of homoenolates catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja711130p

N-Heterocyclic carbenes derived from N-mesityl-N-methyltriazolium salts are effective catalysts for generating homoenolate species from α,β-unsaturated aldehydes. The unique intermediate adds to the electrophilic nitrogen of 1-acyl-2-aryldiazenes, and the

Full text of DOI:10.1021/ja711130p

Published on Web 02/09/2008
Direct Amination of Homoenolates Catalyzed by N-Heterocyclic Carbenes
Audrey Chan and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received December 14, 2007; E-mail: scheidt@northwestern.edu
Scheme 1. Reaction Pathway
The de novo construction of â-amino acids by the direct
construction of the C-N bond continues to be an objective because
of the continuing utility of these compounds.1,2 A conventional
method to access these molecules is the conjugate addition of a
nucleophilic nitrogen source such as azide or an aliphatic amine to
an activated ester or ketone (eq 1).3 Alternatively, formal [3+2]
reactions with hydroxylamines provide isoxazolidines in which the
N-O bond can be easily cleaved.4 A polarity reversal strategy to
access â-amino acid derivatives would employ unusual reactivity
patterns, such as homoenolates, in the context of a formal
cycloaddition. In this Communication, we report the catalytic
amination of homoenolates by combining R,â-unsaturated aldehydes
with diazenes in the presence of N-heterocyclic carbenes (NHCs)
to generate pyrazolidinones (3, eq 2).
ldehyde (1a) with heteroazolium salts A-D (Table 1). Diethyl
azodicarboxylate provided no desired products (entry 1), but to our
delight, diphenyl diazene afforded low yields of pyrazolidinones
(entries 2, 3) in the presence of benzimidazolium salts A,B. An
intensive investigation of different diazo compounds and azolium
salts led to the identification of a new triazolium salt D, which in
combination with acylarydiazenes 2d afforded the highest yields
of the pyrazolidinone product as a single regioisomer.
During our optimization studies, we isolated varying amounts
of 1-benzoyl-2-phenylhydrazine (4) when employing diazene 2d
Table 1. Optimization of Amination Conditionsa
The direct electrophilic amination of a homoenolate generated
under catalytic conditions is an unrealized transformation with
significant potential. This approach presents the opportunity to
obviate the liabilities of standard azide and hydroxylamine nucleo-
philes and has potential for stereochemical control over the newly
formed asymmetric center. A key caveat to the successful realization
of electrophilic amination of carbene-generated homoenolates is
identifying reactants and conditions that favor carbene addition to
the aldehyde over the nonproductive addition to the electrophilic
nitrogen reagent.
Our previous efforts in the area of N-heterocyclic carbene
catalysis5 have generated new ways to form C-H and C-C bonds6
by accessing unique homoenolates from R,â-unsaturated aldehydes.7
In these processes, the aldehyde is converted into an intermediate
that possesses nucleophilic character at the â-carbon which upon
addition to an electrophile yields an activated carbonyl species. With
this general reactivity pattern, the anticipated catalytic pathway for
our amination involves the addition of an NHC to the R,â-
unsaturated aldehyde 1 to afford the tetrahedral intermediate I. Upon
rearrangement, the extended diene homoenolate equivalent II is
generated, which undergoes addition to the diazene 2 and subse-
quently generates ketone III after tautomerization. This activated
carbonyl species facilitates catalyst turnover by intramolecular
acylation to produce pyrazolidinone 3.
entry
catalyst
R1
R2
yield (%)b
1
2
3
4
5
6
7
8
9
A, B, C, or D
CO2Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CO2Et (2a)
Ph (2b)
Ph (2b)
Ph (2b)
Ph (2b)
SO2Ph (2c)
SO2Ph (2c)
COPh (2d)
COPh (2d)
COPh (2d)
COPh (2d)
COPh (2d)
0
26
29
18
28
16
16
0
42
49
63
54
A
B
C
D
C
D
A or B
C
10
11c
12d
D
D
D
Ph
Ph
Ph
a 20 mol % DBU and 3 equiv of 2, 23 °C. b Isolated yields. c 30 mol %
DBU, 3 equiv of 2, and 4 Å molecular sieves, 0 °C. d 30 mol % DBU, 2
equiv of 2, and 4 Å molecular sieves, 0 °C.
The first goal for the direct amination was to identify a suitable
nitrogen-containing electrophile. We began by screening cinnama-
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10.1021/ja711130p CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction Scopea
In summary, we have developed a direct electrophilic amination
of homoenolates catalyzed by N-heterocyclic carbenes. The addition
of a carbene derived from triazolium salt D to an R,â-unsaturated
aldehyde generates a homoenolate intermediate which undergoes
a formal [3+2] cycloaddition with an 1-acyl-2-aryldiazene to afford
pyrazolidinones as a single regioisomer. A chiral triazolium salt
can be used to control the newly formed stereocenter of the product,
which results in good selectivity. The pyrazolidinone products can
be converted into â-amino acid derivatives in excellent yields.
Carbene catalysis continues to facilitate new strategies for the
creation of valuable molecules from simple precursors.
entry
R
Ar
R1
yield (%)b
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
63 (5)
60 (6)
66 (7)
64 (8)
3-OMe-Ph
2-OMe-Ph
2-Naphthyl
4-Cl-Ph
2-OMe-Ph
Me
61 (9)
6
7
3-Me-Ph
2-Me-Ph
3-Me-Ph
4-Cl-Ph
4-F-Ph
3-Me-Ph
Ph
64 (10)
82 (11)
84 (12)
68 (13)
61 (14)
73 (15)
71 (16)
63 (17)
Acknowledgment. Support for this work was generously
provided by NIGMS (RO1 GM73072), Abbott Laboratories,
Amgen, AstraZeneca, GlaxoSmithKline, 3M, the Sloan Foundation,
and Boehringer-Ingelheim. A.C. thanks Dow Chemical Co. for a
graduate fellowship.
8
9
CH2CH2CH3
Ph
10
11
12
13
Ph
Ph
Ph
Ph
3-Me-Ph
4-Me-Ph
Ph
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
a 3 equiv of 2. b Isolated yields after chromatography.
as the electrophile. On the basis of our carbene-catalyzed hydroa-
cylation studies,5a we postulate that tetrahedral intermediate I
(Scheme 1) can form the desired homoenolate intermediate (path
A) or collapse to afford an acyl heteroazolium species with
concomitant hydride transfer to the diazene (path B). The undesired
reaction reduces 2d to the observed hydrazine and sacrifices an
equivalent of unsaturated aldehyde. Fortunately, by tuning the
structure of the carbene catalyst to D and lowering the reaction
temperature, we can maximize the desired homoenolate amination
(Table 1, entry 11).8
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