Highly efficient copper-catalyzed nitro-Mannich type reaction: Cross-dehydrogenative-coupling between sp3 C-H bond and sp 3 C-H bond

Article abstract of DOI:10.1021/ja050058j

A novel C-C bond formation method was developed via the cross-dehydrogenative-coupling (CDC) reaction catalyzed by using copper bromide in the presence of an oxidizing reagent, tert-BuOOH. The CDC reaction provides a simple and efficient catalytic method

Full text of DOI:10.1021/ja050058j

Published on Web 02/25/2005
Highly Efficient Copper-Catalyzed Nitro-Mannich Type Reaction:
3
3
Cross-Dehydrogenative-Coupling between sp C-H Bond and sp C-H Bond
Zhiping Li and Chao-Jun Li*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Received January 5, 2005; E-mail: cj.li@McGill.ca
C-C Bond formation reactions are among the most important
processes in chemistry because they provide key steps in building
more complex molecules from simple precursors. Transition metal-
catalyzed C-H bond activations and subsequent C-C bond
Scheme 1. Various Cross-Coupling Methods for the Formation of
C-C Bonds
1
formations have attracted great interest in recent years. On the
other hand, transition metal-catalyzed cross-coupling reactions of
various reactive functional groups are powerful methods for
2
constructing C-C bonds (Scheme 1, path A). From a practical
point of view, a cross-dehydrogenative-coupling (CDC) reaction
from two C-H bonds will avoid the preparation of functional
groups and thus make synthetic schemes shorter and more efficient
Table 1. Optimization of Reaction Conditionsa
(
Scheme 1, path B). Some excellent pioneering progress had been
3
achieved on this subject. To our best knowledge, there are no
3
3
examples of efficient CDC reactions between sp C-H and sp
C-H.4 Herein, we report the first simple and efficient CDC
reactions to construct â-nitroamine catalyzed by copper bromide
entry
catalyst
X mol %
reaction time (NMR yield%)b
3
in the presence of tert-BuOOH via combined reactions of sp C-H
and sp C-H followed by C-C bond formations.
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
CuOTf
CuCl2
CuBr2
Cu(OTf)2
Cu(OAc)2‚H2O
CuBr
10
10
10
10
10
10
10
10
5
3 h (70); 6 h (75)
3 h (90)
3
3 h (60); 6 h (80)
3 h (20); 6 h (50)
3 h (60); 6 h (80)
3 h (40); 6 h (92)
3 h (5); 6 h (35)
3 h (50); 6 h (80)
6 h (92)
Vicinal diamines are important compounds in biologically active
natural products in medicinal chemistry and more recently (as a
core unit) in chiral auxiliaries and chiral ligands in asymmetric
5
catalyses. An efficient approach toward such compounds is via
the nitro-Mannich (aza-Henry) reaction. The nucleophilic addition
of nitroalkanes to imines gives â-nitroamine derivatives;6 1,2-
diamines or R-amino carbonyl compounds are then readily obtained
c
9
0
d
1
CuBr
no
2
0
3 h (60); 6 h (90)
3 h (0)
11
7
by the reduction of the nitro group or the Nef reaction of
a
â-nitroamine derivatives.8
0.1 mmol tetrahydroisoquinoline, 1.0 mL of nitromethane, and 0.02
mL of BuOOH (5-6 M in decane). Reported yields were based on
tetrahydroisoquinoline and determined by NMR using an internal standard.
t
b
Recently, we reported two new types of C-C bond formation:
3
c
CuBr-catalyzed alkynylation of sp C-H bonds adjacent to a
0.2 mmol tetrahydroisoquinoline, 1.0 mL of nitromethane, and 0.04 mL
nitrogen atom3
Aa, b
of tBuOOH (5-6 M in decane). d 0.5 mmol tetrahydroisoquinoline, 2.0 mL
3
and AuCl /AgOTf-catalyzed addition of activated
t
9
of nitromethane, and 0.1 mL of BuOOH (5-6 M in decane).
methylene compounds to alkene. To address the even more
3
challenging CDC reaction, our attentions are focused on sp C-H
of nitromethane was used, the desired products of 3a and 3c were
obtained in 63% and 67% isolated yields respectively (Table 2).
The use of nitroethane instead of nitromethane also gave the desired
compounds with good isolated yields (the ratios of two diastereo-
isomers are 1.5-2:1). In the case of N,N-dimethylaniline, a low
yield was obtained which was attributed to the formation of
demethylated compound and other unidentified byproducts.
Other cyclic amines such as 1-phenyl-pyrrolidine also generated
the desired product in good yield (Scheme 2). In this case, bis-
CDC product is also formed in 4% isolated yield along with the
mono-CDC product (53%).
3
and sp C-H cross-coupling reaction to generate â-nitroamine
derivatives.
To begin our study, we examined various copper salts, the
reaction time, and the amount of catalysts for the desired CDC
reaction (Table 1). Among the copper salts tested, CuBr and CuBr
were the most effective catalysts for this reaction (entries 2, 6, 9,
and 10). Interestingly, CuOTf and Cu(OTf) were less effective
2
2
under the present conditions (entries 4 and 7). Although other copper
salts are also effective, the reactions need a relatively longer time
to reach reasonable yields (entries 1, 3, 5, and 8). The reaction
also provided an excellent yield even when the amount of CuBr
was reduced to 2 mol % (entry 10). No reaction was observed in
the absence of the copper salts (entry 11).
The exact mechanism for the product formation is not clear at
the present stage. However, on the basis of the results that we
obtained in this paper and in the previous one,3
Aa,Ab
three types of
Under the optimized conditions, various â-nitroamine derivatives
were generated by this new methodology. Representative results
obtained via the CDC reaction are summarized in Table 2. 1,2,3,4-
Tetrahydroisoquinoline derivatives and 4-substituted N,N-dimethyl-
aniline gave excellent yields of the desired products based on NMR
analysis of the reaction mixture.10 Moreover, when one equivalent
intermediates are most likely involved in the reaction. (1) Copper
catalyzed the formation of an imine-type intermediate 4 (coordinated
3
11
to copper) through H-abstraction of sp C-H adjacent to nitrogen.
(2) The copper catalyst also activated the nitroalkanes to form
intermediate 5,12 and subsequent coupling of the two intermediates,
4 and 5, resulted in the desired product (and regenerated the copper
3672
9
J. AM. CHEM. SOC. 2005, 127, 3672-3673
10.1021/ja050058j CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. CDC Reaction of Tertiary Amines with Nitroalkanesa
pharmaceuticals, this catalytic reaction will be an efficient method
for the synthesis of such compounds. The scope, mechanism, and
synthetic application of this reaction are under investigation.
Acknowledgment. We are grateful to the Canada Research
Chair (Tier I) foundation (to C.J.L.), the CFI, NSERC, Merck
Frosst, and McGill University for support of our research.
Supporting Information Available: Representative experimental
procedure and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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a
t
0
.2 mmol amine, 1.0 mL of nitroalkane, and 0.04 mL of BuOOH (5-6
b
c
M in decane). Isolated yields were based on amines. 1 equiv (0.2 mmol)
of nitromethane was used.
Scheme 2. Reaction of 1-Phenyl-pyrrolidine with Nitromethane
3
3
(
4) Cross-coupling between sp C-H and sp C-H has been reported. In
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1
11, 2935.
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(
(
(
2
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(
(
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(
1
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(
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4
875 and references therein. For a recent review, see: (c) Luzio, F. A.
In summary, CDC reaction represents a new chemical transfor-
mation. We report here the first highly efficient C-C bond
formation via CDC reaction between sp C-H bond and sp C-H
bond catalyzed by copper bromide. Because nitrogen-containing
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(
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