Copper-Catalyzed conjugate addition of diboron reagents to α,β-unsaturated amides: Highly reactive copper-1,2- bis(diphenylphosphino)benzene catalyst system

Article abstract of DOI:10.1002/adsc.200900040

An efficient copper catalyst system for the β-boration of α,β-unsaturated amides has been developed. Copper-bisphosphine complexes with small bite angles generate efficient catalyst systems for the successful conjugate addition of bis(pinaco-lato)diboron

Full text of DOI:10.1002/adsc.200900040

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DOI: 10.1002/adsc.200900040
Copper-Catalyzed Conjugate Addition of Diboron Reagents
to a,b-Unsaturated Amides: Highly Reactive Copper-1,2-
Bis(diphenylphosphino)benzene Catalyst System
Heesung Chea,a Hak-Suk Sim,a and Jaesook Yuna,*
a
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 440-746, Korea
Fax : (+82)-31-290-7075; e-mail: jaesook@skku.edu
Received: January 19, 2009; Revised: March 24, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900040.
Abstract: An efficient copper catalyst system for
the b-boration of a,b-unsaturated amides has been
developed. Copper-bisphosphine complexes with
small bite angles generate efficient catalyst systems
for the successful conjugate addition of bis(pinaco-
lato)diboron to a variety a,b-unsaturated amides
under mild conditions. This method was utilized in
the formal synthesis of (S)-fluoxetine.
gate addition of organometallic reagent to simple a,b-
unsaturated amides.
In our previous study on the copper-catalyzed b-bo-
ration of a,b-unsaturated esters, the active catalyst
was generated in situ from CuCl, NaO-t-Bu and DPE-
phos ligand in the presence of bis(pinacolato)diboron
(1) and a dramatic rate acceleration was observed by
the use of methanol.[2a] This method expanded the
substrate scope from enones to challenging a,b-unsa-
turated esters and nitriles. However, the b-boration of
a,b-unsaturated amides, which are less reactive Mi-
chael acceptors, turned out to be more challenging;[5]
the same catalytic system drove the reaction with a,b-
unsaturated amides 2a and 2b only to partial conver-
sion (Scheme 1).
Keywords: amides; boron; conjugate addition;
copper; ligand effects; phosphine ligands
Construction of chemical bonds via conjugate addi-
In the course of studying the copper-catalyzed bo-
tion of organometallic nucleophiles to electron-defi- ration of a,b-alkynoates,[6] we noticed slight ligand ef-
cient olefins is one of the most fundamental methods fects on the reactivity from the ratio of mono- and di-
in organic synthesis. In recent years, transition metal- borylated products while the overall reactivity was
catalyzed addition of diboron reagents to a,b-unsatu- greatly affected by the methanol additive. The Xant-
rated carbonyl compounds[1] has become a subject of phos ligand[7] with a large bite angle and rigid back-
interest for the synthesis of organoboron derivatives bone was more selective for the formation of mono-
and we recently reported an efficient copper catalyst
system where a copper-boryl complex could conjuga-
tively add to a,b-unsaturated esters and efficiently
generate b-borylated products.[2]
Although a number of copper-catalyzed conjugate
additions of organometallic reagents to a,b-unsaturat-
ed carbonyl compounds have been reported,[3] catalyt-
ic systems effective for simple a,b-unsaturated amides
with no suitable protecting/activating groups on the
nitrogen are rare due to their inherent low reactivi-
ty.[4] Herein, we report an efficient conjugate addition
reaction of diboron reagents to a,b-unsaturated
amides catalyzed by copper(I) complexes coordinated
to chelating bisphosphines with narrow bite angles. To
the best of our knowledge, this transformation consti-
tutes the first example of the copper-catalyzed conju-
Scheme 1. Boration of a,b-unsaturated amides using DPE-
phos as a ligand.
Adv. Synth. Catal. 2009, 351, 855 – 858
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855

Heesung Chea et al.
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addition product than DPEphos. The dppf ligand
The catalytic b-boration of various a,b-unsaturated
yielded more of the diborylated product than DPE- amides was examined by using dppbz or dtpf as the
phos and Xantphos. Although copper complexes coor- ligand and MeOH as an additive (Table 2). First, a va-
dinated with phosphines with large bite angles were riety of amide derivatives (2b–2e) of cinnamic acid
known as effective catalysts for similar addition reac- were investigated. All the structurally different pri-
tions,[8] we presumed that they might not be the best mary (2c), secondary (2d, 2e) and tertiary amides (2b,
ligands for the b-boration and decided to investigate
the ligand effects on the b-boration of a,b-unsaturat-
ed amides.
Table 2. Copper-catalyzed conjugate addition of diboron to
various a,b-unsaturated amides.
For ligand screening, we focused on the bidentate
phosphine ligands[9] that had been reported to chelate
a single copper center, affording mononuclear Cu(I)
complexes[10] or halogen-bridged binuclear complexes,
[LCuACHTUNGTRENNUNG
(m-X)2CuL].[11] Ligands, such as bis(diphenyl-
phosphino)methane (dppm) and bis(diphenylphosphi-
no)ethane (dppe) possessing short and flexible chains
were excluded[12] since these ligands were reported to
bridge two copper atoms to form multinuclear com-
Entry Substrate (2)
Ligand (L) T [h] Yield [%][a]
plexes.[13] 1,2-Bis(diphenylphosphino)benzene (dppbz)
1
dppbz
dtpf
2
96
92
89
[14]
À
À
having a narrow P Cu P angle
substitute for the flexible dppe.
was chosen as a
2
3
2b
2d
2f
3
The b-boration of the methyl amide 2a with bis(pi-
nacolato)diboron was conducted with the selected li-
gands, and the influence of the ligands on catalyst re-
activity was investigated (Table 1). With dppf as a
ligand, the reaction proceeded with greater conver-
sion than with DPEphos (entry 1). It was found that
dppp and dppbz drove the reaction to completion in
2 h and formed the desired compound in high yield
(entries 2 and 3). The (di-tert-butyl)phosphine ana-
logue of dppf, which is more-electron rich than dppf,
brought the reaction to completion as well (entry 4).
These new ligands formed more reactive catalytic sys-
tems with copper than the phosphines used in our
original procedures.
dppbz
12
4
dppbz
dtpf
2
3
1
96
92
95
5[b]
6
dppbz
7
8
9
dppbz
dtpf
5
8
1
96
92
87
dppbz
Table 1. Ligand screening for the copper-catalyzed b-bora-
tion of 2a.
10
11
12
dppbz
dtpf
2
6
3
90
88
95
2h
dppbz
Entry Ligand (L)[a] T [h] Conversion [%][b] Yield [%][c]
[d]
1
2
3
4
dppf
dppp
dppbz
dtpf
2
2
2
2
78
–
13
14
dppbz
dppbz
1
95
100
100
100
88
91
91
15
74[c]
[a]
Abbreviaitions: dppf=1,1’-bis(diphenylphosphino)ferro-
cene, dppp=1,3-bis(diphenylphosphino)propane, dtpf=
1,1’-bis(di-tert-butylphosphino)ferrocene.
Determined by GC analysis.
[a]
[b]
[c]
Isolated yield.
[b]
[c]
[d]
6 mol% of NaO-t-Bu was used.
Conversion determined by GC analysis with an internal
standard.
Isolated yield.
Not cleanly isolable from 2a.
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Adv. Synth. Catal. 2009, 351, 855 – 858

Copper-Catalyzed Conjugate Addition of Diboron Reagents to a,b-Unsaturated Amides
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Scheme 2. Asymmetric synthesis of b-hydroxy amides.
2f) tested gave the addition products in high yields depressant drug and currently marketed as a race-
within reasonable reaction times. In general, the mate. This application demonstrates the usefulness of
dppbz ligand displayed a better reactivity than dtpf. this current method.
N-Alkyl- and N-phenyl-substituted amides were all
In conclusion, we have developed a highly efficient
reactive and b-alkyl-substituted a,b-unsaturated copper catalyst system that works for the b-boration
amides also provided the corresponding products of a variety of a,b-unsaturated amides. Copper-
within hours. However, neither ligand was effective bisphosphine complexes with small bite angles gener-
for complete reaction of sterically demanding b,b-di- ated more efficient catalyst systems and led to suc-
ACHTUNGTRENNUNG
Oshima and et al. recently reported a nickel-cata- (S)-fluoxetine. Further studies are in progress.
lyzed system that showed excellent reactivity for the
b-boration of a,b-unsaturated esters and amides, even
for sterically demanding substrates.[1g] However, the
types of substituent allowed at the b-position and the
nitrogen[16] seemed to be limited to alkyl, as aromatic
groups such as phenyl and furanyl gave very low
yields. Therefore, this new copper-catalyst system
complements the nickel system.
Experimental Section
General Procedure for the b-Boration of a,b-
Unsaturated Amides using the Dppbz Ligand[18]
Next, the enantioselective b-boration of amide 2b
In a resealable Schlenk tube were placed CuCl (0.015 mmol,
was briefly conducted by using chiral bisphosphine li- 1.5 mg), NaO-t-Bu (0.045 mmol, 4.5 mg) and dppbz ligand
(0.015 mmol, 6.7 mg). THF (0.40 mL) was added under ni-
trogen. The reaction mixture was stirred for 30 min at room
temperature, after which time bis(pinacolato)diboron
(0.55 mmol, 141 mg) in THF (0.30 mL) was added. The reac-
tion mixture was stirred for 10 min and then the a,b-unsatu-
rated amide (0.50 mmol) in THF (0.30 mL) was added, fol-
lowed by MeOH (1.0 mmol, 40 mL). The reaction tube was
washed with THF (0.30 mL), sealed, and stirred until no
starting material was detected by TLC. The reaction mixture
was filtered through a pad of Celite and concentrated. The
gands Duphos and Josiphos, whose backbones or
chain lengths are similar to those of dppbz or dppp,
respectively. Both ligands led the reaction to comple-
tion in hours and yielded the enantioenriched boron-
addition product 4b (Scheme 2). In particular, the b-
hydroxy product (S)-4a was obtained from 2a in 99%
ee by the asymmetric boration reaction with the
(R,S)-Josiphos ligand and consecutive oxidation of 3a.
(S)-4a is an appropriate intermediate for the construc-
tion of optically active fluoxetine,[17] which is an anti- product was purified by silica gel chromatography.
Adv. Synth. Catal. 2009, 351, 855 – 858
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Heesung Chea et al.
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Acknowledgements
[9] In our study on the asymmetric b-boration of acyclic
enones, we found that a rigid and strong coordination
between ligand and catalyst would be needed for high
enantioselectivity. Therefore, we excluded P,N- and
N,N-type ligands and monophosphine ligands for future
application of this current study on the asymmetric syn-
thesis of b-borylamides: H.-S. Sim, X. Feng, J. Yun,
Chem. Eur. J. 2009, 15, 1939–1943.
This work was supported by a Korea Science and Engineer-
ing Foundation (KOSEF) grant funded by the Korea govern-
ment (MEST) (No. R01-2008-000-20332-0).
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AHCTUNGTRENNUNG
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858
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Adv. Synth. Catal. 2009, 351, 855 – 858