Reductive coupling reactions: A new strategy for C(sp3)-P bond formation

Article abstract of DOI:10.1016/j.tet.2012.11.064

The C(sp³)-P bond forming reaction utilizing N-tosylhydrazones as readily available alkylating reagents was developed, which provides a new opportunity for preparing phosphine oxide derivatives with moderate to good yields. This reductive coupling reaction is proposed to proceed through an insertion of copper carbene into P-H bond of H-phosphorus oxides. The salient features of the reaction are operational simplicity and functional-group tolerance.

Full text of DOI:10.1016/j.tet.2012.11.064

Tetrahedron 69 (2013) 1065e1068
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Tetrahedron
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Reductive coupling reactions: a new strategy for C(sp3)eP bond
formation
Zi-Sheng Chen a, Zhao-Zhao Zhou a, Hui-Liang Hua a, Xin-Hua Duan b, Jian-Yi Luo a,
,
Jia Wang a, Ping-Xin Zhou a, Yong-Min Liang a
*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
b Department of Applied Chemistry, Faculty of Science, Xi’an Jiaotong University, Xi’an 710049, PR China
a r t i c l e i n f o
a b s t r a c t
The C(sp3)eP bond forming reaction utilizing N-tosylhydrazones as readily available alkylating reagents
was developed, which provides a new opportunity for preparing phosphine oxide derivatives with
moderate to good yields. This reductive coupling reaction is proposed to proceed through an insertion of
copper carbene into PeH bond of H-phosphorus oxides. The salient features of the reaction are opera-
tional simplicity and functional-group tolerance.
Article history:
Received 16 September 2012
Received in revised form 14 November 2012
Accepted 20 November 2012
Available online 27 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Reductive coupling
CeP bond
Copper carbene
Diazo compounds
N-Tosylhydrazones
1. Introduction
Transition metal-catalyzed heteroatomehydrogen bond in-
sertions via a metal carbene intermediate in situ generated from-
Organophosphorus compounds play important roles in various
areas of functional materials science1 and biochemistry,2 and par-
ticularly in catalysis chemistry as ligands.3 Among the enormous
variety of CeP bonds forming reactions,4 transition metal-catalyzed
cross-couplings stand as some of the more versatile and reliable
methodologies. Despite tremendous developments of cross-
coupling reactions in the construction of C(sp2)eP and C(speP)
bonds,5,6 the corresponding formation of C(sp3)eP bonds remains
a great challenge utilizing alkyl halides as coupling partners,7
presumably due to the following reasons: (1) alkyl halides, espe-
cially secondary alkyl halides, are relatively unstable and not easily
diazo compounds represent one of the most efficient approaches
for the construction of carboneheteroatom (CeX) bonds.9 How-
ever, compared with remarkable advances achieved in
catalytic XeH (X¼N, O, S, Si, etc.) insertion reactions, transition
metal-catalyzed PeH insertion reactions are rather less well in-
vestigated.10 Recently, N-tosylhydrazones have emerged as di-
vergent reagents that have been used as an in situ source of diazo
compounds in metal-catalyzed and metal-free transformations.11
In particular, remarkable progress has been made in the forma-
tion of CeC, CeO, CeN, CeS, and CeP bonds by using N-tosylhy-
drazones as a new type of alkyl reagents.12 We have previously
reported the palladium-catalyzed coupling reaction of propargylic
carbonates with N-tosylhydrazones13 and the copper-catalyzed the
construction of C(sp2)eP and C(speP) bonds.6b It occurred to us
that N-tosylhydrazones could be used for C(sp3)eP bonds forma-
tion. Herein, we further present the construction of C(sp3)eP bonds
via copper-catalyzed reductive coupling of N-tosylhydrazones with
H-phosphorus oxides (Scheme 1).
accessible; (2) b-hydride elimination is a common problem for the
cross-coupling with alkyl halides. One alternative to the creation of
C(sp3)eP bonds is the MichaeliseArbuzov rearrangement.8 How-
ever, this method is mostly limited to afford the phosphine oxides
bearing primary P-alkyl groups. In light of the limitations and
drawbacks of the established process, it is highly desirable to de-
velop alternative methodologies for the formation of C(sp3)eP
bonds, which could be advantageous in terms of operational sim-
plicity, functional-group tolerance and the use of readily available
and stable starting materials.
* Corresponding author. Tel.: þ86 931 891 2593; fax: þ86 931 891 2582; e-mail
Scheme 1. The strategy for C(sp3)eP bond formations.
address: liangym@lzu.edu.cn (Y.-M. Liang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.064

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Z.-S. Chen et al. / Tetrahedron 69 (2013) 1065e1068
Table 2
At the outset of this investigation, diphenylphosphine oxide 1a
Copper-catalyzed reductive coupling of N-tosylhydrazones derived from ketones
and N-tosylhydrazones 2a derived from acetophenone were chosen
as model substrates. When 1a and 2a were catalyzed with CuI in the
presence of Cs2CO3 at 80 ꢀC, the desired product 3a was obtained in
10% yield (Table 1, entry 1). Encouraged by this initial result, we
then optimized the reaction. As the base plays an important role in
this reaction, after screening a series of bases, they are all less ef-
ficient compared with K2CO3 (Table 1, entries 2e4). In addition,
other catalysts were also examined (for details, see the
Supplementary data).14 To our delight, the reaction was subjected
to notable temperature effects. By increasing temperature, the yield
could be markedly improved (Table 1, entry 5). When the reaction
temperature was raised to reflux, the yield was further improved
(Table 1, entry 6). But CH3CN, Toluene, DCE, nor DME under the
similar reaction conditions were found to be essentially ineffective
in this reaction (Table 1, entries 7e10). It was noteworthy that
product 3a was not detected in the absence of copper catalysts
(Table 1, entry 11).
and H-phosphorus oxidesa
Table 1
Optimization of reaction conditionsa
Entry
Catalysis (mol %)
Base
T [ꢀC]
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
d
Cs2CO3
tBuOK
tBuOLi
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
80
80
80
80
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
CH3CN
DMF
10
0
0
38
69
75
15
12
30
42
0
100
Reflux
Reflux
110
Reflux
Reflux
Reflux
9
10
11
DCE
DME
Dioxane
aAll the reaction were carried out with 1 (0.1 M, 1.0 equiv), 2 (0.12 M, 1.2
equiv), CuI (10 mol %), and K2CO3 (0.3 M, 3.0 equiv) in dioxane at reflux,
all the yields refer to isolated product after chromatography with silica gel. b
1/2 = 1.0:2.0. c 1/2 = 2.0:1.0. d DMF as solvent.
a
All the reactions were carried out with 1a (0.1 M, 1.0 equiv), 2a (0.12 M,
1.2 equiv), and base (0.3 M, 3.0 equiv).
b
All the yields refer to isolated product after chromatography with silica gel.
Under the optimized reaction conditions, (Table 1, entry 6) the
scope and generality of this transformation was subsequently in-
vestigated. As illustrated in Table 2, an array of N-tosylhydrazones
derived from ketones could be converted into the corresponding
phosphane oxides in moderate to good yields. The reaction is mar-
ginally affected by the substituents on the aromatic ring of N-
tosylhydrazones. Both electron-donating and electron-withdrawing
groups were tolerated in this process (3aes, Table 2). Moreover,
halogen groups, which enable further derivatizations via transition
metal-catalyzed cross-coupling techniques, are also compatible
with the reaction conditions (3h, 3i, Table 2). Interestingly, the
cyclopropyl group remains intact in the reaction, which a carbene
adjacent to a cyclopropyl group would undergo a ring-expanding
rearrangement or be protonated (3o, Table 2).15 However, the ex-
pected product could not be obtained from diphenyl substituent
hydrazone due to hindrance (3p, Table 2). It is noteworthy that N-
tosylhydrazones derived from heteroaromatic ketones could also be
converted into the corresponding alkyldiphenylphosphine oxides
(3qes, Table 2). Furthermore, the reductive coupling is not restricted
to aromatic ketones. Cyclohexanone tosylhydrazone 2u was also
successfully coupled with diphenylphosphine oxide 1a, albeit in low
efficiency (3u, Table 2). Finally, the molecular structure of 3i was
unambiguously confirmed through X-ray crystallography (Fig. 1).16
Inspired by these results, we wished to further investigate the
scope of the reaction by using N-tosylhydrazones derived from al-
dehydes. However, this copper-catalyzed alkylphosphonation
Fig. 1. X-ray crystal structure of 3i.
depends greatly on the reaction conditions (For details, see the
Supplementary data). It was found that catalytic CuI(10), combined
with Cs2CO3/DME, was a suitable condition for this transformation,
which can convert the N-tosylhydrazone of benzaldehyde to the

Z.-S. Chen et al. / Tetrahedron 69 (2013) 1065e1068
1067
desired alkylphosphonate 4a.12k The optimized reaction conditions
were then applied to the construction of alkylphosphonates
(Table 3). A series of substituted alkylphosphonates 4aei were
synthesized in moderate to good yields. Both electron-donating
(4b,c, Table 3) and electron-withdrawing (4de4g, Table 3) groups
are well tolerated in this reaction. The present catalytic reaction
was also successfully applied to aliphatic aldehyde in moderate
yield (4i, Table 3). In addition, we were delighted to find that a-
diazocarbonyl compound was also suitable substrate for P-alkyl-
ation (Scheme 2).
Table 3
Copper-catalyzed reductive coupling of N-tosylhydrazones derived from aldehydes
Scheme 3. One-pot synthesis of phosphine oxide derivatives.
and H-phosphonatea
Scheme 4. Proposed mechanism of the reaction.
aAll the reaction were carried out with 1b (0.4 M, 1.0 equiv), 22 (0.48 M, 1.2
equiv), CuI (10 mol %), and Cs2CO3 (0.6 M, 1.5 equiv) in DME at 85oC, all
the yields refer to isolated product after chromatography with silica gel.
which are easily prepared from commercially available ketones and
aldehydes. The protocol is very simple and effective for the syn-
thesis of phosphine oxide derivatives with moderate to good yields.
In addition, this reaction involves an unexploited copper-catalyzed
PeH insertion process. The scope and functional-group tolerance of
the reaction are also wide.
Acknowledgements
Scheme 2. The copper-catalyzed P-alkylation using a-diazocarbonyl compound.
We thank the National Science Foundation (NSF 21072080) and
National Basic Research Program of China (973 Program)
2010CB833203 and ‘111’ program of MOE for financial support. X.-
H.D. thanks the Fundamental Research Funds for the Central Uni-
versities, and the Doctoral Fund of the Ministry of Education of
China (20110201120076).
Next, the one-pot methodology was further applied to the
synthesis of phosphine oxide derivatives. We investigated that the
reaction could be carried out directly from carbonyl compounds
without the isolation of tosylhydrazone intermediates. We were
glad to find that the phosphine oxide derivatives were also ob-
tained, albeit in decrease yields (Scheme 3).
Supplementary data
Although the precise mechanism of our reaction remains un-
clear at this moment, we assume that the reaction proceeds as
shown in Scheme 4. Initially, diazo compound A was simulta-
neously generated in situ from N-tosylhydrazones 2 under basic
and thermal conditions.11 Then the Cu(I) catalyst would react with
A to give the Cu(I) carbene complex B.9c Insertion of Cu(I) carbene B
into PeH bond of H-phosphorus oxides 1 might proceed with at-
tack of the phosphorus atom on the electrophilic carbene B to
generate Cu(I)-associated ylide C, followed by hydrogen transfer to
afford product 3.10,12j,k
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.064.
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