A novel copper-catalyzed reductive coupling of N-tosylhydrazones with H-phosphorus oxides

Article abstract of DOI:10.1039/c2ob26414e

We report here a novel C(sp³)-P bonds formation via copper-catalyzed reductive coupling of N-tosylhydrazones with H-phosphorus oxides. A variety of aliphatic and aromatic substrates bearing electron-rich and electron-deficient substituents affords phosphine oxide derivatives with moderate to good yields. This work suggests a new transformation of aldehydes/ketones via N-tosylhydrazones to organophosphorus compounds.

Full text of DOI:10.1039/c2ob26414e

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 7859
www.rsc.org/obc
COMMUNICATION
A novel copper-catalyzed reductive coupling of N-tosylhydrazones with
H-phosphorus oxides†‡
Lei Wu,*a,b Xiǎo Zhang,§b Qing-Qing Chen§b and An-Kun Zhoub
Received 20th July 2012, Accepted 13th August 2012
DOI: 10.1039/c2ob26414e
2007.2 Leading scientists such as Barluenga and Valdés’s group,
Wang’s group and others have contributed various transition
metal catalyzed cross-coupling reactions of N-tosylhydrazones
with alkynes,3 azoles,4 amines,5 aryl boronic acids,6 aryl sulfo-
nates,7 benzylic halides,8 isocyanides,9 trialkylsilylethynes,10
and in the cascade carbonylations etc.,11 which have shown ver-
satility and generality of this reagent to build useful functional-
ities for synthetic compounds. It is noteworthy that all of the
above processes went through metal–carbenes intermediates
which were generated in situ from N-tosylhydrazones while
exposed to transition metals under basic and thermal conditions.
For instance, Wang et al.3a proposed a copper-carbene intermedi-
ate in the copper(I)-catalyzed cross-coupling of N-tosylhydra-
zones with terminal alkynes to afford trisubstituted allenes.
However, to the best of our knowledge, the catalytic coupling
reaction of N-tosylhydrazones with H-phosphorus oxides such
as diarylphosphine oxides and H-phosphonates has never been
reported.12
Organophosphorus compounds play a vital role in organic
synthesis, catalysis, biochemistry, and materials chemistry, which
qualify the great importance to build C–P bonds.13 Although
various methods to prepare organophosphorus compounds have
been developed, the traditional approaches including Michaelis–
Arbuzov reaction still suffered from low efficiency, poor selectiv-
ity, and sometimes higher temperature with long time
heating.13c,14 Until recently, Han et al. demonstrated a serial
breakthrough in the transition metal catalyzed addition of H–P
(O) bonds to unsaturated carbon–carbon bonds.15 Of particular
interest among them is the palladium catalyzed hydrophosphory-
lation of alkenes towards the formation of C(sp3)–P bond with
excellent yields, albeit acyclic and six-membered cyclic H-phos-
phonates were proven to be inert15a [Scheme 1(a)]. Stawinski
et al.16 reported a palladium-catalyzed cross-coupling of H-phos-
phonate diesters with benzyl halides, however, the substrates
couldn’t be expanded to benzylic halides with side chains or ali-
phatic halides owing to β-H elimination during the palladium
catalytic cycle [Scheme 1(b)]. Polozov and co-workers demon-
strated a one-pot synthesis of dialkyl phosphonates from diazo
compounds and dialkyl hydrogen phosphites catalyzed by Cu-
(acac)2, to be noted, the substrate scopes were restricted with
diazo compounds with electron-withdrawing substituents17
[Scheme 1(c)]. Although some achievements have been made,18
the catalytic approaches to build C(sp3)–P bond are still very
We report here a novel C(sp3)–P bonds formation via copper-
catalyzed reductive coupling of N-tosylhydrazones with
H-phosphorus oxides. A variety of aliphatic and aromatic
substrates bearing electron-rich and electron-deficient substi-
tuents affords phosphine oxide derivatives with moderate to
good yields. This work suggests a new transformation of
aldehydes/ketones via N-tosylhydrazones to organophos-
phorus compounds.
Introduction
N-Tosylhydrazones, well-known as the key reagents in Shapiro
reaction, have been versatile synthetic intermediates for almost
60 years from their discovery in the mid-20th century.1 The
renewed interest in N-tosylhydrazones has occurred since the
first palladium catalyzed cross-coupling of N-tosylhydrazones
with aromatic bromides was documented by Barluenga group in
aDepartment of Chemistry, College of Sciences, Nanjing Agricultural
University, Nanjing 210095, Peoples’ Republic of China.
E-mail: rickywu@iccas.ac.cn
bThe Academy of Fundamental and Interdisciplinary Sciences, Harbin
Institute of Technology, Harbin 150080, Peoples’ Republic of China.
E-mail: rickywu@hit.edu.cn
†Electronic supplementary information (ESI) available: Experimental
procedures and products characterizations. See DOI: 10.1039/
c2ob26414e
‡Typical procedure for the copper-catalyzed reductive coupling reaction:
2 mmol diaryl phosphine oxide or H-phosphonate, 1 mmol N-tosylhy-
drazone and 3 mmol K2CO3 were charged into 25 mL oven-dried flask,
and backfilled with nitrogen for three times. 5 mL fresh-distilled 1,4-
dioxane or DMF was then injected into the flask, following by heating
up to 110 °C for 2 h. The reaction was monitored by TLC until starting
materials consumed, then removed all the volatiles for further purifi-
cation on silica chromatography.
1
Compound (3a) White solids. H NMR (400 MHz, CDCl3) δ: 1.56
(dd, J = 16, 7.6 Hz, 3H), 3.59 (qu, J = 14.8, 7.6 Hz, 1H), 3.76 (s, 3H),
6.75 (d, J = 8.8 Hz, 2H), 7.16 (dd, J = 8.4, 2.4 Hz, 2H), 7.27–7.40 (m,
3H), 7.47–7.58 (m, 5H), 7.88–7.93 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ: 15.60 (d, JC,P = 2.0 Hz), 39.97 (d, JC,P = 67.4 Hz), 55.20,
113.70 (d, JC,P = 1.20 Hz), 127.99, 128.11, 128.58, 128.69, 129.77 (d,
JC,P = 5.60 Hz), 130.14, 130.20, 131.13, 131.22, 131.24, 131.27,
131.35, 131.43, 131.63, 131.66, 131.69, 132.60 (d, JC,P = 13.5 Hz),
158.51 (d, JC,P = 2.2 Hz). 31P NMR δ: 33.48. HR-MS: calcd for
C21H22O2P 337.1357 ([M + H+]), found 337.1355.
§These two authors contributed equally to this paper.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7859–7862 | 7859

View Online
limited as aforementioned, thus, it is highly desirable to develop
a transition metal catalyzed method for this kind of transform-
ations with broad substrate scopes, higher selectivity/efficiency,
and lower cost. We conceived that H-phosphorus compounds
such as diaryl phosphine oxides and H-phosphonates, with labile
H–P(O) bonds, might react efficiently with [M]-carbenes in situ
generated from N-tosylhydrazones then undergo rearrangement
to form organophosphorus compounds. As our continuing inter-
est in the synthesis and application of organophosphorus com-
pounds,19 herein we would like to report, for the first time, the
copper-catalyzed reductive coupling of N-tosylhydrazones with
H-phosphorus oxides.
Results and discussion
The investigation was initiated by exploring the reaction of 1-
(1-(4-methoxyphenyl)ethylidene)-2-tosylhydrazine (1a) with
diphenylphosphine oxide (2a) under basic conditions. Although
no product was detected under metal-free conditions within short
reaction time,20 the cross-coupling proceeded smoothly in the
presence of 20 mol% CuI/1,10-phenanthroline to afford product
3a with 64% yield in two hours21 (Table 1, entries 1, 2). To our
delight, the reaction still proceeded with comparable efficiency
without adding any ligands. Excess diphenylphosphine oxide,
which might suppress the decomposition of N-tosylhydrazones,
improved the yield up to 71% (entries 5, 6). Various combi-
nations of bases and solvents were then screened to get the
optimal conditions, eventually, K2CO3/Dioxane was found to be
the best combinations (entries 7–9). A number of Cu(I) and
Cu(II) salts were applied in this reductive coupling reaction,
other Cu(I) salts such as CuCl, CuBr, Cu2O showed worse
results than CuI (entries 10–12). Notably, CuCl2 as the catalyst
afforded superior result to CuI and Cu(CN)4PF6, with 80%
isolated yield, albeit increasing the temperature and reaction time
did not augment the yield (entry 15).
With the optimized conditions in hand,22 studies on the expan-
sion of substrate scopes were then carried out. Various
Scheme 1 Catalytic approaches to build C(sp3)–P bonds.
Table 1 Screening conditions for copper-catalyzed reductive coupling of N-tosylhydrazones with diphenylphosphine oxidea
Entry
Catalyst loading/ligand
Solvent/base
Yieldb (%)
1
2
3
4
5
6
7
0
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
DIPEA/THF
0c
20 mol% CuI/1,10-phenanthroline
20 mol% CuI/1,10-phenanthroline
10 mol% CuI
20 mol% CuI
20 mol% CuI
64d
70
66
71
69c
60
20 mol% CuI
8
9
20 mol% CuI
20 mol% CuI
DBU/Dioxane
Cs2CO3/DMF
65
70
10
11
12
13
14
15
16
17
18
20 mol% CuCl
20 mol% CuBr
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
K2CO3/Dioxane
52
66
Trace
47
61
80
Trace
43
20 mol% Cu2O(nano)
20 mol% Cu(OAc)2
20 mol% Cu(acac)2
20 mol% CuCl2
20 mol% CuSO4
20 mol% Cu(OTf)2
20 mol% Cu(CN)4PF6
71
a 1 mmol N-tosylhydrazone (1a), 2 mmol diphenylphosphine oxide (2a), 3 mmol base, 5 mL solvent, reflux temperature or 110 °C, 2 h. b Isolated
yield based on N-tosylhydrazones. c 1a/2a = 1 : 1. d 1a/2a = 2 : 1.
7860 | Org. Biomol. Chem., 2012, 10, 7859–7862
This journal is © The Royal Society of Chemistry 2012

View Online
Table 2 Substrate scopes of the cross-coupling of N-tosylhydrazones
with diphenylphosphine oxide catalyzed by 20 mol% CuCl2
Table 3 Substrate scopes of the cross-coupling of N-tosyl-
a
hydrazones with various H-phosphorus oxides catalyzed by 20 mol%
a
CuCl2
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
p-MeOC6H4
p-MeC6H4
C6H5
Me
Me
Me
Et
Me
Me
Me
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
80
70
66
60
55
63
56
65
79c
67c
82
80
51
50
C6H5
p-ClC6H4
p-CF3C6H4
2,4-Dimethyl-C6H3
Naphthyl
Cyclohexyl
n-C3H7
p-MeOC6H4
C6H5
p-FC6H4
9
10
11
12
13
14
Me
H
H
H
H
i-C3H7
a 1 mmol N-tosylhydrazone (1), 2 mmol diphenylphosphine oxide (2a),
3 mmol K2CO3, 5 mL dioxane, 110 °C, 2 h. b Isolated yield based on
N-tosylhydrazones. c DMF as solvent.
a 1 mmol N-tosylhydrazone (1a), 2 mmol H-phosphorus oxides (2),
3 mmol K2CO3, 5 mL dioxane, 110 °C, 2 h.
substituted N-tosylhydrazones were synthesized as substrates, as
shown in Table 2, N-tosylhydrazones derived from both electron-
rich (MeO–, Me–, Dimethyl–) or electron-deficient (Cl–, CF3–,
F–) aryl ketones or aldehydes could afford the corresponding
organophosphorus compound (3) in medium to good yields
(entries 1–8, 11–13). Electron-withdrawing groups on aromatic
rings impaired the reaction efficiency to some extent (entries 5,
6, 13), this could be attributed to the stabilization of electron-
withdrawing groups to carbene intermediates, which in turn
decreased the reaction rate. It is worth to mention that alkyl
derivative N-tosylhydrazones were also shown to be viable sub-
strates with moderate to good yields (entries 9, 10, 14). For some
cases with unsatisfied yields, DMF was found to be better solvent
(entries 9, 10), however, this is not general for all substrates.
To further demonstrate the general effectiveness of this
copper-catalyzed reductive coupling, various H-phosphorus
oxides including diarylphosphine oxides and H-phosphonates
were also investigated. As shown in Table 3, diarylphosphine
oxides bearing electron-deficient group (2o) and steric ortho-
substituents (2p) were applicable with 53% and 76% yields,
respectively. Delightfully, the substrate scopes could be extended
to H-phosphonates with cyclic or acyclic moieties, affording the
corresponding phosphine oxide products (3q–3t) in moderate to
good yields.
Scheme 2 Plausible catalytic mechanism.
A
plausible mechanism was proposed and shown in
Scheme 2. Firstly, Cu(II) species are in situ reduced to Cu(I)
species by the diazo compound generated from N-tosylhydra-
zones (1) under basic and thermal conditions.5,23 Decomposition
of diazo compound by Cu(I) species leads to the formation of
the copper(I)–carbene complex (A). Then, nucleophilic attack of
the Ph2P(O)− on the carbene center would generate copper
species (B), the latter is protonated to produce the final coupling
product 3.
Conclusions
In summary, a novel C(sp3)–P bonds formation via copper-cata-
lyzed reductive coupling of N-tosylhydrazones with H-phos-
phorus oxides has been developed. The reaction proceeded
smoothly with a wide range of substrate scopes to afford phos-
phine oxide derivatives with moderate to good yields. This work
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7859–7862 | 7861

View Online
along with limited substrate scopes excluding various aliphatic substrates.
See: S. H. Bertz and G. Dabbagh, J. Am. Chem. Soc., 1981, 103, 5932–
5934.
suggests a new transformation of aldehydes/ketones via N-tosyl-
hydrazones to organophosphorus compounds. Further appli-
cation of this approach to asymmetric C(sp3)–P bonds formation
is under way.
13 (a) L. D. Quin, A Guide to Organophosphorus Chemistry, Wiley-Inter-
science, New York, 2000; (b) K. V. L. Crepy and T. Imamoto, Top. Curr.
Chem., 2003, 229(1), 111–141; (c) C. S. Demmer, N. Krogsgaard-Larsen
and L. Bunch, Chem. Rev., 2011, 111, 7981–8006.
14 Q. Xu and L.-B. Han, J. Organomet. Chem., 2011, 696, 130–140.
15 Hydrophosphorylation of alkenes: (a) L.-B. Han, F. Mirzaei, C.-Q. Zhao
and M. Tanaka, J. Am. Chem. Soc., 2000, 122, 5407–5408;
(b) F. Mirzaei, L.-B. Han and M. Tanaka, Tetrahedron Lett., 2001, 42,
297–299. Hydrophosphorylation of alkynes: (c) L.-B. Han, R. Hua and
M. Tanaka, Angew. Chem., Int. Ed., 1998, 37, 94–96; (d) L.-B. Han,
C.-Q. Zhao and M. Tanaka, J. Org. Chem., 2001, 66, 5929–5932;
(e) L.-B. Han, Y. Ono and S. Shimada, J. Am. Chem. Soc., 2008, 130,
2752–2753. And also see references cited in. ref. 14.
Acknowledgements
The authors are thankful to the National Natural Science Foun-
dation of China (NSFC, Grant No. 21002019), the China Post-
doctoral Science Foundation (Grant No. 2011 M500096). L. Wu
would also like to thank Nanjing Agricultural University and
Harbin Institute of Technology for financial support.
16 G. Lavén, M. Kalek, M. Jezowska and J. Stawinski, New J. Chem., 2010,
34, 967–975.
17 A. M. Polozov, N. A. Polezhaeva, A. H. Mustaphin, A. V. Khotinen and
B. A. Arbuzov, Synthesis, 1990, 515–517.
Notes and references
1 (a) R. H. Shapiro, J. H. Duncan and J. C. Clopton, J. Am. Chem. Soc.,
1967, 89, 471–472; (b) R. M. Adlington and A. G. M. Barrett, Acc.
Chem. Res., 1983, 16, 55–59; (c) Z.-H. Shao and H.-B. Zhang, Chem.
Soc. Rev., 2012, 41, 560–572; (d) Y. Zhang and J.-B. Wang, Top. Curr.
Chem., 2012, 1, 1–31.
18 (a) O. Tayama, A. Nakano, T. Iwahama, S. Sakaguchi and Y. Ishii,
J. Org. Chem., 2004, 69, 5494–5496; (b) M. Hosseini-Sarvari and
S. Etemad, Tetrahedron, 2008, 64, 5519–5523; (c) S. Sobhani and
S. Rezazadeh, Synlett, 2010, 1485–1488; (d) R. J. Barney,
R. M. Richardson and D. F. Wiemer, J. Org. Chem., 2011, 76, 2875–
2879; (e) P.-Y. Renard, P. Vayron, E. Leclerc, A. Valleix and
C. Mioskowski, Angew. Chem., Int. Ed., 2003, 42, 2389–2392.
19 (a) L. Wu, B.-L. Li, Y.-Y. Huang, H.-F. Zhou, Y.-M. He and Q.-H. Fan,
Org. Lett., 2006, 8, 3605–3608; (b) L. Wu, Z.-W. Li, F. Zhang, Y.-M. He
and Q.-H. Fan, Adv. Synth. Catal., 2008, 350, 846–862; (c) L. Wu,
J. Ling and Z.-Q. Wu, Adv. Synth. Catal., 2011, 353, 1452–1456;
(d) L. Wu, X. Zhang and Z.-M. Tao, Catal. Sci. Technol., 2012, 2, 707–
710.
2 J. Barluenga, P. Moriel, C. Valdés and F. Aznar, Angew. Chem., Int. Ed.,
2007, 46, 5587–5590.
3 (a) Q. Xiao, Y. Xia, H. Li, Y. Zhang and J.-B. Wang, Angew. Chem., Int.
Ed., 2011, 50, 1114–1117; (b) L. Zhou, Y. Shi, Q. Xiao, Y.-Z. Liu, F. Ye,
Y. Zhang and J.-B. Wang, Org. Lett., 2011, 13, 968–971.
4 (a) X. Zhao, G.-J. Wu, Y. Zhang and J.-B. Wang, J. Am. Chem. Soc.,
2011, 133, 3296–3299; (b) T. Yao, K. Hirano, T. Satoh and M. Miura,
Angew. Chem., Int. Ed., 2012, 51, 775–779.
5 A. Hamze, B. Tréguier, J.-D. Brion and M. Alami, Org. Biomol. Chem.,
2011, 9, 6200–6204.
6 X. Zhao, J. Jing, K. Lu, Y. Zhang and J.-B. Wang, Chem. Commun.,
2010, 46, 1724–1726.
7 B. Tréguier, A. Hamze, O. Provot, J.-D. Brion and M. Alami, Tetrahedron
Lett., 2009, 50, 6549–6552.
8 Q. Xiao, J. Ma, Y. Yang, Y. Zhang and J.-B. Wang, Org. Lett., 2009, 11,
4732–4735.
20 The reactions of N-tosylhydrazones with various nucleophiles under
metal-free conditions are also hot research topics recently, see: (a) H. Li,
L. Wang, Y. Zhang and J.-B. Wang, Angew. Chem., Int. Ed., 2012, 51,
2943–2946; (b) J. Barluenga, M. Tomás-Gamasa and C. Valdés, Angew.
Chem., Int. Ed., 2012, 51, 5950–5952; (c) J. Barluenga, M. Tomás-
Gamasa, F. Aznar and C. Valdés, Nat. Chem., 2009, 1, 494–499;
(d) J. Barluenga, M. Tomás-Gamasa, F. Aznar and C. Valdés, Angew.
Chem., Int. Ed., 2010, 49, 4993–4996.
9 F.-T. Zhou, K. Ding and Q. Cai, Chem.–Eur. J., 2011, 17, 12268–12271.
10 F. Ye, X.-S. Ma, Q. Xiao, H. Li, Y. Zhang and J.-B. Wang, J. Am. Chem.
Soc., 2012, 134, 5742–5745.
11 Z.-H. Zhang, Y.-Y. Liu, M.-X. Gong, X.-K. Zhao, Y. Zhang and
J.-B. Wang, Angew. Chem., Int. Ed., 2010, 49, 1139–1142.
12 Bertz et al. reported the reaction of diphenylphosphine oxide with tosyl-
hydrazones under base-free and metal-free conditions, however, long
reaction times, up to 29 days, were applied to obtain moderate yields,
21 Although Yu et al. reported the copper-catalyzed decomposition of
N-tosylhydrazones to synthesize aryl and alkyl sulfones, we did not
isolate any competitive byproducts as sulfones under our conditions. See:
X.-W. Feng, J. Wang, J. Zhang, J. Yang, N. Wang and X.-Q. Yu, Org.
Lett., 2010, 12, 4408–4411.
22 For some cases, DMF instead of dioxane was used to get better yields.
23 R. G. Salomon and J. K. Kochi, J. Am. Chem. Soc., 1973, 95, 3300–
3310.
7862 | Org. Biomol. Chem., 2012, 10, 7859–7862
This journal is © The Royal Society of Chemistry 2012