N-Alkylation of tosylhydrazones via a metal-free reductive coupling procedure

Article abstract of DOI:10.1016/j.tetlet.2012.11.124

A simple metal-free route for the N-alkylation of tosylhydrazones is described via the NaOMe-promoted reductive coupling of tosylhydrazones under mild conditions. A wide variety of N-alkylated tosylhydrazones were obtained in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2012.11.124

Tetrahedron Letters 54 (2013) 891–895
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N-Alkylation of tosylhydrazones via a metal-free reductive coupling procedure
Jin-Biao Liu a, Hui Yan a, Gui Lu a,b,
⇑
a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China
b Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple metal-free route for the N-alkylation of tosylhydrazones is described via the NaOMe-promoted
reductive coupling of tosylhydrazones under mild conditions. A wide variety of N-alkylated tosylhydra-
zones were obtained in moderate to good yields.
Received 13 September 2012
Revised 24 November 2012
Accepted 27 November 2012
Available online 3 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diazo compounds
Hydrazone
Cross-coupling
N-alkylation
Tosylhydrazone
Tosylhydrazones represent a useful class of synthons that can
be further converted into numerous pharmaceutical and biologi-
cally active compounds.1 One example is PIK-75, a preferential
Me
S
Me
NO2
N
N
O
inhibitor of the p110a/c forms of phosphatidylinositol 3-kinase
O
(PI3K) (Fig. 1).2 The efficient syntheses of N-alkylated sulfonylhyd-
razones are of interest to medicinal chemistry and the synthesis of
screening libraries. The most common route for their preparation is
through nucleophilic substitution of tosylhydrazones with alkyl
halides.1b Furthermore, tosylhydrazones can substitute alcohol un-
der Mitsunobu reaction conditions (DEAD/PPh3) (Scheme 1a).3a
Tris(pentafluorophenyl)borane [B(C6F5)3] catalyzed reactions of
alcohols with tosylhydrazones have also been reported.3b
Br
N
N
Figure 1. Structure of PIK-75.
R'
N
R'OH
Tosylhydrazones are widely used as precursors of diazo com-
pounds and carbenes,4 which are valuable and readily available re-
agents in C–C,5 C–O,6 C–N,7 C–S,8 and C–B9 bond-forming reactions
through both metal-catalyzed and metal-free processes. In partic-
ular, metal-free reactions have attracted widespread attention in
recent years. Barluenga et al. reported a new metal-free carbon–
carbon bond-forming reaction between tosylhydrazones and boro-
nic acids.5e Subsequently, Barluenga et al. and Ding et al. developed
procedures that can insert the incipient carbenes into the O–H
bond and S–H bond to prepare ethers6 and thioethers8c via me-
tal-free reductive coupling of tosylhydrazones with alcohols or thi-
ols. Recently, a metal-free reaction to convert tosylhydrazones into
pinacol boronates was explored by Wang and co-workers.9
a
b
R
N
Ts
Ts
DEAD/PPh3
ref.3a
R
NNHTs
R
N
R
NNHTs
N
R
base
this work
Scheme 1. (a) Mitsunobu reaction of tosylhydrazones and alcohols. (b) Metal-free
reductive coupling of tosylhydrazones discussed in this work (Ts = tosyl).
using N-tosylhydrazone as nucleophile remains less developed.11
In view of tosylhydrazone’s nucleophilicity and ability to generate
carbene in situ, a direct nucleophilic substitution reaction between
tosylhydrazone and its in situ-generated carbene may result in N-
alkylated tosylhydrazone (Scheme 1b). Further research may lead
Although Shi and co-workers used N-tosylhydrazones as nucle-
ophiles in Michael addition,10 the reductive coupling reaction
⇑
Corresponding author. Tel./fax: +86 20 3994 3048.
E-mail address: lugui@mail.sysu.edu.cn (G. Lu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.124

892
J.-B. Liu et al. / Tetrahedron Letters 54 (2013) 891–895
Table 1
to the development of highly efficient metal-free N-alkylation
reaction of tosylhydrazones, which represents a novel access to
these compounds.
Influences of the reaction conditions on the formation of N-alkylated tosylhydrazone
2aa
Ph
To test our hypothesis, we selected tosylhydrazone 1a derived
from benzaldehyde as the model substrate for reaction condition
screening. The results were summarized in Table 1. Initially, we
examined the reaction of tosylhydrazone 1a (0.3 mmol) in the
presence of K2CO3 (1.5 equiv) in dioxane at 110 °C. To our delight,
the expected N-alkylated tosylhydrazone 2a was obtained in 56%
yield (Table 1, entry 1). Encouraged by this result, we screened a
variety of bases for this reaction. Slightly lower yields were ob-
tained when DBU and Na2CO3 were employed as the bases (Table 1,
entries 2 and 3). In the presence of KOH, the reaction proceeded
less efficiently. The reductive coupling product 2a produced a yield
of 21% (Table 1, entry 4). Lowering the temperature produced no
better results (Table 1, entries 5 and 6). Further evaluation showed
that NaOMe was the best base for this transformation because it
afforded the desired product 2a in 83% yield (Table 1, entry 11).
Increasing the amount of base loading to 2.0 equiv resulted in a
comparable yield (Table 1, entry 11 vs entry 12). However, a signif-
icant drop in yield was observed when 1.0 equiv of NaOMe was
used (Table 1, entry 13). Different solvents were subsequently
screened, and methanol proved to be the most efficient solvent
(Table 1, entries 15 and 16). The yield was strongly dependent
on the base used, as evidenced by the observed trace target
product in MeOH with K2CO3 even with prolonged reaction time
(Table 1, entry 17).
base
Ph
Ph
+
NNHTs
1a
NNHTs
N
Ph
N
Ts
solvent
2a
Entry
Base
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
DBU
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
MeOH
EtOH
tBuOH
MeOH
MeOH
MeOH
MeOH
THF
110
110
110
110
100
70
56
43
48
21
55
37
64
78
70
45
83
82
70
67
59
45
Trace
Na2CO3
KOH
K2CO3
K2CO3
NaOMe
NaOMe
NaOEt
tBuOK
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
K2CO3
110
65
9
80
80
50
50
50
25
50
50
10
11
12c
13d
14
15
16
17
CH3CN
MeOH
50
The bold values indicated the optimal reaction conditions and the best result.
a
Reaction conditions: 1a (0.3 mmol), base (1.5 equiv), solvent (2 mL), 12 to 48 h.
b
Isolated yield.
NaOMe (2.0 equiv).
c
Table 2
Reductive coupling of tosylhydrazone 1a
Ar
R
R
H
N
NaOMe, MeOH
50°C, 12-48h
R
2
N
N
Ts
Ar
Ar
N
Ts
1
2
Entry
Tosylhydrazone
Product
Yieldb (%)
H
N
83
N
Ts
N
N
Ts
(1a)
1
(2a)
Me
H
N
N
Ts
86
N
N
Ts
(1b)
2
Me
(2b)
Me
MeO
H
N
N
N
Ts
81
N
N
Ts
3
4
MeO
MeO
(1c)
(2c)
MeO
MeO
OMe
N
H
N
70
Ts
N
(1d)
Ts
(2d)

J.-B. Liu et al. / Tetrahedron Letters 54 (2013) 891–895
893
Table 2 (continued)
Entry
Tosylhydrazone
Product
Yieldb (%)
OMe
OMe
H
MeO
N
74
76
57
N
Ts
(1e)
N
5
N
Ts
(2e)
Cl
H
N
N
Ts
N
N
6
7
Ts
(2f)
Cl
(1f)
Cl
Cl
N
Cl
H
N
Cl
N
Ts
(1g)
N
Ts
(2g)
Cl
Cl
Cl
H
Cl
N
N
N
Ts
8
69
Cl
Cl
N
(1h)
N
N
Ts
(2h)
H
N
Br
Ts
Br
(1i)
74
N
9
Ts
Br
(2i)
F
H
N
N
Ts
85
N
10
11
N
Ts
F
(1j)
F
(2j)
Me
O
H
N
91
89
N
Ts
(1k)
O2N
(2k)
O2N
NO2
Me
NO2
O
N
H
N
N
N
Ts
(2l)
12
13
(1l)
H
O
N
64
Ts
N
Ts
O
(1m)
O
(2m)
(continued on next page)

894
J.-B. Liu et al. / Tetrahedron Letters 54 (2013) 891–895
Table 2 (continued)
Entry
Tosylhydrazone
Product
Yieldb (%)
H
S
N
14
82
N
Ts
(1n)
N
N
Ts
S
S
(2n)
Me
H
Me
Me
N
15c
52
N
Ts
N
N
Ts
(1o)
(2o)
Cl
Me
H
N
Me
16c
N
Ts
50
Me
N
(1p)
Cl
N
Ts
Cl
(2p)
H
N
17
—
N
N
Ts
N
Ts
(2q)
(1q)
a
Reaction conditions: 1 (0.3 mmol), NaOMe (1.5 equiv), MeOH (2 mL), 50 °C, 12 h to 48 h.
Isolated yield.
60 °C.
b
c
NHTs
N
NHTs
N
F
MeO
NaOMe/MeOH
50 °C, 24 h
2c + 2j +
+
+
N
N
N
Ts
N
Ts
MeO
F
OMe
1c
F
2cj
2jc
1j
2c : 2j : 2cj : 2jc = 1 : 1 : 1 : 1.5
overall yield = 73%
Scheme 2. The reductive coupling between 1c and 1j.
After the optimal conditions were obtained (1.5 equiv of
respectively (Table 2, entries 11 and 12). Not only aryl-substituted
but also heteroaryl-substituted tosylhydrazones gave high yields
(Table 2, entries 13 and 14). In the case of ketone-derived sub-
strates such as tosylhydrazones 1o and 1p, higher temperature
was needed because of the large steric hindrance of the substrates
(Table 2, entries 15 and 16). The alkyl-substituted tosylhydrazone
1q derived from propanal was completely inert in this reaction
(Table 2, entry 17).
We have also tried the reductive coupling reaction between dif-
ferent tosylhydrazones as 1c (with electron-donating substitute)
and 1j (with electron-withdrawing substitute), and obtained a
mixture of N-alkylated tosylhydrazones 2c, 2j, 2cj, and 2jc with
the ratio of 1:1:1:1.5 (Scheme 2). The current chemoselectivity
was poor, and we are still screening the reaction conditions in de-
tail to further improve the chemoselectivity and to explore its
practical applications in organic synthesis.
NaOMe, MeOH as solvent, 50 °C), we explored the generality
and scope of the reductive coupling of tosylhydrazones. The re-
sults were presented in Table 2. The reaction could be performed
through hydrazones derived from both aldehydes and ketones. For
instance, tosylhydrazones 1b and 1c with electron-donating
groups could be successfully converted into the desired products
in high yields (Table 2, entries 2 and 3). Slightly lower yields were
obtained with tosylhydrazones 1d and 1e for their larger steric
hindrances of methoxy substituents (Table 2, entries 4 and 5).
Halogen substituents on phenyl rings (Table 2, entries 6–10) were
observed to be tolerant in this reaction, which enabled further
derivation of the adducts through various cross-coupling tech-
niques. Interestingly, when substrates 1k and 1l were used, the
desired products were not detected, but methyl ethers for the
participation of MeOH were isolated in 91% and 89% yields,

J.-B. Liu et al. / Tetrahedron Letters 54 (2013) 891–895
895
Ph
N
Supplementary data
O
a) TsNHNH2, MeOH, 50 °C, 1h
b) NaOMe, 50 °C, 24h
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.11.124.
Ph
Ts
Ph
H
2a, 70% yield
Scheme 3. One-pot synthesis of N-benzyl tosylhydrazone 2a.
References and notes
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R2
V
IV
Figure 2. Proposed mechanism.
To further simplify the reaction procedure, we carried out a
one-pot synthesis of tosylhydrazone 2a starting from benzalde-
hyde (Scheme 3) and obtained the desired product in a slightly
lower yield.
A possible mechanism for this reaction was also proposed,
which involved the formation of a diazo compound III by decom-
position of the tosylhydrazone salt II (Fig. 2).4,5e A carbene IV, gen-
erated from the diazo compound III by thermally induced N2
release, could then be inserted into the N–H bond of tosylhydraz-
one, giving rise to the corresponding N-alkylated tosylhydrazone V.
In summary, we have described a new method for the synthesis
of N-alkylated tosylhydrazone by a metal-free reductive coupling
procedure. In the presence of NaOMe, a variety of N-alkylated
tosylhydrazones were obtained in moderate to high yields under
a simple and mild condition. Efforts are underway to extend the
scope of the reaction between different tosylhydrazones.
Acknowledgments
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Y.; Shi, M. Eur. J. Org. Chem. 2010, 4088–4097.
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Chem.-Eur. J. 2011, 17, 6918–6921.
This work was financially supported by the European Commis-
sion through the project FP7-201431(CATAFLU.OR) and the Intro-
duction of Innovative R&D Team Program of Guangdong Province
(No. 2009010058).