Copper(i)-catalyzed wittig olefination reactions of N-tosylhydrazones with trifluoromethylketones

Article abstract of DOI:10.1002/cctc.201300583

Cuprous iodide-catalyzed Wittig olefination reactions of N-tosylhydrazones with trifluoromethylketones are reported. This procedure provides an efficient method for the synthesis of various trifluoromethyl-substituted alkenes in moderate to good yields (up to 89 % yield) and good stereoselectivity (up to 93 % E-selectivity). To the best of our knowledge, it is the first report of a Wittig reaction of N-tosylhydrazones with ketones. Copyright

Full text of DOI:10.1002/cctc.201300583

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DOI: 10.1002/cctc.201300583
Copper(I)-Catalyzed Wittig Olefination Reactions of
N-Tosylhydrazones with Trifluoromethylketones
Qiang Sha and Yunyang Wei*[a]
Abstract: Cuprous iodide-catalyzed Wittig olefination reactions
of N-tosylhydrazones with trifluoromethylketones are reported.
This procedure provides an efficient method for the synthesis
of various trifluoromethyl-substituted alkenes in moderate to
good yields (up to 89% yield) and good stereoselectivity (up
to 93% E-selectivity). To the best of our knowledge, it is the
first report of a Wittig reaction of N-tosylhydrazones with ke-
tones.
Since Wittig and Geissler first reported the reaction 60 years
ago,[1] the Wittig reaction has become one of the most com-
monly used methods for constructing carbon-carbon double
Scheme 1. Wittig reaction of in situ generated diazo compounds with car-
bonyl compounds.
bonds. Several variants, including Horner–Wadsworth–Emmons
(HWE) reaction and Schlosser modification, were also devel-
oped during the years. From the end of the 1980s, diazo com-
pounds were emerged as a new type of Wittig reaction sub-
strates and were extensively used in Wittig reaction.[2]
the low reactivity of ketones, which significantly limited the
application of N-tosylhydrazones participated Wittig reactions.
Trifluoromethylated compounds are important synthetic tar-
gets in pharmaceutical and agrochemical industries, owing to
their highly desirable physical, physiological, and pharmacoki-
netic properties.[8] So trifluoromethylketones, which are more
reactive than general ketones, came into our sight. Here we
present our original work on developing a highly efficient and
practical catalytic Wittig olefination of trifluoromethylketones
with CuI as catalyst for the synthesis of trifluoromethyl-substi-
tuted alkenes.[9] (Scheme 1, Equation (3))
However diazo compounds without an electron-withdrawing
group are usually unstable and thus difficult to handle, which
significantly limit the scope of this type of reactions. N-tosylhy-
drazones, which could be utilized as safe diazo precursors,
have been used in organic synthesis a long time ago.[3] In
recent years, N-tosylhydrazones were widely used in cross-cou-
pling reactions and XÀH (X=C, O, S, N, P) insertion reactions.[4]
The Wittig reaction of N-tosylhydrazones with carbonyl com-
pounds is meaningful because it provides a new way to
couple two different carbonyl groups, forming olefins directly.
But less attention has been paid to the Wittig olefination using
N-tosylhydrazones. In 2003, Aggarwal and co-workers[5] report-
ed ClFeTPP catalyzed Wittig reaction of aldehyde-derived tosyl-
hydrazones with aldehydes (Scheme 1, Equation (1)). The al-
kenes were formed in high yields and high E-selectivity. In
Initially, tosylhydrazone 1a and 2,2,2-trifluoro-1-phenyletha-
none 2a were chosen as model substrates for optimization of
the reaction conditions (Table 1). The desired alkene products
were formed in 50% yield with an E/Z ratio of 87:13 (Table 1,
entry 1) under conditions that we reported recently for the ole-
fination of aldehydes with N-tosylhydrazones.[7] Optimization of
the copper catalysts (Table 1, entries 2–5) was performed and
revealed that CuI was the best, resulting in an increase of yield
to 87% with 88% E-selectivity. Other phosphines or phos-
phides, such as P(nBu)3, P(OMe)3, P(OEt)3, P(OiPr)3 were tested
in order to improve the E-selectivity and it was found that the
E-selectivity of the alkene products was improved. However,
the yield of the products was decreased (Table 1, entries 6–9).
A variety of solvents (Table 1, entries 10–15) and bases (Table 1,
entries 16–19) were then screened. Among the bases tested,
tBuOLi gave the best result. As to the solvent, toluene is supe-
rior to other solvents tested. When the catalyst loading was
decreased from 10 mol% to 5 mol% or 1 mol% (Table 1, en-
tries 20–21), the yield of the products seriously declined which
indicated that 10 mol% of CuI was needed to carry out this re-
action smoothly. In summary, the optimal conditions for the
2004, Zhu and co-workers[6] described
a straightforward
method for the synthesis of trans pentafluorophenyl-contain-
ing alkenes from aldehydes in moderate to good yields using
Rh(OAc)2 as catalyst (Scheme 1, Equation (2)). We have also re-
ported Cu(acac)2-catalyzed Wittig reaction of ketone-derived
tosylhydrazones with aldehydes.[7]
To the best of our knowledge, there was no report about
the Wittig reaction of N-tosylhydrazones with ketones due to
[a] Dr. Q. Sha, Prof. Y. Wei
School of Chemical Engineering
Nanjing University of Science and Technology
Nanjing 210094 (P.R. of China)
Fax: (+86)25-84317078
E-mail: ywei@mail.njust.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201300583.
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N-tosylhydrazones with electron-donating group on
the aromatic ring (methyl, methoxyl, and dimethyla-
mino) give the products in good yields and good E-
selectivity (Table 2, 3ba–3da). N-tosylhydrazones pos-
sess of weak electron-withdrawing group (bromo,
chloro), no matter on the ortho, meta, or the para po-
sition, all give the products in moderate to good
yields with good E-selectivity (Table 2, 3ea–3ia).
When strong electron-withdrawing group (cyano and
nitro) substituted N-tosylhydrazones were used, the
desired products were formed in low yields (Table 2,
3ja–3ka). The major by-products were correspond-
ing azines (Table 2, 4ja–4ka). Heterocyclic hydra-
zones were tested subsequently and they give the al-
kenes in good to excellent yield with high E-selectivi-
ty (Table 2, 3la–3ma). N-tosylhydrazone derived from
cinnamaldehyde was also used, the product was ob-
tained in 55% yield with 80% E-selectivity. (Table 2,
3na). However when tosylhydrazones derived from
aliphatic aldehydes were used, no alkenes were ob-
tained which showed that more efficient catalytic
conditions need to be developed (Table 2, 3oa–3pa).
Ketones derived tosylhydrazones gave the alkenes in
very low yields may be attributed to the stereohin-
drance of the methyl group (Table 2, 3qa–3ra).
Table 1. Reaction results of 1 with 2 in different reaction conditions.[a]
Entry
Catalyst
Phosphine
Base
Solvent
Yield [%][b]
Z:E[c]
1
2
3
4
5
6
7
8
Cu(acac)2
CuCl2
Cu(OAc)2
Cu(MeCN)4PF6
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
PPh3
PPh3
PPh3
PPh3
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
THF
50
72
10
48
87
21
30
33
15
72
56
77
66
17
50
57
44
73
2
13:87
10:90
12:88
9:91
12:88
8:92
7:93
6:94
8:92
9:91
11:89
12:88
9:91
11:89
10:90
8:92
11:89
11:89
7:93
10:90
12:88
PPh3
P(OMe)3
P(OEt)3
P(OiPr)3
P(nBu)3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
PhCF3
CH2ClCH2Cl
MeCN
DMF
toluene
toluene
toluene
toluene
toluene
toluene
tBuONa
tBuOK
DBU
tBuOLi
tBuOLi
CuI
CuI
CuI
CuI
46
25
Effects of substituents attached to trifluoromethyl-
ketones on the reaction were also investigated.
(Table 3) It was found that electron-withdrawing
(bromo, chloro, nitro), as well as electron- donating
(methyl, methoxyl) groups all tolerated the reaction
(Table 3, 3ab–3ah). The alkenes were all formed in
good yields with good E-selectivity. 2,2,2-Trifluoro-1-
[a] Reaction Conditions: 1a (0.6 mmol), 2a (0.5 mmol), Catalyst (10 mol%), Base
(0.7 mmol), Solvent (5 mL), PPh3 (0.7 mmol), under N2 atmosphere, 908C, 10 h; [b] Iso-
lated yield, yield of Z+E; [c] Determined by GC; [d] 5 mol% of CuI was used;
[e] 1 mol% of CuI was used.
copper-catalyzed Wittig olefination of trifluoromethyl ketone
with tosylhydrazone involved a combination of CuI (10 mol%),
PPh3 (1.4 equiv), tBuOLi (1.4 equiv), and toluene (5 mL) under
N2 at 908C for 10 h (Table 1, entry 5).
Encouraged by these results, we next investigated the scope
of the process with respect to the N-tosylhydrazone substrate
(See Table 2). A variety of N-tosylhydrazones derived from aro-
matic aldehydes were allowed to react with 2,2,2-trifluoro-1-
phenylethanone under the optimized reaction conditions.
(thiophen-2-yl)ethanone also reacted well under optimized
conditions, alkenes were formed in 73% yield with 92% Z-se-
lectivity. (Table 3, 3ai). 1,1,1-Trifluoropropan-2-one, which be-
longs to an aliphatic trifluromethylketone, was investigated
and the products were obtained in moderate yields with good
E-selectivity. (Table 3, 3nj, 3sj).
A possible mechanism for the above reported reaction is de-
picted in Scheme 2. Initially, diazo compounds were formed
in situ from corresponding tosylhydrazones 1 under basic con-
Scheme 2. Proposed mechanism of the Wittig reaction of N-tosylhydrazones with trifluoromethylketones.
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were used, the in situ generated
diazo compounds were too
stable to be decomposed by CuI
in time, then the side reaction
occurred as the main reaction.
In conclusion, Wittig olefina-
tion reactions of trifluoromethyl-
ketones with N-tosylhydrazones
were catalyzed efficiently by
cuprous iodide. Trifluoromethyl-
substituted alkenes were formed
in moderate to good yields with
good E-selectivity. To our knowl-
edge, the present procedure
represents the first example of
the Wittig olefination of an acti-
vated ketone with N-tosylhydra-
zones. Further investigations
about the Wittig olefination of
other activated ketones as well
as unactivated ketones or esters
with N-tosylhydrazones are in
progress in our laboratory.
Table 2. Scope of the Wittig reaction of various N-tosylhydrazones 1 with 2,2,2-trifluoro-1-phenylethanone
2a.[a]
Experimental Section
CuI catalyzed Wittig olefination re-
action of N-tosylhydrazones with
trifluoromethylketones. (3aa as an
example)
A Schlenk tube with a magnetic
stir bar charged with N-tosylhydra-
zone 1a (164.4 mg, 0.60 mmol), 2a
(87.0 mg, 0.50 mmol), CuI (9.5 mg,
0.05 mmol),
0.70 mmol),
tBuOLi
PPh3
(56.0 mg,
(183.4 mg,
0.70 mmol) and toluene (5 mL).
The system was heated at 908C
under N2 atmosphere with stirring
for 10 h, The reaction mixture was
then allowed to cool to ambient
temperature and diluted with
10 mL of ethyl acetate, and
washed with brine (30 mL), water
(30 mL), and then the organic layer
was dried over Na2SO4. After con-
centrated in vacuo, the crude
product was purified by column
chromatography.
[a] Reaction Conditions: 1 (0.6 mmol), 2a (0.5 mmol), CuI (10 mol%), tBuOLi (0.7 mmol), Toluene (5 mL), PPh3
(0.7 mmol), under N2 atmosphere, 908C, 10 h; [b] The yields were isolated yields and the ratio of Z/E was deter-
1
mined by H NMR and 19F NMR.
ditions. In the presence of copper catalyst, the diazo com-
Acknowledgements
pounds were converted to copper carbenoids, which subse-
quently react with PPh3 to form the free ylide A. Reaction of
We thank A Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
free ylide A with trifluoromethylketones 2 gave olefination
products 3. At the same time, a side reaction is proposed as
a competitive reaction. The diazo compounds react with PPh3
to form the intermediate B which reacts with trifluoromethyl-
ketones 2 to form corresponding unsymmetric azines 4. When
N-tosylhydrazones with strong electro-withdrawing groups
Keywords: alkenes
·
copper
·
diazo compounds
·
tosylhydrazones · trifluoromethylketones · Wittig reaction
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Received: July 18, 2013
Revised: September 7, 2013
Published online on October 23, 2013
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