Reduction of propargylic sulfones to (Z)-allylic sulfones using zinc and ammonium chloride

Article abstract of DOI:10.1016/j.tetlet.2007.04.099

Propargylic sulfones can be cis-hydrogenated using commercial zinc powder and ammonium chloride in THF-water at room temperature, the major products being the corresponding (Z)-allylic sulfones. Other reducible groups (alkene, benzyloxy) are not affected. Allenylsulfones are implicated in one of the possible reaction pathways.

Full text of DOI:10.1016/j.tetlet.2007.04.099

Tetrahedron Letters 48 (2007) 4407–4411
Reduction of propargylic sulfones to (Z)-allylic sulfones using
zinc and ammonium chloride
Helen M. Sheldrake and Timothy W. Wallace*
School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 23 January 2007; revised 13 April 2007; accepted 17 April 2007
Available online 25 April 2007
Abstract—Propargylic sulfones can be cis-hydrogenated using commercial zinc powder and ammonium chloride in THF–water at
room temperature, the major products being the corresponding (Z)-allylic sulfones. Other reducible groups (alkene, benzyloxy) are
not affected. Allenylsulfones are implicated in one of the possible reaction pathways.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The partial hydrogenation of the alkyne bond of a prop-
argylic sulfone 1 (Scheme 1) is a potentially valuable
process. The derived allylic sulfones 2 are useful inter-
mediates, with applications in the Julia olefination reac-
tion,1 various sequences involving metallation and
reaction with electrophiles,2 radical processes3 and cycli-
sations.4 Published routes to allylic sulfones include the
base-induced isomerisation of vinylic sulfones,5 the
addition of nucleophiles to alka-1,3-dienylsulfones,6
C–S coupling reactions,7 regioselective additions to
1,2-allenylsulfones8 and diverse rearrangements.9 The
sequence in Scheme 1 offers a simple and convergent
route to such compounds from readily available thio-
ethers 3.10
SO2Ar
R
SO2Ar
R
1
3
2
SAr
Scheme 1.
stituted alkyne is reduced under non-acidic conditions.
Our interest in this subject led us to investigate the
hitherto unexamined combination of propargylic sulf-
ones with zinc and we herein describe our results, which
indicate that for some substrates the cis-hydrogenation
of the alkyne bond can be conveniently brought about
with an excess of commercial zinc powder and ammo-
nium chloride in THF–water at room temperature.
Surprisingly few examples of the reduction of propargy-
lic sulfones to allylic sulfones are documented in the lit-
erature,11,12 the simple cases involving hydrogenation
over Lindlar catalyst and proceeding with the expected
(Z)-selectivity.11 In the wider context, several groups
have described the reduction of other types of alkyne
to alkenes using different forms of zinc, including zinc–
copper couple,13 Zn powder activated with 1,2-di-
bromoethane,14 Rieke zinc15,16 and zinc powder
produced by a combination of electroreduction and
ultrasonication.17 The reactivity and chemoselectivity
of these different forms of zinc can vary considerably,
but the (Z)-alkene generally predominates when a disub-
The results of a series of reductions of sulfones are
shown in Table 1.18–20 The reduction of the parent sys-
tem 4 to the allyl sulfone 5 proceeded smoothly using
a large excess of zinc, although in later experiments it
was established that 5 mol. equiv was sufficient for this
particular substrate (vide infra). A methyl or phenyl
substituent on the alkyne (entries 2, 3) appeared to inhi-
bit the reaction, with significant amounts of starting
materials 6 and 8 remaining unreacted, but the prefer-
ence for the formation of the respective (Z)-alkenyl sulf-
ones 7 and 9 was evident. The reduction of sulfone 8
also gave rise to significant quantities of a third product
which was identified as allenic sulfone 11 on the basis of
Keywords: Propargylic sulfone; Allylsulfone; cis-Hydrogenation;
Reduction; Zinc.
*
Corresponding author. Fax: +44 (0) 161 275 4598; e-mail:
tim.wallace@manchester.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.099

4408
H. M. Sheldrake, T. W. Wallace / Tetrahedron Letters 48 (2007) 4407–4411
Table 1. Reductions of alkynyl and allenyl sulfones with Zn18 and NH4Cl in water–THF19,20
Entry
1
Starting material
Zn equiv
57
Time (h)
21
Products
Yielda
(%)
Ratio
Z:Ea
73
—
SO2Ph
SO2Ph
5
4
SO2Ph
Me
Ph
SO2Ph
SO2Ph
c
Me
Ph
2
56
66
26b
—
7
6
SO2Ph
Ph
SO2Ph
3
4
5
25
56
25
18
21
25
26d
40e
59
3.4:1
3.9:1
15:1
10
9
8
8
9 + 10
HO
SO2Ph
HO
SO2Ph
HO
HO
SO2Ph
14
13
12
Ph
SO2Ph
SO2Ph
Ph
SO2Ph
SO2Ph
HO
HO
SO2Ph
SO2Ph
6
25
19
99
27:1
Ph
HO
17
20
15
18
16
Prn
HO
Prn
HO
7
8
9
25
25
30
19
22
18
99
59f
32g
>25:1
10.5:1
Prn
19
Prn
HO
SO2Ph
SO2Ph
19 + 20
•
21
Prn
Prn
AcO
SO2Ph
c
—
AcO
23
24
O
O
MeO
H
MeO
SO2Ph
H
H
H
c
10
11
57
40
22
20
99
—
SO2Ph
OBn
OBn
26
27
PhO2S
SO2Ph
SO2Ph
68h
5.2:1
SO2Ph
28
29
a Based on the analysis of isolated products by 1H NMR spectroscopy.
b Also unreacted 6 (70%).
c E-isomer not detected.
d Also unreacted 8 (43%) and 11 (19%).
e Also unreacted 8 (7%) and 11 (31%).
f Also 22 (5%).
g Also unreacted 23 (25%) and 25 (5%).
h Major component of a complex mixture.
Ph
SO2Ph
•
11
22
Prn
HO
SO2Ph
AcO
SO2Ph
Prn
•
25

H. M. Sheldrake, T. W. Wallace / Tetrahedron Letters 48 (2007) 4407–4411
4409
H
i
i
SPh
H
H
SPh
+ 30 (40%)
R
•
SO2Ar
SO2Ar
30
31
32 (48%)
R
H
1
38
SOPh
SOPh
+ 31 (15%)
32 (15%)
Scheme 4. Propargyl to allenyl isomerisation.
33 (23%)
mixture containing only small amounts of the desired
sulfoxide 34, together with unreacted starting material
and the over-reduction product 32. Given that the par-
tial hydrogenation of 1-decyne is relatively slow using
sonication-activated electrodeposited zinc and aq
ammonium chloride (100 ꢁC, 16 h),17 we surmise that
for propargylic sulfones this type of reduction is
strongly facilitated by coordination of the substrate to
the zinc surface via the sulfone group. The transfer of
an electron into the sulfur functional group, which is
implicit in the formation of thioether 32 from sulfoxide
31,22 could initiate such coordination. The presence of
an oxygen substituent at the other end of the alkyne
bond (Table 1, entries 5–7, 11) also appears to assist
the reduction process, as discussed previously.15
Scheme 2. Reagents and conditions: (i) Zn (25 equiv), NH4Cl, H2O,
THF, 25 ꢁC, ca. 24 h.
NMR data and by comparison with related compounds
discussed below. When the extra substituent incorpo-
rated a hydroxyl group adjacent to the alkyne bond
(entries 5–7), both the efficiency and the (Z)-selectivity
of the process dramatically improved, the transforma-
tions of 15 into 16 and of 18 into 19 being almost
quantitative.
Other experiments provided additional insight into the
scope and limitations of this reduction protocol. A sam-
ple of allenyl sulfone 21 was obtained from its alkynyl
tautomer 18 and subjected to the standard reduction
conditions (entry 8). Isomeric allylic sulfones 19 and
20 were once again obtained, with lower selectivity,
along with a small quantity of the conjugated sulfone
22. With the acetylated system 23 (entry 9) the reaction
was sluggish but the alkyne bond was once again hydro-
genated selectively, and a small quantity of the corre-
sponding allenyl sulfone 25 was observed. The
potentially labile benzyloxy and cyclobutene compo-
nents of sulfone 26 (entry 10) were both tolerant to
the reaction conditions, with clean conversion to the
highly functionalised sulfone 27 proving possible. A
‘double’ reduction of the conjugated diyne 28 was less
effective, giving a product mixture in which the symmet-
rical (Z,Z)-diene 29 was tentatively identified as the
major component (entry 11).
The results of isotopic labelling experiments (Scheme 3)
are consistent with the operation of mechanistically dis-
tinct routes to the observed products. The deuterium
label at the terminal position of alkyne 34 was distrib-
uted almost evenly in the reduced product 35, a result
which contrasts sharply with the high (Z)-selectivity
observed in the hydrogenation of many of the internal
alkynes tested. With the triply-labelled substrate 36,
much of the deuterium in the methylene group was lost
in the course of the reduction, and given their involve-
ment and viability as intermediates (Table 1, entries 3,
4 and 8–10), we propose that allene formation partially
accounts for this. The propargyl-to-allenyl isomerisation
(Scheme 4) has been exploited in the development of a
series of DNA-cleaving agents which operate in a pH-
dependent manner.23 The process is rapid under basic
conditions and can be induced with alumina,24 but is
inhibited by acid.25 We speculate that this isomerisation,
or its equivalent, is rendered possible by the hetero-
geneous conditions of the zinc/ammonium chloride
reduction and/or the participation of partially reduced
species.
In recent studies on the use of zinc in alkyne reductions,
Kaufman and coworkers16,21 emphasised the intriguing
interplay of mechanistic possibilities, and in seeking to
interpret our own results we carried out some additional
experiments. Firstly, the reactivity of the parent sulfone
4 was compared with those of analogous thioether 30
and sulfoxide 31 (Scheme 2). Thioether 30 was reduced
fairly cleanly to 32 but proved less reactive than the
sulfone 4, with only 60% conversion after 24 h. Under
similar conditions sulfoxide 31 gave a more complex
In summary, propargylic sulfones can be cis-hydro-
genated using commercial zinc powder and ammonium
chloride in THF–water at room temperature, the major
products from internal alkynes being (Z)-allylic sulf-
ones. The optimal substrates possess a potential coordi-
nation site in the second propargylic position, and other
reducible groups (alkene, benzyloxy) are not affected.
Allenylsulfones are implicated in one of the possible
reaction pathways.
H
SO2Ph
SO2Ph
SO2Ph
H
H
H
H
D
i
ca. 1.2:1
75%
D
H
≥ 95%
D
34
(Z)-35
(E)-35
≥ 85%
D
SO2Ph
≤ 20%
D
25%
D
D
D
i
25%
D
SO2Ph
95%
Acknowledgement
≥ 90%
H
≥
50%
D
36
37
We thank the Engineering and Physical Sciences
Research Council (EPSRC) for a postdoctoral research
award (GR/S82671).
Scheme 3. Reagents and conditions: (i) Zn (5 equiv), NH4Cl, H2O,
THF, 25 ꢁC, 23 h.

4410
H. M. Sheldrake, T. W. Wallace / Tetrahedron Letters 48 (2007) 4407–4411
19. Typical procedure (entry 7): To a stirred solution of
Supplementary data
sulfone 18 (25 mg, 0.10 mmol) in THF (1.9 mL) at room
temperature was added zinc powder (161 mg, 2.46 mmol)
followed by saturated aq ammonium chloride (1.9 mL).
The resulting mixture was vigorously stirred for 19 h,
diluted with water (10 mL) and extracted with EtOAc
(3 · 3 mL). The combined extract was dried (MgSO4),
filtered and concentrated in vacuo. Flash chromatography
of the residue, eluting with EtOAc–hexane (3:7), yielded a
mixture of 19 and 20 (25 mg, 99%) as a colourless oil. The
products were often sufficiently pure for use without
chromatography.
Preparative details for most of the starting materials
in Table 1 and Schemes 2 and 3. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.04.099.
References and notes
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20. All compounds are racemic and new compounds gave
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experiment using standard conditions. Characterising data
(unless stated, all NMR spectra at 400 MHz in CDCl3):
Compound 5, dH 5.77 (1H, tdd, J 7.3, 10.0, 17.1 Hz, 2-H),
5.32 (1H, d, J 10.0 Hz, 3-H), 5.13 (1H, d, J 17.1 Hz, 3-H),
3.81 (2H, d, J 7.3 Hz, 1-H2); Compound 7, dH (300 MHz)
5.82 (1H, qd, J 7.0, 10.5 Hz, 3-H), 5.43 (1H, qtd, J 1.5, 7.5,
10.5 Hz, 2-H), 3.85 (2H, d, J 7.5 Hz, 1-H), 1.33 (1H, dd, J
1.5, 7.0 Hz, 5-H); Compound 9, dH 6.80 (1H, br d, J
11.5 Hz, 3-H), 5.72 (1H, td, J 8.0, 11.5 Hz, 2-H), 4.06 (2H,
dd, J 1.5, 8.0 Hz, 1-H2); Compound 10, dH 6.37 (1H, br d, J
15.9 Hz, 3-H), 6.10 (1H, td, J 7.5, 15.9 Hz, 2-H), 3.96 (2H,
dd, J 1.0, 7.5 Hz, 1-H2); Compound 11, dH 6.95–7.00 (2H,
m); Compound 13, dH 6.06 (1H, ttd, J 1.0, 6.5, 11.0 Hz, 2-
H), 5.48 (1H, ttd, J 1.5, 8.0, 11.0 Hz, 3-H), 4.06 (2H, dd, J
1.5, 6.5 Hz, 1-H2), 3.98 (2H, dd, J 1.0, 8.0 Hz, 4-H2);
Compound 14, dH 5.8–5.6 (2H, m, 2-H and 3-H), 4.11 (2H,
br d, J 4.5 Hz, 1-H2), 3.80 (2H, br d, J 6.5 Hz, 4-H2);
Compound 16, dH (300 MHz) 6.05 (1H, dd, J 8.1, 10.5 Hz,
2-H), 5.52 (1H, ddd, J 7.9, 8.7, 10.5 Hz, 3-H), 5.36 (1H, d, J
8.1 Hz, 1-H), 4.19 (1H, dd, J 8.7, 13.9 Hz, 4-H), 4.03 (1H,
dd, J 7.9, 13.9 Hz, 4-H); Compound 17, dH (300 MHz) 5.84
(1H, ddd, J 9.0, 10.5, 16.1 Hz, 3-H), 5.73 (1H, dd, J 5.5,
16.1 Hz, 2-H); Compound 19, dH 5.84 (1H, dd, J 8.5,
10.8 Hz, 3-H), 5.41 (1H, ddd, J 7.5, 8.5, 10.7 Hz, 2-H), 4.22
(1H, br td, J 7.0, 8.5 Hz, 4-H), 4.05 (1H, ddd, J 1.0, 8.5,
13.8 Hz, 1-H), 3.91 (1H, dd, J 7.5, 13.8 Hz, 1-H);
Compound 20, dH 5.62 (1H, td, J 7.0, 15.5 Hz, 2-H), 5.56
(1H, dd, J 5.5, 15.5 Hz, 3-H), 3.79 (2H, d, J 7.0 Hz, 1-H2);
Compound 22, dH 7.03 (1H, td, J 7.5, 15.1 Hz, 2-H), 6.41
(1H, td, J 1.5, 15.1 Hz, 1-H), 2.41 (1H, dddd, J 1.5, 4.0, 7.0,
14.7 Hz, 3-H), 2.32 (1H, dtd, J 1.0, 7.5, 14.7 Hz, 3-H);
Compound 24, dH 5.67–5.57 (2H, m, J2,3 11.0 Hz, 2-H and
3-H), 5.15 (1H, dt, J 4.5, 8.5 Hz, 4-H), 4.25 (1H, dd, J 8.0,
14.1 Hz, 1-H), 3.89 (1H, dd, J 5.0, 14.1 Hz, 1-H);
Compound 25, dH 6.37 (0.53H, dd, J 2.0, 6.0 Hz, 1-HA),
6.32 (0.47H, dd, J 2.5, 6.0 Hz, 1-HB), 5.91 (0.47H, t, J
6.0 Hz, 3-HB), 5.87 (0.53H, t, J 6.0 Hz,3-HA) (A, B
diastereoisomers); Compound 29, dH 5.97 (1H, s, 7-H),
5.81 (1H, dd, J 6.3, 10.3, 10-H), 5.53 (1H, td, J 8.8, 10.3 Hz,
20-H), 4.69 (1H, s, 2-H), 4.28 (1H, t, J 6.3 Hz, 4-H), 4.05
(1H, dd, J 8.8, 14.1 Hz, 30-H), 3.97–3.87 (1H, m, 30-H);
Compound 31, dH 6.20 (2H, d, J 9.0 Hz, 3,4-H), 5.44 (2H,
td, J 8.0, 9.0 Hz, 2,5-H), 3.89 (4H, d, J 8.0 Hz, 1,6-H).
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