Tandem thiyl radical addition and cyclization of chiral hydrazones using a silicon-tethered alkyne

Article abstract of DOI:10.1016/S0957-4166(03)00540-8

A diastereoselective method for addition of a trans-2-(phenylthio)vinyl group to α-hydroxy hydrazones is presented. An ethynyl group, tethered to α-hydroxy hydrazones via a silicon tether, undergoes thiyl radical addition and cyclization under neutral tin-free conditions. In the same pot, desilylation with potassium fluoride or tetrabutylammonium fluoride affords (E)-vinylsulfides. The one-pot process is the synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol.

Full text of DOI:10.1016/S0957-4166(03)00540-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2853–2856
Tandem thiyl radical addition and cyclization of chiral
hydrazones using a silicon-tethered alkyne
Gregory K. Friestad,* Tao Jiang and Gina M. Fioroni
Department of Chemistry, University of Vermont, Burlington, VT 05405, USA
Received 2 May 2003; accepted 13 June 2003
Abstract—A diastereoselective method for addition of a trans-2-(phenylthio)vinyl group to a-hydroxy hydrazones is presented. An
ethynyl group, tethered to a-hydroxy hydrazones via a silicon tether, undergoes thiyl radical addition and cyclization under
neutral tin-free conditions. In the same pot, desilylation with potassium fluoride or tetrabutylammonium fluoride affords
(E)-vinylsulfides. The one-pot process is the synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol.
© 2003 Elsevier Ltd. All rights reserved.
Polyhydroxylated amines are found in a variety of
common compound classes of interest for their biologi-
cal activity, including sphingolipids,1 hydroxylated
pyrrolidines and piperidines (‘azasugars’),2 and
aminosugars.3 Asymmetric synthesis of amino alcohols
also provides access to chiral auxiliaries and ligands for
asymmetric catalysis.4
thiyl radical addition–cyclization to install a 2-
(phenylthio)vinyl fragment in diastereoselective fashion.
Intermolecular addition of heteroatom radicals to an
alkene or alkyne can initiate a cyclization event when a
second radical acceptor moiety is appropriately situ-
ated.15 Previously we have shown that thiyl radical
addition to a vinylsilane temporarily tethered to a
chiral a-hydroxyhydrazone facilitates such a cyclization
with excellent stereocontrol. Subsequent fluoride-
induced thiolate elimination occurred during removal
of the silicon tether, returning the vinyl functionality.
We hypothesized that an analogous sequence might
take place at a higher oxidation level using an ethynyl-
silane as the silicon-tethered radical precursor group, a
reaction type which, to our knowledge, is without direct
precedent.16 Because of the additional options available
for functionalization of alkynes, an ethynyl group addi-
tion would be a potentially useful complement to our
vinyl addition methodology.
A carbonꢀcarbon bond construction approach to a-
branched amines may create both a stereogenic center
and a CꢀC bond in a single synthetic transformation.
We have exploited radical addition to CꢁN bonds as a
general strategy;5,6 the radical intermediates are non-
basic, avoiding aza-enolization,7 and are chemoselective
and can be generated under mild conditions, avoiding
some of the problems inherent in additions of carban-
ion-type organometallic reagents to aldehyde imino
derivatives.8 Acyclic stereocontrol of alkyl radical addi-
tion to CꢁN acceptors is rare, appearing only in the last
6 years.9–11 We have found that hydroxymethyl12 and
vinyl13 units can be installed with ‘formal acyclic stereo-
control’ using a temporary silicon tether to allow con-
formational constraints to control diastereoselectivity in
radical cyclization (Fig. 1).
Because no viable intermolecular additions of vinyl or
aryl radicals to CꢁN bonds are yet available, installa-
tion of these unsaturated groups warrants a temporary
silicon tether approach,14 which renders the addition
intramolecular. Here, we report a new variant of this
strategy which engages a tethered alkyne for tandem
* Corresponding author. E-mail: gregory.friestad@uvm.edu
Figure 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00540-8

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G. K. Friestad et al. / Tetrahedron: Asymmetry 14 (2003) 2853–2856
To test this hypothesis, we began by silylating glycol-
aldehyde N,N-diphenylhydrazone13 (1a, Scheme 1) with
chloroethynyldimethylsilane 217 to afford addition–
cyclization substrate 3a18 (83% yield). Treatment with
thiophenol and AIBN (cyclohexane, reflux) resulted in
efficient CꢀC bond construction to furnish a cyclic
silane, which was not amenable to standard flash chro-
matography on silica gel. Exposure to fluoride led to
removal of the silicon tether, but surprisingly, none of
the alkyne was observed. In contrast to our previous
work with the vinylsilane, the thiolate elimination did
not occur; simple protodesilylation was observed
instead, preserving the sulfide functionality in a 2-
(phenylthio)vinyl adduct 4a18 (68% yield, two steps).
The one-pot process accomplishes addition of a func-
tionalized vinyl radical to a CꢁN bond under neutral
conditions, without toxic and difficult-to-remove stan-
nane reagents.
Scheme 2.
Table 1. Product ratios and diastereoselectivities of
tandem radical addition/cyclization of 3a–3e
Entry
R
Product ratioa
drb
1
2
3
4
5
H
1.4:1c
–
Me
iBu
iPr
Ph
71.8:6.6:19.2:2.3
74.4:11.3:11.2:3.1
87.0:8.7:3.6:<1
90.1:9.9:<1:0
78:22
86:14
96:4
>98:2d
Conditions: (1) 1.2 equiv. PhSH added via syringe pump, 10 mol%
AIBN, 0.1–0.3 mmol hydrazone in refluxing cyclohexane (0.1 M),
2–3 h with TLC monitoring. If necessary (TLC), additional AIBN
was added and the reaction was continued until complete. See Ref.
27 for a representative example. (2) 2.2 equiv. TBAF in THF, rt, 1
h.
a Ratios (E-anti:Z-anti:E-syn:Z-syn) from integration of 500 MHz
1H NMR spectra of product mixtures, given in order of elution on
SiO2 (hexane/EtOAc).
b Diastereomer ratio (anti/syn), sum of E and Z isomers.
c E/Z ratio (anti/syn not applicable).
Scheme 1.
d Trace amount of isomer (E)-syn-3e was detected by 1H NMR.
Although the planned elimination to form the alkyne
was not realized, we were cognizant of some advantages
of the vinylsulfide functional group for further manipu-
lations. Specifically, because vinylsulfides are aldehyde
equivalents, these reactions can be considered the radi-
cal equivalent of an acetaldehyde Mannich reaction.19
Furthermore, a vinylsulfide can undergo direct acid-cat-
alyzed cyclization with a remote hydroxyl group to
afford cyclic hemithioacetals (i.e. thioglycosides).20
chromatographic purification. We suspected that the
minor Z-isomer might be formed to some extent.
Indeed, in some experiments involving more rapid addi-
tion of PhSH, significant amounts of Z-alkene products
were found upon careful chromatography. Because the
formation of the Z-alkene was suppressed by maintain-
ing a lower concentration of PhSH, it is reasonable to
speculate that the E-alkene is susceptible to alkene
isomerization via an addition–elimination mechanism
after the key CꢀC bond construction.
Next we explored the diastereoselectivity of the process
using cyclization substrates 3b–3d18,21 (Scheme 2), easily
prepared from enantiomerically pure a-hydroxy hydra-
zones 1b–1d12,13 by silylation with 2. Sequential treat-
ment with thiophenol/AIBN and refluxing methanolic
KF led to allylic anti-hydrazino alcohols 4b–4d.18 Sub-
sequently, we found that tetrabutylammonium fluoride
was a preferred fluoride source in this reaction, excising
the silicon tether smoothly and in improved yield at
room temperature. Silyl ether 3e reacted in similar
fashion, though less cleanly. In this case, even though
some inseparable by-products prevented accurate deter-
mination of the product ratio, only a trace of (E)-syn-
4e, and no trace at all of (Z)-syn-4e was detected in the
The relative configuration of 4d was assigned by chem-
ical correlation with the corresponding vinyl adduct 5,
lacking the sulfide. Upon treatment with Raney nickel,
both 4d and 5 were converted to the same saturated
1
crude product mixture by H NMR. In all cases, the
anti/syn diastereoselectivity in this process ranged
upward from about 4:1 (Table 1) and is clearly corre-
lated with the steric demand of the substituent R.
In preliminary stages of this work, only the E-alkene22
was observed after removal of the silicon tether and
Scheme 3.

G. K. Friestad et al. / Tetrahedron: Asymmetry 14 (2003) 2853–2856
2855
product 6 (Scheme 3). This established the anti relative
configuration of 4d.23
vinyl radical addition methods are currently unavail-
able, this silicon-tethered approach offers a potentially
valuable alternative.27
The favored anti diastereomer is that predicted by the
Beckwith–Houk model,24 i.e. the preferred chair-like
transition state with minimized allylic strain. The minor
syn product would be expected from disfavored chair-
axial and/or boat conformations. Interestingly, the
selectivity of these ethynylsilane addition/cyclization
reactions is slightly lower than that observed in the
corresponding reactions of vinylsilanes, which proceed
via 5-exo cyclization of an alkyl radical.13 Considering
the differences in reactivity of alkenyl and alkyl radi-
cals, the slightly lower selectivity in this work may be
attributable to an earlier chair-like transition state,
which would presumably exhibit diminished energetic
differences between chair–equatorial and the competing
chair–axial and/or boat conformations (Fig. 2).
Acknowledgements
We thank NSF (CHE-0096803), Research Corporation,
Petroleum Research Fund, Vermont EPSCoR, and the
University of Vermont for generous support.
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Scheme 4.
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reaction with acyclic stereocontrol. Since intermolecular

2856
G. K. Friestad et al. / Tetrahedron: Asymmetry 14 (2003) 2853–2856
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27. Representative procedure: A solution of ethynylsilyl ether
3c (204 mg, 0.56 mmol) in cyclohexane (5.6 mL) was
deoxygenated (N2, via syringe needle) for ca. 10 min, then
heated to reflux. A solution of 2,2%-azobis(isobutyroni-
trile) (AIBN, 10 mg, 0.06 mmol) and thiophenol (0.080
mL, 0.78 mmol) in benzene (0.8 mL), was added via
syringe pump (0.34 mL/h). Additional portions of AIBN
(3×10 mg) were added in 3 h intervals until the reaction
was complete (as judged by TLC), then the cooled reac-
tion mixture was concentrated. The residue was dissolved
in THF (1 M) and treated with tetrabutylammonium
fluoride (1.5 mL, 1 M in THF, 1.5 mmol) at room
temperature for ca. 1 h. When complete (as judged by
TLC), the reaction was diluted with hexane, washed with
water, dried over Na2SO4, and concentrated. Flash chro-
matography (hexane/ethyl acetate) furnished the vinyl
sulfide 4c as a mixture of diastereomers (157 mg, 67%),
from which the major diastereomer (E)-anti-4c (120 mg,
51% yield) was isolated by radial chromatography (hex-
ane/ethyl acetate) as a pale yellow oil: [h]2D8=−12.0 (c
1.25, CHCl3); IR (film, CHCl3) 3447, 3060, 2955, 1588,
1495, 1272, 1071, 1025 cm−1 1H NMR (500 MHz,
;
CDCl3) l 7.31–7.22 (m, 9H), 7.14–7.11 (m, 4H), 7.05–
7.00 (m, 2H), 6.35 (d, J=15.1 Hz, 1H), 5.90 (dd, J=15.2,
8.9 Hz, 1H), 4.09 (s, 1H), 4.00–3.95 (m, 1H), 3.52 (dd,
J=8.9, 2.4 Hz, 1H), 2.35 (s, 1H), 1.80–1.72 (m, 1H), 1.45
(ddd, J=14.0, 9.3, 5.6 Hz, 1H), 1.12 (ddd, J=13.1, 8.1,
3.6 Hz, 1H), 0.92 (d, J=6.7 Hz, 3H), 0.89 (d, J=6.6 Hz,
3H); 13C NMR (125 MHz, CDCl3) l?147.96, 134.65,
129.96, 129.28, 129.08, 128.79, 127.70, 126.93, 122.72,
120.36, 68.70, 65.28, 41.85, 24.65, 23.34, 22.08; MS (CI)
m/z (relative intensity) 419 ([M+H]+, 80%), 164 (100%).
Anal. calcd for C26H30N2OS: C, 74.60; H, 7.22; N, 6.69.
Found: C, 74.32; H, 7.28; N, 6.43.
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combustion analyses and spectroscopic data (1H and 13C
NMR, IR, MS).
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