O-directed free-radical hydrostannations of propargyl ethers, acetals, and alcohols with Ph3SnH and Et3B

Article abstract of DOI:10.1021/ol051936l

(Chemical Equation Presented) The O-directed hydrostannation of various propargyloxy substrates is reported with Ph₃SnH/Et₃B.

Full text of DOI:10.1021/ol051936l

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5369-5372
O-Directed Free-Radical
Hydrostannations of Propargyl Ethers,
Acetals, and Alcohols with Ph3SnH and
Et3B
Paschalis Dimopoulos, Audrey Athlan, Soraya Manaviazar, Jonathan George,
Marcus Walters, Linos Lazarides, Abil E. Aliev, and Karl J. Hale*
The Christopher Ingold Laboratories, The Chemistry Department,
UniVersity College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom
k.j.hale@ucl.ac.uk
Received August 10, 2005
ABSTRACT
The O-directed hydrostannation of various propargyloxy substrates is reported with Ph3SnH/Et3B.
Although disubstituted alkyl propargyl alcohols are reported
to undergo highly regio- and stereoselective, O-directed, free-
radical hydrostannation reactions1-4 with 0.36-1.5 equiv of
neat Bu3SnH and cat. AIBN (2,2′-azobisisobutyronitrile) at
temperatures of 60-120 °C (see eqs 1 and 21), there are
many substrates that perform poorly under these conditions
(see, for example, eqs 3-5).1-3
The frequently encountered variability and/or poor prac-
alkynes recently prompted us to search for milder and more
effective alternatives. After giving the problem some con-
ticality of much of the currently available technology1-7 for
the O-directed free-radical hydrostannation of substituted
(4) (a) Benechie, M.; Skrydstrup, T.; Khuong-Huu, F. Tetrahedron Lett.
1991, 32, 7535. (b) Addi, K.; Skrydstrup, T.; Benechie, M.; Khuong-Huu,
F. Tetrahedron Lett. 1993, 34, 6407. (c) Lautens, M.; Huboux, A. H.
Tetrahedron Lett. 1990, 31, 3105. (d) Betzer, J.-F.; Delaloge, F.; Muller,
B.; Pancrazi, A.; Prunet, J. J. Org. Chem. 1997, 62, 7768.
(1) Konoike, T.; Araki, Y. Tetrahedron Lett. 1992, 33, 5093.
(2) Nativi, C.; Taddei, M. J. Org. Chem. 1988, 53, 820.
(3) Ensley, H. E.; Buescher, R. R.; Lee, K. J. Org. Chem. 1982, 47,
404.
10.1021/ol051936l CCC: $30.25
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Scheme 1. Transition-State Considerations That Guided
Development of the O-Directed Free-Radical Hydrostannation of
Disubstituted Alkyl Acetylenes with Ph3SnH/Et3B
Scheme 2 O-Directed Free-Radical Hydrostannation of Alkyl
Acetylenes Bearing a Terminal Propargyl 1,3-Dioxolanea
siderable thought, we eventually decided to examine the
utility of Ph3SnH and cat. Et3B in PhMe at rt for this purpose,
based on the following considerations.
Because the central tin atom in Ph3SnH is connected to
three electron-withdrawing phenyl groups, we believed that
it would have enhanced Lewis acidity compared with Bu3-
SnH and that it would therefore coordinate to the O-atom of
propargylically oxygenated alkyl acetylenes much more
effectively than the latter. We also believed that O-coordi-
nated Ph3SnH would more readily undergo H-atom abstrac-
tion than uncoordinated Ph3SnH and that O-coordinated
triphenylstannyl radicals would have a longer lifetime in
solution compared with their uncoordinated counterparts, due
to the Sn atom of the former species being significantly more
hindered. We reasoned that by creating a much longer-lived
O-coordinated tin-centered radical, we might potentially
improve the prospects for delivering the tin unit to the
R-acetylenic carbon of 14. We further postulated that if Ph3-
SnH was employed for hydrostannation (as opposed to Bu3-
SnH), greatly magnified steric repulsive effects would operate
in the vinyl radical H-atom abstraction step, owing to the
bent nature of alkylvinyl radicals 158 and the likelihood that
such radicals would abstract hydrogen from the stannane via
a transition state that would minimize steric repulsions
between the bulky Ph3Sn group of 15 and the incoming
stannane, while simultaneously avoiding A1,3 strain (Scheme
1). All told, we predicted that the transition state that would
lead to 16 would be considerably more favored with Ph3-
SnH than the corresponding one with Bu3SnH, and as
consequence, we postulated that higher regio- and stereo-
selectivity would result with the former stannane.
a N.B.: minor isomer structures are only assigned tentatively.
and highly reliable protocol for obtaining vinylstannanes of
general structure 16 with excellent levels of regio- and
stereocontrol, in good yield (Scheme 1). Our preferred
procedure utilizes 1.5 equiv of commercially available Ph3-
SnH and 0.1 equiv of Et3B in PhMe at rt9 and conducts the
hydrostannation for anywhere between 3 and 72 h at 0.1 M
concentration with respect to the starting disubstituted alkyne.
Initially, we examined the acetylenes 18, 21, 24, 27, and
30 (Scheme 2) in the Ph3SnH/cat. Et3B rt process. In every
case, the anticipated vinylstannanes 19, 22, 25, 28, and 31
all emerged with selectivities that exceeded 22:1 (Scheme
2) and yields that ranged between 51 and 86%. The modest
yields encountered in some runs are merely a reflection of
the difficulties sometimes encountered in separating certain
of these products from hexaphenylditin by SiO2 flash
chromatography. In all cases, the hydrostannation reactions
were themselves very clean according to TLC analysis, and
the starting alkyne was always fully consumed (Scheme 2).
In view of these successes, we decided to examine the
scope and utility of our O-directed hydrostannation process
in other propargylically oxygenated disubstituted alkyne
systems where there was additional substitution â- to the
acetylenic carbon (Scheme 3). In the cis-1,3-dioxolane
systems that we studied (33a, 33b, and 33c), a net anti-
addition of the stannane occurred to the alkylacetylene, with
With this picture of the situation in mind, we applied the
Ph3SnH/cat. Et3B hydrostannation process9 to a wide range
of alkylacetylene substrates 14 and now report a convenient
(5) Liron, F.; Le Garrec, P.; Alami, M. Synlett 1999, 246.
(6) Keck, G. E.; Wager, T. T.; Rodriguez, J. F. D. J. Am. Chem. Soc.
1999, 121, 5176.
(7) Dodero, V. I.; Koll. L. C.; Mandolesi, S. D.; Podesta, J. C. J.
Organomet. Chem. 2002, 650, 173.
(8) The ESR data that is available on simple R-alkylvinyl radicals suggests
that they adopt a rapidly equilibrating sp2 bent structure. See, for example:
(a) Rubin, H.; Fischer, H. HelV. Chim. Acta 1996, 79, 1670. (b) Fessenden,
R. W. J. Chem. Phys. 1967, 71, 74.
(9) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron 1989, 45, 923.
5370
Org. Lett., Vol. 7, No. 24, 2005

Scheme 3. Substituted Acetylene Substrates Bearing a
Scheme 4. Alkyl Acetylene Substrates with Pyranosidic
Substituted Propargyl 1,3-Dioxolanea
Propargyloxy and Propargylic Ether Protecting Groupsa
a N.B.: minor isomer structures are only assigned tentatively.
product 42 predominated in the mixture of vinylstannanes
that resulted; the latter was isolated in 57-87% yield and
with >53:1 selectivity.
a N.B.: minor isomer structures are only assigned tentatively.
A particularly pleasing outcome was obtained when the
di-O-TBDPS ether 44a was hydrostannylated. It reacted
efficiently under the standard rt conditions (Scheme 4), with
all of the starting alkyne generally being consumed within
16-21 h, and the expected vinylstannane 45a predominating
in the E:Z mixture of alkenes that formed. Together, this
mixture was isolated in 78-81% yield with a selectivity level
that exceeded 20:1.
The observation that a bulky propargylic OTBDPS group
could effectively direct the course of a free radical hy-
drostannation with Ph3SnH under these very mild conditions
is highly noteworthy and beautifully illustrates the enormous
scope and potential of the Ph3SnH/cat. Et3B rt protocol for
the hydrostannylation of oxygenated alkyl propargyl systems.
Presumably, the long Si-O bond pushes the bulky silyl
group away from the acetylenic R-carbon, allowing the
propargyl O-atom to still efficiently direct the regio- and
stereochemical course of the hydrostannation process.
excellent levels of stereocontrol typically manifesting them-
selves. For the phenylacetylene 33d even better results were
obtained; in this instance, R-regiocontrol was total and
stereoselectivity was again very high (>60:1). Alkyne 37a,
which had a trans-1,3-dioxolane ring positioned directly
adjacent to the two alkyne carbons, also reacted to give the
expected addition product 38a as the primary reaction
product; it was formed alongside 39a in 80-84% yield and
with >49:1 selectivity. The arylacetylenic acetal 37b was
also an excellent substrate for this reaction, it reacted in good
yield and with high stereoselectivity.
Notwithstanding us having obtained some impressive
results with a significant number of propargylically oxygen-
ated arylacetylenes, we must emphasize that such substrates
generally do not work as well as their alkyl acetylene
counterparts in the O-directed Ph3SnH/cat. Et3B hydrostan-
nation process.10 Our work on aryl and heteroarylpropargyl-
oxy substrates will be discussed in a more detailed full paper
that will be written up shortly.
(10) ESR investigations on R-styryl radicals suggest that they adopt an
sp linear structure. See: ref 8a and the following earlier references: (a)
Panek, E. J.; Kaiser, L. R.; Whitesides, G. M. J. Am. Chem. Soc. 1977, 99,
3708. (b) Neilson, G. W.; Symons, M. C. R. J. Chem. Soc., Perkin Trans.
2 1973, 1405. This difference in vinyl radical structure may go some way
to explaining the poorer stereochemical outcome in certain instances with
arylacetylene substrates.
In an effort to gauge whether a pyranosidic propargylic-O
could exert a substantial directing effect in this reaction, we
subjected pyranoside 41 to our standard rt conditions
(Scheme 4). To our great delight, the anticipated reaction
Org. Lett., Vol. 7, No. 24, 2005
5371

Scheme 5. Tertiary Acetylenic Alcohol and Ether Substratesa
Scheme 6. Primary Propargylic Alcohol Alkyl Acetylene
Substrates in the Ph3SnH/Et3B Room-Temperature
Hydrostannation Processa
As one might expect, the much less sterically encumbered
propargylic-O in 44b gave even higher levels of stereo- and
regiocontrol in this process (48-199:1 selectivity). Signifi-
cantly, the corresponding 1,2-diol 44c only hydrostannylated
slowly, possibly due to the Ph3SnH tightly chelating with
the terminal 1,2-diol grouping. Although, this reaction
proceeded very cleanly, starting alkyne did always remain
after 18 h, on the two occasions it was examined. Notwith-
standing 44c not always being fully consumed, a 45-69%
yield of 45c was nevertheless obtained with >73:1 selectiv-
ity.
Other commonly used ether protecting groups that can
readily serve as efficient regio- and stereochemical directors
include benzyl (Bn) and p-methoxybenzyl (PMB) ethers. In
this regard, the O-benzylated alkyne 48 performed admirably
in its orchestration of the desired hydrostannation event, it
affording a 44:1 and 59:1 mixture of the two vinylstannanes
49 and 50 (Scheme 4).
Our experience with tertiary propargyloxy systems has not
been especially good; the reactions are typically very hard
to drive to completion. Although the tertiary alkynol 51
reacted cleanly under the standard rt conditions to give
vinylstannane 52 as the major reaction product (Scheme 5),
it could never be isolated in more than 30-45% yield.
Alkyne 54 also reacted very slowly but, in this instance, an
inseparable mixture of vinylstannanes and starting 54 was
obtained in ca. 1:1 ratio.
Other alkylpropargyloxy systems that we have hydrostan-
nylated successfully include 55, 58, and 61 (Scheme 6).
With regard to the conversion of alkylpropargyloxy
systems such as 14 into alkylvinyltriphenylstannanes 16
(Scheme 1), a general guideline can now be adumbrated.
For high stereo- and regiocontrol to be predictably observed
in this process, the R3 group must be either an ethyl or a
higher alkyl substituent when R2 ) H. Likewise, if R3 )
Me, the R2 group must be either an alkyl or an alkyloxy
substituent for good results generally to be obtained.
Direct comparison of the rt Bu3SnH/cat. Et3B method with
its Ph3SnH/cat. Et3B counterpart, on several of the alkynes
reported herein, has revealed that the Ph3SnH system is
uniformly superior in every respect for effecting the O-
directed free radical hydrostannation reaction. Not only does
the Ph3SnH/cat. Et3B partnership more readily convert
propargylically oxygenated disubstituted alkynes into vinyl-
a N.B.: minor isomer structures are only assigned tentatively.
stannanes of general structure 16, it also delivers them with
improved stereo- and regiocontrol. In our experience, when
the Bu3SnH/cat. Et3B system is employed, large excesses of
reagent and prolonged heating are often necessary to get a
satisfactory hydrostannation rate, conversion, and yield, and
such conditions typically erode the levels of stereo- and
regiocontrol one finally attains.
It is our belief that Ph3SnH and cat. Et3B in PhMe at rt
currently represents the best and most convenient reagent
combine available for effecting the highly regio- and
stereocontrolled O-directed hydrostannation of propargyli-
cally oxygenated alkyl acetylene substrates under free radical
conditions. Although a significant number of arylpropargyl-
oxy systems have also proven good substrates for the Ph3-
SnH/cat. Et3B process, our cumulative data on this class has
revealed that they can on occasion give a less certain
outcome.
Acknowledgment. We thank the EPSRC (Project Grant
Nos. GR/N20959/01 and GR/S27733/01), the University of
London Central Research Fund, Novartis Pharma AG (USA/
Basel), Merck Sharp & Dohme (Harlow), and Pfizer
(Sandwich) for their generous financial support.
Supporting Information Available: Full experimental
procedures and detailed spectral data, a range of 500 MHz
1H and 125 MHz 13C spectra, and IR and HRMS spectra for
all new compounds are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
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