Crotylations of alpha-carbonyl radicals with crotylstannane.

Article abstract of DOI:10.1021/ol026510a

Electrophilic radicals undergo crotylation with crotylstannane with moderate to good efficiency. The reaction provides the syn isomer as the major product. The present methodology is complementary to Claisen protocols for the synthesis of gamma,delta-unsa

Full text of DOI:10.1021/ol026510a

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3435-3438
Crotylations of r-Carbonyl Radicals with
Crotylstannane
Mukund P. Sibi* and Hideto Miyabe
Department of Chemistry, North Dakota State UniVersity,
Fargo, North Dakota, 58015-5516
mukund.sibi@ndsu.nodak.edu
Received July 12, 2002
ABSTRACT
Electrophilic radicals undergo crotylation with crotylstannane with moderate to good efficiency. The reaction provides the syn isomer as the
major product. The present methodology is complementary to Claisen protocols for the synthesis of γ,δ-unsaturated carboxylic acid derivatives.
Details of the new radical methodology are presented.
Free radical fragmentation reactions have enjoyed immense
popularity in organic synthesis.1 Seminal work from the
laboratories of Keck2 and Curran3 have firmly established
convenient protocols for the installation of an allyl group
using simple allylstannane as well as 2-substituted allylstan-
nanes and a radical precursor.1 However, reactions with
3-substituted allylstannanes are not well explored and have
generally met with failure. Either they show low reactivity
or they provide byproducts.4 Some examples of successful
allylations involving 3-substituted allylstannane5 or alterna-
tives6 have been reported in the literature. Generally inter-
molecular radical addition to unactivated nonterminal alkenes
is difficult.7 The failure of reactions with crotylstannane may
be attributed to the low reactivity of the radical partner, the
reduced reactivity of crotylstannanes, the high temperatures
used for the allylation reactions, and the isomerization to
more reactive 1-substituted allylstannanes that can occur at
high temperatures. We have previously shown that R-car-
bonyl radicals undergo highly selective allylation reactions
with allylstannanes at low temperatures using catalytic
amounts of a Lewis acid.8 We surmised that the higher
electrophilicity9 of the Lewis acid-coordinated R-carbonyl
radical in combination with low reaction temperature might
allow for crotylation with the nucleophilic crotylstannane.
This work reports successful examples of crotylation of
R-carbonyl radicals in moderate to good yields (1 to 2,
Scheme 1). Additionally, the stereoselectivity10 (syn to anti
(1) For a recent review, see: Rosenstein, I. In Radicals in Organic
Synthesis, Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany,
2001; Vol. 1, Chapter 1.4.
(2) (a) Keck, G. E.; Yates, J. B. J. Org. Chem. 1982, 47, 3590. (b) Keck,
G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R. Tetrahedron 1985, 41,
4079.
(3) (a) Curran, D. P. Synthesis 1988, 489. (b) Jasperse, C. P.; Fevig, T.
L.; Curran, D. P. Chem. ReV. 1991, 91, 1237.
(4) (a) For general information, see: Clive, D. L. J.; Paul, C. C.; Wang,
Z. J. Org. Chem. 1997, 62, 7028. (b) For formation of butadiene, see: Keck,
G. E.; Yates, J. B. J. Organomet. Chem. 1983, 248, C21.
(5) Intermolecular reactions: (a) Grignon, J.; Pereyre, M. J. Organomet.
Chem. 1973, 61, C33. (b) Kosugi, M.; Kurino, K.; Takayama, K.; Migita,
T. J. Organomet. Chem. 1973, 56, C11 (c) Easton, C. J.; Scharfbillig, I. M.
J. Org. Chem. 1990, 55, 384. (d) Hamon, D. P. G.; Massy-Westropp, R.
A.; Razzino, P. Tetrahedron 1995, 51, 4183. Intramolecular reactions: (e)
Danishefsky, S. J.; Panek, J. S. J. Am. Chem. Soc. 1987, 109, 917. (f) Keck,
G. E.; Cressman, E. N. K.; Enholm, E. J. J. Org. Chem. 1989, 54, 4345.
(6) Allylsufides: (a) Keck, G. E.; Byers, J. H. J. Org. Chem. 1985, 50,
5442. Allylgallanes: (b) Usugi, S.-i.; Yorimitsu, Y.; Oshima, K. Tetrahedron
Lett. 2001, 42, 4535.
(7) For information on rate data on intermolecular addition to nonterminal
alkenes, see: Free Radicals in Organic Chemistry; Fossey, J., Lefort, D.,
Sorba, J., Eds.; Wiley: Paris, 1995, Chapter 12. Also see ref 9.
(8) (a) Sibi, M. P.; Ji, J. J. Org. Chem. 1996, 61, 6090. (b) Sibi, M. P.;
Chen, J. J. Am. Chem. Soc. 2001, 123, 9472.
(9) Pereyre et al. (ref 5a) and Easton (ref 5c) have previously noted the
higher reactivity of electrophilic radicals with 3-substituted allylstannanes.
(10) For diastereoselective radical allylation, see: (a) Stereochemistry
of Radical Reactions; Curran, D. P., Porter, N. A., Giese, B.; VCH:
Weinheim, 1995. (b) Curran, D. P.; Shen, W.; Zhang, J.; Heffner, T. A. J.
Am. Chem. Soc. 1990, 112, 6738. (c) Sibi, M. P.; Ji, J. J. Org. Chem. 1996,
61, 6090. (d) For recent reviews on enantioselective radical reactions, see:
Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163. Sibi, M. P.;
10.1021/ol026510a CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

Table 2. Effect of Templates on Reactivity and Selectivitya
Scheme 1
ratio) in the coupling of prochiral radicals with crotylstannane
is also discussed.
Our experiments began with the establishment of reaction
conditions for the addition/trapping reaction with acrylimide
1 (Table 1, eq 1). Reaction of the acrylimide with 2 equiv
Table 1. Effect of Lewis Acid on Radical Crotylationsa
entry
Lewis acid (eqs) allyltin (equiv) yield (%)b
drc
1
2
3
4
5
6
7
no Lewis acid
Yb(OTf)3 (2)
Yb(OTf)3 (1)
Yb(OTf)3 (0.3)
Zn(OTf)2 (1)
Mg(ClO4)2 (1)
Hf(OTf)4 (1)
3
2
5
5
5
5
5
<5
55
68
70
19
22
45
a Lewis acid (1 equiv) was used. For reaction conditions, see Supporting
Information. b Isolated yield. c Diastereomer ratio was determined by 1H
NMR (500 MHz).
3.6:1
3.5:1
3.5:1
2.3:1
3.2:1
3.4:1
cycloaddition product formed from crotylstannane, and the
enone was obtained in the absence of an initiator. Porter and
co-workers have also observed the formation of similar
cyclopentanes in their work on enantioselective radical
allylation reactions.12 These clearly establish that reactions
with crotylstannane and 1 occur via radical intermediates.
We have previously shown that achiral templates can have
a significant impact on the outcome of conjugate radical
addition reactions.13 In light of this, we undertook a brief
study on the effect of achiral templates on reactivity and
selectivity in crotylations, and these results are tabulated in
Table 2, eq 2.
Changing the oxazolidinone template (1) to a pyrrolidinone
(4) gave a slight improvement in yield; however, there was
no improvement in diastereoselectivity (compare entry 1 with
2). Similar levels of selectivity were observed with the
N-phenylimidazolidinone template 5 (entry 3). In contrast,
benzoxazolidinone (6)- and 3,5-dimethylpyrazole (7)-derived
substrates gave much lowered selectivity (entries 4 and 5).
We have recently shown 1,8-naphthosultam is a superior
auxiliary in enantioselective H-atom transfer reactions.13
However, compound 8 showed only moderate reactivity and
the diastereoselectivity was lower than that observed with
substrates 1 and 4 (compare entry 6 with 1 or 2).
a For reaction conditions, see Supporting Information. b Isolated yield.
c Diastereomer ratio determined by H NMR (500 MHz).
1
of the crotylstannane11 and ethyl iodide in the absence of
any Lewis acid gave none of the desired product (entry 1).
In contrast, when ytterbium triflate was used as a Lewis acid
for the reaction, the crotylated product 3 was obtained in
55% yield. The product was formed as a mixture of
diastereomers in a ratio of 3.6:1 (entry 2). The reaction was
effective using either stoichiometric or catalytic amounts of
the Lewis acid and excess stannane (entry 3 and 4). Of the
different Lewis acids examined, ytterbium triflate performed
the best (compare entry 4 with 5-7).
Two control experiments were conducted to establish that
the crotylation reactions did indeed proceed via radical
intermediates. Reaction in the absence of triethylborane as
a radical initiator in the conversion of 1 to 3 gave no
crotylated product. Similarly, carrying out the reaction in
the presence of galvinoxyl, a radical inhibitor, gave none of
the desired compound 3. A minor amount of a 3 + 2
Rheault, T. R. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, Chapter 4.5. (e)
Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562. (f) Nguyen,
P. Q.; Scha¨fer, H. J. Org. Lett. 2001, 3, 2993.
(12) Wu, J. H.; Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995, 117,
11029.
(13) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984 and
references therein.
(11) Crotylstannane was >98% (E)-configuration.
3436
Org. Lett., Vol. 4, No. 20, 2002

Table 3. Effect of Substituents on Radical Allylation
Table 4. Crotylations of R-Bromo Acyloxazolidinones
temp
°C
yield
(%)a
entry
starting material
product
drb
entry
RX
product
3 R ) Et
14 R ) MeOCH2
15 R ) i-Bu
16 R ) n-Bu
17 R ) i-Pr
18 R ) c-hexyl
19 R ) adamantyl
20 R ) t-Bu
yield (%)a
drb
1
2
3
4
5
21 R ) R1 ) H
-78
-78
-78
20
25
26
3
27
27
78
78
85
74
82
3.0:1
2.1:1
2.9:1
1:1
22 R ) H, R1 ) Me
23 R ) H, R1 ) Et
24 R ) R1 ) Me
24 R ) R1 ) Me
1
2
3
4
5
6
7
8
EtI
68
48
63
58
63
62
69
75
3.5:1
2.0:1
2.6:1
3.4:1
3.0:1
3.5:1
5.6:1
5.4:1
MeOCH2Br
i-BuI
n-Bu
-78
1.2:1
i-PrI
a Isolated yield. b Diastereomer ratio was determined by H NMR (500
1
c-hexyl I
adamantyl I
t-BuI
MHz).
addition of prochiral radicals to prochiral acceptors.17 The
stereochemistry for 16 and 26 was determined by hydrolysis
to the corresponding carboxylic acids. The syn configuration
for the major product was assigned by comparison of spectral
characteristics of the acids with those of known compounds.18
In the present work, the formation of the syn diastereomer
with moderate selectivity as the major product can be
rationalized through an open transition state A shown in
Figure 1.19 An alternative transition state B leading to the
1
a Isolated yield. b Diastereomer ratio was determined by H NMR (500
MHz).
With the reaction conditions for the crotylation established,
the scope of the reaction was examined using various radical
precursors, and these results are presented in Table 3, eq 3.
As can be discerned form the table, primary, secondary,
tertiary, and R-alkoxyalkyl radicals all gave the addition/
trapping product in good yields (entries 1-8). It is interesting
to note that the size of the radical precursor had a large
impact on the diastereoselectivity: the adamantyl (entry 7)
and tert-butyl radicals (entry 8) gave the highest selectivities
of 5.6:1 and 5.4:1, respectively.14
To determine if the method of formation of the radical
intermediate affects the reaction, we have examined the
crotylation of the bromides 21-24 with crotylstannane (Table
4, eq 4). The allylation reactions proceeded with slightly
better efficiency (entries 1-5) than those reported for
reactions with 1. The formation of 3 with comparable
selectivity (3.5:1 vs 2.9:1; compare entry 1, Table 3, and
entry 3, Table 4) from two different radical precursors
suggests that the method of formation may have a small
influence on the stereochemical outcome. Similarly, the
substituent on the radical once again shows an impact on
selectivity.15 Interestingly, increasing bulk near the reaction
center led to nearly equal amounts of diastereomers (entry
4) and temperature had little impact on the levels of
selectivity (compare entry 4 with 5). The low selectivity in
crotylations of 24 is in contrast to the formation of 3 with
moderate selectivity.16
We have recently shown that steric effects play a minor
role in determining the levels of diastereoselectivity in the
Figure 1. Transition states for diastereoselective crotylations.
(14) (a) The size of the exocyclic substituent has been shown to have an
impact on H-atom transfer reactions: Giese, B.; Damm, W.; Witzel, T.;
Zeitz, H.-G. Tetrahedron Lett. 1993, 34, 7053. (b) For effect of radical
size on enantioselective H-atom transfer, see: Sibi, M. P.; Asano, Y.;
Sausker, J. B. Angew. Chem., Int. Ed. 2001, 40, 1293. (c) For steric effects
on enantioselective allylations, see: Wu, J. H.; Zhang, G.; Porter, N. A.
Tetrahedron Lett. 1997, 38, 2067.
anti product has a slightly more severe gauche interaction
between the methylene group of the allyl tin moiety and the
(15) We have recently shown that temperature and precursor stereo-
chemistry impact selectivity in allylation reactions. See: Sibi, M. P.; Rheault,
T. R. J. Am. Chem. Soc. 2000, 122, 8873. For variation in enantioselectivity
with changes in the formation of the radical intermediate, see ref 14c.
(16) Tandem ethyl radical addition-crotylation to the analogue of 1 gave
29 (R ) Et, R1 ) Et) with a similarly low 1.4:1 level of diastereoselectivity.
(17) Sibi, M. P.; Rheault, T. R.; Chandramouli, S. V.; Jasperse, C. P. J.
Am. Chem. Soc. 2002, 124, 2924.
Org. Lett., Vol. 4, No. 20, 2002
3437

R substituent on the radical. This analysis is consistent with
the observed higher selectivity with larger R groups: the
tert-butyl and adamantyl radical additions gave 5.4:1 and
5.6:1 selectivities, respectively (entries 6 and 7, Table 3). In
reaction with 24, severe gauche interactions in both transition
states C or D lead to nearly equal amounts of the syn and
anti products. Thus, a secondary substituent on the radical
gives better selectivity (increasing with the size of R)14c than
a tertiary substituent (R and R1 ) alkyl). At the present, time
we do not have a clear explanation for the selectivity
dependence on the achiral template (contrast entries 1-3 with
4 and 5, Table 2).
diastereoselectivity in the reaction is modest. It is important
to note that the present methodology is a complementary
method to Claisen protocols for the synthesis of γ,δ-
unsaturated carboxylic acid derivatives.20 The extension of
the present methodology to γ-alkoxy stannanes and the
development of procedures for enantiocontrol in the croty-
lation reaction are underway in our laboratory.
Acknowledgment. This work was supported by a grant
from the National Institutes of Health NIGMS-54656. Hideto
Miyabe thanks JSPS for a postdoctoral fellowship.
Supporting Information Available: Characterization
data for compounds 1-28 and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have shown that allylation of electro-
philic radicals with crotylstannane is efficient and the
(18) Eriksson, M.; Hjelmencrantz, A.; Nilsson, M.; Olsson, T. Tetrahe-
dron 1995, 46, 12631.
OL026510A
(19) Both antiperiplanar and synclinal transition states have been proposed
for Lewis acid-catalyzed addition of crotylstannanes to aldehydes. For recent
reviews on this subject, see: (a) Marshall, J. A. Chem. ReV. 1996, 96, 31.
(b) Denmark, S. E.; Almstead, N. A. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Chapter 10, pp 299-
401.
(20) For Claisen rearrangements leading to products with structures
similar to those reported here, see: (a) ref 18. (b) Miller, J. F.; Termin, A.;
Koch, K.; Piscopio, A. D. J. Org. Chem. 1998, 63, 3158. (c) Takai, K.;
Ueda, T.; Kaihara, H.; Sunami, Y.; Moriwake, T. J. Org. Chem. 1996, 61,
8728.
3438
Org. Lett., Vol. 4, No. 20, 2002