Intermolecular nonreductive alkylation of enamides via radical-polar crossover

Article abstract of DOI:10.1021/ol8028077

A carbon-carbon bond construction method is disclosed which involves radical addition of α-haloesters or iodoacetonitrile to enamides. Despite the presence of tri-n-butylstannane, nonreductive addition was predominant; H-atom transfer from tin hydride was

Full text of DOI:10.1021/ol8028077

ORGANIC
LETTERS
2009
Vol. 11, No. 4
819-822
Intermolecular Nonreductive Alkylation
of Enamides via Radical-Polar
Crossover
Gregory K. Friestad* and Yaoping Wu
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
gregory-friestad@uiowa.edu
Received December 4, 2008
ABSTRACT
A carbon-carbon bond construction method is disclosed which involves radical addition of r-haloesters or iodoacetonitrile to enamides.
Despite the presence of tri-n-butylstannane, nonreductive addition was predominant; H-atom transfer from tin hydride was not observed.
Rapid iodine atom transfer to (or electron transfer from) the radical adduct, resulting in an iminium ion intermediate and radical chain propagation,
is consistent with the observed reactivity.
Carbon-carbon bond constructions via free radical addition
reactions offer practical advantages in chemoselectivity
which complement ionic methods1 and are amenable to
development of tandem processes involving multiple bond-
forming events.2 Developments in the application of radical
additions to synthesis of chiral amines have been progressing
over the past few years, mainly through radical additions to
the carbon of imino compounds.3 An alternative approach
could entail addition to enamines or enamides, such that the
resulting R-amino- or R-amidoalkyl radical could be trapped
to generate a chiral R-branched amine.4 This process would
generate two C-C bonds and a stereocenter (Figure 1), and
more substituted cases with two or more stereocenters could
also be easily envisioned with appropriate substitution of the
enamine, R1, and R3. Proper matching of the electronic
properties of the coupling components would be required,
such that addition of R1 to the enamine would occur, rather
than direct reaction of R1 with R3 or polymerization.5
Figure 1. Hypothesized tandem C-C bond construction approach
to chiral tert-alkylamines. The open circle of °R3 denotes radical
acceptor behavior.
Examples of intermolecular radical additions to enamines
and enamides are known,6 but with the exception of
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley-
VCH: New York, 2001. (b) Zimmerman, J.; Sibi, M. P. In Topics in Current
Chemistry: Radicals in Synthesis I; Gansauer, A., Ed.; Springer: Berlin,
2006; Vol. 263, pp 107-162.
(5) Giese, B.; He, J.; Mehl, W. Chem. Ber. 1988, 121, 2063–2066.
(6) (a) Renaud, P.; Schubert, S. Synlett 1990, 624–626. (b) Russell, G. A.;
Kulkarni, S. V.; Khannat, R. K. J. Org. Chem. 1990, 55, 1080–1086. (c)
Russell, G. A.; Wang, K. J. Org. Chem. 1991, 56, 3475–3479. (d) Renaud,
P.; Carrupt, P.; Schenk, K.; Schubert, S. Synlett 1992, 211–213. (e) Renaud,
P.; Schubert, S.; Carrupt, P.; Schenk, K. HelV. Chim. Acta 1993, 76, 2473–
2489. (f) Curran, D. P.; Eichenberger, E.; Collis, M.; Roepel, M. G.; Thoma,
G. J. Am. Chem. Soc. 1994, 116, 4279–4288. (g) Chuang, C.-P.; Wu, Y.-L.
Tetrahedron 2004, 60, 1841–1847. (h) Tsai, A.-I.; Chuang, C.-P. Tetrahe-
dron 2006, 62, 2235–2239. (i) Aurrecoechea, J. M.; Coy, C. A.; Patin˜o,
O. J. J. Org. Chem. 2008, 73, 5194–5197.
(2) Reviews: (a) McCarroll, A. J.; Walton, J. C. Angew. Chem., Int.
Ed. 2001, 40, 2225–2248. (b) Albert, M.; Fensterbank, L.; Lacote, E.;
Malacria, M. In Topics in Current Chemistry: Radicals in Synthesis II;
Gansauer, A., Ed.; Springer: Berlin, 2006; Vol. 264, pp 1-62. Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134–7186.
(3) Reviews: Friestad, G. K. Eur. J. Org. Chem. 2005, 315, 7–3172.
Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140–1157. Friestad, G. K.
Tetrahedron 2001, 57, 5461–5496.
(4) Renaud, P.; Giraud, L. Synthesis 1996, 913–926.
10.1021/ol8028077 CCC: $40.75
Published on Web 01/21/2009
2009 American Chemical Society

numerous additions to dehydroalanine and related amino
acids,7 these reactions have rarely been applied in general
synthetic methods. Two instructive precedents illustrate the
potential for generating nitrogen-bearing stereocenters in the
course of C-C bond construction (Figure 2). Renaud and
Schubert examined the stereocontrol in additions of sulfo-
nylmethyl radical to chiral enamines followed by H-atom
transfer (Figure 2a)6a and Curran et al. reported addition of
methylmalononitrile radical to N-vinylpyrrolidinone (Figure
2b) as part of a broader study of phenylselenenyl group
transfer additions to electron-rich alkene acceptors.6f
Table 1. Initial Results for Radical Addition of Ethyl
Iodoacetate to Vinyloxazolidinones
entry alkene method base (equiv) iodide, equiv yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
A
A
B
B
B
B
B
B
none
none
none
NEt3 (1)
4 (1)
NEt3 (0.5)
NEt3 (0.5)
NEt3 (0.5)
NEt3 (0.5)
NEt3 (0.5)
NEt3 (0.5)
3
3
3
3
3
3
10
1.3
0b
31
45
69
69
76
63
57
36
0
Bc
Bd
Be
3
3
3
10
11
6
a Conditions: (method A) Et3B, CH2Cl2, -78 °C, slow addition of O2
over 5 h then warm to rt; (method B) slow addition of AIBN and Bu3SnH
over 10 h, PhH, reflux. b Cyclized product 2 (48% yield) was obtained.
c Portionwise addition of AIBN and Bu3SnH. d Bu3SnH and AIBN omitted.
e Galvinoxyl was added (1 equiv).
Figure 2. Instructive precedents: (a) addition to enamine followed
by H-atom transfer;6a (b) addition to enamide followed by SePh
group transfer.6f
In the initial reactions, addition to 1a with triethylborane
as the initiator was accompanied by a substitution of the
aromatic ring in the pendant benzyl group, leading to the
cyclized product 2 as a single diastereomer (Table 1, entry
1). This cyclization was not observed with the phenylox-
azolidinone 1b;10 instead this reaction gave nonreductive
addition product 3b in modest yield (entry 2). This dif-
ferential reactivity for 5- versus 6-membered ring formation
may be mechanistically relevant (vide infra).
Despite these precedents, our experiments directed toward
the tandem C-C bond construction concept outlined in Figure
1 took a rather different course, leading to the discovery of an
efficient nonreductive coupling of R-haloesters and enamides.
The net result is reminiscent of the Heck reaction, essentially
accomplishing a substitution of an alkenyl hydrogen of enam-
ides by an organic halide. Here we report discovery and
development of conditions to accomplish this interesting
transformation, along with some mechanistic control experi-
ments and a preliminary evaluation of the scope.
In considering potential substrates for an experimental test
of Figure 1, we noted a considerable body of evidence
regarding reactivity, conformation, and stereocontrol of
alkenyl oxazolidinones,8 as well as their ease of prepara-
tion.9,10 Mindful of the electronic character of these enam-
ides, for initial screening we selected the addition of the
moderately electron-deficient radical derived from ethyl
R-iodoacetate to N-vinyl-4-benzyloxazolidinone 1a.10
We next examined the typical reductive addition conditions
using tri-n-butylstannane (Bu3SnH). With 0.5 equiv of
azobisisobutyronitrile (AIBN) and 2 equiv of Bu3SnH as the
initiating system, the addition of ethyl iodoacetate to 1a gave
3a, the product of nonreductive addition (Table 1, entry 3);
the yield diminished to 26% using 1.2 equiv of Bu3SnH.
The modest yields appeared to be a consequence of hydroly-
(7) For examples, see: Crich, D.; Davies, J. W. Tetrahedron 1989, 45,
5641–5654. Beckwith, A. L. J. J. Chem. Soc., Chem. Commun. 1990, 1087–
1088. Chai, C. L. L.; King, A. R. Tetrahedron Lett. 1995, 36, 4295–4298.
Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron: Asymmetry
2002, 13, 503–510. Miyabe, H.; Asada, R.; Takemoto, Y. Tetrahedron 2005,
61, 385–393.
(8) For examples, see: Epoxidation: (a) Adam, W.; Bosio, S. G.; Wolff,
B. T. Org. Lett. 2003, 5, 819–822. Hetero-Diels-Alder: (b) Dhal, R.;
Dujardin, G. Org. Lett. 2007, 9, 211–214. Hydrogenation: (c) Reetz, M. T.;
Mehler, G.; Meiswinkel, A.; Sell, T Tetrahedron Lett. 2002, 43, 7941–
7943. Oxidative cleavage: (d) Sivaguru, J.; Solomon, M. R.; Turro, N. J
Tetrahedron 2006, 62, 6707–6717[2 + 2]-Cycloaddition: (e) Hegedus, L. S.;
Bates, R. W.; Soderberg, B. C. J. Am. Chem. Soc. 1991, 113, 923–927.
Cyclopropanation: (f) Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.;
Ko, C.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 4069–4072.
(9) (a) Jiang, L.; Job, G. E.; Klapers, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667–3669. (b) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am.
Chem. Soc. 2003, 125, 12996–12997. (c) Brice, J. L.; Meerdink, J. E.; Stahl,
S. S. Org. Lett. 2004, 6, 1845–1848. (d) Pan, X.; Cai, Q.; Ma, D. Org.
Lett. 2004, 6, 1809–1812.
(10) (a) Gaulon, C.; Gizecki, P.; Dhal, R.; Dujardin, G. Synlett 2002,
952–956. (b) Gaulon, C.; Dhal, R.; Dujardin, G. Synthesis 2003, 2269–
2272.
820
Org. Lett., Vol. 11, No. 4, 2009

transfer. Common intermediate 6 can explain the formation
of both 2 and 3a: Intramolecular Friedel-Crafts reaction at
the ortho position of the benzyl group of 6 would provide
2,12,14 and simple proton loss from 6 would afford 3a. The
differential reactivity of 1a and 1b (Table 1, entries 1 and
2) with respect to cyclization is consistent with precedent
regarding iminium ions similar to 6, produced by another
means.14a This offers further support for the proposed
Friedel-Crafts cyclization mode. Thus, the radical addition
is followed by one of two polar reactions in a radical-polar
crossover tandem process15 which offers considerable po-
tential for broadening the scope of the C-C bond construc-
tions outlined here. In particular, formation of 2 accomplishes
the general transformation hypothesized in Figure 1, albeit
in an unexpected way. Other nucleophilic partners might be
expected to serve the role of R3 in Figure 1, and the fact
that 2 forms as a single diastereomer is noteworthy in this
broader synthetic context.
Expanding the scope of the nonreductive addition reaction
was our next objective. For this purpose, various oxazoli-
dinones 1a-d9,10 were subjected to the reaction with ethyl
iodoacetate under the optimized conditions, and yields of
3a-d ranged from 68 to 76% (Table 2, entries 1-4). In
nearly the same yields, iodoacetonitrile was also effective
in the coupling to furnish nitriles 3e and 3f (entries 5 and
6).
Scheme 1
sis,11 which suggested that an improved result might be
obtained by buffering the reaction mixture with a basic
additive. Indeed, a significant improvement, up to 76% yield,
was observed in the presence of amine bases (triethylamine
and proton sponge (4), entries 3-6). Larger or smaller
excesses of iodide led to no improvement (entries 7 and 8),
and slow addition of AIBN and Bu3SnH afforded superior
results (compare entries 6 and 9).
The wider availability of bromides could be advantageous
to the scope of the reaction, prompting experiments to test
whether R-bromoesters could be incorporated, but ethyl
bromoacetate gave no reaction (Table 2, entry 7). Fortunately,
however, the reaction accommodated the presence of tet-
rabutylammonium iodide, which conferred the desired re-
activity upon ethyl bromoacetate (entry 8), presumably by
in situ conversion of the bromide to iodide. A variety of
R-bromo esters was then employed in the reaction, affording
the nonreductive addition products 3a and 3g-j in good yield
for primary and secondary halides (entries 9-12). A
decreased yield of 3k was observed with a tertiary bromide
(entry 13); this is unsurprising since the added iodide ion
In all these reactions, there was no detected formation of
the saturated adduct analogous to 3a, predicted by the
hypothesis in Figure 1 via H-atom abstraction from Bu3SnH
according to the precedent of Figure 2a. While this was
unexpected, nonreductive addition to an enamide in the
presence of Bu3SnH has previously been observed in a
radical cyclization.12
Control experiments examined whether a nonradical
pathway could be involved. There was no reaction in the
absence of AIBN and Bu3SnH (entry 10) nor in the presence
of AIBN and Bu3SnH at ambient temperature. The presence
of galvinoxyl suppressed the reaction; at 0.2 equiv of
galvinoxyl, the yield was diminished to 40% (not shown),
and at stoichioimetric quantities, galvinoxyl largely sup-
pressed the reaction (entry 11).
The formation of the nonreductive addition product 3a,
together with the control experiments and observation of
cyclized product 2, suggests the mechanism proposed in
Scheme 1. The addition of ethoxycarbonylmethyl radical to
1a would afford R-amido radical 5, which would then react
with ethyl iodoacetate, either by iodine atom transfer13 or
by single electron transfer.6b,c,12 Each of these alternatives
would ultimately provide iminium ion 6 while propagating
a radical chain. The absence of the saturated product of
H-atom transfer from Bu3SnH to 5 indicates this reduction
is slow relative to either the iodine atom transfer or electron
(14) Closely related cyclizations have been observed previously, using
a different method to access the iminium ion: (a) Mecozzi, T.; Petrini, M.;
Profeta, R Tetrahedron: Asymmetry 2003, 14, 1171–1178. (b) Formation
of 2 via radical cyclization of 5 followed by oxidative rearomatization by
O2 (method A) has not been ruled out. Cyclization to 2 was not observed
with method B. (c) For a related discussion, see: Curran, D. P.; Keller,
A. I. J. Am. Chem. Soc. 2006, 128, 13706–13707. Beckwith, A. L. J.; Bowry,
V. W.; Bowman, W. R.; Mann, E.; Parr, J.; Storey, J. M. D. Angew Chem.,
Int. Ed. 2004, 43, 95–98. (d) The possibility of AIBN as the oxidant of
radical 5 was suggested by a reviewer and has not been rigorously excluded.
However, this would be inconsistent with precedent (see ref 14c) as our
optimal conditions use low concentrations of AIBN (0.5 equiv, syringe pump
addition).
(15) For other types of radical-polar crossover reactions, see: Callaghan,
O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A J. Chem. Soc., Perkin
Trans. 1 1999, 99, 5–1001. Jahn, U.; Muller, M.; Aussieker, S. J. Am. Chem.
Soc. 2000, 122, 5212–5213. Harrowven, D. C.; Lucas, M. C.; Howes, P. D.
Tetrahedron 2001, 57, 791–804. Rivkin, A.; Nagashima, T.; Curran, D. P.
Org. Lett. 2003, 5, 419–422. Denes, F.; Chemla, F.; Normant, J. F. Angew.
Chem., Int. Ed. 2003, 42, 4043–4046. Bazin, S.; Feray, L.; Vanthuyne, N.;
Bertrand, M. P. Tetrahedron 2005, 61, 4261–4274. Ueda, M.; Miyabe, H.;
Sugino, H.; Miyata, O.; Naito, T. Angew. Chem., Int. Ed. 2005, 44, 6190–
6193. Denes, F.; Cutri, S.; Perez-Luna, A.; Chemla, F. Chem.sEur. J. 2006,
12, 6506–6513. Maruyama, T.; Suga, S.; Yoshida, J. Tetrahedron 2006,
62, 6519–6525. Maruyama, T.; Mizuno, Y.; Shimizu, I.; Suga, S. J. Am.
Chem. Soc. 2007, 129, 1902–1903.
(11) Loss of the N-vinyl group from 3a was observed, along with
1
byproducts which exhibited aldehyde signals in the H NMR.
(12) Guerrero, M. A.; Miranda, L. Tetrahedron 2003, 59, 4953–4958.
(13) (a) Curran, D. P.; Chen, M. H.; Kim, D. J. Am. Chem. Soc. 1989,
111, 6265–6276. (b) Thoma, G.; Curran, D. P.; Geib, S. V.; Giese, B.;
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Org. Lett., Vol. 11, No. 4, 2009
821

Scheme 2
Table 2. Addition to Various N-Vinyloxazolidinonesa
aldehyde enolate.17 This C-C bond construction reaction
appears to involve a radical-polar crossover from R-ami-
doalkyl radicals to N-acyliminium ions en route to the
enamide products. Advantageous synthetic utility of the
R-amidoalkyl radical and/or the N-acyliminium ion inter-
mediate for further bond constructions may be
envisioned.4,13c,18
b
a Conditions: see Table 1, method B. In some cases, i-Pr2NEt was
substituted for Et3N. b NBu4I (1 equiv) was added.
may be ineffective with tertiary bromides, and the less
electron-deficient tertiary radical may have a poorer
SOMO-HOMO match with the enamide acceptor.
Finally, the substitution pattern of the alkene was varied
(Scheme 2). Commercially available N-vinylformamide (1e)
proved to be a very effective acceptor, furnishing 82% yield
of adduct 3l as a mixture of E and Z isomers (E/Z ) 1:1.4).
The 2-propenyl acceptor 1f16 led to adduct 3m in 50% yield,
whereas the (Z)-2-butenyl acceptor 1g16 gave a lower yield
of 3n (34%) as a mixture of alkene regioisomers. When
adduct 3a (from Table 1) was resubjected to the addition
conditions, a second ethoxycarbonylmethyl group was added,
leading to 3o, albeit in only 30% yield. Thus, substitution at
the R-carbon of the vinyl group was tolerated, but ꢀ-substitu-
tion diminished the yield.
Acknowledgment. We thank the University of Iowa and
the NSF (CHE-0749850) for support of this work.
Supporting Information Available: Preparative details
and characterization data for 2 and 3a-o. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8028077
(17) The results disclosed herein appear to be mechanistically congruent
with a remarkable asymmetric alkylation of aldehydes via radical addition
to transient chiral enamines, reported in September 2008 during preparation
of this manuscript. (a) Nicewicz, D. A.; MacMillan, D. W. C Science 2008,
322, 77–80. (b) A related radical R-oxidation has also been reported: Sibi,
M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124–4125.
In conclusion, an unusual nonreductive coupling of ena-
mides with R-haloesters and iodoacetonitrile is disclosed, a
transformation of synthetic equivalence to alkylation of
(18) For examples of the synthetic utility of R-amidoalkyl radicals, see:
Aurrecoechea, J. M.; Suerro, R.; de Torres, E. J. Org. Chem. 2006, 71,
8767–8778. Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Am. Chem. Soc.
2005, 127, 11610–11611. Khim, S.-K.; Schultz, A. G. J. Org. Chem. 2004,
69, 7734–7736. Quirante, J.; Vila, X.; Escolano, C. J. Org. Chem. 2002,
67, 2323–2328. (b) For synthetic utility of N-acyliminimum ions see:
(16) Copper-mediated coupling of vinyl halides afforded access to the
enamides 1f and 1g. See ref 9d.
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856.
822
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