Tin-free giese reaction and the related radical carbonylation using Alkyl iodides and cyanoborohydrides

Article abstract of DOI:10.1021/ol7031043

Tin-free Giese reaction and the related radical carbonylation process proceeded efficiently in the presence of sodium cyanoborohydride and tetrabutylammonium cyanoborohydride. The reaction took place chemoselectively at the carbon-iodine bond but not at the carbon-bromine and carbon-chlorine bonds. The iodine atom transfer followed by hydride reduction of the resulting carbon-iodine bond is proposed as a possible mechanism.

Full text of DOI:10.1021/ol7031043

ORGANIC
LETTERS
2008
Vol. 10, No. 5
1005-1008
Tin-Free Giese Reaction and the Related
Radical Carbonylation Using Alkyl
Iodides and Cyanoborohydrides
Ilhyong Ryu,* Shohei Uehara, Hidefumi Hirao, and Takahide Fukuyama
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received December 26, 2007
ABSTRACT
Tin-free Giese reaction and the related radical carbonylation process proceeded efficiently in the presence of sodium cyanoborohydride and
tetrabutylammonium cyanoborohydride. The reaction took place chemoselectively at the carbon iodine bond but not at the carbon bromine
and carbon chlorine bonds. The iodine atom transfer followed by hydride reduction of the resulting carbon iodine bond is proposed as a
−
−
−
−
possible mechanism.
The carbon-carbon bond-forming reactions by radical ad-
dition have found wide applications in modern organic
synthesis.1 Alkyl radicals, which have a nucleophilic char-
acter, add to electron-deficient alkenes more smoothly than
do ordinary and electron-rich alkenes.2,3 The Giese reaction,
which represents the radical addition of organic halides to
electron-deficient alkenes, utilizes this “nucleophilic” radical
C-C bond-forming process as a key step and typically uses
tributyltin hydride as a radical mediator.4 In an example
shown in eq 1 of Scheme 1, Giese-type addition of
iodocyclohexane to methyl acrylate was successfully achieved
by using a catalytic amount of tributyltin hydride precursor
in the presence of a source of a stoichiometric amount of
Scheme 1. Giese Reaction and the Related Tin-Free Processes
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vols. 1 and 2. (b) Zard, S. Z. Radical
Reactions in Organic Synthesis; Oxford University Press: Oxford, 2003.
(c) Also see a leading review, see: Srikanth, G. S. C.; Castle, S. L.
Tetrahedron 2005, 61, 10377.
(2) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753. (b) Giese,
B. Angew. Chem., Int. Ed. 1985, 24, 553.
hydride under photoirradiation conditions.4 The role of
borohydride reagents here is thought to be the conversion
of tributyltin halides to tributyltin hydride.5 Since photoin-
duced cyclization of ω-iodoalkenes using borohydride re-
agents can work,6,7 we concluded that the system in which
(3) For kinetic work, see: Jent, F.; Paul, H.; Roduner, E.; Heming, M.;
Fischer, H. Int. J. Chem. Kinet. 1986, 18, 1113.
(4) (a) Giese, B.; Gonza´lez-Go´mez, J. A.; Witzel, T. Angew. Chem., Int.
Ed. Engl. 1984, 23, 69. (b) Curran, D. P.; Hadida, S.; Kim, S.-Y.; Luo, Z.
J. Am. Chem. Soc. 1999, 121, 6607.
(5) (a) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303. (b)
Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 2554. (c) Poupon, J.-C.;
Marcoux, D.; Cloarec, J.-M.; Charette, A. B. Org. Lett. 2007, 9, 3591.
10.1021/ol7031043 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/07/2008

tributyltin reagent is simply eliminated from eq 1 should
work, thereby achieving a tin-free Giese reaction (eq 2)8,9
and the related radical carbonylation (eq 3).10,11 In this paper,
we report that a variety of alkyl iodides can undergo a tin-
free Giese reaction and the related radical carbonylation
reaction in the presence of sodium cyanoborohydride or
tetrabutylammonium cyanoborohydride as a hydrogen source.
We examined the reaction of 1-iodooctane (1a) with ethyl
acrylate (2a) as a model reaction under a variety of conditions
(Table 1). When a mixture of 1a, 2a, and NaBH4 in ethanol
product 3a was obtained in only 10% yield, in which simple
reduction of 1a became a predominant reaction course (entry
1). Interestingly, however, the use of NaBH3CN increased
the yield of 3a up to 75%. In this reaction, 1:2 product 4a
was also formed as a byproduct. The thermal reaction
conditions using a radical initiator such as V-65 (2,2′-azobis-
(2,4-dimethylvaleronitrile)) also gave 3a and 4a in 72% and
14% yield, respectively (entry 3). This strongly supported
the hypothesis that a radical chain mechanism is involved
in this reaction. Tetrabutylammonium cyanoborohydride also
gave 3a in comparable yield (entry 4), whereas sodium
triacetoxyborohydride did not give 3a (entry 5). In the latter
case, 1a was recovered almost unchanged. Interestingly, no
reaction took place when the corresponding 1-bromooctane
(1b) and 1-chlorooctane (1c) were used. Thus, in the present
Giese-type process iodoalkanes appear to be crucial.
Table 1. Tin-Free Giese Reaction of 1a with 2aa
yieldb (%)
entry
borohydride
solvent
EtOH
conditions
3a
4a
1
2
3
4
5
NaBH4
hν (Xe, Pyrex)
10
75
72
66
0
0
9
14
16
0
NaBH3CN
NaBH3CN
n-Bu4NBH3CN
NaBH(OAc)3
MeOH hν (Xe, Pyrex)
MeOH V-65c
MeOH hν (Xe, Pyrex)
C6H6
hν (Xe, Pyrex)
Having identified optimal conditions, we then studied the
generality of the tin-free Giese reaction for a variety of alkyl
iodides and electron-deficient alkenes (Table 2). Primary
alkyl iodides 1a, 1f, 1g, and 1h reacted with ethyl acrylate
(2a) to give the corresponding esters in good yields (entries
1, 6, 7, and 8). The reactions of alkyl iodides 1g and 1h
were chemoselective to give the corresponding chlorine- and
bromine-retaining products 3g and 3h, respectively (entries
7 and 8). These products can serve as the second radical
precursors, when the ordinary tin hydride mediated system
is applied. Under similar conditions, secondary and tertiary
iodoalkanes, such as iodocyclohexane (1d) and 1-iodoada-
mantane (1e), reacted with 2a to give the corresponding
addition products 3d and 3e in good yields (entries 4 and
5). The reaction of 1a with methyl crotonate (2b) gave the
corresponding adduct 3b in 67% yield (entry 2), whereas
methyl methacrylate (2c) gave a poor yield of adduct 3c due
to the formation of significant amounts of 1:2 and 1:3
products (entry 3). Using a stainless steel autoclave and CO
pressure conditions, we applied the thermally induced
reaction system using n-Bu4NBH3CN-AIBN (2,2′-azobis-
(isobutyronitrile)) for the carbonylative three-component
coupling reaction (entries 9-11) for which tributyltin hydride
or (TMS)3SiH had to be used in the original procedures.10
Whereas the procedure A with sodium cyanoborohydride can
be applied to the addition of 1a to acrylonitrile (2e) (entry
12), the reaction using ethyl vinyl ketone (2f) suffered from
undesirable reduction courses of 2f.12 Fortunately, this
problem was circumvented by the use of a milder reagent,
n-Bu4NBH3CN, instead of NaBH3CN (entries 13-16).
a Reaction was conducted on a 1 mmol scale with [1a] ) 0.5 M and 2a
(1.5 equiv), borohydride reagent (5.0 equiv). b Isolated yield by flash
chromatography on SiO2. c 2,2′-Azobis(2,4-dimethylvaleronitrile).
was irradiated with a 500 W xenon lamp through a Pyrex
filter (>280 nm) for 3 h under argon, the expected addition
(6) (a) Abe, M.; Hayashikoshi, T.; Kurata, T. Chem. Lett. 1994, 1789.
(b) Kurata, T.; Kinoshita, R. J. Oleo Sci. 2001, 50, 759. (c) Liu, Q.; Han,
B.; Zhang, W.; Yang, L.; Liu, A.-L.; Yu, W. Synlett 2005, 2248.
(7) For nickel-catalyzed addition of iodoalkanes to electron-deficient
alkenes using borhydride exchange resin, see: Sim, T. B.; Choi, J.; Joung,
M. J.; Yoon, N. M. J. Org. Chem. 1997, 62, 2357. Also see an indium(III)
chloride catalyzed system: Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J.
Am. Chem. Soc. 2002, 124, 906.
(8) For different approaches of tin-free reactions using organoboron
compounds, see: (a) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc.
Jpn. 1991, 64, 403. (b) Ollivier, C.; Renaud, P. Chem. Eur. J. 1999, 5,
1468. (c) Ollivier, C.; Renaud, P. Angew. Chem., Int. Ed. 2000, 39, 925.
(d) Yajima, T.; Saito, C.; Nagano, H. Tetrahedron 2005, 61, 10203.
(9) For reviews on tin-free radical reactions, see: (a) Baguley, P. A.;
Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3073.(b) Studer, A. Synthesis
2002, 835. (c) Kim, S.; Kim, S. Bull. Chem. Soc. Jpn. 2007, 80, 809. Also
see some recent work: (d) Smith, D. M.; Pulling, M. E.; Norton, J. R. J.
Am. Chem. Soc. 2007, 129, 770. (e) Guin, J.; Mu¨ck-Lichtenfeld, C.; Grimme,
S.; Studer, A. J. Am. Chem. Soc. 2007, 129, 4498. (f) Carta, P.; Puljic, N.;
Robert, C.; Dhimane, A.-L.; Fensterbank, L.; Lacoˆte, E.; Malacria, M. Org.
Lett. 2007, 9, 1061. (g) Kim, S.; Lim, K.-C.; Kim, S.; Ryu, I. AdV. Synth.
Catal. 2007, 349, 527.
(10) (a) Ryu, I.; Kusano, K.; Yamazaki, H.; Sonoda, N. J. Org. Chem.
1991, 56, 5003.(b) Ryu, I.; Hasegawa, M.; Kurihara, A.; Ogawa, A.; Tsunoi,
S.; Sonoda, N. Synlett 1993, 143. (c) Kishimoto, Y.; Ikariya, T. J. Org.
Chem. 2000, 65, 7656.
(11) For reviews on radical carbonylation, see: (a) Ryu, I.; Sonoda, N.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (b) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. ReV. 1996, 96, 177. (c) Ryu, I. Chem. Soc. ReV. 2001,
30, 16. Also see a review on acyl radicals: (d) Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
1006
Org. Lett., Vol. 10, No. 5, 2008

(Scheme 2). The result can be rationally explained by the
formation of cyclopropylcarbinyl radical A and its rapid ring-
Table 2. Tin-Free Giese Reaction and Radical Carbonylationa
Scheme 2. Tandem Radical Processes Leading to 3q
opening to give homoallyl radical B,13 which then undergoes
addition to 2a. The resulting radical C would undergo 5-exo
Scheme 3. Radical/Ionic Hydrid Reaction Mechanism
a Procedure A: [1] ) 0.5 M, 2 (1.5-2.0 equiv), NaBH3CN (4.9-5.4
equiv), MeOH, 3 h, light (500 W xenon lamp, Pyrex). Procedure B: [1] )
0.017 M, 2 (2-4 equiv), n-Bu4NBH3CN (5-5.6 equiv), AIBN (10 mol
%), benzene (MeOH for entry 9), CO (90 atm), 10-19 h, 80 °C. Procedure
C: [1] ) 0.5 M, 2 (3.0 equiv), n-Bu4NBH3CN (3 equiv), MeOH, 6 h, light
(500 W xenon lamp, Pyrex). b Isolated yield by flash chromatography on
SiO2. c Products containing two and three molecules of 2c were also formed.
d Acrylonitrile (3 equiv), 20 h, (3 h, 57% yield).
cyclization to give D, which would add to a second molecule
of 2a to give E, a precursor radical for 3q.
To gain insight into the mechanism of the final hydrogen-
delivering process, we conducted a deuterium-labeling
We then examined a radical cascade sequence using
cyclopropylmethyl iodide (1k) as the substrate (eq 4). When
the reaction of 1k with 2a was carried out, 3q, originating
from one molecule of 1k and two molecules of 2a was
formed as the major product (66% yield, cis/trans ) 67/33)
(12) We checked the background reaction by treating octyl vinyl ketone
(2g) with 1 equiv of NaBH3CN in MeOH at rt for 6 h, which gave a mixture
of 1-undecen-3-ol (17%), 3-undecanone (31%), and 3-undecanol (5%).
(13) (a) Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc. 1991, 113, 5699.
(b) Newcomb, M. Tetrahedron 1993, 49, 1151.
Org. Lett., Vol. 10, No. 5, 2008
1007

experiment. When we used NaBD3CN, 87% of deuterium
incorporation at the carbon R to carbonyl group was observed
(eq 5). This result led us to postulate a radical/ionic hybrid
reaction mechanism, in which R-iodo ester forms via iodine
atom transfer from alkyl iodide to the Giese adduct radical
(Scheme 3).14 This is an reversible process; however, the
subsequent facile hydride reduction at iodine R to a carbonyl
shifts the reaction to give the final adduct.15 Thus, borohy-
dride reagents likely act as a hydride source in the final step
but not as a hydrogen source.16 The failure of bromides and
chlorides may be due to the less capable atom transfer ability
in the energetically unfavorable atom transfer step.
In summary, we have demonstrated that the Giese reaction
using alkyl iodides as starting materials and cyanoborohy-
drides as reducing reagents proceeds without the use of tin
hydride or its precursors. The process can be applied to
carbonylative three-component coupling and tandem radical
reactions. We are now applying the present radical/ionic
reaction concept to some other radical reactions.
Acknowledgment. I.R. acknowledges a Grant-in-Aid for
Scientific Research on Priority Areas “Advanced Molecular
Tansformation of Carbon Resources” from MEXT Japan and
Scientific Research (B) from JSPS.
(14) For radical/ionic hybrid mechanism in other radical reactions
involving atom transfer radical addition, see: (a) Curran, D. P.; Ko, S. B.
Tetrahedron Lett. 1998, 39, 6629. (b) Joung, M. J.; Ahn, J. H.; Lee, D. W.;
Yoon, N. M. J. Org. Chem. 1998, 63, 2755. (c) ref. 11c
(15) In a separate experiment, ethyl R-iodododecanoate was reduced very
Supporting Information Available: Experimental pro-
cedures and characterization of all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
smoothly with NaBH3CN/MeOH at rt (98%, 30 min).
(16) We have not precluded fully an alternative SRN1 mechanism that
involves direct hydrogen abstraction of the R-keto radical from BH3CN-.
Cf. Kropp, M.; Schuster, G. B. Tetrahedron Lett. 1987, 28, 5295. Also see
ref 5c.
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