Black-light-induced radical/ionic hydroxymethylation of alkyl iodides with atmospheric co in the presence of tetrabutylammonium borohydride

Article abstract of DOI:10.1021/ol1002847

(Figure Presented) Tin-free radical/ionic hydroxymethylation of secondary and tertiary alkyl iodides proceeded efficiently in the presence of tetrabutylammonium borohydride as the hydrogen source under atmospheric pressure of CO In conjunction with photoirradiation using black light. Two possible mechanisms were proposed, both of which involve hybrid radical/ionic processes.

Full text of DOI:10.1021/ol1002847

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1548-1551
Black-Light-Induced Radical/Ionic
Hydroxymethylation of Alkyl Iodides
with Atmospheric CO in the Presence of
Tetrabutylammonium Borohydride
Shoji Kobayashi, Takuji Kawamoto, Shohei Uehara, Takahide Fukuyama, and
Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received February 3, 2010
ABSTRACT
Tin-free radical/ionic hydroxymethylation of secondary and tertiary alkyl iodides proceeded efficiently in the presence of tetrabutylammonium
borohydride as the hydrogen source under atmospheric pressure of CO in conjunction with photoirradiation using black light. Two possible
mechanisms were proposed, both of which involve hybrid radical/ionic processes.
CO is among the most prominent sources of C1 in organic
synthesis. A number of valuable transformations utilizing
CO have been investigated thus far, irrespective of the
reactive species.1,2 One-carbon homologation generating
alcohol derivatives is an important class of synthetic trans-
formations,3 and the use of CO for such processes is highly
desirable. The related hydroxymethylation reaction process
using organohalides was achieved by methodologies based
on radical carbonylation and in situ reduction. In these
processes, a combination of group 14 metal hydrides and
cyanoborohydride reagents was used (Scheme 1, eq 1).4
Scheme 1. Hydroxymethylation of RX
(1) For reviews on radical carbonylations and acyl radicals, 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) Chatgilialoglu,
C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991. (d)
Schiesser, C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc. Chem. Res. 2007,
40, 303
.
(2) For reviews on metal-catalyzed carbonylation processes, see: (a)
Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation, Direct
Synthesis of Carbonyl Compounds; Plenum Press: New York, 1991. (b)
Tsuji, J. Palladium Reagents and Catalysis: InnoVation in Organic Synthesis;
John Wiley & Sons: Chichester, U. K., 1995. (c) Beller, M.; Cornils, B.;
Frohning, C. D.; Kohlpaintner, C. W. J. Mol. Catal. A 1995, 104, 17. (d)
In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., de Meijere, A., Eds.; Wiley: New York, 2002; Vol. 2, p 2309. (e) In
Modern Carbonylation Method; Kolla´r, L., Ed.; Wiley-VCH: Weinheim,
2008. (e) Fukuyama, T.; Ryu, I. Carbon Monoxide. In e-eros, Encyclopedia
Recently, we reported that the Giese reaction and the
related radical carbonylation reaction proceeded in the
presence of cyanoborohydrides under tin-free conditions.5
(4) For hydroxymethylation with triphenylgermane-NaBH3CN system,
see: (a) Gupta, V.; Kahne, D. Tetrahedron Lett. 1993, 34, 591. For
hydroxymethylation with a fluorous tin hydride-NaBH3CN system, see: (b)
Ryu, I.; Niguma, T.; Minakata, S.; Komatsu, M.; Hadida, S.; Curran, D. P.
Tetrahedron Lett. 1997, 38, 7883. (c) Matsubara, H.; Yasuda, S.; Sugiyama,
H.; Ryu, I.; Fujii, Y.; Kita, K. Tetrahedron 2002, 58, 4071.
of Reagents for Organic Synthesis; John Wiley & Sons, online source
(3) For a recent example, see: Taber, D. F.; Paquette, C. M.; Reddy,
.
P. G. Tetrahedron Lett. 2009, 50, 2462.
10.1021/ol1002847  2010 American Chemical Society
Published on Web 03/03/2010

The reaction is thought to involve iodine atom transfer from
alkyl iodides to Giese adduct radicals followed by hydride
reduction of the resulting carbon-iodine bond by cy-
anoborohydride. These results led us to consider that
hydroxymethylation would also be possible without the aid
of organotin reagents (Scheme 1, eq 2). Herein, we report
that tertiary and secondary alkyl iodides can efficiently
undergo a tin-free radical/ionic hydroxymethylation in the
presence of tetrabutylammonium borohydride (n-Bu4NBH4)
as a hydrogen donor. It is important to note that in many
cases carbonylation proceeded under atmospheric pressure
of CO. This method is simple and less toxic compared to
the traditional conditions.
n-Bu4NBH3CN proved to be optimal in the tin-free Giese
reactions;5 therefore, we initially examined the reaction of
1-iodoadamantane (1a) and CO (82 atm) in the presence of
n-Bu4NBH3CN (3 equiv) under thermal initiation conditions
using AIBN as the radical initiator (eq 3). The excepted
hydroxymethylation product 2a was obtained in 48% yield
along with 1-adamantane carboxaldehyde (5%) and, unex-
pectedly, its cyanohydrin (25%). It is noteworthy that the
direct reduction product, adamantane (3a), was obtained in
less than 1% yield and that the expected course of the
reaction progressed even with a high concentration of the
substrate (0.5 M). Another advantage is that this reaction
does not require a very efficient hydrogen source, such as
tin hydride. Hydrogen abstraction by alkyl radicals com-
monly competes with CO trapping, and high dilution
conditions are typically required to make the relative
concentrations of CO to tin hydride high.4,6 It is reasonable
to assume that 2a forms by reduction of the initially formed
1-adamantane carboxaldehyde. On the other hand, the
unexpected cyanohydrin was thought to form as a result of
transfer of the cyano group from the borohydride reagent.7
Table 1. Hydroxymethylation of 1-Iodoadamantane (1a) with
n-Bu4NBH4
yield (%)a
entry
CO (atm)
solvent
conditions
2a
3a
1b
2
3
4
5
85
20
10
5
1
1
1
1
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
A
A
A
A
A
B
B
B
B
88
79
76
73
27
78
74
74
64
1
2
4
8
33
8
16
14
12
6c, d
7d
8
9d e
CH3CN
,
a For 2a, isolated yield after column chromatography on SiO2. For 3a,
yield was determined by GC analysis using n-nonane as an internal standard.
b 3 equiv of n-Bu4NBH4 was used. c 500 W xenon lamp was used for
irradiation. d The reaction was performed at a concentration of 0.25 M 1a.
e NaBH4 (1.1 equiv) was used instead of n-Bu4NBH4.
reduction product, adamantane (3a), was detected by GC.
This suggests that the carbonylation step by adamantyl rad-
ical was not hampered by the presence of n-Bu4NBH4.
Neither aldehyde nor cyanohydrin was detected under the
reaction conditions. Acetonitrile was found to be superior
to hexane (50% yield), benzene (83% yield), toluene (72%
yield), THF (78% yield), tetrahydropyran (73% yield), and
EtOH (21% yield).
We next sought to determine whether the present hy-
droxymethylation would proceed under very low CO pres-
sures. This may be possible because for this reaction an
efficient hydrogen source (such as n-Bu3SnH) is not present
to quench alkyl radicals. In order to investigate this,
1-iodoadamantane (1a) was exposed to tin-free thermal
radical conditions with n-Bu4NBH4 under low CO pressures
(entries 2-5). Results indicated that hydroxymethylation
product 2a was obtained in 73% yield even under 5 atm of
CO (entry 4).
Interestingly, when the reaction was performed using a
CO balloon (1 atm), 2a was still formed, albeit in low yield
(entry 5). In this case, the yield of the reduction product 3a
increased up to 33% yield. This insufficient yield of 2a was
not improved by decreasing the concentration of the substrate
or by lowering the reaction temperature to 40 °C with V-70
as the radical initiator.8 At 1 atm of CO, a simple reduction
course plagued the carbonylation. However, notable im-
provement was achieved by using photoirradiation conditions
in place of thermal radical initiation. When a solution of 1a
and n-Bu4NBH4 in CH3CN was irradiated with a 500 W
xenon lamp through a Pyrex filter (>280 nm) for 3 h under
In an effort to improve the yield of the hydroxymethylation
product, screening of borohydride reagents was undertaken.
Reductants such as NaBH4, NaBH(OAc)3, or BH3·NMe3 gave
poor results, whereas application of n-Bu4NBH4 provided
the hydroxymethylation product 2a in 88% yield (Table 1,
entry 1). It should be noted that less than 2% yield of the
(5) Ryu, I.; Uehara, S.; Hirao, H.; Fukuyama, T. Org. Lett. 2008, 10,
1005
.
(6) (a) Ryu, I.; Kusano, K.; Ogawa, A.; Kambe, M.; Sonoda, N. J. Am.
Chem. Soc. 1990, 112, 1295. (b) Ryu, I.; Hasegawa, M.; Kurihara, A.;
Ogawa, A.; Tsunoi, S.; Sonoda, N. Synlett 1993, 143
.
(7) Although a mechanism to produce cyanohydrin is unclear at this
stage, either of the following pathways may be involved: addition of cyanide
ion to an intermediate aldehyde or direct cyanation of the acyl radical to
produce acylcyanide followed by hydride reduction. Further investigation
to obtain the cyanohydrin product as a major component is currently
underway in our laboratory.
(8) (a) Kita, Y.; Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.;
Matsugi, M. Tetrahedron Lett. 1997, 38, 3549. (b) Kita, Y.; Gotanda, K.;
Sano, A.; Oka, M.; Murata, K.; Suemura, M.; Matsugi, M. Tetrahedron
Lett. 1997, 38, 8345.
Org. Lett., Vol. 12, No. 7, 2010
1549

Table 2. Radical/Ionic Hydroxymethylation of a Variety of Alkyl Iodides
a Conditions A: [1] ) 0.5 M, CO (80-85 atm), AIBN (20 mol %), n-Bu4NBH4 (3 equiv), 80 °C, 3 h. Conditions B: [1] ) 0.5 M, CO (1 atm), n-Bu4NBH4
(1.2 equiv), black light, 25 °C, 3 h. b Isolated yield after column chromatography on SiO2. c Reaction time was 6 h. d 44% of n-octane was detected by GC.
e Performed in benzene/CH3CN (2:1) for 17 h with 0.17 M 1g. f AIBN (30 mol %), n-Bu4NBH4 (1.2 equiv), 5 h. g 75% of n-decane was detected by GC.
a CO atmosphere, 2a was obtained in 78% yield (entry 6).
A similar result was obtained when a more energy-saving
15 W black light (peak wavelength 352 nm) was used (entry
7). The reaction was also effected in DMF (entry 8). To the
best of our knowledge, this is the first example of a highly
efficient radical carbonylation under atmospheric pressure
of CO.
After identifying the optimal conditions, we next explored
the generality of the tin-free radical hydroxymethylation by
varying the alkyl iodides (Table 2). Among the substrates
tested, tertiary iodides gave the best results (entries 1, 2, 4,
and 5). This may be due to the facility of the iodine atom
transfer step to cause the generation of the stable tertiary
radical. In contrast, alkyl bromide was insusceptible to these
conditions (entry 3). When the reactions were carried out
with secondary iodides, yields were varied according to the
structure of the substrate (entries 6-13). Photoirradiated
hydroxymethylation of 2-iodoadamantane (1c) and 2-iodo-
norbornane (1d) at atmospheric CO afforded alcohols 2c and
2d in 64% and 70% yield, respectively (entries 7 and 8).
On the other hand, simpler secondary iodides such as
1-iodocyclohexane (1e) and 2-iodooctane (1f) resulted in a
lower yield, in which the reduction course preceded (entries
9 and 10).
These results suggested that the steric factor played a
crucial role in efficient hydroxymethylation; the major side
reaction was an SN2-type hydride reduction by n-Bu4NBH4,
which was suppressed by increasing the bulkiness around
the reaction center. It is important to note that functionalized
iodides such as cholesteryl iodide 1g and iodolactone (()-
1h underwent hydroxymethylation to give alcohols 2g and
(()-2h, the latter of which is a key synthetic intermediate
of the polyketide natural product (entries 11 and 12).9 We
found that primary iodides were not suited for hydroxy-
methylation, due to competition by hydride reduction (entry
14).
Thus, we have succeeded in efficient hydroxymethylation
of tertiary and secondary iodides without the use of group
14 radical mediators. It seems unusual that a significant
(9) Recently we completed the total synthesis of the polyketide natural
product from (()-2h. This report is being prepared.
1550
Org. Lett., Vol. 12, No. 7, 2010

amount of reduction product was formed in the reaction of
a bulky tertiary iodide, such as 1a, in the absence of a
powerful hydrogen donor such as n-Bu3SnH (see Table 1).
1a can not undergo direct reduction through an ionic SN2
process; therefore, the adamantyl radical arising from 1a
directly abstracted a hydrogen from borohydride and certain
electron transfer processes were thought to propagate the
radical chain. In an effort to gain further insight, we
performed some control experiments without CO. When a
mixture of 3,5-dimethyl-1-iodoadamantane (1b), AIBN, and
n-Bu4NBH4 in CH3CN was refluxed for 3 h without shading,
the corresponding reduction product 3b was obtained in 53%
yield along with 25% recovery of 1b (eq 4). On the other
hand, the reaction in the absence of AIBN under dark
conditions afforded a trace amount of 3b (4%) and the
starting iodide 1b was recovered (85%) (eq 4). Similarly,
3b was obtained in 35% yield together with 51% recovery
of 1b upon exposure of 1b to black light in the presence of
n-Bu4NBH4 for 3 h at room temperature. These results
indicated that radical processes were involved in the reduc-
tion of 1b and n-Bu4NBH4 served as the hydrogen source.
Scheme 3
.
Alternative Radical Chain Mechanism Involving
Electron Transfer
-
abstract hydrogens from borohydride (BH4 ) to form alde-
hydes and generates the borane radical anions (BH3• -). While
aldehydes undergo hydride reduction by borohydride anions
• -
to give alcohols, the generated borane radical anions (BH3
)
react with alkyl iodides (R-I) through electron transfer to
give radical anions ([R-I]• -) that fragment to alkyl radicals
(R•) and iodide ions (I-), thus completing a radical chain.
The reduction product formed at low CO pressure gives
strong indication that this mechanism is feasible.
In conclusion, we have developed a novel hydroxymethyl-
ation reaction using CO and borohydride reagents without
the use of toxic radical mediators such as trialkyltin hydrides
or its precursors.15 The reaction can be applied to tertiary
and secondary iodides. Furthermore, a combined system
involving atmospheric pressure of CO and black light
irradiation was successfully employed. We have proposed a
mechanism in which the borohydride reagents work both as
a hydrogen source and a hydride source, and therefore act
as a radical mediator.16 The reaction conditions are simple
and mild. Therefore, this reaction represents a useful method
for introducing the hydroxymethyl unit into organic mol-
ecules.
Taking the above results into consideration, two possible
reaction mechanisms are conceivable for the present tin-free
hydroxymethylation reaction. The first mechanism involves
iodine atom transfer from alkyl iodides to acyl radicals
followed by hydride reduction of the resulting acyl iodide
(Scheme 2).10-12
Scheme 2. Atom-Transfer-Based Radical Chain Mechanism
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from MEXT and JSPS, Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The second mechanism shown in Scheme 3 involves an
electron transfer mediated by borohydride reagent13 (SRN
1
mechanism14). Thermal initiation or photoirradiation of alkyl
iodides generates the initiating alkyl radicals (R•), which react
with CO to form acyl radicals (RCO•). The acyl radicals
OL1002847
(13) A single electron transfer from borane radical anions to aryl halides
has been proposed: (a) Barltrop, J. A.; Bradbury, D. J. Am. Chem. Soc.
1973, 95, 5085. (b) Kropp, M.; Schuster, G. B. Tetrahedron Lett. 1987,
28, 5295. (c) Liu, Q.; Han, B.; Zhang, W.; Yang, L.; Liu, Z.; Yu, W. Synlett
2005, 2248.
(10) For atom transfer carbonylation, see: (a) Ryu, I. Chem. Soc. ReV.
2001, 30, 16. Also see: (b) Nagahara, K.; Ryu, I.; Komatsu, M.; Sonoda,
N. J. Am. Chem. Soc. 1997, 119, 5465. (c) Ryu, I.; Nagahara, K.; Kambe,
N.; Sonoda, N.; Kreimerman, S.; Komatsu, M. Chem. Commun. 1998, 1953.
(d) Kreimerman, S.; Ryu, I.; Minakata, M.; Komatsu, M. Org. Lett. 2000,
2, 389. (e) Kreimerman, S.; Ryu, I.; Minakata, S.; Komatsu, M. C. R. Acad.
(14) Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413.
(15) For a review on TEMPO-mediated tin-free radical chemistry, see:
Vogler, T.; Studer, A. Synthesis 2008, 1979.
Sci., Paris, Chim. 2001, 4, 497
(11) For theoretical work, see: Matsubara, H.; Ryu, I.; Schiesser, C. H.
Org. Biomol. Chem. 2007, 5, 3320
.
(16) For examples of radical hydrogen abstraction from borane based
reagents, see: (a) Ueng, S.-H.; Solovyev, A.; Yuan, X.; Geib, S. J.;
Fensterbank, L.; Lacote, E.; Malacria, M.; Newcomb, M.; Walton, J. C.;
Curran, D. P. J. Am. Chem. Soc. 2009, 131, 11256. (b) Barton, D. H. R.;
Jacob, M. Tetrahedron Lett. 1998, 39, 1331. (c) Baban, J. A.; Roberts, B. P.
J. Chem. Soc., Perkin Trans. 2 1998, 1195.
.
(12) For Pd-boosted atom transfer carbonylations, see: (a) Fukuyama,
T.; Nishitani, S.; Inouye, T.; Morimoto, K.; Ryu, I. Org. Lett. 2006, 8,
1383. (b) Ryu, I.; Kreimerman, S.; Araki, F.; Nishitani, S.; Oderaotoshi,
Y.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2002, 124, 3812
.
Org. Lett., Vol. 12, No. 7, 2010
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