Effective acceleration of atom transfer carbonylation of alkyl iodides by metal complexes. Application to the synthesis of the hinokinin precursor and dihydrocapsaicin

Article abstract of DOI:10.1021/ol060123+

Atom transfer carbonylation (ATC) of alkyl iodides leading to carboxylic acid esters is effectively accelerated by Pd(PPh₃)₄ and Mn₂(CO)₁₀ under photoirradiation conditions. In the presence of amines, Pd(0) complexes affected double carbonylations leading to α-keto amides, whereas Mn₂(CO)₁₀ accelerated only a single carbonylation reaction leading to the corresponding amides. The Pd(0)-accelerated ATC system was successfully applied to the synthesis of hinokinin and dihydrocapsaicin.

Full text of DOI:10.1021/ol060123+

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1383-1386
Effective Acceleration of Atom Transfer
Carbonylation of Alkyl Iodides by Metal
Complexes. Application to the Synthesis
of the Hinokinin Precursor and
Dihydrocapsaicin
Takahide Fukuyama, Satoshi Nishitani, Takaya Inouye, Keisuke Morimoto, and
Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received January 16, 2006
ABSTRACT
Atom transfer carbonylation (ATC) of alkyl iodides leading to carboxylic acid esters is effectively accelerated by Pd(PPh3)4 and Mn2(CO)10
under photoirradiation conditions. In the presence of amines, Pd(0) complexes affected double carbonylations leading to -keto amides,
r
whereas Mn2(CO)10 accelerated only a single carbonylation reaction leading to the corresponding amides. The Pd(0)-accelerated ATC system
was successfully applied to the synthesis of hinokinin and dihydrocapsaicin.
The design and implementation of atom transfer radical
carbonylation (ATC) reactions has led to efficient carbon-
ylation approaches to basic carbonyl compounds, such as
aliphatic carboxylic acid esters, amides, and the related
heterocyclic compounds, in which readily available alkyl
iodides and carbon monoxide can be employed as key
substrates (Scheme 1).1,2 Recent applications by the Koba-
yashi group and the Långstro¨m group have expanded this
system to include the synthesis of carboxylic acids3 and a
series of compounds in which radioactive 11CO is incorpo-
rated.4 In terms of the feasibility of the iodine atom transfer
step from alkyl iodides to acyl radicals, atom transfer
carbonylation proceeds more efficiently with secondary and
tertiary alkyl iodides, whereas the reaction is sluggish with
primary alkyl iodides, in which the longer reaction time
required leads to undesirable side reactions such as the
Scheme 1. Original Radical/Ion Hybrid Concept of Atom
Transfer Carbonylation of Alkyl Iodides and the Reactivity Issue
Associated with Primary Alkyl Iodides
(1) Ryu, I. Chem. Soc. ReV. 2001, 30, 16.
(2) (a) Nagahara, K.; Ryu, I.; Minakata, S.; Komatsu, M.; Sonoda, N. J.
Am. Chem. Soc. 1997, 119, 5465. (b) Ryu, I.; Nagahara, K.; Kambe, N.;
Sonoda, N.; Kreimerman, M.; Komatsu, M. Chem. Commun. 1998, 1953.
(c) Kreimerman, S.; Ryu, I.; Minakata, S.; Komatsu, M. Org. Lett. 2000,
2, 389. (d) Kreimerman, S.; Ryu, I.; Minakata, S.; Komatsu, M. C. R. Acad.
Sci. Paris Chim. 2001, 4, 497. (e) Ryu, I. Chem. Rec. 2002, 2, 1691.
(3) Sugiura, M.; Hagio, H.; Kobayashi, S. Chem. Lett. 2003, 898.
(4) (a) Itsenko, O.; Långstro¨m, B. Org. Lett. 2005, 7, 4661. (b) Itsenko,
O.; Kihlberg, B.; Långstro¨m, B. Synlett 2005, 3160.
10.1021/ol060123+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/01/2006

decomposition of alkyl iodides via ionic reactions.5 The
recent success of the cascade carbonylations of 4-alkenyl
iodides,6 which are affected by a Pd/irradiation system, led
us to reexamine some atom transfer carbonylations of
ordinary alkyl iodides leading to esters and amides in the
presence of metal complexes under similar metal/light
combined conditions.7 Herein, we report that the atom
transfer carbonylation of primary, secondary, and tertiary
alkyl iodides leading to the corresponding esters is success-
fully accelerated by metal complexes, such as palladium(0)
phosphine complexes and dimanganese decacarbonyl.
Using three types of primary alkyl iodides 1a-c, we
examined the atom transfer carbonylation under photoirra-
diation conditions (Xenon, Pyrex) in the presence of a
catalytic amount of Pd(PPh3)4. The results are summarized
in Table 1. The findings show that ester formation is
competition by intramolecular SN2 reactions leading to the
corresponding oxetane as a side-reaction product;2c however,
the addition of the Pd catalyst resulted in a very effective
acceleration to give the desired γ-lactone 2c in 83% yield
with the undesirable ionic reaction being negligible (entry
7). The sole formation of the ring-opening product in the
case of 1b can be rationalized by the intervention of a
cyclopropylcarbinyl radical to homoallyl radical ring opening,
which is the fastest class of radical reactions.8
In contrast to primary alkyl iodides, the atom transfer
carbonylation of secondary and tertiary alkyl iodides pro-
ceeds smoothly to give good to high yields of esters under
the original conditions (Xenon, Pyrex, 16 h). To determine
whether Pd(0) exerts an acceleration effect even in secondary
and tertiary substrates, we examined the reaction of 1d and
1e using a shorter reaction time, such as 6.5 h, in which the
reactions are typically incomplete. Again, Pd(0) accelerated
the reaction results for both secondary and tertiary iodides
(entries 9 and 12). Watanabe and co-workers previously
reported that dimanganese decacarbonyl catalyzes the car-
bonylation of alkyl iodides under a variety of conditions
including photoirradiation.7a Consistent with their original
findings, we also found that the presence of dimanganese
decacarbonyl accelerates the atom transfer carbonylation of
secondary and tertiary alkyl iodides in our ATC system
(entries 10 and 13), whereas the acceleration for a primary
alkyl iodide 1a was only modest (entry 3).
Table 1. Acceleration of Atom Transfer Carbonylation of
Primary Alkyl Iodides Leading to Esters and Lactone by Pd(0)
and Mn(0)a
The proposed mechanism for the Pd-accelerated reaction
is outlined in Scheme 2. Thus, at the initial stage, Pd(0) reacts
Scheme 2. Possible Reaction Mechanism
a Conditions: 1 (0.5 mmol); catalyst, Pd(PPh3)4 (5-5.7 mol %) or
Mn2(CO)10 (3-4 mol %); base, NEt3 (1.4-1.7 equiv) plus DMAP (10 mol
%) or K2CO3 (2.0 equiv, entries 1-3); EtOH (5 mL, entries 1-3); benzene
(5 mL, entries 6 and 7); benzene/BuOH (5/0.18 mL, entries 4, 5, 8-13);
CO (45 atm); light (500 W xenon lamp, Pyrex). b Isolated yield by silica
1
gel chromatography. c Cis/trans ratio determined by H NMR.
accelerated in the presence of Pd(0) in all the cases examined
(entries 2, 5, and 7). Thus, 1-iodooctane (1a) was converted
to the corresponding ethyl nonanoate (2a) in 87% yield with
a considerably shortened reaction time (16 h). Cyclopropyl-
carbinyl iodide (1b) gave a ring-opened product, butyl
4-butenoate (2b), in 83% yield. The original atom transfer
carbonylation of 1-hydroxyalkyl iodide 1c suffers from
with RI to generate Pd(I)I and R• via a one-electron transfer.
In the final stage, Pd(I)I couples with acyl radical species to
form an acylpalladium,9 which undergoes alcoholysis to give
the ester and Pd(0). Previous studies reported that Mn2-
(CO)10 and Pd(PPh3)4 can act as an effective radical
initiator, whereas the promotion of the initiation step does
10
11
(5) Kropp, P. J. Acc. Chem. Res. 1984, 17, 131.
(6) Ryu, I.; Kreimerman, S.; Araki, F.; Nishitani, S.; Oderaotoshi, S.;
Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2002, 124, 3812.
(7) For pioneering efforts on metal-catalyzed carbonylation under pho-
toirradiation conditions, see: (a) Kondo, T.; Sone, Y.; Tsuji, Y.; Watanabe,
Y. J. Organomet. Chem. 1994, 473, 163. (b) Ishiyama, T.; Murata, M.;
Suzuki, A.; Miyaura, N. J. Chem. Soc., Chem. Commun. 1995, 295.
(8) Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc. 1991, 113, 5699.
(9) There are many mechanistic possibilities about the role of Pd, which
includes the direct reaction of the acyl radical with the Pd(0) to form
RCOPd(I) species, as one referee suggested.
(10) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123, 9922.
1384
Org. Lett., Vol. 8, No. 7, 2006

not appear to be the only function of the Pd(0) catalyst in
the present carbonylation system. Indeed, when the reaction
was conducted in the presence of amines, the presence of
Pd(0) led to the formation of double carbonylated products
(Scheme 3). Because the carbonylation of an acyl radical is
(p-methoxyphenyl)phosphine gave slightly better results for
the double carbonylation. Some other transition-metal com-
plexes, such as Ru3(CO)12 and Re2(CO)10, were found to
promote double carbonylation, but the extent of the reaction
was inferior to Pd(0). It is noteworthy that the fact that more
single carbonylation products are formed in the cases of
secondary and tertiary alkyl iodides is due to the relatively
facile background atom transfer reaction for these substrates.2
For the purpose of obtaining singly carbonylated amides
selectively, the use of Mn2(CO)10 appears to be promising.
Having an effective method for atom transfer carbonylation
of primary alkyl iodides in hand, we then applied the
established procedure to the synthesis of the (-)-hinokinin
precursor 2h (Scheme 4).14 The chiral iodo alcohol 1h
Scheme 3. Transition-Metal Accelerated Atom Transfer
Carbonylation with Diethylamine
Scheme 4. Synthesis of the (-)-Hinokinin Precursor and
Dihydrocapsaicin Based on Pd-Accelerated Atom Transfer
Carbonylation
required for the carbonylation was prepared on the basis of
Itoh’s method.14a The carbonylation of 1h under irradiation
conditions in the presence of Pd(0) gave the γ-lactone 2h in
74% yield. Coupled with a subsequent enolate alkylation,
the formal synthesis of (-)-hinokinin 5 was achieved.14 We
also successfully carried out the concise synthesis of dihy-
drocapsaicin (6),15 a hot-tasting compound contained in red
pepper. Hexamethyldisilazane (HMDS) was added for the
rarely observed in radical carbonylation reactions,12 the
intervention of an acylcarbamoylpalladium complex as the
precursor to the keto amide is strongly suggested.13 We
examined several ligands for the reaction and found that tri-
(13) (a) Yamamoto, A. Bull. Chem. Soc. Jpn. 1995, 68, 433. (b) Lin,
Y.-S.; Yamamoto, A. Orgametallics 1998, 17, 3466. (c) Yamamoto, A. J.
Chem. Soc., Dalton Trans. 1999, 1027. (d) Ozawa, F.; Yamamoto, A. Chem.
Lett. 1982, 865. (e) Urata, H.; Yoshimitsu, I.; Fuchigami, T. Tetrahedron
Lett. 1989, 30, 4407.
(14) (a) Itoh, T.; Chika, J.; Takagi, Y.; Nishiyama, S. J. Org. Chem.
1993, 58, 5717. (b) Tomioka, K.; Koga, K. Tetrahedron Lett. 1979, 3315.
(c) Bode, J. W.; Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L. J. Org.
Chem. 1996, 61, 9146. (d) Yoda, H.; Naito, S.; Takabe, K.; Tanaka, N.;
Hosoya, K. Tetrahedron Lett. 1990, 31, 7623. (e) Honda, T.; Kimura, N.;
Sato, S.; Kato, D.; Tominaga, H. J. Chem. Soc., Perkin Trans. 1 1994,
1043.
(11) (a) Curran, D. P.; Chang, C.-T. Tetrahedron Lett. 1990, 31, 933 (b)
Qui, Z.-M. Burton, D. J. J. Org. Chem. 1995, 60, 5570. (c) Nagashima, H.;
Isono, Y.; Iwamatsu, S. J. Org. Chem. 2001, 66, 315. (d) Chen, Q. Y.;
Yang, Z. Y.; Zhao, C. X.; Qui, Z.-M. J. Chem. Soc., Perkin Trans. 1 1988,
563.
(12) For reviews, 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. Also, see a review on acyl radicals: (c) Chatgilialoglu, C.;
Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
Org. Lett., Vol. 8, No. 7, 2006
1385

purpose of the in situ silyl protection of the phenol portion,
to prevent the formation of the phenol ester in a competing
reaction. Thus, the carbonylation of 1-iodo-7-methyloctane
(1i) in the presence of p-hydroxy-m-methoxybenzylamine
and HMDS, followed by treatment with TBAF, gave
dihydrocapsaicin (6) in 82% yield.
In summary, the findings herein show that the atom
transfer carbonylation of a variety of alkyl iodides can be
effectively accelerated by the use of Pd(0) phosphine
complexes and dimanganese decacarbonyl. The procedure
involving Pd(0) is particularly useful for the carbonylation
of primary alkyl iodides, the original procedure for which,
using photoirradiation, was particularly sluggish. The pro-
cedure using Pd(0) can be successfully applied to the
synthesis of the (-)-hinokinin precursor and dihydrocapsai-
cin.
Acknowledgment. I.R. acknowledges a Grant-in-Aid for
Scientific Research on Priority Areas (A), “Reaction Control
of Dynamic Complexes” from MEXT, Japan for financial
support.
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.
(15) Gannet, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.; Sharpe, J.;
Toth, B. J. Org. Chem. 1988, 53, 1064.
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