Stereoselective synthesis of trisubstituted E-iodoalkenes by indium-catalyzed syn-addition of 1,3-dicarbonyi compounds to 1-iodoaikynes

Article abstract of DOI:10.1021/ol800105r

Indium-catalyzed addition of 1,3-dlcarbonyl compounds to 1-lodo-1-alkynes takes place exclusively In a syn-fashlon to produce E-iodoalkenes. The iodine atom serves both as an activating group and as a group that controls the regloselectlvlty of the addition. The E-alkenyl iodide product can be further derivatized using either a one-pot or a two-pot procedure Into trisubstituted olefins In high overall yield with retention of the stereochemistry.

Full text of DOI:10.1021/ol800105r

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1219-1221
Stereoselective Synthesis of
Trisubstituted E-Iodoalkenes by
Indium-Catalyzed syn-Addition of
1,3-Dicarbonyl Compounds to
1-Iodoalkynes
Hayato Tsuji, Taisuke Fujimoto, Kohei Endo,† Masaharu Nakamura,‡ and
Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received January 16, 2008
ABSTRACT
Indium-catalyzed addition of 1,3-dicarbonyl compounds to 1-iodo-1-alkynes takes place exclusively in a syn-fashion to produce E-iodoalkenes.
The iodine atom serves both as an activating group and as a group that controls the regioselectivity of the addition. The E-alkenyl iodide
product can be further derivatized using either a one-pot or a two-pot procedure into trisubstituted olefins in high overall yield with retention
of the stereochemistry.
Addition of a metal enolate to an unactivated olefin1 and an
unactivated acetylene2,3 is an emerging class of reactions in
metal enolate chemistry. We previously developed an in-
dium-catalyzed addition reaction for a variety of 1,3-
dicarbonyl compounds to alkynes2 that results in alkenylation
of the carbonyl compounds at the 2-position. The reaction,
however, tolerates the use of only 1-alkynes (and 1-silyl-1-
alkyne) but not internal alkynes, and hence the reaction is
useful only for the synthesis of 1,1-disubstituted alkenes.
During our attempt to expand the scope of the reaction, we
found that an iodine atom assists the addition reaction, and
thus the reaction with 1-iodoalkyne produces, in high yield
and with 100% regio- and stereoselectivity, the expected
substituted iodoalkenes (eq 1), from which the synthesis of
trisubstituted olefins4-8 has been achieved readily through
conversion of the iodine atom to an organic group.
† Present address: Department of Chemistry and Biochemistry School
of Advanced Science and Engineering, Waseda University, Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan.
‡ Present address: International Research Center for Elements Science
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011,
Japan.
(1) (a) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. Engl. 1997,
36, 2491-2493. (b) Nakamura, M.; Hatakeyama, T.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 11820-11825. (c) Lorthiois, E.; Marek, I.; Normant,
J. F. J. Org. Chem. 1998, 63, 566-574. (d) Rodriguez, A. L.; Bunlaksana-
nusorn, T.; Knochel, P. Org. Lett. 2000, 2, 3285-3287. (e) Pei, T.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290-11291. (f) Yao,
X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884-6885.
(2) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002-13003. (b) Nakamura, M.; Endo, K.; Nakamura, E. Org. Lett.
2005, 7, 3279-3281. (c) Nakamura, M.; Endo, K.; Nakamura, E. AdV. Synth.
Catal. 2005, 347, 1681-1686. (d) Endo, K.; Hatakeyama, T.; Nakamura,
M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264-5271. (e) Tsuji, H.;
Yamagata, K.-i.; Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura, E. Angew.
Chem., Int. Ed. 2007, 46, 8060-8062.
(3) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 4526-4527. (b) Staben, S. T.; Kennedy-Smith, J. J.; Huang,
D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed.
2006, 45, 5991-5994. (c) Ochida, A.; Ito, H.; Sawamura, M. J. Am. Chem.
Soc. 2006, 128, 16486-16487. (d) Kuninobu, Y.; Kawata, A.; Takai, K.
Org. Lett. 2005, 7, 4823-4825. (e) Corkey, B. K.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 17168-17169. (f) Gao, Q.; Zheng, B.-F.; Li, J.-H.;
Yang, D. Org. Lett. 2005, 7, 2185-2188.
(4) Horner-Wadsworth-Emmons-type reactions: (a) Boutagy, J.; Tho-
mas, R. Chem. ReV. 1974, 74, 87-99. (b) Tago, K.; Kogen, H. J. Syn.
Org. Chem. Jpn. 2001, 59, 971-984.
10.1021/ol800105r CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/27/2008

1, we consider that the observed regioselectivity indicates
that the intermediate of the reaction is an indium carbenoid
species.
The structure of the product was unambiguously deter-
mined by X-ray crystallographic analysis of the product
obtained from ethyl 2-oxocyclopentanecarboxylate and 1-iodo-
2-phenylacetylene (which appears in Table 1, entry 8) as
The use of 1-haloalkyne as an acceptor for the addition
of a metal enolate was a priori not a rational synthetic
strategy for several reasons. For instance, the use of a halogen
atom for activation of a π-conjugated system is unprec-
edented, and the possible intermediate of the reaction would
be an indium carbenoid (Scheme 1) that may be too unstable
Table 1. Examples of 1,3-Dicarbonyl Compounds Used in
Eq 2
substrate
entry
R1
R2
R3
time (h)
yield (%)
1
2
Me
Me
Ph
Me
Me
Me
Me
Ph
F
OEt
OAllyl
OEt
OMe
OEt
OEt
OEt
OEt
OBn
Me
4
4
92
89
93
0
3
60
24
24
16
48
6
Scheme 1. Proposed syn-Addition and Formation of an
E-Product
4
t-Bu
5
Me
0
6
Me
93
81
90
94
89
7
EtO
Me
8
-(CH2)3-
-(CH2)3-
-(CH2)3-
9
6
24
10
shown in Figure 1: the configuration of the compound is E.
We assume that other reactions shown in Table 1 took place
in the same manner.
to exist. Nonetheless, we tried the reaction for 1-chloro-,
1-bromo-, and 1-iodo-2-phenylacetylenes. Thus, ethyl 2-
methylacetoacetate (1) and 1.5 equiv of (haloethynyl)benzene
(2a-c) were allowed to react in the presence of 5 mol % of
In(NTf2)3 in toluene at 50 °C for 12 h, and we obtained the
expected haloalkenes 3a-c as a single isomer in all cases.
The yield increased in the order of the chloro, bromo, and
iodo group, and the iodoacetylene gave the desired product
in the best yield of 92%. It was essential to use a powerful
catalyst In(NTf2)3 instead of In(OTf)3 to obtain a synthetically
significant yield.2c,e The reaction was entirely regioselective
and E-stereoselective. When we used ethyl acetoacetate in
place of 1, we obtained an intractable product mixture. On
the basis of the mechanistic hypothesis illustrated in Scheme
Figure 1. ORTEP drawing (50% probability for thermal ellipsoid).
Hydrogen atoms are omitted for clarity.
The E configuration and the regioselectivity of the product
is consistent with the cyclic transition state shown in Scheme
1, which is based on the one proposed previously for
1-alkyne on the basis of calculations.2d In this transition state,
the indium and the iodine atoms are attached to the same
atom, and the latter is considered to exert special stabilization
effects. The difference among 2a, 2b, and 2c suggests that
the iodine atom has a particularly favorable effect on the
addition reaction.
A variety of 1,3-dicarbonyl compounds reacted smoothly
with (iodoethynyl)benzene (2c) at 70 °C, and the results are
summarized in Table 1 (eq 2, R4 ) Ph).9 All of the addition
reactions in this study afforded a single stereo- and regio-
isomer.
(5) Transition-metal-catalyzed cross-coupling reactions: (a) Tamao, K.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, p 435, and references therein. (b)
Knight, D. W. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 481. (c) Sonogashira, K.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 3, p 521. (d) Tonogaki, K.; Soga, K.;
Itami, K.; Yoshida, J.-i. Synlett 2005, 11, 1802-1804, and references cited
therein.
(6) Hydrometalation- and carbometalation-type addition reactions to
alkynes: (a) Normant, J. F.; Bourgain, M. Tetrahedron Lett. 1971, 12,
2583-2586. (b) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978,
100, 2252-2254. (c) Knochel, P. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p
865. (d) Marfat, A.; McGuirk, P. R.; Helquist, P. J. Org. Chem. 1979, 44,
3888-3901. (e) Qian, M.; Huang, Z.; Negishi, E. Org. Lett. 2004, 6, 1531-
1534. (f) Pommier, A.; Stepanenko, V.; Jarowicki, K.; Kocienski, P. J. J.
Org. Chem. 2003, 68, 4008-4013. (g) Konno, T.; Daitoh, T.; Noiri, A.;
Chae, J.; Ishihara, T.; Yamanaka, H. Org. Lett. 2004, 6, 933-936. (h)
Nishihara, Y.; Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue, E.;
Tanemura, K.; Takagi, K. J. Am. Chem. Soc. 2007, 129, 12634-12635.
(7) For reviews of platform synthesis of multisubstituted alkenes: (a)
Itami, K.; Yoshida, J.-i. Bull. Chem. Soc. Jpn. 2006, 79, 811-824. (b) Itami,
K.; Yoshida, J.-i. Chem.-Eur. J. 2006, 12, 3966-3974.
(8) Heck-type reactions: (a) Biffis, A.; Zecca, M.; Basato, M. J. Mol.
Catal. A: Chem. 2001, 173, 249-274. (b) Knowles, J. P.; Whiting, A.
Org. Biomol. Chem. 2007, 5, 31-44. (c) Beletskaya, I. P.; Cheprakov, A.
V. Chem. ReV. 2000, 100, 3009-3066.
The reaction of 2-methyl-3-oxobutanoic acid ethyl and
allyl esters was complete in 4 h and afforded the desired
1220
Org. Lett., Vol. 10, No. 6, 2008

product in 92 and 89% yield, respectively (entries 1 and 2).
When the R1 group was a phenyl group, the reaction slowed
down but still afforded the product in good yield (93%, entry
3). However, the reaction did not take place at all when R1
was a tert-butyl group (entry 4). The R2 group at the
2-position also exerts a large effect. When R2 was a phenyl
group, the reaction did not take place at all (entry 5). We
consider that the phenyl group inhibited the reaction by its
steric bulk. A 2-fluoroester was less reactive than 1, but still
afforded the product in 93% yield (entry 6). A cyclic
ketoester also took part in the reaction and afforded the
expected adduct in 90% yield (entry 8). Diethyl methyl-
malonate and a cyclic diketone were found to be quite
reactive toward the iodoacetylene and gave the expected
products in high yields (entries 7 and 10). They were less
reactive than the corresponding ketoester counterparts (entry
1, 92% after 4 h, vs entry 7, 81% after 48 h; entry 8, 90%
after 6 h, vs entry 10, 89% after 24 h).
substituted iodoacetylene afforded the product in high yield
as a 1:1.5 diastereomeric mixture (entry 4). The diastereo-
isomerism is due to the central chirality at the 2-position of
the 1,3-dicarbonyl group and the axial chirality between the
naphthyl and the iodovinyl moieties. An aliphatic alkyne
afforded the desired product in moderate yield (48%, entry 5).
Finally, we describe the transformation of the addition
product into trisubstituted olefins. As illustrated in eq 3, the
alkenyl iodide 3c was quantitatively and stereospecifically
coupled with phenylacetylene under the Sonogashira condi-
tions to give the conjugated enyne. Similarly, the Suzuki
coupling with phenylboronic acid stereospecifically afforded
the diphenyl-substituted alkenes in excellent yield (eq 4).
Equation 5 illustrates a one-pot coupling of 1,3-dicarbonyl
compound 1, iodoacetylene, and phenylboronic acid, which
took place in 91% overall yield. Thus, the seemingly
problematic presence of the indium catalyst in the second
palladium-catalyzed step did not pose any serious problems.
We next examined the scope of the iodoalkynes using
â-ketoester 1 (Table 2). Electron-rich iodoalkynes are
Table 2. Examples of Iodoalkynes R4-CtC-Ia
In conclusion, we have found that 1-iodo-1-alkynes serve
as useful acceptors in the catalytic addition of the indium
enolate of 1,3-dicarbonyl compounds. The role of the iodine
atom in this reaction is intriguing in several respects. The
observed regioselectivity implies the involvement of a rather
stable transient indium carbenoid and also suggests that this
stability is responsible for the regioselectivity observed in
this reaction. The reaction can be viewed as an electrophilic
addition of an indium enolate to the acetylene2d rather than
a nucleophilic addition that is the standard reactivity of metal
enolates, and it is in this context that the iodine group
activates the alkyne and controls the regioselectivity. The
expected synthetic utilities of the products are no less
interesting than the mechanism and will be the subject of
further studies.
a All reactions were carried out using the same reaction conditions shown
in eq 2 except for the reaction temperatures for some reactions. b Ca. 1:1.5
mixture of diastereomer was obtained.
somewhat thermally labile but quite reactive under the
present reaction conditions. Thus, the reaction of the ketoester
1 with p-(iodoethynyl)anisole was complete in 1.5 h at 70
°C and afforded the product in 89% yield (entry 1). In
contrast, electron-deficient alkynes are thermally stable but
less reactive. The reaction at higher temperature and for a
longer time, however, afforded the product in excellent yield
(entries 2 and 3). This reactivity profile agrees more closely
with the lower reactivity of 2a and 2b than with 2c (eq 1),
suggesting that the reaction is an electrophilic addition
reaction. Interestingly, the reaction of the naphthalene-
Acknowledgment. This research was supported by
KAKENHI provided by MEXT/JSPS (to E.N., Grant No.
18105004) and the Global COE Program for Chemistry
Innovation (to H.T. and T.F.).
(9) Caution: Haloalkynes are unstable under light, particularly at high
temperature and therefore the reaction vessel must be protected from ambient
light. A Typical Procedure: (E)-Ethyl 2-ethanoyl-4-iodo-2-methyl-3-
phenylbut-3-enoate (3c). A mixture of ethyl 2-methylacetoacetate (288 mg,
2.00 mmol), (iodoethynyl)benzene (684 mg, 3.00 mmol), and In(NTf2)3
(95.5 mg, 0.100 mmol) in toluene (2.0 mL) was heated in the dark at 70
°C for 4 h. The mixture was filtered through a pad of silica gel and
concentrated. The crude product was purified by silica gel column
chromatography (hexane/ethyl acetate ) 95/5) to obtain the title compound
as a yellow oil (655 mg, 88%). The yields on 100 mg runs averaged close
to 92%.
Supporting Information Available: Experimental details
and CIF file of the compound shown in Figure 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800105R
Org. Lett., Vol. 10, No. 6, 2008
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