Diastereoselective production of homoallylic alcohols bearing quaternary centers from γ-substituted allylic indiums and ketones

Article abstract of DOI:10.1021/jo701899j

(Chemical Equation Presented) Highly stereoselective In-employed addition of γ-substituted allylic halides (cyclohexenyl halides, cinnamyl halides, and ethyl 4-bromocrotonate) to ketones is established to produce homoallyl alcohols bearing quaternary cent

Full text of DOI:10.1021/jo701899j

need for the prior preparation of allylic metal reagents before
their reactions with ketones.
Diastereoselective Production of Homoallylic
Alcohols Bearing Quaternary Centers from
γ-Substituted Allylic Indiums and Ketones
In recent years, the In-mediated allylations5a of carbonyl
compounds have attracted many synthetic chemists5 because
this protocol has the advantage that the direct use of In and
allylic halides in the allylations of carbonyl compounds is highly
possible, thereby skipping the prior preparation of allylic
indiums. The utility of unsubstituted allyl halides was well-
studied even in aqueous conditions,5-7 but the employment of
γ-substituted allylic halides is often limited to reactions with
aldehydes.5-7 Hence, it remains a challenging task that the direct
stereoselective addition of γ-substituted allylic halides to simple
ketones needs to be established.
Srinivasarao Arulananda Babu, Makoto Yasuda, and
Akio Baba*
Department of Applied Chemistry, Graduate School of
Engineering, Osaka UniVersity, 2-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
In recent years, we have been involved on the establishment
of metal-employed diastereoselective reactions of simple
ketones.3a,8a-d Thus, herein we report an efficient stereo- and
regio-controlled production of homoallyl alcohols bearing
quaternary centers from the direct reaction of the γ-substituted
allylic halides, ketones, and In, in which plausibly, a highly
reactive RIn(I) species is generated and the addition of water
crucially controls the outcome of the stereoselection.
ReceiVed August 29, 2007
Reactions with Cyclohexenyl Halides. Primarily, the opti-
mization of the In-mediated direct reactions of cyclohexenyl
halides and 4-chloroacetophenone (1a) was carried out. Smooth
Highly stereoselective In-employed addition of γ-substituted
allylic halides (cyclohexenyl halides, cinnamyl halides, and
ethyl 4-bromocrotonate) to ketones is established to produce
homoallyl alcohols bearing quaternary centers. The reactivity
patterns and relative stability of allylic indiums were studied.
The addition of water characteristically affected the reactions.
Cyclohexenyl indium addition was completely disturbed, but
a clear reaction was observed in the cinnamyl and crotonate-
indium addition. In the case of ethyl 4-bromocrotonate, an
interesting conversion of a γ-adduct into an R-adduct was
observed in anhydrous conditions.
(3) For stereoselective additions to simple ketones, see: (a) Using tin-
based reagents see: Yasuda, M.; Hirata, K.; Nishino, M.; Yamamoto, A.;
Baba, A. J. Am. Chem. Soc. 2002, 124, 13442 and see references cited
therein. (b) For a zinc version (allylic zincs were prepared from Zn (5 equiv),
LiCl (1.2 equiv), and allyl halides (1 equiv)) see: Ren, H.; Dunet, G.; Mayer,
P.; Knochel, P. J. Am. Chem. Soc. 2007, 129, 5376. (c) In another Zn
version, using a pre-prepared dry Zn, a mixture of both γ-adduct and
R-adduct with a moderate to very good selectivity was observed for
aldehydes and ketones, and the stereochemistry assignment of the γ-adducts
was not established due to their decomposition. And only a pre-prepared
Zn-Cu couple under acidic condition afforded the R-adducts, see: Rice,
L. E.; Boston, M. C.; Finklea, H. O.; Suder, B. J.; Frazier, J. O.; Hudlicky,
T. J. Org. Chem. 1984, 49, 1845. (d) A cinnamyl Grignard reagent with
acetophenone gave a modest selectivity (ds 70:30), see ref 3a. (e) Tietze,
L F.; Kinzel, T.; Schmatz, S. J. Am. Chem. Soc. 2006, 128, 11483. (f) Wada,
R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
8910. (g) Wadamoto, M.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127,
14556.
(4) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (b)
Yasuda, M.; Kitahara, N.; Fujibayashi, T.; Baba, A. Chem. Lett. 1998, 743.
(c) Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999, 1, 1061.
(5) (a) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
(b) Peppe, C. Curr. Org. Synth. 2004, 1, 227. (c) Araki, S.; Hirashita, T.
Main Group Met. Org. Synth. 2004, 1, 323. (d) Frost, C. G.; Hartley, J. P.
Mini-ReV. Org. Chem. 2004, 1, 1. (e) Nair, V.; Ros, S.; Jayan, C. N.; Pillai,
B. S. Tetrahedron 2004, 60, 1959. (f) Podlech, J.; Maier, T. C. Synthesis
2003, 633. (g) Marshall, J. A. In Lewis Acids in Organic Synthesis;
Yamamoto, H., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1, p
453. (h) Ranu, B C. Eur. J. Org. Chem. 2000, 2347. (i) Babu, G.; Perumal,
P. T. Aldrichim. Acta 2000, 33, 16. (j) Cintas, P. Synlett 1995, 1087. (k)
Loh, T.-P. Sci. Synth. 2004, 7, 413.
(6) For some innovative reports on In-mediated diastereoselective
allylations with unsubstituted allyl halides, see: (a) Lobben, P. C.; Paquette,
L. A. J. Org. Chem. 1998, 63, 6990. (b) Paquette, L. A.; Bennett, G. D.;
Isaac, M. B.; Chhatriwala, A. J. Org. Chem. 1998, 63, 1836. (c) Paquette,
L. A.; Lobben, P. C. J. Org. Chem. 1998, 63, 5604. (d) Paquette, L. A.;
Rothhaar, R. R. J. Org. Chem. 1999, 64, 217.
(7) (a) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149. (b) Li, C. J.;
Chan, T. H. Tetrahedron Lett. 1991, 32, 7017. (c) Chan, T. H.; Li, C.-J.;
Lee, M. C.; Wei, Z. Y. Can. J. Chem. 1994, 72, 1181. (d) Chan, T. H.;
Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228. (e) Miao, W.; Chung, L. W.;
Wu, Y.-D.; Chan, T. H. J. Am. Chem. Soc. 2004, 126, 13326. (f) Tan, K.-
T.; Chng, S.-S.; Cheng, H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125,
2958. (g) Isomers and their ratio could not be precisely determined.
The C-C bond-forming reactions between carbonyl com-
pounds and allylic metals are one of the outstanding processes.1,2
In this line, the diastereoselective addition of the γ-substituted
allylic metals to aldehydes has been extensively studied. The
addition with ketones is a promising protocol for the stereose-
lective construction of quaternary centers; however, there exist
only a few exceptional methods in this regard.1-3 This is perhaps
because of (a) the lower reactivity of ketones than aldehydes4
and (b) smaller difference in steric demand between two
substituents on the carbonyl carbon of ketones than that of
aldehydes. We have reported the highly diastereoselective
additions of the γ-substituted allylic tin(II) species generated
in situ with simple ketones.3a Recently, during the course of
our investigations, the preparation of γ-substituted allylic zinc
as well as its reaction with ketone appeared.3b Notably, in these
versatile methods (e.g., tin,3a zinc,3b,c and Grignard3d) there is a
(1) (a) ComprehensiVe Organic Syntheses; Trost, B. M., Ed.; Pergamon
Press: Oxford, U.K., 1991; Vol. 2. (b) ComprehensiVe Organic Syntheses;
Trost, B. M., Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 1. (c)
Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (d) Denmark S. E.;
Fu, J. Chem. ReV. 2003, 103, 2763. (e) Hall, D. G. Synlett 2007, 1644.
(2) (a) Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Chapter 10. (b)
Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Chapter 11.
10.1021/jo701899j CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/29/2007
10264
J. Org. Chem. 2007, 72, 10264-10267

TABLE 1. Stereoselective Addition of 2a,b with Ketonesa
SCHEME 1. Plausible Transition States
TABLE 2. Optimization of Cinnamyl Halides with 1aa
2c/
time/
h
entry mmol
solvent (mL)
THF (2)
DMF (2)
THF (5)-H2O (10) 39 (2:98)
THF (10)-H2O (5) 50 (2:98)
THF (5)-H2O (10) 95 (2:98)
4a; yield/% (ds syn:anti)
1
2
3
4
5
2
2
1
2
3
5
12
24
24
24
37 (mixture of isomers)b
68 (mixture of isomers)b
a Ketone 1a (1 mol) was used. b A complex mixture was formed and
the ratio could not be precisely determined including 5a.
TABLE 3. Stereoselective Addition of 2c,d,e to Ketonesa
a In (1.2 mmol), ketone 1 (1 mmol) and halide 2a (2-2.5 mmol) or 2b
(1.7 mmol) were used. b Single isomer was obtained.
reactions in THF or DMF furnished the syn isomer 3a with a
quaternary center (yield 99% and ds >95, entries 1 and 2, Table
1). The reactions in (presence of) water strongly disturbed the
formation of the product 3a (entries 3 and 4). The reactions of
analogous ketones 1b-e with cyclohexenyl bromide (2a) were
also afforded the respective syn isomers 3b-e (entries 6-9).
Employing the cyclohexenyl chloride (2b) also afforded the syn
isomer 3a in a moderate yield (entry 5).
Next, the treatment of 2-methoxyacetophenone (1f) with 2a
gave the anti isomer 3f (95%) in THF (entry 10). Similarly,
2-methoxyacetone (1g) and 2-hydroxyacetone (1h) were af-
forded the anti isomers 3g and 3h bearing a quaternary center
(entries 11 and 12). The reaction of 2b with 1h was also afforded
the anti isomer 3h (93%, entry 13). Benzoin methyl ether (1i)
also smoothly afforded the single product 3i (90%, syn-anti ds
>98, entry 15) with three contiguous stereogenic centers. The
stereochemistries of the syn isomers 3a-e could be proposed
via the chair-type TS involving a Z-allylic In (model A, Scheme
1). The stereochemistries of the anti isomers 3f-h and the syn-
anti isomer 3i8b,e could be proposed via a chelation-type TS9
(model B). The presence of water apparently suppressed the
allylations (entries 3, 4, and 14). An exceptional formation of
the product 3i in a longer reaction period was plausibly due to
the strong acceleration by the chelation and electron-withdraw-
ing effect of OMe moiety (entry 16).
a All the reactions were carried out with ln (1.2 mmol), ketone (1 mmol),
and 2c/2d/2e (2-2.5 mmol) at rt. 2e E/Z ratio 85:15.
Reactions with Cinnamyl Halides (E-geometry). In contrast
to the cyclohexenyl halides (Z-geometry), the addition of water
was required for the clear reaction of cinnamyl halides (2c,d)
with ketones. The reactions in dry THF or DMF gave only a
complicated mixture with low selectivity (entries 1 and 2, Table
2). Other solvents such as 1,4-dioxane, MeCN, toluene, DCM,
MeOH, and water were ineffective (<5-10% yields). Fortu-
nately, the combination of THF and water was found to promote
the selective formation of the anti isomer 4a bearing a
quaternary center (39% ds >98:2, entry 3). A further optimized
condition gave the desired product 4a with high diastereose-
lectivity, in which an excess of allylic species 2c was required
(95% yield and ds 98:2, entry 5).
Next, the scope of these aquatic reactions was tested with
various simple ketones and hydroxy/alkoxy ketones, using 2c,d
(Table 3). Aryl alkyl ketones such as 1b,j afforded the anti
stereoisomers 4b,c in very good yields (entries 1 and 2).
However, the aromatic ketone 1d having an electron-donating
group (OMe) failed to furnish the product perhaps due to a low
electrophilicity (entry 3).
(8) For our aimed studies on the stereoselective metal-employed additions
to ketones, see: (a) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. J. Org.
Chem. 2005, 70, 10408. (b) Babu, S. A.; Yasuda, M.; Okabe, Y.; Shibata,
I.; Baba, A. Org. Lett. 2006, 8, 3029 and references cited therein. (c) Yasuda,
M.; Okamoto, K.; Sako, T.; Baba, A. Chem. Commun. 2001, 157. (d) Babu,
S. A.; Yasuda, M.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4475. (e) The
stereochemistry of the product 3i was unambiguously established from X-ray
analysis. (f) During our comprehensive investigations on the In-based stereo-
selective additions of the substituted allylic halides to simple ketones and
alkoxy/hydroxy ketones, recently, a partial report with few examples limited
to benzoin and cinnamyl bromide appeared; Kumar, S.; Kaur, P.; Mittal, A.;
Singh, P. Tetrahedron 2006, 62, 4018. (g) The stereochemistries of 6e (syn
isomer) and 6g (syn-syn isomer, from benzoinmethyl ether 1i) were unam-
biguously determined from the X-ray structure analyses. For an analogue
compound obtained from the reaction of benzoin and cinnamyl bromide
(E-geometry), a syn-anti stereochemistry was proposed, see ref 8f.
2-Methoxy and 2-hydroxy ketones (1f-h,k) were reacted with
cinnamyl bromide (2c) and chloride (2d) to furnish the
(9) (a) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. (b) Sato, K.; Kira,
M.; Sakurai, H. J. Am. Chem. Soc. 1989, 111, 6429.
J. Org. Chem, Vol. 72, No. 26, 2007 10265

TABLE 4. Optimization of the Reaction of 1a with 2fa
TABLE 5. Stereoselective Syntheses of r/γ-Adducts from 2fa,c
additive
(mmol)
time/ 6a; yield/
entry solvent (mL)
h
% (ds)
7a; yield/%
1
THF (5)-
H2O (10)
THF (2)
THF (2)
THF (2)
THF (2)
THF (2)
THF (2)
THF (2)
45
<5
0
2
3
4
5
6
7
8
H2O (1.2)
17
<10
<5
0
30
0
<5
64
tBuOH (1.2) 48
0.5 50 (90:10)
4
8
17
2
40 (90:10)
<5 (-)
0
>95
50b
-
<5
a 1a (1 mmol) and 2f (1.7 mmol) were used. b Reflux temperature.
corresponding syn isomers in high yields and selectivities. Crotyl
bromide (2e E/Z ratio 85:15) also afforded the syn isomer 4i3a
(87%, entry 12). In contrast, using Zn under similar conditions
failed to afford 4e (entry 6), perhaps because of the instability
of the generated allyl zinc species in aqueous conditions. The
stereochemistries obtained here strongly indicated that the
involvement of a cyclic chair TS (model C) and chelation TS
(model D, derived from E-geometry of cinnamyl indium) is
highly possible even in aqueous conditions similar to the
nonaqueous Sn or Zn systems.3a,b
a Ketone (1 mmol), halide 2f (1.7 mmol), and In (1.2 mmol) were used
at rt. b Refluxed for 2 h. c Runs 1-13 were carried out in THF. d See ref
7g. e 2f (2 mmol) and In (1.5 mmol) were used. f Zn (1.5 mmol) was used
instead of In. g 1g (2 mmol), 2f (4 mmol), and In (3 mmol) were used.
result indicated a fast transformation from an γ- into an R-adduct
and the presence of an equilibrium reaction route.
Fortunately, the reactions of 2-methoxy ketones (1f,g) with
2f in MeOH or THF-H2O solvent exclusively afforded the
γ-adducts 6e and 6f bearing a quaternary carbon with high syn
stereoselectivity (ds >99:1, entries 15, 16, and 18).8g Next, the
reaction of benzoinmethyl ether 1i and 2f in THF-H2O went
smoothly to afford the stereoselective γ-adduct 6g8g with three
stereocenters (syn-syn ds >99, entry 19). Employing Zn instead
of In did not promote the addition in any way in aqueous
conditions (entries 17 and 20), perhaps because the allyl In
species tolerated the aqueous condition very well though the
reactivity was considerably decreased.
Reactions with Ethyl 4-Bromocrotonate (functionalized).
Next, a functionalized allylic halide ethyl 4-bromocrotonate (2f)
having E-geometry was employed. At first the optimization of
the reaction conditions was performed. Surprisingly, unlike the
cinnamyl halides, even a small amount of water or alcohol
strongly depressed the reaction (entries 1-3, Table 4). The
reaction in anhydrous THF at rt for 30 min furnished the
γ-adduct 6a (anti isomer) bearing a quaternary carbon (50%,
ds 90:10, entry 4). In 4 h, a small amount of the R-adduct 7a
(5%) was accompanied by 6a (40%, entry 5). Further prolonga-
tion of the reaction time for 17 h afforded the R-adduct 7a,
regioselectively, in excellent yield (95%, entry 7). An attempt
to accelerate the reaction by refluxing for 2 h resulted in 50%
yield of 7a. Notably, to the best of our knowledge except for
some rare reports with aldehydes,7f there exists no report for
the direct In-mediated production of R-adducts from simple
ketones.5-7
MechanismoftheConversionofγ-AdductintoR-Adduct.10a
To a solution of ethyl 4-bromocrotonate (2f) in THF-d8 was
1
added In with vigorous stirring for 3.5 h at rt. The H NMR
spectrum revealed the formation of two new In species: species
[a] (doublets at δ 1.98 (J ) 9.6 Hz) and 5.46 (J ) 15.6 Hz))
and species [b] (doublets at δ 2.18 (J ) 9.6 Hz) and 5.59 (J )
15.6 Hz)) with other minor peaks (Figure 1, A). Addition of
ketone 1a to this solution revealed the disappearance of species
[a] in 2 min (Figure 1, B). Species [b] remained even after 30
min (Figure 1, C) and then slowly disappeared. At this stage it
is notable that the initial formation of the transient In intermedi-
ate of the γ-adduct took place (11, Scheme 2). After 20 h, the
transient In intermediate of the R-adduct appeared ((12, Figure
1, D), spectrum E corresponds to the R-adduct 7a after workup).
Now, we were focused on producing various R-adducts. Un-
activated simple ketones 1b,c,j,l furnished the respective R-ad-
ducts 7b-e in a longer reaction period at rt (Table 5). In
contrast, the ketones 1f,i and 1m-o which are activated by the
R-alkoxy moieties required a shorter reaction period to produce
the corresponding R-adducts (entries 5-10). The reactions of
benzoin alkyl ethers 1i,m-o with 2f successfully gave the
stereoselective R-adducts 7g-j (syn, entries 7-10). The ster-
eochemistry of the products 7g-j was assigned from the X-ray
structure analysis of 7g.
(10) (a) See SI, for full 1H NMR spectral region. (b) In the case of
cinnamyl bromide with In also a facile formation of two species in THF-
d8-D2O was observed, which indicated that the γ-substituted allyl In species
are also stable in aqueous condition. They would be RIn(I) and RIn(III)-
type species as already discussed in refs 7d and 8a-c. Based on the observed
astonishing diastereoselectivities and strong chelation as the key point;
plausibly, a low-valent RIn(I)-type transient species could be projected as
very reactive intermediate, see SI. (c) As noted in ref 3c about the instability
of products in column purification, in our case, the homoallyl alcohols 7g-
j/6a-g were stable even after several months. But the products 7a-f were
slowly decomposed after several months. We unambiguously assigned the
stereochemistry of the γ-adducts 6a-g/7g-j, see SI.
Subsequently, we also investigated the formation of various
γ-adducts. In the case of the reactions involving simple ketones
1b,j,p, quenching treatment with water in 30 min was the best
condition to give 50% yields of the anti isomers (entries 11-
13). However, 2-methoxy acetophenone (1f) gave a complicated
mixture including a small amount of R-adduct and syn/anti
isomers of the γ-adduct (85%, syn/anti ) 60/40, R/γ ) 1:2)7g
even when quenching the reaction in 30 min (entry 14). This
10266 J. Org. Chem., Vol. 72, No. 26, 2007

Plausibly, allylic In species that are employed here are tolerant
to water, because even in a longer reaction period the allylation
of ketones took place in aqueous conditions. Apparently, the
reactions in (the presence of) water suppressed (decelerate) the
reactivity of allylic indiums toward ketones. Characteristically,
un-activated and activated ketones behaved in slightly contrast-
ing manners. But, it is apparent that once allylic In species
slowly reacted with ketones, the resulting transient In alkoxides
were immediately hydrolyzed (trapped) to furnish γ-adducts
successively.
In summary, we have established an expedient and direct
method of In-employed regio- and diastereoselective addition
of γ-substituted allylic halides to ketones for the production of
homoallylic alcohols bearing quaternary centers.
FIGURE 1. 1H NMR study; conversion of γ- into R-adduct.10a
SCHEME 2. Mechanism: Conversion of γ- into r-Adduct
Experimental Section
Representative Procedure: Preparation of 6a/7a. To a flame-
dried flask were sequentially added 1a (1 mmol), 2f (1.65 mmol),
and dry THF (2 mL). Then, to this solution In powder (1.2 mmol)
was added. The reaction mixture was rapidly stirred at rt for 30
min, quenched with water (5 mL), and subjected to ultrasonication
for 1 min. Extraction with diethyl ether and evaporation afforded
a crude mixture. Purification through silica gel column (EtOAc/
hexanes 1:10) and Kugel-rohr distillation afforded the γ-adduct 6a
(ds 90:10) as a colorless thick oil. Under similar experimental
condition the above reaction in 17 h afforded the R-adduct 7a
(purified in a silica gel column EtOAc/hexanes 1:3). 6a: IR (CDCl3)
ν max 3490, 1708 1184 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.38
(d, J ) 8.0 Hz, 2H), 7.29 (d, J ) 8.0 Hz, 2H), 6.08 (ddd, J1 )
17.2 Hz, J2 ) 10.0 Hz, J3 ) 10.0 Hz, 1H), 5.36 (d, J ) 10.0 Hz,
1H), 5.33 (d, J ) 17.2 Hz, 1H), 4.39 (s, 1H, D2O-exchangeable),
3.98-3.85 (m, 2H), 3.50 (d, J ) 9.2 Hz, 1H), 1.39 (s, 3H), 0.98 (t,
J ) 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.7, 145.5,
132.7, 131.6, 128.2, 126.2, 121.0, 74.8, 61.0, 59.3, 27.8, 13.7. MS
(CI) m/z 269 (M+ + 1, 0.1), 253 (32), 251 (100), 207 (1.3), 179
(2.7), 157 (14.8), 155 (45.2), 115 (31.3%). HRMS (CI) calcd for
This process clearly indicated that an initially formed kinetically
favored γ-adduct intermediate is converting into the thermo-
dynamically favored R-adduct in a nonprotogenic solvent.
On the basis of these results, a plausible reaction path is
shown in Scheme 2. At first, an allyl In species 9 is generated
that reacts with a ketone via TS 11 to give transient γ-adduct
11′, which gave 6a when the reaction was quenched spontane-
ously or performed in water. In the absence of water and longer
reaction time, the reaction leads to a thermodynamically favored
transient R-adduct 12′, thus giving 7a.
C14H18ClO3 269.0944, found m/z 269.0950 (M+ + 1). 7a: IR
1
(CDCl3) ν
3482, 1735 cm-1. H NMR (400 MHz, CDCl3) δ
The transformation of a γ-adduct into an R-adduct was
observed only in the case of ethyl 4-bromocrotonate. This is
perhaps because of the intramolecular coordination from the
ester moiety to In center, which would well accelerate the
formation of an allylic In-type 10 by a retro-reaction under
thermodynamic equilibrium. As a result, various R-adducts could
be very effectively produced in the case of ethyl 4-bromocro-
tonate rather than cinnamyl-type halides which are not having
such functional moieties. Notably, the 1H NMR spectra A and
D also revealed an initial formation and the involvement of two
E-types of transient In species 9 (J ) 15.6 Hz corresponds to
the olefin proton of 9 and 7a). They would be RIn(I)- and RIn-
(III)-type species as already discussed in the case of In enolates
and the former might be a very reactive species.8a-c,10b However,
an isomeric allylic intermediate 10 could not be detected.
The stereochemistry of isomers 6a-d (anti) could be
proposed through the chair-type TS 11. The formation of syn
R-adducts 7g-j could be explained via the bicyclic chelation
TS 14 having an In-centered three-oxygen coordination.8b,9
Similarly, the bicyclic chelation TS 13 could be proposed for
the γ-adducts 6e,f (syn) and 6g (syn-syn).10c
max
7.35 (d, J ) 8.0 Hz, 2H), 7.29 (d, J ) 8.0 Hz, 2H), 6.82 (dt, J1 )
15.6 Hz, J2 ) 7.2, Hz, 1H), 5.79 (d, J ) 15.6 Hz, 1H), 4.10 (q, J
) 7.6 Hz, 2H), 3.16 (s, 1H, D2O-exchangeable), 2.69-2.57 (m,
2H), 1.52 (s, 3H), 1.22 (t, J ) 7.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 166.1, 146.0, 144.7, 132.4, 128.1, 126.1, 124.4, 73.4,
60.2, 46.5, 29.4, 13.9. MS (CI) m/z 269 (M+ + 1, 2.9), 253 (33.5),
251 (100), 217 (1.1), 179 (3.2), 155 (15.8), 114 (4.7%). HRMS
(CI) calcd for C14H18ClO3 269.0944, found m/z 269.0942 (M+
+
1).
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. We thank Mr.
H. Moriguchi, Faculty of Engineering, for MS spectra.
Supporting Information Available: Experimental details, X-ray
1
analyses, spectral data of products, and H and 13C NMR charts.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO701899J
J. Org. Chem, Vol. 72, No. 26, 2007 10267