In- or In(I)-employed diastereoselective Reformatsky-type reactions with ketones: 1H NMR investigations on the active species

Article abstract of DOI:10.1021/ol0482846

(Chemical equation presented) An efficient In- or In(I)-based stereoselective C-C bond formation is reported; the diastereoselective Reformatsky-type reactions of ketones. The predominant formations of anti isomers, confirmed by the X-ray structure analys

Full text of DOI:10.1021/ol0482846

ORGANIC
LETTERS
2
004
Vol. 6, No. 24
475-4478
In- or In(I)-Employed Diastereoselective
Reformatsky-Type Reactions with
Ketones: H NMR Investigations on the
4
1
Active Species
Srinivasarao Arulananda Babu, Makoto Yasuda, Ikuya Shibata, and Akio Baba*
Department of Molecular Chemistry and Handai Frontier Research Center,
Graduate School of Engineering, Osaka UniVersity, 2-1 Yamadaoka, Suita,
Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received August 27, 2004
ABSTRACT
An efficient In- or In(I)-based stereoselective C−C bond formation is reported; the diastereoselective Reformatsky-type reactions of ketones.
The predominant formations of anti isomers, confirmed by the X-ray structure analyses of ester derivatives of respective alcohols 9a
1
and
1
13a
1
, conclusively revealed the stereochemistry of the reaction path. H NMR investigations revealed the formation of two types of
r
-metalated
transient species from
r-halo esters with In or In(I) halides.
Stereoselective carbon-carbon bond formation is the foun-
dation for synthetic organic chemistry, and organometallic
reactions are among the superior processes. A classic
problem remains to be explored, that is, an efficient diaste-
reoselective addition of the branched R-halo ester derivatives
to ketones. In view of the stereochemical synthetic point,
this process would produce two stereogenic centers; however,
there have been a few examples with only moderate
diastereoselectivity. This is probably because the conditions
to achieve the additions to ketones are too severe to control
the stereoselectivity in contrast to the facile additions to
aldehydes (Scheme 1). In addition, the difference in the rigid
1
procedure in this respect is the Reformatsky-type reaction.
2
Many processes have been developed using zinc. For very
high efficiency, new methods were developed, e.g., Rieke-
3
a
3b
3c
Zn, Zn-Cu couple, and Zn/Ag-graphite, utilizing other
3d
3e
3f
3g,h
4
metals such as Cd, Ni, Ce, Mg, and indium; however,
some of these reagents must be freshly prepared. Despite
3
these developments and considering the applicability and
versatility of the Reformatsky-type reaction, an enduring
Scheme 1
(
1) Reformatsky, S. Chem. Ber. 1887, 20, 1210.
(2) (a) F u¨ rstner. A. Synthesis 1989, 571. (b) Rathke, M. W.; Weipert, P.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 2, p 277.
(3) (a) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 452. (b) Santaniello, E.;
Manzocchi, A. Synthesis 1977, 698. (c) Csuk, R.; F u¨ rstner, A.; Weidmann,
H. J. Chem. Soc., Chem Commun. 1986, 775. (d) Burkhardt, E.; Rieke, R.
D. J. Org. Chem. 1985, 50, 416. (e) Inaba, S.-I.; Rieke, R. D. Tetrahedron
Lett. 1985, 26, 155. (f) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.;
Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984,
steric demand between the two substituents on the carbonyl
carbon importantly decides the degree of stereoselection. This
difference is much lower in the case of ketones than
aldehydes. In fact, a survey of the existing examples on the
4
9, 3904. (g) Moriwake, T. J. Org. Chem. 1966, 31, 983. (h) Borno, A.;
Bigley, D. B. J. Chem. Soc., Perkin Trans. 2 1983, 1311. (i) Paresh, J. D.;
Shelton, D. R.; Little, R. D. Org. Lett. 2003, 5, 3615. (j) Shibata, I.; Suwa,
T.; Sakakibara, H.; Baba, A. Org. Lett. 2002, 4, 301 and references therein.
1
0.1021/ol0482846 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/27/2004

addition of the branched R-halo esters to ketones revealed
5
,6
the difficulty in achieving good diastereoselectivity, e.g.,
Table 1. Indium-Based Diastereoselective Reformatsky-type
Reaction of Ketones 5 with 6a-ca
6
5a
Zn dust/I
and low-valent tantalum (ds 17:13).
Taking an impetus from the recently advancing selective
2
(anti/syn 3:2), Et
2
Zn/RhCl(PPh
)
3 3
(anti/syn 1:1),
5b
4,7
reactions based on indium, we envisioned the indium-based
diastereoselective Reformatsky-type reactions of ketones. We
herein report our investigations on the stereoselective C-C
bond formations using In or In(I)X.
The scope and result of the reactions of the branched
R-halo ester derivatives such as 6a-c with ketones in the
Reformatsky-type condition and the degree of stereoselection
would depend on two essential things: (a) a large difference
in steric demand between the two substituents on the carbonyl
carbon of ketones and (b) the strict conformation of a six-
membered cyclic transition state that would result from a
transient indium enolate (“E” or “Z”). In an initial experi-
ment, to a mixture of acetophenone and ethyl 2-bromopro-
pionate in dry THF was added indium metal powder at room
temperature, and the resulting mixture was heated to reflux
to afford the product 7a5 in 98% yield with diastereose-
lectivity of 75:25 (anti/syn) (Table 1, entry a). We found
that dipping the flask containing all the contents in dry THF
into a preheated bath for 1 h gave the product with higher
selectivity 84:16 (anti/syn) (entry b). Then we were interested
in employing the indium(I) halides for the above stereose-
lective reaction. Indium(I) bromide is found to be more
efficient than indium(I) chloride or indium(I) iodide. Em-
ploying indium(I) bromide gave significantly higher dia-
steroselectivity with very good yield. The generality of this
important stereoselective reaction was demonstrated with a
variety of ketones as summarized in Table 1. Electron-
withdrawing and donating groups slightly altered the dia-
stereoselectivities. The reactions with the R-halo ester
derivative 6c having a long carbon chain length also afforded
the products 7c and 10c with high diastereoselectivities
,6
(
entries j, k, and q). Employing other conditions such as
ultrasonication/rt, solvents such as MeCN and DMF, or using
4
,7
MeCH(Cl)COOEt or RX/NaI -in DMF/rt systems were
ineffective. Compared to the existing methods, the indium-
8
based reagents behaved in a distinctive manner with respect
9
a
to the diastereoselectivity.
a
In all reactions, 5 (1 mmol), 6a-c (1.6-1.8 mmol), In/In(I)X (∼1.2
Stereochemistry. We have isolated both the major and
minor isomers in pure form in some cases. The ester
derivatives (of alcohols) of major isomers 9a
mmol), and dry THF (∼2 mL) were used. Ratios of anti/syn isomers are
b
shown in parentheses. See the Supporting Information for the details of
9c c
methods A-C.
The contents of the reaction mixture were dipped into
1
and 13a
1
were
a preheated bath at reflux temperature (∼66-69 °C). 5a (1 mmol), 6c (2
mmol), and indium (2 mmol) were used. e Isolated as a mixture of
diastereomers.
d
(
4) For recent reviews, see: (a) Cintas, P. Synlett 1995, 1087. (b) Podlech,
J.; Maier, T. C. Synthesis 2003, 633. (c) Nair, V.; Ros, S.; Jayan, C. N.;
Pillai, B.; S. Tetrahedron 2004, 60, 1959. (d) Chan, T. H.; Li, C.-J.; Lee,
M. C.; Wei, Z. Y. Can. J. Chem. 1994, 72, 1181.
9
b
(5) (a) Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549
prepared according to the literature method in the crystalline
forms, suitable for the X-ray structure analyses. The stereo-
and references therein. (b) Aoyagi, Y.; Tanaka, W.; Ohta, A. J. Chem. Soc.,
Chem. Commun. 1994, 1225. (c) Delaunay, J.; Orliac-Le Moing, A.;
Simonet, J. Tetrahedron 1988, 44, 7089. (d) Canceill, J.; Basselier, J. J.;
Jacques, J. Bull. Soc. Chim. Fr. 1967, 1024.
(8) For early works dealing with nondiastereoselective Reformatsky-type
reactions, see: (a) Chao, L.-C.; Rieke, R. D. J. Org. Chem. 1975, 40, 2253.
(b) Nair, V.; Jayan, C. N.; Ros, S. Tetrahedron 2001, 57, 9453. (c) Araki,
S.; Ito, H.; Butsugan, Y. Synth. Commun. 1988, 18, 453. (d) Araki, S.;
Katsumura, N.; Kawasaki, K.-I.; Butsugan, Y. J. Chem. Soc., Perkin Trans.
1 1991, 499. (e) Schick, H.; Ludwig, R.; Schwarz, K.-H.; Kleiner, K.;
Kunath, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1191. (f) Araki, S.;
Katsumura, N.; Kawasaki, K.; Butsugan, Y. J. Chem. Soc., Perkin Trans.
1 1991, 499. (g) Yi, X.-H.; Meng, Y.; Li, C.-J. Tetrahedron Lett. 1997, 38,
4731.
(
6) Ross, N. A.; Bartsch, R. A. J. Org. Chem. 2003, 68, 360 and
references therein.
7) For some recent papers, see: (a) Kumar, S. Kaur, P. Tetrahedron
(
Lett. 2004, 45, 3413. (b) Loh, T.-P.; Yin, Z.; Song, H.-S.; Tan, K.-L.
Tetrahedron Lett. 2003, 44, 911. (c) Yi, X.-H.; Meng, Y.; Li, C.-J. J. Chem.
Soc., Chem. Commun. 1998, 449. (d) Hirashita, T.; Kamei, T.; Satake, M.;
Horie, T.; Shimizu, H.; Araki, S. Org. Biomol. Chem. 2003, 1, 3799. (e)
Babu, S. A.; Yasuda, M.; Shibata, I., Baba, A. Synlett 2004, 1223. (f)
Paquette, L., A. Synthesis 2003, 765.
4476
Org. Lett., Vol. 6, No. 24, 2004

Scheme 2
chemistry of products was unambiguously derived from the
single-crystal X-ray structure analyses of the ester derivatives.
Representative X-ray structure analyses of derivatives of
products unequivocally revealed the formation of anti
isomers as the major products.
9c
1
Figure 2. Partial H NMR spectrum of ICH
2
COOEt-indium in
THF-d for 60 min and then with benzaldehyde.
8
(
Figure 2), and the peak at δ 2.08 was also slowly consumed
over 3 h. But the peak at δ 1.84 was unchanged even after
3 h. Later, this singlet peak at δ 1.84 was proved to be the
methyl protons of CH COOEt, which could result from the
Reaction Pathway. Theoretically, an acyclic mechanism
(path “a”) is expected to give anti/syn isomers in the ratio
4
of 50:50; however, the high diastereoselectivities in the
present indium-based experiments undoubtedly indicate an
involvement of a highly favored cyclic transition intermediate
mechanism (path b). Further, the predominant formations of
anti isomers over syn isomers, which was confirmed in the
single-crystal X-ray structure analyses, noticeably suggest
the participation of the stereochemically preferred transient
E enolates in the transition state of the reaction pathway.
Thus, the interesting reaction pathway involved in the
indium-employed Reformatsky-type reactions could be pre-
dicted as shown in the Scheme 2.
3
active species in the presence of adventitious water.
1H NMR Studies. We next intensively investigated the
active species formed from an alkyl halide with In or indium-
(
I) halide (Figures 1-5). An NMR tube containing an
equimolar mixture of ICH COOEt and indium powder in
THF-d was subjected to ultrasonication at rt. H NMR
2
1
8
spectra were recorded at different intervals. Three indepen-
dent singlet peaks at δ 2.08, 1.85, and 1.84 appeared (∼10
min, Figure 1a). The intensity of the peak at δ 1.84 was
1
Figure 3. Partial H NMR spectra of ICH
2
COOEt with In(I)I in
8
THF-d for (a) 20 min and (b) 90 min.
Surprisingly, a similar trend was observed from an
equimolar mixture of ICH COOEt and In(I)I in THF-d
Figure 3a,b). Initially, the subsequent appearance of two
2
8
(
(9) (a) With respect to yields and diastereoselection, In and InBr afforded
a similar trend. But InCl and InI furnished relatively a moderate selectivity.
One of the reasons might be that dissimilar halide ions react with the
R-bromo ester to form the active enolates. (b) Vedejs, E.; Daugulis, O. J.
Org. Chem. 1996, 61, 5702. (c) Typical Experimental Procedure (Method
A). To a solution of 5c (1 mmol) and 6a (1.8 mmol) in dry THF (1.8 mL)
was added indium powder (1.2 mmol) at room temperature. The flask was
dipped into an oil bath and stirred, the bath temperature was allowed to
rise until it reached 67-69 °C, and the reaction was continued for a total
of 3 h. Then, the reaction mixture was cooled to room temperature. Cold
water (6 mL) addition, ultrasonication (1 min), ether extraction, concentra-
tion, and repetitive column chromatography afforded both anti/syn isomers
(9a1 and 9a2, respectively) in pure form. See the Supporting Information
for the experimental details and the X-ray structure analyses of ester
derivatives 9a1B and 13a1B, respectively, prepared from the respective
alcohols 9a1 and 13a1 (anti isomers).
1
Figure 1. Partial H NMR spectra of ICH
2
COOEt-indium in THF-
8
d for (a) 10 min and (b) 60 min.
gradually enhanced over a period of 1 h (Figure 1b, see the
Supporting Information). Quenching with benzaldehyde
caused an immediate disappearance of the peak at δ 1.85
Org. Lett., Vol. 6, No. 24, 2004
4477

1
Figure 4. Partial H NMR spectra of (a) ICH
in THF-d for 90 min and then with benzaldehyde and (b) BrCH
COOEt-indium in THF-d for 15 min.
2
COOEt with In(I)I
1
Figure 5. Partial H NMR spectra of (a) MeCH(Br)COOMe with
indium in THF-d
8
2
-
8
, heated at 70-72 °C for 30 min, and (b) with
8
addition of 4-chloroacetophenone.
new singlet peaks (δ 2.08 and 1.86) was observed (about 8
and 20 min). A third peak at δ 1.84 (CH COOEt) appeared
0 min later. Quenching with benzaldehyde caused the
selective disappearance of the peak at δ 1.86 (Figure 4a).
The peak at δ 2.08 was also consumed slowly. In the case
active species involved in the case of R-halo esters with
indium reagents revealed the following inferences:1 (a) the
chemical shift values corresponding to the methylene/
methane proton suggest that two independent alkyl indium
species having an R-metalated structure with different
oxidation states are formed; (b) one of them is very active,
the real precursor of a transient indium enolate; (c) it is
informative that the same kinds of transient active species
are involved in both the indium metal and In(I)X systems.
Although these results may be correlated with allyl halide
case,1 we observed two kinds of active species in the case
of R-halo esters with In or In(I)X under anhydrous condi-
tions. Hence, the structures of active species with respect to
the chemical shift values will be accounted for in due time.
In conclusion, we have shown that indium-based reagents
exhibit a distinctive diastereoselective pattern for the Re-
formatsky-type reactions of ketones with the branched R-halo
esters. In or In(I)X afforded the similar types of active species
and reactivity trend. Demonstrations of the reaction path and
groundwork investigations on the transient active species
formed from the R-halo esters and indium reagents were
carried out.
3
1b
5
of BrCH COOEt with In, three singlet peaks at δ 1.96, 1.84,
2
and 1.81 (∼15 min, Figure 4b) were observed, the peaks
corresponding to δ 1.96 and 1.81 were found to be active,
and the singlet peak at δ 1.84 was inactive and found to be
the methyl protons of MeCOOEt (see the Supporting
Information).
2
In a further experiment, a mixture of MeCH (Br)COOMe
and indium in THF-d
8
was heated at 70 °C for 30 min. The
1
H NMR spectrum revealed the formation of two new doublet
1
1a
signals at δ 1.29 and 1.27 (J ) ∼7 Hz), corresponding to
the methyl protons (Figure 5a, protons denoted as A2*) of
two new active species.1
0a,b
In addition, we also found the
formation of methyl propionate (Figure 5a, B1 and B2).
Plausibly, in the cases of MeCH (Br)COOMe and
XCH COOEt, MeCH COOMe and MeCOOEt, respectively,
2 2
could result from the highly active species or the highly
unstable indium enolate derived from an ester carbonyl group
in the presence of adventitious water. Thus, this quenching
of active species indicates why no Reformatsky reaction
occurs in water as the solvent.8g
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan. We
thank the reviewers for their kind suggestions. Thanks are
due to Mr. H. Moriguchi, Faculty of Engineering, for
assistance in obtaining MS spectra.
It has been envisaged that in the case of allyl halide with
In or In(I)X the formation of sesquihalide-type active
species1 (R
2a
12b
3
In
2 3
X ) in DMF and RIn-type active species
in H
2
O, respectively. Our preliminary investigations on the
(10) (a) At this stage, 4-chloroacetophenone was added and the mixture
heated for 30 min, which revealed the disappearances of peaks corresponding
to the active species. Further usual workup and the H NMR spectrum
Supporting Information Available: Experimental pro-
cedures, spectral data of products, H NMR spectra, and
details of X-ray structure analyses. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
1
revealed the formation of anti/syn isomers of the respective alcohols (Figure
1
5
b). (b) See the Supporting Information for the full H NMR spectral region.
(11) (a) In a different experiment, when the reaction mixture was left
overnight, only methyl propionate was observed. (b) In the case of InCl
with ICH2COOEt three singlet peaks at δ 1.92 (broad), 1.84 and 1.75 were
observed. The singlet peak at 1.84 was inactive and accounted for CH3
protons of MeCOOEt and the other two were found to be active. Similarly,
InCl with BrCH2COOEt, two singlet peaks were observed, δ 1.88 (active)
and 1.84 (accounted for CH3 protons of MeCOOEt). InCl2 with ClCH2-
COOEt did not afford any new signal.
OL0482846
1
(12) For earlier H NMR studies on allyl indium cases, see: (a) Chan,
T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228. (b) Araki, S.; Ito, H.;
Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
4478
Org. Lett., Vol. 6, No. 24, 2004