Samarium(II) Iodide-Mediated Synthesis of Chlorohydrins

Full text of DOI:10.1021/jo9803838

J . Org. Chem. 1998, 63, 4551-4553
4551
Ta ble 1. Rea ction of P h en eth yl Dich lor oa ceta te,
Sa m a r iu m (II) Iod id e-Med ia ted Syn th esis of
Ch lor oh yd r in s†
Aceton e, a n d Sm I2
Bastien Castagner, Patrick Lacombe, and R e´ jean Ruel*
Merck Frosst Centre for Therapeutic Research,
P.O. Box 1005, Pointe-Claire-Dorval,
Qu e´ bec H9R 4P8, Canada
entry
conditions
yield (%)
1
2
3
4
Barbier procedure (acetone before SmI2)
Grignard procedure (acetone after SmI2)
“Barbier” + 2 equiv of HMPA
63
0
71
33
Received March 2, 1998
“Barbier” + 8 equiv of HMPA
The reductive coupling between a carbonyl and an
organic halide with samarium diiodide produces the
corresponding alcohol efficiently, as first shown by Kagan
Ta ble 2. Rea ctivity of P h en eth yl Dich lor oa ceta te
Der iva tives a n d Ca r bon yl Com p ou n d s w ith Sm I2
1
et al. in their introductory paper on SmI
2
.
It was also
shown by several groups that these reactions did not
proceed well when the carbonyl compounds were added
1
,2
subsequently to the halides and SmI
2
.
A subset of these
reactions, namely the samarium(II) iodide-mediated Re-
formatsky-type reaction of monohaloacetates with alde-
hydes and ketones (eq 1), is also well precedented.1
entry
X
R1
R2
product
yield (%)
,3
1
2
3
4
5
6
Me
Bn
Cl
H
H
H
Me
Me
Me
Ph
Ph
Ph
Me
Me
Me
Me
Ph
H
2
3
4
55
66
65
45
0
a
6
7
8
0
a
1
:1 mixture of diastereomers.
We have studied the SmI
2
-mediated reaction of dichlo-
the zinc-mediated reactions.3b For example, no activation
roacetates with carbonyl compounds. The corresponding
4
5
4a,5
zinc- and magnesium -mediated reactions (eq 2) have
been thoroughly studied,6 but to the best of our knowl-
agent (such as BF
3
)
is required, and the reaction time
reaction compared
,7
is considerably shorter for the SmI
2
edge, the use of SmI
reaction has not been reported. Also, like the samari-
2
as the reducing agent in this
to the Zn reaction (typically 30 min for SmI
for Zn).
2
and 24 h
Table 1 summarizes the results we obtained using 2.5
equiv of samarium iodide and a mixture of phenethyl
dichloroacetate and acetone in THF at 0 °C. A Barbier-
2
type procedure (i.e., SmI added last) afforded the chlo-
rohydrin 1 in 63% yield (Table 1, entry 1) while the
Grignard-type procedure (acetone added last) failed to
provide any of the desired material (Table 1, entry 2). In
the latter case, several decomposition products were
obtained from which the only clearly identified product
was phenethyl alcohol (ca. 25%). Chlorohydrin 1 was
um(II) iodide-mediated Reformatsky-type reaction of
monohaloacetates with aldehydes and ketones, the method
described herein offers several advantages compared to
†
This paper is dedicated to Professor Yoshito Kishi on the occasion
of his 60th birthday.
therefore obtained only when the carbonyl compound was
(
1) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
02, 2693.
2) (a) Namy, J . L.; Collin, J .; Bied, C.; Kagan, H. B. Synlett 1992,
33. (b) Curran, D. P.; Fevig, T. L.; J asperse, C. P.; Totleben, M. J .
8
added before SmI
2
.
The addition of 2 equiv of HMPA
1
(Table 1, entry 3) resulted in only a slightly improved
(
7
conversion (71%), whereas the addition of a larger
amount of HMPA (Table 1, entry 4) was detrimental to
the formation of chlorohydrin 1.
Synlett 1992, 943. (c) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem.
Lett. 1987, 1485.
(
3) (a) Tabuchi, T.; Kawamura, K.; Inanaga, J .; Yamaguchi, M.
Tetrahedron Lett. 1986, 27, 3889. (b) Molander, G. A.; Etter, J . B. J .
Am. Chem. Soc. 1987, 109, 6556. (c) Molander, G. A. Chem. Rev. 1992,
The reaction also proceeded in moderate to good yields
with substituted dichloroacetates.9 Under the optimized
9
3
2
2, 29. (d) Kagan, H. B.; Namy, J . L.; Girard, P. Tetrahedron 1981,
7, 175, Suppl. I. (e) Vedejs, E.; Ahmad, S. Tetrahedron Lett. 1988,
9, 2291. (f) Moriya, T.; Handa, Y.; Inanaga, J .; Yamaguchi, M.
Tetrahedron Lett. 1988, 29, 6947.
4) (a) Benincasa, M.; Forti, L.; Ghelfi, F.; Libertini, E.; Pagnoni,
(6) See also, Pb: (a) Zhang, X. L.; Han, Y.; Tao, W. T.; Huang, Y. Z.
J . Chem. Soc., Perkin Trans. 1 1995, 189. (b) Tanaka, H.; Yamashita,
S.; Yamanoue, M.; Torii, S. J . Org. Chem. 1989, 54, 444.
(
U. M. Synth. Commun. 1996, 26(22), 4113. (b) Curran, T. T. J . Org.
Chem. 1993, 58, 6360. (c) Braun, M.; Vonderhagen, A.; Waldm u¨ ller,
D. Liebigs Ann. Chem. 1995, 1447. (d) Kim, K. S.; Qian, L. Tetrahedron
Lett. 1993, 34, 7195. Tsukamoto, T.; Kitazume, T. J . Chem. Soc., Perkin
Trans. 1 1993, 1177. (e) Shen, Y.; Qi, M. J . Chem. Res., Synop. 1993,
(7) See also, tris(dimethylamino)phosphine: Hayon, A.-F.; Fehrentz,
J .-A.; Chapleur, Y.; Castro, B. Bull. Soc. Chim. Fr. 1983, II, 207.
(8) One recent report describes the successful reaction when the
ketone was added last; however, see: Utimoto, K.; Takai, T.; Matsui,
T.; Matsubara, S. Bull. Soc. Chim. Fr. 1997, 134, 365.
(9) R-Methyl- and R-benzyl-substituted dichloroacetate were pre-
pared from phenethyl dichloroacetate as described in: Villieras, J .;
Perriot, P.; Bourgain, M.; Normant, J . F. Synthesis 1975, 533.
Phenethyl trichloroacetate was prepared from commercially available
phenethyl alcohol and trichloroacetyl chloride.
2
22. (f) Linderman, R. J .; Graves, D. M. J . Org. Chem. 1989, 54, 661.
g) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. Tetrahedron Lett. 1988,
9, 1803.
5) (a) Darzens, G.; C. R. Acad. Sc. Paris, S e´ r. C 1910, 151, 883. (b)
Miller, R. E.; Nord, F. F. J . Org. Chem. 1951, 16, 728.
(
2
(
S0022-3263(98)00383-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/11/1998

4
552 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
Sch em e 1
8
reaction conditions described above (Table 1, entry 3),
compounds 2, 3, and 4 were obtained in 55%, 66%, and
dented samarium iodide-induced pinacol coupling,10
whereas dimer 10 was recently reported by Fang and co-
workers.11
6
5% yields, respectively (Table 2). It should be pointed
out that none of the corresponding epoxides resulting
from chlorohydrins 1-4 was isolated from the reactions
described in Tables 1 and 2. On the other hand, when
chlorohydrin 1 was treated with sodium hydride in THF
at room temperature for 30 min, epoxide 5 was obtained
in 76% yield (eq 3). However, all attempts to obtain
We have also examined the reaction of (1S,2R,5S)-
(
-)-8-phenylmenthyl dichloroacetate (11) with acetone
and samarium iodide (Scheme 1). No asymmetric induc-
tionwas observed, and a 1:1 mixture of 12 and 13 was
obtained in 52% combined yield. Nevertheless, the use
of chiral dichloroacetate 11 allowed us to make an
observation on the stability of the species obtained when
a dichloroacetate was treated with SmI . Unlike all
2
reactions reported in Tables 1 and 2 that resulted in
complex reaction mixtures when no carbonyl compounds
2
epoxide 5 directly from the SmI -mediated reaction failed.
Some of these attempts included the following: (i)
reaction run at 65 °C for 12 h (51% yield of 1 obtained)
and (ii) reactions performed with large amount (10-25
equiv) of HMPA at 0 °C or refluxing THF for 12 h (yield
of 1, ∼20%). Presumably, the strong Sm-O bond pre-
vents epoxide formation.
was added, exposure of 11 to SmI
2
without acetone
We also studied the reactivity of other carbonyl com-
provided chloroacetate 14 in 71% yield. The correspond-
ing monochloroacetates were not isolated when Grignard-
type (ketone added last or no ketone added) procedures
were used in the reactions described in the aforemen-
tioned Tables 1 and 2. It should also be pointed out that
pounds with SmI
matic ketones and aldehydes reacted sluggishly (Table
, entries 4-6), as was the case with Kagan’s original
2
and phenethyl dichloroacetate. Aro-
2
1
samarium Barbier procedure, and with the exception of
acetophenone, the expected products were not obtained.
In fact, when samarium(II) iodide was added to a mixture
of acetophenone and phenethyl dichloroacetate, a (1:1)
diastereomeric mixture of chlorohydrin 6 was obtained
in a low 45% yield (Table 2, entry 4). Several unidenti-
fied byproducts were also observed. On the other hand,
we did not isolate any of the desired expected product 8
when the reaction was carried out with benzaldehyde
attempts to carry out the reaction between 11 and SmI
2
in which acetone is added last (Grignard procedure)
provided none of the expected products 12 and 13, even
at higher temperature. In these cases, monochlorinated
product 14 was obtained in good yield. Consequently, it
would seem that steric hindrance around the dichloro-
acetate-derived reactive species dictates its stability.
There is a possibility that less hindered dichloroacetates
form a species more reactive toward self-condensation
processes similar to those we12 and others have re-
ported. These self-condensation processes would in turn
generate reactive species, hence providing a complex
reaction mixture. In other words, the reactive intermedi-
(Table 2, entry 6). In this case, several unidentified
products were obtained along with dimers 9 and 10 (20%
combined yield, eq 4). Diol 9 originates from the prece-
13
(
10) Namy, J . L.; Souppe, J .; Kagan, H. B. Tetrahedron Lett. 1983,
2
4, 765.
ate, be it radical,3d transient anion, or organosamarium,
3d
2b
(
11) Shiue, J .-S.; Lin, M.-H.; Fang, J .-M. J . Org. Chem. 1997, 62,
4
643.
is more stable when generated from 11, compared to
when generated from any of the other dichloroacetates
described in this report.
(
(
12) Balaux, E.; Ruel, R. Tetrahedron Lett. 1996, 37, 609.
13) Park, H. S.; Lee, I. S.; Kim, Y. H. Tetrahedron Lett. 1995 36,
1
673.

Notes
Failure to provide products in related Grignard pro-
J . Org. Chem., Vol. 63, No. 13, 1998 4553
(2H, t, J ) 7.0 Hz), 1.46 (6H, s); 13C NMR (75 MHz, CDCl
) δ
3
ppm 166.2, 136.5, 128.8, 128.5, 126.7, 65.4, 60.1, 59.1, 34.8, 24.1,
18.0; MS (m/z) 293 (3), 291 (5), 135 (6), 117 (11), 105 (100). Anal.
2 3
Calcd for C13H16Cl O : C, 53.63; H, 5.54. Found: C, 53.56; H,
cedures has been rationalized as favoring the radical-
ketyl coupling mechanism.3d Considering, however, the
complexity of the mechanistic possibilities of reductions
5
.54.
2
of halides and radicals with SmI that has been recently
P h en eth yl 2,3-ep oxy-2-h yd r oxy-2-m eth ylbu ta n oa te (5):
reviewed by Curran et al.,2b the mechanism of the
samarium iodide-mediated coupling of dichloroacetate
remains unclear until further evidence becomes available.
-1
1
IR (neat) 1730 cm
3
; H NMR (300 MHz, CDCl ) δ ppm 7.30
(5H, m), 4.42 (2H, t, J ) 7.0 Hz), 3.30 (1H, s), 2.98 (2H, t, J )
7.0 Hz), 1.40 (3H, s), 1.30 (3H, s); 13C NMR (75 MHz, CDCl
) δ
ppm 168.5, 137.6, 128.7, 128.4, 126.5, 71.6, 66.3, 64.2, 34.6, 26.3,
5.4; MS (m/z) 221 (9), 154 (43), 137 (36), 105 (100). Anal. Calcd
for C13 : C, 70.89; H, 7.32. Found: C, 70.98; H, 7.42.
P h en eth yl 3-ch lor o-2-h yd r oxy-2-p h en ylbu ta n oa te (6):
3
2
Exp er im en ta l Section
16 3
H O
P h en eth yl 3-Ch lor o-2-h yd r oxy-2-m eth ylbu ta n oa te (1).
To a solution of phenethyl dichloroacetate (200 mg, 0.86 mmol),
acetone (0.5 mL, 6.9 mmol), and HMPA (0.33 mL, 1.9 mmol) at
-
1 1
IR (neat) 3560, 1730 cm ; H NMR (300 MHz, CDCl
high R diastereomer, 7.44 (10H, m), 4.51 (1H, s), 4.32 (2H, t, J
) 7.0 Hz), 3.33 (1H, s), 2.86 (2H, t, J ) 7.0 Hz), 1.63 (3H, s), low
diastereomer, 7.40 (10H, m), 4.55 (1H, s), 4.10 (2H, t, J ) 7.0
3
) δ ppm,
f
-
78 °C was added a 0.1 M THF solution of samarium iodide
20.6 mL, 2.4 mmol) (purchased from Aldrich). The mixture was
warmed to 0 °C and stirred at 0 °C for 30 min. A 5% solution of
NaHCO (30 mL), ether (30 mL), and hexanes (30 mL) were
added, and the separated aqueous layer was extracted with 1:1
), filtered, and
(
R
f
1
3
Hz), 3.94 (1H, s), 2.86 (2H,m), 1.63 (3H, s); C NMR (two
diastereomers) (75 MHz, CDCl ) δ ppm 169.1, 168.5, 143.1,
3
3
142.6, 136.8, 136.7, 128.7, 128.6, 128.5, 128.4, 128.3, 128.1, 127.6,
127.5, 126.6, 126.5, 125.1, 124.9, 74.8, 74.7, 66.4, 66.2, 64.8, 62.7,
34.5, 34.2, 26.7, 26.2; MS (m/z) 319 (3), 303 (8), 301 (22), 154
ether-hexanes (3 × 50 mL), dried (anhyd MgSO
4
evaporated. Flash chromatography of the residue (EtOAc/
hexanes 1:8) yielded 156 mg (71%) of 1: IR (neat) 3560, 1730
(31), 105 (100). Anal. Calcd for C18
Found: C, 67.74, H, 6.13.
3
H19ClO : C, 67.82; H, 6.01.
-
1 1
cm ; H NMR (300 MHz, CDCl
3
) δ ppm 7.25 (5H, 2m), 4.42 (2H,
t, J ) 7.0 Hz), 4.18 (1H, s), 3.50 (1H, br s), 2.99 (2H, t, J ) 7.0
Hz), 1.30 (3H, s), 1.29 (3H, s); C NMR (75 MHz, CDCl
68.7, 136.9, 128.7, 128.4, 126.6, 71.6, 66.3, 64.2, 34.6, 26.3, 25.4;
(1S,2R,5S)-5-Met h yl-2-(1-m et h yl-1-p h en ylet h yl)cyclo-
1
3
3
) δ ppm
h exyl 3-ch lor o-2-h yd r oxy-2-m et h ylb u t a n oa t e (12) a n d
-
1 1
1
(13): IR (neat) 3560, 1730 cm ; H NMR (300 MHz, CDCl ) δ
3
MS m/z 257 (15), 153 (100). Anal. Calcd for C13
H
17ClO
3
: C,
ppm 7.25 (8H, m), 7.12 (2H, m), 4.80 (2H, m), 3.39, 3.32, 3.27,
2.55 (4H, s), 2.15-0.9 (46H); 13C NMR (75 MHz, CDCl ) δ ppm
6
0.82; H, 6.67. Found: C, 60.81; H, 6.82.
P h en et h yl 3-ch lor o-2,3-d im et h yl-2-h yd r oxyb u t a n oa t e
3
168.5, 167.7, 151.5, 151.0, 127.9, 127.8, 125.6, 125.3, 125.1, 125.0,
124.9, 76.8, 76.6, 71.4, 71.3, 65.4, 62.5, 50.4, 49.7, 41.1, 40.4,
39.5, 39.4, 34.2, 31.1, 27.9, 27.3, 27.0, 26.4, 26.3, 26.1, 25.9, 25.5,
25.1, 24.4, 21.5; MS (m/z) 367 (36), 333 (100), 313 (31), 247 (87).
-
1
1
(
2): IR (neat) 3560, 1725 cm ; H NMR (300 MHz, CDCl
ppm 7.24 (5H, m), 4.42 (2H, t, J ) 7.0 Hz), 3.16 (1H, s), 3.00
2H, t, J ) 7.0 Hz), 1.73 (3H, s), 1.30 (3H, s), 1.26 (3H, s); 13
NMR (75 MHz, CDCl ) δ ppm 171.4, 136.9, 128.7, 128.4, 126.6,
5.4, 74.4, 66.7, 34.6, 25.0, 24.8, 24.2; MS (m/z) 271 (7), 253 (4),
3
) δ
(
C
3
Anal. Calcd for C21H31ClO : C, 68.74; H, 8.52. Found: C, 68.91;
3
7
1
6
H, 8.82.
97 (9), 135 (32), 105 (100). Anal. Calcd for C14
2.11; H, 7.07. Found: C, 62.49; H, 6.67.
3
H19ClO : C,
Ack n ow led gm en t. We are grateful to Dr. Claudio
Sturino and Mr. Edward G. Corley for helpful criticism
during the preparation of this manuscript.
P h en eth yl 3-ben zyl-3-ch lor o-2-h yd r oxy-2-m eth ylbu ta n -
-
1 1
oa te (3): IR (neat) 3560, 1730 cm ; H NMR (300 MHz, CDCl
δ ppm 7.20 (8H, m), 7.16 (2H, m), 4.31 (2H, m), 3.78 (1H, d, J )
4.0 Hz), 3.51 (1H, br s), 3.14 (1H, d, J ) 14.0 Hz), 2.73 (2H, t,
3
)
1
1
3
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
J ) 7.0 Hz), 1.44 (3H, s), 1.35 (3H, s); C NMR (75 MHz, CDCl
δ ppm 170.9, 136.9, 135.5, 130.5, 128.7, 127.8, 127.0, 126.6, 81.4,
5.6, 66.8, 41.2, 34.4, 26.1, 24.6; MS (m/z) 347 (6), 289 (4), 195
19), 154 (25), 136 (21), 105 (100). Anal. Calcd for C20
3
)
spectra of compounds 1-6, 12, and 13 (17 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
7
(
H
23ClO
3
:
C, 69.26; H, 6.68. Found: C, 69.02; H, 6.61.
P h en et h yl 3,3-d ich lor o-2-h yd r oxy-2-m et h ylb u t a n oa t e
-
1
1
(
4): IR (neat) 3550, 1730 cm ; H NMR (300 MHz, CDCl
3
) δ
ppm 7.26 (5H, m), 4.50 (2H, t, J ) 7.0 Hz), 3.32 (1H, br s), 3.04
J O9803838