LaCl3·2LiCl-catalyzed addition of Grignard reagents to ketones

Article abstract of DOI:10.1055/s-0029-1217169

The addition of Grignard reagents to ketones using substoichiometric amounts of LaCl₃·2LiCl was studied. Catalytic amounts of LaCl₃·2LiCl (30 mol%) provide, in most cases, yields similar to those obtained using a stoichiometric amoun

Full text of DOI:10.1055/s-0029-1217169

LETTER
1433
LaCl3·2LiCl-Catalyzed Addition of Grignard Reagents to Ketones
L
aCl ·2LiCl-Catal
l
yzed A
b
G
r
R
e
e
agents to
c
K
etones ht Metzger, Andrei Gavryushin, Paul Knochel*
3
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 18 February 2009
R1MgX (1; 1.1 equiv),
LaCl3⋅2LiCl (6; 0–100 mol%)
OH
O
Abstract: The addition of Grignard reagents to ketones using sub-
stoichiometric amounts of LaCl3·2LiCl was studied. Catalytic
amounts of LaCl3·2LiCl (30 mol%) provide, in most cases, yields
similar to those obtained using a stoichiometric amount.
R2
R2
R1
R3
R3
0 °C to 25 °C
2
3
Key words: 1,2-addition, lanthanides, Grignard reagents, function-
alized organometallics, lanthanum trichloride
Scheme 2 Reaction of Grignard reagents with ketones mediated by
LaCl3·2LiCl (6)
Thus, the reaction of cyclohexylmagnesium bromide (1a)
with the readily enolizable ketone 2a in the presence of
one equivalent of LaCl3·2LiCl (6) provided the tertiary
alcohol 3a in 93% yield (entry 1 of Table 1). By using 30
mol% of LaCl3·2LiCl (6) a similar yield (87%) was
achieved. Without the addition of LaCl3·2LiCl (6) only
33% of the alcohol 3a was isolated.
The addition of Grignard reagents 1 to ketones 2 leading
to tertiary alcohols of type 3 is a standard transformation
in organic synthesis (Scheme 1).1
OMgX
R3
OMgX
R3
OMgCl
R2
R3
O
H
THF
R2
1
+
R MgX
R1
+
+
R3
XXXX
R2
R2
1
2
3
4
5
The reaction of the secondary alkylmagnesium reagent (i-
PrMgCl; 1b) with 1,3-diphenylacetone (2b) was strongly
influenced by the addition of LaCl3·2LiCl (6). Thus, the
alcohol 3b was obtained in 86% with stoichiometric
amount of 6 and in 65% yield in the presence of 30 mol%
of 6 (entry 2). In the absence of LaCl3·2LiCl (6), only trac-
es of the alcohol 3b were obtained due to the occurrence
of competing reduction and enolization reactions. With
MeMgCl (1c) which does not possess b-hydrogen atoms,
similar yields were obtained regardless of the amount of
lanthanum salts added (entry 3). Reaction of phenylmag-
nesium chloride (1d) with enolizable ketone 2b led to the
desired alcohol 3d in 93–97% yield in the presence of ei-
ther 30 mol% or 100 mol% of LaCl3·2LiCl (6; entry 4).
Without LaCl3·2LiCl (6), a yield of 67% was achieved. In
the reaction of naphthylmagnesium chloride (1e) with less
sterically hindered cyclohexyl methyl ketone (2d), the in-
fluence of LaCl3·2LiCl (6) was relatively strong (entry 5).
The uncatalyzed reaction afforded the product in 22%
yield; in the presence of 30 mol% of LaCl3·2LiCl (6) a
yield of 66% was obtained. Using stoichiometric amounts
of LaCl3·2LiCl (6) led to the product 3e in 76% yield. In
the absence of a catalyst, sterically hindered Grignard re-
agents did not react satisfactorily with ketones bearing
acidic protons. Thus, reaction of 2-(trifluoromethyl)phe-
nylmagnesium chloride (1f) and acetophenone (2e) fur-
nished the corresponding alcohol 3f in 72% yield only in
the presence of LaCl3·2LiCl (6), regardless of whether
100 mol% or 30 mol% were used (entry 6). A poor yield
of 3f (13%) was observed in the absence of LaCl3·2LiCl
(6). Treatment of dicyclopropyl ketone (2f), cyclopropyl
methyl ketone (2g) and cyclohexane (2h) with various or-
ganomagnesium reagents 1g–i led to the desired alcohols
3g–i in similar yields almost independent of the
Scheme 1 Possible products of the reaction of a Grignard reagent
with a ketone
Such 1,2-addition is often complicated if sterically hin-
dered or unreactive Grignard reagents are used. In these
cases, several side reactions such as enolization (leading
to 4) or b-hydride transfer (leading to secondary alcohols
5) are observed. The formation of byproducts 4 and 5 can
be considerably reduced by using a Lewis acid activation
of the ketone 2. Lanthanide halides such as CeCl3 intro-
duced by Imamoto have proven to be especially effec-
tive.2 However, the low solubility of CeCl3 in THF
requires the use of a stoichiometric amount of these rela-
tively expensive salts.
Recently, we have reported the preparation of THF-solu-
ble LaCl3·2LiCl complex (6, 0.52–0.6 M in THF)3 which
has been found highly efficient for improving of the addi-
tion of various Grignard reagents to ketones and imines.4
This method was later applied for the synthesis of
tryptamines.5 However, LaCl3·2LiCl (6) has been used so
far only in stoichiometric amounts, while a catalytic ver-
sion of this reaction should also be possible.6 Herein, we
report the comparative study of the stoichiometric and cat-
alytic 1,2-addition reaction of various Grignard reagents7
to ketones using 30 mol% of LaCl3·2LiCl (6) (Scheme 2
and Table 1).
SYNLETT 2009, No. 9, pp 1433–1436
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x.
x
x.
2
0
0
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Advanced online publication: 18.05.2009
DOI: 10.1055/s-0029-1217169; Art ID: G07109ST
© Georg Thieme Verlag Stuttgart · New York

1434
A. Metzger et al.
LETTER
LaCl3·2LiCl (6) amount (entries 7–9). However, the posi- nesium reagents 1e and 1l and enolizable ketones 2i and
tive influence of LaCl3·2LiCl (6) was well demonstrated 2j the alcohols 3l and 3m (entries 12 and 13) were ob-
in the case of heteroaromatic organomagnesium com- tained in lower yields with LaCl3·2LiCl (6) than without
pounds such as the thiophenylmagnesium reagent 1j and the use of 6. These results show that for the addition of
especially 2-pyridylmagnesium chloride (1k; entries 10 electron-rich organomagnesium species the influence of
and 11). Reaction with ketones 2d and 2a led to the LaCl3·2LiCl (6) on the product yield can be negative.
desired alcohols 3j and 3k in 71–86% yield only in the
presence of LaCl3·2LiCl (6). Using electron-rich arylmag-
Table 1 Reaction of Grignard Reagents of Type 1 with Different Ketones of Type 2 in the Presence of LaCl3·2LiCl (6)8,9
Entry Grignard reagent of type 1
Ketone of type 2
Product of type 3
Yield (%)a
Yield (%)a
Yield (%)a
[LaCl3·2LiCl [LaCl3·2LiCl [LaCl3·2LiCl
(6; 100 mol%)] (6; 30 mol%)] (6; 0 mol%)]
HO
Me
Ph
O
33b
MgBr⋅LiCl
1
93
87
Ph
Me
1ac
2a
3a
OH
O
i-PrMgCl
Ph
Ph
2
86
95
65
94
<3
69
1bd
Ph
Ph
2b
3b
O
HO Me
MeMgCl
3
1cd
3c
2c
OH
Ph
Ph
O
67b
MgCl
4
97
93
Ph
Ph
1dd
2b
3d
O
O
Me OH
5
Me
76
72
66
72
22
13
MgCl⋅LiCl
1ee
2d
2e
2f
3e
3f
CF3
HO Me
CF3
6
Me
MgCl⋅LiCl
1fe
O
O
HO
NC
MgCl⋅LiCl
7
8
77
76
84
83
87
81
1ge
CN
3g
3h
HO Me
EtO2C
MgCl⋅LiCl
Me
1he
CO2Et
2g
Synlett 2009, No. 9, 1433–1436 © Thieme Stuttgart · New York

LETTER
LaCl3·2LiCl-Catalyzed Addition of Grignard Reagents to Ketones
1435
Table 1 Reaction of Grignard Reagents of Type 1 with Different Ketones of Type 2 in the Presence of LaCl3·2LiCl (6)8,9 (continued)
Entry Grignard reagent of type 1
Ketone of type 2
Product of type 3
Yield (%)a
Yield (%)a
Yield (%)a
[LaCl3·2LiCl [LaCl3·2LiCl [LaCl3·2LiCl
(6; 100 mol%)] (6; 30 mol%)] (6; 0 mol%)]
OMe
O
OH
MeO
MgCl⋅LiCl
9
73
74
84
1ie
2h
3i
O
10
11
Me
54
71
86
67
65
22
S
HO Me
3j
MgCl⋅LiCl
S
1je
2d
HO Me
O
Ph
N
Ph
Me
N
1ke
MgCl⋅LiCl
MgCl⋅LiCl
2a
3k
O
OH
12
13
59
55
65
62
75
70
2i
1ee
1le
3l
Me OH
MeS
SMe
O
MeO
OMe
Me
MgCl⋅LiCl
2j
3m
a Isolated yields.
b Yields determined by 1H NMR.
c Grignard reagent prepared by direct magnesium insertion in the presence of LiCl according to ref. 7a.
d Grignard reagent is commercially available by Chemetall GmbH (Frankfurt).
e Grignard reagent prepared by halogen–magnesium exchange reaction using i-PrMgCl·LiCl according to ref. 7b.
An upscaling of the above described procedure gave sat- to improve the scope of this catalytic activation of ketones
isfactory results (Scheme 3). Reaction of ketone 2b either with LaCl3·2LiCl (6) is underway in our laboratory.
with secondary alkylmagnesium reagent 1b in the pres-
ence of LaCl3·2LiCl (6; 100 mol%) or with arylmagne-
sium reagent 1d in the presence of LaCl3·2LiCl (6; 30
Acknowledgment
We thank the Fonds der Chemischen Industrie, and the DFG for
financial support. We thank Chemetall GmbH (Frankfurt) for the
generous gift of Grignard reagents and LaCl3·2LiCl solution.
mol%) furnished the expected alcohols 3b and 3d in 83–
88% yield.
OH
RMgCl (1.1 equiv)
O
LaCl3⋅2LiCl (6; 30–100 mol%)
Ph
Ph
References and Notes
Ph
Ph
0 °C to 25 °C
R
(1) For recent reviews, see: (a) Kobayashi, S.; Sugiura, M.;
Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002, 102, 2227.
(b) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727.
(2) (a) Imamoto, T.; Sugiyura, Y.; Takiyama, N. Tetrahedron
Lett. 1984, 25, 4233. (b) Imamoto, T. Pure Appl. Chem.
1990, 62, 747. (c) Martin, C. L.; Overman, L. E.; Rohde,
J. M. J. Am. Chem. Soc. 2008, 130, 7568. (d) Wang, Q.;
Chen, C. Org. Lett. 2008, 10, 1223.
2b
3b,d
3b R = i-Pr 83% (100 mol% 6)
3d R = Ph 88% (30 mol% 6)
Scheme 3 Upscaled reaction (20 mmol) of ketone 2b with either
i-PrMgCl (2b) using 100 mol% of 6 or PhMgCl (3d) using 30 mol%
of 6.
(3) LaCl3·2LiCl solution in THF is commercially available from
In conclusion, we have shown that it is possible to per-
form the addition of alkyl-, aryl- and heteroarylmagne-
sium reagents to various ketones in satisfactory yields
using catalytic amount of LaCl3·2LiCl (6). Further studies
Chemetall GmbH, Frankfurt (Germany).
(4) Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int.
Ed. 2006, 45, 497.
(5) Nicolaou, K. C.; Krasovskiy, A.; Trepanier, V. E.; Chen,
D. Y.-K. Angew. Chem. Int. Ed. 2008, 47, 4217.
Synlett 2009, No. 9, 1433–1436 © Thieme Stuttgart · New York

1436
A. Metzger et al.
LETTER
(6) The addition of Grignard reagents to imines requires only
10 mol% of LaCl3·2LiCl(6). An isolated example of the
addition of PhMgBr to camphor using 10 mol% of
1.1 Hz), 129.9, 129.5 (q, 2JCF = 31.6 Hz), 128.8 (q, 3JCF = 6.7
Hz), 128.4, 127.7, 127.1, 126.5 (q, 4JCF = 0.8 Hz), 125.4, (q,
1JCF = 273.4 Hz), 76.7, 33.0 (q, 5JCF = 1.7 Hz). MS (70 eV,
EI): m/z (%) = 266 (2) [M+], 251 (100), 231 (61), 211 (29),
183 (6), 169 (5), 121 (5). HRMS (EI): m/z calcd for
C15H13F3O: 266.0918; found: 266.0905. IR (ATR): 3463
(vw), 2983 (vw), 1602 (w), 1494 (w), 1446 (m), 1304 (vs),
1271 (s), 1164 (s), 1122 (vs), 1095 (s), 1032 (vs), 928 (m),
910 (m), 765 (vs), 754 (s), 698 (vs) cm–1.
LaCl3·2LiCl has also been reported (ref. 4).
(7) (a) For the preparation of Grignard reagents via direct
magnesium insertion into aromatic halides in the presence of
LiCl, see: Piller, F. M.; Appukkuttan, P.; Gavryushin, A.;
Helm, M.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47,
6802. (b) For the preparation of Grignard reagents via
halogen–magnesium exchange reaction, see: Krasovskiy,
A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(8) Typical Procedure 1 [30 mol% LaCl3·2LiCl (6)];
Preparation of 1-Phenyl-1-[2-(trifluoromethyl)-
(9) Typical Procedure 2 [100 mol% LaCl3·2LiCl (6)]:
Preparation of 1-Methyl-1,2,3,4-tetrahydronaphthalen-
1-ol (3c): In a flame-dried flask, flushed with argon, a-
tetralone (2c; 292 mg, 2.00 mmol) was added followed by
LaCl3·2LiCl (6; 3.85 mL, c = 0.52 M in THF, 100 mol%) and
the reaction mixture was stirred for 1 h. Then, MeMgCl (1c;
0.74 mL, c = 2.99 M in THF, 2.20 mmol) was added at 0 °C.
The ice-bath was removed. After GC analysis of a
phenyl]ethanol (3f): In a flame-dried flask, flushed with
argon, acetophenone (2e; 240 mg, 2.00 mmol) was added
followed by LaCl3·2LiCl (6; 1.15 mL, c = 0.52 M in THF, 30
mol%) and the mixture was stirred for 1 h. Then, THF (2.5
mL) was added. Into another flame-dried and argon-flushed
flask 2-(trifluoromethyl)bromobenzene (495 mg, 2.20
mmol) was added followed by i-PrMgCl·LiCl (1.32 mL,
c = 1.64 M in THF, 2.16 mmol). After GC analysis of a
hydrolyzed aliquot showed full conversion, the resulting
aromatic Grignard reagent 1f was added to the ketone at 0
°C. The reaction mixture was stirred at this temperature until
full conversion was achieved. Then, sat. NH4Cl solution (50
mL) was added and the layers were separated followed by
extraction using Et2O (3 × 50 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo.
Flash column chromatography (pentane–Et2O = 7:1 + 1.0
vol% Et3N) furnished the alcohol 3f as a pale yellow liquid
(381 mg, 72%). 1H NMR (600 MHz, C4D10O): d = 7.80 (d,
J = 7.6 Hz, 1 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.49 (t, J = 7.4
Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 2 H),
7.18 (t, J = 7.6 Hz, 2 H), 7.11 (t, J = 7.4 Hz, 1 H), 4.31 (s, 1
H), 1.93 (s, 3 H). 13C NMR (150 MHz, C4D10O): d = 149.9
hydrolyzed aliquot showed full conversion sat. NH4Cl
solution (50 mL) was added and the layers were separated
followed by extraction using Et2O (3 × 50 mL). The
combined organic layers were dried over Na2SO4 and
concentrated in vacuo. Flash column chromatography
(pentane–Et2O = 9:1 + 1.0 vol% Et3N) furnished the alcohol
3c as a white solid (307 mg, 95%); mp 92–94 °C. 1H NMR
(300 MHz, C6D6): d = 7.52–7.58 (m, 1 H), 7.04–7.11 (m, 1
H), 6.98–7.04 (m, 1 H), 6.84–6.90 (m, 1 H), 2.39–2.60 (m,
2 H), 1.42–1.70 (m, 5 H), 1.39 (s, 3 H). 13C NMR (75 MHz,
C6D6): d = 143.7, 136.2, 128.8, 127.1, 126.9, 126.5, 70.2,
40.0, 31.1, 30.2, 20.7. MS (70 eV, EI): m/z (%) = 162 (1)
[M+], 147 (100), 129 (56), 119 (17), 91 (32), 84 (34), 44 (6).
HRMS (EI): m/z calcd for C11H14O: 162.1045; found:
162.1040. IR (ATR): 3313 (m), 2969 (w), 2933 (m), 2865
(w), 1487 (m), 1440 (m), 1366 (m), 1337 (m), 1284 (m),
1230 (w), 1184 (m), 1152 (m), 1103 (s), 1066 (m), 1048 (m),
990 (m), 949 (m), 930 (s), 854 (m), 761 (vs), 728 (s), 686 (s)
cm–1.
(q, 5JCF = 1.6 Hz), 148.4 (q, 3JCF = 1.4 Hz), 131.6 (q, 4JCF
=
Synlett 2009, No. 9, 1433–1436 © Thieme Stuttgart · New York

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