A concise synthesis of (S)-(+)-ginnol based on catalytic enantioselective addition of commercially unavailable Di(n -alkyl)zinc to aldehydes and ketones

Article abstract of DOI:10.1055/s-0030-1258129

Catalytic, enantioselective n-alkyl addition of commercially unavailable di(n-alkyl)zinc reagents, which were prepared by a refined version of Charettes procedure with Grignard reagents, to aldehydes and ketones was developed. To minimize the side reactions in the catalysis by chiral phosphoramide ligand (1) or 3,3-diphosphoryl-BINOL ligand (2), a preparation of di(n-alkyl)zinc reagents with a 1:2.5:1.6 molar ratio of ZnClNaOMe/RMgCl under solvent-free conditions was essential. Optically pure (S)-(+)-ginnol (17) was readily synthesized in one step for the first time by the catalytic enantioselective n-nonylation of icosanal. Georg Thieme Verlag.

Full text of DOI:10.1055/s-0030-1258129

2024
CLUSTER
A Concise Synthesis of (S)-(+)-Ginnol Based on Catalytic Enantioselective
Addition of Commercially Unavailable Di(n-alkyl)zinc to Aldehydes
and Ketones
Synthesis of
(S)-(+)-Ga
a
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Japan Science and Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Fax +81(52)7893222; E-mail: ishihara@cc.nagoya-u.ac.jp
b
Received 15 May 2010
byproduct.5 In this regard, we found that even much short-
er n-propylation of benzaldehyde did not work well due to
a recovery of the starting material (18%) and a reduction
side product (11% yield) under Charrete’s original condi-
Abstract: Catalytic, enantioselective n-alkyl addition of commer-
cially unavailable di(n-alkyl)zinc reagents, which were prepared by
a refined version of Charette’s procedure with Grignard reagents, to
aldehydes and ketones was developed. To minimize the side reac-
tions in the catalysis by chiral phosphoramide ligand (1) or 3,3¢- tions (1:2:2 molar ratio of ZnCl2/NaOMe/RMgCl) in Et2O
with the use of our chiral phosphoramide ligand 17
diphosphoryl-BINOL ligand (2), a preparation of di(n-alkyl)zinc re-
agents with a 1:2.5:1.6 molar ratio of ZnCl2/NaOMe/RMgCl under
(Scheme 1).
solvent-free conditions was essential. Optically pure (S)-(+)-ginnol
(17) was readily synthesized in one step for the first time by the cat-
alytic enantioselective n-nonylation of icosanal.
ZnCl2 + NaOMe + n-PrMgCl (molar ratio = 1:2:2) in Et2O
r.t. for 2 h, then centrifugation
(– NaOMe, – NaCl, – Zn(OMe)2, – MeOMgCl)
Key words: alcohol, asymmetric catalysis, ginnol, Grignard
reagent, zinc
O
1-Naph
N
HN P
1-Naph
Traditional Grignard reagents are some of the most useful
and safe reagents for alkylating carbonyl compounds in
academic and industrial research and process chemistry.1
Today, more than 200 inexpensive Grignard reagents can
be purchased. In particular, the transmetallation of alkyl
groups in Grignard reagents to other less-reactive metal
complexes such as ZnII and TiIV should be attractive for
the catalytic enantioselective alkylation of carbonyl com-
pounds because the reaction would proceed only when the
catalysts are present.2,3 In this regard, Harada et al. recent-
ly reported a catalytic enantioselective ZnII-free second-
ary alcohol synthesis from aldehydes and Grignard
reagents/Ti(Oi-Pr)4.4 Moreover, Côté and Charette report-
ed the preparation of salt-free di(n-alkyl)zinc reagents
from ZnCl2, NaOMe, and Grignard reagents.5 Except for
Me2Zn, Et2Zn, i-Pr2Zn, n-Bu2Zn, and Ph2Zn, dialkylzinc
reagents are not commercially available. Therefore,
Charette’s method for preparing di(n-alkyl)zinc reagents
under salt-free conditions is valuable. In that report, they
presented a few examples of the catalytic enantioselective
addition of di(n-alkyl)zinc reagents {i.e., Et2Zn,
[TBSO(CH2)4]2Zn, and (n-C10H21)2Zn} to 2-naphthalde-
hyde. However, addition of long n-alkyl chains to alde-
hydes might still be an unresolved problem since, in their
report, the representative (–)-MIB [(2S)-(–)-3-exo-(N-
morpholino)isoborneol]6-catalyzed n-decylation of 2-
naphthaldehyde gave the desired product in 63% yield
with 97% ee in addition to the undesired reduction
i-Pr
1 (10 mol%)
OH
OH
O
O
+
+
+
n-Pr2Zn
Et2O, r.t., 2 h Ph
H
n-Pr Ph
Ph
18%
H
Ph
H
(3 equiv)
4, 71%, 90% ee 11%
Scheme 1 n-Propylation under Charette’s original conditions with
the use of chiral phosphoramide ligand 1
To overcome this problematic low reactivity and/or side
reaction, we report here a catalytic enantioselective addi-
tion of various di(n-alkyl)zinc reagents to aldehydes and
ketones using chiral phosphoramide ligand (1) or chiral
3,3¢-diphosphoryl-BINOL ligand (2)8.
By taking advantage of Charette’s report,5 we found that
solvent-free di(n-alkyl)zinc reagents were effective both
to increase the reactivity and to minimize formation of the
reduction side product in the catalytic enantioselective ad-
dition to aldehydes with the use of 1. Moreover, the re-
fined 1:2.5:1.6 molar ratio of ZnCl2/NaOMe/RMgCl was
critical to suppress the adventitious racemic pathway trig-
gered by a small amount of remaining Grignard reagent.9
To expand the scope of n-alkyl groups, we prepared di(n-
alkyl)zinc reagents and performed the subsequent addi-
tion reaction to benzaldehyde under the optimized condi-
tions with the use of chiral ligand 1 (Table 1). Ethylation
(see 3), n-propylation (see 4), n-butylation (see 5), n-pen-
tylation (see 6), n-heptylation (see 7), and n-octylation
(see 8) proceeded smoothly, and the corresponding sec-
ondary alcohols were obtained in almost quantitative
yields with 92–97% ee. To our delight, as a representative
long n-alkyl chain, n-decylation also proceeded, and the
desired product 9 was obtained in >99% yield with 95%
SYNLETT 2010, No. 13, pp 2024–2028
x
x
.x
x
.2
0
1
0
Advanced online publication: 09.07.2010
DOI: 10.1055/s-0030-1258129; Art ID: Y01510ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Synthesis of (S)-(+)-Ginnol
2025
Table 1 n-Alkylation of Benzaldehyde
ZnCl2 + NaOMe + RMgCl (molar ratio = 1:2.5:1.6) in Et2O
r.t. for 2 h, then centrifugation
(– NaOMe, – NaCl, – Zn(OMe)2, – MeOMgCl).
concentration (–Et2O)
OH
O
1 (10 mol%)
R2Zn
+
solvent-free, r.t., 2 h
Ph
R
Ph
H
(3 equiv)
Product
Yield (%)
92
Enantioselectivity (% ee)
94
Alkyl source
(EtMgCl)
OH
Ph
3
OH
99
98
97
96
96
92
96
(n-PrMgCl)
Ph
4
OH
(n-BuCl·LiCl + Mg)
Ph
5
OH
>99
98
(n-C5H11Cl·LiCl + Mg)
(n-C7H15Cl·LiCl + Mg)
(n-C8H17Cl·LiCl + Mg)
Ph
6
OH
Ph
7
OH
98
Ph
8
OH
>99
95
(n-C10H21Cl·LiCl + Mg)
Ph
9
ee. When the reaction was performed in a solvent (e.g., in and the adduct 16 was obtained with high enantioselectiv-
hexane or toluene)7 a comparatively prolonged reaction ity (82% ee).11
time (2–6 h) was required, whereas under solvent-free
conditions, the reaction was completed within two hours
We next examined the synthesis of a chiral long-chain al-
iphatic alcohol, (S)-(+)-ginnol (17),12 which is an optical-
without side reactions. Remarkably, the use of Grignard
ly active natural product that has been noted in chiral
bilayers of the wax tubes of higher plants. The reaction of
icosanal (n-C19H39CHO) with di(n-nonyl)zinc [(n-
reagents prepared in situ (RCl + Mg + LiCl10) appeared to
have no negative effects (see 5–9).
The addition of other commercially unavailable di(n- C9H19)2Zn] in the presence of chiral ligand 2 (20 mol%)
alkyl)zinc reagents to a variety of aldehydes was exam- proceeded in toluene–THF (2:1) at room temperature for
ined (Table 2). Aromatic aldehydes with electron-donat- 12 hours, and enantioenriched (S)-(+)-ginnol was ob-
ing and electron-withdrawing groups and heteroaromatic tained in one step in 81% yield with 97% ee (Scheme 2).
aldehydes were acceptable for highly enantioselective To the best of our knowledge, this is the first one-step ex-
n-propylation (see 12 and 13), n-pentylation (see 10), and ample, and is thus the simplest asymmetric synthesis of
n-heptylation (see 11). n-Pentylation of aliphatic aldehyde (S)-(+)-ginnol. Fortunately, a single recrystallization in n-
gave the corresponding product 14 with moderate enan- hexane provided optically pure (S)-(+)-ginnol (>99% ee).
tioselectivity. The addition of di(n-alkyl)zinc to a,b-un-
Finally, n-alkyl addition to much less reactive ketones, in
saturated aldehydes was also examined. Although the
place of aldehydes, was examined (Scheme 3). Unfortu-
n-propylation of 1-cyclohexene-1-carbaldehyde showed
nately, n-propylation of acetophenone (18a) provided the
high enantioselectivity (15; 91% ee), phenylpropargyl al-
desired product 19a in low yield (31%), and the undesired
dehyde gave the corresponding n-propyl-adduct 16 in
aldol condensation product 20a was instead obtained. In
90% yield but with 6% ee with the use of chiral ligand 1.
sharp contrast, n-propylation of CF3-activated 3¢,5¢-
In sharp contrast, our previous chiral BINOL-derived
bis(trifluoromethyl)acetophenone (18b) proceeded with-
out aldol formation at room temperature in 24 hours, in
ligand 2 in toluene–THF (2:1)8 was found to be effective,
Synlett 2010, No. 13, 2024–2028 © Thieme Stuttgart · New York

2026
M. Hatano et al.
CLUSTER
Table 2 n-Alkylation of Aldehydes
ZnCl2 + NaOMe + RMgCl (molar ratio = 1:2.5:1.6) in Et2O
r.t. for 2 h, then centrifugation
(– NaOMe, – NaCl, – Zn(OMe)2, – MeOMgCl).
concentration (–Et2O)
1 (10 mol%)
solvent-free, r.t., 2 h
OH
O
+
R2Zn
R'
R
R'
H
(3 equiv)
Product
Yield (%)
>99
Enantioselectivity (% ee)
88
Alkyl source
OH
(n-C5H11Cl·LiCl + Mg)
Cl
10
OH
>99
98
94
87
(n-C7H15Cl·LiCl + Mg)
MeO
11
OH
O
(n-PrMgCl)
12
OH
S
98
85
98
76
(n-PrMgCl)
13
OH
(n-C5H11Cl·LiCl + Mg)
Ph
14
OH
97
91
(n-PrMgCl)
(n-PrMgCl)
15
OH
90
6
90a
82a
Ph
16
a In place of 1, chiral ligand 2 (10 mol%) was used in toluene–THF (2:1).
Ph Ph
P
O
OH
OH
O
P
Ph Ph
2
the presence of 10 mol% chiral ligand 1, and the desired ther improved the yield (70%) and enantioselectivity
tertiary alcohol 19b was obtained in 59% yield with 98% (>99% ee) of 19b; in this case, 18b was recovered (30%)
ee. Moreover, the presence of 20 mol% chiral ligand 1 fur- without any side products.
Synlett 2010, No. 13, 2024–2028 © Thieme Stuttgart · New York

CLUSTER
Synthesis of (S)-(+)-Ginnol
2027
O
References and Notes
(1) Textbooks and reviews for Grignard reagents: (a) Lai,
Y.-H. Synthesis 1981, 585. (b) Wakefield, B. J.
H
+
Organomagnesium Methods in Organic Chemistry;
Zn
Academic Press: San Diego / CA, 1995. (c) Silverman,
G. S.; Rakita, P. E. Handbook of Grignard Reagents; Marcel
Dekker: New York, 1996. (d) Richey, H. G. Jr. Grignard
Reagents: New Development; Wiley: Chichester / UK,
2000. (e) Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A.
Angew. Chem. Int. Ed. 2003, 42, 4302. (f) Knochel, P.
Handbook of Functionalized Organometallics; John Wiley
& Sons: Weinheim / Germany, 2005. (g) Rappoport, Z.;
Marek, I. The Chemistry of Organomagnesium Compounds
In The Patai Series: The Chemistry of Functional Groups;
Wiley: Chichester / UK, 2008.
(3 equiv, prepared from n-C9H19Cl⋅LiCl + Mg and Zn(OMe)2)
OH
(S)
2 (20 mol%)
toluene–THF (2:1)
r.t., 12 h
(S)-(+)-ginnol (17)
81%, 97% ee [>99% ee]a
Scheme 2 Synthesis of (S)-(+)-ginnol (17) (a Enantioselectivity af-
ter recrystallization from n-hexane.)
(2) Textbooks for preparations of organometallic reagents from
Grignard reagents: (a) Schlosser, M. Organometallics in
Synthesis, A Manual, 2nd ed.; Wiley: Chichester, 2001.
(b) Yamamoto, H.; Oshima, K. Main Group Metals in
Organic Synthesis; Wiley-VCH: Weinheim, 2004.
(c) Knochel, P. Handbook of Functionalized
ZnCl2 + NaOMe + n-PrMgCl (molar ratio = 1:2.5:1.6) in Et2O
r.t. for 2 h, then centrifugation
(– NaOMe, – NaCl, – Zn(OMe)2, – MeOMgCl)
concentration (– Et2O)
O
O
HO
Ar
Organometallics; Wiley-VCH: Weinheim, 2005.
1 (10 mol%)
+
+
n-Pr2Zn
(d) Crabtree, R. H.; Mingos, D. M. P. Comprehensive
Organometallic Chemistry III; Elsevier: Oxford, 2006.
(3) For reviews, see: (a) Soai, K.; Niwa, S. Chem. Rev. 1992,
92, 833. (b) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
(c) Bolm, C.; Hildebrand, J. P.; Muñiz, K.; Hermanns, N.
Angew. Chem. Int. Ed. 2001, 40, 3284. (d) Hatano, M.;
Miyamoto, T.; Ishihara, K. Curr. Org. Chem. 2007, 11, 127.
(e) Hatano, M.; Ishihara, K. Synthesis 2008, 1647.
(4) (a) Muramatsu, Y.; Harada, T. Angew. Chem. Int. Ed. 2008,
47, 1088. (b) Muramatsu, Y.; Harada, T. Chem. Eur. J.
2008, 14, 10560. (c) Muramatsu, Y.; Kanehira, S.;
Tanigawa, M.; Miyawaki, Y.; Harada, T. Bull. Chem. Soc.
Jpn. 2010, 83, 19.
(5) Côté, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771.
(6) MIB is an advantageous alternative to Noyori’s DAIB
[3-exo-(dimethylamino)isoborneol], see: (a) Kitamura, M.;
Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986,
108, 6071. (b) Nugent, W. A. Chem. Commun. 1999, 1369.
(c) Rosner, R.; Sears, P. J.; Nugent, W. A.; Blackmond,
D. G. Org. Lett. 2000, 2, 2511.
Ar
n-Pr
Ar
Ar
solvent-free
r.t., 24 h
(3 equiv)
18
19
20
Ar = Ph (18a): 31%, 93% ee (19a)
Ar = 3,5-(CF3)2C6H3 (18b): 59%, 98% ee (19b)
[70%, >99% ee (19b)a
69% (20a)
0% (20b)
0% (20b)]
Scheme 3 Catalytic enantioselective addition of di(n-propyl)zinc
reagents to ketones (a Yield and enantioselectivity when 20 mol%
chiral ligand 1 was used.)
In summary, we have developed a catalytic, enantioselec-
tive n-alkyl addition to aromatic and aliphatic aldehydes
and to activated aromatic ketones, with Grignard reagent-
derived di(n-alkyl)zinc reagents.13 Optically active alco-
hols with either short- or long-chain n-alkyl groups could
be successfully synthesized in high yields with high enan-
tioselectivities. To minimize the side reactions in the ca-
talysis by chiral phosphoramide ligand 1 or 3,3¢-
diphosphoryl-BINOL ligand 2, a preparation of di(n-
alkyl)zinc reagents in a refinement of Charette’s molar ra-
tio (ZnCl2/NaOMe/RMgCl, 1:2.5:1.6) under solvent-free
conditions was essential. Remarkably, optically pure (S)-
(+)-ginnol was readily synthesized by the catalytic enan-
tioselective n-nonylation of icosanal in one step. Since in-
expensive Grignard reagents are now widely available,
whereas di(n-alkyl)zinc reagents are commercially less
common, this simple method for the synthesis of optically
active alcohols may be effective, particularly for process
chemistry based on green technology.
(7) Hatano, M.; Miyamoto, T.; Ishihara, K. Org. Lett. 2007, 9,
4535.
(8) (a) Hatano, M.; Miyamoto, T.; Ishihara, K. Adv. Synth.
Catal. 2005, 347, 1561. (b) Hatano, M.; Miyamoto, T.;
Ishihara, K. Synlett 2006, 1762. (c) Hatano, M.; Miyamoto,
T.; Ishihara, K. J. Org. Chem. 2006, 71, 6474.
(9) Significantly low enantioselectivities (<20% ee) of the
products in the n-alkylation of aldehydes were sometimes
observed using a 1:2:2 molar ratio of ZnCl2/NaOMe/
RMgCl. Probably, from a small amount of remaining
RMgCl, a highly active zinc(II)-ate complex [R3Zn]–
[MgCl]+ would be generated. See: (a) Hatano, M.; Suzuki,
S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998.
(b) Hatano, M.; Suzuki, S.; Ishihara, K. Synlett 2010, 321.
(10) It has been reported that LiCl generally improves the activity
of Grignard reagents, see: (a) Krasovskiy, A.; Knochel, P.
Angew. Chem. Int. Ed. 2004, 43, 3333. (b) Armstrong,
D. R.; García-Álvarez, P.; Kennedy, A. R.; Mulvey, R. E.;
Parkinson, J. A. Angew. Chem. Int. Ed. 2010, 49, 3185.
(11) During the preliminary investigation, we found that chiral
ligand 1 was less suitable for the n-alkylation of non-
aromatic aldehydes. This is probably due to the flexibility of
non-aromatic aldehydes, which can avoid significant
Acknowledgment
Financial support for this project was provided by JSPS. KAKENHI
(20245022), MEXT. KAKENHI (21750094, 21200033), and the
Global COE Program of MEXT. We are grateful to Tosoh Fine-
chem Corp. for providing organometallic reagents.
Synlett 2010, No. 13, 2024–2028 © Thieme Stuttgart · New York

2028
M. Hatano et al.
CLUSTER
suspension was allowed to stir at 35 °C for 12 h before
repulsion in the transition states using chiral ligand 1
(Figure 1). Also see refs. 7 and 8.
titration]. The mixture was centrifuged for 10 min (4,000
rpm) and the Et2O solution of R2Zn reagent was gently
transferred via cannula into a well-dried pyrex Schlenk tube
to be stored prior to use.
H
General Procedure for the Catalytic Enantioselective
Addition of Di(n-alkyl)zinc Reagents to Aldehydes: A
well-dried pyrex Schlenk tube was charged with 1 (22.8 mg,
0.05 mmol) and the salt-free R2Zn reagent (0.4–0.6 M in
Et2O, 1.5 mmol) at r.t. under a nitrogen atmosphere. Et2O
was removed under reduced pressure to generate the solvent-
free R2Zn reagent containing 1 in situ. Aldehyde (0.5 mmol)
was added to the mixture at r.t. and the resulting mixture was
stirred at r.t. for 2 h. After hydrolysis with saturated NH4Cl
(10 mL), the product was extracted with Et2O (3 × 10 mL)
and washed with brine (10 mL). The combined extracts were
dried over MgSO4, the organic phase was concentrated
under reduced pressure and the crude product was purified
by neutral silica gel column chromatography (n-hexane–
Et2O) to give the desired products.
R'
R'
H
O
O
N
N
Zn
Zn
Zn
P
Zn
P
O
O
N
N
R
R
R
R
favored
disfavored
H
R''
R''
R'
R'
H
O
O
N
N
Zn
Zn
Zn
Zn
P
O
R
O
R
N
N
R
R
Catalytic, Enantioselective Synthesis of (S)-(+)-Ginnol
(17): A well-dried pyrex Schlenk tube was charged with 2
(68.7 mg, 0.10 mmol) and the salt-free (n-C9H19)2Zn reagent
(0.44 M in Et2O, 3.4 mL, 1.5 mmol) at r.t. under a nitrogen
atmosphere. Et2O was removed under reduced pressure to
generate the solvent-free (n-C9H19)2Zn reagent containing 2
in situ. Toluene (1.5 mL) and THF (0.7 mL) were then added
and the mixture was stirred at r.t. for 1 h. Icosanal (148.3 mg,
0.5 mmol) was added to the mixture, which was stirred at r.t.
for 12 h. After hydrolysis with saturated aqueous NH4Cl (10
mL), the product was extracted with EtOAc (3 × 10 mL) and
washed with brine (10 mL). The combined extracts were
dried over MgSO4, and the organic phase was concentrated
under reduced pressure. The crude product was purified by
neutral silica gel column chromatography (n-hexane–Et2O)
to give ginnol (172.5 mg, 81% yield). 1H NMR (400 MHz,
CDCl3): d = 0.88 (t, J = 6.9 Hz, 6 H), 1.20–135 (m, 48 H),
1.42 (m, 4 H), 1.56 (s, 1 H), 3.58 (m, 1 H). 13C NMR (100
MHz, CDCl3): d = 14.2, 22.7, 25.7, 29.3, 29.4, 29.8, 32.0,
37.6, 72.1. IR (KBr): 3449, 2917, 2850, 1467, 1561, 1101
cm–1. HRMS (EI): m/z [M]+ calcd for C29H60O: 406.4538;
found: 406.4535. [a]D20 +1.8 (>99% ee, c 2.0, CHCl3)
{Lit.12a [a]D20 +2.18 (c 1.1, CHCl3) for (S)-ginnol}.
Enantioselectivity was confirmed by HPLC analysis of the
diastereotopic (R)-MTPA-esters of the resulting ginnol.
Chiral HPLC, Daicel chiralpack AD-3 × 2 at 4 °C; n-
hexane–i-PrOH, 2000:1; flow rate = 0.1 mL/min; tR = 100.3
min [major, (S)-derivative], 103.5 min [minor, (R)-
derivative].
P
Figure 1
(12) (a) Beckmann, S.; Schühle, H. Z. Naturforsch., B 1968, 23,
471. (b) Fuhrhop, J.-H.; Bedurke, T.; Hahn, A.; Grund, S.;
Gatzmann, J.; Riederer, M. Angew. Chem., Int. Ed. Engl.
1994, 33, 350. (c) Kusumi, T.; Takahashi, H.; Hashimoto,
T.; Kan, Y.; Asakawa, Y. Chem. Lett. 1994, 23, 1093.
(d) Schwink, L.; Knochel, P. Tetrahedron Lett. 1994, 35,
9007. (e) Langer, F.; Schwink, L.; Devasagayaraj, A.;
Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 61, 8229.
(f) Berkenbusch, T.; Brückner, R. Tetrahedron 1998, 54,
11471. (g) Dommisse, A.; Wirtz, J.; Koch, K.; Barthlott, W.;
Kolter, T. Eur. J. Org. Chem. 2007, 3508.
(13) General Procedure for the Preparation of Salt-free Di(n-
alkyl)zinc Reagents: To a test tube equipped with a
magnetic stirrer and charged with ZnCl2 (682 mg, 5 mmol)
and NaOMe (676 mg, 12.5 mmol), was added Et2O (5 mL)
at r.t. under a nitrogen atmosphere. The suspension was
stirred for 20 min and cooled to 0 °C for another 10 min.
RMgCl in Et2O (8 mmol, titrated before use) was added
dropwise with vigorous stirring over 10 min at 0 °C [If
RMgCl in Et2O solution was not commercially available,
RMgCl was prepared from RCl (1 equiv), LiCl (1.1 equiv),
and magnesium turnings (1.5 equiv) in Et2O, and the
Synlett 2010, No. 13, 2024–2028 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.