Convenient method for the preparation of the 2-methyl thiophen-3-yl magnesium bromide lithium chloride complex and its application to the synthesis of 3-substituted 2-methylthiophenes

Article abstract of DOI:10.1080/00397911.2011.606391

Lithium chloride was found to accelerate formation of the Grignard reagent from inactive 3-bromo-2-methylthiophene (1) and commercial magnesium metal. Based on this finding, a convenient and potentially scalable preparation of ethyl 2-methylthiophene-3-ca

Full text of DOI:10.1080/00397911.2011.606391

This article was downloaded by: [Illinois State University Milner Library]
On: 24 November 2012, At: 07:34
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Convenient Method for the Preparation
of the 2-Methyl Thiophen-3-yl
Magnesium Bromide Lithium Chloride
Complex and Its Application to
the Synthesis of 3-Substituted 2-
Methylthiophenes
Masakazu Kogami a & Nobuhide Watanabe a
a Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd.,
Mie, Japan
Accepted author version posted online: 21 Feb 2012.Version of
record first published: 13 Nov 2012.
To cite this article: Masakazu Kogami & Nobuhide Watanabe (2013): Convenient Method for the
Preparation of the 2-Methyl Thiophen-3-yl Magnesium Bromide Lithium Chloride Complex and Its
Application to the Synthesis of 3-Substituted 2-Methylthiophenes, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:5, 681-688
To link to this article: http://dx.doi.org/10.1080/00397911.2011.606391
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,

demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 43: 681–688, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.606391
CONVENIENT METHOD FOR THE PREPARATION
OF THE 2-METHYL THIOPHEN-3-YL MAGNESIUM
BROMIDE LITHIUM CHLORIDE COMPLEX AND ITS
APPLICATION TO THE SYNTHESIS OF 3-SUBSTITUTED
2-METHYLTHIOPHENES
Masakazu Kogami and Nobuhide Watanabe
Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie,
Japan
GRAPHICAL ABSTRACT
Abstract Lithium chloride was found to accelerate formation of the Grignard reagent from
inactive 3-bromo-2-methylthiophene (1) and commercial magnesium metal. Based on this
finding, a convenient and potentially scalable preparation of ethyl 2-methylthiophene-3-
carboxylate (3) was achieved. In addition, this process has been found to provide a new,
general approach to 3-substituted 2-methylthiophenes.
Keywords Activator; 3-bromo-2-methylthiophene; Grignard reagent; lithium chloride
INTRODUCTION
Thiophenes serve as the central pharmacophore in drug discovery and their bioi-
sosteric replacement of a benzene ring is widely accepted as a powerful strategy to
improve biological activity and pharmacodynamic and pharmacokinetic properties.[1]
Therefore, use of thiophenes as building blocks undoubtedly continues to receive much
attention in the pharmaceutical industry.
In the course of our program for development of a new and convenient method for
preparation of 3-substituted 2-methylthiophenes, we reported a safe and efficient pro-
cess for preparation of ethyl 2-methylthiophene-3-carboxylate (3).[2] This process relies
on the LiCl-catalyzed halogen–metal exchange reaction of 3-bromo-2-methylthiophene
(1) with i-PrMgCl, wherein the highly reactive 3-(2-methylthienyl)magnesium chloride
Received May 24, 2011.
Address correspondence to Nobuhide Watanabe, Drug Discovery Laboratories, Sanwa Kagaku
Kenkyusho Co., Ltd., 363 Shiosaki, Houkusei-cho, Inabe, Mie 511-0406, Japan. E-mail:
no_watanabe@skk-net.com
681

682
M. KOGAMI AND N. WATANABE
Scheme 1. Synthesis of 3 via Grignard reagents 2 or 4.
LiCl complex (2ꢀLiCl) was generated, and has successfully been applied to the 5-kg
input-scale production of 3 at a yield of 63% and a purity of 91% by high-performance
liquid chromatography (HPLC). As a logical extension, we were interested in appli-
cation of the process to preparation of 3-substituted 2-methylthiophenes. Herein, we
are pleased to report a more efficient procedure for the preparation of 4ꢀLiCl and the
scope and limitations of this methodology.
RESULTS AND DISCUSSION
Scalability of our process was limited by the cost and volume efficiency of a
commercial Grignard solution, consisting of i-PrMgCl in tetrahydrofuran (THF).
Poor reactivity of 1, however, had hampered the use of the traditional method utiliz-
ing Mg metal.[2,3] Nevertheless, we persisted in screening for an activator of Mg
metal because there seemed to be no alternative solution, and we were gratified to
find that LiCl itself could accelerate the formation of 4 from 1 and commercial
Mg metal. Thus, by using 0.1 molar equivalent of LiCl, formation of the Grignard
reagent was immediately initiated at room temperature and conversion was greater
than 80% complete within 1 h of addition of 1. Based on these findings, we addition-
ally examined whether 0.1 molar equivalent of TurboGrignard reagent accelerated
the formation and observed that the catalytic reagent had virtually the same effect
as LiCl (data not shown). From a viewpoint of cost of the goods, we chose the
use of LiCl for further investigation. In the context of Knochel protocols, the use
of diisobutylaluminiumhydride (DIBAL) has usually been applied for the formation
of TurboGrignard reagents with Mg metal, and potential of LiCl as the activator has
not been reported. Few literature precedents drove us to confirm the performance of
LiCl.[4] As shown in Table 1, the rate of formation was slightly improved with
increases in LiCl loading, and 1.5 molar equivalents of LiCl led to the maximum con-
version of 88% within 0.5 h. The trap experiments with ethyl chloroformate gave the

3-SUBSTITUTED 2-METHYLTHIOPHENES
683
Table 1. Effect of LiCl on formation of 4 and 3
Conversion (%)
Product composition
(area%)
Amount of LiCl
(mol eq.)
30 min
4a:1
60 min
4a:1
Entry
3b:5:6
1
2
3
4
0.1
0.5
1.0
1.5
67:33
80:20
84:16
88:12
83:17
87:13
88:12
88:12
75 (62):19:1.7
78 (66):17:0.3
80 (68):15:0.2
81 (66):15:0.1
aDetermined by HPLC analysis after conversion into 8.
bIsolated yields (%) are given in parentheses.
expected product 3 accompanied by by-product 5 in 15 to 19 area% yields, which
reveals formation of the more stable magnesiated species 7 in the reaction mixture.
This not only would explain the observed incompleteness of the conversion of 1 to 4
but also implies that LiCl might suppress the formation of 7. The remarkable
acceleration observed with LiCl shows this process to be reliable. To demonstrate
its robustness, we used LiCl to successfully implement a 300-g input-scale synthesis
of 3 with a yield of 64% after vacuum distillation.
With the successful results in hand, we next investigated the scope of the pro-
cess by introduction of various functional groups at C-3 of 4 (Table 2). The Grignard
Table 2. Synthesis of functionalized thiophenes 3 or 9 by the reaction of 4 ꢀ LiCl with
various electrophiles
Entry
Electrophile
E
Product
Yielda (%)
1
2
PhCHO
t-BuCHO
i-PrCHO
DMF
CH(OH)Ph
CH(OH)Bu-t
CH(OH)Pr-i
CHO
9a
9b
9c
9d
9e
9f
76
57
73
68
56
86
82
37
83
66
55
38
72
50
89
3
4
5
MeSO2SMe
I2
=
PhCH NTs
SMe
I
6
7
PhCHNHTs
CN
9g
9h
9i
8
TsCN
Boc2O
CO2
9
CO2Bu-t
CO2H
CO2Et
10
11
12
13
14
15
9j
EtOCOCN
Me2NCOCl
PhCOPh
PhCOMe
MeCOPr-i
3
CONMe2
PhC(OH)Ph
PhC(OH)Me
MeC(OH)Pr-i
9k
91
9m
9n
aIsolated yield after column chromatography.

684
M. KOGAMI AND N. WATANABE
stock solution was prepared using 1.5 molar equivalents of LiCl on a 30-mmol scale
and could be stored at room temperature for several days without any significant
decomposition. Despite of much latitude of LiCl loadings, we chose the use of
1.5 molar equivalents of LiCl as a precaution. All electrophiles were added at
ꢁ5 ꢂC and the reaction mixtures were allowed to warm to room temperature to bring
the reactions to completion. As expected, a large array of electrophiles was tolerated,
especially carbonyl functional groups such as ketones or aldehydes (entries 1–3 and
13–15), resulting in relatively good yields. In addition, the hindered electrophiles
(entries 2, 13, and 15) reacted with good to excellent yields. These data are thought
to provide a new method for preparation of 3-substituted 2-methylthiophenes.
In summary, on the basis of the findings that LiCl accelerated the formation of
Grignard reagents from inactive 1 and commercial Mg metal, we achieved a con-
venient and potentially scalable preparation of 3. The process has been applied to
the synthesis of 3-substituted 2-methylthiophenes and was found to be compatible
with various functional groups. The underlying mechanism of the LiCl acceleration
will be reported in due course.
EXPERIMENTAL
All reagents and solvents were commercially available and were used without
1
further purification. The H NMR spectra were recorded by a Bruker Avance III
spectrometer operating at 400 MHz in CDCl3 at 25 ꢂC with tetramethylsilane
(TMS) as the internal standard. The data are reported as follows: chemical shift in
ppm (d), integration, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
br ¼ broad, m ¼ multiplet), and coupling constant (Hz). Liquid chromatography=
mass spectrometry (LC=MS) data were obtained on an Agilent 1200RRLC=6140
SQ system. Gas chromatography (GC) data were obtained on an Agilent
Technologies 7890A GC system coupled to a 5975C VLMSD mass spectrometer with
a 7683B series injector. High-resolution mass spectra (HRMS) were obtained from a
Bruker Daltonics Apex III 7.0 Tesla FTMS. Infrared (IR) spectra were recorded as
a thin film on sodium chloride plates or as dilute chloroform solutions using a
Shimadzu Prestige-21 instrument. The following systems were used for quantitative
HPLC analysis: HPLC detector, Waters 2489 UV=visible detector, HPLC column,
Capcellpak C18 MGII column (3.0 mM, 20 ꢃ 2.0 mm, Shiseido) at 40 ꢂC. The flow rate
of the mobile phase was 0.4 ml=min, and detection was performed at 254 nm.
Demonstration Batch on a 300-g Input Scale
A three-necked, 3-L, round-bottomed flask equipped with a reflux condenser
was charged with magnesium turnings (50.3 g, 2.07 mol, >99.5% purity; Wako Pure
Chemical Industries, Japan), lithium chloride (87.7 g, 2.07 mol, >99% purity; Wako
Pure Chemical Industries, Japan), and THF (310 ml) at 25 ꢂC. To this mixture,
one-tenth of a solution of 3-bromo-2-methylthiophene (312.3 g, ca. 1.38 mol) in
THF (620 ml) was added at 25 ꢂC. After the transient exotherm subsided, the remain-
ing solution was added dropwise to the mixture at such a rate that gentle refluxing
was maintained. After the addition was complete, the reaction mixture was stirred
for an additional 1 h at room temperature, at which time HPLC analysis indicated

3-SUBSTITUTED 2-METHYLTHIOPHENES
685
that 8.6% of 1 was left. The mixture was cooled to ꢁ20 ꢂC, and then ethyl chlorofor-
mate (197 ml, 2.07 mol) was added dropwise to the mixture over 40 min at such a rate
that the internal temperature was below 0 ꢂC during the addition. The mixture was
stirred for an additional 2 h at 0 ꢂC and then quenched with 2 M hydrochloric acid
(1000 ml). The resulting mixture was stirred for 30 min and extracted with n-heptane
(1000 ml). The organic layers were washed with H2O (800 ml) and brine (800 ml) and
dried over anhydrous sodium sulfate. After evaporation of the solvents, the residue
was purified by distillation under reduced pressure to afford compound 3[2] (168.6 g,
yield 64%, purity 93% by HPLC) as a pale yellow oil. Bp 90–111 ꢂC (6 mmHg).
Preparation of a Stock Solution of 4
A three-necked flask equipped with a reflux condenser was charged with
magnesium turnings (1.09 g, 45 mmol, >99.5% purity; Wako Pure Chemical Indus-
tries, Japan), lithium chloride (1.91 g, 45 mmol, >99% purity; Wako Pure Chemical
Industries, Japan), and THF (5 ml) at 25 ꢂC. To this solution, one-tenth of a solution
of 3-bromo-2-methylthiophene (5.33 g, 30 mmol) in THF (10 ml) was added at 25 ꢂC.
After the transient exotherm subsided, the remaining solution was added dropwise to
the mixture at such a rate that gentle refluxing was maintained. After the addition
was complete, the reaction mixture was stirred for an additional 1 h at room
temperature. The yield and the concentration of the Grignard solution were
calculated to be 84% and 1.25 M, respectively, by a standard titration method.[5]
Representative Procedure for Preparation of 9l
A solution of benzophenone (182mg, 1 mmol) in THF (0.2 ml) was added drop-
wise to the stock solution described previously (0.8 ml, 1.25M) over 10 min at ꢁ5 ꢂC
under a nitrogen atmosphere. The reaction mixture was allowed to warm to room
temperature and stirring was continued for an additional 2 h. Then, the reaction was
quenched with saturated. aqueous NH4Cl (2ml) and extracted with n-heptane
(2mlꢃ 2). The combined organic layers were washed with brine and dried over Na2SO4.
After evaporation of the solvents, the residue was purified by preparative TLC (PE=
1
EA¼ 10=1) to give 202 mg of 9l as white solids (yield 72%). Mp 61–63 ꢂC. H NMR
d 7.43–7.21 (m, 10H), 6.89 (d, J ¼ 5.3 Hz, 1H), 6.44 (d, J ¼ 5.3 Hz, 1H), 2.79 (s, 1H),
2.15 (s, 3H). FT-IR (film): 3473.80, 3057.17, 3026.31, 2954.95, 2920.23 cmꢁ1. MS (ESIþ)
m=z: 280, HRMS (ESIþ) m=z calcd. for C18H16NaOS: 303.0820; found: 303.0820.
1-(2-Methylthiophen-3-yl)phenylmethanol (9a)
1
Yield 76%; H NMR (400 MHz, CDCl3) d 7.39–7.28 (m, 4H), 7.28–7.21 (m,
1H), 6.99 (d, J ¼ 5.2 Hz, 1H), 6.89 (d, J ¼ 5.2 Hz, 1H), 5.88 (s, 1H), 2.43 (s, 3H),
2.24 (br s, 1H). FT-IR (film): 3383.14, 3061.03, 2918.30 cmꢁ1. MS (ESIþ) m=z: 187
[M-OH], HRMS (ESIþ) m=z calcd. for C12H11S: 187.0581 [M-OH]; found: 187.0580.
2,2-Dimethyl-1-(2-methylthiophen-3-yl)propan-1-ol (9b)
1
Yield 57%; mp 35–37 ꢂC. H NMR (400 MHz, CDCl3) d 7.01 (d, J ¼ 0.8 Hz,
2H), 4.50 (s, 1H), 2.40 (s, 3H), 1.72 (br s, 1H), 0.95 (s, 9H). FT-IR (film): 3387.00,

686
M. KOGAMI AND N. WATANABE
2954.95, 2906.73 cmꢁ1. MS (ESIþ) m=z: 167 [M-OH], HRMS (ESIþ) m=z calcd. for
C10H15S: 167.0894 [M-OH]; found: 167.0890.
2-Methyl-1-(2-methylthiophen-3-yl)propan-1-ol (9c)
1
Yield 73%; H NMR (400 MHz, CDCl3) d 7.03 (d, J ¼ 5.2 Hz, 1H), 6.98 (d,
J ¼ 5.2 Hz, 1H), 4.40 (d, J ¼ 8.0 Hz, 1H), 2.41 (s, 3H), 2.03–1.86 (m, 1H), 1.73 (br
s, 1H), 1.07 (d, J ¼ 6.6 Hz, 3H), 0.76 (d, J ¼ 6.8 Hz, 3H). FT-IR (film): 3385.07,
2956.87, 2870.08 cmꢁ1. MS (ESIþ) m=z: 153 [M-OH], HRMS (ESIþ) m=z calcd.
for C9H14NaOS: 193.0663; found: 193.0660.
2-Methylthiophene-3-carbaldehyde (9d)
Yield 68%; 1H NMR d 10.04 (s, 1H), 7.38 (d, J ¼ 5.3 Hz, 1H), 7.06 (d,
J ¼ 5.3 Hz, 1H), 2.79 (s, 3H). IR (film): 2924.09, 2831.50, 2736.99, 1674.21 cmꢁ1
.
MS (EIþ) m=z: 126, HRMS (EIþ) m=z calcd. for C6H6OS: 126.0139; found: 126.0137.
2-Methyl-3-(methylthio)thiophene (9e)
1
Yield 56%; H NMR d 7.07 (d, J ¼ 5.3 Hz, 1H), 6.96 (d, J ¼ 5.3 Hz, 1H), 2.47
(s, 3H), 2.36 (s, 3H). IR (film): 2922.16, 1614.42 cmꢁ1. MS (EIþ) m=z: 144, HRMS
(EIþ) m=z calcd. for C6H8S2: 144.0067; found: 144.0065.
3-Iodo-2-methylthiophene (9f)
1
Yield 86%; H NMR d 7.07 (d, J ¼ 5.3 Hz, 1H), 6.96 (d, J ¼ 5.3 Hz, 1H), 2.43
(s, 3H). IR (film): 2920.23, 2856.58, 1438.90 cmꢁ1. MS (EIþ) m=z: 223, HRMS (EIþ)
m=z calcd. for C5H5IS: 223.9157; found: 223.9157.
4-Methyl-N-((2-methylthiophen-3-yl)(phenyl)methyl)benze
nesulfonamide (9g)
Yield 82%; mp 136–138 ꢂC. 1H NMR d 7.52 (d, J ¼ 8.3 Hz, 2H), 7.28–7.16 (m,
5H), 7.12 (d, J ¼ 8.0 Hz, 2H), 6.85 (d, J ¼ 5.3 Hz, 1H), 6.57 (d, J ¼ 5.3 Hz, 1H), 5.65
(d, J ¼ 7.0 Hz, 1H), 5.11 (d, J ¼ 7.0 Hz, 1H), 2.37 (s, 3H), 2.22 (s, 3H). IR (film):
3439.08, 3271.27, 2918.30, 1323.17, 1157.29 cmꢁ1. MS (ESIþ) m=z: 380 [M þ Na],
HRMS (EIþ) m=z calcd. for C19H19NNaO2S2: 380.0755; found: 380.0759.
2-Methylthiophene-3-carbonitrile (9h)
1
Yield 37%; H NMR d 7.06 (d, J ¼ 5.4 Hz, 1H), 7.03 (d, J ¼ 5.4 Hz, 1H), 2.58
(s, 3H). IR (film): 3115.04, 2924.09, 2223.92 cmꢁ1. MS (EIþ) m=z: 123, HRMS (EIþ)
m=z calcd. for C6H5NS: 123.0143; found: 123.0143.

3-SUBSTITUTED 2-METHYLTHIOPHENES
687
tert-Butyl 2-methylthiophene-3-carboxylate (9i)
1
Yield 83%; H NMR d 7.27 (d, J ¼ 5.4 Hz, 1H), 6.87 (d, J ¼ 5.4 Hz, 1H), 2.63
(s, 3H), 1.50 (s, 9H). IR (film): 3001.24, 2929.87, 1707.00 cmꢁ1. MS (EIþ) m=z: 198,
HRMS (EIþ) m=z calcd. for C10H14O2S: 198.0715; found: 198.0717.
2-Methylthiophene-3-carboxylic Acid (9j)
Yield 66%; mp 112–115 ꢂC. 1H NMR d 7.45 (d, J ¼ 5.4 Hz, 1H), 7.00 (d,
J ¼ 5.4 Hz, 1H), 2.77 (s, 3H). IR (film): 3122.75, 2922.16, 2619.33, 2536.39,
1676.14, 1533.41, 1282.66 cmꢁ1. MS (ESIþ) m=z: 142, HRMS (ESIþ) m=z calcd.
for C6H5O2S: 141.0010; found: 141.0016.
N,N,2-Trimethylthiophene-3-carboxamide (9k)
1
Yield 38%; H NMR d 7.00 (d, J ¼ 5.2 Hz, 1H), 6.84 (d, J ¼ 5.2 Hz, 1H), 2.95
(d, J ¼ 59.1 Hz, 6H), 2.40 (s, 3H). IR (film): 2922.16, 2682.36, 1633.71 cmꢁ1. MS
(ESIþ) m=z: 169, HRMS (ESIþ) m=z calcd. for C8H11NNaOS: 192.0459; found:
192.0459.
1-(2-Methylthiophen-3-yl)-1-phenylethanol (9m)
1
Yield 50%; H NMR d 7.40–7.34 (m, 2H), 7.34–7.27 (m, 2H), 7.25–7.20 (m,
1H), 7.09 (d, J ¼ 5.3 Hz, 1H), 7.00 (d, J ¼ 5.3 Hz, 1H), 2.14 (s, 4H), 1.92 (s, 3H).
IR (film): 3450.65, 2974.23, 2924.09 cmꢁ1. MS (ESIþ) m=z: 200 [M-OH], HRMS
(ESIþ) m=z calcd. for C13H14NaOS: 241.0663; found: 241.0659.
3-Methyl-2-(2-methylthiophen-3-yl)butan-2-ol (9n)
1
Yield 89%; H NMR d 6.92 (d, J ¼ 5.4 Hz, 1H), 6.85 (d, J ¼ 5.4 Hz, 1H), 2.56
(s, 3H), 2.10 (hept, J ¼ 6.8 Hz, 1H), 1.74 (br s, 1H), 1.51 (s, 3H), 0.88 (dd, J ¼ 14.3,
6.8 Hz, 6H). IR (film): 3471.87, 2968.45, 2933.73 cmꢁ1. MS (ESIþ) m=z: 167 [M-OH],
HRMS (ESIþ) m=z calcd. for C10H15S: 167.0894; found: 167.0896.
REFERENCES
1. For a recent review, see Matsuoka, H.; Ohta, M. Heterocyclic bioisostere, fundamentals,
and applications. Farumashia. 2010, 46, 215.
2. Kogami, M.; Watanabe, N. Practical preparation of ethyl 2-methylthiophene-3-carboxylate.
Chem. Pharm. Bull. Jpn. 2011, 59, 797.
3. (a) Rieke, R. D.; Kim, S.-H.; Wu, X. Direct preparation of 3-thienyl organometallic
reagents: 3-Thienylzinc and 3-thienylmagnesium iodides and 3-thienylmagnesium bromides
and their coupling reactions. J. Org. Chem. 1997, 62, 6921; (b) Alcaraz, M.-L.; Atkinson,
S.; Cornwall, P.; Foster, A. C.; Gill, D. M.; Humphries, L. A.; Keegan, P. S.; Kemp, R.;
Merifield, E.; Nixon, R. A.; Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowan,
P.; Sadler, P.; Singleton, J. T.; Tornos, J.; Watts, A. J.; Woodland, I. A. Efficient synthesis
of AZD4407 via thioester formation by nucleophilic attack of organometallic species on
sulfur. Org. Process Res. Dev. 2005, 9, 555.

688
M. KOGAMI AND N. WATANABE
4. For reviews for activation of magnesium metal, see (a) Tilstam, U.; Weinmann, H.
Activation of Mg metal for safe formation of Grignard reagents on plant scale. Org. Pro-
cess Res. Dev. 2002, 6, 906; (b) Furstner, A. Chemistry of and with highly reactive metals.
Angew. Chem., Int. Ed. Engl. 1993, 32, 164; (c) Lai, Y.-H. Grignard reagents from chemi-
cally activated magnesium. Synthesis 1981, 585; (d) For a recent review, see Preparation of
polyfunctional arylmagnesium, arylzinc, and benzylic zinc reagents by using magnesium in
the presence of LiCl. Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.; Gavryushin,
A.; Knochel, P. Chem. Eur. J. 2009, 15, 7192.
5. Krasovskiy, A.; Knochel, P. Convenient titration method for organometallic zinc, magnes-
ium, and lanthanide reagents. Synthesis 2006, 890.