The chemistry of alkylstrontium halide analogues: Barbier-type alkylation of imines with alkyl halides

Article abstract of DOI:10.1246/cl.2005.760

The chemistry of alkylstrontium halide analogues was examined. In the presence of metallic strontium, the Barbier-type alkylation of imines with alkyl iodides proceeded smoothly at room temperature under an argon atmosphere to afford the corresponding alk

Full text of DOI:10.1246/cl.2005.760

760
Chemistry Letters Vol.34, No.6 (2005)
The Chemistry of Alkylstrontium Halide Analogues:
Barbier-type Alkylation of Imines with Alkyl Halides
Norikazu Miyoshi,Ã Daitetsu Ikehara, Tadashi Kohno, Aki Matsui, and Makoto Wada
Department of Chemistry, Faculty of Integrated Arts and Sciences, The University of Tokushima,
1-1 Minamijosanjima, Tokushima 770-8502
(Received March 18, 2005; CL-050368)
The chemistry of alkylstrontium halide analogues was ex-
First, using N-benzylideneaniline (PhCH=NPh), the alkyla-
amined. In the presence of metallic strontium, the Barbier-type
alkylation of imines with alkyl iodides proceeded smoothly at
room temperature under an argon atmosphere to afford the cor-
responding alkylated amines in good yields.
tion of imine with methyl iodide was examined under various re-
action conditions. As shown in Table 1, when 1.3 molar amount
of methyl iodide was added to a THF10 suspension of 2.0 molar
amounts of metallic strontium11 and 1.0 molar amount of N-ben-
zylideneaniline at room temperature, reaction proceeded to af-
ford C-monomethylated amine and N,C-dimethylated amine in
23% and 27% yields, respectively (Entry 2). Increasing the
amount of methyl iodide led to a corresponding increase in
N,C-dimethylated amine, which was obtained as a sole product
in 90% yield using 3.3 molar amounts of methyl iodide and
1.5 molar amounts of metallic strontium to the imine (Entry 4).
Next, the scope and versatility of the present reaction were
investigated by using various alkyl iodides, and the results are
summarized in Table 2. We found that, in contrast to using meth-
yl iodide, N-Benzylideneaniline reacted with other alkyl iodides
to afford the corresponding C-monoalkylated adducts as main or
sole products in good yields. It is assumed that, during reaction,
the steric hindrance presented by these more bulky alkyl halides,
influenced the products obtained.12 It was noteworthy, as shown
in Entries 4 and 5, that the reactions of N-benzylideneaniline
with a sec-alkyl or tert-alkyl iodide, such as isopropyl iodide
or tert-butyl iodide, proceeded smoothly to give the correspond-
ing adducts in moderate to good yields (55% or 61%, respective-
ly). It is well-known that as the size and branching of alkyl
groups at imines increases, addition yields decrease and reduc-
tion products such as pinacol-type self-coupling products are
often generated.13 However, in the reaction of organometallic
reagents with N-benzylideneaniline, the addition of MgBr2 (2
equiv.) to solutions of organometallic reagents (such as ethyl-
magnesium bromide, diethylcadmium, or diethylzinc) results
in dramatic yield improvements.14 In the absence of other metal
salts, increasing yield requires a 1:2 ratio of N-benzylideneani-
line to Grignard reagent.15 However, with our method it is not
necessary to use any additives, and it is sufficient to use 1.5
Organometallic compounds are some of the most versatile
reagents, and among them are organometallic compounds of al-
kaline-earth elements.1,2 Numerous reports have been published
on the Grignard (or Barbier) reaction using metallic magnesium
and alkyl halides, which is one of the most useful and convenient
methods in organic synthesis.3 Also there are various reports on
the preparation and reactivity of the organometallic compounds
of calcium and barium.2 In contrast, fewer studies on the prepa-
ration and reactivity of organostrontium compounds are found in
the literature.4,5 We have investigated synthetic reactions using
strontium compounds and have already reported the alkylation
of aldehydes with alkyl iodides using metallic strontium.6 When
we extended our investigation to include the addition reaction of
imines, we found that alkylation of imines with alkyl iodides
using strontium metal proceeded smoothly to afford the
corresponding adducts in good yields. Although the addition
of organometallic reagents to C=N bonds of imine derivatives
is an established and well-known reaction,7 it’s development
has been limited compared to additions to aldehydes and ke-
tones. One of reasons may be the poor electrophilicity of the azo-
methine carbon. To increase the electrophilicity of C=N bonds,
several strategies were developed such as the introduction of
electron-withdrawing groups at N atoms, or the activation of
the C=N bonds by coordination to a Lewis acid.8 Nevertheless,
Barbier-type additions of simple imines have been severely
limited, except for allylations.9 Thus, to our knowledge, stronti-
um-mediated Barbier-type alkylations are hitherto unknown in
the literature.
Table 1. Investigation of the molar ratio of methyl iodide to
N-benzylideneanilinea
Table 2. Investigation of alkylation using several alkyl iodidesa
Ph
Ph
R
Ph
Me
Ph
Ph
H
Ph
H
HN
HN
N
N
Sr, R-I
rt, THF
Sr, Me-I
rt, THF
N
N
+
+
Ph
R
Ph
Me
product A
Ph
product B
R
Ph
product B
Me
Ph
Ph
product A
Entry m.a.(Sr) m.a.(MeI) Yield(A)/%a Yield(B)/%b
Entry R- m.a.(Sr) m.a.(R-I) Yield(A)/%b Yield(B)/%b
1
2
3
4
5
1.0
2.0
2.0
1.5
2.0
1.3
1.3
2.2
3.3
5.2
19
23
14
trace
trace
b
41
27
82
90
93
1
2
3
4
5
Et
1.5
1.5
2.0
2.0
3.0
1.5
1.5
2.2
2.2
3.0
87
95
82
55
61
trace
trace
trace
trace
trace
n-Bu
i-Bu
i-Pr
t-Bu
aSee ref. 16 for a reaction procedure. Isolated yields.
aSee ref. 16 for a reaction procedure. Isolated yields.
b
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.6 (2005)
761
Table 3. Investigation of alkylation using several iminesa
ences cited therein. c) N. Miyoshi, ‘‘Product Class 8: Strontium
Compounds,’’ in ‘‘Houben-Weyl: Methods of Molecular Transfor-
mation, Science of Synthesis,’’ ed. by H. Yamamoto, Thieme,
Stuttgart (2004), Vol. 7, p 685, and see also ‘‘Product 5, 6, 7 and
9’’ in ‘‘Science of Synthesis’’ Vol. 7 for Beryllium, Magnesium,
Calcium and Barium, respectively.
For the synthesis of alkylcalcium halide and the reaction using Rieke
calcium, see: a) K. Mochida, S. Ogura, and T. Yamanishi, Bull.
Chem. Soc. Jpn., 59, 2633 (1986). b) T. Wu, H. Xiong, and R. D.
Rieke, J. Org. Chem., 55, 5045 (1990). c) R. A. O’Brien, T. Chen,
and R. B. Rieke, J. Org. Chem., 57, 2667 (1992). For the reaction
using Rieke barium, see: d) A. Yanagisawa, S. Habaue, and H.
Yamamoto, J. Am. Chem. Soc., 113, 8955 (1991). e) A. Yanagisawa,
S. Habaue, K. Yasue, and H. Yamamoto, J. Am. Chem. Soc., 116,
6130 (1994).
R2
R2
N
HN
R1
1.5 m.a. Sr,
1.5 m.a. n-Bu-I
R1
1.0 m.a.
H
rt, THF
Bu-n
2
Entry
R1-
R2-
Yield/%b
1
2
3
4
5
6
7
8
9
10
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
C6H5CH=CH
C6H5
C6H5
//
//
82
84
65
66
95
83
74
49
40
29
//
//
4-CH3OC6H4
4-ClC6H4
//
//
//
//
//
3
4
B. J. Wakefield, ‘‘Organomagnesium Methods in Organic Synthe-
sis,’’ Academic Press, UK (1995).
CH3
Bn
t-Bu
b
Lindsell et al. reported that alkylstrontium halides reacted with
carbonyl compounds to afford the corresponding products in low
yields, with the exception of the reaction with benzophenone. a)
G. Gowenlock, W. E. Lindsell, and B. Singh, J. Organomet. Chem.,
101, C37 (1975). b) G. Gowenlock, W. E. Lindsell, and B. Singh,
J. Chem. Soc., Dalton Trans., 1978, 657.
a) M. S. Sell and R. D. Rieke, Synth. Commun., 25, 4107 (1995). b)
L. N. Cherkasov, V. I. Panov, and V. N. Cherkasov, Russ. J. Org.
Chem., 29, 411 (1993). c) L. N. Cherkasov and S. I. Radchenko,
Russ. J. Org. Chem., 30, 456 (1994). d) L. N. Cherkasov and
V. N. Cherkasov, Russ. J. Org. Chem., 31, 267 (1995).
N. Miyoshi, K. Kamiura, H. Oka, A. Kita, R. Kuwata, D. Ikehara,
and M. Wada, Bull. Chem. Soc. Jpn., 77, 341 (2004).
a) R. Bloch, Chem. Rev., 98, 1407 (1998). b) R. A. Volkmann,
‘‘Nucleophilic Addition to Imines and Imine Derivatives,’’ in ‘‘Com-
prehensive Organic Synthesis,’’ ed. by B. M. Trost and I. Fleming,
Pergamon Press, Oxford (1991), Vol. 1, Chap. 1.12, pp 355–396,
and references cited therein.
M. Wada, Y. Sakurai, and K. Akiba, Tetrahedron Lett., 25, 1079
(1984).
Recently there have been a few reports on zinc-promoted alkylation
reactions of aldimines with simple alkyl halides. a) T. Huang,
C. C. K. Keh, and C.-J. Li, Chem. Commun., 2002, 2440. b) T. Iwai,
T. Ito, T. Mizuno, and Y. Ishino, Tetrahedron Lett., 45, 1083 (2004).
aSee ref. 16 for a reaction procedure. Isolated yields.
molar amounts of alkylstrontium halide analogues to the imine.
Furthermore, the applications of the present reaction were
investigated by using various imines. The results are summariz-
ed in Table 3. The reaction with the imines derived from aromat-
ic aldehydes and aniline, 4-chloroaniline or 4-methoxyaniline
gave the corresponding adducts in good yields (Entries 1–7).
However using N-aliphatic imines, the reaction became compli-
cated and yields decreased (Entries 8–10).
When the reaction was applied to imines derived from eno-
lizable aldehydes, poor results were obtained. Under similar con-
ditions, the reaction of ethyl iodide with the imine formed from
3-phenylpropanal and isopropyl amine gave ꢀ-ethylated alde-
hyde, 2-ethyl-3-phenylpropanal, in 30% yield. This result indi-
cated to us that alkylstrontium halide analogues had strong nu-
cleophilicity besides strong basicity. Using 4.0 molar amounts
of ethyl iodide and 2.0 molar amounts of metallic strontium to
1.0 molar amount of the imine, the ꢀ-ethylated reaction proceed-
ed to afford 2-ethyl-3-phenylpropanal in 57% yields (Eq 1).
5
6
7
8
9
10 The reaction also proceeded in DMF or DMSO, but THF gave the
best result.
11 Commercially available metallic strontium ingot in liquid paraffin
was cut into small pieces using a sharp knife in preparation for
the start of each reaction.
12 Using excess amount of alkyl iodide other than methyl iodide, the
C,N-dialkylated product was obtained in very low yield.
13 a) H. Thies and H. Schoenenberger, Arch. Pharm. (Weinheim, Ger.),
289, 408 (1956). b) B. L. Emling, R. J. Horvath, A. J. Saraceno, E. F.
Ellermeyer, L. Haile, and L. D. Hudac, J. Org. Chem., 24, 657
(1959).
14 J. Thomas, Bull. Soc. Chim. Fr., 1973, 1296, 1300; 1975, 209.
15 R. E. Dessy and R. M. Salinger, J. Am. Chem. Soc., 83, 3530 (1961).
16 A typical reaction procedure: Under an argon atmosphere, N-ben-
zylideneaniline (188 mg, 1.04 mmol) and butyl iodide (281 mg,
1.53 mmol) were added successively to a THF (5 mL) suspension
of metallic strontium (138 mg, 1.57 mmol) at room temperature.
After stirring for 2 h, the reaction mixture was quenched with an
aqueous solution of 0.2 M hydrochloric acid (5 mL) (1 M = 1
mol dmÀ3), and successively with 5% Na2SO4 aqueous solution
(30 mL), filtered through a cake of celite. The organic materials were
extracted with diethyl ether (30 mL Â 3), and the combined organic
layers were washed successively with 5% NaHSO3 aqueous solution
and brine, and dried over anhydrous MgSO4. After evaporation of
the solvent, the residue was purified by column chromatography
on aluminum oxide (hexane:ethyl acetate = 20:1–4:1) to give the
corresponding alkylated product, N-(1-phenylpentyl)aniline (218
mg, 95% yield) as a colorless oil.
4.0 m.a.
Et-I
O
N
2.0 m.a. Sr
rt, THF
(1)
H
Ph
Ph
H
1.0 m.a.
57%
In summary, alkyl halides reacted with metallic strontium to
produce alkylstrontium halide analogues, which strong nucleo-
philicity besides strong basicity presented some difficulty in con-
trolling their reactions. Nevertheless, the Barbier-type alkylation
of imines with alkyl iodides proceeded smoothly at room tem-
perature under an argon atmosphere to afford the corresponding
alkylated amines in good yields. Investigation of the reaction
mechanism and further applications are now progress.
References and Notes
1
a) N. A. Bell, ‘‘Beryllium,’’ and W. E. Lindsell, ‘‘Magnesium, Cal-
cium, Strontium and Barium,’’ in ‘‘Comprehensive Organometallic
Chemistry,’’ ed. by G. Wilkinson, F. G. A. Stone, and E. W. Abel,
Pergamon Press, Oxford (1982), Vol. 1, Chap. 3 and 4, p 121 and
p 155, respectively. b) W. E. Lindsell, ‘‘Beryllium Magnesium, Cal-
cium, Strontium and Barium,’’ in ‘‘Comprehensive Organometallic
Chemistry II,’’ ed. by E. W. Abel, F. G. A. Stone, and G. Wilkinson,
Pergamon Press, Oxford (1995), Vol. 1, Chap. 3, p 57, and refer-
Published on the web (Advance View) April 30, 2005; DOI 10.1246/cl.2005.760