Zinc metal-promoted nucleophilic addition of nonactivated alkyl iodides to aromatic aldimines in the presence of chlorotrimethylsilane in ethyl acetate-DMI

Article abstract of DOI:10.1016/j.tetlet.2003.11.076

A variety of aromatic aldimines react with nonactivated alkyl iodides in the presence of zinc powder and a catalytic amount of chlorotrimethylsilane (TMSCl) in ethyl acetate-DMI to afford the corresponding α- alkylbenzylamine derivatives in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2003.11.076

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1083–1086
Zinc metal-promoted nucleophilic addition of nonactivated
alkyl iodides to aromatic aldimines in the presence of
chlorotrimethylsilane in ethyl acetate–DMI
Toshiyuki Iwai, Takatoshi Ito, Takumi Mizuno and Yoshio Ishino*
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Received 14 October 2003; revised 14 November 2003; accepted 14 November 2003
Dedicated to Prof. N. Sonoda on the occasion of his 70th birthday
Abstract—A variety of aromatic aldimines react with nonactivated alkyl iodides in the presence of zinc powder and a catalytic
amount of chlorotrimethylsilane (TMSCl) in ethyl acetate–DMI to afford the corresponding a-alkylbenzylamine derivatives in good
to excellent yields.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Organozinc reagents are very useful and versatile
reagents for a variety of transformations in organic
synthesis,1 because of their high functional group com-
patibility. The Reformatsky2 and the Barbier reactions
of activated organic halides such as a-halo esters and
allyl halides have been widely studied. However, alkyl-
zinc reagents prepared from nonactivated halides are
generally unreactive towards carbon nucleophiles due to
their low nucleophilicity. Thus, these reactions usually
require the aid of other metals or additives.1;3 Several
methods have been reported1;4–8 for these purposes, such
as the use of a Zn–Cu couple5 or Rieke zinc6 and the
electro reduction of a zinc salt.7 However, the synthetic
utility of these methods may be considerably limited
because special equipment, expensive reagents and
multi-step procedures are required. Recently, we have
reported that metallic zinc with TMSCl markedly pro-
motes the reaction of halides with aldehydes and
ketones to provide the corresponding olefins and alco-
hols.9
Nucleophilic addition of aromatic aldimines with
organozinc reagents seems one of the most useful and
efficient methods to synthesize benzylamine derivatives.
Especially, the addition of organometallic reagents to
the C@N bonds of imines and imine derivatives is a well-
known process. Numerous studies have been reported,10
for example, reactions with organozinc reagents such as
diorganozinc10a–c;e;11 and triorganozincates.12 However,
the addition of nonactivated alkylzinc halides to imines
has been scarcely reported.13 In this letter, we wish to
report a mild, efficient and convenient zinc-promoted
alkylation reaction of aldimines with nonactivated
halides in the presence of additives (TMSCl and DMI)
to provide the corresponding a-alkylbenzylamines in
good to excellent yields (Scheme 1). To our knowledge,
PMP
R
TMSCl,
Zn
Ar
N
PMP
R
I
R ZnI
Ar
N
H
DMI in AcOEt
AcOEt
Scheme 1.
Keywords: Amines; Imines; Nucleophilic addition; TMSCl; Zinc.
* Corresponding author. Tel.: +81-6-6963-8057; fax: +81-6-6963-8049; e-mail: ishino@omtri.city.osaka.jp
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.076

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T. Iwai et al. / Tetrahedron Letters 45 (2004) 1083–1086
Table 1. Reaction of n-heptyl iodide (1a) with imine 2a
PMP
2a
cat.TMSCl
PMP
Ph
N
Zn / additive
TMSCl
HN
Ph
ZnI
I
4
4
Solvent
rt, 18h
4
3a
1a
60 oC, 1~2h
Entry
Additive (equiv)
Solvent
THF
TMSCl (equiv)
Yield (%)a
1
2
3
4
5
6
7
8
NMP (2.0)
NMP (2.0)
NMP (2.0)
NMP (2.0)
NMP (2.0)
––
3.0
3.0
3.0
3.0
––
42
63
71
70
21
48b
73
72
Toluene
CH3CN
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
3.0
3.0
1.5
DMI (2.0)
DMI (2.0)
a GCyield.
b Adduct of 2a and AcOEt, ethyl 3-(N-PMP)-amino-3-phenylpropionate (4), was isolated in 42% as a by-product.
PMP
HN
COOEt
Ph
4
Table 2. The zinc-promoted reactions of n-heptyl iodide (1a) with
aldimines 2
nucleophilic addition of nonactivated alkyl halides to
aromatic aldimines using zinc metal has not yet been
reported.
1) TMSCl
PMP
2) Zn / DMI / n-C7H15I (1a)a
HN
PMP
Ar
N
Organozinc reagents were usually prepared at 60 ꢁC for
1–2 h in a solvent containing powdered metallic zinc
(4.6 mmol), n-heptyl iodide (1a) (4.5 mmol) and a cata-
lytic amount of TMSCl (0.14 mmol) in the presence of
additives, and then TMSCl (9.0 mmol) and a solution of
benzaldehyde N-(p-methoxyphenyl) imine (N-PMP
imine) 2a (3.0 mmol) in AcOEt (2.0 mL) was added at
room temperature to the reaction mixture. Commercially
available zinc powder (purity; 99.9%) were used without
any pre-treatment. Detailed studies on the reaction of 1a
with 2a to a-alkylbenzylamine derivative 3a showed that
this addition reaction is considerably influenced by
the additives and the solvent as shown in Table 1.
AcOEt, rt, 18h
Ar
2a-i
3a-i
Entry
Imine
Ar
Product (yield, %)b
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
Ph
3a (70)
3b (64)c
3c (43)c
3d (62)
3e (87)
3f (88)
3g (73)
3h (68)
3i (82)
p-Me–C6H4
p-MeO–C6H4
p-Cl–C6H4
o-Cl–C6H4
p-CN–C6H4
4-Pyridyl
3-Pyridyl
2-Pyridyl
2g
2h
2i
aReagents and conditions: n-heptyl iodides (1a) (4.5 mmol), zinc metal
(4.6 mmol), DMI (6.0 mmol), TMSCl (0.14 mmol) and AcOEt
(4.5 mL) at 60 ꢁC for 2 h.
The reaction of 1a with 2a smoothly took place in the
presence of additives and a catalytic amount of TMSCl.
Especially, 1,3-dimethyl-2-imidazolidinone (DMI) and
N-methyl-2-pyrrolidone (NMP) as additives showed
high reactivity and alkylzinc reagents were generated in
situ. Though 3a was obtained in the absence of additives
and TMSCl, the reaction proceeded more smoothly and
efficiently by the addition of NMP or DMI and TMSCl.
As shown in Table 1, the best result for formation of 3a
was obtained when DMI and TMSCl were used in 2.0
and 3.0 equiv, respectively. AcOEt was found to be a
much better solvent14 for this reaction than other aprotic
solvents.
b Isolated yield.
c After silica gel chromatography purification, imines 2b,c were
recovered as the corresponding aldehydes in the yields of 17% and
44%, respectively.
That is, the aryl aldimines with electron-withdrawing
groups such as cyano and chloro gave the corresponding
amines 3 in higher yields compared with those with
electron-donating groups. Hetero aromatic aldimines
also smoothly reacted (entries 7–9).
Further applications of the reaction were studied by
using various types of alkyl iodides and iodo esters
(Table 3). The reaction of 2f with nonactivated primary
and secondary alkyl iodides gave the corresponding
a-alkylbenzylamines in good to excellent yields (entries
1–3). Iodo esters such as ethyl 6-iodohexanoate (1e),
ethyl 4-iodobutyrate (1f), ethyl 3-iodopropionate (1g),
also smoothly reacted with 2f in the presence of zinc
powder to provide the corresponding amino acids in
good yields; especially in the case of 1f and 1g, lactams 6
To demonstrate the generality and efficiency of this
reaction, we applied this combination system to a vari-
ety of aryl aldimines 2a–i. Under the optimized condi-
tions,15 n-heptyl iodide (1a) was treated with a variety of
imines 2a–i in the presence of zinc powder to produce
amines 3a–i in good to excellent yields (Table 2). The
yields of amines 3a–i for the reaction were slightly
dependent on the substituents on the aromatic ring.

T. Iwai et al. / Tetrahedron Letters 45 (2004) 1083–1086
Table 3. The zinc-promoted reactions of alkyl iodides 1 with aldimine 2f
1085
1) TMSCl
PMP
R
2) Zn / DMI / R-I (1b-g)a
HN
PMP
Ar
N
AcOEt, rt
Ar
Ar = p-CN-C6H4 (2f)
5
Entry
1
R–I
Time (h)
Product (yield, %)b
PMP
HN
I
I
2
2
1b
1c
Ar
Ar
5a (82)
5b (91)
PMP
HN
2
3
4
5
6
PMP
PMP
HN
HN
I
18
18
18
18
Ph
I
1d
Ar
Ar
Ph
5c (78)
COOEt
1e
COOEt
5d (65)
PMP
O
PMP
PMP
I
I
COOEt
HN
HN
N
1f
+
COOEt
Ar
Ar
Ar
PMP
5e (10)
6 (78)
O
N
COOEt
1g
+
COOEt
Ar
5f (15)
7 (45)
aReagents and conditions: alkyl iodides (4.5 mmol), zinc metal (4.6 mmol), DMI (6.0 mmol), TMSCl (0.14 mmol) and AcOEt (4.5 mL) at 60 ꢁC for 2 h.
bIsolated yield.
CRC: Boca Raton, FL, 1996; (c) Organozinc Reagents: A
Practical Approach; Knochel, P., Jones, P., Eds.; Oxford
University Press: New York, 1999; (d) Knochel, P.; Millot,
N.; Rodrigguez, A. L.; Tucker, C. E. Org. React. 2001, 58,
417.
and 7 were predominantly obtained in the yields of 78%
and 45%, respectively.
Although the mechanistic details still remain ambigu-
ous, the reaction may proceed through in situ generated
zinc reagents as the reaction intermediate. These
organozinc compounds gave the product amines
through a subsequent nucleophilic addition of aldi-
mines. In this reaction, the role of the additives (DMI or
NMP) may be postulated mainly in two ways, that is,
one is enhancement of nucleophilicity and the other is
reduction of the basicity of organozinc compounds by
coordination of additives to zinc reagents. TMSCl may
activate the zinc metal surface1c;8 and the C@N bond of
aldimines by coordination.16
€
2. Furstner, A. Synthesis 1989, 571.
3. (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem.
1977, 42, 1821; (b) Negishi, E. Acc. Chem. Res. 1982, 15,
340; (c) Erdik, E. Tetrahedron 1992, 48, 9577.
4. Erdik, E. Tetrahedron 1987, 43, 2203.
5. (a) Organic Syntheses; Wiley: New York, 1973; Collect.
Vol. V, p 855; (b) Tamaru, Y.; Ochiai, H.; Nakamura, T.;
Yoshida, Z. Tetrahedron Lett. 1985, 26, 5559; (c) Tamaru,
Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetrahedron
Lett. 1986, 27, 955; (d) Tamaru, Y.; Ochiai, H.; Nakam-
ura, T.; Yoshida, Z. Angew. Chem., Int. Ed. Engl. 1987, 26,
1157; (e) Tamaru, Y.; Nakamura, T.; Sakaguchi, M.;
Ochiai, H.; Yoshida, Z. J. Chem. Soc., Chem. Commun.
1988, 610; (f) Yasui, K.; Tanaka, S.; Tamaru, Y. Tetra-
hedron 1995, 51, 6881.
6. (a) Rieke, R. D. Science 1989, 246, 1260; (b) Zhu, L.;
Wehmemer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56,
1445.
7. Durant, A.; Delplancke, J.; Libert, V.; Reisse, J. Eur. J.
Org. Chem. 1999, 2845.
In summary, we have demonstrated that the in situ
generated zinc reagents from the reaction of zinc powder
with nonactivated iodides in the presence of TMSCl and
DMI smoothly reacted with aromatic aldimines to give
the corresponding a-alkylbenzylamine derivatives in
good to excellent yields. Adaptation of this system to
aliphatic aldimines and application to an asymmetric
version are now under investigation.
ꢀ
8. (a) Gawronski, J. K. Tetrahedron Lett. 1984, 24, 2605; (b)
Picotin, G.; Miginiac, P. J. Org. Chem. 1987, 52, 4796.
9. (a) Ishino, Y.; Mihara, M.; Kageyama, M.; Nishiguchi, I.
Bull. Chem. Soc. Jpn. 1998, 71, 2669; (b) Ishino, Y.;
Mihara, M.; Kageyama, M. Tetrahedron Lett. 2002, 43,
6601; (c) Ito, T.; Ishino, Y.; Mizuno, T.; Ishikawa, A.;
Kobayashi, J. Synlett 2002, 2116.
References and notes
1. (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117;
(b) Erdik, E. Organozinc Reagents in Organic Synthesis;

1086
T. Iwai et al. / Tetrahedron Letters 45 (2004) 1083–1086
10. (a) Denmark, S. E.; Nicaise, O. J.-C. J. Chem. Soc., Chem.
Commun. 1996, 999; (b) Enders, D.; Reinhold, U. Tetra-
hedron: Asymmetry 1997, 8, 1895; (c) Blosh, R. Chem. Rev.
1998, 98, 1407; (d) Saito, S.; Hatanaka, K.; Yamamoto, H.
Synlett 2001, 1859; (e) Alvaro, G.; Savoia, D. Synlett 2002,
651.
11. Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc.
2000, 122, 12055.
12. (a) Alvaro, G.; Pacioni, P.; Savoia, D. Chem. Eur. J. 1997,
3, 726; (b) Alvaro, G.; Martelli, G.; Savoia, D. J. Chem.
Soc., Perkin Trans. 1 1998, 775.
13. Chiev, K. P.; Roland, S.; Mangeney, P. Tetrahedron:
Asymmetry 2002, 13, 2205.
14. (a) Hunsdiecker, H.; Erlbach, H.; Vogt, E. German Patent
722467, 1942; Chem. Abstr. 1943, 37, 5080; (b) Klaus, S.;
Herrman, P. Eur. Pat. Appl. EP 1167325, 2002; Chem.
Abstr. 2002, 136, 85751.
15. Representative procedure is as follow: Under argon
atmosphere, to a mixture of zinc metal (303 mg, 4.6 mmol)
and DMI (0.65 mL, 6.0 mmol) in AcOEt (4.5 mL) was
added TMSCl (0.02 mL, 0.14 mmol) at 60 ꢁC and stirred
for 5 min, followed by addition of n-heptyl iodide (1a)
(0.74 mL, 4.5 mmol) and stirring at the same temperature
for 2 h and cooling to room temperature. Under argon
atmosphere, to a suspension of imine 2f (709 mg,
3.0 mmol) in AcOEt (2.0 mL) was added TMSCl
(0.57 mL, 4.5 mmol) at room temperature and stirred for
10 min, followed by addition of organozinc reagent and
stirring at same temperature. After stirring for 18 h, 1 M
HCl was added to the reaction mixture and extracted with
AcOEt (2 · 20 mL). The combined AcOEt extract was
washed with 10% NaHSO3 aq and brine and dried over
MgSO4, filtered and concentrated in vacuo. The residue
was purified by chromatography on silica gel (6:1, hexane/
AcOEt) to give the product 3f (883 mg, 88%) as yellow oil.
All new compounds were fully characterized by 1H, 13C
NMR and MS spectrometry. Selected spectra data: 3f, 1H
NMR (300 MHz, CDCl3) d 7.58 (2H, d, J ¼ 8:3 Hz), 7.44
(2H, d, J ¼ 8:3 Hz), 6.67 (2H, d, J ¼ 9:0 Hz), 6.39 (2H, d,
J ¼ 9:0 Hz), 4.25 (1H, t, J ¼ 6:6 Hz), 3.84 (1H, br s), 3.68
(3H, s), 1.76–1.67 (2H, m), 1.40–1.19 (10H, m), 0.86 (3H, t,
J ¼ 6:6 Hz); 13C NMR (75 MHz, CDCl3) d 152.1, 150.5,
141.0, 132.4, 127.2, 118.9, 114.8, 114.4, 110.6, 58.88, 55.65,
38.75, 31.67, 29.35, 29.03, 26.92, 26.12, 22.53, 13.98; EI-
MS m=z (relative intensity) 336 [Mþ, 33], 237 (100), 122
(4.9); EI-HRMS calcd for C22H29N2O [Mþ] 336.2202,
found 336.2209.
16. Dilman, A. D.; Ioffe, S. L. Chem. Rev. 2003, 103, 733.