Zinc-mediated allylation and alkylation of aminals in the presence of TMSCl and diisopropylamine

Article abstract of DOI:10.1021/jo8019797

(Chemical Equation Presented) An alkylation of aminals with organozinc reagents derived from allyl bromide, benzyl bromide, α-bromoacetate, and α-bromonitrile proceeded efficiently in the presence of TMSCl and diisopropylamine. This reaction system was applied to the synthesis of an antispasmodic: butaverine.

Full text of DOI:10.1021/jo8019797

TABLE 1. Influence of Bases, Metals, Chlorosilanes, and Solvents
on Allylation of 1aa
Zinc-Mediated Allylation and Alkylation of
Aminals in the Presence of TMSCl and
Diisopropylamine
Bunpei Hatano,* Keita Nagahashi, and Tatsuro Kijima
DiVision of Chemistry, Graduate School of Science and
Engineering, Yamagata UniVersity, 4-3-16 Jonan,
Yonezawa, 992-8510, Japan
entry
M
chlorosilane
base
none
solvent
yield (%)b
1
2
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
TMSCl
none
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
31
0
none
hatano@yz.yamagata-u.ac.jp
3
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
i-Pr2NH
i-Pr2NH
i-Pr2NH
Et3N
pyridine
Na2CO3
K2CO3
NaOH
86
65
70
80
4c
5d
6
ReceiVed September 8, 2008
e
7
8
9
10
-
69
80
70
11
12
13
14
Mn
In
TMSCl
TMSCl
TMSCl
TMSCl
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
benzene
benzene
benzene
benzene
0
68
0
Sn
Smf
0
15
16
17
Zn
Zn
Zn
TESCl
TBSCl
SiCl4
i-Pr2NH
i-Pr2NH
i-Pr2NH
benzene
benzene
benzene
68
28
78
An alkylation of aminals with organozinc reagents derived
from allyl bromide, benzyl bromide, R-bromoacetate, and
R-bromonitrile proceeded efficiently in the presence of
TMSCl and diisopropylamine. This reaction system was
applied to the synthesis of an antispasmodic: butaverine.
18
19
20
21
22
Zn
Zn
Zn
Zn
Zn
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
i-Pr2NH
toluene
Et2O
THF
CH3CN
DMF
59
72
80
trace
32
a Reaction conditions: 1a (2.0 mmol), 2a (6.0 mmol), Zn (6.0 mmol),
TMSCl (6.0 mmol), base (12.0 mmol), solvent (10 mL), rt, 6 h, under
N2. b Isolated yield. c 2a (3.0 mmol), Zn (3.0 mmol), TMSCl (3.0
mmol), i-Pr2NH (6.0 mmol). d 2a (4.0 mmol), Zn (4.0 mmol), TMSCl
(4.0 mmol), i-Pr2NH (8.0 mmol). e The complex mixture was obtained.
f A small piece of I2 was added to activate Sm.
Nucleophilic additions to carbonyl compounds and imines
with organometallic reagents are important for syntheses of
functionalized alcohols and amines. Among them, addition using
organozinc reagents based on Barbier- and Reformatsky-type
reactions is a useful method in organic synthesis because the
organozinc reagents are readily prepared in situ from the
corresponding alkyl bromide, such as allyl bromide and R-bro-
moacetate, in the presence of zinc.1,2 Moreover, the organozinc
reagents show a much lower reactivity. Consequently, they show
higher chemoselectivity than their lithium and magnesium
counterparts. Several synthetic methods using these reactions
have been developed, giving homoallyl alcohols and ꢀ-hydroxy
esters from the corresponding aldehydes and ketones. Further-
more, imines are used as substrates in the same manner.
Compared to the methods used for carbonyl compounds and
imines, several reports describe acetals and aminals; in particu-
lar, the applications for aminals have remained an attractive
research area because functionalized amines are prepared
directly in one step.3-5 Herein, we report an alkylation of
aminals with organozinc reagents based on Barbier- and
Reformatsky-type reaction. This reaction proceeded smoothly
in the presence of TMSCl and diisopropylamine, affording the
corresponding functionalized amines.
(1) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207–2293. (b)
Knochel, P. In ComprehensiVe Organic Synthesis; Trost, B. M., FlemingI., Eds.;
Pergamon: Oxford, UK, 1991; Vol 1, pp 211-229.
(2) (a) Ocampo, R.; Dolbier, W. R. Tetrahedron 2004, 60, 9325–9374. (b)
Rathke, M. W., Weipert, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
FlemingI., Eds.; Pergamon: Oxford, UK, 1991; Vol. 1, pp 277-299. (c) Fu¨rstner,
A. Synthesis 1989, 571–590.
(3) References for acetals using Barbier- and Reformatsky-type reaction, see:
(a) Surendra, K.; Krishnaveni, N. S.; Rao, K. R. Tetrahedron Lett. 2006, 47,
2133–2136. (b) Zhang, J.; Blazecka, P. G.; Berven, H.; Belmont, D. Tetrahedron
Lett. 2003, 44, 5579–5582. (c) Tanaka, H.; Nakahata, S.; Watanabe, H.; Zhao,
J. F.; Kuroboshi, M.; Torii, S. Inorg. Chim. Acta 1999, 296, 204–207. (d) Maeda,
H.; Shono, K.; Ohmori, H. Chem. Pharm. Bull. 1994, 42, 1808–1812. (e) Tanaka,
H.; Yamashita, S.; Ikemoto, Y.; Torii, S. Tetrahedron Lett. 1988, 29, 1721–
1724.
Our initial experiments were carried out in the reaction of
benzaldehyde-derived aminal 1a with allylzinc bromide as a
model substrate at room temperature (Table 1). When 1,1′-
benzylidenedipiperidine (1a) and allyl bromide (2a) were stirred
for 6 h in the presence of zinc and TMSCl, the corresponding
homoallylamine 3aa was obtained in 31% yield along with
unreacted benzaldehyde (entry 1). For this reaction, the addition
of TMSCl was extremely important: formation of 3aa was not
observed at all in the absence of TMSCl (entry 2). These facts
suggest that TMSCl would likely activate not only zinc metal
9188 J. Org. Chem. 2008, 73, 9188–9191
10.1021/jo8019797 CCC: $40.75 2008 American Chemical Society
Published on Web 10/24/2008

but also the aminal substrate.6 We next examined the influence
of several typical bases on the reaction of 1a because the
recovery of benzaldehyde was considered to be attributed to
the interaction of 1a with zinc chloride or zinc bromide
generated in situ. As expected, the yield of 3aa increased
dramatically when diisopropylamine base was used (entry 3).
For this reaction, the amounts of reagents are important: the
use of 1.5 or 2.0 mol equiv amounts of reagents (2a, Zn, TMSCl,
and i-Pr2NH) against 1a resulted in the moderate yield of 3aa
(entries 4 and 5).7 Other typical bases were also effective, except
pyridine, giving 3aa in moderate to good yields (entries 6-10).
We also found that zinc was more effective than other metals.
Surprisingly, no allylation took place with manganese, tin, and
samarium, except indium (entries 11-14). Furthermore, this
allylation was affected by the substituent bearing silyl chloride.
As expected, both sterically hindered TESCl and TBSCl
impeded the reaction to give 3aa in low to moderate yields
(entries 15 and 16). The use of tetrachlorosilane, which may
be expected to work as a strong Lewis acid, led to 3aa in good
yield (entry 17). Moreover, the formation of 1a is also achieved
in THF and Et2O, in which a Barbier-type reaction took place,
giving 3aa in 80% and 72% yields, respectively (entries 18-22).
The reaction system with TMSCl and diisopropylamine was
useful for other aminal derivatives (Table 2). Similar treatment
of aminals 1 gave the corresponding homoallylamines 3 in
moderate to good yields (entries 1-5). Although the formation
of homoallylamine took place slightly in the case of 1g derived
from morpholine, this problem was circumvented by the
treatment of 1g at 50 °C for 24 h (entry 6). In dimethyl
derivative 1h, the product was purified by Kugelrohr distillation
because dimethyl derivatives 3ha decomposed during purifica-
tion on silica gel columns (entry 7). The allylation of aliphatic
aminals (1i and 1j)8 proceeded efficiently in THF rather than
benzene because of their poor solubility in benzene (in benzene:
3ia 56%, 3ja 30%, respectively, entries 8 and 9).
TABLE 2. Reaction of 1 with Allylzinc Bromide in the Presence
of TMSCl and i-Pr2NHa
This reaction procedure is applicable to several highly reactive
alkyl bromides. The results are presented in Table 3. Treatment
of 1a with 2b or 2c at room temperature for 6 h gave the
corresponding homoallylamines (3ab and 3ac) in moderate to
good yields (entries 1 and 2).9 The crotyl derivatives (2d and
2e) were also used in this reaction, which displayed no marked
stereoselectivity (entries 3 and 4).9 The reaction of 1a took place
in the case of benzyl bromide (2f) to give 3af in 46% yield
(entry 5). The use of R-bromoacetate (2g) and R-bromonitrile
(2h), a Reformatsky-type reaction, does not present a problem,
giving the corresponding ꢀ-amino ester (3ag) and ꢀ-amino nitrile
(3ah) in 68% and 52% yields, respectively (entries 6 and 7).
a Reaction conditions: 1 (2.0 mmol), 2a (6.0 mmol), Zn (6.0 mmol),
TMSCl (6.0 mmol), i-Pr2NH (12.0 mmol), benzene (10 mL), rt, 6 h,
under N2. b Isolated yield. c The reaction was carried out at 50 °C for
24 h. d Product (3ha) was purified by Kugelrohr distillation. e THF was
used instead of benzene.
Recently, ꢀ-amino acids have been shown to have biologically
important properties and have been used as intermediates in
natural product syntheses.10 We finally achieved direct access
to ꢀ-amino carbonyl derivatives from aminals.
Our direct access to ꢀ-amino ester from aminal was applied
to the synthesis of butaverine (3ai), which is an antispasmodic
agent bearing a ꢀ-amino ester.11 For example, the preparation
of 1a in the presence of alumina and subsequent reaction of 1a
with n-propyl R-bromoacetate under these reaction conditions
afforded 3ai in 66% yield in two steps from benzaldehyde
(Scheme 1). Reportedly, butaverine (3ai) had been synthesized
(4) References for aminals and related compounds using Barbier- and
Reformatsky-type reaction, see: (a) Katritzky, A. R.; Manju, K.; Singh, S. K.;
Meher, N. K. Tetrahedron 2005, 61, 2555–2581. (b) Tan, C. Y. K.; Wainman,
D.; Weaver, D. F. Bioorg. Med. Chem. 2003, 11, 113–122. (c) Wang, X.; Li, J.;
Zhang, Y. Synth. Commun. 2003, 33, 3575–3582. (d) Katritzky, A. R.; Shobana,
N.; Harris, P. A. Tetrahedron Lett. 1991, 32, 4247–4248.
(5) For recently selected examples using Barbier- and Reformatsky-type
reaction, see: (a) Petrini, M.; Profeta, R.; Righi, P. J. Org. Chem. 2002, 67,
4530–4535. (b) Choucair, B.; Leon, H.; Mire, M. A.; Lebreton, C.; Mosset, P.
Org. Lett. 2000, 2, 1851–1853. (c) Saidi, R. M.; Khalaji, R. H.; Ipaktschi, J.
J. Chem. Soc., Perkin Trans. 1 1997, 1, 1983–1986.
(6) Picotin, G.; Miginiac, P. J. Org. Chem. 1987, 52, 4796–4798.
(7) The silylated amines (N-trimethylsilylpiperidine and N-trimethylsilyldi-
isopropylamine) and allylated piperidine (3-piperidino-1-propene) were observed
by GC-MS, which were removed by hydrolysis and evaporation. In contrast,
allylated diisopropylamine was not observed.
(10) Juaristi, E. EnantioselectiVe Synthesis of ꢀ-amino Acids, Wiley-VCH:
New York, 1997.
(11) (a) Cerbai, G.; Di Paco, G. F. Boll. Chim. Farm. 1966, 105, 45–53. (b)
Pacheco, H.; Dreux, M.; Beauvillain, A. Bull. Soc. Chim. Fr. 1962, 1379–1387.
(c) Pollard, C. B.; Mattson, G. C. J. Am. Chem. Soc. 1956, 78, 4089–4090.
(8) Aminals (1i and 1j) were prepared according to a modified procedure of
a known method, see: Katritzky, A. R.; Drewniak, M. J. Chem. Soc., Perkin
Trans. 1 1988, 2339–2344.
(9) No regioisomer was detected from 1H NMR of crude product.
J. Org. Chem. Vol. 73, No. 22, 2008 9189

TABLE 3. Reaction of 1a with Organozinc Reagents in the
SCHEME 2. Plausible Reaction Pathways for Alkylation of
1 with Organozinc Reagents
Presence of TMSCl and i-Pr2NHa
triggered by the activation of 1 with chlorosilane: the chlorosi-
lane serves as an activator of not only zinc metal but also aminal,
generating an iminium salt intermediate (4) and silylated amine
(Scheme 2). Then, the reaction of 4 with organozinc reagent
leads to the alkylated product 3.
In conclusion, our study demonstrated the alkylation of
aminals with organozinc reagents derived from allyl bromide,
benzyl bromide, R-bromoacetate, and R-bromonitrile. This
reaction proceeded efficiently in the presence of TMSCl and
diisopropylamine. Furthermore, this reaction system is applicable
to the synthesis of butaverine, which is well-known as an
antispasmodic agent. Further detailed studies of aminals are in
progress.
Experimental Section
Representative Procedure for Homoallylamines (3). To a
suspension of zinc (392 mg, 6.0 mmol) in benzene (10 mL) was
added allyl bromide (6.0 mmol) followed by diisopropylamine (1.7
mL, 12 mmol) and 1 (2.0 mmol) at room temperature under nitrogen
atmosphere. After cooling in an ice-water bath, chlorotrimethyl-
silane (761 µL, 6.0 mmol) was added to the mixture in one portion.
The reaction mixture was stirred for 10 min in an ice bath, and
then allowed to warm to room temperature. After the mixture was
stirred for 6 h at room temperature, aqueous NaOH (1N, 30 mL)
was added. The mixture was then stirred for an additional 30 min,
during which zinc hydroxide precipitated. The resulting suspension
was filtered in suction, and the filtered solid was washed with ether
(3 × 10 mL). The ethereal solution was separated and washed with
aqueous NaOH (1N, 30 mL), water (30 mL), and brine (30 mL).
After drying over Na2SO4, and subsequent evaporation, the residue
was purified with column chromatography on silica gel (30 g;
eluent, CH2Cl2/MeOH ) 100:0, 98:2, 96:4, 94:6, 92:8, 90:10, 100
mL × each). The results are presented in Tables 1, 2, and 3.
Representative Procedure for Homoallylamide (3ia and
3ja). The same procedure as that described above was followed
except that benzene was replaced by THF, because aminals (1i and
1j) did not dissolve enough in benzene. After the mixture was stirred
for 6 h at room temperature, the reaction mixture was poured into
saturated NH4Cl (30 mL). The mixture was extracted with ether (2
× 30 mL), and the combined organic extract was washed with
aqueous NaOH (1 N, 30 mL), water (30 mL), and brine (30 mL).
After drying over Na2SO4, and subsequent evaporation, the residue
was purified with column chromatography on silica gel (30 g;
eluent, haxane/AcOEt ) 75:25, 300 mL). The results are presented
in Table 2.
a Reaction conditions: 1a (2.0 mmol), 2 (6.0 mmol), Zn (6.0 mmol),
TMSCl (6.0 mmol), i-Pr2NH (12.0 mmol), benzene (10 mL), rt, 6 h,
c
under N2. b Isolated yield. Determined with H NMR.
1
SCHEME 1. Synthesis of Butaverine (3ai) Using the
Alkylation of 1a with Reformatsky Reagent
Representative Procedure for ꢀ-Amino Derivatives (3af,
3ag, and 3ah). The same procedure as that described above was
followed except that allyl bromide was replaced by benzyl bromide
(713 µL, 6.0 mmol), ethyl R-bromoacetate (662 µL, 6.0 mmol), or
R-bromonitrile (400 µL, 6.0 mmol). In the case of ethyl R-bro-
moacetate, workup was performed by the addition of saturated
NaHCO3 (30 mL) instead of aqueous NaOH to prevent possible
de-esterification. The results are presented in Table 3.
by Michael addition of piperidine to n-propyl cinnamate;
unfortunately, the yield of 3ai was not quite satisfactory.12
Finally, our developed method has some advantages for
synthesis of butaverine.
Although the detailed pathway is not clear for this alkylation
of 1 with organozinc reagents, the alkylation seems to be
Synthesis of Butaverine (3ai) Using Alkylation of 1a with
Organozinc Reagents. To a suspension of zinc (392 mg, 6.0 mmol)
(12) In previous reports, butaverine was obtained by Michael addition of
piperidine to n-propyl cinnamate in 20-50% yields, see ref 11.
9190 J. Org. Chem. Vol. 73, No. 22, 2008

in benzene (10 mL) was added n-butyl R-bromoacetate13 (867 µL,
6.0 mmol) followed by diisopropylamine (1.7 mL, 12 mmol) and
1a (2.0 mmol) at room temperature under nitrogen atmosphere.
After cooling in an ice-water bath, chlorotrimethylsilane (761 µL,
6.0 mmol) was added to the mixture in one portion. The reaction
mixture was stirred for 10 min in an ice bath and then allowed to
warm to room temperature. After the mixture was stirred for 6 h at
room temperature, saturated NaHCO3 (30 mL) was added. The
mixture was then stirred for an additional 30 min. Then the resulting
suspension was filtered in suction, and the filtered solid was washed
with ether (3 × 10 mL). The ethereal solution was separated and
washed with saturated NaHCO3 (30 mL), water (30 mL), and brine
(30 mL). After drying over Na2SO4, and evaporation, the residue
was purified with column chromatography on silica gel (30 g;
eluent, CH2Cl2/MeOH ) 100:0, 98:2, 96:4, 94:6, 92:8, 90:10, 100
mL × each). Pure butaverine was obtained in 74% yield (427 mg,
1.49 mmol).
70.2, 51.2, 37.1, 26.3, 24.6; MS (EI) m/z (%) 175 (17), 174 ([M -
C3H5], 100), 91 (56); HRMS (ESI) calcd for C15H22N1 216.1752
[M + H]+, found 216.1746.
4-Benzoylamino-5-methyl-1-hexene (3ia): white solid; mp
109.0-110.2 °C; IR (KBr) νmax 3322, 3069, 2964, 1636, 1546,
1322, 1289, 1152, 914, 700 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.75-7.73 (m, 2H), 7.50-7.47 (m, 1H), 7.42 (dd, 2H, J ) 7.5, 7.5
Hz), 5.91 (br, 1H), 5.83 (dddd, 1H, J ) 17.2, 10.2, 7.1, 7.1 Hz),
5.10 (dd, 1H, J ) 17.2, 1.6 Hz), 5.07 (dd, 1H, J ) 10.2, 1.6 Hz),
4.09 (ddd, 1H, J ) 7.8, 6.1, 5.0 Hz), 2.40 (ddd, 1H, J ) 12.8, 7.1,
5.0 Hz), 2.26 (ddd, 1H, J ) 12.8, 7.8, 7.1 Hz), 1.92-1.83 (m, 1H),
0.99 (d, 3H, J ) 6.8 Hz), 0.97 (d, 3H, J ) 6.8 Hz); 13C NMR (125
MHz, CDCl3) δ 167.2, 135.1, 134.8, 131.3, 128.5, 126.7, 117.6,
53.9, 36.6, 31.5, 19.3, 18.2; MS (EI) m/z (%) 176 ([M - C3H5],
17), 105 (100), 77 (35), 51 (10); HRMS (ESI) calcd for C14H20N1O1
218.1545 [M + H]+, found 218.1549.
4-Phenyl-4-piperidino-1-butene (3aa): colorless oil; IR (neat)
Acknowledgment. We thank Mr. Shigeru Matsuba, Dr.
Hiroshi Katagiri, and members of the technical staff of the
Instrumental Analysis Center, Faculty of Engineering, Yamagata
University for assistance in obtaining high-resolution mass
spectra.
1
νmax 2933, 1639, 1446, 1111, 991, 914, 758, 710 cm-1; H NMR
(500 MHz, CDCl3) δ 7.35 (dd, 2H, J ) 7.3, 7.3 Hz), 7.24 (d, 1H,
J ) 7.3 Hz), 7.21 (d, 2H, J ) 7.3 Hz), 5.67-5.56 (m, 1H), 4.96
(dd, 1H, J ) 17.0, 3.7 Hz), 4.89 (dd, 1H, J ) 10.5, 3.7 Hz), 3.39
(dd, 1H, J ) 9.3, 5.3 Hz), 2.66 (ddd, 1H, J ) 14.5, 7.0, 5.3 Hz),
2.57 (ddd, 1H, J ) 14.5, 9.3, 7.5 Hz), 2.36-2.33 (m, 4H),
1.59-1.48 (m, 4H), 1.35 (ddd, 2H, J ) 15.0, 7.5, 5.8 Hz); 13C
NMR (125 MHz, CDCl3) δ 139.8, 136.1, 128.8, 127.8, 126.8, 116.0,
Supporting Information Available: Experimental details,
characterization data, and copies of NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Preparation of butyl R-bromoacetate, see: Zhu, X.-F.; Schaffrer, A.-P.;
Li, R. C.; Kwon, O. Org. Lett. 2005, 7, 2977–2980.
JO8019797
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