Catalytic reactions of titanium alkoxides with Grignard reagents and imines: A mechanistic study

Article abstract of DOI:10.1002/asia.200900711

The reactivity of Grignard reagents towards imines in the presence of catalytic and stoichiometric amounts of titanium alkoxides is reported. Alkylation, reduction, and coupling of imines take place. Whereas reductive coupling is the major reaction in sto

Full text of DOI:10.1002/asia.200900711

FULL PAPERS
DOI: 10.1002/asia.200900711
Catalytic Reactions of Titanium Alkoxides with Grignard Reagents and
Imines: A Mechanistic Study
Akshai Kumar and Ashoka G. Samuelson*[a]
Abstract: The reactivity of Grignard
reagents towards imines in the pres-
ence of catalytic and stoichiometric
amounts of titanium alkoxides is re-
ported. Alkylation, reduction, and cou-
pling of imines take place. Whereas re-
ductive coupling is the major reaction
in stoichiometric reactions, alkylation is
favored in catalytic reactions. Mecha-
nistic studies clearly indicate that inter-
mediates involved in the two reactions
are different. Catalytic reactions in-
volve a metal–alkyl complex. This has
been confirmed by reactions of deuteri-
um-labeled substrates and different al-
kylating agents. Under the stoichiomet-
ric conditions, however, titanium olefin
complexes are formed through reduc-
tive elimination, probably through a
multinuclear intermediate.
Keywords: alkylation · catalysis ·
Grignard
reagents
·
isotopic
labeling · titanium isopropoxide
Introduction
catalytic enantioselective allylation of hydrazones and
imines.[10]
The alkylation of imines is one of the most promising routes
to amines, which are important precursors to bioactive mol-
ecules.[1,2] Imines are less reactive than carbonyl compounds
towards Grignard reagents. The reduced reactivity is attrib-
uted to the reduced electrophilicity of the imine carbon
atom relative to a carbonyl carbon atom. Tomioka et al.
were the first to report the stoichiometric addition of orga-
nolithium reagents to imines.[3] A combination of either
indium–silver or zinc–silver is known to bring about the al-
kylation of imines in a one-pot three-component condensa-
tion of various aldehydes, amines, and unactivated alkyl io-
dides in aqueous media, which leads to a large library of
amines.[4] Addition of dialkylzinc to aldimines promoted by
Lewis acids such as zinc salts are well documented.[5,6]
Copper complexes are known to catalyze the diorganozinc
additions to activated imines.[7] There are also few reports of
Early transition metals like TiIV[11,12] and ZrIV[13–15] are
good Lewis acids and hence suitable for the catalytic alkyla-
tion of imines. However, in these reports, more than stoi-
chiometric amounts of alkylating agents are used to ensure
complete alkylation (Scheme 1). In some instances, the me-
Scheme 1. Ethylation of aldimine 1a catalyzed by [Cp2ZrCl2] (Cp=cyclo-
pentadienyl).[13b]
[Cu
G
(salen=N,N’-bis(salicylidene)ethyl-
A
thoxy group that is ortho to N in the imine has been shown
to be essential to achieve a good yield.[14] It has also been re-
ported that Grignards are limited to EtMgBr because higher
magnesium alkyls, namely, nPrMgBr and nBuMgBr, do not
give alkylated products.[11,13]
fer conditions.[8] Many palladium complexes are widely used
to catalyze the allylation of imines with allyl tributylstan-
nane.[9] Cook and co-workers have extensively studied the
We report here a mechanistic investigation of the alkyla-
tion of imines with a variety of Grignard reagents promoted
by Group IV metal alkoxide. The reactions carried out
under catalytic and stoichiometric amounts of TiIV alkoxide
are distinctly different. The catalytic conditions are suitable
for synthetic purposes.
[a] Dr. A. Kumar, Prof. A. G. Samuelson
Department of Inorganic and Physical Chemistry
Indian Institute of Science, Bangalore, 560012 (India)
Fax : (+91)80-2360-1552
E-mail: ashoka@ipc.iisc.ernet.in
1830
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Chem. Asian J. 2010, 5, 1830 – 1837

Results and Discussion
The primary aim of this study is to examine the utility of
Group IV metal alkoxides, both chiral and achiral, in chang-
ing the reactivity of imines with Grignard reagents.
For this purpose, N-benzylidineaniline 1a was used as a
test imine and its reactivity towards ethylmagnesium bro-
mide (EtMgBr) tested in the presence of stoichiometric and
catalytic amounts of titanium isopropoxide (Ti
ACHTUNGTNER(NUNG OiPr)4).
Equivalent amounts of imine 1a and Ti(OiPr)4 maintained
AHCTUNGTRENNUNG
at À788C in dry THF were reacted with two equivalents of
EtMgBr in a dropwise fashion. Subsequent workup showed
the presence of a mixture of products. The reaction (Table 1,
Table 1. Reaction of ethylmagnesium bromide with N-benzylidineaniline
1a mediated by titanium alkoxide.
Scheme 2. a) Plausible steps involved in the reaction of ethylmagnesium
bromide with 1a catalyzed by titanium isopropoxide. b) A mechanistic
scheme to explain the reaction of ethylmagnesium bromide with 1a
mediated by stoichiometric amounts of titanium isopropoxide.
Entry
Ti(OR)4
Ti(OR)4
[mol%]
Yield of isolated product [%][a]
G
2a
3
4
1
2
3
4
5
6
7
Ti
Ti
Ti
Ti
Ti
Ti
Ti
A
100.0
10.0
1.0
100.0
1.0
20
42
74
12
79
94
96
48
33
8
84
6
22
15
9
–
10
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[b]
[b]
R
metric (Scheme 2b) paths. In the absence of any catalyst,
EtMgBr reacted with 1a to give very low yields (16%) of
the ethylated product 2a.[13b] A reaction with a catalytic
amount of titanium isopropoxide (1%) preferentially pro-
duced the alkylated product 2a in excellent yields (74%)
along with small amounts of 3 and 4. The reduction in the
yield of 2a with stoichiometric amounts of titanium isoprop-
oxide can be attributed to the formation of polynuclear tita-
nium species such as 6b, which in turn led to low-valent TiII
species 8. The intermediate 8 gave rise to alkylation through
path B and reduced products through path C, as suggested
by Eisch et al.[16–18] To verify the hypothesis that alkylation
proceeded along path B under stoichiometric conditions and
predominantly along path A under catalytic conditions, a de-
tailed study of the reaction mechanism was taken up.
When isopropylmagnesium bromide (iPrMgBr) or n-pro-
pylmagnesium bromide (nPrMgBr) was used as the alkylat-
ing agent in the presence of stoichiometric amounts of tita-
nium alkoxide, 12 was the exclusive product (Table 2, en-
tries 1 and 2). On the other hand, in the presence of catalyt-
ic amounts of titanium alkoxide, iPrMgBr gave only 12
(Table 2, entry 3). The sole product obtained with nPrMgBr
was 13 (Table 2, entry 4). If the reaction proceeds along
path B during the catalytic reaction, both iPrMgBr and
N
T
1.0
0.1
–
–
G
–
[a] All yields of isolated product are wt% with respect to imine 1a and
are an average of two runs. [b] One equivalent of ethylmagnesium bro-
mide was used.
entry 1) produces, in addition to the alkylated product 2a,
the reduced product 4 along with significant amounts of
coupled product 3. The formation of reduced imine 4 and
À
the C C coupled diamine 3 have been reported earlier by
Eisch and Gitua, who have studied the stoichiometric reac-
tion in great detail.[16]
Since the stoichiometric reaction gives a mixture of prod-
ucts, a catalytic reaction was attempted (Table 1, entry 2).
Surprisingly, with a reduction of the amount of Ti
there was an increase in the yield of 2a (Table 1, entry 3).
Catalytic amounts of Ti(OR)4, especially Ti(BINOL)2
(BINOL=1,1’-binaphthalene-2,2’-diol), were found to give
the best yield of the addition product (Table 1, entries 6 and
7).
A mechanistic scheme was proposed to serve as a working
hypothesis for the catalytic (Scheme 2a) and the stoichio-
ACHTUNGTNER(NUNG OiPr)4,
AHCTUNGTRENNUNG
Chem. Asian J. 2010, 5, 1830 – 1837
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1831

A. Kumar and A. G. Samuelson
FULL PAPERS
Table 2. Ratio of alkylated products formed in the reaction of isopropyl-
magnesium bromide and n-propylmagnesium bromide with N-benzylidi-
neaniline 1a in the presence of titanium isopropoxide.
beling. So it is likely that 2a1 was the major product, which
has three deuterium atoms on the methyl carbon. This as-
sumption was further confirmed by 13C NMR spectra of the
crude product. A septet centered at d=10.38 ppm was ob-
served that corresponds to the trideuterated methyl carbon
2
atom. The H NMR spectra of the crude product was also
recorded, and it indicates the presence of the trideuterated
species 2a1 and dideuterated species 2a3 in the ratio 1:0.05.
The major product formed in this reaction is 2a1, and the
relative ratios of products were determined from 1H and
2H NMR spectroscopy (Table 3, entry 5).
Entry
t [h]
Ti
A
G
R
Yield of isolated product [%][a]
12
13
1
2
3
4
15
15
18
18
100.0
100.0
1.0
iPr
nPr
iPr
24
22
88
–
–
–
–
On the other hand, when 1a was treated with
CD3CH2MgBr in the presence of stoichiometric amounts of
TiACTHNUTRGNEUNG
(OiPr)4, 2H NMR spectroscopy revealed that two dideu-
nPr
74
terated species 2a2 and 2a3 were obtained in the ratio 1.44:1
(Table 3, entry 2). In this case, the H NMR spectra of the
[a] All yields of isolated product are wt% with respect to imine 1a and
are an average of two runs.
1
crude product indicates that the ratios of the CH/CH2/CH3
protons are 1.00:1.02:1.89, which is consistent with the ratio
2
nPrMgBr should lead to the same intermediate 8a. This
should result in a mixture of 12 and 13 in the same ratio
with either alkylating agent (Scheme 3). Clearly catalytic re-
actions are proceeding through path A without the interme-
diacy of an olefin complex.
obtained from H NMR spectroscopy.
2
The H NMR spectra for the stoichiometric and catalytic
reactions are given in Figure 1. Three peaks were obtained
in the 2H NMR spectra at d=0.98, 1.03, and 1.87 ppm,
which correspond to 2a1, 2a2, and 2a3, respectively. These
peaks were assigned relative to the deuterium peak of
CDCl3 at d=7.26 ppm. When CD3CH2MgBr was used as
the alkylating agent, the trideuterated species 2a1 arose
from a direct addition of the alkyl group of metal alkyl com-
plex 6e (Scheme 4). The formation of the dideuterated spe-
cies 2a2 and 2a3 is best explained by the formation of an in-
termediate metal olefin complex 8b. If this hypothesis is
true, then when one uses CH3CD2MgBr, one should obtain
2a3 (which arises from a metal alkyl complex 6 f) as a major
product with catalytic amounts of Ti
ACHTUNGTERN(NNUG OiPr)4 and a mixture
of 2a2 and 2a3 (which arises from a metal olefin complex
8b) when stoichiometric amounts of TiACTHNUTRGENUG(N OiPr)4 are used
(Scheme 4).
When imine 1a was treated with CH3CD2MgBr in the
presence of catalytic amounts of Ti(OiPr)4, 2a3 was obtained
AHCTUNGTRENNUNG
as a major product. The ratios of CH/CH2/CH3 protons were
1
found to be 1.00:0.00:3.00 from the H NMR spectra of the
crude product. The 13C NMR spectra of the crude product
have a quintet centered at d=31.46 ppm that corresponds to
2
the dideuterated methylene carbon atom. Further H NMR
spectroscopy of the crude product showed a major peak at
d=1.87 ppm. These data confirm the presence of a large
excess amount of about 98% of 2a3 in the crude product
(Table 3, entry 6).
Scheme 3. Formation of 8a, which leads to 12 and 13.
The product obtained in the reaction of 1a with
CH3CD2MgBr in the presence of stoichiometric amounts of
TiACHTNURTGNE(UGN OiPr)4 was similar to that obtained with CD3CH2MgBr.
However, this reaction gave a mixture of 2a2 and 2a3 in the
ratio 1:1 (Table 3, entry 3). The 1H NMR spectra of the
crude product indicated the ratios of CH/CH2/CH3 protons
to be 1.00:1.00:2.08. The 13C NMR spectra of the crude
product showed two quintets centered at d=31.42 and
10.42 ppm that correspond to the dideuterated methylene
carbon and the dideuterated methyl carbon atoms, respec-
Deuterium-labeled alkylating agents CD3CH2MgBr and
CH3CD2MgBr were utilized to confirm the reaction path.
The imine 1a was treated with CD3CH2MgBr in the pres-
ence of catalytic amounts of TiACHTNUGTRENUNG(OiPr)4, and the crude prod-
uct obtained after workup was analyzed by 1H, 2H, and
1
13C NMR spectroscopy. The H NMR spectra of the crude
product indicated that the ratio of CH/CH2/CH3 protons is
1.00:1.98:0.16, whereas one would have expected this ratio
to be 1.00:2.00:3.00 for compound 2a with no deuterium la-
1832
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Catalytic Reactions of Titanium Alkoxides with Grignard Reagents and Imines
Table 3. Reaction of ethylmagnesium bromide with N-benzylidineaniline 1a mediated by titanium isopropox-
ide.
and CH3CD2MgBr in the pres-
ence of stoichiometric and cata-
lytic amounts of TiACHTNUTRGNEUNG(OiPr)4 is
given in Figures 2 and 3, respec-
tively. All observations point to
the formation of an olefin inter-
mediate (path B) when stoi-
chiometric amounts of Ti-
AHCTUNGTRENNUNG
Grignard reagent in the pres-
ence of catalytic amounts of ti-
tanium(IV) alkoxides is very
useful for synthetic applications
because it leads to preferential
formation of alkylated products.
The best results were obtained
when a modified procedure was
Entry
RMgBr
Ti
A
G
Product ratio [%][a]
2a (2a1/2a2/2a3)[b]
3
4
1
2
3
4
5
6
CH3CH2MgBr
CD3CH2MgBr
CH3CD2MgBr
CH3CH2MgBr
CD3CH2MgBr
CH3CD2MgBr
100.0
100.0
100.0
1.0
29
39
41
30
11
6
32
17
36
16
13
5
42 (0.0:59.0:41.0)
34 (0.0:50.0:50.0)
73
81 (95.0:0.0:5.0)
91 (0.0:2.0:98.0)
followed with TiACHTNUGTRENUNG(BINOL)2 as a
catalyst in the alkylation reac-
tion in which only one equiva-
lent of the Grignard is added to
the imine at room temperature.
The reactions give slightly
better yields at room tempera-
ture and proceed smoothly for
a variety of alkylating agents
(Table 4). This suggests that the
Ti–alkyl intermediate is stable
enough at room temperature in
the presence of imines, which
capture them before they de-
compose.
4
[a] Ratios of products were determined by 1H NMR spectroscopy of the crude product and are an average of
two runs. [b] The ratios of 2a1/2a2/2a3 were determined by 2H NMR spectroscopy of the crude product and
are an average of two runs.
Conclusion
Grignard reagents react rapidly
with imines in the presence of
catalytic amounts of titanium
alkoxides. These reactions are
different from the stoichiomet-
ric reactions reported by Eisch
and Gitua.[16] The stoichiomet-
ric reactions permit intermolec-
ular reactions of Ti species that
lead to the reduction and cou-
pling of imines in addition to
alkylation. Under catalytic re-
action conditions, the large
ratio of the imine relative to Ti
promotes alkylation rather than
Figure 1. 2H NMR spectra of the products that arise from the reaction of CH3CD2MgBr or CD3CH2MgBr with
1a in the presence of catalytic amounts of titanium isopropoxide (a, d, respectively) and stoichiometric
amounts of titanium isopropoxide (b, c, respectively).
2
tively. Only two peaks were observed in the H NMR spec-
tra at d=1.87 and 1.03 ppm, which correspond to the deute-
rium atom on 2a3 and 2a2, respectively. A comparison of
coupling reactions of Ti intermediates, with high turnover
numbers under ambient conditions. Only one equivalent of
the alkylating agent is required. The alternative procedure
for the alkylation of imines with Grignard reagents, cata-
lyzed by simple Group IV metal alkoxides is more useful
1
the H NMR spectrum of the crude product obtained in the
reaction of imine 1a with CH3CH2MgBr, CD3CH2MgBr,
Chem. Asian J. 2010, 5, 1830 – 1837
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A. Kumar and A. G. Samuelson
FULL PAPERS
Experimental Section
General
All manipulations were carried out
under an inert atmosphere of dry ni-
trogen with a standard double mani-
fold. Tetrahydrofuran was freshly dis-
tilled from sodium/benzophenone
prior to use. Grignard-grade magnesi-
um turnings, 2,2,2-[D3]ethyl bromide,
1,1-[D2]ethyl bromide, and titaniu-
m(IV) isopropoxide were obtained
from Aldrich USA. Ethyl bromide, n-
propyl bromide, and isopropyl bro-
mide were purchased from Spectro-
chem India. The imines[19] and Ti-
[11,20]
G
were prepared by stan-
dard literature procedures.
Physical Measurements
1H and 13C{H} NMR spectra were re-
corded with a Bruker AMX 400 oper-
ating at 400 MHz for 1H NMR spec-
troscopy and 100 MHz for 13C NMR
spectroscopy, with tetramethylsilane or
CDCl3 as internal reference. 2H NMR
spectroscopy was carried out with a
Bruker DRX 500 operating at
76.7 MHz for 2H NMR spectroscopy
with CDCl3 as internal reference. All
spectra were recorded in CDCl3.
ESIMS measurements were done with
an Esquire 3000 Plus ESI (Bruker
Daltonics) or a Thermo Finnigan LCQ
Deca Plus instrument. Elemental anal-
yses were performed using a Thermo
Finnigan Flash EA 1112 CHNS ana-
lyzer.
Scheme 4. Pathways that lead to the formation of 2a1, 2a2, and 2a3.
Reaction of Ethylmagnesium Bromide
with Imine 1a in the Presence of
Catalytic Amounts of Titanium
Isopropoxide (1 mol%)
Ethyl bromide (0.40 mL, 5.35 mmol)
was dissolved in dry THF (5 mL) and
a small portion was added to magnesi-
um turnings (0.65 g, 26.8 mmol) dilut-
ed with dry THF (10 mL). The reac-
tion was initiated with gentle warming.
The remainder of the ethyl bromide/
THF solution was added dropwise
with constant stirring over a period of
half an hour while cooling the reaction
mixture to maintain the temperature
around 508C. After the addition of
ethyl bromide, the reaction mixture
was heated at reflux for an additional
hour to ensure completion of reaction.
The above Grignard was added in
drops to a solution of imine 1a (0.49 g,
1
Figure 2. Comparison of the H NMR spectra of the products that arise from the reaction of a) CH3CD2MgBr,
b) CD3CH2MgBr, and c) CH3CH2MgBr with 1a in the presence of stoichiometric amounts of titanium isoprop-
oxide.
2.67 mmol) and Ti
ACHTUNGTERN(NUNG OiPr)4 (0.008 g,
0.03 mmol) in dry THF (10 mL) main-
tained at À788C with a dry-ice–acetone slush bath. After addition, the re-
action mixture was allowed to attain room temperature and stirred at
room temperature over a period of 12 h. It was quenched by the addition
of a saturated NH4Cl solution and filtered through a Celite pad; the fil-
trate was extracted with diethyl ether. The organic layer was separated
and dried over anhydrous Na2SO4. The solvent was then removed under
than the stoichiometric reaction. Deuterium labeling experi-
ments conclusively reveal that the alkylation observed in
stoichiometric reactions arises from the involvement of a
metal–olefin complex, whereas the alkyl intermediate is the
active species in catalytic reactions.
1834
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Catalytic Reactions of Titanium Alkoxides with Grignard Reagents and Imines
Reaction of Ethylmagnesium Bromide
with Imine 1a in the Presence of
Stoichiometric Amounts of Titanium
Isopropoxide (100 mol%)
Ethyl bromide (0.40 mL, 5.35 mmol)
was dissolved in dry THF (5 mL) and
a small portion was added to magnesi-
um turnings (0.65 g, 26.8 mmol) dilut-
ed with dry THF (10 mL). The reac-
tion was initiated with gentle warming.
The remainder of the ethyl bromide/
THF solution was added dropwise
with constant stirring over a period of
half an hour while cooling the reaction
mixture to maintain the temperature
around 508C. After the addition of
ethyl bromide, the reaction mixture
was heated at reflux for an additional
hour to ensure completion of the reac-
tion. The above Grignard was added
in drops to a solution of imine 1a
(0.49 g, 2.67 mmol) and TiACHTUNGTRENNUNG(OiPr)4
(0.76 g, 2.67 mmol) in dry THF
(10 mL) maintained at À788C using
an dry ice–acetone slush bath. After
addition, the reaction mixture was al-
lowed to attain room temperature and
1
Figure 3. Comparison of the H NMR spectra of the products that arise from the reaction of a) CH3CD2MgBr,
stirred at room temperature over
a
b) CD3CH2MgBr, and c) CH3CH2MgBr with 1a in the presence of catalytic amounts of titanium isopropoxide.
period of 12 h. It was quenched by the
addition of saturated NH4Cl solution
and filtered through a Celite pad; the
filtrate was extracted with diethyl
ether. The organic layer was separated
Table 4. Reaction of 1a with various alkylating agents catalyzed by Ti-
ACHTUNGTRENNUNG(BINOL)2 (0.1 mol%) at room temperature.
and dried over anhydrous Na2SO4. The solvent was then removed under
reduced pressure to yield a yellow oil. This yellow oil was treated with
petroleum ether to precipitate compound 3. Subsequently, it was passed
through a silica gel column and eluted with petroleum ether, ethyl ace-
tate, and triethylamine in the ratio 98:1:1. Compound 2a was the first to
elute and this was followed by compound 4. Solvent was evacuated from
the desired fraction to obtain 2a as a pale yellow oil. Yields: 2a=0.11 g
(20%), 3=0.23 g (48%), and 4=0.11 g (22%).
A similar experimental procedure was followed in the reaction of isopro-
pylmagnesium
bromide,
n-propylmagnesium
bromide,
2,2,2-
[D3]ethylmagnesium bromide, and 1,1-[D2]ethylmagnesium bromide with
imine 1a in the presence of stoichiometric amounts of titanium isoprop-
oxide (100 mol%).
Entry
R
t [h]
Product
Yield of isolated product [%][a]
1
2
3
Et
iPr
nPr
15
17
18
2a
12
13
97
92
80
Reaction of Ethylmagnesium Bromide with Imine 1a in the Presence of
Substoichiometric Amounts of Titanium Isopropoxide (10 mol%)
[a] All yields of isolated product are wt% with respect to imine 1a and
are an average of two runs.
Ethyl bromide (0.40 mL, 5.35 mmol) was dissolved in dry THF (5 mL)
and
a small portion was added to magnesium turnings (0.65 g,
26.8 mmol) diluted with dry THF (10 mL). The reaction was initiated
with gentle warming. The remainder of the ethyl bromide/THF solution
was added dropwise with constant stirring over a period of half an hour
while cooling the reaction mixture to maintain the temperature around
508C. After the addition of ethyl bromide, the reaction mixture was
heated at reflux for an additional hour to ensure completion of reaction.
The above Grignard was added in drops to a solution of imine 1a (0.48 g,
reduced pressure to yield a yellow oil. This yellow oil was treated with
petroleum ether to precipitate the 3 present. Subsequently, it was passed
through a silica gel column and eluted with petroleum ether, ethyl ace-
tate, and triethylamine in the ratio 98:1:1. Compound 2a was the first to
elute and this was followed by compound 4. Solvent was evacuated from
the desired fraction to obtain 2a as a pale yellow oil. Yields: 2a=0.42 g
(74%), 3=0.04 g (8%), and 4=0.04 g (9%).
2.67 mmol) and TiACTHNUTRGNEUNG(OiPr)4 (0.08 g, 0.27 mmol) in dry THF (10 mL) main-
tained at À788C using an dry ice–acetone slush bath. After addition, the
reaction mixture was warmed to room temperature and stirred at room
temperature over a period of 12 h. It was quenched by the addition of sa-
turated NH4Cl solution and filtered through a Celite pad; the filtrate was
extracted with diethyl ether. The organic layer was separated and dried
over anhydrous Na2SO4. The solvent was then removed under reduced
pressure to yield a yellow oil. This yellow oil was treated with petroleum
ether to precipitate compound 3. Subsequently, it was passed through a
silica gel column and eluted with petroleum ether, ethyl acetate, and tri-
A similar experimental procedure was followed in the reaction of isopro-
pylmagnesium
bromide,
n-propylmagnesium
bromide,
2,2,2-
[D3]ethylmagnesium bromide, and 1,1-[D2]ethylmagnesium bromide with
imine 1a in the presence of catalytic amounts of titanium isopropoxide
(1 mol%).
Chem. Asian J. 2010, 5, 1830 – 1837
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
1835

A. Kumar and A. G. Samuelson
FULL PAPERS
ACHTUNGTRENNUNGethylamine in the ratio 98:1:1. Compound 2a was the first to elute, and
Acknowledgements
this was followed by compound 4. The solvent was evacuated from the
desired fraction to obtain 2a as a pale yellow oil. Yields: 2a=0.24 g
(42%), 3=0.16 g (33%), and 4=0.07 g (15%).
A.K. gratefully acknowledges a senior research fellowship from CSIR
and a PDF from IISc. A.G.S. thanks DST, New Delhi, for the award of a
research grant and for a 400 MHz NMR spectrometer through FIST. We
Reaction of Ethylmagnesium Bromide with Imine 1a in the Presence of
2
thank Mr. Uday Prabhu of NMRRC, IISc for recording H NMR spectra.
Catalytic Amounts of Ti
ACHTUNGTRENNUNG(BINOL)2 (0.1 mol%) at Room Temperature
Ethyl bromide (0.50 mL, 6.70 mmol) was dissolved in dry THF (5 mL)
and small portion was added to magnesium turnings (0.80 g,
a
33.50 mmol) diluted with dry THF (10 mL). The reaction was initiated
with gentle warming. The remainder of the ethyl bromide/THF solution
was added dropwise with constant stirring over a period of half an hour
while cooling the reaction mixture to maintain the temperature around
508C. After the addition of ethyl bromide, the reaction mixture was
heated at reflux for an additional hour to ensure completion of the reac-
tion. The above Grignard was added in drops to a solution of imine 1a
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(1.21 g, 6.70 mmol) and TiACHTNUGTRNEUNG(BINOL)2 (0.004 g, 0.007 mmol) in dry THF
(10 mL) maintained at room temperature. After addition, the reaction
mixture was stirred at room temperature over a period of 15 h and
quenched by addition of saturated NH4Cl solution. It was filtered
through a Celite pad and the filtrate was extracted with diethyl ether.
The organic layer was separated and dried over anhydrous Na2SO4. The
solvent was then removed under reduced pressure to yield a yellow oil.
This yellow oil was passed through a silica gel plug and eluted with petro-
leum ether, ethyl acetate, and triethylamine in the ratio 98:1:1. The sol-
vent was evacuated from this fraction to obtain 2a as a pale yellow oil.
Yield: 2a=1.370 g (97%).
A similar experimental procedure was followed in the reaction of isopro-
pylmagnesium bromide and n-propylmagnesium bromide with imine 1a
in the presence of catalytic amounts of TiACTHNUTRGEN(UNG BINOL)2 (0.1 mol%).
Compound 2a
Benzenemethanamine, a-ethyl-N-phenyl- 1H NMR (400 MHz): d=7.34
(m, 4H), 7.23 (m, 1H), 7.09 (t, J=8.0 Hz, 2H), 6.63 (t, J=7.2 Hz, 1H),
6.51 (d, J=8.0 Hz, 2H), 4.20 (t, 6.8 Hz, 1H), 4.1 (brs, 1NH), 1.84 (m,
2H), 0.96 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz): d=10.86, 31.64,
59.78, 113.30, 117.18, 126.44, 126.77, 128.56, 129.15, 143.99, 147.59 ppm;
MS (ESI): m/z: 212.1 [M+H]+, m/z:240.1 [M+K]+.
Compound 3
d,l,meso 1,2-Ethanediamine, N,N’,1,2-tetraphenyl- 1H NMR (400 MHz,
CDCl3): d=6.5–7.5 (m, 40H), 4.98 (2H, meso-NCH, d, J=8.0 Hz),
4.55 ppm (6H; brs, d,l and meso NH, d,l NCH); 13C NMR (100 MHz,
CDCl3): d=62.43, 64.50, 114.25, 114.60, 118.35, 118.61, 127.88, 128.06,
128.81, 128.95, 129.65, 129.96, 138.69, 140.43, 147.00, 147.56 ppm; MS
(ESI): m/z: 365.2 [M+H]+; elemental analysis calcd (%) for C26H24N2: C
85.68, H 6.64, N 7.69; found: C 84.74, H 5.58, N 7.56.
Compound 4
Benzenemethanamine, N-phenyl- 1H NMR (400 MHz): d=7.37 (m, 4H),
7.18 (t, J=8.0 Hz, 2H), 6.72 (t, J=7.6 Hz, 2H), 6.63 (d, J=8.4 Hz, 2H),
4.34 ppm (s, 2H); 13C NMR (100 MHz): d=48.35, 112.87, 117.60, 127.27,
127.55, 128.68, 129.31, 139.45, 148.18 ppm.
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Compound 12[6a]
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Commun. 2001, 31–32; b) V. Gandon, P. Bertus, J. Szymoniak, Eur.
J. Org. Chem. 2001, 3677–3681.
1
Benzenemethanamine, a-(1-methylethyl)-N-phenyl- H NMR (400 MHz):
d=7.29 (m, 4H), 7.2 (m, 1H), 7.05 (t, J=6.0 Hz, 2H), 6.62 (t, J=7.6 Hz,
1H), 6.49 (d, J=5.6 Hz, 2H), 4.12 (d, J=6.0 Hz, 1H), 2.03 (m, 1H), 0.98
(d, J=6.8 Hz, 3H), 0.93 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz):
d=18.71, 19.82, 34.79, 63.83, 113.29, 117.06, 126.85, 127.26, 128.28,
129.14, 142.66, 147.80 ppm.
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Chem. Soc. 2001, 123, 984–985; c) F. T. John, A. H. Hoveyda, M. L.
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Compound 13[6a]
Benzenemethanamine, N-phenyl-a-propyl- 1H NMR (400 MHz): d=7.29
(m, 4H), 7.20 (m, 1H), 7.08 (t, J=8.4 Hz, 2H), 6.63 (t, J=7.6 Hz, 1H),
6.52 (d, J=8.4 Hz, 2H), 4.31 (t, J=6.8 Hz, 1H), 1.79 (m, 2H), 1.45 (m,
2H) 0.97 ppm (t, J=6.8 Hz, 3H); 13C NMR (100 MHz): d=14.01, 19.64,
41.22, 58.18, 113.32, 117.24, 126.92, 128.43, 129.16, 144.41, 147.60 ppm.
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Chem. Asian J. 2010, 5, 1830 – 1837

Catalytic Reactions of Titanium Alkoxides with Grignard Reagents and Imines
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Received: December 14, 2009
[19] K. Neuvonen, F. Flp, H. Neuvonen, A. Koch, E. Kleinpeter, K. Pih-
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Revised: February 19, 2010
Published online: June 16, 2010
Chem. Asian J. 2010, 5, 1830 – 1837
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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