Tetrabenzylhafnium as a new organometallic reagent for imine addition resulting in α-branched amines

Article abstract of DOI:10.1002/ejoc.201100820

Tetrabenzylhafnium has been explored as a new organometallic reagent for the imine addition reaction. This reagent tolerates a wide scope of imines, affording α-branched amines in excellent yields without the use of any additive or catalyst. This new reag

Full text of DOI:10.1002/ejoc.201100820

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100820
Tetrabenzylhafnium as a New Organometallic Reagent for Imine Addition
Resulting in α-Branched Amines
Haibo Mei,[a] Xiaoyun Ji,[a] Jianlin Han,*[a] and Yi Pan*[b]
Keywords: Hafnium / Imines / Amines / Nucleophilic addition
Tetrabenzylhafnium has been explored as a new organome- amines in excellent yields without the use of any additive or
tallic reagent for the imine addition reaction. This reagent
tolerates a wide scope of imines, affording α-branched
catalyst. This new reagent shows higher efficiency than that
observed for classic Grignard and organolithium reagents.
now, there were only limited examples reported for hafnium
derivatives as catalysts used in organic methodologies[14]
and olefin polymerization.[15] In 2009, Shibata and co-
workers reported a highly α-selective addition reaction of
prenyltributyltin to imines, which was believed to proceed
through transmetalation between allyl-SnBu3 and HfCl4 in
situ.[16] Meanwhile, many reports have shown that tetraalk-
ylhafniums could be conveniently prepared from HfCl4.[17]
Tetraalkylhafnium reagents are sensitive to air and moist-
ure. Furthermore, these organometallic compounds show
the ability to coordinate with amines and carbonyl
groups.[18] Inspired by these reports and our recent studies
on hafnium, we conceived that a tetraalkylhafnium may be
developed as a new type of organometallic nucleophile for
the addition reaction to imines. Herein, we report that tet-
rabenzylhafnium was used as an efficient organometallic
reagent for the addition to imines, affording α-branched
amines under mild and convenient conditions (Scheme 1).
It is noteworthy that hafnium is yet another metal that can
be used as an organometallic reagent in nucleophilic ad-
dition reactions, in addition to previously reported lithium,
magnesium, zinc, stannum, silicon, copper, and boron.[4–11]
Introduction
The development of addition reactions between organo-
metallic reagents and imines has become an interesting and
challenging topic in modern organic chemistry,[1] because
this approach has served as one of the most attractive
routes to α-branched amines, which belong to an extremely
important class of compounds used in synthetic methodol-
ogies and in bioorganic and medicinal chemistry, and such
functionalities have been found in many natural products
as well as pharmaceutically related compounds.[2,3] In the
past decades, several main group metals and early transition
metals have been developed as organometallic nucleophiles
for addition reactions to imines, especially in their asym-
metric forms. Pioneering work in this area included the
study of organolithium,[4] Grignard,[5] and dialkylzinc[6]
reagents. Following these early successes, more organome-
tallic reagents, such as organostannanes,[7] allylsilanes,[8] ar-
yltitaniums,[9] alkylcoppers,[10] and arylboroxines,[11] were
explored for addition reactions to imines, but such reactions
usually required additional catalysts.
Group 4 halides and their derivatives have been devel-
oped as precursors for use in chemical vapor deposition and
atomic layer deposition of microelectronic thin films.[12]
Furthermore, titanium and zirconium compounds have
been widely used as efficient catalysts or reagents in a vari-
ety of organic reactions during the past few years.[13] In
contrast, related applications of hafnium compounds in or-
ganic synthesis still remain in their preliminary stages. Until
Scheme 1. Tetrabenzylhafnium nucleophilic addition to imines.
[a] School of Chemistry and Chemical Engineering,
Nanjing University,
Nanjing 210093, P. R. China
Fax: +86-25-83593153
Results and Discussion
E-mail: hanjl@nju.edu.cn
[b] State Key Laboratory of Coordination Chemistry,
Nanjing University,
At the beginning of the exploration, N-tosylimine (1a)
and tetrabenzylhafnium (2) were chosen as substrates. The
reaction was carried out with acetonitrile as solvent at
15 °C (Table 1).[16] Fortunately, the reaction proceeded
smoothly, affording α-branched amine 3a in good yield af-
Nanjing 210093, P. R. China
Fax: +86-25-83592846
E-mail: yipan@nju.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100820.
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H. Mei, X. Ji, J. Han, Y. Pan
SHORT COMMUNICATION
ter 2 h (81%; Table 1, Entry 1). Encouraged by the initial tolerated in this reaction, and the corresponding product
result, the optimization of the reaction conditions was then was obtained in high yield (88%; Table 2, Entry 11).
carried out to improve the reaction efficiency. Various sol- Furthermore, these obtained α-branched N-tosyl-protected
vents were screened (Table 1, Entries 2–7), and THF was amines belong to an important class of biologically active
found to be the best choice, resulting in 88% yield. Screen- compounds, and the reported synthetic methods for them
ing of the reaction time disclosed that this transformation were limited to the ring opening of aziridines until now.[19]
proceeded quickly and was complete within 30 min
Table 2. Scope of imines for the addition with HfBn4.[a]
(Table 1, Entry 9). Extending the reaction time resulted in
a slight decrease in the yield. Further examination revealed
that the temperature was not crucial for this reaction. Low-
ering the reaction temperature to 0 or to –20 °C showed no
obvious effect on the yield (Table 1, Entries 10 & 11). Fi-
nally, the loading of tetrabenzylhafnium was examined, and
it was found that the use of 1.2 equiv. of 2a gave the highest
yield (92%; Table 1, Entry 13). Further investigation found
that a very low yield was obtained when 0.3 equiv. of tet-
rabenzylhafnium was used in the reaction (17%; Table 1,
Entry 14), and this is probably because only one benzyl
group could be transferred from the hafnium reagent dur-
ing the addition process.
Entry
Substrate
Ar
Product
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
2-ClC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
91
93
93
89
85
86
92
84
98
88
2-BrC6H4
2-CH3C6H4
2-OCH3C6H4
3-ClC6H4
3-BrC6H4
4-FC6H4
4-CH3C6H4
4-OCH3C6H4
2-naphthyl
Table 1. Optimization of reaction conditions.[a]
9
10
11
1j
1k
3j
3k
[a] Reaction conditions: imine (0.5 mmol), HfBn4 (0.6 mmol), THF
(5 mL), 15 °C. [b] Isolated yield.
Entry Solvent
Time
[min]
T
[°C]
HfBn4
[equiv.]
Yield
[%][b]
Then, the optimized reaction conditions were applied to
other less-active imines, which were generated from aniline
(Scheme 2). To our delight, tetrabenzylhafnium could also
add directly to these imines to afford the desired products,
although obvious lower chemical yields were observed, es-
pecially for imines lacking a substituent.
1
2
3
4
5
6
CH3CN
toluene
CH2Cl2
CHCl3
hexane
Et2O
120
120
120
120
120
120
120
15
30
30
30
30
15
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.2
0.3
81
20
54
31
trace
74
88
81
90
86
89
83
92
17
15
15
15
15
15
15
15
15
–20
0
7
8
THF
THF
9
THF
THF
THF
THF
THF
THF
10
11
12
13
14
15
15
15
30
30
[a] Reaction conditions: imine (0.5 mmol), solvent (5 mL). [b] Iso-
lated yield.
Scheme 2. Tetrabenzylhafnium addition to imines 1l and 1m.
After determining the optimized reaction conditions, a
variety of N-tosylimines was studied to investigate the scope
The reactivity of this new organometallic reagent was
of the new addition process (Table 2). Tetrabenzylhafnium then examined by comparing it with well-known organome-
could directly add to all the imines without any catalyst or tallic reagents, such as benzylmagnesium chloride and benz-
additive, resulting in good to excellent yields of the products yllithium (Table 3). Tetrabenzylhafnium, benzylmagnesium
(84–98%). Variation of the substituents on the aromatic chloride, and benzyllithium were used as nucleophiles in the
rings did not have a significant effect on the chemical yield. addition reaction to add N-tosylimine (1a) under the same
Both electron-rich (Table 2, Entries 4 & 9) and electron-de- conditions at 15 °C. As shown in Table 3, tetrabenzylhaf-
ficient (Table 2, Entries 2, 3, 6, and 7) aryl-substituted nium showed the highest efficiency. BnMgCl added to 1a,
imines worked well, and even substituents such as fluoride although an obvious lower yield was observed (46%;
(Table 2, Entry 8) and methoxy (Table 2, Entries 5 & 10) Table 3, Entry 2) and no byproduct was detected. When
were tolerated. Notably, 2-naphthylimine (1k) was also well using benzyllithium as the nucleophile, only a trace amount
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Tetrabenzylhafnium as an Organometallic Reagent for Imine Addition
of the desired product was detected (Table 3, Entry 3) and a
large amount of the imine substrate was recovered. Similar
results were observed when the reaction temperature was
decreased to –20 °C (Table 3, Entries 4–6). These above re-
sults disclosed that the preliminary trend for the addition
reactivity is in the order of tetrabenzylhafnium Ͼ benzyl-
magnesium chloride Ͼ benzyllithium.
Conclusions
In summary, tetrabenzylhafnium has been developed as
a new organometallic reagent for the addition to imines,
which can greatly expand the research on hafnium metal.
The new system allowed the reaction to proceed smoothly
under mild conditions and tolerates a wide scope of sub-
strates, affording α-branched amines in excellent yields
without the use of any additive or catalyst. This reagent
also shows higher efficiency when compared with classic
Grignard and organolithium reagents. Further research will
focus on the investigation of the asymmetric reaction and
the application of this organometallic reagent to other nu-
cleophilic addition reactions.
Table 3. Addition to imine 1a with different organometallic rea-
gents.[a]
Experimental Section
General Information: All imine addition reactions were performed
Entry
RM
T [°C]
Yield [%][b]
in oven-dried vials under a N2 atmosphere. THF was dried and
[17]
distilled prior to use. HfBn4 and all the imines[20] were prepared
1
2
3
4
5
6
HfBn4
BnMgCl[c]
BnLi[d]
15
15
15
–20
–20
–20
92
46
trace
86
41
n.r.
according to reported methods. Other chemicals were used as ob-
tained from commercial sources without further purification. Flash
chromatography was performed using silica gel 60 (200–300 mesh).
Thin-layer chromatography was carried out on silica gel 60 F-254
TLC plates (20 cmϫ20 cm). IR spectra were collected with a
HfBn4
BnMgCl[c]
BnLi[d]
1
Bruker Vector 22 in KBr pellets. H and 13C NMR (TMS used as
[a] Reaction conditions: imine (0.5 mmol), RM (0.6 mmol), solvent
(5 mL). [b] Isolated yield. [c] 20 wt.-% in THF. [d] 1.2 m in hexane.
internal standard) spectra were recorded with a Bruker ARX 300
spectrometer. High-resolution mass spectra for all the new com-
pounds were obtained by using a Micromass Q-Tof instrument
(ESI).
Based on previous reports of the addition of organome-
tallic reagents to imines,[1] one proposed pathway to ac-
count for this new process is offered in Scheme 3. In the
initial step, tetrabenzylhafnium coordinates with the lone
pair of electrons on the nitrogen atom of the imine and
activates imine 1a, resulting in intermediate A. This coordi-
nation mode has also been found in other reported hafnium
complexes.[18] Then, intermediate A undergoes nucleophilic
addition by the benzylic anion, giving intermediate B. The
reaction is finally quenched by aqueous NH4Cl to form
product 3a. In this process, coordination with the strong
Lewis acid hafnium compound is believed to significantly
enhance the electrophilicity of the C=N bond, which makes
the addition of the benzyl carbanion easier. This may con-
tribute to the very smooth and quick transformation with-
out any catalyst.
Tetrabenzylhafnium (2): Powdered Mg (50 mmol), diethyl ether
(5 mL), I2 (one grain) were combined in a 100-mL round-bottomed
flask equipped with a positive flow of nitrogen and a condenser.
After initiation (the color of I2 disappeared), the corresponding
substituted benzyl chloride (46 mmol) dissolved in diethyl ether
(50 mL) was added dropwise over 30 min with stirring. The reac-
tion mixture was heated at reflux for 1 h and then cooled to –40 °C.
HfCl4 (13 mmol) was added to the mixture, which was then stirred
for 3 h in the dark, covering the flask with aluminum foil. The
solvent was removed under vacuum, and the residue was extracted
with CH2Cl2. Again, CH2Cl2 was removed under vacuum to afford
the yellow solid, which was recrystallized from hot heptane to give
desired product 2.
Procedure for the Addition of HfBn4 to N-Tosylimines: To an oven-
dried reaction vial flushed with N2 was added HfBn4 (0.6 mmol),
anhydrous THF (5.0 mL), and the respective N-tosylimine
(0.5 mmol). The reaction mixture was stirred at 15 °C for 0.5 h and
quenched with saturated NH4Cl (3.0 mL), followed by H2O
(5.0 mL). The organic layer was removed, and the aqueous layer
was extracted with EtOAc (2ϫ20 mL). The combined organic lay-
ers were dried with anhydrous Na2SO4, filtered, and concentrated
to give the crude product, which was purified by TLC plate (hex-
ane/EtOAc, 6:1).
Procedure for the Addition of HfBn4 to N-Phenylimines: To an oven-
dried reaction vial flushed with N2 was added HfBn4 (0.6 mmol),
anhydrous THF (5.0 mL), and the respective N-phenylimine
(0.5 mmol). The reaction mixture was stirred at 15 °C for 1 h and
then quenched with saturated NH4Cl (3.0 mL), followed by H2O
(5.0 mL). The organic layer was removed, and the aqueous layer
was extracted with EtOAc (2ϫ20 mL). The combined organic lay-
ers were dried with anhydrous Na2SO4, filtered, and concentrated
Scheme 3. Proposed mechanism for the addition of tetrabenzylhaf-
nium.
Eur. J. Org. Chem. 2011, 5783–5786
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H. Mei, X. Ji, J. Han, Y. Pan
SHORT COMMUNICATION
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Acknowledgments
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 20772056 and
20932004) and the Fundamental Research Funds for the Central
Universities (No. 1107020522 and No. 1082020502). The Jiangsu
333 program (for Y.P.) is also acknowledged.
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Received: June 7, 2011
Published Online: September 5, 2011
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