A novel and efficient method for the preparation of unstable tetramethylzirconium and its application using a microflow system

Article abstract of DOI:10.1246/cl.2012.73

We have developed a novel and efficient method for the preparation of unstable tetramethylzirconium and its application to the synthesis of tetrakis(N-methylethylamido)zirconium and dimethylbis(indenyl)zirconium using a microflow system.

Full text of DOI:10.1246/cl.2012.73

doi:10.1246/cl.2012.73
Published on the web December 30, 2011
73
A Novel and Efficient Method for the Preparation of Unstable Tetramethylzirconium
and Its Application Using a Microflow System
Koji Uehata,1,2 Mayumi Nishida,2 and Atsushi Nishida*1
1Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675
2Koei Chemical Company, Ltd., 25 Kitasode, Sodegaura, Chiba 299-0266
(Received October 13, 2011; CL-111007; E-mail: nishida@p.chiba-u.ac.jp)
We have developed a novel and efficient method for the
preparation of unstable tetramethylzirconium and its application
to the synthesis of tetrakis(N-methylethylamido)zirconium and
dimethylbis(indenyl)zirconium using a microflow system.
with MeOD. Next, we also studied the methylation of 2 with
tetramethylzirconium (1) under batch conditions. A suspension of
ZrCl4 in ether was treated with 4 equiv of MeLi in ether for
10 min at ¹78 °C. The suspension was warmed to ¹30 °C and
stirred for 2 h at the same temperature to complete the preparation
of 1. An ether solution of 2 was added to the resulting suspension
of LiCl and 1, and the mixture was stirred for 2 h at ¹20 °C. After
the reaction was quenched, 3 was obtained in 74% yield (Table 1,
Run 1).6,14 Prolongation of the reaction time and an increase in
the reaction temperature improved the yield of 3 to 90% (Run 2).
However, these conditions are not suitable for a flow system
because ZrCl4 and LiCl are insoluble in ether. Therefore, we
attempted this methylation in THF, in which both ZrCl4 and LiCl
are soluble. When ZrCl4 was dissolved in THF-toluene (11/1)
and reacted with MeLi in ether at ¹78 °C and then warmed to
¹30 °C, 3 was not obtained at all (Run 3). However, when the
temperature of the reaction of ZrCl4 with MeLi was raised to 0 °C
followed by addition of a solution of 2, desired 3 was obtained
in 52% yield (Run 4). These results showed that the reaction of
zirconium species was much slower in THF than in ether and
required higher temperature to proceed with reasonable reaction
rate. Although the yield of 3 was lower than that of the reaction in
ether, the reaction in a THF/toluene solvent system was
applicable in the microflow system. We then began study of the
preparation of 1 in a microflow system.
Over the past decade, flow reactions with microflow systems
have been used for chemical reactions because of numerous
advantages over conventional macrobatch reactions.1-3 The
features of the flow reaction are as follows; 1) extremely fast
mixing due to the short diffusion path, 2) ability to control the
reaction residence time, which is the length of time that the
solution remains inside the reactor, and 3) efficient heat transfer
due to a high surface-to-volume ratio.1 In addition, 4) an increase
in the number of microflow systems makes it possible to increase
the production capacity, which may be beneficial from the
viewpoint of industrial production. Especially, the features of 1),
2), and 3) are quite advantageous for the precise control of
reactive intermediates and thereby facilitate highly selective
reactions that are difficult to achieve in conventional reactors.3 We
report here a novel method for the synthesis of tetrakis(N-
methylethylamido)zirconium and dimethylbis(indenyl)zirconium
via thermally unstable tetramethylzirconium (1)4 with the use of a
microflow system.
The preparation of 1 can be checked by the reaction with
2,4,6-trimethylacetophenone (2) to afford 2-mesityl-2-propanol
(3). Reetz et al. reported that MeLi and MeMgI induce 100%
enolization of 2. However, 1 methylated 2 to give the corre-
sponding alcohol 3 in 45% yield under batch conditions
(Scheme 1).5 In this study, we examined the same methylation.
The reaction of 2 with MeLi failed to give 3, and instead induced
the enolization of 2, which was detected by 91% incorporation of
deuterium at an acetyl group when the reaction was quenched
A microflow system consisted of T-shaped micromixers (M-0
and M-1) and microtube reactor (R-1). The mixers and tube
reactor were immersed in a water bath (Figure 1).14 A solution of
¹1
1.0 M MeLi in ether (flow rate: 0.8 mL min¹1, 0.8 mmol min
)
was diluted with THF (flow rate: 2.4 mL min¹1) to prevent
clogging of the flow system by introduction to M-0 (º =
1000 ¯m) at 20 °C using syringe pumps. The resulting solution
of 0.25 M MeLi in ether-THF and a solution of 0.1 M ZrCl4 in
¹1
THF-toluene (11:1, flow rate: 2.0 mL min¹1, 0.2 mmol min
)
O
were introduced to M-1 (º = 500 ¯m) at 20 °C using syringe
pumps. After the resulting solution was passed through R-1
(º = 1000 ¯m, length = 200 cm, residence time = 18.1 s), the
reaction mixture was added to 0.2 M of 2 in THF solution
(1.0 mL, 0.2 mmol) at ¹20 °C over 1 min (5.2 mL, which contains
0.2 mmol of 1) and stirred for 12 h at ¹20 °C and then for 2 h at
25 °C. After workup, compound 3 was obtained in 49% yield with
HO
4 MeLi
2
ZrCl4
ZrMe4
1
3
Scheme 1. Reaction of ZrCl4 with MeLi followed by a reaction with
2,4,6-trimethylacetophenone (2).
Table 1. Reaction of ZrCl4 with MeLi followed by a reaction with 2 under batch reactions
Reaction of ZrCl4 with MeLi
Reaction of 1 with 2
Yield/%a
2/solvent
(0.2 M)
Run
ZrCl4/solvent
Conditions
Temp/°C
Time/h
2
3
4
1
2
3
4
ether
ether
THF/Tol. (11/1)
THF/Tol. (11/1)
¹30 °C, 2 h
¹30 °C, 2 h
¹30 °C, 2 h
0 °C, 30 min
ether
ether
THF
THF
¹20
2
18
4
91
30
74
90
0
1
2
0
8
¹20 ¼ 25
¹20 ¼ 25
¹20 ¼ 25
12 + 2
12 + 2
12 + 2
52
aDetermined by GC with phenanthrene as an internal standard.
Chem. Lett. 2012, 41, 73-75
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

74
L = 100 or 200 cm
N
M-0
φ
= 1000 μm
THF
(φ = 1000 μm)
N
Zr
N
4 MeLi
H
5
2.4 mLmin−1
N
N
ZrCl4
ZrMe4
R-1
1
ZrMe4(1)
1.0 M (ether)
MeLi
6
0.8 mLmin−1
M-1
N2
φ
= 500 μm
Scheme 2. Reaction of 1 with N-methylethylamine (5).
0.1 M (THF/Tol.)
ZrCl4
HO
2.0 mLmin−1
water bath
O
T = 20, 25, 30 or 35 o
C
+
L = 100, 200 cm
2
M-0
φ
= 1000 μm
(φ = 1000 μm)
3
4
THF
25 o
C
2.4 mLmin−1
-20
R-1
1.0 M (ether)
MeLi
L = 200 cm
Figure 1. Microflow system for the preparation of 1 followed by a
reaction with 2.
(
φ
= 1000 μm)
0.8 mLmin−1
M-1
φ
= 500 μm
R-2
0.1 M (THF/Tol.)
ZrCl4
Table 2. Reaction of ZrCl4 with MeLi followed by a reaction with 2
using a microflow system
N
Zr
N
2.0 mLmin−1
N
N
M-2
Yield/%a
φ
= 500 μm
R-1
N
6
Run
H
Temp
/°C
Residence time
/s
5
2
3
4
water bath T = 0, 25 or 35 oC
Outlet solution
0.35 M (Tol/THF)
2.4 mLmin−1
1
2
3
4
5
6
20
25
35
25
30
35
18.1
18.1
18.1
9.1
9.1
9.1
37
32
41
49
36
36
49
56
44
40
53
55
6
6
7
6
7
6
Figure 2. Microflow system for the reaction of 1 with 5.
Table 3. Reaction of 1 with 5
Residence time
in R-1/s
Temp
/°C
Run
Yield/%a
aDetermined by GC with phenanthrene as an internal standard.
1
2
3
4
5
6
7
18.1
18.1
9.1
9.1
0
25
35
25
35
¹78c
25c
58
70
61
53
76
66
54
recovered 2, 37% and dehydrated 4, 6% (Table 2, Run 1).14 As
shown in Table 2, various temperatures and residence times in
R-1, which was controlled by changing the length of R-1 with a
fixed flow rate, were tested.
At a residence time in R-1 of 18.1 s, the highest 56% yield of
3 was observed at 25 °C (Run 2). On the other hand, when the
residence time in R-1 was 9.1 s, 3 was obtained in 55% yield at
35 °C (Run 6). In the scale-up reaction (0.9 mmol) under the
conditions Run 2 followed by quenching with MeOD for 5 min
at ¹20 °C, 3 was obtained in 53% isolated yield along with
9.1
batch reactionb
batch reactionb
1
aDetermined by H NMR with mesitylene as an internal standard.
b1 was prepared under the same conditions as Table 1, Run 1.
cTemperature of the reaction of 1 with 5.
1
recovered 2 (31%). A H NMR study of recovered 2 showed that
hand, when the residence time in R-1 was shorter (9.1 s), the yield
was further increased to 76% at 35 °C (Run 5). In a conventional
batch reaction, much lower temperatures were required for the
generation and reactions of 1 (Runs 6 and 7).14 However, with a
microflow system, the reaction has been completed with shorter
reaction times at higher temperatures with better yield. As a result
of Tables 2 and 3, the yield of tetramethylzirconium (1) should be
more than 76% yield without the contamination of MeLi.
Then, we studied the reaction of 1 with indene (7) to afford
dimethylbis(indenyl)zirconium (8) (Scheme 3). Metallocene-based
catalysts have been used for the production of novel polyolefins
with tailor-made properties, since these catalysts can easily
control the molecular weight, the narrow molecular weight
distribution and polymer stereochemistry.11 Dimethylzircono-
cenes are usually produced by the three-step procedure shown
in Scheme 4. However, the use of three steps with the isolation
of dichlorozirconocene intermediates gives unsatisfactory total
yields.12
the incorporation of deuterium at the acetyl group was only 1%.
This result suggests that at least 99.9% of MeLi reacted with
ZrCl4 under these flow conditions. Therefore, under these
conditions, 1 was produced in at least the same level as under
batch conditions.
Generation of tetramethylzirconium under
a microflow
system was further tested by the reaction with N-methylethyl-
amine (5) to give tetrakis(N-methylethylamido)zirconium (6),
which has been used as a Zr gaseous precursor in ALD (atomic
layer deposition) for the deposition of zirconia films (Scheme 2). 9
It has been reported that processes for producing 6 require the
transfer of ZrCl4 to a slurry of a lithium alkylamide under
conventional batch conditions.10 It is difficult to introduce
hazardous solids (ZrCl4) to a reaction mixture on a commercial
scale. A solution of 1 was prepared under microflow conditions
as described above and mixed with a solution of 5 at M-2, and
then the resulting solution was passed through R-2 (Figure 2:
º = 1000 ¯m, length = 200 cm, residence time = 12.4 s).14 Prod-
uct 6 was isolated by evaporation of the solvents. As shown in
Table 3, the results were obtained under varying temperature and
residence time in R-1. At a residence time of 18.1 s in R-1, the
highest yield was observed at 25 °C (Run 2; 70%). On the other
Resconi and co-workers reported a simpler method for the
preparation of 8 by reacting 7 with a twofold excess of MeLi,
followed by the addition of slurries of ZrCl4 in pentane.13 In this
method, 8 was produced in 87% yield. However, the complete
transfer of slurries of ZrCl4 in pentane to the mixture of MeLi
Chem. Lett. 2012, 41, 73-75
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

75
indene
7
mally unstable tetramethylzirconium using a microflow system.
We expect to produce dimethylzirconocenes with functional
groups which might be difficult to prepare by conventional
methods.
4 MeLi
(Ind)2ZrMe2
ZrCl4
ZrMe4
8
Scheme 3. Reaction of 1 with indene (7).
Financial support from Koei Chemical Co., Ltd. is gratefully
acknowledged.
R
R
Li
methylation
BuLi
ZrCl4
Me
Me
Cl
Cl
Zr
Zr
R
R
R
R
References and Notes
Scheme 4. Conventional method for dimethylzirconocenes.
1
a) W. Ehrfeld, V. Hessel, H. Löwe, Microreactors: New Technology for
Modern Chemistry, Wiley-VCH, Weinheim, 2000. b) P. Watts, C.
Wiles, Chem. Commun. 2007, 443.
2
a) H. Hisamoto, T. Saito, M. Tokeshi, A. Hibara, T. Kitamori, Chem.
Commun. 2001, 2662. b) S. Saaby, K. R. Knudsen, M. Ladlow, S. V.
Ley, Chem. Commun. 2005, 2909. c) H. Wakami, J.-i. Yoshida, Org.
Process Res. Dev. 2005, 9, 787. d) T. Kawaguchi, H. Miyata, K. Ataka,
K. Mae, J.-i. Yoshida, Angew. Chem., Int. Ed. 2005, 44, 2413. e) A.
Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae, J.-i. Yoshida, J. Am.
Chem. Soc. 2005, 127, 11666. f) M. T. Rahman, T. Fukuyama, N.
Kamata, M. Sato, I. Ryu, Chem. Commun. 2006, 2236. g) C. H.
Hornung, M. R. Mackley, I. R. Baxendale, S. V. Ley, Org. Process Res.
Dev. 2007, 11, 399. h) A. Hartung, M. A. Keane, A. Kraft, J. Org.
Chem. 2007, 72, 10235. i) A. Nagaki, N. Takabayashi, Y. Tomida, J.-i.
Yoshida, Org. Lett. 2008, 10, 3937. j) D. Grant, R. Dahl, N. D. P.
Cosford, J. Org. Chem. 2008, 73, 7219. k) A. Palmieri, S. V. Ley, K.
Hammond, A. Polyzos, I. R. Baxendale, Tetrahedron Lett. 2009, 50,
3287. l) I. R. Baxendale, S. V. Ley, A. C. Mansfield, C. D. Smith,
Angew. Chem., Int. Ed. 2009, 48, 4017. m) M. O’Brien, I. R.
Baxendale, S. V. Ley, Org. Lett. 2010, 12, 1596.
Yoshida and co-workers studied the monolithiation of o-dibromoben-
zene using a microflow system to generate o-bromophenyllithium
which is well-known to rapidly decompose to benzyne and gives
various undesired products even at ¹78 °C. The generation and
reactions of o-bromophenyllithium can be accomplished by precise
control of the residence time and temperature in a microflow system. H.
Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami, J.-i. Yoshida,
J. Am. Chem. Soc. 2007, 129, 3046.
L = 100, 200 cm
M-0
φ
= 1000 μm
φ
( = 1000 μm)
THF
2.4 mLmin−1
R-1
1.0 M (ether)
MeLi
L = 200, 400 cm
= 1000 μm)
(
φ
0.8 mLmin−1
M-1
φ
= 500 μm
R-2
0.1 M (THF/Tol.)
ZrCl4
2.0 mLmin−1
(Ind)2ZrMe2
8
M-2
φ
= 250 or 500 μm
Outlet solution
water bath T = 25 or 35 oC
7
0.91 M (THF)
Figure 3. Microflow system for the reaction of 1 with 7.
Table 4. Reaction of 1 with 7
3
Inner
Residence time/s
7
Temp diameter Yield
Run
/equiv /°C
of M-2
/¯m
/%a
R-1
R-2
4
5
H. J. Berthold, G. Groh, Angew. Chem., Int. Ed. Engl. 1966, 5, 516.
a) M. T. Reetz, J. Westermann, R. Steinbach, B. Wenderoth, R. Peter,
R. Ostarek, S. Maus, Chem. Ber. 1985, 118, 1421. b) M. T. Reetz, R.
Steinbach, J. Westermann, R. Urz, B. Wenderoth, R. Peter, Angew.
Chem., Int. Ed. Engl. 1982, 21, 135.
1
2
3
4
9.1
9.1
18.1
batch reactionb
16.7
15.0
29.9
2
5
5
5
35
35
25
25b
500
500
250
®
22
55
61
1
6
1H NMR data for 2-mesityl-2-propanol (3), but not the 13C NMR
results, were identical to those reported in the literature.7 While the
second carbon position was observed at 75.83 ppm in our case, the
corresponding carbon was reported to be at 56.09 ppm in ref. 7. Further
NMR experiments that included DEPT, HMQC, and HMBC methods
clearly showed that our product had the structure shown as compound
3. In addition, in the 13C NMR spectrum of 2-phenyl-2-propanol, the
second position has been reported to be at 72.46 ppm.8
J. W. Timberlake, D. Pan, J. Murray, B. S. Jursic, T. Chen, J. Org.
Chem. 1995, 60, 5295.
T. Tokuyasu, S. Kunikawa, A. Masuyama, M. Nojima, Org. Lett. 2002,
4, 3595.
1
aDetermined by H NMR with mesitylene as an internal standard.
b1 was prepared under the same conditions as Table 1, Run 1 and
then an ether solution of 7 was added to 1. The reaction was
continued for 1 h at 25 °C.
and ³-ligand is difficult at low temperature in the industrial
production.
7
8
9
We examined the reaction of 1 with 7 (0.91 M THF solution)
using a microflow system to provide 8, as shown in Figure 3. The
results are summarized in Table 4. We successfully obtained 8 in
22% yield with this microflow system at 35 °C (Run 1; flow rate
D. Monnier, I. Nuta, C. Chatillon, M. Gros-Jean, F. Volpi, E. Blanquet,
J. Electrochem. Soc. 2009, 156, H71, and references cited therein.
of 0.91 M indene: 0.44 mL min¹1, 0.40 mmol min¹1). The H and
1
10 a) D. C. Bradley, I. M. Thomas, J. Chem. Soc. 1960, 3857. b) T.
Kamimoto, Jpn. Kokai Tokkyo Koho, JP2007-314437.
11 H. H. Brintzinger, D. Fischer, R. Mülhaupt, B. Rieger, R. M.
Waymouth, Angew. Chem., Int. Ed. Engl. 1995, 34, 1143.
12 a) E. Samuel, M. D. Rausch, J. Am. Chem. Soc. 1973, 95, 6263. b) E.
Samuel, H. G. Alt, D. C. Hrncir, M. D. Rausch, J. Organomet. Chem.
1976, 113, 331. c) A. R. Siedle, R. A. Newmark, W. M. Lamanna, J. N.
Schroepfer, Polyhedron 1990, 9, 301. d) A. D. Horton, A. G. Orpen,
Organometallics 1991, 10, 3910. e) J. C. W. Chien, W.-M. Tsai, M. D.
Rausch, J. Am. Chem. Soc. 1991, 113, 8570. f) A. R. Siedle, R. A.
Newmark, J. Organomet. Chem. 1995, 497, 119.
13C NMR data of 8 were identical to those reported in the
literature.13 The yield of 8 increased with an increase in the molar
equivalent of 7/ZrCl4 (Run 2; 55% yield, flow rate of 0.91 M of
7: 1.1 mL min¹1, 1.0 mmol min¹1). Under further optimization, a
decrease in the diameter of M-2 and increase in the length of R-1
and R-2 at 25 °C gave 8 in the highest yield (Run 3; 61% yield).
On the other hand, a trace amount of 8 was observed under batch
conditions using 1 prepared under the same conditions as Table 1,
Run 1 (Run 4).14 This result indicated a microflow system is more
effective than a batch system in the reaction of 1 with 7.
13 D. Balboni, I. Camurati, G. Prini, L. Resconi, S. Galli, P. Mercandelli,
A. Sironi, Inorg. Chem. 2001, 40, 6588.
14 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
In this work we synthesized tetrakis(N-methylethylamido)-
zirconium (6) and dimethylbis(indenyl)zirconium (8) via ther-
Chem. Lett. 2012, 41, 73-75
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/