Reactions of organolithiums with dialkyl oxalates. A flow microreactor approach to synthesis of functionalized α-keto esters

Article abstract of DOI:10.1039/c3cc40392k

Reactions of functionalized aryllithiums with dialkyl oxalates were achieved using a flow microreactor to obtain α-keto esters with high selectivity by virtue of fast 1:1 micromixing.

Full text of DOI:10.1039/c3cc40392k

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Reactions of organolithiums with dialkyl oxalates.
A flow microreactor approach to synthesis of
functionalized a-keto esters†
Cite this: Chem. Commun., 2013,
49, 3242
Received 17th January 2013,
Accepted 28th February 2013
Aiichiro Nagaki, Daisuke Ichinari and Jun-ichi Yoshida*
DOI: 10.1039/c3cc40392k
www.rsc.org/chemcomm
Reactions of functionalized aryllithiums with dialkyl oxalates were such as cyano, nitro, alkoxycarbonyl and ketone carbonyl groups
achieved using a flow microreactor to obtain a-keto esters with were successfully generated and used for reactions with electro-
high selectivity by virtue of fast 1 : 1 micromixing.
philes using flow microreactor systems.13
With such information in hand, we set out to investigate
a-Keto carboxylic acids and esters play an important role in organic reactions of functionalized organometallics with dialkyl oxalates
synthesis as useful building blocks for synthesizing a variety of complex using flow microreactor systems and found that selective formation
molecules such as biologically active natural products.1,2 Various of a-keto esters was achieved.
methods for synthesizing a-keto carboxylic acids and esters have been
Before studying flow microreactor reactions, we examined the
reported so far,3 and the most commonly used method is the reaction reaction in a flask (a 50 mL round bottom glass flask with a magnetic
of organometallics with dialkyl oxalates or oxalyl chloride. However, the stirrer). Thus, phenyllithium, which was generated by the halogen–
method often suffers from low yields of the desired products because lithium exchange reaction of bromobenzene with n-BuLi, was allowed
the initial products react with another molecule of organometallics to to react with one equivalent of diethyl oxalate (Fig. 1). The yields of
produce byproducts such as alcohols and diketones even if one ethyl 2-oxo-2-phenylacetate (2, mono-addition product), 1,2-diphenyl-
equivalent of the organometallics is used (the problem of competitive ethane-1,2-dione (3, di-addition product), ethyl 2-hydroxy-2,2-diphenyl-
consecutive reactions).4 Therefore, alkyl oxalyl chloride, alkyl cyanofor- acetate (4, di-addition product), and 2-hydroxy-1,2,2-triphenylethanone
mate, and alkyl a-oxo-1H-imidazole-1-acetate are often used to suppress (5, tri-addition product) were determined by GC. The addition of
such side reactions.5 However, these reagents are more expensive and, diethyl oxalate to a stirred solution of phenyllithium at À78 1C gave
therefore, are not suitable for large-scale synthesis. These methods 2 and 3 in low yields (Table 1). In contrast, the simultaneous addition
using organometallics suffer from another problem, i.e. functional and the reverse addition gave better results, but the yield of 2 and
group compatibility in preparation and reactions of organometallics.6 selectivity were not enough. The selectivity and yield decreased with an
Therefore, it is highly desired to develop a method for synthesizing increase in the temperature, and a significant amount of 3, and 5 was
a-keto esters bearing functional groups on a large scale. However, to the produced. It is interesting to note that di-addition product 4 was not
best of our knowledge, no study to solve these problems has yet been obtained at all indicating that the ester carbonyl group of 2 is more
reported in the literature. We envisaged that the use of a flow reactive than the ketone carbonyl group presumably because of the
microreactor system7,8 would be effective in solving these problems.
steric effect. In addition, it should be kept in mind that the batch
We have already reported that the problem of disguised chemical method cannot be applied to functionalized organolithium species
selectivity9 in competitive consecutive reactions is solved by extremely because they decompose very quickly.
fast 1 : 1 micromixing based on short diffusion paths and that product
In the next step, we examined the reaction using a flow micro-
selectivity close to the kinetically based one is obtained.10 We have reactor system composed of two T-shaped micromixers (M1 and M2)
also reported that highly reactive and unstable reactive intermediates and two microtube reactors (R1 and R2) as shown in Fig. 2.
could be generated and used before they decompose by virtue of
short residence times in flow microreactors11 (flash chemistry12).
For example, aryllithiums bearing electrophilic functional groups
Department of Synthetic and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Nishikyo-ku, 615-8510 Kyoto, Japan.
E-mail: yoshida@sbchem.kyoto-u.ac.jp; Fax: +81-75-383-2725; Tel: +81-75-383-2726
† Electronic supplementary information (ESI) available: Experimental section.
See DOI: 10.1039/c3cc40392k
Fig. 1 Reaction of diethyl oxalate and phenyllithium generated from bromobenzene.
c
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Table 1 Reaction of diethyl oxalate and phenyllithium using a conventional
Table 3 Reaction of diethyl oxalate and phenyllithium generated from bromo-
macro-batch system
benzene using a flow microreactor system. The effect of mixing
Yield (%)
Yield (%)
Conversion
of 1 (%)
Inner diameter of Total flow rate at M2
Conversion of
1 (%)
T2 (1C) Method of addition
2
3
4 5
M2 (mm)
(mL minÀ1
)
2 3 4 5
À78
À78
À78
À60
À40
À20
0
Addition of 1 to PhLi
Simultaneous addition of 1 and PhLi 66
59
25 21 0
56 17 0
63 9 0
66 13 0
62 15 0
55 18 0
53 15 0
1
6
7
3
5
9
7
250
250
250
250
250
500
800
17.5
14.0
10.5
7.0
3.5
14.0
14.0
98
98
96
92
60
88
72
95 5 0 0
93 5 0 0
90 5 0 0
80 8 0 2
29 10 0 5
77 17 0 2
47 22 0 8
Addition of PhLi to 1
Addition of PhLi to 1
Addition of PhLi to 1
Addition of PhLi to 1
Addition of PhLi to 1
Addition of PhLi to 1
70
71
81
83
82
72
20
43 18 0 10
total flow rate at M2 = 14.0 mL minÀ1) in hand, we next examined
reactions of various aryllithiums generated from functionalized
halobenzenes. In the case of bromobenzenes n-BuLi was used as a
lithiating agent. In the case of iodobenzenes PhLi was used as a
lithiating agent. The halogen–lithium exchange was conducted with
the residence times (tR1) optimized for each halobenzenes.13 As
shown in Table 4, dimethyl oxalate and di-tert-butyl oxalate in
addition to diethyl oxalate could be used and the corresponding
a-keto esters were obtained in good yields and selectivity. Notably,
various aryllithiums bearing electrophilic functional groups such as
cyano, nitro, and alkoxycarbonyl groups at ortho-, meta- and para-
positions reacted with diethyl oxalate to give the corresponding
a-ketoesters in high yields and selectivity. In the case of aryllithiums
bearing an alkoxycarbonyl group, the reactions with diethyl oxalate
were carried out at T1 = T2 = À60 1C in order to avoid their
decomposition. Such transformations are very difficult or impossible
Fig. 2 A flow microreactor system for reaction of diethyl oxalate and phenyl-
lithium generated from bromobenzene.
The results were obtained by varying the temperature (T1 = T2 =
À78–20 1C), the inner diameter of M2, and the flow rate. The effect of
the temperature is interesting. As shown in Table 2, the yield of 2 and
selectivity were much higher than those for flask reactions, and the
highest yield and selectivity were obtained at À60 1C. The yield and
selectivity gradually decrease with an increase in T. It is noteworthy
that satisfactory yield and selectivity were obtained at À20 1C and
thereafter we carried out the reactions at this temperature from a
practical point of view because it was difficult to achieve lower
temperatures using brine, which is a common coolant in industry.
To examine the effect of mixing, we carried out the reactions
by varying the total flow rate at M2 because it is well known that
mixing efficiency of micromixers strongly depends on the flow
rate.14 As shown in Table 3, the yield of 2 and the selectivity
decreased with a decrease in the flow rate, indicating the
importance of mixing efficiency. The fact that the yield of 2
and selectivity decreased with an increase in the diameter of
micromixer M2 also indicates the importance of mixing. There-
fore, it is reasonable to conclude that extremely fast 1 : 1 mixing
is responsible for selective formation of a-ketoester 2.
Table 4 Selective reaction of dialkyl oxalate with organometallics using flow
microreactors
T1, T2
(1C)
Dialkyl
Yield
(%)
Halobenzene
tR1 (s) oxalate
Product
À20 4.71
À20 4.71
À20 4.71
À20 2.35
93
90
75
91
With the optimized conditions for selective synthesis of
a-ketoester 2 (T1 = T2 = À20 1C, inner diameter of M2 = 250 mm,
À20 2.35
95
Table 2 Reaction of diethyl oxalate with phenyllithium generated from bromo-
benzene using a flow microreactor system. The effect of the temperature
À20 2.35
À20 0.28
À20 0.28
94
75
87
Yield (%)
Conversion
of 1 (%)
T1, T2 (1C)
tR1 (s)
2
3
4
5
À78
À60
À40
À20
0
9.42
9.42
2.35
2.35
2.35
2.35
96
100
100
98
95
93
87
96
96
93
88
82
3
1
2
5
7
9
0
0
0
0
0
0
0
0
0
0
0
1
20
The reactions were carried out under the following conditions: the flow
rates: PhBr solution 8 mL minÀ1, BuLi solution 2 mL minÀ1, diethyl
oxalate solution 4 mL minÀ1; the inner diameter of M2 250 mm.
À20 0.28
63
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Table 4 (continued )
V. S. Oleg, K. M. Pavel, A. Z. Olga and A. Andrey, Synthesis, 2011,
1633.
T1, T2
(1C)
Dialkyl
Yield
(%)
3 (a) E. J. Corey and B. W. Erickson, J. Org. Chem., 1971, 36, 3553;
(b) K. Yamada, M. Kato, M. Iyoda and Y. Hirata, J. Chem. Soc., Chem.
Commun., 1973, 499; (c) J. M. Photis, Tetrahedron Lett., 1980, 21, 3539;
(d) A. J. L. Cooper, J. Z. Ginos and A. Meister, Chem. Rev., 1983, 83, 321;
(e) J. P. Burkhart, N. P. Peet and P. Bey, Tetrahedron Lett., 1988, 29, 3433;
( f ) H. H. Wasserman and W. B. Ho, J. Org. Chem., 1994, 59, 4364;
(g) L. S. Li and Y. L. Wu, Tetrahedron Lett., 2002, 43, 2427; (h) M. Ma, C. Li,
L. Peng, F. Xie, X. Zhang and J. Wang, Tetrahedron Lett., 2005, 46, 3927;
(i) J. Zhuang, C. Wang, F. Xie and W. Zhang, Tetrahedron, 2009, 65, 9797;
( j) A. Raghunadh, S. B. Meruva, N. A. Kumar, G. S. Kumar, L. V. Rao and
U. K. S. Kumar, Synthesis, 2012, 283.
Halobenzene
tR1 (s) oxalate
Product
À20 0.041
À20 0.041
89
92
4 F. Hollwedel and G. Koßmehl, Synthesis, 1998, 1241.
5 (a) J. S. Nimitz and H. S. Mosher, J. Org. Chem., 1981, 46, 211;
(b) F. Babudri, V. Fiandanese, G. Marchese and A. Punzi, Tetrahedron,
1996, 52, 13513 and references cited therein; (c) G. Guercio, S. Bacchi,
A. Perboni, C. Leroi, F. Tinazzi, I. Bientinesi, M. Hourdin, M. Goodyear,
S. Curti, S. Provera and Z. Cimarosti, Org. Process Res. Dev., 2009, 13, 1100.
6 P. Knochel, Handbook of Functionalized Organometallics, Wiley-VCH,
Weinheim, 2005.
À20 0.041
À60 0.041
90
88
7 Microreactor: (a) P. Watts and S. J. Haswell, Chem. Soc. Rev., 2005, 34, 235;
(b) K. Geyer, J. D. C. Codee and P. H. Seeberger, Chem.–Eur. J., 2006,
12, 8434; (c) G. Whitesides, Nature, 2006, 442, 368; (d) A. J. deMello, Nature,
2006, 442, 394; (e) J. Kobayashi, Y. Mori and S. Kobayashi, Chem.–Asian J.,
2006, 1, 22; ( f) M. Brivio, W. Verboom and D. N. Reinhoudt, Lab Chip,
2006, 6, 329; (g) B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan and
D. T. McQuade, Chem. Rev., 2007, 107, 2300; (h) B. Ahmed-Omer, J. C.
Brandtand and T. Wirth, Org. Biomol. Chem., 2007, 5, 733; (i) P. Watts and
C. Wiles, Chem. Commun., 2007, 443; ( j) T. Fukuyama, M. T. Rahman,
M. Sato and I. Ryu, Synlett, 2008, 151; (k) W. Lin, Y. Wang, S. Wang and
H. Tseng, Nano Today, 2009, 4, 470; (l) K. Geyer, T. Gustafsson and
P. H. Seeberger, Synlett, 2009, 2382; (m) S. Marrea and K. F. Jensen, Chem.
Soc. Rev., 2010, 39, 1183; (n) D. Webb and T. F. Jamison, Chem. Sci., 2010,
1, 675; (o) J. Yoshida, H. Kim and A. Nagaki, ChemSusChem, 2011, 4, 331.
8 Recent examples: (a) A. Nagaki, K. Kawamura, S. Suga, T. Ando,
M. Sawamoto and J. Yoshida, J. Am. Chem. Soc., 2004, 126, 14702;
(b) L. Ducry and D. M. Roberge, Angew. Chem., Int. Ed., 2005, 44, 7972;
(c) P. He, P. Watts, F. Marken and S. J. Haswell, Angew. Chem., Int. Ed., 2006,
45, 4146; (d) K. Tanaka, S. Motomatsu, K. Koyama, S. Tanaka and K. Fukase,
Org. Lett., 2007, 9, 299; (e) H. R. Sahoo, J. G. Kralj and K. F. Jensen, Angew.
Chem., Int. Ed., 2007, 46, 5704; ( f) C. H. Hornung, M. R. Mackley,
I. R. Baxendale and S. V. Ley, Org. Process Res. Dev., 2007, 11, 399; (g) T.
Fukuyama, M. Kobayashi, M. T. Rahman, N. Kamata and I. Ryu, Org. Lett.,
2008, 10, 533; (h) D. L. Browne, M. Baumann, B. H. Harji, I. R. Baxendale and
S. V. Ley, Org. Lett., 2011, 13, 3312; (i) C. F. Carter, H. Lange, D. Sakai,
I. R. Baxendale and S. V. Ley, Chem.–Eur. J., 2011, 17, 3398; ( j) N. Zaborenko,
M. W. Bedore, T. F. Jamison and K. F. Jensen, Org. Process Res. Dev., 2011,
15, 131; (k) Y. Tomida, A. Nagaki and J. Yoshida, J. Am. Chem. Soc., 2011,
133, 3744; (l) A. C. Gutierrez and T. F. Jamison, Org. Lett., 2011, 13, 6414.
9 Recent examples: P. Rys, Acc. Chem. Res., 1976, 9, 345.
À60 0.041
À60 0.041
83
89
À20 4.71
À20 2.35
À20 0.28
73
91
93
À40 0.28
À20 2.35
75
85
to achieve using conventional batch reactors. Moreover, the mono-
selective Br–Li exchange reaction of p-dibromobenzene followed by
the reaction with diethyl oxalate gave the corresponding bromo-
substituted a-keto esters in a good yield. Highly sterically hindered
mesityllithium could also be used for the present transformation.
In conclusion, we have developed an efficient method for
introduction of a-ketoester groups into the aromatic ring based on
the generation and reaction of organometallics such as aryllithiums
at temperatures that are easily accessible in industry by virtue of fast
mixing in flow microreactor systems. The generation of various
highly unstable functionalized aryllithiums followed by the selective
formation of a-ketoesters can be achieved by using integrated flow
microreactor systems. The method adds a new dimension in the
selective synthesis of complex molecules having a-ketoester groups.
10 (a) A. Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae and J. Yoshida, J. Am.
Chem. Soc., 2005, 127, 11666; (b) S. Suga, A. Nagaki and J. Yoshida,
Chem. Commun., 2003, 354; (c) A. Nagaki, N. Takabayashi, Y. Tomida
and J. Yoshida, Org. Lett., 2008, 10, 3937; (d) A. Nagaki, Y. Tomida and
J. Yoshida, Macromolecules, 2008, 41, 6322; (e) J. Yoshida, A. Nagaki,
T. Iwasaki and S. Suga, Chem. Eng. Technol., 2005, 3, 259.
11 (a) H. Usutani, Y. Tomida, A. Nagaki, H. Okamoto, T. Nokami and
J. Yoshida, J. Am. Chem. Soc., 2007, 129, 3047; (b) A. Nagaki, E. Takizawa
and J. Yoshida, J. Am. Chem. Soc., 2009, 131, 1654; (c) A. Nagaki,
A. Kenmoku, Y. Moriwaki, A. Hayashi and J. Yoshida, Angew. Chem.,
Int. Ed., 2010, 49, 7543; (d) Y. Tomida, A. Nagaki and J. Yoshida, J. Am.
Chem. Soc., 2011, 133, 3744; (e) A. Nagaki, C. Matsuo, S. Kim, K. Saito,
A. Miyazaki and J. Yoshida, Angew. Chem., Int. Ed., 2012, 51, 3245.
12 (a) J. Yoshida, Flash Chemistry. Fast Organic Synthesis in Microsystems,
Wiley-Blackwell, 2008; (b) J. Yoshida, A. Nagaki and T. Yamada, Chem.–
Eur. J., 2008, 14, 7450; (c) J. Yoshida, Chem. Rec., 2010, 10, 332.
13 (a) A. Nagaki, H. Kim and J. Yoshida, Angew. Chem., Int. Ed., 2008, 47, 7833;
(b) A. Nagaki, H. Kim and J. Yoshida, Angew. Chem., Int. Ed., 2009, 48, 8063;
(c) A. Nagaki, H. Kim, Y. Moriwaki, C. Matsuo and J. Yoshida, Chem.–Eur. J.,
2010, 16, 11167; (d) A. Nagaki, H. Kim, C. Matsuo, H. Usutani and
J. Yoshida, Org. Biomol. Chem., 2010, 8, 1212; (e) H. Kim, A. Nagaki and
J. Yoshida, Nat. Commun., 2011, 2, 264.
Notes and references
1 (a) E. J. Corey, D. H. Hua, B. C. Pan and S. P. Seitz, J. Am. Chem. Soc.,
1982, 104, 6818; (b) T. Takahashi, T. Okano, T. Harada, K. Imamura
and H. Yamada, Synlett, 1994, 121.
2 (a) M. R. Angelastro, S. Mehdi, J. P. Burkhart, N. P. Peet and P. Bey, 14 W. Ehrfeld, K. Golbig, V. Hessel, H. Lowe and T. Richter, Ind. Eng.
J. Med. Chem., 1990, 33, 11; (b) V. G. Oleksandr, V. K. Pavel,
Chem. Res., 1999, 38, 1075.
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3244 Chem. Commun., 2013, 49, 3242--3244
This journal is The Royal Society of Chemistry 2013