Selective mono addition of aryllithiums to dialdehydes by micromixing

Article abstract of DOI:10.1246/cl.170899

Micromixing enables highly selective mono addition of aryllithiums to dialdehydes. Because the unchanged formyl group in the products can be used for further transformations, the present approach serves as a powerful method for protecting-group-free synthesis.

Full text of DOI:10.1246/cl.170899

Advance Publication Cover Page
Selective Mono Addition of Aryllithiums to Dialdehydes by Micromixing
Aiichiro Nagaki,* Hiroki Yamashita, Yusuke Takahashi, Satoshi Ishiuchi,
Keita Imai, and Jun-ichi Yoshida*
Advance Publication on the web November 1, 2017
doi:10.1246/cl.170899
© 2017 The Chemical Society of Japan
Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire
manuscripts and a portion of the graphical abstract can be released on the web as soon as the submission is accepted. Note that the
Chemical Society of Japan bears no responsibility for issues resulting from the use of information taken from unedited, Advance
Publication manuscripts.

1
Selective Mono Addition ofAryllithiums to Dialdehydes by Micromixing
Aiichiro Nagaki,* Hiroki Yamashita, Yusuke Takahashi, Satoshi Ishiuchi,
Keita Imai, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto
615-8510, Japan
(E-mail: yoshida@sbchem.kyoto-u.ac.jp, anagaki@sbchem.kyoto-u.ac.jp)
Micromixing enables highly selective mono addition of
aryllithiums to dialdehydes. Because the unchanged formyl
group in the products can be used for further transformations,
the present approach serves as a powerful method for
protecting-group-free synthesis.
3.0 min at –78 oC in a 50 mL round bottom glass flask
equipped with a magnetic stirrer, the mono addition product 2
was obtained in only 33% yield. A significant amount of the
di-addition product 3 was obtained in 23% yield while some 1
remained unreacted (Table 1). Reactions at higher
temperatures led to a decrease in the yield of desired product
2. In addition, when a solution of 4-formylbenzaldehyde (1)
was added to a stirred solution of one equivalent of
phenyllithium, less 2 was generated. In contrast, the use of
phenylmagunesium bromide improved the yield of 2 (52%)
(See the Supporting information for details).
Despite it is well known that the selectivity generally
depends on the stirring method, the size and shape of the
reactor, as well as the speed of the addition, the results
revealed that controlling the selectivity of such fast reactions
is extremely difficult, if not impossible, with batch reactors.
Chemoselectivity,1 i.e. the differentiation of one of two
or more different functional groups, is one of the central
issues in organic synthesis, and extensive studies on
chemoselective reactions have been reported so far.2 On the
other hand, the selective reactions of one of two identical
functional groups remains rather unexplored. Because the
remaining functional group in the initial product has similar
reactivity to that of the starting material, it is difficult to avoid
the subsequent reaction. Eventually, the two functional groups
in the starting material react to give the final product.
Therefore, controlling such reactions is still a big challenge in
current synthetic chemistry.3
Table 1. Reactions of 4-formylbenzaldehyde (1) and
phenyllithium using a conventional macro batch reactor
Recent investigations have revealed that the product
selectivity of fast competitive parallel and serial reactions can
be significantly improved by using extremely fast
micromixing.4 Based on these reports, we have come up with
the following working hypothesis. Extremely fast
micromixing in flow microreactors5-7 enables the selective
reaction with one among several identical functional groups.
The method would serve as a powerful and straightforward
technique of synthesizing molecules bearing unreacted
functional groups without protecting them. However, to the
best of our knowledge, such an approach has not yet been
reported so far. We report herein the results of this proof-of-
principle study.
In the next step, we examined the reactions using a flow
microreactor system consisting of V-shaped micromixer ( =
250 m) (M) and a microtube reactor (R) shown in Figure 1.
Scheme 1. Selective reaction with one among several
identical functional groups
Selective mono addition of highly reactive nucleophiles
to dialdehydes are not easy even when one equivalent of a
nucleophile is used, because the second reaction is too fast.
For example, when one equivalent of phenyllithium was
added to a stirred solution of 4-formylbenzaldehyde (1) for
Figure 1. A flow microreactor system for the reaction of 1
with one equiv of PhLi.

2
Notably, at high flow rates (total flow rate: 30 mL/min,
We have already reported that aryllithiums bearing
electrophilic functional groups can be rapidly generated and
used in a subsequent reaction before they decompose by
virtue of high-resolution reaction time control in flow
microreactor systems.9 The present finding prompted us to
integrate10 the generation of functional aryllithiums and their
selective reactions with dialdehydes using an integrated flow
microreactor system (Figure 2). The residence time (tR1) was
optimized individually for the halogen-lithium exchange
reactions of each functionalized aryl halides (See Supporting
Information for the details). In this case we have to worry
about the competition between the formyl groups on the
2: 71%, 3: 7%), the selectivity was remarkably high, and the
o
desired compound 2 was obtained in good yield at -78 C.
Generally, the mixing speed in a micromixer increases with
an increase in the flow speed.8 In fact, an increase in the total
flow rate led to the increase in the yield of 2 and the decrease
in the yield of 3 as shown in Table 2. The results indicate that
extremely fast mixing accounts for high selectivity.
Table 2. Reactions of 4-formylbenzaldehyde (1) and
phenyllithium using flow microreactors
electrophile (FG1)11 and
a functional group on the
nucleophile (FG2)12 as well. The reactions of various
aryllithiums bearing electrophilic functional groups were
examined. As shown in Table 4, selective mono addition to
dialdehydes occurred without affecting nitro13, and cyano
groups in the aryllitiums to give desired products in good
yields.
Based on the great influence of mixing greatly on the
reaction selectivity, we next examined the reactions of other
compounds having two formyl groups with phenyllithium. As
shown in Table 3, high selectivity was achieved with flow
microreactor system, whereas the use of a batch reactor led to
much poorer selectivity. Moreover, the other unaffected
formyl group will be able to use for further transformations in
order to generate more complex compounds.
Figure 2. An integrated flow microreactor system for
selective reactions of dialdehydes with functional
organolithiums generated by halogen-lithium exchange.
Table 3. The reaction of dialdehydes with PhLi using the flow
microreactor system.
Table 4. Reactions of dialdehydes with functional
aryllithiums.
In conclusion, we have developed a flash method for
highly selective mono addition of aryllithiums to aromatic and
aliphatic compounds having two formyl groups using an

3
I. R. Baxendale, J. Chem. Technol. Biotechnol. 2013, 88, 519. w) J.
Yoshida, A. Nagaki, D. Yamada, Drug Discov. Today Tech. 2013, 10,
e53. x) T. Fukuyama, T. Totoki and I. Ryu, Green Chem. 2014, 16,
2042. y) B. Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem., Int. Ed.
2015, 54, 6688.
integrated flow microreactor system. Notably, aryllithiums
bearing electrophilic functional groups can be used without
affecting their functionality. The present approach serves as a
powerful method for protecting-group-free synthesis using
organolithium compounds and opens a new possibility in the
synthesis of polyfunctional organic molecules.
7 Some selected recent examples: a) D. Cantillo, M. Baghbanzadeh, C. O.
Kappe, Angew. Chem., Int. Ed. 2012, 51, 10190. b) W. Shu, S. L.
Buchwald, Angew. Chem., Int. Ed. 2012, 51, 5355. c) F. Lévesque, P.
H. Seeberger, Angew. Chem., Int. Ed. 2012, 51, 1706. d) K. C.
Basavaraju, S. Sharma, R. A. Maurya, D. P. Kim, Angew. Chem., Int.
Ed. 2013, 52, 6735. e) C. Brancour, T. Fukuyama, Y. Mukai, T.
Skrydstrup, I. Ryu, Org. Lett. 2013, 15, 2794. f) J. D. Nguyen, B. Reiß,
C. Dai, C. R. J. Stephenson, Chem. Commun. 2013, 49, 4352. g) C.
Battilocchio, J. M. Hawkins, S. V. Ley, Org. Lett. 2013, 15, 2278. h) A.
S. Kleinke, T. F. Jamison, Org. Lett. 2013, 15, 710. i) K. Asano, Y.
Uesugi, J. Yoshida, Org. Lett. 2013, 15, 2398. j) L. Guetzoyan, N.
Nikbin, I. R. Baxendale, S. V. Ley, Chem. Sci. 2013, 4, 764. k) S. Fuse,
Y. Mifune, T. Takahashi, Angew. Chem., Int. Ed. 2014, 53, 851. l) Z,
He, T. F. Jamison, Angew. Chem., Int. Ed. 2014, 53, 3353. m) M. R.
Becker, P. Knochel, Angew. Chem., Int. Ed. 2015, 54, 12501. n) M.
Chen, S. Ichikawa, S. L. Buchwald, Angew. Chem., Int. Ed. 2015, 54,
263. o) S. Fuse, Y. Mifune, H. Nakamura, H. Tanaka, Nat. Commun.
2016, 7, 13491. p) A. Nagaki, Y. Takahashi, J. Yoshida, Angew. Chem.,
Int. Ed. 2016, 55, 5327. q) H. Seo, M. H. Katcher, T. F. Jamison, Nat.
Chem. 2017, 9, 453.
Acknowledgment. This work was partially supported by the
Grant-in-Aid for Scientific Research (B) (no. 26288049),
Scientific Research on Innovative Areas 2707 Middle
molecular strategy from MEXT (no. 15H05849), Scientific
Research (S) (no. 26220804), Scientific Research (S) (no.
25220913), Asahi Glass Foundation, Ogasawara Foundation,
Seiken Foundation, and Sumitomo Electric Group Foundation
for the promotion of science and engineering.
References and Notes
1 a) R. W. Hoffmann, Synthesis 2006, 3531. b) N. A. Afagh, A. K. Yudin,
Angew. Chem., Int. Ed. 2010, 49, 262.
8 W. Ehrfeld, K. Golbig, V. Hessel, H. Löwe, T. Richter, Ind. Eng. Chem.
Res. 1999, 38, 1075.
2 a) A. Morcuende, M. Ors, S. Valverde, B. Herradón, J. Org. Chem.
1996, 61, 5264. b) J. E. Baldwin, R. M. Williams, Organolithiums:
Selectivity for Synthesis, Pregamon, Amsterdam, 2002. c) N. Chinkov,
H. Chechik, S. Majumdar, A. Liard, I. Marek, Synthesis 2002, 17, 2473.
d) M. Uchiyama, T. Furuyama, M. Kobayashi, Y. Matsumoto, K.
Tanaka, J. Am. Chem. Soc. 2006, 128, 8404. e) S. Das, F. D. Bobbink,
G. Laurenczy, P. J. Dyson, Angew. Chem., Int. Ed. 2014, 53, 12876.
3 a) T. Kawabata, W. Muramatsu, T. Nishio, T. Shibata, H. Schedel, J.
Am. Chem. Soc. 2007, 129, 12890. b) C. L. Allen, S. J. Miller, Org. Lett.
2013, 15, 6178. c) D. Lee, M. S. Taylor, J. Am. Chem. Soc. 2011, 133,
3724. d) P. A. Lichtor, S. J. Miller, Nat. Chem. 2012, 4, 990. e) X. Sun,
H. Lee, S. Lee, K. L. Tan, Nat. Chem. 2013, 5, 790.
4 a) P. Rys, Acc. Chem. Res. 1976, 9, 345. b) P. Rys, Angew. Chem. Int.
Ed. Engl. 1977, 16, 807. c) A. Nagaki, M. Togai, S. Suga, N. Aoki, K.
Mae, J. Yoshida, J. Am. Chem. Soc. 2005, 127, 11666. d) J. Yoshida, A.
Nagaki, T. Iwasaki, S. Suga, Chem. Eng. Technol. 2005, 28, 259. e) A.
Nagaki, N. Takabayashi, Y. Tomida, J. Yoshida, Org. Lett. 2008, 10,
3937. f) A. Nagaki, D. Ichinari, J. Yoshida, Chem. Commun. 2013, 49,
3242. g) A. Nagaki, K. Imai, S. Ishiuchi, J. Yoshida, Angew. Chem. Int.
Ed. 2015, 54, 1914.
5 Books on flow microreactor synthesis: a) W. Ehrfeld, V. Hessel and H.
Löwe, Microreactors, Wiley-VCH, Weinheim, Germany, 2000. b) V.
Hessel, S. Hardt and H. Löwe, Chemical Micro Process Engineering,
Wiely-VCH, Weinheim, Germany, 2004. c) V. Hessel, A. Renken, J. C.
Schouten and J. Yoshida, Micro Process Engineering, Wiley-
Blackwell, Chichester, United Kingdom, 2009. d) T. Wirth,
Microreactors in Organic Chemistry and Catalysis, Wiley, New York,
United States, 2013. e) T. Noël, Organometallic Flow Chemistry,
Springer International Publishing, Gewerbestrasse, Switzerland,
2016.
9 a) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. Int. Ed. 2008, 47,
7833. b) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. Int. Ed. 2009,
48, 8063. c) A. Nagaki, H. Kim, Y. Moriwaki, C. Matsuo, J. Yoshida,
Chem. Eur. J. 2010, 16, 11167. d) A. Nagaki, H. Kim, C. Matsuo, H.
Usutani, J. Yoshida, Org. Biomol. Chem. 2010, 8, 1212. e) H. Kim, A.
Nagaki, J. Yoshida, Nat. Commun. 2011, 2, 264. f) A. Nagaki, Y.
Moriwaki, J. Yoshida, Chem. Commun. 2012, 48, 11211. g) A. Nagaki,
D. Ichinari, J. Yoshida, J. Am. Chem. Soc. 2014, 136, 12245. h) A.
Nagaki, Y. Takahashi, J. Yoshida, Chem. Eur. J. 2014, 20, 7931.
10 a) S. Suga, D. Yamada, J. Yoshida, Chem. Lett. 2010, 39, 404. b) A.
Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi, J. Yoshida, Angew.
Chem. Int. Ed. 2010, 49, 7543. c) J. Yoshida, K. Saito, T. Nokami, A.
Nagaki, Synlett 2011, 1189.
11 a) K. D. Safa, J. V. Mardipour, Y. M. Oskoei, J. Organomet. Chem.
2011, 696, 802.
12 a) P. Knochel, Handbook of Functionalized Organometallics, Wiley-
VCH, Weinheim, 2005. b) A. Boudier, L. O. Bromm, M. Lotz, P.
Knochel, Angew. Chem. Int. Ed. 2000, 39, 4414. c) W. E. Parham, C. K.
Bradsher, Acc. Chem. Res. 1982, 15, 300.
13 It has been reported that aryllithiums react with nitroarenes to give
diarylamines. T. Yang, B. P. Cho, Tetrahedron Lett. 2003, 44, 7549.
6 Reviews on flow microreactor synthesis: a) K. Jähnisch, V. Hessel, H.
Löwe, M. Baerns, Angew. Chem., Int. Ed. 2004, 43, 406. b) G. N. Doku,
W. Verboom, D. N. Reinhoudt, A. van den Berg, Tetrahedron 2005, 61,
2733. c) J. Yoshida, A. Nagaki, T. Iwasaki, S. Suga, Chem. Eng. Tech.
2005, 3, 259. d) P. Watts, S. J. Haswell, Chem. Soc. Rev. 2005, 34, 235.
e) K. Geyer, J. D. C. Codée, P. H. Seeberger, Chem. Eur. J. 2006, 12,
8434. f) A. J. deMello, Nature 2006, 442, 394. g) H. Song, D. L. Chen,
R. F. Ismagilov, Angew. Chem., Int. Ed. 2006, 45, 7336. h) J.
Kobayashi, Y. Mori, S. Kobayashi, Chem. Asian. J. 2006, 1, 22. i) M.
Brivio, W. Verboom, D. N. Reinhoudt, Lab Chip 2006, 6, 329. j) B. P.
Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan, D. T. McQuade,
Chem. Rev. 2007, 107, 2300. k) B. Ahmed-Omer, J. C. Brandt, T.
Wirth, Org. Biomol. Chem. 2007, 5, 733. l) P. Watts, C. Wiles, Chem.
Commun. 2007, 443. m) T. Fukuyama, M. T. Rahman, M. Sato, I. Ryu,
Synlett 2008, 151. n) Hartman, R. L. Jensen, K. F. Lab Chip 2009, 9,
2495. o) McMullen, J. P. Jensen, K. F. Annu. Rev. Anal. Chem. 2010, 3,
19. p) J. Yoshida, H. Kim, A. Nagaki, ChemSusChem 2011, 4, 331. q)
C. Wiles, P. Watts, Green Chem. 2012, 14, 38. r) A. Kirschining, L.
Kupracz, J. Hartwig, Chem. Lett. 2012, 41, 562. s) D. T. McQuade, P.
H. Seeberger, J. Org. Chem. 2013, 78, 6384. t) K. S. Elvira, X. C.
Solvas, R. C. R. Wootton, A. J. deMello, Nat. Chem. 2013, 5, 905. u) J.
C. Pastre, D. L. Browne, S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849. v)