Harnessing [1,4], [1,5], and [1,6] Anionic Fries-type Rearrangements by Reaction-Time Control in Flow

Article abstract of DOI:10.1002/anie.201704006

A series of anionic Fries-type rearrangements of carbamoyl-substituted aryllithium intermediates were controlled by using flow microreactor systems. For the [1,4] and [1,5] rearrangements, the aryllithium intermediate formed before carbamoyl migration and

Full text of DOI:10.1002/anie.201704006

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Accepted Article
Title: Harnessing [1,4]-, [1,5]-, and [1,6]-Anionic Fries-type
Rearrangements by Reaction Time Control in Flow
Authors: Jun-ichi Yoshida, Heejin Kim, and Keita Inoue
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10.1002/anie.201704006
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Harnessing [1,4]-, [1,5]-, and [1,6]-Anionic Fries-type
Rearrangements by Reaction Time Control in Flow
Heejin Kim, Keita Inoue, and Jun-ichi Yoshida*
Abstract:
A
series of anionic Fries-type rearrangements of
anionic Fries-type rearrangements can be harnessed based on
precise reaction time control using flow microreactors.
carbamoyl-substituted aryllithiums can be controlled by using flow
microreactor systems. For [1,4]- and [1,5]-rearrangements, either the
carbamoyl-maintained or migrated aryllithium intermediates can be
subjected to the subsequent reactions with electrophiles at will based
on precise residence time and the temperature (-25 oC to -50 oC)
control. In contrast, the [1,6]-rearrangement is rather slow even at -25
oC. The absence of cross-over products indicates the intramolecular
nature of the carbamoyl group migration.
Controllability of extremely fast reactions is one of the most
powerful advantages of flow chemistry using microreactors.1-3 By
using flow microreactors, we can accomplish a desired reaction
before an undesired fast reaction proceeds. Based on the concept
of flash chemistry,4 various synthetic transformations involving
short-lived intermediates have been developed using flow
microreactors.5 In flash chemistry the reaction time can be
precisely adjusted even to milliseconds or less, allowing switching
of reactions from go to stop, or vice versa, at will according to the
synthetic plan.
Figure 1. Anionic Fries-type rearrangements.
Rearrangement reactions serve as important methods for
constructing organic molecules because they change molecular
skeletons dramatically, and many of them take place
intramolecularly. Because such intramolecular reactions proceed
at a rate irrespective of the mixing speed or the concentration of
reaction components, the control of intramolecular reactions still
remains challenging.
Anionic Fries rearrangement6 is well-known as an
intramolecular [1,3]-rearrangement and comprise the migration of
a carbamoyl group from an oxygen atom to a carbanion (typically
an organolithium) carbon atom to generate an oxyanion (a lithium
alkoxide) (Figure 1a). The reaction proceeds by a 4-exo-trig type
intramolecular cyclization. Based on the concept of flash
chemistry, we recently reported that the fast 1,3-migration of acyl
group as well as carbamoyl group in Fries rearrangement can be
effectively controlled by using microfluidic devices.7 The
intramolecular [1,4]- and [1,5]-rearrangements, however, are
typically much faster than [1,3]-rearrangement, because 5- and 6-
exo-trig type cyclization is usually faster than 4-exo-trig cyclization.
(Figure 1).8 It is also interesting to know how fast the
corresponding 7-exo-trig type cyclization takes place ([1,6]-
rearrangement). We report herein that [1,4]-, [1,5], and [1,6]-
First, we examined the reactions in a batch reactor at -78 oC,
and the results are summarized in Table 1. The iodobenzenes
bearing a carbamate group 1a-1d (n=0-3) were prepared as
starting materials. The reaction of 1a (n=0), which is a substrate
for normal Fries rearrangement, with n-BuLi at -78 oC followed by
the reaction with ethyl chloroformate after 10 min exclusively gave
product 3a (81% yield) via carbamoyl-remained intermediate 2a
(entry 1, Table 1). Compound 5a, which is derived from
carbamoyl-migrated intermediate 4a was not detected. The result
indicates that normal anionic Fries rearrangement is not too fast
at -78 oC to trap carbanion intermediate 2a (n=0) by the
subsequent bimolecular reaction. In contrast, the reaction of
substrate 1b gave no 3b, which is derived from carbamoyl-
maintained intermediate 2b under the same conditions. Instead,
5b derived from carbamoyl-migrated intermediate 4b was
obtained selectively (entry 2, Table 1). With a shorter reaction
time (1 min), a small amount of 3b (7%) was obtained but the
major product was 5b (87%, entry 3, Table 1). Similarly, the
reaction of 1c also gave 5c derived from carbamoyl-migrated
intermediate 4c as a major product with a small amount of 3c
(entries 4 and 5, Table 1). These results indicate that the [1,4]-
and [1,5]-rearrangements of 2b and 2c, respectively, are much
faster than [1,3]-rearrangement of 2a. This is consistent with a
general tendency that five- and six-membered ring cyclization
reactions are faster than four-membered ring cyclization reactions.
The corresponding seven-membered ring cyclization is slower.
The reaction of compound 1d gave 3d (82%), which is derived
from carbamoyl-maintained intermediate 2d with a small amount
of 5d (8%), which is derived from carbamoyl-migrated
[*]
Dr. H. Kim, K. Inoue, Prof. Dr. J. –i. 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
Homepage:
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201704006
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intermediate 4d (entry 6, Table 1). The rearrangement of 2d
seems to be slightly faster than that of 2a, but much slower than
those of 2b and 2c.
a)
time [ms]
R1
M1
Table 1: Anionic Fries-type rearrangements using a batch reactor at
-78 oC.
n-BuLi
M2
R2
T [oC] 25 oC
ClCO2Et
b)
c)
100
50
0
100
5b
3b
5c
3c
-25 oC
-25 oC
50
0
0
0
100
200
300
0
0
0
0
100
200
300
time [ms]
time [ms]
100
50
0
100
50
0
-30 oC
-30 oC
5b
5c
3b
3c
100
time [ms]
200
300
100
200
300
time [ms]
100
50
0
100
50
0
-40 oC
-40 oC
5b
3b
5c
3c
0
0
100
time [ms]
200
300
100
time [ms]
200
300
Next, we examined the reactions of 1b, 1c, and 1d as well as
1a using a flow microreactor system consisting of two micromixers
(inner diameter: 250 m for M1 and 500 m for M2) and two
microtube reactors (R1 and R2, Figure 2a). The reactions with n-
BuLi were carried out at higher temperatures (T oC) than that for
the batch reaction with varying the residence time. Ethyl
chloroformate was added at the same temperature. Then, the
temperature was raised to 25 oC to ensure the full conversion (for
details, see the Supporting Information). The results were
summarized in Figure 2b-2e.
The rearrangement of 2b (n=1) to give 4b was complete
within 110 ms at -25 oC (Figure 2b). The product 5b derived from
4b was obtained exclusively with the residence time longer than
110 ms at this temperature. At lower temperatures such as -30, -
40 and -50 oC, the rearrangement is slower. The product 3b
derived from 2b was obtained exclusively with the residence time
of 14 ms at -50 oC. The rearrangement of 2c (n=2) to give 4c is
slightly faster (Figure 2c), indicating that [1,5]-rearrangement is
slightly faster than [1,4]-rearrangement. The rearrangement of 2d
(n=3) is much slower than those of 2b and 2c (Figure 2d),
indicating that the [1,6]-rearrangement is much slower than [1,4]
and [1,5]-rearrangements. However, at 25 oC [1,6]-rearrangement
is complete within 220 ms (For details, see the Supporting
Information). Also, the rearrangement of 2a (n=0) is somewhat
slower than that of 2d (Figure 2e).
100
50
0
100
50
0
5c
3b
-50 oC
-50 oC
5b
3c
100
time [ms]
200
300
100
time [ms]
200
300
d)
e)
100
50
0
100
50
0
-25 oC
-25 oC
0
100
200
300
0
100
200
300
time [ms]
time [ms]
Figure 2. Anionic Fries-type rearrangements using a flow microreactor system.
a) A flow microreactor system consisting of two micromixers (M1 and M2) and
two microreactors (R1 and R2). b-d) Plots of the yield of 3 derived from the
carbamoyl-maintained intermediate and that of 5 derived from the carbamoyl-
migrated intermediate against the residence time in R1.
Both the unrearranged intermediates (2b, 2c, and 2d) and the
rearranged intermediates (4b, 4c, and 4d) could be successfully
trapped with various electrophiles at will by optimizing the
residence time and temperature, and the desired products were
obtained in high selectivity. The results are summarized in Table
2 (For details, see the Supporting Information).
Therefore, the rate of the rearrangement increases in the
order [1,3] < [1,6] ≪ [1,4] ≤ [1,5].
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Table 2: The control of [1,4]-, [1,5]-, and [1,6]-anionic Fries-type
rearrangements using various electrophiles
Figure 3. Crossover experiments of [1,4]- and [1,5]-anionic Fries-type
rearrangements.
It is important to know whether the rearrangement takes place
intramolecularly or intermolecularly. To answer to this question,
the crossover experiments were carried out using the flow
microreactor system, wherein an equimolar mixture of two
substrates was reacted with BuLi followed by the reaction with
ethyl chloroformate. As shown in Figure 3, any possible crossover
products were not observed, indicating that carbamate-migration
occurs truly intramolecularly.
The present systematic studies on [1,3]-, [1,4]-, [1,5]-, and
[1,6]-anionic Fries-type rearrangements using the flow
microreactor system revealed that the rerrangement rate
increases in the order [1,3] < [1,6] ≪ [1,4] ≤ [1,5]. Also, the product
derived from unrearranged intermediates could be obtained
selectively at will even for extremely fast [1,4]- and [1,5]-cases,
indicating the power of the flash method using flow microreactor
systems. Further work aimed at exploration and control of various
type of fast rearrangements using flow microreactors is currently
in progress in our laboratory.
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Dev. 2016, 20, 327; q) D. Cambie, C. Bottecchia, N. J. W. Straathof, V.
Hessel, T. Noel, Chem. Rev. 2016, 116, 10276; r) S. Kobayashi, Chem.
Asian J. 2016, 11, 425. s) L. Degennaro, C. Carlucci, S. de Angelis, R.
Luisi, J. Flow Chem. 2016, 6, 136.
[3]
For selected recent examples, see: a) T. Tsubogo, H. Oyamada, S.
Kobayashi, Nature 2015, 520, 329; b) R. Telmesani, S. H. Park, T.
Lynch-Colameta, A. B. Beeler, Angew. Chem. Int. Ed. 2015, 54, 11521;
Angew. Chem. 2015, 127, 11683; c) L. Vanoye, M. Pablos, C. de
Bellefon, A. Favre-Reguillon, Adv. Synth. Catal. 2015, 357, 739; d) A.
Nagaki, Y. Tsuchihashi, S. Haraki, J. Yoshida, Org. Biomol. Chem. 2015,
13, 7140; e) H. Kim, H. Lee, D. Kim, Angew. Chem. Int. Ed. 2016, 55,
1422, Angew. Chem. 2016, 128, 1444; f) A. Adamo, R. L. Beingessner,
M. Behnam, J. Chen, T. F. Jamison, K. F. Jensen, J. -C. M. Monbaliu, A.
S. Myerson, E. M. Revalor, D. R. Snead, T. Stelzer, N. Weeranoppanant,
S. Y. Wong, P. Zhang, Science 2016, 352, 61; g) T. Fukuyama, Y. Fujita,
M. A. Rashid, I. Ryu, Org. Lett. 2016, 18, 5444; h) L. Degennaro, D.
Maggiulli, C. Carlucci, F. Fanelli, G. Romanazzi, R. Luisi, Chem.
Commun. 2016, 52, 9554; i) A. Nagaki, T. Takahashi, J. Yoshida, Anew.
Chem. Int. Ed. 2016, 55, 5327. Angew. Chem. 2016, 128, 5413; j) J. -S.
Poh, S. Makai, T. v. Keutz, D. N. Tran, C. Battilocchio, P. Pasau, S. V.
Ley, Angew. Chem. Int. Ed. 2017, 56, 1864; Angew. Chem. 2017, 129,
1890; k) D. Cambie, F. Zhao, V. Hessel, M. G. Debije, T. Noel, Angew.
Chem. Int. Ed. 2017, 56, 1050; Angew. Chem. 2017, 129, 1070; l) J. L.
Monteiro, P. F. Carneiro, P. Elsner, D. Roberge, P. G. M. Wuts, K. Kurjan,
B. Gutmann, C. O. Kappe, Chem. Eur. J. 2017, 23, 176; m) P. Xie, K.
Wang, P. Wang, Y. Xia, G. Luo, AIChE J. 2017, 63, 1002; n) X. Tang, R.
K. Allemann, T. Wirth, Eur. J. Org. Chem. 2017, 414.
Experimental Section
General method.
A flow microreactor system consisting of two
micromixers (M1 and M2) and two microtube reactors (R1 and R2) was
used. The reaction system was immersed in a cooling bath (T oC). A
solution of substrate 1 (0.1 M in THF, 6 mL/min) and a solution of n-BuLi
(0.42 M in hexane, 1.5 mL/min) were introduced to M1 (inner diameter
Φ=250 μm) by syringe pumps. The resulting solution was passed through
R1 and was mixed with a solution of electrophile (0.22 M in THF, 3.0
mL/min) in M2 (Φ=500 μm). The resulting solution was passed through R2
(Φ=1000 μm, length=450 cm; 50 cm at T oC and 400 cm at 25 oC). After a
steady state was reached, the product solution was collected for 30 s,
while being quenched with saturated NH4Cl aqueous solution. The crude
product was extracted with diethyl ether (15 mL x 3) washed with brine (15
mL). The organic phase was dried over Na2SO4 and concentrated. The
crude product was purified by column chromatography.
Acknowledgements
This work was partially supported by the Grant-in-Aid for Scientific
Research (S) (no. 26220804) and the Grant-in-Aid for Young
Scientists (B) (no. 16K17898).
[4]
[5]
a) A. Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae, J. Yoshida, J. Am.
Chem. Soc. 2005, 127, 11666; b) J. Yoshida, Chem. Commun. 2005,
4509; c) J. Yoshida, A. Nagaki, T. Yamada, Chem. Eur. J. 2008, 14,
7450; d) P. J. Nieuwland, K. Koch, N. van Harskamp, R. Wehrens, J. C.
M. van Hest, F. P. J. T. Rutjes, Chem. Asian J. 2010, 5, 799; e) J.
Yoshida, Chem. Rec. 2010, 10, 332; f) J. Yoshida, Y. Takahashi, A.
Nagaki, Chem. Commun. 2013, 49, 9896.
Keywords: Intramolecular rearrangement • flow chemistry •
microreactor • Fries rearrangement • reactive intermediates
[1]
For books on flow chemistry and microreactor synthesis, see: a) V.
Hessel, S. Hardt, H. Lowe, Chemical Micro Process Engineering, Wiley-
VCH, Weinheim, 2004; b) Micro Process Engineering; (Eds.: V. Hessel,
A. Renken, J. C. Schouten, J. Yoshida), Wiley-Blackwell, Oxford, 2009;
c) Microreactors in Organic Chemistry and Catalysis, 2nd ed. (Ed.: T.
Wirth), Wiley, Hoboken, 2013; d) Sustainable Flow Chemistry: Methods
and Applications; (Ed. L. Vaccaro), Wiley-VCH, Weinheim, 2017.
a) A. Nagaki, H. Kim, J. Yoshida, Angew. Chem. Int. Ed. 2008, 47, 7833;
Angew. Chem. 2008, 120, 7951; b) A. Nagaki, E. Takizawa, J. Yoshida,
J. Am. Chem. Soc. 2009, 131, 1654; c) A. Nagaki, H. Kim, J. Yoshida,
Angew. Chem. Int. Ed. 2009, 48, 8063; Angew. Chem. 2009, 121, 8207;
d) A. Nagaki, H. Kim, Y. Moriwaki, C. Matsuo, J. Yoshida, Chem. Eur. J.
2010, 16, 11167; e) A. Nagaki, H. Kim, C. Matsuo, H. Usutani, J. Yoshida,
Org. Biomol. Chem. 2010, 8, 1212; f) A. Nagaki, C. Matsuo, S. Kim, K.
Saito, A. Miyazaki, J. Yoshida, Angew. Chem. Int. Ed. 2012, 51, 3245;
Angew. Chem. 2012, 124, 3299; g) A. Nagaki, K. Imai, S. Ishiuchi, J.
Yoshida, Angew. Chem. Int. Ed. 2015, 54, 1914; Angew. Chem. 2015,
127, 1934.
[2]
For reviews on flow chemistry and microreactor synthesis, see: a) R. L.
Hartman, K. F. Jensen, Lab Chip 2009, 9, 2495; b) J. P. McMullen, K. F.
Jensen, Annu. Rev. Anal. Chem. 2010, 3, 19; c) D. Webb, T. F. Jamison,
Chem. Sci. 2010, 675; d) J. Yoshida, H. Kim, A. Nagaki, ChemSusChem
2011, 4, 331; e) J. Yoshida, K. Saito, T. Nokami, A. Nagaki, Synlett 2011,
1189; f) C. Wiles, P. Watts, Green Chem. 2012, 14, 38; g) Kirschning, L.
Kupracz, J. Hartwig, Chem. Lett. 2012, 41, 562; h) D. T. McQuade, P. H.
Seeberger, J. Org. Chem. 2013, 78, 6384; i) K. S. Elvira, X. C. Solvas,
R. C. R. Wootton, A. J. deMello, Nat. Chem. 2013, 5, 905; j) J. C. Pastor,
D. L. Browne, S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849; k) I. R.
Baxendale, J. Chem. Technol. Biotechnol. 2013, 88, 519; l) J. Yoshida,
A. Nagaki, D. Yamada, Drug Discovery Today Technol. 2013, 10, e53;
m) T. Fukuyama, T. Totoki, I. Ryu, Green Chem. 2014, 16, 2042; n) B.
Gutmann, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2015, 54,
6688; Angew.Chem. 2015, 127, 6788; o) M. Movsisyan, E. I. P. Delbeke,
J. K. E. T. Berton, C. Battilocchio, S. V. Ley, C. V. Stevens, Chem. Soc.
Rev. 2016, 45, 4892; p) C. J. Mallia, I. R. Baxendale, Org. Process Res.
[6]
a) K. Fries, G. Finck, Ber. Dtsch. Chem. Ges. 1908, 41, 4271; b) R. Martin,
Org. Prep. Proced. Int. 1992, 24, 369; c) M. P. Sibi, V. Snieckus, J. Org.
Chem. 1983, 48, 1935; d) J. C. Riggs, K. J. Singh, M. Yun, D. B. Collum,
J. Am. Chem. Soc. 2008, 130, 13709.
[7]
[8]
H. Kim, K. -I. Min, K. Inoue, D. J. Im, D. -P. Kim, J. Yoshida, Science
2016, 352, 691.
a) J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734; b) J. E.
Baldwin, R. C. Thomas, L. I. Kruse, L. Silberman, J. Org. Chem. 1977,
42, 3846.
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Entry for the Table of Contents (Please choose one layout)
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Heejin Kim, Keita Inoue, Jun-ichi
Yoshida*
Page No. – Page No.
Harnessing [1,4]-, [1,5]-, and [1,6]-
Anionic Fries-type Rearrangements
by Reaction Time Control in Flow
A series of anionic Fries-type rearrangements of carbamoyl-substituted aryllithiums
can be controlled by using flow microreactor systems. For [1,4]- and [1,5]-
rearrangements, either the carbamoyl-maintained or migrated aryllithium
intermediates can be subjected to the subsequent reactions with electrophiles at will
based on precise residence time and the temperature control.
This article is protected by copyright. All rights reserved.