Asymmetric carbolithiation of conjugated enynes: A flow microreactor enables the use of configurationally unstable intermediates before they epimerize

Article abstract of DOI:10.1021/ja110898s

We found that a flow microreactor system enables the generation of a configurationally unstable chiral organolithium intermediate and allows for its use in a reaction with an electrophile before it epimerizes. Based on this method, the enantioselective ca

Full text of DOI:10.1021/ja110898s

COMMUNICATION
pubs.acs.org/JACS
Asymmetric Carbolithiation of Conjugated Enynes: A Flow
Microreactor Enables the Use of Configurationally Unstable
Intermediates before They Epimerize
Yutaka Tomida, Aiichiro Nagaki, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto
615-8510, Japan
S Supporting Information
b
ABSTRACT: We found that a flow microreactor system
enables the generation of a configurationally unstable chiral
organolithium intermediate and allows for its use in a
reaction with an electrophile before it epimerizes. Based
on this method, the enantioselective carbolithiation of
conjugated enynes followed by the reaction with electro-
philes was accomplished to obtain enantioenriched chiral
allenes.
Figure 1. Flow microreactor system for enantioselective carbolithiation
followed by trapping with electrophiles.
hiral organometallics1,2 provide powerful intermediates for
C
the synthesis of enantioenriched compounds. In general,
intermediates, and the subsequent reaction with electrophiles
using a flow microreactor system consisting of three T-shaped
micromixers (M1, M2, and M3) and three microtube reactors
(R1, R2, and R3) (Figure 1). The reaction of n-BuLi and the
chiral ligand 1 forms a complex n-BuLi/1 (M1 and R1). Carbo-
lithiation of 2 with n-BuLi/1 gives the chiral organolithium
intermediate 3 (M2 and R2), which is trapped with MeOH as
an electrophile (M3 and R3) to give product 4 (R = Bu, E = H).
We began by searching for a suitable ligand and directing
group. The reaction of conjugated enyne 2a, having a carbamoyl-
oxy group as the directing group, with n-BuLi in the presence of
(-)-sparteine 1a as the ligand, followed by trapping with MeOH
gave the desired allene 4a in a high yield with a high enantio-
selectivity (Table 1, entry 1). The use of a slight excess of (-)-
sparteine increased the enantioselectivity (entry 2). In contrast,
the reaction of 2b, having no directing group, gave the desired
allene 4b in a low enantioselectivity, presumably because the
enantiofacial selectivity in the addition of n-BuLi was low (entry
3, see the Supporting Information [SI] for details). Moreover,
the reaction of 2b also formed a significant amount of 1-phenyl-1-
octyne as a byproduct (14%). In the case of 2c, having a
methoxymethoxy group, the desired product 4c was not obtained
at all, and 2c was quantitatively recovered (entry 4). In the case of
other ligands 1b-1e16 the enantioselectivity and the yield were
low (entries 5-8). Thereafter, we used the carbamoyloxy group
as the directing group and (-)-sparteine 1a as the ligand. To best
of our knowledge, this is the first example of the synthesis of
enantioenriched chiral allenes via asymmetric carbolithiation.
configurationally stable organometallics are used for highly
enantioselective transformations because the use of configura-
tionally unstable organometallics3 usually leads to rapid epimer-
ization before they can react with electrophiles, even if such
intermediates are produced enantioselectively. In this commu-
nication, we report that flow microreactor systems,4-7 on the
basis of high-resolution control of the residence time,8 enable the
rapid generation of configurationally unstable organometallics
and allow their reaction with electrophiles before they epimer-
ize. Our flow microreactor method9 opens up new possibilities in
asymmetric synthesis.
Asymmetric carbolithiation10 is an attractive reaction in
asymmetric synthesis, because carbon-carbon bond formation
leads to the formation of chiral organolithium intermediates,11
which can be used for further transformations.12 In particular,
asymmetric carbolithiation of conjugated enynes has received
significant research interest, because the reactions of the resulting
chiral organolithium intermediates with electrophiles give chiral
allenes,13 which serve as versatile building blocks. However, to
the best of our knowledge, no such study has yet been reported in
the literature, presumably because of the configurational instabil-
ity of organolithium intermediates.
Recently, we proposed the concept of flash chemistry,14
involving fast chemical synthesis using flow microreactors. On
the basis of high resolution control of the residence time, flash
chemistry enables the use of highly reactive intermediates before
they decompose.15 We envisioned that the concept could also be
applied to epimerization of reactive intermediates. Thus, we
examined the addition of organolithium species to conjugated
enynes bearing an appropriate directing group (2) in the
presence of a chiral ligand (1) to generate chiral organolithium
Received: December 4, 2010
Published: February 28, 2011
r
2011 American Chemical Society
3744
dx.doi.org/10.1021/ja110898s J. Am. Chem. Soc. 2011, 133, 3744–3747
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Enantioselective Carbolithiation of 2 with n-BuLi in
the Presence of Various Ligands in a Flow Microreactor
Systema
Table 2. Carbolithiation of Conjugated Enynes Followed by
the Reaction with Electrophilesa
% yield of productb % recovery
entry substrate ligand product (enantiomeric ratio) of substrate
1
2a
2a
2b
2c
2a
2a
2a
2a
1a
1a
1a
1a
1b
1c
1d
1e
4a
4a
4b
4c
4a
4a
4a
4a
91 (88:12)
82 (93:7)
83 (61:39)
0
4
10
1
2c
3c
4c
5
91
36
88
98
>99
57 (52:48)
<1 (45:55)
<1 (34:66)
0
6
7
8
a Reaction condition: n-BuLi (0.40 M in toluene/hexane, 3.0 mL/min),
ligand (0.40 M in toluene, 3.0 mL/min), 2 (0.40 M in toluene, 1.5 mL/
min), and MeOH (neat, 3.0 mL/min). Temperature in M1 and R1
(0 °C) and M2-4 and R2-4 (-78 °C). Residence time in R2 (13 s).
b Determined by chiral HPLC. Enantiomeric ratio (er) is shown in
parentheses. c 1a (0.67 M in toluene, 3.0 mL/min).
Figure 2. Temperature-residence time (in R2) map for the reaction of
2a in the presence of 1a. Contour plot with scatter overlay of
enantiomeric composition (ec) of 4a (upper), contour plot with scatter
overlay of the yield of 4a (lower), and the domain that gave the highest
yield (>90%) and highest ec (>90%) (middle).
a Reaction condition: substrate (0.40 M in toluene, 1.5 mL/min), n-BuLi
(0.40 M in toluene/hexane, 3.0 mL/min), HexLi (0.40 M in toluene/
hexane, 3.0 mL/min), EtLi (0.10 M in toluene/benzene/cyclohexane,
3.0 mL/min), (-)-sparteine (0.67 M in toluene, 3.0 mL/min), MeOH
(neat, 3.0 mL/min), Me3SiCl (2.0 M in toluene, 3.0 mL/min), Bu3SnCl
(0.80 M in THF, 3.0 mL/min), Ph2CO (0.80 M in toluene/HMPA,
3.0 mL/min), and PhNCO (0.80 M in toluene/HMPA, 3.0 mL/min).
b Determined by chiral HPLC. Enantiomeric ratio (er) is shown in
parentheses. c c = 0.57-2.3, in CH2Cl2. d Isolated yield. e Concentrations
of RLi, 1a, and 2a were one-half of the standard ones. f Concentrations of
1a, 2a, and Me3SiCl were one-fourth of the standard ones.
To obtain a deeper insight into the features of the reaction, we
next carried out the reaction varying the residence time in R2 (tR)
at various temperatures (Figure 2, also see the SI for details). As
profiled in Figure 2, the yield increased with increasing tR and
temperature. In contrast, the enantiomeric composition (ec)17
decreased with increasing tR and temperature, presumably be-
cause of epimerization of the intermediate 3a.18 This result
means that the decrease of enantiomeric composition resulted
from epimerization of the lithiated species rather than its
formation step. The residence time-temperature domain that
gave both a high yield (>90%) and a high ec (>90%) was very
small. However, it is noteworthy that, when we carried out the
reaction in this domain (e.g., tR = 25 s, T = -78 °C), the desired
3745
dx.doi.org/10.1021/ja110898s |J. Am. Chem. Soc. 2011, 133, 3744–3747

Journal of the American Chemical Society
COMMUNICATION
Scheme 1. Determination of Absolute Configuration of 3a
’ REFERENCES
(1) Chiral organometallics: (a) Hoffmann, R. W. Chem. Soc. Rev.
2003, 32, 225. (b) Marshall, J. A. J. Org. Chem. 2007, 72, 8153.
(c) Crudden, C. M.; Glasspoole, B. W.; Lata, C. J. Chem. Commun.
2009, 6704.
(2) Chiral organolithiums: (a) Clayden, J. Organolithiums: Selectivity
for Synthesis; Pergamon: Amsterdam, The Netherlands, 2002; Chapters
5 and 6. (b) Hodgson, D. M. Organolithiums in Enantioselective Synthesis;
Springer: Berlin, Germany, 2003. (c) Hoppe, D.; Hense, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2282. (d) Basu, A.; Thayumanavan, S.
Angew. Chem., Int. Ed. 2002, 41, 716. (e) Beak, P.; Anderson, D. R.;
Curtis, M. D.; Laumer, J. M.; Pippel, D. J.; Weisenburger, G. A. Acc.
Chem. Res. 2000, 33, 715. (f) Lee, W. K.; Park, Y. S.; Beak, P. Acc. Chem.
Res. 2009, 42, 224.
product 4a was obtained in a high yield (91%) with a high
selectivity (91% ec). In contrast, the reaction using a batch macro
reactor (reaction time: 25 s, T = -78 °C) gave 4a in 99% yield
with a low selectivity (61% ec). Batch reactions under several
conditions also led to low ec (See SI for details). These results
show that a flow microreactor system is a powerful tool for
enantioselective reactions.
(3) Enantioselective transformations could be sometimes achieved
by dynamic kinetic resolution. Beak, P.; Basu, A.; Gallagher, D. J.; Park,
Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552.
(4) Microreactor: (a) Fletcher, P. D. I.; Haswell, S. J.; Pombo-Villar,
E.; Warrington, B. H.; Watts, P.; Wong, S. Y. F.; Zhang, X. Tetrahedron
2002, 58, 4735. (b) J€ahnisch, K.; Hessel, V.; L€owe, H.; Baerns, M. Angew.
Chem., Int. Ed. 2004, 43, 406. (c) Kiwi-Minsker, L.; Renken, A. Catal.
Today 2005, 110, 2. (d) Doku, G. N.; Verboom, W.; Reinhoudt, D. N.;
van den Berg, A. Tetrahedron 2005, 61, 2733. (e) Watts, P.; Haswell, S. J.
Chem. Soc. Rev. 2005, 34, 235. (f) Geyer, K.; Codee, J. D. C.; Seeberger,
P. H. Chem.-Eur. J. 2006, 12, 8434. (g) Whitesides, G. Nature 2006,
442, 368. (h) deMello, A. J. Nature 2006, 442, 394. (i) Song, H.; Chen,
D. L.; Ismagilov, R. F. Angew. Chem., Int. Ed. 2006, 45, 7336.
(j) Kobayashi, J.; Mori, Y.; Kobayashi, S. Chem. Asian J. 2006, 1, 22.
(k) Brivio, M.; Verboom, W.; Reinhoudt, D. N. Lab Chip 2006, 6, 329.
(l) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade,
D. T. Chem. Rev. 2007, 107, 2300. (m) Ahmed-Omer, B.; Brandtand,
J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 733. (n) Watts, P.; Wiles, C.
Chem. Commun. 2007, 443. (o) Fukuyama, T.; Rahman, M. T.; Sato, M.;
Ryu, I. Synlett 2008, 151. (p) Yoshida, J.; Nagaki, A.; Yamada, T. Chem.-
Eur. J. 2008, 14, 7450. (q) Lin, W.; Wang, Y.; Wang, S.; Tseng, H. Nano
Today 2009, 4, 470. (r) McMullen, J. P.; Jensen, K. F. Annu. Rev. Anal.
Chem. 2010, 3, 19.
Reactions with various electrophiles were examined under the
optimized conditions, and the results are summarized in Table 2.
Chlorotrimethylsilane, tributylchlorostannane, benzophenone,
and phenyl isocyanate were effective as electrophiles and gave
the corresponding allenes (4d, 4f-4h) with a high enantioselec-
tivity. The reactions of 2a with other organolithium compounds,
such as hexyllithium (HexLi) and ethyllithium (EtLi), and the
reactions of other conjugated enynes bearing a carbamoyloxy
group (2d and 2e) were also examined, and the corresponding
products (4i-4o) were obtained in good yields and high
enantioselectivity.
The absolute configuration of the major stereoisomer of 4e,
which was obtained from 2a and 4,40-dibromobenzophenone,
was determined as R using X-ray analysis employing an anom-
alous dispersion technique. Since the similar propargyllithium/
1a complex has been shown to proceed in an anti-SE0 manner,20
the absolute configuration of the organolithium intermediate 3a
was estimated to be S (Scheme 1).
(5) Asymmetric synthesis in microreactor: (a) Wiles, C.; Watts, P.;
Haswell, S. J.; Pombo-Villar, E. Lab Chip 2004, 4, 171. (b) J€onsson, C.;
Lundgren, S.; Haswell, S. J.; Moberg, C. Tetrahedron 2004, 60, 10515.
(c) de Bellefon, C.; Lamouille, T.; Pestre, N.; Bornette, F.; Pennemann,
H.; Neumann, F.; Hessel, V. Catal. Today 2005, 110, 179. (d) Hamberg,
A.; Lundgren, S.; Wingstrand, E.; Moberg, C.; Hult, K. Chem.-Eur. J.
2007, 13, 4334. (e) Sakeda, K.; Wakabayashi, K.; Matsushita, Y.;
Ichimura, T.; Suzuki, T.; Wada, T.; Inoue, Y. J. Photochem. Photobiol.,
A 2007, 192, 166. (f) Solodenko, W.; Jas, G.; Kunz, U.; Kirschning, A.
Synthesis 2007, 583. (g) Mak, X. Y.; Laurino, P.; Seeberger, P. H. Beilstein
J. Org. Chem. 2009, 5, No19.
In conclusion, we have developed a method for asymmetric
synthesis based on suppressing the epimerization of a config-
urationally unstable chiral organolithium intermediate based on
high-resolution control of the residence time using a flow
microreactor system. Enantioenriched allenes were synthesized
from the asymmetric carbolithiation of conjugate enynes using
this method, demonstrating its potential. Thus, our method adds
a new dimension to asymmetric synthesis.
(6) Recent examples: (a) de Bellefon, C.; Tanchoux, N.; Cara-
vieilhes, S.; Grenouillet, P.; Hessel, V. Angew. Chem., Int. Ed. 2000,
39, 3442. (b) Watts, P.; Wiles, C.; Haswell, S. J.; Pombo-Villar, E.;
Styring, P. Chem. Commun. 2001, 990. (c) Hisamoto, H.; Saito, T.;
Tokeshi, M.; Hibara, A.; Kitamori, T. Chem. Commun. 2001, 2662.
(d) Suga, S.; Okajima, M.; Fujiwara, K.; Yoshida, J. J. Am. Chem. Soc.
2001, 123, 7941. (e) Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E.
Chem. Commun. 2002, 1034. (f) Fukuyama, T.; Shinmen, M.; Nishitani,
S.; Sato, M.; Ryu, I. Org. Lett. 2002, 4, 1691. (g) Ueno, M.; Hisamoto, H.;
Kitamori, T.; Kobayashi, S. Chem. Commun. 2003, 936. (h) Garcia-
Egido, E.; Spikmans, V.; Wong, S. Y. F.; Warrington, B. H. Lab Chip
2003, 3, 73. (i) Lai, S. M.; Martin-Aranda, R.; Yeung, K. L. Chem.
Commun. 2003, 218. (j) Mikami, K.; Yamanaka, M.; Islam, M. N.;
Kudo, K.; Seino, N.; Shinoda, M. Tetrahedron Lett. 2003, 44, 7545.
(k) Kobayashi, J.; Mori, Y.; Okamoto, K.; Akiyama, R.; Ueno, M.;
Kitamori, T.; Kobayashi, S. Science 2004, 304, 1305. (l) Nagaki, A.;
Kawamura, K.; Suga, S.; Ando, T.; Sawamoto, M.; Yoshida, J. J. Am.
Chem. Soc. 2004, 126, 14702. (m) Kawaguchi, T.; Miyata, H.; Ataka, K.;
Mae, K.; Yoshida, J. Angew. Chem., Int. Ed. 2005, 44, 2413. (n) Lee, C.-C.;
et al. Science 2005, 310, 1793. (o) Ducry, L.; Roberge, D. M. Angew.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
spectroscopic data of compounds, and complete ref 6n. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yoshida@sbchem.kyoto-u.ac.jp
’ ACKNOWLEDGMENT
This work was partially supported by the Grant-in-Aid for
Scientific Research. We thank Rigaku Corporation for the X-ray
analysis.
3746
dx.doi.org/10.1021/ja110898s |J. Am. Chem. Soc. 2011, 133, 3744–3747

Journal of the American Chemical Society
COMMUNICATION
Chem., Int. Ed. 2005, 44, 7972. (p) Nagaki, A.; Togai, M.; Suga, S.; Aoki,
N.; Mae, K.; Yoshida, J. J. Am. Chem. Soc. 2005, 127, 11666. (q) He, P.;
Watts, P.; Marken, F.; Haswell, S. J. Angew. Chem., Int. Ed. 2006,
45, 4146. (r) Uozumi, Y.; Yamada, Y.; Beppu, T.; Fukuyama, N.; Ueno,
M.; Kitamori, T. J. Am. Chem. Soc. 2006, 128, 15994. (s) Tanaka, K.;
Motomatsu, S.; Koyama, K.; Tanaka, S.; Fukase, K. Org. Lett. 2007,
9, 299. (t) Ushiogi, Y.; Hase, T.; Iinuma, Y.; Takata, A.; Yoshida, J. Chem.
Commun. 2007, 2947. (u) Sahoo, H. R.; Kralj, J. G.; Jensen, K. F. Angew.
Chem., Int. Ed. 2007, 46, 5704. (v) Hornung, C. H.; Mackley, M. R.;
Baxendale, I. R.; Ley, S. V. Org. Process Res. Dev. 2007, 11, 399. (w)
Fukuyama, T.; Kobayashi, M.; Rahman, M. T.; Kamata, N.; Ryu, I. Org.
Lett. 2008, 10, 533. (x) Tricotet, T.; O’Shea, D. F. Chem.-Eur. J. 2010,
16, 6678.
(16) 1b: (R,R)-(-)-2,3-Dimethoxy-1,4-bis(dimethylamino)butane;
1c: 2,2-bis((4S)-(-)-4-isopropyloxazoline)propane; 1d: (S)-(-)-N,R-
dimethylbenzylamine; 1e: (S)-(-)-1-methyl-2-pyrrolidine methanol.
(17) Enantiomeric composition, that enantiomeric ratio normalizes
to a percent, proposed by Kagan. Kagan, H. B. Recl. Travl. Chim. Pays-Bas
1995, 114, 203.
(18) To verify that the enantioselectivity was determined by the
epimerizaiton, Hoffman19 test was carried out using Me3SiCl as an
electrophile in a batch macro reactor. The enantiomeric ratio of 4d
obtained with 0.10 equiv of Me3SiCl was different from that obtained
with 1.5 equiv of Me3SiCl. The result indicates that the activation
enegies for the reactions of 3a and epi-3a (epimer of 3a) with an
electrophile are different. It also indicates that the activation energy for
the epimerization of 3a and epi-3a is much higher than those for the
reactions with an electrophile. This means that the enantiomeric ratio of
the allene product reflects the ratio of organolithium intermediates 3a
and epi-3a, if a stoichiometric amount of an electrophile is used.
(7) Mesoreactor: (a) Jas, G.; Kirschning, A. Chem.-Eur. J. 2003,
9, 5708. (b) Baxendale, I. R.; Ley, S. V. In New Avenues to Efficient
Chemical Synthesis: Emerging Technologies; Seeberger, P. H., Ed.;
Springer: Berlin, 2007; pp 151-185. (c) Baxendale, I. R.; Hayward,
J. J.; Lanners, S.; Ley, S. V.; Smith, C. D. In Microreactors in Organic
Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH: Weinheim, 2008;
Chapter 4.2, pp 84-122. (d) Ceylan, S.; Kirschning, A. In Recoverable
and Recyclable Catalysts; Benaglia, M., Ed.; Wiley: New York, 2009;
Chapter 13, pp 379-411.
(8) Yoshida, J. Chem. Record 2010, 10, 332.
(9) By using a continuous flow microreactior system, the reaction
can be performed in a large-scale synthesis. See: (a) Wakami, H.;
Yoshida, J. Org. Process Res. Dev. 2005, 9, 787. (b) Iwasaki, T.; Kawano,
N.; Yoshida, J. Org. Process Res. Dev. 2006, 10, 1126.
(10) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J.-F. J. Am.
Chem. Soc. 1995, 117, 8853. (b) Hogan, A.-M., L.; O’Shea, D. F. J. Am.
Chem. Soc. 2006, 128, 10360. (c) Hogan, A.-M., L.; O’Shea, D. F. Chem.
Commun. 2008, 3839.
(19) (a) Hoffmann, R. W; Julius, M.; Chemla, F.; Ruhland, T.;
Frenzen, G. Tetrahedron 1994, 50, 6049. (b) Hirsch, R.; Hoffmann,
R. W. Chem. Ber. 1992, 125, 975. (c) Basu, A.; Gallagher, D. J.; Beak, P.
J. Org. Chem. 1996, 61, 5718.
(20) Chedid, R. B.; Br€ummer, M.; Wibbeling, B.; Fr€ohlich, R.;
Hoppe, D. Angew. Chem., Int. Ed. 2007, 46, 3131.
(11) Recent example: (a) Weisenburger, G. A.; Faibish, N. C.;
Pippel, D. J.; Beak, P. J. Am. Chem. Soc. 1999, 121, 9522. (b) Gawley,
R. E.; Low, E.; Zhang, Q.; Harris, R. J. Am. Chem. Soc. 2000, 122, 3344.
(c) Nakamura, S.; Nakagawa, R.; Watanabe, Y.; Toru, T. J. Am. Chem.
Soc. 2000, 122, 11340. (d) Schultz-Fademrecht, C.; Tius, M. A.;
Grimme, S.; Wibbeling, B.; Hoppe, D. Angew. Chem., Int. Ed. 2002,
41, 1532. (e) Seppi, M.; Kalkofen, R.; Reupohl, J.; Fro€hlich, R.; Hoppe,
D. Angew. Chem., Int. Ed. 2004, 43, 1423. (f) McGrath, M. J.; O’Brien, P.
J. Am. Chem. Soc. 2005, 127, 16378. (g) Genet, C.; Canipa, S. J.; O’Brien,
P.; Taylor, S. J. Am. Chem. Soc. 2006, 128, 9336. (h) Stymiest, J. L.;
Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778.
(i) Klein, R.; Gawley, R. E. J. Am. Chem. Soc. 2007, 129, 4126. (j) Beng,
T. K.; Yousaf, T. I.; Coldham, I.; Gawley, R. E. J. Am. Chem. Soc. 2009,
131, 6908. (k) Stead, D.; Carbone, G.; O’Brien, P.; Campos, K. R.;
Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260. (l) Beng,
T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 12216.
(12) Integration of reactions: Suga, S.; Yamda, D.; Yoshida, J. Chem.
Lett. 2010, 39, 404.
(13) Reviews for chiral allenes: (a) Hoffmann-R€ober, A.; Krause, N.
Angew. Chem., Int. Ed. 2004, 43, 1196. (b) Ma, S. Chem. Rev. 2005,
105, 2829. (c) Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 6, 795.
(14) Flash chemistry is defined as a field of chemical synthesis where
extremely fast reactions are conducted in a highly controlled manner to
produce the desired compounds with high selectivity. (a) Yoshida, J.
Flash Chemistry. Fast Organic Synthesis in Microsystems: Wiley-Blackwell,
2008. (b) Yoshida, J. Chem. Commun. 2005, 4509. (c) Yoshida, J.;
Nagaki, A.; Yamada, T. Chem.-Eur. J. 2008, 14, 7450. (d) Nieuwland,
P. J.; Koch, K.; van Harskamp, N.; Wehrens, R.; van Hest, J. C. M.;
Rutjes, F. P. J. T. Chem. Asian J. 2010, 5, 799.
(15) (a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami,
T.; Yoshida, J. J. Am. Chem. Soc. 2007, 129, 3047. (b) Nagaki, A.;
Takabayashi, N.; Tomida, Y.; Yoshida, J. Org. Lett. 2008, 10, 3937.
(c) Nagaki, A.; Kim, H.; Yoshida, J. Angew. Chem., Int. Ed. 2008,
47, 7833. (d) Nagaki, A.; Takizawa, E.; Yoshida, J. J. Am. Chem. Soc.
2009, 131, 1654. (e) Tomida, Y.; Nagaki, A.; Yoshida, J. Org. Lett. 2009,
11, 3614. (f) Nagaki, A.; Kim, H.; Yoshida, J. Angew. Chem., Int. Ed. 2009,
48, 8063.
3747
dx.doi.org/10.1021/ja110898s |J. Am. Chem. Soc. 2011, 133, 3744–3747