Modular synthesis of bis- and tris-1,2,3-triazoles by permutable sequential azide-aryne and azide-alkyne cycloadditions

Article abstract of DOI:10.1039/c4ob01654h

A modular synthetic method for bis- and tris-1,2,3-triazoles that include a benzotriazole structure was developed on the basis of sequential azide-aryne and azide-alkyne cycloadditions. The key to success was efficient halogen-metal exchange reaction-medi

Full text of DOI:10.1039/c4ob01654h

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Modular synthesis of bis- and tris-1,2,3-triazoles
by permutable sequential azide–aryne and
azide–alkyne cycloadditions†
Cite this: Org. Biomol. Chem., 2014,
12, 7489
Received 4th August 2014,
Accepted 5th August 2014
Suguru Yoshida, Takako Nonaka, Takamoto Morita and Takamitsu Hosoya*
DOI: 10.1039/c4ob01654h
www.rsc.org/obc
A modular synthetic method for bis- and tris-1,2,3-triazoles that aryne precursor bearing a terminal alkyne moiety that served
include a benzotriazole structure was developed on the basis of as a good diyne equivalent.
sequential azide–aryne and azide–alkyne cycloadditions. The key
Unsymmetrical bistriazoles typically have been prepared by
to success was efficient halogen–metal exchange reaction- sequential click reactions toward a platform molecule with
mediated generation of aryne from ortho-iodoaryl triflates bearing two alkynes or two azido groups (Scheme 1A).7a,h In these
a base-sensitive terminal alkyne moiety, which was achieved using methods, the reactivities of the two groups were differentiated
trimethylsilylmethyl Grignard reagent.
by protecting or activating either one of them: the first cycliza-
tion was selectively conducted at the more reactive moiety, and
then the second cyclization at the remaining side.
The breakthrough discovery that copper(I) catalyst significantly
accelerates the Huisgen cycloadditions1 between terminal
alkyne and azide under mild conditions2 triggered the explo-
sive diffusion of click chemistry.3 This method made the con-
nection of molecules quite easy over broad disciplines such as
materials chemistry and chemical biology.4 Moreover, the
ready accessibility of a number of 1,2,3-triazoles from various
azides and alkynes enabled a massive chemical library to be
streamlined for high-throughput screening assays in drug dis-
covery research.5 The robust triazole skeleton structure has
also been recognized as a stable bioisostere of an amide bond
due to the physicochemical similarities between them in
terms of size, dipole moment, and hydrogen bonding ability,
allowing triazoles to serve as good peptide surrogates.6 These
attractive features of triazole have encouraged chemists to syn-
thesize unsymmetrical bistriazoles, which are useful not only
for expanding the diversity of the chemical library but also for
preparing bifunctional molecules by connecting two different
functional molecules.7,8 In this context, we recently developed
a “double-click” reaction using a 1,5-cyclooctadiyne derivative,
enabling facile chemical modification of azido-incorporated
biomolecules with a small functional azido compound.9
Herein, we introduce an efficient synthetic method for diverse
unsymmetrical bistriazoles based on sequential azide–aryne
and azide–alkyne cycloadditions, which was achieved using an
Since 1,2,3-benzotriazole is also a pharmacologically impor-
tant scaffold,10 bistriazoles containing this structure are attrac-
tive candidates as bioactive compounds. We presumed that
this type of bistriazole could be easily prepared from an
aryne11–14 that bears a terminal alkyne moiety, such as diyne
A,15 by consecutive cycloadditions with two azides
(Scheme 1B). This approach differs from the previous ones, in
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku,
Tokyo 101-0062, Japan. E-mail: thosoya.cb@tmd.ac.jp
†Electronic supplementary information (ESI) available: Experimental proce-
dures and characterization data including copies of NMR spectra. See DOI:
10.1039/c4ob01654h
Scheme 1 Synthesis of unsymmetrical bistriazoles by sequential azide–
alkyne cycloadditions.
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which the order of the cycloadditions can be reversed if aryne addition, other solvents, such as ether and toluene, could be
generation and cycloaddition with azide can be performed equally used in place of THF (entries 10 and 11). On the other
before and after the triazole formation at the terminal alkyne hand, ortho-bromoaryl triflate 1b was essentially inert under
moiety. To prove the feasibility of this idea, we designed the optimized conditions for the iodo substrate 1a (entry 12).
2-iodo-3-(propargyloxy)phenyl triflate (1a) as an aryne precur-
The low nucleophilicity and weak basicity of the reagent for
sor bearing an alkyne moiety. The compound 1a was readily aryne generation allowed the reaction with a broad range of
prepared by the Mitsunobu etherification16 of propargyl azides, including those with an electrophilic ester moiety and/
alcohol with known 3-hydroxy-2-iodophenyl triflate,17 which or acidic protons (Table 2). The reactions of aryne generated
was easily obtained from resorcinol in three steps. 3-(Propargyl- from 1a with alkyl azides, such as trimethylsilylmethyl azide
oxy)benzyne was supposed to be generated from 1a by the (2b), tert-butyl α-azidoacetate (2c), and bulky 1-adamantyl
treatment with an organometallic reagent that triggers the azide (2d), proceeded uneventfully to afford benzotriazoles 3b–3d
iodo-metal exchange reaction.
in high yields (entries 1–3). Diverse aryl azides bearing either
Although the reported conditions for aryne generation from a para-electron-donating or electron-withdrawing group also
ortho-iodoaryl triflates were found unsuitable for that purpose served as good substrates (entries 4 and 5). To our surprise,
from 1a, we succeeded in finding appropriate conditions after the reaction with sterically hindered 2,6-diisopropylphenyl
extensive screening for the reaction with benzyl azide (2a) azide (2g) afforded the cycloadduct 3g in an excellent yield
(Table 1). An initial attempt under original conditions13g using (entry 6). This result might be attributed to the enhanced dis-
n-butyllithium in THF at −78 °C furnished complex mixtures tortability of the azido group, caused by the steric inhibition of
probably due to the competing deprotonation of highly acidic resonance, which is similar to the enhanced clickability of 2g
proton at the terminal alkyne (entry 1). Fortunately, another observed in the reaction with a cyclooctyne derivative.8 Other
attempt using isopropylmagnesium chloride–lithium chloride multisubstituted aryl azides, such as multihalogenated phenyl
complex13k afforded desired benzotriazole 3a, although the azide 2h, 3,4-ethylenedioxyphenyl azide (2i), and 2,4-disubsti-
yield was not satisfactory (entry 2). We therefore looked for a tuted 3-azidothiophene 2j, also sufficiently provided benzo-
better Grignard reagent and observed that some reagents sig- triazoles 3h–3j (entries 7–9).
nificantly increase the reaction efficiency (entries 3–7). In par-
ticular, (trimethylsilyl)methylmagnesium chloride with lower
nucleophilicity and weaker basicity18 than the others, provided
the best result (entry 7). Under these conditions, the reaction
Table 2 Reactions of aryne generated from 1a with various azides
could be performed uneventfully at gram scale, showing the
practicality of the method.19 Bulkiness on the silyl group of
the reagent slightly retarded the reaction (entry 8). The use of
corresponding lithium reagent instead of Grignard reagent
greatly decreased the yield of the cyclized product, indicating
the importance of counter cation for this reaction (entry 9). In
Entry
N3–R1
2
3
Yielda (%)
1
2
N3CH2SiMe3
N3CH2CO2t-Bu
2b
2c
3b
3c
89
75
Table 1 Optimization of azide–aryne cycloaddition
3
2d
3d
87
4
5
N3C6H4-p-OMe
N3C6H4-p-CF3
2e
2f
3e
3f
83
71
6b
2g
3g
92
Entry
R–Mtl
X
1
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
n-BuLi
i-PrMgCl·LiCl
n-BuMgCl
MeMgBr
i-PrMgCl
I
I
I
I
I
I
I
I
I
I
I
Br
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Toluene
THF
NDb
46
44
61
82
70
93
70
31
93
89
0c
7
2h
3h
81
8
2i
2j
3i
3j
85
79
PhMgBr
Me3SiCH2MgCl
Me2(Ph)SiCH2MgCl
Me3SiCH2Li
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
9c
9
10
11
12
a Isolated yields. b Reaction was performed using 1a (1.0 equiv.), 2g (1.5
a Isolated yields. b Product 3a was not detected (ND), although most of equiv.) and Me3SiCH2MgCl (2.0 equiv.). c Reaction was performed
1a was consumed. c Most of 1b was recovered.
7490 | Org. Biomol. Chem., 2014, 12, 7489–7493
using 1a (2.1 equiv.), 2j (1.0 equiv.) and Me3SiCH2MgCl (2.0 equiv.).
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Table 3 Synthesis of bistriazoles by metal-catalyzed azide–alkyne cycloadditions
Entry
1
R1
3
N3–R2
2
Conditiona
A
4 or 6
Yieldb (%)
80
Bn
3a
2j
4a
2
3
4
3d
3h
3j
N3CH2SPh
2k
2l
A
A
A
4b
4c
4d
86
69
80
2m
5
6
3i
N3SO2-p-Tol
2n
2o
B
C
4e
6a
83
70
Bn
3a
N3CH2CO2Et
a Condition A: reaction of 3 (1.0 equiv.) with 2 (1.0 equiv.) in the presence of (CH3CN)4CuBF4 (6–7 mol%) and TBTA (5–6 mol%) in t-BuOH/H2O
(1/1) at room temperature for 7–64 h. TBTA = tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine. Condition B: reaction of 3 (1.2 equiv.) with 2 (1.0
equiv.) in the presence of CuI (10 mol%) and 2,6-lutidine (1.2 equiv.) in CHCl3 at room temperature for 21 h. Condition C: reaction of 3 (1.2
equiv.) with 2 (1.0 equiv.) in the presence of Cp*RuCl(PPh3)2 (20 mol%) in benzene at 80 °C for 4 h. b Isolated yields.
Benzotriazole 3 with the remaining terminal alkyne moiety sor 5a. The aryne generation from 5a and cycloaddition with
was applied to metal-catalyzed cyclization with various azides, benzyl azide (2a) was feasible under conditions similar to
easily affording bistriazoles bearing a variety of groups often those from 1a, providing bistriazole 4f in high yield without
used as pharmacophores (Table 3). Under the copper(I)- any detectable side products originating from undesired intra-
catalyzed conditions, 1,4-substituted triazole formation3,4 pro- molecular reactions.
ceeded not only with alkyl and aryl azides (entries 1–4) but
Two ways of orthogonal conjugation of azides that allowed
also with sulfonyl azide (entry 5),20 efficiently providing bistri- facile construction of the bistriazole library could be further
azoles 4a–4e. On the other hand, bistriazole 6a with a 1,5-sub- expanded to the synthesis of tristriazoles with a combination
stituted triazole structure was obtained from the reaction of another bis-reactive junction molecule (Scheme 3). For
using a ruthenium catalyst,21 which is favorable for diversify- instance, trimethylsilylmethyl Grignard-triggered azide–aryne
ing the bistriazole library (entry 6).
cycloaddition using 3-(4-ethynylbenzyl)oxybenzyne precursor
The orthogonality between azide–aryne and azide–alkyne 1c and 4-(trimethylsilylethynyl)phenyl azide (2p) provided
cycloadditions enabled us to reverse the order of the reactions, benzotriazole 3k, including two different alkyne moieties, a
largely increasing the number of available bistriazoles terminal and a silyl-protected alkyne. Second cyclization of 3k
(Scheme 2). For instance, we could first perform the copper(I)- with azide 2o under copper(I)-catalyzed conditions proceeded
catalyzed click reaction at the terminal alkyne moiety of 1a selectively at the terminal alkyne moiety to afford bistriazole
with p-anisyl azide (2e) to afford triazole-bearing aryne precur- 4g quantitatively. The modified silver-mediated desilylation7a
of 4g, followed by third cyclization with azide 2q at the resulting
terminal alkyne moiety furnished tristriazole 7a in high yield.
On the other hand, performing copper(I)-catalyzed cyclization
first at the terminal alkyne moiety of 1c with azide 2r afforded
aryne precursor 5b in excellent yield. Generation of aryne from
5b with (trimethylsilyl)methylmagnesium chloride could be
conducted in the presence of azide bearing a terminal alkyne
moiety such as 4-ethynylphenyl azide (2s), which provided bis-
triazole 4h. Finally, copper(I)-catalyzed click conjugation at the
terminal alkyne moiety of 4h with azide 2t afforded tristriazole
Scheme 2 Bistriazole synthesis by sequential azide–alkyne/azide–
aryne cycloadditions.
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explore the scope of aryne generation using trimethylsilyl-
methyl Grignard reagent, are now in progress.
Acknowledgements
The authors thank Central Glass Co., Ltd for their generous
gift of Tf2O. This work was supported by Platform for Drug
Discovery, Informatics, and Structural Life Science from
MEXT, Japan, JSPS KAKENHI grant number 24310164 (T.H.),
the Kurata Memorial Hitachi Science and Technology Foun-
dation (S.Y.), and the Sumitomo Electric Group Corporate
Social Responsibility Foundation (S.Y.).
Notes and references
1 R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 565.
2 (a) C. W. Tornøe, C. Christensen and M. Meldal, J. Org.
Chem., 2002, 67, 3057; (b) V. V. Rostovtsev, L. G. Green,
V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed.,
2002, 41, 2596.
3 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
Int. Ed., 2001, 40, 2004.
4 (a) M. Meldal and C. W. Tornøe, Chem. Rev., 2008, 108,
2952; (b) Click Chemistry for Biotechnology and Materials
Science, ed. J. Lahann, John Wiley & Sons, Chichester, UK,
2009.
5 (a) S. K. Mamidyala and M. G. Finn, Chem. Soc. Rev., 2010,
39, 1252; (b) S. G. Agalave, S. R. Maujan and V. S. Pore,
Chem. – Asian J., 2011, 6, 2696; (c) X.-P. He, J. Xie, Y. Tang,
J. Li and G.-R. Chen, Curr. Med. Chem., 2012, 19, 2399.
6 (a) D. S. Pedersen and A. Abell, Eur. J. Org. Chem., 2011,
2399; (b) I. E. Valverde, F. Lecaille, G. Lalmanach,
V. Aucagne and A. F. Delmas, Angew. Chem., Int. Ed., 2012,
51, 718; (c) M. Tischler, D. Nasu, M. Empting, S. Schmelz,
D. W. Heinz, P. Rottmann, H. Kolmar, G. Buntkowsky,
D. Tietze and O. Avrutina, Angew. Chem., Int. Ed., 2012, 51,
3708; (d) I. E. Valverde, A. Bauman, C. A. Kluba,
S. Vomstein, M. A. Walter and T. L. Mindt, Angew. Chem.,
Int. Ed., 2013, 52, 8957.
7 (a) V. Aucagne and D. A. Leigh, Org. Lett., 2006, 8, 4505;
(b) V. Fiandanese, D. Bottalico, G. Marchese, A. Punzi
and F. Capuzzolo, Tetrahedron, 2009, 65, 10573;
(c) J. M. Aizpurua, I. Azcune, R. M. Fratila, E. Balentova,
M. Sargartzazu-Aizpurua and J. I. Miranda, Org. Lett., 2010,
12, 1584; (d) H. Elamari, F. Meganem, J. Herscovici and
C. Girard, Tetrahedron Lett., 2011, 52, 658; (e) B. C. Doak,
M. J. Scanlon and J. S. Simpson, Org. Lett., 2011, 13, 537;
(f) I. Ehlers, P. Maity, J. Aubé and B. König, Eur. J. Org.
Chem., 2011, 2474; (g) D. M. Beal, V. E. Albrow, G. Burslem,
L. Hitchen, C. Fernandes, C. Lapthorn, L. R. Roberts,
M. D. Selby and L. H. Jones, Org. Biomol. Chem., 2012, 10,
548; (h) Z. Yuan, G.-C. Kuang, R. J. Clark and L. Zhu, Org.
Lett., 2012, 14, 2590; (i) T.-f. Niu, L. Gu, L. Wang, W.-b. Yi
and C. Cai, Eur. J. Org. Chem., 2012, 6767.
Scheme 3 Synthesis of tristriazoles by three sequential cycloadditions.
See ESI† for details of the conditions.
7b. This facile approach to diverse tristriazoles, with several
pharmacophoric groups having molecular weights over 500,
would facilitate the discovery of druggable molecules like a
protein–protein interaction (PPI) inhibitor22 that interacts with
a target having a larger binding pocket.
In summary, we established a modular synthetic method
for bis- and tris-1,2,3-triazoles based on sequential azide–
aryne and azide–alkyne cycloadditions. The key to success was
efficient generation of aryne from ortho-iodoaryl triflates
bearing a base-sensitive terminal alkyne moiety, which was
achieved using trimethylsilylmethyl Grignard reagent. Ortho-
gonality between the cycloadditions is of great advantage for
constructing a multitriazole library containing diversified com-
pounds with various pharmacophores in a broad range of
molecular weights. Further studies to expand the library by
applying the method to the reaction of diyne equivalents with
arynophiles and ynophiles other than azides, as well as to
7492 | Org. Biomol. Chem., 2014, 12, 7489–7493
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8 We reported a bilateral character of 2,6-disubstituted 1,4-
diazidobenzene: a cyclic alkyne selectively reacted at the
sterically-hindered azido group, but base-catalyzed cycliza-
tion with a terminal alkyne occurred predominantly at the
unhindered side. See: S. Yoshida, A. Shiraishi, K. Kanno,
T. Matsushita, K. Johmoto, H. Uekusa and T. Hosoya, Sci.
Rep., 2011, 1, 82.
9 I. Kii, A. Shiraishi, T. Hiramatsu, T. Matsushita, H. Uekusa,
S. Yoshida, M. Yamamoto, A. Kudo, M. Hagiwara and
T. Hosoya, Org. Biomol. Chem., 2010, 8, 4051.
10 (a) R. R. Kale, V. Prasad, P. P. Mohapatra and V. K. Tiwari,
Monatsh. Chem., 2010, 141, 1159; (b) K. Takahashi,
G. Yamagishi, T. Hiramatsu, A. Hosoya, K. Onoe, H. Doi,
H. Nagata, Y. Wada, H. Onoe, Y. Watanabe and T. Hosoya,
Bioorg. Med. Chem., 2011, 19, 1464.
Synth., 1968, 48, 12; (f) Y. Himeshima, T. Sonoda and
H. Kobayashi, Chem. Lett., 1983, 1211; (g) T. Matsumoto,
T. Hosoya, M. Katsuki and K. Suzuki, Tetrahedron Lett.,
1991, 32, 6735; (h) T. Kitamura and M. Yamane, J. Chem.
Soc., Chem. Commun., 1995, 983; (i) M. Uchiyama,
T. Miyoshi, Y. Kajihara, T. Sakamoto, Y. Otani, T. Ohwada
and Y. Kondo, J. Am. Chem. Soc., 2002, 124, 8514;
( j) I. Sapountzis, W. Lin, M. Fischer and P. Knochel, Angew.
Chem., Int. Ed., 2004, 43, 4364; (k) T. Ikawa, A. Takagi,
Y. Kurita, K. Saito, K. Azechi, M. Egi, K. Kakiguchi, Y. Kita
and S. Akai, Angew. Chem., Int. Ed., 2010, 49, 5563;
(l) T. Hamura, Y. Chuda, Y. Nakatsuji and K. Suzuki, Angew.
Chem., Int. Ed., 2012, 51, 3368; (m) T. R. Hoye, B. Baire,
D. Niu, P. H. Willoughby and B. P. Woods, Nature, 2012,
490, 208; (n) Y. Sumida, T. Kato and T. Hosoya, Org. Lett.,
2013, 15, 2806; (o) S. Yoshida, K. Uchida and T. Hosoya,
Chem. Lett., 2014, 43, 116.
11 (a) R. W. Hoffmann, Dehydrobenzene and Cycloalkynes,
Academic Press, New York, 1967; (b) T. L. Gilchrist, in
The Chemistry of Functional Groups, ed. S. Patai and 14 For azide–aryne cycloaddition, see: (a) R. Huisgen and
Z. Rappoport, Wiley, Chichester, 1983, ch. 11;
(c) S. V. Kessar, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991,
vol. 4, ch. 2.3; (d) H. Hart, in The Chemistry of Triple-Bonded
R. Knorr, Naturwissenschaften, 1961, 48, 716; (b) F. Shi,
J. P. Waldo, Y. Chen and R. C. Larock, Org. Lett., 2008, 10,
2409; (c) N. Saito, K.-i. Nakamura and Y. Sato, Heterocycles,
2014, 88, 929, and references therein.
Functional Groups, ed. S. Patai, Wiley, Chichester, 1994, 15 W. Yuan and S. Ma, Org. Lett., 2014, 16, 193.
ch. 18.
16 (a) O. Mitsunobu, Synthesis, 1981, 1; (b) D. L. Hughes, Org.
React., 1992, 42, 335; (c) K. C. K. Swamy, N. N. B. Kumar,
E. Balaraman and K. V. P. P. Kumar, Chem. Rev., 2009, 109,
2551.
12 For some recent reviews on arynes, see: (a) D. Peña,
D. Pérez and E. Guitián, Angew. Chem., Int. Ed., 2006, 45,
3579; (b) R. Sanz, Org. Prep. Proced. Int., 2008, 40, 215;
(c) C. Wentrup, Aust. J. Chem., 2010, 63, 979; 17 T. Hamura, T. Hosoya, H. Yamaguchi, Y. Kuriyama,
(d) T. Kitamura, Aust. J. Chem., 2010, 63, 987; (e) H. Yoshida
and K. Takaki, Heterocycles, 2012, 85, 1333; (f) H. Yoshida
M. Tanabe, M. Miyamoto, Y. Yasui, T. Matsumoto and
K. Suzuki, Helv. Chim. Acta, 2002, 85, 3589.
and K. Takaki, Synlett, 2012, 23, 1725; (g) S. S. Bhojgude 18 (a) H. Yorimitsu and K. Oshima, Pure Appl. Chem., 2006,
and A. T. Biju, Angew. Chem., Int. Ed., 2012, 51, 1520;
(h) A. Bhunia, S. R. Yetra and A. T. Biju, Chem. Soc. Rev.,
2012, 41, 3140; (i) C. M. Gampe and E. M. Carreira, Angew.
Chem., Int. Ed., 2012, 51, 3766; ( j) P. M. Tadross and
B. M. Stoltz, Chem. Rev., 2012, 112, 3550; (k) C. Wu and
F. Shi, Asian J. Org. Chem., 2013, 2, 116; (l) A. V. Dubrovskiy,
N. A. Markina and R. C. Larock, Org. Biomol. Chem., 2013,
78, 441; (b) T. Fujioka, T. Nakamura, H. Yorimitsu and
K. Oshima, Org. Lett., 2002, 4, 2257; (c) W. Affo, H. Ohmiya,
T. Fujioka, Y. Ikeda, T. Nakamura, H. Yorimitsu,
K. Oshima, Y. Imamura, T. Mizuta and K. Miyoshi, J. Am.
Chem. Soc., 2006, 128, 8068; (d) T. Kobayashi, H. Ohmiya,
H. Yorimitsu and K. Oshima, J. Am. Chem. Soc., 2008, 130,
11276.
11, 191; (m) R. W. Hoffmann and K. Suzuki, Angew. Chem., 19 See ESI† for details.
Int. Ed., 2013, 52, 2655.
20 E. J. Yoo, M. Ahlquist, S. H. Kim, I. Bae, V. V. Fokin,
13 For representative aryne precursors and generation
methods, see: (a) M. Stiles and R. G. Miller, J. Am. Chem.
K. B. Sharpless and S. Chang, Angew. Chem., Int. Ed., 2007,
46, 1730.
Soc., 1960, 82, 3802; (b) L. Friedman and F. M. Logullo, 21 B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang,
J. Am. Chem. Soc., 1963, 85, 1549; (c) G. Wittig and
R. W. Hoffmann, Org. Synth., 1967, 47, 4;
H. Zhao, Z. Lin, G. Jia and V. V. Fokin, J. Am. Chem. Soc.,
2008, 130, 8923.
(d) C. D. Campbell and C. W. Rees, J. Chem. Soc. C, 1969, 22 V. Azzarito, K. Long, N. S. Murphy and A. J. Wilson, Nat.
742; (e) F. M. Logullo, A. H. Seitz and L. Friedman, Org.
Chem., 2013, 5, 161.
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