Microwave-assisted regiospecific synthesis of pseudohalohydrin esters

Article abstract of DOI:10.1055/s-0031-1291015

N-Acylbenzotriazoles react regiospecifically with epoxides under palladium catalysis to give novel -(benzotriazol-1-yl)ethyl esters (52-87%) constituting halohydrin ester surrogates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291015

1384▌
LETTER
lMetteircrowave-Assisted Regiospecific Synthesis of Pseudohalohydrin Esters
Synthesis of Regiospecific Pseudohalohydrin Esters
Mirna El Khatib,a Mohamed Elagawany,a,b,c Ekaterina Todadze,a Levan Khelashvili,a Said A. El-Feky,b
Alan R. Katritzky*a,d
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
E-mail: katritzky@chem.ufl.edu
b
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
c
Department of Organic Chemistry, College of Pharmacy, Misr University for Science and Technology, Al-Motamayez District, P.O. Box 77,
6th of October City, Egypt
d
Department of Chemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Received: 06.01.2012; Accepted after revision: 22.02.2012
zotriazoles have thus enabled advantageous Friedel–
Abstract: N-Acylbenzotriazoles react regiospecifically with epox-
Crafts and Vilsmeier–Haack acylations.21,23 Obase et al.24
ides under palladium catalysis to give novel β-(benzotriazol-1-
previously synthesized a pseudohalohydrin ester (Scheme
1) from an N-acylbenzotriazole. However, the single ex-
ample reported gave a mixture of three products, the par-
ent benzotriazole, and two isomeric pseudohalohydrin
yl)ethyl esters (52–87%) constituting halohydrin ester surrogates.
Key words: regioselectivity, catalysis, palladium, esters, ring
opening
esters A and B. The structures of A (yield 13%) and B
(yield 19%) were assigned on the basis of their UV spectra
Halohydrin esters are important intermediates in asym-
as the ‘1-’ and ‘2-’ substituted benzotriazoles. No mention
metric syntheses of a wide range of biologically active
is made that there could be three possible isomeric benzo-
natural and synthetic products1–6 including drugs,7 β-ami-
triazole products; in addition to A and B, there is also
no alcohols,8 pyrrolidines,9 and functionalized cyclopro-
structure C. The only evidence advanced for the structures
panes.10
of A and B was derived from UV spectroscopy. This
Halohydrin esters11–13 are commonly prepared by (i) di-
rect reaction of an epoxide with an acyl halide,1,4,5,12,13 (ii)
the ring-opening of epoxides by halogen nucleophiles fol-
lowed by the O-acylation of the resulting halohydrin de-
rivatives,14–19 and (iii) from 1,2-diols.6,20 In general, these
strategies produce mixtures of regioisomers and side
products. No previous general method has achieved the
high regioselectivity which we now report.
work24 is limited to a single example and neither substrate
scope nor optimization of reaction conditions were inves-
tigated.
To the best of our knowledge, the palladium-catalyzed
synthesis of pseudohalohydrin esters from N-acylbenzo-
trizoles and epoxides was not previously attempted. We
now report an improved protocol for the regiospecific
synthesis of β-(benzotriazol-1-yl)ethyl pseudohalohydrin
esters 4, with palladium catalysis under microwave-assist-
ed, solvent-free conditions. Microwave heating is a pow-
erful tool in promoting a variety of applications in organic
N-Acylbenzotriazoles, which are more stable than acid
chlorides and have advantageously replaced them in many
acylations, often reducing side reactions.21,22 N-Acylben-
O
O
N
N
HO
N
N
+
N
N
H
O
O
Cl
O
HO
N
A
Cl
N
Cl
N
K2CO3
O
O
N
N
Ac
O
N
O
O
N
N
O
+
N
Cl
O
B
C
O
Scheme 1 Reported24 synthesis of a pseudohalohydrin ester from an N-acylbenzotrizole and an epoxide
SYNLETT 2012, 23, 1384–1388
Advanced online publication: 14.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291015; Art ID: ST-2012-S0012-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Regiospecific Pseudohalohydrin Esters
1385
synthesis and functional-group transformations without
solvents. The use of a single-mode cavity microwave syn-
thesizer helps to achieve reproducibility, safety, reduced
pollution, and simplicity in processing and handling.25–31
Table 1 Optimization of Reaction Conditions for 4a
Entry Catalyst
(mol%)
Reaction conditions
Yield of
4a (%)
1
2
none
130 °C, 50 W, 30–90 min
130 °C, 50 W, 30 min
r.t., CHCl3, 12 h
0
87
0
We found that palladium-catalyzed thermal reaction of N-
acylbenzotriazole 1a32–34 with epoxide 3a gave the single
regioisomer β-(benzotriazol-1-yl)ethyl ester 4a. Al-
though, as reported33 recently, thermal isomerization of
1a to 1a′, followed by oxidative addition of 1a′ to palladi-
um(0) gives 1a′′, we found no 1,4-benzoxazine 2a
(Scheme 2).35
Pd(PPh3)4 (10)
Pd(Ph3)4 (10)
Pd(Ph3)4 (10)
Pd(Ph3)4 (10)
Pd(Ph3)4 (5)
3
4
reflux, CHCl3, 12 h
130 °C, 12 h
0
5
0
6
130 °C, 50 W, 30 min
130 °C, 50 W, 30 min
130 °C, 50 W, 30 min
130 °C, 50 W, 90 min
130 °C, 50 W, 40 min
45
0
Our reaction of (1H-benzotriazol-1-yl)(4-ethylphe-
nyl)methanone (1a) with styrene oxide (3a) in the pres-
ence of 10 mol% of Pd(PPh3)4 under microwave
irradiation (130 °C, 50 W) for 30 minutes, gave 2-(1H-
benzotriazol-1-yl)-1-phenylethyl 4-ethylbenzoate (4a) as
a single regioisomer in 87% yield (Scheme 2). These con-
ditions proved to be generally successful while in the ab-
sence of palladium catalyst these reactions did not
progress during 30 minutes and prolonged reaction times
resulted in decomposition.
7
anhyd CuSO4 (10)
CuSO4·5H2O4 (10)
Pd(OAc)2 (10)
Ph3P (10)
8
20
30
35
9
10
We propose that initially Pd(0) and 1 forms 6.46 The inter-
action of 6 with epoxide 3 forms 6′, which is then attacked
by benzotriazole giving 4 as a single regioisomer (Scheme
3).
Other catalyst systems including anhydrous CuSO4,
CuSO4·5H2O, Pd(OAc)2 were less effective (Table 1, as
were lower temperatures, power, and catalyst loadings
[100 °C, 20 W and 100 °C, 50 W, 130 °C, 50 W, 5 mol%
Pd(PPh3)4].
The mechanism appears to be similar to the recent report
of coupling reaction of acyl halides and epoxides afford-
ing halohydrin esters as mixtures of regioisomers
(Scheme 4).1 However, our palladium-catalyzed pathway
provided single regioisomers.
We examined the scope of the palladium-catalyzed reac-
tion of N-acylbenzotriazoles 1a–f with epoxides 3a–c, us-
ing the optimized conditions as summarized in Table 2. β-
(Benzotriazol-1-yl)ethyl esters were obtained as single
isomers in 52–87% yields. The reaction proceeded faster
with N-aroylbenzotriazoles (reaction time, 30 min) than
with N-alkylbenzotriazoles (reaction time, 60 min) and ar-
omatic as well as alkyl-substituted epoxides were tolerat-
ed (Table 2).36–45
N
N
N
N
N
Pd(PPh3)4
O
N
+
O
neat, 130 °C
50 W, 30 min
O
3a
O
1a
4a, 371-Da
Δ
thermal
isomerization
O
3a
X
N2
N
Pd
N
N
– N2
oxidative
addition
R
R
O
O
O
1a'
1a''
2a, 343-Da
Scheme 2 Palladium-catalyzed thermal reaction of N-acylbenzotriazole 1a with epoxide 3a
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1384–1388

1386
M. El Khatib et al.
LETTER
Table 2 Synthesis of β-(Benzotriazol-1-yl)ethyl Esters36
However, reaction of (Z)-L-Phe-Bt (1g) with 3c gave 5a,
the alcohol derived from ring opening of the epoxide by
the benzotriazole anion (Scheme 5): in 7 the epoxide oxy-
gen becomes protonated.
N
N
N
N
O
R2
N
Pd(PPh3)4
R3
N
+
R3
MW, 130 °C, 50 W,
30–60 min
R2
R1
O
3a–c
O
O
1a–f
R1
O
4a–i
Bt
O
N
H
Entry Substrate 1
Substrate 3
Yield of 4
O
(%)
1g
Pd(PPh3)4
+
N
N
1
2
3
4
5
6
7
8
9
1a R1 = 4-EtC6H4
1a R1 = 4-EtC6H4
1b R1 = PhCH2CH2
1c R1 = 1-naphthyl
1c R1 = 1-naphthyl
3a R2 = Ph, R3 = H 4a 87
MW, 130 °C, 50 W
70%
OH
N
3b R2 = Ph, R3 = Ph 4b 62
3c R2 = Bu, R3 = H 4c 72
3a R2 = Ph, R3 = H 4d 62
3c R2 = Bu, R3 = H 4e 73
3a R2 = Ph, R3 = H 4f 70
3a R2 = Ph, R3 = H 4g 75
3c R2 = Bu, R3 = H 4h 76
O
5a
3c
Scheme 5 Synthesis of pseudohalohydrin 5a37,47,48
In conclusion, Pd-catalyzed reactions of readily available
N-acylbenzotriazoles with epoxides under solvent-free
conditions gives β-(benzotriazol-1-yl)ethyl esters as sin-
gle regioisomers in an efficient, one-step procedure.
1d R1 = 4-O2NC6H4
1e R1 = Ph
1e R1 = Ph
1f R1 = 1-adamantane-CH2 3c R2 = Bu, R3 = H 4i 52
Acknowledgment
We thank the University of Florida, The Kenan Foundation and
King Abdulaziz University, Jeddah, Saudi Arabia for financial sup-
port. We thank Dr. C. D. Hall for helpful discussions.
N
N
N
R2
O
N
N
Supporting Information for this article is available online at
N
O
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
R1
Pd(0)
R1
O
1
4
References
(1) Nakano, K.; Kodama, S.; Permana, Y.; Nozaki, K. Chem.
Commun. 2009, 6970.
(2) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev.
1999, 99, 779.
(3) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. Rev. 2004, 104, 3453.
(4) Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.; Javan, M. J.;
Farimani, M. M.; Seirafi, M. Heteroat. Chem. 2009, 20, 157.
(5) Akiyama, Y.; Fukuhara, T.; Hara, S. Synlett 2003, 1530.
(6) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
(7) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J.;
Jackson, W. R.; Gountzos, H.; Matthews, B. R. J. Chem.
Soc., Chem. Commun. 1990, 1018.
O
R1
6'
Pd(II)Ln
O
R2
O
R1
Pd(II)BtLn
6
N
N
N
7
O
R2
(8) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986.
3
(9) Chung, J. Y. L.; Cvetovich, R.; Amato, J.; McWilliams, J.
C.; Reamer, R.; DiMichele, L. J. Org. Chem. 2005, 70, 3592.
(10) Singh, A. K.; Rao, M. N.; Simpson, J. H.; Li, W.-S.;
Thornton, J. E.; Kuehner, D. E.; Kacsur, D. J. Org. Process
Res. Dev. 2002, 6, 618.
(11) Träff, A.; Bogár, K.; Warner, M.; Bäckvall, J.-E. Org. Lett.
2008, 10, 4807.
(12) Gros, P.; Perchec, P. L.; Senet, J. P. J. Org. Chem. 1994, 59,
4925.
(13) Azizi, N.; Mirmashhori, B.; Saidi, M. R. Catal. Commun.
2007, 8, 2198.
(14) Bentley, P. A.; Mei, Y.; Du, J. Tetrahedron Lett. 2008, 49,
1425.
Scheme 3 Possible mechanism
O
O
R2
X
R1
O
R2
O
3-MeO-pyridine
+
+
R1
X
O
X
R1
O
R2
Scheme 4 Acid halides and epoxides in halohydrin ester synthesis1
Synlett 2012, 23, 1384–1388
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Regiospecific Pseudohalohydrin Esters
1387
(15) Das, B.; Venkateswarlu, K.; Krishnaiah, M. Helv. Chim.
Acta 2007, 90, 149.
29.0, 15.2. HRMS: m/z calcd for C23H22N3O2 [M + H]+:
372.1707; found: 372.1703.
(16) Constantino, M. G.; Júnior, V. L.; Invernize, P. R.; da Silva
Filho, L. C.; da Silva, G. V. J. Synth. Commun. 2007, 37,
3529.
(17) Shibata, I.; Baba, A.; Matsuda, H. Tetrahedron Lett. 1986,
27, 3021.
(18) Oriyama, T.; Ishiwata, A.; Hori, Y.; Yatabe, T.; Hasumi, N.;
Koga, G. Synlett 1995, 1004.
(19) Stamatov, S. D.; Stawinski, J. Tetrahedron Lett. 2006, 47,
2543.
(20) Villorbina, G.; Tomàs, A.; Escribà, M.; Oromí-Farrús, M.;
Eras, J.; Balcells, M.; Canela, R. Tetrahedron Lett. 2009, 50,
2828.
(21) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 1656.
(22) (a) El Khatib, M.; Jauregui, L.; Tala, S.; Khelashvili, L.;
Katritzky, A. R. Med. Chem. Commun. 2011, 2, 1087.
(b) Katritzky, A. R.; Jishkariani, D.; Narindoshvili, T. Chem.
Biol. Drug Des. 2009, 73, 618. (c) Katritzky, A. R.; El
Khatib, M.; Bol’shakov, O.; Khelashvili, L.; Steel, P. J.
J. Org. Chem. 2010, 75, 6532.
(23) Katritzky, A. R.; Jiang, R.; Suzuki, K. J. Org. Chem. 2005,
70, 4993.
(24) Obase, H.; Tatsuno, H.; Goto, K.; Shigenobu, K.; Kasuya,
Y.; Yamada, Y.; Fujii, K.; Yada, S. Chem. Pharm. Bull.
1978, 26, 1143.
(38) 2-(1H-Benzotriazol-1-yl)-1,2-diphenylethyl
4-Ethylbenzoate (4b)
Purified by gradient silica gel column chromatography
(hexanes to hexanes–CH2Cl2 = 3:2, then hexanes–CH2Cl2 =
1:1) to obtain beige microcrystals (62%); mp 109.0–
110.0 °C. 1H NMR (300 MHz, CDCl3): δ = 8.09 (dd, J = 8.3,
1.4 Hz, 1 H), 7.68–7.60 (m, 2 H), 7.54–7.47 (m, 1 H), 7.45–
7.30 (m, 6 H), 7.27–7.20 (m, 6 H), 7.14–7.11 (m, 2 H), 6.34
(dd, J = 9.2, 1.4 Hz, 1 H), 2.82–2.73 (m, 1 H), 2.65 (q, J =
7.5 Hz, 2 H), 1.35–1.28 (m, 2 H), 1.22 (td, J = 7.8, 2.1 Hz, 3
H). 13C NMR (75 MHz, CDCl3): δ = 165.0, 149.9, 136.8,
134.6, 133.3, 130.2, 129.6, 128.8, 128.7, 128.7, 128.6,
128.5, 128.4, 128.2, 128.0, 127.7, 127.3, 127.2, 126.8,
125.9, 123.9, 120.1, 109.6, 76.8, 67.4, 28.8, 15.1. HRMS:
m/z calcd for C29H26N3O2 [M + H]+: 448.2020; found:
448.2022.
(39) 1-{1H-Benzo[d][1,2,3]triazol-1-yl}hexan-2-yl
3-Phenylpropanoate (4c)
Purified by gradient silica gel column chromatography
(hexanes to hexanes–EtOAc = 4:1) to obtain a yellow oil
(72%). 1H NMR (300 MHz, CDCl3): δ = 8.05–8.01 (m, 1 H),
7.49–7.42 (m, 2 H), 7.36–7.31 (m, 1 H), 7.29–7.07 (m, 5 H),
5.28–5.21 (m, 1 H), 4.74 (dd, J = 14.6, 4.8 Hz, 1 H), 4.69 (dd,
J = 14.5, 6.1 Hz, 1 H), 2.97–2.40 (m, 4 H), 1.59–1.52 (m, 2
H), 1.30–1.19 (m, 4 H), 0.83 (t, J = 7.0 Hz, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 172.4, 145.9, 140.27, 133.7, 128.6,
128.4, 127.7, 126.5, 124.2, 120.2, 109.7, 72.5, 50.9, 35.9,
31.5, 30.9, 27.3, 22.6, 14.1.
(25) Hayes, B. L. In Microwave Synthesis: Chemistry at the
Speed of Light; CEM Publishing: Matthews (NC, USA),
2002.
(26) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
(27) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(40) 2-{1H-Benzo[d][1,2,3]triazol-1-yl}-1-phenylethyl
1-Naphthoate (4d)
(28) Varma, R. S. Green Chem. 1999, 1, 43.
(29) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
(30) Pchelka, B. K.; Loupy, A.; Petit, A. Tetrahedron 2006, 62,
10968.
(31) Katritzky, A. R.; Cai, C.; Singh, S. K. J. Org. Chem. 2006,
71, 3375.
(32) Katritzky, A. R.; Ji, F.-B.; Fan, W.-Q.; Gallos, J. K.;
Greenhill, J. V.; King, R. W.; Steel, P. J. J. Org. Chem. 1992,
57, 190.
(33) Nakamura, I.; Nemoto, T.; Shiraiwa, N.; Terada, M. Org.
Lett. 2009, 11, 1055.
Purified by gradient silica gel column chromatography
(hexanes to hexanes–EtOAc = 9.3:0.7) to obtain a white
solid (62%); mp 62.0–63.0 °C. 1H NMR (300 MHz, CDCl3):
δ = 8.60–8.56 (m, 1 H), 8.09–7.97 (m, 3 H), 7.85–7.79 (m, 1
H), 7.50–7.26 (m, 11 H), 6.58 (dd, J = 7.5, 4.7 Hz, 1 H), 5.19
(dd, J = 14.6, 7.5 Hz, 1 H), 5.11 (dd, J = 14.6, 4.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 166.1, 146.0, 136.9, 134.0,
133.9, 133.6, 131.4, 130.6, 129.2, 128.7, 128.1, 127.7,
126.6, 126.5, 125.7, 124.6, 124.1, 120.3, 109.5, 74.7, 53.1.
Anal. Calcd for C25H19N3O2: C, 76.32; H, 4.87; N, 10.68.
Found: C, 75.97; H, 5.31; N, 10.45.
(34) Katritzky, A. R.; Heck, K. A.; Li, J.; Wells, A.; Garot, C.
Synth. Commun. 1996, 26, 2657.
(41) 1-{1H-Benzo[d][1,2,3]triazol-1-yl}hexan-2-yl
1-Naphthoate (4e)
(35) Zhou, Y.-G.; Yang, P.-Y.; Han, X.-W. J. Org. Chem. 2005,
70, 1679.
Purified by gradient silica gel column chromatography
(hexanes to EtOAc–hexanes = 9.3:0.7) to obtain a yellow oil
(73%). 1H NMR (300 MHz, CDCl3): δ = 8.64–8.59 (m, 1 H),
8.02–7.89 (m, 3 H), 7.79–7.75 (m, 1 H), 7.51–7.17 (m, 6 H),
5.61–5.53 (m, 1 H), 4.88 (d, J = 5.3 Hz, 2 H), 1.78–1.70 (m,
2 H), 1.51–1.22 (m, 4 H), 0.81 (t, J = 7.2 Hz, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 166.8, 146.1, 133.9, 133.7, 131.5,
130.5, 128.7, 128.0, 127.6, 126.5, 126.4, 125.7, 124.6,
124.1, 120.2, 109.9, 72.8, 51.0, 31.7, 27.6, 22.6, 14.1. Anal.
Calcd for C69H73N9O8: C, 71.67; H, 6.36; N, 10.90. Found:
C, 71.53; H, 6.38; N, 10.93.
(36) General Procedure for the Preparation of β-
(Benzotriazol-1-yl)ethyl Esters 4 and Alcohol 5a
To a mixture of the N-acylbenzotriazole 1 (0.20 mmol) and
Pd(PPh3)4 (23.11 mg, 10 mol%) in a microwave tube was
added epoxide 3 (1.5 equiv). The mixture was stirred at
130 °C and 50 W for 30 min (N-aroylbenzotriazoles) to 60
min (N-alkylbenzotriazoles). The residue was dissolved in
MeOH and purified by silica gel column chromatography to
obtain the corresponding hydrin esters 4.
(37) 2-(1H-Benzotriazol-1-yl)-1-phenylethyl 4-ethylbenzoate
(4a)
(42) 2-{1H-Benzo[d][1,2,3]triazol-1-yl}-1-phenylethyl
4-Nitrobenzoate (4f)
Purified by gradient silica gel column chromatography
(hexanes to hexanes–EtOAc = 7:3) to obtain a yellow oil,
(87%). 1H NMR (300 MHz, CDCl3): δ = 7.83 (d, J = 8.1 Hz,
1 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.27–7.14 (m, 10 H), 7.06–
7.01 (m, 1 H), 6.29–6.25 (m, 1 H), 5.00–4.86 (m, 2 H), 2.48
(q, J = 7.4 Hz, 2 H), 1.03 (t, J = 7.5 Hz, 3 H). 13C NMR (75
MHz, CDCl3): δ = 165.3, 150.3, 136.7, 133.4, 129.9, 128.9,
128.0, 127.4, 126.3, 125.7, 123.9, 120.0, 109.3, 74.3, 52.8,
Purified by gradient silica gel column chromatography
(hexanes to hexanes–EtOAc = 9:1) to obtain a yellow oil
(70%). 1H NMR (300 MHz, CDCl3): δ = 8.31–8.11 (m, 7 H),
7.52–7.34 (m, 5 H), 6.44 (dd, J = 8.4, 3.6 Hz, 1 H), 4.82 (dd,
J = 12.0, 8.4 Hz, 1 H), 4.71(dd, J =12.2, 3.8 Hz, 1 H). 13
C
NMR (75 MHz, CDCl3): δ = 164.5, 164.0, 151.0, 135.6,
135.2, 135.1, 131.1, 131.0, 129.5, 129.3, 126.9, 123.9, 75.1,
67.3.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1384–1388

1388
M. El Khatib et al.
LETTER
(43) 2-(1H-Benzotriazol-1-yl)-1-phenylethyl Benzoate (4g)
Purified by gradient silica gel column chromatography
(hexanes to hexanes–EtOAc = 9:1) to obtain a yellow oil
(75%). 1H NMR (300 MHz, CDCl3): δ = 8.02–7.93 (m, 3 H),
7.55–7.27 (m, 11 H), 6.46 (dd, J = 7.5, 4.8 Hz, 1 H), 5.15 (dd,
J = 14.5, 7.3 Hz, 1 H), 5.07 (dd, J = 14.5, 4.8, 1 H). 13C NMR
(75 MHz, CDCl3): δ = 165.4, 145.9, 136.8, 133.6, 129.9,
129.5, 129.2, 129.1, 128.6, 127.6, 126.5, 124.1, 120.2,
109.4, 74.7, 52.9. HRMS: m/z calcd for C21H18N3O2 [M +
H]+: 344.1394; found: 344.1384.
(hexanes to hexanes–EtOAc = 9.3:0.7) to obtain a yellow oil
(52%). 1H NMR (300 MHz, CDCl3): δ = 8.00–7.97 (m, 1 H),
7.56 (d, J = 8.4 Hz, 1 H), 7.47–7.41 (m, 1 H), 7.33–7.28 (m,
1 H), 5.27–5.19 (m, 1 H), 4.72–4.69 (m, 2 H), 2.05–1.88 (m,
3 H), 1.84–1.80 (m, 2 H), 1.63–1.55 (m, 8 H), 1.49–1.46 (m,
2 H), 1.37–1.18 (m, 8 H), 0.82 (t, J = 7.0 Hz, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 171.3, 146.0, 133.8, 127.7, 124.1,
120.2, 109.9, 71.9, 50.9, 49.0, 42.5, 42.4, 36.9, 36.8, 32.9,
31.7, 28.8, 28.7, 27.5, 22.6, 14.1. HRMS: m/z calcd for
C24H33N3O2Na [M + Na]+: 418.2465; found: 418.2480.
(46) Tsuji, J. Palladium Reagents and Catalysts: New
Perspectives for the 21st Century; John Wiley and Sons:
New York, 2005.
(44) 1-{1H-Benzo[d][1,2,3]triazol-1-yl}hexan-2-yl Benzoate
(4h)
Purified by gradient silica gel column chromatography
(hexanes to hexanes–EtOAc = 9:1) to obtain a yellow oil
(76%). 1H NMR (300 MHz, CDCl3): δ = 8.03–8.00 (m, 1 H),
7.91–7.88 (m, 2 H), 7.55–7.49 (m, 2 H), 7.40–7.28 (m, 4 H),
5.55–5.48 (m, 1 H), 4.90 (d, J = 5.2 Hz, 2 H), 1.76–1.67 (m,
2 H), 1.47–1.26 (m, 4 H), 0.85 (t, J = 7.2 Hz, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 166.1, 146.1, 133.7, 133.5, 129.9,
129.7, 128.6, 127.6, 124.1, 120.2, 109.9, 72.9, 50.9, 31.5,
27.5, 22.6, 14.0. HRMS: m/z calcd for C19H22N3O2 [M + H]+:
324.1707; found: 324.1719.
(47) 1-(1H-Benzotriazol-1-yl)hexan-2-ol (5a)
Purified by gradient silica gel column chromatography
(hexanes to EtOAc–hexanes = 4:1) to obtain a yellow oil48
(70%); 1H NMR (300 MHz, CDCl3): δ = 7.96 (dd, J = 8.4,
0.9 Hz, 1 H), 7.60 (dd, J = 8.7, 0.9 Hz, 1 H), 7.50–7.45 (m,
1 H), 7.36–7.30 (m, 1 H), 4.71–4.64 (m, 2 H), 4.56–4.49 (m,
1 H), 4.25 (br s, 1 H), 1.65–1.34 (m, 6 H), 0.92 (t, J = 7.5 Hz,
3 H). 13C NMR (75 MHz, CDCl3): δ = 145.5, 133.8, 128.5,
127.4, 124.0, 119.7, 109.9, 71.0, 54.0, 34.3, 27.6, 22.6, 14.0.
HRMS: m/z calcd for C12H17N3ONa [M + Na]+: 242.1264;
found: 242.1266.
(45) 1-{1H-Benzo[d][1,2,3]triazol-1-yl}hexan-2-yl
2-[(3R,5R,7R)-Adamantan-1-yl]acetate (4i)
Purified by gradient silica gel column chromatography
(48) Li, Z.; Zhang, Y. J. Chem. Res., Synop. 2001, 522.
Synlett 2012, 23, 1384–1388
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