Synthesis of 1-(1H-tetrazol-5-yl)-2H-isoindole derivatives through Ugi four-component and silver-catalyzed reactions

Article abstract of DOI:10.1002/ejoc.201402098

A facile and efficient one-pot, two-step synthesis of 1,2-disubstituted 3-(1H-tetrazol-5-yl)-2H-isoindoles through Ugi four-component reaction/AgNO ₃-catalyzed reaction of 2-alkynylbenzaldehydes, amines, isonitriles, and Me₃SiN₃ is described. This transformation proceeds through 5-exo-dig cyclization, [1,3]-H shift, and [1,5]-H shift to generate the products in moderate to excellent yields. Copyright

Full text of DOI:10.1002/ejoc.201402098

Job/Unit: O42098
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Date: 14-04-14 11:22:28
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201402098
Synthesis of 1-(1H-Tetrazol-5-yl)-2H-isoindole Derivatives through Ugi Four-
Component and Silver-Catalyzed Reactions
Ran Wu,[a] Shang Gao,[a] Xu Chen,[a] Guanghui Yang,[a] Lingling Pan,[a] Gaobo Hu,[a]
Ping Jia,[a] Weihui Zhong,[a] and Chuanming Yu*[a]
Keywords: Multicomponent reactions / Cyclization / Nitrogen heterocycles / Alkynes / Silver
A facile and efficient one-pot, two-step synthesis of 1,2-di-
scribed. This transformation proceeds through 5-exo-dig cy-
substituted 3-(1H-tetrazol-5-yl)-2H-isoindoles through Ugi clization, [1,3]-H shift, and [1,5]-H shift to generate the prod-
four-component reaction/AgNO3-catalyzed reaction of 2-alk-
ynylbenzaldehydes, amines, isonitriles, and Me3SiN3 is de-
ucts in moderate to excellent yields.
Introduction
the synthesis of various isoindole moieties.[9] For example,
Suginome and co-workers used a Pd-catalyzed reaction of
isoindolines to prepare 1-borylisoindoles.[10] Stevens et al.
have synthesized 1-cyanoisoindoles[9d] and phosphorylated
isoindoles.[11] Wu et al.[12] reported the synthesis of 2H-iso-
indol-1-ylphosphonates, some of which displayed promising
activity as HCT-116 (human colon cancer cells) inhibitors.
Li and co-workers[13] reported the synthesis of 1-carbox-
amidoisoindoles from ortho-phthalaldehydes. Tetrazoles
have been developed as important nitrogen-rich hetero-
cycles that exhibit interesting biological properties[14] such
as anti-inflammatory,[15] antihypertensive,[16] antibacterial,
and antiallergy activities.[17] The attractive properties of this
latter group has prompted its rapid development, and has
led to the construction of a class of antihypertension drugs
of angiotensin II receptor blockers – sartans.
Recently, 2-alkynylbenzaldehydes have been used as im-
portant building blocks to synthesize various cyclic com-
pounds, such as 1H-isochromenes, benzofurans, naphthal-
enes, isoquinolines, quinolones, indoles, and isoindoles.[18]
To the best of our knowledge, there have been no reports
on the synthesis of 1-(1H-tetrazol-5-yl)-2H-isoindole deriv-
atives. Herein, we consider the possibility of exploiting a
MCR/silver-catalyzed strategy to synthesize 1-(1H-tetrazol-
5-yl)-2H-isoindole derivatives from 2-alkynylbenzaldehydes.
We hypothesized that in the presence of a suitable silver
catalyst, compound 5, formed by Ugi four-component reac-
tion (Ugi-4CR) (for example 5a, see Exp. Sect.), might serve
as a nucleophile when a triple bond is available in the mo-
lecule to give 1-(1H-tetrazol-5-yl)-2H-isoindole 6 through
Rapid advances in medicinal chemistry continue to high-
light the need for practical and efficient routes to generate
drug-like compounds.[1] Due to their high degree of atom
economy, convergence and productivity, isocyanide-based
multicomponent reactions (IMCRs) have been shown to be
a promising approach through which to efficiently generate
drug-like nitrogen heterocycles in medicinal chemistry.[2]
For many years, there has been growing interest in combi-
nations of IMCRs such as Ugi reaction,[2a] Passerini reac-
tion,[3] and Van Leusen reaction[4] with subsequent second-
ary transformations to increase scaffold and molecular
complexity.[5] Recently, silver-catalyzed reactions have
gained considerable attention owing to their ability to acti-
vate various π-systems such as alkenes, alkynes, and allenes
under mild conditions with low-catalyst loading.[1b,1d,6] Es-
pecially, the silver-catalyzed intramolecular addition of ni-
trogen nucleophiles to alkynes giving rise to a variety of N-
heterocycles, has recently emerged as an important syn-
thetic method for many organic transformations.[5f,7]
Among heterocycles, isoindoles are interesting skeletons
because of their fluorescent properties and potential medici-
nal value.[8] Therefore, continuous efforts have focused on
[a] Synergetic Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, Key Laboratory for Green
Pharmaceutical Technologies and Related Equipment of
Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology,
Hangzhou 310014, P. R. China
E-mail: ycm@zjut.edu.cn
5-exo-dig cyclization and/or 1,2-dihydroisoquinoline
7
http://www.zjut.edu.cn/
through 6-endo-dig cyclization. The proposed synthetic
route is presented in Scheme 1.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402098.
Eur. J. Org. Chem. 0000, 0–0
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FULL PAPER
Scheme 1. The proposed Ugi-4CR/silver-catalyzed reaction.
lyst was decreased, the yield of 6a was reduced (Table 1,
entry 8). Thus, the optimized conditions were identified
(Table 1, entry 7).
With this promising result in hand, we started to investi-
gate the scope of this reaction under the optimized condi-
tions [MeOH, room temp., AgNO3 (10 mol-%), MeCN,
80 °C]. The results are summarized in Table 2. We found
that these conditions were effective for the four-component
reactions. For most cases, 2-alkynylbenzaldehyde 1 reacted
Results and Discussion
To examine the hypothesis, 2-alkynylbenzaldehyde 1a, p-
toluidine (2a), (2-isocyanoethyl)benzene (3a), and trimeth-
ylsilyl azide (TMSN3; 4) were chosen as substrates
(Table 1). We investigated the effects of various parameters
in the second step to optimize the reaction conditions. At
the outset, catalysts such as AgOTf (Tf = triflate), PdCl2,
AgOAc, and AgNO3 were employed in the reaction
(Table 1, entries 1–6). To our delight, only the 5-exo-dig cy-
clization product 1-(1H-tetrazol-5-yl)-2H-isoindole 6a was
obtained. When 10 mol-% AgNO3 was employed, com-
pound 6a was obtained in 77% yield (Table 1, entry 6). We
further explored the reaction in various solvents, such as
MeCN (Table 1, entries 7, 8, and 15), H2O (entry 9), MeOH
(entries 10 and 11), EtOH (entries 12 and 13), and iPrOH
(entry 14). Among them, acetonitrile was demonstrated as
the best choice (Table 1, entry 7). When the amount of cata-
Table 2. Synthesis of 1,2-disubstituted 3-(1H-tetrazol-5-yl)-2H-iso-
indoles 6 through Ugi-4CR/AgNO3-catalyzed reaction of 2-alk-
ynylbenzaldehyde 1, amine 2, isonitrile 3, and TMSN3 4.
Table 1. Optimization of reaction conditions.[a]
Entry R1
R2
R3
Yield
[%][a]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-EtOC6H4
Ph
Bn
4-BrC6H4
4-MeOC6H4 C6H5(CH2)2
4-MeOC6H4 C6H5(CH2)2
4-MeC6H4
4-EtOC6H4
1-cyclohexyl C6H5(CH2)2
4-BrC6H4 C6H5(CH2)2
4-MeOC6H4 1-cyclohexyl
C6H5(CH2)2
1-cyclohexyl
tBu
C6H5(CH2)2
C6H5(CH2)2
C6H5(CH2)2
C6H5(CH2)2
89 (6a)
93 (6b)
61 (6c)
47 (6d)
56 (6e)
54 (6f)
80 (6g)
50 (6h)
82 (6i)
77 (6j)
50 (6k)
70 (6l)
52 (6m)
52 (6n)
69 (6o)
40 (6p)
60 (6q)
50 (6r)
53 (6s)
44 (6t)
69 (6u)
52 (6v)
47 (6w)
56 (6x)
67 (6y)
70 (6z)
(R1 = H)
Entry Cat. [mol-%] Solvent
A
Solvent
B
T
[°C]
t
Yield
[h][b] [%][c]
1
2
3
4
5
6
7
8
AgOTf (10)
AgOTf (10)
AgOTf (20)
PdCl2 (10)
AgOAc(10)
AgNO3 (10) MeOH
AgNO3 (10) MeOH
AgNO3 (5)
AgNO3 (10) MeOH
AgNO3 (5) MeOH
AgNO3 (10) MeOH
AgNO3 (5) EtOH
AgNO3 (10) EtOH
AgNO3 (10) iPrOH
AgNO3 (10) MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
toluene
toluene
MeCN
MeCN
toluene
MeCN
MeCN
H2O
MeOH
MeOH
EtOH
EtOH
iPrOH
MeCN
80
110
110
80
80
80
80
80
85
60
60
60
60
80
80
12
12
12
36
36
2
2
2
2
5.5
2
25
25
30
20
9
77
89
56
trace
73
46
68
60
37
34
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
C6H5(CH2)2
C6H5(CH2)2
4-ClC6H4
C6H5(CH2)2
C6H5(CH2)2
MeOH
1-cyclopropyl 4-MeC6H4
9
1-cyclopropyl 1-cyclohexyl C6H5(CH2)2
1-cyclopropyl Ph C6H5(CH2)2
1-cyclopropyl 4-MeOC6H4 C6H5(CH2)2
10
11
12
13
14
15
4
6
12
3
1-cyclopropyl 4-FC6H4
C6H5(CH2)2
C6H5(CH2)2
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Me3Si
Ph
4-MeOC6H4 C6H5(CH2)2
4-MeOC6H4 Bn
1-cyclohexyl C6H5(CH2)2
4-BrC6H4
4-ClC6H4
[a] Reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (1.0 equiv.),
3a (1.2 equiv.), 4 (1.2 equiv.), solvent A (2 mL), room temperature.
After completion of the reaction as indicated by TLC, catalyst was
added and the mixture was heated in solvent B. [b] Reaction time
for the second step. [c] Isolated yield based on 1a.
C6H5(CH2)2
C6H5(CH2)2
[a] Isolated yield based on 2-alkynylbenzaldehyde 1.
2
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Synthesis of 1-(1H-Tetrazol-5-yl)-2H-isoindole Derivatives
Scheme 2. Plausible reaction mechanism.
with amines 2, isoindoles 3 and TMSN3 4 to generate target halogen groups (Br, Cl) provide the possibility for further
compounds 6 in 40–93% yields.
functionalization through cross-coupling reactions.
It was found that when R1 was an aryl group (Table 2,
As shown in Table 2, the desired isoindole compounds
entries 1–15) the reactions showed better reactivity and gave were obtained in moderate to excellent yields by using com-
higher yields than aliphatic groups (Table 2, entries 16–25). mercially available isonitriles, such as tert-butyl isocyanide,
We reasoned that the aryl group attached to the triple bond cyclohexyl isocyanide, benzyl isocyanide, and (2-isocyano-
might facilitate its [1,5]-H shift after 5-exo-dig cyclization ethyl)benzene. Even with the hindered tert-butyl isocyanide,
in the reaction process.[12b] Moreover, the reaction condi- the reaction proceeded smoothly to give the corresponding
tions were proved to be useful for anilines (Table 2, en- product 6c in 61% yield (Table 2, entry 3). 2-[(Trimethyl-
tries 1–5, 7–11, 13–16, 18–23, 25, and 26) and aliphatic silyl)ethynyl]benzaldehyde reacted smoothly under the stan-
amines (Table 2, entries 6, 12, 17, and 24). Both electron- dard experimental conditions and an unexpected product
rich (Table 2, entries 1–6, 8–11, 14, 16, 18, 19, and 21–23) 6z was generated in 70% yield, because trimethylsilyl is an
and electron-poor anilines (Table 2, entries 7, 13, 15, 20, 25, easy leaving group (Table 2, entry 26). The structure of iso-
and 26) were suitable partners in the process. Different indole 6b was further determined by X-ray crystallographic
functional groups such as methyl, methoxyl, ethoxyl, and analysis (see Figure 1).
halogen groups such as Br (Table 2, entries 7, 13, 25), Cl
Based on the results described above, a plausible reaction
(Table 2, entries 15, 26), and F (Table 2, entry 20), were mechanism is depicted in Scheme 2. At first, 2-alkynylbenz-
well-tolerated under the reaction conditions. Some of these aldehydes, amines, isonitriles, and TMS-azides react to pro-
duce compound 5 through Ugi-4CR, then the triple bond
of compound 5 coordinates to the silver nitrate, and the
nitrogen atom attacks the triple bond through 5-exo-dig cy-
clization to afford ammonium b. Finally aromatization oc-
curs by a [1,3]-H shift and a [1,5]-H shift to afford the more
stable compound 6 (Scheme 2).
Conclusions
We have developed a facile and efficient route for the
synthesis of diverse 1,2-disubstituted 3-(1H-tetrazol-5-yl)-
2H-isoindoles through Ugi-4CR/AgNO3-catalyzed reaction
of 2-alkynylbenzaldehydes with amines, isonitriles, and
TMSN3. The reaction proceeds with high efficiency through
Ugi-4CR, 5-exo-dig cyclization, [1,3]-H shift and [1,5]-H
shift. The products could be isolated in moderate to excel-
lent yields. Work is ongoing to investigate the further syn-
thetic applications and biological properties of the new
compounds.
Experimental Section
General Information: All reagents were obtained from commercial
Figure 1. X-ray crystallographic analysis of compound 6b.
sources (purity Ͼ 99%) and used without further purification, un-
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C. Yu et al.
FULL PAPER
less otherwise indicated. Reactions were stirred with Teflon-coated
magnetic stir bars. Elevated temperatures were maintained by using
thermostat-controlled silicone oil baths. Organic solutions were
concentrated using a rotary evaporator with a desktop vacuum
pump. Thin-layer chromatography (TLC) was performed on silica
gel G plates and visualized by UV light (254 nm). The products
were isolated by column chromatography on silica gel (200–
300 mesh) using petroleum ether (60–90 °C) and ethyl acetate as
eluent. All yields described are isolated yields after column
chromatography.
m.p. 168.5–170.5 °C; Rf 0.65 (petroleum ether/ethyl acetate, 75:25
v/v). 1H NMR (400 MHz, CDCl3): δ = 7.57 (dd, J = 8, 4 Hz, 1 H),
7.20–7.10 (m, 11 H), 6.89–6.86 (m, 4 H), 6.65 (d, J = 8 Hz, 2 H),
4.33 (t, J = 8 Hz, 2 H), 4.23 (s, 2 H), 3.06 (t, J = 8 Hz, 2 H), 2.33
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.2, 138.8,
138.7, 136.2, 134.0, 129.5 (2ϫC), 128.5 (2ϫC), 128.4 (2ϫC), 128.3
(2ϫC), 128.1 (2ϫC), 127.9, 127.2 (2ϫC), 126.8, 126.1, 126.0, 124.5,
123.2, 121.6, 120.0, 117.7, 103.4, 49.1, 35.4, 31.2, 21.3 ppm. IR
(KBr): ν = 1628, 1572, 1515, 1454, 1385, 1372, 1088 cm–1. MS
˜
(ESI): m/z (%) = 470.2 (100) [M + H]+. HRMS (ESI): m/z calcd.
for C31H28N5 [M + H]+ 470.2339; found 470.2336.
Melting points are reported uncorrected. NMR spectra were re-
corded in CDCl3, unless otherwise indicated, at ambient tempera-
ture, operating at 400 MHz for 1H and 100 MHz for 13C. Data
1-Benzyl-3-(1-cyclohexyl-1H-tetrazol-5-yl)-2-(p-tolyl)-2H-isoindole
(6b): The product was obtained as a white solid (208 mg, 93%);
m.p. 127.4–127.8 °C; Rf 0.57 (petroleum ether/ethyl acetate, 80:20
1
for H NMR spectra are reported as follows: chemical shift (ppm,
1
referenced to TMS; s = singlet, d = doublet, t = triplet, q = quartet,
dd = doublet of doublets, dt = doublet of triplets, m = multiplet),
coupling constant [Hz], and integration. Data for 13C NMR spectra
are reported as chemical shift (ppm) relative to residual solvent
peak (CDCl3: 77.2 ppm). IR absorption spectra were recorded as
a film on KBr. Mass spectra were measured with a Finnigan Trace
DSQ instrument or GCT Premier mass spectrometer. High-resolu-
tion mass spectra (HRMS) were recorded with a Bruker Apex III
mass spectrometer (ESI) with an FT-ICR analyzer.
v/v). H NMR (400 MHz, CDCl3): δ = 7.57 (dt, J = 8.4, 1 Hz, 1
H), 7.33 (dt, J = 8.4, 1 Hz, 1 H), 7.18–7.02 (m, 7 H), 6.92 (m, 4
H), 4.27 (s, 2 H), 2.34 (s, 3 H), 1.90–1.76 (m, 4 H), 1.62 (d, J =
12.4 Hz, 1 H), 1.48 (d, J = 12.4 Hz, 2 H), 1.26–1.11 (m, 4 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 147.3, 139.2, 138.9, 134.5, 129.7
(2ϫC), 128.5 (2ϫC), 128.2 (2ϫC), 127.7, 127.5 (2ϫC), 126.7,
126.4, 124.5, 123.4, 121.8, 120.0, 117.9, 104.1, 58.2, 33.2 (2ϫC),
31.5, 25.5 (2ϫC), 25.0, 21.4 ppm. IR (KBr): ν = 2934, 2858, 1632,
˜
1566, 1494, 1453, 1383, 1367, 1339, 1155, 1050 cm–1. MS (ESI):
m/z (%) = 470.1 (100) [M + Na]+. HRMS (ESI): m/z calcd. for
C29H29N5Na [M + Na]+ 470.2315; found 470.2308.
4-Methyl-N-{(1-phenethyl-1H-tetrazol-5-yl)[2-(phenylethynyl)-
phenyl]methyl}aniline (5a). Typical Procedure: To a round-bot-
tomed single-necked flask (10 mL) equipped with a magnetic stir-
ring bar, was added 2-(phenylethynyl)benzaldehyde (1a; 0.5 mmol,
103 mg), p-toluidine (2a; 0.5 mmol, 54 mg, 1.0 equiv.), and MeOH
(2 mL). The reaction was stirred for 30 min at room temperature,
then (2-isocyanoethyl)benzene (0.6 mmol, 79 mg, 1.2 equiv.) and
azidotrimethylsilane (0.6 mmol, 69 mg, 1.2 equiv.) were added. Af-
ter completion of the reaction as indicated by TLC, the solvent was
removed under reduced pressure and the residue was purified by
column chromatograph on silica gel (ethyl acetate/petroleum ether,
1:4 v/v) to give the desired product 5a (202 mg, 86%) as a light-
yellow liquid. Rf 0.45 (petroleum ether/ethyl acetate, 80:20 v/v). 1H
NMR (400 MHz, CDCl3): δ = 7.58–7.54 (m, 1 H), 7.35–7.20 (m, 8
H), 7.14–7.07 (m, 3 H), 6.93–6.90 (m, 4 H), 6.56 (d, J = 8 Hz, 2
H), 6.25 (s, 1 H, C-H), 4.85 (s, 1 H, N-H), 4.55–4.43 (m, 2 H),
3.11–3.03 (m, 1 H), 2.89–2.82 (m, 1 H), 2.19 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.4, 143.4, 139.2, 136.0, 132.6,
131.4 (2ϫC), 129.7 (2ϫC), 129.4, 128.8, 128.6 (2ϫC), 128.4 (5ϫC),
128.1, 127.5, 126.9, 122.3, 122.1, 114.1 (2ϫC), 95.8, 86.7, 51.6,
1-Benzyl-3-[1-(tert-butyl)-1H-tetrazol-5-yl]-2-(p-tolyl)-2H-isoindole
(6c): The product was obtained as a white solid (128 mg, 61%);
m.p. 154.5–154.7 °C; Rf 0.50 (petroleum ether/ethyl acetate, 80:20
v/v). 1H NMR (400 MHz, CDCl3): δ = 7.53 (dt, J = 8, 1 Hz, 1 H),
7.18–7.10 (m, 4 H), 7.07–6.96 (m, 6 H), 6.91 (dd, J = 7.2, 1.6 Hz,
2 H), 4.34 (d, J = 16.8 Hz, 1 H), 4.17 (d, J = 16.8 Hz, 1 H), 2.30
(s, 3 H), 1.34 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
146.4, 139.4, 139.0, 134.2, 129.5 (3ϫC), 128.4 (3ϫC), 128.1 (2ϫC),
126.8, 126.3, 126.1, 123.9, 123.2, 121.5, 119.9, 118.3, 104.7, 62.2,
31.4, 30.2 (3ϫC), 21.3 ppm. IR (KBr): ν = 2986, 2931, 1627, 1602,
˜
1585, 1558, 1514, 1495, 1454, 1395, 1371, 1354, 1336, 1279, 1240,
1176, 1118, 1087, 1031 cm–1. MS (ESI): m/z (%) = 444.1 (100) [M
+ Na]+. HRMS (ESI): m/z calcd. for C27H28N5 [M + H]+ 422.2339;
found 422.2340.
1-Benzyl-2-(4-ethoxyphenyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-2H-
isoindole (6d): The product was obtained as a white solid (117 mg,
47%); m.p. 131.0–133.0 °C; Rf 0.67 (petroleum ether/ethyl acetate,
75:25 v/v). 1H NMR (400 MHz, CDCl3): δ = 7.57 (dt, J = 8.4,
1 Hz, 1 H), 7.21–7.09 (m, 8 H), 7.06–7.02 (m, 1 H), 6.88–6.85 (m,
8 H), 6.69–6.63 (m, 4 H), 4.34 (t, J = 7.2 Hz, 2 H), 4.22 (s, 3 H),
3.97 (q, J = 6.8 Hz, 2 H), 3.07 (t, J = 7.2 Hz, 2 H), 1.41 (t, J =
6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.1, 148.5,
139.0, 136.5, 129.3, 128.8 (5ϫC), 128.6 (2ϫC), 128.5 (2ϫC), 128.2
(2ϫC), 127.0, 126.4, 126.2, 124.6, 123.3, 121.8, 120.2, 117.9, 114.7
48.8, 35.8, 20.5 ppm. IR (KBr): ν = 3389 (N–H), 3028, 2930, 2832,
˜
2213, 1604 (C=N), 1511, 1455, 1235, 1180, 1105, 1035 cm–1. MS
(ESI): m/z (%) = 492.2 (100) [M + Na]+. HRMS (ESI): m/z calcd.
for C31H27N5Na [M + Na]+ 492.2164; found 492.2158.
Synthesis of 6. General Procedure: To a round-bottomed single-
necked flask (10 mL) equipped with a magnetic stirring bar, was
added 2-alkynylbenzaldehyde 1 (0.5 mmol), amine 2 (0.5 mmol,
1.0 equiv.), and MeOH (2 mL). After 30 min, isocyanide 3 (0.6 mol,
1.2 equiv.) and azidotrimethylsilane 4 (0.6 mmol, 69 mg, 1.2 equiv.)
were added and the mixture was stirred for 3–10 h. After comple-
tion of the reaction as indicated by TLC, the solvent was removed
under reduced pressure, then AgNO3 (0.05 mmol, 8.5 mg, 10 mol-
%) and MeCN (2 mL) were added. The mixture was stirred for 1–
8 h at 80 °C under a nitrogen atmosphere. After completion of the
reaction as indicated by TLC, the solvent was removed under re-
duced pressure and the residue was purified by column chromato-
graph on silica gel (ethyl acetate/petroleum ether) to give the de-
sired product 6.
(2ϫC), 103.8, 64.0, 49.3, 35.6, 31.5, 15.0 ppm. IR (KBr): ν = 2977,
˜
1625, 1604, 1569, 1512, 1475, 1454, 1393, 1384, 1369, 1345, 1292,
1246, 1170, 1150, 1112, 1087, 1043, 1009 cm–1. MS (ESI): m/z (%)
= 500.2 (100) [M + H]+. HRMS (ESI): m/z calcd. for C32H30N5O
[M + H]+ 500.2445; found 500.2448.
1-Benzyl-3-(1-phenethyl-1H-tetrazol-5-yl)-2-phenyl-2H-isoindole
(6e): The product was obtained as a white solid (128 mg, 56%);
m.p. 162.0–164.0 °C; Rf 0.55 (petroleum ether/ethyl acetate, 75:25
1
v/v). H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.4 Hz, 1 H),
7.31 (tt, J = 7.4, 1 Hz, 1 H), 7.22–7.18 (m, 3 H), 7.15–7.11 (m, 6
H), 7.08–7.01 (m, 2 H), 6.88–6.83 (m, 4 H), 6.75 (d, J = 7.2 Hz, 2
1-Benzyl-3-(1-phenethyl-1H-tetrazol-5-yl)-2-(p-tolyl)-2H-isoindole H), 4.34 (t, J = 7.2 Hz, 2 H), 4.23 (s, 2 H), 3.08 (t, J = 7.2 Hz, 2
(6a): The product was obtained as a white solid (209 mg, 89%);
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.4, 138.8, 136.9,
4
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/KAP1
Date: 14-04-14 11:22:28
Pages: 9
Synthesis of 1-(1H-Tetrazol-5-yl)-2H-isoindole Derivatives
136.4, 129.1 (3ϫC), 128.8 (2ϫC), 128.6 (2ϫC), 128.5 (2ϫC), 128.3,
128.1 (2ϫC), 127.8 (2ϫC), 127.1, 126.4, 126.3, 124.8, 123.5, 121.9,
49.3, 35.6, 31.0, 21.3 ppm. IR (KBr): ν = 2925, 1699, 1683, 1635,
˜
1568, 1514, 1456, 1385, 1370, 1252, 1300, 1252, 1110, 1025 cm–1.
MS (ESI): m/z (%) = 522.1 (100) [M + Na]+. HRMS (ESI): m/z
calcd. for C32H29N5NaO [M + Na]+ 522.2264; found 522.2257.
120.2, 118.0, 103.8, 49.3, 35.6, 31.5 ppm. IR (KBr): ν = 3053, 3027,
˜
1628, 1597, 1568, 1494, 1453, 1423, 1367, 1350, 1291, 1231, 1153,
1115, 1087, 1075, 1028 cm–1. MS (ESI): m/z (%) = 478.1 (100) [M
+ Na]+. HRMS (ESI): m/z calcd. for C30H26N5 [M + H]+ 456.2183;
found 456.2176.
1-(4-Methylbenzyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-2-(p-tolyl)-
2H-isoindole (6j): The product was obtained as a white solid
(186 mg, 77%); m.p. 160.7–162.2 °C; Rf 0.67 (petroleum ether/ethyl
1,2-Dibenzyl-3-(1-phenethyl-1H-tetrazol-5-yl)-2H-isoindole (6f): acetate, 75:25 v/v). 1H NMR (400 MHz, CDCl3): δ = 7.55 (dd, J =
The product was obtained as a white solid (126 mg, 54%); m.p.
46.0–48.0 °C; Rf 0.44 (petroleum ether/ethyl acetate, 80:20 v/v). H
NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.4 Hz, 1 H), 7.29–7.20
(m, 4 H), 7.13–7.00 (m, 11 H), 6.81 (dd, J = 6.8, 1.6 Hz, 2 H), 6.67
8, 4 Hz, 1 H), 7.20–7.09 (m, 5 H), 7.05–6.96 (m, 5 H), 6.86 (t, J =
4 Hz, 2 H), 6.78 (d, J = 4 Hz, 2 H), 6.67 (d, J = 4 Hz, 2 H), 4.32
(t, J = 6 Hz, 2 H), 4.18 (s, 2 H), 3.05 (t, J = 6 Hz, 2 H), 2.33 (s, 3
H), 2.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.5,
1
(m, 2 H), 5.21 (s, 2 H), 4.36 (s, 2 H), 4.26 (t, J = 7.6 Hz, 2 H), 2.81 139.0, 136.4, 135.9, 135.8, 134.2, 129.7 (2ϫC), 129.1 (2ϫC), 128.7
(t, J = 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.5,
138.2, 136.7, 136.4, 128.9 (3ϫC), 128.7 (5ϫC), 128.6 (2ϫC), 128.2
(3ϫC), 128.6 (2ϫC), 128.0 (2ϫC), 127.4 (2ϫC), 127.0, 126.2,
124.6, 123.3, 121.7, 120.2, 117.9, 103.4, 49.3, 35.6, 31.0, 21.4,
(2ϫC), 127.7, 127.0, 126.9, 126.4, 125.5, 124.6, 123.7, 121.4, 120.2, 21.3 ppm. IR (KBr): ν = 2921, 1627, 1569, 1514, 1455, 1385, 1371,
˜
117.2, 102.4, 49.4, 49.3, 35.7, 31.1 ppm. IR (KBr): ν = 3060, 3027,
1111, 1088, 1046, 1021 cm–1. MS (ESI): m/z (%) = 506.1 (100) [M
+ Na]+. HRMS (ESI): m/z calcd. for C32H30N5 [M + H]+ 484.2496;
found 484.2495.
˜
2925, 1629, 1602, 1567, 1537, 1494, 1453, 1384, 1353, 1220, 1157,
1108, 1077, 1029, 1001 cm–1. MS (ESI): m/z (%) = 492.2 (100) [M
+ Na]+. HRMS (ESI): m/z calcd. for C31H28N5 [M + H]+ 470.2339;
found 470.2320.
2-(4-Ethoxyphenyl)-1-(4-methylbenzyl)-3-(1-phenethyl-1H-tetrazol-
5-yl)-2H-isoindole (6k): The product was obtained as a light-yellow
solid (128 mg, 50%); m.p. 44.5–47.9 °C; Rf 0.63 (petroleum ether/
1-Benzyl-2-(4-bromophenyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-2H-
isoindole (6g): The product was obtained as a white solid (214 mg,
1
ethyl acetate, 75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.56 (d,
80%); m.p. 164.7–166.7 °C; Rf 0.66 (petroleum ether/ethyl acetate,
75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.4 Hz, J = 7.6 Hz, 2 H), 6.86 (m, 2 H), 6.77 (d, J = 8 Hz, 2 H), 6.68 (s, 4
1 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.18–7.06 (m, 9 H), 6.87–6.82 (m, H), 4.33 (t, J = 7.2 Hz, 2 H), 4.17 (s, 2 H), 3.98 (q, J = 6.8 Hz, 2
J = 8.4 Hz, 1 H), 7.20–7.11 (m, 5 H), 7.06–7.01 (m, 1 H), 6.96 (d,
1
4 H), 6.45 (d, J = 7.6 Hz, 2 H), 4.49 (t, J = 7 Hz, 2 H), 4.19 (s, 2
H), 3.17 (t, J = 7 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 148.3, 138.5, 136.4, 135.8, 132.1 (2ϫC), 129.4 (2ϫC), 128.8
H), 3.07 (t, J = 7.2 Hz, 2 H), 2.28 (s, 3 H), 1.41 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 148.5, 136.4,
135.9, 135.8, 130.2, 129.1 (2ϫC), 128.8 (5ϫC), 128.6 (2ϫC), 128.0,
(2ϫC), 128.7 (2ϫC), 128.6, 128.5, 128.1, 127.6, 127.1, 126.6, 125.9, 127.0, 126.1, 124.6, 123.2, 121.6, 120.2, 117.8, 114.6 (2ϫC), 107.7,
125.1, 123.5, 123.2, 122.1, 120.3, 117.7, 116.8, 103.7, 49.5, 35.7,
103.5, 63.9, 49.3, 35.6, 31.0, 21.3, 15.0 ppm. IR (KBr): ν = 2978,
˜
31.4 ppm. IR (KBr): ν = 1628, 1569, 1493, 1454, 1386, 1370, 1068,
1625, 1604, 1565, 1514, 1495, 1454, 1384, 1345, 1292, 1118, 1043,
1009 cm–1. MS (ESI): m/z (%) = 514.1 (100) [M + H]+. HRMS
(ESI): m/z calcd. for C33H32N5O [M + H]+ 514.2602; found
˜
1013 cm–1. IR (KBr): ν = 1627, 1568, 1493, 1453, 1385, 1370, 1067,
˜
1013 cm–1. MS (ESI): m/z (%) = 556.0 (100) [M + Na]+. HRMS
(ESI): m/z calcd. for C30H24BrN5Na [M + Na]+ 556.1107; found 514.2579.
556.1113.
2-Cyclohexyl-1-(4-methylbenzyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-
1-Benzyl-2-(4-methoxyphenyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-
2H-isoindole (6h): The product was obtained as a white solid
(121 mg, 50%); m.p. 141.9–143.0 °C; Rf 0.77 (petroleum ether/ethyl
2H-isoindole (6l): The product was obtained as a white solid
(166 mg, 70%); m.p. 112.0–113.1 °C; Rf 0.70 (petroleum ether/ethyl
acetate, 80:20 v/v). H NMR (400 MHz, CDCl3): δ = 7.53 (d, J =
8.4 Hz, 1 H), 7.29–7.13 (m, 3 H), 7.04–6.86 (m, 9 H), 4.42 (s, 4 H),
3.21 (t, J = 7.4 Hz, 2 H), 2.29 (s, 3 H), 1.61–0.95 (m, 11 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 149.8, 136.5, 136.1, 135.8, 129.4,
129.3 (2ϫC), 128.8 (2ϫC), 128.7 (2ϫC), 127.9 (2ϫC), 127.1, 126.8,
126.3, 124.0, 123.4, 121.0, 120.0, 117.0, 59.5 (2ϫC), 49.6, 35.7, 31.3
1
1
acetate, 67:33 v/v). H NMR (400 MHz, CDCl3): δ = 7.58 (t, J =
8.4, 1 Hz, 1 H), 7.19–7.10 (m, 8 H), 7.07–7.03 (m, 1 H), 6.88–6.86
(m, 4 H), 6.70–6.65 (m, 4 H), 4.36 (t, J = 7.2 Hz, 2 H), 4.22 (s, 2
H), 3.77 (s, 3 H), 3.08 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.7, 148.5, 138.9, 136.5, 129.5, 128.8
(2ϫC), 128.7 (3ϫC), 128.6 (2ϫC), 128.5 (2ϫC), 128.2 (2ϫC), (2ϫC), 26.6 (2ϫC), 25.1, 21.3 ppm. IR (KBr): ν = 3025, 2931,
˜
127.1, 126.4, 126.1, 124.7, 123.3, 121.8, 120.2, 117.9, 114.2 (2ϫC),
2852, 1626, 1563, 1510, 1453, 1429, 1401, 1369, 1348, 1223, 1114,
1018 cm–1. MS (ESI): m/z (%) = 476.2 (100) [M + H]+. HRMS
(ESI): m/z calcd. for C31H33N5Na [M + Na]+ 498.2634; found
103.8, 55.7, 49.3, 35.6, 31.5 ppm. IR (KBr): ν = 3053, 3028, 3002,
˜
2934, 2836, 1625, 1606, 1590, 1566, 1512, 1494, 1453, 1442, 1388,
1367, 1351, 1302, 1251, 1178, 1153, 1111, 1086, 1031 cm–1. MS 498.2630.
(ESI): m/z (%) = 508.2 (100) [M + Na]+. HRMS (ESI): m/z calcd.
2-(4-Bromophenyl)-1-(4-methylbenzyl)-3-(1-phenethyl-1H-tetrazol-
5-yl)-2H-isoindole (6m): The product was obtained as a white solid
2-(4-Methoxyphenyl)-1-(4-methylbenzyl)-3-(1-phenethyl-1H- (142 mg, 52%); m.p. 155.0–156.0 °C; Rf 0.70 (petroleum ether/ethyl
for C31H27N5NaO [M + Na]+ 508.2113; found 508.2110.
1
tetrazol-5-yl)-2H-isoindole (6i): The product was obtained as a
white solid (205 mg, 82%); m.p. 150.6–152.1 °C; Rf 0.51 (petroleum
ether/ethyl acetate, 75:25 v/v). 1H NMR (400 MHz, CDCl3): δ =
7.57 (d, J = 8.4 Hz, 1 H), 7.19–7.10 (m, 5 H), 7.04 (t, J = 7.2 Hz,
1 H), 6.97 (d, J = 8 Hz, 2 H), 6.88–6.86 (m, 2 H), 6.77 (d, J =
8 Hz, 2 H), 6.69 (t, J = 9.6 Hz, 4 H), 4.35 (t, J = 7.2 Hz, 2 H), 4.17
(s, 2 H), 3.80 (s, 3 H), 3.08 (t, J = 7.2 Hz, 2 H), 2.28 (s, 3 H) ppm.
acetate, 75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.59 (dt, J =
8.4, 1 Hz, 1 H), 7.30–7.27 (m, 2 H), 7.18–7.04 (m, 6 H), 6.97 (d, J
= 8 Hz, 2 H), 6.86 (dd, J = 7.6, 1 Hz, 2 H), 6.72 (d, J = 8 Hz, 2
H), 6.47 (d, J = 8 Hz, 2 H), 4.48 (t, J = 7 Hz, 2 H), 4.15 (s, 2 H),
3.17 (t, J = 7 Hz, 2 H), 2.29 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 148.3, 136.0, 132.1 (2ϫC), 129.4 (3ϫC), 129.2 (2ϫC),
128.8 (3ϫC), 128.7 (2ϫC), 127.9 (2ϫC), 127.1, 125.9, 125.1, 124.2,
13C NMR (100 MHz, CDCl3): δ = 159.6, 148.5, 136.4, 135.8, 129.4, 123.4, 123.2, 122.4, 121.9, 120.4, 117.6, 103.5, 49.5, 35.7, 30.9,
129.1 (2ϫC), 128.8, 128.7 (5ϫC), 128.6 (2ϫC), 128.0 (2ϫC), 127.0,
126.0, 124.6, 123.2, 121.6, 120.2, 117.8, 114.1 (2ϫC), 103.5, 55.6,
21.3 ppm. IR (KBr): ν = 2917, 1634, 1568, 1494, 1455, 1385, 1370,
˜
1068, 1013 cm–1. MS (ESI): m/z (%) = 570.1 (100) [M + Na]+.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42098
/KAP1
Date: 14-04-14 11:22:28
Pages: 9
C. Yu et al.
FULL PAPER
HRMS (ESI): m/z calcd. for C31H26BrN5Na [M + Na]+ 570.1264;
found 570.1260.
1-(Cyclopropylmethyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-2-phenyl-
2H-isoindole (6r): The product was obtained as a white solid
(105 mg, 50%); m.p. 136.0–137.0 °C; Rf 0.59 (petroleum ether/ethyl
1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-(4-methoxyphenyl)-3-(4-meth-
ylbenzyl)-2H-isoindole (6n): The product was obtained as a white
solid (124 mg, 52%); m.p. 171.6–173.6 °C; Rf 0.63 (petroleum ether/
1
acetate, 75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.69 (dt, J =
8.4, 1 Hz, 1 H), 7.41–7.26 (m, 4 H), 7.18–7.09 (m, 4 H), 7.07–7.03
(m, 1 H), 6.97 (d, J = 7.6 Hz, 2 H), 6.92–6.90 (m, 2 H), 4.37 (t, J
= 7.2 Hz, 2 H), 3.12 (t, J = 7.2 Hz, 2 H), 2.82 (d, J = 6.4 Hz, 2 H),
0.85–0.78 (m, 1 H), 0.41–0.36 (m, 2 H), 0.04–0.01 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 148.5, 137.3, 136.6, 130.5, 129.1
(4ϫC), 128.8 (2ϫC), 128.7, 128.1 (2ϫC), 127.1, 126.3, 124.7, 122.8,
121.4, 120.5, 117.8, 103.3, 49.3, 35.6, 30.2, 11.5, 5.6 (2ϫC) ppm.
1
ethyl acetate, 75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.58 (d,
J = 8.4 Hz, 1 H), 7.31 (d, J = 8.8 Hz, 1 H), 7.14–7.10 (m, 1 H),
7.06–7.02 (m, 1 H), 7.00–6.95 (m, 4 H), 6.81–6.78 (m, 4 H), 4.22
(s, 2 H), 3.78 (s, 3 H), 2.28 (s, 3 H), 1.92–1.77 (m, 4 H), 1.63 (d, J
= 11.2 Hz, 2 H), 1.54 (d, J = 12 Hz, 2 H), 1.25–1.12 (m, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 159.8, 147.3, 135.8, 129.8, 129.1
(3ϫC), 128.9 (2ϫC), 128.2, 128.0 (2ϫC), 126.6, 124.4, 123.3, 121.7,
120.1, 117.8, 114.3 (2ϫC), 104.1, 58.2, 55.7, 33.2 (2ϫC), 31.1, 25.5
IR (KBr): ν = 3053, 2940, 2924, 1627, 1597, 1566, 1507, 1496, 1455,
˜
1437, 1388, 1363, 1348, 1293, 1226, 1212, 1165, 1112, 1076, 1044,
1015 cm–1. MS (ESI): m/z (%) = 442.2 (100) [M + Na]+. HRMS
(ESI): m/z calcd. for C27H25N5Na [M + Na]+ 442.2002; found
442.1999.
(2ϫC), 25.0, 21.2 ppm. IR (KBr): ν = 2935, 2857, 1627, 1565, 1513,
˜
1451, 1398, 1384, 1365, 1301, 1253, 1174, 1107, 1024 cm–1. MS
(ESI): m/z (%) = 478.2 (100) [M + H]+. HRMS (ESI): m/z calcd.
for C30H32N5O [M + H]+ 478.2601; found 478.2598.
1-(Cyclopropylmethyl)-2-(4-methoxyphenyl)-3-(1-phenethyl-1H-
tetrazol-5-yl)-2H-isoindole (6s): The product was obtained as a
white solid (119 mg, 53%); m.p. 128.5–131.5 °C; Rf 0.53 (petroleum
ether/ethyl acetate, 75:25 v/v). 1H NMR (400 MHz, CDCl3): δ =
7.68 (dt, J = 8.4, 1 Hz, 1 H), 7.26–6.87 (m, 10 H), 6.80 (dt, J =
7.6, 1.2 Hz, 2 H), 4.39 (t, J = 7.4 Hz, 2 H), 3.81 (s, 3 H), 3.13 (t, J
= 7.2 Hz, 2 H), 2.80 (d, J = 6.8 Hz, 2 H), 0.88–0.79 (m, 1 H),
0.42–0.37 (m, 2 H), 0.08–0.01 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.7, 148.6, 136.6, 130.7, 129.9, 129.0 (2ϫC), 128.7
(4ϫC), 127.0, 126.1, 124.6, 122.7, 121.2, 120.5, 117.7, 114.2 (2ϫC),
2-(4-Chlorophenyl)-1-(4-methylbenzyl)-3-(1-phenethyl-1H-tetrazol-
5-yl)-2H-isoindole (6o): The product was obtained as a white solid
(174 mg, 69%); m.p. 166.0–168.0 °C; Rf 0.58 (petroleum ether/ethyl
1
acetate, 75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.59 (d, J =
8.4 Hz, 1 H), 7.16–7.05 (m, 8 H), 6.96 (d, J = 7.6 Hz, 2 H), 6.87
(d, J = 6.4 Hz, 2 H), 6.72 (d, J = 8 Hz, 2 H), 6.53 (d, J = 7.6 Hz,
2 H), 4.48 (t, J = 6.8 Hz, 2 H), 4.15 (s, 2 H), 3.17 (t, J = 6.8 Hz, 2
H), 2.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.3,
136.5, 136.1, 135.5, 135.4, 135.1, 129.2 (7ϫC), 128.9, 128.8 (2ϫC),
128.7, 128.0 (2ϫC), 127.1, 126.1, 125.1, 123.5, 122.0, 120.4, 117.7,
103.3, 55.7, 49.3, 35.6, 30.2, 11.5, 5.6 (2ϫC) ppm. IR (KBr): ν =
˜
1626, 1561, 1514, 1386, 1349, 1301, 1250, 1183, 1108, 1029 cm–1.
MS (ESI): m/z (%) = 472.2 (100) [M + Na]+. HRMS (ESI): m/z
calcd. for C28H28N5O [M + H]+ 450.2288; found 450.2292.
103.8, 49.5, 35.7, 31.0, 21.3 ppm. IR (KBr): ν = 2974, 1634, 1569,
˜
1496, 1455, 1385, 1090, 1049 cm–1. MS (ESI): m/z (%) = 504.1 (100)
[M + H]+. HRMS (ESI): m/z calcd. for C31H26ClN5Na [M +
Na]+ 526.1774; found 526.1754.
1-(Cyclopropylmethyl)-2-(4-fluorophenyl)-3-(1-phenethyl-1H-
tetrazol-5-yl)-2H-isoindole (6t): The product was obtained as a
white solid (96 mg, 44%); m.p. 126.0–128.0 °C; Rf 0.71 (petroleum
ether/ethyl acetate, 80:20 v/v). 1H NMR (400 MHz, CDCl3): δ =
7.69 (d, J = 8.4 Hz, 1 H), 7.21–7.11 (m, 5 H), 7.08–7.04 (m, 1 H),
6.97 (t, J = 8.4 Hz, 2 H), 6.92–6.90 (m, 2 H), 6.85–6.82 (m, 2 H),
4.50 (t, J = 7 Hz, 2 H), 3.20 (t, J = 7 Hz, 2 H), 2.78 (d, J = 6.8 Hz,
2 H), 0.83–0.76 (m, 1 H), 0.43–0.38 (m, 2 H), 0.04–0.01 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.7, 161.2, 148.4,
136.6, 133.1, 130.9, 129.9, 128.8 (4ϫC), 127.1, 125.9, 124.9, 122.7,
121.4, 120.6, 117.5, 116.2, 115.9, 103.5, 49.4, 35.7, 30.1, 11.5, 5.6
1-(Cyclopropylmethyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-2-(p-tolyl)-
2H-isoindole (6p): The product was obtained as a white solid
(87 mg, 40%); m.p. 118.0–120.0 °C; Rf 0.64 (petroleum ether/ethyl
1
acetate, 75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.68 (dt, J =
8.4, 1 Hz, 1 H), 7.19–7.09 (m, 7 H), 7.06–7.02 (m, 1 H), 6.91 (dd,
J = 7.6, 1.6 Hz, 2 H), 6.85 (d, J = 7.6 Hz, 2 H), 4.35 (t, J = 7.2 Hz,
2 H), 3.11 (t, J = 7.2 Hz, 2 H), 2.81 (d, J = 7.2 Hz, 2 H), 2.37 (s,
3 H), 0.83 (m, 1 H), 0.41–0.37 (m, 2 H), 0.04–0.01 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 148.5, 139.1, 136.5, 134.6, 130.4
(2ϫC), 129.7, 128.7 (2ϫC), 128.6, 127.7 (2ϫC), 127.0, 126.2, 124.5,
122.7, 121.2, 120.4, 120.4, 117.7, 103.2, 49.2, 35.6, 30.1, 21.4, 11.5,
(2ϫC) ppm. IR (KBr): ν = 3076, 3004, 2945, 2908, 1720, 1626,
˜
1562, 1508, 1455, 1392, 1351, 1219, 1149, 1103, 1091 cm–1. MS
(ESI): m/z (%) = 438.1 (100) [M + H]+. HRMS (ESI): m/z calcd.
for C27H24FN5Na [M + Na]+ 460.1908; found 460.1895.
5.5 (2ϫC) ppm. IR (KBr): ν = 3032, 2997, 2923, 1625, 1565, 1514,
˜
1494, 1454, 1389, 1365, 1350, 1108, 1018 cm–1. MS (ESI): m/z (%)
= 434.3 (100) [M + H]+. HRMS (ESI): m/z calcd. for C28H28N5
[M + H]+ 434.2339; found 434.2329.
1-Butyl-3-(1-phenethyl-1H-tetrazol-5-yl)-2-phenyl-2H-isoindole (6u):
The product was obtained as a white solid (145 mg, 69%); m.p.
117.4–117.9 °C; Rf 0.63 (petroleum ether/ethyl acetate, 75:25 v/v).
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.4 Hz, 1 H), 7.37–
7.26 (m, 4 H), 7.18–7.12 (m, 4 H), 7.06–7.02 (m, 1 H), 6.91 (t, J =
7 Hz, 4 H), 4.37 (t, J = 7.2 Hz, 2 H), 3.11 (t, J = 7.2 Hz, 2 H),
1.49–1.41 (m, 2 H), 1.22–1.15 (m, 2 H), 0.78 (t, J = 7.4 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.5, 137.2, 136.6,
131.0, 129.1 (2ϫC), 129.0, 128.8 (2ϫC), 128.7 (2ϫC), 127.8 (2ϫC),
127.1, 126.2, 124.7, 122.6, 121.1, 120.3, 117.8, 102.9, 49.3, 35.6,
2-Cyclohexyl-1-(cyclopropylmethyl)-3-(1-phenethyl-1H-tetrazol-5-
yl)-2H-isoindole (6q): The product was obtained as a colorless semi-
solid (128 mg, 60%); Rf 0.70 (petroleum ether/ethyl acetate, 80:20
1
v/v). H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.4 Hz, 1 H),
7.34–7.31 (m, 1 H), 7.19–7.14 (m, 3 H), 7.02–6.93 (m, 3 H), 6.83
(d, J = 8.4 Hz, 1 H), 4.31 (t, J = 7.2 Hz, 2 H), 3.24 (t, J = 7.2 Hz,
2 H), 3.05 (d, J = 6 Hz, 2 H), 1.79–0.88 (m, 12 H), 0.59–0.53 (m,
2 H), 0.32–0.26 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
150.0, 136.6, 128.9 (2ϫC), 128.7 (2ϫC), 128.4, 127.1, 126.6, 123.9,
122.8, 120.5, 120.3, 116.9, 59.4, 49.6, 35.7, 30.1 (2ϫC), 26.8 (3ϫC),
32.4, 25.1, 22.7, 14.0 ppm. IR (KBr): ν = 3049, 2949, 2921, 2855,
˜
1628, 1597, 1566, 1535, 1507, 1496, 1455, 1433, 1388, 1367, 1325,
1293, 1230, 1166, 1103, 1076, 1024 cm–1. MS (ESI): m/z (%) = 444.2
(100) [M + Na]+. HRMS (ESI): m/z calcd. for C27H27N5Na [M +
Na]+ 444.2159; found 444.2186.
25.2, 11.8, 5.7 (2ϫC) ppm. IR (KBr): ν = 2930, 2854, 1708, 1681,
˜
1626, 1559, 1496, 1453, 1374, 1349, 1269, 1216, 1111, 1078, 1049,
1018 cm–1. MS (ESI): m/z (%) = 426.1 (100) [M + H]+. HRMS
(ESI): m/z calcd. for C27H31N5Na [M + Na]+ 448.2472; found
448.2453.
1-Butyl-2-(4-methoxyphenyl)-3-(1-phenethyl-1H-tetrazol-5-yl)-2H-
isoindole (6v): The product was obtained as a white solid (117 mg,
6
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Synthesis of 1-(1H-Tetrazol-5-yl)-2H-isoindole Derivatives
52%); m.p. 123.9–124.9 °C; Rf 0.70 (petroleum ether/ethyl acetate,
75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8 Hz, 1
H), 7.26 (d, J = 8.4 Hz, 2 H), 7.21–7.11 (m, 5 H), 7.08–7.04 (m, 1
H), 6.90 (m, 2 H), 6.73 (d, J = 8.4 Hz, 2 H), 4.48 (t, J = 7 Hz, 2
H), 3.20 (t, J = 7 Hz, 2 H), 2.43 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 148.4, 136.5, 135.6, 135.0, 129.4 (2ϫC), 128.9 (2ϫC),
128.8 (4ϫC), 127.1, 126.3, 126.1, 125.1, 122.9, 121.4, 120.3, 117.6,
1
H), 7.17–7.08 (m, 5 H), 7.03 (t, J = 8 Hz, 1 H), 6.91 (q, J = 4 Hz,
2 H), 6.82 (q, J = 8 Hz, 4 H), 4.38 (t, J = 8 Hz, 2 H), 3.81 (s, 3 H),
3.12 (t, J = 8 Hz, 2 H), 2.86 (t, J = 8 Hz, 2 H), 1.49–1.42 (m, 2 H),
1.25–1.16 (m, 2 H), 0.80 (t, J = 8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.7, 148.6, 136.6, 131.2, 129.8, 128.8
(5ϫC), 128.7, 127.1, 126.1, 124.6, 122.5, 121.0, 120.4, 117.7, 114.3
(2ϫC), 103.1, 55.7, 49.3, 35.7, 32.5, 25.2, 22.7, 14.0 ppm. IR (KBr):
103.0, 49.5, 35.7, 11.3 ppm. IR (KBr): ν = 3061, 2927, 2933, 1628,
˜
1564, 1508, 1493, 1454, 1402, 1365, 1346, 1282, 1231, 1163, 1091,
1013 cm–1. MS (ESI): m/z (%) = 414.1 (100) [M + H]+. HRMS
(ESI): m/z calcd. for C24H21ClN5 [M + H]+ 414.1480; found
ν = 2960, 2933, 2871, 1625, 1607, 1566, 1512, 1450, 1439, 1367, 414.1461.
˜
1299, 1248, 1173, 1101, 1024 cm–1. MS (ESI): m/z (%) = 452.1 (100)
X-ray Crystal Data of 6b: CCDC-986608 contains the supplemen-
[M + H]+. HRMS (ESI): m/z calcd. for C28H30N5O [M + H]+
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam. ac. uk/data_request/cif.
452.2445; found 452.2453.
1-(1-Benzyl-1H-tetrazol-5-yl)-3-butyl-2-(4-methoxyphenyl)-2H-iso-
indole (6w): The product was obtained as a white solid (103 mg,
47%); m.p. 136.7–137.7 °C; Rf 0.47 (petroleum ether/ethyl acetate,
75:25 v/v). 1H NMR (400 MHz, CDCl3): δ = 7.66 (dt, J = 8.8,
1 Hz, 1 H), 7.26–7.21 (m, 2 H), 7.18–7.13 (m, 3 H), 7.07–7.03 (m,
1 H), 6.74–6.68 (m, 4 H), 6.59 (d, J = 8 Hz, 2 H), 5.47 (s, 2 H),
3.78 (s, 3 H), 2.81 (t, J = 7.6 Hz, 2 H), 1.45–1.38 (m, 2 H), 1.24–
1.15 (m, 2 H), 0.80 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.7, 148.5, 134.0, 131.1, 129.6, 128.9 (2ϫC), 128.7
(2ϫC), 128.5, 128.1 (2ϫC), 125.6, 124.6, 122.5, 120.9, 120.6, 117.5,
113.9 (2ϫC), 55.6, 55.6, 51.7, 32.5, 25.1, 22.6, 14.0 ppm. IR (KBr):
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all compounds, crystal data and
details of X-ray experiments for 6b.
Acknowledgments
The authors gratefully acknowledge financial support from the
National Natural Science Foundation of China (NSFC) (grant
numbers 21006097, 21176222).
ν = 3052, 2957, 2929, 2857, 1627, 1605, 1573, 1513, 1441, 1368,
˜
1297, 1246, 1177, 1101, 1020 cm–1. MS (ESI): m/z (%) = 438.1 (100)
[M + H]+. HRMS (ESI): m/z calcd. for C27H28N5O [M + H]+
438.2294; found 438.2289.
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1-Butyl-2-cyclohexyl-3-(1-phenethyl-1H-tetrazol-5-yl)-2H-isoindole
(6x): The product was obtained as a colorless semisolid (120 mg,
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1
56%); Rf 0.78 (petroleum ether/ethyl acetate, 80:20 v/v). H NMR
(400 MHz, CDCl3): δ = 7.55 (d, J = 8.4 Hz, 1 H), 7.18–7.11 (m, 3
H), 7.02–6.93 (m, 4 H), 6.85 (d, J = 8.4 Hz, 1 H), 4.40 (s, 2 H),
3.23 (t, J = 7.2 Hz, 2 H), 3.07 (t, J = 7.8 Hz, 2 H), 1.76–1.62 (m,
8 H), 1.49–1.39 (m, 3 H), 1.31–1.26 (m, 3 H), 1.14–1.08 (m, 1 H),
0.98 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
149.9, 136.6, 129.3, 128.8 (2ϫC), 128.6 (2ϫC), 127.0, 126.4, 123.9,
122.6, 120.2, 120.1, 116.9, 99.3, 59.1, 49.5, 35.6, 33.0 (3ϫC), 26.7
(2ϫC), 25.7, 25.2, 22.9, 14.1 ppm. IR (KBr): ν = 3028, 2930, 2856,
˜
[3] M. Passerini, Gazz. Chim. Ital. 1921, 51, 126.
1709, 1681, 1633, 1560, 1453, 1415, 1397, 1370, 1266, 1209, 1163,
1127, 1030, 1016 cm–1. MS (ESI): m/z (%) = 428.2 (100) [M +
H]+. HRMS (ESI): m/z calcd. for C27H33N5Na [M + Na]+
450.2634; found 450.2626.
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2-(4-Bromophenyl)-1-butyl-3-(1-phenethyl-1H-tetrazol-5-yl)-2H-
isoindole (6y): The product was obtained as a white solid (168 mg,
67%); m.p. 151.0–151.7 °C; Rf 0.50 (petroleum ether/ethyl acetate,
1
80:20 v/v). H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.4 Hz,
1 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.20–7.13 (m, 5 H), 7.07–7.03 (m,
1 H), 6.90 (dd, J = 7.4, 1.4 Hz, 2 H), 6.64 (d, J = 7.6 Hz, 2 H),
4.50 (t, J = 6.8 Hz, 2 H), 3.20 (t, J = 6.8 Hz, 2 H), 2.84 (t, J =
7.6 Hz, 2 H), 1.47–1.40 (m, 2 H), 1.25–1.15 (m, 2 H), 0.80 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.4, 136.6,
136.1, 132.3 (2ϫC), 131.2, 129.4 (2ϫC), 128.8 (4ϫC), 127.1, 126.0,
125.0, 123.2, 122.7, 121.3, 120.5, 117.5, 103.0, 49.5, 35.7, 32.5, 25.1,
22.7, 14.0 ppm. IR (KBr): ν = 2949, 2927, 2867, 1626, 1562, 1508,
˜
1490, 1454, 1397, 1371, 1350, 1098, 1067, 1010 cm–1. MS (ESI):
m/z (%) = 522.0 (100) [M + Na]+. HRMS (ESI): m/z calcd. for
C27H26BrN5Na [M + Na]+ 522.1264; found 522.1248.
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isoindole (6z): The product was obtained as a white solid (145 mg,
70%); m.p. 168.0–169.0 °C; Rf 0.64 (petroleum ether/ethyl acetate,
1
75:25 v/v). H NMR (400 MHz, CDCl3): δ = 7.6 (d, J = 8.4 Hz, 1
Eur. J. Org. Chem. 0000, 0–0
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C. Yu et al.
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Received: February 18, 2014
Published Online: ᭿
8
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Date: 14-04-14 11:22:28
Pages: 9
Synthesis of 1-(1H-Tetrazol-5-yl)-2H-isoindole Derivatives
Heterocycles
R. Wu, S. Gao, X. Chen, G. Yang, L. Pan,
G. Hu, P. Jia, W. Zhong, C. Yu* ...... 1–9
Synthesis of 1-(1H-Tetrazol-5-yl)-2H-iso-
indole Derivatives through Ugi Four-Com-
ponent and Silver-Catalyzed Reactions
Keywords: Multicomponent reactions
Cyclization Nitrogen heterocycles
Alkynes / Silver
/
/
A one-pot, two-step synthesis of 1-(1H-
tetrazol-5-yl)-2H-isoindole derivatives
through Ugi four-component reaction/
AgNO3-catalyzed reaction of 2-alkynyl-
benzaldehydes, amines, isonitriles, and
Me3SiN3 has been developed. The trans-
formation proceeds through 5-exo-dig
cyclization, [1,3]-H shift, and [1,5]-H shift
to generate the products in moderate to ex-
cellent yields.
/
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9