A three-component reaction of C,N-cyclic N′-acyl azomethine imines, isocyanides, and azide compounds: Effective synthesis of 1,5-disubstituted tetrazoles with tetrahydroisoquinoline skeletons

Article abstract of DOI:10.1039/c3ob27297d

A multicomponent reaction of isocyanides and C,N-cyclic N′-acyl azomethine imines in the presence of TMSCl and NaN₃ leads to tetrazole derivatives. These reactions proceeded cleanly to afford the corresponding 1,5-disubstituted tetrazoles conta

Full text of DOI:10.1039/c3ob27297d

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A three-component reaction of C,N-cyclic N’-acyl
azomethine imines, isocyanides, and azide compounds:
effective synthesis of 1,5-disubstituted tetrazoles with
tetrahydroisoquinoline skeletons†
Cite this: DOI: 10.1039/c3ob27297d
Takahiro Soeta,* Kaname Tamura, Shuhei Fujinami and Yutaka Ukaji*
Received 27th November 2012,
Accepted 29th January 2013
A multicomponent reaction of isocyanides and C,N-cyclic N’-acyl azomethine imines in the presence of
TMSCl and NaN3 leads to tetrazole derivatives. These reactions proceeded cleanly to afford the corres-
ponding 1,5-disubstituted tetrazoles containing a tetrahydroisoquinoline skeleton in high to excellent
yields.
DOI: 10.1039/c3ob27297d
www.rsc.org/obc
1,3-dipolar cycloaddition between a nitrilium intermediate
and hydrazoic acid.3,4 Tetrazoles have long been recognized as
Introduction
The multi-component reactions of isocyanides are powerful carboxylic acid isosters5 and are important heterocycles in
synthetic tools for preparation of diverse complex molecules in medicinal chemistry because of greater stability toward the
practical, time-saving one-pot operations through combinator- metabolic degradation pathway.6 The 1,5-disubstituted tetra-
ial strategies or parallel syntheses. Classically, the reaction of zole is an analog for the cis-amide bond, making it a valuable
an isocyanide with an imine and a carboxylic acid—the Ugi tool in the design of conformationally constrained peptide-
reaction—is one of the most important multi-component reac- mimetics.7 Several methods have been developed for the syn-
tions to synthesize α-amino amides.1 After discovery around thesis of 1,5-disubstituted tetrazoles.8 This is the first example
1960, various modifications have been developed;2 however, of the synthesis of novel 1,5-disubstituted tetrazoles contain-
the use of components other than carboxylic acids has been ing tetrahydroisoquinoline skeletons based on the isocyanide-
limited. One of the reasons why carboxylic acid is crucial in based multicomponent reaction.9,10
this reaction depends on the reaction mechanism. The mech-
Among the imine analogs, C,N-cyclic N′-acyl azomethine
anism of the Ugi reaction has been studied thoroughly and imines are promising candidates11 because they possess an
involves activation of the imine by a carboxylic acid followed acyl group, which can activate the CvN bond and strongly
by addition of an isocyanide and trapping of the resulting coordinate to metals. A previous study already reported that
nitrilium intermediate by the carboxylate to afford the final [5 + 1] cycloaddition of isocyanides and C,N-cyclic N′-acyl azo-
product by migration of the acyl group onto the nitrogen atom methine imines as an “isocyanophile” gave imin-1,3,4-oxadi-
originating from the imine. Therefore, a carboxylic acid is azin-6-one derivatives in high yields.12,13 This cyclization
necessary for the reaction of an isocyanide with an imine in reaction was expanded to a three-component reaction. There-
the Ugi reaction, i.e., the use of a carboxylic acid limits appli- fore, a molecule (Z–X) consisting of an electrophilic (Z) and a
cation of this reaction to the construction of a broad range of nucleophilic group (X) could suppress the intramolecular trap-
molecules. However, after considering these issues, an azide ping of the nitrilium intermediate through an N′-acyl group (A)
compound was chosen for the isocyanide-based multicompo- and undergo nucleophilic trapping by X (B) to achieve a multi-
nent reaction. Ugi first reported that the reaction of an alde- component reaction (Scheme 1).
hyde with an isocyanide in the presence of hydrazoic acid
instead of
a carboxylic acid afforded 1H-tetrazoles via
Results and discussion
Division of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Initial studies began using the C,N-cyclic N′-acyl azomethine
imine 1a14 and tert-butyl isocyanide (2a) in the presence of
MgCl2 or ZnCl2 in acetonitrile (MeCN); however, only the cycli-
zation product imin-1,3,4-oxadiazin-6-one derivative 3aa was
obtained in 70% yield (eqn (1)).12 In contrast, when the
E-mail: soeta@se.kanazawa-u.ac.jp, ukaji@staff.kanazawa-u.ac.jp
†Electronic supplementary information (ESI) available. CCDC 911829. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob27297d
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Table 1 Reaction conditions for a three-component reaction
Entry
Solvent
x Equiv.
y Equiv.
z Equiv.
Yield/%
1
2
3
4
5
6
7
8
MeCN
Toluene
CH2Cl2
AcOEt
Et2O
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
0.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.0
1.0
94
82
84
93
96
66
99
89
93
90
45a
Scheme 1 Working hypothesis.
reaction was conducted in the presence of chlorotrimethyl-
silane (TMSCl) in MeCN at room temperature, the reaction gave
the 1,2,3,4-tetrahydroisoquinoline-1-carboxylamide 4aa in 93%
yield (eqn (2)). As expected, TMSCl suppressed the cyclization
pathway and the nitrilium intermediate was trapped by a chlo-
ride anion, followed by hydrolysis to afford 4aa.15 Based on this
result, the reaction of 1a and 2a in the presence of trimethylsilyl
azide (TMSN3) in MeCN was examined. The reaction was
THF
MeOH
MeOH
MeOH
MeOH
MeOH
9
10
11
a 3aa was also obtained in 45% yield.
complete within 10 min to afford the 1,5-disubstituted tetrazole 90% yield (entries 8–10). The cyclized compound 4aa was
5aa in 93% yield (eqn (3)). In addition, the X-ray structure obtained in 45% yield when 0.5 equiv. of TMSCl was used
of the product 5aa was obtained,
(entry 11).
After an efficient method for addition of the isocyanide to
the C,N-cyclic N′-acyl azomethine imine was established, silyl
halides containing other substituents were evaluated (Table 2).
The use of bromotrimethylsilane (TMSBr) or iodotrimethyl-
silane (TMSI) resulted in lower reactivity to afford 5aa in 86%
or 85% yield, respectively (entries 2 and 3). For chlorotriethyl-
silane (TESCl), chlorotriisopropylsilane (TIPSCl), or tert-butyl-
chlorodimethylsilane (TBDMSCl), reactivity similar to TMSCl
was observed (entries 4–6). Using a more hindered silyl com-
pound such as tert-butylchlorodiphenylsilane (TBDPSCl), 3aa
was formed in 26% yield and 5aa was produced in 65% yield
(entry 7). These results indicate that the less sterically
ð1Þ
ð2Þ
Table 2 Effect of silyl halides for a three-component reaction
ð3Þ
Furthermore, the combination of TMSCl and sodium azide,
which are less expensive than TMSN3, was also effective in this
reaction to afford the tetrazole 5aa in 94% yield after 10 min
(Table 1, entry 1). This reaction proceeded smoothly in
toluene, ethyl acetate, dichloromethane, and ether to afford
5aa in good to high yields (entries 2–5). In THF, the reaction
was sluggish to afford 5aa in a lower yield (entry 6). The
solvent MeOH was very effective in this reaction, affording the
product in 99% yield, probably due to the solubility of the sub-
strate 1a (entry 7). By decreasing the amount of TMSCl, NaN3,
and/or the isocyanide to 1.0 equiv., 5aa was still obtained in
Entry
Z–X
Yield/%
1
2
3
4
TMSCl
TMSBr
TMSI
90
86
85
92
88
90
65
TESCl
5
TIPSCl
TBDMSCl
TBDPSCl
6
7a
a 3aa was also obtained in 26% yield.
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and 1.0 equiv. of 2a. The 5-, 6-, and 7-methyl substituents were
all tolerated, furnishing the corresponding tetrazoles (entries
10–12). The only exception was incorporation of the 8-methyl
substituent, which did not result in the desired product 5ea
due to a complicated reaction (entry 13). The C,N-cyclic azo-
methine imine 1f with an electron-donating group was utilized
as well (entry 14). In addition, the C,N-cyclic azomethine imine
1g with an electron-withdrawing group on the aromatic ring
reacted slowly to afford the product 5ga in 64% yield (entry
15). The influence of the substituent of the benzoyl group on
the nitrogen was also examined. The results showed that a
methyl group on the aromatic moiety was more effective than
a chloride group to afford the products in 90% and 77%
yields, respectively (entries 16 and 17).
Table 3 Scope of isocyanides and azomethine imines
Entrya
R1
R2
Time
Yield/%
1
H (1a)
H (1a)
H (1a)
H (1a)
t-Bu (2a)
t-Oct (2b)
c-Hex (2c)
Bn (2d)
10 min
20 min
20 min
3 h
90 (5aa)
90 (5ab)
89 (5ac)
99 (5ad)
2
3b
4b
5b
H (1a)
(2e)
30 min
91 (5ae)
6b
H (1a)
H (1a)
H (1a)
H (1a)
5-Me (1b)
6-Me (1c)
7-Me (1d)
8-Me (1e)
6-MeO (1f)
7-Cl (1g)
H (1h)
Ph (2f)
3 h
3 h
82 (5af)
95 (5ag)
84 (5ah)
91 (5ai)
95 (5ba)
97 (5ca)
92 (5da)
— (5ea)
89 (5fa)
64 (5ga)
90 (5ha)
77 (5ia)
7b
4-MeOC6H4 (2g)
4-BrC6H4 (2h)
4-O2NC6H4 (2i)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
t-Bu (2a)
8b
4 min
27 h
10 min
10 min
10 min
24 h
10 min
1 h
10 min
16 h
9b
ð4Þ
10
11
12
13
14
15
16c
17d
In addition, structurally distinct azomethine imine was
examined. The reaction of C,N-cyclic azomethine imines not
fused to the aromatic ring, which were generated in situ from
1j and 1k in the presence of 2,6-di-tert-butyl-4-methylpyridine
(DTBMP) as a base, was conducted with tert-butylisocyanide
(2a) in the presence of TMSCl and NaN3 to afford the products
5ja and 5ka in 69% and 93% yields, respectively (eqn (4)).
To determine the reaction mechanism, control experiments
were conducted. The reaction of the isocyanide 2a to the C,N-
cyclic azomethine imine 1a in the presence of NaN3 without
TMSCl afforded the cyclized compound 3aa (eqn (5)). In
addition, when the reaction of the cyclized compound 3aa
with TMSCl and NaN3 was conducted, the desired tetrazole
5aa was obtained (eqn (6)).
H (1i)
t-Bu (2a)
a R3 = H otherwise mentioned. b Reaction was conducted at 50 °C.
c R3 = Me. d R3 = Cl.
hindered Si atom and Cl anion were crucial for efficient com-
pletion of the reaction.
The scope of isocyanides and C,N-cyclic N′-acyl azomethine
imines applicable to the multicomponent reaction was investi-
gated as shown in Table 3. For isocyanides, optimal amounts
of the azomethine imine 1a (1.0 equiv.) and isocyanides 2a–i
(1.0 equiv.) in the presence of TMSCl (1.0 equiv.) and NaN3
(1.0 equiv.) were used in MeOH (entries 1–9).
The results showed that the conditions were applicable to a
wide variety of isocyanides. Most of the reactions were com-
plete within 24 h. The reaction of aliphatic isocyanides (R3
=
ð5Þ
ð6Þ
t-Bu, t-Oct, c-Hex, and Bn) with 1a gave the 1,5-disubstituted
tetrazole derivatives in high yields (entries 1–4). The azo-
methine imine 1a was consumed within 20 min when tert-octyl-
isocyanide (2b) was used, giving 5ab in 90% yield (entry 2).
For cyclohexylisocyanide (2c) and benzylisocyanide (2d), reac-
tivity was lower at room temperature; however, the desired tetra-
zoles were obtained in 89% and 99% yields, respectively,
when the reactions were conducted at 50 °C (entries 3 and 4).
The chiral isocyanide 2e, prepared from the corresponding
amino acid, gave the desired product in 91% yield; however,
no chiral induction was observed (entry 5). Phenylisocyanide These results indicate that the [5 + 1] cycloaddition of isocya-
(2f) and aromatic isocyanides with electron-withdrawing or nides and C,N-cyclic N′-acyl azomethine imines proceeded very
-donating groups at the para position also afforded the corres- quickly to afford 3, whose imin-1,3,4-oxadiazin-6-one ring was
ponding tetrazoles in high yields, although the reactions were cleaved by TMSCl to generate the corresponding nitrilium
performed at 50 °C (entries 6–9). Reactivity toward various C, intermediate (C) in situ. Subsequent 1,3-dipolar cycloaddition
N-cyclic N′-acyl azomethine imines using tert-butylisocyanide between the nitrilium intermediate (C) and an azide ion pro-
(2a) was examined using 1.0 equiv. of azomethine imines 1a–i ceeded to afford the corresponding tetrazole (Scheme 2).
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(3 mL) and brine (3 mL) and dried over Na2SO4, then concen-
trated. The residue was purified by silicagel column chromato-
graphy to give the corresponding product.
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-3,4-dihydroisoquinolin-
2(1H)-yl)benzamide (5aa)
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
gave 5aa (68 mg, 90%) as a white solid of mp = 193–194 °C.
1H NMR (400 MHz, CDCl3): 1.67 (s, 9H), 3.01 (m, 1H), 3.38
(m, 2H), 3.67 (m, 1H), 6.15 (s, 1H), 6.55 (d, J = 7.8 Hz, 1H), 7.11
(t, J = 7.8 Hz, 1H), 7.22–7.26 (m, 2H), 7.32 (t, J = 7.3 Hz, 2H),
7.35 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.3 Hz, 2H).
13C NMR (100 MHz, CDCl3): 27.8, 30.1, 52.0, 61.4, 63.8, 126.6,
127.1, 128.3, 128.6, 129.1, 131.8, 132.9, 133.1, 133.4, 154.0,
Scheme 2 Proposed reaction mechanism.
166.2. IR (KBr): 3240, 2940, 1670, 1580, 1530, 1450, 1280 cm−1
.
HRMS–FAB (m/z): Calcd for C21H25N6O [M+ + H]: 377.2090.
Conclusions
Found: 377.2092.
In conclusion, a multicomponent reaction of isocyanides, C,N-
cyclic N′-acyl azomethine imines, and azide compounds was
developed. The reaction proceeded cleanly to afford 1,5-disub-
stituted tetrazole derivatives containing a tetrahydroisoquino-
line skeleton in high yields. A wide range of C,N-cyclic N′-acyl
azomethine imines and isocyanides were suitable for this
reaction.
N-(1-(1-(2,4,4-Trimethylpentan-2-yl)-1H-tetrazol-5-yl)-3,4-
dihydroisoquinolin-2(1H)-yl)benzamide (5ab)
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
1
gave 5ab (78 mg, 90%) as a yellow amorphous solid. H NMR
(400 MHz, CDCl3): 0.78 (s, 9H), 1.77 (s, 3H), 1.80 (s, 3H), 2.07
(s, 2H), 2.99 (m, 1H), 3.31 (m, 2H), 3.69 (m, 1H), 6.08 (s, 1H),
6.70 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.23–7.28 (m,
2H), 7.35 (t, J = 7.3 Hz, 2H), 7.37 (s, 1H), 7.47 (t, J = 7.8 Hz,
1H), 7.56 (d, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): 27.1,
28.7, 30.4, 30.9, 31.4, 51.3, 54.4, 61.3, 67.8, 126.5, 126.9, 127.1,
127.9, 128.5, 129.2, 131.6, 132.5, 133.1, 133.5, 153.9, 165.9. IR
(KBr): 3260, 2960, 1680, 1520, 1490, 1400, 1280 cm−1. HRMS–
FAB (m/z): Calcd for C25H33N6O [M+ + H]: 433.2716. Found:
433.2720.
Experimental section
General method
1H NMR spectra were recorded on a 400 MHz NMR spectro-
meter. Chemical shifts δ are reported in ppm using TMS as an
internal standard. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), coupling constant (J) and integration. 13C NMR
spectra were recorded on a 100 MHz NMR spectrometer. The
chemical shifts were determined in the δ-scale relative to
CDCl3 (δ = 77.0 ppm). The wave numbers of maximum
N-(1-(1-Cyclohexyl-1H-tetrazol-5-yl)-3,4-dihydroisoquinolin-
2(1H)-yl)benzamide (5ac)
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
gave 5ac (72 mg, 89%) as a white solid of mp = 232–234 °C.
1H NMR (400 MHz, CDCl3): 0.80–2.23 (m, 10H), 3.00 (m, 1H),
3.34 (m, 1H), 3.50 (m, 1H), 3.61 (m, 1H), 4.54 (m, 1H), 5.92 (s,
1H), 6.59 (d, J = 7.7 Hz, 1H), 7.09 (m, 1H), 7.25 (m, 2H), 7.35 (t, J =
7.3 Hz, 2H), 7.45 (m, 2H), 7.56 (d, J = 7.3 Hz, 2H). 13C NMR
(100 MHz, CDCl3): 24.9, 25.4, 25.5, 29.5, 32.0, 32.2, 53.0, 58.7,
60.3, 126.7, 126.9, 127.2, 128.0, 128.5, 128.9, 131.6, 131.7,
133.2, 133.4, 153.6, 166.2. IR (KBr): 3250, 2940, 1670, 1520,
absorption peaks of IR spectroscopy are presented in cm−1
.
HRMS (FAB, positive) was measured with a quadrupole mass
spectrometer. All of the melting points were measured with a
micro melting point apparatus. Toluene was dried and
distilled over sodium. THF was freshly distilled from sodium
diphenylketyl. All other solvents were distilled and stored over
drying agents.
1450, 1310 cm−1
. HRMS–FAB (m/z): Calcd for C23H27N6O
[M+ + H]: 403.2246. Found: 403.2254.
General procedure for the multicomponent reaction of
azomethine imines, isocyanides, and azide ion
N-(1-(1-Benzyl-1H-tetrazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-
yl)benzamide (5ad)
To a suspension of 1 (0.2 mmol, 1.0 equiv.) and NaN3
(0.2 mmol, 1.0 equiv.) in MeOH (1.1 mL), TMSCl (0.2 mmol, Silicagel column chromatography (hexane/ethyl acetate = 1/1)
1.0 equiv.) in MeOH (0.2 mL) was added at room temperature. gave 5ad (83 mg, 99%) as a white solid of mp = 188–189 °C.
After stirring for 10 min, 2 (0.2 mmol, 1.0 equiv.) in MeOH 1H NMR (400 MHz, CDCl3): 2.94 (m, 1H), 3.45 (m, 2H), 3.58
(0.2 mL) was added dropwise and stirred at room temperature. (m, 1H), 5.59 (d, J = 15.1 Hz, 1H), 5.89 (d, J = 15.1 Hz, 1H), 5.95
After the completion of reaction (monitored by TLC), water (s, 1H), 6.30 (d, J = 7.8 Hz, 1H), 6.83 (m, 3H), 7.08 (t, J = 7.3 Hz,
(1.5 mL) was added and extracted with ethyl acetate (2 mL × 3). 2H), 7.13 (m, 3H), 7.30 (t, J = 7.8 Hz, 2H), 7.42 (t, J = 7.3 Hz,
Combined organic layers were washed with sat. NaHCO3 aq 1H), 7.51 (d, J = 7.3 Hz, 2H), 7.72 (brs, 1H). 13C NMR
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(100 MHz, CDCl3): 29.3, 51.9, 53.0, 60.7, 126.6, 127.0, 127.1, CDCl3): 2.73 (m, 1H), 2.92 (m, 1H), 3.28 (m, 1H), 3.53 (m, 1H),
127.9, 127.9, 128.0, 128.3, 128.5, 128.9, 130.8, 131.7, 132.9, 3.79 (s, 3H), 5.89 (s, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.78 (d, J =
133.4, 154.1, 166.5. IR (KBr): 3270, 3020, 1650, 1520, 8.7 Hz, 2H), 6.97 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H),
1290 cm−1. HRMS–FAB (m/z): Calcd for C24H23N6O [M+ + H]: 7.10 (t, J = 7.8 Hz, 1H), 7.34–7.41 (m, 5H), 7.49 (t, J = 7.3 Hz,
411.1933. Found: 411.1940.
1H), 7.63 (d, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): 28.9,
52.2, 55.5, 60.2, 113.6, 126.3, 126.4, 126.5, 126.7, 127.1, 127.7,
127.9, 128.6, 131.1, 131.9, 133.0, 133.8, 155.1, 160.5, 166.4. IR
(KBr): 3240, 2940, 1650, 1520, 1460, 1250 cm−1. HRMS–FAB
(m/z): Calcd for C24H22N6O2 [M+ + H]: 427.1882. Found:
(2S)-N-(1-(1-(1-((tert-Butyldimethylsilyl)oxy)-3-methylbutan-
2-yl)-1H-tetrazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)
benzamide (5ae)
Silicagel column chromatography (hexane/ethyl acetate = 1/1) 427.1878.
gave 5ae (95 mg, 91%) as a yellow amorphous solid. Diastereo-
meric ratio was determined to be ca. 1 : 1 by 1H NMR.
N-(1-(1-(4-Bromophenyl)-1H-tetrazol-5-yl)-3,4-
dihydroisoquinolin-2(1H)-yl)benzamide (5ah)
Diastereomer (Rf = 0.3, hexane/ethyl acetate = 2/1 × 2).
1H NMR (400 MHz, CDCl3): −0.01 (s, 3H), 0.00 (s, 3H), 0.48 (d,
J = 6.9 Hz, 3H), 0.86 (s, 9H), 0.97 (d, J = 6.9 Hz, 3H), 2.07 (m,
1H), 3.08 (m, 1H), 3.23 (m, 1H), 3.48 (m, 1H), 3.84 (m, 1H),
4.16 (m, 1H), 4.24 (t, J = 8.7 Hz, 1H), 5.05 (m, 1H), 6.29 (s, 1H),
6.96 (d, J = 7.7 Hz, 1H), 7.19 (m, 2H), 7.30 (m, 2H), 7.39 (t, J =
7.3 Hz, 2H), 7.51 (m, 3H). 13C NMR (100 MHz, CDCl3): −5.8,
−5.7, 18.0, 18.5, 19.4, 25.6, 28.7, 29.1, 51.2, 59.4, 61.3, 65.9,
126.8, 127.0, 128.1, 128.3, 128.6, 129.1, 131.3, 131.9, 133.0,
133.5, 154.7, 166.3. IR (KBr): 3250, 2970, 1690, 1540, 1470,
1290, 1120 cm−1. HRMS–FAB (m/z): Calcd for C28H41N6O2Si
[M+ + H]: 521.3060. Found: 521.3070.
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
gave 5ah (40 mg, 84%, 0.1 mmol scale) as a white solid of mp
1
= 196–198 °C. H NMR (400 MHz, CDCl3): 2.73 (m, 1H), 2.92
(m, 1H), 3.28 (m, 1H), 3.53 (m, 1H), 5.84 (s, 1H), 6.56 (d, J = 7.7
Hz, 1H), 6.99 (m, 2H), 7.11 (t, J = 7.3 Hz, 1H), 7.36 (brs, 1H),
7.38–7.51 (m, 7H), 7.63 (d, J = 7.3 Hz, 2H). 13C NMR (100 MHz,
CDCl3): 29.0, 52.6, 60.7, 124.2, 126.3, 126.5, 127.1, 127.9,
128.2, 128.6, 128.7, 130.7, 131.6, 131.9, 132.9, 133.0, 133.7,
155.0, 166.4. IR (KBr): 3220, 3060, 1650, 1540, 1490,
1300 cm−1. HRMS–FAB (m/z): Calcd for C23H20BrN6O [M+ + H]:
475.0882. Found: 475.0883.
Diastereomer (Rf = 0.25, hexane/ethyl acetate = 2/1 × 2).
1H NMR (400 MHz, CDCl3): −0.15 (s, 3H), −0.21 (s, 3H), 0.82
(s, 9H), 0.90 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 2.10 N-(1-(1-(4-Nitrophenyl)-1H-tetrazol-5-yl)-3,4-
(m, 1H), 2.70 (m, 1H), 3.03 (m, 1H), 3.30 (m, 1H), 3.37 (m, 1H), dihydroisoquinolin-2(1H)-yl)benzamide (5ai)
3.63 (m, 2H), 4.62 (m, 1H), 6.20 (s, 1H), 6.82 (d, J = 7.9 Hz, 1H),
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
7.19 (t, J = 7.3 Hz, 1H), 7.30 (m, 2H), 7.41 (t, J = 7.9 Hz, 2H),
7.52 (t, J = 7.3 Hz, 1H), 7.64 (d, J = 7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3): −5.8, −5.7, 18.0, 18.5, 19.4, 25.6, 28.7, 29.1,
51.2, 59.4, 61.3, 65.9, 126.8, 127.0, 127.5, 128.1, 128.6, 129.1,
131.3, 131.9, 133.0, 133.5, 154.7, 166.3. IR (KBr): 3250, 2970,
1690, 1540, 1470, 1290, 1120 cm−1. HRMS–FAB (m/z): Calcd for
C28H41N6O2Si [M+ + H]: 521.3060. Found: 521.3054.
gave 5ai (40 mg, 91%, 0.1 mmol scale) as a white solid of mp =
223–224 °C. 1H NMR (400 MHz, CDCl3): 2.78 (m, 1H), 3.00
(m, 1H), 3.21 (m, 1H), 3.66 (m, 1H), 5.83 (s, 1H), 6.54 (d, J = 7.8
Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 7.01 (t, J = 7.3 Hz, 1H), 7.09
(t, J = 7.3 Hz, 1H), 7.32 (brs, 1H), 7.41 (t, J = 7.3 Hz, 2H), 7.51
(t, J = 7.3 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.94 (m, 2H), 8.12
(d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): 29.1, 52.1,
61.4, 123.6, 126.2, 126.8, 127.1, 127.7, 128.3, 128.7, 128.8,
130.4, 132.1, 132.7, 133.6, 138.9, 148.1, 155.1, 166.6. IR (KBr):
N-(1-(1-Phenyl-1H-tetrazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-
yl)benzamide (5af)
3240, 3070, 2930, 1680, 1600, 1530, 1340, 1110 cm−1
.
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
gave 5af (65 mg, 82%) as a yellow solid of mp = 177–178 °C.
1H NMR (400 MHz, CDCl3): 2.73 (m, 1H), 2.91 (m, 1H), 3.29
(m, 1H), 3.57 (m, 1H), 5.90 (s, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.94
(d, J = 7.7 Hz, 1H), 7.02 (t, J = 7.3 Hz, 1H), 7.08 (t, J = 7.3 Hz,
1H), 7.26–7.36 (m, 5H), 7.40 (t, J = 7.7 Hz, 2H), 7.50 (t, J = 7.7
HRMS–FAB (m/z): Calcd for C23H20N7O3 [M+ + H]: 442.1628.
Found: 442.1629.
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-5-methyl-3,4-
dihydroisoquinolin-2(1H)-yl)benzamide (5ba)
Hz, 3H), 7.64 (d, J = 7.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): Silicagel column chromatography (hexane/ethyl acetate = 1/1)
28.9, 52.3, 60.3, 126.4, 126.5, 126.5, 127.1, 127.7, 128.3, 128.5, gave 5ba (71 mg, 95%) as a white solid of mp = 225–227 °C.
128.6, 130.0, 131.0, 131.9, 133.0, 133.8, 134.0, 155.0, 166.4. 1H NMR (400 MHz, CDCl3): 1.64 (s, 9H), 2.30 (s, 3H), 2.91
IR (KBr): 3240, 3060, 1650, 1500, 1460, 1280 cm−1. HRMS–FAB (m, 1H), 3.09 (m, 1H), 3.37 (m, 1H), 3.68 (m, 1H), 6.08 (s, 1H),
(m/z): Calcd for C23H21N6O [M+ + H]: 397.1777. Found: 6.44 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 7.16 (d, J =
397.1774.
7.8 Hz, 1H), 7.34–7.37 (m, 3H), 7.46 (t, J = 7.3 Hz, 1H), 7.56 (d,
J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): 19.3, 25.1, 30.1,
51.3, 61.7, 63.7, 124.5, 126.4, 127.0, 128.6, 129.3, 131.8, 131.9,
132.6, 133.0, 136.9, 154.1, 166.1. IR (KBr): 3210, 2940,
N-(1-(1-(4-Methoxyphenyl)-1H-tetrazol-5-yl)-3,4-
dihydroisoquinolin-2(1H)-yl)benzamide (5ag)
Silicagel column chromatography (hexane/ethyl acetate = 1/1) 1670, 1540, 1460, 1290 cm−1. HRMS–FAB (m/z): Calcd for
gave 5ag (81 mg, 95%) as a yellow oil. 1H NMR (400 MHz, C22H27N6O [M+ + H]: 391.2246. Found: 391.2244.
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N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-6-methyl-3,4-dihydro-
isoquinolin-2(1H)-yl)benzamide (5ca)
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-3,4-dihydroisoquinolin-
2(1H)-yl)-4-methylbenzamide (5ha)
Silicagel column chromatography (hexane/ethyl acetate = 1/1) Silicagel column chromatography (hexane/ethyl acetate = 1/1)
gave 5ca (36 mg, 97%, 0.1 mmol scale) as a white solid of mp = gave 5ha (35 mg, 90%, 0.1 mmol scale) as a white solid of
1
166–168 °C. H NMR (400 MHz, CDCl3): 1.67 (s, 9H), 2.32 (s, mp = 221–224 °C. 1H NMR (400 MHz, CDCl3): 1.65 (s, 9H),
3H), 2.94 (m, 1H), 3.35 (m, 2H), 3.64 (m, 1H), 6.09 (s, 1H), 6.42 2.32 (s, 3H), 2.97 (m, 1H), 3.35 (m, 2H), 3.67 (m, 1H), 6.18
(d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 7.03 (s, 1H), 7.33 (s, 1H), 6.51 (d, J = 7.3 Hz, 1H), 7.09 (m, 3H), 7.24 (m, 2H), 7.44
(m, 2H), 7.45 (m, 1H), 7.53 (d, J = 7.3 Hz, 2H), 7.62 (brs, 1H). (d, J = 8.3 Hz, 2H), 7.72 (brs, 1H). 13C NMR (100 MHz, CDCl3):
13C NMR (100 MHz, CDCl3): 21.0, 27.6, 30.1, 52.0, 61.3, 63.7, 21.4, 27.8, 30.1, 52.0, 61.5, 63.8, 126.5, 126.6, 127.0, 127.9,
126.4, 127.0, 127.4, 128.5, 129.6, 129.9, 131.7, 133.1, 137.6, 129.1, 129.2, 130.2, 133.0, 133.4, 142.3, 154.1, 166.2. IR (neat):
154.1, 166.2. IR (KBr): 3260, 2970, 1670, 1530, 1490, 3200, 2980, 1670, 1530, 1500, 1290 cm−1. HRMS–FAB (m/z):
1270 cm−1. HRMS–FAB (m/z): Calcd for C22H27N6O [M+ + H]: Calcd for C22H27N6O [M+ + H]: 391.2246. Found: 391.2254.
391.2246. Found: 391.2245.
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-3,4-dihydroisoquinolin-
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-7-methyl-3,4-dihydro-
isoquinolin-2(1H)-yl)benzamide (5da)
2(1H)-yl)-4-chlorobenzamide (5ia)
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
Silicagel column chromatography (hexane/ethyl acetate = 1/1) gave 5ia (63 mg, 77%, 0.1 mmol scale) as a white solid of
gave 5da (76 mg, 92%) as a white solid of mp = 197–198 °C. mp = 231–232 °C. 1H NMR (400 MHz, CDCl3): 1.67 (s, 9H),
1H NMR (400 MHz, CDCl3): 1.68 (s, 9H), 2.21 (s, 3H), 2.95 2.99 (m, 1H), 3.37 (m, 2H), 3.69 (m, 1H), 6.17 (s, 1H), 6.49
(m, 1H), 3.29 (m, 2H), 3.64 (m, 1H), 6.01 (s, 1H), 6.41 (s, 1H), (d, J = 7.3 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.22–7.28 (m, 4H),
7.07 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.21 (brs, 1H), 7.48 (d, J = 8.7 Hz, 2H), 7.82 (brs, 1H). 13C NMR (100 MHz,
7.37 (t, J = 7.8 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 CDCl3): 27.7, 30.1, 52.1, 61.6, 63.8, 126.7, 126.8, 128.1, 128.5,
Hz, 2H). 13C NMR (100 MHz, CDCl3): 21.0, 26.9, 30.1, 51.8, 129.0, 129.2, 131.4, 132.7, 133.3, 138.2, 153.9, 165.1. IR (KBr):
61.8, 63.7, 127.0, 127.2, 128.7, 129.0, 129.1, 130.1, 131.9, 132.4, 3220, 3000, 1670, 1600, 1530, 1480, 1280 cm−1. HRMS–FAB
133.1, 136.5, 153.9, 165.9. IR (KBr): 3250, 2920, 1680, 1530, (m/z): Calcd for C21H24ClN6O [M+ + H]: 411.1700. Found:
1490, 1280 cm−1. HRMS–FAB (m/z): Calcd for C22H27N6O 411.1709.
[M+ + H]: 391.2246. Found: 391.2236.
N-(2-(1-(tert-Butyl)-1H-tetrazol-5-yl)-3,3-dimethylpiperidin-1-yl)-
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-6-methoxy-3,4-dihydro-
isoquinolin-2(1H)-yl)benzamide (5fa)
benzamide (5ja)
To a suspension of 1j (0.3 mmol) in MeOH (0.6 mL), 2,6-di-
Silicagel column chromatography (hexane/ethyl acetate = 1/1) tert-butyl-4-methylpyridine (DTBMP) (0.36 mmol, 1.2 equiv.)
gave 5fa (73 mg, 89%) as a yellow solid of mp = 206–208 °C. was added at room temperature. After 30 min, a solution of
1H NMR (400 MHz, CDCl3): 1.69 (s, 9H), 2.98 (m, 1H), 3.33 TMSCl (0.3 mmol) and NaN3 (0.3 mmol) in MeOH (1.2 mL),
(m, 2H), 3.36 (m, 1H), 3.80 (s, 3H), 6.01 (s, 1H), 6.53 (d, J = 8.2 which was prepared in another flask, was transferred via a
Hz, 1H), 6.68 (dd, J = 8.2, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), cannula at room temperature and the whole mixture was
7.24 (m, 1H), 7.36 (t, J = 7.3 Hz, 2H), 7.47 (t, J = 7.3 Hz, 1H), stirred for 30 min. 2 (0.2 mmol, 1.0 equiv.) in MeOH (0.2 mL)
7.53 (d, J = 7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): 27.9, 30.1, was added dropwise and stirred at room temperature. After the
51.7, 55.2, 61.4, 63.7, 113.0, 113.6, 124.9, 127.0, 127.8, 128.6, completion of reaction (monitored by TLC), water (1.5 mL) was
131.8, 133.1, 134.8, 154.2, 159.0, 166.1. IR (KBr): 3240, 2940, added and extracted with ethyl acetate (2 mL × 3). Combined
1670, 1610, 1510, 1280 cm−1. HRMS–FAB (m/z): Calcd for organic layers were washed with sat. NaHCO3 aq (3 mL) and
C22H27N6O2 [M+ + H]: 407.2195. Found: 407.2189.
brine (3 mL) and dried over Na2SO4, and then concentrated.
Silicagel column chromatography (hexane/diethyl ether = 5/1)
gave 5ja (74 mg, 69%, 0.3 mmol scale) as a white solid of
mp = 183–185 °C. 1H NMR (400 MHz, CDCl3): 0.87 (s, 3H),
1.25 (s, 3H), 1.72 (s, 9H), 1.82–2.05 (m, 4H), 3.35 (m, 1H), 3.57
(m, 1H), 5.06 (s, 1H), 6.95 (brs, 1H), 7.31–7.46 (m, 5H).
13C NMR (100 MHz, CDCl3): 21.6, 26.0, 28.0, 31.0, 33.9, 36.0,
51.0, 63.2, 64.0, 126.7, 128.6, 131.8, 132.9, 152.6, 166.0. IR (neat):
3210, 3060, 2950, 1650, 1550, 1450, 1300, 1230 cm−1. HRMS–FAB
(m/z): Calcd for C19H29N6O [M+ + H]: 357.2403. Found: 357.2404.
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-7-chloro-3,4-
dihydroisoquinolin-2(1H)-yl)benzamide (5ga)
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
gave 5ga (53 mg, 64%) as a white solid of mp = 197–200 °C.
1H NMR (400 MHz, CDCl3): 1.71 (s, 9H), 2.99 (m, 1H), 3.26
(m, 1H), 3.46 (m, 1H), 3.65 (m, 1H), 6.13 (s, 1H), 6.55 (s, 1H),
7.17 (d, J = 8.1 Hz, 1H), 7.24 (m, 1H), 7.32 (t, J = 8.1 Hz, 2H),
7.45 (t, J = 7.3 Hz, 1H), 7.53 (d, J = 7.3 Hz, 2H), 7.70 (brs, 1H).
13C NMR (100 MHz, CDCl3): 26.9, 30.2, 51.1, 60.7, 63.9, 126.7,
127.0, 128.3, 128.7, 130.7, 131.9, 132.0, 132.4, 132.9, 134.5,
N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-azaspiro[5.5]undecan-
2-yl)benzamide (5ka)
153.5, 166.3. IR (KBr): 3210, 2920, 1680, 1490, 1280 cm−1
.
HRMS–FAB (m/z): Calcd for C21H24ClN6O [M+ + H]: 411.1700. Silicagel column chromatography (hexane/diethyl ether = 5/1)
Found: 411.1692.
gave 5ka (111 mg, 93%, 0.3 mmol scale) as a white solid of
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mp = 219–220 °C. 1H NMR (400 MHz, CDCl3): 1.01 (m, 1H),
1.18 (m, 2H), 1.42 (m, 3H), 1.68 (s, 9H), 1.80–1.83 (m, 3H), 1.99
(m, 1H), 2.13 (m, 1H), 2.30 (brs, 2H), 2.57 (m, 1H), 3.21
(m, 1H), 3.62 (m, 1H), 4.97 (s, 1H), 6.91 (brs, 1H), 7.34
(t, J = 6.9 Hz, 2H), 7.44 (d, J = 6.9 Hz, 1H), 7.49 (m, 2H).
13C NMR (100 MHz, CDCl3): 20.6, 21.0, 21.2, 23.9, 26.2, 31.2,
34.5, 34.7, 38.8, 50.2, 63.2, 65.0, 126.9, 128.4, 131.6, 132.9,
151.2, 165.6. IR (KBr): 3240, 2930, 1650, 1540, 1460,
1290 cm−1. HRMS–FAB (m/z): Calcd for C22H33N6O [M+ + H]:
397.2716. Found: 397.2723.
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2-Benzamido-N-(tert-butyl)-1,2,3,4-tetrahydroisoquinoline-
1-carboxamide (4aa)
Silicagel column chromatography (hexane/ethyl acetate = 1/1)
gave 4aa (68 mg, 93%) as a white solid of mp = 168–170 °C.
1H NMR (400 MHz, CDCl3): 1.18 (s, 9H), 2.77 (m, 1H), 2.96
(m, 1H), 3.34 (m, 2H), 4.28 (s, 1H), 7.05–7.17 (m, 3H), 7.31
(brs, 1H), 7.36 (m, 3H), 7.45 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H),
7.67 (d, J = 7.8 Hz, 2H). 13C NMR (100 MHz, CDCl3): 28.2, 29.4,
50.8, 52.6, 71.2, 126.2, 126.4, 127.2, 127.2, 128.4, 128.7, 131.8,
131.9, 132.4, 133.3, 166.1, 170.2. IR (KBr): 3310, 2960, 1650,
1540, 1290, 1230 cm−1
.
HRMS–FAB (m/z): Calcd for
C21H26N3O2 [M+ + H]: 352.2025. Found: 352.2027.
Acknowledgements
This work was supported by a Grant-in-Aid for Young Scientist
(B) (24750037) and a Grant in-Aid for Scientific Research (B)
(24350022) from the Japan Society for the Promotion of
Science.
Notes and references
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