N,N-Disubstituted propargylamines as tools in the sequential 1,3-dipolar cycloaddition/arylation processes to the formation of polyheterocyclic systems

Article abstract of DOI:10.1016/j.tet.2008.06.042

Starting from N,N-disubstituted propargylamines, through a one-pot sequential 1,3-dipolar cycloaddition/Pd-catalyzed arylation, polyheterocyclic systems were obtained in only one step. The outcome of the cycloadditions, performed with 1,3-dipoles nitrilox

Full text of DOI:10.1016/j.tet.2008.06.042

Tetrahedron 64 (2008) 8182–8187
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N,N-Disubstituted propargylamines as tools in the sequential 1,3-dipolar
cycloaddition/arylation processes to the formation of polyheterocyclic systems
,
b
b
a
Luca Basolo a, Egle M. Beccalli a , Elena Borsini , Gianluigi Broggini , Sara Pellegrino
*
a
`
`
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia, Universita di Milano, via Venezian 21, 20133 Milano, Italy
Dipartimento di Scienze Chimiche e Ambientali, Universita dell’Insubria, via Valleggio 11, 22100 Como, Italy
b
`
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from N,N-disubstituted propargylamines, through a one-pot sequential 1,3-dipolar cycloaddi-
tion/Pd-catalyzed arylation, polyheterocyclic systems were obtained in only one step. The outcome of the
cycloadditions, performed with 1,3-dipoles nitriloxide and azide, was totally regioselective. The sub-
sequent Pd-catalyzed arylation achieved using ligand-free conditions involved the unsubstituted carbon
of the heterocyclic ring.
Received 29 February 2008
Received in revised form 27 May 2008
Accepted 12 June 2008
Available online 14 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
According to the planned strategy, we selected as suitable
starting materials the N,N-disubstituted propargylamines 1. Cy-
Synthesis of fused heteroaromatic compounds is of considerable
interest due to a wide variety of such molecules showing biological
activities as pharmaceuticals and agrochemicals. Aza-heterocyclic
systems such as quinoline, benzazepine and benzazocine fused to
five-membered rings having more than one heteroatom are ex-
amples of such attractive compounds with activities ranging from
MRP1inhibitors (Fig. 1, compound A) to bronchodilator (compound
B) or anxiolytic effects (compound C), as documented by many
recent patents.1
cloaddition with the 1,3-dipoles selected, nitriloxide and azide (2
and 5), gave the five-membered rings having more than one het-
eroatom (isoxazoles 3 and 1,2,3-triazoles 6). The choice of the
nitriloxide 2 was connected to the stability of the 2,4,6-trimethyl-
3,5-dichlorophenyl derivative. The reaction conditions to isolate
and to identify the heterocycle intermediates required the use of
different solvents depending on the cycloaddition reaction. While
the reaction of azide occurred at rt, in the case of nitriloxide the
cycloaddition reaction was performed under conventional heating,
for 24 h at 110 ꢀC, and also under microwave irradiation, for 1 h at
100 ꢀC and 400 W. In the latter case the yields were improved
giving the intermediates 3 practically in quantitative yield. In line
with the literature data dealing with nitriloxide and azide cyclo-
additions to terminal alkynes,5 total regioselectivity was observed
for compounds 3 and 6.
2. Results and discussion
On continuing our researches to plan synthetic pathway for the
synthesis of multi-ring heterocycles,2 we developed new strategy
to achieve this goal through a sequential process involving 1,3-di-
polar cycloaddition and Pd-catalyzed intramolecular cyclization.3
The combination of such methodologies generates heterocycles of
significant molecular complexity, by simultaneous formation of
two or more bonds, starting from readily available material. 1,3-
Dipolar cycloadditions, which usually require gentle reaction con-
ditions and simple workup and purification procedures, can rapidly
create molecular diversity through the use of reactive modular
building blocks (1,3-dipolar species). On the other hand, Pd-pro-
moted intramolecular arylation of the C–H bond of (hetero)arenes
is the method of choice to obtain annulation through carbon–car-
bon bond formation.4
The cycloaddition of azides and alkynes to give 1,2,3-triazoles
has become the best example of ‘click chemistry’ as suggested by
the definition of Sharpless for this process,6 due to its reliability,
R1
O
N
N
Cl
R
N
N
N
N
N
N
O
N
R3
O
O
R2
C4H9
Ph
N
H
A
B
C
* Corresponding author. Tel.: þ39 02 50314479; fax: þ39 02 50314476.
E-mail address: egle.beccalli@unimi.it (E.M. Beccalli).
Figure 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.042

L. Basolo et al. / Tetrahedron 64 (2008) 8182–8187
8183
_
+
Ar
N
N
Ar
C N O
2
O
O
Ar
Y
Y
X
A or B
Y
toluene
110 °C
N
( )n
N
( )n
R
R
3
4
Y
X
N
( )n
R
_
N
+
Ar'
Y
N
1
N
(
Ar'
N
N
N
N
N
N
Ar'
A or B
5
X
sodium ascorbate
CuSO4
H2O / t-BuOH 1:1
r.t.
N
( )n
N
)
R
n
R
6
7
compounds
n
R
X
Y
Me
Me
Cl
Cl
a
b
c
d
0
0
1
2
Boc
Boc
Me
I
CH
N
Br
I
Ar =
Ar' =
NO2
Me
CH
CH
Boc
Br
n = 0,1 A = Pd(OAc)2 2% mol, TBAC 1eq, AcOK 2eq, DMA
n = 2 B = Pd(OAc)2 2% mol, Cs2CO3 2eq, PPh3 4% mol, CuI 2eq, DMA
Scheme 1.
Ar
N
specificity, and biocompatibility. Although copper(I) salts were ef-
O
fective catalysts for this cycloaddition,7 reaction under an inert
atmosphere was required to prevent oxidation to the inactive
copper(II) salt, which actually promoted side-reactions.8 As an
economical and practical alternative to oxygen-free conditions,
copper(II) salt and a reducing agent can be used as catalytic system.
Good results were obtained by the addition of ascorbate to the
reaction mixture with no organic co-solvent.7 In these conditions
the cycloaddition reaction proceeds smoothly to completion at rt
and the triazoles 6 were isolated in good yields and high purity
after simple filtration.
Y
N
( )n
1) 2 or 5
DMA
2)
A or B
R
N
4
Y
X
N
Ar'
Y
N
N
( )n
R
1
N
( )n
R
7
The compounds 3 and 6 were submitted to a variety of
conditions potentially suitable for the palladium-catalyzed
intramolecular heteroarylation. The coupling process leads to
fused nitrogenated heterocyclic systems, quinolines and benz-
azepines 4 and 7, using ligand-free conditions (DMA as solvent,
Pd(OAc)2 as catalyst, TBAC as additive, and AcOK as base)
(Scheme 1). In the case of benzazocine derivatives superior re-
sults can be achieved in the presence of ligand (PPh3) and by
using Cs2CO3 instead of AcOK. Also the addition of CuI as additive
enhanced reactivity of low-reactive substrates. It is commonly
compounds
n
R
X
Y
a
b
c
d
0
0
1
2
Boc
Boc
Me
I
CH
N
Br
I
CH
CH
Boc
Br
n = 0,1 A = Pd(OAc)2 2% mol, TBAC 1eq, AcOK 2eq
n = 2 B = Pd(OAc)2 2% mol, Cs2CO3 2eq, PPh3 4% mol, CuI 2eq
Scheme 2.
accepted that, in direct arylation reactions,
p-electron-rich sub-
strates can react via an electrophilic palladation step and that the
arylations are facilitated by the highly nucleophilic nature of
these arenes.4a,b To the best of our knowledge, only one Pd-
catalyzed arylation of 1,2,3-triazoles9 and isoxazoles10 has been,
respectively, reported.
In conclusion we have successfully developed a telescoped
process showing the increasing significance of this methodology
aimed to the construction of polyheterocyclic systems. Moreover
the reaction conditions and catalytic reagents used can expand this
procedure in different heterocyclic syntheses.
With the aim to convert the synthetic sequence in a one-pot
process (telescoped process),11 the whole pathway was per-
formed in DMA without isolating the intermediate or changing
the solvent. This lowers waste, saves energy, and reduces oper-
ating time as there is no workup of the individual reaction steps
(Scheme 2). In this case both steps were realized under micro-
wave irradiation. The reaction temperature was 100 ꢀC for step
one (50 ꢀC with the azide) then after addition of the catalytic
systems the temperature was increased to 120 ꢀC (150 ꢀC for
compound 1d).
3. Experimental
3.1. General
Melting points were determined on a Bu¨chi B-540 heating ap-
paratus and are uncorrected. 1H NMR and 13C NMR spectra were
obtained on an AVANCE Bruker 400 MHz. Chemical shifts are given
in parts per million downfield from SiMe4. 13C NMR spectra are 1H-
decoupled and the determination of the multiplicities was achieved
by the APT pulse sequence. IR spectra were recorded on a Jasco FT/
IR 5300 spectrophotometer. Mass spectra were determined with
LCQ Advantage Thermo Finningan.
Table 1 reports the yields comparing the two methods, showing
better results for the one-pot sequential method in almost all of the
reactions. Furthermore the use of microwave procedure reduced
considerably the reaction times.

8184
L. Basolo et al. / Tetrahedron 64 (2008) 8182–8187
Table 1
Arylation/cycloaddition results of N,N-disubstituted propargylamines
Entry
Substrates
1,3-Dipole
Products
Step by step
total yield %
One-pot sequential
yield %
Ar
N
O
1
2
57
60
4a
I
N
O
O
N
N
Ar'
O
O
N
N
N
1a
2
5
2
50
49
73
90
7a
O
N
O
Ar
O
N
N
3a
4b
N
Br
N
N
O
O
Ar'
O
O
N
N
N
N
1b
4
5
28
30
7b
O
O
Ar
N
O
5
6
2
5
15
34
12
35
4c
I
N
N
Ar'
N
N
N
N
1c
7c
N
Ar
O
7
2
5
15
49
40
4d
O
O
N
Br
O
N
N
Ar'
N
N
O
O
8
5
7d
N
1d
O
a
The reaction was carried out under microwave heating.
3.2. General procedure for the synthesis of N,N-
propargylamine derivatives 1a,b
3.2.1. N-(2-Iodophenyl)-N-tert-butoxycarbonyl-2-
propynylamine (1a)13
Pale yellow solid, yield 61%, mp 53–54 ꢀC. Anal. Calcd for
C14H16INO2 (357.19): C, 47.08; H, 4.52; N, 3.92. Found: C, 47.23; H,
A mixture of either 2-iodo-N-tert-butoxycarbonylaniline or 2-
bromo-3-[N-(tert-butoxycarbonyl)amino]pyridine12 (1.5 mmol) in
benzene (10 mL), triethylbenzylammonium chloride (5 mol %,
17 mg), NaOH (50% w/w, 8 mL), and propargylbromide (80% in
toluene, 1.5 mmol, 0.16 mL) was stirred at rt for 24 h. After this time
the organic layer was separated, dried (Na2SO4), and the solvent
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent see later).
4.43; N, 4.01. Elution solvent: hexane/CH2Cl2 8:1. IR (KBr): 3466,
2105, 1697 cmꢁ1 1H NMR (CDCl3):
.
d
7.88–7.86 (1H, m), 7.38–7.36
(2H, m), 7.03–7.01 (1H, m), 4.79 and 3.89 (2H, AB system,
J¼17.7 Hz), 2.21 (1H, s), 1.40 (9H, s). 13C NMR (CDCl3):
d 153.9 (s),
143.8 (s), 139.7 (d), 130.5 (d), 129.6 (d), 129.3 (d), 100.5 (s), 81.4 (s),
79.6 (s), 72.8 (d), 38.5 (t), 28.7 (3q). MS (ESI) m/z (%): 379.2
([MþNa]þ, 100), 357.2 (M, 9), 301.1 (35).

L. Basolo et al. / Tetrahedron 64 (2008) 8182–8187
8185
3.2.2. N-(2-Bromo-3-pyridyl)-N-tert-butoxycarbonyl-2-
propynylamine (1b)
7.07–7.05 (2H, m), 6.11 (1H, s), 5.29 and 4.57 (2H, AB system,
J¼15.9 Hz), 2.55 (3H, s), 2.11 (6H, s), 1.38 (9H, s). 13C NMR (CDCl3):
Amber-colored solid, yield 66%, mp 84–85 ꢀC. Anal. Calcd for
d 169.4 (s), 162.4 (s), 154.2 (s), 143.9 (s), 140.3 (s), 139.9 (d), 135.9 (s),
C
13H15BrN2O2 (311.17): C, 50.18; H, 4.86; N, 9.00. Found: C, 50.30; H,
4.93; N, 8.90. Elution solvent: hexane/AcOEt 10:1. IR: (KBr): 3439,
2107, 1690 cmꢁ1. 1H NMR (CDCl3):
134.3 (2s), 133.8 (2s), 130.6 (d), 129.0 (d), 128.6 (d), 105.8 (d), 100.4
(s), 81.8 (s), 44.5 (t), 28.8 (q), 28.5 (2q), 19.5 (q), 19.1 (2q). MS (ESI)
m/z (%): 611.0 (11), 610.0 (66), 609.0 ([MþNa]þ, 100), 587.0 (M, 5),
532.2 (16), 531.2 (25).
d
8.32 (1H, d, J¼4.8 Hz), 7.70 (1H,
d, J¼7.8 Hz), 7.31 (1H, dd, J¼4.8, 7.8 Hz), 4.94 and 3.97 (2H, AB
system, J¼17.6 Hz), 2.23 (1H, s), 1.36 (9H, s). 13C NMR (CDCl3):
d
153.3 (s), 148.9 (s), 143.9 (d), 139.2 (d), 137.8 (s), 123.2 (d), 82.0 (s),
3.3.2. N-(2-Bromopyridyl)-N-tert-butoxycarbonyl-(3-(3,5-
dichloro-2,4,6-trimethylphenyl)isoxazol-5-yl)methanamine (3b)
Light yellow solid, yield 85%, mp 57–59 ꢀC. Anal. Calcd for
79.0 (s), 73.2 (d), 37.9 (t), 28.3 (3q). MS (ESI) m/z (%): 335.1 (97),
333.1 ([MþNa]þ, 100), 313.1 (55), 311.1 (M, 57), 255.1 (80).
C
23H24BrCl2N3O3 (541.26): C, 51.04; H, 4.47; N, 7.76. Found: C,
52.20; H, 4.39; N, 7.69. Elution solvent: hexane/Et2O 10:1. IR (KBr):
1713, 1601 cmꢁ1 1H NMR (CDCl3):
8.34–8.32 (1H, m), 7.55–7.53
3.2.3. Synthesis of N-(2-iodophenylmethyl)-N-methyl-2-
propynylamine (1c)14
.
d
To a solution of 2-iodobenzylbromide (4 mmol, 119 mg) in
CH2Cl2 (3 mL) cooled at 0 ꢀC, a solution of N-methylpropargyl-
amine (4.6 mmol, 0.39 mL) and triethylamine (6 mmol, 0.83 mL) in
CH2Cl2 (1 mL) was added in 20 min. The mixture was heated to
reflux 6 h then the product purified by silica gel column chro-
(1H, m), 7.30–7.28 (1H, m), 6.16 (1H, s), 5.30 and 4.63 (2H, AB
system, J¼15.9 Hz), 2.56 (3H, s), 2.11 (6H, s), 1.39 (9H, s). 13C NMR
(CDCl3): d 168.8 (s), 162.5 (s), 153.7 (s), 149.3 (d), 144.1 (s), 138.9 (d),
138.2 (s), 134.3 (s), 134.2 (2s), 133.9 (2s), 129.0 (s), 123.6 (d), 105.9
(d), 82.6 (s), 44.2 (t), 28.4 (3q), 19.5 (q), 19.1 (2q). MS (ESI) m/z (%):
566.0 (46), 564.0 ([MþNa]þ, 100), 562 (61), 544.0 (23), 542.0 (M,
50), 540 (30), 488.1 (41), 486.1 (90), 484.1 (55), 413.4 (35), 391.2
(40).
matography. Yellow oil, yield 90%. Anal. Calcd for
C11H12IN
(285.12): C, 46.34; H, 4.24; N, 4.91. Found: C, 46.49; H, 4.18; N,
4.82. Elution solvent: hexane/CH2Cl2 8:1. IR (KBr): 3295,
2102 cmꢁ1
.
1H NMR (CDCl3):
d
7.72–7.70 (1H, m), 7.29–7.27 (2H,
m), 7.09–7.07 (1H, m), 3.90 (2H, s), 3.67 (2H, s), 2.40 (3H, s), 2.19
(1H, s). 13C NMR (CDCl3):
139.7 (d), 130.5 (d), 129.9 (d), 128.3 (d),
3.3.3. N-(2-Iodophenylmethyl)-N-methyl-(3-(3,5-dichloro-
2,4,6-trimethylphenyl)isoxazol-5-yl)methanamine (3c)
White solid, yield 81%, mp 155–158 ꢀC. Anal. Calcd for
d
121.9 (s), 81.4 (s), 79.1 (s), 74.8 (d), 66.0 (t), 52.5 (t), 42.6 (q). MS
(ESI) m/z (%): 286.1 ([MþH]þ, 100).
C
21H21Cl2IN2O (515.2): C, 48.96; H, 4.11; N, 5.44: Found: C, 49.19; H,
4.05; N, 5.50. Elution solvent: hexane/CH2Cl2 5:1. IR (KBr):
1606 cmꢁ1. 1H NMR (CDCl3):
7.73–7.71 (1H, m), 7.30–7.26 (2H, m),
7.08–7.06 (1H, m), 6.10 (1H, s), 3.93 (2H, s), 3.61 (2H, s), 2.51 (3H, s),
2.41 (3H, s), 2.16 (6H, s). 13C NMR (CDCl3):
169.4 (s), 162.4 (s), 143.9
3.2.4. Synthesis of N-(2-(2-bromophenyl)-ethyl)-N-tert-
butoxycarbonyl-2-propynylamine 1d
d
To a solution of N-(tert-butoxycarbonyl)-2-(2-bromophenyl)-
ethylamine15 (1.5 mmol, 450 mg) in benzene (6 mL), tetrabutyl-
ammonium hydrogensulfate (5 mol %, 25 mg), NaOH (6 mmol,
240 mg), and potassium carbonate (1.5 mmol, 207 mg) were added.
The mixture was vigorously stirred for 3 h at rt then a solution of
propargylbromide (1.65 mmol, 0.18 mL) in toluene (3 mL) was
added and the reaction heated at 45 ꢀC for 24 h. After this time
water was added (30 mL) and the solution was extracted with Et2O
(2ꢂ40 mL). The combined organic layer was dried (Na2SO4), fil-
tered, and the solvent evaporated under vacuum. Finally the
product was purified by silica gel column chromatography, eluent
hexane/Et2O 15:1. Light yellow oil, yield 60%. Anal. Calcd for
d
(s), 139.5 (s), 135.9 (s), 134.3 (2s), 133.8 (2s), 130.3 (d), 129.9
(d), 129.1 (d), 128.3 (d), 123.3 (d), 105.8 (s), 66.2 (t), 52.5 (t), 42.4 (q),
19.6 (2q), 19.3 (q). MS (ESI) m/z (%): 517.1 (11), 516.1 (66), 515.1 (M,
100).
3.3.4. N-(2-(2-Bromophenyl)-ethyl)-N-tert-butoxycarbonyl-
(3-(3,5-dichloro-2,4,6-trimethylphenyl)isoxazol-5-yl)-
methanamine (3d)
White solid, yield 95%, mp 94–96 ꢀC. Anal. Calcd for
C
26H29BrCl2N2O3 (568.33): C, 54.95; H, 5.14; N, 4.93: Found: C,
56.03; H, 5.09; N, 5.04. Elution solvent: hexane. IR (KBr): 1695,
1595 cmꢁ1. 1H NMR (CDCl3, mixture 1:1 of rotamers):
7.56–7.54
C
16H20BrNO2 (338.24): C, 56.82; H, 5.96; N, 4.14. Found: C, 56.95; H,
6.03; N, 4.09. IR (KBr): 3496, 2101, 1684 cmꢁ1 1H NMR (CDCl3):
7.53–7.51 (1H, m), 7.25–7.21 (2H, m), 7.09–7.07 (1H, m), 4.06 (2H,
br s), 3.57 (2H, t, J¼7.1 Hz), 3.01 (2H, t, J¼7.1 Hz), 2.21 (1H, s), 1.40
(9H, s). 13C NMR (CDCl3):
155.1 (s), 138.8 (s), 133.0 (d), 131.4 (d),
d
.
(2H, m), 7.27–7.25 (2H, m), 7.13–7.11 (4H, m), 6.14 (1H, s), 6.03 (1H,
s), 4.59 (2H, s), 4.45 (2H, s), 3.63–3.57 (4H, m), 3.04–2.98 (4H, m),
d
2.57 (6H, s), 2.17 (12H, s), 1.39 (18H, s). 13C NMR (CDCl3):
d 169.4 (s),
d
162.4 (s),154.2 (s), 138.5 (s),135.9 (s),134.3 (2s),134.2 (s),133.8 (2s),
133.3 (d), 131.5 (d), 128.8 (d), 128.1 (d), 124.9 (s), 104.4 (d), 81.1 (s),
48.0 (t), 43.2 (t), 35.7 (t), 28.7 (3q), 19.5 (q), 19.1 (2q). MS (ESI) m/z
(%): 592.3 (46), 590.3 ([MþNa]þ, 100), 588.3 (61), 570.3 (9), 568.3
(M, 20), 566.2 (13), 513.1 (41), 511.1 (90), 509.1 (60).
128.3 (d), 127.8 (d), 124.8 (s), 80.5 (s), 80.0 (s), 71.8 (d), 46.7 (t), 36.4
(t), 35.0 (t), 28.5 (3q). MS (ESI) m/z (%): 361.2 (97), 359.2 ([MþNa]þ,
100), 339.1 (39), 337.1 (M, 40), 283.1 (60), 281.1 (90).
3.3. General procedure for the cycloaddition of N,N-
propargylamine derivatives 1a–d and 3,5-dichloro-2,4,6-
trimethylbenzonitriloxide 2: synthesis of compounds 3
3.4. General procedure for the cycloaddition of N,N-
propargylamine derivatives 1a–d and 4-nitrophenylazide 5:
synthesis of triazole derivatives 6
To a solution of compound 1 (1 mmol) in toluene (10 mL) the
nitriloxide 2 (1.1 mmol, 253 mg) was added. After 24 h of reflux the
solvent was evaporated and the residue purified by column chro-
matography on silica gel (eluent see later).
The compounds 1 (3 mmol) and 5 (3 mmol, 492 mg) were sus-
pended in a mixture of tert-butyl alcohol/water 1:1 (10 mL) then
a solution of 1 M sodium ascorbate (0.3 mmol) and Cu2SO4$5H2O
(0.03 mmol, 9 mg) was added. After 24 h under vigorous stirring at
rt the solution was diluted with cold water (50 mL). In the case of
compound 6c a precipitate was formed and recovered by simple
filtration. For other compounds the solution was extracted with
Et2O (2ꢂ40 mL). The combined organic layers were dried (Na2SO4),
filtered, and the solvent evaporated under vacuum. Finally the
product was purified by silica gel column chromatography.
3.3.1. N-(2-Iodophenyl)-N-tert-butoxycarbonyl-(3-(3,5-dichloro-
2,4,6-trimethylphenyl)isoxazol-5-yl)methanamine (3a)
White solid, yield 88%, mp 147–148 ꢀC. Anal. Calcd for
C
24H25Cl2IN2O3 (587.28): C, 49.08; H, 4.29; N, 4.77. Found: C, 49.20;
H, 4.23; N, 4.68. Elution solvent: hexane/CH2Cl2 5:1. IR (KBr): 1703,
1626 cmꢁ1. 1H NMR (CDCl3):
7.90–7.87 (1H, m), 7.32–7.30 (1H, m),
d

8186
L. Basolo et al. / Tetrahedron 64 (2008) 8182–8187
3.4.1. N-(2-Iodophenyl)-N-tert-butoxycarbonyl-(1-(4-nitrophenyl)-
1H-1,2,3-triazol-4-yl)methanamine (6a)
Yellow oil, yield 69%. Anal. Calcd for C20H20IN5O4 (521.3): C,
46.08; H, 3.87; N, 13.43. Found: C, 45.95; H, 3.97; N, 13.36. Elution
solvent: hexane/AcOEt 5:1. IR (KBr): 1699, 1531, 1472 cmꢁ1. 1H NMR
3.5.1. 5-(tert-Butoxycarbonyl)-1-(3,5-dichloro-2,4,6-
trimethylphenyl)-4,5-dihydro-isoxazolo[5,4-c]quinoline (4a)
Light yellow solid, yield 57%, one-pot yield 60%, mp 172–174 ꢀC.
Anal. Calcd for C24H24Cl2N2O3 (459.36): C, 62.75; H, 5.27; N, 6.10.
Found: C, 62.58; H, 5.17; 6.00. Elution solvent: hexane. IR (KBr):
(CDCl3):
d
8.44 (2H, d, J¼8.9 Hz), 8.27 (1H, s), 8.01 (2H, d, J¼8.9 Hz),
1703, 1626 cmꢁ1
.
1H NMR (CDCl3):
d
7.65–7.63 (1H, m), 7.18–7.16
(1H, m), 6.96–7.94 (1H, m), 6.61 (1H, dd, J¼1.5, 7.7 Hz), 5.15 (2H, s),
2.63 (3H, s), 2.16 (6H, s), 1.55 (9H, s). 13C NMR (CDCl3):
166.0 (s),
7.87 (1H, d, J¼7.8 Hz), 7.33 (1H, dd, J¼7.7, 7.8 Hz), 7.17 (1H, d,
J¼7.7 Hz), 7.01 (1H, dd, J¼7.7, 7.8 Hz), 5.06 and 4.55 (2H, AB system,
d
J¼15.3 Hz), 1.39 (9H, s). 13C NMR (CDCl3):
d
154.5 (s), 147.6 (s), 146.5
157.8 (s), 153.2 (s), 136.4 (s),134.6 (s), 134.4 (2s),134.0 (2s),128.0 (s),
127.1 (d), 125.7 (d), 125.4 (d), 121.9 (d), 121.7 (s), 111.9 (s), 82.7 (s),
42.3 (t), 28.5 (3q), 19.4 (q), 18.8 (2q). MS (ESI) m/z (%): 483.0 (11),
482.0 ([MþNa]þ, 66), 481.0 (100), 460.1 (13), 459.1 (M, 20), 404.1
(26), 403.1 (40).
(s), 144.8 (s), 141.6 (s), 139.8 (d), 130.2 (d), 129.6 (2d),129.5 (d),125.9
(d), 122.0 (2d), 120.8 (d), 100.5 (s), 81.4 (s), 45.0 (t), 28.6 (3q). MS
(ESI) m/z (%): 543.1 ([MþNa]þ, 100), 522.1 ([MþH]þ, 75), 466.2 (22).
3.4.2. N-(2-Bromopyridyl)-N-tert-butoxycarbonyl-
(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methanamine (6b)
Yellow oil, yield 68%. Anal. Calcd for C19H19BrN6O4 (475.3): C,
48.01; H, 4.03; N, 17.68. Found: C, 47.80; H, 4.11; N, 17.55. Elution
solvent: hexane/AcOEt 5:1. IR (KBr): 1697, 1528, 1469 cmꢁ1. 1H NMR
3.5.2. 5-(tert-Butoxycarbonyl)-9-(3,5-dichloro-2,4,6-trimethyl-
phenyl)-5,6-dihydro-isoxazolo[5,4-c][1,5]naphthyridine (4b)
White solid, yield 49%, one-pot yield 90%, mp 159–161 ꢀC. Anal.
Calcd for C23H23Cl2N3O3 (460.35): C, 60.01; H, 5.04; N, 9.13. Found:
C, 60.14; H, 4.96; N, 9.08. Elution solvent: hexane/AcOEt 7:1. IR
(CDCl3):
d
8.43 (2H, d, J¼8.4 Hz), 8.33–8.31 (1H, m), 8.26 (1H, s),
8.00 (2H, d, J¼8.4 Hz), 7.63 (1H, d, J¼7.7 Hz), 7.31 (1H, dd, J¼4.9,
(KBr): 1699, 1623 cmꢁ1. 1H NMR (CDCl3):
7.94 (1H, m), 7.09–7.07 (1H, m), 5.30 (2H, s), 2.60 (3H, s), 2.17 (6H, s),
1.57 (9H, s). 13C NMR (CDCl3):
167.8 (s), 158.4 (s), 152.8 (s), 145.7
d 8.12–8.10 (1H, m), 7.96–
7.7 Hz), 5.19 and 4.58 (2H, AB system, J¼15.4 Hz), 1.38 (9H, s). 13
C
NMR (CDCl3):
d
154.0 (s), 148.9 (d), 147.6 (s), 145.9 (s), 145.8 (s),
d
144.0 (s), 141.5 (s), 139.1 (d), 125.9 (d), 123.8 (2d), 121.9 (2d), 120.8
(d), 82.1 (s), 44.5 (t), 28.5 (3q). MS (ESI) m/z (%): 476.0 (97), 474.0 (M,
100), 420.0 (32), 418.0 (33).
(d), 141.3 (s), 135.7 (s), 134.5 (2s), 133.4 (2s), 131.4 (d), 131.3 (s), 127.9
(s), 121.3 (d), 113.4 (s), 83.4 (s), 42.6 (t), 28.5 (3q), 19.4 (q), 19.1 (q),
14.3 (q). MS (ESI) m/z (%): 483.1 ([MþNa]þ, 26), 482.1 (40), 462.2
(11), 461.2 (66), 460.2 (M, 100), 405.2 (10), 404.2 (15).
3.4.3. N-(2-Iodophenylmethyl)-N-methyl-(1-(4-nitrophenyl)-1H-
1,2,3-triazol-4-yl)methanamine (6c)
3.5.3. 1-(3,5-Dichloro-2,4,6-trimethylphenyl)-5-methyl-5,6-
dihydro-4H-isoxazolo[5,4-d][2]benzazepine (4c)
White solid, yield 80%, mp 115–116 ꢀC. Anal. Calcd for
C
17H16IN5O2 (402.25): C, 45.45; H, 3.59; N,15.59. Found: C, 45.29; H,
White solid, yield 15%, one-pot yield 12%, mp 201–203 ꢀC.
Anal. Calcd for C21H20Cl2N2O (387.3): C, 65.12; H, 5.20; N, 7.23.
Found: C, 65.33; H, 5.16; N, 7.17. Elution solvent: CH2Cl2. IR (KBr):
3.46; N, 15.45. IR (KBr): 1526, 1441 cmꢁ1 1H NMR (CDCl3):
.
d
8.42
(2H, d, J¼8.8 Hz), 8.08 (1H, s), 7.98 (2H, d, J¼8.8 Hz), 7.86 (1H, d,
J¼7.8 Hz), 7.47 (1H, d, J¼7.4 Hz), 7.34 (1H, dd, J¼7.4, 7.8 Hz), 6.97
(1H, dd, J¼7.4, 7.8 Hz), 3.91 (2H, s), 3.67 (2H, s), 2.36 (3H, s). 13C NMR
1628 cmꢁ1
.
1H NMR (CDCl3):
d
7.19–7.21 (2H, m), 7.09–7.07 (1H,
m), 6.59–6.57 (1H, m), 4.14 (2H, s), 3.79 (2H, s), 2.51 (3H, s), 2.41
(3H, s), 2.16 (6H, s). 13C NMR (CDCl3):
157.8 (s), 153.2 (s), 134.1
(CDCl3):
d
147.8 (s), 147.5 (s), 141.7 (s), 141.1 (s), 140.1 (d), 130.9 (d),
d
129.4 (d), 128.5 (d), 125.9 (2d), 121.0 (d), 120.8 (2d), 101.0 (s), 66.0
(t), 52.5 (t), 42.6 (q). MS (ESI) m/z (%): 424.2 ([MþNa]þ, 80), 402.2
(M, 100).
(2s), 133.4 (2s), 131.0 (2s), 128.2 (s), 127.3 (s), 125.4 (d), 125.0 (d),
123.1 (d), 122.9 (d), 107.9 (s), 52.5 (t), 52.3 (t), 19.2 (q), 18.5 (3q).
MS (ESI) m/z (%): 411.3 (11), 410.3 ([MþNa]þ, 66), 409.3 (100),
388.2 (26), 387.2 (M, 40).
3.4.4. N-(2-(2-Bromo)phenyl-ethyl)-N-tert-butoxycarbonyl-
(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methanamine (6d)
Light yellow oil, yield 33%. Anal. Calcd for C22H24BrN5O4
(502.36): C, 52.60; H, 4.82; N, 13.94. Found: C, 52.49; H, 4.74; N,
13.82. Elution solvent: hexane/Et2O 3:1. IR (KBr): 1689, 1527,
3.5.4. 5-(tert-Butoxycarbonyl)-1-(4-nitrophenyl)-[1,2,3]triazolo-
[4,5-c]quinoline (7a)
Orange solid, yield 50%, one-pot yield 73%, mp 108–109 ꢀC. Anal.
Calcd for C20H19N5O4 (393.4): C, 61.06; H, 4.87; N, 17.80. Found: C,
60.91; H, 4.92; N, 17.71. Elution solvent: hexane/AcOEt 10:1. IR
1458 cmꢁ1. 1H NMR (CDCl3):
d
8.39 (2H, d, J¼8.9 Hz), 8.12 (1H, s),
7.96 (2H, d, J¼8.9 Hz), 7.50 (1H, d, J¼7.6 Hz), 7.21 (1H, dd, J¼7.5,
7.6 Hz), 7.14 (1H, d, J¼6.6 Hz), 7.06 (1H, dd, J¼7.5, 6.6 Hz), 4.52–4.58
(2H, m), 3.60 (2H, s), 2.99–3.05 (2H, m), 1.39 (9H, s). 13C NMR
(KBr): 1697, 1530, 1454 cmꢁ1 1H NMR (CDCl3):
. d 8.47 (2H, d,
J¼8.9 Hz), 7.87 (2H, d, J¼8.9 Hz), 7.76 (1H, d, J¼8.3 Hz), 7.36 (1H,
ddd, J¼1.6, 7.4, 8.3 Hz), 7.06 (1H, dd, J¼7.4, 7.8 Hz), 7.00 (1H, dd,
(CDCl3):
d
156.0 (s), 147.5 (s), 141.6 (s), 138.8 (s), 133.2 (d), 133.0 (s),
J¼1.6, 7.8 Hz), 5.11 (2H, s), 1.58 (9H, s). 13C NMR (CDCl3):
d 153.2 (s),
131.6 (d), 128.6 (d), 127.9 (d), 125.9 (2d), 125.0 (s), 121.4 (d), 120.8
(2d), 80.6 (s), 48.0 (t), 42.7 (t), 35.6 (t), 28.7 (3q). MS (ESI) m/z (%):
503.1 (97), 501.1 (M, 100), 447.1 (29), 445.1 (30).
148.6 (s), 144.9 (s), 141.9 (s), 137.5 (s), 130.0 (s), 129.7 (d), 127.3 (d),
126.0 (2d), 125.6 (2d), 125.3 (d), 123.2 (d), 118.4 (s), 82.8 (s), 42.1 (t),
28.7 (3q). MS (ESI) m/z (%): 416.1 ([MþNa]þ, 100), 394.0 (M, 80),
338.2 (20).
3.5. General procedure for the arylation reaction: syntheses
of compounds 4 and 7
3.5.5. 5-(tert-Butoxycarbonyl)-1-(4-nitrophenyl)-5,6-dihydro-1H-
[1,2,3]triazolo[4,5-c][1,5]naphthyridine (7b)
The quartz reactor of a microwave oven was charged with a
solution of 3 or 6 (0.5 mmol) in DMA (4 mL) then Pd(OAc)2
(0.025 mmol, 5.6 mg), tetrabutylammonium chloride (0.5 mmol,
139 mg), and potassium acetate (1 mmol, 98 mg) were added. The
mixture was heated with microwaves for 1 h at 120 ꢀC and 400 W.
After cooling, brine (30 mL) was added and the mixture extracted
with Et2O (3ꢂ30 mL). The combined organic layer was dried
(Na2SO4), filtered, and the solvent was evaporated under vacuum.
Finally the product was purified by silica gel column
chromatography.
Orange solid, yield 28%, one-pot yield 30%, mp 153–155 ꢀC. Anal.
Calcd for C19H18N6O4 (394.38): C, 57.86; H, 4.60; N, 21.31. Found: C,
58.02; H, 4.52; N, 21.22. Elution solvent: hexane/AcOEt 10:1. IR
(KBr): 1711, 1526, 1456 cmꢁ1 1H NMR (CDCl3):
. d 8.40 (2H, d,
J¼8.9 Hz), 8.21 (1H, d, J¼3.7 Hz), 8.10 (1H, d, J¼8.4 Hz), 8.02 (2H, d,
J¼8.9 Hz), 7.27 (1H, dd, J¼3.7, 8.4 Hz), 5.19 (2H, s), 1.56 (9H, s). 13
C
NMR (CDCl3): d 152.9 (s),148.2 (s),146.2 (s),145.3 (d),141.9 (s),137.8
(s), 134.5 (s), 133.3 (d), 129.5 (s), 126.2 (2d), 124.6 (2d), 123.9 (d),
83.5 (s), 42.4 (t), 28.6 (3q). MS (ESI) m/z (%): 417.1 ([MþNa]þ, 50),
395.0 (M, 100).

L. Basolo et al. / Tetrahedron 64 (2008) 8182–8187
8187
3.5.6. 5-Methyl-1-(4-nitrophenyl)-1,4,5,6-tetrahydro-[1,2,3]-
triazolo[4,5-d][2]benzazepine (7c)
400 W. Then brine was added (30 mL) and the mixture extracted
with Et2O (3ꢂ30 mL). The combined organic layer was dried
(Na2SO4), filtered, and the solvent was evaporated under vacuum.
Finally the product was purified by silica gel column
chromatography.
Yellow oil, yield 34%, one-pot yield 35%. Anal. Calcd for
C
17H15N5O2 (321.33): C, 63.54; H, 4.71; N, 21.79. Found: C, 63.68; H,
4.64; N, 21.70. Elution solvent: hexane/Et2O 3:1. IR (KBr): 1526,
1440 cmꢁ1 1H NMR (CDCl3):
.
d
8.38 (2H, d, J¼8.9 Hz), 7.67 (2H, d,
J¼8.9 Hz), 7.41 (1H, d, J¼6.7 Hz), 7.36 (1H, dd, J¼7.4, 6.7 Hz), 7.18
(1H, dd, J¼7.4, 7.8 Hz), 6.88 (1H, d, J¼7.8 Hz), 4.14 (2H, s), 3.79 (2H,
3.8. General one-pot procedure for compounds 7
s), 2.53 (3H, s). 13C NMR (CDCl3):
d 148.1 (s), 145.4 (s), 142.4 (s), 139.1
The quartz reactor of microwave oven was charged with a so-
lution of 1a–c (0.5 mmol) in DMA (3.5 mL) then azide 5 (0.6 mmol,
98 mg), triethylamine (0.5 mmol, 0.07 mL), and CuI (0.2 mmol,
38 mg) were added and the mixture heated for 1 h at 50 ꢀC and
300 W power. After this period Pd(OAc)2 (0.025 mmol, 5.6 mg),
tetrabutylammonium chloride (0.5 mmol, 139 mg), and potassium
acetate (1 mmol, 98 mg) were added. The mixture was heated again
for 1 h at 120 ꢀC (150 ꢀC for 1d) and 400 W. After cooling, brine was
added (30 mL) and the mixture extracted with Et2O (3ꢂ30 mL). The
combined organic layer was dried (Na2SO4), filtered, and the sol-
vent was evaporated under vacuum. Finally the product was puri-
fied by silica gel column chromatography.
(s),133.1 (s), 131.3 (d),129.8 (d),128.5 (d),128.0 (d),126.1 (2d),125.9
(s), 125.4 (2d), 59.5 (t), 53.9 (t), 44.9 (q). MS (ESI) m/z (%): 343.3
([MþNa]þ, 100), 321.3 (M, 65).
3.6. General procedure for the arylation reaction: syntheses
of compounds 4d and 7d
The quartz reactor of a microwave oven was charged with a so-
lution of 3d or 6d (0.5 mmol) in DMF (5 mL) then Pd(OAc)2
(0.025 mmol, 5.6 mg), triphenylphosphine (0.05 mmol, 13 mg), CuI
(1 mmol, 190 mg), and cesium carbonate (1 mmol, 326 mg) were
added. The mixture was heated with microwaves for 1 h at 150 ꢀC
and 400 W. After cooling, brine (30 mL) was added and the mixture
extracted with Et2O (3ꢂ30 mL). The combined organic layer was
dried (Na2SO4), filtered, and the solvent was evaporated under
vacuum. Finally the product was purified by silica gel column
chromatography.
Acknowledgements
The authors gratefully acknowledge the MUR for financial
support.
References and notes
3.6.1. 5-(tert-Butoxycarbonyl)-1-(3,5-dichloro-2,4,6-trimethyl-
phenyl)-4,5,6,7-tetrahydro-isoxazolo[5,4-e][3]benzazocine (4d)
White solid, yield 38%, one-pot yield 49%, mp 218–220 ꢀC
(decomp.). Anal. Calcd for C26H28Cl2N2O3 (487.42): C, 64.07; H,
5.79; N, 5.75. Found: C, 64.20; H, 5.70; N, 5.82. Elution solvent:
1. (a) Bonjouklian, R.; Cohen, J. D.; Gruber, J. M.; Johnson, D. W.; Jungheim, L. N.;
Kroin, J. S.; Lander, P. A.; Lin, H.-s.; Lohman, M. C.; Muehl, B. S.; Norman, B. H.;
Patel, V. F.; Richett, M. E.; Thrasher, K. J.; Vepachedu, S.; White, W. T.; Xie, Y.;
York, J.; Schulenburg P.; Brandon L. PCT WO 2001046199, 2001 (Eli Lilly and Co.,
USA); Chem. Abstr. 2001, 135, 76865; (b) Bonjouklian, R.; Johnson, D. W.; Lander,
P. A.; Lohman, M. C.; Patel, V. F.; Vepachedu, S.; Xie, Y. PCT WO 2001027116,
2001 (Eli Lilly and Co., USA); Chem. Abstr. 2000, 134, 311201; (c) Merrill, B. A.;
Danielson, M. E.; Hays, D. S.; Amos, D. T.; Heppner, P. D.; Kshirsagar, T. A.;
Lundquist, G. D., Jr.; Moser, W. H. PCT WO 2006107771, 2006 (3M Innovative
Properties Co.); Chem. Abstr. 2006, 145, 419140; (d) Hays, D. S.; Prince, R. B.;
Haraldson, C. A.; Bonk, J. D. PCT WO 2006107851, 2006 (3M Innovative Prop-
erties Co.); Chem. Abstr. 2006, 145, 419133; (e) Suzuki, F.; Kuroda, T.; Nakasato,
Y.; Manabe, H.; Ohmori, K.; Kitamura, S.; Ichikawa, S.; Ohno, T. J. Med. Chem.
1992, 35, 4045.
2. (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Synthesis 2008,
136; (b) Abbiati, G.; Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.
Synlett 2006, 73; (c) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.;
Rossi, E. Synthesis 2006, 2404; (d) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Paladino, G.; Zoni, C. Eur. J. Org. Chem. 2005, 2091; (e) Beccalli, E. M.; Broggini,
G.; Paladino, G.; Penoni, A.; Zoni, C. J. Org. Chem. 2004, 69, 5627.
3. Beccalli, E. M.; Broggini, G.; Martinelli, M.; Masciocchi, N.; Sottocornola, S. Org.
Lett. 2006, 8, 4521.
4. (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (b) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36,1173; (c) Campeau, L.-C.; Stuart, D. R.;
Fagnou, K. Aldrichimica Acta 2007, 40, 35; (d) Bellina, F.; Cauteruccio, S.; Rossi, R.
J. Org. Chem. 2007, 72, 8543; (e) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 581; (f) Garcia-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066; (g) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; (h) Glover, B.; Harvey,
K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301.
5. Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, NY, 1984; pp 1–95.
hexane/Et2O 7:3. IR (KBr): 1697,1622 cmꢁ1. 1H NMR (CDCl3):
d 7.25–
7.21 (2H, m), 6.97–6.95 (1H, m), 6.59–6.57 (1H, m), 4.24–4.15 (2H,
m), 3.43–3.41 (2H, m), 2.95–2.82 (2H, m), 2.55 (3H, s), 2.53 (6H, s),
1.46 (9H, s). 13C NMR (CDCl3):
d 166.4 (s), 162.4 (s), 153.2 (s), 136.9
(s), 136.4 (2s), 135.8 (s), 130.3 (s), 129.1 (2s), 129.0 (d), 128.7 (d),
128.6 (d), 128.5 (d), 127.3 (s), 127.0 (s), 80.4 (s), 49.7 (t), 45.2 (t), 33.5
(t), 28.5 (2q), 28.0 (3q), 19.5 (q). MS (ESI) m/z (%): 511.3 (9), 510.3
(60), 509.3 ([MþNa]þ, 90), 487.4 (M, 8), 476.4 (12), 475.4 (18), 453.4
(5), 433.4 (11), 432.4 (66), 431.4 (100), 397.5 (20).
3.6.2. 5-(tert-Butoxycarbonyl)-1-(4-nitrophenyl)-4,5,6,7-
tetrahydro-1H-[1,2,3]triazolo[4,5-e][3]benzazocine (7d)
Orange solid, yield 17%, one-pot yield 40%, mp 133–135 ꢀC. Anal.
Calcd for C22H23N5O4 (421.45): C, 62.70; H, 5.50; N, 16.62. Found: C,
62.80; H, 5.42; N, 16.55. Elution solvent: hexane/AcOEt 10:1. IR
(KBr): 1690, 1528, 1458 cmꢁ1 1H NMR (CDCl3):
. d 8.23 (2H, d,
J¼8.9 Hz), 7.44–7.40 (2H, m), 7.34 (2H, d, J¼8.9 Hz), 7.08–7.06 (1H,
m), 6.71 (1H, d, J¼7.8 Hz), 5.35 (1H, d, J¼17.2 Hz), 4.38 (1H, d,
J¼17.2 Hz), 4.16–4.14 (1H, m), 3.57–3.45 (1H, m), 3.06–2.90 (2H, m),
1.37 (9H, s). 13C NMR (CDCl3):
d 155.2 (s),147.7 (s),145.4 (s),141.8 (s),
138.4 (s), 132.1 (s), 131.1 (d), 130.7 (d), 130.3 (d), 127.4 (d), 126.5 (s),
126.1 (2d),125.1 (2d), 80.1 (s), 49.7 (t), 45.0 (t), 34.2 (t), 27.7 (3q). MS
(ESI) m/z (%): 443.2 ([MþNa]þ, 100), 421.2 (M, 80), 366.2 (40).
6. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
7. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596.
8. Rappoport, Z. In Supplement C2, The Chemistry of Triple-Bonded Functional
Groups; Patai, S., Ed.; Wiley and Sons: New York, NY, 1983; pp 529–534.
9. Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett. 2007, 9,
2333.
3.7. General one-pot procedure for compounds 4
10. Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449.
The quartz reactor was charged with
a solution of 1a–
´
´
11. For the definition of telescoped process: Rodrıguez Gonzalez, R.; Gambarotti, C.;
Liguori, L.; Bjørsvik, H.-R. J. Org. Chem. 2006, 71, 1703.
12. Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. J. Med.
Chem. 1988, 31, 2136.
d (0.5 mmol) in DMA (3.5 mL) then nitriloxide 3 was added
(0.6 mmol, 138 mg) and the mixture heated for 1 h at 100 ꢀC and
300 W (130 ꢀC, 400 W for 1d). After this period Pd(OAc)2
(0.025 mmol, 5.6 mg), tetrabutylammonium chloride (0.5 mmol,
139 mg), and potassium acetate (1 mmol, 98 mg) were added. The
mixture was heated again for 1 h at 120 ꢀC (150 ꢀC for 1d) and
13. Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5, 2214.
14. Yokoyama, M.; Kawano, S.; Sugiyama, K. JP 39015673, 1964 (Eisai Co., Ltd.);
Chem. Abstr. 1965, 62, 6431.
15. Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35.