Synthesis of N-Heteroaromatic Compounds through Cyclocarbonylative Sonogashira Reactions

Article abstract of DOI:10.1002/ejoc.201601392

A protocol based on cyclocarbonylative Sonogashira reactions has been developed for the synthesis of nitrogen-containing heterocycles. The process is carried out under CO pressure, in the presence of a small amount of PdCl₂(PPh₃)

Full text of DOI:10.1002/ejoc.201601392

A Journal of
Accepted Article
Title: A new synthesis of N-heteroaromatic compounds via
cyclocarbonylative Sonogashira reactions
Authors: Laura Antonella Aronica, Gianluigi Albano, Luca Giannotti,
and Elisa Meucci
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10.1002/ejoc.201601392
European Journal of Organic Chemistry
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A new synthesis of N-heteroaromatic compounds via
cyclocarbonylative Sonogashira reactions
Laura Antonella Aronica*[a], Gianluigi Albano[a], Luca Giannotti[a] and Elisa Meucci[a]
Abstract: In this study, a protocol based on cyclocarbonylative
Sonogashira reactions has been developed for the synthesis of
N-containing heterocycles. The process is carried out under CO
pressure, in the presence of a small amount of PdCl2(PPh3)2
(0.2-0.4 mol%) as catalytic precursor and without copper salts
as co-catalyst. Suitable tosylamides reacted successfully with
iodoarenes bearing both electron withdrawing and electron
(Scheme 1).
donating
methylbenzenesulfonamide
groups.
In
particular
afforded
N-(2-ethynylbenzyl)-4-
carbonylmethylene
Figure 1. Indole, isoindole and isoindoline scaffolds.
isoindolines with complete chemo-stereoselectivity. On the other
hand, the reaction between iodoarenes and N-(2-
ethynylphenethyl)-4-methylbenzenesulfonamide did not yield
tetrahydroisoquinolines as expected, but dihydrobenzoazepines
were obtained.
Introduction
The chemistry of heterocycles has attracted much attention in
recent times due to its increasing importance in the field of
pharmaceuticals and industrial chemicals. In particular, N-
containing heterocycles are important substructures found in
numerous natural or synthetic alkaloids[1] and are the basis for
industrial applications such as pigments, brighteners for coatings
and organic fluorophors for electrolumiscent devices[2].
Scheme 1. Synthesis of dihydroisobenzofuranes and isochromanes.
In this paper we present an extension of our protocol to benzylic
and homobenzylic amines in order to investigate the application
of this method to the synthesis of N-containing heterocycles
such as isoindolines and tetrahydroisoquinolines (Scheme 2).
Therefore, several procedures dedicated to the construction of
such heterocycles have been developed. Many of them are
based on cyclization of suitable substrates. For instance indole
derivatives (Figure 1, a) can be generated[3] via multicomponent
processes, transition metal-catalysed intramolecular C-H
activation, hydroamination of alkynes and cyclisation of
alkynylanilines. On the other hand isoindoles (Figure 1, b) can
be obtained[4] by means of cycloisomerization reactions and 1,3-
dipolar cycloadditions of azides, nitrogen ylides or isocyanides.
The hydrogenated analogue of isoindole is isoindoline, whose
scaffold (Figure 1, c) represents a useful building block for the
synthesis of biologically active compounds[5]. Isoindolines may
be prepared[6] starting from chalcones and glycine through a
cascade process involving aza-Michael addition and
decarboxylation steps, via [2+2+2] cycloaddition reactions of
suitable alkynes and diyines and by TBAF promoted cyclisation
of ethynylbenzylamine derivatives.
Scheme 2. Possible synthesis of isoindolines and tetrahydroisoquinolines.
Recently we reported[7] that 1,3-dihydroisobenzofuranes and
isochromanes can be easily obtained starting from suitable
alkynylalcohols via cyclocarbonylative Sonogashira reaction
Results and Discussion
We started our study with the synthesis of (2-
ethynylphenyl)methanamine (1) which was obtained according
to the sequence depicted in Scheme 3. Commercially available
2-iodobenzonitrile (2) was submitted to a Sonogashira reaction
with trimethylsilylacetylene affording the coupling product 3 in
high yield. Subsequent desilylation and reduction of the nitrile
moiety generated the desired product 1.
[a]
Dipartimento di Chimica e Chimica Industriale
University of Pisa
Via G. Moruzzi 13, 56124 Pisa, Italy
Fax: (+)390502219260
E-mail: laura.antonella.aronica@unipi.it
Supporting information for this article is given via a link at the end of
the document
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Scheme 3. Synthesis of (2-ethynylphenyl)methanamine (1).
Scheme 6. Synthesis of N-(2-ethynylbenzyl)-4-methylbenzenesulfonamide
(8b).
Unfortunately, when ethynylbenzylamine 1 was reacted with
iodobenzene (5a) under cyclocarbonylative Sonogashira
experimental conditions (CO, PdCl2(PPh3)2, Et3N, 100°C)[7] no
isoindoline derivative was obtained (Scheme 4), even if a total
consumption of both reagents was observed together with the
formation of significant amounts of unidentified by-products.
A preliminary cyclocarbonylative Sonogashira reaction was
performed reacting tert-butyl 2-ethynylbenzylcarbamate (8a) with
iodobenzene (5a) in a triethylamine/toluene mixture, at 100°C,
with PdCl2(PPh3)2 (0.2 mol%) and under 20 atmosphere of CO
(Scheme 7, Table 1 entry 1). After 4h, a complete consumption
1
of the reagents was observed but H-NMR analysis highlighted
the formation of two different products in a 19/81 ratio. Indeed,
after purification isoindoline 12aa was isolated with a 14% yield,
while
tert-butyl
2-(3-oxo-3-phenylprop-1-yn-1-
yl)benzylcarbamate (13) resulted to be the principal product
(Scheme 7, 49%), deriving from carbonylative Sonogashira
coupling between iodobenzene (5a) and the alkynyl moiety of
amide 8a before cyclization[7].
Scheme 4. Reaction of (2-ethynylphenyl)methanamine (1) with iodobenzene
(5a) under Sonogashira cyclocarbonylative conditions.
This result could tentatively be ascribed to a chemical instability
of the isoindoline derivative under the experimental conditions or
to a possible interaction between NH2 moiety and palladium
complex which could change its catalytic activity. In order to
avoid these side effects, we decided to protect the amine 1 with
tert-butylcarbamoyl and tosyl groups. The corresponding amides
were easily synthesized starting from commercial precursors N-
Boc-2-bromobenzylamine (6) and 2-iodonitrile (2) as described
Scheme 7. Cyclocarbonylative reaction of tert-butyl 2-ethynylbenzylcarbamate
(8a).
in Schemes
5
and
6
respectively. Indeed, N-Boc-2-
bromobenzylamine (6) was coupled with trimethylsilylacetylene
generating intermediate 7 which was then desilylated by means
of tetrabutylamonium fluoride affording N-BOC amide 8a
(Scheme 5).
Even though Baldwin’s rules[8] allow the formation of both 5-exo-
dig and 6-endo-dig derivatives, no traces of the possible
dihydroisoquinoline were detected. Moreover, the formation of
the five-membered isoindoline
12aa
resulted
totally
stereoselective, i.e. only the E isomer was obtained. According
to our previous work on the cyclocarbonylative reactions of
ethynylbenzylalcohols, the configuration of 12aa was determined
by means of the analysis of its 1H-NMR spectrum. Indeed,
proton Ha was found at an unusually high chemical shift (9.08
ppm), due to its strong interaction with the carbonyl deshielding
cone (Figure 2).
Scheme 5. Synthesis of tert-butyl 2-ethynylbenzylcarbamate (8a).
Reduction of 2-iodonitrile
2
treatment of the obtained
benzylamine with p-toluenesulphonyl chloride and
9
Sonogashira-desilylation sequence performed on tosylamide 10
afforded N-(2-ethynylbenzyl)-4-methyl benzenesulfonamide (8b)
in good yield (Scheme 6).
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To our delight, the cyclocarbonylative Sonogashira reaction of
8b yielded quantitatively (E)-1-phenyl-2-(2-tosylisoindolin-1-
ylidene)ethanone (12ab) with complete stereoselectivity (Table 1,
entry 3). Moreover, the reaction time could be reduced till 2h
without loss of conversion or selectivity (Table 1, entries 3-6).
On the contrary, the decrease of the temperature from 100 to
30°C resulted in a dramatic reduction of chemoselecivity. Indeed,
in this case, a small quantity of the desired product 12ab was
Figure 2. E configuration of tert-butyl 1-(2-oxo-2-phenylethylidene)isoindoline-
2-carboxylate (12aa).
formed, together with
a large amount of 4-methyl-N-(2-
(phenylethynyl)benzyl)benzenesulfonamide (14) (Schema 8)
derived from non carbonylative Sonogashira reaction of
iodobenzene (5a) with tosylamide 8b.
When the cyclocarbonylative reaction of amide 8a with
iodobenzene (5a) was carried out for a longer reaction time
(24h), higher chemoselectivity towards the cyclization product
12aa was observed (86%, Table 1, entry 2).
Table 1. Cyclocarbonylative Sonogashira reactions of amides 8 and
aryliodides 5.
Scheme 8. Sonogashira cyclocarbonylative reaction of N-(2-ethynylbenzyl)-4-
methylbenzenesulfonamide (8b) and iodobenzene (5a) at 30°C.
As a consequence, 100°C was chosen as operation temperature
and the cyclocarbonylation process was extended to iodoarenes
5 having both electron donating and electron withdrawing
substituents in ortho or para position. As described in Table 1
(entries 8-12), a quantitative conversion of the reagents was
detected in all experiments after 2-4hs and the reactions
generated the isoindolines 12ab-fb with good yields (55-72%,
not optimized) and complete stereoselectivity towards the
formation of the (E)-isomer, regardless the stereo-electronic
features of the aryl iodides employed.
Prompted by the good results obtained with the Sonogashira
carbonylative reactions of ethynyl benzyl amide 8b and aryl
iodides, we decided to extend our investigation to the reactivity
of N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide (15)
(Figure 3).
Entry[a]
Ar
5
X
8
t
12
Selectivity[b]
(h)
1
Ph
a
a
a
a
a
a
b
b
c
d
e
f
Boc
a
a
b
b
b
b
b
b
b
b
b
b
4
aa
aa
ab
ab
ab
ab
bb
bb
cb
db
eb
fb
19 (14)
86
2
Ph
Boc
24
24
8
3
Ph
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
100 (72)
100
4
Ph
5
Ph
4
100
6
Ph
2
100
7[c]
8
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-NCC6H4
2-naphthyl
2-MeOC6H4
2
100
4
100 (72)
100 (65)
100 (60)
100 (68)
100 (55)
9
4
10
11
12
4
4
Figure 3. N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide (15).
4
[a] Reactions were carried out with 8 (0.5-1 mmol), 5 (0.6-1.2 mmol),
PdCl2(PPh3)2 (0.2 mol%), in Et3N (1.5-3 mL) and toluene (1-2 mL), at
100°C, under CO (2.0 MPa). Conversions (100% unless otherwise
specified) were evaluated by GC and 1H-NMR spectroscopic analysis. [b]
Selectivity was estimated by 1H-NMR spectroscopy; isolated yields of
pure products are reported in parentheses. [c] 60% conversion was
observed in this run.
The homobenzylic amide 15 was easily prepared following the
same synthetic sequence used for N-(2-ethynylbenzyl)-4-methyl
benzenesulfonamide (8b) (Scheme 9). Indeed, 2-(2-
Iodophenyl)acetonitrile
corresponding amine 17 which was then protected with the tosyl
group affording N-(2-iodophenethyl)-4-
methylbenzenesulfonamide (18). Subsequent
ethynylation/desilylation steps yielded amide 15 (70%).
(16)
was
converted
into
the
In order to verify if the results obtained with benzylcarbamate 8a
could be ascribed to its steric hindrance, tosyl derivative 8b was
tested under the same experimental conditions.
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It is noteworthy that the generation of the seven membered ring
is permitted by Baldwin rules since a 7-endo-dig cyclisation is
favored compared with the 6-exo-dig one[8].
Scheme 9. Synthesis of N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide
(15).
Scheme 10. Conformational isomers of phenyl(3-tosyl-2,3-dihydro-1H-
benzo[d]azepin-4-yl)methanone (21a).
A preliminary cyclocarbonylative Sonogashira reaction was
performed
between
N-(2-ethynylphenethyl)-4-
methylbenzenesulfonamide (15) and iodobenzene (5a), under
the experimental conditions previously optimised for the tosyl
derivative 8b, i.e. 20 atm CO, 100°C, 0.2 mol % PdCl2(PPh3)2, in
a toluene-triethylamine mixture. After 4h, the 1H-NMR analysis of
the crude product indicated a complete conversion of the
reagents and the formation of three main compounds. In
particular, 13C-NMR spectrum showed the signals of three CO
groups (177.69, 191.28, 193.28 ppm) together with those of two
acetylenic carbon atoms (90.77, 91.18 ppm). When the crude
product was purified by means of silica gel column
chromatography, a partial decomposition occurred, but small
amounts of the products were obtained. First, 4-methyl-N-(2-(3-
oxo-3-phenylprop-1-yn-1-yl)phenethyl)benzenesulfonamide (20)
(Figure 4), deriving from carbonylative Sonogashira reaction
(see also Scheme 7) was isolated, thus confirming the observed
13C-NMR C=O and C≡C signals.
The serendipitous formation of the dihydrobenzoazepine
derivatives was extremely interesting considering that these
substrates could be precursors to the corresponding
tetrahydrobenzoazepines which have been studied for more
than 30 years due to their very important biological and
pharmacological properties[9].
A
few
tests
reacting
N-(2-ethynylphenethyl)-4-
methylbenzenesulfonamide (15) with iodobenzene (5a) under
different experimental conditions have been performed in order
to optimise the chemoselectivity of the cyclocarbonylative
Sonogashira process (Table 2).
Table 2. Cyclocarbonylative Sonogashira reactions between amide 15
and iodobenzene (5a).
Selectivity (%)[b]
(s-trans/s-cis)
Entry[a]
Pd (mol%)
t (h)
T (°C)
Figure 4. 4-methyl-N-(2-(3-oxo-3-phenylprop-1-yn-1-
yl)phenethyl)benzenesulfonamide (20).
1
0.2
4
100
100
100
110
50
80[c] (40/60)[d]
91[c] (64/36)
93[c] (65/35)
100 (60/40)
68[c] (36/64)[d]
75[f] (67/33)
2
0.4
0.4
0.4
0.4
5
4
The analysis of 1H-NMR, 13C-NMR and LC-MS spectra of a
second chromatographic fraction indicated the unexpected
formation of phenyl(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-
yl)methanone (21a) as a mixture of two conformational isomers
(s-trans and s-cis). Under the spectra recording conditions (20°C,
CDCl3), the interconversion equilibrium of these compounds was
shifted towards the s-trans conformer (60/40, Scheme 10). This
result was in agreement with molecular mechanics calculations
(MMFF as a force field) that predicted higher energy for the s-cis
isomer (+0.5 Kcal/mol). The structure of both conformers was
confirmed by ROESY (Rotating frame Overhauser Effect
Spectroscopy) experiments which evidenced not only the
correlation between vinylic Ha, Ha’ and aromatic Hb, Hb’
hydrogens (Scheme 10) , but also the presence of cross peaks
due to proton exchange of the two isomers.
3[e]
4
6
6
5
24
24
6
50
[a] Reactions were performed with 15 (0.5-1 mmol), 5a (0.6-1.2 mmol), in
Et3N (1.5-3 mL) and toluene (1-2 mL), under CO (2.0 MPa). [b] Selectivity
was estimated by 1H-NMR spectroscopy of crude products; conformers
ratio is reported in parentheses. [c] Remainder of product is 4-methyl-N-
(2-(3-oxo-3-phenylprop-1-yn-1-yl)phenethyl)benzenesulfonamide (20). [d]
After purification the conformer ratio resulted always around 60/40 (s-
trans/s-cis). [e] Reaction carried out under CO 4.0 MPa pressure. [f]
Remainder of product is 20 (15%) and N,N'-((buta-1,3-diyne-1,4-
diylbis(2,1-phenylene))bis(ethane-2,1-diyl))bis(4-
methylbenzenesulfonamide) (22).
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As reported in Table 2, all the reactions proceeded with
complete conversion of the reagents, but a substantial increase
of the selectivity was observed when a major amount of catalyst
was employed (Table 2, entries 1,2). Longer reaction times or
higher CO pressure did not improve effectively the reaction
(Table 2, entry 3), while, when the cross coupling was performed
Figure 6. By-products generated in the reaction of 4-iodobenzonitrile (5d) with
N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide (15).
1
at 110°C and in the presence of 0.4 mol% of PdCl2(PPh3)2, H-
NMR analysis showed the exclusive formation of the two
conformers of dihydrobenzoazepine 21a (Table 2, entry 4). The
last result indicated an important effect of the temperature on the
selectivity of the reaction. Two more tests were then carried out
at 50°C but in both cases relevant amount of by-products were
detected (Table 2, entries 5,6). In particular, not only the
carbonylated derivative 20 was present in the reaction mixture
but also the formation of N,N'-((buta-1,3-diyne-1,4-diylbis(2,1-
phenylene))bis(ethane-2,1-diyl))bis(4-ethylbenzenesulfonamide)
(22) was detected (Figure 5).
The formation of 23 was easily ascribed to a direct Sonogashira
reaction of tosylamide 15 with 5d. On the other hand, the
presence of 24 could be explained with a detosylation of
benzoazepine 21d probably favoured by the presence of a
strong electronwithdrawing group (CN) and by the formation of
an intramolecular hydrogen bond (Figure 6).
Table 3. Cyclocarbonylative Sonogashira reactions of amide 15 with
iodoarenes 5.
Selectivity (%)[b]
(s-trans/s-cis)
Entry[a]
5
Ar
21
Yield[c]
Figure 5. Glaser by-product N,N'-((buta-1,3-diyne-1,4-diylbis(2,1-
phenylene))bis(ethane-2,1-diyl))bis(4-methylbenzenesulfonamide) (22).
1
2
3
4
5
a
b
f
Ph
a
b
f
100 (40/60)[d]
91[e] (50/50)
100 (65/35)[d]
100 (64/36)
68[f] (78/22)
52
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
4-NCC6H4
65
46
61
63
The structure of compound 22 could be explained with an
oxidative homo-coupling process (i.e. Glaser reaction) of N-(2-
ethynylphenethyl)-4-methylbenzenesulfonamide (15), probably
favoured by low temperature condition and large quantity of
c
d
c
d
catalyst[10]
.
[a] Reactions were performed with 15 (0.5 mmol), 5a (0.6 mmol), in Et3N (1.5
mL) and toluene (1 mL), under CO (2.0 MPa), 6h. [b] Selectivity was
estimated by 1H-NMR spectroscopy of crude products; conformers ratio is
reported in parentheses. [c] Remainder of product is 4-methyl-N-(2-(3-oxo-3-
phenylprop-1-yn-1-l)phenethyl)benzenesulfonamide (20). [d] After purification
the conformer ratio resulted 60/40 (s-trans/s-cis). [e] Reaction carried out
under CO 4.0 MPa pressure. [f] Remainder of product is N-(2-((4-
cyanophenyl)ethynyl)phenethyl)-4-methylbenzenesulfonamide (23) (21%) and
(2,3-dihydro-1H-benzo[d]azepin-4-yl)(phenyl)methanone (24) (11%).
Once we had found suitable experimental conditions to obtain
exclusively dihydrobenzoazepine 21a (Table 2, entry 4), several
efforts to purify the crude product were made. Column
chromatography on neutral (pH 7) aluminum oxide (n-
hexane/AcOEt 3:1 as eluent) resulted the best methodology to
isolate pure 21a in satisfying yield (52%).
The cyclocarbonylative Sonogashira reaction was then applied
to iodoarenes with different steric and electronic features (Table
3). In all cases a quantitative conversion of the reagents was
observed and the benzoazepine derivatives were obtained
chemically pure with good yields (46-65%). As is evident from
Table 3, the chemoselectivity of the reaction was dependent on
the nature of the functional group present on the benzene ring.
Indeed, while methoxy or chloro derivatives (Table 3, entries 2-
4) afforded exclusively dihydrobenzoazepine 21b, 21f and 21c,
the coupling between 4-iodobenzonitrile (5d) and N-(2-
ethynylphenethyl)-4-methylbenzenesulfonamide (15) yielded
21d together with by-products. After purification, N-(2-((4-
cyanophenyl)ethynyl)phenethyl)-4-methylbenzenesulfonamide
Indeed, when the same reaction was performed for a longer
reaction time, (24hs, Scheme 11), the selectivity towards 23 did
not change significantly (20% vs. 21% Table 3, entry 5), while
the amount of 21d lowered from 68% to 38% with the
corresponding increase of 24 (42% vs. 11% Table 3, entry 5).
(23)
(18%)
and
(2,3-dihydro-1H-benzo[d]azepin-4-
yl)(phenyl)methanone (24) (9%, s-trans) were isolated and
identified (Figure 6).
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10.1002/ejoc.201601392
European Journal of Organic Chemistry
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chemoselectivity, while in the presence of electron withdrawing
groups (CN, NO2), more complex results were obtained, i.e.
detosylation and reduction occurred.
Experimental Section
General information. All chemicals were from commercial sources and
Scheme 11. Synthesis of 4-(3-tosyl-2,3-dihydro-1H-benzo[d]azepine-4-
carbonyl)benzonitrile (21d) and its in situ detosylation to 24.
used as received. Solvents were purified by conventional methods,
1
distilled and stored under argon. H-NMR (600 MHz) and 13C-NMR (150
MHz) spectra were recorded in CDCl3 or DMSO-d6 solution with a Varian
INOVA – 600 spectrometer, with Me4Si or CHCl3 as internal standard; 
values are given in parts per million (ppm) and coupling constants (J) in
hertz. Mass spectra were obtained with a Perkin–Elmer Q-Mass 910
connected to a Perkin–Elmer 8500 gas chromatograph or with an Applied
Biosystems- MDS Sciex API 4000 triple quadrupole mass spectrometer
(Concord, Ont., Canada), equipped with a Turbo-V ion-spray (TIS)
source. In the second case, the operative parameters were as follows:
ion-spray voltage (IS), 5.0 kV; gas source 1(GS1), 25; gas source 2(GS2),
25; turbo temperature (TEM), 0°C; entrance potential (EP), 10 V;
declustering potential (DP), 20 V; scan range, 300–1500 m/z. MS–MS
spectra were produced by collision-induced dissociation (CID) of selected
precursor ions in a LINAC collision cell (Q2) and mass-analyzed in the
second mass filter (Q3). Column chromatography was performed on
silica gel 60 (70-230 mesh) or neutral alumina. All products were
identified and characterized by spectroscopic and spectrometric data.
General procedure for the cyclocarbonylative Sonogashira
reactions. A Pyrex Schlenk tube under CO atmosphere was charged
with ethynylamide (0.5-1.0 mmol), iodoarene (0.6-1.2 mmol), Et3N (1.5-3
mL) and toluene (1-2 mL). This solution was introduced by a steel siphon
into a 25 mL stainless steel autoclave, fitted with a Teflon inner crucible
and a stirring bar, previously carried with PdCl2(PPh3)2 (0.2-0.4 mol%)
and placed under vacuum (0.1 Torr). The reactor was pressurized with
CO (2.0 MPa) and the mixture was stirred for 2-6hs at a selected
temperature (100-110°C). After removal of excess CO (fume hood), the
reaction mixture was diluted with CH2Cl2, washed with brine, dried over
anhydrous Na2SO4 and the solvent was removed under vacuum. The
Finally
a
cyclocarbonylative Sonogashira reaction of
sulfonamide 15 was carried out in the presence of 1-iodo-4-
nitrobenzene (5g). As depicted in Scheme 12, in this case (4-
aminophenyl)(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-
yl)methanone (21g) was obtained as the sole product (30%,
purified compound). This result is in agreement with our
previous reactions of benzyl and homobenzyl alcohols and 5g[7].
Indeed, in all these tests the quantitative reduction of NO2 to
NH2 was detected.
Scheme
12.
Sonogashira
cyclocarbonylative
reaction
of
N-(2-
ethynylphenethyl)-4-methylbenzenesulfonamide
nitrobenzene (5g).
(15) and
1-iodo-4-
Conclusions
We have developed a new approach for the synthesis of
alkylideneisoindolines and dihydrobenzoazepine through a Pd-
catalyzed copper-free cyclocarbonylative coupling reaction. This
sequence involves a carbonylative Sonogashira reaction[11]
between a suitable amide and a iodoarene followed by a
spontaneous cyclization process. In particular, when N-(2-
ethynylbenzyl)-4-methylbenzenesulfonamide was employed, the
reaction took place with complete chemo- and stereoselectivity
towards the exclusive formation of the five-membered
isoindoline derivatives with E configuration. On the other hand,
1
reagent conversion and the product composition were determined by H-
NMR spectroscopic analysis. All crude products were purified through
column chromatography on silica gel or neutral alumina and
characterized with 1H-NMR, 13C-NMR and LC-MS techniques.
(E)-tert-butyl 1-(2-oxo-2-phenylethylidene)isoindoline-2-carboxylate
(12aa). Following the general procedure, PdCl2(PPh3)2 (0.8 mg, 0.0011
mmol), tert-butyl 2-ethynylbenzylcarbamate (8a) (151 mg, 0.50 mmol)
and iodobenzene (5a) (0.07 mL, 0.63 mmol) were mixed in Et3N (1.5 mL)
and toluene (1 mL). The mixture was stirred for 4 h at 100°C. The crude
product was purified through column chromatography (SiO2, n-
hexane/AcOEt 9:1); 28 mg of 12aa (yield 14%) and 100 mg of the side
product tert-butyl 2-(3-oxo-3-phenylprop-1-yn-1-yl)benzylcarbamate (13)
(yield 49 %) were obtained.
the Sonogashira cyclocarbonylative
reaction of N-(2-
ethynylphenethyl)-4-methylbenzenesulfonamide with iodoarenes
generated dihydrobenzoazepines instead of the expected
tetrahydroisoquinolines. In this case a fine tuning of the reaction
conditions (110°C, 0.4 mol% PdCl2(PPh3)2, 6h) and purification
technique was necessary to achieve the seven member rings
with good yields. Moreover, the chemoselectivity of the reaction
depended on the features of the substituent on the benzene
ring. Indeed if the reaction was carried out with iodoarenes
characterized by an electron donating group such as OMe, the
benzoazepine was generated with almost complete
12aa: 1H-NMR (CDCl3), δ (ppm): 1.61 (9H, s), 4.89 (2H, s), 7.35-7.40 (2H,
m), 7.47 (3H, t, J = 7.4 Hz), 7.50-7.54 (1H, m), 8.09 (2H, d, J = 7.4 Hz),
8.22 (1H, s), 9.08 (1H, d, J = 8.1 Hz).
13C-NMR (CDCl3), δ (ppm): 28.29 (3C), 54.07, 82.46, 103.70, 121.54,
127.81, 127.99, 128.31 (2C), 128.34 (2C), 131.16, 131.88, 133.77,
138.56, 140.43, 152.00, 153.10, 190.51.
LC-MS APCI (+) [M+H]+: 336.1.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601392
European Journal of Organic Chemistry
FULL PAPER
1
13: H-NMR (CDCl3), δ (ppm): 1.46 (9H, s), 4.60 (2H, d, J = 5.1 Hz), 5.14
(CDCl3), δ (ppm): 21.58, 55.47, 101.15, 121.87, 127.45 (2C), 128.29,
128.32, 128.74 (2C), 129.66 (2C), 130.08 (2C), 131.89, 132.89, 134.53,
138.31, 138.33, 138.56, 145.23, 153.16, 187.56. LC-MS APCI (+)
[M+H]+: 420.2.
(1H, bs), 7.32-7.35 (1H, m), 7.46-7.48 (2H, m), 7.54 (2H, t, J = 7.6 Hz),
7.65 (1H, t, J = 7.3 Hz), 7.69 (1H, d, J = 7.6 Hz), 8.22 (2H, d, J = 7.6 Hz).
13C-NMR (CDCl3), δ (ppm): 28.35 (3C), 43.17, 79.66, 90.51, 91.29,
118.87, 127.45, 128.15, 128.70 (2C), 129.52 (2C), 131.15, 133.87,
134.18, 136.77, 142.64, 155.81, 177.77.LC-MS APCI (+) [M+H]+: 336.1.
(E)-1-phenyl-2-(2-tosylisoindolin-1-ylidene)ethanone (12ab) (100°C)
Following the general procedure, PdCl2(PPh3)2 (1.4 mg, 0.0020 mmol),
N-tosyl-2-(ethynyl)benzylamine (8b) (289 mg, 1.0 mmol) and
iodobenzene (5a) (0.15 mL, 1.3 mmol) were mixed in Et3N (3 mL) and
toluene (2 mL). The mixture was stirred for 24 h at 100°C. The crude
product was purified through column chromatography (SiO2, n-
hexane/AcOEt 4:1), obtaining 280 mg (yield 72%) of 12ab. 1H-NMR
(CDCl3), δ (ppm): 2.32 (3H, s), 5.07 (2H, s); 7.24 (2H, d, J = 8.4 Hz),
7.30-735 (2H, m); 7.41-7.53 (5H, m); 7.78 (2H, d, J = 8.4 Hz); 7.99 (2H,
d, J = 6.9 Hz); 8.99 (1H, d, J = 8.7 Hz). 13C-NMR (CDCl3), δ (ppm):
21.48, 55.35, 101.88, 121.78, 127.42 (2C), 128.19 (4C), 128.42 (2C),
129.97 (2C), 131.62, 132.18, 132.94, 134.65, 138.21, 139.88, 145.00,
152.48, 188.89.LC-MS APCI (+) [M+H]+: 390.2.
(E)-4-(2-(2-tosylisoindolin-1-ylidene)acetyl)benzonitrile
(12db).
Following the general procedure, PdCl2(PPh3)2 (0.7 mg, 0.0010 mmol),
N-tosyl-2-(ethynyl)benzylamine (8b) (142 mg, 0.50 mmol) and 4-
iodobenzonitrile (5d) (144 mg, 0.63 mmol) were mixed in Et3N (1.5 mL)
and toluene (1 mL). The mixture was stirred for 4 h at 100°C. The crude
product was purified through column chromatography (SiO2, n-
hexane/AcOEt 4:1), obtaining 124 mg (yield 60%) of 12db: 1H-NMR
(CDCl3), δ (ppm): 2.40 (3H, s), 5.13 (2H, s), 7.23 (2H, d, J = 8.4 Hz),
7.32-7.35 (2H, m), 7.45-7.48 (1H, m), 7.71 (4H, dd, J = 8.4, 1.5 Hz), 7.98
(2H, d, J = 8.4 Hz), 9.01 (1H, d, J = 8.4 Hz). 13C-NMR (CDCl3), δ (ppm):
21.59, 55.62, 100.29, 115.27, 118.22, 121.95, 127.43 (2C), 128.42,
128.46, 128.56 (2C), 130.14 (2C), 132.32, 132.36 (2C), 132.80, 134.44,
138.58, 143.57, 145.44, 154.61, 186.79.
(E)-1-(naphthalen-2-yl)-2-(2-tosylisoindolin-1-ylidene)ethanone
(12eb). Following the general procedure, PdCl2(PPh3)2 (0.7 mg, 0.0010
mmol), N-tosyl-2-(ethynyl)benzylamine (8b) (142 mg, 0.50 mmol) and 2-
iodonaphthalene (5e) (0.09 mL, 0.62 mmol) were mixed in Et3N (1.5 mL)
and toluene (1 mL). The mixture was stirred for 4 h at 100°C. The crude
product was purified through column chromatography (SiO2, n-
hexane/AcOEt 7:3), obtaining 149 mg (yield 68%) of 12eb: 1H-NMR
(CDCl3), δ (ppm): 2.41 (3H, s), 5.16 (2H, s), 7.19 (1H, s), 7.26 (2H, d, J =
6.6 Hz), 7.42 (2H, t, J = 8.5 Hz), 7.48-7.56 (4H, m), 7.73 (2H, d, J = 7.8
Hz), 7.90-7.92 (1H, m), 7.98 (1H, d, J = 8.4 Hz), 8.50-8.51 (1H, m), 9.15
(1H, d, J = 7.8 Hz). 13C-NMR (CDCl3), δ (ppm): 21.58, 21.61, 55.55,
105.57, 105.62, 121.87, 124.61, 125.77, 126.18, 127.22, 127.63, 128.37
(2C), 128.41, 129.99, 130.03, 130.33, 131.57, 131.90, 133.04, 133.89,
134.52, 138.35, 139.20, 145.10, 152.47, 192.57. LC-MS APCI (+)
[M+H]+: 440.2.
(E)-1-phenyl-2-(2-tosylisoindolin-1-ylidene)ethanone (12ab) (30°C)
Following the general procedure, PdCl2(PPh3)2 (0.7 mg, 0.0010 mmol),
N-tosyl-2-(ethynyl)benzylamine (8b) (142 mg, 0.50 mmol) and
iodobenzene (5a) (0.07 mL, 0.62 mmol) were mixed in Et3N (1.5 mL) and
toluene (1 mL). The mixture was stirred for 4 h at 30°C. The crude
product was purified through column chromatography (SiO2, n-
hexane/AcOEt 4:1), obtaining 19 mg (yield 10%) of 12ab and 162 mg
(yield 90%) of the side product 4-methyl-N-(2-(phenylethynyl)
benzyl)benzenesulfonamide (14): 1H-NMR (CDCl3), δ (ppm): 2.29 (3H,
s), 4.28 (2H, s), 4.94 (1H, bs), 7.09-7.12 (2H, m), 7.14-7.21 (3H, m),
7.27-7.39 (6H, m), 7.63 (2H, d, J = 8.4 Hz).13C-NMR (CDCl3), δ (ppm):
21.48, 46.25, 86.47, 94.40, 122.24, 122.51, 127.10 (2C), 127.83, 128.39
(2C), 128.69 (2C), 128.79, 129.55 (2C), 131.52 (2C), 132.27, 136.87,
137.73, 143.25.
(E)-1-(2-methoxyphenyl)-2-(2-tosylisoindolin-1-ylidene)ethanone
(12fb). Following the general procedure, PdCl2(PPh3)2 (0.7 mg, 0.0010
mmol), N-tosyl-2-(ethynyl)benzylamine (8b) (142 mg, 0.50 mmol) and 2-
iodoanisole (5f) (0.08 mL, 0.62 mmol) were mixed in Et3N (1.5 mL) and
toluene (1 mL). The mixture was stirred for 4 h at 100°C. The crude
product was purified through column chromatography (SiO2, n-
hexane/AcOEt 7:3), obtaining 115 mg (yield 55%) of 12fb: 1H-NMR
(CDCl3), δ (ppm): 2.38 (3H, s), 3.97 (3H, s), 5.06 (2H, s), 7.02-7.04 (2H,
m), 7.26-7.47 (6H, m), 7.62 (1H, s), 7.71-7.73 (1H, m), 7.81 (2H, d, J=
7.2 Hz), 9.16 (1H, d, J = 7.8 Hz). 13C-NMR (CDCl3), δ (ppm): 21.56,
29.68, 55.27, 55.82, 106.76, 111.77, 120.57, 121.69, 127.47, 128.19,
128.36, 129.90 (2C), 130.53, 131.54, 131.89, 132.69, 133.47, 134.67,
138.16, 144.85, 152.17, 158.05, 189.70. LC-MS APCI (+) [M+H]+: 420.2.
Phenyl(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-yl)methanone (21a)
(100°C). Following the general procedure, PdCl2(PPh3)2 (0.7 mg, 0.0010
mmol), N-tosyl-2-(2-(ethynyl)phenyl)ethanamine (15) (150 mg, 0.50
mmol) and iodobenzene (5a) (0.07 mL, 0.62 mmol) were mixed in Et3N
(1.5 mL) and toluene (1.0 mL). The mixture was stirred for 4 h at 100°C.
The crude product was purified through column chromatography (SiO2,
CHCl3/EtOH 99:1), obtaining 52 mg (yield 26%) of 21a as two
conformational isomers, s-trans and s-cis, in the molar ratio 60/40, and 6
mg (yield 3%) of the side product 4-methyl-N-(2-(3-oxo-3-phenylprop-1-
yn-1-yl)phenethyl) benzenesulfonamide (20). 21a: 1H-NMR (CDCl3), δ
(ppm): 2.30 (CH3, s, 1.8H), 2.35 (CH3, s, 1.2H), 2.58 (CH2, t, J = 6.0 Hz,
1.2H), 2.87 (CH2, t, J = 6.0 Hz, 0.8H), 3.71 (CH2, t, J = 6.0 Hz, 1.2H),
(E)-1-(4-methoxyphenyl)-2-(2-tosylisoindolin-1-ylidene)ethanone
(12bb). Following the general procedure, PdCl2(PPh3)2 (0.7 mg, 0.0010
mmol), N-tosyl-2-(ethynyl)benzylamine (8b) (142 mg, 0.50 mmol) and 4-
iodoanisole (5b) (147 mg, 0.63 mmol) were mixed in Et3N (1.5 mL) and
toluene (1 mL). The mixture was stirred for 4 h at 100°C. The crude
product was purified through column chromatography (SiO2, n-
hexane/AcOEt 4:1), obtaining 150 mg (yield 72%) of 12bb:1H-NMR
(CDCl3), δ (ppm): 2.26 (3H, s), 3.77 (3H, s), 4.97 (2H, s), 6.86 (2H, d, J =
9 Hz), 7.17 (2H, d, J = 8.2 Hz), 7.21-7.26 (2H, m), 7.32-7.37 (2H, m),
7.69 (2H, d, J = 8.2 Hz); 7.90 (2H, d, J = 9.0 Hz), 8.80 (1H, d, J = 8.7 Hz).
13C-NMR (CDCl3), δ (ppm): 21.44, 55.22, 55.36, 102.06, 113.58 (2C),
121.75, 127.34 (2C), 127.98, 128.06, 129.91 (2C), 130.41 (2C), 131.35,
132.56, 132.87, 134.52, 138.01, 144.88, 151.51 (2C), 162.92, 187.73.
LC-MS APCI (+) [M+H]+: 420.2.
(E)-1-(4-chlorophenyl)-2-(2-tosylisoindolin-1-ylidene)ethanone
(12cb). Following the general procedure, PdCl2(PPh3)2 (0.7 mg, 0.0010
mmol), N-tosyl-2-(ethynyl)benzylamine (8b) (142 mg, 0.50 mmol) and 1-
chloro-4-iodobenzene (5c) (149 mg, 0.62 mmol) were mixed in Et3N (1.5
mL) and toluene (1 mL). The mixture was stirred for 4 h at 100°C. The
crude product was purified through column chromatography (SiO2, n-
hexane/AcOEt 4:1), obtaining 138 mg (yield 65%) of 12cb: 1H-NMR
(CDCl3), δ (ppm): 2.34 (3H, s), 5.06 (2H, s), 7.25 (2H, d, J = 8.1 Hz),
7.33-7.36 (3H, m), 7.41 (2H, d, J = 8.4 Hz), 7.43-7.46 (1H, m), 7.74 (2H,
d, J = 8.1 Hz), 7.88 (2H, d, J = 8.4 Hz), 8.94 (1H, d, J = 7.8 Hz). 13C-NMR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601392
European Journal of Organic Chemistry
FULL PAPER
3.74 (CH2, t, J = 6.0 Hz, 0.8H), 6.93-6.95 (Ar, m, 0.6H), 6.96-6.99 (Ar, m,
0.8H), 7.05-7.08 (Ar, m, 1.6H), 7.11 (=CH, s, 0.6H), 7.17-7.26 (Ar, m,
3H), 7.35 (=CH, s, 0.4H), 7.43-7.49 (Ar, m, 2H), 7.53-7.57 (Ar, m, 2H),
7.68 (Ar, d, J = 8.4 Hz, 0.8H), 7.73-7.75 (Ar, m, 0.6H), 7.93-7.97 (Ar, m,
2H). 13C-NMR (CDCl3), δ (ppm): (21.37, 21.42), (26.10, 28.68), (44.41,
45.59), (111.79, 119.63), (124.33, 125.88), (126.41, 126.85), (127.31,
127.35) (2C), (128.04, 128.49) (2C), 128.61 (2C), (129.06, 129.10),
(129.28, 129.55) (2C), (129.70, 129.75), (130.59, 130.89), (132.19,
132.92), (134.87, 135.17), (136.34, 136.61), (138.15, 138.71), (140.98,
143.68), (144.11, 144.13), (191.41, 193.42). LC-MS APCI (+) [M+H]+:
404.6.
20: 1H-NMR (CDCl3), δ (ppm): 2.31 (3H, s), 3.10 (2H, t, J = 7.1 Hz), 3.28-
3.31 (2H, m), 5.51 (1H, t, J = 6.0 Hz), 7.28-7.30 (1H, m), 7.32-7.35 (2H,
m), 7.50-7.53 (2H, m), 7.59 (2H, d, J = 7.6 Hz), 7.66 (1H, d, J = 7.6 Hz).
13C-NMR (CDCl3), δ (ppm): 21.38, 34.76, 43.46, 90.77, 91.18, 126.94,
127.38, 128.12 (4C), 128.93 (4C), 130.16, 131.06, 133.98, 134.19,
137.32, 137.67, 142.06, 143.08, 177.69.
mg, 0.50 mmol) and 2-iodoanisole (5f) (0.08 mL, 0.62 mmol) were mixed
in Et3N (1.5 mL) and toluene (1.0 mL). The mixture was stirred for 6 h at
110°C. The crude product was purified through column chromatography
(neutral Al2O3, n-pentane/AcOEt 3:2), obtaining 99 mg (yield 46%) of 21f
as two conformational isomers, s-trans and s-cis, in the molar ratio 60/40.
1H-NMR (CDCl3), δ (ppm): 2.27 (CH3, s, 1.8H), 2.33 (CH3, s, 1.2H), 2.49
(CH2, t, J = 6.0 Hz, 1.2H), 2.81 (CH2, t, J = 6.0 Hz, 0.8H), 3.65-3.68 (CH2,
m, 2H), 3.88 (CH3, s, 1.8H), 3.95 (CH3, s, 1.2H), 6.86-6.87 (Ar, m, 0.6H),
6.92-6.95 (Ar, m, 1H), 6.97 (Ar, d, J = 8.4 Hz, 0.8H), 7.01-7.03 (Ar, m,
1.6H), 7.06 (Ar, t, J = 7.2 Hz, 0.6H), 7.14-7.23 (Ar, m, 2.6H), 7.27 (=CH, s,
0.6H), 7.30 (Ar, d, J = 7.8 Hz, 0.4H), 7.41 (=CH, s, 0.4H), 7.42-7.43 (Ar,
m, 0.4H), 7.45-7.48 (Ar, m, 0.6H), 7.51 (Ar, d, J = 7.8 Hz, 1.2H), 7.59 (Ar,
dd, J = 7.8, 1.6 Hz, 0.4H), 7.67-7.69 (Ar, m, 1.2H), 7.77 (Ar, dd, J = 7.8,
1.6 Hz, 0.6H). 13C-NMR (CDCl3), δ (ppm): (21.33, 21.40), (25.84, 28.60),
(44.25, 45.72), (55.68, 55.84), (111.29, 111.49), (120.32, 120.54), 122.16,
(123.79, 124.32), (125.49, 125.92), 126.70, (127.27, 127.36) (2C),
(128.96, 129.12) (2C), (129.35, 129.41), (129.55, 129.63), (130.65,
131.50), (131.18, 131.35), (132.64, 133.35), (134.69, 135.24), (136.27,
136.86), (139.46, 143.41), (143.68, 143.82), (157.97, 158.63), (191.18,
192.87). LC-MS APCI (+) [M+H]+: 434.3.
Phenyl(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-yl)methanone (21a)
(50°C). Following the general procedure, PdCl2(PPh3)2 (17.5 mg, 0.025
mmol), N-tosyl-2-(2-(ethynyl)phenyl)ethanamine (15) (150 mg, 0.50
mmol) and iodobenzene (5a) (0.07 mL, 0.62 mmol) were mixed in Et3N
(1.5 mL) and toluene (1.0 mL). The mixture was stirred for 24 h at 50°C.
The crude product was purified through column chromatography (SiO2,
CH2Cl2/acetone 49:1), obtaining 58 mg (yield 29%) of 21a as two
conformational isomers, s-trans and s-cis, in the molar ratio 67/33, 16 mg
(4-Chlorophenyl)(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-
yl)methanone (21c). Following the general procedure, PdCl2(PPh3)2 (1.4
mg, 0.0020 mmol), N-tosyl-2-(2-(ethynyl)phenyl)ethanamine (15) (150
mg, 0.50 mmol) and 1-chloro-4-iodobenzene (5c) (148 mg, 0.62 mmol)
were mixed in Et3N (1.5 mL) and toluene (1.0 mL). The mixture was
stirred for 6 h at 110°C. The crude product was purified through column
chromatography (neutral Al2O3, n-pentane/AcOEt 4:1), obtaining 133 mg
(yield 61%) of 21c as two conformational isomers, s-trans and s-cis, in
the molar ratio 64/36. 1H-NMR (CDCl3), δ (ppm): 2.31 (CH3, s, 0.64H),
2.35 (CH3, s, 0.36H), 2.56 (CH2, t, J = 6.3 Hz, 1.28H), 2.87 (CH2, t, J =
6.0 Hz, 0.72H), 3.71 (CH2, t, J = 6.3 Hz, 1.28H), 3.74 (CH2, t, J = 6.0 Hz,
0.72H), 6.94-6.95 (Ar, m, 0.64H), 6.98-7.00 (Ar, m, 0.36H), 7.05 (=CH, s,
0.64H), 7.07-7.09 (Ar, m, 1.64H), 7.18-7.25 (Ar, m, 2.72H), 7.29 (=CH, s,
0.36H), 7.40 (Ar, d, J = 7.8 Hz, 0.72H), 7.44 (Ar, d, J = 8.4 Hz, 1.28H),
7.53 (Ar, d, J = 7.8 Hz, 1.28H), 7.67 (Ar, d, J = 7.8 Hz, 0.72H), 7.72-7.73
(Ar, m, 0.64H), 7.86-7.88 (Ar, m, 2H). 13C-NMR (CDCl3), δ (ppm): (26.11,
26.94), (28.79, 29.66), (44.47, 45.56), (116.66, 119.06), (124.38, 125.96),
(126.51, 126.96), 127.37 (2C), (128.40, 128.81) (2C), (129.14, 129.37),
(129.63, 129.88), 130.03 (4C), (130.39, 130.73), (134.92, 135.16),
(136.47, 136.52), (136.67, 137.18), (138.40, 139.27), (141.34, 143.86),
(144.26, 144.88), (190.12, 192.34).
(yield
8%)
of
4-methyl-N-(2-(3-oxo-3-phenylprop-1-yn-1-
yl)phenethyl)benzenesulfonamide (20) and 12 mg (yield 4%) of the side
product N,N'-((buta-1,3-diyne-1,4-diylbis(2,1-phenylene)) bis(ethane-2,1-
diyl))bis(4-methylbenzenesulfonamide) (22): 1H-NMR (CDCl3), δ (ppm):
2.38 (6H, s), 3.00-3.03 (4H, m), 3.25-3.28 (4H, m), 4.84 (2H, t, J = 6.0
Hz), 7.16 (2H, d, J = 7.8 Hz), 7.20-7.30 (8H, m), 7.50 (2H, d, J = 7.8 Hz),
7.72 (4H, d, J = 7.8 Hz). LC-MS APCI (+) [M+H]+: 597.4.
(4-Methoxyphenyl)(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-
yl)methanone (21b). Following the general procedure, PdCl2(PPh3)2 (1.4
mg, 0.0020 mmol), N-tosyl-2-(2-(ethynyl)phenyl)ethanamine (15) (150
mg, 0.50 mmol) and 4-iodoanisole (5b) (145 mg, 0.62 mmol) were mixed
in Et3N (1.5 mL) and toluene (1.0 mL). The mixture was stirred for 6 h at
110°C. The crude product was purified through column chromatography
(neutral Al2O3, n-hexane/AcOEt 3:1), obtaining 140 mg (yield 65%) of
21b as two conformational isomers, s-trans and s-cis, in the molar ratio
50/50. 1H-NMR (CDCl3), δ (ppm): 2.29 (CH3, s, 1.5H), 2.32 (CH3, s,
1.5H), 2.62 (CH2, t, J = 6.0 Hz, 1H), 2.84 (CH2, t, J = 6.0 Hz, 1H), 3.72
(CH2, t, J = 6.0 Hz, 1H), 3.75 (CH2, t, J = 6.0 Hz, 1H), 3.87 (CH3, s,
1.5H), 3.88 (CH3, s, 1.5H), 6.92-6.98 (Ar, m, 3.5H), 7.01 (Ar, d, J = 7.2
Hz, 0.5H), 7.05-7.07 (Ar, m, 1H), 7.09 (=CH, s, 0.5H), 7.14-7.17 (Ar, m,
2.5H), 7.21-7.23 (Ar, m, 0.5H), 7.29 (=CH, s, 0.5H), 7.54 (Ar, d, J = 7.8
Hz, 0.5H), 7.65 (Ar, d, J = 7.8 Hz, 1H), 7.70-7.72 (Ar, m, 0.5H), 7.92 (Ar,
d, J = 7.8 Hz, 1H), 7.98 (Ar, d, J = 8.4 Hz, 1H). 13C-NMR (CDCl3), δ
(ppm): (21.42, 21.44), (26.32, 28.59), (44.63, 45.64), (55.39, 55.46),
(113.40, 113.79) (2C), (119.21, 120.04), (124.32, 125.92), (126.50,
126.81), (127.34, 127.50) (2C), (128.78, 129.14), (129.26, 129.53) (2C),
(130.91, 131.05) (2C), 131.52, (134.88, 135.30), (136.18, 136.64),
140.21, (142.70, 143.60), 143.99, (163.05, 163.57), (190.30, 191.71).
LC-MS APCI (+) [M+H]+: 434.3.
LC-MS APCI (+) [M+H]+: 438.2.
4-(3-tosyl-2,3-dihydro-1H-benzo[d]azepine-4-carbonyl)benzonitrile
(21d). Following the general procedure, PdCl2(PPh3)2 (1.4 mg, 0.0020
mmol), N-tosyl-2-(2-(ethynyl)phenyl)ethanamine (15) (150 mg, 0.50
mmol) and 4-iodobenzonitrile (5d) (142 mg, 0.62 mmol) were mixed in
Et3N (1.5 mL) and toluene (1.0 mL). The mixture was stirred for 6 h at
110°C. The crude product was purified through column chromatography
(neutral Al2O3, n-hexane/AcOEt 7:3), obtaining 135 mg (yield 63%) of
21d as two conformational isomers, s-trans and s-cis, in the molar ratio
78/22, 36 mg (yield 18%) of N-(2-((4-cyanophenyl)ethynyl)phenethyl)-4-
methylbenzenesulfonamide (23) and 12 mg (yield 9%) of 4-(2,3-dihydro-
1H-benzo[d]azepine-4-carbonyl)benzonitrile (24).
21d: 1H-NMR (CDCl3), δ (ppm): 2.30 (CH3, s, 2.34H), 2.36 (CH3, s,
0.66H), 2.48 (CH2, t, J = 6.0 Hz, 1.56H), 2.88 (CH2, t, J = 6.0 Hz, 0.44H),
3.64 (CH2, t, J = 6.0 Hz, 1.56H), 3.75 (CH2, t, J =
(2-Methoxyphenyl)(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-
yl)methanone (21f). Following the general procedure, PdCl2(PPh3)2 (1.4
mg, 0.0020 mmol), N-tosyl-2-(2-(ethynyl)phenyl)ethanamine (15) (150
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10.1002/ejoc.201601392
European Journal of Organic Chemistry
FULL PAPER
6.0 Hz, 0.44H), 6.92-6.93 (Ar, m, 0.78H), 6.98-7.00 (Ar, m, 0.22H), 7.03
(=CH, s, 0.78H), 7.07-7.08 (Ar, m, 2H), 7.20-7.26 (Ar, m, 2.44H), 7.27
(=CH, s, 0.22H), 7.49 (Ar, d, J = 7.8 Hz, 1.56H), 7.68-7.70 (Ar, m, 1H),
7.73-7.76 (Ar, m, 2H), 7.93 (Ar, d, J = 8.4 Hz, 0.44H), 7.96 (Ar, d, J = 8.4
Hz, 1.56H). 13C-NMR (CDCl3), δ (ppm): 21.45, 25.88, 44.30, 115.04,
118.38, 118.42, 124.49, 127.14, 127.25 (2C), 128.98 (4C), 129.17,
129.52, 130.27, 131.93 (2C), 134.91, 136.38, 142.45, 142.62, 144.16,
192.65. LC-MS APCI (+) [M+H]+: 429.3.
23: 1H-NMR (CDCl3), δ (ppm): 2.39 (3H, s), 3.05 (2H, t, J = 7.2 Hz), 3.29-
3.32 (2H, m), 4.69 (1H, t, J = 6.0 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.22-7.26
(3H, m), 7.28-7.31 (m, 1H), 7.50-7.51 (m, 1H), 7.60 (2H, d, J = 8.4 Hz),
7.63 (2H, d, J = 8.4 Hz); 7.68 (2H, d, J = 7.8 Hz). 13C-NMR (CDCl3), δ
(ppm): 21.48, 34.95, 43.36, 91.65, 91.78, 111.59, 118.45, 121.96, 126.93,
126.96 (2C), 127.85, 129.55, 129.66, 132.05 (4C), 132.77, 136.85,
139.97, 143.36. LC-MS APCI (+) [M+H]+: 400.3.
This study was supported by the Università di Pisa under PRA 2015
(project No. 2015_0038). The authors are indebted to prof. Gennaro
Pescitelli for molecular mechanisc calculations.
Keywords: Synthetic methods / Carbonylation / Cyclisation /
Isoindoline / benzoazepine
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(4-Aminophenyl)(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-
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mg, 0.0020 mmol), N-tosyl-2-(2-(ethynyl)phenyl)ethanamine (15) (150
mg, 0.50 mmol) and 1-iodo-4-nitrobenzene (5g) (154 mg, 0.62 mmol)
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stirred for 6 h at 110°C. The crude product was purified through column
chromatography (neutral Al2O3, n-pentane/AcOEt 3:2), obtaining 63 mg
(yield 30%) of 21g as two conformational isomers, s-trans and s-cis, in
the molar ratio 45/55. 1H-NMR (CDCl3), δ (ppm): 2.29 (CH3, s, 1.35H),
2.31 (CH3, s, 1.65H), 2.65 (CH2, t, J = 6.0 Hz, 0.9H), 2.82 (CH2, t, J = 6.0
Hz, 1.1H), 3.72 (CH2, t, J = 6.0 Hz, 1.1H), 3.77 (CH2, t, J = 6.0 Hz, 0.9H),
4.25 (NH2, bs, 2H), 6.63 (Ar, d, J = 8.4 Hz, 1.1H), 6.65 (Ar, d, J = 8.4 Hz,
0.9H), 6.93-6.95 (Ar, m, 1H), 6.99-7.00 (Ar, m, 0.55H), 7.06 (Ar, d, J =
7.8 Hz, 0.9H), 7.10 (=CH, s, 0.55H), 7.11-7.16 (Ar, m, 2H), 7.19-7.22 (Ar,
m, 1H), 7.26 (=CH, s, 0.45H), 7.55 (Ar, d, J = 7.8 Hz, 0.9H), 7.64 (Ar, d, J
= 7.8 Hz, 1.1H), 7.69-7.71 (Ar, m, 0.55H), 7.79 (Ar, d, J = 8.4 Hz, 0.9H),
7.86 (Ar, d, J = 8.4 Hz, 1.1H). 13C-NMR (CDCl3), δ (ppm): (20.41, 20.43),
(25.35, 27.41), (43.73, 44.69), (112.64, 112.81) (2C), (119.65, 119.71),
(123.30, 124.91), (125.53, 125.74); (126.32, 126.54) (2C), (127.59,
128.14), (128.23, 128.47) (2C), (128.26, 128.37), (130.14, 130.28),
(130.20, 130.36) (2C), (131.14, 131.82), (133.80, 134.35), (134.99,
135.65), (138.59, 140.36), (142.56, 142.88), (150.07, 150.61), (189.13,
190.03). LC-MS APCI (+) [M+H]+: 419.2.
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FULL PAPER
A one-step synthesis of functionalised
isoindolines and
Cyclocarbonylative cross coupling
Laura Antonella Aronica*, Gianluigi
Albano, Luca Giannotti, Elisa Meucci
dihydrobenzoazepines was developed
through copper-free, palladium-
catalysed cyclocarbonylative
Sonogashira reactions between
tosylamides and iodoarenes.
Page No. – Page No.
A new synthesis of N-heteroaromatic
compounds via cyclocarbonylative
Sonogashira reactions
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