Palladium-catalyzed cycloaminocarbonylation of 2-aminomethyl- and 2-alkylcarbamoylaryl tosylates with CO

Article abstract of DOI:10.1016/j.tetlet.2015.08.088

The palladium-catalyzed cycloaminocarbonylation of 2-(aminomethyl)aryl tosylates with CO has been established, by which a variety of salicylaldehyde derived 2-(aminomethyl)aryl tosylates may be cyclocarbonylated in the presence of CO, to afford the corresponding substituted isoindolinones in moderate to excellent yields. Furthermore, the method is also effective for the synthesis of isoindoline-1,3-diones and 2-alkyl-1H-benzo[e]isoindol-3(2H)-ones from 2-(N-alkylcarbamoyl)aryl tosylates and 1-(aminomethyl)naphthalene-2-yl tosylates, respectively.

Full text of DOI:10.1016/j.tetlet.2015.08.088

Tetrahedron Letters 56 (2015) 5776–5780
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed cycloaminocarbonylation of 2-aminomethyl-
and 2-alkylcarbamoylaryl tosylates with CO
a,c,
Bin Liu a,b, Yan Wang a, Benren Liao b, Chunlei Zhang b, , Xigeng Zhou
⇑
⇑
a Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, People’s Republic of China
b Technology Research Institute of Shanghai Huayi (Group) Company, Shanghai 200241, People’s Republic of China
c State Key Laboratory of Organometallic Chemistry, Shanghai 200032, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium-catalyzed cycloaminocarbonylation of 2-(aminomethyl)aryl tosylates with CO has been
established, by which a variety of salicylaldehyde derived 2-(aminomethyl)aryl tosylates may be cyclo-
carbonylated in the presence of CO, to afford the corresponding substituted isoindolinones in moderate to
excellent yields. Furthermore, the method is also effective for the synthesis of isoindoline-1,3-diones and
2-alkyl-1H-benzo[e]isoindol-3(2H)-ones from 2-(N-alkylcarbamoyl)aryl tosylates and 1-(aminomethyl)-
naphthalene-2-yl tosylates, respectively.
Received 15 July 2015
Revised 28 August 2015
Accepted 31 August 2015
Available online 1 September 2015
Keywords:
Palladium
Ó 2015 Elsevier Ltd. All rights reserved.
Cycloaminocarbonylation
C–O bond activation
Aryl tosylates
Isoindolinones
Introduction
(Scheme 1, path a).8 The cycloaminocarbonylation of 2-bromoben-
zaldehyde with primary amines under CO pressure leading to
Substituted isoindolinones are important structural compo-
nents of a vast array of naturally occurring and pharmacologically
active molecules. For example, currently many drugs, such as indo-
profen (antiinflammatory),1 lactonamycin (antibacterial),2 and
hericenone B (platelet aggregation inhibitory),3 hold such types
of heterocycles as their core structure. Furthermore, such types
of heterocycles are also valuable intermediates4 in organic synthe-
sis. The importance of these lactam derivatives justifies a long-
standing interest in the development of efficient and versatile
approaches to their synthesis and new isoindolinone-based struc-
tures for the fine-tuning of their biological or physical properties
for final application.
Transition metal-catalyzed carbonylative coupling reactions
have become a powerful tool in organic synthesis.5–7 A particularly
attractive route to the formation of the isoindolinone core is based
on cycloaminocarbonylation of suitable preformed or in situ gener-
ated o-halobenzylamine precursors, which can allow the regiose-
lective preparation of the final heterocycles with the desired
substitution pattern. The synthesis of isoindolinone derivatives
via palladium-catalyzed cycloaminocarbonylation of o-halobenzyl
amines was first described by Ban and co-workers in 1978
isoindolinones was later developed by Cho and Ren (Scheme 1,
path b).9 The use of 2-iodobenzyl bromide has also been investi-
gated in cycloaminocarbonylation (Scheme 1, path c).10 Orito and
co-workers developed an elegant approach for the synthesis of
isoindolinones by direct cyclocarbonylation of aromatic C–H bonds
with CO in benzylamines using a Pd(OAc)2/Cu(OAc)2/air system in
toluene solution at 120 °C (Scheme 1, path d),11 but further studies
are required, in particular with regard to the regiochemistry of the
reactions when meta-substituted aniline derivatives are employed.
2-(Aminomethyl)aryl tosylates are attractive alternatives to
conventional o-halobenzylamines due to their easy synthesis from
cheap salicylal precursors by routine synthetic reactions.12 In addi-
tion, 2-(aminomethyl)aryl tosylates are typically cheaper and
lower toxic than the corresponding aryl halides. Aryl arenesul-
fonates have been a difficult class of substrates toward transi-
tion-metal-catalyzed C–C bond formation.13 Among these
transformations, a few examples of alkoxycarbonylation12,14 and
aminocarbonylation14a,15 of aryl sulfonates have been reported.
Despite
significant
recent
advances
in
this
area,
aminocarbonylation of aryl tosylates remains
a
significant
challenge. In the most aminocarbonylative cases attempts to
switch from aryl perfluoroalkanesulfonate substrates to the
corresponding tosylates were unsuccessful even under more
forceful conditions.15a To the best of our knowledge, no method
has been established for the catalytic transformation of aryl
⇑
Corresponding authors. Tel.: +86 21 6564 3769.
E-mail address: xgzhou@fudan.edu.cn (X. Zhou).
http://dx.doi.org/10.1016/j.tetlet.2015.08.088
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

B. Liu et al. / Tetrahedron Letters 56 (2015) 5776–5780
5777
PCy3ÁHBF4, 1,3-bis(diphenyphosphino)ethane (dppe), and 1,3-bis
(diphenyphosphino)butane (dppb) tend to shut down the reacting
system. Shortening the reaction time was adverse to the reaction
(Table 1, entry 7). Among the solvents screened, CH3CN gave the
most promising results. In general, the use of organic bases (e.g.,
Et3N) provides the desired 2a in low yield, and other inorganic
bases, such as Cs2CO3 and Na2CO3, were also less effective (Table 1,
entries 10–12). The ratio of reagents, particularly substrate/Pd/
dppp, was found to be important for the reaction (Table 1, entries
13–17). In addition, reducing the reaction temperature to 120 °C
would lead to a dramatically lowered yield (Table 1, entry 18).
With the optimum reaction conditions in hand, we subse-
quently explored the scope of the reaction to various 2-(amino-
methyl)aryl tosylates. As shown in Table 2, 2-(aminomethyl)aryl
tosylates bearing various alkyl (entries 1–4), benzyl (entry 6, 7),
and aryl (entries 8–13) substituents at the nitrogen atom were
appropriate substrates for this methodology, and the correspond-
ing isoindolinone derivatives were obtained in satisfactory to
Scheme 1. Comparison of the prior cycloaminocarbonylative works to the current
work.
excellent yields. Aromatic amine bearing
a strong electron-
donating group afforded the corresponding isoindoline-1-one
derivative in 94% yield (entry 12). Several functional groups are
tolerated under these conditions (entries 7, 9, 10, 11, 12, 13). It is
well-known that C–Cl bonds are generally more reactive than
C–O bonds in metal-mediated transformations of carbon–
heteroatom bonds via oxidative/reductive mechanism.16
Significantly, products bearing chlorine were also obtained in
42% and 63% under the current conditions (Table 2, entries 7,
10). Substrates bearing electron-withdrawing groups such as F
and CO2CH3 at the N-aromatic ring, could also give the desired
products in moderate yields (Table 2, entries 11, 13). However,
reaction with primary amine (2-(aminomethyl)phenyl tosylate)
gave a complex mixture with a recovery of part starting material.
The effect of the substituent on the arene ring is examined.
Regardless of whether a m-methyl or p-NEt2 substituted aniline
derivative was used, the reaction in the presence of Pd(OAc)2 and
dppp gave the corresponding isoindolinone products in
satisfactory to excellent yields (entries 14–17). To our delight,
1-(aminomethyl)naphthalen-2-yl tosylates also proved to be suit-
able substrates for the cyclization, affording the desired 2-substi-
tuted-1H-benzo[e]isoindol-3(2H)-ones in good to excellent yields
(entries 18–23). In addition, 2-(1-(ethylamino)ethyl)phenyl
tosylate was also an appropriate substrate, and the corresponding
2-ethyl-3-methylisoindolin-1-one was obtained in satisfactory
yield (entry 24). The structure of 2v was further confirmed by
the X-ray crystal diffraction analysis (Fig. 1).17
The presence of isoindoline-1,3-dione skeletons in naturally
occurring compounds and synthetic materials,18 coupled with the
utility of isoindoline-1,3-dione-based reagents as intermediates19
and ligands20 in synthetic methodology, illustrates the need for
efficient and versatile strategies for the construction of such types
of heterocycles. However, cycloaminocarbonylation accessible to
such N-heterocyclic skeletons from aryl tosylates have remained
almost unexplored to date. Encouraged by the above results, the
cycloaminocarbonylation of 2-(alkylcarbamoyl)phenyl 4-methyl-
benzenesulfonates with CO under the same conditions was inves-
tigated. As shown in Scheme 2, isoindoline-1,3-dione derivatives
with various substitution patterns could also be synthesized in
moderate to good yields.
tosylates to the corresponding benzolactams. Herein, we describe
our results on the development of a practical process for the
cycloaminocarbonylation of 2-(aminomethyl)aryl tosylates.
Results and discussion
Our initial screening of reaction conditions focused on the
cycloaminocarbonylation
of
2-(N-methylaminomethyl)aryl
tosylate (1a) with CO in the presence of Pd(OAc)2 (Table 1). We
elected to employ Pd(OAc)2 as the catalyst, as Pd(OAc)2 has
provided good results in aminocarbonylation of aryl and vinyl
sulfonates. Influence of various factors such as ligands, solvents,
and bases on the reaction was examined. In a series of preliminary
screening of ligands (Table 1, entries 1–6), it was found that 1,3-bis
(diphenyphosphino)propane (dppp), seem to be ideal for
the cycloaminocarbonylation, whereas P(tBu)3ÁHBF4, Xantphos,
Table 1
Ligand, Solvent, and Base Effectsa
Entry
Solvent
Ligand (mol %)
Base (equiv)
Yieldb (%)
1
2
3
4
5
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMAc
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
P(tBu)3ÁHBF4 (10)
Xantphos (10)
PCy3ÁHBF4 (10)
dppe (10)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
Na2CO3 (2.0)
NEt3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (1.2)
K2CO3 (3.0)
K2CO3 (1.2)
Trace
Trace
Trace
10
Trace
60
33
59
6
13
32
30
38
89
89
88
91
10
dppb (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (15)
dppp (20)
dppp (15)
dppp (15)
dppp (15)
7c
8d
9
10
11
12
13e
14
15
16
17
18f
In summary, we have developed an efficient and versatile
method for the synthesis of isoindolinone derivatives by the
Pd-catalyzed cycloaminocarbonylation of 2-(aminomethyl)aryl
tosylates with carbon monoxide. Significantly, this methodology
can also be applied in synthesis of isoindoline-1,3-diones from 2-
(alkylcarbamoyl)aryl tosylates in good yields. The easy synthesis
of 2-(aminomethyl)aryl and 2-(alkylcarbamoyl)aryl tosylates from
cheap salicylaldehyde or salicylic acid as well as their low toxicity
a
Conditions: 2 mmol substrate, 1 MPa CO, 10 mol % Pd(OAc)2, Ligand, Base,
Solvent, 140 °C, 21 h.
b
Isolated yield.
11 h.
27 h.
5 mol % Pd(OAc)2.
c
d
e
f
Reaction conducted at 120 °C.

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B. Liu et al. / Tetrahedron Letters 56 (2015) 5776–5780
Table 2
Cycloaminocarbonylation of 2-aminomethylaryl tosylatesa
Entry
1
Substrate
Product
Yieldb (%)
88
2
3
4
82
77
79
5
6
82
91
7
8
42
93
9
81
64
10
11
12
13
62
94
66
14
15
16
17
83
91
70
97

B. Liu et al. / Tetrahedron Letters 56 (2015) 5776–5780
5779
Table 2 (continued)
Entry
Substrate
Product
Yieldb (%)
18
93
19
20
21
22
85
86
89
95
23
83
65
24
a
Conditions: 2 mmol substrate, 10 mol % Pd(OAc)2, 15 mol % dppp, 2.4 mmol K2CO3, 70 ml CH3CN, 1 MPa CO, 140 °C, 21 h.
Isolated yield.
b
makes them an attractive and practical alternative to commonly
used organic halides as counterparts in aminocarbonylation
protocols.
Experimental section
General procedure for the intramolecular cycloamino-carbony-
lation of 2-aminomethyl- and 2-alkylcarbamoylaryl tosylates.
2-(Aminomethyl)aryl tosylate (2 mmol), Pd(OAc)2 (10 mol %),
dppp (15 mol %), K2CO3 (2.4 mmol), and CH3CN (70 ml) were
charged in a 200 ml-autoclave. The autoclave was flushed and then
pressurized with carbon monoxide to 1 MPa, the mixture was stir-
red at 140 °C for 21 h. The mixture was cooled to room tempera-
ture and vented to discharge the excess CO. After filtration,
solvent was removed under reduced pressure and the crude
residue was purified by column chromatography on silica gel with
petroleum ether–ethyl acetate as the eluent to afford the desired
product.
Figure 1. ORTEP diagram of the X-ray single-crystal structure of 2v.
2-(tert-Butyl)-5-methylisoindolin-1-one (2o)
1H NMR (CDCl3, 400 MHz): d 7.67 (d, J = 7.7 Hz, 1H), 7.22 (d,
J = 7.8 Hz, 1H), 7.19 (s, 1H), 4.40 (s, 2H), 2.43 (s, 3H), 1.55 (s, 9H).
13C NMR (CDCl3, 100 MHz): d 169.0, 141.4, 141.1, 131.9, 128.8,
122.9, 122.8, 54.1, 48.2, 27.9, 21.2. HRMS (ESI) Calcd for
C
13H18NO [M+H]+: 204.1388; Found: 204.1394.
Scheme 2. Cycloaminocarbonylation of 2-(alkylcarbamoyl)phenyl toyslates.

5780
B. Liu et al. / Tetrahedron Letters 56 (2015) 5776–5780
6-(Diethylamino)-2-methylisoindolin-1-one (2p)
Supplementary data
1H NMR (CDCl3, 400 MHz): d 7.23 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H),
6.83 (d, J = 8.3 Hz, 1H), 4.25 (s, 2H), 3.39 (q, J = 7.0 Hz, 4H), 3.17 (s,
3H), 1.16 (t, J = 7.0 Hz, 6H). 13C NMR (CDCl3, 100 MHz): d 169.4,
148.0, 134.0, 127.5, 123.0, 115.2, 105.6, 51.5, 44.6, 29.6, 12.4. HRMS
(ESI) Calcd for C13H19N2O [M+H]+: 219.1497; Found: 219.1497.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.
088.
References and notes
6-(Diethylamino)-2-phenylisoindolin-1-one (2q)
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1H NMR (CDCl3, 400 MHz): d 7.88 (d, J = 7.7 Hz, 2H), 7.40–7.44
(m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.14–7.18 (m, 2H), 6.91 (dd,
J = 8.4, 2.6 Hz, 1H), 4.76 (s, 2H), 3.42 (q, J = 7.0 Hz, 4H), 1.19 (t,
J = 7.0 Hz, 6H). 13C NMR (CDCl3, 100 MHz): d 168.4, 148.2, 140.0,
134.3, 129.1, 126.7, 124.1, 123.2, 119.4, 116.3, 105.7, 50.2, 44.7,
12.4. HRMS (ESI) Calcd for C18H21N2O [M+H]+: 281.1654; Found:
281.1655.
2-Ethyl-1H-benzo[e]isoindol-3(2H)-one (2s)
1H NMR (CDCl3, 400 MHz): d 7.85–7.97 (m, 4H), 7.59–7.62 (m,
2H), 4.72 (s, 2H), 3.77 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).
13C NMR (CDCl3, 100 MHz): d 168.9, 140.1, 134.8, 130.6, 129.1,
128.9, 127.9, 127.5, 127.1, 123.0, 120.1, 48.5, 37.2, 13.9. HRMS
(ESI) Calcd for C14H14NO [M+H]+: 212.1075; Found: 212.1079.
2-(n-Propyl)-1H-benzo[e]isoindol-3(2H)-one (2t)
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2H), 4.70 (s, 2H), 3.67 (t, J = 7.3 Hz, 2H), 1.72–1.79 (m, 2H), 1.00
(t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz): d 169.2, 140.1,
134.8, 130.5, 129.1, 128.8, 127.9, 127.5, 127.1, 122.9, 120.1, 49.1,
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C
15H16NO [M+H]+:
2-(n-Butyl)-1H-benzo[e]isoindol-3(2H)-one (2u)
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1H NMR (CDCl3, 400 MHz): d 7.92–7.96 (m, 1H), 7.82–7.89 (m,
3H), 7.56–7.59 (m, 2H), 4.67 (s, 2H), 3.69 (t, J = 7.3 Hz, 2H), 1.67–
1.75 (m, 2H), 1.37–1.46 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR
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127.9, 127.5, 127.0, 122.9, 120.0, 49.0, 42.1, 30.7, 20.0, 13.8. HRMS
(ESI) Calcd for C16H18NO [M+H]+: 240.1388; Found: 240.1383.
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2-(tert-Butyl)-1H-benzo[e]isoindol-3(2H)-one (2v)
1H NMR (CDCl3, 400 MHz): d 7.94–7.96 (m, 1H), 7.80–7.90 (m,
3H), 7.56–7.60 (m, 2H), 4.78 (s, 2H), 1.64 (s, 9H). 13C NMR (CDCl3,
100 MHz): d 169.6, 139.5, 134.8, 131.9, 129.2, 128.8, 127.8, 127.4,
127.0, 122.9, 119.9, 54.5, 47.6, 28.2. HRMS (ESI) Calcd for
C
16H18NO [M+H]+: 240.1388; Found: 240.1394.
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2-benzyl-1H-benzo[e]isoindol-3(2H)-one (2w)
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1H NMR (CDCl3, 400 MHz): d 7.92–7.96 (m, 3H), 7.76 (dd, J = 7.6,
2.0 Hz, 1H), 7.53–7.60 (m, 2H), 7.28–7.36 (m, 5H), 4.90 (s, 2H), 4.59
(s, 2H). 13C NMR (CDCl3, 100 MHz): d 169.2, 140.4, 137.2, 134.9,
130.0, 129.1, 128.9, 128.8, 128.2, 128.1, 127.9, 127.7, 127.1,
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Acknowledgements
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We thank the National Natural Science Foundation of China,
973 program (2015CB856600) and the Research Fund for the
Doctoral
Program
of
Higher
Education
of
China
(20130071130009) for financial support.