Silver-catalyzed intramolecular cyclization of o-(1-Alkynyl)benzamides: Efficient synthesis of (1H)-isochromen-1-imines

Article abstract of DOI:10.1002/adsc.200900381

An efficient avenue for the facile and atom-economic synthesis of (1H)-isochromen-1imines has been developed, and a broad spectrum of substrates can participate in the process effectively to produce the desired products in good yields. Significantly, this is the first report of the synthesis of (1H)-isochromen-l-imines that involves a silver(I)-catalyzed, regiocontrolled intramolecular addition of the carbonyl group of the amide moiety towards an alkyne.

Full text of DOI:10.1002/adsc.200900381

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DOI: 10.1002/adsc.200900381
Silver-Catalyzed Intramolecular Cyclization of o-(1-Alkynyl)-
A
Guannan Liu,a Yu Zhou,a Deju Ye,a Dengyou Zhang,a Xiao Ding,a
Hualiang Jiang,a,b and Hong Liua,*
a
Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203,
Peopleꢀs Republic of China
Fax : (+86)-21-5080-7088; e-mail: hliu@mail.shcnc.ac.cn
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, Peopleꢀs Republic of China
b
Received: May 31, 2009; Revised: July 20, 2009; Published online: October 21, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900381.
Abstract: An efficient avenue for the facile and
atom-economic synthesis of (1H)-isochromen-1-
imines has been developed, and a broad spectrum
of substrates can participate in the process effec-
tively to produce the desired products in good
yields. Significantly, this is the first report of the
synthesis of (1H)-isochromen-1-imines that involves
a silver(I)-catalyzed, regiocontrolled intramolecular
addition of the carbonyl group of the amide moiety
towards an alkyne.
Figure 1. Known (1H)-isochromen-1-imine analogues.
requires long reaction time and high reaction temper-
ature, and moreover it suffers from a relatively
narrow scope of substrates. Thus, new and improved
methodologies for synthesis of (1H)-isochromen-1-
imine analogues are desired.
Keywords: intramolecular cyclization; (1H)-isochro-
men-1-imines; organic catalysis; regioselectivity;
silver catalyst; synthetic methods
The transition metal-catalyzed construction of het-
erocycles is one of the frontier areas in organic
chemistry, because of the exceptional ability to acti-
vate p systems, especially alkynes, towards intermo-
Isocoumarins are key core structural subunits that lecular and intramolecular nucleophilic attack.[5] In
occur in a wide variety of biologically active natural comparison with other transition metal salts, Ag(I)
products and complex synthetic molecules,[1] as well salts have long been believed to have low catalytic ef-
as being useful and versatile synthetic intermediates.[2] ficiency, and most commonly served as either co-cata-
Recently, the activity of isocoumarins as potent anti- lysts or Lewis acids. Only recently, have Ag(I) salts
cancer agents invoked additional interest in the inves- have been demonstrated to be important and versatile
tigation of them and their analogues.[3] Since there is catalysts for the synthesis of functionalized heterocy-
a remarkable similarity in reactivity and bioactivities cles, such as isoquinolines, (2H)-isoquinolines, (2H)-
between the oxygen species and their nitrogen coun- 1,2-oxaphosphorin 2-oxides, 5-substituted proline de-
terparts, one would anticipate that (1H)-isochromen- rivatives, pyrroles, silyl ketene aminals, benzothia-
1-imine analogues might have potential bioactivities zines, and other heterocycles, in efficient and atom-
similar to those of the isocoumarins. So far, only four economic ways.[6,7]
(1H)-isochromen-1-imine analogues have been re-
However, no investigation has been reported on
ported in the literature (compounds 1–4, Figure 1). the synthesis of (1H)-isochromen-1-imines using an
Deady et al. reported the synthesis of 1 via the acety- Ag(I)-catalyzed system. In this communication, we
lation of a-cyano-o-tolunitrile,[4a] and they prepared 2, present our preliminary results for the synthesis of di-
3, and 4 by thermal cyclization reactions six years versely substituted (1H)-isochromen-1-imines from o-
later.[4b] Unfortunately, the described method usually (1-alkynyl)benzamides under optimized Ag(I)-cata-
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Guannan Liu et al.
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lyzed conditions. Several distinguished features of the particular, we identified an exciting lead that stood
process are worthy of mention: (i) it is the first report out unambiguously in the series of experiments. As
of the synthesis of (1H)-isochromen-1-imines that in- depicted in Table 1, AgSbF6 seems to be the optimal
volves the regiocontrolled intramolecular addition of choice for this reaction. The target product, (1H)-3-
the carbonyl group of an amide moiety toward al- phenyl-N-propylisochromen-1-imine (6a), was ob-
kynes; (ii) it uses AgSbF6 as catalyst without requiring tained in 81% yield (Table 1, entry 5). Some other
any other additives; and more significantly (iii) o-(1- acids, including the ones reported to promote the
alkynyl)benzamides with a wide range of structural analogous reactions,[10] were also investigated as acti-
diversity can efficiently participate in the process with vator, but only a trace amount of imine 6a was detect-
good yields.[8]
ed when utilizing TfOH (Table 1, entries 8–11). Sub-
2-(Phenylethynyl)-N-propylbenzamide (5a) was sequently, we screened different solvents and found
first used as the model substrate to optimize the reac- that the solvent plays an important role in this trans-
tion conditions, including different catalysts, various formation (Table 1, entries 5 and 12–17). While no de-
solvents, reaction temperatures, and reaction times sired product was observed in H2O under the same
(Table 1). Since no desired product was observed catalytic conditions (Table 1, entry 16), the reaction in
without catalysis, various Ag(I) salts were then tetrahydrofuran (THF) afforded the best yield of
screened in toluene,[9] and all of them displayed 85% (Table 1, entry 17).[11] The reaction temperature
proper catalytic activities (Table 1, entries 1–7). In was found to be an important factor on the process.
Compound 6a was obtained in 65% yield when the
temperature was reduced to 608C and there is no im-
Table 1. Cyclization of N-propyl-2-(2-phenylethynyl)benza-
mide (5a).[a]
provement in yield when the temperature was raised
up to 1008C (Table 1, entries 18 and 19). The decrease
in the yield resulting from the decrease in the reaction
time under heating was significant (Table 1, entry 20).
With these promising synthesis conditions
(25 mol% of AgSbF6, THF, 808C, 8 h), we investigat-
ed the substrate scope of the intramolecular cycliza-
tion catalyzed by AgSbF6, and the results are summar-
ized in Table 2 and Table 3. As listed in Table 2, 2-
(substituted ethynyl)-N-propylbenzamides 5 bearing
aryl (Table 2, entries 1–9) or alkyl (Table 2, entries 10
and 11) substituents are well suitable for the cycliza-
tion reaction. A lower yield was observed in the cases
of 2-[(o-methylphenyl)ethynyl]-N-propylbenzamide,
presumably due to steric hindrance (Table 2, entry 2).
Excellent yields were obtained irrespective of the
presence of electron-withdrawing, electron-donating,
or halide groups (Table 2, entries 4–8). Furthermore,
good yields were also obtained when the R1 groups
were heteroaromatic or aliphatic groups (Table 2, en-
tries 9–11). When introducing a methyl group into the
5-position of 2-(phenylethynyl)-N-propylbenzamide, a
good yield of target compound 6l was obtained. How-
ever, introduction of a methyl group to the 3-position
resulted in a loss of yield of 6m (Table 2, entries 12
and 13). In additional, the result was better when R2
group was an electron-withdrawing substituent, pre-
sumably owing to electronic effects (Table 2, en-
tries 12, 14 and 15).
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
–
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
EtOH
THF
0
CF3COOAg
CH3COOAg
AgOTf
AgSbF6
AgNO3
Ag2CO3
TsOH
73
28
55
81
49
30
0
9
TFA
0
10
11[c]
12
13
14
15
16
17
18[d]
19[e]
20[f]
TfOH
HBF4
THF
trace
0
CH2Cl2
CH2Cl2
CH3COCH3
CH3CN
DMF
H2O
THF
THF
THF
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
82
78
21
63
0
85
65
84
59
THF
[a]
The reaction was carried out using 5a in the presence of
catalyst (25 mol%) in the solvent at 808C under argon
for 8 h.
Yields of isolated products.
The reaction was carried out with HBF4 (25 equiv.) at
room temperature for 5 h.
The reaction was carried out at 608C for 8 h.
The reaction was carried out at 1008C for 8 h.
The reaction was carried out at 808C for 4 h.
We further examined the cyclization reactions for a
wide array of electronically and structurally diverse
R3 groups. As shown in Table 3, the tolerance of the
catalytic system was remarkable, and moderate to ex-
cellent yields of the desired products were obtained.
The substrates bearing aliphatic groups gave excellent
yields (Table 3, entries 1 and 2), however, lower yields
were observed with substrates involving bulky groups
[b]
[c]
[d]
[e]
[f]
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Silver-Catalyzed Intramolecular Cyclization of o-(1-Alkynyl)benzamides
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Table 2. Synthesis of (1H)-N-propylisochromen-1-imines via AgSbF6-mediated cyclization.[a]
Entry
1
Product
Yield [%][b]
85
Entry
9
Product
Yield [%][b]
6a
6b
6c
6d
6i
71
86
80
78
2
3
4
31
72
81
10
11
12
6j
6k
6l
5
6e
6f
73
86
13
6m
39
6
7
14
15
6n
6o
89
67
6g
6h
81
75
8
[a]
The reaction was carried out using 5 in the presence of AgSbF6 (25 mol%) in the THF at 808C under argon for 8 h.
Yields of isolated products.
[b]
such as the tert-butyl group, which causes large steric markably, a shorter reaction time was needed and ex-
hindrance under the same reaction conditions cellent yields were obtained for substrates with a het-
(Table 3, entry 3). When both the R1 and R3 substitu- eroaromatic R3 group (Table 3, entries 11 and 12).
ents were aromatic groups, the reaction did not go to
The cyclization of alkynes possessing nucleophiles
completion even after 24 h at 1008C (Table 3, in proximity to the triple bond can construct various
entry 4), and the situation did not improve until the heterocycles in different pathways. As shown in
R1 group was replaced with an aliphatic group Scheme 1, in principle, there are six possible products
(Table 3, entry 5). Further study showed that relative- for the cyclization of 5: O-cyclization via 6-endo or 5-
ly higher yields were afforded when the R3 group was exo mechanisms, leading to 7 or 7’, respectively (path
a para-substituted aromatic, presumably owing to a); N-cyclization via 6-endo or 5-exo mechanisms,
smaller stereospecific blockade (Table 3, entries 6–8). leading to 8 or 8’, respectively (path b); and hydroly-
In addition, electron-donating and electron-withdraw- sis of the imino moiety of 7 or 7’, leading to 9 or 9’,
ing substituents on the amide moiety had no percepti- respectively (path c). The results disclosed in the text
ble effect on the yields (Table 3, entries 9 and 10). Re- suggested that the present Ag-mediated reaction of 5
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Guannan Liu et al.
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Table 3. Synthesis of (1H)-isochromen-1-imines via AgSbF6-mediated cyclization.[a]
Entry
1
Product
Yield [%][b]
88
Entry
7
Product
Yield [%][b]
7a
7b
7g
66
82
2
3
87
48
8
9
7h
7i
7c
71
75
4
5
7d
23[c]
10
7j
7e
7f
68
52
11
12
7k
7l
89[d]
6
90[d]
[a]
The reaction was carried out using 5 in the presence of AgSbF6 (25 mol%) in the THF at 808C under argon for 8 h.
Yields of isolated products.
The reaction was carried out at 1008C for 24 h.
[b]
[c]
[d]
The reaction was completed within 5 h.
Scheme 1. Intramolecular cyclization of o-(1-alkynyl)benzACTHUNTGRNEUNGamides 5.
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Silver-Catalyzed Intramolecular Cyclization of o-(1-Alkynyl)benzamides
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showed very high reactivity for the oxygen of the
amide moiety to form imine 7. This unique O-cycliza-
tion is different from N-cyclizations catalyzed by pal-
ladium where isoquinolin-1-one 8 or isoindolone 8’
could be formed.[12] In parallel, the AgSbF6-catalyzed
system, where the imine moiety could be reserved, is
distinct from the acid-catalyzed conditions, under
which the isocoumarin derivative 9 was obtained di-
rectly from amide starting materials.[10] In addition,
the regiocontrolled intramolecular cyclization formed
the six-membered ring 7 following a “6-endo-dig” cyc-
lization probably due to the transition metal nature of
AgSbF6 which forms p complexes with alkynes rather
than activating the oxygenated functions.[7m] However,
Scheme 2. Possible mechanism for the Ag(I)-catalyzed intra-
the detailed mechanism of this transformation is still
unclear.
molecular cyclization.
All the (1H)-isochromen-1-imines synthesized were
characterized by spectral and analytical data. The rel- termediates and potent biologically active compounds.
ative stereochemistry (Z/E) of the products was deter- It is our expectation that the biologically intriguing
mined by X-ray analyses of 6a and 7l, and the abso- structures will find broad applications in our related
lute configurations are shown in Figure 2.
medicinal chemistry program. This interesting trans-
A plausible catalytic mechanism for the above cyc- formation has motivated us to further investigate the
lization is shown in Scheme 2. This scheme is based reaction pathway as a part of future endeavors.
on the Ag(I)-catalyzed reactions published by Asao[7c]
and Patil.[7i] First, the carbon-carbon triple bond of 5a
is activated by coordination with the transition metal
salt to form the Ag-alkyne p-complex A. Subsequent
Experimental Section
attack of the oxygen atom at the electron-deficient
triple bond leads to the intermediate B, which is fol-
lowed by proton transfer to produce the final product
6a and regenerate the Ag(I) catalyst.
In summary, we developed a mild and efficient
route for Ag(I)-catalyzed intramolecular cyclization
of o-(1-alkynyl)benzamides. Significantly, the strategy
affords an attractive means for the facile and atom-
economic synthesis in moderate-to-good yields of a
General Procedure for the Ag-Catalyzed Synthesis of
(1H)-Isochromen-1-imines
To a 10-mL reaction flask containing THF (6 mL) under
argon was added o-(1-alkynyl)benzamides (0.4 mmol) and
AgSbF6 (0.1 mmol). The resulting mixture was heated at
808C for 8 h, and then diluted with 20 mL of EtOAc,
washed with saturated NaHCO3 (twice), and brine, and
dried by anhydrous Na2SO4. The solvent was evaporated
under reduced pressure, and the product was isolated by
wide range of (1H)-isochromen-1-imines, which are column chromatography with petroleum ether (PE)/EtOAc
(25/1, v/v) as eluent to yield the desired (1H)-isochromen-1-
imine products.
important motifs in both useful versatile synthetic in-
Figure 2. X-ray crystal structures of 6a and 7l.[13]
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Guannan Liu et al.
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c) M. ꢂlvarez-Corral, M. MuÇoz-Dorado, I. Rodrꢃguez-
Garcꢃa, Chem. Rev. 2008, 108, 3174–3198.
Supporting Information
Experimental details and copies of H/13C NMR spectra of
1
[7] a) Q. Huang, J. A. Hunter, R. C. Larock, J. Org. Chem.
2002, 67, 3437–3444; b) Y. Luo, Z. Li, C.-J. Li, Org.
Lett. 2005, 7, 2675–2678; c) N. Asao, S. Yudha T.
Nogami, Y. Yamamoto, Angew. Chem. 2005, 117, 5662–
5664; Angew. Chem. Int. Ed. 2005, 44, 5526–5528;
d) A.-Y. Peng, Y.-X. Ding, Org. Lett. 2005, 7, 3299–
3301; e) B. C. J. van Esseveldt, P. W. H. Vervoort, F. L.
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1791–1795; f) S. Agarwal, H.-J. Knolker, Org. Biomol.
Chem. 2004, 2, 3060–3062; g) J. Sun, S. A. Kozmin,
Angew. Chem. 2006, 118, 5113–5115; Angew. Chem.
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Nishad, N. K. Swamy, V. Bandameedi, D. Kumar, B. R.
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[8] The required o-(1-alkynyl)benzamides were prepared
from the corresponding reagants according to the
known procedures (see the Supporting Information).
[9] While all the reactions were carried out with 25 mol%
of the catalyst, an attempt to reduce the catalyst load-
ing without changing the other reaction conditions re-
sulted in lower product yields.
[10] a) H. Sashida, A. Kawamukai, Synthesis 1999, 1145–
1148; b) N. G. Kundu, M. W. Khan, Tetrahedron 2000,
56, 4777–4792.
all products are available as supporting information.
Acknowledgements
We gratefully acknowledge financial support from the Na-
tional Natural Science Foundation of China (grants 20721003
and 20872153), International Collaboration Projects (grants
2007DFB30370 and 20720102040) and the 863 Hi-Tech Pro-
gram of China (grants 2006AA020602 and 2006AA10A201).
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