Solvent effects on aza-anionic cycloaromatization of 2-(2-substituted-ethynyl)benzonitriles

Article abstract of DOI:10.1002/jccs.200100035

The methanolysis of 2-(2-aryl ethynyl)benzonitriles is accelerated when the polar aprotic solvents are added, which could enhance the 6-endo pathway and give isoquinolones, though the 5-exo pathway is occupied mostly. The yields of products would also be

Full text of DOI:10.1002/jccs.200100035

JournaloftheChineseChemicalSociety, 2001, 48, 211-214
211
Solvent Ef fects on Aza-anionic Cycloaromatization of
2-(2-Substituted-ethynyl)benzonitriles
Chi-Fong Lin (
Wen-Der Lu (
SchoolofChemistry,KaohsiungMedicalUniversity,Kaohsiung,Taiwan
), Jia-Huei Yang (
), Pei-Chen Hsieh (
),
) and Ming-Jung Wu* (
)
The methanolysis of 2-(2-aryl ethy nyl)benzonitriles is ac cel er ated when the po lar aprotic solvents are
added, which could en hance the 6-endo path way and give isoquinolones, though the 5-exo path way is oc cu-
pied mostly. The yields of prod ucts would also be in creased.
The biradical cycloaromatization of enediynes have at-
tractedextensiveattention,1 and enor mous ef fort has been
Table 1.
Ph
NH
Ph
Ph
poured into elu ci dat ing the bi o log i cal modes of ac tion of
these novel natural products.2 The synthesis of natural
enediynes3 andthedevelopmentofsimplifiedsyntheticana-
logues 4 havealsobeenpursuedinearnest.However,manyre-
ac tions in which enediynes could pro ceed still re main un-
solved.
Wehavepreviouslyreportedanioniccycloaromatiza-
tion of 2-(2-substituted- ethy nyl)benzonitriles5 to give the
3-benzylideneisoindol-2-ones (equ. 1) in mod est yield. It is
considered that the low yield could be due to the poor
regioselectivity of the nucleophilic ad di tion to the con ju gate
system. Wethenanticipatedthatintroducingapolaraprotic
sol vent could in crease the nucleophilicity of nucleophile
which would pro mote the cycloaromatization of 2-(2- sub-
stituted-ethynyl)benzonitriles in better yields and regio -
selectivity.
Na, MeOH
+
NH
i-v, reflux 16hrs
CN
O
O
1
2
3
additive
yield
i
10% THF
30%THF
88%
56%
ii
7%
iii
iv
v
10%DMF
no reaction
50%
10%DMSO
30%DMSO
12%
17%
45%
the 10% DMF con di tion, no ex pected re ac tion oc curred,
which perhaps is owing to the reaction between sodium
methoxide and DMF. On the other hand, when ei ther 10% or
30% DMSO was min gled, ei ther isoindolone 2 or iso quino-
lone 3 were ob tained. The isoqunolone 3 could not be sep a-
rated from isoindolone 2 by column chromatography; it
would only be ob served from the NMR spec trum.
The ap pear ance of isoquinolone 3 was unexpected,
which sug gested that when the amount of po lar aprotic sol-
ventwasincreased, theregioselectivityofthereactionwould
be low ered. It re vealed that the en ergy dif fer ence of the tran-
si tion states be tween 6-endo and 5-exo path way would be
less ened, al though the 5-exo path way was mostly oc cu pied
(Scheme I).
Preparation of 2-(2-aryl ethynyl)benzonitriles 9-12
were ac com plished by the di rect pal la dium-catalyzed cou-
pling re ac tion of 2-ethynylbenzonitrile 4 with aryl io dides
5-8 (Scheme II). Com pounds 9-12were then heated to re flux
withsodiummethoxideinmethanolcontaining10%THF,re-
spectively. TheresultsaresummarizedinSchemeIII.
When the aryl group had the elec tron-donating group at
R
( R = aryl )
NH
R
Na, MeOH
O
( equ 1 )
10% THF
R
CN
reflux 16hrs
( R = alkyl )
NH
O
Our first at tempt was car ried out by mix ing 2-(2-phenyl
ethynyl)benzonitrile1 with so dium methoxide in meth a nol
con tain ing 10% THF, and the re ac tion mix ture was refluxed
for16hrs.Aftertheusualworkupandchromatography,com-
pound 2 wasobtainedin88%yield. Variouspercentagesand
po lar aprotic sol vents were then em ployed in the same re ac-
tion. The results are summarized in Table 1. When the
amount of THF was in creased to 30%, isoindolone 2 was ob-
tained in 65% yield along with 7% yield of isoquinolone3. In

212 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Lin et al.
trastabilizationofthe5-exocyclizationintermediateI by the
Scheme I
coordinationofoxygenwithsodium.
R
R
H+
Me
N
NH
O
Na
OMe
5-exo
O
N
R
R
OMe
Na, MeOH
N
10% THF
CN
reflux 16hrs
OMe
I
6-endo
There are sev eral sig nif i cant points aris ing from this
study in clud ing the fol low ing: (1) The an ionic cyclo aro-
matiz ation of 2-(2-arylethynyl)benzonitriles would be pro-
motedbyaddingpolaraproticsolvents.(2)Thegenerationof
6-endo prod ucts ex plored a novel re ac tion mode of the aza-
anionic cycloaromatization of enediynes. (3) The yields of
cyclized prod ucts were aug mented,5 while po lar aprotic sol-
vents were added; as the amount of aprotic sol vents were in-
creased, the yield of 6-endo prod ucts were also in creased.
R
R
N
H+
NH
O
OMe
Scheme II
Y
Y
Pd(PPh3)4, CuI
n-BuNH2, Et2O
X
+
I
CN
CN
EXPERIMENTAL SECTION
X
4
5 X= H, Y= CH3
6 X= H, Y= OCH3
7 X= OCH3, Y= H
8 X= CF3, Y= H
9 (69%)
General Procedure for Coupling of 2-Ethynylbenzonitrile
with Aryl Iodide
10 (45%)
11 (48%)
12 (55%)
To a degassed solution of 2-ethynylbenzonitrile (1
mmol) in dry ether (20 mL) con tain ing CuI (0.03 g, 0.15
mmol), n-BuNH2 (0.2 g, 0.25 mmol) was added a de gassed
solutionofaryliodide(1.2mmol)containingPd(PPh3)4 (0.03
g, 0.15 mmol) in dry ether (10 mL). The re ac tion mix ture was
stirred for 6 hrs and quenched with sat. NH4Cl(aq). The aque-
ous layer was ex tracted with EtOAc (30 mL*3) and the com-
bined or ganic lay ers were washed with sat. NaHCO3(aq) and
driedoveranhydrousMgSO4(s).Afterfiltrationandremoval
of sol ventin vacuo,theresiduewaspurifiedbycolumnchro-
matographytogivethesoleproducts.
Scheme III
R
R
R
Na, MeOH
NH
+
NH
10% THF
CN
O
reflux 16hrs
O
9
R = p-CH3-C6H4
9a (67%)
10a (45%)
11a (94%)
12a (65%)
9b (12%)
10b (7%)
2-(2-(4-Methyl)phenyl)ethynyl)benzonitrile (9)5
Ob tained in 69% as a yel low oil.1H NMR (CDCl3, 200
MHz) 7.68~7.49 (m, 5H), 7.39 (td, 1H, J = 7.8, 2.0 Hz),
7.18 (d, 2H, J = 8.0 Hz), 2.38 (s, 3H).
10
11
12
R = p-CH3O-C6H4
R = o-CH3O-C6H4
R = o-CF3-C6H4
2-(2-(4-Methoxy)phenyl)ethynyl)benzonitrile (10)6
Ob tained in 45% as a yel low oil.1H NMR (CDCl3, 200
MHz) 7.69~7.51 (m, 5H), 7.38 (td, 1H, J = 7.8, 2.0 Hz),
6.89 (dd, 2H,J = 7.8, 2.0 Hz), 3.83 (s, 3H), 13C NMR (CDCl3,
the para-position, both isoindolone and isoquinolone prod-
ucts were ob served. How ever, cyclization of 2-(2-(2- meth-
oxyphenyl)ethynyl)benzonitrile 11 gave the isoindolone 11a
in 94% yield as the only prod uct. This could be due to the ex-

Sol vent Ef fects on Aza-anionic Cycloaromatization
J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 213
50 MHz) 160.4, 133.6, 132.6, 132.3, 132.1, 131.8, 127.8,
127.7, 117.7, 115.1, 114.1, 96.4, 84.6, 55.3.
Hz), 7.49 (td, 1H, J = 7.6, 1.2 Hz), 7.39 (dd, 2H, J = 7.4, 2.0
Hz), 6.97 (dd, 2H, J = 7.4, 2.0 Hz), 6.52 (s, 1H), 3.86 (s, 3H),
13C NMR (CDCl3, 50 MHz) 168.9, 159.2, 138.2, 132.2,
131.7, 129.8, 128.9, 127.5, 123.6, 119.6, 114.8, 105.9, 55.4.
The fol low ing peaks of spec trum be long to 10b. 1H NMR
(CDCl3, 200 MHz) 9.37 (bs, 0.16H), 6.72 (s, 0.16H), 3.87
(s, 0.5H), the other peaks of ar o matic could not be sep a rated
from 10a.
2-(2-(2-Methoxy)phenyl)ethynyl)benzonitrile (11)6
Ob tained in 48% as a yel low oil.1H NMR (CDCl3, 200
MHz) 7.67~7.64 (m, 2H), 7.59~7.53 (m, 2H), 6.97~6.91
(m, 2H), 3.94 (s, 3H), 13C NMR (CDCl3, 50 MHz) 160.4,
133.9, 132.6, 132.2, 132.1, 130.8, 127.9, 127.6, 120.5, 117.6,
115.2, 111.4, 110.8, 92.7, 89.5, 55.8.
3-(2-Methoxybenzylidene)isodol-1-one (11a)8
2-(2-(2-Trifluoromethyl)phenyl)ethynyl)benzonitrile (12)6
Ob tained in 55% as a col or less oil.1H NMR (CDCl3,
200 MHz) 7.80 (d, 1H, J = 8.0 Hz), 7.73~7.59 (m, 4H),
7.56~7.41 (m, 3H).
Ob tained in 94% as a yel low solid. 1H NMR (CDCl3,
200 MHz) 8.33 (bs, 1H), 7.84 (t, 2H, J = 8.4 Hz), 7.62 (td,
1H, J = 7.4, 1.4 Hz), 7.51 (dd, 1H, J = 7.4, 1.4 Hz), 7.46~7.27
(m, 2H), 7.06~6.95 (m, 2H), 6.63 (s, 1H), 3.93 (s, 3H), 13
C
NMR (CDCl3, 50 MHz) 168.5, 156.4, 138.4, 132.9, 132.0,
130.4, 130.3, 129.4, 128.9, 123.8, 123.5, 121.4, 119.9, 111.6,
102.3, 55.8; mp = 196-197 C.
General Procedure for Methanolysis of 2-Alkynyl-
benzonitrile
To a so lu tion of 2-alkynylbenzonitrile (1 mmol) in 10
mL of methanol was added freshly cut sodium metal (5
mmol);thesolutionwasheatedtorefluxandstirredfor16hr.
After cool ing to room tem per a ture, the meth a nol was re-
moved in vacuo. To the res i due, sat NaCl (aq) was added and
extractedwithEtOAc. Thecombinedorganiclayerwasdried
overanhydrousMgSO4(s). Af ter fil tra tion and re moval of
solvent,theresiduewaspurifiedbycolumnchromatography
to give the sole prod ucts.
3-(2-Trifluoromethylbenzylidene)isoindol-1-one (12a)
Ob tained in 65% as a white solid.1H NMR (CDCl3, 200
MHz) 7.89 (dd, 1H, J = 3.6, 0.4 Hz), 7.84 (dd, 1H, J = 3.6,
0.4 Hz), 7.76 (d, 1H, J = 4.2 Hz), 7.68 (td, 1H, J = 3.6, 0.4
Hz), 7.63~7.44 (m, 3H), 7.48~7.42 (m, 1H), 6.76 (s, 1H); mp
= 206-207 C.
ACKNOWLEDGMENT
3-(4-Methylbenzylidene)isoindol-1-one (9a)5 and
3-(4-Methylphenyl)isoquinolin-1-one (9b)
WewouldliketothanktheNationalScienceCouncilof
theRepublicofChinaforfinancialsupport.
Ob tained in 79% as a white solid, from 1H NMR spec-
trum, it shows as a mix ture of 9a (67%) and 9b (12%). The
fol low ing peaks of spec trum be long to9a. 1H NMR (CDCl3,
200 MHz) 8.18 (bs, 1H), 7.88 (dt, 2H, J = 8.0, 0.8 Hz), 7.63
(td, 1H, J = 6.6, 1.2 Hz), 7.51 (td, 1H, J = 6.6, 1.2 Hz), 7.35 (d,
2H, J = 8.0 Hz), 7.25 (d, 2H,J = 8.0 Hz), 6.53 (s, 1H), 2.39 (s,
3H), 13C NMR (CDCl3, 50 MHz) 168.8, 137.8, 132.4,
132.2, 132.1, 129.9, 129.0, 128.3, 123.5, 119.7, 106.0, 21.3.
Received October 19, 2000.
Key Words
Enediyne; Methanolysis; Regioselectivity;
Anionic cycloaromatization.
1
The following peaks of spectrum belong to 9b. H NMR
(CDCl3, 200 MHz) 9.71 (bs, 0.2H), 6.83 (s, 0.2H), 2.45 (s,
0.6H); the other peaks of ar o matic could not be sep a rated
from 9a.
REFERENCES
1. (a) Wendi, M. D.; Kerwin, S. M. J. Am. Chem. Soc. 1997,
119, 1464. (b) Shi, C. S.; Wang, K. K. J. Org. Chem.
1998, 63, 3517. (c) Wu, M. J.; Lin, C. F.; Wu, J. S.; Chen,
H. T. TetrahedronLett. 1994, 35, 1879.
2. Nicolaou, K. C.; Dai, W. M. Angew. Chem. Int. Ed. Engl.
1991, 30, 1387.
3-(4-Methoxybenzylidene)isoindol-1-one (10a)7 and
3-(4-Methoxyphenyl)isoquinolin-1-one (10b)
10a and10b ob tained in 52% as a yel low solid, from1H
NMR spec trum, it shows as a mix ture of 10a (45%) and 10b
1
(7%). The following spectrum belong to 10a. H NMR
(CDCl3, 200 MHz) 8.15 (bs, 1H), 7.87 (dd, 1H, J = 7.6, 1.2
Hz), 7.77 (dd, 1H, J = 7.6, 1.2 Hz), 7.62 (td, 1H, J = 7.6, 1.2
3. (a) Nicolaou, K. C. Angew. Chem. Int. Ed. Engl. 1993, 32,
1377. (b) Hichcock, S. A.; Boyer, S. H.; Chu-Moyer, M.

214 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Lin et al.
Y.; Olson, S. H.; Denishesky, S. D. Angew. Chem. Int.
Ed. Engl. 1994, 33, 858. (c) Meyer, A. G.; Fraley, M. E.;
Tom, N. J.; Co hen, S. B.; Madar, D. J. Chem. Biol. 1995,
2, 33.
dron 1999, 55, 13193.
6. Pschirer, N. G.; Bunz, U. H. F. TetrahedronLett. 1999,
40, 2481.
7. Guillaume, J.; Boccara, N.; Demerseman, P.; Royer, R.;
Bideau, J. P. J. Heterocycl. Chem. 1990, 3, 605.
8. Yoshiaki, K.; Masumi, T.; Kazuo, A. Chem. Pharm. Bull.
1993, 11 , 2003.
4. (a) Maier, M. E. Synlett. 1995, 13. (b) Nicolaou, K. C.;
Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci. U. S. A.
1993, 90, 5881.
5. Wu, M. J.; Chang, L. J.; Wei, L. M.; Lin, C. F. Tetrahe-