A novel alkyne-induced recyclization of 4-hydroxymethyl or 4-formyl-1H-2,3-dihydroisoindoles-an effective pathway to substituted isobenzofurans

Article abstract of DOI:10.1016/j.tetlet.2009.06.036

2-Alkyl or 2-benzyl-substituted 4-hydroxymethyl(formyl)isoindoles readily react with electron-deficient alkynes undergoing intramolecular cyclization to produce 1-aminomethyl-substituted isobenzofurans in good yields.

Full text of DOI:10.1016/j.tetlet.2009.06.036

Tetrahedron Letters 50 (2009) 4851–4853
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Tetrahedron Letters
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A novel alkyne-induced recyclization of 4-hydroxymethyl
or 4-formyl-1H-2,3-dihydroisoindoles—an effective pathway
to substituted isobenzofurans
*
Leonid G. Voskressensky , Larisa N. Kulikova, Alexey Kleimenov,
Natalia Guranova, Tatiana N. Borisova, Alexey V. Varlamov
Organic Chemistry Department of Russian Peoples’ Friendship University, 6, Miklukho-Maklaya St., Moscow 117198, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Alkyl or 2-benzyl-substituted 4-hydroxymethyl(formyl)isoindoles readily react with electron-deficient
alkynes undergoing intramolecular cyclization to produce 1-aminomethyl-substituted isobenzofurans in
good yields.
Received 25 April 2009
Revised 22 May 2009
Accepted 5 June 2009
Available online 11 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Recyclization reactions of carbo-, and especially heterocyclic
compounds, are a valuable synthetic tool in organic chemistry.
Recyclization in the presence of various nucleophiles, electrophiles,
or dipolar reagents occurs via ring opening in the initial molecule
followed by its subsequent closure. This process is often accompa-
nied by ring expansion or contraction, introduction of a hetero-
atom in the ring or its replacement by another heteroatom, etc.
Nevertheless, from a preparative viewpoint, all these complex
transformations take place in a one-pot reaction, thus making pos-
sible effective syntheses of compounds that are difficult to obtain
by other protocols.
Several transformations of this type are known, including the
Hafner reaction,1 the Dimroth,2 Boulton–Katritzky,3 Cornforth,
and Kost–Sagitullin rearrangements.4,5 Rearrangements of hetero-
cyclic rings by temporary opening and subsequent closure to new
molecules are of particular interest both synthetically and
theoretically.
We have recently presented several examples of tetrahydropyr-
ido-6 and tetrahydroazepino-7 annulated (hetero)cycle transforma-
tions promoted by activated alkynes to yield the N-containing ring
expansion products. The present Letter reports on unusual recycli-
zations of related dihydroisoindoles 1–10 under the action of acti-
vated alkynes.
The starting 4-hydroxymethyldihydroisoindoles 1–8 required
for the present study were obtained by LiAlH4 reduction of the cor-
responding isoindole carboxylic acids, synthesized according to the
procedure previously described8 (Scheme 1, Table 1). Hydroxy-
methyl derivatives and were oxidized by pyridinium
3
6
chlorochromate (PCC) to give the aldehydes
Supplementary data for details).
9 and 10 (see
By analogy to the previously reported results6,7,9 we expected
that the reactions of 1–10 with activated alkynes would yield the
corresponding benzazepine derivatives A, or, in the case of deriva-
tives 9 and 10, containing a potent electron-withdrawing group,
the products of Stevens rearrangement of an intermediate ylide B
(Scheme 2).
The reactions of dihydroisoindoles 1–7 with methyl propiolate
(MP), dimethyl acetylenedicarboxylate (DMAD), or acetyl acety-
lene proceeded smoothly,10 but to our surprise, none of the ex-
pected derivatives were obtained. The only products isolated in
good preparative yields were substituted phthalan derivatives
11–17, 19, and 22–24. (Scheme 3, Table 2). We presume that the
reaction starts with the Michael addition of the alkyne to the ter-
tiary N-atom of the starting compound followed by abstraction
of H+ from the hydroxy group in intermediate C. The resulting
zwitterion D undergoes intramolecular recyclization to yield the
phthalan derivatives 1111–17, 19, and 22–24 (Scheme 3).
In the case of iso-pentyl derivative 6, a small amount of a deb-
enzylation by-product, N-vinyl-substituted isoindole 18 was iso-
lated. 2-Phenyl-substituted isoindole 8 was unreactive toward
activated alkynes even under forcing conditions (48 h refluxing
in methanol or acetonitrile, sixfold molar excess of alkyne). This
is most likely due to the low basicity of the aniline nitrogen atom,
which fails to undergo Michael addition with the alkyne. The pro-
posed reaction mechanism is consistent with that reported for the
synthesis of isobenzofuran derivatives by alkali-catalyzed transfor-
mations of dialkyl(4-hydroxy-2-butynyl)(3-alkenylpropargyl)
ammonium salts.12
* Corresponding author. Fax: +7 495 9550779.
E-mail address: lvoskressensky@sci.pfu.edu.ru (L.G. Voskressensky).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.036

4852
L. G. Voskressensky et al. / Tetrahedron Letters 50 (2009) 4851–4853
O
OH
O
OH
HO
O
O
O
HN
R
O
H+
LAH
O
O
N
R
N
R
N
R
O
1-8
HO
O
H
PCC
N
R
N R
3,6
9,10
Scheme 1. Synthesis of the starting compounds.
Table 1
Table 2
Characteristics of the starting compounds
Reactions of starting compounds 1–10 with alkynes
Product #
R
Yield (%)
Mp (°C)
Product
O
R
R1
R2
R3
Yield Mp
(%)
(°C)
1
2
3
4
5
6
7
8
9
i-Pr
Bn
(CH2)3OCH3
i-Bu
i-Pentyl
3,4-(MeO)2 C6H3CH2
CH2(CH2)3CH3
4-F-C6H4
(CH2)3OCH3
3,4-(MeO)2C6H3CH2
63
67
61
64
69
71
68
73
30
32
114–115
136–137
84–86
73–74
76–77
140–141
88–89
127–128
Oil
R
N
R3
R1
R2
11
12
13
14
15
16
17
19
20
21
22
23
24
25
i-Pr
i-Pr
i-Pr
i-Bu
H
CO2Me
H
H
H
H
H
H
H
H
64
67
50
71
64
59
88
43
99–101
175
Oil
Oil
133–135
Oil
CO2Me CO2Me
H
H
H
H
COMe
10
Oil
CO2Me
CO2Me
CO2Me
Bn
(CH2)3OCH3
(CH2)3OCH3
CH2(CH2)3CH3
(CH2)3OCH3
3,4(MeO)2C6H3
i-Pentyl
i-Pentyl
i-Pentyl
(CH2)3OCH3
CO2Me CO2Me
Oil
Oil
CH2OH
R1
Y
R
H
H
H
H
CO2Me
CO2Me OCH3 36
CO2Me OCH3 40
X
Oil
Oil
Y
X
X
N
R
N
X
CO2Me
H
H
H
63
65
24
20
Oil
87–88
Oil
CO2Me CO2Me
H
H
A
COMe
CO2Me @O
Y
Oil
Y
Y
R
CHO
Me
CHO
[1,2]
X
OH
O
CO2Me
N
R
O
CO2Me
N
B
N
R
MeOH
N
R
Scheme 2.
9,10
R1
R2
R1
CH2OH
CH2OH
O
O
R2
R
N
N
(MeOH or
CH3CN)
R
O
O
CO2Me
Me
1-7
C
N
R
N
R2
R1
CH2O
R
CO2Me
20,21
O
R
O
N
N
O
CO2Me
R
R1
O
OH
R2
D
[O]
25
(20%)
11-17, 19, 22-24
9
CH2OH
N
R
MeCN
N
R
N
E
CO2Me
CO2Me
18
Scheme 3.
Scheme 4.

L. G. Voskressensky et al. / Tetrahedron Letters 50 (2009) 4851–4853
4853
6. (a) Voskressensky, L. G.; Borisova, T. N.; Kulikova, L. N.; Varlamov, A. V.; Catto,
M.; Altomare, C.; Carotti, A. Eur. J. Org. Chem. 2004, 3128–3135; (b)
Voskressensky, L. G.; Borisova, T. N.; Kostenev, I. S.; Kulikova, L. N.;
Varlamov, A. V. Tetrahedron Lett. 2006, 47, 999–1001; (c) Voskressensky, L.
G.; Borisova, T. N.; Kostenev, I. S.; Vorobiev, I. V.; Varlamov, A. V. Tetrahedron
Lett. 2005, 46, 1975–1979; (d) Voskressensky, L. G.; Listratova, A. V.; Borisova,
T. N.; Alexandrov, G. G.; Varlamov, A. V. Eur. J. Org. Chem. 2007, 6106–6117.
7. Voskressensky, L. G.; Akbulatov, S. V.; Borisova, T. N.; Varlamov, A. V.
Tetrahedron 2006, 62, 12392–12397.
4-Formyl-substituted derivatives 9 and 10 reacted readily with
MP in methanol at room temperature, providing cyclic semi-acetal
derivatives 2013 and 21, however, their reactions with MP in aceto-
nitrile were not as efficient and required a rather long-reaction
time (72 h). The only product that was successfully isolated from
the reaction mixtures was the phthalide derivative 2514 (20%),
which was most likely formed from the corresponding carboxylic
acid E, generated in situ from 9 (Scheme 4).
8. Varlamov, A. V.; Boltukhina, E. V.; Zubkov, F. I.; Sidorenko, N. V.; Chernyshev, A.
I.; Grudinin, D. G. Chem. Heterocycl. Compd. 2004, 40, 27–33.
In conclusion, we have reported a novel synthetic approach to-
ward 4-aminomethyl-substituted dihydroisobenzofuran deriva-
tives, based on a new alkyne-induced recyclization of easily
available 4-hydroxymethyl(formyl) dihydroisoindoles. Work,
aimed at exploring the reaction scope and limitations is underway
and will be reported in due course.
9. Voskressensky, L. G.; Vorobiev, I. V.; Borisova, T. N.; Varlamov, A. V. J. Org. Chem.
2008, 73, 4596–4601.
10. General method for the reaction of 1–10 with activated alkynes. DMAD, methyl
propiolate, or acetyl acetylene (2.5 mmol) was added to
a solution of
dihydroisoindole 1–10 (1.7 mmol) in methanol or acetonitrile (10 ml). The
reaction mixture was stirred for 24–32 h at 25 °C (TLC monitoring). The solvent
was evaporated under reduced pressure and the resulting residue was purified
by flash column chromatography on SiO2 with ethyl acetate as eluent to give
isobenzofurans 11–25.
Acknowledgment
11. Methyl (E)-3-[1,3-dihydro-4-isobenzofuranylmethyl (isopropyl)amino]-2-propenoate
(11): white solid, mp 99–101 °C. 1H NMR (400 MHz, CDCl3): d = 1.23 [d, 6H,
J = 6.7 Hz, CH(CH3)2], 3.58–3.61 [m, 1H, CH(CH3)2], 3.63 (s, 3H, OCH3), 4.16 (s, 2H,
NCH2), 4.53 (d, 1H, J = 13.1 Hz, @CH), 5.08 (s, 2H, CH2O), 5.12 (s, 2H, CH2O), 7.05
(d, 1H, J = 7.9 Hz, CH-Ar), 7.13 (d, 1H, J = 7.9 Hz, CH-Ar), 7.24 (t, 1H, J = 7.9 Hz, CH-
Ar), 7.69 (d, 1H, J = 13.1 Hz, N–CH@) ppm. 13C NMR (151 MHz, CDCl3): d = 21.3
(2 Â C), 31.1, 50.5 (2 Â C), 54.7, 72.4, 73.8, 86.0, 120.1, 125.1, 128.3 (2 Â C), 136.5,
150.2, 170.1 ppm. ESI MS 276 (M++1). Anal. Calcd for C16H21NO3 (275.34): C,
69.79; H, 7.69; N, 5.09. Found: C, 69.83; H, 7.64; N, 5.14.
This work was supported by the Russian Foundation for Basic
Research (Grant # 08-03-90451 Ukr-a).
A. Supplementary data
12. Gevorkyan, A. R.; Chukhadzhyan, E. O.; Chukhadzhyan, El. O.; Panosyan, G. A.
Chem. Heterocycl Compd. 2004, 40, 177–181.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tetlet.2009.06.036.
13. Methyl (2E)-3-{[(1-methoxy-1,3-dihydro-2-benzofuran-4-yl)methyl](3-methoxy-
propyl)amino} acrylate (20): yellow oil. 1H NMR (600 MHz, CDCl3): d = 1.73–
1.82 (m, 2H, CH2-2), 3.20 (t, 2H, J = 5.6 Hz, CH2-3), 3.30 (s, 3H, OCH3), 3.33 (t, 2H,
J = 5.5 Hz, CH2-1), 3.45 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 4.27 (s, 2H, NCH2), 4.65
(d, 1H, J = 13.1 Hz, CH@), 4.97 (d, 1H, J = 13.0 Hz, OCH), 5.11 (dd, 1H, J = 13.0 Hz,
4J = 2.0 Hz, OCH,) 6.16 (d, 1H, 4J = 2.0 Hz, CHOCH3), 7.15–7.18 (m, 1H, CH-Ar),
7.33–7.34 (m, 2H, CH-Ar), 7.56 (d, 1H, J = 13.1 Hz, N–CH@) ppm. 13C NMR
(151 MHz, CDCl3): d = 29.2, 50.2, 54.2 (2 Â C), 54.7, 58.2, 68.8, 70.9, 84.9, 107.0,
122.0, 128.1, 132.8, 135.5, 136.8, 137.8, 151.5, 169.5 ppm. ESI MS 336 (M++1).
Anal. Calcd for C18H25NO5 (335.17): C, 64.46; H, 7.51; N, 4.18. Found: C, 64.87;
H, 7.13; N, 4.25.
14. Methyl (2E)-3-{(3-methoxypropyl)[(1-oxo-1,3-dihydro-2-benzofuran-4-yl)methyl]-
amino}acrylate (25): yellow oil. 1H NMR (600 MHz, CDCl3): d = 1.79–1.84 (m, 2H,
CH2-2), 3.23 (t, 2H, J = 6.6 Hz, CH2-3), 3.31 (s, 3H, OCH3), 3.37 (t, 2H, J = 6.6 Hz,
CH2-1), 3.67 (s, 3H, OCH3)), 4.40 (s, 2H, CH2N), 4.68 (d, 1H, J = 13.1 Hz, CH@), 5.25
(s, 2H, CH2O), 7.50 (t, 1H, J = 7.9 Hz, CH-Ar), 7.61–7.56 (m, 2H, CH-Ar and NCH@),
7.87 (d, 1H, J = 7.9 Hz, CH-Ar) ppm. 13C NMR (151 MHz, CDCl3): d = 28.7, 50.8,
51.7, 53.3 (2 Â C), 58.7, 68.7, 70.4, 86.1, 122.3, 123.9, 130.1, 133.1 (2 Â C), 149.1,
169.5, 171.4. ESI MS 320 (M++1). Anal. Calcd for C17H21NO5 (319.14): C, 63.94; H,
6.63; N, 4.39. Found: C, 64.35; H, 6.25; N, 4.47.
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