Studies dealing with the cycloaddition/ring opening/elimination sequence of 2-amino-substituted isobenzofurans

Article abstract of DOI:10.1021/jo962358c

The α-thiocarbocation generated from the Pummerer reaction of an o-amido-substituted sulfoxide is intercepted by the adjacent amido carbonyl group to produce a 2-amino-substituted isobenzofuran as a transient intermediate. In the presence of an electron-deficient dienophile, the reactive isobenzofuran undergoes a Diels-Alder cycloaddition followed by ring opening to furnish a vinylogous C-acyliminium ion that readily aromatizes. The one-pot intramolecular cascade process only occurs either if the olefinic tether is activated by an ester or if a carbonyl group is located adjacent to the nitrogen atom of the 2-amino-substituted isobenzofuran. To examine the amine vs amide influence on the course of intramolecular cycloaddition, density functional theory (DFT) calculations have been carried out for both ground and transition states. The results strongly suggest that the amide-substituted isobenzofurans are destabilized by steric effects between the aromatic ring and the nitrogen-containing side chain. Raising of the ground-state amide energies thereby reduces the activation energy for internal cycloaddition and leads to Diels-Alder adducts more rapidly than for the corresponding amines. Amide tethers emerge as remote-site promoters of intramolecular cycloaddition for tandem processes yielding products with multiple fused rings.

Full text of DOI:10.1021/jo962358c

2786
J . Org. Chem. 1997, 62, 2786-2797
Stu d ies Dea lin g w ith th e Cycloa d d ition /Rin g Op en in g/Elim in a tion
Sequ en ce of 2-Am in o-Su bstitu ted Isoben zofu r a n s†
Albert Padwa,* C. Oliver Kappe, J ohn E. Cochran, and J ames P. Snyder
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received December 17, 1996X
The R-thiocarbocation generated from the Pummerer reaction of an o-amido-substituted sulfoxide
is intercepted by the adjacent amido carbonyl group to produce a 2-amino-substituted isobenzofuran
as a transient intermediate. In the presence of an electron-deficient dienophile, the reactive
isobenzofuran undergoes a Diels-Alder cycloaddition followed by ring opening to furnish a
vinylogous C-acyliminium ion that readily aromatizes. The one-pot intramolecular cascade process
only occurs either if the olefinic tether is activated by an ester or if a carbonyl group is located
adjacent to the nitrogen atom of the 2-amino-substituted isobenzofuran. To examine the amine vs
amide influence on the course of intramolecular cycloaddition, density functional theory (DFT)
calculations have been carried out for both ground and transition states. The results strongly
suggest that the amide-substituted isobenzofurans are destabilized by steric effects between the
aromatic ring and the nitrogen-containing side chain. Raising of the ground-state amide energies
thereby reduces the activation energy for internal cycloaddition and leads to Diels-Alder adducts
more rapidly than for the corresponding amines. Amide tethers emerge as remote-site promoters
of intramolecular cycloaddition for tandem processes yielding products with multiple fused rings.
Sch em e 1
The synthesis of polycyclic systems from readily avail-
able precursors with a minimum number of steps and
with regio- and stereochemical control constitutes an
important synthetic challenge.1-3 In this regard, one of
the most powerful ring-forming reactions currently used
for this purpose is the Diels-Alder cycloaddition.4,5
Furans6 and isobenzofurans7 have frequently been em-
ployed as dienes in the Diels-Alder reaction to afford
substituted 7-oxabicyclo[2.2.1]heptanes (1) that serve as
key intermediates in the synthesis of a variety of natural
products.8-15 The large number of selective transforma-
tions possible with the oxabicyclic system endow this
nucleus with impressive versatility. A crucial synthetic
transformation employing these intermediates (Scheme
1) involves the cleavage of the oxygen bridge to produce
functionalized cyclohexene derivatives 2 or 3. Many
groups have developed different approaches including
â-elimination of suitable derivatives,16 treatment with
strong acids,17 reductive elimination of endo functional-
ities (R1 ) Cl or SO2Ph),18 fragmentation,19 hydrolytic
ring openings,20 and alkylative bridge cleavage reac-
tions.21
Prompted by our recent work dealing with the Pum-
merer-promoted cyclization of o-amido-substituted sul-
foxides,22 we have become interested in the Diels-Alder
reaction of 2-amino-5-(alkylthio)-substituted isobenzo-
furans. We envisioned that the resulting 7-oxabicyclo-
† This paper is dedicated to my good friend, Waldemar Adam, on
the occasion of his 60th birthday.
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
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S0022-3263(96)02358-4 CCC: $14.00 © 1997 American Chemical Society

Reactions of 2-Amino-Substituted Isobenzofurans
J . Org. Chem., Vol. 62, No. 9, 1997 2787
Sch em e 2
Sch em e 3a
[2.2.1]heptane system (i.e., 6) could be used for the
synthesis of a variety of 1-hydroxy-4-aminonaphthalene
derivatives (Scheme 2). These substituted naphthy-
lamines are important starting materials for the prepa-
ration of heterocyclic compounds and pharmaceuticals.23-25
Notable examples of biologically active molecules con-
taining derivatized anilines in their structure include
antibiotics,26 analgesics,27 and â-adrenergic blockers.28 In
this paper, we report a full account of our efforts in this
field.
a
Reagents: (a) SOCl2; (b) Et2NH; (c) NaIO4; (d) Ac2O, p-TsOH;
(e) N-phenylmaleimide or maleic anhydride.
product obtained from the cascade process utilized a
mixture of acetic anhydride and a catalytic quantity of
p-toluenesulfonic acid in refluxing toluene.31 Treatment
of sulfoxide 10 with either N-phenylmaleimide or maleic
anhydride under these conditions led to the formation of
the bright yellow amino-substituted naphthols 11 or 12
in 72 and 76% yield, respectively (Scheme 3). Slightly
higher yields were obtained by using acetic anhydride
as the solvent, although, under these conditions, the
O-acetylated cycloadducts 13 and 14 were obtained. The
formation of these naphthols is fully compatible with
a ring-opening/ iminium ion/ deprotonation sequence
(Scheme 4).
Resu lts a n d Discu ssion
The required sulfoxide precursors necessary for the
Pummerer-induced cyclization-cycloaddition sequence
were easily obtained from 2-[(ethylthio)methyl]benzoic
acid (8). This acid was available in large quantities and
in high yield by the ring-opening reaction of phthalide
with sodium ethylthiolate. Treatment of 8 with thionyl
chloride at room temperature and subsequent reaction
of the crude acid chloride with diethylamine in CH2Cl2
provided amide 9 in 87% overall yield. Sulfoxide 10 was
obtained in 91% yield from the oxidation of sulfide 9
using sodium periodate.29 It is well known that the
classical Pummerer reaction can be initiated by a variety
of electrophilic reagents (Pummerer promoters).30 Acetic
anhydride is by far the most commonly used promoter
and is often utilized as the solvent at reflux temperature
or in combination with other solvents or cocatalysts. The
more electrophilic trifluoroacetic anhydride has also been
employed, as it allows the reaction to proceed under very
mild conditions.30
Interestingly, when a less reactive dienophile such as
dimethyl maleate was employed, R-acetoxy sulfide 17 was
the only product isolated from the reaction mixture. This
same product was isolated in high yield when the
Pummerer reaction was performed without using p-TsOH
as a cocatalyst. Apparently, the initially generated
thionium ion 15 is either captured internally by the
adjacent carbonyl group32 to give oxonium ion 16, which
subsequently deprotonates to produce the isobenzofuran
intermediate 18, or else it reacts with an external
nucleophile (i.e., AcO-) to furnish the acetoxy sulfide 17
(Scheme 4). The presence of p-TsOH effectively drives
the reaction in the desired direction (15 f 18) probably
by assisting in the ejection of the acetoxy group (17 f
15). This interpretation is supported by a control experi-
ment that showed that the treatment of 17 with p-TsOH
in toluene in the presence of N-phenylmaleimide pro-
duced cycloadduct 11 in 61% yield. Once the 2-ami-
noisobenzofuran intermediate 18 is generated, it under-
goes ready Diels-Alder reaction with any reactive
dienophile present in solution.33 Fragmentation of the
initially formed oxa-bridged cycloadduct 19 produces the
After some experimentation with a variety of Pum-
merer promoters, we found that the highest yield of
(23) Lindsay, R. J . Comprehensive Organic Chemistry; Sutherland,
I. O., Ed.; Pergamon Press: Oxford, 1979; Part 6.3.
(24) Sugasawa, T.; Toyoda, T.; Adachi, M.; Sasakura, K. J . Am.
Chem. Soc. 1978, 100, 4842. Adachi, M.; Sugasawa, T. Synth. Commun.
1990, 20, 71.
(25) Zenchoff, G. S.; Walser, A.; Fryer, R. I. J . Heterocycl. Chem.
1976, 13, 33.
(26) Thiericke, R., J r.; Zeeck, A. J . Chem. Soc., Perkin Trans. 1 1988,
2123.
(27) Ameer, B.; Greenblatt, D. J . Ann. Intern. Med. 1977, 87, 202.
(28) Basil, B.; J ordan, R.; Lovelass, A. H.; Maxwell, D. R. Br. J .
Pharmacol. 1973, 48, 198.
(29) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282.
(30) For a review of the Pummerer reaction and different triggering
methods, see: DeLucchi, O.; Miotti, U.; Modena, G. Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1991; Chapter 3, pp 157-184.
(31) Watanabe, M.; Nakamori, S.; Hasegawa, H.; Shirai, K.; Kuma-
moto, T. Bull. Chem. Soc. J pn. 1981, 57, 817.
(32) DeGroot, A.; J ansen, B. J . M. J . Org. Chem. 1984, 49, 2034.
J ansen, B. J . M.; Bouwman, C. T.; DeGroot, A. Tetrahedron Lett. 1994,
35, 2977. J ommi, G.; Pagliarin, R.; Sisti, M.; Tavecchia, P. Synth.
Commun. 1989, 2467.

2788 J . Org. Chem., Vol. 62, No. 9, 1997
Padwa et al.
Sch em e 4
Sch em e 6a
a
Reagents: (a) SOCl2; (b) MeNH2; (c) NaIO4; (d) Ac2O, p-TsOH;
(e) N-phenylmaleimide.
as a byproduct and was converted to tetralone 23 by
further heating with DMAD in the presence of p-TsOH.
Compound 23 was slowly converted to naphthol 24 in
65% yield upon further heating. This process presumably
proceeds by elimination of thioacetaldehyde in a hetero-
retro-ene fashion, for which there is ample precedence in
the literature.34
In order to access synthetically more valuable targets,
we focused our attention on an intramolecular variation
of the tandem-amido-Pummerer-Diels-Alder reaction
sequence. The requisite tethered amido sulfoxide precur-
sors 28 and 29 were readily prepared from 8 by treatment
with thionyl chloride followed by reaction with methy-
lamine to furnish N-methylamide 25 in 72% yield (Scheme
6). Alkylation of 25 with butenyl or pentenyl bromide
provided N-alkenylamides 26 and 27 in high yield.
Oxidation with sodium periodate in methanol gave the
desired sulfoxides 28 and 29. Surprisingly, subjection
of either sulfoxide to a variety of “Pummerer” reaction
conditions failed to provide any product derived from an
intramolecular cycloaddition.4,5,35 Instead, R-acetoxy sul-
fides of type 17 were the only products formed. However,
it was possible to trap the isobenzofuran intermediate
(i.e., 30 or 31) with N-phenylmaleimide to furnish cy-
cloadducts 32 and 33 in good yields. These results
suggest that the unactivated olefinic tether present on
the 2-amino isobenzofuran is not sufficiently reactive to
participate in an intramolecular Diels-Alder reaction.
On the basis of FMO considerations,36 we anticipated
that activation of the CdC double bond with an electron-
withdrawing group would promote the intramolecular [4
+ 2]-cycloaddition.35 The p-tolylsulfonyl functionality
was first examined as an activating group since the
requisite sulfoxide 34 could be readily prepared from the
Sch em e 5
exocyclic iminium species 20, which undergoes a depro-
tonation followed by subsequent aromatization to furnish
the amino-substituted naphthols 11 or 12.
When dimethyl acetylenedicarboxylate is used as the
trapping agent, the initially formed iminium ion 22
cannot undergo proton loss (Scheme 5). Instead, 22
rearranges by means of a 1,2-ethylthio shift to afford the
tetralone derivative 23. Here, best results were achieved
by using xylene as the solvent and by employing a large
excess of the dienophile. R-Acetoxy sulfide 17 was formed
(34) Ripoll, J .-L.; Vallee, Y. Synthesis 1993, 659.
(35) For reviews on intramolecular Diels-Alder reactions, see:
Ciganek, E. Org. React. 1984, 32, 1. Fallis, A. G. Can. J . Chem. 1984,
62, 183. Craig, D. Chem. Soc. Rev. 1987, 16, 187. Ciganek, E. Org.
React. 1984, 32, 1. Fallis, A. G. Can. J . Chem. 1984, 62, 183. Craig, D.
Chem. Soc. Rev. 1987, 16, 187.
(33) For an alternative approach and cycloaddition reactions of
R-amino isobenzofurans, see: Chen, C.-W.; Beak, P. J . Org. Chem.
1986, 51, 3325. Peters, O.; Friedrichsen, W. Tetrahedron Lett. 1995,
36, 8581.
(36) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1976.

Reactions of 2-Amino-Substituted Isobenzofurans
J . Org. Chem., Vol. 62, No. 9, 1997 2789
Sch em e 7a
Sch em e 8a
a
Reagents: (a) ToISO2I/CuCl2; (b) Et3N; (c) NaIO4; (d) Ac2O,
p-TsOH; (e) N-phenylmaleimide.
alkenyl-tethered amide 26. Copper-catalyzed addition of
tosyl iodide to 26 followed by triethylamine-assisted
dehydroiodination of the initially formed â-iodo sulfone37
furnished the corresponding (E)-vinyl sulfone in 54%
overall yield. Oxidation with sodium periodate provided
the desired amido sulfoxide 34. As was the case with
the unactivated alkenyl group, no intramolecular cy-
cloaddition was encountered when sulfoxide 34 was
subjected to a variety of Pummerer conditions, even
though the bimolecular trapping product 36 was formed
in good yield when N-phenylmaleimide was present in
the reaction mixture (Scheme 7).
The failure of isobenzofuran 35 to undergo intramo-
lecular cycloaddition may be a consequence of unfavor-
able steric interactions in the transition state.35 We
reasoned that a sterically less demanding group might
help overcome the potential problems associated with the
bulky tosyl substituent. Consequently, the acrylic sub-
stituted esters 40 and 41 were synthesized in four steps
from amide 25 as outlined in Scheme 8. Alkylation of
25 with 2-(2-bromoethyl)-1,3-dioxolane followed by hy-
drolysis of the cyclic acetal with oxalic acid provided
aldehyde 37 in 72% yield. Wittig olefination using
methyl (triphenylphosphorylidene)acetate afforded a mix-
ture of (E)-38 (94%) and (Z)-39 (4%) esters that were
separated by careful silica gel chromatography. Each
isomer was independently oxidized to the corresponding
sulfoxide (40-E and 41-Z). Treatment of the individual
sulfoxides using acetic anhydride/p-TsOH in refluxing
xylene provided the same amino-substituted naphthol 43
in nearly identical yield (65%), suggesting that the
relative orientation of the ester functionality in the
isobenzofuran intermediate 42 is not a crucial factor for
the intramolecular cycloaddition. Similar results were
achieved using trifluoroacetic anhydride/triethylamine or
trimethylsilyl trifluoromethanesulfonate/triethylamine as
Pummerer promoters.30 The hydroxy indoline ester 43
proved to be sensitive to air and was readily oxidized to
benzo[g]indole 44.
a
Reagents: (a) BrCH2CH2CH(OCH2CH2O); (b) oxalic acid; (c)
Ph3PdCHCO2Me; (d) NaIO4; (e) Ac2O, p-TsOH.
We have also examined the Pummerer-induced reac-
tion of sulfoxide 45 (Scheme 9). Slow addition of 45 to a
refluxing mixture of xylene and acetic anhydride contain-
ing a catalytic amount of p-TsOH afforded a mixture of
the N,S-ketal 49 (43%) as well as amino-substituted
naphthol 50 (22%). Whereas 50 originates from the
previously encountered deprotonation/aromatization se-
quence of the endocyclic iminium ion 48, ketal 49 is
formed by nucleophilic attack of ethylthiolate onto the
N-acyliminium π-bond. Heating a pure sample of 49 in
xylene at reflux in the presence of p-TsOH resulted in
clean conversion to naphthol 50. By increasing the
amount of p-TsOH to 5 mol %, it was possible to isolate
the O-acylated derivative 51 in a one-pot reaction from
sulfoxide 45 in 59% overall yield.
Similar results were obtained when the dienophile
tether was shortened by one methylene unit as illustrated
in Scheme 10 for the conversion of sulfoxide 52 into
benzo[g]indole 55. High yields (75%) were achieved in
the one-pot conversion of 52 into 55 by using 5 mol % of
p-TsOH as cocatalyst for the tandem cyclization-cy-
cloaddition sequence.
For comparison purposes, we have also investigated
the chemistry of the closely related imido sulfoxide 57
where the carbonyl group has been switched from “inside”
the tether to the “outside” position (Scheme 11). Sulfox-
ide 57 was prepared from acid 8 in three steps by
conversion to the corresponding N-butenylamide 56,
followed by N-acetylation and subsequent oxidation with
sodium periodate. Cycloadduct 60 was formed in 82%
(37) Liu, L. K.; Chi, Y.; J en, K.-Y. J . Org. Chem. 1980, 45, 406.
(38) Padwa, A.; Cochran, J . E.; Kappe, C. O. J . Org. Chem. 1996,
61, 3706.

2790 J . Org. Chem., Vol. 62, No. 9, 1997
Padwa et al.
Sch em e 9a
Sch em e 11a
a
Reagents: (a) SOCl2; (b) but-3-enylamine; (c) MeCOCl; (d)
NaIO4; (e) Ac2O, p-TsOH.
group is striking. Five and six ring precursors 53 and
46, respectively, deliver cyclized products bearing a
carbonyl within the newly formed rings in good to
excellent yields. Externalization of the CdO as in 58
likewise leads to facile internal cyclization. Removal of
the CdO functionality, however (30, 31), suppresses
intramolecular cycloaddition in favor of bimolecular
attack by acetic acid (e.g., 10f17). The amine-amide
effect is not limited to isobenzofurans. In a previous
study of the intramolecular cycloaddition of incipient
carbonyl ylide dipoles and tethered alkenyl π-bonds, a
similar phenomenon was observed.39 Intermediates with
carbonyl groups in the tether provided cycloaddition
products. Those lacking the CdO failed to cyclize. Since
FMO theory was unable to predict the result in these
cases, full-scale ab initio transition-state optimizations
were carried out. The reactivity discrepancy was traced
to steric effects in the transition states leading to the
intervention of low energy boat conformations.
a
Reagents: (a) pent-4-enoyl chloride; (b) NaIO4; (c) Ac2O,
p-TsOH.
Sch em e 10a
To probe the forces responsible for intramolecular ring
formation in the present series, we have carried out
similar calculations for the isobenzofurans. The char-
acteristics of the reaction were explored within the five-
membered ring series (30, 53, and 58), while the SEt
group was modeled as SH. The structures in question
are 61-63 and 64†-66†. For a discussion of preliminary
calculations leading to choices of molecular structures for
subsequent ab initio refinement, see the Experimental
Section. Final optimized geometries were obtained with
the density functional theory (DFT)40 B3LYP/3-21G*
basis set, while energies were taken at the B3LYP/6-31G*
level (i.e., B3LYP/6-31G*// B3LYP/3-21G*). A similar
approach has been successfully applied to a number of
cycloaddition reactions.41
a
Reagents: (a) but-3-enoyl chloride; (b) NaIO4; (c) Ac2O, p-
TsOH.
when 57 was subjected to the standard Pummerer
conditions.
(39) Weingarten, M. D.; Prein, M.; Price. A. T.; Snyder, J . P.; Padwa,
A. J . Org. Chem. 1997, 62, 2001-2010.
(40) Becke, A. D. J . Chem. Phys. 1993, 98, 5648. Stevens, P. J .;
Devlin, F. F.; Chablowski, C. F.; Frisch, M. J . J . Chem. Phys. 1994,
99, 11623.
Th e Am in e vs Am id e Con u n d r u m
The intramolecular cycloaddition behavior of incipient
isobenzofurans in response to the presence of a CdO
(41) Wiest, O.; Black, K. A.; Houk, K. N. J . Am. Chem. Soc. 1994,
116, 10336.

Reactions of 2-Amino-Substituted Isobenzofurans
J . Org. Chem., Vol. 62, No. 9, 1997 2791
Ta ble 1. DF T En er gies (a u )a for Op tim ized Low En er gy
Con for m a tion s of Gr ou n d Sta tes 61-63 a n d Tr a n sition
Sta tes 64†-66† ∆E(ts-gs), k ca l/m ol
energies
compd
3-21G*a
∆E(ts-gs)c
6-31G*b
∆E(ts-gs)c
61
-1027.194 46
-1027.168 95
-1100.813 56
-1100.811 16
-1100.798 53
-1139.918 70
-1139.916 97
-1139.897 60
-1139.891 26
-871.060 53
-871.058 78
-871.048 37
-1032.514 34
-1032.480 67
-1106.549 05
-1106.527 27
-1100.811 16
-1145.867 73
-1145.859 90
-1145.837 62
-1145.831 46
-875.526 88
-875.527 30
-875.521 75
-248.522 14
-174.478 60
-287.838 69
64†
62a
16.0
21.1
62b
65†
63a
63b
66a †
66b†
67
9.4
13.7
18.9
17.2
68
69
MeNHCOMe -247.158 29
MeNHEt
MeCONHEt
-173.526 70
-286.262 93
Table 1 lists the energies for various optimized struc-
tures including ground-state (gs) and transition-state (ts)
conformations. The energy differences between ground
and transition states for the amine (61, 64†), the internal
carbonyl (62, 65†), and the external carbonyl (63, 66†) are
in qualitative agreement with experiment, ∆E† ) 21.1,
18.9, and 13.7 kcal/mol, respectively. That is, the amine
structure experiences the greatest energy barrier; the
amides, 2.2 (66†) and 7.4 (65†) kcal/mol lower. Figure 1
depicts the three transition states. The conformer of 66†
with an all-trans alkyl moiety is lowest (∆E [66a † - 66b†]
) -4.0 kcal/mol). The new bonds forming within the
pericycles are calculated to differ by no more than 0.09-
0.15 Å. This is relatively symmetric by comparison with
the transition states for intramolecular cyclization of
carbonyl ylides with similar tethers (∆r ) 0.29-0.30 Å).39
All of the activiation complexes in Figure 1 reveal that
the fused five-membered azacycle exists in an envelope
conformation. Furthermore, the latter is disposed such
that there is no conjugation between nitrogen and the
aromatic π-system. The nitrogen lone-electron pairs are
essentially coplanar with the isobenzofuran bicycle.
3-D graphics inspection and analysis of atom-atom
distances for transition states 64†-66† reveals no struc-
tural features that suggest fundamental stability differ-
ences as was the case for the carbonyl ylides. To examine
this point further, the structures of methylethylamine,
N-methylacetamide, and N-ethylacetamide were opti-
mized with the B3LYP/3-21G* protocol in their all-trans
conformations and subjected to single-point B3LYP/6-
31G* energy evaluations. These unstrained structures
were then combined with the transition states in the
following isodesmic42 reactions.
a
b
3-21G* ) B3LYP/3-21G*//B3LYP/3-21G*. 6-31G* ) B3LYP/
6-31G*//B3LYP/3-21G*. c Difference between the lowest ground
state and transition state, respectively.
F igu r e 1. B3LYP/3-21G*-optimized transition states for
isobenzofuran intramolecular cycloaddition. Ring closure bond
lengths shown with dotted lines; Å.
A similar pair of isodesmic reactions has been applied to
the lowest energy conformations of the ground state
isobenzofurans. These comparisons imply that the amine-
substituted furan is considerably more stable than the
amide analogs. Examination of the optimized ground-
state isobenzofurans (Figure 2) provides insight as to
why.
In the absence of mediating factors, it can be safely
assumed that the nitrogen atom of the side chains in 61-
63 prefers to be conjugated to the aromatic π-system.
Thus, the nitrogen atom in amine 61 is predicted by
optimization to be planar, although it sustains a non-
bonded H- - -H contact of 2.27 Å. The latter is just under
the sum of the van der Waals radii (2.40 Å).43 Several
attempts to optimize to a nonconjugated local minimum
by starting with pyramidal nitrogen, and a conformation
similar to 62a consistently yielded planar 61. Resonance
The amine transition state 64† is calculated to be
slightly less stable than the CdO internal amide struc-
ture 65† and slightly more stable than the corresponding
CdO external polycycle 66†. In view of the calculated
cycloaddition barrier height for the amine, the diminutive
∆Eiso values suggest that transition-state structure is not
the source of the apparent increase in rate for the amides.
(42) Hehre, W. J .; Radom, L.; Schleyer, P. v.R.; Pople, J . A. ab initio
Molecular Orbital Theory; J ohn Wiley and Sons: New York, 1986.
(43) Bondi, A. J . Phys. Chem. 1964, 68, 441.

2792 J . Org. Chem., Vol. 62, No. 9, 1997
Padwa et al.
F igu r e 3. B3LYP/3-21G*-optimized N-methylacetamide-
substituted mercaptofuran ground states; cis (67) and trans
(68, 69) amide isomer conformations, respectively. Close
nonbonded atom-atom contacts are indicated; Å.
nonplanar conformation likewise falls 4.3 kcal/mol above
62a . The lowest energy conformation found for isoben-
zofuran 63a , the precursor to external amide 66†, is an
all-trans species predicted to resemble the nonplanar
form 62a . The crowded conjugated planar form 63b
(r(H- - -X) ) 2.021 (O) and 2.193 (H) Å) is found 4.9 kcal/
mol higher in energy. Again, conjugative stabilization
is overtaken by steric effects.
F igu r e 2. B3LYP/3-21G*-optimized isobenzofuran ground
states. Close nonbonded atom-atom contacts are indicated;
Å.
The results described in this section reveal that
utilization of an amide tether raises the energy of the
intermediate isobenzofuran ground states and thereby
reduces the intramolecular Diels-Alder activation bar-
rier relative to the corresponding amine.
The outcome is not exclusive, however, since certain
dienophile-activating substitutents (e.g., CO2Me, 42) can
override it, while others (e.g., SO2Tol, 36) cannot. Simi-
larly, even though the aminoisobenzofurans 30 and 31
do not ring-form with unactivated internal dienophiles,
hotter external substrates such as N-phenylmaleimide
are able to readily mount the Diels-Alder barrier (e.g.,
32, 33).
effects manifestly outweigh opposing van der Waals
interactions.
For the amide system, the preference for planarity was
tested by optimizing conformations of the N-methylac-
etamide derivative of mercaptofuran, 67-69 (Figure 3).
Unconjugated trans-67 with a side-chain twist of 56° is
isoenergetic with planar cis-68 in spite of the short
nonbonded contacts in the latter (∆E ) 0.3 kcal/mol;
B3LYP/6-31G*; Table 1). Resonance and steric effects
exactly balance. A third conformer corresponding to the
ring-nitrogen rotamer of 68 optimized to the nonplanar
species 69, 3.2 kcal/mol above 67. Its moderately el-
evated energy results from the side-chain cis-alkyl amide
orientation. Quite clearly, the planarizing effect of
conjugation can be attenuated in different ways by
adverse in-plane interactions between the furan ring and
the coupled amide fragment.
Con clu sion
In conclusion, the results presented herein demon-
strate the potential of the tandem-amido-Pummerer-
Diels-Alder reaction sequence as an efficient protocol for
generating vinylogous C-acyliminium ions. The cascade
sequence allows for ready access to a number of highly
functionalized amino-substituted naphthols and can be
utilized in both a bimolecular and a intramolecular
fashion. The novelty of the method lies in the unprec-
edented manner in which C- and N-acyliminium ion
intermediates are produced.
Three conformations were optimized for the precursor
to amide 65†. The lowest, 62a (Figure 2), has the side
chain in an all-trans conformation and nearly perpen-
dicular to the bicyclic ring. A second planar conformer
with a cis-dialkyl conformation around the NCO func-
tionality, 62b, tolerates very short 1,7 H- - -O and 1,6
H- - -H nonbonded contacts of 2.040 and 2.058 Å, respec-
tively. The latter distances arise as a consequence of the
amide’s drive for planarity. At the B3LYP/6-31G* level
of theory, the conformer is 4.2 kcal/mol higher in energy
than 62a . This instability results from an imbalance
between steric congestion (van der Waal sums: H- - -O
2.72 and H- - -H 2.40 Å)43 and conjugation. A third
Incorporation of a CdO group R to nitrogen either
internal or external to the tether promotes intramolecu-
lar cycloaddition, whereas an amine-only tether reacts
only sluggishly, if at all. The amine versus amide
substitution pattern may be general in its overall reactiv-
ity consequence, since the same result has been observed
for intramolecular dipolar cycloaddition of carbonyl ylide
intermediates.39 Surprisingly, while amide incorporation
influences the latter chemistry by lowering transition-
state energies, the presently investigated isobenzofurans
experience an amide perturbation that raises the energies
of the ground states. Both effects serve to shorten the
path between a ground state and the corresponding

Reactions of 2-Amino-Substituted Isobenzofurans
J . Org. Chem., Vol. 62, No. 9, 1997 2793
xylene, or acetic anhydride), 0.5 mL of acetic anhydride, 2.0
mmol of the dienophile, and a catalytic amount of p-toluene-
sulfonic acid (ca. 1 mg) was heated at reflux under argon. To
this mixture was added dropwise a 0.5 mmol solution of the
appropriate sulfoxide in 3 mL of solvent via syringe over a 20
min period. After the addition was complete, the solution was
heated at reflux for an additional 20 min until no sulfoxide
was detected by TLC. The mixture was concentrated under
reduced pressure, and the crude residue was purified by flash
silica gel chromatography.
transition state and, thus, reduce the activation barrier.
The outcome is clearly of synthetic advantage as it offers
the opportunity to accelerate intramolecular cycloaddi-
tion by steric adjustment of ground-state and transition-
state energies either separately or simultaneously. To
our knowledge, an example of the latter phenomenon has
yet to be discerned.
The two examples underscore the unexpected complex-
ity of intramolecular cycloaddition processes that create
several fused rings in a single step and simultaneously
induce steric effects remote from the reacting centers. For
such situations, the application of FMO theory or any
other mechanistic procedure that focuses only on the
pericycle MO’s or the accompanying nascent bonds is
likely to give misleading results. Other examples of this
phenomenon are under active investigation. We are
currently exploring the possibility of intercepting these
highly electrophilic species with additional nucleophilic
tethers incorporated on the backbone of these molecules
and the use of this method for the synthesis of the
erythrina family of alkaloids.
4-(Dieth ylam in o)-9-h ydr oxy-2-ph en ylben zo[f]isoin dole-
1,3-d ion e (11) was obtained from 130 mg (0.5 mmol) of
sulfoxide 10 and 170 mg (1 mmol) of N-phenylmaleimide
(toluene) in 72% yield as a bright yellow solid: mp 146-147
1
°C; IR (KBr) 3380, 1744, 1694, 1372 cm-1; H-NMR δ 1.05 (t,
6H, J ) 7.5 Hz), 3.46 (q, 4H, J ) 7.5 Hz), 7.38-7.55 (m, 5H),
7.68-7.74 (m, 2H), 8.37 (dd, 1H, J ) 6.0, 2.5 Hz), 8.61 (dd,
1H, J ) 6.0, 2.5 Hz), 9.02 (s, 1H); 13C-NMR δ 14.0, 48.1, 106.4,
119.1, 123.8, 126.4, 127.7, 128.0, 128.7, 128.8, 129.0, 129.6,
131.7, 138.7, 143.2, 151.2, 165.3, 169.7. Anal. Calcd for
C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C, 73.18; H,
5.58; N, 7.65.
4-(Diet h yla m in o)-9-h yd r oxyn a p h t h o[2,3-c]fu r a n -1,3-
d ion e (12) was obtained from 130 mg (0.5 mmol) of sulfoxide
10 and 100 mg (1 mmol) of maleic anhydride (toluene) in 76%
yield as a bright yellow solid: mp 174-175 °C; IR (KBr) 3428,
Exp er im en ta l Section
1
1802, 1794, 1751, 1307 cm-1; H-NMR δ 1.06 (t, 6H, J ) 7.5
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using an ethyl
acetate-hexane mixture as the eluent unless specified other-
wise. All NMR spectra were determined in CDCl3 at 300 MHz
for 1H-NMR and 75 MHz for 13C-NMR.
N,N-Dieth yl-2-[(eth ylth io)m eth yl]ben za m id e (9). To a
stirred suspension containing 4.9 g (25 mmol) of 2-[(ethylthio)-
methyl]benzoic acid (8)38 in 50 mL of dry benzene was added
6.0 g (50 mmol) of thionyl chloride. After being stirred at rt
for 1 h, the solution was concentrated under reduced pressure.
The crude acid chloride was dissolved in 20 mL of dry CH2-
Cl2, and the solution was added dropwise to a solution of 8.7
g (120 mmol) of diethylamine in 50 mL of dry CH2Cl2 at 0 °C
under argon. After being stirred at rt for 2 h, the mixture
was washed successively with 5% HCl, a saturated Na2CO3
solution, and brine. The organic layer was dried over Na2SO4
and concentrated under reduced pressure. The remaining oil
was purified by flash silica gel chromatography to give 5.5 g
(87%) of amide 9 as a colorless oil: IR (neat) 1629, 1430, 1287
cm-1; 1H-NMR δ 1.09 (t, 3H, J ) 7.5 Hz), 1.23 (t, 3H, J ) 7.5
Hz), 1.27 (t, 3H, J ) 7.5 Hz), 2.47 (q, 2H, J ) 7.5 Hz), 3.13 (q,
2H, J ) 7.5 Hz), 3.33 (brs, 2H), 3.55 (brs, 2H), 7.16-7.39 (m,
4H); 13C-NMR δ 12.5, 13.8, 14.4, 25.9, 33.0, 38.5, 43.2, 125.7,
Hz), 3.47 (q, 4H, J ) 7.5 Hz), 7.72-7.78 (m, 2 H), 8.40 (d, 1 H,
J ) 7.5 Hz), 8.52 (d, 1 H, J ) 7.5 Hz); 13C-NMR δ 14.3, 47.8,
105.5, 120.6, 125.1, 127.2, 129.1, 130.5, 131.9, 138.8, 140.9,
156.0, 162.5, 163.4. Anal. Calcd for C16H15NO4: C, 67.36; H,
5.30; N, 4.91. Found: C, 67.23; H, 5.36; N, 4.85.
9-Acetoxy-4-(dieth ylam in o)-2-ph en ylben zo[f]isoin dole-
1,3-d ion e (13) was obtained from 130 mg (0.5 mmol) of
sulfoxide 10 and 170 mg (1 mmol) of N-phenylmaleimide
(acetic anhydride) in 82% yield as a pale yellow solid: mp 139-
140 °C; IR (neat) 1776, 1757, 1711, 1386, 1260 cm-1; 1H-NMR
δ 1.09 (t, 6H, J ) 7.5 Hz), 2.54 (s, 3H), 3.53 (q, 4H, J ) 7.5
Hz), 7.34-7.51 (m, 5H), 7.65-7.70 (m, 2H), 8.10-8.13 (m, 1H),
8.56-8.58 (m, 1H); 13C-NMR δ 14.0, 20.6, 48.0, 117.2, 119.7,
123.2, 126.6, 127.5, 127.9, 128.8, 129.0, 129.4, 131.5, 131.6,
137.9, 140.9, 147.4, 164.7, 165.0, 168.7. Anal. Calcd for
C24H22N2O4: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.88; H,
5.76; N, 6.74.
9-Acetoxy-4-(d ieth yla m in o)n a p h th o[2,3-c]fu r a n -1,3-d i-
on e (14) was obtained from 130 mg (0.5 mmol) of sulfoxide
10 and 100 mg (1 mmol) of maleic anhydride (acetic anhydride)
in 81% yield as a yellow solid: mp 81-82 °C; IR (neat) 1825,
1
1776, 1387, 1226, 1179 cm-1; H-NMR δ 1.12 (t, 6H, J ) 7.5
Hz), 2.57 (s, 3H), 3.59 (q, 4H, J ) 7.5 Hz), 7.75-7.80 (m, 2H),
8.13-8.17 (m, 1H), and 8.48-8.50 (m, 1H); 13C-NMR δ 13.8,
20.6, 48.1, 116.5, 116.9, 123.8, 127.8, 129.9, 130.4, 132.1, 137.4,
141.8, 149.7, 160.0, 168.3. Anal. Calcd for C18H17NO5: C,
66.05; H, 5.23; N, 4.27. Found: C, 65.93; H, 5.30; N, 4.16.
126.7, 128.6, 130.1, 135.4, 137.0, 170.3; HRMS calcd for C14H21
NOS 251.1345, found 251.1339.
-
Acetic a cid [2-(d ieth ylca r ba m oyl)p h en yl](eth ylth io)-
m eth yl Ester (17) was obtained from 130 mg (0.5 mmol) of
sulfoxide 10 (toluene) in 65% yield as a colorless oil: IR (neat)
N,N-Dieth yl-2-[(eth ylsu lfin yl)m eth yl]ben za m id e (10).
To a solution containing 2.5 g (10 mmol) of amide 9 in 50 mL
of methanol was added 2.25 g (10.5 mmol) of sodium periodate
at 0 °C. Water was added to the mixture until the solution
began to turn cloudy (ca. 5-10 mL). After the solution was
stirred for 5 h at rt, water and CH2Cl2 were added, the aqueous
layer was extracted with CH2Cl2, and the combined organic
fractions were washed with water, dried over Na2SO4, and
concentrated under reduced pressure. The crude residue was
purified by flash silica gel chromatography to give 2.4 g (91%)
of sulfoxide 10 as a colorless oil: IR (neat) 1627, 1432, 1053
cm-1; 1H-NMR δ 1.10 (t, 3H, J ) 7.5 Hz), 1.26 (t, 3H, J ) 7.5
Hz), 1.33 (t, 3H, J ) 7.5 Hz), 2.68-2.86 (m, 2H), 3.16-3.20
(m, 2H), 3.60 (brs, 2H), 3.92 and 4.10 (brs, 2H), 7.10-7.40 (m,
4H); 13C-NMR δ 6.4, 12.3, 13.5, 38.6, 43.0, 45.2, 55.0, 125.7,
127.6, 127.7, 128.8, 131.2, 137.0, 169.3; HRMS (FAB) calcd
for C14H22NO2S (M + H) 268.1371, found 268.1373.
1
1738, 1628, 1429, 1218 cm-1; H-NMR δ 1.08-1.13 (m, 3H),
1.24-1.32 (m, 6H), 2.13 (s, 3H), 2.51-2.79 (m, 2H), 3.10-3.17
(m, 2H), 3.40 and 3.80 (2 m, 2H), 6.92 (s, 1H), 7.21 (dd, 1H, J
) 7.5, 1.2 Hz), 7.32 (ddd, 1H, J ) 7.5, 7.5, 1.2 Hz), 7.39 (ddd,
1H, J ) 7.5, 7.5, 1.2 Hz), 7.61 (dd, 1H, J ) 7.5, 1.2 Hz); 13C-
NMR δ 12.5, 13.7, 14.5, 21.0, 25.9, 38.7, 43.0, 125.7, 126.7,
128.1, 128.8, 134.6, 134.8, 169.1, 169.4; HRMS (FAB) calcd
for C16H23NO3SLi (M + Li) 316.1559, found 316.1544.
A 60 mg (0.2 mmol) sample of ester 17 in 1 mL of toluene
was added dropwise to a mixture of 5 mL of toluene and 170
mg (1 mmol) of N-phenylmaleimide containing a catalytic
amount of p-toluenesulfonic acid. After the addition was
complete, the solution was heated at reflux for an additional
20 min. The mixture was concentrated under reduced pres-
sure and the crude reside purified by flash silica gel chroma-
tography to give 45 mg (61%) of cycloadduct 11, which was
identical in all respects to a sample obtained directly from
sulfoxide 10.
Gen er a l P r oced u r e for th e Ta n d em P u m m er er Cy-
cliza tion Diels-Ald er Cycloa d d ition Sequ en ce. A mix-
ture containing 10 mL of the appropriate solvent (toluene,

2794 J . Org. Chem., Vol. 62, No. 9, 1997
Padwa et al.
Dim eth yl 4-(d ieth yla m in o)-2-(eth ylth io)-1-oxo-1,2-d i-
h yd r on a p h th a len e-2,3-d ica r boxyla te (23) a n d Dim eth yl
1-(d ieth yla m in o)-4-h yd r oxyn a p h th a len e-2,3-d ica r boxy-
la te (24) were obtained from 130 mg (0.5 mmol) of sulfoxide
10 and 360 mg (2.5 mmol) of DMAD (xylene). The crude
mixture was purified by flash silica gel chromatography to give
7 mg (4%) of naphthol 24, 70 mg (36%) of tetralone 23, and 80
mg (50%) of ester 17. Treatment of a sample of pure ester 17
with 5 equiv of DMAD in xylene (trace p-TsOH) at reflux for
20 min provided an additional amount of tetralone 23 (54%
overall yield). Prolonged heating (2 h) of tetralone 23 at reflux
in xylene led to a 65% isolated yield of naphthol 24. Tetralone
23 exhibited the following spectral properties: IR (neat) 1752,
32.6, 37.4, 45.4, 45.5, 46.4, 50.7, 55.2, 55.4, 117.0, 117.6, 126.7,
126.8, 127.9, 128.0, 128.2, 129.3, 129.4, 131.5, 131.6, 134.0,
135.2, 136.8, 137.2, 170.1, 170.3; HRMS (FAB) calcd for C15H22
-
NO2S (M + H) 280.1371, found 280.1375.
N -Me t h yl-N -p e n t -4-e n yl-2-[(e t h ylsu lfin yl)m e t h yl]-
ben za m id e (29). A sample of N-methyl-N-pent-4-enyl-2-
[(ethylthio)methyl]benzamide (27) was obtained from 2.1 g (10
mmol) of amide 25 and 2.2 g (15 mmol) of 5-bromo-1-pentene
in 84% yield as a colorless oil as a mixture of two rotamers:
1H-NMR δ 1.21 (t, 3H, J ) 7.5 Hz), 1.55-1.83 (m, 2H), 1.92
and 2.18 (dt, 2H, J ) 7.0, 7.0 Hz), 2.46 (q, 2H, J ) 7.5 Hz),
2.82 and 3.09 (s, 3H), 3.50-3.96 (m, 4H), 4.85-5.12 (m, 2H),
5.58-5.71 and 5.82-5.95 (m, 1H), 7.13-7.41 (m, 4H); 13C-NMR
δ 14.8, 26.3, 26.5, 27.1, 32.0, 33.1, 33.4, 34.1, 37.4, 46.3, 52.6,
115.3, 115.6, 126.6, 126.7, 126.9, 127.0, 128.5, 128.6, 130.5,
130.6, 135.8, 135.9, 136.4, 137.1, 137.9, 138.1, 171.1, 171.4;
HRMS calcd for C16H23NOS 277.1500, found 277.1498.
A 2.8 g (10 mmol) sample of sulfide 27 was oxidized in the
standard manner to give sulfoxide 29 (92%) as a colorless oil
that appears as a mixture of two rotamers in solution: 1H-
NMR δ 1.34 (t, 3H, J ) 7.5 Hz), 1.55-1.81 (m, 2H), 1.88 and
2.15 (dt, 2H, J ) 7.0, 7.0 Hz), 2.61-2.83 (m, 2H), 2.88 and
3.08 (s, 3H), 3.23 and 3.58 (t, 2H, J ) 7.0 Hz), 3.95 (d, 1H, J
) 13.0 Hz), 4.13 (d, 1H, J ) 13.0 Hz), 4.88-5.12 (m, 2H), 5.56-
5.71 and 5.79-5.91 (m, 1H), 7.21-7.45 (4H); HRMS (FAB)
calcd for C16H24NO2S (M + H) 294.1528, found 294.1526.
1732, 1721, 1684 cm-1
;
1H-NMR δ 1.05 (t, 3H, J ) 7.5 Hz),
1.14 (t, 6H, J ) 7.5 Hz), 2.31-2.44 (m, 1H), 2.82-2.94 (m, 1H),
3.04-3.33 (m, 4H), 3.78 (s, 3H), 3.79 (s, 3H), 7.51 (ddd, 1H, J
) 7.0, 7.0, 1.0 Hz), 7.66 (ddd, J ) 7.0, 7.0, 1.0 Hz), 7.76 (dd,
1H, J ) 7.0, 1.0 Hz), 8.01 (dd, J ) 7.0, 1.0 Hz); 13C-NMR δ
13.2, 13.3, 25.6, 46.4, 51.8, 53.1, 65.5, 115.7, 126.9, 127.5, 130.2,
130.9, 133.9, 136.9, 151.0, 166.3, 168.9, 188.4; HRMS (FAB)
calcd for C20H26NO5S (M + H) 392.1532, found 392.1544.
Naphthol 24 exhibited the following properties: mp 115-
116 °C; IR (KBr) 1735, 1655, 1433, 1335, 1221 cm-1; 1H-NMR
δ 1.00 (t, 6H, J ) 7.5 Hz), 3.14-3.30 (m, 4H), 3.91 (s, 3H),
3.95 (s, 3H), 7.49-7.62 (m, 2H), 7.96 (d, 1H, J ) 8 Hz), 8.48
(d, 1H, J ) 8 Hz), 12.37 (s, 1H); 13C-NMR δ 14.6, 49.2, 51.8,
52.7, 102.0, 124.7, 124.9, 126.1, 126.3, 129.5, 131.5, 136.5,
136.6, 159.9, 169.3, 170.2. Anal. Calcd for C18H21NO5: C,
65.24; H, 6.52; N, 4.23. Found: C, 65.14; H, 6.32; N, 4.23.
N-Meth yl-2-[(eth ylth io)m eth yl]ben za m id e (25). To a
stirred suspension containing 4.9 g (25 mmol) of 2-[(ethylthio)-
methyl]benzoic acid (8) in 50 mL of dry benzene was added
6.0 g (50 mmol) of thionyl chloride. After being stirred at rt
for 1 h, the solution was concentrated under reduced pressure.
The resulting crude acid chloride was added dropwise to an
ice-cooled mixture of 20 mL of methylamine (40% aqueous
solution) and 15 mL of dioxane. The clear solution was stirred
at rt for 1 h and was then poured onto 200 g of ice-water to
give 3.8 g (72%) of amide 25: mp 74-75 °C; IR (KBr) 3288,
4-(N-Bu t-3-en yl-N-m eth yla m in o)-9-h yd r oxy-2-p h en yl-
ben zo[f]isoin d ole-1,3-d ion e (32) was obtained from 140 mg
(0.5 mmol) of sulfoxide 28 and 170 mg (1 mmol) of N-
phenylmaleimide (toluene) in 62% yield as a bright yellow
solid: mp 73-74 °C; IR (KBr) 3376, 1743, 1689, 1381, 905,
1
730 cm-1; H-NMR δ 2.34 (dt, 2H, J ) 7.0, 7.0 Hz), 3.06 (s,
3H), 3.47 (t, 2H, J ) 7.0 Hz), 4.94-5.06 (m, 2H), 5.74-5.83
(m, 1H), 7.38-7.75 (m, 7H), 8.36-8.40 (m, 1H), 8.54-8.57 (m,
1H), 8.99 (s, 1H); 13C-NMR δ 33.2, 41.2, 55.9, 106.2, 115.8,
117.9, 123.8, 126.4, 127.2, 127.9, 128.6, 128.8, 128.9, 129.5,
131.6, 136.5, 137.1, 144.3, 151.0, 165.2, 169.5. Anal. Calcd
for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 74.12;
H, 5.43; N, 7.47.
1
1630, 1545, 1403, 1317 cm-1; H-NMR δ 1.27 (t, 3H, J ) 7.5
4-(N-Meth yl-N-p en t-4-en yla m in o)-9-h yd r oxy-2-p h en yl-
ben zo[f]isoin d ole-1,3-d ion e (33) was obtained from 150 mg
(0.5 mmol) of sulfoxide 29 and 170 mg (1 mmol) of N-
phenylmaleimide (toluene) in 68% yield as a bright yellow
solid: mp 68-69 °C; IR (KBr) 3382, 1743, 1689, 1375, 1002,
760 cm-1; 1H-NMR δ 1.62-1.72 (m, 2H), 2.07 (dt, 2H, J ) 7.0,
7.0 Hz), 3.05 (s, 3H), 3.40 (t, 2H, J ) 7.0 Hz), 4.88-4.96 (m,
2H), 5.70-5.81 (m, 1H), 7.39-7.76 (m, 7H), 8.37-8.41 (m, 1H),
8.53-8.56 (m, 1H), 9.00 (s, 1H); 13C-NMR δ 27.9, 31.3, 41.6,
55.8, 106.3, 114.6, 117.8, 123.9, 126.5, 127.2, 128.0, 128.7,
128.9, 129.0, 129.6, 131.7, 137.3, 138.4, 144.7, 151.1, 165.3,
169.7. Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25.
Found: C, 74.32; H, 5.81; N, 7.19.
N-Meth yl-N-[4-(p-tolu en esu lfon yl)bu t-3(E)-en yl]-2-[(eth -
ylsu lfin yl)m eth yl]ben za m id e (34). A mixture of 1.2 g (4.5
mmol) of sulfide 26, 1.3 g (4.7 mmol) of p-toluenesulfonyl
iodide, 30 mg (0.22 mmol) of cupric chloride, 30 mg (0.22 mmol)
of triethylamine hydrochloride, and 3 mL of dry acetonitrile
was stirred at rt under argon in the dark for 90 min. The
solvent was removed under reduced pressure, and the crude
mixture was dissolved in CH2Cl2, washed with brine, dried
over Na2SO4, filtered through a short column of silica gel, and
concentrated under reduced pressure. The resulting residue
was dissolved in 5 mL of benzene and treated with 500 mg (5
mmol) of triethylamine. After being stirred for 10 min at rt,
the mixture was diluted with ether and washed sucessively
with 5% aqueous HCl and water. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure to
afford a dark oil that was purified by flash silica gel chroma-
Hz), 2.53 (q, 2H, J ) 7.5 Hz), 3.00 (d, 3H, J ) 5.0 Hz), 3.90 (s,
2H), 6.60 (brs, 1H), 7.26-7.50 (m, 4H); 13C-NMR δ 14.5, 26.0,
26.5, 33.6, 127.2, 128.2, 129.8, 130.6, 135.6, 136.4, 167.0. Anal.
Calcd for C11H15NOS: C, 63.12; H, 7.22; N, 6.69. Found: C,
63.19; H, 7.19; N, 6.74.
N -Bu t -3-e n yl-N -m e t h yl-2-[(e t h ylt h io)m e t h yl]b e n z-
a m id e (26). A mixture of 2.09 g (10 mmol) of amide 25, 480
mg (12 mmol) of NaH (60% dispersion in mineral oil), and 40
mL of toluene was heated at 60-70 °C for 1 h until the
evolution of hydrogen gas ceased. After the addition of 2.0 g
(15 mmol) of 4-bromo-1-butene, the mixture was heated at
reflux for 4 h until all the starting material was consumed.
After being cooled to rt, the mixture was poured onto 200 g of
ice-water, and the organic layer was washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The
crude product was purified by flash silica gel chromatography
to give 2.3 g (88%) of amide 26 as a colorless oil that appeared
as a mixture of two rotamers in solution: IR (neat) 1635, 1397,
1065, 911, 769 cm-1; 1H-NMR δ 1.12 (t, 3H, J ) 7.5 Hz), 2.11
and 2.37 (m, 4H), 2.73 and 2.99 (s, 3H), 3.55 and 3.71 (m, 4H),
4.89-5.11 (m, 2H), 5.51 and 5.80 (m, 1H), 7.04-7.31 (m, 4H);
13C-NMR δ 14.3, 25.7, 25.8, 31.3, 32.1, 32.5, 32.9, 33.0, 37.3,
46.2, 50.6, 116.6, 117.2, 126.2, 126.3, 126.6, 126.7, 128.5, 128.6,
130.0, 134.2, 135.3, 135.5, 136.4, 136.7, 170.6, 170.9; m/z 263
(M+), 234, 203, 202, 188, 179, 151, 149 (base); HRMS calcd for
C15H21NOS 263.1344, found 263.1340.
N-Bu t -3-en yl-N-m et h yl-2-[(et h ylsu lfin yl)m et h yl]b en -
za m id e (28). A 2.6 g (10 mmol) sample of sulfide 26 was
oxidized using conditions similar to those described for 10 to
give sulfoxide 28 (91%) as a colorless oil that appears as a
mixture of two rotamers in solution: IR (neat) 1627, 1444,
1400, 1050 cm-1; 1H-NMR δ 1.34 (t, 3H, J ) 7.5 Hz), 2.28 and
2.45 (dt, 2H, J ) 7.0, 7.0 Hz), 2.62-2.79 (m, 2H), 2.87 and
3.09 (s, 3H), 3.22 and 3.63 (t, 2H, J ) 7.0 Hz), 3.94 (d, 1H, J
) 13.0 Hz), 4.12 (d, 1H, J ) 13.0 Hz), 4.99-5.21 (m, 2H), 5.56
and 5.93 (m, 1H), 7.22-7.46 (m, 4H); 13C-NMR δ 6.7, 31.5, 32.4,
tography to give 1.29
g (54%) of pure N-methyl-N-[4-
(p-toluenesulfonyl)but-3(E)-enyl]-2-[(ethylthio)methyl]benz-
amide as a colorless oil that exists as a mixture of two rotamers
in solution: IR (neat) 1627, 1595, 1397, 1312, 1141 cm-1; 1H-
NMR δ 1.17-1.23 (m, 3H), 2.37-2.47 (m, 6H), 2.61-2.68 (m,
1H), 2.80-3.12 (m, 3H), 3.63-3.78 (m, 4H), 6.29-6.52 (m, 1H),
6.69-7.37 (m, 7H), 7.70-7.83 (m, 2H); 13C-NMR δ 14.3, 21.4,

Reactions of 2-Amino-Substituted Isobenzofurans
J . Org. Chem., Vol. 62, No. 9, 1997 2795
25.5, 28.9, 32.8, 37.6, 45.3, 125.9-144.3, 170.9; HRMS (FAB)
calcd for C22H27NO3S2Li (M + Li) 424.1592, found 424.1596.
A 4.2 g (10 mmol) sample of the above sulfide was oxidized
in the standard manner to give 34 (96%) as colorless oil that
exists as a mixture of two rotamers in solution: IR (neat) 1627,
3.74 (s, 3H), 5.80 and 5.97 (d, 1H, J ) 16.0 Hz), 6.74 and 7.03
(dt, 1H, J ) 16.0, 7.0 Hz), 7.13-7.36 (m, 4H); 13C-NMR δ 14.0,
25.3, 25.5, 30.6, 31.8, 32.6, 37.1, 45.3, 49.5, 51.0, 122.4, 122.7,
125.9, 126.0, 126.4, 128.3, 128.5, 129.8, 135.3, 135.5, 135.9,
136.1, 144.1, 145.3, 165.8, 166.1, 170.4, 170.6; m/z 321 (M+)
1
1595, 1397, 1312, 1141, 1045 cm-1; H-NMR δ 1.33 (t, 3H, J
261, 202, 188, 179, 149 (base), 119, 90; HRMS calcd for C17H23
NO3S 321.1399, found 321.1394.
-
) 7.5 Hz), 2.43 and 2.45 (s, 3H), 2.59-2.82 (m, 4H), 2.87 and
2.95 (s, 3H), 3.33 and 3.67 (m, 2H), 3.97 (d, 1H, J ) 13.0 Hz),
4.07 (d, 1H, J ) 13 Hz), 6.25-6.52 (m, 1H), 6.68-7.04 (m, 1H),
7.08-7.83 (m, 8H); 13C-NMR δ 6.6, 21.4, 28.9, 37.6, 45.3, 45.4,
54.8, 126.4-144.4, 170.3; HRMS (FAB) calcd for C22H28NO4S2
(M + H): 434.1460, found 434.1468.
Isomer 39-Z showed the following properties: 1H-NMR δ
1.22, (t, 3H, J ) 7.5 Hz), 2.44 (q, 2H, J ) 7.5 Hz), 2.87 and
3.13 (s, 3H), 2.93-3.29 (m, 2H), 3.71 and 3.73 (s, 3H), 3.69-
3.85 (m, 4H), 5.84 and 5.92 (d, 1H, J ) 12.0 Hz), 6.03 and
6.41 (dt, 1H, J ) 12.0, 7.0 Hz), 7.11-7.40 (m, 4H).
4-H yd r oxy-9-[4-(p -t olu en esu lfon yl)b u t -3(E)-en yl]m e-
th yla m in o]-2-p h en ylben zo[f]isoin d olo-1,3-d ion e (36) was
obtained from 220 mg (0.5 mmol) of sulfoxide 34 and 430 mg
(2.5 mmol) of N-phenylmaleimide (xylene) in 71% yield as a
bright yellow solid: mp 151-152 °C; IR (KBr) 3373, 1746,
1687, 1382, 1137 cm-1; 1H-NMR δ 2.41 (s, 3H), 2.48 (ddt, 2H,
J ) 6.5, 6.5, 1.2 Hz), 3.01 (s, 3H), 3.60 (t, 2H, J ) 6.5 Hz),
6.25-6.30 (m, 1H), 6.94 (dt, 1H, J ) 15.0, 6.5 Hz), 7.42-7.73
(m, 11H), 8.38-8.46 (m, 2H), 8.98 (s, 1H); 13C-NMR δ 21.4,
30.7, 41.5, 54.2, 106.1, 118.5, 123.9, 126.4, 126.8, 127.4, 128.0,
128.8, 128.9, 129.6, 130.0, 131.5, 131.6, 136.8, 137.3, 143.1,
5-[2-[(Eth ylsu lfin yl)m eth yl]ben zoyl]m eth ylam in o]pen t-
2-en oic Acid Meth yl Ester (40, 41). A 970 mg (3 mmol)
sample of sulfide 38-E was oxidized in the standard manner
to give sulfoxide 40-E (94%) as a colorless oil that exists as a
mixture of two rotamers in solution: IR (neat) 1718, 1632,
1
1440, 1402, 1269, 1039 cm-1; H-NMR δ 1.34 (t, 3H, J ) 7.5
Hz), 2.44 and 2.61 (dt, 2H, J ) 7.0, 7.0 Hz), 2.63-2.80 (m,
2H), 2.90 and 3.09 (s, 3H), 3.32 and 3.68 (t, 2H, J ) 7.0 Hz),
3.72 and 3.75 (s, 3H), 3.95 (d, 1H, J ) 13.0 Hz), 4.10 (d, 1H, J
) 13.0 Hz), 5.80 and 5.97 (d, 1H, J ) 16.0 Hz), 6.71 and 7.00
(dt, 1H, J ) 16.0, 7.0 Hz), 7.21-7.47 (m, 4H); 13C-NMR δ 6.5,
6.6, 29.6, 30.7, 32.1, 37.4, 45.3, 45.6, 49.7, 51.3, 53.3, 54.8, 54.9,
122.7, 123.2, 126.4, 126.5, 127.8, 128.2, 129.2, 129.3, 131.4,
131.5, 136.4, 136.7, 143.9, 145.2, 165.9, 166.2, 170.0, 170.2;
HRMS (FAB) calcd for C17H24NO4S (M + H) 338.1426, found
338.1437.
A sample of sulfoxide 41-Z was obtained in analogous
fashion in 94% yield: 1H-NMR δ 1.33 (t, 3H, J ) 7.5 Hz), 2.62-
2.81 (m, 2H), 2.91 and 3.13 (s, 3H), 2.94-3.09 (m, 2H), 3.25-
3.34 and 3.62-3.79 (m, 2H), 3.73 and 3.70 (s, 3H), 3.95 and
4.10 (d, 2H, J ) 13.0 Hz), 5.83 and 5.92 (d, 1H, J ) 12.0 Hz),
6.02 and 6.38 (dt, 1H, J ) 12.0, 7.0 Hz), 7.21-7.47 (m, 4H).
144.0, 144.3, 155.4, 165.3, 169.4. Anal. Calcd for C30H26
-
N2O5S: C, 68.42; H, 4.98; N, 5.32. Found: C, 68.08; H, 5.00;
N, 5.25.
2-[(E t h ylt h io)m et h yl]-N-m et h yl-N-(3-oxop r op yl)b en -
za m id e (37). A mixture of 2.1 g (10 mmol) of amide 25, 480
mg (12 mmol) of NaH (60% dispersion in mineral oil), and 40
mL of toluene was heated at 60-70 °C for 1 h until the
evolution of hydrogen gas had ceased. After the addition of
2.7 g (15 mmol) of 2-(2-bromoethyl)-1,3-dioxolane, the mixture
was heated at reflux for 4 h until all the starting material was
consumed. After being cooled to rt, the mixture was poured
onto 200 g of ice-water. The organic layer was washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by flash silica gel
chromatography to give 2.5 g (79%) of N-(2-1,3-dioxolan-2-
ylethyl)-2-[(ethylthio)methyl]-N-methylbenzamide as a color-
less oil that consisted of a mixture of two rotamers in
Meth yl 5-Hyd r oxy-1-m eth yl-2,3-d ih yd r o-1H-ben zo[g]-
in d ole-4-ca r boxyla te (43) was obtained from 170 mg (0.5
mmol) of sulfoxide 40-E (25 mL of xylene) in 64% yield as a
bright yellow solid: mp 91-92 °C; IR (KBr) 1654, 1627, 1445,
1
1354, 1236 cm-1; H-NMR δ 2.93 (s, 3H), 3.37-3.54 (m, 4H),
3.98 (s, 3H), 7.46 (t, 1H, J ) 8.0 Hz), 7.60 (t, 1H, J ) 8.0 Hz),
7.95 (d, 1H, J ) 8.0 Hz), 8.41 (d, 1H, J ) 8.0 Hz), 12.07 (s,
1H); 13C-NMR δ 31.9, 43.9, 52.0, 56.5, 103.5, 122.3, 124.8,
124.9, 125.0, 126.8, 127.5, 129.3, 140.3, 158.5, 171.9. Anal.
Calcd for C15H15NO3: C, 70.02; C, 5.88; N, 5.44. Found: C,
69.75; H, 5.98; N, 5.37.
solution: IR (neat) 1633, 1597, 1396, 1134, 1062, 1031 cm-1
;
1H-NMR δ 1.21 (t, 3H, J ) 7.5 Hz), 1.92-2.11 (m, 2H), 2.44
(q, 2H, J ) 7.5 Hz), 2.84 and 3.09 (s, 3H), 3.59-4.02 (m, 8H),
4.73 and 5.03 (t, 1H, J ) 5.0 Hz), 7.10-7.39 (m, 4H); 13C-NMR
δ 14.3, 25.7, 31.0, 32.1, 32.8, 32.9, 34.0, 37.3, 42.5, 46.3, 64.6,
64.7, 64.8, 66.7, 70.0, 101.9, 102.1, 102.7, 125.9, 126.2, 126.7,
128.4, 128.6, 129.6, 130.0, 130.4, 135.5, 135.6, 136.6, 170.5,
170.8; MS calcd for C16H23NO3S 309.1399, found 309.1395.
A mixture containing 1.6 g (5 mmol) of the protected
aldehyde, 50 mL of ethanol, 80 mL of H2O, and 15 g of oxalic
acid was heated at reflux for 20 h. After removal of most of
the ethanol under reduced pressure, the mixture was extracted
with CH2Cl2. The organic layer was washed with a saturated
aqueous NaHCO3 solution, dried over K2CO3, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to give 1.22 g (92%) of aldehyde 37
as a colorless oil that consisted of a mixture of two rotamers
Meth yl 5-Hyd r oxy-1-m eth yl-1H-ben zo[g]in d ole-4-ca r -
boxyla te (44). To a solution containing 25 mg (0.1 mmol) of
indoline 43 in 2 mL of CH2Cl2 was added 50 mg of silica gel.
The solvent was allowed to evaporate upon standing, and the
resulting solid was kept in the open air for 1 week. After the
oxidation was complete, indole 44 was extracted with CH2Cl2
and purified by flash silica gel chromatography to give 25 mg
(100%) of 44 as a colorless solid: mp 129-130 °C; IR (KBr)
1644, 1618, 1441, 1340, 1239 cm-1 1H-NMR δ 4.06 (s, 3H),
;
4.15 (s, 3 H), 6.90 (d, 1H, J ) 3.0 Hz), 7.96 (d, 1 H, J ) 3.0
Hz), 7.42 (t, 1H, J ) 8.0 Hz), 7.60 (t, 1H, J ) 8.0 Hz), 8.27 (d,
1H, J ) 8.0 Hz), 8.52 (d, 1H, J ) 8.0 Hz), 12.39 (s, 1H); 13C-
NMR δ 38.6, 52.0, 99.6, 103.1, 120.0, 121.4, 122.8, 123.1, 124.4,
125.2, 126.7, 129.1, 129.3, 157.7, 172.9. Anal. Calcd for
C15H13NO3: C, 70.57; H, 5.13; N, 5.49. Found: C, 70.57; H,
5.16; N, 5.47.
1
in solution: IR (neat) 1718, 1627, 1397, 1060, 767 cm-1; H-
NMR δ 1.22 (t, 3H, J ) 7.5 Hz), 2.43 (q, 2H, J ) 7.5 Hz), 2.70-
2.92 (m, 2H), 2.88 and 4.07 (s, 3H), 3.47-3.90 (m, 4H), 7.14-
7.34 (m, 4H), 9.70 and 9.90 (s, 1H); 13C-NMR δ 14.4, 25.7, 33.0,
37.9, 41.4, 41.6, 126.5, 126.8, 128.8, 130.3, 135.9, 136.1, 171.1,
200.7; HRMS calcd for C14H19NO2S 265.1137, found 265.1131.
5-[2-[(Eth ylth io)m eth yl]ben zoyl]m eth yla m in o]p en t-2-
en oic Acid Meth yl Ester (38, 39). To a solution of 1.1 g (4
mmol) of aldehyde 37 in 50 mL of CH2Cl2 was added 1.5 g
(4.5 mmol) of methyl (triphenylphosphoranylidene)acetate at
0 °C. After the mixture was stirred for 2 h at rt, the solvent
was removed under reduced pressure and the remaining
residue was purified by flash silica gel chromatography to give
50 mg (4%) of 39-Z and 1.21 g (94%) of 38-E as colorless oils.
Compound 38-E consisted of a mixture of two rotamers in
solution that exhibited the following spectral data: IR (neat)
2-[(E t h ylsu lfin yl)m et h yl]-N-m et h yl-N-p en t -4-en oyl-
ben za m id e (45). A mixture containing 1.1 g (5 mmol) of
amide 25, 890 mg (7.5 mmol) of pent-4-enoyl chloride, 4.0 g of
powdered molecular sieves (4 Å), and 30 mL of CH2Cl2 was
stirred for 24 h at rt. The reaction mixture was filtered
through a pad of silica gel, the solvent was evaporated under
reduced pressure, and the resulting crude oil was purified by
flash silica gel chromatography to give 1.19 g (82%) of
2-[(ethylthio)methyl]-N-methyl-N-pent-4-enoylbenzamide as a
colorless oil: IR (neat) 1691, 1659, 1317, 1210, 1050 cm-1; 1H-
NMR δ 1.21 (t, 3H, J ) 7.5 Hz), 2.37-2.47 (m, 4H), 2.90 (t,
2H, J ) 7.0 Hz), 3.10 (s, 3H), 3.89 (s, 2H), 4.97-5.12 (m, 2H),
5.78-5.91 (m, 1H), 7.24-7.38 (m, 4H); 13C-NMR δ 14.0, 25.4,
28.6, 32.7, 33.6, 37.4, 114.9, 126.8, 126.9, 129.9, 130.1, 135.4,
1
1723, 1632, 1434, 1269, 1194 cm-1; H-NMR δ 1.21 (t, 3H, J
) 7.5 Hz), 2.44 (q, 2H, J ) 7.5 Hz), 2.59-2.67 and 3.21-3.29
(m, 2H), 2.84 and 3.10 (s, 3H), 3.62-3.79 (m, 4H), 3.72 and

2796 J . Org. Chem., Vol. 62, No. 9, 1997
Padwa et al.
136.8, 137.1, 172.9, 175.6; HRMS (FAB) calcd for C16H22NO2S
(M + H) 292.1371, found 292.1371.
(m, 1H), 7.36-7.53 (m, 4H); 13C-NMR δ 6.5, 34.2, 42.5, 45.2,
54.0, 118.2, 127.4, 128.0, 129.8, 130.6, 130.9, 132.3, 135.7,
172.8, 174.2; HRMS (FAB) calcd for C15H20NO3S (M + H)
294.1164, found 294.1167.
A 1.16 g (4 mmol) sample of the above sulfide was oxidized
in the standard manner to give sulfoxide 45 (95%) as a
colorless oil: IR (neat) 1680, 1659, 1322, 1210, 1044 cm-1; 1H-
NMR δ 1.35 (t, 3H, J ) 7.5 Hz), 2.43 (dt, 2H, J ) 7.0, 7.0 Hz),
2.65-2.78 (m, 2H), 2.86 (t, 2H, J ) 7.0 Hz), 3.10 (s, 3H), 4.08
(d, 1H, 13.0 Hz), 4.25 (d, 1H, J ) 13.0 Hz), 4.98-5.09 (m, 2H),
5.72-5.89 (m, 1H), 7.29-7.53 (m, 4H); 13C-NMR δ 6.5, 28.7,
33.9, 37.1, 45.1, 54.1, 115.1, 127.3, 127.9, 129.7, 130.8, 132.2,
135.9, 136.7, 172.8, 175.5; HRMS (FAB) calcd for C16H22NO3S
(M + H) 308.1322, found 308.1324.
6-Hydr oxy-3,4-dih ydr o-1H-1-m eth ylben zo[h ]qu in olin e-
2,6-d ion e (50) a n d 10b-(eth ylth io)-1-m eth yl-1,3,4,4a ,5,10b-
h exa h yd r oben zo[h ]qu in olin e-2,6-d ion e (49) were obtained
from 150 mg (0.5 mmol) of sulfoxide 45 (xylene) as a 1:2
mixture. The crude mixture was purified by flash silica gel
chromatography to give 25 mg (22%) of naphthol 50 and 63
mg (43%) of N,S-ketal 49. Heating a pure sample of ketal 49
in xylene at reflux for 30 min in the presence of a catalytic
amount of p-TsOH provided naphthol 50 in 98% yield. Naph-
thol 50 exhibited the following properties: mp 189-190 °C;
IR (KBr) 3150, 1639, 1626, 1385, 1248, 1196 cm-1; 1H-NMR δ
2.68 (t, 2H, J ) 7.5 Hz), 2.92 (t, 2H, J ) 7.5 Hz), 3.56 (s, 3H),
6.77 (s, 1H), 7.44-7.54 (m, 2H), 7.83 (dd, 1H, J ) 8.0, 1.0 Hz),
8.26 (dd, 1H, J ) 8.0, 1.0 Hz); 13C-NMR δ 26.7, 32.9, 37.9,
108.1, 122.8, 122.9, 124.4, 124.5, 126.3, 126.6, 128.0, 130.8,
149.4, 174.3. Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77;
N, 6.16. Found: C, 73.91; H, 5.81; N, 6.05.
Ketal 49 exhibited the following properties: mp 115-116
°C; IR (KBr) 1682, 1646, 1592, 1350, 985 cm-1; 1H-NMR δ 1.23
(t, 3H, J ) 7.5 Hz), 1.64-1.74 (m, 1H), 2.21-2.29 (m, 1H),
2.38-2.81 (m, 6H), 3.25-3.28 (m, 1H), 3.31 (s, 3H), 7.45 (t,
1H, J ) 8.0 Hz), 7.62 (t, 1H, J ) 8.0 Hz), 7.70 (d, 1H, J ) 8.0
Hz), 8.03 (d, 1H, J ) 8.0 Hz); 13C-NMR δ 13.2, 23.3, 41.6, 24.8,
29.9, 32.9, 38.2, 41.4, 74.4, 127.7, 128.0, 129.0, 131.2, 133.8,
141.6, 170.6, 195.2. Anal. Calcd for C16H19NO2S: C, 66.41;
H, 6.62; N, 4.84. Found: C, 66.53; H, 6.66; N, 4.80.
6-Acet oxy-3,4-d ih yd r o-1-m et h ylb en zo[h ]q u in olin -2-
on e (51) was obtained from 150 mg (0.5 mmol) of sulfoxide
45 as described above. Instead of working up the reaction
mixture after all the sulfoxide had been consumed, an ad-
ditional 5 mg of p-TsOH was added to the reaction mixture
and was subsequently heated at reflux for an additional 15
min. After concentration under reduced pressure, the crude
product was purified by flash silica gel chromatography to give
80 mg (59%) of cycloadduct 51 as a colorless solid: mp 145-
146 °C; IR (KBr) 1749, 1670, 1387, 1181 cm-1; 1H-NMR δ 2.41
(s, 3H), 2.65 (t, 2H, J ) 7.5 Hz), 2.93 (t, 2H, J ) 7.5 Hz), 3.52
(s, 3H), 7.10 (s, 1H), 7.46-7.49 (m, 2H), 7.84-7.90 (m, 2H);
13C-NMR δ 20.7, 26.2, 32.4, 37.6, 117.5, 121.6, 123.4, 125.6,
125.9, 126.1, 126.6, 126.8, 135.9, 142.8, 169.3, 173.3. Anal.
Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C,
71.42; H, 5.65; N, 5.13.
5-Acetoxy-1-m eth yl-2,3-d ih yd r o-1H-ben zo[g]in d ole-2-
on e (55) was obtained from 150 mg (0.5 mmol) of sulfoxide
52 (xylene, 5 mg of p-TsOH) in 75% yield as a colorless solid:
1
mp 164-165 °C; IR (KBr) 1756, 1700, 1462, 1202 cm-1; H-
NMR δ 2.42 (s, 3H), 3.51 (s, 2H), 3.63 (s, 3H), 7.08 (s, 1H),
7.36-7.45 (m, 2H), 7.82 (dd, 1H, J ) 8.0, 1.0 Hz), 8.24 (dd,
1H, J ) 8.0, 1.0 Hz); 13C-NMR δ 20.7, 30.2, 36.0, 114.7, 119.2,
121.1, 121.3, 121.9, 125.6, 125.9, 126.6, 137.6, 141.5, 169.5,
175.8. Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49.
Found: C, 70.47; H, 5.16; N, 5.46.
N-Bu t-3-en yl-2-[(eth ylth io)m eth yl]ben za m id e (56). To
a stirred suspension containing of 4.9 g (25 mmol) of 2-[(eth-
ylthio)methyl]benzoic acid (8)38 in 50 mL of dry benzene was
added 6.0 g (50 mmol) of thionyl chloride. After being stirred
at rt for 1 h, the solution was concentrated under reduced
pressure. The crude acid chloride was dissolved in 20 mL of
dry CH2Cl2, and this was added dropwise to a solution
containing 5.3 g (75 mmol) of but-3-enylamine in 50 mL of dry
CH2Cl2 at 0 °C under argon. After being stirred at rt for 2 h,
the mixture was washed successively with 5% HCl, a saturated
NaHCO3 solution, and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resi-
due was purified by flash silica gel chromatography to give
4.7 g (76%) of amide 56 as a colorless solid: mp 48-49 °C; IR
(KBr) 3291, 1637, 1537, 1317, 701 cm-1 1H-NMR δ 1.26 (t,
;
3H, J ) 7.5 Hz), 2.39 (dt, 2H, J ) 7.0, 7.0 Hz), 2.52 (q, 2H, J
) 7.0 Hz), 3.54 (dt, 2H, J ) 7.0, 7.0 Hz), 3.92 (s, 2H), 5.09-
5.19 (m, 2H), 5.78-5.91 (m, 1H), 6.53 (brs, 1H), 7.25-7.49 (m,
4H); 13C-NMR δ 14.3, 25.8, 33.5, 33.6, 38.9, 117.0, 127.0, 128.1,
129.6, 130.4, 135.2, 135.7, 136.4, 169.2. Anal. Calcd for
C
14H19NOS: C, 67.43; H, 7.68; N, 5.62. Found: C, 67.51; H,
7.75; N, 5.61.
N-Acet yl-N-b u t -3-en yl-2-[(et h ylsu lfin yl)m et h yl]b en z-
a m id e (57). A mixture containing 1.3 g (5 mmol) of amide
56, 590 mg (7.5 mmol) of acetyl chloride, 4.0 g of powdered
molecular sieves (4 Å), and 30 mL of CH2Cl2 was stirred for
24 h at rt. The reaction mixture was filtered through a pad
of silica gel, the solvent was removed under reduced pressure,
and the resulting crude oil was purified by flash silica gel
chromatography to give 1.2 g (81%) of N-acetyl-N-but-3-enyl-
2-[(ethylthio)methyl]benzamide as a colorless oil: IR (neat)
1
1696, 1654, 1440, 1345, 1262, 1215 cm-1; H-NMR δ 1.22 (t,
3H, J ) 7.5 Hz), 2.18 (s, 3H), 2.36-2.47 (m, 4H), 3.80 (t, 2H,
J ) 7.0 Hz), 3.92 (s, 2H), 4.99-5.07 (m, 2H), 5.68-5.77 (m,
1H), 7.29-7.44 (m, 4H); 13C-NMR δ 14.2, 25.8, 26.7, 33.0, 33.1,
44.9, 117.0, 126.9, 130.5, 130.8, 134.8, 135.5, 137.3, 173.2,
173.3; HRMS (FAB) calcd for C16H21NO2SLi (M + Li) 298.1453,
found 298.1441.
A 1.2 g (4 mmol) sample of the above sulfide was oxidized
in the standard manner to give sulfoxide 57 in 95% yield as a
colorless oil: IR (neat) 1691, 1649, 1440, 1351, 1047 cm-1; 1H-
NMR δ 1.37 (t, 3H, J ) 7.5 Hz), 2.18 (s, 3H), 2.39 (dt, 2H, J )
7.0, 7.0 Hz), 2.68-2.86 (m, 2H), 3.83 (t, 2H, J ) 7.0 Hz), 4.05
(d, 1H, J ) 13.0 Hz), 4.26 (d, 1H, J ) 13.0 Hz), 5.02-5.10 (m,
2H), 5.63-5.82 (m, 1H), 7.38-7.52 (m, 4H); 13C-NMR δ 6.7,
26.7, 33.1, 45.1, 45.8, 55.2, 117.4, 128.1, 128.2, 130.5, 131.4,
N -Bu t -3-e n oyl-2-[(e t h ylsu lfin yl)m e t h yl]-N -m e t h yl-
ben za m id e (52). A mixture of 1.1 g (5 mmol) of amide 25,
780 mg (7.5 mmol) of but-3-enoyl chloride, 4.0 g of powdered
molecular sieves (4 Å), and 30 mL of CH2Cl2 was stirred for
24 h at rt. The reaction mixture was filtered through a pad
of silica gel, the solvent was evaporated under reduced
pressure, and the crude oil was purified by flash silica gel
chromatography to give 1.12 g (81%) of N-but-3-enoyl-2-
[(ethylthio)methyl]-N-methylbenzamide as a colorless oil: IR
(neat) 1691, 1659, 1418, 1317, 1210, 1050 cm-1; 1H-NMR δ 1.21
(t, 3H, J ) 7.5 Hz), 2.41 (q, 2H, J ) 7.5 Hz), 3.09 (s, 3H), 3.63
(d, 2H, J ) 7.0 Hz), 3.89 (s, 2H), 5.11-5.19 (m, 2H), 5.98-
6.12 (m, 1H) 7.27-7.39 (m, 4H); 13C-NMR δ 13.9, 25.5, 32.7,
33.8, 42.7, 117.9, 126.7, 126.8, 126.9, 130.5, 130.8, 135.2, 137.1,
173.0, 174.3; HRMS calcd for C15H19NO2S 277.1137, found
277.1129.
132.5, 134.6, 135.9, 173.0, 173.3; HRMS (FAB) calcd for C16H22
NO3S 308.1320, found 308.1311.
-
5-Acetoxy-1-a cetyl-2,3-d ih yd r o-1H-ben zo[g]in d ole (60)
was obtained from 150 mg (0.5 mmol) of sulfoxide 57 (xylene,
5 mg of p-TsOH) in 81% yield as a colorless solid: mp 141-
142 °C; IR (KBr) 1760, 1656, 1622, 1592, 1400, 1326, 1217
1
cm-1; H-NMR δ 2.34 (brs, 3H), 2.46 (s, 3H), 3.20 (t, 2H, J )
7.0 Hz), 4.29 (brs, 2H), 7.19 (s, 1H), 7.42-7.55 (m, 2H), 7.80-
7.91 (m, 2H); 13C-NMR δ 20.8, 24.0, 30.2, 51.8, 115.0, 121.2,
125.0, 125.5, 125.6, 125.7, 125.8, 130.9, 136.4, 144.4, 169.3.
Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20.
Found: C, 71.20; H, 5.70; N, 5.23.
A 1.1 g (4 mmol) sample of the above sulfide was oxidized
in the standard manner to afford sulfoxide 52 (94%) as a
colorless oil: IR (neat) 1691, 1685, 1656, 1317, 1210, 1050
1
cm-1; H-NMR δ 1.34 (t, 3H, J ) 7.5 Hz), 2.65-2.81 (m, 2H),
3.17 (s, 3H), 3.58 (d, 2H, J ) 7.0 Hz), 4.09 (d, 1H, J ) 13.0
Hz), 4.27 (d, 1H, J ) 13.0 Hz), 5.11-5.19 (m, 2H), 5.96-6.05
Com p u ta tion a l P r oced u r es. Preliminary optimizations
of 61-63 and 64†-66† were carried out with MM3* in

Reactions of 2-Amino-Substituted Isobenzofurans
J . Org. Chem., Vol. 62, No. 9, 1997 2797
Macromodel, v.4.5,44 to identify the lower energy conformations
of the nitrogen-containing substituent. All-trans starting
geometries for 61-63 consistently reorganized to other forms
in the force-field framework. The lowest energy for each was
subsequently optimized by the DFT procedure B3LYP/3-21G*
(B3LYP ) Becke3LYP) encapsulated in Gaussian-94.45 In
addition, each of the structures was graphically converted to
an all-trans conformer. These too were subjected to DFT
optimization. Transition states 64†-66† were modeled by
constraining the newly formed pericyclic bonds to 2.2-2.5 Å
and optimized with MM3*. A variety of ring conformations
and N-methyl orientations were explored. In each case, one
force-field conformer proved considerably lower in energy than
the rest. Each was subsequently DFT optimized, as were both
N-COCH3 rotameric forms of 66†. To construct the isodesmic
reactions, N-methylacetamide, N-ethylacetamide, and meth-
ylethylamine were optimized with DFT in the all-trans
conformations. Finally, all DFT-optimized structures were re-
evaluated for energy by a single-point 6-31G* calculation using
Gaussian-94: B3LYP/6-31G*//B3LYP/3-21G*. The resulting
relative energies have been used throughout the computational
discussion.
Ack n ow led gm en t. We gratefully acknowledge the
National Science Foundation and the National Cancer
Institute (CA-26750), DHEW, for generous support of
this work. C.O.K. wishes to acknowledge the Austrian
Science Foundation (FWF) for an Erwin-Schro¨dinger-
Postdoctoral Fellowship. Use of the high-field NMR
spectrometer used in these studies was made possible
through equipment grants from the NIH and NSF.
(44) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J . Comput. Chem.
1990, 11, 440; http://www.columbia.edu/cu/chemistry/mmod/mmod.ht-
ml.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR and 13C-
NMR spectra for new compounds lacking analyses (21 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(45) Gaussian 94: Frish, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill,
P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T. A.;
Petersson, G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M.
A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.; Replogle, E. S.; Gomperts,
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