Rearrangements and intramolecular diels-alder reactions of normal and vinylogous aza-morita-baylis-hillman products leading to isoindoline derivatives

Article abstract of DOI:10.1021/jo1005087

Figure presented Aza-Morita-Baylis-Hillman (aza-MBH) products derived from arylimines and methyl acrylate or acrylonitrile were N-alkylated with (E)-5-bromopenta-1,3-diene, and the resulting trienes were subjected to intramolecular Diels-Alder (IMDA) cyloadditions to afford the corresponding trans- and cis-fused tetrahydroisoindolines as the major and minor products, respectively. Catalysis with boron trichloride improved the IMDA diastereoselectivities of the nitrile derivatives, while yields were improved in both the nitrile and ester series. Treatment of the nitrile-substituted trienes with DABCO in DMF resulted in unexpected transposition of the N-(pentadienyl)sulfonamide group to the β-position of the acrylonitrile moiety. Subsequent IMDA cycloadditions produced cis-fused positional isomers of the previous tetrahydroisoindolines. When the products of vinylogous aza-MBH reactions in the nitrile series were N-propargylated, the resulting dienynes underwent a similar transposition and IMDA reaction, producing trans and cis diastereomers of the corresponding dihydroisoindolines as the major and minor products, respectively. In all but one case, only the former products were observed in the presence of methylaluminum dichloride, while the corresponding aromatized isoindolines were obtained when the IMDA reactions were carried out in the presence of DDQ. Thus, a variety of aryl-substituted isoindoline products with different levels of unsaturation and complementary substitution patterns and stereochemistry are readily available through these processes.

Full text of DOI:10.1021/jo1005087

pubs.acs.org/joc
Rearrangements and Intramolecular Diels-Alder Reactions of Normal
and Vinylogous Aza-Morita-Baylis-Hillman Products Leading to
Isoindoline Derivatives
Kristen N. Clary, Masood Parvez, and Thomas G. Back*
Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4
tgback@ucalgary.ca
Received March 17, 2010
Aza-Morita-Baylis-Hillman (aza-MBH) products derived from arylimines and methyl acrylate or
acrylonitrile were N-alkylated with (E)-5-bromopenta-1,3-diene, and the resulting trienes were
subjected to intramolecular Diels-Alder (IMDA) cyloadditions to afford the corresponding trans-
and cis-fused tetrahydroisoindolines as the major and minor products, respectively. Catalysis with
boron trichloride improved the IMDA diastereoselectivities of the nitrile derivatives, while yields
were improved in both the nitrile and ester series. Treatment of the nitrile-substituted trienes with
DABCO in DMF resulted in unexpected transposition of the N-(pentadienyl)sulfonamide group to
the β-position of the acrylonitrile moiety. Subsequent IMDA cycloadditions produced cis-fused
positional isomers of the previous tetrahydroisoindolines. When the products of vinylogous aza-
MBH reactions in the nitrile series were N-propargylated, the resulting dienynes underwent a similar
transposition and IMDA reaction, producing trans and cis diastereomers of the corresponding
dihydroisoindolines as the major and minor products, respectively. In all but one case, only the
former products were observed in the presence of methylaluminum dichloride, while the correspond-
ing aromatized isoindolines were obtained when the IMDA reactions were carried out in the presence
of DDQ. Thus, a variety of aryl-substituted isoindoline products with different levels of unsaturation
and complementary substitution patterns and stereochemistry are readily available through these
processes.
Introduction
catalyzed by a tertiary amine or phosphine and proceeds
by conjugate addition of the nucleophilic catalyst to the
activated alkene, followed by attack of the resulting zwitter-
ion upon the aldehyde carbonyl group, proton transfer, and
finally elimination of the catalyst (Scheme 1). Numerous
The Morita-Baylis-Hillman reaction was discovered
more than 40 years ago1,2 but was largely ignored for several
decades. More recently, it has attracted considerable atten-
tion as a widely applicable synthetic method for coupling the
R-position of an alkene, activated by a suitable electron-
withdrawing group (EWG), with the carbonyl group of an
aldehyde or related electrophile. The reaction is typically
(2) For reviews, see: (a) Ma, G.-N.; Jiang, J.-J.; Shi, M.; Wei, Y. Chem.
Commun. 2009, 5496–5514. (b) Singh, V.; Batra, S. Tetrahedron 2008, 64,
4511–4574. (c) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007,
36, 1581–1588. (d) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811–891. (e) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001–8062. (f) Ciganek, E. Org. React. 1997, 51, 201–350.
(g) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049–3052. (h) Drewes,
S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653–4670.
(1) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815. (b) Morita, K. Jpn. Patent 43003364, 1968; Chem Abstr. 1968, 69, 58828s.
(c) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. 2,155,113, 1972; Chem. Abstr.
1972, 77, 34174q.
DOI: 10.1021/jo1005087
r
Published on Web 05/05/2010
J. Org. Chem. 2010, 75, 3751–3760 3751
2010 American Chemical Society

Clary et al.
JOCArticle
SCHEME 1
SCHEME 2
variations in the structures of the reactants and catalyst are
tolerated,2 and several mechanistic investigations have been
completed.3 Enantioselective variations, frequently effected
by the use of chiral catalysts,4 and numerous studies of
further transformations of the products have been reported.2
A particularly useful modification is based on employing
aldimines instead of aldehydes, resulting in the aza-Morita-
Baylis-Hillman (aza-MBH) reaction.5,6 This permits the
formation of allylic amines instead of the more conventional
allylic alcohol products.
Werecently reported the useof activated dienes2 in place of
simple alkenes in a novel vinylogous aza-MBH reaction with
imines 1. The activating groups can be sulfonyl,7a,b ester,7b
ketone,7b or nitrile7c moieties, resulting in products 3 with
predominantly (where EWG is Ts, CO2Me, or C(dO)Ph) or
exclusively (where EWG is C(dO)Me) the E-configuration.
In contrast, the corresponding nitriles (where EWG is CN)
were obtained as essentially pure Z-isomers. In the case of
the E-isomers of the products 3,7a,b a subsequent intramole-
cular conjugate addition afforded substituted piperidines 4.
Although the corresponding Z-isomers were unreactive in this
process, insitu photoisomerizationofE,Z mixtures of the aza-
MBH adducts 3 (where EWG is Ts) during the cyclization
reaction resulted in equilibration of the E- and Z-isomers,
with the ultimate consumption of both geometrical isomers
(Scheme 2).7a,b
intramolecular Diels-Alder (IMDA) reactions to afford the
corresponding 1-aryl-substituted tetra- or dihydroisoindo-
line derivatives 6-8.8 The corresponding E-isomers were
unsuitable for this purpose because of their competing intra-
molecular conjugate additions, as was shown in Scheme 2.
The products were converted into the corresponding isoin-
dolines 9 by aromatization and isoindolinones 10 by further
oxidation (Scheme 3).
Isoindolines and their congeners display a remarkable
variety of biological activities. They serve as inhibitors of
the enzymes prolyl dipeptidases DPP8 and DPP9,9 which are
of interest in therapies for Type II diabetes, while other
members of this class inhibit COX-2,10 a key target for anti-
inflammatory drugs. Certain derivatives serve as antagonists
of the receptors ETA,11 NMDA,12 and 5-HT2C 13 which are
,
implicated in vasoconstriction, neurodegenerative diseases,
and neuropsychiatric disorders, respectively. Some isoindo-
lines act as selective serotonin uptake inhibitors,14 while others
exhibit antitumor,15 diuretic,16 and herbicidal17 activity. Many
of the biologically active isoindolines contain additional aryl
and other substituents. While numerous methods have been
reported for the synthesis of isoindoline derivatives, they are
During further investigations of useful transformations of
aza-MBH products, we prepared the corresponding N-allyl
and N-propargyl derivatives 5 from (Z)-3, which underwent
(7) (a) Back, T. G..; Rankic, D. A.; Sorbetti, J. M.; Wulff, J. E. Org. Lett.
2005, 7, 2377–2379. (b) Sorbetti, J. M.; Clary, K. N.; Rankic, D. A.; Wulff,
J. E.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72, 3326–3331. (c) Clary,
K. N.; Back, T. G. Synlett 2007, 2995–2998.
(8) Clary, K. N.; Parvez, M.; Back, T. G. Org. Biomol. Chem. 2009, 7,
1226–1230.
(9) (a) Jiaang, W.-T.; Chen, Y.-S.; Hsu, T.; Wu, S.-H.; Chien, C.-H.;
Chang, C.-N.; Chang, S.-P.; Lee, S.-J.; Chen, X. Biorg. Med. Chem. Lett. 2005,
15, 687–691. (b) Van Goethem, S.; Van der Veken, P.; Dubois, V.; Soroka, A.;
(3) For lead references, see: (a) Roy, D.; Patel, C.; Sunoj, R. B. J. Org.
Chem. 2009, 74, 6936–6943. (b) Krafft, M. E.; Haxell, T. F. N.; Seibert, K. A.;
Abboud, K. A. J. Am. Chem. Soc. 2006, 128, 4174–4175. (c) Price, K. E.;
Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005, 70,
3980–3987. (d) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T.
Org. Lett. 2005, 7, 147–150. (e) Robiette, R.; Aggarwal, V. K.; Harvey, J. N.
J. Am. Chem. Soc. 2007, 129, 15513–15525. (f) Aggarwal, V. K.; Fulford,
S. Y.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1706–1708.
(g) Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N.
Angew. Chem., Int. Ed. 2004, 43, 4330–4333. (h) Aggarwal, V. K.; Emme, I.;
Fulford, S. Y. J. Org. Chem. 2003, 68, 692–700. (i) Hill, J. S.; Isaacs, N. S.
J. Phys. Org. Chem. 1990, 3, 285–288. (j) Hill, J. S.; Isaacs, N. S. Tetrahedron
Lett. 1986, 27, 5007–5010. (k) Bode, M. L.; Kaye, P. T. Tetrahedron Lett.
1991, 32, 5611–5614. (l) Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron
1992, 48, 6371–6384. (m) Drewes, S. E.; Njamela, O. L.; Emslie, N. D.;
Ramesar, N.; Field, J. S. Synth. Commun. 1993, 23, 2807–2815.
(4) For reviews, see: (a) Krishna, P. R.; Sachwani, R.; Reddy, P. S.
Synlett 2008, 2897–2912. (b) Masson, G.; Housseman, C.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 4614–4628. (c) Kataoka, T.; Kinoshita, H. Eur.
J. Org. Chem. 2005, 45–48.
ꢀ
Lambeir, A.-M.; Chen, X.; Haemers, A.; Scharpe, S.; De Meester, I.;
Augustyns, K. Biorg. Med. Chem. Lett. 2008, 18, 4159–4162.
(10) (a) Portevin, B.;Tordjman, C.; Pastoureau, P.; Bonnet, J.; De Nanteuil,
G. J. Med. Chem. 2000, 43, 4582–4593. (b) Mancilla, T.; Correa-Basurto, J.;
Alaves Carbajal, K. S.; Sanchez Escalante, E. T. J.; Ferrara, J. T. J. Mex. Chem.
Soc. 2007, 51, 96–102.
(11) (a) Kukkola, P. J.; Bilci, N. A.; Ikeler, T. J. Tetrahedron Lett. 1996, 37,
5065–5068. (b) Kukkola, P. J.; Bilci, N. A.; Ikler, T.; Savage, P.; Shetty, S. S.;
DelGrande, D.; Jeng, A. Y. Biorg. Med. Chem. Lett. 2001, 11, 1737–1740.
(12) Bare, T. M.; Draper, C. W.; McLaren, C. D.; Pullan, L. M.; Patel, J.;
Patel, J. B. Biorg. Med. Chem. Lett. 1993, 3, 55–60.
(13) Hamprecht, D.; Micheli, F.; Tedesco, G.; Checchia, A.; Donati, D.;
Petrone, M.; Terreni, S.; Wood, M. Biorg. Med. Chem. Lett. 2007, 17, 428–433.
(14) Kapples., K. J.; Shutske, G. M. J. Heterocycl. Chem. 1997, 34, 1335–
1338.
(15) Berger, D.; Citarella, R.; Dutia, M.; Greenberger, L.; Hallett, W.;
Paul, R.; Powell, D. J. Med. Chem. 1999, 42, 2145–2161.
(16) Cornish, E. J.; Lee, G. E.; Wragg, W. R. Nature 1963, 197, 1296–
1297.
(5) For the first examples, see: Perlmutter, P.; Teo, C. C. Tetrahedron
Lett. 1984, 25, 5951–5952.
(6) For reviews, see: (a) Declerck, V.; Martinez, J.; Lamaty, F. Chem.
Rev. 2009, 109, 1–48. (b) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905–
2916.
(17) Huang, M.-Z.; Huang, K.-L.; Ren, Y.-G.; Lei, M.-X.; Huang, L.;
Hou, Z.-K.; Liu, A.-P.; Ou, X.-M. J. Agric. Food Chem. 2005, 53, 7908–7914.
3752 J. Org. Chem. Vol. 75, No. 11, 2010

Clary et al.
JOCArticle
SCHEME 3
SCHEME 4
TABLE 1. Preparation and IMDA Cycloadditions of 13 and 14
products 13 and IMDA products
14 (yield, %)a
entry
Ar
EWG
(yield, %)a
drb
1
2
3
4
5
6
7
8
9
Ph
p-Cl-Ph
p-MeO-Ph CO2Me
p-NC-Ph CO2Me
1-naphthyl CO2Me
Ph
p-Cl-Ph
p-MeO-Ph CN
p-NO2-Ph CN
CO2Me
CO2Me
13a (98)
13b (97)
13c (94)
13d (99)
13e (98)
14a (98)
14b (98)
14c (94)
14f (-)
15a þ 17a (89) 65:35
15b þ 17b (67) 75:25
15c þ 17c (72) 70:30
15d þ 17d (77) 70:30
15e þ 17e (86) 75:25
16a þ 18a (61) 75:25
16b þ 18b (84) 75:25
16c þ 18c (88) 70:30
16f þ 18f (70)c 70:30
CN
CN
aIsolated yields of 13 and 14 and of unseparated mixtures of 15 þ 17
and 16 þ 18 are reported. bDiastereomeric ratio (dr) determined by inte-
gration of 1H NMR spectra of the unseparated mixtures. cOverall yield
from 12f is shown.
generallylimitedwith respect tothe level of unsaturationof the
products and the types and locations of substituents. Versatile
synthetic approaches that are able to provide these products
with diverse substituent patterns and in various oxidation
states are therefore in demand.
We now report that aza-MBH products derived either
from simple alkenes or dienes undergo a facile isomerization
of the sulfonamide moiety to the terminal position of the
alkene or diene. When the sulfonamide is suitably N-func-
tionalized with pentadienyl or propargyl substituents, the
isomerization and subsequent IMDA cycloaddition can be
exploited in the preparation of complementary isoindoline
derivatives that differ in stereo- and regiochemistry com-
pared to those we had prepared previously8 via Scheme 3.
the N-substituent comprised the dienophile and reacted with
a diene moiety activated by an electron-withdrawing group
via inverse electron demand, cycloadditions of 13 and 14
were expected to proceed through normal electron demand.
When trienes 13 and 14 were refluxed in anisole, IMDA
cycloadditions afforded the corresponding tetrahydroisoin-
doline products as mixtures of two diastereomers 15 and 17
for the methyl esters and 16 and 18 in the nitrile series. Yields
are summarized in Table 1 and were generally moderate to
good, with both electron-withdrawing and electron-donating
substituents on the aryl moiety tolerated by the reaction
conditions. Diastereoselectivities ranged from 65:35 (entry 1)
to 75:25 (entries 2, 5, 6, and 7). The major isomers 15a-15e,
16a-16c, and 16f could be isolated essentially free of their
minor diastereomers, but minor isomers 17 and 18 could not be
completely separated from their counterparts, except for 17c.
The structures of the major diastereomers 15b and 16c were
unequivocally confirmed by X-ray crystallography (see Sup-
porting Information), which indicated trans-fused rings and a
trans orientation of the aryl substituent with the electron-
withdrawing group. This stereochemistry is consistent with
endo transition state B in Scheme 5, in contrast to the previous
cis-fused products 6 and 7 that had been obtained by inverse
electron demand IMDA reactions (Scheme 3). The stereo-
chemistry of the minor diastereomer 17c in the ester series was
also confirmed by X-ray crystallography (see Supporting
Information), which indicated the cis-fused ring system aris-
ing from the exo transition state C in Scheme 5. Presumably,
transition state endo-B is favored over exo-C because of
Results and Discussion
The aza-MBH adducts 11 and 12 were obtained from the
simple activated alkenes methyl acrylate and acrylonitrile
according to literature procedures.18 The products were then
N-alkylated in good yield with (E)-5-bromopenta-1,3-
diene19 to provide trienes 13 and 14 (Scheme 4). It was
expected that the latter compounds would provide IMDA
cycloadducts similar to 6 and 7 in Scheme 3, but differing in
the position of the double bond and possibly the stereochem-
istry. In contrast to the preparation of 6 and 7 from 5, where
(18) (a) Balan, D.; Adolfsson, H. J. Org. Chem. 2001, 66, 6498–6501.
(b) Xu, Y.-M.; Shi, M. J. Org. Chem. 2004, 69, 417–425.
ꢀ
(19) Prevost, C.; Miginiac, P.; Miginiac-Groizeleau, L. Bull. Soc. Chim.
Fr. 1964, 2485–2492.
J. Org. Chem. Vol. 75, No. 11, 2010 3753

Clary et al.
JOCArticle
SCHEME 5
TABLE 2. Lewis Acid Catalyzed IMDA Reactions of 14a (Ar = Ph;
EWG= CN)
entry Lewis acid equiv temp (°C)a solventb 16a þ 18a (yield, %)c drd
1
2
3
4
5
6
7
8
9
AlCl3
1
0-rt
0-rt
-78
0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
(45)
(82)
(45)
(38)
(70)
(68)
(73)
(63)
(70)
(98)
(93)
80:20
80:20
85:15
85:15
90:10
85:15
85:15
85:15
90:10
90:10
90:10
MeAlCl2
BBr3
BF3 OEt2
1
1
1
3
BCl3
BCl3
BCl3
BCl3
BCl3
1
0-rt
-78
-55
0
1
1
2
1
rt
10 BCl3
11 BCl3
1
0.5
0-rt
0-rt
DCE
art = room temperature. bDCM = dichloromethane; DCE = 1,2-
c
dichloroethane. Isolated yields are reported. dDetermined by integra-
tion of 1H NMR spectra of the crude mixtures.
TABLE 3. Boron Trichloride Catalyzed IMDA Cycloadditions of
Trienes 13 and 14a
entry
Ar
EWG
products (yield, %)b
drc
1
2
3
4
5
6
7
8
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
15a þ 17a (90)
15b þ 17b (95)
15c þ 17c (98)
15d þ 17d (94)
15e þ 17e (90)
16a þ 18a (98)
16b þ 18b (86)
16c þ 18c (92)
65:35
75:25
70:30
70:30
75:25
90:10
90:10
90:10
p-Cl-Ph
p-MeO-Ph
p-NC-Ph
1-naphthyl
Ph
p-Cl-Ph
p-MeO-Ph
CN
CN
aAll reactions were conducted in 1,2-dichloroethane with 1 equiv of
BCl3;thosewithEWG= CO2Me wereperformedatrefluxandthosewith
EWG = CN were carried out at 0 °C-rt. bIsolated yields are reported.
cDetermined by integration of 1H NMR spectra of the crude mixtures.
secondary orbital interactions that compensate for the inci-
pient formation of the less stable trans-fused product. The
failure to observe products derived from transition states A
and D is attributed to the destabilizing steric interactions
between the aryl moiety and the ester or nitrile group. The
stereochemistry of the other products in Table 1 was inferred
by analogy and from the similarity of their respective NMR
spectra to those of the corresponding compounds of known
configuration described above.
Attempts to increase the diastereoselectivity and decrease
the required temperature of the IMDA reaction of 14a by
means of Lewis acid catalysis are summarized in Table 2. While
the inclusion of several Lewis acids permitted the reactions to
proceed at temperatures as low as -78 °C (entries 3 and 6),
boron trichloride afforded the highest diastereomeric ratio (dr)
of 90:10 (entries 5 and 9-11), while the conditions of entries 10
and 11 provided the highest yields of 98% and 93%, respec-
tively. A decrease to 0.5 equiv of boron trichloride decreased
the yield slightly (entry 11), while the use of only 0.1 equiv
resulted in a very sluggish reaction and markedly lower yield.
The most satisfactory combination of d.r and yield was there-
fore obtained in entry 10 in 1,2-dichloroethane at 0 °C-room
temperature with 1 equiv of the catalyst.
observed in both the ester and nitrile series, high diastereos-
electivities were confined to the latter. An exception was noted
with the p-nitrophenyl derivative 14f (Ar=p-nitrophenyl),
which failed to produce the corresponding cycloadduct under
these conditions.
Numerous methods have been reported for the cleavage
of N-benzenesulfonyl groups from their parent amines.20a As
an illustrative example, N-desulfonylation of tetrahydroisoin-
doline 16c was carried out in 85% yield with magnesium in
methanol20b (see SupportingInformation), whileseveral other
methods (HBr/phenol, sodium amalgam-Na2HPO4-MeOH,
sodium in isopropanol) afforded less satisfactory results.
Several examples have been reported in which allylic
substitutions of activated hydroxyl groups from MBH ad-
ducts derived from aldehydes (i.e., X = O in Scheme 1) were
effected by bromide,21 azides,22 amines, and other nitrogen
nucleophiles.22a,23 However, similar reactions in the case of
(20) (a) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis, 3rd ed., Wiley: New York, 1999; pp 604-607. (b) For a similar
procedure for N-desulfonylation with magnesium in methanol, see: Tichenor,
M. S.; Trzupek, J. D.; Kastrinsky, D. B.; Shiga, F.; Hwang, I.; Boger, D. L. J. Am.
Chem. Soc. 2006, 128, 15683–15696.
(21) Brown, J. M.; James, A. P.; Prior, L. M. Tetrahedron Lett. 1987, 28,
Unfortunately, similar attempts to enhance the diastereo-
selectivity of the cycloadditions of esters 13 with Lewis acids
were unsuccessful, although boron trichloride did improve
the combined yields of products 15 and 17 in refluxing 1,2-
dichloroethane. Consequently, further IMDA reactions of
trienes 13 and 14 were conducted with 1 equiv of boron
trichloride in refluxing 1,2-dichloroethane for the esters 13
and at 0 °C-room temperature for nitriles 14. The results are
shown in Table 3. Thus, while high combined yields were
2179–2182.
(22) (a) Foucaud, A.; El Guemmout, F. Bull. Soc. Chim. Fr. 1989, 403–
408. (b) Patra, A.; Roy, A. K.; Batra, S.; Bhaduri, A. P. Synlett 2002, 1819–
1822. (c) Yadav, J. S.; Gupta, M. K.; Pandey, S. K.; Reddy, B. V. S.; Sarma,
A. V. S. Tetrahedron Lett. 2005, 46, 2761–2763.
(23) (a) Park, D. Y.; Lee, M. J.; Kim, T. H.; Kim, J. N. Tetrahedron Lett.
2005, 46, 8799–8803. (b) Rajesh, S.; Banerji, B.; Iqbal, J. J. Org. Chem. 2002,
67, 7852–7857. (c) Pathak, R.; Singh, V.; Nag, S.; Kanojiya, S.; Batra, S.
Synthesis 2006, 813–816. (d) Drewes, S. E.; Horn, M. M.; Ramesar, N. Synth.
Commun. 2000, 30, 1045–1055. (e) Park, Y. S.; Cho, M. Y.; Kwon, Y. B.; Yoo,
B. W.; Yoon, C. M. Synth. Commun. 2007, 37, 2677–2685. (f) Krawczyk, E.;
ꢀ
Owsianik, K.; Skowronska, A. Tetrahedron 2005, 61, 1449–1457.
3754 J. Org. Chem. Vol. 75, No. 11, 2010

Clary et al.
JOCArticle
SCHEME 6
TABLE 4. Rearrangements and IMDA Cycloadditions of 14
rearrangement
product (yield, %)a
IMDA product
(yield, %)a
entry
Ar
1
2
3
4
5
6
Ph
p-Cl-Ph
p-MeO-Ph
p-NO2-Ph
m-Cl-Ph
19a (97)
19b (95)
19c (98)
19f (-)
19g (96)
19h (85)
20a (59)
20b (73)
20c (71)
20f (72)b
20g (72)
20h (58)
p-MeO2C-Ph
aIsolated yields are reported. bOverall yield from12f via 14f and 19f is
shown.
SCHEME 7
aza-MBH products (where X = NTs in Scheme 1) are confined
to examples of overall allylic substitutions of p-toluenesulfon-
amide groups by the p-toluenesulfonamide anion, as reported
by Xu and Shi24 and by Kim et al.,25 who employed a multistep
process mediated by methoxide anion generated from DMF
dimethyl acetal. We now report that the aza-MBH derivatives
14 underwent the base-catalyzed isomerizations shown in
Scheme 6, in which the entire N-(2,4-pentadienyl)sulfonamide
group was translocated to the β-position of the unsaturated
nitrile moiety to afford 19. These processes occurred smoothly
at room temperature in DMF with catalytic amounts of
DABCO in the nitrile series, whereas the corresponding esters
13 produced complex mixtures under similar conditions. The
rearranged products 19 then underwent IMDA cycloadditions
in refluxing anisole, affording tetrahydroisoindolines 20 in
moderate yields as single diastereomers. The results are sum-
marized in Table 4. Attempts to further improve the yields by
means of Lewis acid catalysis were unsuccessful. The stereo-
chemistry of 20g was determined to be cis,cis by X-ray diffrac-
tion (see Supporting Information), which implicates the exo
transition state E in this process and confirms the cis orienta-
tion of the nitrile and aryl groups in the dienophile component
of triene 19g. Thus, in this case, the dominant stereochemistry
appears to be determined by the greater thermodynamic
stability of the cis-fused rings, rather than by secondary orbital
interactions.
exhibit not only different substitution patterns and levels of
unsaturation, but perhaps also stereochemistries complemen-
tary to the ones in Schemes 4 and 6 and to those we had
previously synthesized8 via Scheme 3.
The N-propargyl derivatives 22a, 22b, 22e, 22g, and 22h
were easily obtained from the corresponding aza-MBH
adducts 217c and propargyl bromide. They underwent re-
arrangements similar to those in Scheme 6 in the presence of
catalytic amounts of DABCO to afford the corresponding
transposed products 23. Migration of the N-(propargyl)-
benzenesulfonamide group occurred exclusively to the
δ-position of the dienyl nitrile moiety, and β-substituted
products were not isolated (Scheme 7). The results are sum-
marized under method A in Table 5. Other catalysts such as
aqueous sodium hydroxide or DBU produced more complex
mixtures or slower reactions and DABCO was found to be the
optimal catalyst of those investigated. We postulate that a
vinylogous substitution of the sulfonamide group by the
catalyst, followed by the further direct substitution of the
latter by the sulfonamide anion occurs in a fashion similar to
that shown in Scheme 6. The transposed products 23 were
obtained as inseparable mixtures of geometrical isomers.
Attempts at chromatographic separation failed to improve
their purity and in some cases resulted in further decomposi-
tion. It was therefore more expedient to perform subsequent
transformations (vide infra) directly on the crude products.
We next investigated the as yet unexplored rearrangements
analogous to those in Scheme 6 in the products of vinylogous
aza-MBH reactions, in which an activated diene is employed
instead of a monoalkene. The installation and transposition of
the N-(propargyl)benzenesulfonamide moieties of dienynes22
would result in the reversal of the frontier MO interactions of
subsequent IMDA reactions, relative to those in Scheme 6.
Thus, the propargylic N-substituent would now serve as an
electron-rich dienophile and interact with an electron-deficient
diene moiety. The resulting cycloadducts would be expected to
(24) Xu, Y.-M.; Shi, M. J. Org. Chem. 2004, 69, 417–425.
(25) Lee, H. J.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 1999, 40, 4363–
4366.
J. Org. Chem. Vol. 75, No. 11, 2010 3755

Clary et al.
JOCArticle
TABLE 5. Preparation of Dienynes 23 and 24
SCHEME 8
entry starting material methoda
Ar
product (yield, %)b
1
2
3
4
5
6
7
8
22a
21a
21a
22b
21b
21b
22e
21e
21e
22g
21g
21g
22h
21h
21h
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
Ph
23a (87)
23a (96)
24a (68)
23b (90)
23b (92)
24b (67)
23e (92)
23e (85)
24e (65)
23g (88)
23g (81)
24g (60)
23h (69)
23h (83)
24h (73)
p-Cl-Ph
1-naphthyl
m-Cl-Ph
9
10
11
12
13
14
15
p-MeO2C-Ph
aMethod A: DABCO, DMF. Method B: N-(propargyl)benzenesulfon-
amide (1.1 equiv), K2CO3 (1.2 equiv), DMF. Method C: N-(propargyl)-
benzenesulfonamide (1.1 equiv), K2CO3 (2.0 equiv), DMF. bIsolated
yields are reported.
A NOESY experiment with 23a revealed that the major
geometrical isomer produced an interaction between the two
protons located β to the nitrile group (singlet at δ 7.05 and
doublet at δ 6.41ppm, respectively), indicating theZ geometry
for the trisubstituted double bond, while the 1H NMR coup-
ling constant J = 15.4 Hz confirmed the trans configuration
of the disubstituted double bond of both geometrical isomers.
Similar assignments to the major isomers of 23b, 23e, 23g, and
23h were made on the basis of their NMR spectra. We also
discovered that treatment of aza-MBH adducts 21a, 21b, 21e,
21g, and 21h with a slight excess (1.1 equiv) of N-(propargyl)-
benzenesulfonamide and potassium carbonate (1.2 equiv) in
DMF produced good yields of the same δ-substituted products
as obtained from the DABCO-catalyzed reactions (Scheme 7
and method B in Table 5). Interestingly, the use of a larger
excess of potassium carbonate (2.0 equiv) and longer reaction
times under otherwise similar conditions resulted in the forma-
tion of the corresponding enamine derivatives 24, which were
obtained as essentially pure geometrical isomers (Scheme 7).
These results are listed under method C in Table 5. A control
experiment revealed that 24a was produced from the isomeriza-
tion of the initially formed 23a under these conditions and not
via an independent pathway. The assignment of E,Z-config-
uration to products 24 is tentative as NOESY and ROESY
experiments failed to give clear results for the trisubstituted
alkene moiety, while the coupling constants of ca. 14 Hz suggest
the trans configuration for the disubstituted double bond.
The rearranged dienynes 23a, 23b, 23e, 23g, and 23h were
then subjected to IMDA cycloadditions in refluxing anisole,
affording ca. 2:1 mixtures of the corresponding diastereo-
mers 25 and 26, as well as varying amounts of the aromatized
isoindolines 27. The major products 25 were isolated in pure
form by chromatography. However, the minor diastereo-
mers 26 could not be separated from the aromatic isoindo-
lines 27.26 The stereochemistry of the major isomer 25a was
determined by X-ray crystallography (see Supporting Infor-
mation), while those of the other major epimers 25b, 25e,
25g, and 25h were inferred from the similarity of their NMR
spectra to those of 25a. The minor isomers 26 are tentatively
assigned the structures of the epimers of 25 where the aryl
substituent is cis to the ring-fusion hydrogen. This is con-
sistent with the formation of 25 from the Z isomer (with
respect to the trisubstituted double bond) of 23 via transition
state F and of 26 from the corresponding E isomer via
transition state G (Scheme 8). Equilibration between 25
and 26 subsequent to their initial formation was ruled out
by control experiments in which 25a and 26a were separately
refluxed in anisole without any noticeable formation of the
other diastereomer.
The aromatized products 27 were evidently formed by in
situ air oxidation of the initial IMDA products. The mixtures
of 25-27 obtained above could be fully converted to the
corresponding isoindolines 27 by refluxing in anisole with
DDQ. Alternatively, the isoindolines were also obtained in
excellent yields in one step, without the accompanying
formation of 25 and 26, by simply refluxing dienynes 23 in
anisole with DDQ for 24 h (Scheme 8). Thus, pure samples of
27 could be obtained for characterization. The results are
summarized in Table 6.
The use of several Lewis acids (AlCl3, MeAlCl2, BCl3,
BBr3, TiCl4) in the IMDA step to improve the yield of the
dihydroisoindoline product 25a and the selectivity of its
formation relative to its diastereomer 26a was also investi-
gated. The most favorable conditions were observed when
the IMDA reaction of 23a was repeated in refluxing 1,2-
dichloroethane in the presence of 1 equiv of methylalumi-
num dichloride, providing 25a in 93% yield with no detect-
able amount of 26a (entry 1 in Table 6). Similarly, only one
diastereomer could be detected in the cycloadditions of 23b,
(26) A small amount of pure 26a was obtained by conducting the reaction
with exclusion of oxygen to avoid the formation of 27a.
3756 J. Org. Chem. Vol. 75, No. 11, 2010

Clary et al.
JOCArticle
TABLE 6. IMDA Cycloadditions and Aromatizations of Dienynes 23
uncatalyzed IMDA
products (yield, %)a
uncatalyzed IMDA and
DDQ oxidation products (yield, %)c
MeAlCl2-catalyzed
IMDA products (yield, %)d
entry
1
Ar
ratio 26:27b
Ph
25a (37)
26a þ 27a (38)
1.0:0.9
27a (91)
27b (82)
27e (81)
27g (86)
27h (88)
25a (93)
2
3
4
5
p-Cl-Ph
25b (26)
26b þ 27b (49)
25e (33)
1.0:2.3
1.0:1.8
1.0:1.7
1.0:0.06
25b (85)
1-naphthyl
m-Cl-Ph
p-MeO2C
25e þ 26e (82)e
25g (86)
26e þ 27e (46)
25g (34)
26g þ 27g (47)
25h (42)
25h (91)
26h þ 27h (25)
aIsolated yields of 25 and of unseparated mixtures of products 26 and 27 are reported from 23 in the absence of DDQ and Lewis acids. bThe ratios of
26:27 were determined by NMR integration. cIsolated yields of 27 are reported from the one-pot cycloadditions and DDQ oxidations of 23 in the absence
of Lewis acids. dPerformed in the presence of 1 equiv of MeAlCl2 in 1,2-dichloroethane in the absence of oxygen; isolated yields are reported. eObtained
as an unseparated 2:1 mixture, as determined by NMR integration.
SCHEME 9
TABLE 7. Friedel-Crafts Reactions of Vinylogous MBH Adducts
entry solvent
R0 EWG product (yield, %)a o:p ratiob
R
1
2
3
4
5
benzene H
H
Me
OMe CN
CN
CN
(Z,E)-28 (56)
(Z,E)-29 (80)
(Z,E)-30 (97)
(Z,E)-29 (88)
(E,E)-31 (74)
toluene
anisole
H
H
1:2
1:9
1:2
1:1
toluene propargyl Me
toluene Me
CN
Ts
H
b
aIsolated yields are reported. Ratios determined by NMR integra-
tion.
products were obtained as mixtures of o- and p-isomers when
toluene and anisole were used, favoring the p-isomers. The
Z-configuration for the trisubstituted double bond of 28,
where EWG = CN, was indicated by a NOESY experiment
that produced a correlation between HA and HB (singlet at δ
6.96 ppm and doublet at δ 6.17 ppm with J = 15.5 Hz, respec-
tively). No such correlationwas detected in 31, whereEWG =
Ts, tentatively suggesting that it may have the corresponding
E-configuration. The disubstituted double bonds of all of the
products were assigned the E-configuration, based on coup-
ling constants J = 15-16 Hz for HB and HC. Aza-MBH
adducts derived from simple alkenes rather than dienes have
been reported to undergo similar Friedel-Crafts reactions,
forming E double bonds preferentially in the case where the
EWG is an ester substituent, but with complete selectivity for
the Z-configuration where the EWG is a nitrile.28 The latter
examples are therefore in accord with our observations with
the vinylogous nitrile systems 28-30.
In conclusion, we have demonstrated that a wide variety of
isoindoline analogues, with different levels of unsaturation,
as well as complementary regio- and stereochemistry, can
be synthesized from aza-MBH or vinylogous aza-MBH
products via IMDA cycloadditions of the corresponding
N-pentadienyl and N-propargyl derivatives. The facile base-
catalyzed rearrangement of the N-substituted benzenesulfon-
amide group to the terminal position of the nitrile-activated
diene moiety prior to cycloaddition is noteworthy and
permits further variation to the types of products that
are made accessible. It is therefore possible to employ
the pendant N-substituent as either the diene or dienophile
component of the IMDA reaction and to perform the
cycloaddition via either normal or inverse electron demand.
While direct IMDA cycloadditions of N-substituted aza-
MBH adducts provide only 1-aryl-substituted isoindoline
23g, and23h (entries 2, 4, and 5), whereas that of the 1-naphthyl
derivative 23e (entry 3) resulted in a 2:1 mixture of 25e and
26e.27 These reactions were performed under nitrogen or
argon atmospheres, thereby avoiding air oxidation of the
products and preventing the formation of the correspond-
ing isoindolines 27.
These experiments demonstrate that the IMDA dienyne
precursors 23 can be obtained effectively by the DABCO-
catalyzed rearrangement of N-propargyl derivatives 22. Sub-
sequent cycloadditions of 23 in the presence of DDQ afforded
high yields of the aromatic products 27. On the other hand,
IMDA reactions of 23 were also carried out under anaerobic
conditions in the presence of the Lewis acid methylaluminum
dichloride to afford dihydroisoindolines 25 in generally high
yield and as single diastereomers. Thus, with the exception of
entry 3 in Table 6, the choice of appropriate conditions makes
it possible to obtain either 25 or the oxidized products 27 as
essentially unique cycloadducts.
While attempting to improve the conditions for some of the
above IMDA cycloadditions by the addition of Lewis acids,
we discovered that exposure of several vinylogous aza-MBH
products to 1 equiv of aluminum trichloride in toluene or
other aromatic solvents resulted in intermolecular Friedel-
Crafts reactions, producing 28-31 (Scheme 9). As expected,
the most electron-rich solvent anisole afforded the highest
yield (entry 3, Table 7), while unsubstituted benzene provided
the lowest yield (entry 1). No products arising from reactionat
the β-position of the dienyl nitrile moiety or by the direct
substitution of the sulfonamide group were observed. The
(27) The precise role of the Lewis acid in improving the stereoselectivity of
formation of 25 relative to 26 is not known. However, when 26b (mixture with
27b) in 1,2-dichloroethane was refluxed in the presence of methylaluminum
dichloride, it did not produce any detectable 25b. It is possible that the Lewis
acid promotes E,Z isomerization of dienyne 23 prior to the IMDA reaction
rather than the epimerization of 26 to 25 after the cycloaddition.
(28) Lee, H. J.; Seong, M. R.; Kim, J. N. Tetrahedron Lett. 1998, 39, 6223–
6226.
J. Org. Chem. Vol. 75, No. 11, 2010 3757

Clary et al.
JOCArticle
derivatives (Schemes 3 and 4), the use of rearranged trienes
or dienynes permits installation of the aryl substituent at
either the proximal or distal position (4-aryl in Scheme 6 or
6-aryl in Scheme 8, respectively) of the six-membered ring.
Similarly, the nitrile group, which is a potentially useful
functionality for further transformations, can be incorpo-
rated at either the ring-fusion position or adjacent to the aryl
substituent on the six-membered ring. This methodology
therefore provides a concise route to diverse aryl-substituted
isoindolines and their dihydro and tetrahydro analogues.
(300 MHz) δ 5.69-5.58 (m, 1 H), 5.44-5.42 (m, 1 H), 5.05 (s,
1 H), 4.04 (dd, J = 11.6, 7.9 Hz, 1 H), 3.61 (s, 3 H), 3.26 (t, J =
11.5 Hz, 1 H), 2.76-2.70 (m, 1 H), 1.35-1.24 (m, 1 H), 0.86-0.79
(m, 1 H) ; 13C NMR (75 MHz) δ 173.8, 137.6, 137.5, 133.0, 129.2,
129.1, 127.9, 127.6, 127.4, 127.3, 122.9, 71.1, 54.6, 54.3, 52.3, 41.6,
22.9, 22.8.
Typical Procedure for the BCl3-Catalyzed IMDA Cycloaddi-
tion of 13 and 14 (see Table 3). Preparation of 16a and 18a. The
aza-MBH adduct 12a (Ar = phenyl; EWG = CN) was con-
verted into the triene 14a in 98% yield by the same procedure
used for the preparation of 13a from 11a. N-(2-Cyano-1-
phenylallyl)-N-(penta-2,4-dienyl)benzenesulfonamide (14a) was
obtained as a colorless oil: IR (film) 2223, 1346, 1161, 1091 cm-1
;
Experimental Section
1H NMR (400 MHz) δ 7.86-7.82 (m, 2 H), 7.63-7.59 (m, 1 H),
7.54-7.50 (m, 2 H), 7.36-7.28 (m, 3 H), 7.14-7.11 (m, 2 H), 6.23
(d, J= 1.6 Hz, 1 H), 6.10-6.00 (m, 2 H), 5.86 (s, 1 H), 5.82 (dd, J=
15.2, 10.4 Hz, 1 H), 5.16-5.03 (m, 3 H), 3.87 (d, J = 6.8 Hz, 2 H);
13C NMR (100 MHz) δ 140.3, 135.7, 134.4, 134.1, 133.9, 133.0,
129.2, 129.1, 129.0, 128.9, 128.4, 127.5, 122.1, 118.2, 117.4, 63.4,
47.5; mass spectrum (m/z, %) 364 (17, Mþ), 118 (100), 91(44);
HRMS calcd for C21H20N2O2S: 364.1245; found: 364.1233.
Boron trichloride (0.064 mL of a 1.0 M solution in dichloro-
methane, 0.064 mmol) was added dropwise to a stirred
solution of 14a (23.2 mg, 0.0636 mmol) in 1,2-dichloroethane
(1 mL) under nitrogen at 0 °C. This was slowly warmed to
room temperature and stirred for 14 h. The reaction was
poured into water and extracted with dichloromethane. The
combined organic fractions were dried and concentrated in
vacuo. The crude product was chromatographed over silica
gel (toluene/ethyl acetate, 16:1) to afford 22.7 mg (98%) of a
90:10 mixture of diastereomers of N-benzenesulfonyl-3-
phenyl-3a-cyano-1,2,3,4,5,7a-hexahydroisoindole (16a and
18a). Further chromatography produced 16a as a colorless
NMR spectra were recorded in deuteriochloroform and mass
spectra were obtained by electron impact, unless otherwise
indicated. Chromatography refers to flash chromatography on
silica gel (230-400 mesh). Compounds 37,8 were prepared as
described previously, while 11 and 12 were prepared by the same
general procedure18 as reported for the corresponding N-p-
toluenesulfonyl derivatives. Compounds 13, 14 and 23 could
not be completely purified by rapid flash chromatography,
while further attempts at chromatographic separation, particu-
larly with 23, resulted in gradual decomposition. Products 23
were therefore typically used in subsequent steps in crude form.
Typical Procedure for the Alkylation and Uncatalyzed IMDA
Cycloaddition of 11 and 12 (see Table 1). Preparation of 13a, 15a,
and 17a. The aza-MBH adduct 11a18a(Ar = phenyl; EWG =
CO2Me) (132 mg, 0.398 mmol), 1-bromo-2,4-pentadiene19 (63.9mg,
0.438 mmol), and potassium carbonate (82.4 mg, 0.597 mmol)
were stirred in DMF (3 mL) at room temperature for 3 h. The
reaction was poured into water and extracted with ethyl acetate.
The combined organic fractions were washed with brine, dried,
and concentrated under reduced pressure. The product was
chromatographed over silica gel (toluene/ethyl acetate, 16:1) to
afford 154 mg (98%) of methyl 3-[(N-benzenesulfonyl-N-penta-
2,4-dienyl)amino]-2-methylene-3phenylpropanoate (13a) as
oil: IR (film) 2243, 1348, 1167 cm-1 1H NMR (300 MHz)
;
major isomer 16a: δ 7.89 (d, J = 7.2 Hz, 2 H), 7.68-7.49 (m,
3 H), 7.37-7.22 (m, 5 H), 5.64 (s, 2 H), 5.10 (s, 1 H), 4.04 (dd,
J = 8.2, 7.5 Hz, 1 H), 3.19 (dd, J = 12.3, 8.5 Hz, 1 H),
2.88-2.78 (m, 1 H), 2.37-2.24 (m, 1 H), 2.15-2.02 (m, 1 H),
1.85 (dd, J = 13.2, 6.9 Hz, 1 H), 0.83 (ddd, J = 13.1, 11.1,
7.1 Hz, 1 H); 13C NMR (75 MHz) δ 136.6, 136.6, 133.3, 129.3,
129.2, 128.6, 128.5, 127.6, 127.0, 121.5, 120.1, 68.9, 50.0,
48.6, 40.3, 27.4, 23.6; mass spectrum (m/z, %) 364 (1, Mþ),
118 (100), 91 (32); HRMS: calcd for C21H20N2O2S, calcd
364.1245, found 364.1228.
a colorless oil: IR (film) 1725, 1340, 1161 cm-1 1H NMR
;
(400 MHz) δ 7.83-7.81 (m, 2 H), 7.60-7.55 (m, 1 H), 7.50-7.46
(m, 2 H), 7.25-7.23 (m, 2 H), 7.05-7.01 (m, 2 H), 6.46 (d, J =
0.9 Hz, 1 H), 6.16 (s, 1 H), 6.04 (dt, J = 16.9, 10.3 Hz, 1 H),
5.81-5.74 (m, 2 H), 5.11-5.00 (m, 3 H), 3.89 (t, J = 6.7 Hz, 2 H),
3.63 (s, 3 H); 13C NMR (101 MHz) δ 166.2, 140.9, 139.4, 136.9,
135.9, 133.9, 132.5, 129.1, 128.8, 128.6, 128.5, 128.2, 128.0, 127.5,
61.9, 52.0, 47.8; mass spectrum (CI, m/z, %) 398 (100, Mþ þ 1),
The minor product 18a could not be obtained completely
free of 16a; the following signals were assigned to 18a: 1H NMR
(300 MHz) δ 5.82-5.78 (m, 1 H), 5.51-5.47 (m, 1 H), 4.68 (s,
1 H), 4.16 (dd, J = 10.8, 7.1, 1 H), 3.55 (t, J = 15.2 Hz, 1 H),
2.56-2.46 (m, 1 H), 1.78-1.67 (m, 1 H), 1.06-1.00 (m, 1 H).
Typical Procedure for the Rearrangement and IMDA Cycload-
dition of 14 (see Table 4). Preparation of 20a. Triene 14a (138 mg,
0.378 mmol) was stirred in DMF (4 mL) with two crystals (ca.
2-3 mg) of DABCO for 3 h. The mixture was then poured into
water and extracted with ethyl acetate. The combined organic
fractions were washed with brine, dried and concentrated to
afford 133 mg (96%) of the rearranged product N-[(Z)-2-cyano-
3-phenyl-allyl]-N-[(E)-penta-2,4-dienyl)]benzenesulfonamide (19a)
256 (100), 91 (53), 77 (64); HRMS calcd for C16H18NO2 (Mþ
SO2Ph): 256.1338, found 256.1337.
-
The above triene 13a was refluxed in anisole (8 mL) for 24 h.
The reaction mixture was concentrated in vacuo and chromato-
graphed over silica gel (toluene/ethyl acetate, 16:1) to afford the
product (138 mg, 89%) as a 65:35 mixture of diastereomers 15a
and 17a. Recrystallization from ethyl acetate provided the pure
major diastereomer of N-benzenesulfonyl-3-phenyl-1,2,3,4,5,7a-
hexahydroisoindole-3a-carboxylic acid methyl ester (15a) as
colorless crystals: mp 176-178 °C; IR (film) 1733, 1357, 1162,
1
1090 cm-1; H NMR (300 MHz) δ 7.78 (d, J = 8.4 Hz, 2 H),
7.56-7.43 (m, 3 H), 7.33-7.24 (m, 5 H), 5.74 (dd, J = 10.0,
1.6 Hz, 1 H), 5.42-5.37 (m, 1 H), 4.95 (s, 1 H), 3.91 (t, J = 7.8 Hz,
1 H), 3.63 (dd, J = 12.2, 7.6 Hz, 1 H), 3.19 (s, 3 H), 2.89-2.88
(m, 1 H) 1.98-1.86 (m, 3 H), 0.74-0.69 (m, 1 H); 13C NMR
(100 MHz) δ 173.1, 138.4, 138.1, 132.4, 128.9, 128.2, 127.8, 127.5,
126.8, 126.5, 123.8, 68.8, 56.9, 51.7, 50.3, 40.1, 29.1, 23.8; mass
spectrum (m/z, %) 397 (<1, Mþ), 256 (100), 118 (42), 91 (33);
HRMS calcd for C22H23NO4S: 397.1348, found 397.1340. Anal.
Calcd for C22H23NO4S: C, 66.48; H, 5.83; N, 3.52; found C,
66.32; H, 5.75; N, 3.47.
1
as a colorless oil; IR (film) 2214, 1348, 1167 cm-1; H NMR
(400 MHz) δ 7.91-7.87 (m, 2 H), 7.72 (d, J = 2.2 Hz, 1 H), 7.70
(d, J = 3.4 Hz, 1 H), 7.63-7.59 (m, 1 H), 7.55-7.51 (m, 2 H),
7.46-7.42 (m, 3 H), 7.13 (s, 1 H), 6.33-6.14 (m, 2 H), 5.54 (dt,
J = 15.1, 6.9 Hz, 1 H), 5.23 (d, J = 16.1 Hz, 1 H), 5.15 (d, J =
9.3 Hz, 1 H), 4.16 (s, 2 H), 4.02 (d, J = 7.0 Hz, 2 H); 13C NMR
(100 MHz) δ 146.4, 139.9, 136.1, 135.5, 133.0, 132.7, 130.9,
129.2, 129.0, 128.9, 127.4, 126.7, 126.1, 118.9, 106.2, 50.2, 49.9;
mass spectrum (m/z, %) 364 (4, Mþ), 142 (65), 118 (100), 91
(57), 77 (78); HRMS calcd for C21H20N2O2S: 364.1245; found
364.1228.
The minor diastereomer 17a could not be obtained completely
free of 15a; the following signals were assigned to 17a: 1H NMR
3758 J. Org. Chem. Vol. 75, No. 11, 2010

Clary et al.
JOCArticle
The above rearranged product 19a wasrefluxedinanisole(6mL)
for 2 d, the reaction mixture was concentrated in vacuo and
chromatographed on silica gel (toluene/ethyl acetate, 16:1) to afford
81.2 mg (59% overall yield from 14a) of N-benzenesulfonyl-4-
phenyl-1,2,3,4,5,7a-hexahydro-isoindole-3a-carbonitrile (20a) as
colorless needles: mp 192-195 °C (from ethyl acetate); IR (film)
Typical Procedure for the IMDA Cycloaddition of Dienynes 23
in the Presence of Air (Table 6). Preparation of 25a, 26a, and 27a.
Dienyne 23a (338 mg, 0.931 mmol) was refluxed in anisole for
17 h. The reaction mixture was then concentrated to afford a
crude mixture of 25a, 26a, and 27a in the ratio of 2:1:0.9
(NMR integration). This was chromatographed over silica
gel (toluene/ethyl acetate, 16:1) to afford 125 mg (37%) of 25a
and 128 mg of a mixture of 26a and 27a. Products 25a and 27a
were identical to pure samples prepared by the procedures
described below. The minor isomer 26a could not be isolated
free from 27a, but the following signals from the mixture were
assigned to 26a: 1H NMR (300 MHz) δ 6.63 (d, J = 1.8 Hz,
1 H), 5.77 (d, J = 2.0 Hz, 1 H), 4.17 (d, J = 13.8 Hz, 1 H), 4.00
(t, J = 8.5 Hz, 1 H), 4.08 (t, J = 5.7 Hz, 1 H), 3.41-3.33 (m,
1 H), 2.81 (dd, J = 11.1, 9.0 Hz, 1 H).
Typical Procedure for the Lewis Acid Catalyzed IMDA Cyclo-
addition of Dienynes 23 (Table 6). Preparation of N-Benzenesulfo-
nyl-5-cyano-6-phenyl-2,3,3a,6-tetrahydro-1H-isoindole-5-carboni-
trile (25a). Methylaluminum dichloride (0.059 mL, 0.059 mmol,
1 M solution in hexanes) was added to a stirred solution of
23a (21.3 mg, 0.059 mmol) in 1,2-dichloroethane (1.5 mL)
under nitrogen, and the solution was refluxed for 14 h. The
reaction was then poured into water and extracted with
dichloromethane. The combined organic layers were washed
with brine, dried, and concentrated in vacuo. The crude
product was chromatographed over silica gel (toluene/ethyl
acetate, 16:1) to afford 19.8 mg (93%) of 25a as colorless
crystals: mp 166-168 °C (from ethyl acetate); IR (film) 2224,
1352, 1167, 1090 cm-1; 1H NMR (400 MHz) δ 7.88-7.87 (m,
1 H), 7.87-7.86 (m, 1 H), 7.69-7.65 (m, 1 H), 7.61-7.57 (m,
2 H), 7.36-7.30 (m, 3 H), 7.02 (dd, J = 7.7, 1.7 Hz, 2 H), 6.63
(t, J = 2.6 Hz, 1 H), 5.54 (s, 1 H), 4.13-4.08 (m, 1 H), 4.06-
3.99 (m, 2 H), 3.87 (dd, J = 13.5, 1.3 Hz, 1 H), 3.29-3.19 (m,
1 H), 2.88 (dd, J = 11.2, 9.2 Hz, 1 H); 13C NMR (100 MHz)
δ 140.0, 138.2, 136.7, 133.1, 132.6, 129.3, 129.1, 128.3, 128.0,
127.5, 120.6, 117.8, 117.4, 51.6, 50.4, 43.9, 38.6; mass spec-
trum (m/z, %) 362 (<1, Mþ), 77 (100); HRMS calcd for
C21H18N2O2S: 362.1089, found 362.1089. Anal. Calcd for
1
2238, 1352, 1176 cm-1; H NMR (400 MHz) δ 7.83-7.81 (m,
2 H), 7.69 (ddd, J = 8.8, 2.6, 1.3 Hz, 1 H), 7.63-7.57 (m, 2 H),
7.37-7.32 (m, 3 H), 7.24-7.19 (m, 2 H), 6.03 (ddt, J = 10.1, 5.6,
1.7 Hz, 1 H), 5.73-5.66 (m, 1 H), 3.73 (t, J = 9.3 Hz, 1 H), 3.52 (d,
J = 10.4, 1 H), 3.32-3.20 (m, 2 H), 3.11-3.05 (m, 1 H),
2.83-2.65 (m, 2 H), 2.36 (dt, J = 17.8, 4.3 Hz, 1 H); 13C NMR
(100 MHz) δ 138.3, 136.4, 133.3, 129.6, 129.4, 128.9, 128.7,
128.2, 127.5, 122.2, 119.8, 53.5, 51.8, 45.0, 44.4, 40.9, 29.5; mass
spectrum (m/z, %) 364 (22, Mþ), 223 (100); HRMS calcd for
C21H20N2O2S: 364.1245; found 364.1234. Anal. Calcd for
C21H20N2O2S: C, 69.20; H, 5.53; N, 7.69. Found: C, 68.80; H,
5.55; N, 7.47.
Typical Procedure for the DABCO-Catalyzed Rearrangement
of 22 (Method A in Table 5). Preparation of N-[(2E,4Z)-4-cyano-5-
phenyl-penta-2,4-dienyl]-N-(2-propynyl)benzenesulfonamide (23a).
Dienyne 22a was prepared from 21a and propargyl bromide
as described previously.8
Dienyne 22a (121 mg, 0.335 mmol) was stirred in DMF (3 mL)
at room temperature with 2-3 mg of DABCO for 6 h. The
product was poured into water and extracted with ethyl acetate.
The combined organic fractions were washed with brine, dried,
and concentrated under reduced pressure to afford 105 mg (87%)
of the rearranged product 23a as a colorless oil: IR (film) 3294,
2217, 2121, 1349, 1168, 1096 cm-1; 1H NMR (400 MHz) (major
2E,4Z isomer) δ 7.89-7.85 (m, 4 H), 7.79-7.78 (m, 1 H),
7.62-7.49 (m, 3 H), 7.44-7.41 (m, 2 H), 7.05 (s, 1 H), 6.41 (d,
J = 15.4 Hz, 1 H), 6.12 (dt, J = 15.4, 6.2, Hz, 1 H), 4.19 (d, J =
2.4 Hz, 2 H), 4.04 (d, J = 6.1 Hz, 2 H), 2.15 (t, J = 2.3 Hz, 1 H);
13C NMR (100 MHz) (major 2E,4Z isomer) δ 144.5, 138.8, 133.3,
133.0, 131.3, 130.8, 129.2, 129.1, 129.0, 128.1, 127.7, 116.1, 109.7,
76.2, 74.3, 47.7, 36.5; mass spectrum (m/z, %) 362 (8, Mþ), 141
(39), 125(63), 77(100); HRMScalcd for C21H18N2O2S:362.1089,
found 362.1073.
C
21H18N2O2S: C, 69.59; H, 5.01; N, 7.73. Found: C, 69.36; H,
Typical Procedure for the Reaction of 21 with N-(Propargyl)-
benzenesulfonamide (Method B in Table 5). Preparation of 23a.
A solution of 21a (55.6 mg, 0.172 mmol), N-(propargyl)benzene-
sulfonamide (36.9 mg, 0.189 mmol), and potassium carbonate
(28.2 mg, 0.204 mmol) in DMF (1.5 mL) was stirred at room
temperature for 6 h. The reaction mixture was poured into
water, extracted with ethyl acetate, dried, and concentrated
under reduced pressure. The product was chromatographed on
silica gel (toluene/ethyl acetate, 16:1) to afford 60.0 mg (96%)
of 23a with the same properties as the product obtained via
method A.
Typical Procedure for the Further Reaction of 21 to 24
(Method C in Table 5). Preparation of N-[(1E)-4-Cyano-5-
phenyl-penta-1,3-dienyl]-N-(2-propynyl)benzenesulfonamide (24a).
The above experiment was repeated with compound 21a (168
mg, 0.519 mmol), N-(propargyl)benzenesulfonamide (111 mg,
0.569 mmol), and potassium carbonate (143 mg, 1.04 mmol) in
DMF (3 mL) at room temperature for 4 d. The product was
isolated as in the preceding procedure to afford 127 mg (68%)
of 24a as a colorless oil: IR (film) 3289, 2203, 2127, 1366, 1280,
1164, 1087 cm-1; 1H NMR (400 MHz) δ 7.86-7.82 (m, 2 H),
7.67-7.61 (m, 1 H), 7.57-7.51 (m, 2 H), 7.38-7.32 (m, 2 H),
7.31-7.21 (m, 4 H), 6.59 (d, J = 11.1 Hz, 1 H), 6.06 (dd, J =
13.8, 11.1 Hz, 1 H), 4.37 (d, J = 2.5 Hz, 2 H), 3.58 (s, 2 H), 2.06
(t, J = 2.4 Hz, 1 H); 13C NMR (75 MHz) δ 142.9, 138.1, 136.8,
134.4, 133.8, 129.4, 128.9, 127.4, 127.2, 118.1, 109.3, 107.9,
74.8, 74.6, 40.1, 35.4; mass spectrum (m/z, %) 362 (<1, Mþ),
77 (100); HRMS calcd for C21H18N2O2S: 362.1089, found
362.1106.
4.78; N, 7.64. See Supporting Information for the X-ray
structure of 25a.
Typical One-Pot Procedure for the IMDA Cycloaddition and
Aromatization of Dienynes 23 in the Presence of DDQ (Table 6).
Preparation of N-Benzenesulfonyl-5-cyano-6-phenyl-2,3-dihydro-
1H-isoindole (27a). Dienyne 23a (48.7 mg, 0.133 mmol) and DDQ
(30.1 mg, 0.133 mmol) were refluxed in anisole for 20 h. The
reaction was concentrated in vacuo and chromatographed over
silica gel (toluene/ethyl acetate, 16:1), affording 43.9 mg (91%) of
27a: white solid; mp 164-166 °C (from ethyl acetate); IR (film)
2219, 1348, 1167, 1095 cm-1; 1H NMR (400 MHz) δ 7.93-7.91
(m, 2 H), 7.64-7.56 (m, 4 H), 7.49-7.46 (m, 5 H), 7.32 (s, 1 H),
4.73 (broad s, 2 H), 4,71 (broad s, 2 H); 13C NMR (100 MHz) δ
145.7, 141.7, 137.5, 136.5, 135.8, 133.2, 129.4, 129.0, 128.8, 128.7,
127.8, 127.5, 124.5, 118.2, 111.1, 53.6, 53.0; mass spectrum (CI,
m/z, %) 378 (100, Mþ þ NH4); HRMS calcd for C21H16N2O2S:
360.0932, found 360.0916.
Typical Procedure for the Friedel-Crafts Reactions of aza-
MBH Adducts (Table 7). Preparation of 1,5-Diphenylpenta-1,3-
diene-2-nitrile (28). A solution of 21a (79.4 mg, 0.245 mmol)
and aluminum trichloride (36.0 mg, 0.271 mmol) in benzene
(2 mL) was refluxed for 1 h. The reaction was cooled to room
temperature, poured into water, and extracted with ethyl acetate.
The combined organic layers were washed with brine, dried, and
concentrated in vacuo. The crude product was chromato-
graphed over silica gel (hexanes/ethyl acetate, 8:1) to afford
33.9 mg (56%) of the product 28 as a colorless oil: IR (film) 2214,
1500, 1448 cm-1; 1H NMR (400 MHz) δ 7.78 (d, J = 6.6 Hz,
2 H), 7.49-7.32 (m, 5 H), 7.31-7.16 (m, 3 H), 6.96 (s, 1 H), 6.48
J. Org. Chem. Vol. 75, No. 11, 2010 3759

Clary et al.
JOCArticle
(dt, J = 15.4, 6.7 Hz, 1 H), 6.17 (d, J = 15.5 Hz, 1 H), 3.57 (d,
J = 6.6 Hz, 2 H); 13C NMR (75 MHz) δ 142.4, 138.9, 135.0,
133.7, 130.2, 129.0, 128.9, 128.8, 128.7, 128.4, 126.6, 116.6,
110.9, 38.8; mass spectrum (m/z, %) 245 (85, Mþ), 244 (100),
154 (70); HRMS calcd for C18H15N: 245.1204, found 245.1202.
financial support. KNC thanks NSERC and Alberta In-
genuity for postgraduate scholarships.
Supporting Information Available: Characterization data and
1H and 13C NMR spectra of new compounds; X-ray crystallo-
graphic data for compounds 15b, 16c, 17c, 20g, and 25a including
CIF files. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
3760 J. Org. Chem. Vol. 75, No. 11, 2010