Synthesis of isoindolo[2,1-α]indoles by the palladium-catalyzed annulation of internal acetylenes

Article abstract of DOI:10.1021/jo000997o

A wide variety of substituted isoindolo[2,1-α]indoles have been prepared via annulation of internal alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This methodology provides an extremely efficient route for the synth

Full text of DOI:10.1021/jo000997o

412
J . Org. Chem. 2001, 66, 412-420
Syn th esis of Isoin d olo[2,1-a ]in d oles by th e P a lla d iu m -Ca ta lyzed
An n u la tion of In ter n a l Acetylen es
Kevin R. Roesch and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastat.edu
Received J uly 3, 2000
A wide variety of substituted isoindolo[2,1-a]indoles have been prepared via annulation of internal
alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This
methodology provides an extremely efficient route for the synthesis of these tetracyclic heterocycles
from readily available starting materials. The mechanism of this interesting annulation process
appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) addition
of the resulting vinylic palladium intermediate to the C-N double bond of the imine, (4) either
electrophilic palladation of the resulting σ-palladium intermediate onto the adjacent aromatic ring
derived from the internal alkyne or oxidative addition of the neighboring aryl carbon-hydrogen
bond, and (5) reduction of the tetracyclic product and Pd(0). A variety of internal acetylenes have
been employed in this annulation process in which the aromatic ring of the alkyne contains either
a phenyl or a heterocyclic ring.
In tr od u ction
functionalized indoles that have been synthesized by
employing classical synthetic organic,11 photochemical,12
radical,13,14 and palladium-mediated14,15 methodologies.
The classical synthetic, photochemical, and radical meth-
ods that have been reported all afford relatively low
yields of the tetracyclic products and have yet to be
employed on targets bearing much functionality. Efficient
palladium-catalyzed cyclization methodology has been
reported for the synthesis of these heterocycles. However,
no reports of highly functionalized products, or indoles
containing functional groups other than a carbonyl group
at C-6 of the isoindolo[2,1-a]indole structure, have ap-
peared.
Due to our continuing interest in the palladium-
catalyzed annulation of internal alkynes, we have inves-
tigated the reaction of internal alkynes and imines
derived from o-iodoanilines and aldehydes and have
previously communicated that excellent yields of highly
functionalized isoindolo[2,1-a ]indoles can be synthesized
by employing this methodology.16 Herein, we report the
full details of this new isoindolo[2,1-a]indole synthesis.
The development of efficient and selective synthetic
transformations is a major challenge in organic synthesis.
Consequently, tandem (domino) processes have been
extensively investigated as they are among the most
versatile reactions for the efficient, stereocontrolled
synthesis of complex organic molecules.1 It is not surpris-
ing, therefore, that transition-metal-catalyzed alkyne
annulation processes have received considerable atten-
tion for the synthesis of a variety of complex carbo- and
heterocycles due to the synthetic efficiency of this meth-
odology.2 For example, the palladium-catalyzed annula-
tion of internal alkynes has been employed by us for the
synthesis of indoles,3 benzofurans,4 benzopyrans,4 iso-
coumarins,4,5 indenones,6 isoquinolines,7 R-pyrones,5,8 and
polycyclic aromatic hydrocarbons.9
Considerable attention has been directed toward the
synthesis of compounds containing the indole nucleus, a
structural subunit of a wide variety of biologically active
natural products.10 However, the synthesis of function-
alized indoles still presents a major challenge in organic
synthesis. Isoindolo[2,1-a]indoles are a class of these
(10) (a) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1989, 27, 1113.
(b) Saxton, J . E. Nat. Prod. Rep. 1996, 13, 327. (c) Ihara, M.; Fukumoto,
K. Nat. Prod. Rep. 1997, 14, 413.
(11) (a) Scartoni, V.; Morelli, I.; Marsili, A.; Catalano, S. J . Chem.
Soc., Perkin Trans. 1 1977, 2332. (b) Scartoni, V.; Tognetti, T. J .
Heterocycl. Chem. 1984, 21, 1499. (c) Hooper, M.; Imam, S. H. J . Chem.
Soc., Perkin Trans. 1 1995, 1583. (d) Xiong, Y.; Moore, H. W. J . Org.
Chem. 1996, 61, 9168.
(12) (a) Kanaoka, Y.; Koyama, K. Tetrahedron Lett. 1972, 4517. (b)
Kanaoka, Y.; Nagasawa, C. Heterocycles 1975, 3, 553. (c) Terashima,
M.; Koyama, K.; Kanoka, Y. Chem. Pharm. Bull. 1978, 26, 630. (d)
Kanaoka, Y.; Koyama, K.; Hatanaka, Y. J . Photochem. 1985, 28, 575.
(e) Carruthers, W.; Evans, N. J . Chem. Soc., Perkin Trans. 1 1974,
1523.
* To whom correspondence should be addressed.
(1) (a) Posner, G. H. Chem. Rev. 1986, 86, 831. (b) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (c) Tietze, L.
F. Chem. Rev. 1996, 96, 115. (d) Denmark, S. E.; Thorarensen, A.
Chem. Rev. 1996, 96, 137. (e) Winkler, J . D. Chem. Rev. 1996, 96, 167.
(2) (a) Schore, N. E. Chem. Rev. 1988, 88, 1081. (b) Pfeffer, M. Recl.
Trav. Chim. Pays-Bas 1990, 109, 567. (c) Negishi, E.; Cope´ret, C.; Ma,
S.; Liou, S.; Liu, F. Chem. Rev. 1996, 96, 365. (d) Ojima, I.; Tzamari-
oudaki, M.; Li, Z.; Donovan, R. J . Chem. Rev. 1996, 96, 635.
(3) (a) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J . Org. Chem. 1998, 63,
7652.
(4) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org.
Chem. 1995, 60, 3270.
(5) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.
(6) Larock, R. C.; Doty, M. J .; Cacchi, S. J . J . Org. Chem. 1993, 58,
4579.
(7) Roesch, K. R., Larock, R. C. J . Org. Chem. 1998, 63, 5306.
(8) Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron Lett. 1998, 39,
5713.
(9) (a) Larock, R. C.; Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org.
Chem. 1997, 62, (b) Larock, R. C.; Tian, Q. J . Org. Chem. 1998, 63,
2002.
(13) Caddick, S.; Aboutayab, K.; J enkins, K.; West, R. I. J . Chem.
Soc., Perkin Trans. 1 1996, 675.
(14) Kraus, G. A.; Kim, H. Synth. Commun. 1993, 23, 55.
(15) (a) Itahara, T. Synthesis 1978, 607. (b) Itahara, T. Synthesis
1979, 151. (c) Itahara, T. Chem. Lett. 1982, 1151. (d) Itahara, T.; Ikeda,
M.; Sakakibara, T. J . Chem. Soc., Perkin Trans. 1 1983, 1361. (e)
Itahara, T. Heterocycles 1986, 2557. (f) Grigg, R.; Sridharan, V.;
Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tetrahedron 1990, 46,
4003. (g) Kozikowski, A. P.; Ma, D. Tetrahedron Lett. 1991, 32, 3317.
(h) Desarbre, E.; Merour, J . Heterocycles 1995, 1987.
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10.1021/jo000997o CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/30/2000

Synthesis of Isoindolo[2,1-a]indoles
J . Org. Chem., Vol. 66, No. 2, 2001 413
Ta ble 1. Syn th esis of In d ole 4 by th e P d -Ca ta lyzed
An n u la tion of In ter n a l Acetylen es (Eq 3)a
Resu lts a n d Discu ssion
The palladium-catalyzed reaction of imine 1 and
diphenylacetylene was chosen as the model system for
our initial investigation of this annulation process. We
anticipated that imine 1 might undergo a reaction with
an internal alkyne in the presence of a palladium catalyst
to produce the highly substituted quinoline derivative 2
(eq 1). However, when reaction conditions were employed
that have been used in much of our previous alkyne
annulation chemistry (1 equiv of the aryl imine, 2.0 equiv
of the acetylene, 5 mol % Pd(OAc)2, 1 equiv of Na2CO3,
and 1 equiv of LiCl in DMF at 100 °C),3-9 none of the
anticipated quinoline derivative was observed. Instead,
indole 3 was isolated in 85% yield after an 8 h reaction
time (eq 2). This surprising result encouraged us to
examine the scope and limitations of this intriguing new
indole synthesis.
chloride
source
time
(h)
isolated
yield (%)
entry
base (equiv)
1
2
3
4
5
6
7
8
Na2CO3 (1)
Na2CO3 (1)
Na2CO3 (2)
i-Pr2NEt (1)
i-Pr2NEt (2)
i-Pr2NEt (3)
i-Pr2NEt (2)
i-Pr2NEt (2)
LiCl
72
72
72
72
36
36
36
36
0
65
68
63
75
75
77b
81c
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
a
All reactions were run with 0.5 mmol of the imine, 2.0 mmol
of 1-phenyl-1-butyne, and 1 equiv of the chloride source in 10 mL
b
of DMF at 100 °C unless otherwise noted. 1.2 equiv of 1-phenyl-
1-butyne was used. c 1.2 equiv of 1-phenyl-1-butyne and 5 mL of
DMF were used.
Ta ble 2. Syn th esis of In d ole 3 by th e P d -Ca ta lyzed
An n u la tion of Dip h en yla cetylen ea
chloride
source
time
(h)
isolated
yield (%)
entry
base (equiv)
1
2
3
4
Na2CO3 (1)
i-Pr2NEt (2)
i-Pr2NEt (2)
i-Pr2NEt (2)
LiCl
8
12
12
10
85
n-Bu4NCl
n-Bu4NCl
n-Bu4NCl
84
94b
85c
a
All reactions were run with 0.5 mmol of the imine, 2.0 equiv
of diphenylacetylene, and 1 equiv of the chloride source in 10 mL
b
of DMF at 100 °C unless otherwise noted. 1.2 equiv of diphen-
ylacetylene was used. c 1.2 equiv of diphenylacetylene and 5 mL
of DMF were used.
the concentration of the reaction mixture, the desired
product was obtained in 81% yield (entry 8).
Since the reaction of imine 1 and diphenylacetylene
proceeded in high yield with a short reaction time under
the reaction conditions that were initially employed, we
proceeded to investigate the annulation of 1 with alkynes
of differing functionality to expand the scope of this indole
synthesis. Many of the alkynes that were employed,
however, failed to give yields as good as the reactions
that were run with diphenylacetylene. For example, the
reaction of imine 1 and 1-phenyl-1-butyne under the
reaction conditions that were developed for the diphen-
ylacetylene annulation afforded none of the desired indole
4 (eq 3). Therefore, several optimization reactions were
run to improve this reaction (Table 1).
As a consequence of the results reported in Table 1,
the reaction of imine 1 and diphenylacetylene was
reinvestigated (Table 2). By employing i-Pr2NEt as the
base, the desired indole was obtained in an 84% yield
(entry 2). However, as in the reaction with 1-phenyl-1-
butyne, reducing the amount of alkyne to 1.2 equiv
increased the yield to 94% (entry 3). Upon reducing the
amount of alkyne and solvent as in Table 1, entry 8, the
yield was reduced to 85%.
The results of these optimization studies led to the use
of three general reaction procedures for the synthesis of
the indoles. Procedure A: 0.5 mmol of the aryl imine,
2.0 equiv of the acetylene, 5 mol % Pd(OAc)2, 1 equiv of
Na2CO3, and 1 equiv of LiCl in 10 mL of DMF at 100 °C.
Procedure B: 0.5 mmol of the aryl imine, 1.2 equiv of
the acetylene, 5 mol % Pd(OAc)2, 2 equiv of i-Pr2NEt, and
1 equiv of n-Bu4NCl in 5 mL of DMF at 100 °C. Procedure
C: 0.5 mmol of the aryl imine, 1.2 equiv of the acetylene,
5 mol % Pd(OAc)2, 2 equiv of i-Pr2NEt, and 1 equiv of
n-Bu4NCl in 10 mL of DMF at 100 °C. The procedure
used for these reactions is dependent upon the alkyne
that is employed, as one procedure may not give any of
the desired indole. In general, alkyl-substituted acety-
lenes afford better yields when procedure B is employed
and diaryl acetylenes afford better yields when procedure
C is employed. The other substituted alkynes (ester,
hydroxyl) usually afford better yields when procedure A
is employed. The indoles that have been synthesized
using these procedures are shown in Table 3.
By employing n-Bu4NCl as the chloride source, instead
of LiCl, indole 4 was obtained in 65% yield after a 72 h
reaction time (entry 1). Upon increasing the amount of
Na2CO3 to 2 equiv, virtually no increase in yield or
decrease in the reaction time was observed (entry 3).
Also, no increase in yield was observed by employing
i-Pr2NEt as the base (entry 4). However, by increasing
the amount of i-Pr2NEt to 2 equiv with 1 equiv of n-Bu4-
NCl, the yield increased to 75% and the reaction time
decreased significantly (entry 5). The yield was not
increased, however, by employing 3 equiv of i-Pr2NEt
(entry 6). By reducing the amount of the alkyne to 1.2
equiv, indole 4 was isolated in 77% yield (entry 7).
Finally, by reducing the amount of alkyne and increasing
The reaction of imine 1 with a variety of functionalized
alkynes has afforded the desired indoles in good to
excellent yields. For example, the reaction with diphen-
ylacetylene gave indole 3 in 94% yield by employing
procedure C (entry 3). Also, the reaction of 1 with alkyl-

414 J . Org. Chem., Vol. 66, No. 2, 2001
Roesch and Larock
Ta ble 3. Syn th esis of Isoin d olo[2,1-a ]in d oles by th e P d -Ca ta lyzed An n u la tion of In ter n a l Alk yn esa

Synthesis of Isoindolo[2,1-a]indoles
J . Org. Chem., Vol. 66, No. 2, 2001 415
Ta ble 3. (Con tin u ed )
a
See the text for procedures A-C.
substituted alkynes afforded the desired heterocycles in
excellent yields by employing procedure B (entries 5 and
7). The annulation with ethyl phenylpropiolate afforded
6 in 80% yield using procedure A (entry 8).
The reaction of 3-phenyl-2-propyn-1-ol gave indole 7
in only 51% yield (entry 9). The low yield associated with
this alkyne can possibly be explained by a directive effect
of the hydroxyl substituent on the alkyne, which has been

416 J . Org. Chem., Vol. 66, No. 2, 2001
Roesch and Larock
observed previously in analogous indole chemistry3 and
the palladium-catalyzed hydroarylation of propargylic
alcohols.17 This effect appears to direct alkyne insertion
so that the palladium adds to the least hindered end of
the alkyne (eq 4). Consequently, the tetracyclic product
cannot be formed from this vinylpalladium intermediate,
which would be expected to undergo unknown side
reactions, although no other products were isolated from
this reaction (see the latter mechanistic discussion).
Sch em e 1
In an attempt to avoid the directive effect of the
propargylic alcohol, 1-phenyl-3-methoxy-1-propyne was
subsequently employed in the annulation with imine 1.
However, it appears that the effect of the methyl ether
is still significant, as only a low yield of indole 8 was
observed (46%, entry 10). 6-Phenyl-5-hexyn-1-ol, which
has an additional three-carbon spacer between the triple
bond and the free hydroxyl substituent, was also em-
ployed in the reaction with imine 1. A significant increase
in yield was observed from this alkyne annulation (72%,
entry 11) when compared to that of the propargylic
alcohol or its methyl ether, although some effect of the
heteroatom may still be operating, since the yield was
lower than in the annulation in which 1-phenyl-1-hexyne
was employed (compare entries 7 and 11).
We have also investigated the regiochemistry of ring
closure onto the aryl group of the acetylene (entries 12-
15). This has been done by employing alkynes which bear
substituents meta to the alkynyl substituent. In the case
of the aryl acetylene bearing a methyl group, a single
regioisomer, 10, was obtained in 81% yield (entry 12).
Also, a single regioisomer, 11, was isolated in 78% yield
from the annulation using an aryl acetylene bearing an
electron-donating methoxy group (entry 13). By 1H NMR
spectral analysis, regioisomer 10 was obtained, which has
the methyl substituent in the 9-position of the isoin-
doloindole. However, isoindoloindole 11 has the electron-
donating methoxy substituent in the 7-position. The
excellent regioselectivity of this ring closure and the
reversal of regioselectivity upon switching from the
electron-donating methoxy group to the relatively neutral
methyl group were rather surprising, so we therefore
investigated the use of aryl alkynes bearing electron-
withdrawing substituents.
From these results, it appears that substituents on the
aryl ring of the alkyne are able to control the regioselec-
tivity of ring closure by chelation of the palladium in the
σ-palladium intermediate that is formed during the
reaction (see the latter mechanistic discussion). Thus,
products were isolated in which ring closure had occurred
to place the oxygen-containing alkoxy or ester function-
alities in the 7-position. However, when aryl alkynes were
employed that contained trifluoromethyl or methyl sub-
stituents, products were isolated with these substituents
in the 9-position, presumably due to steric interactions
that inhibit ring closure and thus place these groups in
the 7-position. Thus, it appears that by the appropriate
choice of functionality, it is possible to exclusively prepare
one isoindoloindole isomer.
In addition to the previous examples, ring closure onto
heterocyclic rings has also been investigated. For ex-
ample, 5-pyrimidyl-1-hexyne afforded a 93% yield of the
desired tetracyclic indole in a short reaction time (entry
16). A thienyl-substituted acetylene also undergoes this
annulation process to afford heterocycle 15 in 84% yield
(entry 17).
Finally, the annulation of functionalized imines also
affords the tetracyclic indoles in good yields. For example,
the annulation of imine 16 with diphenylacetylene af-
forded indole 17 in 93% yield (entry 18). This example
not only demonstrates the ease of introduction of ad-
ditional functionality into the tetracyclic structure, but
it also shows the chemoselectivity of the annulation.
Imine 18 bearing an electron-withdrawing methyl ester
has also been employed with diphenylacetylene to afford
indole 19 in good yield (entry 19).
As mentioned previously, the anticipated product from
the annulation of imine 1 and diphenylacetylene was the
highly substituted quinoline derivative 2 (eq 1). To our
surprise, none of this heterocycle was observed and
tetracyclic indole 3 was isolated as the only product in
85% yield. From a mechanistic standpoint, these two
heterocycles can be formed from two different possible
ring closure pathways as illustrated in Scheme 1. Fol-
lowing reduction of Pd(OAc)2 to the actual catalyst Pd-
(0), oxidative addition of the aryl iodide to Pd(0), and
coordination and subsequent insertion of the acetylene,
either a 5-exo or 6-endo addition of the vinylpalladium
intermediate across the adjacent carbon-nitrogen double
bond can occur. The σ-palladium intermediate resulting
from the 5-exo cyclization proceeds to form the observed
When aryl alkynes bearing electron-withdrawing sub-
stituents were employed with imine 1, single regio-
isomers were also obtained. For example, isoindoloindole
12 was obtained in which the trifluoromethyl substituent
appears in the 9-position, as had been observed with the
aryl alkyne bearing a methyl group (entry 14). Surpris-
ingly, an aryl alkyne bearing an electron-withdrawing
ester group reacted in such a manner as to place the ester
functionality in the 7-position, as had been observed with
the aryl alkyne bearing an electron-donating methoxy
group (entry 15).
(17) (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron 1985, 41,
5121. (b) Arcadi, A.; Cacchi, S.; Ianelli, S.; Marinelli, F.; Nardelli, M.
Gazz. Chim. Ital. 1986, 116, 725. (c) Arcadi, A.; Bernocchi, E.; Burini,
A.; Cacchi, S.; Marinelli, F.; Pietroni, B. Tetrahedron 1988, 44, 481.
(d) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1986, 27, 6397.

Synthesis of Isoindolo[2,1-a]indoles
J . Org. Chem., Vol. 66, No. 2, 2001 417
Sch em e 2
tetracyclic products, and the 6-endo pathway might be
expected to form the anticipated quinoline derivative. In
this palladium-catalyzed process, however, the 5-exo
pathway, which forms the tetracyclic products, occurs
exclusively.
Numerous examples have been reported in the litera-
ture in which palladium intermediates can cyclize via exo
or endo pathways in Heck-type reactions. Although the
exo mode cyclizations have generally been observed to
be the dominant ring closure pathway when substrates
are employed that can cyclize via either process, various
examples of the less favored endo mode pathway have
been reported.18 Preliminary data suggest that, by slightly
altering the reaction conditions employed in this annu-
lation process, it is possible to promote the formation of
quinoline derivatives through the 6-exo cyclization path-
way (eq 5).19 However, a significant amount of the
tetracyclic product has also generally been observed.
Work on this process is continuing.
Sch em e 3
On the basis of the previous discussion, we propose a
mechanism for this remarkable isoindoloindole synthesis
involving (1) reduction of Pd(OAc)2 to the actual catalyst
Pd(0), (2) oxidative addition of the aryl iodide to Pd(0),
(3) coordination and subsequent insertion of the acety-
lene, (4) a 5-exo addition of the vinylpalladium interme-
diate across the carbon-nitrogen double bond, (5) either
electrophilic palladation of the σ-palladium intermediate
onto the adjacent aromatic ring (path A) or oxidative
addition of the neighboring aryl carbon-hydrogen bond
of the aromatic ring to the σ-palladium intermediate to
form a Pd(IV) intermediate (path B) and subsequent
elimination of HI by base, and (6) regeneration of the Pd-
(0) catalyst by reductive elimination to form the isoin-
doloindole as shown in Scheme 2. The reduction of the
Pd(II) salt to Pd(0) under the reaction conditions em-
ployed is a well-known process and appears to be the key
step in virtually all of our annulation chemistry, as are
the next two steps, oxidative addition and alkyne inser-
tion. The regiochemistry of alkyne insertion is also
consistent with all of our previous annulation work,
where steric effects dominate and direct the palladium
moiety to the more sterically hindered end of the alkyne.
The addition of the resulting vinylic palladium interme-
diate to the imine double bond is unprecedented. While
most organometallics, including allylic palladium spe-
cies,20 add to imines to form new carbon-carbon bonds,
acylpalladium species have been shown to react with
formation of an amide bond,21 and calculations have been
carried out on the addition of methylpalladium species
to an imine with C-N bond formation.22 The resulting
benzylic palladium compound cannot undergo â-hydride
elimination, but apparently can undergo either electro-
philic substitution on the neighboring arene originating
in the alkyne or perhaps substitution by a process
involving aryl C-H insertion to generate a Pd(IV)
intermediate, which then undergoes reductive elimina-
tion to the final product.
An alternative mechanism for formation of the isoin-
doloindole product might involve substitution of the
palladium moiety in the vinylic palladium intermediate
by the imine functionality to generate an indole iminium
salt, which subsequently undergoes intramolecular elec-
trophilic substitution on the neighboring arene. This
seems less likely on the basis of the unusual substituent
effects reported in entries 12-15 in Table 3. These results
seem more consistent with metal coordination to the
oxygen-containing methoxy and carboalkoxy substitu-
ents.
Likewise, we propose a mechanism for formation of the
quinoline heterocycle involving (1) reduction of Pd(OAc)2
to the actual catalyst Pd(0), (2) oxidative addition of the
aryl iodide to Pd(0), (3) coordination and subsequent
(20) (a) Nakamura, H.; Asao, N.; Yamamoto, Y. J . Chem. Soc., Chem.
Commun. 1995, 1273. (b) Nakamura, H.; Iwama, H.; Yamamoto, Y. J .
Am. Chem. Soc. 1996, 118, 6641. (c) Nakamura, K.; Nakamura, H.;
Yamamoto, Y. J . Org. Chem. 1999, 64, 2614.
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1998, 37, 1251. (b) Dghaym, R. D.; Yaccato, K. J .; Arndtsen, B. A.
Organometallics 1998, 17, 4.
(18) (a) Lemaire-Audoire, S.; Savignac, M.; Dupuis, C.; Geneˆt, J .
Tetrahedron Lett. 1996, 37, 2003 (b) Rigby, J . H.; Hughes, R. C.; Heeg,
M. J . J . Am. Chem. Soc. 1995, 117, 7834. (c) Dankwart, J . W.; Flippin,
L. A. J . Org. Chem. 1995, 60, 2312. (d) Trost, B. M.; Dumas, J .
Tetrahedron Lett. 1993, 34, 19.
(19) Larock, R. C.; Gagnier, S. V. Unpublished results.
(22) Cavallo, L. J . Am. Chem. Soc. 1999, 121, 4238.

418 J . Org. Chem., Vol. 66, No. 2, 2001
Roesch and Larock
1-hexyne (0.99 g, 12.0 mmol) at 90 °C. Column chromatogra-
phy on silica gel using hexanes afforded 1.70 g (99%) of the
desired compound as a yellow oil: 1H NMR (CDCl3) δ 0.96 (t,
J ) 7.2 Hz, 3H), 1.44-1.54 (m, 2H), 1.56-1.65 (m, 2H), 2.32
(s, 3H), 2.42 (t, J ) 6.9 Hz, 2H), 7.08 (d, J ) 7.2 Hz, 1H), 7.15-
7.24 (m, 3H); 13C NMR (CDCl3) δ 13.7, 19.2, 21.3, 22.1, 31.0,
80.7, 90.1, 124.0, 128.2, 128.4, 128.7, 132.3, 137.9.
insertion of the acetylene, (4) a 6-endo addition of the
vinylic palladium intermediate across the carbon-
nitrogen double bond, (5) â-hydride elimination to form
the quinoline, and (6) regeneration of the Pd(0) catalyst
by reductive elimination of HPdI, as shown in Scheme
3.
1-(3-Meth oxyp h en yl)-1-h exyn e. The acetylene was pre-
pared by employing 3-iodoanisole (2.34 g, 10.0 mmol) and
1-hexyne (0.99 g, 12.0 mmol). Column chromatography on
silica gel using 25:1 hexanes/EtOAc afforded 1.88 g (100%) of
the desired compound as a yellow oil with spectral properties
identical to those previously reported.25
Con clu sion
We have developed an efficient, palladium-catalyzed
synthesis of isoindolo[2,1-a]indoles from readily available
starting materials. A wide variety of aryl acetylenes in
which the aromatic ring of the alkyne contains either a
phenyl or a heterocyclic ring undergo this process in
moderate to excellent yields with high regioselectivity.
In addition, preliminary results indicate that the forma-
tion of highly substituted quinoline heterocycles may be
possible by slightly altering the reaction conditions
employed.
1-(3-Tr iflu or om eth ylp h en yl)-1-h exyn e. The acetylene
was prepared by employing 3-iodobenzotrifluoride (2.72 g, 10.0
mmol) and 1-hexyne (0.99 g, 12.0 mmol). Column chromatog-
raphy on silica gel using hexanes afforded 2.26 g (100%) of
the desired compound as a yellow oil: 1H NMR (CDCl3) δ 0.96
(t, J ) 7.2 Hz, 3H), 1.41-1.65 (m, 4H), 2.42 (t, J ) 6.9 Hz,
2H), 7.39 (dd, J ) 7.8, 7.8 Hz, 1H), 7.52 (d, J ) 13.8 Hz, 1H),
7.54 (d, J ) 13.5 Hz, 1H), 7.65 (s, 1H); 13C NMR (CDCl3) δ
1
13.7, 19.1, 22.1, 30.7, 79.3, 92.3, 123.9 (q, J C-F ) 272.6 Hz),
124.1 (q, 3J C-F ) 3.9 Hz), 125.1, 128.4 (q, 4J C-F ) 3.8 Hz), 128.7,
Exp er im en ta l Section
2
130.8 (q, J C-F ) 32.6 Hz), 134.7.
Eth yl 2-(1-h exyn yl)ben zoa te. The acetylene was prepared
by employing ethyl 3-iodobenzoate (2.76 g, 10.0 mmol) and
1-hexyne (0.99 g, 12.0 mmol). Column chromatography on
silica gel using 20:1 hexanes/EtOAc afforded 2.16 g (94%) of
the desired compound as a yellow oil: 1H NMR (CDCl3) δ 0.93
(t, J ) 7.2 Hz, 3H), 1.37 (t, J ) 7.2 Hz, 3H), 1.42-150 (m,
2H), 1.53-1.63 (m, 2H) 2.39 (t, J ) 6.9 Hz, 2H), 4.35 (q, J )
7.2 Hz, 2H), 7.32 (ddd, J ) 0.3, 7.8, 7.8 Hz, 1H), 7.53 (ddd, J
) 1.5, 1.5, 6.3 Hz, 1H), 7.91 (ddd, J ) 1.2, 1.2, 7.8 Hz, 1H),
8.05 (dd, J ) 1.5, 1.5 Hz, 1H); 13C NMR (CDCl3) δ 13.7, 14.4,
19.1, 22.1, 30.8, 61.1, 79.8, 91.5, 124.6, 128.3, 128.5, 130.7,
132.7, 135.7, 166.1.
1-(5-P yr im id yl)-1-h exyn e. The acetylene was prepared by
employing 5-bromopyrimidine (1.59 g, 10 mmol) and 1-hexyne
(0.99 g, 12 mmol). Column chromatography on silica gel using
15:1 hexanes/EtOAc afforded 1.53 g (96%) of the desired
compound as a dark yellow oil with spectral properties
identical to those previously reported.26
1-(2-Th ien yl)-1-h exyn e.27 The acetylene was prepared by
employing 2-iodothiophene (2.10 g, 10 mmol) and 1-hexyne
(0.99 g, 12 mmol). Column chromatography on silica gel using
25:1 hexanes/EtOAc afforded 1.64 g (100%) of the desired
compound as a dark yellow oil: 1H NMR (CDCl3) δ 0.96 (t, J
) 7.2 Hz, 3H), 1.41-1.65 (m, 4H), 2.44 (t, J ) 7.2 Hz, 2H),
6.94 (dd, J ) 3.6, 5.1 Hz, 1H), 7.12 (dd, J ) 1.2, 3.6 Hz, 1H),
7.17 (dd, J ) 1.2, 5.1 Hz, 1H); 13C NMR (CDCl3) δ 13.7, 19.5,
22.1, 30.7, 73.7, 94.6, 124.4, 125.9, 126.8, 130.9.
Im in es P r ep a r ed . Ben zylid en e(2-iod op h en yl)a m in e
(1).28 A mixture of 2-iodoaniline (2.19 g, 10 mmol), benzalde-
hyde (1.06 g, 10 mmol), and p-toluenesulfonic acid monohy-
drate (1 crystal) in benzene (40 mL) was refluxed with the aid
of a Dean-Stark apparatus to remove the water produced. The
reaction was monitored by TLC to establish completion. The
reaction mixture was then cooled to room temperature, and
the solvent was removed under reduced pressure. The oily
residue was dissolved in a minimal amount of 100% ethanol
and cooled. The resulting solid was collected to afford 2.15 g
(70%) of the imine 21 as an off-white solid: mp 56-57 °C; 1H
NMR (CDCl3) δ 6.94 (td, J ) 1.5, 7.8 Hz, 1H), 7.02 (dd, J )
1.5, 8.1 Hz, 1H), 7.38 (td, J ) 1.2, 7.5 Hz, 1H), 7.48-7.55 (m,
3H), 7.93 (dd, J ) 1.2, 7.8 Hz, 1H), 7.99-8.02 (m, 2H), 8.31 (s,
1H); 13C NMR (CDCl3) δ 95.0, 118.6, 127.2, 129.0, 129.3, 129.5,
Gen er a l P r oced u r es. All 1H and 13C NMR spectra were
recorded at 300 and 75.5 MHz, respectively. Thin-layer chro-
matography was performed using commercially prepared 60-
mesh silica gel plates (Whatman K6F), and visualization was
effected with short-wavelength UV light (254 nm) and a basic
KMnO4 solution [3 g of KMnO4 + 20 g of K2CO3 + 5 mL of
NaOH (5%) + 300 mL of H2O]. All melting points are
uncorrected. All reagents were used directly as obtained
commercially unless otherwise noted. Anhydrous forms of Na2-
CO3, LiCl, DMF, ethyl ether, hexanes, and ethyl acetate were
purchased from Fisher Scientific Co. All palladium salts were
donated by J ohnson Matthey Inc. and Kawaken Fine Chemi-
cals Co. Ltd. PPh3 was donated by Kawaken Fine Chemicals
Co. Ltd. Compounds 3-6 and 9-14 have been previously
reported.16 Methyl 3-iodo-4-aminobenzoate was prepared ac-
cording to a previous literature procedure.23 The following
starting materials were prepared as indicated.
Gen er a l P r oced u r e for t h e Syn t h esis of t h e Ar yl
Alk yn es. To a solution of the iodo- or bromoarene (10.0 mmol)
and terminal alkyne (12.0 mmol) in Et3N (40 mL) was added
PdCl2(PPh3)2 (140 mg, 2 mol %). The mixture was then stirred
for 5 min, and CuI (20 mg, 1 mol %) was added. The resulting
mixture was heated under a nitrogen atmosphere at 50 °C.
The reaction was monitored by TLC to establish completion.
The reaction mixture was allowed to cool to room temperature,
and the ammonium salt was removed by filtration. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography on silica gel to afford the
pure alkynes.
Alkyn es P r epar ed. 1-P h en yl-3-m eth oxy-1-pr opyn e. The
acetylene was prepared by employing iodobenzene (2.04 g, 10
mmol) and methyl propargyl ether (0.84 g, 12 mmol). Column
chromatography on silica gel using 20:1 hexanes/EtOAc af-
forded 1.39 g (95%) of the desired compound as a yellow oil
with spectral properties identical to those previously re-
ported.24
6-P h en yl-5-h exyn -1-ol. The acetylene was prepared by
employing iodobenzene (2.04 g, 10 mmol) and 5-hexyn-1-ol
(1.18 g, 12 mmol). Column chromatography on silica gel using
2:1 hexanes/EtOAc afforded 1.70 g (98%) of the desired
compound as a yellow oil: 1H NMR (CDCl3) δ 1.63-1.80 (m,
5H), 2.45 (t, J ) 6.6 Hz, 2H), 3.70 (t, J ) 6.3 Hz, 2H), 7.24-
7.29 (m, 3H), 7.36-7.41 (m, 2H); 13C NMR (CDCl3) δ 19.3, 25.1,
32.0, 62.5, 81.0, 90.0, 124.0, 127.7, 128.3, 131.6.
(25) Chen, Q.; He, Y. Synthesis 1988, 11, 896.
(26) Stu¨demann, T.; Ibrahim-Quali, M.; Knochel, P. Tetrahedron
1998, 54, 1299.
(27) Kooyman, J . G. A.; Hendriks, H. P. G.; Montijn, P. P.;
Brandsma, L.; Arens, J . F. Recl. Trav. Chim. Pays-Bas 1968, 87, 69.
(28) (a) Wheeler, O.; Gore, P. H. J . Org. Chem. 1961, 26, 3298. (b)
Bortolotti, B.; Leardini, R.; Nanni, D.; Zanardi, G. Tetrahedron 1993,
49, 10157.
1-(3-Meth ylp h en yl)-1-h exyn e. The acetylene was pre-
pared by employing 3-bromotoluene (1.71 g, 10.0 mmol) and
(23) Hill, M. L.; Raphael, R. A. Tetrahedron 1990, 46, 4587.
(24) Zhai, D.; Zhai, W.; Williams, R. M. J . Am. Chem. Soc. 1988,
110, 2501.

Synthesis of Isoindolo[2,1-a]indoles
J . Org. Chem., Vol. 66, No. 2, 2001 419
131.9, 135.9, 139.2, 153.1, 161.1; IR (CHCl3, cm-1) 3052, 3001,
1626, 1573; HRMS calcd for C13H10IN 306.9858, found 306.9855.
11-n -Bu tyl-6-p h en ylisoin d olo[2,1-a ]in d ole (5). The reac-
tion was run using procedure B and chromatographed using
25:1 hexanes/EtOAc to afford 137 mg (81%) of the indicated
compound as a white solid: mp 135-136 °C (hexanes/EtOAc);
1H NMR (CDCl3) δ 1.04 (t, J ) 7.5 Hz, 3H), 1.56 (sextet, J )
7.5 Hz, 2H), 1.86 (quintet, J ) 7.5 Hz, 2H), 3.14 (t, J ) 7.5
Hz, 2H), 6.14 (s, 1H), 6.93 (dd, J ) 0.9, 7.5 Hz, 1H), 7.09 (dddd,
J ) 1.2, 7.2, 7.2, 17.7 Hz, 2H), 7.18-7.24 (m, 4H), 7.33-7.44
(m, 4H), 7.71 (dd, J ) 0.6, 8.1 Hz, 1H), 7.81 (d, J ) 7.8 Hz,
1H); 13C NMR (CDCl3) δ 14.3, 22.9, 24.5, 33.5, 64.3, 108.3,
110.0, 119.1, 119.9, 120.9, 121.6, 124.1, 126.8, 127.2, 128.3,
128.4, 129.1, 132.5, 133.1, 133.5, 139.4, 139.5, 147.2; IR
4-Ch lor oben zyliden e(2-iodoph en yl)am in e (16). The imi-
ne was prepared by the same method used for imine 1 by
employing 2-iodoaniline (2.19 g, 10 mmol) and 4-chloroben-
zaldehyde (1.41 g, 10 mmol). Crystallization from 100% ethanol
afforded 2.46 g (72%) of the imine 16 as a yellow solid: mp
1
44-45 °C; H NMR (CDCl3) δ 6.94 (td, J ) 0.9, 5.7 Hz, 1H),
7.00 (dd, J ) 1.2, 6.0 Hz, 1H), 7.37 (td, J ) 0.9, 6.0 Hz, 1H),
7.47 (dt, J ) 1.5, 6.6 Hz, 2H), 7.90-7.93 (m, 3H), 8.26 (s, 1H);
13C NMR (CDCl3) δ 95.0, 118.3, 127.4, 129.2, 129.4, 130.3,
134.3, 137.9, 139.2, 152.7, 159.5; IR (CHCl3, cm-1) 3056, 2997,
(CHCl3, cm-1) 3046, 2922, 1610, 1450; HRMS calcd for C25H23
N
1628, 1569; HRMS calcd for
340.9472.
C13H9ClIN 340.9468, found
337.1831, found 337.1831. Anal. Calcd for C25H23N: C, 88.98;
H, 6.87; N, 4.15. Found: C, 88.72; H, 7.00; N, 4.26.
Meth yl 4-Ben zylid en ea m in o-3-iod oben zoa te (18). The
imine was prepared by the method used for imine 1 by
employing methyl 3-iodo-4-aminobenzoate (4.27 g, 15.4 mmol)
and benzaldehyde (2.45 g, 23.1 mmol). Crystallization from
100% ethanol afforded 1.46 g (40%) of the imine 18 as an off-
white solid: mp 64-65 °C; 1H NMR (CDCl3) δ 3.93 (s, 3H),
7.00 (d, J ) 8.1 Hz, 1H), 7.45-7.57 (m, 3H), 7.98 (dd, J ) 1.5,
6.3 Hz, 2H), 8.04 (dd, J ) 1.5, 8.1 Hz, 1H), 8.30 (s, 1H), 8.5 (d,
J ) 1.2 Hz, 1H); 13C NMR (CDCl3) δ 52.4, 93.6, 118.2, 128.5,
129.0, 129.4, 131.0, 132.3, 135.5, 140.5, 157.2, 162.0, 165.6;
IR (CHCl3, cm-1) 3060, 2949, 1720, 1631, 1585; HRMS calcd
for C15H12INO2 364.9913, found 364.9921.
E t h yl 6-P h en ylisoin d olo[2,1-a ]in d ole-11-ca r b oxyla t e
(6). The reaction was run using procedure A and chromato-
graphed using 7:1 hexanes/EtOAc to afford 141 mg (80%) of
the indicated compound as a white solid: mp 181-182 °C
(hexanes/EtOAc); 1H NMR (CDCl3) δ 1.57 (t, J ) 7.2 Hz, 3H),
4.55 (q, J ) 7.2 Hz, 2H), 6.02 (s, 1H), 6.90 (d, J ) 8.1 Hz, 1H),
7.06-7.13 (m, 3H), 7.24 (dt, J ) 0.9, 14.4 Hz, 2H), 7.30-7.37
(m, 4H), 7.49 (dt, J ) 0.6, 14.7 Hz, 1H), 8.28 (d, J ) 8.1 Hz,
1H), 8.78 (d, J ) 7.5 Hz, 1H); 13C NMR (CDCl3) δ 14.9, 60.0,
64.9, 99.9, 110.4, 122.0, 122.9, 123.4, 125.7, 127.2, 128.8, 129.2,
129.3, 130.7, 131.2, 133.1, 137.5, 148.3, 148.6, 165.8 (two sp2
carbons missing due to overlap); IR (CHCl3, cm-1) 3056, 2980,
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed F or -
m a tion of Isoin d olo[2,1-a ]in d oles. Procedure A: DMF (10
mL), Pd(OAc)2 (6 mg, 0.027 mmol), LiCl (21 mg, 0.5 mmol),
Na2CO3 (56 mg, 0.5 mmol), and the alkyne (1.0 mmol) were
placed in a 4 dram vial. Procedure B: DMF (5 mL), Pd(OAc)2
(6 mg, 0.027 mmol), n-Bu4NCl (139 mg, 0.5 mmol), i-Pr2NEt
(130 mg, 1.0 mmol), and the alkyne (0.6 mmol) were placed in
a 2 dram vial. Procedure C: DMF (10 mL), Pd(OAc)2 (6 mg,
0.027 mmol), n-Bu4NCl (139 mg, 0.5 mmol), i-Pr2NEt (130 mg,
1.0 mmol), and the alkyne (1.2 mmol) were placed in a 4 dram
vial. The chemicals for procedures A-C were mixed, and the
appropriate imine (0.5 mmol) was added. The vial was flushed
with nitrogen and heated in an oil bath at 100 °C for the
indicated period of time. The reaction was monitored by TLC
to establish completion. The reaction mixture was then cooled
to room temperature, diluted with 30 mL of ether, washed with
45 mL (procedures A and C) or 30 mL (procedure B) of
saturated aqueous NH4Cl, dried (Na2SO4), and filtered. The
solvent was evaporated under reduced pressure, and the
product was isolated by chromatography on a silica gel column.
Com p ou n d s P r ep a r ed . 6,11-Dip h en ylisoin d olo[2,1-a ]-
in d ole (Com p ou n d 3; Ta ble 3, En tr y 3). The reaction was
run using procedure C and chromatographed using 25:1
hexanes/EtOAc to afford 168 mg (94%) of the indicated
compound as a white solid: mp 168-169 °C (hexanes/EtOAc);
1H NMR (CDCl3) δ 6.20 (s, 1H), 7.02 (dt, J ) 0.6, 8.1 Hz, 1H),
7.16 (dddd, J ) 1.5, 7.2, 7.2, 22.2 Hz, 2H), 7.25-7.49 (m, 9H),
7.63 (t, J ) 7.5 Hz, 2H), 7.87-7.94 (m, 4H); 13C NMR (CDCl3)
δ 64.5, 109.8, 110.3, 120.3, 120.5, 121.1, 122.4, 124.1, 126.5,
127.3, 127.7, 128.4, 128.6, 128.9, 129.3, 129.5, 131.9, 132.0,
133.7, 135.1, 138.9, 139.5, 147.5; IR (CHCl3, cm-1) 3065, 3028,
1602, 1450; MS m/z (rel intens) 358 (28, M + 1), 357 (100,
M+), 356 (26), 280 (78). Anal. Calcd for C27H19N: C, 90.72; H,
5.36; N, 3.92. Found: C, 90.39; H, 5.61; N, 3.94.
1688, 1559; HRMS calcd for
353.1416.
C24H19NO2 353.1416, found
11-Hyd r oxym eth yl-6-p h en ylisoin d olo[2,1-a ]in d ole (7).
The reaction was run using procedure A and chromatographed
using 1:1 hexanes/EtOAc to afford 80 mg (51%) of the indicated
compound as a white solid: mp 182-183 °C (hexanes/EtOAc);
1H NMR (CDCl3) δ 1.59 (br s, 1H), 5.20 (s, 2H), 6.12 (s, 1H),
6.92 (d, J ) 7.8 Hz, 1H), 7.10 (dddd, J ) 1.2, 6.9, 6.9, 19.5 Hz,
2H), 7.15-7.22 (m, 2H), 7.25, (dd, J ) 0.9, 5.4 Hz, 2H), 7.28-
7.35 (m, 3H), 7.41 (td, J ) 1.8, 8.1 Hz, 1H), 7.76 (d, J ) 7.5
Hz, 1H), 7.92 (d, J ) 7.5 Hz, 1H); 13C NMR (CDCl3) δ 56.2,
64.6, 106.6, 110.2, 119.7, 120.0, 121.8, 122.1, 124.0, 127.2,
127.6, 128.5, 128.6, 129.2, 131.5, 132.1, 133.4, 138.7, 141.3,
147.3; IR (CHCl3, cm-1) 3382, 3047, 1614, 1450; HRMS calcd
for C22H17NO 311.1310, found 311.1307.
11-Meth oxym eth yl-6-p h en ylisoin d olo[2,1-a ]in d ole (8).
The reaction was run using procedure B and chromatographed
using 10:1 hexanes/EtOAc to afford 75 mg (46%) of the
indicated compound as a white solid: mp 144-145 °C (hex-
anes/EtOAc); 1H NMR (CDCl3) δ 3.53 (s, 3H), 5.03 (s, 2H), 6.12
(s, 1H), 6.94 (dd, J ) 0.3, 7.8 Hz, 1H), 7.11 (dddd, J ) 1.2, 7.2,
7.2, 21.6 Hz, 2H), 7.19 (dd, J ) 3.6, 7.5 Hz, 2H), 7.25-7.27
(m, 2H), 7.33-7.36 (m, 3H), 7.43 (td, J ) 2.4, 8.1 Hz, 1H), 7.78
(dd, J ) 0.6, 7.8 Hz, 1H), 7.93 (d, J ) 7.8 Hz, 1H); 13C NMR
(CDCl3) δ 57.6, 64.5, 65.3, 103.8, 110.2, 119.90, 119.94, 121.9,
122.0, 124.0, 127.2, 127.5, 128.5, 128.6, 129.2, 131.8, 132.9,
133.4, 138.83, 141.9, 147.4; IR (CHCl3, cm-1) 3055, 2923, 1612,
1451; HRMS calcd for C23H19NO 325.1467, found 325.1466.
Anal. Calcd for C23H19NO: C, 84.89; H, 5.88; N, 4.30. Found:
C, 84.82; H, 6.16; N, 4.36.
11-(4-Hydr oxybu tyl)-6-ph en ylisoin dolo[2,1-a ]in dole (9).
The reaction was run using procedure B and chromatographed
using 1:1 hexanes/EtOAc to afford 127 mg (72%) of the
indicated compound as a white solid: mp 136-137 °C (hex-
anes/EtOAc); 1H NMR (CDCl3) δ 1.61 (br s, 1H), 1.73-1.82
(m, 2H), 1.89-1.99 (m, 2H), 3.16 (t, J ) 7.2 Hz, 2H), 3.71 (t,
J ) 6.6 Hz, 2H), 6.13 (s, 1H), 6.93 (dd, J ) 1.2, 7.2 Hz, 1H),
7.08 (dddd, J ) 1.2, 7.2, 7.2, 15.9 Hz, 2H), 7.17-7.26 (m, 4H),
7.31-7.43, (m, 4H), 7.68 (dd, J ) 1.2, 6.9 Hz, 1H), 7.80 (d, J
) 7.5 Hz, 1H); 13C NMR (CDCl3) δ 24.4, 27.3, 32.7, 63.1, 64.2,
107.6, 110.1, 119.2, 119.8, 120.8, 121.7, 124.1, 126.9, 127.2,
128.3, 128.4, 129.1, 132.4, 133.0, 133.5, 139.3, 139.6, 147.1;
11-Eth yl-6-p h en ylisoin d olo[2,1-a ]in d ole (Com p ou n d 4;
Ta ble 3, En tr y 5). The reaction was run using procedure B
and chromatographed using 25:1 hexanes/EtOAc to afford 126
mg (81%) of the indicated compound as a white solid: mp 144-
1
145 °C (hexanes/EtOAc); H NMR (CDCl3) δ 1.50 (t, J ) 7.5
Hz, 3H), 3.18 (q, J ) 7.5 Hz, 2H), 6.14 (s, 1H), 6.97 (dd, J )
1.8, 7.8 Hz, 1H), 7.06-7.16 (m, 2H), 7.22-7.26 (m, 4H), 7.35-
7.47 (m, 4H), 7.75 (d, J ) 8.1 Hz, 1H), 7.84 (d, J ) 7.8 Hz,
1H); 13C NMR (CDCl3) δ 15.9, 18.1, 64.3, 109.9, 110.1, 119.1,
119.8, 120.9, 121.7, 124.1, 126.8, 127.2, 128.4, 128.5, 129.1,
132.5, 132.8, 133.6, 139.1, 139.4, 147.2; IR (CHCl3, cm-1) 3057,
2926, 1611, 1451; HRMS calcd for C23H19N 309.1518, found
309.1516. Anal. Calcd for C23H19N: C, 89.28; H, 6.19; N, 4.53.
Found: C, 88.95; H, 6.47; N, 4.66.
IR (CHCl3, cm-1) 3046, 2922, 1610, 1450; IR (CHCl3, cm-1
3365, 3049, 2935, 1610, 1450; HRMS calcd for C25H23NO
353.1780, found 353.1787.
11-n -Bu tyl-9-m eth yl-6-ph en ylisoin dolo[2,1-a ]in dole (10).
The reaction was run using procedure B and chromatographed
using 50:1 hexanes/EtOAc to afford 142 mg (81%) of the
)

420 J . Org. Chem., Vol. 66, No. 2, 2001
Roesch and Larock
indicated compound as a yellow solid: mp 122-124 °C
(hexanes/EtOAc); 1H NMR (CDCl3) δ 1.08 (t, J ) 7.2 Hz, 3H),
1.61 (sextet, J ) 7.5 Hz, 2H), 1.90 (quintet, J ) 7.2 Hz, 2H),
2.51 (s, 3H), 3.18 (t, J ) 7.5 Hz, 2H), 6.11 (s, 1H), 6.95 (dd, J
) 1.2, 6.9 Hz, 1H), 7.05-7.17 (m, 4H), 7.20-7.25 (m, 2H),
7.32-7.40 (m, 3H), 7.65 (s, 1H), 7.74 (dd, J ) 0.6, 7.2 Hz, 1H);
13C NMR (CDCl3) δ 14.4, 21.8, 22.9, 24.5, 33.5, 64.1, 108.2,
110.0, 119.0, 119.9, 121.5, 121.6, 123.8, 127.2, 127.7, 128.3,
129.1, 132.7, 133.2, 133.6, 138.2, 139.6, 139.7, 144.6; IR (CDCl3,
(CDCl3) δ 0.99 (t, J ) 7.2 Hz, 3H), 1.49 (sextet, J ) 7.5 Hz,
2H), 1.82 (quintet, J ) 7.5 Hz, 2H), 3.08 (t, J ) 7.5 Hz, 2H),
6.17 (s, 1H), 6.96 (dddd, J ) 3.6, 3.6, 7.8, 7.8 Hz, 1H), 7.13
(dddd, J ) 1.2, 1.2, 8.1, 8.1 Hz, 2H), 7.19 (dd, J ) 3.6, 7.5 Hz,
2H), 7.35-7.38 (m, 3H), 7.71 (dddd, J ) 3.3, 3.3, 11.1, 11.1
Hz, 1H), 9.00 (s, 1H), 9.04 (s, 1H); 13C NMR (CDCl3) δ 14.2,
22.8, 24.9, 33.2, 64.6, 110.7, 112.4, 120.0, 120.5, 123.2, 125.5,
127.2, 129.0, 129.3, 132.1, 133.5, 134.1, 135.9, 147.8, 156.0,
173.6; IR (CHCl3, cm-1) 3028, 2953, 1495, 1456; HRMS calcd
for C23H21N3 339.1736, found 339.1738.
cm-1) 3058, 2954, 1620, 1452; HRMS calcd for C26H25
351.1987, found 351.1987.
N
Com p ou n d 15 (Ta ble 3, En tr y 17). The reaction was run
using procedure B and chromatographed using 25:1 hexanes/
EtOAc to afford 144 mg (84%) of the indicated compound as
an off-white solid: mp 104-105 °C (hexanes/EtOAc); 1H NMR
(CDCl3) δ 1.01 (t, J ) 7.2 Hz, 3H), 1.50 (sextet, J ) 7.5 Hz,
2H), 1.85 (quintet, J ) 7.2 Hz, 2H), 2.95 (t, J ) 7.5 Hz, 2H),
6.07 (s, 1H), 6.86-6.89 (m, 2H), 7.04 (dddd, J ) 1.5, 6.9, 6.9,
13.8 Hz, 2H), 7.20 (dddd, J ) 4.2, 4.2, 4.2, 6.3 Hz, 2H), 7.27
(d, J ) 4.8 Hz, 1H), 7.30-7.37 (m, 3H), 7.62 (dddd, J ) 0.6,
0.6, 0.6, 8.1 Hz, 1H); 13C NMR (CDCl3) δ 14.3, 22.9, 24.9, 32.8,
63.2, 105.8, 109.3, 118.9, 120.0, 121.5, 121.7, 127.1, 128.3,
128.4, 129.2, 132.5, 133.0, 134.5, 136.7, 138.6, 151.1; IR
11-n -B u t yl-7-m e t h ox y-6-p h e n yliso in d olo [2,1-a ]in -
d ole (11). The reaction was run using procedure B and
chromatographed using 25:1 hexanes/EtOAc to afford 144 mg
(78%) of the indicated compound as a white solid: mp 153-
1
154 °C (hexanes/EtOAc); H NMR (CDCl3) δ 0.99 (t, J ) 7.5
Hz, 3H), 1.52 (sextet, J ) 7.5 Hz, 2H), 1.81 (quintet, J ) 7.5
Hz, 2H), 3.08 (t, J ) 7.5 Hz, 2H), 3.88 (s, 3H), 6.08 (s, 1H),
6.75 (dd, J ) 2.4, 8.4 Hz, 1H), 6.89 (dddd, J ) 0.9, 0.9, 0.9, 8.1
Hz, 1H), 7.04 (dddd, J ) 1.2, 6.9, 6.9, 22.2 Hz, 2H), 7.10 (d, J
) 8.4 Hz, 1H), 7.14-7.20 (m, 2H), 7.28-7.36 (m, 4H), 7.65
(dddd, J ) 0.9, 0.9, 0.9, 7.8 Hz, 1H); 13C NMR (CDCl3) δ 14.4,
22.9, 24.5, 33.5, 55.7, 63.8, 106.7, 108.5, 110.0, 112.3, 119.1,
120.0, 121.7, 124.7, 127.2, 128.3, 129.1, 133.1, 133.6, 133.8,
139.3, 139.6, 139.8, 160.2; IR (CHCl3, cm-1) 3043, 2925, 1626,
1456; HRMS calcd for C26H25NO 367.1936, found 367.1936.
11-n -Bu tyl-9-tr iflu or om eth yl-6-p h en ylisoin d olo[2,1-a ]-
in d ole (12). The reaction was run using procedure B and
chromatographed using 25:1 hexanes/EtOAc to afford 193 mg
(95%) of the indicated compound as a yellow solid: mp 139-
(CHCl3, cm-1) 3041, 2925, 1552, 1454; HRMS calcd for C23H21
NS 343.1395, found 343.1395.
-
11-P h en yl-6-(3-ch lor oph en yl)isoin dolo[2,1-a ]in dole (17).
The reaction was run using procedure C and chromatographed
using 25:1 hexanes/EtOAc to afford 182 mg (93%) of the
indicated compound as a white solid: mp 165-166 °C (hex-
anes/EtOAc); 1H NMR (CDCl3) δ 6.11 (s, 1H), 6.99 (dd, J )
1.2, 7.2 Hz, 1H), 7.13-7.39 (m, 9H), 7.47 (t, J ) 7.5 Hz, 1H),
7.63 (t, J ) 7.5 Hz, 2H), 7.86-7.93 (m, 4H); 13C NMR (CDCl3)
δ 63.7, 110.0, 110.2, 120.5, 120.6, 121.2, 122.5, 123.9, 126.6,
127.8, 128.6, 128.7, 129.0, 129.5, 129.5, 131.8, 132.0, 133.6,
134.4, 134.9, 137.5, 139.3, 147.0; IR (CHCl3, cm-1) 3051, 3016,
1
140 °C (hexanes/EtOAc); H NMR (CDCl3) δ 1.01 (t, J ) 7.2
Hz, 3H), 1.52 (sextet, J ) 7.5 Hz, 2H), 1.83 (quintet, J ) 7.5
Hz, 2H), 3.11 (t, J ) 7.5 Hz, 2H), 6.23 (s, 1H), 6.90 (dd, J )
1.2, 6.3 Hz, 1H), 7.09 (dddd, J ) 1.5, 7.2, 7.2, 14.1 Hz, 2H),
7.15 (d, J ) 1.8 Hz, 1H), 7.17 (d, J ) 4.2 Hz, 1H), 7.29-7.37
(m, 4H), 7.46 (dd, J ) 0.6, 8.1 Hz, 1H), 7.70 (dd, J ) 1.5, 6.9
Hz, 1H), 7.96 (s,1H); 13C NMR (CDCl3) δ 14.2, 22.8, 24.4, 33.3,
64.1, 109.7, 110.1, 117.4 (q, 3J C-F ) 2.8 Hz), 119.4, 120.3, 122.3,
1602, 1489; HRMS calcd for
391.1121.
C27H18ClN 391.1128, found
Meth yl 6,11-Dip h en ylisoin d olo[2,1-a ]in d ole-2-ca r box-
yla te (19). The reaction was run using procedure C and
chromatographed using 15:1 hexanes/EtOAc to afford 172 mg
(83%) of the indicated compound as a white solid: mp 170-
171 °C (hexanes/EtOAc); 1H NMR (CDCl3) δ 3.90 (s, 3H), 6.22
(s, 1H), 6.95 (d, J ) 8.7 Hz, 1H), 7.21-7.47 (m, 9H), 7.60 (t, J
) 7.5 Hz, 2H), 7.77-7.88 (m, 4H), 8.55 (d, J ) 1.8 Hz, 1H);
13C NMR (CDCl3) δ 51.9, 64.5, 109.8, 110.9, 121.3, 122.2, 123.3,
123.8, 124.1, 126.9, 127.2, 128.2, 128.5, 128.7, 129.1, 129.3,
129.5, 131.2, 131.6, 134.1, 136.0, 138.4, 140.7, 147.3, 168.2;
IR (CDCl3, cm-1) 3063, 2947, 1711, 1621, 1437; HRMS calcd
for C29H21NO2 415.1572, found 415.1574.
4
1
123.6 (q, J C-F ) 2.7 Hz), 124.2 (q, J C-F ) 204.1 Hz), 124.4,
2
127.1, 128.7, 129.3, 130.0 (q, J C-F ) 24.2 Hz), 133.0, 133.2,
133.5, 137.9, 138.4, 150.3; IR (CHCl3, cm-1) 3049, 2926, 1455,
1438; HRMS calcd for C26H22F3N 405.1704, found 405.1705.
Eth yl 11-n -Bu tyl-6-p h en ylisoin d olo[2,1-a ]in d ole-7-ca r -
boxyla te (13). The reaction was run using procedure B and
chromatographed using 10:1 hexanes/EtOAc to afford 151 mg
(74%) of the indicated compound as a yellow solid: mp 120-
1
121 °C (hexanes/EtOAc); H NMR (CDCl3) δ 1.02 (t, J ) 7.5
Hz, 3H), 1.44 (t, J ) 7.2 Hz, 3H), 1.53 (sextet, J ) 7.5 Hz,
2H), 1.84 (quintet, J ) 7.5 Hz, 2H), 3.14 (t, J ) 7.5 Hz, 2H),
4.44 (q, J ) 7.2 Hz, 2H), 6.15 (s, 1H), 6.90 (ddd, J ) 0.9, 0.9,
8.1 Hz, 1H), 7.07 (dddd, J ) 1.2, 7.2, 7.2, 14.7 Hz, 2H), 7.15-
7.18 (m, 2H), 7.26 (d, J ) 8.1 Hz, 1H), 7.31-7.36 (m, 3H), 7.68
(ddd, J ) 1.5, 6.6 Hz, 1H), 7.90 (dd, J ) 1.5, 8.1 Hz, 1H), 8.41
(d, J ) 1.2 Hz, 1H); 13C NMR (CDCl3) δ 14.3, 14.5, 22.8, 24.4,
33.4, 61.3, 64.3, 109.3, 110.1, 119.4, 120.2, 121.8, 122.1, 123.9,
127.2, 128.2, 128.6, 129.2, 131.0, 132.9, 133.1, 133.5, 138.4,
138.7, 151.5, 166.4; IR (CDCl3, cm-1) 3056, 2967, 1720, 1437;
HRMS calcd for C26H27NO2 409.2042, found 409.2048.
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research, J ohnson Matthey, Inc. and Kawaken
Fine Chemicals Co., Ltd. for donation of the palladium
salts, and Merck and Co., Inc. for an Academic Develop-
ment Award in Chemistry.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
spectra for compounds 1, 7, and 15-19. This material is
available free of charge via the Internet at http://pubs.acs.org.
Com p ou n d 14 (Ta ble 3, En tr y 16). The reaction was run
using procedure B and chromatographed using 1:1 hexanes/
EtOAc to afford 158 mg (93%) of the indicated compound as
an off-white solid: mp 200-201 °C (hexanes/EtOAc); 1H NMR
J O000997O