Synthesis of substituted carbazoles, indoles, and dibenzofurans by vinylic to aryl palladium migration

Article abstract of DOI:10.1021/jo060727r

Substituted carbazoles, indoles, and dibenzofurans are readily prepared in moderate to excellent yields by the palladium-catalyzed cross-coupling of alkynes and appropriately substituted aryl iodides. This process proceeds by carbopalladation of the alkyn

Full text of DOI:10.1021/jo060727r

Synthesis of Substituted Carbazoles, Indoles, and Dibenzofurans by
Vinylic to Aryl Palladium Migration
Jian Zhao and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed April 5, 2006
Substituted carbazoles, indoles, and dibenzofurans are readily prepared in moderate to excellent yields
by the palladium-catalyzed cross-coupling of alkynes and appropriately substituted aryl iodides. This
process proceeds by carbopalladation of the alkyne, heteroatom-directed vinylic to aryl palladium migration,
and ring closure via intramolecular arylation or a Mizoroki-Heck reaction. Results from the deuterium
labeling experiments are consistent with the proposed mechanism.
Introduction
vinylic to aryl to allylic5 palladium migration processes have
been reported. These novel palladium migration processes are
not only mechanistically important but also synthetically useful
because they afford an alternative way to introduce a palladium
moiety into an organic molecule.
Recently, we reported a nitrogen-directed vinylic to aryl
palladium migration, which provides an efficient way to prepare
biologically interesting carbazoles as shown in Scheme 1.2c,6
This process proceeds by carbopalladation of the internal alkyne,
and then the palladium moiety migrates from the vinylic position
to the aryl position through an intramolecular C-H activation
The palladium-catalyzed activation of unfunctionalized C-H
bonds is considered a highly atom-efficient and environmentally
friendly strategy for organic synthesis.1 Recently, a number of
palladium migration examples involving intramolecular C-H
activation have been disclosed by our group and others. This
through-space shift of palladium appears to be fairly general
and can take place between a wide variety of carbon atoms.
Specifically, vinylic to aryl,2 aryl to aryl,3 alkyl to aryl,4 and
(1) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(b) Li, C.-J. Acc. Chem. Res. 2002, 35, 533. (c) Negishi, E. Handb.
Organopalladium Chem. Org. Synth. 2002, 2, 2905. (d) Jia, C.; Kitamura,
T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (e) Jia, C.; Piao, D.;
Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992.
(2) (a) Larock, R. C.; Tian, Q. J. Org. Chem. 2001, 66, 7372. (b) Bour,
C.; Suffert, J. Org. Lett. 2005, 7, 653. (c) Zhao, J.; Larock, R. C. Org. Lett.
2005, 7, 701. (d) Mota, A. J.; Dedieu, A.; Bour, C.; Suffert, J. J. Am. Chem.
Soc. 2005, 127, 7171.
(3) (a) Karig, G.; Moon, M. T.; Thasana, N.; Gallagher, T. Org. Lett.
2002, 4, 3115. (b) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002,
124, 14326. (c) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R.
C. J. Am. Chem. Soc. 2003, 125, 11506.
(5) Zhao, J.; Campo, M. A.; Larock, R. C. Angew. Chem., Int. Ed. 2005,
44, 1873.
(6) For a recent review, see: (a) Knolker, H.-J.; Kethiri, R. R. Chem.
ReV. 2002, 102, 4303 and references therein. (b) Ito, C.; Ito, M.; Sato, A.;
Hasan, C. M.; Rashid, M. A.; Tokuda, H.; Mukainaka, T.; Nishino, H.;
Furukawa, H. J. Nat. Prod. 2004, 67, 1488. (c) Duval, E.; Cuny, G. D.
Tetrahedron Lett. 2004, 45, 5411. (d) Knolker, H.-J.; Braier, A.; Broicher,
D. J.; Cammerer, S.; Frohner, W.; Gonser, P.; Hermann, H.; Herzberg, D.;
Reddy, K.; Rohde, G. Pure Appl. Chem. 2001, 73, 1075. (e) Moody, C. J.
Synlett 1994, 681. (f) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988,
27, 1113. (g) O’Connor, J. M.; Stallman, B. J.; Clark, W. G.; Shu, A. Y.
L.; Spada, R. E.; Stevenson, T. M.; Dieck, H. A. J. Org. Chem. 1983, 48,
807. (h) Larock, R. C.; Berrios-Pen˜a, N.; Narayanan, K. J. Org. Chem.
1990, 55, 3447.
(4) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2004, 126, 7460.
10.1021/jo060727r CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/17/2006
5340
J. Org. Chem. 2006, 71, 5340-5348

Synthesis of Carbazoles, Indoles, and Dibenzofurans
TABLE 1. Optimization of the Carbazole Synthesis
SCHEME 1. Synthesis of Substituted Carbazoles via Vinylic
to Aryl Palladium Migration
% yield
entry
R
base
ligand
additive time (h)
(1a:1b)a
1
2
3
4
5
6
7
8
9
H
2NaOAc 10% PPh3
2Na2CO3 10% PPh3
24
24
24
24
12
6
6
12
12
trace
0
0
20 (10:1)
60b (10:1)
73 (10:1)
71b (10:1)
trace
H
H
H
H
H
H
2NEt3
10% PPh3
2NaOAc 10% PPh3 1TBAC
2CsPiv
2CsPiv
2CsPiv
10% PPh3
5% dppm
5% dppm
5% dppm
5% dppm
1TBAC
process. The arylpalladium intermediate generated subsequently
undergoes intramolecular arylation to afford the carbazole
products. Herein, we wish to report a complete account on this
nitrogen-directed palladium migration, an extension of this
methodology to the synthesis of biologically interesting diben-
zofurans,7 and the synthesis of indoles8 in which the arylpal-
ladium intermediate is trapped by an intramolecular Mizoroki-
Heck reaction. Furthermore, substrates labeled with deuterium
have also been prepared and employed in this process to explore
the mechanistic details of this rearrangement.
Me 2CsPiv
Ph 2CsPiv
0
a All reactions were conducted on a 0.25 mmol scale at 100 °C in 4 mL
of DMF, and the ratio of aryl iodide to alkyne was 1:1 (sealed vial, under
Ar). The ratio of 1a to 1b, as determined by 1H NMR spectroscopy, is
reported in parentheses. b GC yield.
mol % of Pd(OAc)2, 5 mol % of bis(diphenylphosphino)methane
(dppm), and 2 equiv of CsO2CCMe3 (CsPiv) in DMF at 100
°C.
2. Synthesis of Carbazoles by Nitrogen-Directed Vinylic
to Aryl Palladium Migration. We next examined the reaction
using various internal alkynes to determine the scope and
limitations of this process. The results are shown in Table 2.
Theoretically, when 4,4-dimethyl-2-pentyne was allowed to react
with N-phenyl-3-iodoaniline, the previously reported consecutive
vinylic to aryl to allylic palladium migration could also occur,
and a π-allylpalladium complex I would be generated as shown
in Scheme 2.5 However, as determined by GC-MS analysis, only
the expected carbazole product was found, and a 44% yield of
one regioisomer 2a was isolated (Table 2, entry 2). When
4-octyne was employed as the starting material, the reaction
was very messy, and only a 35% yield of the carbazole 3 was
obtained (entry 3). In this system, the vinylpalladium intermedi-
ate generated from carbopalladation may undergo â-H elimina-
tion to afford an allene, which may account for the low yield
of carbazole in this reaction. To avoid loss of the volatile alkyne
(the boiling point of 4,4-dimethylpentyne is only 70 °C) or
possible â-H elimination, 2,2-dimethyl-3-octyne was prepared
and allowed to react with our diarylamine. However, only a
48% yield of the desired product 4a was isolated (entry 4).
1-Phenyl-1-propyne afforded a 65% yield of two regioisomers
5a and 5b in a 12:1 ratio (entry 5). In the case of dipheny-
lacetylene, the arylpalladium intermediate formed by vinylic to
arylpalladium migration might be expected to undergo direct
arylation of one of the phenyl groups of the diphenylacetylene,
affording phenylamino-substituted benzylidenefluorenes II or
III (Scheme 2).2 Surprisingly, a 69% yield of a single isomer
6 was isolated from this reaction (entry 6), and no benzylidene-
fluorene products were observed. We have also examined the
reaction of this aniline with a couple of other aryl acetylenes
bearing diverse functionalities on the arene. When 1-(4-
nitrophenyl)-1-butyne was employed in our carbazole synthesis,
a very messy reaction was observed and none of the desired
product was evident by GC-MS analysis (entry 7). However,
when a moderate electron-withdrawing ester group (CO2Et) was
present on the phenyl ring of the alkyne, a 71% yield of a single
regioisomer 7a was isolated by flash chromatography (entry 8).
Results and Discussion
1. Optimization of Reaction Conditions. In our initial work
on this carbazole synthesis, we treated N-phenyl-3-iodoaniline
and 1 equiv of 1-phenyl-1-butyne with 5 mol % of Pd(OAc)2,
10 mol % of PPh3, and 2 equiv of NaOAc in N,N-dimethyl-
formamide (DMF) at 100 °C for 24 h (Table 1, entry 1).
Unfortunately, only a trace amount of the desired carbazole
product 1a was observed by GC-MS analysis. This reaction was
subsequently carried out using both an inorganic base Na2CO3
(entry 2) and an organic base NEt3 (entry 3), but none of the
desired carbazole product was observed. When 1 equiv of n-Bu4-
NCl (TBAC) was added to the NaOAc reaction, a 20% yield
of a 10:1 ratio of isomeric carbazoles 1a and 1b was obtained
(entry 4). We next conducted the model reaction in the presence
of 2 equiv of CsO2CCMe3 (CsPiv) because of its superior
solubility in DMF. To our delight, a 60% yield of the desired
products was obtained (entry 5). By simply replacing PPh3 with
a bidentate ligand bis(diphenylphosphino)methane (dppm), we
isolated a 73% yield of the two regioisomers by flash chroma-
tography (entry 6). We then repeated the same reaction in the
presence of 1 equiv of TBAC, but it appears that the presence
of a chloride source is unnecessary for this transformation (entry
7). The lack of a substituent on the aniline nitrogen is also crucial
because the corresponding amines with Me and Ph substituents
produced none of the anticipated carbazoles (entries 8 and 9).
In conclusion, the “optimal” reaction conditions for this
nitrogen-directed vinylic to aryl palladium migration utilize 5
(7) (a) Kikumoto, R.; Tamao, Y.; Ohkubo, K.; Tezuka, T.; Tonomura,
S.; Okamoto, S.; Hijikata, A. J. Med. Chem. 1980, 23, 1293. (b) Robertson,
D. W.; Lacefield, W. B.; Bloomquist, W.; Pfeifer, W.; Simon, R. L.; Cohen,
M. L. J. Med. Chem. 1992, 35, 310. (c) Oliveira, A. A. G.; Raposo, M. M.;
Oliveira-Campos, A. F.; Griffiths, J.; Machado, A. H. HelV. Chim. Acta
2003, 86, 2900. (d) Crich, D.; Grant, D. J. Org. Chem. 2005, 70, 2384.
(8) For recent reviews, see: (a) Nussbaum, F. Angew. Chem., Int. Ed.
2003, 42, 3068. (b) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org.
Chem. 2002, 16, 2671. (c) Black, D. S. C. Synlett 1993, 610. (d) Saxton, J.
E. Nat. Prod. Rep. 1994, 11, 493.
J. Org. Chem, Vol. 71, No. 14, 2006 5341

Zhao and Larock
TABLE 2. Synthesis of Substituted Carbazolesa
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Synthesis of Carbazoles, Indoles, and Dibenzofurans
Table 2 (Continued)
a All reactions were conducted on a 0.25 mmol scale at 100 °C, using 5 mol % of Pd(OAc)2, 5 mol % of bis(diphenylphosphino)methane (dppm), and
2 equiv of CsO2CCMe3 (CsPiv) in DMF (4 mL), and the ratio of aryl iodide to alkyne was 1:1 (sealed vial, under Ar). b The ratio of a to b, as determined
1
by H NMR spectroscopy, is reported in parentheses. c The isolated products contain impurities, which cannot be separated by flash chromatography, thus
the yield has been determined by GC analysis.
SCHEME 2. Other Possible Palladium Migration Reactions
Presumably, the improved regioselectivity is due to the fact that
the electron-withdrawing group tends to stabilize the vinylpal-
ladium intermediate generated9 and thus enhances the regiose-
lectivity of carbopalladation. We can only surmise that the
presence of the NO2 group stabilizes the resulting vinylpalladium
intermediate so much that it no longer undergoes palladium
migration and side reactions ensue, consuming all starting
materials. An analogous alkyne bearing an ortho-methoxy group
on the arene afforded a 68% yield of the anticipated 10:1 mixture
of carbazoles 8a and 8b, respectively (entry 9). When methyl
phenylpropynoate was employed in this process, after a 24 h
reaction, none of the desired carbazole product was evident
(entry 10).
We have also examined the reaction of a number of anilines
bearing functionality on the aromatic ring undergoing substitu-
tion by the arylpalladium intermediate generated by the vinylic
to aryl palladium migration (see the later mechanistic discus-
sion). The reaction of N-(4-methylphenyl)-3-iodoaniline and
diphenylacetylene afforded a 61% yield of carbazole 9 (entry
11). A more electron-rich substrate bearing a methoxy group
afforded a 75% yield of a single carbazole product 10 (entry
12). The reaction of N-(2-methoxyphenyl)-3-iodoaniline and
1-phenyl-1-butyne was also studied (entry 13). Statistically, the
methoxy group ortho to the nitrogen would be expected to
reduce the opportunities for intramolecular arylation, plus the
favored molecular configuration for the arylpalladium interme-
diate is expected to be one in which the aromatic ring is
(9) Zhou, C.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579.
J. Org. Chem, Vol. 71, No. 14, 2006 5343

Zhao and Larock
TABLE 3. Synthesis of Substituted Indolesa
SCHEME 3. Synthesis of Substituted Indoles
perpendicular to the other aromatic ring, which should disfavor
intramolecular arylation. However, a 77% yield of a 10:1
mixture of regioisomeric carbazoles was obtained, probably
because the oxygen atom of the methoxy group coordinates to
the palladium moiety and perhaps stabilizes the arylpalladium
intermediate generated. Substrates bearing either an electron-
withdrawing 4-methoxycarbonyl or a 4-chloro group also
afforded a 71% yield of carbazole 12 and a 65% yield of two
isomeric carbazoles 13a and 13b in a 10:1 ratio, respectively
(entries 14 and 15). We have also examined the regioselectivity
of ring closure by employing N-(3-iodophenyl)naphthalen-1-
amine (entry 16). Here, cyclization might occur at either the 2
position or the 8 position of the naphthalene ring. However,
the only products observed are those formed by ring closure at
the 2 position of the naphthalene by the presumed intermediacy
of a six-membered ring palladacycle, as opposed to the
analogous seven-membered ring palladacycle required to gener-
ate the product of attack at the 8 position of the naphthalene. A
tetrahydronaphthylamine compound was also prepared and
allowed to react with diphenylacetylene, and a 68% yield of
carbazole 15 was isolated by flash chromatography (entry 17).
3. Synthesis of Substituted Indoles by Vinylic to Aryl
Palladium Migration Followed by an Intramolecular Mizo-
roki-Heck Reaction. The arylpalladium intermediates gener-
ated by aryl to aryl palladium migration have been shown to
undergo an intermolecular Mizoroki-Heck reaction and a
Suzuki-Miyaura reaction,10 and the arylpalladium species
generated from alkyl to aryl palladium migration have also been
shown to be easily trapped by an intermolecular Mizoroki-
Heck reaction.4 An arylpalladium species generated from vinylic
to aryl palladium migration has also been trapped by a Stille
coupling reaction.2c Because the intramolecular Mizoroki-Heck
reaction is a very powerful method for C-C bond formation in
organic synthesis and a plethora of natural products and
biologically interesting compounds have been synthesized
employing this methodology,11 we were encouraged by our
carbazole synthesis to examine possible intramolecular Heck
reactions as a trap for the arylpalladium intermediate generated.
As shown in Scheme 3, after carbopalladation, vinylpalladium
intermediate IV is generated. Once the palladium moiety
a These reactions were conducted on a 0.25 mmol scale at 100 °C for 3
h, using 5 mol % of Pd(OAc)2, 5 mol % of bis(diphenylphosphino)methane
(dppm), and 2 equiv of CsO2CCMe3 (CsPiv) in DMF (4 mL), and the ratio
of aryl iodide to alkyne was 1:1 (sealed vial, under Ar). b The ratio of a to
b, as determined by 1H NMR spectroscopy, is reported in parentheses. c The
reaction was conducted at 125 °C, using 10 mol % of Pd(OAc)2, 10 mol %
of bis(diphenylphosphino)methane (dppm), and 2 equiv of CsO2CCMe3
(CsPiv) in DMF (2 mL) for 24 h.
undergoes nitrogen-directed vinylic to aryl migration to afford
arylpalladium species V, an intramolecular Heck reaction,
followed by aromatization, should generate indole derivatives.
N-Allyl-3-iodoaniline and 1 equiv of 1-phenyl-1-butyne were
allowed to react with 5 mol % of Pd(OAc)2, 5 mol % of dppm,
and 2 equiv of CsO2CCMe3 in 4 mL of DMF at 100 °C. After
3 h, the aryl iodide was completely consumed and a 45% yield
of two isomeric indoles 16a and 16b was obtained in a 10:1
ratio (Table 3, entry 1). Two equiv of N-allyl-3-iodoaniline was
allowed to react with this alkyne. However, a lower yield was
obtained. We have been very reluctant to dramatically change
the reaction conditions because the palladium migration chem-
istry is generally very sensitive to variations in the reaction
conditions, especially the base. However, we did try a few things
to optimize the reaction conditions to achieve higher yields. The
reaction was conducted at both 80 °C and 125 °C, in more
concentrated or diluted solutions, in the presence of TBAC or
Ag2CO3, and using electron-rich ligands, such as P(t-Bu)3.
Unfortunately, none of our efforts were fruitful. A set of other
alkynes and imine starting materials have been screened, and
only moderate yields (26-40%) have been obtained (entries
2-4). The major problem in this process is probably the fact
that the arylpalladium intermediate generated by oxidative
addition, the vinylpalladium intermediate IV, and the arylpal-
ladium intermediate V can all react with N-allyl-3-iodoaniline.
Although the desired process is an intramolecular reaction,
which should have some advantage over those intermolecular
processes, at this time we are unable to get higher yields. An
additional complication is that the vinylic to aryl palladium
migration is presumably the slow step in this domino process,
which leaves plenty of time for side reactions.
(10) Campo, M. A.; Zhang, H.; Yao, T.; McCulla, R. D.; Huang, Q.;
Zhao, J.; Jenks, W. S.; Larock, R. C. J. Am. Chem. Soc., submitted.
(11) (a) Negishi, E. Handb. Organopalladium Chem. Org. Synth. 2002,
1, 1223 and references therein. (b) Tsuji, J. Palladium Reagents and
Catalysts; John Wiley & Sons: England, 2004; p 135. (c) Odle, R.; Blevins,
B.; Ratcliff, M.; Hegedus, L. S. J. Org. Chem. 1980, 45, 2709. (d) Larock,
R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291. (e) Caddick, S.; Kofie,
W. Tetrahedron Lett. 2002, 43, 9347.
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Synthesis of Carbazoles, Indoles, and Dibenzofurans
TABLE 4. Synthesis of Substituted Dibenzofuransa
a All reactions were conducted on a 0.25 mmol scale at 100 °C for 12 h, using 5 mol % of Pd(OAc)2, 5 mol % of bis(diphenylphosphino)methane (dppm),
and 2 equiv of CsO2CCMe3 (CsPiv) in DMF (4 mL), and the ratio of aryl iodide to alkyne was 1:1 (sealed vial, under Ar). b The ratio of a to b, as
1
determined by H NMR spectroscopy, is reported in parentheses.
J. Org. Chem, Vol. 71, No. 14, 2006 5345

Zhao and Larock
SCHEME 4. Proposed Mechanism
4. Synthesis of Substituted Dibenzofurans. After having
investigated the nitrogen-directed vinylic to aryl palladium
migration, we wondered if we could expand this protocol to
the synthesis of substituted dibenzofurans, although Pd-O
coordination would be expected to be much weaker than Pd-N
coordination. 3-Iodophenyl phenyl ether and 1-phenyl-1-butyne
were treated with 5 mol % of Pd(OAc)2, 5 mol % of dppm,
and 2 equiv of CsO2CCMe3 in DMF at 100 °C; however, the
reaction was very messy, and only a 30% yield of an 8:1 mixture
of two isomeric dibenzofurans 20a and 20b was observed by
GC-MS analysis (Table 4, entry 1). Previous aryl to aryl
palladium migration studies in our group have indicated that
palladium tends to reside on the more electron-rich aromatic
ring. Thus, we felt that an increase in electron density in the
arene undergoing vinylic to aryl palladium migration should
facilitate this through-space migration. Indeed, the reaction of
1-iodo-3,5-diphenoxybenzene with 1-phenyl-1-butyne afforded
a 75% yield of a 9:1 mixture of two regioisomeric dibenzofurans
21a and 21b (entry 2). The increased reaction efficiency could
be a result of the increased electron density of the arene favoring
Pd migration. However, this process may also be more efficient
because migration to either of the two ortho positions of the
arene is now possible, doubling the probability of intramolecular
arylation. To further examine the effect of an electron-rich
substituent, 3-iodo-5-phenoxyanisole was prepared and allowed
to react with 1-phenyl-1-butyne. A 78% yield of two isomeric
dibenzofurans 22a and 22b was obtained (entry 3), which clearly
suggests that an increase in the electron density of the arene is
the major reason for the improved reaction efficiency. Several
other internal alkynes have been allowed to react with this
iodoarene, and moderate to excellent yields have generally been
obtained. 1-Phenyl-1-propyne afforded a 78% yield of two
regioisomers 23a and 23b in a 9:1 ratio (entry 4). 4,4-Dimethyl-
2-pentyne afforded a 42% yield of a single regioisomer 24, as
expected (entry 5). 4-Octyne afforded a 44% yield of diben-
zofuran 25 (entry 6). When employing diphenylacetylene, a 76%
yield of a single isomer 26 was obtained (entry 7). When methyl
4-(but-1-ynyl)benzoate was employed in this reaction, a 60%
yield of two isomeric dibenzofurans 27a and 27b was obtained
in a 15:1 ratio (entry 8). An analogous alkyne bearing an ortho-
methoxy group afforded a 37% yield of a 7:1 mixture of
dibenzofuran products 28a and 28b (entry 9).
5. Mechanism. A plausible mechanism for this palladium
rearrangement is proposed in Scheme 4. Intermediate A is first
generated by oxidative addition of the aryl iodide to Pd(0).
Subsequent intermolecular carbopalladation would be expected
to afford intermediate B. The resulting vinylic palladium
intermediate B might then undergo palladium migration from
the vinylic position to an aryl position to generate intermediate
F, possibly through an organopalladium(IV) hydride C (route
a), although such Pd(IV) hydride intermediates have not
previously been reported.12 An equilibrium between organo-
palladium(IV) hydride C and organopalladium(II) intermediate
D is also possible, although palladacycle D could also be
generated directly from intermediate B. Intermediate F eventu-
ally undergoes either palladium insertion into the C-H bond
of the neighboring arene or electrophilic aromatic substitution
to afford the six-membered ring palladacycle G. Alternatively,
intermediate D can undergo intramolecular C-H activation to
generate an interesting organopalladium(IV) hydride E; subse-
SCHEME 5. Synthesis of Deuterated Compound 29-da
a (i) NaSMe, DMA, 140 °C; (ii) (a) NaNO2, HCl, (b) Kl; (iii) CF3CO2D,
reflux; (iv) 4CsF, 1.1 2-(trimethylsilyl)phenyl trifluoromethanesulfonate,
MeCN.
quent reductive elimination could also generate intermediate G
(route b). When R is a phenyl group, the palladium moiety can
migrate to either of two ortho positions of the arene originally
bearing the iodo group and then be trapped by arylation to
generate either the observed carbazole (dibenzofuran) or a
fluorene. Although we have previously reported such a fluorene
synthesis,2 only the carbazole (dibenzofuran) products are
observed, which suggests that the palladium only migrates to
the position ortho to the heteroatom. This interesting selectivity
may be due to coordination between the ortho heteroatom and
the palladium moiety, which is not available if the palladium
migrates to the position para to the heteroatom. Alternatively,
the palladium may prefer the position ortho to the heteroatom
due to stabilization of the arylpalladium intermediate by
inductive electron withdrawal, as suggested by recent results
in our laboratories, which are supported by calculations.10
6. Deuterium Labeling Experiments. To clarify the ambi-
guities in the mechanism, we prepared the deuterium labeled
starting material 29-d (90% deuterium incorporation in each
position of the arene, as shown in Scheme 5)13 and allowed
this compound to react with diphenylacetylene under our usual
palladium migration conditions. According to the proposed
(13) For the preparation of 3-hydroxy-5-methoxyaniline, see: Wendt,
M. D.; Rockway, T. W.; Geyer, A.; McClellan, W.; Weitzberg, M.; Zhao,
X.; Mantei, R.; Nienaber, V. L.; Stewart, K.; Klinghofer, V.; Giranda, V.
J. Med. Chem. 2004, 47, 303.
(12) Other organopalladium(IV) species are well-known, however. See:
Canty, A. J. Acc. Chem. Res. 1992, 25, 83.
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Synthesis of Carbazoles, Indoles, and Dibenzofurans
SCHEME 6. Deuterium Labeling Experiment
mechanism shown in Scheme 6, if the reaction only proceeds
through route a, the deuterium originally ortho to the oxygen
atom and the iodine atom will shift to the vinylic position after
the vinylic to aryl palladium migration. Thus, we should obtain
dibenzofuran 26-d. On the other hand, if this reaction only goes
through the mechanism described in route b, product 26-h
should be obtained. Indeed, an 80% yield of dibenzofuran 26-d
was isolated by flash chromatography, with 70% deuterium
of carbazoles; however, only moderate yields can be obtained
in the synthesis of indoles, and excellent yields can be achieved
in the synthesis of dibenzofurans only if electron-rich aryl
iodides are employed. The relatively modest regiochemistry of
alkyne insertion also presents problems. The results of deuterium
labeling experiments showed a high degree of deuterium
incorporation in the vinylic position of the dibenzofuran product
obtained, affording convincing evidence for the proposed
palladium migration mechanism. The H-D exchange also
suggests that the migration process involves an equilibrium
between Pd(II) and Pd(IV) intermediates, which is consistent
with a previously reported consecutive vinylic to aryl to allylic
palladium migration5 and does not favor the direct Pd-H shift
mechanism reported elsewhere.2d
1
incorporation in the vinylic position (determined by H NMR
spectroscopy). This result clearly suggests the involvement of
route a. The loss of deuterium could be due to H-D exchange
through an equilibrium between palladacycle K and palladacycle
P or to the direct H-D exchange between intermediate K and
an H source in the reaction solution. Alternatively, it could be
due to the involvement of route b because the aryl deuterium
presumably would be washed out upon formation of intermedi-
ate P. To address these issues, we conducted the same reaction
in the presence of 10 equiv of D2O, and 85% deuterium
incorporation was observed in the vinylic position of the isolated
dibenzofuran product 26-d, which suggests that the previous
deuterium loss was probably the result of H-D exchange in
intermediate K, instead of the result of the alternative mecha-
nistic route b.
Experimental Section
Representative Procedure for the Palladium-Catalyzed Mi-
gration Reactions. The appropriate aryl iodide (0.25 mmol), Pd-
(OAc)2 (2.8 mg, 0.0125 mmol), 1,1-bis(diphenylphosphino)methane
(dppm) (4.8 mg, 0.0125 mmol), and CsO2CCMe3 (CsPiv) (0.117
g, 0.5 mmol) in DMF (4 mL) were stirred under Ar at 100 °C for
the specified period of time. The reaction mixture was allowed to
cool to room temperature, diluted with diethyl ether (25 mL), and
washed with 5% aq Na2CO3 (25 mL). The aqueous layer was
reextracted with diethyl ether (25 mL) twice. The organic layers
were combined, dried (MgSO4), and filtered, and the solvent was
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel.
Conclusions
In conclusion, we have established the scope and limitations
of a mechanistically important palladium migration process,
which affords an efficient way to prepare biologically interesting
carbazoles, indoles, and dibenzofurans. The advantage of this
chemistry is that an alkenyl substituent can be efficiently
incorporated into the heterocyclic ring during the course of the
cyclization, which can be still further modified to other
functional groups. This reaction is quite general for the synthesis
(E)-4-(1,2-Diphenylvinyl)-9H-carbazole (6). Purification by
flash chromatography (5:1 hexane/EtOAc) afforded 59.5 mg (69%)
1
of the product as a light yellow oil: H NMR (CDCl3) δ 7.03-
7.14 (m, 3H), 7.23-7.42 (m, 14H), 8.03 (s, 1H), 8.37 (d, J ) 8.1
Hz, 1H); 13C NMR (CDCl3) 109.8, 110.8, 119.6, 121.3, 121.7,
123.0, 123.4, 125.7, 125.9, 127.3, 127.7, 128.5, 128.7, 129.8, 130.2,
J. Org. Chem, Vol. 71, No. 14, 2006 5347

Zhao and Larock
131.1, 137.6, 140.0, 140.3, 140.4, 140.7, 141.3; IR (CDCl3) 3414,
3054, 1599, 1455 cm-1; HRMS m/z 345.1522 (calcd for C26H19N,
345.1518).
Hz, 1H), 7.92 (d, J ) 8.1 Hz, 1H); 13C NMR (CDCl3) 56.0, 95.7,
111.5, 112.8, 115.8, 122.0, 122.8, 124.5, 125.9, 127.5, 127.9, 128.5,
128.8, 129.8, 130.3, 131.6, 137.1, 140.0, 140.1, 140.9, 156.8, 158.2,
159.6; IR (CDCl3) 3054, 3022, 2958, 1629 cm-1; HRMS m/z
376.1470 (calcd for C27H20O2, 376.1463).
(E)-3-Methyl-4-(1-phenylbut-1-en-2-yl)-1H-indole (16a). Pu-
rification by flash chromatography (2:1 hexane/EtOAc) afforded
28.2 mg (45%) of the product as a light yellow oil: 1H NMR
(CDCl3) δ 1.09 (t, J ) 7.2 Hz, 3H), 2.36 (s, 3H), 2.77 (q, J ) 7.2
Hz, 2H), 6.47 (s, 1H), 6.96-6.99 (m, 2H), 7.18 (t, J ) 7.8 Hz,
1H), 7.27-7.32 (m, 2H), 7.41 (d, J ) 4.1 Hz, 4H), 7.93 (s, 1H);
13C NMR (CDCl3) 13.2, 13.4, 27.1, 110.0, 112.5, 119.7, 121.7,
122.9, 125.6, 126.6, 128.5, 128.98, 129.0, 137.3, 137.9, 138.4,
144.4; IR (CDCl3) 3418, 3021, 2964, 1598 cm-1; HRMS m/z
261.1518 (calcd for C19H19N, 261.1521).
(E)-1-(1,2-Diphenylvinyl)-3-methoxydibenzofuran (26). Puri-
fication by flash chromatography (10:1 hexane/EtOAc) afforded
71.4 mg (76%) of the product as a colorless oil:1H NMR (CDCl3)
δ 3.86 (s, 3H), 6.72 (s, 1H), 7.06-7.37 (m, 14H), 7.54 (d, J ) 8.1
Acknowledgment. We deeply appreciate the financial sup-
port of the National Science Foundation and thank Johnson
Matthey, Inc. and Kawaken Fine Chemical Co. for donations
of Pd(OAc)2.
Supporting Information Available: Preparation and charac-
terization of the aryl iodides and characterization of the carbazole,
indole, and dibenzofuran products. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO060727R
5348 J. Org. Chem., Vol. 71, No. 14, 2006