Palladium-catalyzed, modular synthesis of highly functionalized indoles and tryptophans by direct annulation of substituted o-haloanilines and aldehydes

Article abstract of DOI:10.1021/jo061471s

(Chemical Equation Presented) One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-haloanilines and aldehydes has been developed. Coupling of ortho-iodoaniline with aldehyde is realized under mild ligandless conditions [Pd(OAc)₂, DABCO, DMF, 85°C], whereas X-Phos is found to be the ligand of choice for coupling reactions involving ortho-chloroanilines/ortho-bromoanilines and aldehydes. A variety of orthohaloanilines with different electronic properties are suitable substrates, and aldehydes including chiral ones participated in this reaction without racemization. Coupling of (S)-2-N,N-di-tert-butoxycarbonyl-5-oxopentanoate, derived from L-glutamic acid, with ortho-haloanilines provides a rapid access to the ring-A-substituted tryptophans in good to excellent yields.

Full text of DOI:10.1021/jo061471s

Palladium-Catalyzed, Modular Synthesis of Highly Functionalized
Indoles and Tryptophans by Direct Annulation of Substituted
o-Haloanilines and Aldehydes
Yanxing Jia and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
ReceiVed July 15, 2006
One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-haloanilines and aldehydes
has been developed. Coupling of ortho-iodoaniline with aldehyde is realized under mild ligandless
conditions [Pd(OAc)2, DABCO, DMF, 85 °C], whereas X-Phos is found to be the ligand of choice for
coupling reactions involving ortho-chloroanilines/ortho-bromoanilines and aldehydes. A variety of ortho-
haloanilines with different electronic properties are suitable substrates, and aldehydes including chiral
ones participated in this reaction without racemization. Coupling of (S)-2-N,N-di-tert-butoxycarbonyl-
5-oxopentanoate, derived from L-glutamic acid, with ortho-haloanilines provides a rapid access to the
ring-A-substituted tryptophans in good to excellent yields.
Introduction
context, palladium-catalyzed transformations have had a major
impact on indole synthesis, and indeed a range of catalytic
protocols has been developed for the synthesis of functionalized
indoles from simple starting materials.5,6 Thus the intramolecular
Heck reaction7 involving 5-exo cyclization followed by double-
bond isomerization has been widely used for the synthesis of
substituted indole derivatives since the initial disclosure of Mori8
The indole nucleus is one of the most important heterocycles
due to its presence in a vast number of bioactive natural
products, pharmaceuticals, and agrochemicals.1 Since the dis-
covery of Fischer indole synthesis in 1883, synthesis and
functionalization of indoles has been the subject of intensive
research for over 100 years, and a variety of well-documented
traditional and modern methods are now available.2,3 However,
the development of general and efficient methods for preparation
of functionalized indoles from simple and easily accessible
starting materials remains an active research field.4 In this
(4) For recent reports on indoles synthesis without a Pd catalyst, see:
(a) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem.,
Int. Ed. 2002, 41, 4732-4734. (b) Coleman, C. M.; O’Shea, D. F. J. Am.
Chem. Soc. 2003, 125, 4054-4055. (c) Shimada, T.; Nakamura, I.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546-10547. (d) Dunetz, J.
R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776-5777. (e) Taber,
D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058-1059. (f) Davies, H.
M. L.; Manning, J. R. J. Am. Chem. Soc. 2006, 128, 1060-1061.
(5) For reviews on palladium-catalyzed synthesis of indoles, see: (a)
Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113-1126. (b) Zeni, G.;
Larock, R. C. Chem. ReV. 2004, 104, 2285-2309. (c) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198. (d) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079-3160. (e) Cacchi,
S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873-2920.
(6) For recent reports on Pd-catalyzed indole synthesis, see: (a)
Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 15168-15169. (b) Siebeneicher, H.; Bytschkov, I.; Doye, S. Angew.
Chem., Int. Ed. 2003, 42, 3042-3044. (c) Willis, M. C.; Brace, G. N.;
Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44, 403-406. (d) Barluenga,
J.; Fernandez, M. A.; Aznar, F.; Valde´s, C. Chem.sEur. J. 2005, 11, 2276-
2283. (e) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549-3552. (f)
Mukai, C.; Takahashi, Y. Org. Lett. 2005, 7, 5793-5796.
(1) For recent reviews on indole-containing natural products, see: (a)
Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278-311. (b) Somei,
M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73-103. (c) Kawasaki, T.;
Higuchi, K. Nat. Prod. Rep. 2005, 22, 761-793. For leading references on
the physiological activity of indole derivatives, see: (d) Van Zandt, M. C.;
Jones, M. L.; Gunn, D. E.; Geraci, L. S.; Jones, J. H.; Sawicki, D. R.;
Sredy, J.; Jacot, J. L.; DiCioccio, A. T.; Petrova, T.; Mitschler, A.; Podjarny,
A. D. J. Med. Chem. 2005, 48, 3141-3152. For recent references on the
total synthesis of indole alkaloids, see: (e) Herzon, S. B.; Myers, A. G. J.
Am. Chem. Soc. 2005, 127, 5342-5344. (f) Baran, P. S.; Guerrero, C. A.;
Hafensteiner, B. D.; Ambhaikar, N. B. Angew. Chem., Int. Ed. 2005, 44,
3892-3895. (g) Yamashita, T.; Kawai, N.; Tokuyama, H.; Fukuyama, T.
J. Am. Chem. Soc. 2005, 127, 15038-15039.
(2) Gribble, G. W. Contemp. Org. Synth. 1994, 1, 145-172.
(3) For a recent general review on the construction of the indole ring,
see: Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
10.1021/jo061471s CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/06/2006
7826
J. Org. Chem. 2006, 71, 7826-7834

Pd-Catalyzed Synthesis of Indoles and Tryptophans
and Hegedus.9 Arguably, the palladium-catalyzed cyclization
of ortho-alkynylanilines/anilides10 and Larock annulation of
ortho-haloanilines with internal alkynes11 are among the most
powerful synthetic methods recently developed for the construc-
tion of indoles. On the other hand, palladium-catalyzed cycliza-
tion of ortho-haloanilino enamines has also been developed since
the initial report of Kibayashi.12 In most cases, enamines are
stabilized by conjugation with a carbonyl group (enaminones)
and are synthesized in a separate step by one of the following
methods: (a) condensation of ortho-haloanilines with 1,3-
dicarbonyl compound13 or R-keto ester;14 (b) Michael addition
of anilines to ethynyl ketone;15 (c) palladium-catalyzed oxidative
amination of electron-deficient olefins;16 (d) Buchwald-Hartwig
amination of vinylogous amides;17 and (e) Wittig reaction of
trifluoroanilides.18 A breakthrough came in 1997 when Chen
and co-workers at Merck Research Laboratories19 reported a
one-pot annulation process starting from the ortho-iodoaniline
and cyclic ketones.20,21 Surprisingly, aldehydes have not been
used as a reaction partner in this annulation process, though
this would produce highly demanding 2-unsubstituted indole
derivatives. Indeed, it has been noted in Chen’s original paper
that this annulation works well with cyclic ketones, but less
efficiently with acyclic ketones. To get the parent 2-unsubsti-
tuted indoles, the authors advocated the use of acylsilane or
pyruvic acid since both carboxyl and silyl groups can be
removed after the annulation reaction. In connection with a total
synthesis project, we had occasion to examine this reaction, and
we detail herein that ortho-iodoaniline reacted efficiently with
a variety of aldehydes in the presence of palladium catalyst to
afford the 2-unsubstituted indoles, including enantiomerically
pure tryptophan derivatives.22 We document also the develop-
ment of conditions that allow the use of ortho-chloroaniline and
ortho-bromoaniline as coupling partners, extending thus sig-
nificantly the application scope of this reaction.
Results and Discussion
Annulation of ortho-Iodoanilines and Aldehydes. In the
course of our efforts toward the total synthesis of complestatin
(chloropeptin II),23 we needed an efficient method for the
preparation of benzenoid-substituted tryptophan. Literature
search indicated that a variety of methodologies have been
developed, including (a) enzymatic resolution of racemic
compounds;24 (b) tryptophan synthetase catalyzed alkylation of
indole by L-serine;25 (c) functionalization of the cyclic tautomer
of tryptophan;26 (d) enantioselective hydrogenation of dehy-
drotryptophan;27 (e) diastereoselective28 and enantioselective29
alkylation of indole derivatives; (f) enantioselective ene reac-
tion;30 (g) The Fischer indole synthesis;31 and (h) palladium-
catalyzed Larock heteroannulation reaction.32 However, most
of these methodologies suffer from a number of disadvantages.
Thus, the alkylation strategy is complicated by competitive
nucleophilicity at C-3 versus C-2, N-1 and requires a presyn-
thesis of the indole core,33 whereas the traditional Fischer indole
synthesis often failed to deliver indoles with electron-deficient
hydrazines and m-substituted phenylhydrazines usually yielded
a mixture of 4- and 6-substituted indoles.34 The synthesis of
substituted tryptophans by Larock annulation reaction required
multistep synthesis of chiral internal silylalkynes.32 The limita-
tion of the current available synthetic approaches to access ring-
A-substituted tryptophan derivatives prompted us to develop
an alternative synthesis of this class of amino acids, and Chen’s
one-step annulation protocol seems to be highly promising in
order to reach this goal.
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J. Org. Chem, Vol. 71, No. 20, 2006 7827

Jia and Zhu
TABLE 1. Palladium-Catalyzed Heteroannulation of o-Iodoaniline
(1a, R1 ) R2 ) H) and ω-Amino Aldehyde 4aa
SCHEME 1
yield (%)b
SCHEME 2
entry
base
additive
T (°C)
time (h)
1
2
3
4
5
6
7d
K2CO3
PMP
85
85
85
85
85
8
10
8
8
20
7
0
0
81
0
48
40
0
DABCO
DABCO
DABCO
DABCO
DABCO
TBAClc
TBAIc
TBAIc
105
85
8
a General reaction conditions: concentration ) 0.2 M in DMF, Pd(OAc)2
(0.05 equiv) as palladium source except for entry 7, mole ratio ) 1a/4a )
1.1/1 in the presence of 3 equiv of base. b Isolated yield. c Three equivalents.
d Pd(PPh3)4 was used as catalyst. Abbreviations: PMP ) 1,2,2,6,6-
pentamethylpiperidine; DABCO ) 1,4-diazabicyclo[2,2,2]octane; TBACl
) tetrabutylammonium chloride; TBAI ) tetrabutylammonium iodide.
the effect of additives and found that the yield of 5a decreased
in the presence of tetrabutylammonium iodide (TBAI) or
tetrabutylammonium chloride (TBACl) (entries 4-6).38 The
palladium source also played an important role since no desired
product was isolated when Pd(PPh3)4 was used under otherwise
identical conditions (entry 7). The enantiomeric purity of 5a
was determined to be higher than 92% by its conversion to 8
(CeCl3‚7H2O, NaI, MeCN)39 and subsequent chiral HPLC
analysis (cf. Supporting Information).
Having established the optimal reaction conditions, the scope
of this reaction was examined with respect to anilines by varying
systematically the electronic properties of the aromatic ring. As
is shown in Table 2, the reaction turned out to be very general
and is applicable to both electron-rich and electron-deficient
o-iodoanilines. Thus, even with 4-nitroaniline (1f), the corre-
sponding tryptophan 5f was isolated in 74% yield, although the
basicity of the amino function in 1f was significantly reduced
(entry 6). Steric hindrance was also well tolerated since both
4-methoxytryptophan 5c (entry 3) and 7-methoxytryptophan 5i
(entry 9) can be synthesized by this methodology, although 2
equiv of aniline 1c had to be used for the synthesis of 5c. The
reaction of N-methylanilines (1b, 1e) with 4a proceeded
smoothly, leading to the corresponding tryptophan derivatives
(5b, 5e) in excellent yield. 6-Azatryptophan can be similarly
prepared starting from 4-iodo-3-aminopyridine (entry 11).
Furthermore, the reaction is site-selective since the reaction of
2-iodo-5-chloroaniline with 4a afforded the corresponding
6-chlorotryptophan in 74% yield (5l, entry 12). The presence
of a chlorine atom in 5l provided a valuable handle for further
functionalization by way of transition-metal-catalyzed pro-
cesses.40
We initially examined the annulation reaction of o-iodoaniline
1a (R1 ) R2 ) H) and (2S)-2-N-Boc-5-oxopentanoic acid methyl
ester (6a). The aldehyde (6a) was synthesized from N-Boc-L-
glutamic acid R-methyl ester 7 via a reduction/oxidation
sequence and was found to exist mainly as the cyclic hemiaminal
form 6b (Scheme 2).35 Submitting 6a/6b and 1a to Chen’s
conditions [Pd(OAc)2, DMF, DABCO, 85 °C] afforded indeed
the desired L-tryptophan (8) but in only 15% isolated yield.
Although yield remained low, the result was nevertheless
encouraging since it proved the feasibility of this approach,
which constituted probably one of the shortest routes to 8.
Parallel to our work, Baran and co-workers reported a synthesis
of racemic 6-hydroxytryptophan using a similar strategy in
connection with their total synthesis of stephacidin A.36
Reasoning that hemiacetal 6b may not react properly with
aniline to produce the enamine intermediate required for the
subsequent key C-C bond forming process, we turned our
attention to the enantiomerically pure methyl (S)-2-N,N-di-tert-
butoxycarbonyl-5-oxopentanoate 4a (Scheme 2), readily syn-
thesized in four conventional steps from L-glutamic acid.37 The
reaction of 1a and 4a in DMF in the presence of palladium
acetate was performed under a variety of conditions, and some
representative results are summarized in Table 1. As it is seen,
the choice of base is of utmost importance since no annulation
product was formed when potassium carbonate (entry 1) and
1,2,2,6,6-pentamethylpiperidine (entry 2) were used as bases.
However, in the presence of 1,4-diazabicyclo[2,2,2]octane
(DABCO), the desired L-N,N-di-Boc-tryptophan methyl ester
(5a) was produced in 81% yield. We have also briefly examined
(38) For halide effects on metal-catalyzed transformations, see: Fagnou,
K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26-47.
(39) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S. Synlett 2002, 468-
470.
(35) Bold, G.; Steiner, H.; Moesch, L.; Walliser, B. HelV. Chim. Acta
1990, 73, 405-410.
(36) (a) Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner,
B. D. Angew. Chem., Int. Ed. 2005, 44, 606-609. (b) Baran, P. S.;
Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J.
Am. Chem. Soc. 2006, 128, 8678-8693.
(37) (a) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.; Martin,
V. S. J. Org. Chem. 1998, 63, 3741-3744. (b) Padron, J. M.; Kokotos, G.;
Martin, T.; Markidis, T.; Gibbons, W. A.; Martin, V. S. Tetrahedron:
Asymmetry 1998, 9, 3381-3394.
(40) For a review of palladium-catalyzed cross-coupling reactions of aryl
chlorides, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
41, 4176-4211. For recent examples, see: (b) Kudo, N.; Perseghini, M.;
Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282-1284. (c) Billingsley, K.
L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45,
3484-3488. (d) For a recent example of catalytic direct arylation of aryl
chloride, see: Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581-591.
7828 J. Org. Chem., Vol. 71, No. 20, 2006

Pd-Catalyzed Synthesis of Indoles and Tryptophans
TABLE 2. Synthesis of Ring-A-Substituted Tryptophans by Palladium-Catalyzed One-Pot Annulation Reactiona
a General reaction conditions: concentration ) 0.2 M in DMF, 0.05 equiv of Pd(OAc)2, 1.1 equiv of o-iodoaniline 1, 1.0 equiv of aldehyde 4a, 3.0 equiv
of DABCO, 85 °C. b Isolated yield.
To evaluate the application scope of this one-pot annulation
protocol with respect to aldehydes, coupling of ortho-iodoaniline
with different aldehydes was next investigated, and the results
are summarized in Table 3. As expected, the annulation reaction
proceeded without event to afford the corresponding ring-A-
functionalized C-3-substituted indoles in good yields. The
presence of a free hydroxy group was well tolerated since
5-hydroxypentanal can be used directly in the annulation
reaction to afford indole 5r (entry 6). The 3-phenyl-substituted
indole 5o was prepared in good yield from the corresponding
phenylacetaldehyde.41 Indole 5p bearing an asymmetric center
adjacent to the C-3 carbon was obtained by annulation of (S)-
citronellal with ortho-iodoaniline without racemization (cf.
Supporting Information). The synthesis of this type of indole
has been the recent focus, and most of the reported methods
called for the asymmetric functionalization of indole, requiring
thus the presynthesis of the substituted indole nucleus.42-45 The
N-methyl ortho-iodoaniline (1b) reacted with 3-phenylpropi-
naldehyde efficiently to provide 5s in 76% yield (entry 7).
Annulation of ortho-Chloroanilines and Aldehydes. With
these results in hand, we were interested in exploring the
possibility of replacing the ortho-iodoaniline with much cheaper
and readily accessible ortho-chloroaniline and ortho-bromo-
aniline as the reaction partners of the present annulation process.
Although remarkable progress has been achieved in palladium-
catalyzed coupling reactions of aryl chlorides,40 examples using
highly deactivated chloroanilines remained relatively rare. As
a model reaction, the union of o-chloroaniline 2a with 3-(3,4,5-
trimethoxyphenyl)propanal 4b in DMA with (t-Bu3P)HBF4 (9)
as a supporting ligand20,46 was examined in the presence of a
variety of bases and palladium sources. As shown in Table 4,
potassium acetate turned out to be the base of choice (entry 1),
and DABCO was also capable of promoting the reaction but
(44) For organo-catalyzed additions of indoles to R,â-unsaturated systems,
see: (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172-1173. (b) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura,
R.; Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437-3440. (c)
Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 6576-6579.
(41) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett
1997, 1363-1366. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 8050-8057.
(42) For a review of stereoselective Friedel-Crafts alkylation reaction,
see: Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
2004, 43, 550-556.
(45) (a) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978,
1759-1762. (b) Dardennes, E.; Kovacs-Kulyassa, A.; Renzetti, A.; Sapi,
J.; Laronze, J.-Y. Tetrahedron Lett. 2003, 44, 221-223.
(43) For metal-catalyzed additions of indoles to R,â-unsaturated systems,
see: (a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu,
J. J. Am. Chem. Soc. 2003, 125, 10780-10781. (b) Zhou, J.; Ye, M.-C.;
Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309-1320. (c) Palomo,
C.; Oiarbide, M.; Kardak, B. G.; Garc´ıa, J. M.; Linden, A. J. Am. Chem.
Soc. 2005, 127, 4154-4155. (d) Evans, D. A.; Fandrick, K. R.; Song, H.-
J. J. Am. Chem. Soc. 2005, 127, 8942-8943.
(46) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,
39, 617-620. (b) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-
2724. (c) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298. (d)
Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343-
6348.
J. Org. Chem, Vol. 71, No. 20, 2006 7829

Jia and Zhu
TABLE 3. Synthesis of Indoles by Palladium-Catalyzed One-Pot
Annulation Reactiona
TABLE 4. Annulation Reaction of o-Chloroaniline 2a and
Aldehyde 4b, Conditions Surveya
entry
Pd cat.
base
additive
time (h)
yield (conv.)b
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(Ph3P)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
KOAc
KOAc
KOAc
K3PO4
K3PO4
K2CO3
DABCO
Cs2CO3
PMP
KOAc
KOAc
DABCO
DABCO
5
5
7
7
8
4
5
6
20
25
12
20
10
57
51c
57
MgSO4
HOAc
51
14
38
58 (46)
17
33 (56)
15
47
51(78)
0d
a General reaction conditions: concentration ) 0.2 M in DMA, 0.10
equiv of palladium source, 0.20 equiv of (t-Bu3P)HBF4, 1.0 equiv of
o-chloroaniline 2a, 1.0 equiv of aldehyde 4b, 3.0 equiv of base, 120 °C.
b Isolated yield. c 1.5 equiv of KOAc. d No ligand used. Abbreviations: PMP
) 1,2,2,6,6-pentamethylpiperidine; DABCO ) 1,4-diazabicyclo[2,2,2]octane.
a General reaction conditions: concentration ) 0.2 M in DMF, 0.05 equiv
of Pd(OAc)2, 1.1 equiv of o-iodoaniline 1, 1.0 equiv of aldehyde 4, 3.0
equiv of DABCO, 85 °C. b Isolated yield. c 5-Hydroxypentanal (open-chain
form) was used as coupling partner.
FIGURE 1. Structure of ligands screened for the annulation of ortho-
chloroaniline (2a) and 3-(3,4,5-trimethoxyphenyl)propanal (4b).
with low conversion (entry 7). On the other hand, potassium
phosphate, potassium carbonate, cesium carbonate, and PMP
were less effective as bases. The addition of magnesium sulfate
as dehydrating agent did not exert any positive effect. Palladium
acetate can also act as palladium source, albeit with slightly
reduced yield and longer reaction time (entries 11 and 12).
Overall, under optimum conditions [Pd(dba)2, (t-Bu3P)HBF4,
KOAc, DMA, 120 °C], the desired indole 5n was isolated in
57% yield. It has to be noted that, in the absence of (t-Bu3P)-
HBF4, no reaction occurred under otherwise identical conditions
(entry 13). To further optimize the reaction conditions, a
screening of ligands was carried out (Table 5). The electron-
rich but sterically less demanding monophosphines (tricyclo-
hexyl phosphine (10), tri-nbutyl phosphine (11), and dicyclohexyl-
(2,4,6-triisopropylphenyl)phosphine (12)) were found to be
ineffective for the present transformation (entries 1-3). The
bulky electron-rich biphenyl phosphines, such as 13 (cyclohexyl
JohnPhos), 14 (JohnPhos), and 15 (DavePhos), gave inferior
results relative to those of (t-Bu3P)HBF4 (entries 4-6), while
ligand 16 (2-dicyclohexylphosphino-2′-methylbiphenyl) was as
efficient as (t-Bu3P)HBF4. The best result was obtained when
X-phos 17 was employed as supporting ligand affording indole
5n in 83% yield (entry 7). As for many other palladium-
catalyzed transformations, the present annulation process is very
sensitive to the ligand structure. Thus switching from X-Phos
to the structurally very similar but bulkier ligand 18 (tert-butyl
XPhos) completely suppressed the desired transformation (entry
9). It is evident that the ability of these biphenyl phosphines as
supporting ligands to catalyze, in association with palladium,
the annulation reaction relied on the proper combination of two
steric factors: the substituent at the phosphorus center and the
ortho substituents on the ring B. Moderately encumbered
dicyclohexylphosphinyl substituent (ring A) in combination with
a hindered 2′,4′,6′-triisopropylphenyl (ring B) was apparently
optimum as a supporting ligand for the present transformation.
While 0.1 equiv of palladium was used in the above survey
of reaction conditions, we were pleased to find that catalyst
loading can be decreased. Thus performing the annulation of
2a and 4b in the presence of 0.025 equiv of Pd(dba)2 and 0.050
equiv of ligand 17 provided the desired indole 5n in 85% yield.
It is worthy noting that X-Phos is known to be an excellent
7830 J. Org. Chem., Vol. 71, No. 20, 2006

Pd-Catalyzed Synthesis of Indoles and Tryptophans
TABLE 5. Ligand Screening for Annulation Reaction of
TABLE 6. Synthesis of Indoles from ortho-Chloroanilinesa
o-Chloroaniline 2a with Aldehyde 4ba
entry
ligand
PCy3
(n-Bu)3P
12
13
14
15
16
17
18
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
25
20
20
20
20
20
5
4
10
5
<5
<5
5
40
30
53
59
83
<5
85c
10
17
a General reaction conditions: concentration ) 0.2 M in DMA, 0.10
equiv of Pd(dba)2, 0.20 equiv of ligand, 1.0 equiv of o-chloroaniline 2a,
1.0 equiv of aldehyde 4b, 3.0 equiv of KOAc, 120 °C. b Isolated yield.
c With 0.025 equiv of Pd(dba)2 and 0.05 equiv of ligand.
ligand for the palladium-catalyzed amination reaction.47 How-
ever, under the present reaction conditions, products resulting
from the potentially competitive dimerization or oligomerization
of ortho-chloroaniline 2a were not observed.11d,48 This may
indicate that the condensation of aniline and aldehyde preceded
the oxidative addition of palladium(0) to the aryl chloride.49
To illustrate the generality of this new protocol, annulation
of a variety of o-chloroanilines and aldehydes was examined,
and the results are depicted in Table 6. In most cases, the yield
of desired indole is comparable with that obtained from
o-iodoaniline, except for the reaction of 2d with phenylacetal-
dehyde. In this latter case, the desired indole was obtained in
only 24% yield together with the dehalogenated product, the
methyl 4-amino-2-methoxybenzoate, in 55% yield. Tryptophan
derivatives can be similarly prepared, and indeed yield of 5g
obtained from annulation of 2-chloro-5-methoxyaniline with 4a
(73%, entry 5) is higher than that obtained from 2-iodo-5-
methoxyaniline (58%, entry 7, Table 2).
Annulation of ortho-Bromoanilines and Aldehydes. With-
out further optimization, the catalytic conditions developed for
o-chloroanilines were directly applied to o-bromoanilines. As
is seen from Table 7, good to excellent yields of indoles were
obtained from o-bromoanilines with different electronic proper-
ties. 6-Phenyltryptophan and related aromatic-substituted tryp-
tophans have previously been synthesized via a multistep
sequence.50 Thus a one-step synthesis of 5z from 2-bromo-5-
phenylaniline and aldehyde 4a is particularly attractive. The
presence of a nitro group has an adverse effect on the reaction
as it is seen from entry 5. Nevertheless, one might keep in mind
that, as in most palladium-catalyzed processes, fine-tuning of
a General reaction conditions: concentration ) 0.2 M in DMA, 0.05
equiv of Pd(dba)2, 0.10 equiv of X-Phos 17, 1.0 equiv of o-chloroaniline
2, 1.0 equiv of aldehyde, 3.0 equiv of KOAc, 120 °C. b Isolated yield.
reaction conditions may be necessary for an individual substrate
in order to optimize the reaction outcome.
Conclusions
In summary, we have developed an efficient synthesis of
highly functionalized indoles by a palladium-catalyzed annu-
lation reaction between ortho-haloanilines and aldehydes. The
reaction is very general, and a variety of o-haloanilines with
different electronic properties and aldehydes, including chiral
ones, can be used to afford indoles in good to excellent yield.
Coupling of ortho-iodoaniline with aldehyde is realized under
mild ligandless conditions [Pd(OAc)2, DABCO, DMF, 85 °C],
whereas X-Phos is found to be the ligand of choice for coupling
reactions involving ortho-chloroanilines/ortho-bromoanilines
and aldehydes [Pd(dba)2/ligand 17 (X-Phos), KOAc, DMA at
120 °C]. Coupling of (S)-2-N,N-di-tert-butoxycarbonyl-5-oxo-
pentanoate, derived from L-glutamic acid, with ortho-halo-
anilines provides the corresponding ring-A-substituted tryp-
tophans in good to excellent yields. This represents one of the
shortest routes for the synthesis of tryptophan derivatives.
Further application of this chemistry to the synthesis of natural
products is currently in progress.
(47) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655. (b) Nguyen,
H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818-
11819. (c) Willis, M. C.; Brace, G. N.; Holmes, I. P. Synthesis 2005, 3229-
3234.
(48) For N-arylation of ortho-chloroaniline, see: Bedford, R. B.; Cazin,
C. S. J. Chem. Commun. 2002, 2310-2311.
(49) For synthesis of indole via arylation of ortho-halonitroarenes
followed by reductive cyclization, see: Rutherford, J. L.; Rainka, M. P.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 15168-15169.
(50) Wang, W.; Xiong, C.; Zhang, J.; Hruby, V. J. Tetrahedron 2002,
58, 3101-3110.
J. Org. Chem, Vol. 71, No. 20, 2006 7831

Jia and Zhu
TABLE 7. Synthesis of Indoles from ortho-Bromoanilinesa
3.71 (s, 3H), 3.60 (dd, J ) 4.7, 14.9 Hz, 1H), 3.38 (dd, J ) 10.1,
14.9 Hz, 1H), 1.29 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 171.0,
151.6 (2C), 136.9, 128.0, 127.7, 121.4, 118.8, 118.8, 110.1, 109.0,
82.7 (2C), 59.1, 52.1, 32.5, 27.6 (6C), 25.7; HRMS (ESI) m/z calcd
for C23H32N2O6Na (M + Na)+ 455.2158; found 455.2144.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(4-methoxy-1H-indol-
23
3-yl)propionic acid methyl ester 5c: Yellow oil; yield 55%; [R]D
-102° (c 1.00, CHCl3); IR (CHCl3) 3344, 2980, 2952, 1782, 1745,
1697, 1508, 1456, 1383, 1368, 1277, 1257, 1140, 1094, 853 cm-1
;
1H NMR (300 MHz, CDCl3) δ 8.45 (br s, 1H), 7.02 (t, J ) 7.9 Hz,
1H), 6.93 (d, J ) 7.9 Hz, 1H), 6.78 (d, J ) 2.0 Hz, 1H), 6.44 (d,
J ) 7.6 Hz, 1H), 5.39 (dd, J ) 4.0, 10.8 Hz, 1H), 3.88 (s, 3H),
3.88-3.83 (m, 1H), 3.77 (s, 3H), 3.27 (dd, J ) 10.8, 14.2 Hz,
1H), 1.22 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 171.4, 154.7,
151.4, 138.2, 122.5, 122.2, 117.4, 111.5, 104.7, 99.2, 82.5, 59.7,
55.1, 52.0, 27.9, 27.5 (6C); HRMS (ESI) m/z calcd for C23H32N2O7-
Na (M + Na)+ 471.2107; found 471.2119.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(5-methoxy-1H-indol-
3-yl)propionic acid methyl ester 5d: Colorless oil; yield 51%;
[R]D23 -62° (c 0.50, CHCl3); IR (CHCl3) 3348, 2977, 1781, 1736,
1696, 1486, 1455, 1438, 1382, 1367, 1271, 1216, 1136, 1089 cm-1
;
1H NMR (300 MHz, CDCl3) δ 8.17 (br s, 1H), 7.22 (d, J ) 8.8
Hz, 1H), 7.02 (d, J ) 2.4 Hz, 1H), 6.97 (d, J ) 2.4 Hz, 1H), 6.82
(dd, J ) 2.4, 8.8 Hz, 1H), 5.18 (dd, J ) 4.7, 10.1 Hz, 1H), 3.85 (s,
3H), 3.77 (s, 3H), 3.57 (dd, J ) 4.7, 14.9 Hz, 1H), 3.35 (dd, J )
10.1, 14.9 Hz, 1H), 1.29 (s, 18H); 13C NMR (75 MHz, CDCl3) δ
171.2, 154.0, 151.6 (2C), 131.4, 127.8, 123.9, 112.3, 111.8, 111.3,
100.4, 82.9 (2C), 59.0, 55.9, 52.2, 27.7 (6C), 25.9; HRMS (ESI)
m/z calcd for C23H32N2O7Na (M + Na)+ 471.2107; found 471.2117.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(5-methoxy-1-methyl-
1H-indol-3-yl)propionic acid methyl ester 5e: Colorless oil; yield
84%; [R]D23 -72° (c 1.00, CHCl3); IR (CHCl3) 2978, 1790, 1743,
a General reaction conditions: concentration ) 0.2 M in DMA, 0.05
equiv of Pd(dba)2, 0.10 equiv of X-Phos 17, 1.0 equiv of o-bromoaniline
3, 1.0 equiv of aldehyde, 3.0 equiv of KOAc, 120 °C. b Isolated yield.
1
1697, 1492, 1366, 1270, 1225, 1171, 1138 cm-1; H NMR (300
MHz, CDCl3) δ 7.13 (d, J ) 8.8 Hz, 1H), 7.02 (d, J ) 2.3 Hz,
1H), 6.87-6.83 (m, 2H), 5.15 (dd, J ) 4.7, 9.9 Hz, 1H), 3.85 (s,
3H), 3.76 (s, 3H), 3.68 (s, 3H), 3.56 (dd, J ) 4.7, 14.9 Hz, 1H),
3.32 (dd, J ) 9.9, 14.9 Hz, 1H), 1.30 (s, 18H); 13C NMR (75 MHz,
CDCl3) δ 171.1, 153.8 (2C), 151.6, 132.3, 128.3, 128.2, 111.9,
109.8, 109.7, 100.7, 82.7 (2C), 59.1, 55.9, 52.1, 32.7, 27.7 (6C),
25.8; HRMS (ESI) m/z calcd for C24H34N2O7Na (M + Na)+
485.2264; found 485.2262.
Experimental Section
A Typical Experimental Procedure for Annulation of o-
Iodoanilines with Aldehydes: A mixture of o-iodoaniline 1 (0.33
mmol), aldehyde 4 (0.30 mmol), and DABCO (101.0 mg, 0.90
mmol) in dry DMF (1.5 mL) was degassed for 20 min. Pd(OAc)2
(3.4 mg, 0.015 mmol) was added to the reaction, and the resulting
reaction mixture was heated at 85 °C until the reaction was complete
(usually 6-12 h; the progress of the reactions was monitored by
TLC). The reaction mixture was cooled to room temperature and
was diluted with water. The aqueous phase was extracted with
EtOAc, and the combined organic phases were washed with brine,
dried (Na2SO4), and evaporated to dryness under reduced pressure.
Purification of crude product by flash column chromatography
provided the desired product 5.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propi-
onic acid methyl ester 5a: Yellow oil; yield 81%; [R]D23 -60° (c
1.00, CHCl3); IR (CHCl3) 3348, 2980, 1782, 1741, 1457, 1369,
1273, 1140, 1092, 852 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.45
(br s, 1H), 7.58 (d, J ) 7.7 Hz, 1H), 7.34 (d, J ) 7.9 Hz, 1H), 7.15
(dt, J ) 1.2, 7.7 Hz, 1H), 7.09 (dt, J ) 1.2, 7.9 Hz, 1H), 6.98 (d,
J ) 2.1 Hz, 1H), 5.20 (dd, J ) 4.7, 10.3 Hz, 1H), 3.77 (s, 3H),
3.62 (dd, J ) 4.7, 14.9 Hz, 1H), 3.40 (dd, J ) 10.3, 14.9 Hz, 1H),
1.28 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 171.1, 151.5, 136.3,
127.5, 123.2, 121.7, 119.2, 118.5, 111.2, 82.8, 59.0, 52.1, 27.6 (6C),
25.8; HRMS (ESI) m/z calcd for C22H30N2O6Na (M + Na)+
441.2002; found 441.1975.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(5-nitro-1H-indol-3-
yl)propionic acid methyl ester 5f: Yellow solid; yield 74%; mp
23
55-57 °C (heptane/EtOAc); [R]D -52° (c 1.00, CHCl3); IR
(CHCl3) 3307, 2979, 1779, 1745, 1697, 1519, 1472, 1456, 1434,
1
1368, 1334, 1273, 1230, 1140, 1097, 851 cm-1; H NMR (300
MHz, CDCl3) δ 9.76 (br s, 1H), 8.56 (d, J ) 2.0 Hz, 1H), 8.06
(dd, J ) 2.1, 9.0 Hz, 1H), 7.42 (d, J ) 9.0 Hz, 1H), 7.10 (d, J )
1.9 Hz, 1H), 5.19 (dd, J ) 4.8, 10.5 Hz, 1H), 3.80 (s, 3H), 3.63
(dd, J ) 4.8, 14.9 Hz, 1H), 3.42 (dd, J ) 10.6, 14.9 Hz, 1H), 1.26
(s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.6, 151.5, 141.4, 139.4,
126.9 (2C), 117.4, 116.0, 113.5, 111.5, 83.6, 58.7, 52.4, 27.6 (6C),
25.6; HRMS (ESI) m/z calcd for C22H29N3O8Na (M + Na)+
486.1852; found 486.1827.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(6-methoxy-1H-indol-
23
3-yl)propionic acid methyl ester 5g: Yellow oil; yield 58%; [R]D
-69° (c 1.00, CHCl3); IR (CHCl3) 3353, 2980, 1782, 1742, 1631,
1456, 1369, 1306, 1255, 1143, 1092, 853 cm-1; H NMR (300
1
MHz, CDCl3) δ 8.49 (br s, 1H), 7.43 (d, J ) 8.6 Hz, 1H), 6.86-
6.85 (m, 2H), 6.76 (dd, J ) 2.2, 8.6 Hz, 1H), 5.18 (dd, J ) 4.8,
10.3 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.56 (dd, J ) 4.7, 14.8
Hz, 1H), 3.34 (dd, J ) 10.3, 14.8 Hz, 1H), 1.28 (s, 18H); 13C NMR
(75 MHz, CDCl3) δ 171.2, 156.4, 151.5, 137.0, 122.1, 122.0, 119.1,
111.1, 109.3, 94.8, 82.9, 59.0, 55.7, 52.2, 27.7 (6C), 25.9; HRMS
(ESI) m/z calcd for C23H32N2O7Na (M + Na)+ 471.2107; found
471.2105.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(1-methyl-1H-indol-
3-yl)propionic acid methyl ester 5b: Colorless oil; yield 85%;
[R]D23 -72° (c 1.00, CHCl3); IR (CHCl3) 2978, 1790, 1742, 1695,
1
1473, 1366, 1324, 1269, 1137, 848 cm-1; H NMR (300 MHz,
CDCl3) δ 7.58 (d, J ) 7.9 Hz, 1H), 7.25 (d, J ) 8.1 Hz, 1H), 7.19
(ddd, J ) 1.1, 7.9, 8.1 Hz, 1H), 7.09 (ddd, J ) 1.1, 7.9, 8.1 Hz,
1H), 6.87 (s, 1H), 5.16 (dd, J ) 4.7, 10.1 Hz, 1H), 3.76 (s, 3H),
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(6-nitro-1H-indol-3-
yl)propionic acid methyl ester 5h: Yield 64%; mp 75-77 °C;
[R]D23 -68° (c 1.00, CHCl3); IR (CHCl3) 3307, 2979, 1779, 1747,
7832 J. Org. Chem., Vol. 71, No. 20, 2006

Pd-Catalyzed Synthesis of Indoles and Tryptophans
1696, 1508, 1458, 1369, 1331, 1272, 1143, 1129, 1095, 1059, 851
cm-1; 1H NMR (300 MHz, CDCl3) δ 9.91 (br s, 1H), 8.41 (d, J )
1.9 Hz, 1H), 7.99 (dd, J ) 1.9, 8.8 Hz, 1H), 7.62 (d, J ) 8.8 Hz,
1H), 7.26 (d, J ) 2.2 Hz, 1H), 5.18 (dd, J ) 5.0, 10.3 Hz, 1H),
3.79 (s, 3H), 3.62 (dd, J ) 5.0, 14.9 Hz, 1H), 3.41 (dd, J ) 10.3,
14.9 Hz, 1H), 1.28 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.6,
151.5, 143.0, 134.7, 132.0, 129.6, 118.3, 114.6, 111.8, 108.7, 83.6,
58.6, 52.3, 27.6 (6C), 25.5; HRMS (ESI) m/z calcd for C22H29N3O8-
Na (M + Na)+ 486.1852; found 486.1858.
31.6; HRMS (ESI) m/z calcd for C15H13NNa (M + Na)+ 230.0946;
found 230.0970.
3-(3,4,5-Trimethoxybenzyl)-1H-indole 5n: Yellow solid; yield
67%; mp 128-130 °C (heptane/EtOAc); IR (CHCl3) 3365, 2929,
1
1589, 1505, 1455, 1418, 1329, 1227, 1119, 1005, 908 cm-1; H
NMR (300 MHz, CDCl3) δ 8.15 (br s, 1H), 7.57 (d, J ) 7.8 Hz,
1H), 7.37 (d, J ) 8.0 Hz, 1H), 7.21 (dt, J ) 1.2, 7.0 Hz, 1H), 7.11
(dt, J ) 1.1, 8.0 Hz, 1H), 6.93 (s, 1H), 6.55 (s, 2H), 4.08 (s, 2H),
3.85 (s, 3H), 3.80 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 153.0,
137.0, 136.4, 136.1, 127.3, 122.4, 122.0, 119.3, 119.0, 115.5, 111.1,
105.7, 60.8, 56.0, 31.9; HRMS (ESI) m/z calcd for C18H19NO3Na
(M + Na)+ 320.1263; found 320.1277.
3-Phenyl-1H-indole 5o: Yield 78%; mp 86-88 °C; [mp52 86-
87 °C]; IR (CHCl3) 3415, 3393, 3056, 3035, 2925, 1597, 1538,
1486, 1456, 1416, 1338, 1259, 1237, 1186, 1121, 1014, 954, 907
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.97 (br s, 1H), 7.86 (d, J )
7.6 Hz, 1H), 7.58 (dd, J ) 1.5, 7.9 Hz, 2H), 7.35 (t, J ) 7.9 Hz,
2H), 7.28 (dd, J ) 1.7, 7.5 Hz, 1H), 7.22-7.05 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 136.6, 135.5, 128.7, 127.4, 125.9, 125.7, 122.4,
121.8, 120.3, 119.8, 118.2, 111.4.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(7-methoxy-1H-indol-
3-yl)propionic acid methyl ester 5i: Yellow solid; yield 71%; mp
23
133-135 °C (heptane/EtOAc); [R]D -65° (c 1.00, CHCl3); IR
(CHCl3) 3374, 2979, 1787, 1742, 1697, 1579, 1502, 1451, 1368,
1
1258, 1149, 1131, 1091, 1057, 853 cm-1; H NMR (300 MHz,
CDCl3) δ 8.32 (br s, 1H), 7.20 (d, J ) 8.0 Hz, 1H), 7.01 (t, J )
7.8 Hz, 1H), 6.98 (d, J ) 2.1 Hz, 1H), 6.62 (d, J ) 7.6 Hz, 1H),
5.19 (dd, J ) 4.8, 10.1 Hz, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 3.59
(dd, J ) 4.7, 14.9 Hz, 1H), 3.38 (dd, J ) 10.1, 14.9 Hz, 1H), 1.30
(s, 18H); 13C NMR (75 MHz, CDCl3) δ 171.1, 151.6, 146.1, 128.9,
126.6, 122.6, 119.7, 112.0, 111.5, 101.8, 82.7, 59.0, 55.3, 52.1,
27.6 (6C), 25.9; HRMS (ESI) m/z calcd for C23H32N2O7Na (M +
Na)+ 471.2107; found 471.2091.
3-((1S)-1,5-Dimethylhex-4-enyl)-1H-indole 5p: Colorless oil;
yield 43%; [R]D23 5.6° (c 0.80, CHCl3); IR (neat) 3414, 2959, 2919,
(2S)-3-(1H-Benzo[f]indol-3-yl)-2-(di-tert-butoxycarbonylami-
no)propionic acid methyl ester 5j: Yield 60%; mp 64-66 °C
(heptane/EtOAc); [R]D23 -69° (c 1.00, CHCl3); IR (CHCl3) 3348,
2978, 1781, 1732, 1693, 1428, 1385, 1367, 1271, 1225, 1130, 1087,
1
2852, 1455, 1417, 1374, 1336, 1224, 1094, 1010 cm-1; H NMR
(300 MHz, CDCl3) δ 7.88 (br s, 1H), 7.67 (d, J ) 7.9 Hz, 1H),
7.36 (d, J ) 8.0 Hz, 1H), 7.19 (dt, J ) 1.1, 8.0 Hz, 1H), 7.11 (dt,
J ) 1.1, 7.9 Hz, 1H), 6.96 (d, J ) 2.3 Hz, 1H), 5.17 (m, 1H), 3.07
(m, 1H), 2.03 (m, 2H), 1.86 (m, 1H), 1.70 (s, 3H), 1.66 (m, 1H),
1.56 (s, 3H), 1.37 (d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 136.5, 131.3, 126.9, 124.8, 122.6, 121.7, 119.9, 119.4, 118.9,
111.1, 37.6, 30.4, 26.2, 25.7, 21.4, 17.7; HRMS (ESI) m/z calcd
for C16H22N (M + H)+ 228.1752; found 228.1758.
1
906, 852 cm-1; H NMR (300 MHz, CDCl3) δ 8.36 (br s, 1H),
8.06 (s, 1H), 7.92 (dd, J ) 2.1, 7.1 Hz, 1H), 7.84 (dd, J ) 2.1, 7.1
Hz, 1H), 7.75 (s, 1H), 7.37-7.28 (m, 2H), 7.19 (d, J ) 2.4 Hz,
1H), 5.32 (dd, J ) 4.7, 10.3 Hz, 1H), 3.81 (s, 3H), 3.73 (dd, J )
4.7, 14.9 Hz, 1H), 3.52 (dd, J ) 10.3, 14.9 Hz, 1H), 1.24 (s, 18H);
13C NMR (75 MHz, CDCl3) δ 171.1, 151.6 (2C), 137.0, 130.2,
129.5, 128.4, 128.1, 127.3, 127.2, 123.5, 122.4, 115.9, 110.5, 106.4,
82.9 (2C), 58.9, 52.2, 27.6 (6C), 26.0; HRMS (ESI) m/z calcd for
C26H32N2O6Na (M + Na)+ 491.2158; found 491.2172.
3-Hexyl-1H-indole 5q: Colorless oil; yield 55%; IR (neat) 3414,
1
2923, 2852, 1455, 1418, 1337, 1225, 1089, 1009 cm-1; H NMR
(300 MHz, CDCl3) δ 7.86 (br s, 1H), 7.64 (d, J ) 8.2 Hz, 1H),
7.36 (d, J ) 8.0 Hz, 1H), 7.19 (dt, J ) 1.4, 8.1 Hz, 1H), 7.14 (dt,
J ) 1.2, 7.9 Hz, 1H), 6.97 (d, J ) 2.2 Hz, 1H), 2.78 (t, J ) 7.6
Hz, 2H), 1.79-1.69 (m, 2H), 1.46-1.29 (m, 6H), 0.92 (t, J ) 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 136.3, 127.6, 121.8, 120.9,
119.0 (2C), 117.2, 111.0, 31.8, 30.1, 29.3, 25.2, 22.7, 14.1; HRMS
(ESI) m/z calcd for C14H20N (M + H)+ 202.1596; found 202.1585.
3-(1H-Indol-3-yl)propan-1-ol 5r:53 Colorless oil; yield 41%;
IR (neat) 3409, 2933, 1455, 1338, 1028 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.00 (br s, 1H), 7.63 (d, J ) 7.2 Hz, 1H), 7.36 (d, J )
7.9 Hz, 1H), 7.21 (dt, J ) 1.2, 8.1 Hz, 1H), 7.13 (dt, J ) 1.2, 7.9
Hz, 1H), 6.98 (d, J ) 2.2 Hz, 1H), 3.74 (t, J ) 6.4 Hz, 2H), 2.87
(t, J ) 7.3 Hz, 2H), 2.00 (m, 2H), 1.53 (br s, 1H); 13C NMR (75
MHz, CDCl3) δ 136.3, 127.4, 121.9, 121.3, 119.1, 118.8, 115.9,
111.1, 62.6, 32.9, 21.3; HRMS (ESI) m/z calcd for C11H13NONa
(M + Na)+ 198.0895; found 198.0881.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(1H-pyrrolo[2,3-c]py-
ridin-3-yl)propionic acid methyl ester 5k: Yield 60%; mp 52-
23
54 °C (CH2Cl2); [R]D -66° (c 1.00, CHCl3); IR (CHCl3) 3318,
2979, 1780, 1741, 1694, 1460, 1383, 1366, 1271, 1251, 1136, 1091,
1
908 cm-1; H NMR (300 MHz, CDCl3) δ 10.84 (br s, 1H), 8.74
(s, 1H), 8.14 (d, J ) 5.5 Hz, 1H), 7.46 (d, J ) 5.5 Hz, 1H), 7.17
(s, 1H), 5.09 (dd, J ) 4.9, 10.1 Hz, 1H), 3.71 (s, 3H), 3.53 (dd, J
) 4.9, 14.9 Hz, 1H), 3.34 (dd, J ) 10.1, 14.9 Hz, 1H), 1.21 (s,
18H); 13C NMR (75 MHz, CDCl3) δ 170.7, 151.6 (2C), 137.2,
134.1, 133.7, 132.4, 128.2, 113.5, 110.5, 83.2 (2C), 58.9, 52.2, 27.6
(6C), 25.5; HRMS (ESI) m/z calcd for C21H30N3O6 (M + H)+
420.2135; found 420.2119.
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(6-chloro-1H-indol-
23
3-yl)propionic acid methyl ester 5l: Yield 74%; [R]D -73° (c
1.00, CHCl3); IR (CHCl3) 3334, 2978, 1779, 1737, 1693, 1455,
1384, 1367, 1271, 1230, 1140, 1128, 1089, 905, 849 cm-1; 1H NMR
(300 MHz, CDCl3) δ 8.87 (br s, 1H), 7.47 (d, J ) 8.5 Hz, 1H),
7.36 (d, J ) 1.8 Hz, 1H), 7.05 (dd, J ) 1.8, 8.5 Hz, 1H), 6.94 (d,
J ) 2.2 Hz, 1H), 5.16 (dd, J ) 4.8, 10.3 Hz, 1H), 3.77 (s, 3H),
3.57 (dd, J ) 4.8, 14.9 Hz, 1H), 3.36 (dd, J ) 10.3, 14.9 Hz, 1H),
1.28 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.9, 151.5 (2C),
136.6, 127.5, 126.0, 124.1, 119.8, 119.3, 111.3, 111.1, 83.1 (2C),
58.8, 52.2, 27.6 (6C), 25.7; HRMS (ESI) m/z calcd for C22H29N2O6-
NaCl (M + Na)+ 475.1612; found 475.1609.
3-Benzyl-1-methyl-1H-indole 5s: Yield 76%; IR (CHCl3) 3024,
2910, 1600, 1492, 1473, 1452, 1423, 1373, 1326, 1250, 1153, 1011
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.63 (d, J ) 7.9 Hz, 1H),
7.45-7.24 (m, 7H), 7.18 (m, 1H), 6.83 (s, 1H), 4.21 (s, 2H), 3.79
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.4, 137.1, 128.6, 128.3,
127.8, 127.1, 125.8, 121.5, 119.2, 118.7, 114.3, 109.1, 32.5, 31.5;
HRMS (MALDI) m/z calcd for C16H16N (M + H)+ 222.1275; found
222.1282.
3-Benzyl-1H-benzo[f]indole 5t: Yield 45%; IR (CHCl3) 3422,
3024, 1630, 1600, 1537, 1493, 1469, 1446, 1423, 1359, 1274, 1260,
1085, 857 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.96-
7.24 (m, 11H), 7.09 (s, 1H), 4.25 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 140.9, 137.3, 130.4, 129.5, 128.7, 128.4, 128.3, 127.6,
3-Benzyl-1H-indole 5m: Yellow solid; yield 55%; mp 105-
106 °C (CHCl3), [mp51 104-106 °C]; IR (CHCl3) 3415, 3025, 2918,
2847, 1665, 1618, 1600, 1493, 1453, 1418, 1337, 1224, 1090, 1009
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.92 (br s, 1H), 7.56 (d, J )
7.9 Hz, 1H), 7.38-7.23 (m, 7H), 7.10 (t, J ) 7.8 Hz, 1H), 6.91 (s,
1H), 4.16 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 141.2, 136.4,
128.7, 128.3, 127.4, 125.8, 122.3, 122.0, 119.3, 119.1, 115.8, 111.0,
(52) (a) Russell, G. A.; Yao, C.-F.; Tashtoush, H. I.; Russell, J. E.;
Dedolph, D. F. J. Org. Chem. 1991, 56, 663-669. (b) Fu¨rstner, A.; Jumbam,
D. N. Tetrahedron 1992, 48, 5991-6010.
(53) Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett.
2004, 6, 79-82.
(51) Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org.
Lett. 2003, 5, 2497-2500.
J. Org. Chem, Vol. 71, No. 20, 2006 7833

Jia and Zhu
127.3, 126.4, 126.0, 123.8, 122.5, 116.6, 115.0, 106.3, 31.7; HRMS
(MALDI) m/z calcd for C19H15N (M+) 257.1204; found 257.1202.
A Typical Experimental Procedure for Annulation of o-
Chloroanilines/o-Bromoanilines with Aldehydes. A mixture of
o-chloroaniline/o-bromoaniline (0.30 mmol), aldehyde 4 (0.30
mmol), and KOAc (88 mg, 0.90 mmol) in dry DMA (1.5 mL) was
degassed for 20 min. Pd(dba)2 (8.0 mg, 0.015 mmol) and X-Phos
(14.3 mg, 0.03 mmol) were added to the reaction, and the resulting
reaction mixture was heated at 120 °C until the reaction was
complete (usually 2-6 h; the progress of the reactions was
monitored by TLC). The reaction mixture was cooled to room
temperature and was diluted with water. The aqueous phase was
extracted with EtOAc, and the combined organic phases were
washed with brine, dried (Na2SO4), and evaporated to dryness under
reduced pressure. Purification of crude product by flash column
chromatography provided the desired product 5.
(m, 1H), 3.05 (m, 1H), 2.49 (s, 3H), 2.04 (m, 2H), 1.86 (m, 1H),
1.72 (s, 3H), 1.67 (m, 1H), 1.58 (s, 3H), 1.38 (d, J ) 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 134.8, 131.3, 128.0, 127.1, 124.8,
123.3, 122.1, 120.0, 119.1, 110.7, 37.6, 30.4, 26.2, 25.7, 21.6, 21.4,
17.7; HRMS (ESI) m/z calcd for C17H24N (M + H)+ 242.1909;
found 242.1918.
5-Fluoro-3-phenyl-1H-indole 5y: Yield 81%; IR (CHCl3) 3417,
3027, 1627, 1601, 1578, 1543, 1478, 1453, 1416, 1351, 1311, 1291,
1274, 1261, 1231, 1176, 1105, 1072, 923, 855 cm-1; 1H NMR (300
MHz, CDCl3) δ 8.22 (br s, 1H), 7.68-7.61 (m, 3H), 7.49 (t, J )
7.4 Hz, 2H), 7.39 (d, J ) 2.6 Hz, 1H), 7.37-7.31 (m, 2H), 7.03
(dt, J ) 2.5, 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 158.4 (d,
J ) 235 Hz), 135.0, 133.1, 128.8, 127.2, 126.1, 126.1, 123.4, 118.4,
112.0 (d, J ) 9.8 Hz), 110.8 (d, J ) 26.4 Hz), 104.7 (d, J ) 24.1
Hz); HRMS (ESI) m/z calcd for C14H10NF (M+) 211.0783; found
211.0797.
3-Benzyl-6-methoxy-1H-indole 5u: Yield 56%; mp 102-104
°C (heptane/CH2Cl2); IR (CHCl3) 3386, 3025, 2922, 2833, 1627,
1553, 1501, 1451, 1348, 1302, 1250, 1199, 1162, 1122, 1084, 1051,
(2S)-2-(Di-tert-butoxycarbonylamino)-3-(6-phenyl-1H-indol-
3-yl)propionic acid methyl ester 5z: Yield 42%; mp 177-179
°C (CH2Cl2); [R]D23 -67° (c 0.50, CHCl3); IR (CHCl3) 3342, 2978,
1780, 1742, 1695, 1456, 1384, 1367, 1257, 1133, 1091, 909, 851
1
1023, 941, 806 cm-1; H NMR (300 MHz, CDCl3) δ 7.67 (br s,
1
1H), 7.27 (d, J ) 8.6 Hz, 1H), 7.20-7.16 (m, 4H), 7.11 (m, 1H),
6.71-6.64 (m, 3H), 3.98 (s, 2H), 3.72 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 156.4, 141.2, 137.1, 128.6, 128.3, 125.8, 121.9, 121.1,
119.7, 115.6, 109.2, 94.6, 55.6, 31.6; HRMS (ESI) m/z calcd for
C16H16NO (M + H)+ 238.1232; found 238.1241.
cm-1; H NMR (300 MHz, CDCl3) δ 8.34 (br s, 1H), 7.66-7.61
(m, 3H), 7.55 (d, J ) 1.2 Hz, 1H), 7.43 (t, J ) 7.8 Hz, 2H), 7.37
(dd, J ) 1.5, 8.3 Hz, 1H), 7.31 (m, 1H), 7.03 (d, J ) 2.0 Hz, 1H),
5.22 (dd, J ) 4.8, 10.2 Hz, 1H), 3.78 (s, 3H), 3.63 (dd, J ) 4.8,
14.9 Hz, 1H), 3.43 (dd, J ) 10.2, 14.9 Hz, 1H), 1.30 (s, 18H); 13
C
3-Hexyl-7-methyl-1H-indole 5v: Yield 31%; IR (CHCl3) 3418,
3050, 2954, 2923, 2853, 1614, 1454, 1432, 1340, 1275, 1223, 1166,
NMR (75 MHz, CDCl3) δ 171.1, 151.6, 142.4, 136.8, 135.5, 128.6,
127.3, 126.9, 126.5, 123.8, 119.3, 118.9, 111.5, 109.7, 82.9, 59.0,
52.2, 27.7 (6C), 25.9; HRMS (ESI) m/z calcd for C28H34N2O6Na
(M + Na)+ 517.2315; found 517.2322.
1
1094, 1063, 932 cm-1; H NMR (300 MHz, CDCl3) δ 7.80 (br s,
1H), 7.49 (d, J ) 7.6 Hz, 1H), 7.06 (t, J ) 7.6 Hz, 1H), 7.01 (d,
J ) 7.6 Hz, 1H), 6.98 (s, 1H), 2.77 (t, J ) 7.5 Hz, 2H), 2.49 (s,
3H), 1.73 (m, 2H), 1.45-1.28 (m, 6H), 0.91 (t, J ) 6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 135.9, 127.1, 122.3, 120.7, 120.1,
119.2, 117.7, 116.7, 31.8, 30.2, 29.3, 25.3, 22.7, 16.6, 14.1; HRMS
(ESI) m/z calcd for C15H22N (M + H)+ 216.1752; found 216.1747.
6-Methoxy-3-phenyl-1H-indole-5-carboxylic acid methyl ester
5w: Yield 24%; mp 163-165 °C (heptane/EtOAc); IR (CHCl3)
3287, 2923, 1713, 1624, 1601, 1566, 1546, 1462, 1434, 1404, 1344,
3-Hexyl-6-nitro-1H-indole 5aa: Yield 12%; mp 95-98 °C
(heptane/EtOAc); IR (CHCl3) 3358, 2921, 2854, 1501, 1462, 1324,
1274, 1208, 1101, 1056, 876, 831 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 8.46 (br s, 1H), 8.33 (d, J ) 1.9 Hz, 1H), 8.01 (dd, J )
1.9, 8.8 Hz, 1H), 7.63 (d, J ) 8.8 Hz, 1H), 7.28 (s, 1H), 2.77 (t, J
) 7.5 Hz, 2H), 1.70 (m, 2H), 1.42-1.25 (m, 6H), 0.89 (t, J ) 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 143.2, 134.6, 132.3, 127.1,
118.9, 118.3, 114.7, 108.0, 31.7, 30.1, 29.2, 24.8, 22.6, 14.1; HRMS
(MALDI) m/z calcd for C14H19N2O (MH - O)+ 231.1490; found
231.1497.
1
1266, 1231, 1201, 1172, 1125, 1103, 1068, 907 cm-1; H NMR
(300 MHz, CDCl3) δ 8.63 (br s, 1H), 8.44 (s, 1H), 7.64 (d, J ) 7.3
Hz, 2H), 7.46 (t, J ) 7.4 Hz, 2H), 7.31 (t, J ) 7.3 Hz, 1H), 7.28
(d, J ) 2.0 Hz, 1H), 6.88 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 167.5, 156.3, 139.8, 134.8, 128.8, 127.4,
126.3, 124.4, 121.8, 119.3, 119.2, 114.2, 94.3, 56.2, 51.9; HRMS
(ESI) m/z calcd for C17H15NO3Na (M + Na)+ 304.0950; found
304.0924.
Acknowledgment. Financial support from CNRS and the
Institut de Chimie des Substances Naturelles is gratefully
acknowledged. We thank Dr. G. Mignani of Rhodia, Lyon, for
the generous gift of ligands 12-18.
1
Supporting Information Available: Copies of H NMR, 13C
3-((1S)-1,5-Dimethylhex-4-enyl)-5-methyl-1H-indole 5x: Yield
NMR spectra of compounds 5a-5z-5aa, and HPLC diagram of
chiral indoles 5p, 5x, chiral N-Boc tryptophan 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
23
46%; [R]D 0.2° (c 0.50, CHCl3); IR (CHCl3) 3412, 2960, 2919,
2854, 1480, 1455, 1419, 1374, 1225, 1094, 984, 867 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.80 (br s, 1H), 7.45 (s, 1H), 7.26 (d, J ) 8.3
Hz, 1H), 7.03 (d, J ) 8.3 Hz, 1H), 6.93 (d, J ) 2.3 Hz, 1H), 5.19
JO061471S
7834 J. Org. Chem., Vol. 71, No. 20, 2006