Palladium-catalyzed direct and regioselective C-H bond functionalization/ oxidative acetoxylation of indoles

Article abstract of DOI:10.1021/jo101584k

The first general examples of palladium-catalyzed direct and selective oxidative C3-acetoxylation of indoles are presented. The mild reaction conditions (70 °C and with weak base, KOAc) in this indole C-H-acetoxylation are notable.

Full text of DOI:10.1021/jo101584k

pubs.acs.org/joc
Palladium-Catalyzed Direct and Regioselective C-H Bond
Functionalization/Oxidative Acetoxylation of Indoles†
Pui Ying Choy, Chak Po Lau, and Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
bcfyk@inet.polyu.edu.hk
Received August 14, 2010
The first general examples of palladium-catalyzed direct and selective oxidative C3-acetoxylation of
indoles are presented. The mild reaction conditions (70 °C and with weak base, KOAc) in this indole
C-H-acetoxylation are notable.
Introduction
area for the construction of carbon-carbon and carbon-
heteroatom bonds.3,4
Employing a modular approach for generating a new
series of compounds has been one of the most important
themes in modern organic synthesis1 since it offers a direct
and simple route to prepare an array of structurally similar
yet diversified pharmaceutically attractive molecules.2 Certainly,
the transition-metal-catalyzed C-H bond functionalization
sequences have become a cutting-edge methodology in this
Among the field of C(sp2)-heteroatom cross-couplings,
the C-O bond-forming reaction (from ArX electrophile and
ROH nucelophile) is the most problematic and difficult
process.5 Thus, it would be of considerable interest if this
catalytic process is free of expensive tailor-made phosphine
ligand and can be done by applying the more atom-economical
C-H cleavage/functionalization cascade protocol. More-
over, it would be advantageous if it is in a highly regioselec-
tive manner, yet requiring no chelating-assisted groups.
In regard to the repertoire of acetoxylation (Csp2-O bond-
forming reaction), Sanford6 and Yu7 recently reported land-
mark explorations concerning the arene acetoxylation which
are directed by o-pyridyl or -iminyl moieties and catalyzed by
palladium or copper complexes, respectively. 1,2-Disubsti-
tuted indoles could be acetoxylated together with 3,30-biin-
dolyl products using lead tetraacetate.8 In 2009, one notable
example was reported by Suna on an acetoxylation of 2,3-
unsubstituted indole to give 3-acetoxyindole accompany-
ing with a mixture of oxidative products.9 In 2010, Zhang
† Dedicated to Professor Albert S. C. Chan (currently the President of Hong
Kong Baptist University) on the occasion his 60th birthday.
(1) (a) Beller, M.; Bolm, C. Transition Metals for Organic Synthesis,
Building Blocks and Fine Chemicals, 2nd ed.; Wiley-VCH: Weinheim, 2004;
Vols. 1 and 2. (b) Nigeshi, E., Ed. Handbook of Organopalladium for Organic
Synthesis; Wiley-Interscience: New York, 2002; Vols. 1-2.
(2) For reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4442. (b) Nicolaou, K. C.; Sorensen, E. J. Classics in
Total Synthesis II, More Targets, Strategies and Methods; Wiley-VCH:
Weinheim, 2003.
(3) For recent reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174. (b) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (d) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (e) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (f) Dyker, G. Handbook of C-H
Transformations; Wiley-VCH: Weinheim, 2005.
(4) For recent superb advancements in C-H functionalization, see:
(a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Phipps, R. J.;
Gaunt, M. J. Science 2009, 323, 1593. (c) Wang, D.-H.; Engle, K. M.; Shi,
B.-F.; Yu, J.-Q. Science 2010, 327, 315.
(5) Specially designed (exceedingly bulky) phosphine ligands are neces-
sary for this C-O bond-forming process (i.e., being proposed to favor the
difficult reductive elimination); see: (a) Vorogushin, A. V.; Huang, X. H.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146. (b) Stambuli, J. R.;
Weng, Z. Q.; Incarvito, C. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007, 46,
7674. (c) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423.
(d) Sergeev, A. G.; Schulz, T.; Torborg, C.; Spannenberg, A.; Neumann, H.;
Beller, M. Angew. Chem., Int. Ed. 2009, 48, 7595.
(6) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300. (b) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 9542. (c) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett.
2006, 8, 1141. (d) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149.
(7) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790.
(8) Sukari, M. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans. 1 1983,
2219.
(9) For examples of ortho-ester group-directed acetoxylation of indoles
under AcOH medium at 100 °C, see: Mutule, I.; Suna, E.; Olofsson, K.;
Pelcman, B. J. Org. Chem. 2009, 74, 7195.
80 J. Org. Chem. 2011, 76, 80–84
Published on Web 12/06/2010
DOI: 10.1021/jo101584k
r
2010 American Chemical Society

Choy et al.
JOCArticle
TABLE 1. Initial Optimization of Direct C3-Acetoxylation of Indolea
TABLE 2. Palladium-Catalyzed Direct C3-Acetoxylation of Indolesa
entry
catalyst
solvent
base
% yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2
PdCl2
Pd2dba3
Pd(TFA)2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,2-DCE
DMF
dioxane
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
K3PO4
KOH
70
60
58
59
trace
55
50
26
22
30
56
51
53
16
31
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NaOAc
Et3N
aReaction conditions: catalyst (0.01 mmol, 2 mol %), N-benzylindole
(0.5 mmol), PhI(OAc)2 (1.0 mmol), base (0.5 mmol), and solvent (2.0 mL)
were stirred at 70 °C under nitrogen for 2 h. bCalibrated GC yields were
reported using dodecane as the internal standard.
disclosed the 2,30-biindole synthesis together with the
C3-acetoxylated products using AgOAc under O2.10 Despite
these remarkable developments, the direct and regioselective
acetoxylation (via C-H bond cleavage/C-O bond coupling
sequence) without the assistance from the ortho-directing
group remained sporadically studied.
Indole is an important class of compounds in the pharma-
ceutical chemistry as it possesses unique biological activities.11
In particular, 3-hydroxyindoles (and their alkoxy derivatives)
are common scaffolds in medicinal chemistry. They have
been used in the development of COX-2 inhibitors12 as well
as applied as Mcl-1 inhibitors in the design of novel anti-
tumor agents.13 Moreover, they could serve as 5-HT6 recep-
tor ligand mimics.14 Literature methods for accessing these
3-hydroxyl(-alkoxyl)indoles in moderate to good yields were
mainly from the precursors of 3-bromoindoles15,16 or 3-for-
mylindoles.17 Recently, Beller and co-workers reported the
Ti- and Zn-mediated hydroamination of silyl-protected
propargylic alcohol with arylhydrazine for accessing 3-sily-
loxy-2-methylindoles.18 Despite these limited 3-oxyindole
(10) Liang, Z.; Zhao, J.; Zhang, Y. J. Org. Chem. 2010, 75, 170.
(11) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Humphrey,
G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (c) Crich, D.; Banerjee, A.
Acc. Chem. Res. 2007, 40, 151. (d) Eicher, T.; Hauptmann, S. The Chemistry
of Heterocycles, 2nd ed.; Wiley-VCH: Weinheim, 2003.
(12) Campbell, J. A.; Bordunov, V.; Broka, C. A.; Browner, M. F.; Kress,
J. M.; Mirzadegan, T.; Ramesha, C.; Sanpablo, B. F.; Stabler, R.; Takahara,
P.; Villasenor, A.; Walker, K. A. M.; Wang, J.-H.; Welch, M.; Weller, P.
Bioorg. Med. Chem. Lett. 2004, 14, 4741.
aReaction conditions: Pd(OAc)2 (0.01 mmol, 2 mol %), N-benzylindoles
(0.5 mmol), PhI(OAc)2 (1.0 mmol), KOAc (0.5 mmol), and CH3CN (1.0
mL) were stirred at 70 °C under nitrogen for 1-18 h. bIsolated yields.
(13) Bruncko, M.; Song, X.; Ding, H.; Tao, Z.; Kunzer, A. R.
WO130970A1, 2008.
(14) (a) Alex, K.; Schwarz, N.; Khedkar, V.; Sayyed, I. A.; Tillack, A.;
Michalik, D.; Holenz, J.; Dıaz, J. L.; Beller, M. Org. Biomol. Chem. 2008, 6,
´
1802. For a review on 5-HT6-receptor ligands, see: (b) Holenz, J.; Pauwels,
ꢀ
´
P. J.; Dıaz, J. L.; Merce, R.; Codony, X.; Buschmann, H. Drug Discovery
Today 2006, 11, 283.
(15) (a) Gribble, G. W.; Conway, S. C. Heterocycles 1990, 30, 627.
(b) Unangst, P. C.; Connor, D. T.; Miller, S. R. J. Heterocycl. Chem. 1996,
33, 1627.
syntheses, an exploration of a facile protocol for the direct
acetoxylation of indole, and thus hydroxy/alkoxyindoles,
would be highly favorable. Herein, we disclose our efforts on
direct palladium-catalyzed oxidative C3-acetoxylation of
2-unsubstituted indole in a highly regioselective manner via
the C-H bond cleavage/C-O bond formation sequence.
(16) For Pd-catalyzed alkoxylation of 3-bromoindoles, see ref 13.
(17) For a Baeyer-Villiger oxidation sequence, see: (a) Bourlot, A. S.;
Desarbre, E.; Merour, J.-Y. Synthesis 1994, 411. (b) Hickman, Z. L.; Sturino,
C. F.; Lachance, N. Tetrahedron Lett. 2000, 41, 8217.
(18) For Ti-mediated protocol, see: (a) Schwarz, N.; Alex, K.; Sayyed,
I. A.; Khedkar, V.; Tillack, A.; Beller, M. Synlett 2007, 1091. For Zn-mediated
protocol, see: (b) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew.
Chem., Int. Ed. 2008, 47, 2304.
J. Org. Chem. Vol. 76, No. 1, 2011 81

Choy et al.
SCHEME 1. Palladium-Catalyzed Direct Acetoxylation of
N-Alkylated Indoles (Reaction Conditions are the Same as in
JOCArticle
TABLE 3. Palladium-Catalyzed Direct C3-Acetoxylation of
N-Arylindolesa
Table 2, Entry 1)
SCHEME 2. Cascade Deacetylation-Alkylation Process of
Acetoxyindoles
for direct acetoxylation of substituted indoles (Table 2). In
general, 2 mol % of Pd(OAc)2 was sufficient to catalyze the
reaction. Notably, this direct acetoxylation of indole could
be performed at room temperature (entry 2). Functional groups
such as cyano, bromo, fluoro, and methoxy were compatible
under these reaction conditions, entries 4-8). Notably, the
bromo group remained intact throughout this palladium
catalysis. This is beneficial for further functionalization using
other coupling protocols. Apart from various 5-substituted
indoles, 7-substituted indole furnished the desired product
smoothly (entry 9). Azaindole was found to be a feasible
substrate for this reaction (entry 11).
To further evaluate the catalytic system, we examined the
acetoxylation of N-aryl indoles (Table 3). Moderate to good
yields of the corresponding products were obtained (entries
1-5). This protocol was found to be compatible with ortho-,
meta-, and para-substituted aryl rings on the indolyl scaffold.
Apart from N-benzyl- and N-arylindoles, N-alkylated indoles
were feasible substrates for direct acetoxylation (Scheme 1).
N-Isopropyl- and N-allylindoles were transformed to their
corresponding product selectively. Interestingly, no acetoxy-
lation of olefin moiety was observed on the allyl group under
our reaction conditions.19 Sterically congested 2-phenyl-
N-methylindoles furnished the product in slightly lower yield
presumably due to the steric hindrance of the o-phenyl ring.
3-Hydroxyindoles are slightly unstable and preferably have
silyl or acetyl protection for storage. Indeed, the direct acet-
oxylation of indole would be a useful way to prepare the
protected form of 3-oxyindoles, which can be further function-
alized by an easy alkaline hydrolysis to achieve 3-hydroxyin-
dole motifs in situ. In fact, this organic transformation offers a
simple protocol to afford a series of potential 5-HT6 receptor
ligands.14 Thus, the cascade deacetylation and subsequent
alkylation processes provide a versatile pathway to access trypt-
amine-like 5-HT6 receptor ligand scaffolds, which would be
useful for further structural manipulation (Scheme 2).
aReaction conditions: Pd(OAc)2 (0.01 mmol, 2 mol %), N-arylindoles
(0.5 mmol), PhI(OAc)2 (1.0 mmol), KOAc (0.5 mmol), and CH3CN (1.0
mL) were stirred at 70 °C under nitrogen for 1-2 h. bIsolated yields.
Results and Discussion
In order to achieve the C-3 indole functionalization, a
series of reaction parameter screenings were deployed.
N-Benzyl-protected indole substrate was chosen in the pro-
totypical trials (Table 1). In the model catalysis, PhI(OAc)2
was used as the oxidant to provide the acetoxy group to
indole. An array of commonly used catalyst precursors for
coupling reactions were surveyed (Table 1, entries 1-4).
Pd(OAc)2 gave the best conversion and yield of the product
(entry 1). Control experiments revealed that no product was
formed in the absence of palladium catalyst (entry 5). Lewis
acids such as Zn(OTf)2, KAuCl4, AuCl, AgOTf, Cu(OTf)2,
Yb(OTf)3, and Eu(fod)3 gave only 3-6% yields. Among
solvents screened, CH3CN afforded the best results (entry 1
vs entries 6-9). KOAc base was found to be superior to the
other inorganic bases (entry 1 vs entries 10-13). However,
poorer yields were obtained when organic base or base-free
conditions were used (entries 14 and 15).
Conclusion
In summary, we have developed a general palladium-catalyzed
direct and regioselective C3-acetoxylation of 2,3-unsubstituted
With the preliminary optimized reaction conditions in
hand, we next tested the generality of the catalyst system
(19) For the diacetoxylation of styrenes, see: Wang, A.; Jiang, H.; Chen,
H. J. Am. Chem. Soc. 2009, 131, 3846.
82 J. Org. Chem. Vol. 76, No. 1, 2011

Choy et al.
JOCArticle
1-Benzyl-5-methoxy-1H-indol-3-yl acetate (Table 2, entry 7):
indoles, which is complementary to current difficult C-O
bond-coupling processes using aryl halides as electrophiles.
Moreover, this selective C-H bond-cleavage/C-O bond-
coupling sequence is achievable without the aid of ortho-
directing groups. This protocol provides a facile and direct
access to a variety of pharmaceutically useful 3-oxyindole
scaffolds under mild reaction conditions (weak base, KOAc;
at 70 °C for 1-18 h) and is compatible with the bromo group,
which offers potential for further structuralmodification using
other coupling technology. Detailed mechanistic investiga-
tions are currently underway.
1
EA/petroleum ether/Et3N=1:4:0.1, Rf = 0.5; H NMR (400
MHz, CDCl3) δ 2.40 (s, 3H), 3.90 (s, 3H), 5.24 (s, 2H), 6.89-6.92
(m, 1H), 7.05 (s, 1H), 7.14-7.19 (m, 3H), 7.28-7.36 (m, 4H); 13
C
NMR (100 MHz, CDCl3) δ 20.9, 50.1, 55.6, 98.7, 110.7, 113.2,
117.8, 120.4, 126.6, 127.5, 128.6, 129.3, 137.25, 154.0, 168.4; MS
(EI) m/z (relative intensity) 295 (Mþ, 25), 253 (100), 162 (26), 91
(90); HRMS calcd for C18H18NO3þ 296.1287, found 296.1290.
1-Benzyl-5-methyl-1H-indol-3-yl acetate (Table 2, entry 8):
1
EA/petroleum ether/Et3N=1:6:0.1, Rf = 0.5; H NMR (400
MHz, CDCl3) δ 2.40 (s, 3H), 2.51 (s, 3H), 5.27 (s, 2H), 7.06-7.18
(m, 4H), 7.28-7.36 (s, 4H), 7.42 (t, J = 0.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 20.9, 21.3, 50.0, 109.4, 117.1, 117.3, 120.5,
124.2, 126.7, 127.5, 128.6, 128.8, 129.2, 131.8, 137.3; MS (EI) m/
z (relative intensity) 279 (Mþ, 23), 257 (100), 146 (31), 91 (94);
HRMS calcd for C18H18NO2þ 280.1338, found 280.1339.
1-Benzyl-7-methoxy-1H-indol-3-yl acetate (Table 2, entry 9):
EA/petroleum ether/Et3N=1:6:0.1, Rf = 0.45; 1H NMR (400
MHz, CDCl3) δ 2.38 (s, 3H), 3.88 (s, 3H), 5.63 (s, 2H), 6.7
Experimental Section
General Procedures for Acetoxylation of N-Substituted Indoles
(Pd Catalyst Loading Range of 2-5 mol %). Pd(OAc)2, PhI-
(OAc)2 (1.0 mmol), substituted benzylindoles (0.5 mmol), and
KOAc (0.5 mmol) were loaded into a Schlenk tube equipped
with a Teflon-coated magnetic stir bar. The tube was evacuated
and flushed with nitrogen three times. The solvent acetonitrile
(1.0 mL) was then added with stirring at room temperature for
several minutes. The tube was then placed into a preheated oil
bath (70 °C/25 °C) and stirred for the time as indicated in
Tables 2 and 3. After completion of the reaction as judged by
GC analysis, the reaction tube was allowed to cool to room
temperature and quenched with sodium bisulfate solution and
water. EtOAc was then added for dilution. The organic layer
was separated, and the aqueous layer was washed with EtOAc.
The filtrate was concentrated under reduced pressure. The crude
products were purified by flash column chromatography on
silica gel (230-400 mesh) to afford the desired product.
1-Benzyl-1H-indol-3-yl acetate (example from Table 2, entry
1):20 EA/petroleum ether/Et3N = 1:9:0.1, Rf = 0.3; 1H NMR
(400 MHz, CDCl3) δ 2.39 (s, 3H), 5.30 (s, 2H), 7.16-7.26
(m, 4H), 7.29-7.38 (m, 5H), 7.62-7.64 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.9, 50.0, 109.6, 117.2, 117.6, 119.5, 120.3,
122.5, 126.7, 127.6, 128.7, 129.7, 133.3, 137.1, 168.4; MS (EI)
m/z (relative intensity) 265 (Mþ, 20), 223 (89), 91 (100). (See the
Supporting Information for copies of the spectra.)
(d, J = 7.6 Hz, 1H), 7.05-7.10 (m, 1H), 7.18-7.34 (m, 7H); 13
C
NMR (100 MHz, CDCl3) δ 20.8, 52.4, 55.2, 103.3, 110.2, 118.0,
120.0, 122.4, 123.1, 126.7, 127.1, 128.4, 129.8, 139.2, 147.4,
168.3; MS (EI) m/z (relative intensity) 295 (Mþ, 33), 253 (100),
162 (16), 91 (64); HRMS calcd for C18H18NO3þ 296.1287, found
296.1293.
1-Benzyl-7-methyl-1H-indol-3-yl acetate (Table 2, entry 10):
EA/petroleum ether/Et3N=1:9:0.1, Rf = 0.45; 1H NMR (400
MHz, CDCl3) δ 2.38 (s, 3H), 2.54 (s, 3H), 5.55 (s, 2H), 6.92-6.98
(m, 3H), 7.04 (t, J = 7.2 Hz, 1H), 7.25-7.45 (m, 4H), 7.47
(d, J = 0.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.5, 20.9,
52.2, 115.5, 118.9, 119.8, 121.2, 121.4, 125.4, 127.3, 128.8, 129.7,
132.2, 139.2, 168.4; MS (EI): m/z (relative intensity) 279 (Mþ,
25), 237 (83), 146 (41), 91 (100); HRMS calcd for C18H17NO2-
Naþ 302.1157, found 302.1157.
1-Benzyl-1H-pyrrolo[2,3-b]pyridine-3-yl acetate (Table 2, entry
11): EA/petroleum ether/Et3N = 1:6:0.1, Rf = 0.5; 1H NMR (400
MHz, CDCl3) δ 2.34 (s, 3H), 5.50 (s, 2H), 7.10-7.14 (dd,
J = 0.8, 3.2 Hz, 1H), 7.24-7.35 (m, 6H), 7.89 (dd, J = 1.6,
6.4 Hz, 1H), 7.10-8.40 (t, J = 3.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.7, 47.5, 112.7, 115.7, 116.7, 126.2, 127.4, 127.6, 127.9,
128.6, 137.3, 143.8, 144.0; MS (EI) m/z (relative intensity) 266
(Mþ, 16), 224 (92), 147 (18), 91 (100); HRMS calcd. for C16H15-
N2O2þ 267.1134, found 267.1130.
1-Benzyl-5-cyano-1H-indol-3-yl acetate (Table 2, entry 4):
EA/petroleum ether/Et3N=1:2:0.1, Rf = 0.5; H NMR (400
1
MHz, CDCl3) δ 2.38 (s, 3H), 5.29 (s, 2H), 7.13 (dd, J = 1.2, 6.0
Hz, 2H), 7.30-7.41 (m, 5H), 7.50 (s, 1H), 7.96 (dd, J = 0.4, 1.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.7, 50.3, 102.6, 110.5,
119.4, 120.1, 123.5, 125.1, 126.7, 128.0, 128.8, 129.8, 134.2,
135.9; MS (EI) m/z (relative intensity) 290þ(Mþ, 9), 248 (57),
91 (100); HRMS calcd for C18H15N2O2 291.1134, found
291.1140.
1-Benzyl-2-methyl-1H-indol-3-yl acetate (Table 2, entry 12).
EA/petroleum ether/Et3N = 1:4:0.1, Rf = 0.7; 1H NMR (400
MHz, CDCl3) δ 2.28 (s, 3H), 2.44 (s, 3H), 5.31 (s, 2H), 7.04 (d,
J = 6.8 Hz, 2H), 7.14-7.20 (m, 2H), 7.25-7.34 (m, 4H), 7.45-
7.47 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 9.0, 20.5, 46.4,
109.3, 116.7, 119.6, 120.7, 121.4, 125.6, 125.9, 126.5, 127.3,
128.7, 133.9, 137.5, 169.3; MS (EI) m/z (relative intensity) 279
(Mþ, 23), 237 (100), 146 (35), 91 (91); HRMS calcd for C18H18-
NO2þ 280.1338, found 280.1341.
1-Benzyl-5-fluoro-1H-indol-3-yl acetate (Table 2, entry 5):
EA/petroleum ether/Et3N=1:9:0.1, Rf = 0.4; H NMR (400
1
MHz, CDCl3) δ 2.38 (s, 3H), 5.26 (s, 2H), 6.95-7.00 (m, 1H),
7.14-7.21 (m, 3H), 7.26-7.36 (m, 4H), 7.42 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.8, 50.3, 102.5, 102.7, 110.6, 110.7, 110.9,
111.2, 119.0, 120.4, 120.5, 126.7, 127.7, 128.7, 129.5, 129.9,
136.8, 156.5, 158.8, 168.3; MS (EI) m/z (relative intensity) 283
(Mþ, 14), 241 (69), 91 (100); HRMS calcd for C17H15NO2Fþ
284.1087, found 284.1048.
1-Benzyl-5-bromo-1H-indol-3-yl acetate (Table 2, entry 6):
EA/petroleum ether/Et3N = 1:9:0.1, Rf = 0.3; 1H NMR (400
MHz, CDCl3) δ 2.37 (s, 3H), 5.24 (s, 2H), 7.12-7.26 (m, 3H),
7.28-7.33 (m, 4H), 7.38 (s, 1H), 7.76 (dd, J = 0.4, 1.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 20.8, 50.2, 111.2, 112.8, 118.4,
120.2, 121.9, 125.3, 126.6, 127.8, 128.7, 131.8, 136.6, 168.2; MS
(EI) m/z (relative intensity) 343 (Mþ, 8), 301 (43), 91 (100);
HRMS calcd for C17H14NO2NaBrþ 366.0106, found 366.0117.
1-Phenyl-1H-indol-3-yl acetate (Table 3, entry 1):21 EA/pet-
1
roleum ether/Et3N = 1:9:0.1, Rf = 0.4; H NMR (400 MHz,
CDCl3) δ 2.44 (s, 3H), 7.25-7.33 (m, 2H), 7.37-7.41 (m, 1H),
7.54-7.70 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 20.9, 110.5,
116.9, 117.7, 120.3, 121.1, 123.1, 124.3, 126.3, 129.5, 131.4,
132.7, 139.3, 168.3; MS (EI) m/z (relative intensity) 251 (Mþ,
18), 209 (100), 180 (33), 77 (20).
1-(4-Methoxyphenyl)-1H-indol-3-yl acetate (Table 3, entry
2):22 EA/petroleum ether/Et3N = 1: 4: 0.1, Rf = 0.5; 1H
NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 3.90 (s, 3H), 7.04-
7.08 (m, 2H), 7.21-7.30 (m, 2H), 7.43-7.44 (m, 3H), 7.45
(s, 1H), 7.47-7.69 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
(21) Moltzen, E. K.; Perregaard, J. K. EP 518805 A1 19921216.
(22) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Eur. J. Org.
Chem. 2007, 13, 2147.
(20) Haro, T. d.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512.
J. Org. Chem. Vol. 76, No. 1, 2011 83

Choy et al.
JOCArticle
20.8, 55.4, 110.3, 114.6, 117.3, 117.6, 120.0, 120.7, 122.9, 125.9,
130.9, 132.2, 133.2, 158.1, 168.3; MS (EI) m/z (relative intensity)
281 (Mþ, 22), 239 (100), 210 (15), 77 (12).
1-Methyl-2-phenyl-1H-indol-3-yl acetate (Scheme 1): EA/
petroleum ether/Et3N = 1:9:0.1, Rf = 0.5; 1H NMR (400 MHz,
CDCl3) δ 2.33 (s, 3H), 3.72 (s, 3H), 7.21-7.25 (m, 1H),
7.31-7.35 (m, 1H), 7.41-7.57 (m, 7H); 13C NMR (100 MHz,
CDCl3) δ 20.4, 30.8, 109.7, 117.3, 119.9, 120.5, 122.4, 126.4,
128.2, 128.5, 129.4, 130.0, 134.9, 169.8; MS (EI) m/z (relative
intensity) 265 (Mþ, 13), 223 (100); HRMS calcd for C17H16-
NO2þ 266.1181, found 266.1173.
5-Methoxy-1-(4-methylphenyl)-1H-indol-3-yl acetate (Table 3,
entry 3): EA/petroleum ether/Et3N = 1:4:0.1, Rf = 0.5; 1H NMR
(400 MHz, CDCl3) δ 2.44 (d, J = 6.8 Hz, 3H), 3.92 (s, 3H), 6.93
(dd, J = 2.0, 6.8 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 7.32 (d, J =
4.0, 2H), 7.39-7.46 (m, 5H), 7.56 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.8, 20.9, 55.7, 98.8, 111.6, 113.5, 117.5, 121.2, 123.9,
128.1, 130.0, 130.9, 136.0, 136.9, 154.4, 158.3; MS (EI) m/z
(relative intensity) 295 (Mþ, 22), 253 (100), 210 (15); HRMS calcd
for C18H18NO3þ 296.1287, found 296.1295.
1-Methyl-1H-indol-3-yl acetate (Scheme 2):23 EA/hexane/
Et3N = 1:4:0.1, Rf = 0.5; 1H NMR (400 MHz, CDCl3) δ 2.39
(s, 3H), 3.77 (s, 3H), 7.14-7.18 (m, 1H), 7.26-7.34 (m, 3H),
7.57-7.60 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 20.9, 32.7,
109.2, 117.4, 117.8, 119.2, 120.0, 122.2, 129.0, 133.6, 168.7; MS
(EI) m/z (relative intensity) 189 (Mþ, 21), 147 (100), 132 (11), 77
(13).
1-(3,5-Dimethylphenyl)-5-methoxy-1H-indol-3-yl acetate (Table 3,
entry 4): EA/petroleum ether/Et3N = 1:4:0.1, Rf = 0.5; 1H
NMR (400 MHz, CDCl3) δ 2.43 (d, J = 3.6 Hz, 9H), 3.93
(s, 3H), 6.95 (dd, J = 2.8, 6.4 Hz, 1H), 7.00 (s, 1H), 7.07 (d, J =
2.4 Hz, 1H), 7.14 (s, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 20.9, 21.2, 55.7, 98.7, 111.7,
113.5, 117.4, 121.3, 121.7, 127.8, 128.0, 131.0, 139.2, 139.3,
154.4, 158.3; MS (EI) m/z (relative intensity) 309 (Mþ, 24),
N,N-Dimethyl-2-(1-methyl-1H-indol-3-yloxy)ethanamine
(Scheme 2): MeOH/CHCl3 = 1:9, Rf = 0.45; H NMR (400
1
MHz, C6D6) δ 2.18 (s, 6H), 2.64 (t, J = 6.0 Hz, 2H), 2.97 (s, 3H),
3.98 (t, J = 6.0 Hz, 2H), 6.11 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H),
7.09-7.22 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, C6D6) δ 31.9, 46.0, 58.7, 70.0, 109.2, 110.0, 118.5, 118.7,
120.6, 122.5, 135.3, 140.4; MS (EI) m/z (relative intensity) 218
(Mþ, 8), 146 (10), 72 (100), 58 (33) ; HRMS calcd for
C13H19N2Oþ 219.1497, found 219.1506.
þ
267 (100), 251 (18); HRMS calcd for C19H20NO3 310.1443,
found 310.1454.
5-Methoxy-1-o-tolyl-1H-indol-3-yl acetate (Table 3, entry 5):
EA/petroleum ether/Et3N = 1:4:0.1, Rf = 0.7; H NMR (400
1
MHz, CDCl3) δ 2.13 (s, 3H), 2.43 (s, 3H), 3.92 (s, 3H), 6.88-6.97
(m, 2H), 7.09 (d, J = 2.0 Hz, 1H), 7.33-7.43 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 17.5, 20.9, 55.7, 98.7, 111.6, 113.5, 118.3,
120.2, 126.6, 128.1, 128.1, 129.3, 130.4, 131.1, 135.7, 137.8,
154.3, 168.2; MS (EI) m/z (relative intensity) 295 (Mþ, 23),
253 (100), 238 (20); HRMS calcd for C18H17NO3Naþ 318.1106,
found 318.1093.
N,N-Dimethyl-2-(1-benzyl-1H-indol-3-yloxy)ethanamine
(Scheme 2): MeOH/CHCl3 = 1:9, Rf = 0.5; 1H NMR (400
MHz, C6D6) δ 2.16 (s, 6H), 2.62 (t, J = 6.0 Hz, 2H), 3.93 (t, J =
8.0 Hz, 2H), 4.68 (s, 2H), 6.27 (s, 1H), 6.81-6.84 (m, 2H),
6.97-7.03 (m, 4H), 7.07-7.16 (m, 2H), 7.96-7.98 (m, 1H); 13
C
NMR (100 MHz, C6D6) δ 46.6, 50.1, 59.2, 70.4, 109.6, 110.2,
119.4, 119.5, 121.5, 123.6, 127.4, 128.1, 128.3, 129.4, 135.7,
139.1, 141.6; MS (EI) m/z (relative intensity) 294 (Mþ, 7), 91
(32), 72 (100), 58 (23); HRMS calcd for C19H23N2Oþ 295.1810,
found 295.1796.
1-Allyl-1H-indol-3-yl acetate (Scheme 1). EA/petroleum
ether/Et3N = 1:9:0.1, Rf = 0.5; H NMR (400 MHz, CDCl3)
1
δ 2.39 (s, 3H), 4.70-4.72 (m, 2H), 5.12-5.14 (m, 1H), 5.17-5.18
(m, 1H), 5.22-5.26 (m, 1H), 5.96-6.06 (m, 1H), 7.14-7.18 (m,
1H), 7.24-7.28 (m, 1H), 7.31-7.33 (m, 2H), 7.58-7.61 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 20.9, 48.7, 109.5, 116.8, 117.4,
117.5, 119.4, 120.3, 122.3, 129.5, 133.1, 133.1, 168.3; MS (EI)
m/z (relative intensity) 215 (Mþ, 28), 173 (100), 132 (76); HRMS
calcd for C13H13NO2Naþ 238.084, found 238.0851.
1-Isopropyl-1H-indol-3-yl acetate (Scheme 1): EA/petroleum
ether/Et3N = 1:9:0.1, Rf = 0.45; 1H NMR (400 MHz, CDCl3) δ
1.56 (d, J = 6.8 Hz, 6H), 2.41 (s, 3H), 4.68-4.75 (m, 1H),
7.16-7.20 (m, 1H), 7.27-7.31 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H),
7.47 (s, 1H), 7.63 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.8, 22.5, 47.0, 109.3, 112.7, 117.5, 119.1, 120.1,
121.9, 129.5, 132.4, 168.5; MS (EI) m/z (relative intensity) 217
(Mþ, 34), 175 (89), 160 (100), 132 (44); HRMS calcd for
C13H15NO2Naþ 240.1000, found 240.1002.
Acknowledgment. We thank the Research Grants Council
of Hong Kong (CERG: PolyU5008/08P), PolyU Internal
Competitive Research Grant (A-PG13), and the University
Grants Committee Areas of Excellence Scheme (AoE/P-10/01)
for financial support. We are grateful to Prof. Albert S. C.
Chan’s research group for sharing of GC-FID and GC-
MS instruments. Special thanks goes to Dr. Man-Kin Wong,
Ms. Karen Ka-Yan Kung, and Mr. Yat-Sing Fung for pro-
viding some Lewis acids and helpful suggestions.
Supporting Information Available: Detail experimental
procedures and copies of 1H NMR, 13C NMR, and HRMS
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
(23) Capon, B; Kwok, F. C. J. Am. Chem. Soc. 1989, 111, 5346.
84 J. Org. Chem. Vol. 76, No. 1, 2011