Gold-catalyzed intramolecular allylic amination of 2-tosylaminophenylprop- 1-en-3-ols. A concise synthesis of (±)-angustureine

Article abstract of DOI:10.1021/jo900917q

(Chemical Equation Presented) An efficient synthetic route to 1,2-dihydroquinolines that relies on AuCl ₃/AgSbF₆- catalyzed intramolecular allylic amination of 2-tosylaminophenylprop-1-en-3-ols is described herein. Uniquely, the reac

Full text of DOI:10.1021/jo900917q

pubs.acs.org/joc
Gold-Catalyzed Intramolecular Allylic Amination of
2-Tosylaminophenylprop-1-en-3-ols. A Concise Synthesis of
(()-Angustureine
Prasath Kothandaraman, Shi Jia Foo, and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
waihong@ntu.edu.sg
Received May 3, 2009
An efficient synthetic route to 1,2-dihydroquinolines that relies on AuCl3/AgSbF6-catalyzed
intramolecular allylic amination of 2-tosylaminophenylprop-1-en-3-ols is described herein. Un-
iquely, the reactions were found to only proceed rapidly at room temperature in the presence of the
gold and silver catalyst combination and produce the 1,2-dihydroquinoline products in yields of 40-
91%. The method was shown to be applicable to a broad range of 2-tosylaminophenylprop-1-en-3-
ols containing electron-withdrawing, electron-donating, and sterically demanding substrate combi-
nations. The mechanism is suggested to involve activation of the alcohol substrate by the AuCl3/
AgSbF6 catalyst. This is followed by ionization of the starting material, which causes intramolecular
nucleophilic addition of the sulfonamide unit to the allylic cation moiety and construction of the 1,
2-dihydroquinoline. The utility of this N-heterocyclic ring forming strategy as a synthetic tool that
makes use of alcohols as pro-electrophiles was exemplified by its application to the synthesis of the
bioactive tetrahydroquinoline alkaloid (()-angustureine.
Introduction
Prim, and co-workers, who showed benzylation and propar-
gylation of anilines, azides, and sulfonamides with benzylic
and propargylic alcohols to proceed smoothly in the pre-
Gold-catalyzed carbon-nitrogen bond formations have
become a powerful and convenient synthetic route to amines
and amine derivatives in recent years.1-8 Generally, this type
of reaction has relied upon the interaction of the gold catalyst
with the π-bonds of alkenes, alkynes, and allenes followed by
attack of a nitrogen nucleophile.1-3 In contrast, the estab-
lishing of amination strategies in gold catalysis that make use
of other functional groups as electrophiles has received
much less attention and examples have remained sparse. In
this regard, a recent notable advance is that by Campagne,
sence of NaAuCl4 2H2O as catalyst.4 Following this seminal
3
(2) Selected examples: (a) Nishina, N.; Yamamoto, Y. Tetrahedron 2009,
65, 799. (b) Buzas, A.; Istrate, F.; Le Goff, X. F.; Odabachian, Y.; Gagosz, F.
J. Organomet. Chem. 2009, 694, 515. (c) Shapiro, N. D.; Toste, F. D. J. Am.
Chem. Soc. 2008, 130, 9244. (d) Hashmi, A. S. K.; Rudolph, M.; Bats, J. W.;
Frey, W.; Rominger, F.; Oeser, T. Chem.;Eur. J. 2008, 14, 6672. (e) Istrate,
F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.; Gagosz, F. Org. Lett.
2008, 10, 925. (f) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.;
Yamamoto, Y. Chem. Asian J. 2008, 3, 285. (g) Zhang, Z.; Bender, C. F.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 4148. (h) Istrate, F. M.;
Gagosz, F. Org. Lett. 2007, 9, 3181. (i) LaLonde, R. L.; Sherry, B. D.; Kang,
E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. (j) Zhang, Z.; Liu, C.;
Kinder, R. E.; Han, H.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
2006, 128, 9066. (k) Hashmi, A. S. K.; Haufe, P.; Schmid, C.; Nass, A. R.;
Frey, W. Chem.;Eur. J. 2006, 12, 5376. (l) Hashmi, A. S. K.; Rudolph, M.;
Schymura, S.; Visus, J.; Frey, W. Eur. J. Org. Chem. 2006, 4905. (m) Morita,
N.; Krause, N. Eur. J. Org. Chem. 2006, 20, 4634. (n) Shi, M.; Liu, L.-P.;
Tang, J. Org. Lett. 2006, 8, 4043. (o) Nishina, N.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2006, 45, 3314. (p) Zhang, J.; Yang, C.-G.; He, C. J. Am.
Chem. Soc. 2006, 128, 1798. (q) Han, X.; Widenhoefer, R. A. Angew. Chem.,
Int. Ed. 2006, 45, 1747. (r) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 11260. (s) Morita, N.; Krause, N. Org. Lett. 2004, 6,
4121. (t) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349.
(1) For recent reviews on gold-catalyzed reactions, see: (a) Muzart, J.
Tetrahedron 2008, 64, 5815. (b) Hashmi, A. S. K. Angew. Chem., Int. Ed.
2008, 47, 6754. (c) Shen, H. C. Tetrahedron 2008, 64, 3885. (d) Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766. (e) Coinage Metals in
Organic Synthesis; Lipshutz, B. H., Yamamoto, Y., Eds. Chem. Rev. 2008, 108,
2793. (f) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817. (g) Gorin, D. J.; Toste, F.
D. Nature 2007, 446, 395. (h) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
ꢀ
ꢀ ~
(i) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun. 2007, 333.
(j) F€urstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 2. (k) Hashmi,
A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (l) Asao, N.
€
Synlett 2006, 1645. (m) Hoffmann-Roder, A.; Krause, N. Org. Biomol. Chem.
2005, 3, 387.
DOI: 10.1021/jo900917q
r
Published on Web 07/15/2009
J. Org. Chem. 2009, 74, 5947–5952 5947
2009 American Chemical Society

Kothandaraman et al.
JOCArticle
work, Liu and co-workers reported a similar efficient AuCl3-
mediated approach for the allylic alkylation of p-toluenesul-
fonamide with allylic alcohols.5 More recently, we6 and the
groups of Liu7 and Liang8 described gold-catalyzed tandem
amination/intramolecular hydroamination strategies for the
synthesis of pyrrolidines and pyrroles from the respective
cyclopropylmethanol and 1-en-4-yn-3-ol substrates could
also be accomplished. In view of these works and an ongoing
program on C-N bond formations,6,9 we began to turn our
attention to expanding the scope of gold-mediated reactions
of alcohol pro-electrophiles as the basis for developing new
strategies to 1,2-dihydroquinolines.
In addition to their presence in a myriad of bioactive
natural products and therapeutics, partially hydrogenated
quinolines are an immensely important class of building
blocks in organic synthesis.10 Although this has led to many
synthetic methods11 that has also recently included gold
catalysis,3 the reactions have been reported to usually require
high temperatures and/or prolonged reaction times. In addi-
tion, limited examples demonstrating substrate scope, mod-
est selectivities, and, in many cases, the need for more than
stoichiometric amounts of various reagents and additives has
lessened their utility in organic synthesis. We envisioned a
gold-catalyzed strategy involving the use of alcohol pro-
electrophiles12,13 would be attractive from a synthetic stand-
point as the ease of preparing the starting material provides
the possibility to introduce a wide variety of substitution
patterns in one step. Added to this is the potential formation
of H2O as the only side product. To our knowledge, while
methods for quinoline synthesis from alcohols have been
recently described,14 the corresponding studies to 1,2-dihy-
droquinolines have been thus far limited to two reported
literature methods. Lau and co-workers reported the ther-
molytic electrocyclization of N-methyl-2-hydroxyalkylani-
lines and found the reaction to only proceed at high
temperatures (80-180 °C).15 At about the same time, Ko-
bayashi and co-workers showed that intramolecular cycliza-
tion of o-(1-hydroxy-2-alkenyl)phenyl isocyanides could be
accomplished in the presence of BF3 Et2O as catalyst at
3
0 °C.16 However, these methods were shown to give low to
good product yields and only applicable to a limited sub-
strate scope. In this regard, it remains a challenge to develop
catalytic systems that can effect efficient 1,2-dihydroquino-
line formation for a wide variety of alcohol pro-electrophiles
under ambient conditions. Herein, we report an efficient
synthetic route to 1,2-dihydroquinolines involving intramo-
lecular allylic amination of 2-tosylaminophenylprop-1-en-3-
ols catalyzed by AuCl3 with AgSbF6 as a cocatalyst under
mild conditions at room temperature (Scheme 1). Uniquely,
the reaction was found to only efficiently proceed in the
presence of a gold and silver catalyst combination and
provide good to excellent product yields up to 91% for a
wide variety of starting alcohols. The application of this
catalytic 1,2-dihydroquinoline formation process to the
synthesis of (()-angustureine in four steps is also presented.
(3) (a) Yadav, J. S.; Reddy, B. V. S.; Yadav, N. N.; Gupta, M. K.; Sridhar,
B. J. Org. Chem. 2008, 73, 6857. (b) Xiao, F.; Chen, Y.; Liu, Y.; Wang, J.
Tetrahedron 2008, 64, 2755. (c) Waldmann, H.; Karunakar, G. V.; Kumar,
K. Org. Lett. 2008, 10, 2159. (d) Godet, T.; Belmont, P. Synlett 2008, 2513.
(e) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9, 4821.
(f) Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645.
(g) Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.; Thomas, A. W.;
Verron, J.; Masciadri, R. Tetrahedron 2007, 63, 2811. (h) Kuninobu, Y.;
Inoue, Y.; Takai, K. Chem. Lett. 2007, 36, 1422. (i) Arcadi, A.; Chiarini, M.;
Di Giuseppe, S.; Marinelli, F. Synlett 2003, 203. (j) Arcadi, A.; Bianchi, G.;
Di Guiseppe, S.; Marinelli, F. Green Chem. 2003, 5, 64.
(4) (a) Georgy, M.; Boucard, V.; Debleds, O.; Dal Zotto, C.; Campagne,
J.-M. Tetrahedron 2009, 65, 1758. (b) Terrasson, V.; Marque, S.; Georgy, M.;
Campagne, J.-M.; Prim, D. Adv. Synth. Catal. 2006, 348, 2063.
(5) Guo, S.; Song, F.; Liu, Y. Synlett 2007, 964.
(6) Rao, W.; Chan, P. W. H. Chem.;Eur. J. 2008, 14, 10486.
(7) Lu, Y.; Fu, X.; Chen, H.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal.
2009, 351, 129.
SCHEME 1. AuCl3/AgSbF6-Catalyzed Intramolecular Ami-
nation of 2-Tosylaminophenylprop-1-en-3-ols and Its Application
to the Synthesis of (()-Angustuerine
(8) Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-G.; Guo, L.-N.; Liang,
Y.-M. Adv. Synth. Catal. 2008, 350, 243.
(9) (a) Rao, W.; Zhang, X.; Sze, E. M. L; Chan, P. W. H. J. Org. Chem.
2009, 74, 1740. (b) Chang, J. W. W.; Ton, T. M. U.; Zhang, Z.; Xu, Y.; Chan,
P. W. H. Tetrahedron Lett. 2009, 50, 161. (c) Wu, W.; Rao, W.; Er, Y. Q.;
Loh, K. J.; Poh, C. Y.; Chan, P. W. H. Tetrahedron Lett. 2008, 49, 2620;
Tetrahedron Lett. 2008, 49, 4981. (d) Chang, J. W. W.; Chan, P. W. H.
Angew. Chem., Int. Ed. 2008, 47, 1138. (e) Rao, W.; Chan, P. W. H.
Tetrahedron Lett. 2007, 48, 3789. (f) Chang, J. W. W.; Xu, X.; Chan, P. W.
H. Tetrahedron Lett. 2007, 48, 245.
(10) (a) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Ramsden,
C. A., Scriven, E. F. V., Taylor R. J. K., Eds.; Elsevier Science: Oxford, UK,
2008, Vol. 7. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166. (c) Kouznetsov,
ꢀ
ꢀ
V. V.; Mendez, L. Y. V.; Gomez, C. M. M. Curr. Org. Chem. 2005, 9, 141.
(d) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic: New York, 1987;
Vol. 30, pp 251-377. (e) Lewis, J. R. Nat. Prod. Rep. 1994, 11, 329. (f) Jeffs, P.
W. In The Alkaloids; Rodrigo, R. G. A., Ed.; Academic: New York, 1981, Vol.
19, pp 1-80.
(12) For recent reviews on the use of alcohols as pro-electrophiles, see ref
1a and the following: (a) Bandini, M.; Tragni, M. Org. Biomol. Chem. 2009,
7, 1501. (b) Kabalka, G. W.; Yao, M.-L. Curr. Org. Synth. 2008, 5, 28.
(c) Muzart, J. Eur. J. Org. Chem. 2007, 3077. (d) Muzart, J. Tetrahedron 2005,
61, 4179. (e) Tamaru, Y. Eur. J. Org. Chem. 2005, 2647.
(13) For recent examples of amination of alcohol pro-electrophiles with
metal-catalyzed systems other than gold, see: (a) Nishikata, T.; Lipshutz, B.
H. Org. Lett. 2009, 11, 2377. (b) Utsunomiya, M.; Miyamoto, Y.; Ipposhi, J.;
Ohshima, T.; Mashima, K. Org. Lett. 2007, 9, 3371. (c) Piechaczyk, O.;
Thoumazet, C.; Jean, Y.; le Floch, P. J. Am. Chem. Soc. 2006, 128, 14306.
(d) Zhan, Z.-P.; Yu, J.-L.; Cui, Y.-Y.; Yang, R.-F.; Yang, W.-Z.; Li, J.-P. J.
Org. Chem. 2006, 71, 8298. (e) Kinoshita, H.; Shinokubo, H.; Oshima, K.
Org. Lett. 2004, 6, 4085. (f) Kayaki, Y.; Koda, T.; Ikariya, T. J. Org. Chem.
2004, 69, 2595. (g) Ozawa, F.; Ishiyama, T.; Yamamoto, S.; Kawagishi, S.;
Murakami, H.; Yoshifuji, M. Organometallics 2004, 23, 1698. (h) Ozawa, F.;
Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji, M. J.
Am. Chem. Soc. 2002, 124, 10968.
(11) (a) O’Byrne, A.; Evans, P. Tetrahedron 2008, 64, 8067. (b) Rueping,
M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45,
3683. (c) Ryu, J.-S. Bull. Korean Chem. Soc. 2006, 27, 631. (d) Yi, C. S.; Yun,
S. Y. J. Am. Chem. Soc. 2005, 127, 17000. (e) Yi, C. S.; Yun, S. Y.; Guzei, I. A.
J. Am. Chem. Soc. 2005, 127, 5782. (f) Williamson, N. M.; Ward, A. D.
Tetrahedron 2005, 61, 155. (g) Theeraladanon, C.; Arisawa, M.; Nishida, A.;
Nakagawa, M. Tetrahedron 2004, 60, 3017. (h) Ranu, B. C.; Hajra, A.; Dev,
S. S.; Jana, U. Tetrahedron 2003, 59, 813. (i) Cooper, M. A.; Lucas, M. A.;
Taylor, J. M.; Ward, A. D.; Williamson, N. M. Synthesis 2001, 621.
(j) Taylor, E. C.; Macor, J. E.; French, L. G. J. Org. Chem. 1991, 56, 1807.
(k) Taylor, E. C.; Macor, J. E.; French, L. G. J. Org. Chem. 1991, 56, 1807.
(l) Arduini, A.; Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G. Synthesis
1981, 975. (m) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279.
(n) Hennion, G. F.; Hanzel, R. S. J. Am. Chem. Soc. 1960, 82, 4908.
(o) Skraup, Z. H. Ber. 1880, 13, 2086. (p) Wahren, M. Tetrahedron 1964,
20, 2773. (q) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903.
5948 J. Org. Chem. Vol. 74, No. 16, 2009

Kothandaraman et al.
JOCArticle
TABLE 1. Optimization of the Reaction Conditionsa
Results and Discussion
Initially, we chose N-(2-(2-hydroxybut-3-en-2-yl)phenyl)-
4-methylbenzenesulfonamide 1a as the model substrate to
establish the reaction conditions (Table 1). This revealed
treatment of 1 equiv of 1a with 5 mol % of AuCl3 and 15 mol %
of AgSbF6 in toluene at room temperature for 1 h gave the best
result (entry 1). Under these conditions, 4-methyl-1-tosyl-1,2-
dihydroquinoline 2a was furnished as the sole product in 87%
yield. The 1,2-dihydroquinoline product was confirmed by 1H
NMR analysis and X-ray crystal structure determination of
three closely related products vide infra. Lower product yields
of 32-56% were obtained when the reaction was repeated with
lower loadings of 5 or 10 mol % of AgSbF6 or removing the
AgCl formed in situ prior to use (entries 2-4). Similarly, a
lower product yield of 58% was afforded when the reaction
was performed in nitromethane in place of toluene as solvent
(entry 5). In contrast, the analogous reactions in acetonitrile or
1,4-dioxane were found to result in trace product formation
and near-quantitative recovery of the starting alcohol (entries 6
and 7). An inspection of entries 8-25 in Table 1 revealed the
reaction also proceeded less effectively with other Lewis and
entry
catalyst
solvent
PhMe
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgSbF6
AuCl3/AgOTf
AuCl/AgSbF6
AuCl/AgOTf
Ph3PAuCl/AgSbF6
AuCl3
1
4
4
16
16
16
16
16
4
87
PhMe
PhMe
PhMe
MeNO2
MeCN
1,4-dioxane
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
55b
32c
56d
58
e
-
-
e
72
62
60
68
15
4
6
16
16
16
16
16
16
16
16
16
16
16
16
16
f
AuCl
-
f
Ph3PAuCl
AgSbF6
AgOTf
Bi(OTf)3
CuCl2
Cu(OTf)2
Yb(OTf)3
InCl3
FeCl3.6H2O
BF3.Et2O
-
f
-
f
-
f
-
f
Bronsted acid catalysts. In these reactions, the use of AuCl3 in
e
-
combination with AgOTf, AuCl with AgOTf or AgSbF6, or
Ph3PAuCl with AgSbF6 were the only instances that gave
slightly lower product yields of 62-72% (entries 8-11). When
12
7
11
18
16
13
we examined AuCl3, Yb(OTf)3, Cu(OTf)2, InCl3, FeCl3 6
3
H2O, BF3 Et2O, and p-TsOH H2O as the catalyst, markedly
p-TsOH.H2O
TfOH
HCl
3
3
g
0.5
0.5
-
-
lower product yields of 7-18% were afforded (entries 12 and
19-24). However, changing the catalyst to AuCl, Ph3PAuCl,
AgSbF6, AgOTf, Bi(OTf)3, or CuCl2 gave no reaction on the
g
aAll reactions were performed at room temperature with 0.2 mmol of
1a in the presence of 5 mol % of catalyst. bReaction performed with
5 mol % of AuCl3 and 10 mol % of AgSbF6. cReaction performed with
5 mol % of AuCl3 and 5 mol % of AgSbF6. dReaction performed with
5 mol % of AuCl3 and 15 mol % of AgSbF6 with removal of AgCl prior
1
basis of H NMR or TLC analysis of the crude mixtures
(entries 13-18). On the other hand, when TfOH or HCl was
employed as catalyst, the reaction was found to proceed to give
a wide variety of side products that could not be separated by
flash column chromatography or identified by 1H NMR
analysis of the crude mixtures (entries 25 and 26). The con-
trasting catalytic activities observed for the respective AgSbF6-
and TfOH-mediated reactions also provided evidence that the
cationic Au(III) complex is the active species (entries 15 and
25). Additionally, the significantly poorer reactivities found for
the respective reactions catalyzed by AuCl35 and Bi(OTf)317 are
noteworthy as these catalysts were recently reported to effi-
ciently mediate the allylic alkylation of sulfonamides with
e
to use. Trace amount refers to less than 1% of product isolated after
flash column chromatography. fNo reaction based on TLC or 1H NMR
analysis of the crude mixture. gMixture of unknown side products
furnished based on 1H NMR analysis of the crude mixture.
with a methyl- and/or phenyl-substituted terminal alkene
moiety gave the corresponding products 2b-d in excellent
yields (entries 1-3). Similarly, the analogous reaction of 1e,
which contains a pendant m-toluidine ring unit, underwent
intramolecular allylic amination and afforded 2e in 86%
yield (entry 4). Likewise, reaction of p-chloroaniline-substi-
tuted alcohol 1f gave 2f in 59% yield when subjected to the
standard conditions, the yield of which could be increased to
68% on repeating with CH2Cl2 as the solvent at reflux (entry
5). The present procedure was also shown to work well for 2-
tosylaminophenylprop-1-en-3-ols containing electron-with-
drawing or electron-donating groups at the terminal position
of the allylic alcohol moiety, giving 2i-l in 58-90% yield
(entries 8-11). Notably, these cyclizations also demon-
strated that the electronic nature of the CdC bond could
play a role since a gradual decrease in product yields from
78% to 58% was found and longer reaction times from 1 to
4 h were required as the electron-withdrawing ability of the
substitutent increased on going from 1j to 1l. Substituted 2-
tosylaminophenylprop-1-en-3-ols 1m,n bearing a sterically
bulky naphthylene and mesitylene group, respectively, were
found to proceed well and afford 2m,n in excellent yields
(entries 12 and 13). However, moderate yields were obtained
allylic alcohols (entries 12 and 17). Likewise, BF3 Et2O, which
3
was found to catalyze the intramolecular cyclization of o-(1-
hydroxy-2-alkenyl)phenyl isocyanides,16 was shown to be less
effective in this study (entry 23).
To define the scope of the present procedure, we next
turned our attentions to the reactions of a variety of
2-tosylaminophenylprop-1-en-3-ols (Table 2). These experi-
ments showed that with AuCl3/AgSbF6, starting alcohols
ꢀ
nez, R.; Ramon, D. J.; Yus, M.
(14) For selected examples, see: (a) Martı
´
J. Org. Chem. 2008, 73, 9778. (b) Mierde, H. V.; Voort, P. V. D.; Vos, D. D.;
Verpoort, F. Eur. J. Org. Chem. 2008, 1625. (c) Zhang, Z.; Tan, J.; Wang, Z.
Org. Lett. 2008, 10, 173. (d) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo,
G.; Plastina, P. J. Org. Chem. 2007, 72, 6873. (e) Taguchi, K.; Sakaguchi, S.;
Ishii, Y. Tetrahedron Lett. 2005, 46, 4539.
(15) Migneault, D.; Bernstein, M. A.; Lau, C. K. Can. J. Chem. 1995, 73,
1506.
(16) Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi,
H. Chem. Lett. 1995, 24, 575.
(17) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409.
J. Org. Chem. Vol. 74, No. 16, 2009 5949

Kothandaraman et al.
JOCArticle
TABLE 2. AuCl3/AgSbF6-Catalyzed Intramolecular Amination of 1b-qa
aAll reactions were performed in PhMe at room temperature for 1 h with AuCl3:AgSbF6:1 ratio=1:3:20. bReaction conducted in CH2Cl2 as solvent at
40 °C. cNo reaction based on 1H NMR analysis of the crude mixture. dReaction conducted for 2 h. eReaction conducted for 4 h. fReaction conducted
with AuCl:AgOTf ratio=1:3 as catalyst at reflux for 6 h.
5950 J. Org. Chem. Vol. 74, No. 16, 2009

Kothandaraman et al.
JOCArticle
SCHEME 2. Tentative mechanism for AuCl3/AgSbF6-Cata-
lyzed Intramolecular Cyclization of 2-Tosylaminophenylprop-1-
en-3-ols
SCHEME 3. AuCl3/AgSbF6-Catalyzed Intramolecular Ami-
nation of 1r and 1s
SCHEME 4. Synthesis of (()-Angustureine from 2p
for intramolecular cyclizations of alcohols with a pendant
benzo[d][1,3]dioxole group on the allylic moiety or as part of
the aniline unit as in 1h and 1q (entries 7 and 16). On the other
hand, reactions of alcohol substrates with pendant trans
diene functionalities were found to proceed well when sub-
jected to the standard conditions and give 2o,p in good yields
(entries 14 and 15). For the cyclization of 1p, switching the
catalyst to 5 mol % of AuCl and 15 mol % of AgOTf under
reflux conditions was required to shorten the reaction time
from 24 to 6 h. In our hands, reaction of 1g containing a
p-nitroaniline unit was the only case that was found to be
ineffective with no product formation detected by 1H NMR
analysis of the crude mixture and near-quantitative recovery
of the starting alcohol (entry 6).
involve the gold and silver catalyst combination activating the
alcohol substrate 1 by coordinating to the hydroxyl function-
ality. This delivers the Au(III)-coordinated intermediate4 that
can undergo elimination to give the carbocation species 5 and
[Au]-OH, which releases the metal catalyst by protodemeta-
lation.19 It is possible that this newly formed cationic species
promotes cyclization of the pendant sulfonamide group and
subsequent delivery of the product 2. The role of the catalyst in
facilitating dehydroxylation of the alcohol substrate would
account for our earlier results showing moderate yields for the
reactions of 1h and 1q and no product formation for the
cyclization of 1g (entries 6, 7, and 16 in Table 2). It would not
be inconceivable that such interactions are presumably wea-
kened due to competitive coordination with a very electron-
rich neighbor such as a 1,3-dioxole moiety or a strongly
coordinating nitro substitutent on the alcohol substrate. The
possible involvement of a resulting putative allylic carbocation
species prior to formation of the new C-N bond to give the
product is also supported by our findings for the reactions of
1r and its regioisomer 1s. Under the conditions described in
Scheme 3, the 1,2-dihydroquinoline adduct 2r was afforded as
the sole product in both reactions in comparable yields of 91%
At this juncture, we would like to highlight the chemose-
lective nature of the present reaction. Consistent with our
earlier findings for the intramolecular cyclization of 1a, our
studies found that the 1,2-dihydroquinolines described in
Table 2 were obtained as the sole product in all except one
case. As shown in Figures S41-44 in the Supporting Informa-
tion, this was further confirmed by X-ray crystal structure
determination of 2b as well as that for 2c, 2e, and 2i.18 On the
1
basis of H NMR analysis of the crude mixtures, possible
indole formation arising from competitive intramolecular
hydroamination could not be detected under our experimen-
tal conditions. Similarly, a competitive Freidel-Crafts alky-
lation or hydroxyl group elimination process for substrates
containing an aryl or alkyl group on the carbinol carbon that
would give the respective indene and diene products was not
found. Under the standard conditions, intramolecular cycli-
zation of 1c was the only instance in which the indene adduct
3, determined by X-ray crystal analysis (please refer to Figure
S45 in the Supporting Information), was also obtained as a
minor side product in 3% yield.18
Although highly speculative, we propose the present AuCl3/
AgSbF6-catalyzed 1,2-dihydroquinoline forming reaction to
proceed by the mechanism outlined in Scheme 2. This could
(19) A similar reaction mechanism has been suggested in related studies
on gold-catalyzed reactions of alcohol pro-electrophiles, see refs 1a, 4-6 and
the following: (a) Kothandaraman, P.; Rao, W.; Zhang, X.; Chan, P. W. H.
Tetrahedron 2009, 65, 1833. (b) Arcadi, A.; Alfonsi, M.; Chiarini, M.; Marinelli,
F. J. Organomet. Chem. 2009, 694, 576. (c) Rao, W.; Chan, P. W. H. Org. Biomol.
Chem. 2008, 6, 2426. (d) Dai, L.-Z.; Shi, M. Chem.;Eur. J. 2008, 14, 7011.
(e) Kuninobu, Y.; Ishii, E.; Takai, K. Angew. Chem., Int. Ed. 2007, 46, 3296.
(f) Liu, J.; Muth, E.; Floerke, U.; Henkel, G.; Merz, K.; Sauvageau, J.; Schwake,
E.; Dyker, G. Adv. Synth. Catal. 2006, 348, 456. (g) Georgy, M.; Boucard, V.;
Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 14180.
(18) CCDC 720295-720297, 721703, and 724703 contain the supplemen-
tary crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: + 44-1223/336- 033; E-mail: deposit@ccdc.
cam.ac.uk).
J. Org. Chem. Vol. 74, No. 16, 2009 5951

Kothandaraman et al.
JOCArticle
and 87% from 1r and 1s, respectively. The origin of the indene
side product 3 could be due to competitive cyclization of this
resulting carbocation species by the phenyl and p-tosylamino
substituents on 1c. What remains currently unclear is whether
the gold center first coordinates to the CdC bond before
hydroxyauration and elimination to give the allylic carboca-
tion species and if subsequent coordination of this intermedi-
ate to the catalyst takes place prior to the ring-forming step.20
Our earlier findings showing markedly poorer or lack of catal-
also demonstrated by further modifying one adduct obtained
to the synthesis of the bioactive tetrahydroquinoline alkaloid
(()-angustureine. Efforts to develop an enantioselective
approach to this synthetically useful building block are
currently underway and will be reported in due course.
Experimental Section
Experimental Procedure for AuCl3/AgSbF6-Catalyzed Intra-
molecular Allylic Amination of 2-Tosylaminophenylprop-1-en-3-
ols (1). A solution of AuCl3 (15 μmol) and AgSbF6 (47.3 μmol)
was stirred in a solution of toluene (1.5 mL) at room tempera-
ture for 10 min. Then, a toluene solution (1.5 mL) containing 1
(0.31 mmol) was added slowly dropwise and the reaction
mixture was stirred at room temperature and monitored to
completion by TLC analysis. The crude mixture was concen-
trated under reduced pressure and purified by flash column
chromatography on silica gel (n-hexane/EtOAc 20:1 as eluent)
to give the title compound 2.
ytic activity with other Lewis and Bronsted catalysts would
e
certainly suggest that such interactions to be a possibility.
Having established a general and efficient synthetic route
to 1,2-dihydroquinolines, we applied this new methodology
to the synthesis of the biologically active tetrahydroquino-
line alkaloid (()-angustureine.21 As shown in Scheme 4, Pd/
C-mediated hydrogenation of 2p in MeOH gave the tetra-
hydroquinoline 6 in 96% yield. Subsequent treatment of this
newly formed intermediate with a methanolic solution con-
taining an excess amount of magnesium powder furnished
the detosylated tetrahydroquinoline 7 in 98% yield. Finally,
N-methylation of this adduct with MeI and K2CO3 as base at
reflux for 12 h gave (()-angustureine in 96% yield. The 1H
and 13C NMR spectra of (()-angustureine prepared in this
work are identical with the corresponding spectra of the
authentic natural compound (see the Supporting Informa-
tion for spectra).21
4-Methyl-1-tosyl-1,2-dihydroquinoline (2a):11g white solid; 1H
NMR (CDCl3, 400 MHz) δ 7.70 (1H, dd, J=1.36, 8.2 Hz), 7.30
(1H, ddd, J=1.8, 7.8, 7.7 Hz), 7.21-7.26 (3H, m), 7.12 (1H, dd, J
=1.36, 7.32 Hz), 7.06 (2H, d, J=7.8 Hz), 5.31 (1H, m), 4.33 (2H,
m), 2.33 (3H, s), 1.57 (3H, s); 13C NMR (CDCl3, 100 MHz) δ
143.1, 136.1, 135.1, 131.6, 131.4, 128.8, 127.8, 127.4, 127.2, 126.7,
123.2, 120.3, 45.3, 21.4, 17.7; MS (ESI) m/z 300 [M + H]+.
(E)-2-(Pent-1-enyl)-1-tosyl-1,2-dihydroquinoline (2p): color-
less oil; 1H NMR (CDCl3, 500 MHz) δ 7.69 (1H, d, J=8.01 Hz),
7.22-7.29 (3H, m), 7.12 (1H, t, J=7.52 Hz), 7.04 (2H, d, J=
8.19 Hz), 6.92 (1H, d, J=8.42 Hz), 6.05 (1H, d, J=9.54 Hz),
5.57-5.64 (2H, m), 5.26-5.34 (2H, m), 2.32 (3H, s), 1.83-1.92
(2H, m), 1.23-1.28 (2H, m), 0.71 (3H, t, J=7.36 Hz); 13C NMR
(CDCl3, 125 MHz) δ 143.2, 136.4, 133.8, 133.1, 129.0, 128.6,
127.9, 127.4, 127.2, 126.9, 126.2, 126.2, 125.8, 124.5, 55.9, 34.0,
22.0, 21.5, 13.3; IR (NaCl, neat) ν 3025, 1596, 1478, 1342, 1216,
1165 cm-1; MS (ESI) m/z 354 [M + H]+; HRMS (ESI) calcd
for C21H24NO2S (M+ + H) 354.1528, found 354.1526.
(()-Angustureine:21 yellow oil; 1H NMR (CDCl3, 400 MHz)
δ 7.05 (1H, t, J=7.8 Hz), 6.95 (1H, d, J=6.88 Hz), 6.55 (1H, t, J=
7.32 Hz), 6.50 (1H, d, J=8.24 Hz), 3.20-3.24 (1H, m), 2.91 (3H,
s), 2.75-2.79 (1H, m), 2.62-2.67 (1H, m), 1.86-1.90 (2H, m),
1.53-1.58 (2H, m), 1.25-1.41 (6H, m), 0.87 (3H, t, J=6.84 Hz);
13C NMR (CDCl3, 100 MHz) δ 145.4, 128.6, 127.1, 121.9, 115.2,
110.4, 59.0, 38.0, 32.1, 31.2, 25.8, 24.4, 23.6, 22.7, 14,1; MS (ESI)
m/z 218 [M + H]+.
Conclusion
In summary, an efficient gold-catalyzed synthetic route to
1,2-dihydroquinolines based on intramolecular allylic ami-
nation of 2-tosylaminophenylprop-1-en-3-ols under mild
conditions at room temperature has been reported. These
results show the reaction to be applicable to a wide range of
alcohol substrates containing electron-withdrawing, elec-
tron-donating, and sterically demanding substituents. Our
studies also revealed the use of a gold and silver catalyst
combination to be the only Lewis acid among the many
examined in this work that can efficiently mediate the present
cyclization process. The synthetic utility of the present meth-
od to this partially hydrogenated class of heterocycles was
(20) A similar mechanistic rationale for gold-catalyzed nucleophilic sub-
stitutions of propargylic alcohols with sulfonamides was put forward by
Campagne and co-workers, see ref 4a.
Acknowledgment. This work is supported by a University
Research Committee Grant (RG55/06) and Supplementary
Equipment Purchase Grant (RG134/06) from Nanyang
Technological University.
(21) Please refer to refs 11a-c and the following: (a) Fustero, S.;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Moscardo, J.; Jimenez, D.; Perez-Carrion, M. D.; Sanchez-Rosello, M.;
Pozo, C. D. Chem.;Eur. J. 2008, 14, 9868. (b) Shahane, S.; Louafi, F.; Moreau,
J.; Hurvois, J.-P.; Renaud, J.-L.; Weghe, P.; Roisnel, T. Eur. J. Org. Chem. 2008,
4622. (e) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2007, 72, 6577. (d) Lu,
S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45,
2260. (e) Theeraladanon, C.; Arisawa, M.; Nishida, A. Tetrahedron: Asymmetry
2005, 16, 827. (f) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G.
J. Am. Chem. Soc. 2003, 125, 10536. (g) Jacquemond-Collet, I.; Hannedouche,
S.; Fabre, N.; Fouraste, I.; Moulis, C. Phytochemistry 1999, 51, 1167.
Supporting Information Available: 1H and 13C NMR spec-
tra for starting alcohols 1, 1,2-dihydroquinolines 2, 6, and 7,
indene 3, and (()-angustureine, and CIF files of 2b, 2c, 2e, and
2i. This material is available free of charge via the Internet at
http://pubs.acs.org.
5952 J. Org. Chem. Vol. 74, No. 16, 2009