A gallium-catalyzed cycloisomerization/Friedel-Crafts tandem

Article abstract of DOI:10.1021/jo101709n

Under noble (Au, Pt, Ru) and group 13 (Ga, In) metals catalysis, 1,6-arenynes rearrange to give 1,2-dihydronaphthalenes in a high yielding, regiocontrolled fashion. When the reaction is carried out in the presence of electron-rich arenes (anisole, phenol, indole derivatives), Friedel-Crafts addition may follow the cycloisomerization step. Only GaX₃ salts proved able to catalyze these two C-C bond formation events. This specificity of gallium has been exploited for the synthesis of valuable polycyclic compounds that would be very difficult to prepare otherwise. For instance, tetrahydroisoquinolines and tetrahydrobenzoazepines have been obtained by selective 6-exo-dig or 7-endo-dig cyclization of N-tethered 1,6-arenynes. DFT calculations were carried out to shed light on the mechanism and provide a rationale for this regiodivergency. Computations also reveal the fundamental role of the tether in the stabilization of carbocationic species. Differential reactivities of other types of substrates in gallium- and gold-catalyzed cascades are also exposed, showing that the two approaches are complementary. In particular, bimolecular Friedel-Crafts additions are facilitated under gallium catalysis.

Full text of DOI:10.1021/jo101709n

pubs.acs.org/joc
A Gallium-Catalyzed Cycloisomerization/Friedel-Crafts Tandem
ꢀ
Hui-Jing Li, Regis Guillot, and Vincent Gandon*
ꢀ
ICMMO, UMR CNRS 8182, Universite Paris-Sud 11, 91405 Orsay cedex, France
vincent.gandon@u-psud.fr
Received September 2, 2010
Under noble (Au, Pt, Ru) and group 13 (Ga, In) metals catalysis, 1,6-arenynes rearrange to give 1,2-
dihydronaphthalenes in a high yielding, regiocontrolled fashion. When the reaction is carried out in the
presence of electron-rich arenes (anisole, phenol, indole derivatives), Friedel-Crafts addition may follow
the cycloisomerization step. Only GaX3 salts proved able to catalyze these two C-C bond formation
events. This specificity of gallium has been exploited for the synthesis of valuable polycyclic compounds
that would be very difficult to prepare otherwise. For instance, tetrahydroisoquinolines and tetra-
hydrobenzoazepines have been obtained by selective 6-exo-dig or 7-endo-dig cyclization of N-tethered
1,6-arenynes. DFT calculations were carried out to shed light on the mechanism and provide a rationale
for this regiodivergency. Computations also reveal the fundamental role of the tether in the stabilization
of carbocationic species. Differential reactivities of other types of substrates in gallium- and gold-
catalyzed cascades are also exposed, showing that the two approaches are complementary. In particular,
bimolecular Friedel-Crafts additions are facilitated under gallium catalysis.
1. Introduction
GaX3, InX3, BiX3, and relatives turned out to be attractive
and cost efficient alternatives to noble metals in certain
conditions.” Among these salts, GaCl3 is known as both a
powerful σ- and π-Lewis acid.3-5 In the first category,
applications of GaCl3 as catalyst for [4 þ 2]6a or [4 þ 1]6b
cycloadditions, Friedel-Crafts and coupling reactions,6c-g
Mukayama-aldol reactions,6h skeletal rearrangements,6i and
Recent years have witnessed a flurry of activity around the
activation of simple alkynes or olefins toward nucleophilic
attack with carbophilic π-Lewis acids.1 The majority of the
catalysts used are complexes of noble metals, gold being
perhaps one of the most highly regarded nowadays.2 How-
€
ever, as stated by Furstner in his critical review on π-acid
catalysis,2e “conventional Lewis acids may also qualify,
provided they are sufficiently polarizable; in fact, CuX,
(4) For the origin of the difference in Lewis acidity between BCl3, AlCl3,
and GaCl3, see: Ogawa, A.; Fujimoto, H. Inorg. Chem. 2002, 41, 4888.
(5) It becomes a common belief that alkyno- and alkenophilicity are of
thermodynamic origin. However, π-Lewis acids are, thermodynamically
speaking, often more aza- or oxophilic than carbophilic. For a clarification,
see ref 1 and: (a) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817. (b) Gorin,
D. J.; Toste, F. D. Nature 2007, 446, 395.
€
(1) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
ꢀ
ꢀ~
(2) (a) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (b) Jimenez-Nunez,
E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (c) Michelet, V.; Toullec,
^
P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268. (d) Li, Z.; Brouwer,
C.; He, C. Chem. Rev. 2008, 108, 3239. (e) Furstner, A. Chem. Soc. Rev. 2009,
38, 3208. (f) Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371. (g) Shapiro,
D.; Toste, F. D. Synlett 2010, 675.
(6) For selected examples, see: (a) Hirashita, T.; Kawai, D.; Araki, S.
Tetrahedron Lett. 2007, 48, 5421. (b) Chatani, N.; Oshita, M.; Tobisu, M.;
Ishii, Y.; Murai, S. J. Am. Chem. Soc. 2003, 125, 7812. (c) Kobayashi, S.;
Komoto, I.; Matsuo, J.-i. Adv. Synth. Catal. 2001, 343, 71. (d) Amemiya, R.;
Yamaguchi, M. Adv. Synth. Catal. 2007, 349, 1011. (e) Kobayashi, K.;
Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc. 2002, 124, 8528. (f)
Yonehara, F.; Kido, Y.; Sugimoto, H.; Morita, S.; Yamaguchi, M. J. Org.
Chem. 2003, 68, 6752. (g) Amemiya, R.; Fujii, A.; Yamaguchi, M. Tetra-
hedron Lett. 2004, 45, 4333. (h) Li, H.-J.; Tian, H.-Y.; Wu, Y.-C.; Chen, Y.-J.;
Liu, L.; Wang, D.; Li, C.-J. Adv. Synth. Catal. 2005, 347, 1247. (i) Oshita, M.;
Okazaki, T.; Ohe, K.; Chatani, N. Org. Lett. 2005, 7, 331. (j) Viswanathan,
G. S.; Wang, M.; Li, C.-J. Angew. Chem., Int. Ed. 2002, 41, 2138. (k) Bez, G.;
Zhao, C.-G. Org. Lett. 2003, 5, 4991. (l) Usugi, S.-i.; Yorimitsu, H.;
Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 601.
€
(3) (a) Amemiya, R.; Yamaguchi, M. In Acid Catalysis in Modern Organic
Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH: Weinheim,
Germany, 2008; Vol. 1, pp 347-375. (b) Nishimura, Y. Chem. Commun.
2008, 35. (c) Amemiya, R.; Yamaguchi, M. Eur. J. Org. Chem. 2005, 5145. (d)
Yamaguchi, M.; Shibasaki, M. e-EROS Encyclopedia of Reagents for
Organic Synthesis, 2005, Online Posting Date: October 15, 10.1002/
047084289X.rn00118u.pub2; (e) Yamaguchi, M. In Main Group Metals in
Organic Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Wein-
heim, Germany, 2004; Vol. 1, pp 307-322. (f) Barman, D. C. Synlett 2003,
2440.
DOI: 10.1021/jo101709n
r
Published on Web 11/17/2010
J. Org. Chem. 2010, 75, 8435–8449 8435
2010 American Chemical Society

Li et al.
JOCArticle
SCHEME 1. Reaction of Arenyne 1a in Toluene under Ga(III)- and Au(I)-Catalysis (E = CO2Et)
others6j-l have been reported. On the other hand, the carbo-
TABLE 1. Catalyst Screening
philicity of GaCl3 has been revealed through a few cycloisomer-
ization reactions involving enynes, allenynes, or arenynes,7,8 as
well as intermolecular dihydroarylations of alkynes.9 In rare
cases, the two types of acidities of GaCl3 have been fruitfully
exploited to elaborate complex molecules, showing that this
ambivalence is useful in organic synthesis.10 In this context, it
seems clear that gallium salts are not just alternatives to noble
metals, for they can also confer specific elements of selectivity. In
that respect, we have disclosed that GaCl3 catalyzes the trans-
mol
%
temp
(°C)
time
(h)
yield
[%]
entry
1
catalyst
product
formation of arenyne 1a into the bicyclic derivative 3, presum-
ably after cycloisomerization into 2 and bimolecular Friedel-
Crafts type reaction with toluene, used as solvent (Scheme 1).11
In contrast, with Au(I), the reaction stops at the cycloisomer-
ization step.
AuCl(PPh3)/
AgSbF6
AuCl3
[RuCl2(CO)3]2/
AgOTf
[RuCl2(CO)3]2
PtCl2
PtCl4
PtCl4
AlCl3
Ga(OTf)3
GaCl3
GaCl3
GaBr3
InCl3
2/2
rt
6
2
80
a
2
3
5
8/16
rt
80
6
10
-
2
88
a
4
5
6
7
8
8
5
5
5
10
10
10
10
10
10
80
80
rt
80
80
80
rt
80
80
80
10
10
10
10
10
10
10
10
10
10
-
a
-
2
2
-
-
90
71
0
(7) (a) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67, 1414. (b)
Chatani, N.; Inoue, H.; Kotsuma, T.; Murai, S. J. Am. Chem. Soc. 2002, 124,
b
€
10294. (c) Mamane, V.; Hannen, P.; Furstner, A. Chem.;Eur. J. 2004, 10,
b
4556. (d) Lee, S. I.; Sim, S. H.; Kim, S. M.; Kim, K.; Chung, Y. K. J. Org.
Chem. 2006, 71, 7120. (e) Kim, S. M.; Lee, S. I.; Chung, Y. K. Org. Lett. 2006,
8, 5425. (f) Simmons, E. M.; Sarpong, R. Org. Lett. 2006, 8, 2883.
(8) InX3 salts are also effective catalysts, see ref 2c and the references
therein.
(9) Ga: (a) Yadav, J. S.; Reddy, B. V. S.; Padmavani, B.; Gupta, M. K.
Tetrahedron Lett. 2004, 45, 7577. In: (b) Tsuchimoto, T.; Hatanaka, K.;
Shirakawa, E.; Kawakami, Y. Chem. Commun. 2003, 2454. Au: (c) Li, Z.;
Shi, Z.; He, C. J. Organomet. Chem. 2005, 690, 5049. (d) Hashmi, A. S. K.;
Blanco, M. C. Eur. J. Org. Chem. 2006, 4340. (e) Ferrer, C.; Amijs, C. H. M.;
Echavarren, A. M. Chem.;Eur. J. 2007, 13, 1358.
9
0
10
11
12
13
4
4
4
2
62
88c
80
89
aComplex mixture. bNo reaction. c100% yield with anisole as solvent.
The overall result of the gallium-catalyzed tandem is a bimole-
cular double hydroarylation of an alkyne.12 To the best of our
knowledge, only intermolecular double hydroarylations of al-
kynes involving twice the same arene have been reported.9,12a
Also we are not aware of any precedent of bimolecular or fully
intramolecular double hydroarylation reaction. This paper
shows how we have exploited the title reaction for synthetic
purposes and provides mechanistic insights supported by DFT
computations. The differential selectivities induced by gallium
and gold catalysts are illustrated throughout the paper.
(10) (a) Asao, N.; Asano, T.; Ohishi, T.; Yamamoto, Y. J. Am. Chem.
Soc. 2000, 122, 4817. (b) Yadav, J. S.; Reddy, B. V. S.; Biswas, S. K.;
Sengupta, S. Tetrahedron Lett. 2009, 50, 5798.
(11) This transformation is particularly surprising since the GaCl3-cata-
lyzed cycloisomerization of 1a into 2 was previously described by Murai, also
using toluene as solvent, and no double hydroarylation product was men-
tioned (see ref 7a). The only difference between our experimental conditions
and those previously reported lies in the use of a commercially available 0.5
M pentane solution of GaCl3 (Aldrich) in our case, instead of a 1 M
methylcyclohexane solution. With the latter, we eventually obtained the
reported product 2 in 92% yield. The lower activity of the gallium catalysts
might be related to the known interaction between methylcyclohexane and
GaCl3 (see ref 6f). Nevertheless, the transformation of 1a into 3 could be
carried out by using various batches of GaCl3 in pentane and proved
perfectly reproducible.
(12) For reviews on alkyne hydroarylation, see ref 2d and: (a) Kitamura,
T. Eur. J. Org. Chem. 2009, 1111. (b) Nevado, C.; Echavarren, A. M.
Synthesis 2005, 167. For illustrative examples, see: (c) Jia, C.; Piao, D.;
Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992. (d)
Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485. (e) Shi, Z.; He, C.
J. Org. Chem. 2004, 69, 3669. (f) Ferrer, C.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2006, 45, 1105. (g) Biffis, A.; Gazzola, L.; Gobbo, P.;
Buscemi, G.; Tubaro, C.; Basato, M. Eur. J. Org. Chem. 2009, 3189. (h)
Menon, R. S.; Findlay, A. D.; Bissember, A. C.; Banwell, M. G. J. Org.
Chem. 2009, 74, 8901.
2. Results and Discussion
2.1. Experimental Results. 2.1.1. Carbon Tethers. To check
whether the tandem transformation depicted in Scheme 1 was
restricted to the use of GaCl3, various salts of noble and group
13 metals were tested.13 We began our investigations with
arenyne 1a, anisole as nucleophile, and dichloroethane as
solvent (Table 1).
(13) Use of HCl as catalyst gave rise to an intractable mixture of products.
8436 J. Org. Chem. Vol. 75, No. 24, 2010

Li et al.
JOCArticle
SCHEME 2. Deuterium Labeling (E = CO2Et, Ar = 4-MeO-
C6H5)
CHART 1. Incompatible Substrates
Complex mixtures ensued when using AuCl3, [RuCl2(CO)3]2,
or PtCl2 (entries 2, 4, and 5). Conversely, the 1,2-dihydro-
naphthalene derivative 2 could be isolated in good yield
employing cationic complexes of gold(I)14 and Ru(II)
(entries 1 and 3, see also Scheme 1), as well as neutral salts
of platinum(IV) and indium(III) (entries 6, 7, and 13).15
Whereas anhydrous AlCl3 and Ga(OTf)3 did not promote
any reaction (entries 8 and 9), GaCl3 and GaBr3 furnished
the desired 1-aryl-1,2,3,4-tetrahydronaphthalene 4 exclu-
sively (entries 10-12, see also Scheme 1).16 Although the
reaction already took place at room temperature (entry 10),
a higher yield was reached at 80 °C (entry 11).
Thus, only Ga(III) halides seem to possess the required Lewis
acidity to promote both the cycloisomerization and the bimolec-
ular Friedel-Crafts addition.17 Arguably, this tandem reaction
proceeds first by the cycloisomerization step. Isolated samples of
2 were reacted with anisole in dichloroethane or directly in
toluene in the presence of 10 mol % of GaCl3 and transformed
in good yields into 4 or 3, respectively. We also noticed that the
exocyclic/endocyclic migration of the methylene fragment of the
cycloisomerization product was not completely shifted when the
Friedel-Crafts reaction took place, as shown by a deuterium-
labeling experiment giving rise to an accidental 1:1 mixture of the
two possible adducts (Scheme 2).
and 1,3,5-trimethoxybenzene which did not react with the
cycloisomerization intermediate (Chart 1), electron-rich ar-
enes such as anisole (Table 2, entries 1-3), ortho-substituted
anisole derivatives (entries 4-8), and phenols (entries 9-11)
could be used successfully. The products were formed regio-
selectively in high yields. The structures of 9 and 15 were
unambiguously confirmed by X-ray analyses (see the Sup-
porting Information). Of relevance is the possibility to gen-
erate derivatives of 5-aryl-6,7,8,9-tetrahydro-5H-benzo[7]-
annulene (entry 1) and 5-aryl-5,6,7,8,9,10-hexahydrobenzo-
[8]annulene (entry 2) by incremental changes in the respective
starting materials. Whereas 1,2-dimethoxybenzene and 1a
transformed into the expected product 9 in a very good 90%
yield (entry 5), 1,2,3-trimethoxybenzene led to compound 12
in a lower 67% yield (entry 8). Actually two purifications were
necessary to get 12 in pure form, the first one providing it
admixed with a low amount of 13 arising either from the
deprotection of 12 or from the deprotection of 1,2,3-tri-
methoxybenzene itself, which eventually reacted with 1a.18
On the other hand, 13 could be synthesized selectively in good
yield with 2,6-dimethoxyphenol (entry 9).
The nitrogen-containing nucleophiles N,N-dimethylani-
line, pyrrole, indole, N-methylpyrrole, and N-methylindole
(Chart 1) prevented any reaction pathway. Nevertheless,
1-(phenylsulfonyl)-1H-indole allowed the formation of pro-
duct 16, which was isolated in 94% yield (entry 12).
The scope of the bimolecular double hydroarylation was
investigated next. Unlike halobenzenes, methylphenylsulfane,
(14) A few gold-catalyzed bimolecular cycloisomerization/Friedel-
Crafts tandem reactions have been described. For selected examples, see:
Two other carbon-tethered terminal arenynes were tested
(Chart 1, 1e and 1f); however, these substrates gave rise to
decomposition products, both with gallium and gold, even at
room temperature. We next turned our attention to the bis-
homopropargylic diol 1j, a case which also turned out to be
emblematic of the differential reactivity conferred by gallium
and gold catalysts (Scheme 3). In both cases, intramolecular
oxacyclization rather than hydroarylation took place, a
chemoselectivity which could be explained in terms of
alkyne/oxygen chelation control, as described by Yamamoto
et al.10a Although the intermediate dihydrofuran could not
be isolated when using 1j, the corresponding product 17
resulting from the cycloisomerization of the homopropargyl
alcohol 1k could be separated and fully characterized. In the
presence of anisole, a Friedel-Crafts type addition led to
tetrahydrofuran 18 as a 1:1 mixture of diastereomers when
GaCl3 was used as catalyst. In sharp contrast, as reported by
^
(a) Toullec, P. Y.; Genin, E.; Leseurre, L.; Genet, J.-P.; Michelet, V. Angew.
Chem., Int. Ed. 2006, 45, 7427. (b) Amijs, C. H. M.; Ferrer, C.; Echavarren,
A. M. Chem. Commun. 2007, 698. (c) Chen, Y.; Lu, Y.; Li, G.; Liu, Y. Org.
Lett. 2009, 11, 3838. (d) Leseurre, L.; Chao, C.-M.; Seki, T.; Genin, E.;
^
Toullec, P. Y.; Genet, J.-P.; Michelet, V. Tetrahedron 2009, 65, 1911.
(15) For Ru- and Pt-catalyzed cycloisomerization of arenynes, see:
Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J. Org. Chem. 2000, 65, 4913.
(16) 1-Aryl-1,2,3,4-tetrahydronaphthalene derivatives, their higher homo-
logues, and their heteroanalogues represent important classes of compounds
displaying central nervous system activity, notably as dopamine D1 receptor
agonists or antagonists, see inter alia: (a) Zhang, J.; Xiong, B.; Zhen, X.;
Zhang, A. Med. Res. Rev. 2009, 29, 272. (b) Hoffman, B.; Cho, S. J.; Zheng,
W.; Wyrick, S.; Nichols, D. E.; Mailman, R. B.; Tropsha, A. J. Med. Chem.
1999, 42, 3217. (c) Bucholtz, E. C.; Brown, R. L.; Tropsha, A.; Booth, R. G.;
Wyrick, S. D. J. Med. Chem. 1999, 42, 3041. (d) Wyrick, S. D.; Booth, R. G.;
Myers, A. M.; Owens, C. E.; Bucholtz, E. C.; Hooper, P. C.; Kula, N. S.;
Baldessarini, R. J.; Mailman, R. B. J. Med. Chem. 1995, 38, 3857. (e)
Hussain, R. A.; Dickey, J. K.; Rosser, M. P.; Matson, J. A.; Kozlowski,
M. R.; Brittain, R. J.; Webb, M. L; Rose, P. M.; Fernandes, P. J. Nat. Prod.
1995, 58, 1515. (f) Yous, S.; Durieux-Poissonnier, S.; Lipka-Belloli, E.;
Guelzim, H.; Bochu, C.; Audinot, V.; Boutin, J. A.; Delagrange, P.;
Bennejean, C.; Renarde, P.; Lesieur, D. Bioorg. Med. Chem. 2003, 11, 753.
(17) In Friedel-Crafts reactions, it seems that AlCl3 not only generates
the electrophile but also activates the aromatic substrate by back-donation
from Cl 3p orbital to the arene HOMO. This effect could still exist with
GaCl3, but not with Ga(OTf)3. See: (a) Tarakeshwar, P.; Lee, J. Y.; Kim,
K. S. J. Phys. Chem. A 1998, 102, 2253. (b) Tarakeshwar, P.; Kim, K. S.
J. Phys. Chem. A 1999, 103, 9116.
(18) 1,2,3-Trimethoxybenzene is easily demethylated at the most hin-
dered position by using for instance ZnCl2, AlCl3, or BCl3. See inter alia:
Carvalho, C. E.; Russo, A. V.; Sargent, M. V. Aust. J. Chem. 1985, 38, 777.
J. Org. Chem. Vol. 75, No. 24, 2010 8437

Li et al.
JOCArticle
TABLE 2. Bimolecular Dihydroarylation of Terminal Alkynes
(E = CO2Et)
being obtained in 64% yield. Hydration of alkynes is com-
monly observed in gold catalysis as well, even when dry
solvents and inert atmospheres are employed,22 and there is a
growing interest nowadays for such mercury- and acid-free
conditions.23 However, using the AuCl(PPh3)/AgSbF6 cat-
alytic system, no transformation of arenynes 1l-n was
observed.
Going back to terminal alkynes, we wondered whether
substrates bearing two aryl moieties, i.e., diarenynes, could
be cyclized. As mentioned in the Introduction, intramolec-
ular dihydroarylations of alkynes have not been reported so
far. If successful, such transformations would represent an
expedient way to synthesize complex polycyclic molecules
from simple precursors. To our delight, arenynes 1o-r
transformed into the expected products 23, 24,24 25, and 26
in good to excellent yields (Scheme 5) after double or even
triple hydroarylations.25 Interestingly, although gold cata-
lysts proved unable to catalyze the bimolecular Friedel-
Crafts addition step (see Table 1), Ph3PAuCl/AgSbF6 (2 mol %,
dicholoroethane, rt, 10 h) promoted the intramolecular trans-
formation of 1o into 23 in 87% yield.26
The pentacyclic derivative 26 can be considered as the
result of a double hydroarylation at one end and a mono-
hydroarylation at the second end of diyne 1r. A fourth
hydroarylation was also attainable by means of an extra
intermolecular reaction with anisole, as shown by the for-
mation of 27 under Ga-catalysis (Scheme 6). Although four
C-C bonds and three cycles were formed in a single opera-
tion, this product was isolated in a good yield nonetheless,
further illustrating the synthetic potential of the title reac-
tion. Again, gold catalyzed the skeletal rearrangement of 1r
into 26, but not the bimolecular Friedel-Crafts addition.
The complementary features of gallium and gold were
once more emphasized when using the bis-arenyne 1s, one
carbon homologue of 1r (Scheme 7). While gold gave rise to
compound 28 after hydroarylation of one alkyne terminus
and hydration of the second one,22 inspection of the NMR
signals of the reaction product formed under Ga-catalysis
(22) Under common laboratory conditions, the presence of water cannot
be strictly avoided, the more so as very hygroscopic salts are used. For
instance, efficient gold-catalyzed hydration of alkynes in dry CH2Cl2 has
been reported: (a) Davies, P. W.; Detty-Mambo, C. Org. Biomol. Chem.
2010, 8, 2918. The presence of wateþr was attributed to the use of hygroscopic
silver salts for the generation of Au . Traces of water can even play a crucial
role in transition metal-catalyzed transformations, see inter alia: (b) Baum-
garten, S.; Lesage, D.; Gandon, V.; Goddard, J.-P.; Malacria, M.; Tabet,
J.-C.; Gimbert, Y.; Fensterbank, L. ChemCatChem. 2009, 1, 138.
(23) For a seminal paper, see: (a) Teles, J. H.; Brode, S.; Chabanas, M.
Angew. Chem., Int. Ed. 1998, 37, 1415. For a review, see: (b) Hintermann, L.;
Labonne, A. Synthesis 2007, 1121. For selected recent examples, see: (c)
ꢀ
Marion, N.; Ramon, R. S.; Nolan, S. J. Am. Chem. Soc. 2009, 131, 448. (d)
Layva, A.; Corma, A. J. Org. Chem. 2009, 74, 2067. (e) Hashmi, A. S. K.;
^
Michelet and Genet, AuCl, Ph3PAuCl/AgSbF6, or AuCl3 led
to the bicyclic ketal 19.19
A few disubstituted alkynes were tried next, yet the
cyclization proved more difficult. Regioselective hydration
of the triple bond by adventitious water20 was the only
reaction process that could be monitored with the ester-
and phenyl-substituted arenynes 1l and 1m (Scheme 4). With
the brominated alkyne 1n, although the cycloisomerization
product 22B could be isolated in 20% yield,21 the main
reaction pathway remained the hydrative one, ketone 22A
€
Hengst, T.; Lothschutz, C.; Rominger, F. Adv. Synth. Catal. 2010, 352, 1315.
(24) A product similar to 24 has been prepared by Pd-catalyzed alkyl to
aryl migration and cyclization: Huang, Q.; Fazio, A.; Dai, G.; Campo,
M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460.
(25) It is worthy of note that the polycyclic frameworks of 23 (5,6,7,12-
tetrahydro-6,12-methanodibenzo[a,d]cyclooctene) and 24 (1,2,3,10b-tetra-
hydrofluoranthene) can be found in natural and/or biologically active
compounds, see inter alia: (a) Lee, C.-K.; Yeh, M.-H.; Lee, T.-H.; Chiu,
H.-L.; Kuo, Y.-H. Helv. Chim. Acta 2009, 92, 1983. (b) Bai, H.; Li, S.; Yin, F.;
Hu, L. J. Nat. Prod. 2005, 68, 1159. (c) Chen, C.-L.; Chang, H.-M.
Phytochemistry 1978, 17, 779. (d) Day, B. W.; Sahali, Y.; Hutchins, D. A.;
^
(19) Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J.-P. J. Am. Chem.
€
Soc. 2005, 127, 9976.
(20) We can also not exclude the coordination of GaCl3 by the ester
groups and alkyne hydration during workup.
(21) The absence of Friedel-Crafts products might be ascribed to the
electronegativity of bromine, which prevents the development of a positive
charge at the benzylic position.
Wildschutte, M.; Pastorelli, R.; Nguyen, T. T.; Naylor, S.; Skipper, P. L.;
Wishnok, J. S.; Tannenbaum, S. R. Chem. Res. Toxicol. 1992, 5, 779.
(26) For gold-catalyzed intramolecular cycloisomerization/Friedel-
ꢁ
Crafts tandem reactions, see inter alia: Lemiere, G.; Gandon, V.; Agenet,
N.; Goddard, J.-P.; de Kozak, A.; Aubert, C.; Fenstebank, L.; Malacria, M.
Angew. Chem., Int. Ed. 2006, 45, 7596.
8438 J. Org. Chem. Vol. 75, No. 24, 2010

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SCHEME 3. Differential Reactivities of Dihydrofurans under Gallium- and Gold-Catalysis
SCHEME 4. Gallium-Catalyzed Hydration of Disubstituted Alkynes (E = CO2Et)
SCHEME 5. Intramolecular Double and Triple Hydroarylation
of Alkynes (E = CO2Et)
SCHEME 6. Gallium-Catalyzed Quadruple Hydroarylation of
Diyne 1r (E = CO2Et)
as previously described.27 The equilibrium would be shifted
by the double bond Markovnikov hydrogallation promoted
by HGaCl3-. Pertaining to this rationale, GaCl3 is known to
generate cations from alkanes, and the resulting hydride
HGaCl3- can give rise to hydrogallation products.28 In our
case, the possibility of alkene reduction must funnel the
reaction since for 25, also exhibiting a diphenylmethane
moiety, no oxidation product was observed.
2.1.2. Oxygen and Nitrogen Tethers. To build heterocycles,
we next turned our attention to arenynes displaying oxygen-
and nitrogen-tethers. It was already mentioned in the litera-
ture that oxygen-tethers were incompatible because of the
straightforward cleavage of the carbon-oxygen bond.7a
Accordingly, a complex mixture of unidentified products
ensued after mixing arenyne 1g (Chart 1) and anisole with
GaCl3 or AuCl(PPh3)/AgSbF6, even at room temperature.
On the other hand, the cycloisomerization of arenynes
displaying a nitrogen tether was not studied before with
revealed that the expected diphenylmethane moiety was
actually oxidized into a ketone and that the expected alkene
fragment was hydrogenated. All spectral data converged to
the pentacyclic compound 29, which was isolated as a 1:2
mixture of diastereomers in good yield. We suppose that this
product arises from the formation of the dibenzylic B from
the cycloisomerization product A. This cation is then
(27) Roberts, R. M.; El-Khawaga, A. M.; Sweeney, K. M.; El-Zohry,
M. F. J. Org. Chem. 1987, 52, 1591.
(28) See ref 6f and: Oshita, M.; Chatani, N. Org. Lett. 2004, 6, 4323.
trapped by adventitious water to give the alcohol C.22
and C then disproportionate into A and the anthracenone D
B
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SCHEME 7. Hydroarylation of Diyne 1s under Gallium- and
Gold-Catalysis (E = CO2Et)
TABLE 3. 6-exo vs. 7-endo Cyclizations of Arenynes 1t and 1u
GaCl3. While the NBn- and NMe-tethered substrates 1h and
1i proved unreactive (Chart 1),29 full conversion of the NTs-
containing arenynes 1t and 1u was reached at room tem-
perature (Table 3). The expected tetrahydroisoquinolines
30t-32t and tetrahydrobenzo[h]isoquinolines 30u-32u were
isolated as major products (entries 1-6), accompanied
by 10-25% of dihydrobenzoazepine 33t and dihydro-
naphthoazepine 33u depending on the nucleophilic arene used.
This result prompted us to test the cycloisomerization in the
absence of the latter (entries 7 and 8). To our surprise, 33t and
33u were obtained as sole products in high yields.
To show the versatility of the process, i.e., the formation of
either 6- or 7-membered functionalized heterocycles, isolated
samples of dihydroazepines 33t and 33u were submitted to
gallium-catalyzed hydroarylation at 80 °C (Table 4). Satisfy-
ingly, the corresponding tetrahydroazepines 34t-36t and
37u could be isolated in high yields as well.
aSeparated. b63 þ 22 in anisole as solvent at rt.
The one-pot procedure proved also possible as follows: a
dichloroethane solution of arenyne was stirred at rt in the
presence of GaCl3 for 10 h, then the nucleophilic arene was
introduced and the mixture was refluxed for 10 h (Scheme 8).
This procedure provided 34t in 57% yield. In contrast, when the
reaction was carried out at 80 °C with the reagents and GaCl3
already present, 34t was obtained in a lower 22% yield.
Thus, it is clearly possible to control the 6-exo- and 7-endo-
dig pathways depending on the reaction conditions. The
origin of this intriguing chemoselectivity is discussed in the
Theoretical Investigations section (vide infra). Before closing
on the N-tethered diynes series, it has to be mentioned that
under the same experimental conditions, with or without
anisole, AuCl(PPh3)/AgSbF6 converted 1t into 33t in poor
yield accompanied by traces of allenamide 38t (Scheme 9).30
(29) As in the case of indole nucleophiles mentioned above, stronger bases
may lead to catalyst deactivation.
(30) Inamoto, K.; Yamamoto, A.; Ohsawa, K.; Hiroya, K.; Sakamoto, T.
Chem. Pharm. Bull. 2005, 53, 1502.
8440 J. Org. Chem. Vol. 75, No. 24, 2010

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TABLE 4. Gallium-Catalyzed Hydroarylations of Dihydroazepines
Because a quasi-substoichiometric amount of GaCl3 is
usually used in gallium catalysis, one could argue that GaCl3
is just a precatalyst. However, it is commonly accepted that
GaCl3, just like AlCl3 or BCl3, actually is the active species,
but because of its hygroscopic character, a larger amount is
necessary to ensure the presence of active material.
Geometry optimization of the A1 system, comprising a
model arenyne and Ga2Cl6, a well-known dimer of GaCl3
that exists both in the solid state and in solution, was
implemented (Scheme 10). It yielded three distinct minima
in which GaCl3 is coordinated to the triple bond. In B1, the
metal center is bound unsymmetrically to the alkyne frag-
ment. This complex is much more stable than the Cl-stabi-
lized cation B01 or the ion-paired cationic intermediate B00
1
which have been postulated as potential intermediates in Ga-
promoted linear trimerization of silylacetylenes.35
The exo and endo cyclizations could be modeled from
monogallium species of type B only (Scheme 11). In the gem-
diester series, using 1,2-dichloroethane solvation correc-
tions, the 6-exo-dig cyclization transition state was located
13.59 kcal/mol above B1 and led directly to the alkene-
gallium complex D1 (see Figure 1 in the Supporting Informa-
tion for the geometries). This transformation, which involves
simultaneous cyclization and 1,3-proton shift, is appreciably
exergonic by 43.72 kcal/mol. The migration of gallium from
the C-C double bond to one oxygen atom of the ester moiety
to give E1 also proved exergonic and kinetically facile. The
final dissociation of GaCl3 giving F1 was found slightly
endergonic by less than 1 kcal/mol.
2.2. Theoretical Investigations. Contrasting with noble
metals catalysis, investigations on Ga-catalyzed organic
transformations by means of computational chemistry are
quite scarce31 and very few cycloisomerization reactions
have been simulated.31b,d,f To understand some experimen-
tal data, in particular the intriguing selectivities observed
with NTs-tethered arenynes, DFT calculations were carried
out. The chosen level of theory for the present study was
calibrated on the geometry of a recently reported gallium
carbene,32 and on the dissociation energy of Ga2Cl6 into
GaCl3.33
Computational Method. All calculations were performed
with the Gaussian series of programs.34 The geometry opti-
mizations and thermodynamic corrections were carried out
with hybrid density functional theory (B3LYP) with the
6-31G(d) (N, H, C, S, O, Cl) and LANL2DZþECP basis
sets (Ga). Solvation corrections for 1,2-dichloroethane and
anisole were computed by the PCM method as implemented
in Gaussian 09 with single points at the B3LYP/6-31þ
G**(LANL2DZ) level. Unless stated otherwise, all relative
In the N-tether series (X = NTs), the exo cyclization
proceeds in two steps. The first one, leading to the Wheland
intermediate C2, requires an activation free energy of 10.46
kcal/mol and is endergonic by 3.35 kcal/mol. Interestingly,
the 6-membered ring of C2 is strongly folded (see Figure 1 in
the Supporting Information), as the result of the electron
donation from the nitrogen atom to the cationic center.36
Due to this stabilization, and in contrast with the carbon-
tether series, complex C2 does not collapse. Moreover, the
activation energy barrier to reach the 1,3-proton shift transi-
tion state is quite high (12.10 kcal/mol from C2), as it requires
to unfold the 6-membered ring. From D2, gallium migration
to one oxygen atom of the tosyl group to give E2 and
regeneration of the catalyst follow an exergonic pathway.
The study of the 7-endo-dig cyclization pathway also
showed the crucial role of the tethers on the stabilization of
cationic intermediates. Again, in the NTs series, an N-stabi-
lized Wheland intermediate was located (G2). On the other
hand, in the gem-diester series, the corresponding species
converged as the nonclassical cation G1. Although both
barriers to cyclization are similar, the formation of the latter
is much more endergonic than that of the former (6.80 vs 3.10
kcal/mol).37 Rearomatization then follows through 1,2-pro-
ton shift transition states connecting G1/2 to the O-stabilized
energies presented in this paper are free energies (ΔGDCE
ΔGani) in kilocalories per mole.
;
(31) See ref 6i and: (a) Yamabe, S.; Minato, T. J. Org. Chem. 2000, 65,
1830. (b) Xu, K.; Wu, Y.; Xie, D.; Yan, G. Chin. Sci. Bull. 2004, 49, 9883. (c)
Wu, Y.; Xu, K.; Xie, D. Tetrahedron 2005, 61, 507. (d) Soriano, E.; Marco-
Contelles, J. Organometallics 2006, 25, 4542. (e) Wong, C. T.; Wong, M. W.
J. Org. Chem. 2007, 72, 1425. (f) Zhu, Y.; Guo, Y.; Xie, D. J. Phys. Chem. A
2007, 111, 9387.
(35) (a) Kido, Y.; Yoshimura, S.; Yamaguchi, M.; Uchimaru, T. Bull.
Chem. Soc. Jpn. 1999, 72, 1445. (b) Kido, Y.; Yamaguchi, M. J. Org. Chem.
1998, 63, 8086.
ꢀ
(32) Species 3 of: Marion, N.; Escudero-Adan, E. C.; Benet-Buchholz, J.;
(36) Efforts to optimize a corresponding O-stabilized cation C1 using the
esters functionalities failed.
Stevens, E. D.; Fensterbank, L.; Malacria, M.; Nolan, S. P. Organometallics
2007, 26, 3256 (RMSD 0.0942).
(37) It is worthy of note that in the NTs series, it was possible to model
both species G1 and G2. The former is less stable by 4.70 kcal/mol than the
latter. A transition state connecting these complexes lies 5.53 kcal/mol above
G2. Again, in the gem-diester series, it was not possible to stabilize the
Wheland intermediate with the oxygen atoms.
(33) ΔH298 exp = 21.0 kcal mol-1; ΔH298 comp = 19.04 kcal mol-1, see:
3
3
€
Shafer, H.; Binnewies, M. Z. Anorg. Allg. Chem. 1974, 410, 251.
(34) Frisch, M. J.; et al. Gaussian 09, Revision A.1; Gaussian, Inc.,
Wallingford, CT, 2009.
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SCHEME 8. Concomitant vs Stepwise Addition of Reagents and Catalyst
SCHEME 9. Gold-Catalyzed Cycloisomerization of Arenyne 1t
transition state lying 11.25 kcal/mol below B2. However, the
next step, which leads to complex D2, has a higher activation
energy barrier than that of the irreversible H2 f I2 transfor-
mation.
Because an excess of nucleophile and high concentration
of the reagents in 1,2-dichloroethane were used experimen-
tally, we next envisaged that the changes in the exo/endo
scenario could stem from the actual polarity of the reaction
medium. As reported in Table 3, anisole could be used as
solvent, still leading to the six-membered ring product as the
major component of the mixture. Besides, the ratio between
6- and 7-membered ring products proved dependent on the
nucleophile used. In the calculations, replacing 1,2-dichloro-
ethane by anisole as solvent increased the relative energy of
most of the transition states (see Schemes 11 and 12). This
result is consistent with the lower polarity of anisole com-
pared to 1,2-dichloroethane, which limits the stabilization
effects of the solvent on species with strong charge separation
carbocations H1/2, lying approximately 20 kcal/mol below
B1/2. The comparison of all barrier heights displayed in
Scheme 11 shows that, although exo and endo pathways
are close-lying trajectories, the experimental trend is re-
spected. In the gem-diester series, endo cyclization is the
lowest kinetically attainable pathway. However this step in
reversible, as it is endergonic and followed by a second
barrier that is higher than the exo one (14.53 vs 13.59 kcal/
mol). Thus, exo cyclization is expected to prevail, as observed
experimentally. In the NTs series, although both pathways
have reversible first steps, the second one is more accessible
for the endo mode (15.45 vs 13.43 kcal/mol). Consequently,
the preferential formation of 7-membered ring products can
be presumed, in agreement with the experimental data.
The rest of the endo pathway relies on a 1,2-hydride shift
giving the η2 alkene complex I2 (Scheme 12, see also Figure 2
in the Supporting Information for geometries). Also in line
with the experimental results, the H2 f I2 transformation is
kinetically favored over that of enamine I02. The formation of
the latter requires first the formation of the unstabilized
cation L2 to allow the passing of the hydride. Thus, the tether
also plays a role on the control of the regioselectivity.
(Cþ Ga-). On the other hand, the moderately charged
3 3 3
product-like M2 f D2 transition state gets a powerful
stabilization from anisole compared to 1,2-dichloroethane.
As a result, and in agreement with the observations depicted
in Scheme 8, the H2 f M2 f D2 transformation becomes
kinetically favored over H2 f I2, leading to a 6-membered
ring product rather than a 7-membered one. Thus, the way
nucleophiles modify the 6-exo- vs 7-endo-dig could be due to
the modification of the overall polarity of the reaction
medium, switching close-lying trajectories.
3. Conclusion
The preference for the endo cyclization pathway in the NTs
series seems at odds with the experimental results which were
obtained in the presence of nucleophilic arenes. Indeed, the
major compounds arising from the cycloisomerization/
Friedel-Crafts tandem were systematically 6-membered
ring products (see Table 3). We envisaged that in the presence
of the nucleophile, the active species could be modified.
We have developed an elusive polyhydroarylation proto-
col based on the finding that GaCl3 not only catalyzes the
cycloisomerization of arenynes but also traps the intermedi-
ates by electron-rich arenes, even in an intermolecular fash-
ion. In a recent review on π-acid catalysis,2e Furstner stated:
€
“a priori, there is no need to tie the two reaction partners
together, thus making intermolecular transformations fea-
sible, even though the number of successful cases still re-
mains somewhat limited.” In that sense, our study shows that
gallium is not just an alternative to gold or other noble
metals, as it allows us to go one step beyond. DFT computa-
tions have shed light on peculiar cyclization selectivities.
They rationalized the crucial role played by the tether of
arenynes on the stabilization of cationic intermediates and
the regiodivergency between exo and endo cyclizations.
Lastly, some unexpected transformations were uncovered,
in particular a new type of oxidative hydride transfer from
Attempts to use GaCl3 anisole failed because of the sys-
3
tematic expulsion of the arene ligand during optimization.
Conversely, with GaCl3 H2O, water stuck to gallium; how-
3
ever its presence resulted in, at least, doubling the barrier
heights, making them virtually impassable.
We wondered whether an escape lane could be modeled
from 7- to 6-membered ring products, i.e., by ring contrac-
tion of H2. Indeed, the transformation of the latter into the
nonclassical carbocation M2 displaying a nascent piperi-
dine framework could be modeled. Although moderately
endergonic, this step is realized through the most accessible
8442 J. Org. Chem. Vol. 75, No. 24, 2010

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SCHEME 10. Alkyne Complexes of GaCl3 (E = CO2Me, Selected Distances in A)
JOCArticle
˚
SCHEME 11. Free Energy Progress Profile (ΔGDCE in kcal/mol) for the 6-exo and 7-endo Cyclizations (ΔGani Is Indicated in Parentheses)a
aIn red, A1-H1: X = CE2, E = CO2Me. In blue A2-H2: X = NTs, Ar = p-Tol
J. Org. Chem. Vol. 75, No. 24, 2010 8443

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SCHEME 12. Free Energy Progress Profiles (ΔGDCE in kcal/mol) of Intermediate H2 Relatively to B2 (ΔGani Is Indicated in
Parentheses)
diphenylmethane to alkene moieties. Work on the enantio-
selective version of the title reaction is in progress in our
laboratory, as well as the valorization of the side issues that
were revealed during our study.
Et2O (3 ꢀ 10 mL). The combined organic extracts were dried
over anhydrous sodium sulfate, filtered, and concentrated. The
residue was subjected to flash column chromatography on silica
gel to afford compound 3 (86.6 mg) in 91% yield. Colorless oil;
1H NMR (300 MHz, CDCl3) δ 7.24-7.13 (m, 4H), 7.02 (d, J =
8.1, 2H), 6.94 (d, J = 8.1, 2H), 4.17 (q, J = 7.2, 1H), 4.16 (q, J =
7.2, 1H), 3.83 (dq, J = 10.8, 7.2, 1H), 3.47 (dq, J = 10.8, 7.2,
1H), 3.31 (d, J = 15.9, 1H), 3.14 (d, J = 15.9, 1H), 2.91 (d, J =
14.4, 1H), 2.51 (d, J = 14.4, 1H), 2.29 (s, 3H), 1.71 (s, 3H), 1.23
(t, J = 7.2, 3H), 1.04 (t, J = 7.2, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.8, 170.6, 146.2, 142.0, 135.1, 134.2, 128.7, 128.3,
128.2, 127.3, 126.3, 126.2, 61.3, 61.0, 52.5, 43.4, 42.0, 35.0, 31.9,
20.7, 13.9, 13.6; FTIR (film) 2975, 2930, 1713, 1582, 1511, 1493,
1446, 1369, 1335, 1213, 1184, 1115, 1091, 1046, 910, 861, 818,
767, 732, 701 cm-1. HRMS (TOF-QII) m/z calcd for C24H28O4Na
[M þ Na]þ 403.1886, found 403.1820.
4. Experimental Section
General methods, solvent purification procedures, and de-
tails on NMR spectroscopy are described in the Supporting
Information. GaCl3 (0.5 M in pentane) was obtained from
Aldrich. All J values are given in hertz.
Reaction of Arenyne 1a in Toluene under Ga(III)- and Au(I)-
Catalysis. To a solution of substrate 1a (72.1 mg, 0.25 mmol) in
toluene (1 mL) at 80 °C was added AuClPPh3 (2.5 mg, 0.005
mmol) and AgSbF6 (1.7 mg, 0.005 mmol) in one portion. The
mixture was stirred at 80 °C for 16 h, then sat. aq NaHCO3
(1 mL) was added at 0 °C. The two layers were separated, and the
aqueous phase was extracted with Et2O (3 ꢀ 10 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was subjected to
flash column chromatography on silica gel to afford compound
Typical Procedure for Bimolecular Dihydroarylations. To a
solution of substrates 1 (0.25 mmol) and possibly arenes (0.75
mmol) in DCE (1 mL) at 80 °C was added GaCl3 (0.5 M in
pentane, 0.05 mL, 0.025 mmol) in one portion. The mixture was
stirred at 80 °C for 10 h, then sat. aq NaHCO3 (1 mL) was added
at 0 °C. The two layers were separated, and the aqueous phase
was extracted with Et2O (3 ꢀ 10 mL). The combined organic
extracts were dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was subjected to flash column chro-
matography on silica gel to afford products 4-18.
1
27 (49.0 mg) in 68% yield. Colorless oil; H NMR (300 MHz,
CDCl3) δ 7.19-7.12 (m, 4H), 5.90 (s, 1H), 4.15-4.03 (m, 4H),
3.29 (s, 2H), 2.07 (s, 3H), 1.14 (t, J = 7.2, 6H); 13C NMR (75
MHz, CDCl3) δ 170.5, 134.9, 133.5, 132.8, 127.8, 127.7, 126.9,
123.4, 121.4, 61.6, 54.8, 34.6, 19.4, 14.0; FTIR (film) 2983, 1732,
1449, 1365, 1266, 1225, 1133, 1049, 1015, 762 cm-1. HRMS
(TOF-QII) m/z calcd for C17H20NaO4 [M þ Na]þ 311.1254,
found 311.1251.
To a solution of substrate 1a (72.1 mg, 0.25 mmol) in toluene
(1 mL) at 80 °C was added GaCl3 (0.5 M in pentane, 0.05 mL,
0.025 mmol) in one portion. The mixture was stirred at 80 °C for
10 h, then sat. aq NaHCO3 (1 mL) was added at 0 °C. The two
layers were separated, and the aqueous phase was extracted with
1
Compound 4: colorless oil; 88% yield; H NMR (300 MHz,
CDCl3) δ 7.24-7.15 (m, 4H), 6.96 (d, J = 9.0, 2H), 6.75 (d, J =
9.0, 2H), 4.17 (q, J = 7.2, 1H), 4.16 (q, J = 7.2, 1H), 3.84 (dq,
J = 10.8, 7.2, 1H), 3.75 (s, 3H), 3.48 (dq, J = 10.8, 7.2, 1H), 3.33
(d, J = 16.2, 1H), 3.13 (d, J = 16.2, 1H), 2.90 (d, J = 14.4, 1H),
2.49 (d, J = 14.4, 1H), 1.70 (s, 3H), 1.23 (t, J = 7.2, 3H), 1.04 (t,
J = 7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8, 170.5, 157.4,
141.8, 141.1, 134.1, 128.7, 128.4, 128.0, 126.3, 126.2, 112.8, 61.3,
8444 J. Org. Chem. Vol. 75, No. 24, 2010

Li et al.
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61.0, 55.0, 52.3, 43.3, 41.5, 34.9, 32.0, 13.8, 13.6; FTIR (film)
2976, 2934, 2835, 1730, 1607, 1580, 1508, 1462, 1444, 1366, 1332,
6.58 (d, J = 2.4, 1H), 6.50 (dd, J = 8.4, 2.4, 1H), 4.07 (q, J = 7.2,
1H), 4.06 (q, J = 7.2, 1H), 3.76 (dq, J = 10.8, 7.2, 1H), 3.80 (s,
3H), 3.73 (s, 3H), 3.38 (dq, J = 10.8, 7.2, 1H), 3.28 (d, J = 16.2,
1H), 3.09 (d, J = 16.2, 1H), 2.90 (d, J = 14.1, 1H), 2.45 (d, J =
14.1, 1H), 1.69 (s, 3H), 1.20 (t, J = 7.2, 3H), 1.00 (t, J = 7.2, 3H);
13C NMR (75 MHz, CDCl3) δ 171.8, 170.6, 148.0, 146.9, 141.8,
141.7, 134.2, 128.7, 128.0, 126.4, 126.2, 119.7, 111.3, 110.2, 61.3,
61.0, 55.7, 55.6, 52.4, 43.2, 41.9, 34.9, 32.0, 13.9, 13.8; FTIR
(film) 2975, 2934, 2834, 1729, 1604, 1588, 1511, 1463, 1444,
1408, 1366, 1332, 1251, 1236, 1211, 1183, 1165, 1146, 1124, 1093,
1051, 1026, 947, 912, 858, 808, 768, 730, 650 cm-1; HRMS
(TOF-QII) m/z calcd for C25H30O6Na [M þ Na]þ 449.1940,
found 449.1928.
1247, 1215, 1127, 1091, 1030, 860, 810, 830, 768, 732 cm-1
;
HRMS (TOF-QII) m/z calcd for C24H28O5Na [M þ Na]þ
419.1835, found 419.1820.
Compound 5: colorless oil; 81% yield; H NMR (300 MHz,
1
CDCl3) δ 7.26-7.15 (m, 2H), 7.03 (d, J = 9.0, 2H), 6.99-6.78
(m, 2H), 6.75 (d, J = 9.0, 2H), 4.16-4.06 (m, 4H), 3.78 (s, 3H),
3.24 (d, J = 13.8, 1H), 3.18 (d, J = 13.8, 1H), 2.51 (dt, J = 12.9,
4.2, 1H), 1.93 (dt, J = 12.9, 4.2, 1H), 1.68 (dt, J = 13.8, 4.5, 1H),
1.61 (s, 3H), 1.52 (dt, J = 13.8, 4.5, 1H), 1.21 (t, J = 7.2, 3H),
1.18 (t, J = 7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 171.4, 171.2,
157.9, 142.8, 136.8, 136.1, 129.9, 128.0, 127.7, 126.8, 120.4,
112.9, 61.1, 61.0, 58.8, 55.3, 44.2, 37.6, 33.2, 27.1, 26.9, 14.1,
14.0; FTIR (film) 2977, 2936, 1729, 1606, 1510, 1490, 1455, 1368,
1286, 1243, 1219, 1180, 1094, 1032, 914, 862, 829, 740, 702, 623
cm-1; HRMS (TOF-QII) m/z calcd for C25H31O5 [M þ H]þ
411.2166, found 411.2151.
1
Compound 10: 81% yield; H NMR (300 MHz, CDCl3) δ
7.23-7.11 (m, 5H), 6.76 (dd, J = 8.7, 2.1, 1H), 6.71 (d, J = 8.7,
1H), 4.16 (q, J = 7.2, 1H), 4.15 (q, J = 7.2, 1H), 3.86 (dq, J =
10.8, 7.2, 1H), 3.83 (s, 3H), 3.50 (dq, J = 10.8, 7.2, 1H), 3.29 (d,
J = 16.2, 1H), 3.11 (d, J = 16.2, 1H), 2.84 (d, J = 14.4, 1H), 2.47
(d, J = 14.4, 1H), 1.67 (s, 3H), 1.21 (t, J = 7.2, 3H), 1.05 (t, J =
7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 171.7, 170.5, 152.9,
142.4, 141.2, 134.1, 129.1, 128.9, 128.0, 127.0, 126.7, 126.5,
121.7, 111.0, 61.5, 61.2, 56.0, 52.4, 43.2, 41.7, 34.9, 31.9, 13.9,
13.6; FTIR (film) 2977, 1782, 1729, 1602, 1497, 1462, 1443, 1393,
1366, 1332, 1292, 1254, 1220, 1182, 1126, 1095, 1066, 1023, 862,
813, 769, 725, 708, 621 cm-1; HRMS (TOF-QII) m/z calcd for
C24H27ClO5Na [M þ Na]þ 453.1445, found 453.1420.
1
Compound 6: colorless oil; 72% yield; H NMR (300 MHz,
CDCl3) δ 7.26-7.17 (m, 2H), 7.02 (d, J = 8.7, 2H), 7.00-6.77
(m, 2H), 6.75 (d, J = 8.7, 2H), 4.14-4.05 (m, 4H), 3.77 (s, 3H),
3.14 (d, J = 13.8, 1H), 3.09 (d, J = 13.8, 1H), 2.38 (dt, J = 12.0,
4.5, 1H), 1.92 (dt, J = 12.0, 4.5, 1H), 1.74-1.68 (m, 2H), 1.59 (s,
3H), 1.16 (t, J = 7.2, 3H), 1.15 (t, J = 7.2, 3H), 1.09-0.95 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 171.3, 171.2, 156.9, 142.9,
137.2, 136.2, 129.8, 128.1, 127.5, 126.9, 120.3, 112.8, 61.1, 61.0,
58.8, 55.4, 44.5, 39.8, 37.7, 32.2, 27.0, 19.5, 14.0 (2C); FTIR (film)
2960, 1730, 1597, 1510, 1489, 1462, 1369, 1294, 1244, 1213, 1181,
1096, 1032, 925, 830, 701, 618 cm-1; HRMS (TOF-QII) m/z calcd
for C26H33O5 [M þ H]þ 425.2323, found 425.2303.
Compound 11: colorless oil; 88% yield; 1H NMR (300 MHz,
CDCl3) δ 7.32 (d, J = 2.4, 1H), 7.23-7.10 (m, 4H), 6.78 (dd, J =
8.7, 2.4, 1H), 6.68 (d, J = 8.7, 1H), 4.16 (q, J = 7.2, 1H), 4.15 (q,
J = 7.2, 1H), 3.90 (dq, J = 10.8, 7.2, 1H), 3.82 (s, 3H), 3.52 (dq,
J = 10.8, 7.2, 1H), 3.30 (d, J = 16.2, 1H), 3.10 (d, J = 16.2, 1H),
2.83 (d, J = 14.4, 1H), 2.47 (d, J = 14.4, 1H), 1.66 (s, 3H), 1.21
(t, J = 7.2, 3H), 1.05 (t, J = 7.2, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.7, 170.5, 153.8, 142.9, 141.2, 134.1, 132.1, 129.0,
128.0, 127.9, 126.7, 126.5, 111.0, 110.9, 61.5, 61.3, 56.2, 52.4,
43.3, 41.6, 34.9, 32.0, 13.9, 13.7; FTIR (film) 2977, 1730, 1600,
1493, 1462, 1443, 1390, 1366, 1332, 1256, 1220, 1182, 1126, 1095,
1054, 1020, 861, 812, 768 cm-1; HRMS (TOF-QII) m/z calcd for
C24H27BrO5Na [M þ Na]þ 497.0940, found 497.0934.
1
Compound 7: colorless oil; 78% yield; H NMR (300 MHz,
CDCl3, 2:1 mixture of conformers (see below)); major confor-
mer: δ 7.83-7.32 (m, 4H), 7.13 (dd, J = 6.9, 1.5, 1H), 7.10 (dd,
J = 6.9, 1.5, 1H), 6.98 (d, J = 8.7, 2H), 6.73 (d, J = 8.7, 2H),
4.18 (q, J = 7.2, 2H), 3.93 (dq, J = 10.8, 7.2, 1H), 3.75 (s, 3H),
3.65 (dq, J = 10.8, 7.2, 1H), 3.45 (s, 2H), 2.70 (d, J = 14.4, 1H),
2.61 (d, J = 14.4, 1H), 1.90 (s, 3H), 1.24 (t, J = 7.2, 3H), 1.05 (t,
J = 7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 171.7, 170.7, 157.4,
142.3, 136.2, 134.0, 132.5, 131.3, 128.8, 128.1, 128.0, 127.9,
127.8, 124.6, 124.2, 113.4, 61.4, 61.3, 55.2, 51.5, 48.3, 42.3,
36.9, 29.7, 14.0, 13.7; minor conformer: δ 7.83-7.32 (m, 4H),
7.30 (dd, J = 7.8, 1.0, 1H), 7.27 (dd, J = 7.8, 1.0, 1H), 7.13-7.02
(m, 2H), 6.79-6.74 (m, 2H), 4.10 (q, J = 7.2, 2H), 4.05-3.76 (m,
2H), 3.73 (s, 3H), 3.26 (br s, 2H), 3.13 (d, J = 14.7, 1H), 2.51 (d,
J = 14.7, 1H), 1.78 (s, 3H), 1.18 (t, J = 7.2, 3H), 1.14 (t, J = 7.2,
3H); 13C NMR (75 MHz, CDCl3) δ 171.9, 171.2, 157.7, 133.4,
132.6, 132.4, 127.8, 127.1, 127.0, 125.7, 125.6, 125.3, 113.2, 61.5,
53.4, 42.6, 42.5, 13.9 (8 C hidden or accidentally isochronous
with major conformer); FTIR (film) 2979, 2339, 1731, 1607,
Compound 12: colorless oil; 67% yield; 1H NMR (300 MHz,
CDCl3) δ 7.23-7.18 (m, 4H), 6.22 (s, 2H), 4.15 (q, J = 7.2, 1H),
4.14 (q, J = 7.2, 1H), 3.89-3.81 (m, 1H), 3.79 (s, 3H), 3.70 (s,
3H), 3.43 (dq, J = 10.8, 7.2, 1H), 3.30 (d, J = 16.2, 1H), 3.07 (d,
J = 16.2, 1H), 2.90 (dd, J = 14.4, 1.2, 1H), 2.43 (d, J = 14.4,
1H), 1.71 (s, 3H), 1.21 (t, J = 7.2, 3H), 1.00 (t, J = 7.2, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.9, 170.6, 152.2, 144.9, 141.5,
135.8, 134.3, 128.9, 128.2, 126.6, 126.3, 105.2, 61.5, 61.2, 60.6,
55.9, 52.4, 43.2, 42.5, 35.0, 32.0, 14.0, 13.7; FTIR (film) 2983,
1731, 1587, 1508, 1456, 1413, 1256, 1126, 1010, 748, 620 cm-1
;
1509, 1463, 1367, 1296, 1248, 1182, 1102, 1034, 832, 732 cm-1
;
HRMS (TOF-QII) m/z calcd for C26H32O7Na [M þ Na]þ
HRMS (TOF-QII) m/z calcd for C28H30O5Na [M þ Na]þ
479.2040, found 479.2045.
Compound 13: colorless oil; 87% yield; 1H NMR (300 MHz,
CDCl3) δ 7.22-7.19 (m, 4H), 6.23 (s, 2H), 5.34 (br s, 1H, OH),
4.15 (q, J = 7.2, 1H), 4.14 (q, J = 7.2, 1H), 3.89-3.82 (m, 1H),
3.73 (s, 6H), 3.49 (dq, J = 10.8, 7.2, 1H), 3.27 (d, J = 15.9, 1H),
3.08 (d, J = 15.9, 1H), 2.91 (d, J = 14.4, 1H), 2.42 (d, J = 14.4,
469.1985, found 469.1979.
Compound 8: colorless oil; 90% yield; H NMR (300 MHz,
1
CDCl3) δ 7.23-7.13 (m, 4H), 6.90 (d, J = 2.1, 1H), 6.71 (dd, J =
8.7, 2.1, 1H), 6.62 (d, J = 8.7, 1H), 4.17 (q, J = 7.0, 1H), 4.16 (q,
J = 7.0, 1H), 3.84 (dq, J = 10.8, 7.2, 1H), 3.77 (s, 3H), 3.48 (dq,
J = 10.8, 7.2, 1H), 3.31 (d, J = 16.2, 1H), 3.13 (d, J = 16.2, 1H),
2.88 (d, J = 14.4, 1H), 2.48 (d, J = 14.4, 1H), 2.15 (s, 3H), 1.68
(s, 3H), 1.22 (t, J = 7.2, 3H), 1.04 (t, J = 7.2, 3H); 13C NMR (75
MHz, CDCl3) δ 171.9, 170.7, 155.7, 142.1, 140.8, 134.1, 129.6,
128.7, 128.2, 126.3, 126.2, 125.9, 125.5, 108.8, 61.4, 61.1, 55.2,
52.5, 43.4, 41.6, 35.0, 32.0, 16.3, 13.9, 13.6; FTIR (film) 2976,
2934, 2834, 1730, 1608, 1504, 1463, 1444, 1366, 1332, 1296, 1245,
1227, 1191, 1167, 1125, 1095, 1051, 1031, 945, 891, 861, 811, 766,
749, 702, 616 cm-1; HRMS (TOF MS ESþ) m/z calcd for
C25H30O5Na [M þ Na]þ 433.1991, found 433.1996.
1H), 1.69 (s, 3H), 1.21 (t, J = 7.2, 3H), 1.00 (t, J = 7.2, 3H); 13
C
NMR (75 MHz, CDCl3) δ 171.9, 170.7, 146.1, 141.8, 140.3,
134.3, 132.7, 128.8, 128.0, 126.6, 126.3, 104.8, 61.5, 61.2, 56.1,
52.5, 43.3, 42.4, 34.9, 32.0, 13.9, 13.6; FTIR (film) 2967, 2934,
1730, 1612, 1519, 1452, 1420, 1366, 1332, 1317, 1243, 1217, 1169,
1113, 1029, 859, 799, 664, 625 cm-1; HRMS (TOF-QII) m/z
calcd for C25H30O7Na [M þ Na]þ 465.1884, found 465.1867.
Compound 14: colorless oil; 90% yield; 1H NMR (300 MHz,
CDCl3) δ 7.20-7.16 (m, 4H), 6.85 (d, J = 6.6, 2H), 6.61 (d,
J = 6.6, 2H), 5.39 (br s, 1H, OH), 4.16 (q, J = 7.2, 1H), 4.15 (q,
J = 7.2, 1H), 3.81 (dq, J = 10.8, 7.2, 1H), 3.45 (dq, J = 10.8, 7.2,
1H), 3.31(d, J= 16.2, 1H), 3.09 (d, J= 16.2, 1H), 2.86 (d, J=14.1,
Compound 9: white crystals; 90% yield; mp 108 °C; 1H NMR
(300 MHz, CDCl3) δ 7.20-7.15 (m, 4H), 6.67 (d, J = 8.4, 1H),
J. Org. Chem. Vol. 75, No. 24, 2010 8445

Li et al.
JOCArticle
1H), 2.46 (d, J = 14.1, 1H), 1.66 (s, 3H), 1.21 (t, J = 7.2, 3H), 1.03
(t, J = 7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 172.0, 170.9, 153.7,
141.9, 141.0, 134.1, 128.8, 128.7, 128.2, 126.4, 126.3, 114.4, 61.5, 61.3,
52.5, 43.4, 41.6, 35.0, 32.1, 13.9, 13.6; FTIR (film) 3432, 2978, 1729,
1713, 1612, 1511, 1492, 1462, 1444, 1367, 1333, 1262, 1220, 1180,
1127, 1092, 1052, 834, 773 cm-1; HRMS (TOF-QII) m/z calcd for
C23H26O5Na [M þ Na]þ 405.1678, found 405.1665.
sulfate, filtered, and concentrated. The residue was subjected to
flash column chromatography on silica gel to afford compounds
20-22.
Compound 20: colorless oil; 76% yield; 1H NMR (300 MHz,
CDCl3) δ 7.26-7.00 (m, 5H), 4.24-4.14 (m, 6H), 3.43 (s, 2H),
3.38 (s, 2H), 3.06 (s, 2H), 1.28-1.23 (m, 9H); 13C NMR (75
MHz, CDCl3) δ 199.9, 169.9, 166.6, 136.1, 129.9, 128.5, 127.2,
61.8, 61.4, 56.4, 49.5, 44.8, 38.4, 14.1, 13.9; FTIR (film) 2980,
Compound 15: white crystals; 89% yield; mp 156 °C; 1H NMR
(300 MHz, CDCl3) δ 7.20-7.12 (m, 4H), 6.63 (s, 2H), 4.67 (br s,
1H, OH), 4.16 (q, J = 7.2, 2H), 3.86 (dq, J = 10.8, 7.2, 1H), 3.55
(dq, J = 10.8, 7.2, 1H), 3.28 (d, J = 16.2, 1H), 3.14 (d, J = 16.2,
1H), 2.85 (d, J = 14.4, 1H), 2.46 (d, J = 14.4, 1H), 2.14 (s, 6H),
1.65 (s, 3H), 1.22 (t, J = 7.2, 3H), 1.05 (t, J = 7.2, 3H); 13C NMR
(75 MHz, CDCl3) δ 172.0, 170.8, 150.1, 142.3, 140.7, 134.0,
128.7, 128.2, 127.6, 126.9, 126.2, 122.0, 61.4, 61.1, 52.6, 43.5,
41.6, 35.0, 31.9, 16.0, 13.9, 13.6; FTIR (film) 3501, 2976, 2930,
1721, 1602, 1488, 1445, 1366, 1331, 1295, 1256, 1241, 1207, 1193,
1164, 1125, 1096, 1052, 1028, 949, 911, 862, 764, 731, 645, 632
cm-1; HRMS (TOF-QII) m/z calcd for C25H30O5Na [M þ Na]þ
433.1991, found 433.1974.
2340, 1733, 1449, 1366, 1238, 1183, 1057, 1030, 863, 704 cm-1
;
MS (ESI Q1MS) m/z calcd for C20H27O7 [M þ H]þ 379.18,
found 379.22; calcd for C20H26NaO7 [M þ Na]þ 401.16, found
401.22.
Compound 21: colorless oil; 67% yield; 1H NMR (300 MHz,
CDCl3) δ 7.94-7.12 (m, 10H), 4.18 (q, J = 7.2 Hz, 4H), 3.32 (s,
2H), 3.05 (q, J = 7.8 Hz, 2H), 2.26 (q, J = 7.8 Hz, 2H), 1.23 (t,
J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 198.8, 171.0,
135.8, 133.1, 130.0, 128.6, 128.3, 128.02, 127.99, 127.1, 61.4,
58.2, 39.7, 34.0, 27.1, 14.0; FTIR (film) 2981, 2354, 1728, 1686,
1599, 1448, 1367, 1243, 1179, 1091, 1032, 862, 733, 701, 622 cm-1
;
MS (ESI Q1MS) m/z calcd for C23H27O5 [M þ H]þ 383.19, found
383.25; calcd for C23H26NaO5 [M þ Na]þ 405.17, found 405.24.
Compound 22A: colorless oil; 64% yield; 1H NMR (300 MHz,
CDCl3) δ 7.31-7.02 (m, 5H), 4.25 (q, J = 7.2 Hz, 1H), 3.86 (s,
2H), 3.45 (s, 2H), 3.14 (s, 2H), 1.29 (t, J = 7.2 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 199.1, 169.9, 135.9, 129.9, 128.5,
127.3, 61.9, 56.7, 42.0, 38.7, 34.1, 13.9; FTIR (film) 2980, 1733,
1730, 1456, 1275, 1188, 1048, 764, 750, 704 cm-1. HRMS (TOF-
QII) m/z calcd for C17H21BrO5Na [M þ Na]þ 407.0465, found
407.0465.
1
Compound 16: pale yellow foam; 94% yield; H NMR (300
MHz, CDCl3) δ 7.88-7.89 (m, 3H), 7.48-7.35 (m, 3H), 7.18-
6.98 (m, 7H), 6.85 (s, 1H), 4.08 (q, J = 7.2, 2H), 3.40-3.30 (m,
1H), 3.29 (d, J = 16.5, 1H), 3.18 (d, J = 16.5, 1H), 2.99 (d, J =
14.4, 1H), 2.81-2.70 (m, 1H), 2.36 (d, J = 14.4, 1H), 1.66 (s,
3H), 1.13 (t, J = 7.2, 3H), 0.57 (t, J = 7.2, 3H); 13C NMR (75
MHz, CDCl3) δ 171.7, 170.5, 140.2, 138.0, 135.7, 133.7, 133.1,
130.3, 129.2, 129.0, 128.8, 127.8, 127.0, 126.9, 126.6, 124.7,
124.2, 122.8, 121.5, 113.6, 61.4, 60.6, 52.0, 39.5, 38.0, 34.7,
30.1, 13.9, 13.2; FTIR (film) 2982, 1728, 1446, 1368, 1257,
1221, 1174, 1135, 1090, 1071, 1053, 1024, 964, 909, 861, 805,
725, 685, 648, 624 cm-1; HRMS (TOF-QII) m/z calcd for
C31H31NO6SNa [M þ Na]þ 568.1764, found 568.1765.
Compound 22B: colorless oil; 20% yield; 1H NMR (300 MHz,
CDCl3) δ 7.25-7.18 (m, 4H), 6.29 (s, 1H), 4.21-4.15 (m, 4H),
3.33 (s, 2H), 3.03 (s, 2H), 1.23 (t, J = 7.2 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 170.4, 135.1, 134.8, 128.7, 128.2, 127.7, 125.5,
101.5, 61.8, 54.5, 39.5, 35.0, 14.1; FTIR (film) 2972, 1732, 1681,
1454, 1251, 1192, 1159, 1106, 1079, 1054, 1018, 928, 857, 749,
703 cm-1; HRMS (TOF-QII) m/z calcd for C17H19BrO4Na
[M þ Na]þ 389.0359, found 389.0359.
Compound 17: colorless oil; 77% yield; 1H NMR (300 MHz,
CDCl3) δ 7.25-7.16 (m, 5H), 5.53 (s, 1H), 3.65 (d, J = 6.6 Hz,
1H), 3.54 (d, J = 6.6 Hz, 1H), 3.39-3.33 (m, 5H), 2.84 (s, 2H),
2.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 134.7, 134.2, 128.4,
127.3, 126.6, 123.1, 78.0, 68.3, 59.5, 40.7, 33.4, 19.5; FTIR (film)
2926, 1275, 1260, 764, 750, 723, 700 cm-1; HRMS (TOF-QII)
m/z calcd for C14H19O2 [M þ H]þ 219.1380, found 219.1397;
calcd for C14H18NaO2 [M þ Na]þ 241.1199, found 241.1185.
Compound 18: 82% yield. 18a/18b = (1/1 mixture of diaste-
reomers). 18a: colorless oil; 1H NMR (300 MHz, CDCl3) δ
7.33-6.81 (m, 8H), 3.90-3.77 (m, 2H), 3.78 (s, 3H), 3.27-3.19 (m,
2H), 2.96 (d, J = 13.5 Hz, 1H), 2.83 (d, J = 13.5 Hz, 1H), 2.08 (s,
2H), 1.50 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 158.0, 140.7,
138.4, 130.2, 128.3, 126.4, 125.5, 113.5, 84.4, 73.6, 65.3, 55.2, 50.5,
47.5, 40.8, 31.6; FTIR (film) 3424, 2935, 1610, 1510, 1452, 1370,
1298, 1245, 1178, 1108, 1032, 832, 705, 660, 612 cm-1; HRMS
(TOF-QII) m/z calcd for C20H25O3 [M þ H]þ 313.1798, found
313.1781; calcd for C20H24O3Na [M þ Na]þ 335.1618, found
335.1625. 18b: colorless oil; 1H NMR (300 MHz, CDCl3) δ
7.37-6.89 (m, 8H), 3.88-3.67 (m, 2H), 3.83 (s, 3H), 3.58-3.47
(m, 2H), 2.69 (d, J = 13.2 Hz, 1H), 2.55 (d, J = 13.2 Hz, 1H), 2.33
(d, J = 13.2 Hz, 1H), 1.89 (d, J = 13.2 Hz, 1H), 1.50 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 158.1, 140.6, 138.3, 129.9, 128.2, 126.3,
125.8, 113.7, 84.6, 74.2, 66.2, 55.2, 50.5, 47.2, 40.0, 32.0; FTIR (film)
Typical Procedure for Intramolecular Double and Triple Hydro-
arylations. To a solution of substrates 1o-r (0.25 mmol, see text,
Scheme 5) in DCE (1 mL) at 80 °C was added GaCl3 (0.5 M in
pentane, 0.05 mL, 0.025 mmol) in one portion. The mixture
was stirred at 80 °C for 8 h, then sat. aq NaHCO3 (1 mL) was
added at 0 °C. The two layers were separated, and the aqueous
phase was extracted with Et2O (3 ꢀ 10 mL). The combined
organic extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was subjected to flash
column chromatography on silica gel to afford compounds
23-26 in high yields.
Compound 23: colorless oil; 99% yield; 1H NMR (300 MHz,
CDCl3) δ 7.46 (d, J = 4.5, 2H), 7.16-7.06 (m, 6H), 4.29 (q, J =
4.2, 2H), 3.48 (d, J = 10.2, 2H), 2.99 (d, J = 10.2, 2H), 2.22 (s,
2H), 1.89 (s, 3H), 1.36 (t, J = 4.2, 3H); 13C NMR (75 MHz,
CDCl3) δ 177.5, 144.2, 134.1, 129.1, 126.3, 125.6, 124.3, 60.8,
41.3, 40.5, 39.9, 38.3, 25.7, 11.2; FTIR (film) 2934, 2197, 1725,
1574, 1489, 1450, 1367, 1293, 1240, 1210, 1158, 1124, 1083, 1041,
863, 818, 781, 727, 618 cm-1; HRMS (TOF-QII) m/z calcd for
C21H23O2 [M þ H]þ 307.1693, found 307.1690.
3457, 2926, 2339, 1728, 1611, 1510, 1297, 1246, 1032, 833, 704 cm-1
;
1
Compound 24: pasty solid; 95% yield; H NMR (300 MHz,
HRMS (TOF-QII) m/z calcd for C20H25O3 [M þ H]þ 313.1798,
found 313.1793; calcd for C20H24O3Na [M þ Na]þ 335.1618, found
335.1637.
CDCl3) δ 7.64 (d, J = 4.5, 1H), 7.51 (d, J = 4.5, 1H), 7.48 (d,
J = 4.5, 1H), 7.32 (t, J = 4.5, 1H), 7.25 (t, J = 4.5, 1H), 6.86 (d,
J = 4.5, 1H), 4.36-4.31 (m, 2H), 4.04-3.97 (m, 2H), 3.95 (s,
3H), 3.93 (d, J = 7.8, 1H), 3.14 (d, J = 7.8, 1H), 3.13 (d, J = 8.4,
1H), 1.91 (d, J = 8.4, 1H), 1.38 (s, 3H), 1.35 (t, J = 4.2, 3H), 1.09
(t, J = 4.2, 3H); 13C NMR (75 MHz, CDCl3) δ 172.8, 171.9,
156.2, 153.8, 151.1, 139.9, 130.7, 127.2, 126.0, 123.0, 120.6,
119.9, 118.9, 109.6, 61.7, 61.4, 56.0, 55.7, 45.9, 38.2, 26.3, 24.3,
14.1, 13.7; FTIR (film) 2979, 2933, 1728, 1622, 1494, 1458, 1440,
1387, 1355, 1311, 1246, 1190, 1097, 1066, 1046, 1021, 931, 903,
Gallium-Catalyzed Hydrations. To a solution of substrate
1l-n (0.25 mmol) in DCE (1 mL) at 80 °C was added GaCl3
(0.5 M in pentane, 0.05 mL, 0.025 mmol) in one portion. The
mixture was stirred at 80 °C for 10 h, then sat. aq NaHCO3
(1 mL) was added at 0 °C. The two layers were separated, and the
aqueous phase was extracted with Et2O (3 ꢀ 10 mL). The
combined organic extracts were dried over anhydrous sodium
8446 J. Org. Chem. Vol. 75, No. 24, 2010

Li et al.
JOCArticle
858, 811, 782, 748, 699 cm-1; HRMS (TOF-QII) m/z calcd for
C24H26NaO5 [M þ Na]þ 417.1672, found 417.1657.
2 dias); FTIR (film) 2978, 1729, 1608, 1508, 1465, 1365, 1249,
1181, 1094, 1054, 913, 832, 732, 651 cm-1; HRMS (TOF-QII)
m/z calcd for C42H48NaO10 [M þ Na]þ 735.3140, found 735.3145.
Gold-Catalyzed Hydroarylation of Diyne 1s. To a solution of
substrate 1s (154.7 mg, 0.25 mmol) in DCE (1 mL) at room
temperature was added AuClPPh3 (2.5 mg, 0.005 mmol) and
AgSbF6 (1.7 mg, 0.005 mmol) in one portion. The mixture was
stirred at room temperature for 8 h, then sat. aq NaHCO3 (1 mL)
was added at 0 °C. The two layers were separated, and the
aqueous phase was extracted with Et2O (3 ꢀ 10 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was subjected to
flash column chromatography on silica gel to afford compound
28 (118.4 mg) in 71% yield. Colorless oil; 1H NMR (300 MHz,
CDCl3) δ 7.10-6.70 (m, 6 H), 5.95 (q, J = 1.5, 1 H), 4.21-4.01
(m, 8 H), 3.80 (s, 2 H), 3.69 (s, 3 H), 3.39 (s, 2 H), 3.30 (s, 2 H),
2.91 (s, 2 H), 2.10 (d, J = 1.5, 3 H), 1.95 (s, 3 H), 1.24-1.16 (m,
12 H); 13C NMR (75 MHz, CDCl3) δ 205.1, 170.5, 170.4, 156.4,
139.9, 134.9, 133.5, 133.1, 132.1, 130.5, 128.7, 128.2 127.7, 125.1,
124.0, 121.5, 110.6, 61.6, 61.3, 55.7, 55.3, 54.8, 45.1, 40.9, 34.2,
32.0, 29.5, 19.4, 14.0, 13.9; FTIR (film) 2981, 1733 (br), 1611,
1503, 1465, 1445, 1366, 1269, 1236, 1210, 1186, 1127, 1096, 1078,
1046, 1032, 863, 815, 733, 647 cm-1; HRMS (TOF-QII) m/z
calcd for C36H45O10 [M þ H]þ 637.3007, found 637.3011.
Gallium-Catalyzed Hydroarylation of Diyne 1s. To a solution
of substrate 1s (154.7 mg, 0.25 mmol) in DCE (1 mL) at 80 °C
was added GaCl3 (0.5 M in pentane, 0.05 mL, 0.025 mmol) in
one portion. The mixture was stirred at 80 °C for 8 h, then sat. aq
NaHCO3 (1 mL) was added at 0 °C. The two layers were
separated, and the aqueous phase was extracted with Et2O
(3ꢀ10 mL). The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated. The
residue was subjected to flash column chromatography on silica
gel to afford compound 29 (120.6 mg) in 76% yield. Colorless
oil; 1:2 mixture of 2 diastereomers; 1H NMR (300 MHz, CDCl3)
δ 8.25 (d, J = 8.7, 1 H), 8.18 (s, 1 H), 7.44 (s, 1 H), 6.96 (d, J =
8.7, 1 H), 4.35-4.00 (m, 8 H), 3.95 (s, 3 H), 3.76 (d, J = 17.1, 1
H), 3.51 (d, J = 17.1, 1 H), 3.28-3.12 (m, 3 H), 3.03-2.88 (m, 1
H), 2.68-2.56 (m, 2 H), 1.92-1.80 (m, 1 H), 1.48-1.05 (m, 18
H); 13C NMR (75 MHz, CDCl3, major) δ 183.12, 172.48, 171.67,
171.63, 170.76, 160.47, 148.47, 146.48, 139.72, 138.77, 128.68,
128.25, 125.58, 125.51, 123.61, 121.39, 108.97, 61.96, 61.63 (d),
61.47, 55.79, 53.74, 53.04, 39.16, 37.10, 37.03, 35.77, 34.53,
29.83, 25.93, 21.02, 14.08, 14.05, 13.97, 13.83; 13C NMR (75
MHz, CDCl3, minor) δ 183.18, 172.41, 171.63, 171.58, 170.70,
160.47, 148.51, 146.58, 139.75, 138.77, 128.71, 128.25, 125.73,
125.68, 123.68, 121.39, 108.97, 61.96, 61.63 (d), 61.44, 55.79,
53.77, 53.15, 39.44, 37.10, 37.03, 35.95, 34.80, 29.81, 25.93,
21.39, 14.08, 14.05, 13.97, 13.83; FTIR (film) 2970, 1731 (br),
1656, 1608, 1590, 1464, 13685, 1300, 1263, 1244, 1188, 1138,
1095, 1050 cm-1; HRMS (TOF-QII) m/z calcd for C36H43O10
[M þ H]þ 635.2851, found 635.2858.
1
Compound 25: pasty solid; 98% yield; H NMR (300 MHz,
CDCl3) δ 7.58 (dd, J = 8.7, 1.5 Hz), 7.32-7.24 (m, 2H), 7.18 (dt,
J = 8.7, 1.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4
Hz, 1H), 4.31-4.06 (m, 5H), 3.88-3.80 (m, 5H), 3.20 (dd, J =
13.8, 1.5 Hz, 1H), 2.74 (d, J = 11.1 Hz, 1H), 2.69 (d, J = 11.1
Hz, 1H), 1.283 (t, J = 6.9 Hz, 3H), 1.280 (t, J = 6.9 Hz, 3H), 1.20
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.4, 172.3, 155.6, 146.2,
139.1, 136.0, 128.7, 127.7, 126.4, 125.83, 125.78, 123.5, 121.1,
107.7, 61.6, 61.4, 55.6, 38.6, 37.9, 35.5, 27.9, 27.1, 14.0, 13.9;
FTIR (film) 2972, 1731, 1592, 1456, 1260, 764 cm-1; HRMS
(TOF-QII) m/z calcd for C25H28O5Na [M þ Na]þ 431.1829,
found 431.1825.
1
Compound 26: pasty solid; 82% yield; H NMR (300 MHz,
CDCl3) δ 7.51 (s, 1H), 7.47 (d, J = 8.4, 1H), 7.28 (s, 1H), 6.82 (d,
J = 8.4, 1H), 5.98 (s, 1H), 4.35-3.90 (m, 8H), 3.89 (s, 3H), 3.83
(d, J = 2.4, 1H), 3.40 (d, J = 1.5, 2H), 3.11-3.04 (m, 2H), 2.21
(t, J = 1.5, 3H), 1.85 (d, J = 13.2, 1H), 1.35-1.19 (m, 12H), 1.07
(t, J = 7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 172.8, 171.9,
170.6, 170.5, 156.1, 153.4, 151.1, 138.7, 135.2, 132.8, 131.1,
130.7, 122.6, 121.1, 120.6, 118.5, 115.1, 109.6, 61.8, 61.6, 61.4,
56.0, 55.0, 45.9, 42.0, 38.2, 35.1, 26.3, 24.3, 19.8, 14.1, 14.0, 13.9
(2C), 13.8; FTIR (film) 2979, 1732, 1651, 1636, 1508, 1472, 1258,
749, 652, 620 cm-1; HRMS (TOF-QII) m/z calcd for C35H40NaO9
[M þ Na]þ 627.2565, found 627.2547.
Gallium-Catalyzed Quadruple Hydroarylation of Diyne 1r. To
a solution of substrate 1r (151.2 mg, 0.25 mmol) in DCE (1 mL)
at 80 °C was added GaCl3 (0.5 M in pentane, 0.05 mL, 0.025
mmol) and anisole (81.1 mg, 0.75 mmol) in one portion. The
mixture was stirred at 80 °C for 10 h, then sat. aq NaHCO3
(1 mL) was added at 0 °C. The two layers were separated, and the
aqueous phase was extracted with Et2O (3 ꢀ 10 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was subjected to
flash column chromatography on silica gel to afford compound
27 (133.7 mg) in 75% yield. Colorless oil; 1:1 mixture of 2
1
diastereomers; H NMR (300 MHz, CDCl3) δ 7.41-7.33 (m,
4 H, 2 dias), 7.28 (br, s, 2 H, 2 dias), 7.03 (d, J = 9.0, 2 H, 1 dias),
6.96 (d, J = 9.0, 2 H, 1 dias), 6.78 (d, J = 9.0, 1 H, 1 dias), 6.77
(d, J = 9.0, 1 H, 1 dias), 6.76 (d, J = 9.0, 2 H, 1 dias), 6.72 (d, J =
9.0, 2 H, 1 dias), 4.36-4.27 (m, 4 H, 2 dias), 4.20-4.10 (m, 4 H, 2
dias), 3.89 (s, 3 H, 1 dias), 3.88 (s, 3 H, 1 dias), 3.92-3.78 (m, 4 H,
2 dias), 3.75 (s, 3 H, 1 dias), 3.74 (s, 3 H, 1 dias), 4.06-3.90 (m, 4
H, 2 dias), 3.50-3.39 (m, 2 H, 2 dias), 3.38 (d, J = 11.1, 2 H, 2
dias), 3.18-3.07 (m, 4 H, 2 dias), 3.07 (d, J = 11.1, 2 H, 2 dias),
2.90 (d, J = 14.1, 1 H, 1 dias), 2.89 (d, J = 14.1, 1 H, 1 dias), 2.51
(d, J = 14.1, 1 H, 1 dias), 2.48 (d, J = 14.1, 1 H, 1 dias), 1.90 (d,
J = 13.5, 1 H, 1 dias), 1.86 (d, J = 13.5, 1 H, 1 dias), 1.77 (s, 3 H,
1 dias), 1.73 (s, 3 H, 1 dias), 1.40 (s, 3 H, 1 dias), 1.35 (s, 3 H,
1 dias), 1.36-0.98 (m, 24 H, 2 dias); 13C NMR (75 MHz, CDCl3)
δ 172.9 (CdO, 1 dias), 172.8 (CdO, 1 dias), 172.1 (CdO, 1 dias),
172.0 (CdO, 1 dias), 171.9 (2 CdO, 2 dias), 170.7 (CdO, 1 dias),
170.6 (CdO, 1 dias), 157.6 (C, 1 dias), 157.4 (C, 1 dias), 156.1
(2 C, 2 dias), 152.1 (C, 1 dias), 152.0 (C, 1 dias), 152.0 (C, 1 dias),
151.2 (2 C, 2 dias), 141.4 (C, 1dias), 141.3 (C, 1 dias), 140.9 (C,
1 dias), 140.8 (C, 1dias), 138.3 (2 C, 2 dias), 132.2 (C, 1dias),
132.1 (C, 1dias), 130.9 (2 C, 2dias), 128.7 (4 CH, 2 dias), 123.4
(2 C, 2 dias), 120.6 (2 CH, 2 dias), 119.4 (2 CH, 2 dias), 118.7 (2
CH, 2 dias), 112.9 (4 CH, 2 dias), 109.6 (CH, 1 dias), 109.5 (CH,
1 dias), 61.7 (3 CH2, 2 dias), 61.5 (CH2, 1 dias), 61.4 (3 CH2,
2 dias), 61.1 (CH2, 1 dias), 56.1 (2 C, 2 dias), 56.0 (2 C, 2 dias),
55.8 (C, 1 dias), 55.7 (C, 1 dias), 55.2 (2 CH3, 2 dias), 52.6 (2 CH3,
2 dias), 45.6 (2 CH2, 2 dias), 43.6 (C, 1 dias), 43.4 (C, 1 dias), 41.9
(2 CH2, 2 dias), 38.4 (CH2, 1 dias), 38.3 (CH2, 1 dias), 35.5 (CH2,
1 dias), 35.4 (CH2, 1 dias), 32.4 (CH3, 1 dias), 26.3 (CH3, 1 dias),
24.4 (CH3, 1 dias), 24.2 (CH3, 1 dias), 14.1 (2 CH3, 2 dias), 14.0 (2
CH3, 2 dias), 13.9 (CH3, 1 dias), 13.8 (CH3, 1 dias), 13.7 (2 CH3,
Gallium-Catalyzed 6-exo Cyclizations of Arenynes 1t and 1u.
To a solution of substrate 1 (1t or 1u, 0.25 mmol) and possibly
arenes (0.75 mmol) in DCE (1 mL) was added GaCl3 (0.5 M in
pentane, 0.05 mL, 0.025 mmol) in one portion. The mixture was
stirred at room temperature for 10 h, then sat. aq NaHCO3
(1 mL) was added at 0 °C. The two layers were separated, and
the aqueous phase was extracted with Et2O (3ꢀ10 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was subjected to
flash column chromatography on silica gel to afford the corre-
sponding products.
Compound 30t: pasty solid; 75% yield; 1H NMR (300 MHz,
CDCl3) δ 7.64 (d, J = 8.4, 2H), 7.29 (d, J = 8.4, 2H), 7.18-7.05
(m, 5H), 6.88 (dd, J = 7.5, 1.2, 1H), 6.79 (d, J = 9.0, 2H), 4.58
(d, J = 14.7, 1H), 4.03 (d, J = 14.7, 1H), 3.79 (s, 3H), 3.48 (dd,
J = 11.7, 1.2, 1H), 3.02 (d, J = 11.7, 1H), 2.41 (s, 3H), 1.78
J. Org. Chem. Vol. 75, No. 24, 2010 8447

Li et al.
JOCArticle
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.1, 143.6, 142.6, 138.3,
133.3, 131.2, 129.7, 128.8, 128.7, 127.7, 127.1, 126.3, 126.2,
113.4, 57.4, 55.2, 48.3, 43.5, 27.3, 21.5; FTIR (film) 1652,
Compound 33t:38 white solid; mp 98-100 °C; 1H NMR (300
MHz, CDCl3) δ 7.27 (d, J = 8.1, 2H), 7.18-7.06 (m, 3H), 6.95
(d, J = 8.1, 2H), 6.87-6.83 (m, 1H), 6.20 (d, J = 12.6, 1H), 5.55
(dt, J = 12.6, 3.6, 1H), 4.36 (s, 2H), 4.15 (d, J = 3.6, 2H), 2.23
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 142.6, 136.3, 135.8, 135.2,
130.7, 130.0, 129.0, 128.6, 127.8, 127.6, 127.3, 127.0, 52.7, 51.2,
21.3; FTIR (film) 3024, 2922, 1597, 1493, 1439, 1333, 1184, 1155,
1112, 1090, 1066, 899. 827, 813, 784, 750, 734, 710, 685, 654
cm-1; HRMS (TOF-QII) m/z calcd for C17H17NO2SNa
[M þ Na]þ 322.0872, found 322.0872.
1509, 1457, 1340, 1248, 1164, 1091, 1031, 832, 768, 660 cm-1
;
HRMS (TOF-QII) m/z calcd for C24H25NO3Na [M þ Na]þ
430.1447, found 430.1434.
Compound 31t: pasty solid; 81% yield; 1H NMR (300 MHz,
CDCl3) δ 7.66 (d, J = 8.1, 2H), 7.32 (d, J = 8.1, 2H), 7.18-6.90
(m, 6H), 6.74 (d, J = 8.4, 2H), 5.44 (s, br, 1H), 4.57 (d, J = 14.7,
1H), 4.07 (d, J = 14.7, 1H), 3.48 (d, J = 11.7, 1H), 3.07 (d, J =
11.7, 1H), 2.43 (s, 3H), 1.78 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 154.3, 143.7, 142.5, 138.2, 133.1, 131.0, 129.7, 128.9, 128.6,
127.7, 127.1, 126.3, 126.1, 114.9, 57.4, 48.2, 43.4, 27.2, 21.5;
FTIR (film) 3414, 2973, 1612, 1596, 1512, 1491, 1448, 1333,
1264, 1215, 1155, 1089, 1028, 976, 959, 834, 813, 760, 734, 706,
661 cm-1; HRMS (TOF-QII) m/z calcd for C23H23NO3SNa
[M þ Na]þ 416.1291, found 416.1284.
Compound 33u: white solid; mp 127-129 °C; 1:1 mixture
1
of conformers; H NMR (300 MHz, CDCl3) δ 7.77-7.16 (m,
10 H), 7.01 (d, J = 8.7, 0.5 H), 5.27-5.17 (m, 1 H), 4.35-4.22 (m,
1 H), 4.06 (d, J = 10.2, 0.5 H), 3.52 (d, J = 10.5, 0.5 H), 2.96 (d,
J = 10.5, 0.5 H), 2.52-2.42 (m, 2 H), 2.33 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 144.9, 143.9, 143.6, 142.5, 139.3, 134.1, 133.9,
133.0, 132.1, 130.0, 129.87, 129.83, 129.7, 129.0, 128.7, 127.8,
127.6, 127.4, 127.2, 127.04, 127.00, 126.5, 126.2, 126.05, 125.96,
125.6, 125.3, 124.1, 123.9, 121.8, 121.7, 53.1, 52.2, 43.7, 42.1,
27.3, 21.5; HRMS (TOF-QII) m/z calcd for C21H19NO2SNa
[M þ Na]þ 372.1029, found 372.1022.
Compound 32t: pasty solid; 78% yield; 1H NMR (300 MHz,
CDCl3) δ 7.93 (d, J = 7.2, 2H), 7.79-7.13 (m, 15H), 6.75 (d, J =
8.1, 2H), 4.77 (d, J = 15.3, 1H), 4.01 (d, J = 15.3, 1H), 3.60 (d,
J = 12.0, 1H), 3.11 (d, J = 12.0, 1H), 2.38 (s, 3H), 1.88 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 143.7, 140.0, 138.1, 133.9, 130.5,
129.8, 129.4, 129.2, 128.0, 127.5, 127.4, 126.84,126.81, 126.6,
126.3, 124.7, 124.4, 122.8, 121.3, 119.6, 117.2, 113.8, 54.3, 48.1,
40.1, 27.9, 21.5; FTIR (film) 2925, 1447, 1353, 1276, 1260, 1168,
1136, 1092, 820, 764, 750, 724, 684 cm-1; HRMS (TOF-QII)
m/z calcd for C31H28N2O4S2Na [M þ Na]þ 579.1383, found
579.1394.
Gallium-Catalyzed Hydroarylations of Dihydroazepines 33t
and 33u. To a solution of substrates 32 (32t or 32u, 0.25 mmol)
and possibly arenes (0.75 mmol) in DCE (1 mL) at 80 °C was
added GaCl3 (0.5 M in pentane, 0.05 mL, 0.025 mmol) in one
portion. The mixture was stirred at 80 °C for 10 h, then sat. aq
NaHCO3 (1 mL) was added at 0 °C. The two layers were
separated, and the aqueous phase was extracted with Et2O
(3 ꢀ 10 mL). The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated. The
residue was subjected to flash column chromatography on silica
gel to afford the corresponding products.
Compound 30u: pasty solid; 70% yield; 1H NMR (300 MHz,
CDCl3) δ 7.81 (dt, J = 9.0, 1.2, 2H), 7.73 (d, J = 8.1, 2H),
7.61-7.46 (m, 3H), 7.32 (d, J = 8.1, 2H), 7.08 (d, J = 8.7, 2H),
6.96 (d, J = 8.7, 1H), 6.79 (d, J = 9.0, 1H), 5.09 (d, J = 15.3,
1H), 4.40 (d, J = 15.3, 1H), 3.79 (s, 3H), 3.62 (dd, J = 11.7, 0.9,
1H), 3.08 (d, J = 11.7, 1H), 2.42 (s, 3H), 1.88 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 158.2, 143.6, 139.9, 138.1, 133.4, 131.8, 129.8,
129.7, 128.9, 128.6, 127.7, 127.3, 126.7, 126.4, 125.9, 125.8, 122.0,
113.5, 57.2, 55.2, 46.0, 43.9, 26.5, 21.5; FTIR (film) 2963, 1608,
1509, 1461, 1341, 1310, 1251, 1183, 1165, 1090, 1030, 981, 834,
814, 750, 726, 661 cm-1; HRMS (TOF-QII) m/z calcd for
C28H28NO3S [M þ H]þ 458.1784, found 458.1778; calcd for
C28H27NO3SNa [M þ H]þ 480.1604, found 480.1597.
1
Compound 34t: pasty solid; 83% yield; H NMR (300 MHz,
CDCl3) δ 7.56 (d, J = 8.5 Hz, 2H), 7.31-7.12 (m, 5H), 6.98-6.69
(m, 5H) 4.49-4.38 (m, 2H), 4.22 (d, J = 7.5 Hz, 1H), 3.80 (s, 3H),
3.68-3.61 (m, 1H), 3.50-3.43 (m, 1H), 2.39 (m, 1H), 2.21-2.09
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 158.1, 143.7, 143.0, 136.6,
134.5, 129.9, 129.5, 129.2, 129.1, 128.1, 127.2, 126.6, 114.0, 55.2,
52.9, 48.6, 47.6, 33.1, 21.5; FTIR (film) 3301, 2924, 1616, 1540,
1507, 1457, 1337, 1305, 1250, 1178, 1158, 1091, 1032, 888, 797, 764,
714 657 cm-1. HRMS (TOF-QII) m/z calcd for C24H25NO3SNa
[M þ Na]þ 430.1447, found 430.1438.
Compound 31u: pasty solid; 81% yield; 1H NMR (300 MHz,
CDCl3) δ 7.70 (t, J = 8.7, 2H), 7.62 (d, J = 8.1, 2H), 7.50-7.35
(m, 3H), 7.22 (d, J = 8.1, 2H), 6.91-6.84 (m, 3H), 6.62 (d, J =
8.7, 2H), 5.45 (s, br, 1H), 4.97 (d, J = 15.0, 1H), 4.32 (d, J =
15.0, 1H), 3.49 (d, J = 11.4, 1H), 2.99 (d, J = 11.4, 1H), 2.31 (s,
3H), 1.75 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.4, 143.8,
139.8, 137.9, 133.2, 131.8, 129.8, 129.7, 129.0, 128.6, 127.7,
127.3, 126.7, 126.4, 125.8, 125.7, 121.9, 115.0, 57.2, 46.0, 43.8,
26.5, 21.5; FTIR (film) 3429, 2972, 1614, 1586, 1514, 1456, 1335,
1261, 1160, 1091, 817, 764, 747, 678, 664 cm-1; HRMS (TOF-
QII) m/z calcd for C27H25NO3SNa [M þ Na]þ 466.1447, found
466.1445.
Compound 35t: pasty solid; 87% yield; 1H NMR (300 MHz,
CDCl3) δ 7.48 (d, J = 8.1 Hz, 2H), 7,22 (dd, J = 7.2, 1.5 Hz,
1H), 7.13 (d, J = 8.1 Hz, 2H), 7.10-7.02 (m, 2H), 6.82(d, J =
8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H),
6.63 (d, J = 6.9 Hz, 1H), 5.31 (s, br, 1H), 4.39 (d, J = 15.0 Hz,
1H), 4.31 (d, J = 15.0 Hz, 1H), 4.12 (dd, J = 8.4, 3.3 Hz,
1H), 3.59-3.33 (m, 2H), 2.31 (s, 3H), 2.13-2.00 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 154.3, 143.7, 143.1, 136.5,
136.4, 134.4, 129.8, 129.5, 128.1, 127.2, 126.6, 115.5, 52.8,
48.5, 47.5, 33.0, 21.4; FTIR (film) 3411, 2923, 1614, 1596,
1513, 1450, 1327, 1305, 1264, 1214, 1151, 1089, 1015, 948,
889, 834, 814, 764, 736, 714, 654 cm-1; HRMS (TOF-QII)
m/z calcd for C23H23NO3SNa [M þ Na]þ 416.1291, found
416.1286.
Compound 32u: pasty solid; 78% yield; 1H NMR (500 MHz,
CDCl3) δ 7.95-7.50 (m, 16H), 7.15 (t, J = 7.5, 1H), 6.86 (d, J =
8.5, 1H), 6.75 (t, J = 8.0, 1H), 6.33 (d, J = 8.0, 1H), 5.30 (d, J =
15.0, 1H), 4.34 (d, J = 15.0, 1H), 3.70 (d, J = 11.5, 1H), 3.70 (d,
J = 11.5, 1H), 2.39 (s, 3H), 1.96 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 143.8, 138.1, 137.6, 135.8, 134.0, 133.6, 132.1, 129.9,
129.7, 129.4, 128.7, 127.8, 127.6, 127.4, 127.3, 126.9, 126.8,
125.9, 125.4, 124.8, 124.4, 122.8, 122.1, 121.2, 113.7, 53.8,
45.8, 40.5, 27.3, 21.5; FTIR (film) 3433, 2970, 1455, 1270,
1159, 1091, 820, 665 cm-1; HRMS (TOF-QII) m/z calcd for
C35H30N2O4S2Na [M þ H]þ 629.1539, found 629.1542.
Compound 36t: pasty solid; 84% yield; 1H NMR (300 MHz,
CDCl3) δ 8.04 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.7 Hz, 2H),
7.61-7.03 (m, 14H), 6.60 (d, J = 7.5 Hz, 1H), 4.63 (d, J = 15.0
Hz, 1H), 4.52 (d, J = 15.0 Hz, 1H), 4.45-4.41 (m, 2H), 3.63-
3.45 (m, 2H), 2.40 (s, 3H), 2.24-2.14 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 143.1, 141.3, 137.9, 136.4, 135.8, 135.6, 133.8,
129.9, 129.8, 129.5, 129.2, 128.2, 128.1, 127.1, 127.0, 126.6,
124.9, 124.6, 124.1, 123.2, 120.4, 113.9, 52.8, 48.3, 39.9, 32.2,
21.4; FTIR (film) 2922, 1599, 1447, 1367, 1333, 1266, 1173, 1155,
1122, 1089, 1020, 980, 908, 884, 814, 725, 685, 653 cm-1; HRMS
(TOF-QII) m/z calcd for C31H28N2O4S2Na [M þ Na]þ 579.1383,
found 579.1388.
(38) Bradshaw, B.; Evans, P.; Fletcher, J.; Lee, A. T. L.; Mwashimba,
P. G.; Oehlrich, D.; Thomas, E. J.; Davies, R. H.; Allen, B. C. P.; Broadley,
K. J.; Hamrouni, A.; Escargueil, C. Org. Biomol. Chem. 2008, 6, 2138.
8448 J. Org. Chem. Vol. 75, No. 24, 2010

Li et al.
JOCArticle
1
Compound 37u: pasty solid; 82% yield; H NMR (300 MHz,
CDCl3) δ 7.88-7.16 (m, 13H), 6.92 (d, J = 8.7 Hz, 2H), 5.58 (s, br,
1H), 4.38 (d, J = 15.0 Hz, 1H), 3.87 (d, J = 15.0 Hz, 1H), 3.22 (d,
J = 7.5 Hz, 2H), 3.07 (d, J = 15.0 Hz, 1H), 2.78 (dd, J = 11.7, 1.5
Hz, 1H), 2.42 (s, 3H), 2.20 (d, J = 11.7 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 148.2, 139.7, 133.84, 13.75, 130.0, 129.6, 128.7,
128.0, 127.7, 127.4, 127.2, 126.9, 126.01, 125.96, 125.9, 125.7, 123.8,
121.9, 52.3, 50.0, 47.1, 28.1, 21.5; FTIR (film) 3734, 2925, 1456,
1339, 1274, 1161, 1091, 812, 764, 751 cm-1; HRMS (TOF-QII) m/z
calcd for C27H25NO3SNa [M þ Na]þ 466.1447, found 466.1442.
One-Pot Procedure for the Synthesis of Compound 34t. To a
solution of substrate 1t (74.8 mg, 0.25 mmol) in DCE (1 mL) was
added GaCl3 (0.5 M in pentane, 0.05 mL, 0.025 mmol) in one
portion. The mixture was stirred at room temperature for 10 h
and added to anisole (81.1 mg, 0.75 mmol). The resulting
mixture was stirred at 80 °C for 10 h, then sat. aq NaHCO3
(1 mL) was added at 0 °C. The two layers were separated, and
the aqueous phase was extracted with Et2O (3 ꢀ 10 mL).
The combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was subjected to
flash column chromatography on silica gel to afford product 34t
(58.0 mg) in 57% overall yield.
Acknowledgment. This work was supported by UPS (chaire
d’excellence) and CNRS. We deeply thank Prof. Henri Kagan
for useful discussion. Calculations were performed at CRIHAN,
ꢀ
plan interregional du bassin parisien (project 2006-013), and at
the CRI of UPS.
Supporting Information Available: Detailed experimental
procedures for the starting materials, deuterium-labeling experi-
ments, X-ray data for 9 and 15 (CIF), computational details,
and copies of 1H and 13C NMR spectra of the reaction products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8449