Controllable one-step synthesis of spirocycles, polycycles, and di- and tetrahydronaphthalenes from aryl-substituted propargylic alcohols

Article abstract of DOI:10.1021/jo801210n

(Chemical Equation Presented) A novel, convenient, and efficient method has been developed for selective synthesis of spirocycle, polycycle, and di-and tetrahydronaphthalene systems from aryl-substituted propargylic alcohols by FeCl₃- or TsOH-catalyzed multiple activations of unsaturated C-C bonds and C-H bonds.

Full text of DOI:10.1021/jo801210n

SCHEME 1. Intramolecular Cyclization of 1a
Controllable One-Step Synthesis of Spirocycles,
Polycycles, and Di- and Tetrahydronaphthalenes
from Aryl-Substituted Propargylic Alcohols
Wen Huang,† Pengzhi Zheng,† Zhengxing Zhang,†
Ruiting Liu,† Zhenxia Chen,† and Xigeng Zhou*,†,‡
Department of Chemistry, Shanghai Key Laboratory of
Molecular Catalysis and InnoVatiVe Materials, Fudan
UniVersity, Shanghai 200433, People’s Republic of China,
and State Key Laboratory of Organometallic Chemistry,
Shanghai 200032, People’s Republic of China
The direct conversion of C-H bonds to C-C bonds is a
convenient, efficient, and economical strategy for organic
synthesis, because C-H bonds are among the most ubiquitous
and inexpensive chemical linkages in nature.3 Particular attention
has been paid to the synthetic application of the C-H based
intramolecular cyclization, since new methods for useful cyclic
products are anticipated. However, to our knowledge, a synthetic
pathway that is based on multiple intramolecular C-H func-
tionalization, for constructing spirocyclic frameworks, has never
been reported. We have recently developed a FeCl3-catalyzed
intramolecular Friedel-Crafts (IFC) reaction4 that provides
direct access to biologically active di- and tetrahydroisoquinoline
scaffolds from benzylamino-substituted propargylic alcohols.5
In further investigation on the versatility of the propargylic
alcohol system, we found an unprecedented intramolecular
Friedel-Crafts reaction and hydroarylation sequence of aryl-
substituted propargylic alcohols catalyzed by simple
FeCl3 ·6H2O that allows selective one-step synthesis of func-
tionalized spirocyclics and di- and tetrahydronaphthalenes.
Herein, we report the results.
We initially studied the intramolecular cyclization of prop-
argylic alcohol 1a. However, treatment of 1a in nitromethane
with FeCl3 ·6H2O (5 mol %) at room temperature for 30 min
gave a complex mixture. Luckily, an unexpected spirocyclic
product 2a was obtained in good yield, when the reaction
temperature was increased to 80 °C (Scheme 1). The structure
of 2a was confirmed by X-ray single crystal diffraction.
Encouraged by this result, we set out to study the scope and
limitation of the preparation of spirocyclic hydrocarbons directly
xgzhou@fudan.edu.cn
ReceiVed June 5, 2008
A novel, convenient, and efficient method has been devel-
oped for selective synthesis of spirocycle, polycycle, and di-
and tetrahydronaphthalene systems from aryl-substituted
propargylic alcohols by FeCl3- or TsOH-catalyzed multiple
activations of unsaturated C-C bonds and C-H bonds.
Spirocyclic hydrocarbons have attracted considerable attention
as a result of their wide range of biological activities and their
special optoelectronic properties, as well as increasing use in a
range of important chemical and technological processes such
as asymmetric synthesis.1 Although many methodologies for
constructing spirocyclic frameworks have been developed so
far, there are few publications that describe the direct construc-
tion of such motifs from a linear precursor.2 Therefore, the
development of new methods and strategies for the construction
of functionalized spirocyclic frameworks is highly desirable for
the syntheses of delicate natural products, as well as for the
fine-tuning of the biological and/or physical properties of the
compounds for final application.
(2) For selected examples for synthesis of spirocycles from linear precursors,
see: (a) Miyamoto, H.; Okawa, Y.; Nakazaki, A.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2006, 45, 2274. (b) Chang, H.-K.; Datta, S.; Das, A.; Odedra, A.; Liu,
R.-S. Angew. Chem., Int. Ed. 2007, 46, 4744. (c) Huang, J.; Frontier, A. J. J. Am.
Chem. Soc. 2007, 129, 8060. (d) Shibata, T.; Tahara, Y.; Tamura, K.; Endo, K.
J. Am. Chem. Soc. 2008, 130, 3451. (e) Sherry, B. D.; Maus, L.; Laforteza,
B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132. (f) Inui, M.; Nakazaki,
A.; Kobayashi, S. Org. Lett. 2007, 9, 469. (g) Trost, B. M.; Shi, Y. J. Am. Chem.
Soc. 1991, 113, 701. (h) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285.
(3) For selected reviews and reports, see: (a) Dyker, G. Angew. Chem., Int.
Ed. 1999, 38, 1699. (b) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45,
6422. (c) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (d) Jia, C.-G.;
Piao, D.-G.; Oyamada, J.; Lu, W.-J.; Kitamura, T.; Fujiwara, Y. Science 2000,
287, 1992. (e) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485. (f)
Nevado, C.; Echavarren, A. M. Synthesis 2005, 167. (g) Crabtree, R. H. J.
Organomet. Chem. 2004, 689, 4083.
† Fudan University.
‡ State Key Laboratory of Organometallic Chemistry.
(1) (a) Saragi, T. P. I.; Spehr, T.; Siebert, A.; Fuhrmann-Lieker, T.; Salbeck,
J. Chem. ReV. 2007, 107, 1011. (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209. (c) Pradhan, R.; Patra, M.; Behera, A. K.; Mishra, B. K.; Behera,
R. K. Tetrahedron 2006, 62, 779. (d) Sannigrahi, M. Tetrahedron 1999, 55,
9007. (e) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581. (f) Watanabe,
N.; Ikeno, A.; Minato, H.; Nakagawa, H.; Kohayakawa, C.; Tsuji, J. J. Med.
Chem. 2003, 46, 3961.
(4) For recent reviews of Friedel-Crafts and related reactions, see: (a)
Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43,
550. (b) Bandini, M.; Emer, E.; Tommasi, S.; Umani-Ronchi, A. Eur. J. Org.
Chem. 2006, 3527. (c) Jørgensen, K. A. Synthesis 2003, 1117.
(5) Huang, W.; Shen, Q.-S.; Wang, J.-L.; Zhou, X.-G. J. Org. Chem. 2008,
73, 1586.
10.1021/jo801210n CCC: $40.75
Published on Web 08/06/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6845–6848 6845

TABLE 1. One-Step Synthesis of Spirocyclic Compoundsa
SCHEME 2. Plausible Mechanism for FeCl3 ·6H2O-
Catalyzed Spirocyclic Compound Synthesis
Interestingly, the two intramolecular cycloarylation reactions
of compound 1d, in which two aromatic rings at the propargylic
position bear a chloride and the other ring a 4-methoxy group,
appear to occur on the same phenyl ring (the ring with the
4-methoxy substituent), leading to the exclusive formation of
1,3,4,5-tetrahydroacenaphthylene 5d in 76% yield under the
same conditions, as determined by the NMR spectrum and X-ray
structural analysis (Table 1, entry 4).
On the basis of the above results, a plausible mechanism for
the formation of spirocycles is proposed in Scheme 2. The C-OH
activation leads to the formation of propargylic cations.6
Isomerization of propargylic to allenylic cations7 and subsequent
IFC reaction gives tetrahydronaphthalenes 3, while isomerization
of 3 gives 4. The formation of allyl cation intermediates occurred
by the reaction of 4 with FeCl3 followed by attack of the arene
generates 2 or 5d (path a).8,9 These products are likely the result
of the direct hydroarylation of allenes promoted by Lewis acid
(path b).10 The difference for the formation of 5d might be
rationalized by the hydroarylation reaction through the allyl
cation intermediate. Clearly, the steric factor is favorable to the
formation of spirocycles. Presumably, the driving force for the
formation of 5d most likely arises from the stronger nucleo-
philicity of the methoxyphenyl ring compared to the chlorophe-
nyl ring, equalizing the steric disadvantage.
a General reaction conditions: 0.2 mmol substrate,
5 mol % of
FeCl3 ·6H2O in 2 mL of CH3NO2 at 80 °C for 3-9 h. b Isolated yield.
c The structure of the product was further confirmed by X-ray diffraction
analysis. d Carried out in
1
mmol scale. e The reaction gave an
inseparable mixture of spirocycle and polycycle. f Along with ca. 5%
unidentified compounds. g The reaction time was 18 h.
from propargylic alcohols in more detail. A variety of aryl-
substituted propargylic alcohols have been examined, and the
results are summarized in Table 1. When propargylic alcohols
containing phenyl or electron-rich aryl at the propargylic position
were treated with 5 mol % FeCl3 ·6H2O in CH3NO2 at 80 °C,
the corresponding spirocyclic compounds were obtained in
moderate to high yields (Table 1, entries 1, 2, and 8). Notably,
sterically demanding substrate 1e can also give the spirocyclic
product 2e in 86% yield (Table 1, entry 5). However, incorpora-
tion of an electron-withdrawing group on the aryl nucleus at
the propargylic position suppressed the spirocyclization reaction,
and the isolated products were dihydronaphthalenes (Table 1,
entries 6 and 9). As for the substrate 1g, bearing an electron-
withdrawing bromide group on the other benzene ring, the
intramolecular tandem cycloarylation reaction was sluggish and
gave a mixture of 1,2-dihydronaphthalene (4g) and spirocycle
(2g) under the same conditions after 6 h. Prolonged heating for
18 h made 4g convert to 2g completely (Table 1, entry 7).
(6) (a) Georgy, M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc. 2005,
127, 14180. (b) Zhan, Z.-P.; Yang, W.-Z.; Yang, R.-F.; Yu, J.-L.; Li, J.-P.; Liu,
H.-J. Chem. Commun. 2006, 3352. (c) Qin, H.-B.; Yamagiwa, N.; Matsunaga,
S.; Shibasaki, M. Angew. Chem., Int. Ed. 2007, 46, 409. (d) Huang, W.; Wang,
J.-L.; Shen, Q.-S.; Zhou, X.-G. Tetrahedron 2007, 63, 11636. (e) Motokura, K.;
Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int.
´
Ed. 2006, 45, 2605. (f) Sanz, R.; Mart´ınez, A.; Miguel, D.; Alvarez-Gutie´rrez,
J. M.; Rodr´ıguez, F. AdV. Synth. Catal. 2006, 348, 1841. (g) Sanz, R.; Mart´ınez,
´
A.; Alvarez-Gutie´rrez, J. M.; Rodr´ıguez, F. Eur. J. Org. Chem. 2006, 1383.
(7) Mu¨ller, T. J. J. Eur. J. Org. Chem. 2001, 2021.
(8) Kischel, J.; Jovel, I.; Mertins, K.; Zapf, A.; Beller, M. Org. Lett. 2006,
8, 19.
(9) Lomberget, T.; Bentz, E.; Bouyssi, D.; Balme, G. Org. Lett. 2003, 5,
2055.
(10) For selected examples of gold catalyzed intramolecular hydroarylation
of allenes, see: (a) Liu, Z.-S.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc.
2006, 128, 10352. (b) Zhang, Z.-B.; Liu, C.; Kinder, R. E.; Han, X.-Q.; Qian,
H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066. (c) Liu, C.;
Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (d) Tarselli, M. A.; Gagne´, M. R.
J. Org. Chem. 2008, 73, 2439.
6846 J. Org. Chem. Vol. 73, No. 17, 2008

TABLE 2. Selective Synthesis of Functionalized Di- and Tetrahydronaphthalenesa
entry
substrate
condition A
yield (%)b
condition B
yield (%)b
1
2
3
4
5
6
7
8
R1 ) H, R2 ) R3 ) Ph, 1a
3a
3b
3c
3d
3e
3f
3g
3h
3i
93 (89c)
95d
90
85
89
4a
4b
4c
4d
4e
4f
4g
4h
4i
92d
93
91
84
90
86
63
72
89
R1 ) Me, R2 ) R3 ) Ph, 1b
R1 ) MeO, R2 ) R3 ) Ph, 1c
R1 ) MeO, R2 ) R3 ) 4-ClC6H4, 1d
R1 ) t-Bu, R2 ) R3 ) Ph, 1e
R1 ) t-Bu, R2 ) R3 ) 4-ClC6H4, 1f
R1 ) Br, R2 ) R3 ) Ph, 1g
83
37e
76
R1 ) H, R2 ) R3 ) 4-MeC6H4, 1h
R1 ) H, R2 ) R3 ) 4-ClC6H4, 1i
R1 ) H, R2 ) Ph, R3 ) Me, 1j
R1 ) H, R2 ) 4-MeC6H4, R3 ) Me, 1k
9
87
80
64
10f
11f
3j
3k
a General reaction conditions: 0.2 mmol substrate, 2 mL of CH3NO2. Condition A: 5 mol % of FeCl3 ·6H2O, 0-5 °C. Condition B: 5 mol % of
TsOH·H2O, 80 °C. b Isolated yield. c Carried out in 1 mmol scale. d The structure of product was further confirmed by X-ray diffraction analysis.
e Enone was isolated as a major product. f Using condition B gave a complicated mixture.
SCHEME 3. Controllable Synthesis of Spirocycle and
Dihydro- and Tetrahydronaphthalene
functional groups, including halide, methoxy, and ester carbo-
nyls. For instance, the introduction of the electron-donating
groups such as methyl and methoxy in the para-position of the
nucleophilic benzene ring had only a slight influence on the
reactivity as compared to 1a (Table 2, entries 1-3, condition
A). Notably, the sterically demanding tert-butylphenyl ring also
displayed a high reactivity (Table 2, entries 5 and 6, condition
A). Even the presence of an electron-withdrawing bromide group
on the ring, the cyclization product was also obtained in 37%
yield (Table 2, entry 7, condition A).
The present method was further applied to selective synthesis
of 1,2-dihydronaphthalene derivatives under the optimized
reaction conditions. Table 2 (condition B) illustrates the
generality of this reaction. Treatment of a variety of aryl-
substituted propargylic alcohols with TsOH in CH3NO2 at 80
°C afforded the corresponding 1,2-dihydronaphthalenes formed
through the IFC reaction followed by successive isomerization
in moderate to excellent yields, depending on the nucleophilicity
of the aryl nucleus involved and the nature of substituents at
the propargylic position.
The direct reaction of aromatic carbon-hydrogen bonds with
unactivated unsaturated carbon-carbon functionalities represents
a challenging but attractive strategy for the formation of C-C
bonds.3 Although the intramolecular cyclization of propargylic
alcohols and their derivatives have been extensively studied,12,13
to the best of our knowledge, it has not been previously reported
that these substrates undergo the tandem isomerization/func-
tionalition to generate the spirocenter. The present results
To confirm the reaction mechanism, a variety of experiments
for isolating the intermediates 3a and 4a were performed. To
our delight, it was found that the monocyclization allene product
3a could be selectively obtained in 93% isolated yield when
the reaction temperature was lowered to 0-5 °C (Table 2, entry
1, condition A). However, attempts to obtain the sole 1,3-diene
product 4a using this catalytic system were unsuccessful. In
screening several catalysts, we found that a selective procedure
for the preparation of 4a could be developed by replacing
FeCl3 ·6H2O with TsOH (p-toluenesulfonic acid monohydrate).
In addition, it was also feasible to isolate 3a in an excellent
yield using TsOH as a catalyst if the reaction was carried out
at room temperature, despite the fact that the reaction rate is
slower than that in a FeCl3 ·6H2O catalytic system. Remarkably,
both 3a and 4a were converted to 2a, when heated to 80 °C in
CH3NO2 and with the presence of FeCl3 ·6H2O (Scheme 3).
However, no spirocyclic product was obtained in the TsOH
catalytic system even after a prolonged reaction time or at
elevated temperature.
(12) (a) Tang, J. M.; Bhunia, S.; Abu Sohel, S. Md.; Lin, M.-Y.; Liao, H.-
Y.; Datta, S.; Das, A.; Liu, R.-S. J. Am. Chem. Soc. 2007, 129, 15677. (b) Lian,
J.-J.; Liu, R.-S. Chem. Commun. 2007, 1337. (c) Taduri, B. P.; Abu Sohel, S. M.;
Cheng, H.-M.; Lin, G.-Y.; Liu, R.-S. Chem. Commun. 2007, 2530. (d) Trost,
B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763. (e) Belting, V.; Krause,
N. Org. Lett. 2006, 8, 4489. (f) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.;
Sarpong, R. Org. Lett. 2007, 9, 1169. (g) Buzas, A.; Istrate, F.; Gagosz, F. Org.
Lett. 2006, 8, 1957. (h) Yan, B.; Zhou, Y.-B.; Zhang, H.; Chen, J.-J.; Liu, Y.-H.
J. Org. Chem. 2007, 72, 7783. (i) Grise´, C. M.; Barriault, L. Org. Lett. 2006, 8,
5905. (j) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang, S.-H.; Liu,
X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397.
(13) (a) Shi, X.-D.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
5802. (b) Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
7436. (c) Zhang, L.-M.; Wang, S.-Z. J. Am. Chem. Soc. 2006, 128, 1442. (d)
Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am.
Chem. Soc. 2007, 129, 9868. (e) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006,
128, 12614. (f) Marion, N.; D´ıez-Gonza´lez, S.; Fre´mont, P.; Noble, A. R.; Nolan,
S. P. Angew. Chem., Int. Ed. 2006, 45, 3647.
The di- and tetrahydronaphthalene carbon skeletons are found
in a number of naturally occurring and biologically active
molecules.11 With the strategy of controlling selective trans-
formation of aryl-substituted propargylic alcohols in hand, we
next explored the use of the reaction in synthesis of tetrahy-
dronaphthalene derivatives. As shown in Table 2 (condition A),
the results demonstrated good compatibility with various
(11) Selected examples: (a) Sellars, J. D.; Steel, P. G. Eur. J. Org. Chem.
2007, 3815. (b) LaLonde, R. T.; Ramdayal, F.; Sarko, A.; Yanai, K.; Zhang,
M.-J. J. Med. Chem. 2003, 46, 1180. (c) Biswas, S.; Zhang, S.-H.; Fernandez,
F.; Ghosh, B.; Zhen, J.; Kuzhikandathil, E.; Reith, M. E. A.; Dutta, A. K. J. Med.
Chem. 2008, 51, 101.
J. Org. Chem. Vol. 73, No. 17, 2008 6847

δ 169.9, 145.9, 143.0, 140.1, 137.2, 132.9, 132.8, 130.0, 128.3,
128.2, 127.9, 127.8, 127.0, 125.9, 124.8, 124.0, 61.7, 54.7, 34.2,
13.9. HRMS-ESI-TOF: calcd for C30H28O4Na ([M + Na]+)
475.1885, found 475.1877.
The reaction can be synthesized in large scale. To a solution of
1a (2.35 g, 5 mmol) in CH3NO2 (60 mL) at 80 °C was added 5
mol % TsOH, and then the reaction mixture was stirred for about
2 h. The mixture was quenched with 50 mL water, and the aqueous
layer was extracted with ether (3 × 20 mL). The combined organic
layer was washed with brine and dried (Na2SO4), and solvents were
evaporated under reduced pressure to give the crude product (2.11
g, 93% yield), which was identified by NMR spectra as purity
>95% (see Supporting Information for copies of spectrum).
demonstrate the potential for increasing flexibility and reactivity
of alkynes by a hydroxyl group at the propargylic position.
In conclusion, novel, controllable tandem reactions of aryl-
substituted propargylic alcohols catalyzed by a simple Lewis
or Brønsted acid have been established. These transformations
provide facile, efficient, and versatile strategies for selective one-
step construction of a variety of functionalized aromatic
carbocycle skeletons. These skeletons are of interest in organic
synthesis, medicinal chemistry, and materials science. Further
application of this methodology to organic synthesis is currently
under investigation.
Experimental Section
Acknowledgment. We thank the NNSF of China, NSF of
Shanghai, and Shanghai Leading Academic Discipline Project
for financial support (B108).
General Procedure. To a solution of 1 (0.2 mmol) in CH3NO2
(2.0 mL) was added 5 mol % FeCl3 ·6H2O or TsOH. The reaction
mixture was stirred at 0-5 °C or at the temperature noted in the
text (monitored by TLC or NMR). The crude product was purified
by silica gel column chromatography to provide the desired product.
Selected example, diethyl 4-(2,2-diphenylvinyl)naphthalene-2,2(1H)-
dicarboxylate (4a): 1H NMR (CDCl3, 400 MHz, 25 °C): δ 1.10 (t,
J ) 7.3 Hz, 6H), 3.29 (s, 2H), 3.83-3.95 (m, 2H), 4.04-4.13 (m,
2H), 5.77 (d, J ) 1.4 Hz, 1H), 6.69 (d, J ) 1.4 Hz, 1H), 7.08-7.20
(m, 8H), 7.27-7.38 (m, 6H). 13C NMR (CDCl3, 100 MHz, 25 °C):
Supporting Information Available: Experimental details,
spectroscopic characterization data, copies of 1H, 13C NMR of
new compounds, and CIF files giving crystallographic data of
2a, 4a, 3b and 5d. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO801210N
6848 J. Org. Chem. Vol. 73, No. 17, 2008