A new titanium tetrachloride mediated annulation of α -aryl-substituted carbonyl compounds with alkynes: A simple and highly efficient method for the regioselective synthesis of polysubstituted naphthalene derivatives

Article abstract of DOI:10.1021/jo034330o

A new straightforward procedure has been developed for the synthesis of polysubstituted naphthalene derivatives. The reaction of α -aryl-substituted carbonyl compounds with terminal or internal alkynes in the presence of TiCl₄ regioselectively generates substituted naphthalene derivatives in good to excellent yields.

Full text of DOI:10.1021/jo034330o

SCHEME 1
A New Tita n iu m Tetr a ch lor id e Med ia ted
An n u la tion of r-Ar yl-Su bstitu ted Ca r bon yl
Com p ou n d s w ith Alk yn es: A Sim p le a n d
High ly Efficien t Meth od for th e
Regioselective Syn th esis of P olysu bstitu ted
Na p h th a len e Der iva tives
George W. Kabalka,* Yuhong J u, and Zhongzhi Wu
Departments of Chemistry and Radiology,
The University of Tennessee,
SCHEME 2
Knoxville, Tennessee 37996-1600
kabalka@utk.edu
Received March 12, 2003
Abstr a ct: A new straightforward procedure has been
developed for the synthesis of polysubstituted naphthalene
derivatives. The reaction of R-aryl-substituted carbonyl
compounds with terminal or internal alkynes in the presence
of TiCl4 regioselectively generates substituted naphthalene
derivatives in good to excellent yields.
clization of benzynes with alkynes,9 annulations via
Fisher carbenes,1c,10 and cyclization of alkynes.11 How-
ever, these methods involve either expensive catalysts
and substrates or multistep syntheses. In some cases, the
reactions produce mixtures of isomers.
During a recent study focused on boron and titanium
halide-promoted carbon-carbon bond-forming reactions
(Scheme 1),12 we discovered that reactions of 2-phenyl-
substituted aldehydes with alkynes in the presence of
titanium tetrachloride generated substituted naphtha-
lene derivatives with high regioselectively (Scheme 2).
This method provides a straightforward and efficient
procedure for the synthesis of a variety of substituted
naphthalene derivatives from readily available starting
materials.13
TiCl4 has been reported to react with alkynes to form
haloalkenes after hydrolysis.14 However, this reaction has
not been used to generate new carbon-carbon bonds.
Initially, we attempted to generate a titanium-carbonyl
complex by adding 1 equiv of phenylacetaldehyde to TiCl4
in CH2Cl2 at room temperature. This was followed by the
introduction of 1 equiv of phenyacetylene. The reaction
solution immediately turned dark brown. Surprisingly,
after several hours, 1-phenylnaphthalene was formed
along with a small quantity of 2-phenylnaphthalene.
None of the expected allyl alcohol was detected although
aldehydes (without R-aryl substituents) have been re-
Substituted naphthalene compounds are very impor-
tant building blocks for the syntheses of pharmaceuticals1
and polycyclic aromatic electronic materials.2 The devel-
opment of new and efficient methodologies for the
synthesis of polysubstituted naphthalene derivatives has
recently attracted much attention.3 A variety of methods
have been reported which include electrophilic substitu-
tion of naphthalenes,4 annulation of benzene molecules
bearing an unsaturated carbonyl side chain,5 Suzuki
coupling of halonaphthalenes with phenylboronic acids,6
coupling of halonaphthalenes with organolithium or
Grignard reagents,7 reactions of aryl halides or arylmetal
compounds with alkynes using transition metals,8 cy-
(1) (a) Seong, B. L.; Han, M. L. Chem. Lett. 1982, 627. (b) Trujillo,
J . M.; J orge, R. E.; Boada, J . Phytochemistry 1990, 29, 2991. (c) Ward,
R. S. Nat. Prod. Rep. 1995, 12, 183. (d) Ukita, T.; Nakamura, Y.; Kubo,
A.; Yamamoto, Y.; Takahashi, M.; Kotera, J .; Ikeo, T. J . Med. Chem.
1999, 42, 1293. (e) Xie, X.; Kozlowski, M. C. Org. Lett. 2001, 3, 2661.
(2) Watson, M. D.; Fechtenkotter, A.; Mullen, K. Chem Rev. 2001,
101, 1267.
(3) Konig, C. B.; Rousseau, A. L.; Otterlo, W. A. L. Tetrahedron 2003,
59, 7.
(4) Norman, R.; Coxon, J . M. Principles of Organic Synthesis, 3rd
ed.; Chapman & Hall, Inc.: New York, 1993; p 355.
(5) (a) Bradsher, C. K. Chem. Rev. 1987, 87, 1277. (b) Larock, R. C.;
Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org. Chem. 1997, 62, 7536. (c)
Larock, R. C.; Tian, Q. J . Org. Chem. 1998, 63, 2002. (d) Huang, Q.;
Larock, R. C. Org. Lett. 2002, 4, 2505.
(6) (a) Rao, M. L. N.; Yamozaki, O.; Shimada, S.; Tanaka, T.; Suzuki,
Y.; Tanaka, M. Org. Lett. 2001, 3, 4103. (b) Feuerstein, M.; Doucet,
H.; Santelli, M. Tetrahedron Lett. 2001, 42, 6667. (c) Zim, D.; Lando,
V. R.; Dupont, J .; Monteiro, A. L. Org. Lett. 2001, 3, 3049. (d) Hennings,
D. D.; Iwama, T.; Rawel, V. H. Org. Lett. 1999, 1, 1205.
(7) (a) Kamikawa, T.; Hayashi, T. Tetrahedron Lett. 1997, 38, 7087.
(b) Merrill, R. E.; Negishi, E. J . Org. Chem. 1974, 39, 3452.
(8) (a) Wu, G.; Rheingold, A. L.; Feib, S. J .; Heck, R. F. Organo-
metallics 1987, 6, 1941. (b) Wu, G.; Rheingold, A. L.; Heck, R. F.
Organometallics 1986, 5, 1922. (c) Sakakibara, T.; Tanaka, Y.; Ya-
masaki, T. I. Chem. Lett. 1986, 797. (d) Takahashi, T.; Li, Y.; Slepnicka,
P.; Kitamura, M.; Liu, Y.; Nakajima, K.; Kotara, M. J . Am. Chem. Soc.
2002, 124, 576. (e) Takahashi, T.; Kitamura, M.; Shen, B.; Nakajima,
K. J . Am. Chem. Soc. 2000, 122, 12876.
(9) (a) Yoshikawa, E.; Ymamoto, Y. Angew. Chem., Int. Ed. 2000,
39, 173. (b) Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 7533. (c) Yoshikawa, E.; Radhakrishnan,
K. V.; Yamamoto, Y. J . Am. Chem. Soc. 2000, 122, 7280. (d) Pena, D.;
Perez, D.; Guitian, E.; Castedo, L. J . Am. Chem. Soc. 1999, 121, 5827.
(10) Shore, N. E. Chem Rev. 1988, 88, 1081.
(11) (a) Saito, S.; Yamamoto, Y. Chem Rev. 2000, 100, 2901. (b)
Lautens, M.; Klute, W.; Tam, W. Chem Rev. 1996, 96, 49.
(12) (a) Kabalka, G. W.; Wu, Z.; J u, Y. Org. Lett. 2002, 4, 1491. (b)
Kabalka, G. W.; Wu, Z.; J u, Y. Org. Lett. 2002, 4, 3415.
(13) Viswanathan, G. S.; Wang, M.; Li, C.-J . Angew. Chem., Int. Ed.
2002, 41, 2138.
(14) Lemarchand, D.; M’Baye, N.; Braun, J . J . Organomet. Chem.
1972, 39, C69.
10.1021/jo034330o CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/06/2003
J . Org. Chem. 2003, 68, 7915-7917
7915

TABLE 1. Syn th esis of Su bstitu ted Na p h th a len e
Der iva tives (Sch em e 1) via Rea ction of Ald eh yd es w ith
Alk yn es in th e P r esen ce of TiCl4
SCHEME 3
1
2
entry
R
R1
R2
R3 time (h)
3
yielda,b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Ph
Ph
Ph
Ph
p-MePh
p-BrPh
p-ClPh
Ph
H
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3
4
5
2
2
3
4
4
4
4
4
2
12
2
a
88
80
83
77
85
73
70
82
75
76
85
88
88
90
78
65
65
80
85
75
Me
Ph
H
H
H
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
SCHEME 4
Ph
Ph
Me
Ph
H
Me
H
Me
Ph
Me
Ph
H
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
Ph
H
H
4
Ph
Ph
n-Pr
n-Pr Me
n-Pr Ph
10
12
5
5
7
Ph
n-Pr
n-Pr
n-Pr
s
t
a
b
Isolated yields based on starting carbonyl compounds. All
compounds were characterized by elemental analysis and NMR
spectroscopy.
ported to react with alkynes in the presence of titanium
tetrachloride to form allyl alcohols.12b To optimize the
reaction conditions and minimize the self-condensation
of phenylacetaldehyde, phenylacetylene and TiCl4 (1:1
ratio) were dissolved in CH2Cl2 at room temperature. A
dark brown solution formed to which 1 equiv of phenyl-
acetaldehyde was added. 1-Phenylnaphthalene was iso-
lated in excellent yield. A variety of alkynes including
aryl, aliphatic, terminal, and internal alkynes were
subjected to the reaction sequence. Essentially, all alkynes
gave the desired naphthalene derivatives in good to
excellent yields (Table 1).
The reaction of aromatic alkynes with aldehydes
containing an electron-donating group on the phenyl ring
tend to proceed rapidly. Reactions of aliphatic alkynes
are faster than aryl alkynes and produce higher yields.
It was also noted that the reactions of terminal alkynes
generate higher yields of products than internal alkynes.
Several R-aryl-substituted aldehydes such as phenyl-
acetaldehyde, diphenylacetaldehyde, and 2-phenyl-
propionaldehyde were also used in the reaction, and the
corresponding naphthalenes were obtained in high yields.
Deoxybenzoin also gave the corresponding substituted
naphthalene in good yield. For terminal alkynes, the
reaction exclusively generated 1-substituted naphthalene
derivatives. Internal alkynes such as 1-phenylpropyne
produced 1-phenyl-substituted naphthalene derivatives,
whereas unsymmetrical aliphatic internal alkynes such
as 2-hexyne gave mixtures of regioisomers (Scheme 3).
Alkynes containing functional groups such as ester,
nitro, nitrile, and amino groups were also examined, but
none of the desired naphthalenes formed. A variety of
solvents such as hexane, toluene, CH2Cl2, diethyl ether,
and THF were evaluated, and CH2Cl2 was found to
produce the best yields.
by NMR spectroscopy. Phenylacetylene and TiCl4 (1:1
ratio) were dissolved in CDCl3 in an NMR tube, and the
reaction solution immediately turned dark brown. The
NMR spectra revealed only resonances corresponding to
the alkyne group. Then, 1 equiv of phenylacetaldehyde
was introduced into the reaction solution. The NMR data
indicated that 1-phenylnaphthalene gradually formed. No
intermediate was observed. In a separate experiment,
phenylacetaldehyde and TiCl4 (1:1 ratio) were mixed in
CDCl3 in a NMR tube to form a yellow TiCl4-carbonyl
complex.15 Phenylacetylene was then added to the com-
plex. Again, 1-phenylnaphththalene formed. However, if
2 equiv of phenylacetaldehyde was added to TiCl4 (to form
the TiCl4-bis(carbonyl) complex) followed by introduction
of phenylacetylene, no reaction occurred. This result
suggests that coordination between the alkyne and
titanium is an essential step in the reaction. Based on
these experiments, the reaction presumably involves the
coordination of the aldehyde and alkyne to titanium to
form complex 4 followed by cyclization to afford the final
product 3 (Scheme 4). Functional groups presumably
interfere with formation of titanium-alkyne complex by
generating unreactive hexacoordinated titanium species.
In conclusion, we have developed a new, simple,
regioselective, and efficient synthesis of substituted
naphthalene derivatives via the reaction of R-aryl sub-
stituted carbonyl compounds with alkynes in the pres-
ence of TiCl4 at room temperature. The reaction is
To investigate the reaction mechanism, a mixture of
phenylacetaldehyde and phenylacetylene was monitored
7916 J . Org. Chem., Vol. 68, No. 20, 2003

The physical properties and NMR data of all known com-
pounds are in accord with literature values (Supporting Infor-
mation). Data for new compounds are listed below.
applicable to both terminal and internal, aliphatic and
aromatic alkynes.
1-Met h yl-4-p r op yln a p h t h a len e (3l). Colorless oil. 1H
NMR: δ 8.06-7.97 (m, 2H), 7.50-7.46 (m, 2H), 7.21-7.18 (m,
2H), 3.00 (t, 2H, J ) 7.5 Hz), 2.64 (s, 3H), 1.80-1.71 (m, 2H),
1.01 (t, 3H, J ) 7.3 Hz). 13C NMR: δ 136.8, 132.9, 132.0, 126.2,
125.6, 125.2, 124.8, 124.4, 35.1, 24.0, 19.4, 14.3. HRMS: calcd
for C14H16 184.1252, found 184.1251.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All glassware was dried in an oven
at 120 °C and flushed with dry argon. All reactions were carried
out under an argon atmosphere. CH2Cl2 was distilled from CaH2.
All aldehydes and alkynes were purchased and used as received.
Titanium tetrachloride (1 M in CH2Cl2) was used as received.
All products were purified by flash chromatography using silica
4-Met h yl-1,2-d ip h en yln a p h t h a len e (3p ). White solid.
1
Mp: 137-138 °C. H NMR: δ 7.86 (dd, 2H, J ) 8.3 Hz), 7.50-
7.13 (m, 13H), 2.25 (s, 3H). 13C NMR: δ 142.1, 139.2, 138.0,
136.0, 133.7, 132.8, 131.9, 131.6, 130.0, 129.1, 127.7, 127.5, 127.4,
126.6, 126.1, 125.9, 125.5, 124.0, 19.5. HRMS: calcd for C23H18
294.1409, found 294.1408.
1
gel (60 A° , 230-400 mesh) with hexane as eluent. H NMR and
13C NMR were recorded in CDCl3 (250 MHz) with chemical shifts
reported relative to TMS. HRMS data for new compounds were
obtained using an EAB-ZQ mass spectrometer.
4-P h en yl-1,2-d i(p r op yl)n a p h th a len e (3t). Colorless oil. 1H
NMR: δ 8.07-7.19 (m, 10H), 3.12-3.05 (m, 2H), 2.83-2.77 (m,
2H), 1.78-1.66 (m, 4H), 1.13 (t, 3H, J ) 7.3 Hz), 1.03 (t, 3H, J
) 7.3 Hz). 13C NMR: δ 141.1, 138.0, 137.0, 134.9, 132.5, 130.6,
10.1, 129.5, 128.9, 128.4, 128.1, 126.9, 126.5, 125.5, 124.5, 124.2,
35.8, 30.5, 24.8, 24.3, 14.7, 14.3. HRMS: calcd for C22H24
288.1878, found 288.1884.
Rep r esen ta tive P r oced u r e for th e Syn th esis of Com -
p ou n d s 3a -t. Phenylacetalene (0.41 g, 4.0 mmol) was placed
in a dry argon-flushed, 50 mL round-bottomed flask equipped
with a stirring bar and dissolved in dry CH2Cl2 (20 mL).
Titanium tetrachloride (3.0 mmol, 3.0 mL of a 1.0 M CH2Cl2
solution) was added via a syringe at room temperature. The re-
action solution immediately turned dark brown. Then, phenyl-
actaldehyde (0.36 g, 3 mmol) was added via a syringe at room
temperature. The reaction mixture was allowed to stir for 3 h
and then was hydrolyzed with water. The mixture was extracted
into hexanes, and the organic layer separated, dried over
anhydrous MgSO4, concentrated under reduced pressure, and
purified by flash column chromatography to afford 3a as a
colorless liquid (0.54 g, 88%).
Ack n ow led gm en t. We thank the U.S. Department
of Energy and the Robert H. Cole Foundation for
support of this research.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all known compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) For the structures of TiCl4-carbonyl complexes, see: Cozzi, P.
G.; Solari, E.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Chem Ber. 1996,
129, 1361.
J O034330O
J . Org. Chem, Vol. 68, No. 20, 2003 7917