Site-specific preparation of 2-carboalkoxy-4-substituted naphthalenes and 9-alkylphenanthrenes and evidence for an allene intermediate in the novel base-catalyzed cyclization of 2-alkynylbiphenyls

Article abstract of DOI:10.1021/ol0620850

A site-specific preparation of 2-carboalkoxy-4-substituted naphthalenes and 9-alkylphenanthrenes is described. The successful cyclization of an allene intermediate provides supportive evidence for the previously proposed mechanism.

Full text of DOI:10.1021/ol0620850

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5295-5298
Site-Specific Preparation of
2-Carboalkoxy-4-substituted
Naphthalenes and 9-Alkylphenanthrenes
and Evidence for an Allene Intermediate
in the Novel Base-Catalyzed Cyclization
of 2-Alkynylbiphenyls
Yi Wang and Donald J. Burton*
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
donald-burton@uiowa.edu
Received August 23, 2006
ABSTRACT
A site-specific preparation of 2-carboalkoxy-4-substituted naphthalenes and 9-alkylphenanthrenes is described. The successful cyclization of
an allene intermediate provides supportive evidence for the previously proposed mechanism.
Polysubstituted naphthalene derivatives are important build-
ing blocks for the synthesis of pharmaceuticals1 and poly-
cyclic aromatic electronic materials.2 A variety of methods
have been developed for their preparation including elec-
trophilic substitution of naphthalenes,3 coupling of halonaph-
thalenes with organolithium or Grignard reagents,4 annula-
tions via Fischer carbenes,5 palladium-catalyzed cyclization
of alkynes with benzynes6 and cyclization of alkynes,7 [3+3]
benzannulation of benzenoid ring systems,8 reaction of
1-methoxybenzocyclobutene and alkynes,9 TiCl4-mediated
annulations of R-aryl-substituted carbonyl compounds with
alkynes,10 and benzotriazole-assisted aromatic ring annula-
tion.11 However, these methods involve expensive catalysts
or multistep synthesis. In some cases, regioselectivity was
difficult to achieve. Therefore, a new and efficient methodol-
ogy for the site-specific synthesis of polysubstituted naph-
thalenes was of interest to us. Herein, we wish to report a
novel base-catalyzed cyclization to prepare polysubstituted
naphthalene derivatives.
In our previous reported work in the base-catalyzed
cyclization of fluorinated enynes, we found that the presence
of a vinylic fluorine in the enyne successfully promoted
cyclization (with a DABCO or DBU base system) and
provided a site-specific synthesis of 1-alkyl-3-fluoronaph-
thalenes.12 In contrast, (Z)-non-1-en-3-yn-1-ylbenzene gave
no reaction with DABCO or DBU.12 We proposed that the
(1) (a) Xie, X.; Kozlowski, M. C. Org. Lett. 2001, 3, 2661-2663. (b)
Ward, R. S. Nat. Prod. Rep. 1995, 12, 183-205. (c) Perri, S. T.; Moore,
H. W. Tetrahedron Lett. 1987, 28, 4507-4510.
(2) Watson, M. D.; Fechtenkotter, A.; Mullen, K. Chem. ReV. 2001, 101,
1267-1300.
(3) AdVanced Organic Chemistry, 4th ed.; March, J., Ed.; Wiley: New
York, 1992; p 501.
(4) (a) Kamikawa, T.; Hayashi, T. Tetrahedron Lett. 1997, 38, 7087-
7090. (b) Merrill, R. E.; Negishi, E. J. Org. Chem. 1974, 39, 3452-3453.
(5) Schore, N. E. Chem. ReV. 1988, 88, 1081-1119.
(9) Andersen, N. G.; Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1996,
61, 2885-2887.
(6) (a) Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39,
173-175. (b) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. J. Am.
Chem. Soc. 2000, 122, 7280-7286.
(10) Kabalka, G. W.; Ju, Y.; Wu, Z. J. Org. Chem. 2003, 68, 7915-
7917.
(11) Katrizky, A. R.; Zhang, G.; Xie, L. J. Org. Chem. 1997, 62, 721-
725.
(7) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901-2915.
(8) Katrizky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, 55, 8263-8293.
(12) Xu, J.; Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 2555-2558.
10.1021/ol0620850 CCC: $33.50
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Published on Web 10/17/2006

vinylic fluorine increased the acidity of the propargylic
hydrogens and facilitated the formation of an allene inter-
mediate which reacted with the π aryl ring system to form
the cyclized product. However, in the fluorine-containing
enyne system, we were not able to observe the proposed
allene intermediate nor were we successful in independently
synthesizing the allene intermediate. Thus, two key questions
remained: first, was the cyclization specific to fluorine-
containing enynes or would other electron-withdrawing
groups also facilitate cyclization and truly broaden the overall
scope of this novel site-specific approach; and second, could
unequivocal evidence be obtained to support the proposed
allene intermediate in the mechanistic interpretation of this
cyclization process?
that the presence of either an electron-donating or an electron-
withdrawing group on the aromatic ring had little effect on
the outcome of the cyclization step. However, when R is
the 4-nitro group (entry 2), the temperature required for the
cyclization step is somewhat lower (170 °C vs 200 °C in
other cases). These results are summarized in Table 2.
Table 2. Formation of Polysubstituted Ethyl 2-Naphthoates
First, we investigated the effect of a carboalkoxy group
in the enyne to facilitate cyclization. The requisite car-
boalkoxy-substituted enynes were prepared by the Sono-
gashira reaction13 of terminal alkynes with R-bromocinna-
mates, which could be readily prepared from the Wittig
reaction of aromatic aldehydes with Ph3PCBrCO2Et.14 The
Z/E ratio in the products 2a-d was determined by the
chemical shifts of the vinyl protons in the proton NMR
spectra of the Z/E mixtures. The vinyl protons in the Z
isomers appeared at a lower field due to the deshielding effect
from the ester groups.15 These results are summarized in
Table 1.
time isolated yielda
entry
R
R′
product
(h)
(%)
1
2
3
4
5
H
CH2CH2Ph
n-C4H9
3a
3b
3c
3d
3e
3
2.5
5
5
5
64
46
73
59
58
4-O2N
4-MeO n-C4H9
4-MeO n-C10H21
4-MeO CH2CH2Ph
a Two steps, based on the corresponding R-bromocinnamates 2a-c.
When 2-naphthaldehyde was employed as the substrate,
theoretically, there could be two possible products from two
different cyclization directions of the corresponding enyne.
However, phenanthrene derivative 4 was isolated as the sole
product and no anthracene 4′ was observed (Scheme 1). The
Table 1. Preparation of R-Bromocinnamates
Scheme 1. Sole Formation of 4
ratioa (Z/E)
of product product
isolated yieldb
(%)
entry
ArCHO
1c
2c
3c
4d
C6H5
4-O2NC6H4
4-MeOC6H4
2-naphthaldehyde
83:17
96:4
78:22
79:21
2a
2b
2c
2d
67
95
82
94
a Determined by 1H NMR. b Based on aldehyde. c Benzene was the
solvent. d CH2Cl2 was the solvent.
The resultant R-bromocinnamates 2a-c were obtained as
a mixture of Z and E isomers, where the Z isomers were the
major products (these mixtures were utilized in the following
cyclization step). Sonogashira reaction13 of the R-bromocin-
namates 2a-c with terminal alkynes gave the corresponding
enynes. Because it was difficult to separate the Z/E mixtures
from each other and only the (E)-enynes could cyclize with
our base system, the mixtures were used directly for the next
step without characterization. When DBU (0.2 equiv) was
employed as the base, the polysubstituted naphthalene
derivatives 3a-e were obtained in moderate to good yields
for the two steps. The results of these reactions indicated
phenanthrene structure 4 was confirmed by its single X-ray
crystallographic structure determination.16 This selectivity
could be explained by computational work previously
reported in which the total molecular energy of phenanthrene
(16) CCDC 617807 (4) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc-
.cam.ac.uk/data_request/cif or by e-mailing data_request@ccdc.cam.ac.uk
or by contacting The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, U.K.; fax +44 1223 336033. Also see the
Supporting Information.
(13) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
(14) Zhang, X.; Qing, F.; Yu, Y. J. Org. Chem. 2000, 65, 7075-7082.
(15) Olpp, T.; Bruckner, R. Synthesis 2004, 2135-2140.
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Org. Lett., Vol. 8, No. 23, 2006

is lower than that of anthracene.17 Another possible explana-
tion is that, when both structures of the intermediates (prior
to two possible final products) are drawn, it is clear that the
formation of intermediate A is more favorable than A′
because the aromaticity of one benzene ring is retained
whereas in the case of A′ the aromaticity of both benzene
rings is destroyed.18
solvent for the cyclization of 11 and 10b was obtained in
57% yield (Scheme 4). Thus, these experiments provided
Scheme 4. Formation of 10b from Allene 11 without Base
The presence of an aldehyde group on the double bond of
enynes could also facilitate the base-catalyzed cyclization
as well. For example, when R-bromocinnamaldehyde 5 was
employed as the substrate, the enyne 6 could be prepared
from its reaction with 4-phenyl-1-butyne under cocatalysis
of PdCl2(PPh3)2 and CuI in CH3CN/Et3N. 4-Phenethyl-2-
naphthaldehyde 7 was prepared in moderate yield (Scheme
2).
supportive evidence for the allene intermediate in the
mechanism of the cyclization reaction under base-catalyzed
conditions.
Interestingly, when 1,1-dibromo-2,2-diphenylethene 1220
was employed as the substrate, its Sonogashira reaction with
excess 1-hexyne gave the endiyne 13, which could undergo
cyclization to give naphthalene derivative 14 or benzo[c]-
phenanthrene derivative 15 as a function of reaction condi-
tions (Scheme 5). Presumably, 15 was formed from two
Scheme 2. Formation of 7
Scheme 5. Formation of 14 and 15
When the double bond of the enyne was part of an
aromatic ring, the cyclization occurred smoothly under our
conditions as well to afford phenanthrene derivatives. 2-Iodo
biphenyl 8 was reacted with a terminal alkyne under
Sonogashira conditions. The resultant 2-alkynyl-substituted
biphenyls 9a and 9b, when treated with DBU (0.2 equiv) in
refluxing NMP, gave 9-alkyl phenanthrenes 10a and 10b6b
in good yields, respectively (Scheme 3).
Scheme 3. Preparation of Phenanthrenes 10a and 10b
consecutive cyclizations. The first cyclization seemed to
occur very smoothly (3 h). However, much more time (21
h) was required for the subsequent cyclization to form 15.
Accordingly, on the basis of these experiments and the
deuterium experiment reported in the previous communica-
tion, the following mechanism is proposed (Scheme 6).12
In our previous report,12 an allene intermediate was
proposed in the mechanistic interpretation of the overall
cyclization process. To provide support for this proposed
mechanistic intermediate, the following experiment was
performed. When 9b was stirred with KOH (1.0 equiv) and
tetra-n-butylammonium bromide (TBAB) (0.1 equiv) as the
phase-transfer catalyst in toluene at room temperature,19 the
resultant allene 11 was isolated. Subsequently, when 11 was
heated in refluxing NMP, 10b was formed (it was identical
to the product 10b formed from 8 in Scheme 3). To rule out
the possibility of a trace amount of base formed from NMP
at high temperature (200 °C), tetradecane was used as the
Scheme 6. Mechanism for the Formation of Phenanthrenes
First, the base catalyzes the isomerization of 9b to the allene
11,21 which undergoes a 6π cycloaddition to form a three-
ring system followed by isomerization to form the final
product 10b.
(17) Gong, X.; Xiao, H. J. Phys. Org. Chem. 1999, 12, 441-446.
(18) A suggestion from one of the reviewers is acknowledged.
(19) Oku, M.; Arai, S.; Katayama, K.; Shioiri, T. Synlett 2000, 493-
494.
(20) Li, G.; Warner, P. M. Tetrahedron Lett. 1995, 36, 8573-8576.
(21) Allenes in Organic Synthesis; Schuster, H. F., Coppola, G. M., Eds.;
Wiley: New York, 1984.
Org. Lett., Vol. 8, No. 23, 2006
5297

In this communication, we have demonstrated that this
novel base-catalyzed cyclization is not restricted to fluori-
nated substrates. Esters and aldehyde-substituted enynes, as
well as 2-alkynylbiphenyls, could also participate in this
reaction. The previously proposed mechanism was further
strengthened by successful cyclization of an isolated allene
intermediate. Considering the importance of naphthalene and
phenanthrene derivatives, this method should find wide
application in the synthesis of polycyclic aromatic hydro-
carbons.
Dr. Dale Swenson of the University of Iowa for the
determination of the X-ray structure.
Supporting Information Available: Experimental pro-
cedure for the synthesis of 2a-d, 3a-e, 4, 6, 7, 9a,b, 10a,b,
1
11, and 13-15 and their characterization by H NMR, 13C
NMR, and HRMS; copies of 1H and 13C NMR of compounds
2d, 3a-e, 4, 6, 7, 9a,b, 10a, 11, and 13-15; ORTEP plot
of 4; and complete X-ray crystallographic data of compound
4 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the National
Science Foundation is acknowledged. We are indebted to
OL0620850
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