A novel multicomponent reaction of arynes, β-keto sulfones, and Michael-type acceptors: A direct synthesis of polysubstituted naphthols and naphthalenes

Article abstract of DOI:10.1021/jo070241q

(Chemical Equation Presented) A novel multicomponent reaction of arynes, β-keto sulfones, and Michael-type acceptors is presented, providing an efficient method for the synthesis of polysubstituted naphthols and polysubstituted naphthalenes. Further investigation suggests that the tandem reaction may proceed via a sequential nucleophilic attack to arynes, intramolecular nucleophilic substitution followed by a Michael addition, and a ring closure - elimination process.

Full text of DOI:10.1021/jo070241q

by other strategies, multicomponent reactions of the arynes were
rare6 because of the difficulty associated with regulating the
reactivity of arynes.
A Novel Multicomponent Reaction of Arynes,
â-Keto Sulfones, and Michael-Type Acceptors: A
Direct Synthesis of Polysubstituted Naphthols and
Naphthalenes
During our studies on the chemistry of arynes7 and multi-
component reactions,8 we were surprised to find that polysub-
stituted naphthols and naphthalenes could be obtained in
moderate yields by a novel three-component reaction of arynes,
â-keto sulfones, and Michael-type acceptors, in which the
efficiency of bond formations was high with four new carbon-
carbon bonds formed within in one operation (Scheme 1).
Initially, we studied the multicomponent reactions of o-
(trimethylsilyl)phenyl triflate9 1a, benzenesulfonylacetate 2a,
and diethyl fumarate 3a. When â-sulfonylacetate 2a was treated
with 1.5 equiv of triflate 1a and 1 equiv of fumarate 3a in the
presence of 2 equiv each of 18-crown-6 and KF as the source
of fluoride to induce the generation of arynes at room temper-
ature, the naphthol 4a was obtained only in a trace amount by
using 2 equiv of K2CO3 as base after 24 h (entry 1, Table 1).
In order to optimize the reaction conditions, the effects of bases,
amounts of reactants and bases, and temperature on the reaction
were examined (Table 1). The experimental results showed that
NaH is effective as the base to the reaction, while KF, K2CO3,
and tBuOK were ineffective (entries 1-4, Table 1). When 0.75
equiv of fumarate 3a was used, the yield of naphthol 4a
increased to 58% (Table 1, entry 5). By increasing the amount
of sodium hydride, the yield of naphthol 4a could be improved
(entries 6 and 7, Table 1). When the reaction was performed at
65 °C, compound 4a was obtained in a better yield (69%) (entry
8, Table 1).
Xian Huang*,†,‡ and Jian Xue†
Department of Chemistry, Zhejiang UniVersity (Campus Xixi),
Hangzhou 310028, People’s Republic of China, and State Key
Laboratory of Oganometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
huangx@mail.hz.zj.cn
ReceiVed February 5, 2007
A novel multicomponent reaction of arynes, â-keto sulfones,
and Michael-type acceptors is presented, providing an
efficient method for the synthesis of polysubstituted naph-
thols and polysubstituted naphthalenes. Further investigation
suggests that the tandem reaction may proceed via a
sequential nucleophilic attack to arynes, intramolecular
nucleophilic substitution followed by a Michael addition, and
a ring closure-elimination process.
With the optimized reaction conditions in hand (entry 8, Table
1), the scope and the limitation of this reaction were examined.
The results in Table 2 demonstrated that the reaction could
proceed smoothly using maleic esters, fumaric esters, or ethyl
acrylate as the Michael-type acceptors to afford naphthols in
moderate yields (entries 1-4, Table 2). However, when methyl
Polysubstituted naphthalenes have been used in many ap-
plications such as pharmaceuticals, plant protection agents, dyes,
etc. In addition, some natural products that contain a naphthalene
nucleus often exhibit biological activities1 which makes their
preparation of great interest in organic synthesis.2
Recently, the chemistry of arynes has received considerable
attention due to its potential in synthetic applications.3 Although
their application has been extended to insertion of element-
element σ-bond4 and transition-metal-catalyzed reactions5 to
synthesize polysubstituted arenes, which are difficult to prepare
(4) Addition of H-X bonds (X ) N, O, S) to arynes: (a) Liu, Z.; Larock,
R. C. Org. Lett. 2003, 5, 4673-4675. (b) Liu, Z.; Larock, R. C. Org. Lett.
2004, 6, 99-102. Inserts of elment-element σ-bond to arynes: (N-Si)
(c) Yoshida, H.; Minabe, T.; Ohshita, J. Chem. Commun. 2005, 5, 3454-
3456. (C-C) (d) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005,
127, 5340-5341. (e) Yoshida, H.; Watanabe, M.; Ohshita, J. Tetrahedron
Lett. 2005, 46, 6729-6731. (f) Yoshida, H.; Watanabe, M.; Ohshita, J.
Chem. Commun. 2005, 5, 3292-3294. (C-P) (g) Yoshida, H.; Watanabe,
M.; Ohshita, J. Chem. Lett. 2005, 34, 1538-1589. (C-N) (h) Yoshida, H.;
Shirakawa, E.; Honda, Y. Angew. Chem., Int. Ed. 2002, 41, 3247-3249.
(i) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112-13113.
(S-N and S-Sn) (j) Yoshida, H.; Minabe, T.; Ohshita, J. Chem. Commun.
2004, 4, 1980-1981.
(5) (a) Yoshida, H.; Ikadai, J.; Shudo, M. J. Am. Chem. Soc. 2003, 125,
6638-6639. (b) Yoshida, H.; Tanino, K.; Ohshita, J. Angew. Chem., Int.
Ed. 2004, 43, 5052-5055. (c) Yoshida, H.; Tanino, K.; Ohshita, J. Chem.
Commun. 2005, 5, 5678-5680. (d) Yoshida, H.; Honda, Y.; Shirakawa, E.
Chem. Commun. 2001, 1, 1880-1881.
(6) (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew. Chem.,
Int. Ed. 2004, 43, 3935-3938. (b) Yoshida, H.; Fukushima, H.; Ohshita,
J.; Kunai, A. J. Am. Chem. Soc. 2006, 128, 11040-11041. (c) Jeganmoban,
M.; Cheng, C. Chem. Commun. 2006, 6, 1714-1715. (d) Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2004, 45, 8659-
8662.
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) (a) Eich, E.; Pertz, H.; Kaloga, M.; Schulz, J.; Fesen, M. R.;
Mazumder, A.; Pommier, Y. J. Med. Chem. 1996, 39, 86-95. (b) Ward,
R. S. Nat. Prod. Rep. 1995, 12, 183. (c) Ukita, T.; Nakamura, Y.; Kubo,
A.; Yamamoto, Y.; Takahashi, M.; Kotera, J.; Ikeo, T. J. Med. Chem. 1999,
42, 1293-1305. (d) Tyrala, A.; Makosza, M. Synthesis 1994, 264-266.
(2) (a) Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L. Tetrahedron
2003, 59, 7-36. (b) Seong, M. R.; Song, H. N.; Kim, J. N. Tetrahedron
Lett. 1998, 39, 7101-7104 and further references cited therein. (c) Rucker,
M.; Bruckner, R. Synlett 1997, 1187-1189.
(3) For reviews, see: (a) Kessar, S. V. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
4, pp 483-515. (b) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701-
730. (c) Hart, H. In Supplement C2: The Chemistry of Triple-Bonded
Functional Groups; Patai, S., Ed.; Wiley: Chichester, U.K., 1994; Chapter
18, pp 1017-1134.
(7) Huang, X.; Xue, J. Synth. Commun. 2007, 37, in press.
(8) (a) Huang, X.; Xie, M. J. Org. Chem. 2002, 67, 8895-8900. (b)
Huang, X.; Xie, M. Org. Lett. 2002, 4, 1331-1334. (c) Huang, X.; Xiong,
Z. Chem. Commun. 2001, 1, 1714-1715.
(9) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211-
1214.
10.1021/jo070241q CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/12/2007
J. Org. Chem. 2007, 72, 3965-3968
3965

TABLE 2. Synthesis of Polysubstituted Naphthols by the
Three-Component Reactions of Arynesa
SCHEME 1. Multicomponent Reactions of Arynes, â-Keto
Sulfones, and Michael-Type Acceptors
TABLE 1. Optimization of Three-Component Reactions of
Benzyne, â-Sulfonylacetate 2a, and Fumarate 3aa
3a
(equiv)
base
(equiv)
yieldb
(%)
entry
1
2
3
4
5
6
7
8c
1
1
1
1
0.75
0.75
0.75
0.75
K2CO3 (2)
KF (2)
trace
NaH (2)
tBuOK (2)
NaH (2)
NaH (2.5)
NaH (3)
NaH (2.5)
35
mixture
58
63
63
69
a At ambient temperature, 2a in the presence of base was stirred for 10
min, and the mixture was treated with 1a and 3a in the presence of KF and
18-crown-6 in THF for 5 h. b Isolated yields based on 3a. c The reaction
was conducted at 65 °C.
acrylate was employed, a mixture of naphthols 4d and 4e was
isolated. We think naphthol 4d may be the transesterification
product of naphthol 4e with ethanol, which was generated in
the reaction (entry 5, Table 2). Cyclohex-2-enone is also
effective for the reaction (entry 6, Table 2). However, when
chalcone was used as the Michael-type acceptor, only a trace
amount of the product 4g was formed, probably due to the steric
hindrance of the phenyl group in the substrate 3g (entry 7, Table
2).
As well as unsubstituted aryne, substituted arynes could also
be used in this reaction. When 4,5-dimethyl-1-(trimethylsilyl)-
phenyl triflate 1b was selected as a substrate in the reaction,
the naphthol 4h was obtained in good yield (entry 8, Table 2).
The reaction of 3-substituted arynes generated from triflate 1c
with â-sulfonylacetate 2a and maleic esters also took place
smoothly in excellent regioselectivity probably due to the steric
hindrance of the methyl group in the ortho-positions of arynes
(entries 9 and 10, Table 2). The regioselectivities of the products
from 3-substituted arynes were determined by NOE experiment
(Figure 1).
a Reaction conditions: At ambient temperature, 1 mmol of 2a in the
presence of 2.5 mmol of NaH (65% in mineral oil) was stirred for 10 min,
then the mixture was treated with 1.5 mmol of 1 and 0.75 mmol of 3 in the
presence of 2.25 mmol of KF and 2.25 mmol of 18-crown-6 in 10 mL of
THF at 65 °C. b Isolated yields based on 3. c Determined by 1H NMR
analysis.
To extend this protocol, we used other â-ketone sulfones to
prepare corresponding substituted naphthalenes (Table 3). To
our delight, 2-(phenylsulfonyl)acetophenone 2b, 1-(phenylsul-
fonyl)-2-propanone 2c, or 2-(p-tolylsulfonyl)acetophenone 2d
is effective for this reaction, and the corresponding substituted
naphthalenes 4 were obtained in good yields. In this transforma-
tion, it is necessary to increase the amount of sodium hydride
to 3.5 equiv to remove the water generated during the reaction.
Next, we turned our attention to the mechanism of the
reaction. Scheme 2 outlines a plausible pathway, which involves
five reaction steps. First, the enolate of 2a attacks the aryne to
generate aryl anion 5, which could undergo intramolecular
nucleophilic addition to the carbonyl moiety of the ester to form
anion 7 via benzocyclobutene anion 6. Subsequently, the anion
7 would in turn attack the Michael-type acceptor, such as a
fumarate, followed by 1,2-addition and elimination of benzene-
sulfinic acid to generate naphthol 4a.
FIGURE 1. NOE experiment on 4i.
To infer the mechanism better, we tested the two key reaction
steps: (A) the insertion of â-keto sulfones to arynes; (B) the
synthesis of polysubstituted naphthols by the reaction of the
products from (A) with Michael-type acceptors. Initially, our
efforts focused on the reaction of 2-(trimethylsilyl)phenyl triflate
1a with â-sulfonylacetate 2a. When 0.75 equiv of â-sulfonyl-
acetate 2a reacted with triflate 1a in the presence of 2 equiv of
KF and 18-crown-6 in THF at room temperature, the insertion
product 9a was obtained in 85% yield after 4 h (Scheme 3).
ortho-Keto benzyl sulfones are important building blocks in
organic synthesis, so we investigated the reaction of a variety
of precursors of arynes and â-keto sulfones to generate ortho-
3966 J. Org. Chem., Vol. 72, No. 10, 2007

TABLE 3. Synthesis of Polysubstituted Naphthalene by the
Three-Component Reactions of Arynesa
TABLE 4. Insertion Reaction of â-Keto Sulfones to Arynesa
4, yieldb
entry
2
(%)
1
2
3
2b, Ar ) Ph; R2 ) Ph
4k, 67
4l, 70
4k, 68
2c, Ar ) Ph; R2 ) CH3
2d, Ar ) p-(CH3)-Ph; R2 ) Ph
a Reaction conditions: At ambient temperature, 1 mmol of 2 in the
presence of 3.5 mmol of NaH (65% in mineral oil) was stirred for 10 min,
then the temperature was increased to 65 °C and the mixture was treated
with 1.5 mmol of 1a and 0.75 mmol of 3b in the presence of 2 mmol of
KF and 2 mmol of 18-crown-6 at 65 °C. b Isolated yields based on 3b.
SCHEME 2. Plausible Pathway of Multicomponent
Reactions
a At ambient temperature, 1 (1.0 mmol) and 2 (0.75 mmol) in the presence
of 2 mmol of KF and 2 mmol of 18-crown-6 in 10 mL of THF were stirred
1
for 12 h. b Isolated yields based on 2. c Determined by H NMR analysis.
SCHEME 3. Insertion of â-Sulfonylacetate 2a to Aryne
FIGURE 2. NOE experiment on 5g.
keto benzyl sulfones. As shown in Table 4, we initially used
the simple aryne precursor 1a to generate an aryne. When 2a
and 1-(phenylsulfonyl)-2-propanone 2b were treated with arynes,
the insertion products could be obtained smoothly in good yields
(entries 1 and 2, Table 4), but when 2-(p-tolylsulfonyl)-
acetophenone 2d was used, the product was a mixture of 9c
and 10c in a ratio of 3:1. We believe that the product 10c was
formed from the reaction of the intermediate benzyl anion with
a second aryne.
In addition to simple arynes, substituted arynes were also
examined. When 4,5-dimethyl-2-(trimethylsilyl)phenyl triflate
1b and 3-methyl-2-(trimethylsilyl)phenyl triflate 1c were used
to conduct this reaction, the insertion products could be obtained
smoothly. The regioselectivities of the products from 3-substi-
tuted arynes were determined by NOE experiment (Figure 2).
The regioselectivities of the reaction were excellent, and the
products were monosubstituted at the ortho-position.
Next, we examined the reaction of ortho-keto benzyl sulfones
with Michael-type acceptors, which afford the expected polysub-
stituted naphthalenes (Table 5).
TABLE 5. Synthesis of Polysubstituted Naphthols and
Naphthalenes by ortho-Keto Benzyl Sulfones and Michael-Type
Acceptor in the Presence of Sodium Hydridea
Michael-type
acceptor
yieldb
(%)
entry
9
products
1
2
3
4
9a
9a
9a
9b
3a
3c
3f
4a
4c
4f
4l
78
85
76
73
3a
a The mixture of 9 (1.0 mmol) and 3 (1.0 mmol) in the presence NaH
was stirred at 65 °C for 4 h. b Isolated yields.
oped. The reaction may proceed via nucleophilic attack on the
arynes, intramolecular nucleophilic substitution, Michael addi-
tion, ring closure, and elimination. It is the first example of
successful trapping of the intermediate benzyl anion with
electrophiles. To understand the mechanism better, the insertion
In summary, a novel three-component reaction of arynes,
â-keto sulfones, and Michael-type acceptors for the synthesis
of polysubstituted naphthols and naphthalenes has been devel-
J. Org. Chem, Vol. 72, No. 10, 2007 3967

mixture, then diluted with dichloromethane (15 mL) and washed.
The organic layer was dried over MgSO4. Removal of the solvent
in vacuum and purification of the residue by silica gel chromatog-
raphy with n-hexane-EtOAc (4:1) as eluent gave the product 4.
of â-keto sulfones to arynes was also examined. The ortho-
keto benzyl sulfones were obtained with good yields under mild
reaction conditions. Further studies including the generation
methods of arynes, the reaction mechanism, and synthetic
applications of arynes are underway in our laboratory.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 20332060 and
2472072) and the CAS Academician Foundation of Zhejiang
Province.
Experimental Section
General Procedure for Synthesis of Polysubstituted Naphthols
and Naphthalenes via a Multicomponent Reaction of Arynes.
At ambient temperature, 1 mmol of 2 in the presence of 2.5 mmol
or 3.5 mmol of NaH (65% in mineral oil) was stirred for 10 min
in 10 mL of dry THF, then the mixture was treated with 1.5 mmol
of 1 and 0.75 mmol of 3 in the presence of 2 mmol of KF and 2
mmol of 18-crown-6 in THF at 65 °C. After completion of the
reaction (monitored by TLC), 5 mL of water was added to the
Supporting Information Available: Experimental procedures,
spectral data for products, and copies of 1H and 13C NMR spectra
for all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO070241Q
3968 J. Org. Chem., Vol. 72, No. 10, 2007