Platinum(IV)-Catalyzed Synthesis of Unsymmetrical Polysubstituted Benzenes via Intramolecular Cycloaromatization Reaction

Article abstract of DOI:10.1002/adsc.201500573

A one-pot synthesis of polysubstituted benzene derivatives was achieved via a platinum(IV)-catalyzed intramolecular cycloaromatization reaction. The reaction proceeds via a tandem skeletal rearrangment, dehydration and double bond isomerization, which proved to be very useful for the syntheses of a range of interesting polyalkyl-substituted benzenes.

Full text of DOI:10.1002/adsc.201500573

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DOI: 10.1002/adsc.201500573
Platinum(IV)-Catalyzed Synthesis of Unsymmetrical Polysubsti-
tuted Benzenes via Intramolecular Cycloaromatization Reaction
Shuyan Zheng,+a Jinghua Zhang,+a and Zhengwu Shenb,*
a
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China
School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, People’s Republic of China
b
E-mail: Jeff_shen_1999@yahoo.com
+
These authors contributed equally.
Received: June 14, 2015; Published online: September 11, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500573.
Abstract: A one-pot synthesis of polysubstituted
benzene derivatives was achieved via a platinu-
m(IV)-catalyzed intramolecular cycloaromatization
reaction. The reaction proceeds via a tandem skele-
tal rearrangment, dehydration and double bond iso-
merization, which proved to be very useful for the
syntheses of a range of interesting polyalkyl-substi-
tuted benzenes.
dehydration, oxidation, and tautomerization of the
metathesis products.[6c,d]
Herein, we report a novel strategy employing a plat-
inum(IV)-catalyzed 1,7-enyne skeletal rearrange-
ment–aromatization, for the synthesis of polyalkyl-
substituted benzenes (Scheme 1). This reaction is ac-
tually a one-pot combination of skeletal rearrange-
ment, elimination and double bond isomerization.
Hence, we believe it offers a convenient and comple-
mentary approach towards the synthesis of polysubsti-
tuted benzenes that may otherwise be difficult to
obtain via existing methods.
Keywords: cycloaromatization; double bond iso-
merization; platinum(IV); polysubstituted ben-
zenes; rearrangement
To optimize the reaction conditions and identify es-
sential additives for the platinum(IV)-catalyzed pro-
cess, compound 2a was selected as a suitable model
substrate. A number of Lewis acids, solvents and
Polysubstituted aromatics are an important class of noble metal catalysts was screened, and selected re-
organic compounds with wide reaching and significant sults are presented in Table 1. Gratifyingly, although
applications in industry and research laboratories.[1]
the reaction yield was rather low, the target benzan-
A number of methods has been developed for the nulated 2 was formed under the PtCl4 reaction condi-
synthesis of polysubstituted benzene over the years. tions (entry 1, Table 1).
For example, traditional approaches often include the
Next, to assist with the elimination of the tertiary
Friedel–Crafts reaction,[2] transition metal-catalyzed OH group, a selection of Lewis acids was added as
[2+2+2]cyclotrimerization,[3] [4+2]cycloaddition re- co-catalyst (entries 2, 3, 4 and 5, Table 1). Interesting-
actions[4] and dehydrogenation reactions of cyclohexe- ly, each Lewis acid tested improved the reaction per-
nones.[5] Whilst each method has its own merit, there formance, with TBSOTf performing best and leading
is still great interest in developing new and efficient to a 72% yield of 2. In addition to PtCl4, other noble
strategies for the synthesis of polysubstituted ben- metal catalysts were also investigated. PtCl2 (entry 6,
zenes.
Recently, the metal-mediated cycloisomerization of
1,n-enynes has emerged as an extremely attractive ap-
proach for the synthesis of various cyclic compounds,
including substituted benzenes.[6,7] However, the for-
mation of six-membered rings from 1,7-enynes by
metathesis is not always easy and can sometimes be
challenging. In addition, application of ring closure
metathesis–aromatization to the synthesis of benzene
derivatives often requires additional steps that involve Scheme 1. Platinum (IV)-catalyzed cycloaromatization.
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Table 1. Optimization of the reaction conditions[a]
pentane and benzocyclohexane in good yields, respec-
tively (entries 2, 3, 9 and 10, Table 2). This represents
a convenient strategy for the syntheses of such benzo-
cycloalkanes. However, it was found that when the
double bond of the 1,7-enyne is located within a ring
system, ring expansion took place during the reaction
leading to the formation of a benzocycloalkane. The
ring size of benzo-fused cycloalkane depends on the
size of the cycloalkene in the precursors (entry 8,
Table 2). For example, when the cyclohexene moiety
participated in the cycloaromatization reaction, the
final product was the corresponding benzocyclooctene
derivative. The combination of both strategies could
be useful for the synthesis of a poly-membered ring
system (entry 14, Table 2). In order to confirm this hy-
pothesis, compound 27 was synthesized to examine
whether this strategy could be applied for thee forma-
tion of other ring systems instead of an 8-membered
ring. Indeed, as expected, the benzo-fused cyclohep-
tane 28 was formed in 74% yields (Scheme 2). This
finding provides an alternative strategy for the syn-
thesis of benzo-fused cycloalkanes.
Entry Solvent Catalyst
Additive
No
Sc(OTf)3 80
BF3·OEt2 80
TBSOTf 80
LiClO4
TBSOTf 80
TBSOTf 40
t
Yield
[oC] [%][b]
1
2
3
4
5
6
7
8
toluene PtCl4
toluene PtCl4
toluene PtCl4
toluene PtCl4
toluene PtCl4
toluene PtCl2
CH2Cl2 PtCl4
CH2Cl2 PtCl4
toluene Au(PPh3)Cl
toluene PtCl4
toluene PtCl4
(0.1 equiv.)
80
16
23
47
72
12
0
0
0
11
80
No
40
9
10
11
TBSOTf 80
TBSOTf 100 66
TBSOTf 80
68
12[c]
toluene PtCl4
TBSOTf 80
70
[a].Typical reaction conditions: substrate (1.0 mmol); PtCl4,
0.05 equiv.; Lewis acid, 0.06 equiv., stirred at 808C for 12 h.
[b].Isolated yield.
In the course of the synthesis of the compound 12
(entry 12, Table 2), three compounds were isolated in
the absence of the co-catalyst TBSOTf (Scheme 3).
The compound 15 (35%) corresponds to the first
intermediate formed in the 1,7-enyne metathesis. The
[c].Under an air atmosphere.
Table 1) did not yield the desired aromatic product compound 15 simultaneously underwent elimination
under otherwise equivalent reaction conditions. The of the hydroxy group and isomerization of conjugated
Grubbs II catalyst was also tried but the reaction diene to form the compound 12. The isolation of the
gives very complicate products. However, Au(PPh3)Cl compound 16 (24%), indicated that dehydrogenation
could form the compound 2, although the yield was of 15 may take place rather than the elimination of
quite low. Toluene was identified as the most suitable the hydroxy group if the TBSOTf is absent. The iden-
solvent, with an optimal reaction temperature of tification of the compounds 15 and 16 provided sup-
808C. In addition, increasing the amount of the cata- porting evidence for the mechanism of this cycloaro-
lyst (entry 11, Table 1) and the presence of air matization reaction. The compound 15 could be com-
(entry 12, Table 1) in the system seemed to have no pletely converted into 12 when TBSOTf was added to
impact on the yield of the reaction. Hence, the opti- the reaction system. Thus, we speculate that TBSOTf
mal reaction conditions were concluded to be as fol- enhances the acidity of the PtCl4, thereby promoting
lows: substrate (1.0 mmol); PtCl4, 0.05 equiv.; Lewis the elimination of the hydroxy group. Because the
acid, 0.06 equiv., stirred at 808C for 12 h.
PtCl4/TBSOTf mixture efficiently converted 15 into
In order to explore the scope of the reaction, a se- 12, we were interested to examine whether the system
lection of tri-, tetra-, penta- and hexa-substituted ben- could be used to catalyze the isomerization of double
zene derivatives was synthesized. In general, as de- bonds.
picted in Table 2, the standard reaction conditions
Two compounds, namely 4-phenyl-1-butene (17)
gave pleasingly good yields. Multi-substituted biphen- and l-carvone (19) were selected to explore whether
yl derivatives (entries 6, 7, 8, 11, 12 and 13, Table 2) the exocyclic double bonds of these two compounds
could be obtained readily in high yields. Compared underwent the isomerization reaction under the PtCl4/
with other well established methods for biphenyl syn- TBSOTf conditions. As illustrated in Scheme 4, the
thesis, such as Suzuki[8] and Kumada couplings,[9] the compounds 17 and l-carvone (19) were converted
present method provides a useful alternative for the into 1-phenyl-1-butene (18) and 2-methyl-5-isopropyl-
synthesis of biphenyl derivatives. Benzo-fused cycloal- phenol (20), respectively, and with very good yields.
kanes, including benzocyclohexane and benzocyclo- Although a Pt(II) complex was recently reported to
pentane derivatives, can also be obtained via the cy- promote the isomerization of allylbenzenes,[10] the for-
cloaromatization reaction.
mation of compound 20 is the first example of
Both cyclopentane and cyclohexane were used as a Pt(IV)-catalyzed aromatization reaction via isomeri-
tethers in the 1,7-enyne, which yielded benzocyclo- zation of the terminal alkene.
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Pt(IV)-Catalyzed Synthesis of Unsymmetrical Polysubstituted Benzenes
Table 2. Synthesis of polysubstituted benzene derivatives
To further evaluate the scope of this reaction, stituents, arranged on the benzene ring clockwise ac-
a topologically interesting molecule: 1-ethyl-2-propyl- cording to size. Thus, it would be very challenging for
3-butyl-4-pentyl-5-hexyl-toluene (1) (entry 1, Table 2), such compounds to be synthesized by the other cur-
was chosen to be the target molecule for the synthe- rently available methods.
sis. This compound has six different linear alkyl sub-
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As shown in Scheme 5, the synthesis began from
propyl butyl acrolein (25), which was readily obtained
from the pentanal (24) through an aldol condensation
reaction. The aldehyde group of compound 25 was re-
duced to an alcohol by NaBH4 in quantitative yield.
The obtained compound 22 condensed with 7-trideca-
none dimethyl ketal 23 to form the key intermediate
21.[11] Compound 21 underwent a nucleophilic addi-
tion reaction with trimethylsilylbutyne to afford com-
pound 1a, the precursor for the cycloaromatization.
Finally, the compound 1 was prepared under the
standard reaction conditions described above in 78%
yield. The synthesis of the key intermediate 1a from
pentanal required only four steps, demonstrating the
efficiency of this cycloaromatization reaction. A simi-
lar molecule, compound 4 was obtained in 73% yield
using the same strategy (entry 4, Table 2).
Scheme 2. The synthesis of compound 28.
Based on the above results and analyses of the by-
products from the reaction, a preliminary mechanism
was proposed,[12,13] as shown in Scheme 6.
To the best of our knowledge, reports on the forma-
tion of an aromatic ring by enyne cyclization are very
rare.[3,6a,14,15] In some cases, it needs an aromatic ring
in the tether part[6] to form a naphthalene core. The
cycloaromatization method described here is the first
example of a Pt(IV)-mediated cycloaromatization.
This method has the following advantages: (i) The un-
saturated tether unit is not needed for the skeletal re-
arrangement step, and thus the precursors for this re-
action are relatively straightforward to synthesize. (ii)
The aromatic ring was produced via a tandem process
of elimination and double bond isomerization; hence
no additional treatment was needed such as oxidation
or dehydrogenation. PtCl4 exhibits triple roles in the
reaction. (i) As a typical transition metal catalyst,
PtCl4 catalyzes the skeletal rearrangement to produce
the six-membered 1,3-dienes (8f). (ii) As a Lewis
acidic catalyst, PtCl4 assists the elimination of tertiary
OH group. (iii) More importantly, it plays a role as
Scheme 3. Identification of two important by-products.
Scheme 4. The double bond migration catalyzed by PtCl4/
TBSOTf.
Scheme 5. The synthesis of compound 1.
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Pt(IV)-Catalyzed Synthesis of Unsymmetrical Polysubstituted Benzenes
Scheme 6. A proposed reaction mechanism.
a double bond isomerization catalyst to promote the References
isomerization of double bonds toward the aromatic
[1] a) D. S. Tarbell, A. T. Tarbell, Essays on the History of
products. The addition of a Lewis acid, such as
TBSOTf, into the system, actually increases the acidi-
ty of the catalyst, which accelerates the elimination of
the hydroxy group and improves the yield of the reac-
tion. In conclusion, the Pt(IV)/TBSOTf proved not
only to be able to catalyze the cycloaromatization re-
action but was also efficient in promoting the alkene
isomerization. The present procedure provides a new
regiospecific and synthetically useful route to poly-
substituted benzenes, which complements and offers
additional benefits to other existing methods.
Organic Chemistry in the United States, 1875–1955.
Folio, Nashville, TN, 1986, p 139–151; b) D. Astruc,
Modern Arene Chemistry, Wiley-VCH, Weinheim,
2002.
[2] a) G. Olah, Friedel–Crafts and Related Reactions, Wiley
Interscience, New York, 1963, Vols. I–IV; b) R. Taylor,
Electrophilic Aromatic Substitution, Wiley, New York,
1990; c) J. A. Zoltewicz, Top. Curr. Chem. 1975, 59, 33.
[3] a) S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901.
and references cited therein; b) M. Shanmugasundar-
am, M. S. Wu, C. H. Cheng, Org. Lett. 2001, 3, 4233;
c) S. Sato, H. Isobe, T. Tanaka, T. Ushijima, E. Naka-
mura, Tetrahedron 2005, 61, 11449; d) D. Y. Park, S.
Gowrisankar, J. N. Kim, Tetrahedron Lett. 2006, 47,
6641; e) C. G. Yan, X. K. Song, Q. F. Wang, J. Sun, U.
Siemeling, C. Bruhn, Chem. Commun. 2008, 1440.
[4] a) J. A. Marshall, Chem. Rev. 1996, 96, 31; b) Y. Yama-
moto, U. Radhakrishnan, Chem. Soc. Rev. 1999, 28,
199; c) R. Zimmer, C. U. Dinesh, E. Nandanan, F. A.
Khan, Chem. Rev. 2000, 100, 3067; d) A. S. K. Hashmi,
Angew. Chem. 2000, 112, 3737; Angew. Chem. Int. Ed.
2000, 39, 3590; e) S. Saito, M. M. Salter, V. Gevorgyan,
N. Tsuboya, K. Tando, Y. Yamamoto, J. Am. Chem.
Soc. 1996, 118, 3970.
Experimental Section
General Procedure for cycloaromatization Reaction
(Entry 6, Table 2)
PtCl4 (4.5 mg, 1.25 mmol%) and TBSOTf (trifluorometh-
anesulfonic acid tert-butyldimethylsilyl ester, 4.0 mg,
1.5 mmol%) were added into a solution of alcohol 6a
(enyne substrate) (45 mg, 0.25 mmol) in toluene (5 mL).
The resulting mixture was stirred for 12 h at 808C. The reac-
tion mixture was cooled to room temperature and washed
with saturated aqueous NaHCO3 solution (5 mL) and brine
(5 mL), dried over (Na2SO4) and concentrated under
vacuum. Flash column chromatography (silica gel, PE:
EtOAc 50:1) afforded 6 as a colorless oil; yield: 29 mg
(71%).
[5] a) Y. Izawa, D. Pun, S. S. Stahl, Science. 2011, 333, 209;
b) T. Diao, S. S. Stahl, J. Am. Chem. Soc. 2011, 133,
14566; c) T. Diao, T. J. Wadzinski, S. S. Stahl, Chem.
Sci. 2012, 3, 887; d) Y. Izawa, C. W. Zheng, S. S. Stahl,
Angew. Chem. 2013, 125, 3760; Angew. Chem. Int. Ed.
2013, 52, 3672; e) K. Manna, T. Zhang, W. B. Lin, J.
Am. Chem. Soc. 2014, 136, 6566.
[6] a) W. A. L. Otterlo, C. B. Koning, Chem. Rev. 2009,
109, 3743 and references cited therein; b) S. Monfette,
D. E. Fogg, Chem. Rev. 2009, 109, 3783; c) K. Yoshida,
T. Toyoshima, T. Imamoto, Chem. Commun. 2007,
3774; d) H. Takahashi, K. Yoshida, A. Yanagisawa, J.
Org. Chem. 2009, 74, 3632; e) K. Yoshida, Y. Shishi-
kura, H. Takahashi, T. Imamoto, Org. Lett. 2008, 10,
Acknowledgements
We would like to thank the Science & Technology Commis-
sion of Shanghai municipality (grant number: 14401900600)
and Basilea Pharmaceutica China Ltd. for their generous fi-
nancial support
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Shuyan Zheng et al.
2777; f) M. J. Geier, M. R. GagnØ, J. Am. Chem. Soc.
2014, 136, 3032; g) J. A. Feducia, A. N. Campbell,
M. Q. Doherty, M. R. GagnØ, J. Am. Chem. Soc. 2006,
128, 13290.
[11] a) G. W. Daub, D. A. Griffith, Tetrahedron Lett. 1986,
27, 6311; b) J. Poulin, C. M. GrisØ-Bard, L. Barriault,
Angew. Chem. 2012, 124, 2153; Angew. Chem. Int. Ed.
2012, 51, 2111.
[7] a) B. M. Trost, Acc. Chem. Res. 1990, 23, 34; b) B. M.
Trost, Angew. Chem. 1995, 107, 285; Angew. Chem. Int.
Ed. 1995, 34, 259; c) B. Schmidt, Angew. Chem. 2003,
115, 5146; Angew. Chem. Int. Ed. 2003, 42, 4996;
d) I. J. S. Fairlamb, Angew. Chem. 2004, 116, 1066;
Angew. Chem. Int. Ed. 2004, 43, 1048; e) I. Nakamura,
Y. Yamamoto, Chem. Rev. 2004, 104, 2127; f) L. Zhang,
J. Sun, S. A. Kozmin, Adv. Synth. Catal. 2006, 348,
2271.
[8] a) N. Miyauar, A. Suzuki, Chem. Rev. 1995, 95, 2457;
b) A. J. Suzuki, Organomet. Chem. 1999, 576, 147; c) O.
Navarro, R. A. Kelly, S. P. Nolan, J. Am. Chem. Soc.
2003, 125, 16194.
[9] a) A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116,
3396; Angew. Chem. Int. Ed. 2004, 43, 3333; b) R.
Martin, S. L. Buchwald, J. Am. Chem. Soc. 2007, 129,
3844.
[10] a) A. Scarso, M. Colladon, P. Sgarbossa, C. Santo,
R. A. Michelin, G. Strukul, Organometallics 2010, 29,
1487.
[12] a) M. MØndez, M. P. MuÇoz, C. Nevado, D. J. CØrdenas,
A. M. Echavarren, J. Am. Chem. Soc. 2001, 123, 10511.
[13] a) S. Oi, I. Tsukamoto, S. Miyano, Y. Inoue, Organome-
tallics 2001, 20, 3704; b) E. Mainetti, V. Mouri›s, L.
Fensterbank, M. Malacria, J. Marco-Contelles, Angew.
Chem. 2002, 114, 2236; Angew. Chem. Int. Ed. 2002, 41,
2132; c) N. Chatani, H. Inoue, T. Kotsuma, S. Murai, J.
Am. Chem. Soc. 2002, 124, 10294.
[14] a) T. Miura, N. Iwasawa, J. Am. Chem. Soc. 2002, 124,
518; b) H. C. Shen, S. Pal, J. J. Lian, R. S. Liu, J. Am.
Chem. Soc. 2003, 125, 15762; c) K. Imamura, E. Yoshi-
kawa, V. Gevorgyan, Y. Yamamoto, Tetrahedron Lett.
1999, 40, 4081.
[15] a) J. W. Dankwardt, Tetrahedron Lett. 2001, 42, 5809;
b) A. Fürstner, V. Mamane, J. Org. Chem. 2002, 67,
6264; c) B. Martín-Matute, C. Nevado, D. J. Cµrdenas,
A. M. Echavarren, J. Am. Chem. Soc. 2003, 125, 5757.
2808
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