Intramolecular triple heck reaction. An efficient entry to fused tetracycles with a benzene core

Article abstract of DOI:10.1021/jo0258094

Twelve examples of 1,3,5-tribromo-2,4,6-trienylbenzenes were easily synthesized by alkylation, etherification, and amination methods. Under conditions A and B, a series of tetracycles with a benzene core, i.e., fused 5,6,6-, 6,6,6-, and 6,6,7-tetracyclic compounds, were prepared efficiently via this intramolecular triple Heck reaction protocol.

Full text of DOI:10.1021/jo0258094

SCHEME 1
In tr a m olecu la r Tr ip le Heck Rea ction . An
Efficien t En tr y to F u sed Tetr a cycles w ith a
Ben zen e Cor e
Shengming Ma* and Bukuo Ni
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
masm@pub.sioc.ac.cn
Received April 11, 2002
Abstr a ct: Twelve examples of 1,3,5-tribromo-2,4,6-trienyl-
benzenes were easily synthesized by alkylation, etherifica-
tion, and amination methods. Under conditions A and B, a
series of tetracycles with a benzene core, i.e., fused 5,6,6-,
6,6,6-, and 6,6,7-tetracyclic compounds, were prepared ef-
ficiently via this intramolecular triple Heck reaction protocol.
SCHEME 2
Construction of two or more rings in one synthetic
operation is an attractive synthetic strategy. Recently,
we have developed a protocol of bicyclic carbopalladation,
which can be efficiently applied to the synthesis of fused
bicyclic compounds.1 Over the past decade, carbopalla-
dation of unsaturated carbon-carbon bonds has become
one of the most powerful tools for the synthesis of
stereodefined substituted alkenes and cyclic compounds
via intermolecular and intramolecular reactions.2 The
latter has emerged as a potent new synthetic strategy
for construction of oligocyclic systems from acyclic pre-
cursors in just one step.3 Recently, carbon-rich com-
pounds, such as conjugated polyaromatics and dendrim-
ers, have received increasing attention due to their
superior electronic, magnetic, or catalytic properties, thus
effort has been spent in the synthesis of highly symmetric
triannulated benzenes from ketones.4 So far, there is no
report on the synthesis of these analogous compounds
using intramolecular triple Heck reaction. Here, we wish
to report an efficient and versatile general method of the
synthesis of triannulated benzenes. By this protocol,
triannulated benzenes with different ring sizes as well
SCHEME 3
as attached functional groups can be simultaneously
constructed from the corresponding trialkene precursors
in just “one shot”.
Syn th esis of Sta r tin g Ma ter ia ls. 1,3,5-Tribromo-
2,4,6-tris(bromomethyl)benzene (2), which could be syn-
thesized by bromination of 1,3,5-tribromo-2,4,6-trimeth-
ylbenzene (3)5 with NBS, was used as the key building
block for the synthesis of the starting materials 1
(Scheme 1).
1,3,5-Tribromobenzenes having three equal CdC bond
fragments, i.e., 5 and 7, were prepared by the treatment
of 2 with dimethyl 2-allyl malonate 4 and allylmagnesium
bromide 6, respectively (Scheme 2). Triethers 8, 9, and
(S,S,S)-9 were prepared by the reaction of 2 with sodium
2-alkenoxides (Scheme 3).
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447. (d) Negishi, E.-i.; Cope´ret, C.; Ma, S.; Liu, F. Chem. Rev. 1996,
96, 365. (e) Ojima, I.; Tzamarioudaki, M.; Li, Z.-Y.; Donovan, R. J .
Chem. Rev. 1996, 96, 635. (f) Cabri, W.; Candiani, I. Acc. Chem. Res.
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2328. (c) Grigg, R.; Dorrity, M. J .; Malone, J . F.; Sridharan, V.;
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Lamaty, F.; Negishi, E.-i. J . Org. Chem. 1989, 54, 2507. (e) Carpenter,
N. E.; Kucera, D. J .; Overman, L. E. J . Org. Chem. 1989, 54, 5846. (f)
Grigg, R.; Sukirthalingam, S.; Sridharan, V. Tetrahedron Lett. 1991,
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Elmorsy, S. S.; Pelter, A.; Smith, K. Tetrahedron Lett. 1991, 32, 4175.
1,3,5-Tribromobenzenes 12, (S,S)-12, 13, and 15 with
different CdC bond-containing fragments were prepared
(5) Engman, L.; Hellberg, J . S. E. J . Organomet. Chem. 1985, 296,
357.
10.1021/jo0258094 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/23/2002
8280
J . Org. Chem. 2002, 67, 8280-8283

which was observed in many cases.7 The best results were
obtained with 10 mol % Pd(OAc)2, K2CO3 (6 equiv), and
40 mol % PPh3 in CH3CN under refluxing for 32 h
affording fused tetracyclic product 23 in 87% yield (entry
13, Table 1). Here, it is interesting to note that the
reaction catalyzed by Pd(OAc)2 is better than that with
Pd(PPh3)4, probably due to the presence of OAc-.8
SCHEME 4
Th e Scop e of Tr ia n n u la tion Rea ction of Su bsti-
tu ted Tr ibr om oben zen es. Having established the stan-
dard reaction conditions for triannulation reaction of 5,
we tried to investigate the scope and cyclization patterns
of this triannulation reaction. Some typical examples are
summarized in Table 2. From Table 2, it is obvious that
a series of tetracycles, i.e., fused 5,6,6- (entry 10, Table
2), 6,6,6- (entries 1-9, Table 2), and 6,6,7-triannulated
benzenes (entry 11, Table 2), can be efficiently prepared.
To study the stereochemistry of products with chiral
centers 25 and 26, the optically active starting materials
(S,S,S)-9 and (S,S)-12 were cyclized under similar reac-
1
tion conditions. The H and 13C NMR data of correspond-
ing products, i.e., (S,S,S)-25 and (S,S)-26, led us to assign
the complete stereochemistry of each diastereomer of 25
and 26 (entries 2-5, Table 2).
To explore the influence of steric effects on the reactiv-
ity of CdC double bonds, the triannulation reaction of
three additional precursors in which the double bonds
were substituted with one phenyl or methoxycarbonyl
group or two methoxycarbonyl groups was studied.
Product 29 could be synthesized in CH3CN under condi-
tions A in 35% yield, respectively (entry 8, Table 2), while
under conditions B, 21 gives tetracyclic product 30 in
50% yield together with tricyclic product 31 in 11%
yield (eq 1). The stereochemistry of the substituted double
by the etherification of 3-buten-2-ol, (S)-3-buten-2-ol,6 or
alkylation of 4 and 14 with 10, which was prepared from
the etherification of 2 with allylic alcohols in 29% yield.
In this reaction, 11 was also isolated in 30% yield
(Scheme 4).
Compounds 18-22 were easily synthesized by alkyla-
tion, etherification, or amination starting with the com-
mon starting precursor 11 as depicted in Scheme 5.
An n u la t ion of 1,3,5-Tr ib r om o-2,4,6-t r ien ylb en -
zen e. 1,3,5-Tribromo-2,4,6-tris (2′,2′-bis(methoxycarbonyl)-
pent-4′-enyl)benzene (5) was used as the first substrate
to test the triannulation reaction under different reaction
conditions and the results are summarized in Table 1.
As shown in Table 1, when a mixture of 5 and Et3N in
toluene was stirred in the presence of 10 mol % Pd2-
(dba)3-CHCl3 at 85-90 °C for 43 h, the desired tetracy-
clic compound 23 was not formed in a detectable yield
(entry 1, Table 1). Using Et3N as the base and Pd(OAc)2
as the catalyst, the reaction in DMF did not afford
tetracycle 23 (entry 2, Table 1). Under the catalysis of
Pd(OAc)2, using CH3CN as the solvent and Et3N as the
base, 5 cyclized to afford tetracyclic product 23 in low
yields (entries 3 and 4, Table 1). However, 23 was formed
in moderate yields when using 10 mol % Pd(PPh3)4 as
the catalyst, K2CO3 or Et3N as the base, and DMF or CH3-
CN as the solvent (entries 9-12, Table 1). The simplicity
(7) For isomerization see: (a) Larock, R. C.; Babu, S. Tetrahedron
Lett. 1987, 28, 5291. (b) Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L.
S. J . Org. Chem. 1980, 45, 2709. (c) Wu, G.; Lamaty, F.; Negishi, E.-i.
J . Org. Chem. 1989, 54, 2507. For the suppression of isomerization by
silver salt additives, see: (d) Abelman, M. M.; Oh, T.; Overman, L. E.
J . Org. Chem. 1987, 52, 4130. (e) Abelman, M. M.; Overman, L. E. J .
Am. Chem. Soc. 1988, 110, 2328. (f) Larock, R. C.; Song, H.; Baker, B.
E.; Gong, W. H. Tetrahedron Lett. 1988, 29, 2919. (g) Larock, R. C.;
Gong, W. H. J . Org. Chem. 1990, 55, 407. (h) J effery, T. Tetrahedron
Lett. 1993, 34, 1133. (i) Sato, Y.; Sodeoka, M.; Shibasaki, M. J . Org.
Chem. 1989, 54, 4738. (j) J effery, T. Tetrahedron Lett. 1991, 32, 2121.
(k) Nilsson, K.; Hallberg, A. J . Org. Chem. 1992, 57, 4015. (l) Nilsson,
K.; Hallberg, A. J . Org. Chem. 1990, 55, 2464. For the suppression of
isomerization by thallium salt, see: (m) Carfagna, C.; Musco, A.;
Sallese, G. J . Org. Chem. 1991, 56, 261. (n) Grigg, R.; Loganathan, V.;
Santhakumar, V.; Sridharan, V.; Teasdale, A. Tetrahedron Lett. 1991,
32, 687.
1
of the H NMR and 13C NMR spectra led us to come to
the conclusion that there was no isomerization of double
bonds forming thermodynamically more favored alkenes,
(6) Balmer, E.; Germain, A.; J ackson, W. P.; Lygo, B. J . Chem. Soc.,
Perkin Trans. 1 1993, 399.
J . Org. Chem, Vol. 67, No. 23, 2002 8281

SCHEME 5a
a
Conditions: (a) Et2O-THF, rt, 0.5 h; (b) NaH, THF-DMF, rt, 5.5 h; (c) NaH, THF, rt, 14 h; (d) NaH, THF, rt, 12 h; (e) NaH, THF, rt,
4.5 h.
TABLE 1. Tr ia n n u la tion of 5 u n d er Differ en t Rea ction Con d ition s
PPh3
(%)
T
(°C)
time
(h)
yield of
23 (%)
entry
catalysta
solvent
base
1
2
3
4
5
6
7
8
9
10
11
12
13
10 mol % A
10 mol % B
10 mol % B
10 mol % B
5 mol % B
toluene
DMF
Et3N
Et3N
Et3N
0
40
40
40
40
20
40
20
0
0
0
0
40
85-90
85-90
reflux
reflux
reflux
reflux
reflux
reflux
85-90
85-90
reflux
reflux
reflux
43
38
51
22
63
63
35
41
45
45
45
45
32
0
0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
15
33
76
59
89
64
42
64
49
40
87
Et3Nb
K2CO3
K2CO3
Cs2CO3
5 mol % B
10 mol % B
10 mol % B
10 mol % C
10 mol % C
10 mol % C
10 mol % C
10 mol % B
c
K2CO3
Et3N
K2CO3
Et3N
K2CO3
K2CO3
DMF
CH3CN
CH3CN
CH3CN
a
b
A ) Pd2(dba)3‚CHCl3; B ) Pd(OAc)2; C ) Pd(PPh3)4. AgNO3 (1 equiv) was added. c n-Bu4NBr (1 equiv) was added.
bond product 29 was unambiguously detemined by the
X-ray diffraction study.9 From precursor 15, in which
the two CdC bonds were substituted with methoxycar-
bonyl groups, the tetracyclic product 32 can also be
prepared in reasonable yield (entry 9, Table 2). The
configurations of two CdC bonds were determined by
the NOE study.
Under conditions B, the precursor 18 gives 5,6,6-
triannulated benzene 33 in 61% yield (entry 10, Table
2). When 22 was submitted to conditions A, the corre-
(9) Crystal data for 29: C25H26O8, mw ) 454.46, triclinic, space
group P1h, Mo KR, final R indices [I > 2σ(I)], R1 ) 0.0469, wR2 )
0.0875, a ) 8.9173(8) Å, b ) 9.8623(9) Å, c ) 14.4631(13) Å, R )
81.585(2)°, â ) 83.561(2)°, γ ) 64.417(2)°, V ) 1133.20 (18) Å3, T )
293 (2) K, Z ) 2, reflections collected/unique 6797/4840 [R(int) )
0.0363], no observation (I >2.0σ(I)), parameters 403.
(8) Amatore, C.; J utand, A. Acc. Chem. Res. 2000, 33, 314.
8282 J . Org. Chem., Vol. 67, No. 23, 2002

TABLE 2. Syn th esis of Tr ia n n ela ted Ben zen esa
triple Heck reaction. With optically active starting com-
pounds optically active tetracyclic compounds were easily
prepared. Due to the easy availability of the starting
materials, the potentials of the products, and the high
stereoselectivity, this methodology will show its utility
in organic synthesis.
sponding tetracyclic product 34 also formed smoothly in
49% yield (entry 11, Table 2).
Apart from the results given above, we failed to
construct fused 5,5,5-triannulated benzene 35 from 7,
probably due to the ring constrain of the benzo-fused five-
membered cycle (eq 2). This reaction was complicated by
the complete consumption of 7.
Ack n ow led gm en t. Financial support from the Ma-
jor State Basic Research Development Program (Grant
No. G2000077500) and the National NSF of China (No.
20172060) is greatly appreciated. Shengming Ma is the
recipient of the 1999 Qiu Shi Award for Young Scientific
Workers issued by Hong Kong Qiu Shi Foundation of
Science and Technology (1999-2003).
Su p p or tin g In for m a tion Ava ila ble: Experimental Sec-
tion and the analytical data for all the starting materials and
products, the ORTEP presentation of 29, and the NOE results
of 32. This material is available free of charge via the Internet
at http://pubs.acs.org.
In conclusion, a new and highly convenient triannu-
lation reaction was developed. By this protocol, a series
of triannulated benzenes, i.e., 5,6,6-, 6,6,6-, and 6,6,7-
tetracyclic compounds, can be efficiently prepared via a
J O0258094
J . Org. Chem, Vol. 67, No. 23, 2002 8283