A short three-component synthesis of tricyclic compounds

Article abstract of DOI:10.1055/s-2003-36795

A facile reaction sequence, consisting of a palladium-catalyzed Sonogashira coupling, a cobalt-catalyzed Diels - Alder reaction and a subsequent cyclization initiated by a bromine-lithium exchange reaction, allows a three-component synthesis of tricyclic

Full text of DOI:10.1055/s-2003-36795

LETTER
241
A Short Three-Component Synthesis of Tricyclic Compounds
T
hree-Component
e
Synthesis
o
r
f
Tricyc
h
lic Compoun
a
ds rd Hilt,* Tobias J. Korn, Konstantin I. Smolko
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax +49(6421)2825677; E-mail: Hilt@chemie.uni-marburg.de
Received 30 October 2002
I
OTs
Abstract: A facile reaction sequence, consisting of a palladium-
catalyzed Sonogashira coupling, a cobalt-catalyzed Diels–Alder re-
action and a subsequent cyclization initiated by a bromine-lithium
exchange reaction, allows a three-component synthesis of tricyclic
compounds. Thereby, structurally different functionalized com-
pounds can be generated when functionalized dihalo-arenes, tosyl-
FG
n
Br
FG
+
Br
OTs
n
ated alkynols and substituted 1,3-dienes are used as starting
materials.
R1
R1
R2
R2
Key words: alkynes, catalysis, cobalt, cyclization, Diels–Alder re-
actions
FG
FG
OTs
Br
Short reaction sequences with a high degree of variability
allow the preparation of a large number of complex mol-
ecules from commercially available or easily prepared
starting materials in a very efficient way in a short period
of time. When transition metal-catalyzed reactions are in-
volved, many functional groups can be tolerated in each
step to avoid lengthy and tedious protection-deprotection
steps. Herein, we wish to report a short reaction sequence
involving two transition metal-catalyzed reactions fol-
lowed by a stoichiometric bromine-lithium exchange re-
action for the synthesis of tricyclic ring systems. The
general design for the reaction sequence is outlined below
(Scheme 1). The chemoselective Sonogashira coupling
reaction of bromo-iodo arenes or dibromo-heteroarenes
generates the key alkyne intermediates, bearing a sterical-
ly bulky (hetero)aryl substituent and a sterically less-de-
manding alkyl substituent. A regioselective cobalt-
catalyzed neutral Diels–Alder reaction with symmetrical
and unsymmetrical 1,3-dienes was envisioned in order to
generate ring C of the tricyclic compounds and to bring
the aryl bromide and the tosylate group into proximity. A
fast bromine-lithium exchange reaction generates the
aryllithium nucleophile, which displaces the tosylate to
complete the intramolecular ring closure reaction and
forms ring B.
n
n
Scheme 1
corresponding propargylic amines in moderate to good
yields.2 Besides diethylamine (R = Et 92%), other second-
ary amines can also be used, as shown in Scheme 2.
R
OTs
I
N
R
Pd(PPh3)2Cl2
CuI / HNR2
+
toluene, 20 °C
16–24 h
Br
Br
MeO
N
N
OMe
66%
84%
89%
Cl
N
N
94%
F3C
Scheme 2
The Sonogashira coupling reaction of bromo-iodoben-
zene derivatives with different alkynols and their subse-
quent reaction with tosyl chloride gave the corresponding
products in excellent yields and with complete chemose-
lectivity, following standard procedures.1 However, when
the coupling reaction was performed with the tosylated
alkynols (especially propynol derivatives, Scheme 2), the
secondary amine bases displaced the tosylates to give the
When tertiary amine bases such as triethylamine were
used as a substitute for diethylamine, the amount of the
desired tosylated alkynol did not overcome the yields for
the reversed synthetic protocol (see Scheme 3). There-
fore, the Sonogashira coupling reactions were performed
with the free alcohols, which were subsequently tosyl-
ated.3
The key step of the reaction sequence, our recently de-
scribed cobalt-catalyzed neutral Diels–Alder reaction of
internal alkynes with 1,3-dienes was initiated by zinc re-
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2002,0,02,0241,0243,ftx,en;G30702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

242
G. Hilt et al.
LETTER
OH
n
OTs
I
1. Pd(PPh3)2Cl2, CuI, HNEt2
n
+
toluene, 20 °C, 2-20 h
n
2
3
4
1. 2 tBuLi, THF, –95 °C, 81%
2. TsCl, NEt3, CH2Cl2
20 °C, 16-24 h
89%
74%
61%
Br
Br
2. DDQ, 77%
OTs
Br
Scheme 3
duction of the cobalt(II)-dppe complex. In these cases, the
usual reductant of choice, tetrabutylammonium borohy-
dride, gave some triple bond reduction as a side reaction,
but this was avoided when zinc powder was used as the re-
ducing agent.4 The reaction of 2,3-dimethyl-1,3-butadi-
ene (DMBD) and isoprene as simple 1,3-diene test
systems gave the desired dihydroaromatic products in
good yields (Scheme 4) after 14–20 h reaction time at
room temperature.5 In the case of isoprene, the products
were generally formed as an 80:20 mixture of regioiso-
mers where the major product has the methyl group of the
isoprene and the aromatic ring substituent in a 1,4-rela-
tionship.
62%
82%
MeO
S
75%
39%
MeO
Scheme 5
low temperature (–100 °C) and subsequent warming to
room temperature.8 Although the formation of larger ring
systems with a simple SN2 reaction should be more and
more disfavored. Nonetheless, to the best of our know-
ledge, for the first time seven and eight membered ring
systems were generated using the Parham cyclization
methodology and the tetrahydro-dibenzo[a,c]cyclohep-
tene and the hexahydro-dibenzo-[a,c]cyclooctene9 deriv-
atives were isolated in good yields.
OTs
n
CoBr2(dppe), DMBD
Zn, ZnBr2, CH2Cl2, rt
Br
OTs
Br
n
n =
2
3
4
94%
98%
95%
Scheme 4
At this point the stage was set for the formation of ring B.
The final reaction, a bromine-lithium exchange reaction in
the presence of a tosylate, has no precedent in the litera-
ture. However, similar Parham-type cyclization reactions
are described with several functional groups such as ep-
oxides or halides as electrophiles.6 Under these circum-
stances, we were delighted to see that the exchange
reaction proceeded smoothly in THF at –95 °C to produce
the tricyclic phenanthrene derivatives. The products,
which can be isolated as the dihydroaromatic compounds
in good yield, accompanied by some air-oxidized aromat-
ic side products, can be oxidized with various oxidizing
agents, such as DDQ, to the aromatic compound in good
overall yield.7 Following this protocol, several functional-
ized and specifically substituted phenanthrene deriva-
tives, as well as heterocyclic tricyclic compounds, could
be generated (Scheme 5, yields are given for the cycliza-
tion step) in good overall yields.
2 t-BuLi, Et2O
–100 °C
67%
Br
OTs
2 t-BuLi, Et2O
–100 °C
70%
Br
OTs
Scheme 6
In summary, we have developed a new protocol for the
generation of various tricyclic ring systems in a short re-
action sequence. Further variations with more highly
functionalized iodo arene derivatives, substituted
alkynols of different chain lengths, and functionalized
1,3-dienes can be envisioned for the synthesis of a wide
range of compounds. Such investigations are currently
underway in our laboratory.
An even higher degree of flexibility could be realized
when the reaction sequence was performed with higher
homologues of the alkynols leading to tricyclic com-
pounds where ring B consists of a seven- or eight-mem-
bered ring as shown in Scheme 6. In these cases, the
bromine-lithium exchange reaction worked only sluggish-
ly in THF. However, in diethyl ether the desired products
were formed rapidly upon bromine-lithium exchange at
Synlett 2003, No. 2, 241–243 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Three-Component Synthesis of Tricyclic Compounds
243
temperature. After water addition (1.0 mL), the reaction
mixture was extracted with diethyl ether (4 × 50 mL) and the
combined organic phases were dried over MgSO4. The
solvent was removed and the crude product was purified by
column chromatography (SiO2, pentane) affording the
desired product (54 mg, 0.23 mmol, 82%) as a colorless
crystalline solid.
Acknowledgment
We thank the German Science Foundation (DFG-Emmy Noether-
Program) for financial support.
References
1H NMR (300 MHz, CDCl3): δ = 7.13 (d, J = 8.0 Hz, 1 H),
6.75–6.65 (m, 2 H), 3.81 (s, 3 H), 2.94 (t, J = 7.1 Hz, 2 H),
2.84–2.70 (m, 4 H), 2.20 (t, J = 8.3 Hz, 2 H), 1.77 (s, 3 H),
1.72 (s, 3 H); 13C NMR (75 MHz, CDCl3): δ = 157.9, 137.2,
128.8, 128.5, 123.9, 123.5, 122.7, 122.6, 113.6, 110.7, 55.2,
39.0, 33.3, 28.5, 28.1, 18.5, 18.1; MS m/z (%) = 240 (M+,
91), 238(75), 225(100), 210(26), 165(20); HRMS calcd for
C17H20O: m/z = 240.1514, found: m/z = 240.1522. (b) For a
recent flexible synthesis of phenanthrene derivatives see:
Fürstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264; and
references cited therein.
(1) (a) Sonogashira, K. In Comprehensive Organic Synthesis,
Vol. 3; Trost, B.; Flemming, I.; Pattenden, G., Eds.;
Pergamon Press: New York, 1991, 521. (b) Sonogashira, K.
In Metal-catalyzed Cross-coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, 203.
(2) Besides secondary amines, primary amines such as tert-
butylamine, also gave the propargylic amine product in this
three component reaction, albeit in lower yields (46%).
(3) (a) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte,
U. P.; Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1,
447. (b) The tosylation of propargylic alcohols (n = 1) under
these conditions gave the desired products only in moderate
yields (up to 25%) accompanied with the corresponding
propargylic chloride in up to 35% yield and recovered
starting material.
(8) Schlosser, M. In Organometallics in Synthesis; Wiley:
Chichester, 1994, 129–133.
(9) Typical procedure: Preparation of 1,4,5,6,7,8-hexahydro-
2,3-dimethyl-dibenzo[a,c]cyclooctene (Scheme 6, structure
at the bottom): To 4-[2-(2-bromophenyl)-4,5-dimethyl-1,4-
cyclohexadien-1-yl]butyl 4-methylbenzenesulfonate (1.282
g, 2.62 mmol) in dry diethyl ether (5.0 mL) at –100 °C tert-
butyllithium (3.74 mL, 1.4 M in THF, 5.24 mmol, 2.0 equiv)
was added slowly, such that the reaction temperature did not
exceed –80 °C. Then, the reaction mixture was allowed to
warm up to room temperature. After water (2.0 mL) was
added, the reaction mixture was extracted with diethyl ether
(4 × 50 mL) and the combined organic phases were dried
over MgSO4. The solvent was removed and the crude
product was purified by column chromatography (SiO2,
pentane) affording the desired product (437 mg, 1.84 mmol,
70%) as a colorless oil.
(4) For recent cobalt(I)-catalyzed Diels–Alder reactions see:
(a) Hilt, G.; Lüers, S.; Polborn, K. Isr. J. Chem. 2001, 41,
317. (b) Hilt, G.; Smolko, K. I. Synthesis 2002, 686.
(c) Hilt, G.; Smolko, K. I. Synlett 2002, 1081.
(5) Typical procedure: Preparation of 3-[2-(2-bromophenyl)-
4,5-dimethyl-1,4-cyclohexadien-1-yl]propyl 4-
methylbenzenesulfonate (Scheme 4, n = 3): To 5-(2-
bromophenyl)-4-pentynyl-4-methylbenzenesulfonate (321
mg, 0.82 mmol) in dry CH2Cl2 (2.0 mL) were added
CoBr2(dppe) (40 mg, 0.07 mmol, 9 mol%), 2,3-dimethyl-
1,3-butadiene (145 mg, 1.77 mmol, 2.0 equiv), zinc (300 mg,
4.69 mmol, 5.7 equiv) and ZnBr2 (100 mg, 0.45 mmol, 55
mol%) under nitrogen atmosphere. The reaction mixture was
stirred at room temperature overnight. The crude product
was purified by column chromatography (SiO2,
1H NMR (300 MHz, C6D6): δ = 7.22–7.08 (m, 4 H), 3.16–
3.00 (m, 1 H), 2.90–2.75 (m, 1 H), 2.70–2.40 (m, 4 H), 1.98–
1.80 (m, 2 H), 1.77 –1.49 (m, 8 H), 1.44–1.11 (m, 2 H); 13
C
pentane:diethyl ether = 2:1) affording the desired product
(381 mg, 0.80 mmol, 98%) as a colorless oil.
NMR (75 MHz, C6D6): δ = 142.2 (Cq), 141.5(Cq), 132.2(Cq),
129.7 (CH), 128.5 (Cq), 127.4 (CH), 127.1 (CH), 125.8
(CH), 123.7 (Cq), 123.3 (Cq), 38.8 (CH2), 38.6 (CH2), 33.5
(CH2), 32.1 (CH2), 30.4 (CH2), 24.2 (CH2), 18.2 (CH3), 18.1
(CH3); MS m/z (%) = 238 (M+, 100), 223(18), 195(50),
181(57), 165(22); HRMS calcd for C18H22: m/z = 238.1721,
found: m/z = 238.1714.
Analytical data for 1,4,6,7-tetrahydro-2,3-dimethyl-
dibenzo[a,c]cycloheptene (Scheme 6, structure at the top):
1H NMR (300 MHz, CDCl3): δ = 7.25–7.02 (m, 4 H), 2.96–
2.87 (m, 2 H), 2.83–2.74 (m, 2 H), 2.48 (t, J = 7.1 Hz, 2 H),
2.10–1.98 (m, 2 H), 1.77 (t, J = 6.7 Hz, 2 H), 1.64 (s, 6 H);
13C NMR (75 MHz, C6D6): δ = 142.2 (Cq), 140.3 (Cq), 132.4
(Cq), 128.6 (CH), 128.2 (Cq), 126.1 (CH), 125.9 (CH), 125.4
(CH), 123.8 (Cq), 123.2 (Cq), 39.3 (CH2), 36.9 (CH2), 33.6
(CH2), 32.3 (CH2), 29.8 (CH2), 18.3 (CH3), 18.1 (CH3); MS
m/z (%) = 224 (M+, 100), 209(51), 195(24), 181(38),
165(22), 121(27); HRMS calcd for C17H20: m/z = 224.1565,
found: m/z = 224.1572.
1H NMR (300 MHz, C6D6): δ = 7.70–7.64 (m, 2 H), 7.39 (dd,
J = 8.4, 1.1 Hz, 1 H), 7.00–6.85 (m, 2 H), 6.74–6.64 (m, 3
H), 4.77–3.63 (m, 2 H), 3.02–2.84 (m, 1 H), 2.56–2.34 (m, 3
H), 1.82 (s, 3 H), 1.80–1.35 (m, 10 H); 13C NMR (75 MHz,
C6D6): δ = 143.9, 143.6, 134.6, 133.0, 131.8, 130.6, 130.4,
129.7, 128.4, 128.1, 127.8, 123.6, 123.0, 122.8, 70.1, 39.4,
36.6, 29.4, 27.2, 21.1, 18.2, 17.9; MS m/z (%) = 474 (M+, 2),
208(15), 194(24), 179(12), 91(11), 74(100); HRMS calcd
for C24H27BrO3S: m/z = 474.0864, found: m/z = 474.0811.
(6) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15,
300.
(7) (a) Typical procedure: Preparation of 7-methoxy-2,3-
dimethyl-1,4,9,10-tetrahydrophenanthrene (Scheme 5): To
2-[2-(2-bromo-4-methoxyphenyl)-4,5-dimethyl-1,4-
cyclohexadien-1-yl]ethyl 4-methylbenzenesulfonate (134
mg, 0.27 mmol) in anhyd THF (5.0 mL) at –90 °C was added
tert-butyllithium (0.4 mL, 1.7 M in THF, 0.56 mmol, 2.1
equiv) in one portion under nitrogen atmosphere. The
reaction mixture was allowed to warm up to room
Synlett 2003, No. 2, 241–243 ISSN 0936-5214 © Thieme Stuttgart · New York