One-pot synthesis of fused tricyclic heterocycles with quaternary carbon stereocenter by sequential pauson-khand reaction and formal [3+3] cycloaddition

Article abstract of DOI:10.1002/chem.200801453

A novel Rh_I-catalyzed formal cycloaddition reaction of 1-ene-6,8-diynes leading to fused bicyclic 2-(alkyn-1-yl) enones in moderate to good yields was investigated. A solution of enediyne was refluxed under a positive pressure of CO. The reaction was complete in 24 hours, as determined by thin-layer chromatography. The residue was purified by column chromatography on silica gel. The solvent was removed in vacuo and the residue was dissolved in DMF. A solution of acetylacetone in DMF and K₂CO₃ were added to the reaction mixture, which was then stirred at room temperature. It was observed that all the three starting materials are readily available and the cycloadducts are readily converted into more complex ring systems with many convertible functional groups.

Full text of DOI:10.1002/chem.200801453

COMMUNICATION
DOI: 10.1002/chem.200801453
One-Pot Synthesis of Fused Tricyclic Heterocycles with Quaternary Carbon
Stereocenter by Sequential Pauson–Khand Reaction and Formal [3+3]
Cycloaddition
Liyan Fan,[c] Wanxiang Zhao,[a] Weihua Jiang,[a] and Junliang Zhang*[a, b]
Dedicated to Professor Xiyan Lu on the occasion of his 80th birthday
Using transition-metal-catalyzed annulation reactions to
construct complex polycyclic systems represents a powerful
strategy for target-directed synthesis and is thus of continual
interest to the synthetic community.[1] Among numerous
methods which have been developed, the Pauson–Khand an-
nulation reaction,[2] in which tethered enynes undergo a
formal [2+2+1] cycloaddition reaction with carbon monox-
ide to afford bicyclic cyclopentenones, has been a powerful,
reliable and routine transformation for the synthesis of com-
plex polycyclic cyclopentane-containing molecules.[3]
Furthermore, in recent years, 2-(alkyn-1-yl)-2-enones have
been shown to be very useful, reactive, and versatile build-
ing blocks to furnish not only highly substituted heterocycles
such as furans[4,5a] and 4H-pyrans,[5b] but also polyfunctional
electron-deficient 1,3-dienes and allenes.[5b] To study how
fused rings affect the reactivity of 2-(alkyn-1-yl)-2-enones,
we turned our attention to the efficient synthesis of fused bi-
cyclic 2-(alkyn-1-yl)-2-enones. After retrosynthetic analysis,
we envisaged two different strategies for the preparation of
bicyclic 2-(alkyn-1-yl)-2-enones (Scheme 1).
Scheme 1. Retrosynthetic analysis of fused tricyclic 4H-pyrans 4.
For strategy A, TMS-protected 1, 6- or 1,7-enyne 7 under-
goes the Pauson–Khand reaction (PKR)[6] and subsequent
halogenation[7] to give fused bicyclic 2-halide-2-enone 5
which undergoes cross-coupling with terminal alkynes to
give bicyclic 2-(alkyn-1-yl)-2-enones. Strategy B, on the
other hand, starts from the Sonogashira[8] or Cadiot–Chod-
kiewicz[9] cross-coupling reaction (CCR) of readily available
terminal 1, 6-enynes and 1-alkynyl bromide to give 1-ene-
6,8-diynes 2 (or 1-ene-7,9-diynes), followed by the Pauson–
Khand type reaction of 2 to give the bicyclic adduct 3. The
ability to execute ꢀone-potꢁ, sequential reactions, wherein
the product of one reaction is the starting material for the
next, is particularly significant. Strategy B has an obvious
advantage over strategy A in its potential combination of
the Pauson–Khand reaction and the subsequent transforma-
tion in a ꢀone-potꢁ reaction.[10] Herein, we report a novel
[{Rh(CO)2Cl}2]-catalyzed Pauson–Khand-type reaction of 2
with CO to provide bicyclic 2-(alkyn-1-yl)-2-enones in mod-
[a] W. Zhao, W. Jiang, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, Department of Chemistry,
East China Normal University, 3663 N. Zhangshan Road
Shanghai 200062 (P. R. China)
Fax : (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China)
[c] Dr. L. Fan
Department of Chemistry, Tongji University
1239 Siping Road, Shanghai 200092 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801453.
Chem. Eur. J. 2008, 14, 9139 – 9142
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9139

Table 1. Screening conditions for the Pauson–Khand reaction of 2a.[a]
erate to excellent yields (using strategy B). Furthermore,
this Pauson–Khand reaction can be combined with the
K2CO3-catalyzed [3+3] cycloaddition of 2-(alkyn-1-yl)-
enones with b-keto compounds to rapidly assemble tricyclic
heterocycles[11] with a quaternary carbon stereocenter.
As expected, various substituted and tethered enediynes 2
could be prepared in good yields by the Sonogashira cross-
coupling reaction of the corresponding readily available ter-
minal 1, 6-enynes 1[12] with 1-alkynyl bromide, catalyzed by
Entry
RhI Catalyst
Ligand
Solvent
Yield [%][b]
1
2
3
4
5
[{Rh(CO)2Cl}2]
[{Rh(CO)2Cl}2]
[{Rh(CO)2Cl}2]
[{Rh(CO)2Cl}2]
–
–
–
–
–
toluene
CH3CN
DCE
THF
THF
44
38
37
64
0
[Pd(PPh3)4] (5 mol%) and CuI (10 mol%) in the presence
G
of base (Scheme 2).[8]
G
A
6
A
G
–
THF
0
7
8
9
10
11
12
C
N
dppe
dppp
dppp
dppp
binap
binap
THF
14
26
29
43
32
21
CH3CN
toluene
toluene
toluene
THF
[a] Reagents and conditions used: 2a (0.25 mmol), catalyst
A
ligand(6 mol%) in 10 mL of solvent for 24–48 h in the presence of CO
AHCTREUNG
(balloon). [b] Yield of isolated product. DCE=1,2-dichloroethane; cod=
1,5-cyclooctadiene; dppe=1,2-bis(diphenylphosphino)ethane; dppp=1,3-
bis(diphenylphosphino)propane; binap=2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl.
Scheme 2. Synthesis of 1-ene-6,8-diynes 2 by Sonogashira cross-coupling
reaction of terminal 1, 6-enynes with 1-alkynyl bromide.
Following the successful synthesis of 2, we screened the
reaction conditions for the formal [2+2+1] cycloaddition re-
action using enediyne 2a as the standard substrate. The re-
sults are summarized in Table 1. The reaction proceeds
smoothly under the catalysis of [{Rh(CO)2Cl}2] (5 mol%) in
the presence of CO in refluxing THF for 48 h, affording the
desired fused bicyclic 2-(alkyn-1-yl) enone 3a in 64% yield
(Table 1, entry 4). Using other solvents such as toluene (an
oft-used solvent in similar systems), 1,2-dichloroethane
(DCE), and acetonitrile, or other catalysts, such as [RhCl-
A
G
N
ous phosphine ligands), led to lower yields. When using stoi-
chiometric amounts of the classical cobalt complex
[Co2(CO)8] in the absence of CO[13] or catalytic amounts of
[Co2(CO)8] with tetramethyl thiourea in the presence of
CO,[14] only an unidentified red complex was formed, in vari-
ous solvent and at various temperatures, indicating that the
reactivity of 2 is different with that of the corresponding 1,6-
enynes.
Scheme 3. RhI-catalyzed formal [2+2+1] cycloaddition reaction of 1-ene-
Various substituted enediynes were studied to determine
the scope of this transformation. The results, summarized in
Scheme 3, lead to several noteworthy conclusions: a) The
tethered atom could be carbon (dimethyl malonate), nitro-
gen (N-tosylated amine) and as well as oxygen; b) not only
substituted aromatic rings, but also alkyl groups can be in-
troduced as the terminal R group in the enediyne to give bi-
6,8-diynes in the presence of CO.
cyclic cycloadducts in moderate to excellent yields; c) a
methyl group could be incorporated at the 2-position of 1-
ene-6,8-diyne 2i to afford the cycloadduct 3i with a quater-
nary bridging carbon stereocenter; d) fused bicyclic [4.3.0]
9140
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Chem. Eur. J. 2008, 14, 9139 – 9142

Synthesis of Fused Tricyclic Heterocycles
COMMUNICATION
system 3j could be prepared in 77% yield from the corre-
sponding 1-ene-7,9-diyne 2j.
lished by single-crystal X-ray diffraction of fused tricyclic
heterocycle 4ga (Figure 1).[16]
To show the synthetic application of bicyclic 2-(alkyn-1-
yl)-2-enones, we investigated aꢀone-potꢁ synthetic strategy to
construct tricyclic 4H-pyrans from the corresponding acyclic
1-ene-6,8-diynes 2 by the combination of formal [2+2+1] cy-
cloaddition with subsequent base-catalyzed formal [3+3] cy-
cloaddition of the cycloadducts with b-keto compounds.
After several attempts, we discovered that fused tricylic 4H-
pyrans 4 could be synthesized in 40–71% yields (two steps)
with high diastereoselectivity (single diastereoisomer) by a
simple sequential ꢀone-potꢁ operation, that is, RhI-catalyzed
Pasuson–Khand reaction of 1-ene-6,8-diynes in refluxing
THF, followed by removal of solvent and K2CO3-catalyzed
formal [3+3] cycloaddition of the cycloadducts with b-keto
compounds in DMF[15] at room temperature (Scheme 4). It
is noteworthy that five bonds and three fused rings with one
quaternary carbon sterocenter were formed during this
simple ꢀone-potꢁ operation, and all atoms from the three
components were incorporated into the product. The struc-
ture and relative stereochemistry of the product was estab-
In summary, we have demonstrated a novel RhI-catalyzed
formal [2+2+1] cycloaddition reaction of 1-ene-6,8-diynes
leading to fused bicyclic 2-(alkyn-1-yl) enones in moderate
to good yields. Furthermore, we have also developed an effi-
cient, atom-economical, ꢀone-potꢁ sequential process to rap-
idly assemble fused tricyclic heterocycles with one quaterna-
ry carbon stereocenter, with high diastereoselectivity in rea-
sonable yields. All three starting materials are readily avail-
able and the cycloadducts are readily converted into more
complex ring systems with many convertible functional
groups. The reaction scope, asymmetric catalysis, and syn-
thetic applications in natural product synthesis are being
studied in our group.
Experimental Section
A solution of enediyne 2g (174.4 mg, 0.5 mmol),
Synthesis of 3g:
[{RhCl(CO)2}2 (9.8 mg, 5 mol%) in THF (10 mL) was refluxed under a
positive pressure of CO (balloon). The reaction was complete in 24 h, as
determined by thin-layer chromatography. After concentration, the resi-
due was purified by column chromatography on silica gel (hexanes/ethyl
acetate=3:1) to afford 3g (167.8 mg, yield: 89%).1H NMR (500 MHz,
CDCl3): d=7.76 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.37–7.27
(m, 5H), 4.46 (d, J=17.0 Hz, 1H), 4.19 (d, J=17.0 Hz, 1H), 4.07 (dd, J=
9.0, 8.0 Hz, 1H), 3.23–3.21 (m, 1H), 2.74 (dd, J=18.0, 7.0 Hz, 1H), 2.66
(dd, J=9.0, 1.0 Hz, 1H), 2.44 (s, 3H), 2.16 ppm (dd, J=18.0 , 3.0 Hz,
1H); 13C NMR (125.8 MHz, CDCl3): d=203.05, 178.11, 144.25,
133.50,131.92, 130.08, 129.25,128.39, 127.47, 122.44, 121.85, 99.40, 77.91,
52.52, 48.02, 42.41, 39.60, 21.55 ppm; MS (EI): m/z (%): 377 [M+]
(65.45),
G
195 [M+HÀTsÀCH2CO], 222 [MÀTs] (60.480); HRMS calcd for
C22H19NO3S: 377.1086, found: 377.1086.
ꢀOne-potꢁ synthesis of 4ga from enediyne 2g: After the cycloaddition re-
action of enediyne 2g (174.4 mg, 0.5 mmol) was complete (see above),
the solvent was removed in vacuo and the residue was dissolved in DMF
(5 mL). A solution of acetylacetone (100 mg, 1.0 mmol) in DMF (1 mL)
and K2CO3 (13.8 mg, 20 mol%) were added to the reaction mixture,
which was then stirred at room temperature until 3g was consumed.
Water (15 mL) was added and the mixture was extracted with diethyl
ether (3”5 mL). The combined organic phase was washed successively
with water (5 mL) and saturated brine (5 mL) and then dried over
MgSO4. Solvent was removed in vacuo and the residue was purified by
column chromatography on silica gel(hexanes/ethyl acetate=3:1) to give
4ga (163.1 mg, overall yield, 68%) . 1H NMR (500 MHz, CDCl3): d=
7.65 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.32–7.20 (m, 5H), 4.15
(d, J=14.0 Hz, 1H), 4.00 (d, J=14.0 Hz, 1H), 3.38–3.33 (m, 1H), 3.22 (d,
J=10.0 Hz, 1H), 3.10 (d, J=10.0 Hz, 1H), 3.04 (d, J=10.0 Hz, 1H),
2.80–2.74 (m, 1H), 2.69 (dd, J=19.0, 11.0 Hz, 1H), 2.44 (s, 3H), 2.29 (s,
3H), 2.23 (dd, J=19.0,7.0 Hz, 1H), 2.02 ppm (s, 3H); 13C NMR
(125.8 MHz, CDCl3): d=202.04, 200.79, 159.00, 153.24, 143.85, 136.04,
132.10, 129.68, 129.06, 128.59, 127.85, 126.92, 119.21, 115.23, 61.85, 55.35,
49.43, 44.91, 40.78, 34.85, 32.58, 21.56, 18.35 ppm; MS (EI): m/z (%): 477
[M+] (1.14), 322 (100) [MÀTs]; HRMS calcd for C27H27NO5S: 477.1610,
found: 477.1610.
Scheme 4. ꢀOne-potꢁ synthesis of fused tricyclic heterocycles by sequen-
tial, [2+2+1] and [3+3] cycloadditions.
Acknowledgements
Financial support from the National Science Foundation of China
(20702015) and Shanghai Municipal Committee of Science and Technolo-
gy are greatly appreciated. This work was also sponsored by Shanghai
Pujiang Program (07pj14039), Shanghai Shuguang Program (07SG27)
and Shanghai Leading Academic Discipline Project (B409).
Figure 1. Molecular structure of racemic 4ga, determined by X-ray dif-
fraction . Thermal ellipsoids are set at 30% probability.
Chem. Eur. J. 2008, 14, 9139 – 9142
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www.chemeurj.org
9141

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Keywords: cycloaddition · diastereoselectivity · fused-ring
systems · heterocycles · rhodium
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Received: July 18, 2008
Published online: September 9, 2008
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Chem. Eur. J. 2008, 14, 9139 – 9142