Intramolecular coupling of conjugated enynes with cyclopropylcarbene-chromium complexes; a complex reaction pathway

Article abstract of DOI:10.1016/S0020-1693(99)00319-9

The intramolecular coupling of conjugated enynes with cyclopropylcarbene complexes has been investigated. The desired products of the reaction, α-alkenylcyclopentenones, were minor products of the reaction. Competing reaction processes included double bond reduction and allylic C-H activation. Intramolecular coupling of selenium-containing alkynes and cyclopropylcarbene complexes followed by oxidation/elimination provided a more efficient route to α-alkenylcyclopentenones.

Full text of DOI:10.1016/S0020-1693(99)00319-9

www.elsevier.nl/locate/ica
Inorganica Chimica Acta 296 (1999) 273–277
Note
Intramolecular coupling of conjugated enynes with
cyclopropylcarbene–chromium complexes; a complex reaction
pathway
Julius J. Matasi, Jingbo Yan, James W. Herndon *
Department of Chemistry and Biochemistry, Uni6ersity of Maryland, College Park, MD 20742-2021, USA
Received 17 June 1999; accepted 26 July 1999
Abstract
The intramolecular coupling of conjugated enynes with cyclopropylcarbene complexes has been investigated. The desired
products of the reaction, a-alkenylcyclopentenones, were minor products of the reaction. Competing reaction processes included
double bond reduction and allylic CꢀH activation. Intramolecular coupling of selenium-containing alkynes and cyclopropylcar-
bene complexes followed by oxidation/elimination provided a more efficient route to a-alkenylcyclopentenones. © 1999 Elsevier
Science S.A. All rights reserved.
Keywords: Intramolecular coupling; Conjugated enynes; Cyclopropylcarbene complexes; Chromium complexes; Double bond reduction; Allylic
CꢀH activation
1. Introduction
In a series of recent papers, we have demonstrated
that 3-alkoxy-2-cyclopentenones (3, Scheme 1) are read-
ily prepared from the coupling of alkynes and cyclo-
propylcarbene–chromium complexes (1) [1].
A
synthetically very important class of compounds,
prostaglandins (exemplified by PGA1 in Scheme 2),
contain structural features very similar to the products
Scheme 2.
of these coupling reactions. Our general approach for
the synthesis of the prostaglandin ring system [2] is
depicted in Scheme 2, which involves intramolecular
coupling of the cyclopropylcarbene unit with a conju-
gated enyne, followed by ring opening1. In this paper
Scheme 1.
* Corresponding author. Present address: Department of Chemistry
& Biochemistry, New Mexico State University, MSC 3C, Las Cruces,
NM 88003, USA. Tel.: +1-505-646 2487; fax: +1-505-646 2649.
1 A notable problem with this synthesis is the production of a racemic
compound. This problem could be overcome by placement of chiral
auxiliaries in the tethering chain; Ref. [1] focuses on these studies.
0020-1693/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0020-1693(99)00319-9

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J.J. Matasi et al. / Inorganica Chimica Acta 296 (1999) 273–277
our unanticipated observations concerning this cou-
pling are reported.
evaporation using hexane as the eluent gave the pure
carbene complex after solvent removal.
2.3. Synthesis of complex 4A
2. Experimental
General procedure I was followed using enyne alco-
hol 9A (0.280 g, 1.50 mmol), acylate salt 10 (0.512 g,
1.50 mmol), and acetyl chloride (0.110 ml, 1.50 mmol)
in dichloromethane (40 ml). After chromatographic
purification, a yellow oil (0.475 g, 74%) identified as
2.1. General considerations
NMR (1H and 13C) spectra were recorded on a
Bruker AF 200 (200 MHz) or Bruker AF 400 (400
MHz) spectrometer. Chemical shifts are reported in
parts per million (l) downfield from an internal TMS
reference. Coupling constants (J values) are reported
in hertz (Hz), and spin multiplicities are indicated by
the following symbols: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet). IR spectra were
recorded on a Nicolet 5DXC FT-IR spectrometer.
Band positions are reported in reciprocal centimeters
(cm−1). Band intensities are reported relative to the
most intense band and are listed as: br (broad), vs
(very strong), s (strong), m (medium), w (weak). Mass
spectra (MS) were obtained on a VG 7070E spectrom-
eter using electron impact (EI) or chemical ionization
(CI) or on a Hewlett–Packard GC-Mass Spec 5970B
with Mass Selection Detector; m/e values are reported,
followed by the relative intensity in parentheses. Flash
column chromatography was performed using thick-
walled glass columns and ‘flash grade’ silica (Bodmann
230–400 mesh). Routine thin layer chromatography
(TLC) was performed by using precoated 0.25 mm
silica gel plates purchased from Whatman. Combus-
tion analyses were performed by Galbraith Laborato-
ries (Knoxville, TN) or Desert Analytics (Tucson,
AZ). The relative proportion of solvents in mixed
chromatography solvents refers to the volume:volume
ratio. All commercially available reagents and reac-
tants were obtained in reagent grade and used without
purification. All reaction solvents were distilled for
purity. Diethyl ether, THF and dioxane were distilled
from sodium-benzophenone ketyl and dichloro-
methane from calcium hydride prior to use. All
reactions were performed in an inert atmosphere cre-
ated by a slight positive pressure (ca. 0.1 psi) of
nitrogen.
1
carbene complex 4A was obtained. H NMR (CDCl3):
l 7.40–7.20 (m, 5H), 6.90 (d, 1H, J=16.2 Hz), 6.12
(dt, 1H, J=16.2, 2.1 Hz), 5.05 (t, 2H, J=6.1 Hz),
3.50 (m, 1H), 2.60 (td, 2H, J=6.8, 2.1 Hz), 2.20 (tt,
2H, J=6.8, 6.1 Hz), 1.48–1.35 (m, 2H), 1.30–1.16 (m,
2H); 13C NMR (CDCl3): l 352.1, 223.5, 216.8, 140.9,
136.3, 128.7, 128.4, 126.1, 108.2, 89.7, 81.3, 78.9, 41.5,
28.4, 17.8, 16.5; IR (CH2Cl2): 2061, 1979, 1949 cm−1
.
2.4. Synthesis of Complex 4B
General procedure I was followed using enyne alco-
hol 9B (0.113 g, 0.90 mmol), acylate salt 10 (0.310 g,
0.90 mmol), and acetyl chloride (0.065 ml, 0.90 mmol)
in dichloromethane (20 ml). After chromatographic
purification, a yellow oil (0.253 g, 75%) identified as
carbene complex 4B (70:30 Z:E mixture) was obtained.
1H NMR (CDCl3): major isomer l 5.90 (dq, 1H, J=
10.4, 6.2 Hz), 5.02 (t, 2H, J=5.6 Hz), 2.52 (br t, 2H,
J=6.4 Hz), 1.83 (dd, 3H, J=6.2, 1.5 Hz); minor
isomer l 6.05 (dq, 1H, J=15.2, 6.4 Hz), 4.99 (t, 2H,
J=5.6 Hz), 2.48 (br t, 2H, J=5.4 Hz), 1.73 (dd, 3H,
J=6.4, 1.4 Hz); the following peaks are overlapping
in both isomers 5.47 (m, 1H), 3.48 (m, 1H), 2.10 (m,
2H), 1.46–1.32 (m, 2H), 1.31–1.13 (m, 2H); 13C NMR
(CDCl3): l 352.0, 223.5, 216.8, 137.8, 110.0, 91.9, 85.5,
78.9, 41.5, 28.6, 17.8, 16.5; IR (CH2Cl2): 2061, 1979,
1944 cm−1
.
2.5. General procedure II
2.5.1. Intramolecular carbene–alkyne coupling reaction
To a three-neck round-bottom flask equipped with a
reflux condenser and rubber septum, under nitrogen,
was added toluene (100 ml) and water (1 ml), and the
solution was heated to reflux. To this refluxing solu-
tion was added a solution of carbene complex in
toluene (30 ml) via syringe pump over a period of 4 h.
After the addition was complete, the mixture was
heated at reflux for an additional 20 h and then
cooled to room temperature. The resulting green mix-
ture was filtered through Celite and the solvent was
removed on a rotary evaporator. Final purification
was achieved by flash chromatography on silica gel
using 4:1 hexane–ethyl acetate as eluent unless other-
wise noted.
2.2. General procedure I
2.2.1. Synthesis of carbene complexes from alcohols
To the solution of acylate salt 10 [3] (0.40 g, 1.20
mmol) in dichloromethane (20 ml) at 0°C under nitro-
gen was added acetyl chloride (0.08 ml, 1.20 mmol)
via syringe, followed by immediate addition of alkynol
(1.20 mmol). The reaction mixture was stirred at 0°C
for about 1 h and then warmed to 25°C and stirred
for 20 min. The solvent was removed on a rotary
evaporator. Flash chromatography of the residue after

J.J. Matasi et al. / Inorganica Chimica Acta 296 (1999) 273–277
275
2.6. Thermolysis of complex 4A
identified as cyclopentenone 17. The compound in the
third fraction (0.030 g, 20%) was the propenyl derivative
5B.
General procedure II was followed using 0.475 g (1.10
mmol) of carbene complex 4A in dioxane. Purification by
flash chromatography afforded two compounds. The
first fraction (0.133 g, 50%) was identified as saturated
side chain derivative 11A as a cis–trans mixture. The
second fraction (0.008 g, 3%) was the styryl derivative 5A.
11A: 1H NMR (CDCl3): l 7.25–7.04 (m, 5H), 5.25 (s,
1H), 4.38 (m, 1H), 4.12 (m, 1H), 3.02–2.04 (m, 3H),
2.30–2.02 (m, 2H), 2.02–1.80 (m, 3H), 1.80–1.25 (m,
2H); 13C NMR (CDCl3): l 207.0, 205.7, 190.6, 189.9,
141.7, 141.4, 128.4, 128.3, 125.8, 106.0, 105.9, 68.3, 68.1,
52.6, 47.5, 41.5, 38.5, 34.2, 33.6, 31.7, 30.0, 24.8, 22.7,
20.2; IR (CDCl3): 1681, 1606 cm−1; MS (EI): m/e 242
(M, 2), 150 (4), 137 (56, 68 (100). HRMS: Calc. for
C16H16O2 242.1307, found 242.1309.
1
16: H NMR (CDCl3): l 9.50 (s, 1H), 6.91–6.60 (m,
2H), 5.72–5.49 (m, 2H), 3.90 (t, 2H, J=6.6 Hz),
2.10–1.70 (m, 4H), 1.15 (m, 1H), 0.65–0.50 (m, 2H),
0.45–0.30 (m, 2H); 13C NMR (CDCl3): l 194.6, 151.5,
149.4, 143.0, 133.8, 126.0, 99.9, 65.9, 24.7, 22.6, 11.6, 4.1;
IR (CDCl3): 1679 cm−1; MS (EI): m/e 204 (M, 30), 178
(8), 166 (6), 163 (15); HRMS: Calc. for C13H16O2:
204.1150, found 204.1154.
17: 1H NMR (CDCl3): l 7.44 (t, 1H, J=2.8 Hz), 3.89
(t, 2H, J=5.1 Hz), 2.64–2.58 (m, 2H), 2.46–2.40 (m,
2H), 2.15 (t, 2H, J=6.5 Hz), 1.92–1.75 (m, 2H), 1.41 (m,
1H), 0.76–0.65 (m, 2H), 0.52–0.40 (m, 2H); IR (CDCl3):
1697 cm−1
.
5A: 1H NMR (CDCl3): l 7.32–7.05 (m, 5H), 6.48 (dd,
1H, J=15.9, 1.1 Hz), 6.14 (dd, 1H, J=15.9, 7.6 Hz),
5.30 (d, 1H, J=1.5 Hz), 4.33 (m, 1H), 4.08 (m, 1H), 2.92
(ddd, 1H, J=7.6, 4.0, 1.1 Hz), 2.76 (m, 1H), 2.22 (m,
1H), 1.98–1.84 (m, 2H), 1.48 (m, 1H); 13C NMR
(CDCl3): l 203.0, 189.3, 136.8, 133.2, 128.5, 127.5, 126.3,
125.6, 105.9, 68.7, 56.9, 41.9, 24.4, 22.8; IR (CDCl3):
1685, 1604 cm−1; MS (EI): m/e 240 (M, 39), 211 (4), 69
(100).
2.9. Thermolysis and oxidation/elimination of complex
21A
General procedure II was followed using 1.030 g (2.00
mmol) of carbene complex 21A in toluene. Purification
by flash chromatography afforded two fractions. The
first fraction (0.161 g, 25%) was identified as three of the
diastereomers of 22A. The compound in the second
fraction (0.160 g, 25%) was identified as
a cis
diastereomer of cyclopentenone 22A. The combined
mixture of 22A (0.161 g, 0.500 mmol) was dissolved in
methanol (1 ml) and added to a solution of sodium
periodate (0.150 g, 0.600 mmol) in 1:1 methanol:water at
0°C. The mixture was stirred at this temperature for 8 h.
The mixture was poured into water and ether in a
separatory funnel. The ether layer was washed with 1 M
sodium hydroxide solution, dried over magnesium sul-
fate, and the solvent was removed on a rotary evaporator
to give 0.050 g (61%) of residue which appeared to be a
mixture of isomers of compound 23. After purification of
the residue by flash chromatography, a single isomer
(0.033 g, 40%) identified as the E-trans isomer was
separated.
2.7. Thermolysis of complex 4B in dioxane
General procedure II was followed using 0.473 g (1.29
mmol) of carbene complex 4B in dioxane. Purification by
flash chromatography afforded two compounds. The
first fraction (0.046 g, 30%) was identified as saturated
side chain derivative 11B as a cis–trans mixture. The
second fraction (0.007 g, 3%) was assigned as the
propenyl derivative 5B, as a mixture E and Z and cis and
trans isomers.
1
11B: H NMR (CDCl3): l 5.28 (d, 1H, J=0.7 Hz),
4.30 (m, 1H), 4.10 (m, 1H), 2.96–2.59 (m, 2H), 2.57 (m,
1H), 2.21 (q of t, 1H, J=6.9, 5.9 Hz), 2.08 (m, 1H), 1.87
(m, 1H), 1.53–1.31 (m, 4H), 0.92 (t, 3H, J=6.9 Hz);
Irradiate at l 2.59:l 2.08 (dd, 1H, J=8.8, 3.9 Hz). The
spectral data were in agreement with those previously
reported for this compound [4].
1
22A (single isomer fraction): H NMR (CDCl3): l
7.56–7.40 (m, 2H), 7.32–7.10 (m, 3H), 5.05 (d, 1H,
J=1.9 Hz), 4.68 (dd, 1H, J=8.6, 8.4 Hz), 4.45 (ddd, 1H,
J=11.4, 9.1, 4.7 Hz), 3.45 (dt, 1H, J=8.0, 6.9 Hz), 3.14
(quintet of d, 1H, J=6.7, 1.9 Hz), 2.96 (dt, 1H, J=8.4,
1
5B: H NMR (CDCl3): l 5.58 (m, 1H), 5.28 (s, 1H),
5.37 (m, 1H); 4.36 (m, 1H), 4.16 (m, 1H), 2.72 (m, 1H),
6.9 Hz), 1.41 (d, 3H, J=6.9 Hz), 2.10–1.30 (m, 4H); 13
C
2.08–1.86 (m, 4H), 1.70 (d, 3H, J=6.8 Hz); IR: 1689,
NMR (CDCl3): l 208.7, 194.5, 135.2, 128.9, 127.6, 98.6,
1623 cm−1
.
77.9, 47.7, 45.6, 37.3, 25.9, 22.5; IR: 1700, 1696, 1623
cm−1
.
1
2.8. Thermolysis of complex 4B in toluene
23: H NMR (CDCl3): l 5.67 (dq, 1H, J=15.3, 6.6
Hz), 5.18 (d, 1H, J=1.2 Hz), 5.13 (ddq, 1H, J=15.3,
8.5, 1.6 Hz), 4.76 (t, 1H, J=9.0 Hz), 4.54 (ddd, 1H,
J=11.4, 9.0, 5.1 Hz), 3.30 (m, 2H), 2.15–1.78 (m, 2H),
1.67 (dd, 3H, J=6.6, 1.6 Hz); IR (CDCl3): 1698, 1620
cm−1. Anal. Calc. for C10H12O2: C, 73.14; H, 7.37.
Found: C, 73.24; H, 7.62%.
General procedure II was followed using 0.407 g (1.11
mmol) of carbene complex 4B in toluene. Purification by
flash chromatography afforded three compounds. The
first fraction (0.061 g, 45%) was identified as dienal 16.
The compound in the second fraction (0.005 g, 3%) was

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J.J. Matasi et al. / Inorganica Chimica Acta 296 (1999) 273–277
Scheme 3.
3. Results and discussion
Enyne–cyclopropylcarbene complexes (4) were easily
prepared using the synthetic route in Scheme 3. Palla-
dium-catalyzed coupling of alkynol 8 and alkenyl
halides provided enyne alcohols, which were trans-
formed into the corresponding carbene complexes in
good yield using a known procedure [1]. The moder-
ately stable carbene complexes were purified by chro-
matography and used within a few days.
Scheme 5.
The intramolecular coupling of enynes and cyclo-
propylcarbene complexes proved to be a very complex
reaction process, resulting in unanticipated reaction
pathways (Schemes 4 and 5). Thermolysis of the car-
bene complex 4A in dioxane primarily afforded the side
chain-saturated compound 11A (50%) (Scheme 4) ac-
companied by a trace of the desired product 5A. A
similar result was obtained from thermolysis of the
carbene complex 4B (60:40 Z:E mixture), which led to
11B in 32% yield. Formation of 11 has been attributed
to the protonation of the cyclopentadienide intermedi-
ate 13 at the side chain, affording intermediate alkoxy-
fulvene 14. Hydration/protonation of 14 affords
cyclopentadienone 15, which leads to 11 after a second
reduction–protonation sequence [5,6].
(3%). The saturated compound 11B was not observed
under these conditions. A mechanism for the formation
of 16 and 17 involves activation of the allylic CꢀH
bond in the intermediate vinylketene complex derived
from the Z-alkene (19) [7], followed by reductive elimi-
nation of H and pentadienyl to provide aldehyde 16, or
cyclization and reductive elimination to provide cy-
clopentenone 17 [8]. A previous study revealed that an
allylic CꢀH activation process similar to conversion of
4B-Z to 20 was more favorable in hexane than in THF
[8a]. This observation is consistent with our observation
that compounds 16 and 17 are more prevalent in
toluene, which is less polar and less ligating than
dioxane.
Thermolysis of carbene complex 4B (60:40 Z:E mix-
ture) in toluene afforded only a low yield of the desired
product 5B (20%) (Scheme 5). The major product from
this coupling was the dienal derivative 16 (45%), ac-
companied by a trace amount of cyclopentenone 17
Although the direct coupling of enynes and carbene
complexes was problematic, 5-alkenyl-2-cyclopenten-1-
ones could be prepared by a less direct method. Ther-
molysis of the functionalized alkyne–carbene complex
21A provided the anticipated coupling product 22A
without complications (Scheme 6). Oxidation of se-
lenide 22 afforded the alkenyl-substituted cyclopen-
tenone 23 in 61% yield [9]. Similar yields were obtained
Scheme 4.
Scheme 6.

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277
[2] Reviews of prostaglandin synthesis: (a) see M.P.L. Caton, T.W.
Hart, in: J.E. Pike, D.R. Morton (Eds.), Advances in
Prostaglandin, Thromboxane, and Leuoptriene Research, vol.
14, Raven, New York 1985, pp. 73–129. (b) E.J. Corey, X.
Cheung, The Logic of Chemical Synthesis, Wiley, New York,
1989, pp. 250–309. (c) For the use of Fischer carbene complexes
in the synthesis of prostaglandins, see C.K. Murray, D.C. Yang,
W.D. Wulff, J. Am. Chem. Soc. 112 (1990) 5660–5662.
[3] For a procedure for synthesis of this compound, see: J.W.
Herndon, S.U. Tumer, L.A. McMullen, J.J. Matasi, W.F.K.
Schnatter, in: L.S. Liebeskind (Ed.), Advances in Metal-Organic
Chemistry, vol. III, JAI Press, Greenwich, CT, 1994, pp. 51–95.
[4] J.W. Herndon, J.J. Matasi, J. Org. Chem. 55 (1990) 786–788.
[5] For a detailed discussion of the proton transfer processes, see
J.W. Herndon, J. Yan, J. Org. Chem. 63 (1998) 2325–2331.
[6] In a related process involving propargyl-functionalized styry-
lacetylenes, the vinyl group is not affected. J.W. Herndon, J.
Zhu, Org. Lett. 1 (1999) 15–18.
using the acetate and thiophenyl analogs (21B and C),
however, the elimination step [10] proved to be more
problematic in these systems.
In summary, we have shown that synthesis of 5-
alkenyl-2-cyclopenten-1-ones via the direct intramolecu-
lar coupling of conjugated enynes and cyclopropyl-
carbene–chromium complexes is not straightforward
due to competing processes, including reduction of the
double bond and unanticipated reaction pathways of
divinylcarbene and/or divinylketene intermediates. The
desired compounds can be prepared by an indirect
method involving coupling of selenium-containing alky-
nes, which provide a-alkenylcyclopentenones after oxi-
dation and elimination.
A
program to better
understand and control the reaction pathways from the
coupling of substituted enynes and carbene complexes
is presently a very important aspect of our current
research activities [11].
[7] For a detailed discussion of the mechanistic processes of carbene
complexes and alkynes, see W.D. Wulff, in: B.M. Trost, I.
Fleming, L.A. Paquette (Eds.), Comprehensive Organic Synthe-
sis, vol. 5, Pergamon, Oxford, 1991, pp. 1065–1113.
[8] Similar processes have been reported for oxygenated vinylketene
intermediates. (a) C.A. Challener, W.D. Wulff, B.A. Anderson,
S.A. Chamberlin, K.L. Faron, O.K. Kim, C.K. Murray, Y.-C.
Xu, D.C. Yang, S.D. Darling, J. Am. Chem. Soc. 115 (1993)
1359–1376. (b) D.F. Harvey, E.M. Grenzer, P.K. Gantzel, J.
Am. Chem. Soc. 116 (1994) 6719–6732. (c) D.F. Harvey, K.P.
Lund, D.A. Neil, J. Am. Chem. Soc. 114 (1992) 8424–8434.
[9] D.L.J. Clive, Aldrichim. Acta 11 (1978) 43–50.
Acknowledgements
We thank the NIH (GM-40777) and the Petroleum
Research Fund, administered by the American Chemi-
cal Society, for financial support of this research. We
thank Mr Deepack Bansal for experimental assistance.
[10] P.C. Astles, S.V. Mortluck, E.J. Thomas, in: B.M. Trost, I.
Fleming, E. Winterfeldt (Eds.), Comprehensive Organic Synthe-
sis, vol. 6, Pergamon, Oxford, 1991, pp. 1011–1039.
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