Regioselective Pauson-Khand processes with olefins possessing extended phosphonates

Article abstract of DOI:10.1055/s-0029-1219349

Olefins possessing a tethered β-functionalised phosphonate functionality have been shown to be effective cyclisation partners within intermolecular Pauson-Khand processes. The optimised protocol described facilitates intermolecular cyclisations with high levels of olefinic regiocontrol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219349

LETTER
649
Regioselective Pauson–Khand Processes with Olefins Possessing Extended
Phosphonates
R
egioselec
a
tive Pauso
c
n–Khand
P
e
r
ocesses
w
i
k
thOlefins L. Kędzia,a William J. Kerr,*b Allan R. McPhersonb
a
Institute of Organic Chemistry, Technical University of Łódż, Zeromskiego 116, 90-924 Łódż, Poland
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, Glasgow, G1 1XL, Scotland, UK
Fax +44(141)5484246; E-mail: w.kerr@strath.ac.uk
b
Received 23 December 2009
Dedicated to Professor Gerry Pattenden on the occasion of his 70th birthday
regard to the alkene partner is difficult to predict. Indeed
and as illustrated in Scheme 1, with simple unsymmetrical
alkene substrates, it is common to see 1:1 mixtures of ole-
fin insertion products.2c,i,4 In an attempt to establish regio-
chemical control within such intermolecular P–K
reactions, Krafft employed a potentially chelating het-
eroatom, tethered to the olefin in the homoallylic or bish-
omoallylic position, to direct the outcome of the
cyclisation process.5 Indeed, it was shown that the use of
soft sulfur or nitrogen donor atoms induced appreciable
levels of regioselectivity with respect to the alkene reac-
tion partner. More recently, studies within our laborato-
ries have shown how such regioselective intermolecular
P–K processes can be further extended with the use of al-
lylphosphonates. Again, with the phosphonate unit acting
as the potentially chelating moiety, cyclopentenone prod-
ucts were delivered with high levels of regiochemical con-
trol.6
Abstract: Olefins possessing a tethered b-functionalised phospho-
nate functionality have been shown to be effective cyclisation part-
ners within intermolecular Pauson–Khand processes. The
optimised protocol described facilitates intermolecular cyclisations
with high levels of olefinic regiocontrol.
Key words: alkyne complexes, annulations, b-functionalised phos-
phonates, Pauson–Khand reaction, regioselectivity
Over the last few decades, transition-metal-mediated cy-
clisations have provided vast synthetic value to the pre-
parative chemistry community and continue to be applied
as direct and highly efficient methods for the construction
of many challenging carbon skeletons. Of particular note
is the Pauson–Khand (P–K) reaction, which has evolved
as an invaluable tool for the preparation of functionalised
cyclopentenones.1 First discovered in 1971 by Pauson and
co-workers, the reaction involves the cycloaddition of an
alkyne, present as its hexacarbonyldicobalt complex, an
alkene, and carbon monoxide, in a formal [2+2+1] fash-
ion, to furnish functionalised cyclopentenones directly
(Scheme 1).
Following on from the success of our previous work in-
volving allylphosphonates as cyclisation partners, we
were keen to investigate further the efficiency of phospho-
nate ester directing groups and more extensively establish
the scope of this functional unit within intermolecular P–
K annulations. Additionally, due to the wide use of b-
functionalised phosphonates as key reagents within olefi-
nation chemistry,7 the use of olefins with suitably posi-
tioned phosphorus components would allow the
incorporation of such a moiety onto the cyclopentenone
framework. Based on all of this, we herein report the use
of alkenes possessing such extended phosphonates within
regioselective intermolecular P–K processes.
O
R1
RL
RS
R1(2)
R2(1)
RL
RS
+
R2
Co2(CO)6
Scheme 1
Over recent years there has been enormous progress in en-
hancing the efficiency of the P–K annulation to the extent
that this method can now be employed under relatively
mild reaction conditions for the expedient synthesis of cy-
clopentenones and their derivatives.2 Having stated this, it
is the intramolecular variant of the P–K reaction that has
shown the greatest effectiveness, to date, and which has
found prominence as the key step in a number of natural
product total syntheses.3 In contrast, limitations still re-
main within the realm of the intermolecular P–K cyclisa-
tion process. More specifically in relation to this two-
component annulation, the regiochemical outcome with
Our preliminary efforts in this programme focused on P–
K cyclisations involving phenylacetylene cobalt complex
1 and, the relatively easily prepared,8 olefin 2, possessing
the tethered phosphonate ester unit (Scheme 2). At the
outset, a series of conditions were screened with well-es-
tablished chemical promoters of the P–K reaction. Initial
use of the long-chain odourless sulfide additive, dodecyl
methyl sulfide (DodSMe), under conditions previously
established within our laboratory,9 in refluxing 1,2-DCE
led only to decomposition of the starting complex
(Scheme 2, Table 1, entry 1). In contrast, use of the same
promoter at room temperature delivered the desired cyclo-
pentenone products, as a mixture of isomers, in 19% yield
(entry 2). Despite this relatively low reaction efficiency,
we were encouraged by the moderate 5:1 regioselection
SYNLETT 2010, No. 4, pp 0649–0653
0
1.
0
3.
2
0
1
0
Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1219349; Art ID: D38609ST
© Georg Thieme Verlag Stuttgart · New York

650
J. L. Kędzia et al.
LETTER
O
O
(EtO)2P
O
O
P(OEt)2
O
O
conditions
Ph
Ph
+
+
Ph
H
Co2(CO)6
1
P(OEt)2
O
O
O
O
O
2
3
4
Scheme 2
observed. This sulfide-promoted process was repeated us- was obtained in conjunction with a regioisomeric ratio of
ing dichloromethane as the reaction medium resulting in a 7:1 (Scheme 2, Table 2, entry 1). A further simplification
24% yield and a more appreciable 10:1 regioselectivity of the reaction conditions, using only acetonitrile as the
(entry 3). In an attempt to further enhance this reaction reaction medium, resulted in an additional increase to
process, alternative amine N-oxide promoters were inves- both the yield and the selectivity obtained (entry 2). Ex-
tigated.10 In this regard, both trimethylamine N-oxide tended reaction solvent investigations, employing 1,2-
(TMANO·2H2O) and N-methylmorpholine N-oxide dichloroethane and toluene (entries 3 and 4), led to no fur-
(NMO·H2O) unfortunately provided no improvement in ther improvements in the efficiency of this cyclisation
cyclisation efficiencies with the key phosphonate contain- process.
ing olefin 2 (entries 4 and 5). Similarly, use of the cyclo-
hexylamine additive11 led to no cyclopentenone being
Table 2 Solvent Study on Reactions of Phenylacetylene Complex 1
with Olefin 2
isolated (entry 6).
Entry Conditions
Yield
(%)
Selectivity
Table 1 Initial Reactions of Phenylacetylene Complex 1 with Ole-
fin 2
(3/4)
1
2
3
4
MeCN–CH2Cl2 (1:3), reflux, 3 h
31
39
16
18
7:1
10:1
5:1
Entry Conditions
Yield Selectivity
(%)
(3/4)
MeCN, reflux, 3 h
1,2-DCE, reflux, 3 h
toluene, reflux, 3 h
1
2
3
4
5
6
1,2-DCE, DodSMe, reflux, 16 ha
0
–
1,2-DCE, DodSMe, r.t., 16 ha
CH2Cl2, DodSMe, r.t., 16 ha
TMANO·2H2O, CH2Cl2, r.t., 24 hb
NMO.H2O, CH2Cl2, r.t., 24 hb
CyNH2, CH2Cl2, reflux, 24 hc
19
24
5
5:1
10:1
–
2:3
During the solvent-optimisation studies it had become ap-
parent that, in addition to cyclopentenones 3 and 4, the
mass balances of the reaction processes were generally
made up of degradation products. As a result, our con-
cerns focused on the stability of the desired cyclopenten-
ones under the chosen reaction protocol (Table 2, entry 2).
In relation to this, we subjected a sample of the cyclisation
products 3 and 4 to the optimal refluxing acetonitrile con-
ditions. As suspected, complete decomposition was ob-
served after just a few hours, confirming our view that the
desired products were not stable for prolonged periods un-
der the conditions that delivered the most efficient cycli-
sation outcome. Consequently, attention turned to the
overall reaction time. In all reactions performed to this
stage in the programme, the addition of the cobalt com-
plex (in the chosen reaction solvent) had been carried out
over one hour. This mode of addition was maintained,
however, the subsequent reaction time was reduced to just
15 minutes. Using this modified method, a 56% isolated
yield of cyclopentenones 3 and 4, with a 10:1 selectivity
ratio, was achieved (Scheme 2, Table 3, entry 2). In an ef-
fort to enhance the reaction efficiency further, we subse-
quently investigated the effect of the number of
equivalents of the olefinic phosphonate ester 2 employed.
Pleasingly, increasing the number of equivalents of 2
from two to three resulted in a further improved 66% iso-
lated yield, with an elevated selectivity of 12:1 being ob-
5
–
0
–
a Conditions: 3.5 equiv of DodSMe were employed.
b Conditions: 5.0 equiv of N-oxide were employed.
c Conditions: 2.0 equiv of amine additive were employed.
Following these initial investigations, we were encour-
aged by the, at least, acceptable levels of regioselectivity
that could be obtained in some instances with the phos-
phonate-containing olefin 2. However, the levels of cyclic
product recovery were somewhat disappointing. In an ef-
fort to enhance the effectiveness of this process, we recon-
sidered the findings of our previous investigations into
regioselective P–K processes involving allylphosphonate
esters and, in particular, the observation that the omission
of sulfide promoter did not have a detrimental effect on re-
action yield and, indeed, led to enhanced olefin-insertion
regioselectivity.6 With this in mind, our attention turned to
establishing the most effective solvent for our emerging
P–K process, without the presence of a chemical promot-
er. In relation to this, the reaction between complex 1 and
olefin 2 was carried out in a dichloromethane–acetonitrile
mixture, as was shown to be optimal in our previous stud-
ies. Pleasingly, an elevated yield of our desired products
Synlett 2010, No. 4, 649–653 © Thieme Stuttgart · New York

LETTER
Regioselective Pauson–Khand Processes with Olefins
651
O
O
(EtO)2P
O
O
P(OEt)2
O
O
MeCN
reflux, 15 min
R
R
+
+
R
H
P(OEt)2
O
O
O
Co2(CO)6
O
O
1, 5a–e
2
3, 6a–e
4, 7a–e
Scheme 3
tained (entry 3). In a final probe within this overall
optimisation process, the reaction was performed in
refluxing propionitrile to determine whether an elevated
reaction temperature, over this shorter reaction time,
would be beneficial. Unfortunately, this led to a slightly
lower yield being obtained in this instance (entry 4).
Table 4 P–K Cyclisations of a Range of Alkyne-Co2(CO)6 Com-
plexes with Olefin 2a
Entry
R
Yield (%)
Selectivity (6/7)
1
2
3
4
5
6
1 Ph
66
71
65
63
42
47
12:1b
12:1
12:1
10:1
9:1
5a 4-MeC6H4
5b 4-MeOC6H4
5c 4-ClC6H4
5d 1-naphthyl
5e n-Bu
Table 3 Reaction Time Study on P–K Cyclisations of Phenylacety-
lene Complex 1 with Olefin 2
Entry
1b
2 (equiv)
Time (min)a Yield (%) Selectivity (3/4)
2
2
3
3
180
15
39
56
66
41
10:1
10:1
12:1
10:1
7:1
2b
a All reactions were carried out following the general procedure out-
lined in ref. 12.
3b
15
b This represents the ratio for 3/4.
4c
15
a Reaction time following alkyne complex addition over 1 h.
b Reaction performed in refluxing MeCN.
employed under our optimised protocol. Upon reaction of
allylic ester derivative 8 with our standard phenylacety-
lene cobalt complex 1, the desired cyclopentenone prod-
ucts were isolated in a combined 81% yield and with a
diminished regioisomeric ratio of 6:1 (Scheme 4, Table 5,
entry 2). The somewhat elevated yield may be attributed
to the use of a less sterically encumbered olefin or, indeed,
could be accredited to potentially higher product stability
under the developed reaction conditions. In terms of reac-
tion selectivity, the depleted regiochemical ratio in this
case would support the concept that the phosphonate ester
(in 2) is acting as a potentially ligating unit involved in the
regioselective outcome of this process, as in our previous-
ly published and related studies with allylphosphonates.6
Having stated this, the moderate levels of selectivity that
remain when allylic ester 8 is employed would appear to
indicate that the carbonyl functionality may also play an
important role within the regiochemical outcome of this
general annulation process.
c Reaction performed in refluxing propionitrile.
With these optimised conditions in hand,12 we set out to
establish the scope of this new regioselective P–K pro-
cess. Initially, we probed the effectiveness of our optimal
conditions against a range of aryl alkyne substrates. Both
electron-rich (Scheme 3, Table 4, entries 2 and 3) and
electron-deficient (entry 4) aryl substrates resulted in
good yields of the desired cyclopentenone products and in
high regioisomeric ratios; the more sterically encumbered
1-naphthyl alkyne led to a lower cyclisation yield, where-
as the selectivity remained high at 9:1 (entry 5). In addi-
tion to this, we also investigated the effectiveness of an
alkyl-substituted alkyne substrate under our developed
reaction conditions (entry 6). This, again, delivered the
desired products, albeit in a more moderate 47% com-
bined yield and with 7:1 regioselectivity.
To probe this theory further, the reaction was repeated
with b-ketophosphonate 9. Replacement of the oxygen
atom with a methylene unit creates a less Lewis basic car-
bonyl group. Indeed, if the carbonyl functionality is inher-
ently involved in the regiochemical outcome of this
annulation process, a reduced selectivity could be antici-
pated with this substrate 9. As shown in Table 5, entry 3,
Having established an effective protocol that delivered
cyclopentenone products in generally good yields and,
importantly, with high regioisomeric ratios, favouring the
2,5-disubstitued isomers, our thoughts turned to the fac-
tors driving this regioselective P–K annulation process.
To investigate the role of the tethered phosphonate, an
equivalent substrate without this functional group was
O
R
O
R
MeCN
X
O
X
Ph
Ph
+
+
Ph
H
R
X
reflux, 15 min
O
Co2(CO)6
O
1
2, 8, 9
3, 10, 12
4, 11, 13
Scheme 4
Synlett 2010, No. 4, 649–653 © Thieme Stuttgart · New York

652
J. L. Kędzia et al.
LETTER
A.; Shanahan, C. S.; Martin, S. F. Tetrahedron 2008, 64,
6884. (d) Crawford, J. J.; Kerr, W. J.; McLaughlin, M.;
Morrison, A. J.; Pauson, P. L.; Thurston, G. J. Tetrahedron
2006, 62, 11360. (e) Furuya, S.; Terashima, S. Tetrahedron
Lett. 2003, 44, 6875. (f) Ishizaki, M.; Niimi, Y.; Hoshino, O.
Tetrahedron Lett. 2003, 44, 6029.
Table 5 Probing the Alkene Functionality in P–K Cyclisations of
Phenylacetylene Complex 1a
Entry
X
R
Yield (%) Selectivity
1
2
3
O
2 P(O)(OEt)2
8 H
66
81
28
12:1 (3/4)
6:1 (10/11)
3:1 (12/13)
(4) Magnus, P.; Principle, L. M. Tetrahedron Lett. 1985, 26,
4581.
O
(5) (a) Krafft, M. E. J. Am. Chem. Soc. 1988, 110, 968.
(b) Krafft, M. E.; Juliano, C. A.; Scott, I. L.; Wright, C.;
McEachin, M. D. J. Am. Chem. Soc. 1991, 113, 1693.
(c) Krafft, M. E.; Juliano, C. A. J. Org. Chem. 1992, 57,
5106. (d) See also: Krafft, M. E. Tetrahedron Lett. 1988, 29,
999.
(6) Brown, J. A.; Janecki, T.; Kerr, W. J. Synlett 2005, 2023.
(7) (a) Kelly, S. E. In Comprehensive Organic Synthesis, Vol.
1; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 729. (b) Thirsk, C.; Whiting, A. J. Chem. Soc., Perkin
Trans. 1 2002, 999. (c) Wadsworth, W. S.; Emmons, W. D.
J. Am. Chem. Soc. 1961, 83, 1733. (d) Wadsworth, W. S.;
Emmons, W. D. Org. Synth. 1973, 5, 547.
(8) (a) Clarke, H. T. J. Chem. Soc., Trans. 1910, 97, 416.
(b) Tőke, L.; Jászay, Z. M.; Petneházy, I.; Clementis, G.;
Vereczkey, G. D.; Kövesdi, I.; Rockenbauer, A.; Kováts, K.
Tetrahedron 1995, 51, 9167.
(9) (a) Brown, J. A.; Kerr, W. J.; Irvine, S.; Pearson, C. M. Org.
Biomol. Chem. 2005, 3, 2396. See also: (b) Sugihara, T.;
Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett 1999,
771. (c) Kerr, W. J.; Lindsay, D. M.; McLaughlin, M.;
Pauson, P. L. Chem. Commun. 2000, 1467.
(10) (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
Tetrahedron Lett. 1990, 31, 5289. (b) Jeong, N.; Chung,
Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204.
(c) Gordon, A. R.; Johnstone, C.; Kerr, W. J. Synlett 1995,
1083. (d) Donkervoort, J. G.; Gordon, A. R.; Johnstone, C.;
Kerr, W. J.; Lange, U. Tetrahedron 1996, 52, 7391.
(11) Sugihara, T.; Yamada, M.; Ban, H.; Yamaguchi, M.;
Kaneko, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2801.
(12) General Experimental Procedure
CH2
9 P(O)(OMe)2
a All reactions were carried out following the general procedure out-
lined in ref. 12.
when phosphonate 9 was employed, a significantly dimin-
ished 3:1 regioisomeric ratio was obtained, as well as a
low 28% isolated yield. This result supports the hypothe-
sis that the carbonyl functional unit, as well as the phos-
phorus component, plays an influential role in the
regiochemical outcome of the P–K annulations with ex-
tended phosphonate systems as described here.
In summary, as part of an ongoing programme of work
within our laboratory to increase the efficiency and appli-
cability of intermolecular Pauson–Khand reactions, we
have now demonstrated the use of an extended class of
olefins possessing a tethered phosphonate ester unit. Un-
der optimised reaction conditions, and without the re-
quirement for any additional promoters or additives, these
phosphorus-possessing alkenes act as effective P–K cycli-
sation partners and deliver functionalised cyclopenten-
ones, of obvious further synthetic utility, with good levels
of regiochemical control.
Acknowledgment
We thank the Royal Society for an International Incoming Short Vi-
sits grant (JLK; IV0871842), AstraZeneca for generous funding of
our research, and the EPSRC Mass Spectrometry Service, Swansea
University, for analyses.
A 25 mL three-necked round-bottomed flask was fitted with
a condenser, flame-dried under vacuum, and allowed to cool
under nitrogen. The vessel was charged with dry MeCN (7.5
mL) and the phosphonate ester (0.75 mmol). The reaction
mixture was heated slowly to reflux and a solution of the
desired cobalt complex (0.25 mmol) in dry MeCN (2.5 mL)
was then added over 1 h via syringe pump. Following
complete addition, heating was continued at reflux for 15
min. After this time, the reaction mixture was concentrated
to dryness, dissolved in EtOAc, and filtered through Celite
to remove cobalt residues. The filtrate was concentrated, and
the crude product was purified by silica column
References and Notes
(1) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.
J. Chem. Soc., Chem. Commun. 1971, 36. (b) Khand, I. U.;
Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I.
J. Chem. Soc., Perkin Trans. 1 1973, 977.
(2) (a) Pauson, P. L. Tetrahedron 1985, 41, 5855. (b) Schore,
N. E. In Comprehensive Organic Synthesis, Vol. 5; Trost, B.
M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 1037.
(c) Schore, N. E. Org. React. 1991, 40, 1. (d) Schore, N. E.
In Comprehensive Organometallic Chemistry II, Vol. 12;
Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Elsevier:
New York, 1995, 703. (e) Geis, O.; Schmalz, H.-G. Angew.
Chem. Int. Ed. 1998, 37, 911. (f) Chung, Y. K. Coord.
Chem. Rev. 1999, 188, 297. (g) Brummond, K. M.; Kent,
J. L. Tetrahedron 2000, 56, 3263. (h) Chin, C. S.; Won, G.;
Chong, D.; Kim, M.; Lee, H. Acc. Chem. Res. 2002, 35, 218.
(i) Gibson, S. E.; Mainolfi, N. Angew. Chem. Int. Ed. 2005,
44, 3022. (j) Laschat, S.; Becheanu, A.; Bell, T.; Baro, A.
Synlett 2005, 2547. (k) Omae, I. Appl. Organomet. Chem.
2007, 21, 318.
chromatography to yield the desired regioisomeric
cyclopentenones.
Sample Compound Data
Compound 6e: IR (CH2Cl2): n = 1027, 1053, 1256, 1275,
1703, 1740 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.90 (t, 3
H, 3JHH = 7.2 Hz), 1.28–1.37 (m, 8 H), 1.42–1.50 (m, 2 H),
2.15–2.19 (m, 2 H), 2.50–2.53 (m, 1 H), 2.67–2.80 (m, 2 H),
2.92 (d, 2 H, 2JPH = 21.6 Hz), 4.09–4.19 (m, 4 H), 4.28 (dd,
1 H, 2JHH = 11.0 Hz, 3JHH = 6.3 Hz), 4.46 (dd, 1 H,
2JHH = 11.0 Hz, 3JHH = 4.0 Hz), 7.30 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): d = 207.6, 165.8 (d, 2JPC = 6.2 Hz),
156.5, 146.1, 64.8, 62.8 (d, 2JPC = 6.9 Hz), 62.7 (d, 2JPC = 6.7
Hz), 44.6, 34.2 (d, 1JPC = 134.0 Hz), 30.8, 29.7, 24.5, 22.4,
16.34, 16.28, 13.8 ppm. 31P NMR (162 MHz, CDCl3):
d = 19.41 ppm. HRMS (EI): m/z calcd for C16H28O6P
[M++H]: 347.1618; found: 347.1623.
(3) For examples, see: (a) Mahesh, K. P.; Fox, J. M. Org. Lett.
2007, 9, 5625. (b) Kerr, W. J.; McLaughlin, M.; Morrison,
A. J.; Pauson, P. L. Org. Lett. 2001, 3, 2945. (c) Miller, K.
Synlett 2010, No. 4, 649–653 © Thieme Stuttgart · New York

LETTER
Compound 7e: 1H NMR (400 MHz, CDCl3): d = 0.92 (t, 3 H,
Regioselective Pauson–Khand Processes with Olefins
used to determine the representative signals for the
653
3JHH = 7.3 Hz), 1.25–1.50 (m, 10 H), 2.14–2.20 (m, 3 H),
2.59 (dd, 1 H, 2JHH = 18.9 Hz, 3JHH = 6.6 Hz), 2.99 (d, 2 H,
2JPH = 21.5 Hz), 3.14–3.23 (m, 1 H), 4.12–4.24 (m, 6 H),
7.23 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): d = 208.0,
166.0 (d, 2JPC = 6.3 Hz), 156.1, 148.5, 67.3, 63.1 (d,
2JPC = 6.0 Hz), 38.38, 38.36, 34.5 (d, 1JPC = 133.5 Hz), 30.5,
24.7, 22.6, 16.60, 16.56, 14.0 ppm. 31P NMR (162 MHz,
CDCl3): d = 19.35 ppm.
individual proton and carbon atoms. The regiochemistry of
7e was then determined by coupling correlations in the
COSY spectrum and, specifically, with respect to the
cyclopentenone C-4 methine proton showing direct coupling
interactions with the C-3 olefinic proton, as well as the C-5
methylene unit and the O-methylene protons in the pendant
side chain. The COSY spectrum for the 2,5-isomer 6e shows
no coupling between the C-5 methine unit and the C-3
olefinic proton, whereas the same olefinic proton in this
isomer does show a coupling interaction with the C-4
methylene unit. In all other cases (3, 4, 6a–d, 7a–d, 10, 11,
12, 13), the identity of the specific regioisomers was
established more routinely through characteristic olefinic
coupling patterns.
The ratio of 6e/7e in the unseparated mixture was calculated
from the relative integral values of the proton NMR signals
at d = 7.30 ppm (6e) and 7.23 ppm (7e). All other
regioisomeric ratios were established in a similar fashion.
Isomer 7e was identified specifically as the 2,4-disubstituted
cyclopentenone through the use of two-dimensional NMR
experiments. Firstly, HSQC and HMBC techniques were
Synlett 2010, No. 4, 649–653 © Thieme Stuttgart · New York