Tandem Michael/Michael reactions mediated by phosphines or aryl thiolates

Article abstract of DOI:10.1016/S0040-4039(02)02142-1

tri-n-Butyl phosphine was found to effect tandem Michael/Michael cyclisations leading to the formation of cyclopentenes and cyclohexenes in good yields, whilst p-TolSH in conjunction with a catalytic amount of p-TolSNa effected cyclisation to the correspo

Full text of DOI:10.1016/S0040-4039(02)02142-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8707–8710
Tandem Michael/Michael reactions mediated by phosphines or
aryl thiolates
Paul M. Brown, Nina K a¨ ppel and Patrick J. Murphy*
Department of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, UK
Received 3 September 2002; accepted 26 September 2002
Abstract—tri-n-Butyl phosphine was found to effect tandem Michael/Michael cyclisations leading to the formation of cyclopente-
nes and cyclohexenes in good yields, whilst p-TolSH in conjunction with a catalytic amount of p-TolSNa effected cyclisation to
the corresponding cyclopentanes and cyclohexanes. © 2002 Published by Elsevier Science Ltd.
1
We have previously described the ability of a range of
nucleophiles, including secondary amines, thiols and
phosphines to effect a tandem intramolecular Michael/
aldol cyclisation of enones 1 leading to either the
adducts 2 or the eliminated Baylis–Hillman type
cyclisations of this type have also been previously
3
4
reported using a range of carbanions, metal thiolates
5
and metal amides together with sequences initiated by
6
free radicals.
1
product 3 (Scheme 1).
We began our investigation of this process by embark-
ing on an investigation of the scope of the reaction with
regards to the nature of the electron withdrawing group
on the alkene and the ring size of the product formed.
We thus prepared bis-enones 5a–g from the aldehydes 4
We wished to investigate potential developments of this
reaction and envisaged that a similar Michael/Michael
sequence might offer a flexible route to cycloalkenes.
We are prompted to report our findings following the
publication of related work by Roush et al. who have
reported their studies on this reaction which they refer
to as a ‘vinylogous Morita–Baylis–Hillman reaction’ and
1
,7
using our previously reported Wittig methodology
and treated them with a catalytic amount of n-Bu3P
(0.2–0.6 equiv.) in chloroform at rt. (Scheme 2, Table
1). We were pleased to find that the phenyl enones 5a
and 5b both underwent cyclisation to give the corre-
sponding cyclopentene 6a and cyclohexene 6b in high
Krische et al. who refer to this process as the
intramolecular Rauhut–Currier reaction’. Tandem
2
‘
+
Scheme 1. Reagents and conditions: (a) R NH, R P, TolSH, n=1, 2; R=alkyl, Ph, OR; X=R N, R P , TolS.
2
3
2
3
Scheme 2. Reagents and conditions: (a) 2 equiv. RCOCHꢀPPh , 44–63% (see Refs. 1 and 7); (b) see Table 1.
3
Keywords: tandem reactions; Michael additions.
*
Corresponding author.
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02142-1

8
708
P. M. Brown et al. / Tetrahedron Letters 43 (2002) 8707–8710
Table 1.
Entry
5
R=
n
Methoda
6
Yieldb (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
OMe
OMe
Me
Me
1
2
3
1
2
1
2
0.3 equiv., n-Bu P, 16 h
6a
6b
6c
6d
6e
6f
80
68
0
0
0
3
0.3 equiv., n-Bu P, 4 h
3
c
0.3 equiv., n-Bu P, 21 days
3
d
0.3 equiv., n-Bu P, 4 days
3
d
0.3 equiv., n-Bu P, 4 days
3
0.2 equiv., n-Bu P, 5 h
66
58
3
5g
0.2 equiv., n-Bu P, 16 h
6g
3
a
Reactions were performed in chloroform (ca. 1–2 ml per mmol of substrate) at rt.
All new compounds gave satisfactory analytical data.
A further 0.3 equiv. of phosphine added after 1 week.
b
c
d
A further 0.3 equiv. of phosphine added after 1 day and the reaction was refluxed for 16 h.
yield (entries 1, 2), whereas the substrate 5c, which
would generate a seven-membered product, was resis-
tant to cyclisation under these conditions even after
prolonged periods (entry 3). Similarly cyclisation of the
enoate substrates 5d and 5e was also unsuccessful,
possibly reflecting a low reactivity of enoates in
We also investigated the enone 8a and enoate 8b in which
the two Michael acceptors are linked by an aromatic ring
and found that these displayed similar reactivities to the
previous examples. Thus, the enone substrate 8a cyclised
smoothly to give the isomeric indenes 9a and 10a in
excellent overall yield, whilst the enoate 8b was resistant
to cyclisation under these conditions (Scheme 3).
2
Michael addition, (entries 4, 5). We also investigated
the methyl enones 5f and 5g and found that they also
underwent cyclisation in good yield (entries 6, 7)
We investigated the lack of reactivity of the enoate
substrates in more detail and prepared the mixed sub-
(
Scheme 2).
Scheme 3. Reagents and conditions: (a) 2 equiv. RCOCHꢀPPh ; 42% (8a), 85% (8b). (b) 0.3 equiv. n-Bu P, CHCl , rt, 16 h.
3
3
3
Scheme 4. Reagents and conditions: (a) 0.3 equiv. n-Bu P, CHCl , rt, or 0°C–rt, 16 h.
3
3

P. M. Brown et al. / Tetrahedron Letters 43 (2002) 8707–8710
8709
strates 11 and 13. Treatment of 11 with n-Bu P under
Table 2.
3
our standard conditions led to the formation of the
Entry
5
R=
R1
n
18; %
19; %
20; %
cyclised product 12 as the only product, highlighting
the low reactivity of the enoate to phosphine addition,
but confirming that the enoate is a suitable acceptor for
the cyclisation step of the tandem process. Substrate 13
allowed us to investigate the relative reactivity of the
two enones we employed and not surprisingly we found
that a 76:24 mixture of products 14 and 15 were formed
in which the product 14 arising from initial Michael
addition to the phenyl substituted enone was preferred.
Repetition of the reaction at 0°C gave a slightly
improved selectivity for the formation of 14 (Scheme 4).
1
2
3
4
5
5a Ph
5b Ph
5d OMe
5e
11 Ph
Ph
Ph
OMe
OMe
OMe
1
2
1
2
2
18a; 58
18b; 59
18d; 0
18e; 0
–
–
–
–
–
–
67
40
–
OMe
18f; 14
56
mers (entries 1 and 2). Structural determination was
based on the presence of large trans-diaxial coupling
constants for the methine proton at C-2 of the product
1
8b (J=10.5, 11 Hz) and corroborating NOE measure-
ments. Similar reaction of the enoate substrates 5d and
e were unsuccessful under all the conditions employed
We believe that products derived from these tandem
processes have potential applications in synthesis and
have initially investigated the aldol cyclisation of the
enones 6f and 6g. We found that treatment of these
under basic conditions led to the formation of the
bicyclic products 16 and 17 in reasonable yields
5
leading only to the Michael adducts 20d and 20e.
However, when we treated the mixed enone/enoate
substrate 11 under these conditions we were pleased to
find that two cyclisation products 18f and 19 were
formed in high overall yield (entry 5). The reason for
the formation of a mixture of products in this reaction
and the predominance of 19 as the major product is
unclear; however, the steric differences between the
methyl ester and the aryl ketone may be a factor. This
reaction does however demonstrate that an enone is
required for an effective cyclisation, a factor that is
probably associated with the ability to form an enol/
enolate under the conditions employed (Scheme 6).
(
Scheme 5).
We next investigated the thiol catalysed cyclisation of
the substrates 5a,b,d,e and 11 and were disappointed to
find that all these substrates were resistant to cyclisa-
tion when treated with p-TolSH at rt or at reflux and
only the products 20 of a single Michael addition of the
thiol to the enone was observed. We next employed
alternative conditions in which a catalytic amount of
TolSNa was added to the reaction which was then
heated at reflux in THF (Scheme 6). We were pleased to
find that both the enone substrates 5a and 5b under-
went cyclisation to the corresponding carbocycles 18a
and 18b in good yield and as essentially single stereoiso-
In conclusion, we have found that the tandem Michael/
Michael cyclisation of bis-enones is a viable process for
the preparation of five- and six-membered carbocycles;
however, it does not appear to be applicable to the
synthesis of larger ring systems, a fact also largely
apparent in our studies on tandem Michael/aldol reac-
1
tions. In addition the use of bis-enoates in these pro-
cesses does not appear feasible, however they are
suitable acceptor groups in mixed enone/enoate sub-
strates. A general order of reactivity towards addition
of phosphines was also established and appears to be
Ph>Me>>>OR.
Acknowledgements
Thanks are given to the EPSRC for a studentship to
PMB (GR/M50584) and to the EPSRC Mass spec-
trometry centre at Swansea.
t
t
Scheme 5. Reagents and conditions: (a) KO Bu, BuOH, rt, 16
h.
Scheme 6. Reagents and conditions: (a) 0.9 equiv. TolSH, 0.2 equiv. TolSNa, D, THF, 16 h and see Table 2.

8
710
P. M. Brown et al. / Tetrahedron Letters 43 (2002) 8707–8710
4. (a) Voigt, K.; Lansky, A.; Noltemeyer, M.; de Meijere, A.
References
Leibigs 1996, 899–911; (b) Erguden, J.-K.; Moore, H. W.
Org. Lett. 1999, 1, 375–377; (c) Chavan, S. P.; Subbarao,
Y. T.; Chittiboyina, A. G.; Sivappa, R.; Suresh, C. G.
Tetrahedron: Asymmetry 2001, 12, 1101–1103.
. (a) Uyehara, T.; Shida, N.; Yamamoto, Y. J. Chem. Soc.,
Chem. Commun. 1989, 753–754; (b) Uyehara, T.; Shida, N.;
Yamamoto, Y. J. Org. Chem. 1992, 57, 3139–3145; (c)
Shida, N.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1992,
1
. (a) Black, G. P.; Dinon, F.; Fratucello, S.; Murphy, P. J.;
Nielsen, M.; Williams, H. L.; Walshe, N. D. A. Tetrahedron
Lett. 1997, 38, 8561–8564; (b) Dinon, F.; Richards, E. L.;
Murphy, P. J.; Hibbs, D. E.; Hursthouse, M. B.; Malik, K.
M. A. Tetrahedron Lett. 1999, 40, 3279–3282; (c) Richards,
E. L.; Murphy, P. J.; Dinon, F.; Fratucello, S.; Brown, P.
M.; Gelbrich, T.; Hursthouse, M. B. Tetrahedron 2001, 57,
5
5
7, 5049–5051; (d) Urones, J. G.; Garrido, N. M.; Diez, D.;
Dominguez, S. H.; Davies, S. G. Tetrahedron: Asymmetry
997, 8, 2683–2685; (e) Urones, J. G.; Garrido, N. M.; D ´ı ez,
7
771–7784.
2
. (a) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem.
Soc. 2002, 124, 2404–2405; (b) Wang, L.-C.; Luis, A. L.;
Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc.
1
D.; Dominguez, S. H.; Davies, S. G. Tetrahedron: Asymme-
try 1999, 10, 1637; (f) Bull, S. D.; Davies, S. G.; Smith, A.
D. J. Chem. Soc., Perkin Trans. 1 2001, 2931–2938.
2
002, 124, 2402–2403.
3
. (a) Saito, S.; Hirohara, Y.; Narahara, O.; Moriwake, T. J.
Am. Chem. Soc. 1989, 111, 4533–4535; (b) Klimko, P. G.;
Singleton, D. A. J. Org. Chem. 1992, 57, 1733–1740; (c)
Cooke, M. P.; Gopal, D. Tetrahedron Lett. 1994, 35,
6
. (a) Renaud, R. N.; Stephens, C. J.; B e´ rub e´ , D. Can. J. Chem.
1982, 60, 1687–1691; (b) Boger, D. L.; Mathvink, R. J. J.
Am. Chem. Soc. 1990, 112, 4003–4008; (c) Suwa, T.;
Nishino, K.; Miyatake, M.; Shibata, I.; Baba, A. Tetra-
hedron Lett. 2000, 41, 3403–3406.
2
837–2840; (d) Klimko, P. G.; Singleton, D. A. Synthesis
1
994, 979–982; (e) Savchenko, A. V.; Montgomery, J. J.
7. (a) Murphy, P. J.; Williams, H. L.; Hibbs, D. E.; Hurst-
house, M. B.; Malik, K. M. A. Tetrahedron 1996, 52,
8315–8332; (b) Black, G. P.; Murphy, P. J.; Walshe, N. D.
A. Tetrahedron 1998, 54, 9481–9488.
Org. Chem. 1996, 61, 1562–1563; (f) Montgomery, J.;
Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 49,
4
911–4920.