A new manifold for the Morita reaction: Diene synthesis from simple aldehydes and acrylates/acrylonitrile mediated by phosphines

Article abstract of DOI:10.1039/b709157e

Dienes have been formed with good stereoselectivity and in good yield from simple aldehydes and acrylates/acrylonitrile in the presence of a phosphine and a Lewis acid through a modification of the Morita reaction. The Royal Society of Chemistry.

Full text of DOI:10.1039/b709157e

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A new manifold for the Morita reaction: diene synthesis from simple
aldehydes and acrylates/acrylonitrile mediated by phosphines{
Anders Palmelund, Eddie L. Myers, Lik Ren Tai, Steve Tisserand, Craig P. Butts and Varinder K. Aggarwal*
Received (in Cambridge, UK) 18th June 2007, Accepted 6th July 2007
First published as an Advance Article on the web 26th July 2007
DOI: 10.1039/b709157e
particularly in the basic environment of the MBH as described by
Oda et al. (Scheme 2).12 We therefore undertook a re-examination
of the Morita reaction.
Dienes have been formed with good stereoselectivity and in
good yield from simple aldehydes and acrylates/acrylonitrile in
the presence of a phosphine and a Lewis acid through a
modification of the Morita reaction.
The Morita–Baylis–Hillman (MBH) reaction (the phosphine or
amine catalysed hydroxyalkylation of activated alkenes) is an
important tool in organic synthesis as it converts cheap, readily
available substrates into densely functionalised products in an
atom economic process. Reminiscent of earlier work by Rauhut
and Currier1 (the phosphine catalysed dimerisation of acrylates),
the reaction wasintroduced byMoritainthe form ofan(inefficient)
intermolecular phosphine catalysed transformation (Scheme 1).2
Shortly afterwards, Baylis and Hillman filed a patent describing the
more efficient amine catalysed variant that is now commonly
employed.3 Since then there has been substantial development with
regard to enhancement of rates,4 production of enantiomerically
enriched products,5 and expansion of substrate scope.4a,6
Scheme 2 Results by Oda and co-workers.
Using Morita’s conditions and PBu3 as catalyst, we confirmed
the low conversion to MBH adduct 1. However, in addition,
tributylphosphine oxide and traces of dienes 2 were also observed,
indicative of ylidic intermediates and Wittig-type transformations.
Such processes would remove the catalytic amounts of phosphine,
thus slowing down the reaction (Scheme 3). Altering the conditions
to promote diene formation [acrylonitrile (1.0 eq.), PBu3 (1.0 eq.)
and benzaldehyde (2 eq.), 1,4-dioxane, RT, 24 h] resulted in the
formation of all 4 possible stereoisomers of diene 2 in 17% yield.
Scheme 1 Example from Morita’s original work.
Scheme 3 Repeating Morita’s original work.
The mechanism of the amine catalysed reaction is well
understood and the importance of the requisite proton transfer
event (1,3-proton transfer), established as the RDS, has been
highlighted in our laboratory and that of McQuade.7 Recently,
DFT calculations on the phosphine catalysed variant support the
same RDS and a fully and more rapidly reversible reaction
(compared to amines).8 However, it is observed that, whilst amines
are the catalyst of choice for most intermolecular transformations,
phosphines have often been found to be superior in intramolecular
variants.9 In particular, the inefficiency of the seminal work
(Scheme 1) was intriguing. Although the low yield may reflect a
Keq value of less than unity of a fully reversible9c and dilute
reaction at high temperature,10 we were mindful of potentially
important differences between amines and phosphines, such as the
latter’s greater nucleophilicity, inferior leaving group ability11
and much increased propensity to form ylidic intermediates,
A solvent screen suggested that toluene or dichloromethane
were optimum. The phosphine was also varied: PBu3 gave good
conversion, PCy3 resulted in a sluggish reaction and PtBu3 or PPh3
gave no conversion.13 Using 2 equivalents of PBu3 and PhCHO
and 1.6 equivalents of acrylonitrile resulted in an improved yield
(45%). In addition, three side-products were formed and identified
as the Oda-product 3 (EWG 5 CN, 5%), 4-oxo-4-phenylbutane-
nitrile (10%), and 2-hydroxy-1,2-diphenylethanone (21%), the
latter two formed by Stetter reaction and benzoin condensation
respectively. To inhibit these processes, Lewis acids were added to
the reaction mixture. The addition of 2 equivalents of Ti(OiPr)4
improved the yield to 66% and furthermore only two of the four
possible stereoisomers were now formed in a 4 : 1 ratio. With these
optimised conditions in hand the substrate scope with respect to
the aldehyde was evaluated (Table 1).
Aliphatic aldehydes worked well (entries 1–3), although
sterically demanding aldehydes resulted in somewhat reduced
yields but higher stereoselectivity (compare entries 1 and 3).
Aromatic aldehydes with electron donating/neutral groups
worked well (entries 4–7) but increasing electron withdrawing
groups resulted in reduced yields (entries 8 and 9). Employing
School of Chemistry, University of Bristol, Bristol, UK BS8 1TS.
E-mail: V.Aggarwal@bris.ac.uk; Fax: +44 (0) 117 929 8611;
Tel: +44 (0) 117 954 6315
{ Electronic supplementary information (ESI) available: Detailed experi-
mental procedures and analytical data for all products. See DOI: 10.1039/
b709157e
4128 | Chem. Commun., 2007, 4128–4130
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ortho-substituted aromatic and aliphatic dialdehydes gave cyclic
mixture of all four possible dienes indicating a relatively rapid
retro-MBHR (Scheme 4).9c
dienes (entries 10 and 11).
Table 1 Substrate scope with acrylonitrilea
Entry
R
Yieldb
Ratioc
Major product
1
2
3
4
5
6
7
8
9
Et
Cy
86%
96%
59%
80%
66%
71%
61%
43%
0%
3 : 1
4 : 1
4a
4b
4c
4dc
4e
4f
4g
4h
—
4i
tBu
6 : 1
Scheme 4 Initial attempts to form unsymmetrical dienes.
d
Ph–CLC
Ph
In order to inhibit the retro-MBHR, the hydroxyl group was
exchanged for a methoxy ether. Although this compound can be
obtained by alkylation of the MBH adduct, we and others have
found that such compounds can be obtained directly through a
vinylogous Sakurai reaction of acetals (Scheme 5).14,15
4 : 1
4 : 1
5 : 1
3 : 1
—
p-MeO–Ph
o-Me–Ph
p-Br–Ph
p-CN–Ph
o-CHO–Phe
OHC–(CH2)3
10
11
a
76%
41%f
—
—
4j
Reaction conditions: PBu3 (1.0 mmol) added to acrylonitrile
(0.8 mmol), aldehyde (1.0 mmol) and Ti(OiPr)4 (1.0 mmol) in
CH2Cl2 (2 ml) under N2 and stirred for 15 h. Based on aldehyde.
b
c
Z : E ratio of trisubstituted olefin. Disubstituted olefin is always E.
A mixture of several of the possible 8 isomers was isolated.
d
e
f
0.5 mmol of dialdehyde used. 5 mmol glutaraldehyde used, yield
based on acrylonitrile.
Scheme 5
Adduct 6 was treated with tributylphosphine in the presence of
different aldehydes (Table 3). The reaction worked well with both
aliphatic (entries 1–2) and aromatic (entries 3–5) aldehydes and the
stereoselectivity observed in the one-pot procedure was retained.16
The reaction was also performed on ethyl acrylate as the
activated olefin (Table 2). Similar results were obtained, although
in this case the sterically encumbered pivaldehyde failed to react
(entry 3).
Table 3 Preparation of unsymmetrical dienesa
Table 2 Substrate scope with ethyl acrylatea
Entry
R
Yieldb
Ratioc
Major product
Entry
R
Yield
Ratiob
Major product
1
2
3
4
5
6
7
8
9
Et
Cy
89%
74%
Trace
84%
83%
63%
30%
0%
3 : 1
4 : 1
—
5 : 1
4 : 1
5 : 1
3 : 1
—
5a
5b
—
5e
5f
5g
5h
—
5i
1
2
3
4
5
a
Et
Cy
p-MeO–Ph
o-Me–Ph
p-CF3–Ph
57%
75%
75%
68%
95%
5 : 1
7 : 1
5 : 1
4 : 1
4 : 1
7a
7b
7c
7d
7e
tBu
Ph
p-MeO–Ph
o-Me–Ph
p-Br–Ph
p-CN–Ph
o-CHO–Phd
OHC–(CH2)3
Reaction conditions: PBu3 (0.6 mmol) added to 6 (0.5 mmol) and
aldehyde (0.5 mmol) in THF (2 ml) under N2 and the mixture
stirred for 15 h. Z : E ratio of trisubstituted olefin. Disubstituted
olefin is always E.
b
20%
43%e
—
—
10
a
5j
Reaction conditions: PBu3 (1.0 mmol) added to ethyl acrylate
(0.8 mmol), aldehyde (1.0 mmol) and Ti(OiPr)4 (1.0 mmol) in
CH2Cl2 (2 ml) under N2 and stirred for 15 h. Based on aldehyde.
Possible pathways for the formation of dienes are depicted in
Scheme 6. Conjugate addition of the phosphine to the activated
olefin followed by addition to the aldehyde furnishes alkoxide 8.
At this point, three different proton transfers can be envisioned. A
1,4-proton transfer gives the ylide 9, which undergoes a Wittig
reaction followed by elimination of water to give the diene. An
alternative pathway is a 1,3-proton transfer (mediated by RCHO
or traces of water)7 to enolate 10, followed by elimination of
hydroxide to give 11. Deprotonation then furnishes the ylide 12,
which undergoes the Wittig reaction leading to the diene. The
intermediate enolate 10 could also be obtained from 8 through
sequential 1,6- and 1,4-proton transfer events—processes that are
unique to alkyl phosphines. The zwitterions obtained via 1,3- and
b
c
Z : E ratio of trisubstituted olefin. Disubstituted olefin is always E.
0.5 mmol of the dialdehyde used. 5 mmol glutaraldehyde used,
yield based on ethyl acrylate.
d
e
Diene stereochemistry was determined by a combination of
NMR spectroscopy and computational methods and is detailed in
the ESI.{
The products described incorporate two identical aldehyde
molecules. In order to obtain substrates with non-identical groups
we attempted the reaction between a preformed MBH adduct and
a second (different) aldehyde under the same reaction conditions
[PBu3 (1.0 eq.) and Ti(OiPr)4 (1.0 eq.)]. However, this gave a
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1,4-proton transfer (10 and 9 respectively) may be interconvertible
via 1,2-proton transfer. It is also possible that the Oda ylide 13,
formed via 1,2-proton transfer of the initially formed phospho-
nium enolate, could also lead to diene via a Wittig reaction
followed by a Lewis acid-catalysed aldol condensation.
We thank ICI (Dr Charles Sell) and DSM (Prof. Hans de Vries)
for financial support to ST and ELM respectively. We also thank
EPSRC for support of this work and VKA thanks the Royal
Society for a Wolfson Research Merit Award.
Notes and references
1 M. Rauhut and H. Currier, US Patent, 3,074,999, 1963.
2 K. Morita, Z. Suzuki and H. Hirose, Bull. Chem. Soc. Jpn., 1968, 41,
2815.
3 (a) A. B. Baylis and M. E. D. Hillman, Offenlegungsschrift, 2155113,
1972 (US Patent, 3,743,669, 1972); (b) A. B. Baylis and M. E. D.
Hillman, Chem. Abs., 1972, 77, 34174q. For reviews see: (c)
D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003,
103, 811; (d) S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988, 44,
4653; (e) E. Ciganek, Org. React. (N. Y.), 1997, 51, 201; (f)
D. Basavaiah, P. D. Rao and R. S. Hyma, Tetrahedron, 1996, 52, 8001.
4 (a) V. K. Aggarwal, I. Emme and S. Y. Fulford, J. Org. Chem., 2003,
68, 692; (b) K.-S. Park, J. Kim, H. Choo and Y. Chong, Synlett, 2007,
395; (c) J. Cai, Z. Zhou and C. Tang, Org. Lett., 2002, 4, 4723; (d)
V. K. Aggarwal, D. K. Fean, A. Mereu and R. Williams, J. Org. Chem.,
2002, 67, 510; (e) S. Luo, B. Zhang, J. He, A. Janczuk, P. G. Wang and
J.-P. Cheng, Tetrahedron Lett., 2002, 43, 7369; (f) C. Yu, B. Liu and
L. Hu, J. Org. Chem., 2001, 66, 5413; (g) J. Auge, N. Lubin and
A. Lubineau, Tetrahedron Lett., 1994, 35, 7947; (h) F. Ameer,
S. E. Drewes, S. Freese and P. T. Kaye, Synth. Commun., 1988, 18, 495.
5 (a) Y. Iwabuchi, M. Nakatani, N. Yokoyama and S. Hatekeyama,
J. Am. Chem. Soc., 1999, 121, 10219. For reviews on asymmetric MBH
reactions, see: (b) P. Langer, Angew. Chem., Int. Ed., 2000, 39, 3049; (c)
G. Masson, C. Housseman and J. Zhu, Angew. Chem., Int. Ed., 2007,
46, 4614.
6 (a) C. Faltin, E. M. Fleming and S. J. Connon, J. Org. Chem., 2004, 69,
6496; (b) C. Yu and L. Hu, J. Org. Chem., 2002, 67, 219.
7 (a) V. K. Aggarwal, S. Y. Fulford and G. C. Lloyd-Jones, Angew.
Chem., Int. Ed., 2005, 44, 1706; (b) K. E. Price, S. J. Broadwater,
B. J. Walker and D. T. McQuade, J. Org. Chem., 2005, 70, 3980. (c)
Insight into the mechanisms for 1,3-proton transfer have been
established through DFT calculations. See: R. Robiette,
V. K. Aggarwal and J. N. Harvey, J. Am. Chem. Soc., 2007, DOI:
10.1021/ja717865.
Scheme 6 Proposed pathways for diene formation.
The transformation to dienes using the methylated MBH
adducts supports the relevance of dehydration–Wittig sequence (10
A 11 A 12) but the alternative pathways may also be in operation,
particularly in those reactions without Lewis acid. The alternative
proton transfer events presented here, which are specific to alkyl
phosphonium intermediates, may be more relevant in intramole-
cular MBH catalysis where amines but not phosphines require
protic additives.17
8 J. Xu, J. Mol. Struct.: THEOCHEM, 2006, 767, 61.
9 (a) M. E. Kraft, T. F. N. Haxell, K. A. Seibert and K. A. Abboud,
J. Am. Chem. Soc., 2006, 128, 4174; (b) W.-D. Teng, R. Huang,
C. K.-W. Kwong, M. Shi and P. H. Toy, J. Org. Chem., 2006, 71, 368;
(c) F. Roth, P. Gynax and G. Fra´ter, Tetrahedron Lett., 1992, 33, 1045.
In the presence of phenols, the intermolecular reaction can also give
moderate–high yields, see: (d) M. Shi and W. Zhang, Tetrahedron, 2005,
61, 11887; (e) Y. M. A. Yamada and S. Ikegami, Tetrahedron Lett.,
2000, 41, 2165.
10 From DFT calculations it has been found that the BHR is slightly
exothermic (y5 kcal mol21) at RT. However, it is entropically
unfavourable so should have DG at RT y 0 kcal mol21. See ref. 7c.
11 V. K. Aggarwal, J. N. Harvey and R. Robiette, Angew. Chem., Int. Ed.,
2005, 44, 5468.
12 R. Oda, T. Kawabata and S. Tanimoto, Tetrahedron Lett., 1964, 1653.
13 A recent communication has highlighted that while triarylphosphonium
enolates exhibit substantial oxaphosphatane character, trialkylpho-
sphonium enolates do not: X.-F. Zhu, C. E. Henry and O. Kwon,
J. Am. Chem. Soc., 2007, 129, 6722. Considering this, the lack of
catalysis using PPh3 under our conditions (without Lewis acid or protic
additive) may be due to the formation of a stable oxaphosphatane of
poor nucleophilicity.
This analysis may shed some light on the origin of the low yields
in the original Morita reaction involving alkyl phosphines2 and
why in the presence of phenols high yields can be achieved.9d,e In
the original Morita reaction the high temperature will result in Keq
, 1 and some of the myriad intermediates may also follow
alternative pathways; both factors contributing to low yields. In
contrast, at RT, (Keq y 1) and in the presence of phenol rapid
alcohol-assisted 1,3-proton transfer (8 A 10)7a,7c followed by
elimination (10 A 1) occurs and many of the alternative pathways
(presumably now much slower) are not followed. Amine catalysed
reactions (Baylis–Hillman) are much less rapidly reversible,9c Keq
may be greater than unity under standard reaction conditions
(high concentration, RT) and ylide-type intermediates are not
accessible, thus leading to generally higher yields.
14 (a) S. Kim, J. H. Park, Y. G. Kim and J. M. Lee, J. Chem. Soc., Chem.
Commun., 1993, 1188; (b) J. S. Rao, J.-F. Brie`re, P. Metzner and
D. Basavaiah, Tetrahedron Lett., 2006, 3553.
In conclusion, through careful analysis of the original Morita
reaction we have discovered a new efficient synthesis of dienes with
moderate to good control of the double bond geometry from
simple aldehydes and Michael acceptors using PBu3. Since dienes
are not only useful synthetic intermediates but also ubiquitous in
nature, we believe this method could find wide application.
15 (a) E. L. Myers, C. P. Butts and V. K. Aggarwal, Chem. Commun.,
2006, 4434; (b) E. L. Myers, J. G. de Vries and V. K. Aggarwal, Angew.
Chem., Int. Ed., 2007, 46, 1893.
16 The acetate analogue of 6 was also tested in the same reaction but gave
reduced yields compared to 6 itself (cf. entry 3: OAc analogue of 6 gave
28% yield of dienes whereas 6 gave 75% yield of the same dienes).
17 G. E. Keck and D. S. Welch, Org. Lett., 2002, 4, 3687.
4130 | Chem. Commun., 2007, 4128–4130
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