Phosphine-catalyzed annulation of ethyl (arylimino)acetates: Synthesis of highly functionalized oxoimidazolidines

Article abstract of DOI:10.1039/b811167g

This paper describes an unexpected and novel nucleophilic phosphine-catalyzed annulation of ethyl (arylimino)acetates to give polysubstituted oxoimidazolidine derivatives in moderate to good yields from simple and easily available starting materials under

Full text of DOI:10.1039/b811167g

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Phosphine-catalyzed annulation of ethyl (arylimino)acetates: synthesis
of highly functionalized oxoimidazolidinesw
Guang-Ning Ma,a Fei-Jun Wang,a Jun Gaob and Min Shi*ab
Received (in College Park, MD, USA) 1st July 2008, Accepted 5th August 2008
First published as an Advance Article on the web 18th September 2008
DOI: 10.1039/b811167g
This paper describes an unexpected and novel nucleophilic
phosphine-catalyzed annulation of ethyl (arylimino)acetates to
give polysubstituted oxoimidazolidine derivatives in moderate to
good yields from simple and easily available starting materials
under mild conditions. In this reaction, the addition of methyl
vinyl ketone (MVK) is essential to induce the formation of
oxoimidazolidines.
A number of naturally occurring substances have been found
to contain the imidazole nucleus and some of these com-
pounds or their derivatives have important therapeutic value.
Thus far, although the synthesis of the imidazole nucleus has
been the subject of a large body of literature, the construction
of highly functionalized oxoimidazolidine frameworks from
easily available starting materials remains a great challenge.1
Scheme 1 Phosphine-catalyzed aza-Marita–Baylis–Hillman reaction.
Herein, we wish to report a novel and concise synthetic
bases more nucleophilic than PPh3, such as PBu3, PPhMe2
protocol for the construction of multi-substituted oxoimid-
good yields.5 During our ongoing investigation into the search
azolidine frameworks from ethyl (arylimino)acetates.
or PPh2Me, can provide abnormal MBH reaction products in
Recently, phosphine Lewis bases have emerged as efficient
organocatalysts for carbon–carbon or carbon–nitrogen bond
for a more efficient phosphine Lewis base for the aza-MBH
reaction of ethyl (p-bromophenylimino)acetate 1a with MVK,
forming reactions, particularly in the catalysis of Morita–
Baylis–Hillman (MBH) reactions.2 For example, it has been
the catalyst instead of PPh3 under identical conditions
we found that using methyldiphenylphosphine (PPh2Me) as
reported that triphenylphosphine-catalyzed aza-Morita–
Baylis–Hillman (aza-MBH) reactions of ethyl (arylimino)-
(30 mol% of PPh2Me, 1.5 equiv. of MVK, in the presence of
4 A MS (200 mg mmolꢀ1 of 1), CH3CN, 20 1C) afforded a new
product 3a, which was determined by 1H NMR and 13C NMR
spectroscopic data and X-ray diffraction of a single crystal
acetates 1 with methyl vinyl ketone (MVK) or ethyl vinyl
ketone (EVK) produce the corresponding adducts 2 in good
(see ESIw),6 along with a trace of the aza-MBH adduct 2a. We
envisaged that compound 3a is derived from the PPh2Me-
catalyzed annulation of three molecules of 1a. Therefore, our
yields in acetonitrile (MeCN) along with the asymmetric
versions (up to 97% ee) in the presence of bifunctional chiral
phosphine Lewis bases (R)-LB1 and (S)-H8-LB2 (Scheme 1).3,4
Moreover, we also disclosed that using 1,4-diazabi-
next investigation was aimed at the development of optimal
cyclo[2.2.2]octane (DABCO) instead of PPh3 as the catalyst
afforded the corresponding products 20 in moderate to good
yields (Scheme 1).3
It has been known that different phosphine Lewis bases can
give different reaction products in the MBH reaction under
conditions for this unexpected transformation. The results of
these experiments are summarized in Table 1.
Initially, we confirmed that in the absence of phosphine
Lewis base and MVK, as well as in the presence of PPh3
(30 mol%) but without MVK, products 3a and 4a were not
identical conditions. For example, using phosphine Lewis
formed at all (Table 1, entries 1 and 2). Then, we employed
30 mol% of PPh2Me as the catalyst to examine the effect of
a School of Chemistry & Molecular Engineering, East China
MVK in this reaction. Surprisingly, in the absence of MVK, a
University of Science and Technology, Laboratory for Advanced
trace of 3a was formed and a noncyclic compound 4a was
Materials and Institute of Fine Chemicals, 130 Mei Long Road,
Shanghai 200237, China
obtained in 63% yield as a major product under otherwise
identical conditions, indicating that the more nucleophilic
phosphine caused such an unusual reaction outcome (Table 1,
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Lu, Shanghai 200032, China. E-mail: Mshi@mail.sioc.ac.cn;
Fax: +86-21-64166128
1
entry 3). The structure of 4a was confirmed based on the H
w Electronic supplementary information (ESI) available: 1H and 13C
NMR spectroscopic and analytical data of 3a–i and 4, X-ray crystal
structure of 3a, and detailed description of the experimental proce-
dure. CCDC reference number 612928. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b811167g
NMR, 13C NMR, HRMS and DEPT spectroscopic data. Using
1a and MVK in a ratio of 1 : 1.5 led to the formation of
oxoimidazolidine 3a in 65% yield along with MVK dimer
(Table 1, entry 6). Decreasing the employed amounts of
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Table 1 Phosphine-catalyzed annulation of ethyl (p-bromophenyl-
imino)acetate 1a under a variety of conditions at 20 1Ca
Table 2 Phosphine-catalyzed annulation of ethyl (arylimino)acetates
1b–i under the optimized conditionsa
Yield (%)b
3b–i
Yield (%)b
Entry
R
Product
Ratio of
1a : MVK Phosphine
3ac 4a
Entry
Solvent
t/h
1
2
3
4
5
6
7
8
a
p-Cl, 1b
p-F, 1c
3b
3c
3d
3e
3f
3g
3h
3i
40
64c
81c
74
55
57
1
2
3
4
5
6
7
8
1 : 0
1 : 0
—
PPh3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
48
48
48
36
36
36
36
36
24
24
48
48
48
48
48
96
96
48
—
—
Tr.
35
47
65
48
63
47
56
—
30
19
38
—
—
—
63
44
37
m-F, 1d
m-CF3, 1e
m-Br, 1f
p-CF3, 1g
H, 1h
1 : 0
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPhMe2
PMe3
1 : 0.5
1 : 1.0
1 : 1.5
1 : 10
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
60
29d
Tr.
m-CH3, 1i
d
—
Conditions: ethyl (arylimino)acetate (0.6 mmol), MVK (0.9 mmol),
Tr.
Tr.
Tr.
35
—
—
9
methyldiphenylphosphine (0.18 mmol), and 120 mg of 4A MS in
b
1.5 mL of CH3CN. Isolated yields based on the average of two runs.
d
Trace of MVK dimer was included in the product. The
10
11
12
13
14
15
16
17
18e
PBu3
c
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
PPh2Me
CH2Cl2
Toluene
DCE
corresponding normal aza-MBH adduct was formed in 25% yield
along with some other unidentified products.
—
40
Et2O
DMSO
DMF
CH3CN
Complex
Complex
Complex
derivatives 3b–g in moderate to good yields along with MVK
dimer (Table 2, entries 1–6). Ethyl (phenylimino)acetate 1h
gave 3h in 60% yield under identical conditions (Table 2,
entry 7). As for ethyl (meta-methylphenylimino)acetate 1i, the
desired product 3i was obtained in 29% yield along with the
corresponding aza-MBH product in 25% yield and some other
unidentified products (Table 2, entry 8).
a
b
See ESIw for a detailed experimental procedure. Isolated yields
(Tr. = trace). The structure was confirmed by the X-ray analysis of a
d
single crystal. The aza-Morita–Baylis–Hillman product was iso-
c
e
lated. Reaction performed at 80 1C.
MVK produced the corresponding product mixtures of 3a and
4a in lower yields, suggesting that the presence of MVK is
critical in this reaction (Table 1, entries 4 and 5). However,
using 10 equiv. of MVK afforded 3a in 48% yield and some of
the aza-MBH product 2a, without the formation of 4a (Table 1,
entry 7). Encouraged by these results, we also examined other
more nucleophilic phosphine Lewis bases, such as dimethylphe-
nylphosphine (PPhMe2), trimethylphosphine (PMe3), tributyl-
phosphine (PBu3), in this reaction under the standard
conditions. The results obtained indicated that they are not as
effective as PPh2Me in this transformation (Table 1, entries
8–10). An examination of the solvent effect revealed that when
using CH2Cl2, 1,2-dichloroethane (DCE), or toluene as the
solvent, the reaction could proceed smoothly to afford 3a in
19–38% yield as the major products (Table 1, entries 12–14).
But in tetrahydrofuran (THF) or ether, only noncyclic product
4a was produced in moderate yield (Table 1, entries 11 and 15).
In dimethyl sulfoxide (DMSO) and N,N-dimethylformamide
(DMF), complex product mixtures were formed (Table 1, en-
tries 16 and 17). Increasing the reaction temperature did not
give a positive result (Table 1, entry 18).
The mechanism of this unprecedented cyclization reaction has
not been unequivocally established, but one reasonable possibility
is outlined in Scheme 2. Since the starting materials (imines) are
highly hygroscopic and are liable to decompose in spite of all the
solvents being pretreated with the typical procedure and the
addition of 4 A MS to the reaction system to get rid of ambient
moisture, traces of ambient water can still decompose these imines.
With these optimal reaction conditions in hand, the scope
and limitations of this interesting annulation were explored
using a variety of ethyl (arylimino)acetates 1b–i and the results
are outlined in Table 2. For imines 1b–g bearing electron-
withdrawing groups on the benzene rings, the reaction pro-
ceeded smoothly to afford the corresponding oxoimidazolidine
Scheme 2 Mechanistic proposal for the formation of 3 and 4 in the
presence of PPh2Me and MVK.
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Table 3 Transformation of compound 4a to 3a under various
conditionsa
occurred. However, using DBU and NaH (in THF) as the bases,
4a decomposed entirely within 2 h (Table 3, entries 4 and 5).
In conclusion, our efforts to extend the scope and limita-
tions of phosphine-catalyzed Morita–Baylis–Hillman reac-
tions have led us to the unexpected discovery of a novel
route for the synthesis of polysubstituted oxoimidazolidine
derivatives. This method is a potentially powerful synthetic
protocol for construction of the oxoimidazolidine ring from
simple and easily available starting materials. Our future
efforts will focus on applying them to the construction of
other biologically significant natural products.
Yield (%)b
3a
Entry
Base
t/h
1
2
3
4
5
a
PPh2Me–MVK
K2CO3
5
24
2
2
2
499
20
No reaction
Dec.
Dec.
DABCO
DBU
NaHc
We thank the Shanghai Municipal Committee of Science
and Technology (04JC14083, 06XD14005), and the National
Natural Science Foundation of China (20672127 and
20732008) for financial support.
b
See ESIw for a detailed experimental procedure. Isolated yields.
THF was used as a solvent.
c
Therefore, in the reaction system, there is an equilibrium between
imine, ethyl glyoxalate, and aniline. This phenomenon can also be
identified in the previous literature, where those imines bearing
electron-withdrawing groups on the benzene rings are difficult to
purify and products are usually obtained as mixtures of these three
components.6 At first, the more nucleophilic phosphine Lewis base
PPh2Me undergoes a nucleophilic attack at the carbonyl group in
the a-imino ester to produce intermediate A.7 Then epoxy inter-
mediate B is formed by the nucleophilic attack of the CQN
double bond with the oxonium anion. Free aniline acts as a
nucleophile to attack the epoxide in intermediate B, affording
intermediate C and regenerating phosphine PPh2Me. Intermediate
C undergoes subsequent intramolecular proton transfer to give
intermediate 5, which acts as a nucleophile to attack intermediate
B again, providing intermediate D, which furnishes compound 4
via similar intramolecular proton transfer. In this reaction system,
there is a phosphine catalytic cycle to generate MVK dimer. The
first step of this cycle involves the Michael-type nucleophilic
addition of the tertiary phosphine to the activated alkene
(MVK) to produce zwitterionic intermediate F, which adds to
another molecule of MVK to afford zwitterionic intermediate G.
Subsequent proton migration gives zwitterionic intermediate H.
Release of the catalyst provides the MVK dimer (Scheme 2). In the
phosphine catalytic cycle, the zwitterionic intermediates F, G, and
H can act as a base to snatch a proton from 4, providing anionic
intermediate E. Subsequent intramolecular nucleophilic attack
onto the ester carbonyl group produces the desired product 3.
Using the more nucleophilic phosphine PPh2Me can afford
zwitterionic intermediates F, G and H in higher concentration,
which quickly abstract a proton from compound 4 to produce the
final product. In the presence of PPh3, intermediate F is produced
in lower concentration, which only acts as an enolate to react with
imine 1, affording the normal MBH adduct 2. This proposed
mechanism could clearly explain why 3 cannot be produced either
in the absence of MVK or using PPh3 as a catalyst.
Notes and references
1 (a) K. Willi, H. Erwin, I. Heinz, S. Wolfgang and H. Silvin, Chem.
Ber., 1982, 115, 1721–1732; (b) Z. Giancarlo and P. Francesco,
J. Heterocycl. Chem., 1981, 18, 1629–1633; (c) R. Alan, C. Dai, P.
Leeming, I. Ghiviriga, C. M. Hartshorn and P. J. Steel,
J. Heterocycl. Chem., 1996, 33, 1935–1942; (d) B. Hadj, T.
Fernand, G. Pierre, M. Jacques and C. Robert, Tetrahedron,
1978, 34, 1153–1161; (e) S. P. Christof and S. Dieter, Liebigs
Ann. Chem., 1991, 7, 655–668; (f) S. Basra, M. W. Fennie and
M. C. Kozlowski, Org. Lett., 2006, 8, 2659–2662.
2 Selected articles and reviews on the MBH reaction: (a) K. Morita,
Z. Suzuki and H. Hirose, Bull. Chem. Soc. Jpn., 1968, 41, 2815–2819
(using phosphine as a catalyst); (b) A. B. Baylis, M. E. D. Hillman,
Ger. Offen., 1972, 2 155 113A. B. Baylis and M. E. D. Hillman,
Chem. Abstr., 1972, 77, 34174M. E. D. Hillman, A. B. Baylis, U. S.
Patent, 1973, 3 743 669 (using amine as a catalyst); (c) S. E. Drewes
and G. H. P. Roo, Tetrahedron, 1988, 44, 4653–4670; (d) D.
Basavaiah, P. D. Rao and R. S. Hyma, Tetrahedron, 1996, 52,
8001–8062; (e) E. Ciganek, Org. React. (N. Y.), 1997, 51, 201–350;
(f) P. Langer, Angew. Chem., Int. Ed., 2000, 39, 3049–3052; (g) D.
Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103,
811–892. Selected papers on the aza-MBH reaction: ; (h) M. Shi and
Y.-M. Xu, Angew. Chem., Int. Ed., 2002, 41, 4507–4510; (i) M. Shi
and L. H. Chen, Chem. Commun., 2003, 1310–1311; (j) D. Balan and
H. Adolfsson, Tetrahedron Lett., 2003, 44, 2521–2524; (k) K. Matsui,
S. Takizawa and H. Sasai, J. Am. Chem. Soc., 2005, 127, 3680–3681;
(l) M. Shi, L.-H. Chen and C.-Q. Li, J. Am. Chem. Soc., 2005, 127,
3790–3800, and references cited therein; (m) M. Shi, Y.-M. Xu and
Y.-L. Shi, Chem.–Eur. J., 2005, 11, 1794–1802; (n) J. E. Imbriglio, M.
M. Vasbinder and S. J. Miller, Org. Lett., 2003, 5, 3741–3743; (o) S.
J. Miller, Acc. Chem. Res., 2004, 37, 601–610; (p) V. K. Aggarwal, D.
K. Dean, A. Mereu and R. Williams, J. Org. Chem., 2002, 67,
510–514; (q) V. K. Aggarwal, I. Emme and S. Y. Fulford, J. Org.
Chem., 2003, 68, 692–700; (r) V. K. Aggarwal, S. Y. Fulford and G.
C. Lloyd-Jones, Angew. Chem., Int. Ed., 2005, 44, 1706–1708;
(s) Y.-L. Shi and M. Shi, Adv. Synth. Catal., 2007, 349, 2129–2135.
3 J. Gao, G.-N. Ma, Q.-J. Li and M. Shi, Tetrahedron Lett., 2006, 47,
7685–7688.
4 M. Shi, G.-N. Ma and J. Gao, J. Org. Chem., 2007, 72, 9779–9781.
5 (a) A. Palmelund, E. L. Myers, L. R. Tai, S. Tisserand, C. P. Butts
and V. K. Aggarwal, Chem. Commun., 2007, 4128–4130; (b) M. Shi
and Y.-M. Xu, Chem. Commun., 2001, 1876–1877; (c) M. Shi and
Y.-M. Xu, Eur. J. Org. Chem., 2002, 696–701; (d) M. Shi,
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6 For the preparation of ethyl (arylimino)acetates 1, see: E.
Borrione, M. Prato, G. Scorrano and M. Stivanello, J. Heterocycl.
Chem., 1988, 25, 1831–1836.
7 For the example of PPh2Me used as a nucleophile to attack the
carbonyl group, see: R. Appel and M. Montenarh, Chem. Ber.,
1977, 110, 2368–2373.
To prove that the noncyclic product 4 is an important
intermediate for the construction of cyclic product 3, several
control experiments were carried out on the transformation of
4a to 3a and the results are shown in Table 3. Using
PPh2Me–MVK as a base, this reaction proceeded smoothly to
afford 3a in quantitative yield after 5 h (Table 3, entry 1). Other
bases were also evaluated. K2CO3 gave 3a in 20% yield after
24 h (Table 3, entry 2). Using DABCO as a base, no reaction
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This journal is The Royal Society of Chemistry 2008
5000 | Chem. Commun., 2008, 4998–5000