Simple primary anilines as iminium catalysts for the epoxidation of α-substituted acroleins

Article abstract of DOI:10.1002/adsc.200700048

Simple ortho-alkylated anilines have been shown to be excellent iminium catalysts for the epoxidation reaction of α-substituted acroleins. A range of different α-substituted acroleins give the epoxide products in good to excellent yields and good chemoselectivity.

Full text of DOI:10.1002/adsc.200700048

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DOI: 10.1002/adsc.200700048
Simple Primary Anilines as Iminium Catalysts for the
Epoxidation of a-Substituted Acroleins
Anniina Erkkilä,a Petri M. Pihko,a,* and Melanie-Rose Clarkea
a
Laboratory of Organic Chemistry, Department of Chemical Technology, P.O. Box 6100, FI-02015 TKK, Finland
Fax : (+358)-9-451-2538; e-mail: petri.pihko@tkk.fi
Received: December 15, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Simple ortho-alkylated anilines have been
shown to be excellent iminium catalysts for the ep-
oxidation reaction of a-substituted acroleins. A
range of different a-substituted acroleins give the
epoxide products in good to excellent yields and
good chemoselectivity.
anilines are highly versatile and chemoselective cata-
lysts for activating a-substituted enals towards epoxi-
dation of the double bond.
There are ample literature examples of stable
imines formed from aromatic primary amines, includ-
ing an isolable imine formed from aniline and cinna-
maldehyde.[11] Of course, an imine that is too stable
will not be suitable for a catalytic reaction. This might
Keywords: anilines; epoxides; iminium catalysis; or-
ganocatalysis
Since contemporary iminium catalysis began to thrive
in the early 2000s, a single family of catalysts has do-
minated the field.[1] These imidazolidinone catalysts,
developed by the Seebach group[2] and adopted by
MacMillan for iminium catalysis,[3] are effective with explain the low reactivity of the parent aniline. In-
a-unsubstituted substrates, but generally display low creasing the steric hindrance of the aniline with o-
reactivity with a-substituted enals.[4] Alternative hy- and m-substitution is expected to destabilize the
drazide-based catalysts from the laboratories of Tom- imine, allowing hydrolysis and regeneration of the
kinson[5] and Ogilvie[6] have displayed increased reac- catalyst.[12]
tivity towards b-substituted enals, and later discover-
We recently disclosed a simple organocatalytic
ies by Ishihara[7] have addressed the use of a-oxygen- method for the preparation of a-substituted acro-
ated acroleins using more complex primary amines. leins.[13] These compounds were selected as test sub-
From an industrial point of view, the complexity and strates for the iminium-catalyzed epoxidation reac-
cost of the catalysts may prohibit their use in large- tion.[14] Secondary amine catalysts (e.g., pyrrolidine
scale applications, and the recyclability of the imida- and its derivatives, such as 4) did not display useful
zolidinone catalysts appears to be limited.[8] In addi- levels of activity in these reactions. The parent aniline
tion, a-substituted and a,b-disubstituted enals are 1a also displayed poor reactivity. Increasing the steric
often not viable partners for iminium-catalyzed trans- hindrance in the ortho position steadily improved the
formations.
catalytic activity (Table 1). The doubly ortho-substi-
We reasoned that suitably substituted primary tuted 2,6-diisopropylaniline 1i was identified as the
amines should overcome these limitations. Anilines most active catalyst for the epoxidation reaction.
appeared particularly attractive candidates due to
The choice of the acid co-catalyst influenced the ac-
their extremely low cost and ready availability. In tivity of the catalytic system in a significant manner.
spite of their long history in organic chemistry, ani- While very strong acids such as HCl, Tf2NH and
lines have been very rarely used as catalysts.[9] In fact, CH3SO3H failed to promote the reaction, somewhat
the parent aniline has been reported to be entirely in- weaker acids, diphenylphosphoric acid (DPP) and tri-
active in iminium catalysis with enals.[10] Here we fluoroacetic acid (TFA), were found to be the co-cata-
demonstrate that more hindered ortho-substituted lysts of choice[15]. Also, no reaction was observed in
802
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Anilines as Iminium Catalysts for the Epoxidation of a-Substituted Acroleins
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Table 1. Catalyst screening for the epoxidation of a-substi-
tuted acroleins.
Table 2. Screening of oxidizing agents for the epoxidation
reaction. Abbreviations: UHP: urea-hydrogen peroxide, m-
CPBA: m-chloroperbenzoic acid.
Entry
Oxidizing
agent
Concentration
of 5a
Conversion[a] [%]
(at 1 h)
1
2
30% H2O2
50% H2O2
50% H2O2
UHP
0.2M
0.2M
1.0M
0.2M
0.2M
0.2M
0.2M
1.0M
0.2M
0.2M
1.0M
81[b]
65
73
19
74
67
50
96
0
3
4
TBHP[c]
TBHP[d]
TBHP[c,e]
TBHP[c]
m-CPBA
CHP
5
6
Entry
1
Catalyst
HX
Conversion[a] [%]
(at 4.5 h)
62
98
CHP
[a]
1
Conversion by H NMR after 1 h.
4.5 h.
1a
15
[b]
[c]
[d]
[e]
36[b]
29[b]
36
22
40
5m in isooctane.
70% in H2O.
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
1i
DPP
DPP
DPP
DPP
DPP
DPP
DPP
DPP
TFA
TFA
TFA
DPP
DPP
DPP
120 mol%.
34
45[b]
51–56
62
The optimized protocol was then applied to a varie-
ty of a-substituted acroleins and enals. As shown in
Table 3, a wide variety of a-substituted acroleins can
be converted to the corresponding epoxides. The reac-
tion provides the epoxide products in a clean and effi-
cient manner, and considerable variability in the
steric demands of the substrate is possible. The reac-
tion rates are somewhat higher with acroleins contain-
ing an aromatic moiety. To our delight, the reaction
can also accommodate aliphatic b-substitution (en-
tries 3 and 9).[16] Most importantly, a number of func-
tionalities, including acetals (entry 8) and both elec-
tron-rich and electron-deficient alkenes (entries 5, 10
81[c]
100[c,d]
0
10
11
12
1j
2
4
30
0
[a]
1
Conversion by H NMR after 4.5 h.
5.5 h.
20 mol% cat.
[b]
[c]
[d]
50 wt% H2O2.
the absence of acid. The conversions were further im- and 11) are tolerated. No conjugate addition or epox-
proved by the use of 20 mol% of the inexpensive cat- ide opening products are observed. The products can
alyst and the use of more concentrated H2O2 (50% be isolated either after in situ reduction to the epoxy
vs. 30%, entry 8).
alcohol or as the free aldehyde.[15]
To explore the scope and limitations of the epoxi-
In summary, we have identified simple ortho-substi-
dation method, we exposed a variety of a-substituted tuted anilines as efficient and readily available imini-
a,b-unsaturated aldehydes to the epoxidation reac- um catalysts, and have developed the first organocata-
tion. We first optimized the reaction conditions by de- lytic epoxidation of a-substituted a,b-unsaturated al-
fining the optimal oxidizing agent, solvent, concentra- dehydes. Taken together, a wide range of aldehydes
tion and catalysts loading.[15] As shown in Table 2, hy- can now be transformed via a mild two-stage protocol
drogen peroxide, t-BuOOH (TBHP), and cumene hy- into corresponding oxamethylenated products, using
droperoxide (CHP) are all suitable as oxidants. Some- only simple secondary amine (e.g., pyrrolidine) and
what superior rates were obtained with TBHP and primary amine (ortho-substituted aniline) catalysts
CHP.[14] We selected the TBHP conditions for further (Scheme 1). The protocol is extremely versatile and
study.
the simplicity of these aniline catalysts should allow
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803

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Table 3. Substrate scope of the epoxidation of a-substituted a,b-unsaturated aldehydes.
Entry
1
Product
Time [h]
1.5
X[a] [%]
96
Yield[b] [%]
dr[c]
92
99
2
3
5
6
7
1.5
2
100
100
89
2:1
1:1
3:1
83
7
73
67
3
100
80
7
n.d.
8
1
100
100
77[d]
90
9
3.5
10
1
94[e]
99
72 (90[e])
71
11
2.5
[a]
Isolated yield after NaBH4 reduction and FC.
Conversion by H NMR.
Diastereomeric ratio of anti:syn.
120 mol% TBHP. The product was isolated as an aldehyde.
[b]
[c]
[d]
[e]
1
Calculated based on 80% isomeric purity of the starting material.
their incorporation into solid supported catalysts.
These aniline catalysts should also find use in other
iminium-catalyzed reactions, such as the Diels–Alder
reaction.[17]
Full details of the Diels–Alder reaction and the de-
velopment of enantioselective[18] variants of these re-
actions will be reported separately.
Scheme 1. Organocatalytic oxamethylenation of aldehydes.
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Anilines as Iminium Catalysts for the Epoxidation of a-Substituted Acroleins
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[6] a) M. Lemay, W. W. Ogilvie, Org. Lett. 2005, 7, 4141–
4144; b) M. Lemay, W. W. Ogilvie, J. Org. Chem. 2006,
71, 4663–4666.
Experimental Section
General Procedure for the Epoxidation of Aldehydes
[7] a) K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2005,
127, 10504–10505; b) A. Sakakura, K. Suzuki, K.
Nakano, K. Ishihara, Org. Lett. 2006, 8, 2229–2232;
c) A. Sakakura, Suzuki, K Ishihara, Adv. Synth. Catal.
2006, 348, 2457–2465; for primary amine iminium cat-
alysis with enones, see: d) N. J. A. Martin, B. List, J.
Am. Chem. Soc. 2006, 128, 13368–13369; e) J.-W. Xie,
W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen,
Y. Wu, J. Zhu, J.-G. Deng, Angew. Chem. Int. Ed. 2007,
46, 389–392.
To a solution of aldehyde (0.5 mmol, 100 mol%) in CH2Cl2
(0.5 mL, 1.0M) in a 2-mL vial was added catalyst 1i·TFA
(0.1 mmol, 20 mol%) and TBHP solution (5M in isooctane,
0.75 mmol, 150 mol%) at room temperature. The mixture
was allowed to stir at room temperature for 1–48 h. Acrole-
in (50 mL) was then added and the mixture was allowed to
stir for an additional 10 min. The mixture was then poured
into a solution of NaBH4 in EtOH (2 mL) with a CH2Cl2
(1 mL) rinse. The mixture was allowed to stir for 5–10 min
at 08C. The mixture was then quenched with saturated
aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3”
10 mL). The combined organic extracts were washed with
saturated aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated under vacuum. The crude product thus ob-
tained was then purified with flash chromatography (20%
EtOAc in hexanes).
Alternatively, the aldehyde products were isolated directly
after the addition of acrolein as above by aqueous work-up
(10 mL) and extraction with CH2Cl2 (3”10 mL). The com-
bined organic extracts were washed with brine, dried
(Na2SO4), and concentrated under vacuum. The pure epoxy
aldehydes were obtained by preparative TLC or flash chro-
matography (10–20% EtOAc in hexanes).
[8] A. Puglisi, M. Benaglia, M. Cinquini, F. Cozzi, G. Cele-
ntano, Eur. J. Org. Chem. 2004, 567–573.
[9] a) E. H. Cordes, W. P. Jencks, J. Am. Chem. Soc. 1962,
84, 826–831; b) A. Dirksen, T. M. Hackeng, P. E.
Dawson, Angew. Chem. Int. Ed. 2006, 45, 7581–7584;
c) A. Dirksen, S. Dirksen, T. M. Hackeng, P. E.
Dawson, J. Am. Chem. Soc. 2006, 128, 15602–15603.
[10] a) T. Kano, Y. Tanaka, K. Maruoka, Org. Lett. 2006, 8,
2687–2689; b) T. Kano, Y. Tanaka, K. Maruoka, Tetra-
hedron Lett. 2006,47, 3039–3041.
[11] O. Doesbner, W. Miller, Ber. Chem. Dtsch. Ges. 1883,
1664–1667.
[12] Support for this model can be obtained by inspecting
the X-ray crystal structures for range of iminium ions
derived from anilines. A statistical study of these X-ray
structures is not possible due to low number of exam-
ples, but the available data suggests that the iminium
ions derived from parent aniline tend to favor confor-
mations where the iminium ion is conjugated with the
aromatic ring. ortho-Substituted anilines, on the other
hand, tend to favor non-coplanar conformations, with
the iminium ion twisted out of conjugation with the
ring. See the Supporting Information for examples.
[13] A. Erkkilä, P. M. Pihko, J. Org. Chem. 2006, 71, 2538–
2541.
Acknowledgements
Financial support from Academy of Finland (Project No.
203287), Tekes, and TKK is gratefully acknowledged. A. E.
thanks Glycoscience Graduate School and Association of
Finnish Chemical Societies for support. We thank Dr. Tiina
Putkonen and Mr. Esa Kumpulainen for the preparation of
11d and 14d, respectively.
[14] For epoxidation of aldehydes, see: a) M. Marigo, J.
FranzØn, T. B. Poulsen, W. Zhuang, K. A. Jørgensen, J.
Am. Chem. Soc. 2005, 127, 6964–6965; b) W. Zhuang,
M. Marigo, K. A. Jørgensen, Org. Biomol. Chem. 2005,
3, 3883–3885; c) H. SundØn, I. Ibrahem, A. Cꢁrdova,
Tetrahedron Lett. 2006, 47, 99–103; d) S. Lee, D . W. C.
MacMillan, Tetrahedron 2006, 62, 11413–11424; for ep-
oxidation of ketones, see: e) A. Lattanzi, Org. Lett.
2005, 7, 2579–2582; f) Y. Li, X. Liu, Y. Yang, G. Zhao,
J. Org. Chem. 2007, 72, 288–291.
[15] See the supporting information for details.
[16] The lack of stereocontrol in formation of 7b can be ex-
plained by the rapid isomerisation of the double bond.
This is well documented in iminium catalysis, see:
a) J. W. Yang, M. T. Hechavarria Fonseca, B. List,
Angew. Chem. Int. Ed. 2004, 43, 6660–6662; b) J. W.
Yang, M. T. Hechavarria Fonseca, N. Vignola, B. List,
Angew. Chem. Int. Ed. 2005, 44, 108–110; c) S. G.
Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem.
Soc. 2005, 127, 32–33; See also ref.[14b] for similar re-
sults.
References
[1] G. Lelais, D. W. C. MacMillan, Aldrichimica Acta 2006,
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[17] Catalyst 1i·TFA promoted the Diels–Alder reaction be-
tween cyclopentadiene and a-benzylacrolein in 100%
conversion after >3 h. See the Supporting Information
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Anniina Erkkilä et al.
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for details. In addition, catalyst 1i·HCl promoted the
Diels–Alder reaction between cyclopentadiene and cin-
namaldehyde in acetonitrile in 64% conversion after
18 h.
[18] In preliminary experiments, chiral anilines have afford-
ed the epoxidation products in up to 50% ee. Details
of these experiments, including optimization of the pro-
tocol, will be reported separately.
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