Organocatalytic α-oxybenzoylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.03.082

A simple method for the asymmetric α-oxybenzoylation of aldehydes is presented. Treatment of a series of aldehydes with benzoyl peroxide in the presence of a MacMillan imidazolidinone leads directly to the α-oxybenzoylated product with excellent levels of

Full text of DOI:10.1016/j.tetlet.2009.03.082

Tetrahedron Letters 50 (2009) 3625–3627
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Tetrahedron Letters
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Organocatalytic
a-oxybenzoylation of aldehydes
*
Matti J. P. Vaismaa, Sze Chak Yau, Nicholas C. O. Tomkinson
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple method for the asymmetric a-oxybenzoylation of aldehydes is presented. Treatment of a series
Received 15 January 2009
Revised 4 March 2009
Accepted 12 March 2009
Available online 16 March 2009
of aldehydes with benzoyl peroxide in the presence of a MacMillan imidazolidinone leads directly to the
-oxybenzoylated product with excellent levels of asymmetric induction.
Ó 2009 Elsevier Ltd. All rights reserved.
a
1. Introduction
Central to successful development of this catalytic cycle was
modulating the reactivity of the amine. It is established that sec-
ondary amines react with BPO to give either hydroxylamine or
amide products,8 which would terminate the catalytic cycle (e.g.,
5 or 6). Conveniently, the reaction is governed by steric factors.9
In order to prevent reaction of the catalytic amine with BPO it
was therefore necessary to use a hindered nucleophilic amine that
would condense with a carbonyl compound at a faster rate than di-
rect nucleophilic attack on BPO. We established rapidly that the
MacMillan imidazolidinone 710 was a suitable candidate for the
proposed catalytic cycle, with the amine not reacting with the oxi-
dant under the reaction conditions adopted. Significant data on the
development of optimal conditions in the reaction between valer-
aldehyde (8) and BPO (9) are outlined in Table 1.
Dioxygenation of carbon skeletons in a 1,2-manner is ubiqui-
tous in Nature and robust methods for their synthesis are held in
high regard. Development of practical techniques to prepare these
motifs which proceed at room temperature in the presence of both
moisture and air providing products with high levels of asymmet-
ric induction represents a significant chemical challenge that
would considerably augment existing methodology. Over the past
eight years, organocatalysis has provided a wealth of fundamental
bond construction processes of broad applicability which meet
these goals,1 as highlighted by the number of total syntheses of
natural products which exploit this methodology.2
The current benchmark for organocatalytic
a-oxygenation of
carbonyl compounds involves proline-derived secondary amine
catalysts with nitrosobenzene as the stoichiometric oxidant.3,4
Although efficient, it is not possible to isolate the oxyaminated
products of aldehydes directly. It is therefore necessary to either
reduce or functionalise the aldehyde products directly prior to iso-
lation, representing a major drawback.5 Within this Letter we show
In the absence of catalyst 7 no reaction between the aldehyde 8
and BPO (9) was observed (entry 1). Without a co-acid the yield ob-
tained for the reaction was low (13%; entry 2), however, the excep-
tional ee (97%) certainly warranted further investigation. Crucial to
successful development was the choice of co-acid. Stronger acids
(HCl, TsOH) (entries 3 and 4) providedno product, however, decreas-
ing the strength of the co-acid improved the observed yield (entries
it is possible to
a-oxybenzoylate and isolate a range of aldehyde
substrates with high levels of asymmetric induction as well as
manipulate the products into synthetically useful dioxygenated
compounds without compromise in ee.
O
CHO
Possible side products to
turn off the catalytic cycle
BzO
In 1962 Augustine reported that the morpholine-derived enam-
ine of cyclohexanone could be converted to 2-benzoyloxycyclo-
hexanone by treatment with benzoyl peroxide (BPO).6 Given the
number of enamine-catalysed processes reported in recent years,7
we believed this represented an attractive candidate for develop-
ment as a novel organocatalytic strategy and designed the catalytic
cycle outlined in Figure 1. Condensation of the amine 1 with an
aldehyde would give a reactive enamine intermediate 2, which
could react with BPO to give the functionalised iminium ion 3.
Hydrolysis of this iminium ion would give the desired product 4,
releasing the secondary amine 1 back into the catalytic cycle.
R
4
N
H
1
N
H2O
O
Ph
H2O
5
N
N
N
BzO
O
Ph
R
3
R
2
O
6
BPO
Figure 1.
* Corresponding author. Tel.: +44 0 2920874068; fax: +44 0 2920874030.
E-mail address: tomkinsonnc@cardiff.ac.uk (N.C.O. Tomkinson).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.082

3626
M. J. P. Vaismaa et al. / Tetrahedron Letters 50 (2009) 3625–3627
Table 1
Table 2
Development of the catalytic asymmetric oxygenation procedure
Scope of the
a
-oxybenzoylation reaction
O
7 (20 mol%)
4-NO2BzOH (20 mol%)
BPO (1 eq.)
O
N
O
R
NaBH4
R
OH
Bn
N
R
H
O
THF, 23 °C
H
OBz
O
H
OBz
11
7 (20 mol%)
+
BPO
H
12
H
THF, co-acid
23 °C, 24 h
OBz
10
Entry
1
R
% Yield 11a
% Yield 12a
% eeb
8
9
Entrya
Co-acidb
% Yield of 10c
% eed
72
72
93
93
95
93
94
90
60
95
94
94
1e
2
3
4
5
6
7
8
9
None
None
HCl
TsOH
TFA
TCA
DCA
3-NO2C6H4CO2H
4-NO2C6H4CO2H
3-ClC6H4CO2H
BzOH
0
13
0
0
5
25
35
54
72
22
<20%
—
97
—
—
—
92
92
90
93
94
—
2
3
55
71
42
50
57
47
55
—
50
66
40
50
54
42
51
55
55
( )6
4c
5
10
11
TCA—trichloroacetic acid; DCA—dichloroacetic acid.
a
All reactions carried out at 23 °C in THF with 1 equiv of aldehyde 8, 1 equiv of
BPO (9) and imidazolidinone (7) (20 mol %), unless otherwise stated.
b
20 mol % co-acid added.
Isolated yield.
Determined by reduction of the aldehyde (NaBH4) followed by HPLC analysis;
c
Ph
d
6
chiracel OJ, 0.5% IPA/hexane, 0.5 mL minÀ1, 254 nm (t1 = 40.5 min; t2 = 46.2 min).
e
Reaction performed in the absence of catalyst 7.
7
Ph
5–8), with the most efficient co-acid being 4-nitrobenzoic acid (72%
yield; 93% ee) (entry 9). Further reduction in the co-acid strength
was detrimental to the efficiency of the reaction (entries 10 and 11).
A precise explanation for these observations, which mirror the
findings of others,11 is not immediately apparent. Addition of the
acids given in Table 1 to the imidazolidinone 7 would clearly form
the corresponding salt. Therefore, it would be expected that acid
strength would not significantly affect reactivity. However, the
data clearly indicate a remarkable influence on reactivity by the
co-acid and a better understanding of the origins of this effect
would have important implications in the field.
8
TBDMSO
9
PhthN
PhthN
10
—
a
Isolated yield of either aldehyde 11 or diol 12.
Determined by HPLC; chiracel OJ.
b
c
Having established effective reaction conditions for the a-oxy-
Two equivalents of aldehyde used.
benzoylation reaction, a series of alternative substrates were exam-
ined (Table 2). In the majority of cases excellent levels of asymmetric
induction were observed, apart from the functionalisation of ben-
zylic centres (entry 7; 60% ee). The reaction worked well for unfunc-
tionalised alkanes (entries 1–3; 93–95% ee). Yields were reduced
when steric hindrance was increased around the reactive centre,
however, this did not affect the ee’s observed (entry 4; 40% yield;
93% ee). Alkene and aromatic functionalities tolerated the reaction
conditions (entries 5 and 6; 90–94% ee) along with protected oxygen
and nitrogen groups (entries 8–10; 94–95% ee). As well as providing
92% ee)13 also proceeds under standard reaction conditions. Final-
ly, we found it was also possible to undertake standard Wittig
chemistry to provide the
a,b-unsaturated ester 16 (85% yield;
Pr
NaBH4, MeOH
rt, 20 min
OH
OBz
13 98% (92% e.e.)
Pr CO2H
direct access to
a-oxybenzoylated aldehydes, addition of sodium
borohydride directly to the crude reaction mixture efficiently pro-
vided the corresponding mono-protected diol 12, without compro-
mise of ee. Of interest is the fact that with each of these reduced
products, theprotectinggroup resides onthe morehindered second-
ary alcohol, a non-trivial overall transformation.
NaClO2 (3 eq.), KH2PO4
H2O, 0 °C, 18 h
O
OBz
14 87% (91% e.e.)
Pr CO2Me
Pr
H
Oxone,
MeOH/H2O (7:3), 50 °C, 15 h
OBz
10
The ability to isolate the
a-functionalised aldehyde products
OBz
15 75% (92% e.e.)
Pr CO2Et
from the reaction mixture represents a considerable benefit to
the chemistry described with the products being ripe for further
synthetic manipulation. In preliminary investigations we were able
to alter the oxidation level of these compounds without affecting
the ee (Scheme 1). For example, reduction of 10 with sodium boro-
hydride provides the 1,2-diol 13 (98% yield; 92% ee). Oxidation to
either the acid 14 (87% yield; 91% ee)12 or the ester 15 (75% yield;
Ph3P=CHCO2Et (3 eq.)
THF, rt, 20 h
OBz
16 85% (92% e.e.)
Scheme 1.

M. J. P. Vaismaa et al. / Tetrahedron Letters 50 (2009) 3625–3627
3627
and benzoyl peroxide (70% w/w, 201 mg, 0.58 mmol). The reaction
mixture was stirred at 23 °C for 48 h before dilution with aq satu-
rated NaHCO3 solution (5 mL) and extraction of the aqueous phase
with EtOAc (3 Â 20 mL). The organic layer was collected and dried
with anhydrous MgSO4. The solvent was removed under reduced
pressure and purified by flash column chromatography eluting
with light petroleum–EtOAc (9:1) to give 2-oxybenzoylvaleralde-
O
O
N
N
Path A
O
Bn
Bn
N
N
BzO
O
Ph
BzO
hyde 10 as a colourless oil (86 mg, 72%): [
a
]
D À37.4 (c 1.0; CHCl3);
IR (thin film) 2955, 1716, 1267, 1111, 705 cmÀ1
;
1H NMR
(400 MHz, CDCl3) d 9.71 (d, J = 0.67 Hz, 1H), 8.18–8.16 (m, 2H),
7.69–7.65 (m, 1H), 7.56–7.53 (m, 2H), 5.31–5.28 (m, 1H), 2.00–
1.94 (m, 2H), 1.65–1.59 (m, 2H), 1.06 (t, J = 7.37 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 198.5, 166.2, 133.5, 129.9, 129.3, 128.5,
78.6, 30.1, 18.4, 13.8; m/z (ES) 207 [M+H]+; HRMS (ES) calculated
for C12H15O3 207.1016 [M+H]+, found 207.1015.
O
O
N
N
Bn
O
Path B
Bn
N
BzO
N
Ph
O
O
Ph
O
Acknowledgements
Figure 2.
M.V. wishes to thank Professor Marja K. Lajunen and University
of Oulu for the opportunity to carry out this research. Financial
support from the EPSRC, Jenny and Antti Wihuri’s foundation and
Tauno Tönning’s foundation is gratefully acknowledged. The EPSRC
Mass Spectrometry Service, Swansea is thanked for high-resolution
spectra.
92% ee). This suggests that the stereogenic centre in the
a-oxy-
benzoylated aldehydes should be stable to a variety of acidic and
basic reaction conditions allowing the potential of the products
to be revealed.
Two plausible ionic mechanisms can be proposed for the key C–O
bond-forming process (Fig. 2). Direct attack of the enamine carbon on
the peroxide (path A) or N-oxybenzoylation of the enamine followed
by [3,3]-sigmatropic rearrangement14 (Path B). Current work is fo-
cussed on determining the precise pathway this reaction follows.
Confirmation of the proposed sense of asymmetric induction
observed within these transformations came from the reaction of
propanal (17) with BPO (9) followed by in situ reduction to give
the known mono-protected propane diol 1815 (Table 2, entry 2)
(50% yield; 93% ee). The observed (S)-stereochemistry of the prod-
uct is consistent with formation of the E-enamine 19 and approach
of the oxidant from the less hindered Si-face, directed by the ben-
zyl arm of the catalyst (Scheme 2). This proposal is in line with pre-
vious observations.16
References and notes
1. For a recent review on the area see: Dondoni, A.; Massi, A. Angew. Chem., Int. Ed.
2008, 47, 4638. and references therein.
2. de Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575.
3. For selected references see: (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji,
M. Tetrahedron Lett. 2003, 44, 8293; (b) Brown, S. P.; Brochu, M. P.;
Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808; (c)
Zhong, G. Angew. Chem., Int. Ed. 2004, 43, 4247; (d) Momiyama, N.;
Torii, H.; Saito, S.; Yamamoto, H. Proc. Nat. Acad. Sci. 2004, 101, 5374;
(e) Torri, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983.
4. For a review on the
a-amination and a-oxygenation of carbonyl compounds
see: Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292.
In summary, we have described a simple and effective method for
the a-oxybenzoylation of aldehydes using a commercially available
5. For selected references that directly functionalise this product see: Reduction:
(a) Córdova, A.; Sundén, H.; Bøgevig, A.; Johansson, M.; Himo, F. Chem. Eur. J.
2004, 10, 3673; Allylation: (b) Zhong, G. Chem. Commun. 2004, 606;
Wadsworth–Emmons–Horner: (c) Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637;
Wittig: (d) Kumarn, S.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V. Org. Lett. 2005,
7, 4189.
catalyst and reagent which proceeds with excellent levels of asym-
metric induction. The products are stable, isolable compounds that
can be exploited in a series of further transformations. Of note is
the one-pot preparation of the mono-protected 1,2-diol functional-
ity, with the protecting group on the more sterically encumbered
alcohol. The stereochemical course of these reactions is consistent
with formation of an E-enamine followed by direction of the ap-
proach of peroxide by the benzyl arm of the catalyst structure.
6. Augustine, R. L. J. Org. Chem. 1962, 28, 581.
7. For
a recent comprehensive review on enamine-catalysed processes see:
Mukherjee, S.; Woon, Y. J.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
8. Milewska, M. J.; Chimiak, A. Synthesis 1990, 233.
9. Wang, Q. X.; King, J.; Phanstiel, O., IV J. Org. Chem. 1997, 62, 8104.
10. For a review on the use of imidazolidinone catalysts see: Lelais, G.; MacMillan,
D. W. C. Aldrichim. Acta 2006, 39, 79.
11. Examination of literature reactions using 7 in iminium ion and enamine-
catalysed transformations show that the co-acid must be optimised for each
case: Diels–Alder cycloaddition with 7ÁHCl: (a) Ahrendt, K. A.; Borths, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243; Pyrrole conjugate
addition with 7ÁTFA: (b) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370; [3+2] Cycloaddition with 7ÁHClO4: (c) Jen, W. S.; Wiener, J. J. M.;
2. Typical experimental procedure
2.1. 2-Oxybenzoylvaleraldehyde 10
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874;
a-Chlorination with
To a solution of valeraldehyde (62 ll, 0.58 mmol) in tetrahydro-
furan (1 mL) were added imidazolidinone 7 (20 mol %, 25 mg,
0.12 mmol), 4-nitrobenzoic acid (20 mol %, 19 mg, 0.12 mmol)
7ÁTFA: (d) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc.
2004, 126, 8;
J. Am. Chem. Soc. 2005, 127, 4108.
a
-Fluorination with 7ÁDCA: (e) Beeson, T. D.; MacMillan, D. W. C.
12. Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.; Córdova, A.
Angew. Chem., Int. Ed. 2007, 46, 4507.
13. Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031.
14. For the a-oxybenzoylation of aldehydes and ketones using a [3,3]-sigmatropic
O
1. 7 (20 mol%)
rearrangement strategy see: (a) Beshara, C. S.; Hall, A.; Jenkins, R. L.;
Jones, K. L.; Jones, T. C.; Killeen, N. M.; Taylor, P. H.; Thomas, S. P.;
Tomkinson, N. C. O. Org. Lett. 2005, 7, 5729; (b) Beshara, C. S.; Hall, A.;
Jenkins, R. L.; Jones, T. C.; Parry, R. T.; Thomas, S. P.; Tomkinson, N. C.
O. Chem. Commun. 2005, 1478; (c) Jones, T. C.; Tomkinson, N. C. O. Org.
Synth. 2007, 84, 233.
OH
N
4-NO2BzOH (20 mol%)
BPO (1 eq.)
O
Bn
THF, 23 °C
N
H
OBz
18
2. NaBH4, MeOH
50%; 93% e.e.
H
17
15. Santaniello, E.; Casati, S.; Ciuffreda, P.; Gamberoni, L. Tetrahedron: Asymmetry
2005, 16, 1705.
19
16. For proposed stereochemical models involving catalyst
functionalisation of aldehydes see Ref. 11e.
7 in the a-
Scheme 2.