Switching Regioselectivity in Crossed Acyloin Condensations between Aromatic Aldehydes and Acetaldehyde by Altering N-Heterocyclic Carbene Catalysts.pdf
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ORGANIC
LETTERS
Switching Regioselectivity in Crossed
Acyloin Condensations between Aromatic
Aldehydes and Acetaldehyde by Altering
N
2011
Vol. 13, No. 5
880–883
-Heterocyclic Carbene Catalysts
Ming Yu Jin,
†
Sun Min Kim,
‡
Hogyu Han,*
,§
Do Hyun Ryu,*
,†
and Jung Woon Yang*
,‡
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea,
Department of Energy Science, Sungkyunkwan University, Suwon 440-746, Korea, and
Department of Chemistry, Korea University, Seoul 136-701, Korea
jwyang@skku.edu; dhryu@skku.edu; hogyuhan@korea.ac.kr
Received December 4, 2010
ABSTRACT
An unprecedented high level of regioselectivities (up to 96%) in the intermolecular crossed acyloin condensations of various aromatic aldehydes
with acetaldehyde was realized by an appropriate choice of
N
-heterocyclic carbene catalysts.
Carbonyl group polarity reversal is a powerful synthetic
strategy that has been widely recognized in the field of
carbene chemistry.
1
Originally, acyl anion catalysis stemmed
from the use of thiamine-dependent enzymes. Thiamine
diphosphate (ThDP)-dependent enzymes, including pyru-
vate decarboxylase (PDC), benzoylformate decarboxylase
(BFD), and benzaldehyde lyase (BAL), have been charac-
terized as powerful and versatile biocatalysts for the con-
struction of carbon
carbon bonds.
2
Among them, PDC
catalyzes an irreversible nonoxidative decarboxylation of
pyruvate to produce an “active acetaldehyde” (2-
-
-hydro-
xyethyl-thiamine diphosphate) intermediate as an acyl anion
source. In addition, its
R
†
Department of Chemistry, Sungkyunkwan University.
‡
Department of Energy Science, Sungkyunkwan University.
§
Department of Chemistry, Korea University.
(1) For general reviews onNHC catalysts, see: (a) Enders, D.; Breuer,
K. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vol. 3, Ch. 30, pp
1093
-
1102. (b) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37,
534–541. (c) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632–
2634. (d) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506–7510. (e)
Enders, D.; Balensiefer, T.; Niemeier, O.; Christmann, M. In Enantio-
selective Organocatalysis: Reactions and Experimental Procedures;
Dalko, P. I., Ed.; Wiely-VCH: Weinheim, Germany, 2007; pp 331
-carbanion reacts with a variety
of aldehydes through nucleophilic attack to form mixed
R
R
-hydroxy ketones with high enantioselectivities.
3
uller, M.; Gocke, D.; Pohl, M. FEBS J. 2009, 276, 2894–
2904. (b) Pohl, M.; Sprenger, G. A.; Muller, M. Curr. Opin. Biotechnol.
2004, 15, 335–342. (c) Pohl, M.; Lingen, B.; M
(2) (a) M
€
uller, M. Chem.
Eur. J.
€
;
355. (f)
Marion, N.; Dı´ ez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed.
2007, 46, 2988–3000. (g) Enders, D.; Niemeier, O.; Henseler, A. Chem.
Rev. 2007, 107, 5606–5655. (h) Nair, V.; Vellalath, S.; Babu, B. P. Chem.
Soc. Rev. 2008, 37, 2691–2698.
-
2002, 8, 5288–5295.
(3) (a) Kluger, R. In The Enzymes, 3rd ed.; Sigman, D. S., Ed.;
Academic Press: NewYork, 1992; Vol. 20, pp 271
315. (b) Schellenberger,
A. Angew. Chem., Int. Ed. 1967, 6, 1024–1035. (c) Chen, G. C.; Jordan, F.
Biochemistry 1984, 23, 3576–3582.
-
10.1021/ol102937w
r
2011 American Chemical Society
Published on Web 01/31/2011
Table 1. Optimization of the Reaction Conditions for
NHC-Catalyzed Crossed Acyloin Condensation
Scheme 1. NHC-Catalyzed Regioselective Crossed Acyloin
Condensation
yield
c
(%)
solvent
(M)
a
time
(h)
3a
/
4a
b
entry
catalyst
1
I
THF (0.5)
15
95:5
88
2
IIa
THF (0.3)
24
10:90
71
3
IIb
THF (0.3)
24
14:86
52
4
IIc
THF (0.5)
24
35:65
50
IId
5
THF (0.3)
15
17:83
91
6
IId
m
-xylene (0.5)
15
14:86
95
7
III
THF (0.5)
24
-
-
Mixed acyloin skeletons are often found as the key
structural motif for many natural products with interesting
biological activities and synthetic therapeutics.
4
Despite
the synthetic advantages of crossed acyloin condensations
between two carbonyl compounds,
5
there are two draw-
backs, the undesired self-condensations and the uncon-
trolled regiochemistry of crossed condensations.
Given the importance of acetaldehdye as a simple nucleo-
phile in organocatalytic reactions,
6
we hypothesized that
acetaldehdye could be employed as a surrogate for an active
acetaldehyde generated by a combination of pyruvate with
ThDP-dependent enzymes. Such an approach can eliminate
carbon dioxide emission and thus be of substantial benefit to
the development of an environmentally benign process.
Here, we report a facile method for the highly regiose-
lective crossed acyloin condensations between aromatic
a
Molar concentration of 4-chlorobenzaldehyde 1a.
b
Determined by
300MHz
1
HNMR of the unpurified reaction mixture after workup.
c
Isolated
yield of a 3a/4a mixture obtained after flash chromatography.
Figure 1. NHC catalysts I
-
III examined in this study.
aldehydes 1 and acetaldehyde 2 using N-heterocyclic car-
bene (NHC) catalysts I and II (Scheme 1). It is found that
the desiredmixed acyloin product 3 or 4 can be obtained as
a major product when the formation of self-acyloin pro-
duct 5 except for acetoin 6 is suppressed by using excess
acetaldehyde. In addition, we found that the control of
regioselectivity in the crossed acyloin condensations of
aromatic aldehydes with acetaldehyde can be achieved by
properly choosing NHC catalysts.
We initiated our studies by reacting p-chlorobenzalde-
hyde 1a with 10 equiv of acetaldehyde 2 in the presence of
10 mol % NHC (pre)catalysts and 10 mol % Cs
2
CO
3
(Scheme 1 and Table 1). Fortunately, thiazolium I and
triazolium II catalysts afforded the desired
(4) (a) Kakeya, H.; Morishita, M.; Koshino, H.; Morita, T.-I.;
Kobayashi, K.; Osada, H. J. Org. Chem. 1999, 64, 1052–1053. (b) Fang,
Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayake, C. H.; Wald, S. A.
Tetrahedron: Asymmetry 2000, 11, 3659–3663. (c) Kihumbu, D.; Stillger,
T.; Hummel, W.; Liese, A. Tetrahedron: Asymmetry 2002, 13, 1069–
1072. (d) Gonz
na, R. J. Bacteriol. 1989, 171, 2401–2405. (e)
Jordan, F. Nat. Prod. Rep. 2003, 20, 184–201.
(5) For a single report so far on NHC-catalyzed nonasymmetric
intermolecular crossed acyloin condensations of aldehydes with ketones,
see: (a) Enders, D.; Henseler, A. Adv. Synth. Catal. 2009, 351, 1749–
1752. For NHC-catalyzed asymmetric intramolecular crossed acyloin
condensations of aldehydes with ketones, see: (b) Enders, D.; Niemeier,
O. Synlett 2004, 2111–2114. (c) Enders, D.; Niemeier, O.; Balensiefer, T.
Angew. Chem., Int. Ed. 2006, 45, 1463–1467. (d) Enders, D.; Niemeier,
O.; Raabe, G. Synlett 2006, 2431–2434. (e) Takikawa, H.; Hachisu, Y.;
Bode, J. W.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 3492–3494. (f)
Li, Y.; Feng, Z.; You, S.-L. Chem. Commun. 2008, 2263–2265. (g) Ema,
T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T. Org. Lett. 2009, 11,
4866–4869. For NHC-catalyzed nonasymmetric intramolecular crossed
acyloin condensations of aldehydes with ketones, see: (h) Enders, D.;
Niemeier, O. Synlett 2004, 2111–2114. (i) Hachisu, Y.; Bode, J. W.;
Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432–8433.
(6)(a)Yang,J.W.;Chandler,C.;Stadler,M.;Kampen,D.;List,B.
Nature 2008, 452, 453–455. (b) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa,
H. Angew. Chem., Int. Ed. 2008, 47, 2082–2084. (c) Garcı´ a-Garcı´ a, P.;
Ladepeche, A.; Halder, R.; List, B. Angew. Chem., Int. Ed. 2008, 47, 4719–
4721. (d) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 4722–4724. (e) Hayashi, Y.; Okano, T.; Itoh, T.;
Urushima, T.; Ishikawa, H.; Uchimaru, T. Angew. Chem., Int. Ed. 2008,
47, 9053–9058. (f) Hayashi, Y.; Samanta, S.; Itoh, T.; Ishikawa, H. Org.
Lett. 2008, 10, 5581–5583. (g) Kano, T.; Yamaguchi, Y.; Maruoka, K.
Angew. Chem., Int. Ed. 2009, 48, 1838–1840.
alez, B.; Vicu
~
-hydroxy
ketones 3a/4a as a mixture in high yield. Remarkably,
the change of regioselectivity in such crossed reactions was
accomplished by choosing between thiazolium and triazo-
lium as a catalyst. Fortunately, thiazolium catalyst I was
suitable for producing 1-(4-chlorophenyl)-2-hydroxy-
propan-1-one 3a, whereas triazolium catalyst II was sui-
table for producing its regioisomer, 1-(4-chlorophenyl)-1-
hydroxy-propan-2-one 4a. Recently, Zeitler and Connon
found that a similar regioselectivity in a crossed benzoin
R
Org. Lett., Vol. 13, No. 5,
2011
881
Table 2. NHC-Catalyzed Intermolecular Crossed Acyloin
Condensations of Various Aromatic Aldehydes with
Acetaldehyde
a
Scheme 2. Proposed Mechanism for the NHC-Catalyzed
Regioselective Crossed Acyloin Condensation
yield
c
(%)
3
/
4
b
entry
Ar
catalyst
1 4-ClC
6
H
4
I
95:5 88
2 4-ClC
6
H
4
IId
14:86 95
3 4-F
3
CC
6
H
4
I
94:6 87
4 4-F
3
CC
6
H
4
IId
23:77 86
5 4-NCC
6
H
4
I
98:2 90
6 4-NCC
6
H
4
IId
28:72 90
7 Ph
I
93:7 87
8 Ph
IId
13: 87 90
9 4-MeC
6
H
4
I
91:9 78
10 4-MeC
6
H
4
IId
12:88 85
11 4-MeOC
6
H
4
I
92:8 45
d
12 4-MeOC
6
H
4
IId
11:89 53
d
a
Reaction conditions: (a) ArCHO1 (0.5mmol),MeCHO2 (5mmol),
catalyst I (0.05 mmol), Cs
2
CO
3
(0.05 mmol), THF (1 mL) or (b) ArCHO
1 (0.3 mmol), MeCHO 2 (3 mmol), catalyst IId (0.03 mmol), Cs
2
CO
3
(0.03mmol), m-xylene (1mL).
b
Determined by 300MHz
1
HNMRof the
unpurified reactionmixture afterworkup.
c
Isolated yield of a 3/4mixture
obtained after flash chromatography.
d
Moderate yields are due to the
unreacted ArCHO starting materials rather than self-acyloin products.
electron-withdrawing and electron-donating substituents
on their aromatic ring (Table 2). First of all, thiazolium I
and triazoliumIId catalysts afforded a 3/4 product mixture
predominantly favoring 3 and 4, respectively. Regardless
of the variation in the electronic properties of aromatic
aldehydes, such selectivity was achieved quite effectively.
Accordingly, such NHC-catalyzed crossed acyloin conden-
sation served as an efficient and direct route for the
generation of
-hydroxy ketones with excellent regioselec-
tivity (up to 98:2) and high yield (up to 95%). In general,
the chemical yield increased when electron-withdrawing
substituents were introduced into aromatic aldehydes. It is
noteworthy that thiazolium catalyst I gave superior results
in terms of regioselectivity compared to triazolium catalyst
IId in all cases.
The regioselective formation of
R
condensation between benzaldehyde and isobutyraldehyde
may be achieved by employing a triazolium catalyst, but not a
thiazolium catalyst.
7
For further optimization of the reaction conditions, we
investigated the effects of NHC catalysts I
-hydroxy ketones 3
and 4 can be rationalized by Breslow’s mechanism for the
NHC-catalyzed crossed acyloin condensation (Scheme 2).
8
Nucleophilic attack of thiazolium catalyst I on aromatic
aldehydes 1 rather than acetaldehyde 2 affords the most
resonance-stabilized Breslow intermediate 7. The nucleo-
philic carbene thus formed reactswith the incoming second
aldehyde such as acetaldehyde and then releases the more
thermodynamically stable product 3. In contrast, nucleo-
philic attack of the more sterically demanding triazolium
catalyst II on acetaldehyde 2 rather than aromatic alde-
hydes 1 leads to the formation of the intermediate 8.This
carbene then reacts with the second aldehyde such as
aromatic aldehydes, thereby liberating the product 4.
The NHC preference for such reaction pathways may be
due to the steric difference between the intermediates. For
instance, there would be unfavorable steric interactions
between aromatic rings if the intermediates are formed
from triazolium catalyst II and aromatic aldehydes 1 instead
of acetaldehyde 2. Such a steric difference can critically
affect their relative formation from NHC and aldehydes
and their subsequent nucleophilic attack on the second
aldehyde. In addition, such preference also seems to be affected
R
III, counter-
anion, solvent, and concentration on the reaction of 4-
chlorobenzaldehyde 1a with acetaldehyde 2 (Table 1 and
Figure 1). When thiazolium catalyst I was employed, an
88% yield of products 3a/4a as a 95:5 mixture favoring 3a
was obtained (Table 1, entry 1). To be selective for 4a,
triazolium catalysts II with various N-substituents were
employed. Regardless of N-substituents, all triazolium
catalysts II afforded a 3a/4a product mixture favoring 4a
(Table 1, entries 2
-
6). In addition, it is found that the electron-
withdrawing N-substituent on the triazolium ring significantly
increases the chemical yield. As a result, a 95% yield of pro-
ducts 3a/4a as a 14:86 mixture favoring 4a was obtained when
triazolium catalyst IId with the N-pentafluorophenyl substi-
tuent was employed inm-xylene (Table 1, entry 6). The starting
materials 1a and 2 are found to remain nearly intact when
treated with imidazolium catalyst III (Table 1, entry 7).
With these two optimized complementary reaction con-
ditions in hand, we then explored the crossed acyloin
condensation using various aromatic aldehydes with
-
(7) For a related study, see: O’Toole, S. E.; Rose, C. A.; Gundala, S.;
Zeitler, K.; Connon, S. J. J. Org. Chem. 2011, 76, 347
-
357.
(8) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
882
Org. Lett., Vol. 13, No. 5,
2011
tion between an aromatic aldehyde and acetaldehyde.
When p-chlorobenzaldehyde 1a (0.5 M in THF) reacted
with 10 equiv of acetaldehyde 2 in the presence of pyro-
glutamic acid-derived chiral NHC catalyst IIe (10 mol %)
at 20
Scheme 3. NHC-Catalyzed Asymmetric Intermolecular
Crossed Acyloin Condensation
-hydroxy ketone (R)-4a was obtained
with extremely high regioselectivity (>99%) in 41% yield
and 60% ee (Scheme 3).
9
We observed that no racemiza-
tion of the product (R)-4a takes place under the same
reaction conditions. This example demonstrated in princi-
ple that an asymmetric version of NHC-catalyzed inter-
molecular crossed acyloin condensation with acetaldehyde
is possible in this way.
In summary, we have demonstrated for the first time the
control of regioselectivity in the crossed acyloin condensa-
tions of aromatic aldehydes with acetaldehyde by properly
choosing NHC catalysts. Further experimental and com-
putational studies are ongoing and will elucidate a basis
for the regiochemistry of the reactions.
Cfor24h,
R
by electronic properties of aromatic aldehydes. For in-
stance, using thiazolium catalyst I, the regioselectivity is
better (higher 3:4 ratio) for electron-withdrawing substi-
tuents on the aromatic aldehydes. Using triazolium cata-
lyst IId, the regioselectivity is better (higher 4:3 ratio) for
electron-donating substituents on the aromatic aldehydes.
Thus, it appears that the turnover-limiting species 7 and 8
may be favorably generated from catalysts I and IId,
respectively, by the steric and electronic properties of sub-
strates and catalysts.
Finally, we also developed an asymmetric variant of the
NHC-catalyzed intermolecular crossed acyloin condensa-
Acknowledgment. This work was supported by the
NRF WCU program (R31-2008-000-10029-0), the NRF
grant (No. 2010-0023127), and the Faculty Research Fund
(Sungkyunkwan University, 2009) to J.W.Y., the NRF
Priority Research Centers Program (No. 2010-0029698) to
D.H.R, and the NRF grant (No. 2010-0022070) to H.H.
(9) The absolute configuration of the product (R)-4a was determined
by comparing the sign of the optical rotation with that reported
previously: synthetic (R)-4a,[
R
]
2
D
=
-
95.2 (c 0.58, MeOH) with 60%
ee; lit.
10
,[
Supporting Information Available. Detailed synthetic
procedures and characterization data for compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
]
2
D
=
158 (c 0.58, MeOH) with 98% ee.
(10) Borenenann, S.; Crout, D. H. G.; Dalton, H.; Kren, V.; Lobell,
M.; Dean, G.; Thomson, N.; Turner,M. M. J. Chem. Soc., Perkin Trans.
1 1996, 425–430.
R
-
Org. Lett., Vol. 13, No. 5,
2011
883
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