A practical protocol for asymmetric synthesis of wieland-miescher and hajos-parrish ketones catalyzed by a simple chiral primary amine

Article abstract of DOI:10.1055/s-0033-1338891

This article describes a simple chiral primary amine catalyzed efficient and practical protocol for the large-scale synthesis of Wieland-Miescher and Hajos-Parrish ketones as well as their analogues. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338891

FEATURE ARTICLE
▌1939
feature article
A Practical Protocol for Asymmetric Synthesis of Wieland–Miescher and
Hajos–Parrish Ketones Catalyzed by a Simple Chiral Primary Amine
Synthesis of Wieland–Miescher and Hajos–Parrish Ketones
Changming Xu, Long Zhang, Pengxin Zhou, Sanzhong Luo,* Jin-Pei Cheng
Beijing National Laboratory for Molecule Sciences (BNLMS), CAS Key Laboratory for Molecular Recognition and Function,
Institute of Chemistry, The Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax +86(10)62554449; E-mail: luosz@iccas.ac.cn
Received: 18.03.2013; Accepted after revision: 06.05.2013
thesis of Hajos–Parrish and Wieland–Miescher ketones.
In 1997 Barbas and co-workers reported antibody-cata-
lyzed Robinson annulation providing the Wieland–
Miescher ketone with >95% ee.5 While the antibody effi-
ciently catalyzed the cyclodehydration step of this reac-
tion, catalysis of the Michael addition step was very
modest. Barbas and co-workers later reported, in 2000, an
L-proline catalyzed Robinson annulation in the synthesis
of the Wieland–Miescher ketone in 49% yield with 76%
ee.6 In 2009, the binaphthyl prolinamide catalyst devel-
oped by Nájera was utilized in the one-pot, two-step syn-
thesis of Wieland–Miescher ketones, unfortunately this
catalyst was inactive for the Robinson annulation.4i
Abstract: This article describes a simple chiral primary amine cat-
alyzed efficient and practical protocol for the large-scale synthesis
of Wieland–Miescher and Hajos–Parrish ketones as well as their
analogues.
Key words: Wieland–Miescher ketone, Hajos–Parrish ketone, pri-
mary amine catalysis, Hajos–Parrish–Eder–Sauer–Wiechert reac-
tion, Robinson annulation
The enantiopure Wieland–Miescher (W-M) and Hajos–
Parrish (H-P) ketones (Figure 1) have been used exten-
sively in the synthesis of a wide variety of terpenoids and
steroids.1–3 For this reason, a number of chiral organocat-
alysts have been developed for the so-called Hajos–
Parrish–Eder–Sauer–Wiechert (HPESW) reaction, argu-
ably one of the most well-known asymmetric organocata-
lytic processes, which brings about the synthesis of
Wieland–Miescher and Hajos–Parrish ketones.4 To a cer-
tain extent, these newly reported organocatalytic process-
es overcome some shortcomings in the traditional proline
protocol, such as avoiding the use of high-boiling sol-
vents, higher enantioselectivity, and lower catalyst load-
ing.
Recently, we have reported a simple chiral primary amine
derived from an amino acid as an effective catalyst for the
Hajos–Parrish–Eder–Sauer–Wiechert reaction.7 In this ar-
ticle, we further extend the catalysis to the Robinson an-
nulation. Herein, we presented the details of these studies,
which now a highly efficient (2 mol% catalyst loading)
and practical (one-pot Robinson annulations, gram scale,
column-free) protocol for the synthesis of Wieland–
Miescher and Hajos–Parrish ketones.
Based on our previous work on bio-inspired chiral prima-
ry amine catalysis,8 we next examined their practical use
as catalysts for the Hajos–Parrish–Eder–Sauer–Wiechert
reaction. In our previous work,7 we found that chiral pri-
mary amine 4 in combination with the Brønsted acid tri-
flic acid could effectively catalyze this reaction, with
good enantioselectivities being achieved for both
Wieland–Miescher and Hajos–Parrish ketones. In the re-
action, triketones, such as 2-substituted 2-(3-oxobutyl)cy-
clohexane-1,3-dione 2, were prepared from 2-substituted
cyclohexane-1,3-dione 1 and methyl vinyl ketone in the
presence of triethylamine4i (Scheme 1).
O
O
O
O
W-M ketone
H-P ketone
Figure 1
The typical Hajos–Parrish–Eder–Sauer–Wiechert reac-
tion starts with 2-substituted 2-(3-oxobutyl)cyclohexane-
1,3-dione 2, which is prepared from 2-substituted cyclo-
hexane-1,3-dione 1 and methyl vinyl ketone (MVK). A
strategically more convenient process would start directly
with 2-substituted cyclohexane-1,3-dione 1 and methyl
vinyl ketone in a one-pot synthesis with a single catalyst.
In this context, it is surprising to note that although catal-
ysis in the Hajos–Parrish–Eder–Sauer–Wiechert reaction
has been extensively explored, there have been few re-
ports on such a Robinson annulation process for the syn-
Taking into account the extensive application of
Wieland–Miescher and Hajos–Parrish ketones in asym-
metric synthesis, we further intended to develop a proto-
col that is more suitable for the practical production for
Wieland–Miescher and Hajos–Parrish ketones. To this
end, several important factors to be considered are: (1)
one-pot or one-step synthesis starting directly from readi-
ly available diketones, (2) a lower catalyst loading, (3)
simple and minimal purification without column chroma-
tography for both products and catalyst, and (4) easy
scale-up without deterioration in reaction outcomes.
SYNTHESIS 2013, 45, 1939–1945
Advanced online publication: 06.06.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338891; Art ID: SS-2013-E0218-FA
© Georg Thieme Verlag Stuttgart · New York

1940
C. Xu et al.
FEATURE ARTICLE
Biographical Sketches█
Changming Xu was born in 2004 and Master’s degree in Chinese Academy of Sci-
1980 in Gansu province, 2008. After working at ences (ICCAS) under the
China. He studied chemistry Northwest Normal Univer- supervision of Prof. San-
at Northwest Normal Uni- sity for four years, he began zhong Luo in 2012.
versity, where he obtained to pursue a Ph.D. degree at
his Bachelor’s degree in the Institute of Chemistry,
Long Zhang was born in tween Nankai University group after gaining his
1980 in Hebei, China. He and the Institute of Chemis- Ph.D. as an assistant profes-
graduated from Nankai Uni- try, Chinese Academy of sor in July, 2010. His work
versity in 2005 with a major Sciences (ICCAS) under the focuses on the development
in chemistry. He then spent supervision of Prof. Jin-Pei of new asymmetric amino-
five years pursuing a Ph.D. Cheng and Prof. Sanzhong catalysts as well as on DFT
degree in a joint project be- Luo. He joined Prof. Luo’s studies of mechanisms.
Pengxin Zhou was born in Ph.D. degree in a joint proj- now a lecturer in Northwest
1982 in Lanzhou, China. He ect between Nankai Univer- Normal University. His re-
graduated from Northwest sity and the Institute of search interest is to develop
Normal University in 2004 Chemistry, Chinese Acade- novel and highly efficient
with a major in chemistry my of Sciences (ICCAS) synthetic methods for im-
and received his Master’s under the supervision of portant compounds.
degree in 2008. Then he Prof. Jin-Pei Cheng and
spent three years pursuing a Prof. Sanzhong Luo. He is
Sanzhong Luo was born in supervision of Prof. Jin-Pei Trost) in 2009. He is recipi-
1977 in Henan, China. He Cheng in 2005. He started ent of the National Science
graduated from Zhengzhou his independent career since Fund for Distinguished
University in 1999, and then July 2005 in the Institute of Young Scholars (2010) and
spent his graduate studies Chemistry, Chinese Acade- Thieme Chemistry Journal
successively in Nankai Uni- my of Sciences (ICCAS) Award (2012). His research
versity, the Chinese Acade- and became full professor focuses on asymmetric ca-
my of Sciences, and Ohio there in 2011. He was a vis- talysis and synthesis.
State University (USA) and iting scholar in Stanford
obtained his Ph.D. under the University (with Prof. B. M.
Jin-Pei Cheng was born in 1989, he has been a full pro- Academy of Sciences. He
1948 in Tianjin, China. He fessor at Nankai University. has been an adjunct profes-
obtained his Ph.D. from He served as an associate sor at ICCAS since 2002.
Northwestern
University editor for the Journal Physi- His research interests in-
under the supervision of cal Organic Chemistry dur- clude physical organic
Prof. F. G. Bordwell in ing 2007–2008. He has been chemistry, the chemistry of
1987. He then spent one a board member of Accounts organic hydrides and NO
year as a postdoctoral fellow of Chemical Research since donors, and asymmetric ca-
at Duke University with 2008. In 2001, he was elect- talysis.
Prof. E. M. Arnett. Since ed as a fellow of the Chinese
Synthesis 2013, 45, 1939–1945
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Synthesis of Wieland–Miescher and Hajos–Parrish Ketones
1941
°C and the desired adduct 3a was obtained in 87% yield
with 90% ee in three days (entry 3). The use of 1 mol%
loading of catalyst was also attempted, but unfortunately
showed very poor activity (entry 4), and under these con-
ditions the Michael addition was present in trace amounts
only as shown by analysis of the reaction mixture.
O
O
O
O
R
R
O
Et3N
O
1
2
88–98%
Table 1 Substrate Scope of One-Pot Synthesis
NH2
⋅TfOH
N
NH2
N
4
⋅TfOH
O
O
catalyst (10 mol%)
R
O
catalyst (X mol%)
R
R
O
3-O2NC6H4CO2H (5 mol%)
O
3-O2NC6H4CO2H (X/2 mol%)
+
neat, ambient temperature
O
neat, 60 °C
O
3
1a–j
1.0 g
3a–j
75–95%, 65–96% ee
Scheme 1 Chiral primary amine catalyzed Hajos–Parrish–Eder–
Sauer–Wiechert reaction
Entrya Product
X
Time
Yieldb (%) eec (%)
O
1
2
3
4
10d 10 h
73
85
87
trace
92
92
90
88
5e
2
6 h
3 d
3 d
3a
3b
First, we attempted to find a more efficient synthetic route
to the optimal chiral primary amine 4, ideally without col-
umn chromatograph purification, so that it could be easily
synthesized on a large scale. Starting from commercially
available tert-leucine (with both enantiomers), we opti-
mized the previous procedure.9 The target product 4 was
now obtained in 49% total yield (Scheme 2), in a sequence
of routine manipulations without column purification and
the final product was distilled under reduced pressure to
give the analytically pure compound.
1
O
O
O
5
2
3 d
84
88
92
O
O
6
7
3c
2
2
3 d
6 d
81
87
O
O
a) (Boc)2O, NaOH (aq),
1,4-dioxane
Ph
b) Et2NH, DCC, CH2Cl2
c) AcCl, MeOH, reflux
d) LiAlH4, THF, reflux
O
84
3d
(>99.9)f
N
OH
NH2
49%
NH2
4
O
Br
Scheme 2 Synthesis of catalyst 4
8
9
3e
3f
2
2
4 d
3 d
89
86
90
91
We chose 2-methylcyclohexane-1,3-dione (1a) (0.5 mmol)
to test the catalytic performance of 4 in the Robinson an-
nulation with 10 mol% catalyst loading at ambient tem-
perature. To our delight, the reaction was completed in 10
hours to furnish the desired adduct 3a with comparable re-
sults (Table 1, entry 1, 73%, 92% ee) to that of the Hajos–
Parrish–Eder–Sauer–Wiechert reaction. When the cata-
lyst loading was reduced to 5 mol% in a 50-mmol-scale
experiment, the reaction was completed in six hours with
85% yield and 92% ee (entry 2). In the initial stage of the
reaction an enormous release of heat occurred, most likely
during Michael addition, which facilitated a faster reac-
tion under these conditions. Further reduction of catalyst
loading to 2 mol% with 1 g of 1a led to a much slower re-
action at ambient temperature and after one week the in-
termediate 2a was still detected. In this context, the
reaction can be significantly accelerated by heating to 60
O
O
O
O
O
Ph
10
11
3g
3h
2
2
5 d
3 d
80g
62
90
90
O
O
OEt
O
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1939–1945

1942
C. Xu et al.
FEATURE ARTICLE
Table 1 Substrate Scope of One-Pot Synthesis (continued)
(entry 7). This protocol could also be applied to the syn-
thesis of the Hajos–Parrish ketone 3i affording moderate
yield and enantioselectivity (entry 12).
NH2
N
A reaction between 2-methylcyclohexane-1,3-dione (1a)
and methyl vinyl ketone (1.2 equiv) has also been con-
ducted on a 100-gram scale in the presence of 2.0 mol%
of 4/triflic acid at 60 °C (Scheme 4). After two days this
reaction was complete and gave the Wieland–Miescher
ketone 3a in 90% yield and with 90% ee; the product
could be directly distilled from the reaction mixture under
reduced pressure. The enantiomeric excess of Wieland–
Miescher ketone can be easily enriched to >99% by a sin-
gle recrystallization from hexane–ethyl acetate (60% re-
covered yields, unoptimized). The aminocatalyst can be
readily recovered by simple aqueous workup, hence the
reaction could be scaled up further.
⋅TfOH
O
O
catalyst (X mol%)
R
R
O
O
3-O2NC6H4CO2H (X/2 mol%)
+
neat, 60 °C
O
1a–j
1.0 g
3a–j
Entrya Product
X
Time
6 d
Yieldb (%) eec (%)
O
12
3i
2
79
76
O
O
NH2
N
13
3j
2
5 d
81
86
O
O
O
⋅TfOH
O
catalyst (2 mol%)
a Reaction conditions: 1a–j (1.0 g), primary amine 4·TfOH (2 mol%),
m-NO2C6H4CO2H (1 mol%), solvent-free conditions, 60 °C; unless
otherwise stated.
3-O2NC6H4CO2H (1 mol%)
+
neat, 60 °C, 2 d
O
O
1a
3a
90% yield, 90% ee
b Isolated yields.
100 g
(1.2 equiv)
c Determined by chiral HPLC.
>99% ee after recrystallization
(60% yield, unoptimized)
d Conducted at r.t., 0.5-mmol scale.
e Conducted at r.t., 50-mmol scale.
f After recrystallization.
Scheme 4 Synthesis of Wieland–Miescher ketone on a 100-gram
g See Scheme 3.
scale
To discern the catalytic roles of 4, triflic acid, and m-nitro-
benzoic acid in the annulation sequence, i.e. Michael–
aldol condensation, we monitored the Robinson annula-
tion process by employing in situ infra red spectroscopy.
Fortunately, the starting material 1a, intermediate 2a, and
final product Wieland–Miescher ketone 3a have different
characteristic peaks at 1625, 1694, and 1668 cm–1, respec-
tively, which allows for unambiguous assignments of IR
signals (see Supporting Information). Therefore, all three
species can be simultaneously monitored and their reac-
tion profiles can be recorded accordingly. The experiment
was conducted with 1a (0.5 mmol), methyl vinyl ketone
(0.6 mmol), and catalyst 4/triflic acid (5.0 mol%) in di-
methyl sulfoxide (1.0 mL) at room temperature (Figure 2).
With the optimized conditions in hand [catalyst (2 mol%),
solvent-free, 60 °C], the generality of this one-pot proto-
col was examined (Table 1). In all experiments, the reac-
tions were conducted on a 1-gram scale. As clearly
indicated in Table 1, variations of 2-substituted cyclohex-
ane-1,3-dione were well tolerated to give the desired ad-
ducts with results comparable to the two-step Hajos–
Parrish–Eder–Sauer–Wiechert protocol (Scheme 1). In a
single example with 2-phenylcyclohexane-1,3-dione (1g),
the reaction afforded an undehydrated aldol adduct 5 be-
sides the desired condensation product 3g. Adduct 5 can
be quantitatively transformed to 3g under reflux condi-
tions with 4-toluenesulfonic acid (10 mol%) in toluene for
three hours (Scheme 3) giving a total yield of up to 80%
O
O
MVK
4/TfOH (2 mol%)
O
Ph
Ph
Ph
O
3-O2NC6H4CO2H (1 mol%)
+
neat, 60 °C, 5 d
O
O
OH
3g
90% ee
80% yield in total
1g
5
TsOH (10 mol%)
toluene, reflux, 3 h
quantitative conversion
Scheme 3 Synthesis of Wieland–Miescher ketone analogue 3g
Synthesis 2013, 45, 1939–1945
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Synthesis of Wieland–Miescher and Hajos–Parrish Ketones
1943
As shown in Figure 2, the primary amine is also active for
the Michael addition step and the addition of 1a to methyl
vinyl ketone reached completion in two hours. The effect
of acidic additive is evident by comparing Figure 2 (A)
and (B). The addition of weak acid m-nitrobenzoic acid
(2.5 mol%) can significantly enhance the conversion of
intermediate 2a with a slight sacrifice of activity in the
Michael addition step. The observed effect of an acidic
additive in promoting the aldol condensation is consistent
with our previous studies,8 which can be rationalized by
considering acid-facilitating iminium–enamine tautomer-
ization.
The mechanism of the intramolecular aldol process,
particularly the classical Hajos–Parrish–Eder–Sauer–
Wiechert reaction, has been widely investigated both ex-
perimentally and computationally.10 Now it is known that
the reaction proceeds via an enamine mechanism with a
single catalyst participation, and hydrogen-bonding acti-
vation of the carbonyl group is essential for both activity
and stereoselectivity.10j In order to disclose the stereocon-
trol modes in the context of primary aminocatalysis as
presented herein, we carried out DFT calculations on the
possible transition states based on Houk’s recent stud-
ies.10k
All the calculations were carried out on Gaussian 03,11 the
geometries were optimized by using the B3LYP12 func-
tional with 6-31G (d) basis set, which have been well ap-
plied in theoretical studies of enamine based
organocatalytic process.13 Moreover, Houk and co-work-
ers have found that this method could satisfactorily repro-
duce the experimental results of similar intramolecular
aldol reactions catalyzed by proline.10h The nature of the
stationary points was determined by frequency calcula-
tion (with one imaginary frequency). The single point en-
ergy calculations were calculated based on the optimized
structures at the B3LYP/6-311++G(2df,2p) level in gas
Figure 2 Reaction profiles for the condensation of 1a (0.5 M) and
methyl vinyl ketone (0.6 M) catalyzed by 4/TfOH (5 mol%) in
DMSO, in the presence (A) or absence (B) of m-nitrobenzoic acid,
monitored by in situ IR spectroscopy.
phase. Accordingly, four cyclization transition states of
2a, corresponding to the observed stereochemistry, were
located for the catalysis of primary/tertiary diamine 4 in
the stereogenic aldol condensation step (Figure 3).
Figure 3 Transition states for the cyclization of 2a (energy unit: kcal/mol)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1939–1945

1944
C. Xu et al.
FEATURE ARTICLE
H2O (100 mL) was added and pH value was adjusted to 2 with dilute
HCl. The aqueous phase was separated and neutralized to weak al-
kaline (pH 8–10) by the addition of K2CO3, then extracted with
CH2Cl2 (3 × 100 mL). The organic layers were combined and dried
(anhyd Na2SO4). After removal of the solvent, the residue was used
directly in the next step.
It is found that Re-facial attack to form the R,R-enantio-
mer occurs preferably via a syn-enamine addition, where-
as the Si-facial attack is via an anti-enamine addition,
which is in line with Houk’s computational results. The
energy difference (ΔGrel) between the two favored transi-
tion states is 3.47 kcal/mol, corresponding to 99% ee fa-
voring the R,R product, which slightly outweigh the
experimental value, but this is still in accordance with the
observed enantioselectivity (92% ee).
To the above obtained intermediate in a soln of anhyd THF (200
mL) was added LiAlH4 (6.1 g, 160 mmol) portionwise at 0 °C, the
soln was heated to reflux for 4 h. The mixture was cooled to r.t., and
sat. aq Na2SO4 (40 mL) was added. The precipitated solid was fil-
tered and washed with THF several times. The organic layers were
combined, and dried (anhyd Na2SO4), then concentrated to provide
the crude residue. The pure catalyst 4 was obtained as colorless oil
after distillation under reduced pressure (bp 75–78 °C /0.01 kPa).9
We have presented a highly enantioselective and practical
protocol for the synthesis of Hajos–Parrish and Wieland–
Miescher ketones catalyzed by a simple chiral primary
amine, which is amenable to large-scale production as
demonstrated in an experiment on a 100-gram scale.
Mechanistic studies also reveal the roles of 4/triflic acid/
m-nitrobenzoic acid catalytic system as well as the stereo-
control modes in the reactions.
(S)-N1,N1-Diethyl-3,3-dimethylbutane-1,2-diamine (4)9
[α]D20 +124.1 (c 0.50, MeOH).
1H NMR (300 MHz, CDCl3): δ = 0.89 (s, 9 H), 0.97–1.02 (t,
J = 6.90 Hz, 6 H), 1.49 (br, 2 H), 2.07–2.15 (m, 1 H), 2.34–2.45 (m,
3 H), 2.53–2.67 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 12.2, 26.4, 33.2, 47.5, 55.6, 57.4.
Commercial reagents were used as received, unless otherwise indi-
Synthesis of Wieland–Miescher Ketone 3a on a 100-gram Scale
To 2-methylcyclohexane-1,3-dione (1a, 100.8 g, 0.80 mol) in a
500-mL round bottom flask with mechanical stirrer was added
MVK (80 mL, 0.96 mol) followed by chiral amine catalyst 4/TfOH
(2.0 mol%) and 3-nitrobenzoic acid (1.0 mol%) under solvent-free
conditions at 60 °C. The initial thick suspension slowly became
more fluid as the solid slowly dissolved to give a yellow/orange
soln/oil. After 2 d, the mixture was distilled under reduced pressure
to give the Wieland–Miescher ketone 3a as yellow oil that convert-
ed into yellow solid after about 1 h (128.2 g, 90%, 90% ee). Then
the product was recrystallized (hexane–EtOAc, 3:1), giving enan-
tiopure Wieland–Miescher ketone 3a (>99% ee, 60% recovered
yields).
1
cated. H and 13C NMR spectra were measured on a NMR instru-
ment (300 MHz for 1H NMR, 75 MHz for 13C NMR); TMS was the
1
internal standard for H NMR, and CDCl3 for 13C NMR. HPLC
analysis was performed using Chiralcel columns purchased. In situ
FT-IR spectroscopy was carried out on a ReactIR 15 (SiComp
probe) with a spectral range of 2800–650 cm–1 at 4 cm–1 resolution.
All measurements were performed at room temperature.
One-Pot Robinson Annulations; General Procedure
To 2-substituted cyclohexane-1,3-dione 1 (1.0 g) were added MVK
(1.2 equivalent), chiral amine catalyst 4/TfOH (2.0 mol%) and 3-ni-
trobenzoic acid (1.0 mol%) under solvent-free conditions at 60 °C
(1H NMR monitoring). The mixture was directly subjected to flash
chromatography to give the pure product.
All of the obtained final products 3a–f,4i 3g,h,7 3i,4g and 3j4f are
known and the NMR data are identical to those previously reported.
Absolute configurations were determined by correlation to values
reported in the literature.
Acknowledgment
This project was supported by the Natural Science Foundation of
China (NSFC 21202171 and 21025208), the Ministry of Science
and Technology (2011CB808600), and the Chinese Academy of
Sciences.
Synthesis of Catalyst 4 without Column Chromatography
To a soln of NaOH (3.2 g, 80 mmol) and tert-leucine (10.5 g, 80
mmol) in H2O (80 mL), was slowly added (Boc)2O (17.4 g, 80
mmol) in a soln of 1,4-dioxane (80 mL). The mixture was stirred for
12 h at r.t., and the soln was concentrated to ~80 mL under reduced
pressure. Then a cold soln of 4 M HCl (40 mL) and EtOAc (80 mL)
was added and the mixture was extracted. The organic layer was
washed with H2O (80 mL), dried (anhyd Na2SO4), and concentrated
to provide a white solid that was used directly in the next step.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
References
(1) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. 1971,
83, 492. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973,
38, 3239. (c) Hajos, Z. G.; Parrish, D. R. J. Org. Chem.
1974, 39, 1615. (d) Micheli, R. A.; Hajos, Z. G.; Cohen, N.;
Parrish, D. R.; Portland, L. A.; Sciamanna, W.; Scott, M. A.;
Wehrli, P. A. J. Org. Chem. 1975, 40, 675.
(2) For reviews, see: (a) Bradshaw, B.; Bonjoch, J. Synlett 2012,
23, 337. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. Rev. 2007, 107, 5471. (c) List, B. Tetrahedron
2002, 58, 5573.
(3) For examples, see: (a) Danishefsky, S. J.; Masters, J. J.;
Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung,
D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.;
Coburn, C. A.; DiGrandi, M. J. J. Am. Chem. Soc. 1996, 118,
2843. (b) Moher, E. D.; Collins, J. L.; Grieco, P. A. J. Am.
Chem. Soc. 1992, 114, 2764. (c) Paquette, L. A.; Wang, T.
Z.; Philippo, C. M. G.; Wang, S. P. J. Am. Chem. Soc. 1994,
116, 3367. (d) Smith, A. B. III; Kingerywood, J.; Leenay, T.
To a soln of the above solid in anhyd CH2Cl2 (120 mL), was slowly
added DCC (17.3 g, 84 mmol) in anhyd CH2Cl2 (80 mL) at 0 °C.
The mixture was stirred for 30 min, Et2NH (5.8 g, 80 mmol) in an-
hyd CH2Cl2 (40 mL) was added over a 1 h period, and the soln was
stirred at r.t. for an additional 12 h. The white solid formed was fil-
tered and washed with CH2Cl2 (40 mL). The organic layer was com-
bined and washed with 2% HCl (20 mL), 4% NaHCO3 (40 mL), and
brine (40 mL), respectively, then dried (anhyd Na2SO4). After re-
moval of the solvent, CH2Cl2 (20 mL) was added and the precipitat-
ed solid was filtered. The mother liquor was concentrated under
reduced pressure and the residue was used directly in the next step.
To the obtained product was added MeOH (160 mL), then AcCl (20
mL) slowly. The soln was heated to reflux for 1 h, and then cooled
to r.t. The solvent was removed, and then CH2Cl2 (200 mL) and H2O
(150 mL) were added, and the pH value was adjusted to 12 by the
addition of K2CO3. The aqueous phase was extracted with CH2Cl2
(3 × 100 mL), and the organic layers were combined. Additional
Synthesis 2013, 45, 1939–1945
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Synthesis of Wieland–Miescher and Hajos–Parrish Ketones
Puchot, C. J. Chem. Soc., Chem. Commun. 1985, 441.
1945
L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114,
1438. (e) Stahl, P.; Kissau, L.; Mazitschek, R.; Huwe, A.;
(d) Agami, C.; Puchot, C. J. Mol. Catal. 1986, 38, 341.
(e) Brown, K. L.; Damm, L.; Dunitz, J. D.; Eschenmoser, A.;
Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108.
(f) List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5839. (g) Bahmanyar, S.; Houk, K. N.
J. Am. Chem. Soc. 2001, 123, 11273. (h) Bahmanyar, S.;
Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911. (i) Hoang,
L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc.
2003, 125, 16. (j) Clemente, F. R.; Houk, K. N. Angew.
Chem. Int. Ed. 2004, 43, 5766. (k) Clemente, F. R.; Houk, K.
N. J. Am. Chem. Soc. 2005, 127, 11294.
Furet, P.; Giannis, A.; Waldmann, H. J. Am. Chem. Soc.
2001, 123, 11586. (f) Waters, S. P.; Tian, Y.; Li, Y. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 13514.
(g) Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am.
Chem. Soc. 2008, 130, 16864.
(4) (a) Rajagopal, D.; Rajagopalan, K.; Swaminathan, S.
Tetrahedron: Asymmetry 1996, 7, 2189. (b) Rajagopal, D.;
Narayanan, R.; Swaminathan, S. Tetrahedron Lett. 2001, 42,
4887. (c) Davies, S. G.; Sheppard, R. L.; Smith, A. D.;
Thomson, J. E. Chem. Commun. 2005, 3802. (d) D’Elia, V.;
Zwicknagl, H.; Oliver, R. J. Org. Chem. 2008, 73, 3262.
(e) Kanger, T.; Kriis, K.; Laars, M.; Kailas, T.; Müürisepp,
A.-M.; Pehk, T.; Lopp, M. J. Org. Chem. 2007, 72, 5168.
(f) Zhang, X. M.; Wang, M.; Tu, Y. Q.; Fan, C. A.; Jiang, Y.
J.; Zhang, S. Y.; Zhang, F. M. Synlett 2008, 2831. (g) Mori,
K.; Katoh, T.; Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama,
T. Angew. Chem. Int. Ed. 2009, 48, 9652. (h) Fuentes de
Arriba, A. L.; Seisdedos, D. G.; Simón, L.; Alcázar, V.;
Raposo, C.; Morán, J. R. J. Org. Chem. 2010, 75, 8303.
(i) Bradshaw, B.; Etxebarria-Jardi, G.; Bonjoch, J.;
Viózquez, S. F.; Guillena, G.; Nájera, C. Adv. Synth. Catal.
2009, 351, 2482.
(11) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.; Vreven,
T. Jr. Kudin K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S.
S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
revision E.01; Gaussian Inc: Wallingford (CT, USA), 2004.
(12) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(5) Zhong, G.; Hoffmann, T.; Lerner, R. A.; Danishefsky, S.;
Barbas, C. F. III J. Am. Chem. Soc. 1997, 119, 8131.
(6) Bui, T.; Barbas, C. F. III Tetrahedron Lett. 2000, 41, 6951.
(7) Zhou, P. X.; Zhang, L.; Luo, S. Z.; Cheng, J.-P. J. Org.
Chem. 2012, 77, 2526.
(8) For an account, see: (a) Zhang, L.; Luo, S. Synlett 2012, 23,
1575. For recent examples, see: (b) Luo, S. Z.; Li, J. Y.; Xu,
H.; Zhang, L.; Cheng, J.-P. Org. Lett. 2007, 9, 3675. (c) Luo,
S. Z.; Xu, H.; Li, J. Y.; Zhang, L.; Cheng, J.-P. J. Am. Chem.
Soc. 2007, 129, 3074. (d) Luo, S. Z.; Li, J. Y.; Zhang, L.; Xu,
H.; Cheng, J.-P. Chem. Eur. J. 2008, 14, 1273. (e) Luo, S. Z.;
Xu, H.; Chen, L. J.; Cheng, J.-P. Org. Lett. 2008, 10, 1775.
(f) Luo, S. Z.; Xu, H.; Zhang, L.; Li, J. Y.; Cheng, J.-P. Org.
Lett. 2008, 10, 653. (g) Luo, S. Z.; Zheng, X. X.; Cheng, J.-
P. Chem. Commun. 2008, 5719. (h) Luo, S.; Qiao, Y.;
Zhang, L.; Li, J.; Li, X.; Cheng, J.-P. J. Org. Chem. 2009, 74,
9521. (i) Luo, S. Z.; Zhou, P. X.; Li, J. Y.; Cheng, J.-P.
Chem. Eur. J. 2010, 16, 4457. (j) Zhou, P. X.; Luo, S. Z.;
Cheng, J.-P. Org. Biomol. Chem. 2011, 9, 1784.
(13) For a recent review, see: (a) Cheong, P. H.-Y.; Legault, C.
Y.; Um, J. M.; Çelebi-Ölçüm, N.; Houk, K. N. Chem. Rev.
2011, 111, 5042. For selected examples, see refs. 10g, 10h,
10k and: (b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List,
B. J. Am. Chem. Soc. 2003, 125, 2475. (c) Cheong, P. H.-Y.;
Houk, K. N. J. Am. Chem. Soc. 2004, 126, 13912.
(d) Gordillo, R.; Houk, K. N. J. Am. Chem. Soc. 2006, 128,
3543. (e) Allemann, C.; Um, J. M.; Houk, K. N. J. Mol.
Catal. A: Chem. 2010, 324, 31. (f) Antoline, J. E.; Krenske,
E. H.; Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Am. Chem.
Soc. 2011, 133, 14443. (g) Lam, Y.-H.; Houk, K. N.;
Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2012, 134,
6286.
(9) Hu, S. S.; Zhang, L.; Li, J. Y.; Luo, S. Z.; Cheng, J.-P. Eur.
J. Org. Chem. 2011, 3347.
(10) (a) Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.;
Pascard, C. Tetrahedron 1984, 40, 1031. (b) Agami, C. Bull.
Soc. Chim. Fr. 1988, 3, 499. (c) Agami, C.; Levisalles, J.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1939–1945