Development of a robust and practical process for the Darzens condensation and α,β-epoxide rearrangement: Scope and limitations of the methodology

Article abstract of DOI:10.1055/s-2008-1067002

A practical and robust process for the Darzens condensation of substituted benzaldehydes and subsequent α,β-epoxy rearrangement is reported. The process developed is both amenable to large scale and parallel synthesis. While electron-poor benzaldehydes gave mixtures of aryl ketones and 2-substituted aryl ketones in mediocre to low yields, electron-rich benzaldehydes were found to react in high yields with complete regioselectivity to form 2-substituted aryl ketones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067002

PAPER
1221
Development of a Robust and Practical Process for the Darzens Condensation
and a,b-Epoxide Rearrangement: Scope and Limitations of the Methodology
Darzens
C
e
ondensatio
r
n and
a
,
b
e
-Epoxide
Rm
earrangement y Malcolm Zimbron,1 Manuela Seeger-Weibel, Hans Hirt, Fabrice Gallou*
Novartis Pharma AG, Chemical and Analytical Development, 4002 Basel, Switzerland
Fax +41(61)6962711; E-mail: fabrice.gallou@novartis.com
Received 19 December 2007
and afforded the desired ketone 5b in 73% isolated yield
Abstract: A practical and robust process for the Darzens condensa-
tion of substituted benzaldehydes and subsequent a,b-epoxy rear-
rangement is reported. The process developed is both amenable to
large scale and parallel synthesis. While electron-poor benzalde-
at the first attempt (Scheme 2). Careful investigation re-
vealed that the Darzens condensation was not proceeding
at all in the case of the sulfone 3a. A thorough literature
hydes gave mixtures of aryl ketones and 2-substituted aryl ketones search revealed that only sparse results suggesting an
in mediocre to low yields, electron-rich benzaldehydes were found
electronic bias in the Darzens reaction of aromatic alde-
hydes were reported.5 Our project was a perfect opportu-
to react in high yields with complete regioselectivity to form 2-sub-
stituted aryl ketones.
nity to probe the substrate scope of the reaction while
streamlining our process. Particular attention was paid to
the practicality and robustness of the overall process to il-
Key words: condensation, rearrangement, regioselectivity, ho-
mologation, decarboxylation
lustrate the importance of the methodology in process de-
velopment.
In the course of one of our development program, we be-
In the case of aldehyde 3b, the reaction was found to pro-
came interested in the well-documented Darzens conden-
ceed well with the inexpensive ( )-2-chloropropionic acid
sation.2 Since the seminal work of Erlenmeyer and
methyl ester 4 and sodium methoxide at 0 °C in a toluene–
Darzens, the methodology has been extensively used for
aromatic aldehydes as well as for aromatic and aliphatic
Cl
ketones.3 During the reaction, a carbonyl is reacted with
an a-halo ester in the presence of a base to give an ep-
oxide. Of particular interest for us was the opening of the
latter and decarboxylation upon thermolysis, to afford the
corresponding one-carbon homologue of the starting alde-
hyde or ketone.3,4 Development of a practical and robust
metal-free one-carbon homologation process for access to
ketone 1 from substituted and readily available benzalde-
hydes 2 (Scheme 1) was our initial objective. The stereo-
chemistry of the Darzens condensation was of no
relevance in this process.
COOMe
O
H
O
H
4
COOMe
X
MeSO2
NaOMe
MeSO2
toluene/MeOH
0 °C to r.t.
4 h
F
F
3a
6b
0%
1. NaOH
2. HCl
O
MeSO2
F
O
5a
R3
R3
H
COOR4
O
+
X
R2
R2
O
Hal
Hal
Cl
O
COOMe
1
2
X = leaving group
H
COOMe
H
4
Scheme 1 Retrosynthetic analysis
MeS
MeS
NaOMe
F
F
toluene/MeOH
0 °C to r.t.
4 h
A series of potent candidates containing a sulfone moiety
was first brought to our attention (R2 = CH3SO2 in
Scheme 1). Under classical conditions, we found that the
desired product 5a did not form from the benzaldehyde
3a. Interestingly, the 4-methylsulfanyl-substituted benz-
aldehyde 3b reacted smoothly under identical conditions
6b
3b
1. NaOH
2. HCl
O
MeS
F
73% overall yield
5b
SYNTHESIS 2008, No. 8, pp 1221–1226
x
x
.
x
x
.2
0
0
8
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1067002; Art ID: Z29207SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Influence of electronic configuration of the aromatic ring
in the Darzens epoxide rearrangement

1222
J. M. Zimbron et al.
PAPER
methanol solvent system. A solvent screen had shown that
the presence of methanol as a polar co-solvent greatly en-
hanced the rate of the condensation. A base screening had
also revealed that sodium methoxide was a suitable base
for the reaction. Eventually, a commercially available
25% solution of sodium methoxide in methanol was used
directly and gave optimal results for the condensation
step. The subsequent hydrolysis proceeded smoothly with
sodium hydroxide and the carboxylate could be recovered
in high purity directly from the water phase. The epoxide
opening and decarboxylation was carried out in the same
pot under thermal and acidic conditions. This streamlined
three-step one-pot process led to material of high purity,
which could be used without further purification (purity
typically higher than 98%). Careful quantitative analyses
Table 1 Preparation of Functionalized 3-Substituted (4-Methyl-
sulfanylphenyl)propan-2-ones
O
Cl
O
COOMe
H
COOMe
H
4
MeS
MeS
NaOMe/MeOH
toluene, 0 °C to r.t., 4 h
R1
R1
3
6
1. NaOH, toluene/water
r.t. to 40 °C
2. HCl, toluene/water
r.t. to reflux
O
MeS
R1
5
1
by both H NMR and HPLC showed that the hydrolysis
Entry
R1
Substrate
Product
5b
Yield (%)
and epoxide opening–decarboxylation steps proceeded in
almost quantitative yields, indicating that the yield ob-
served at the end of the sequence was representative of the
Darzens condensation.
1
2
3
4
5
6
7
8
9
F
3b
3c
3d
3e
3f
83
58
55
35
42
6
H
5c
Me
NO2
CN
CF3
Cl
5d
The methylsulfanyl benzaldehyde series was of particular
interest to us and the sequence described above was used
to elaborate the various substrates depicted in Table 1.
The electron-rich aromatic aldehydes notably displayed
the best reactivity. The initial condensation proceeded in
moderate to good yield for all benzaldehydes carrying
electron-donating substituents in a position meta to the al-
dehyde (yields ranging from 50–83%) while the yield
dropped to below 45% for electron-withdrawing groups.
Monitoring by NMR showed that the reaction proceeded
in all cases with high selectivity in the epoxide formation
(>95:5) and with minimal side-reaction. Only the a-chloro
ester 4 was found to decompose over time when the alde-
hyde was not reactive enough. The streamlined protocol
allowed for removal of unreacted starting material and by-
products from a-chloro ester by simple extraction. The ep-
oxide opening and subsequent rearrangement proceeded
also smoothly and selectively to the methyl ketone for
electron-rich aromatic rings in almost quantitative yields.
5e
5f
3g
3h
3i
5g
5h
59
50
58
Br
5i
OMe
3j
5j
ture of two products. The first one corresponds to the sim-
ple decarboxylation and is referred to as ‘normal’. The
other product where the decarboxylation is followed by a
migration of the substituent from the a- to the b-position
is referred to as ‘abnormal’. The importance of the aro-
matic substituent R1 during the rearrangement step and in
particular during the formation of the carbocation is also
illustrated here.6
This strategy provided a valuable entry into the alkylated
aryl derivatives (entry 3), and the halogenated aryls (en-
tries 1, 7, 8), precursors to more functionalized products
after SNAr or a metal-mediated cross-coupling reaction.
The bisaldehydes 7g and 7h, although electronically poor,
displayed remarkable and unexpected reactivity
(Scheme 3). When 2 equivalents of a-chloro ester 4 were
used, they were found to afford the methyl ketone prod-
ucts 9g and 9h in 34% and 44% isolated yield, respective-
ly. The low reactivity of the electron-poor benzaldehydes
could apparently be overcome by the change in the elec-
tronic configuration after initiation of the reaction.
These encouraging results prompted a study of more gen-
eral substrates (Table 2). In the case of monosubstituted
benzaldehydes, the presence of electron-donating groups
was again found to favor the condensation and gave the
desired final methyl ketones in moderate to good yield
(from 51–79%). On the other hand, electron-poor aromat-
ic rings were found not only to be poorly reactive under
our conditions, but also to display an opposite selectivity
in the epoxide opening. Indeed, the aryl ethyl ketone 9j¢
was isolated in ca. 15% yield as the major product along
with ca. 5% yield of 9j. The same trend was observed in
the nitrile series (13% aryl ethyl ketone 9k¢ and 3% 9k).
Similar results were observed by Kagan and Singh who
reported that the decarboxylation of a-aryl-b-dimethyl
glycidate in acid medium involved the formation of a mix-
The stereoelectronic contribution of the position of the
substituent was then evaluated in more details with vari-
ous methoxybenzaldehydes 10. As expected, a methoxy
substituent in the para-position (Table 3, entry 3) led to
improved results (79% isolated yield of methyl ketone)
compared to a methoxy substituent in the ortho-position
(entry 1, 63% isolated yield of methyl ketone), presum-
ably due to steric constraint. It also performed better com-
pared to a methoxy substituent in the meta-position (entry
2, 54% isolated yield of methyl ketone), presumably due
Synthesis 2008, No. 8, 1221–1226 © Thieme Stuttgart · New York

PAPER
Darzens Condensation and a,b-Epoxide Rearrangement
1223
Cl
Table 2 Preparation of Functionalized 4-Substituted Phenylpro-
pan-2-ones
O
COOMe
H
CHO
COOMe
O
Cl
O
COOMe
NaOMe/MeOH
toluene, 0 °C to r.t., 4 h
H
OHC
OHC
COOMe
H
5
R2
R2
NaOMe/MeOH
O
toluene, 0 °C to r.t., 4 h
7
8
COOMe
O
O
MeOOC
1. NaOH, toluene/water
r.t. to 40 °C
O
2. HCl, toluene/water
r.t. to reflux
Scheme 3 Proposed rationale for reactivity of bis-aldehydes
O
R2
to poorer electron-donating ability. The latter could be
overcome when a second methoxy substituent was intro-
duced in the ortho- or para-position (entries 4 and 5),
which increased the overall yield to almost 80% isolated
yield.
9
Entry R2
Substrate Product
Yield (%)
1
2
3
4
5
6
OMe
7a
7b
7c
7d
7e
7f
9a
9b
9c
9d
9e
9f
79
H
36
Finally, a series of experiments were carried out in order
to better understand this remarkable difference in reactiv-
ity between electron-rich and electron-poor aromatic
benzaldehydes. One possible explanation for such differ-
ences is the formation of a poorly reactive ketal or
hemiketal. The Darzens condensation of p-cyano-substi-
tuted benzaldehyde with ( )-2-chloropropionic acid
methyl ester was therefore conducted under a variety of
dehydrating conditions (molecular sieves, potassium car-
bonate, sodium sulfate, etc.). None of the attempts result-
ed in an improved yield of the required product. In all
cases, only about 20% carbon–carbon bond-forming
event was observed. Additional spectroscopic analyses
(1H and 13C NMR) did not reveal any change in the start-
ing material under these treatments. The described prelim-
inary experiments do not allow to draw definitive
conclusions and further work to better understand the
trend illustrated in this paper are currently ongoing in our
laboratory.
Me
F
51
64
SO2Me
Ph
no reaction
50
O
7
CHO
7g
34
O
9g
O
O
H
8
44
CHO
7h
O
9h
9i
9
CF3
7i
7j
trace
10
NO2
5 (9j)
15 (9j¢)
Table 3 Stereoelectronic Influence of the Substitution Pattern on
the Darzens Epoxide Rearrangement
O
O2N
9j
1. NaOH, toluene/H2O
Cl
O
r.t. to 40 °C
2. HCl, toluene/H2O
r.t. to reflux
COOMe
O
H
H
4
O
NaOMe
toluene,
0 °C to r.t., 4 h
MeO
O2N
MeO
9j¢
10
11
11
CN
7k
3 (9k)
13 (9k¢)
Entry
Position of OMe Substrate
Product
11a
Yield (%)
O
NC
1
2
3
4
ortho
meta
para
10a
10b
7a
63
54
79
77
9k
O
11b
11a
NC
ortho +
10c
11c
meta
9k¢
5
meta +
10d
11d
80
para
Synthesis 2008, No. 8, 1221–1226 © Thieme Stuttgart · New York

1224
J. M. Zimbron et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 206.2, 136.1, 135.9, 130.5, 130.2,
127.1, 124.8, 50.0, 28.9, 19.3, 15.0.
In conclusion, we have developed a rapid, practical and
robust process for the Darzens condensation of substituted
benzaldehydes and subsequent a,b-epoxy rearrangement. HRMS: m/z calcd for (M + H): 195.07654; found: 195.09464.
The process developed is amenable to both large scale and
parallel synthesis. In the course of our investigation, we
have demonstrated the remarkable regioselectivity in the
epoxide opening and the limitations of the condensation to
1-(4-Methylsulfanyl-3-nitrophenyl)propan-2-one (5e)
1H NMR (400 MHz, CDCl3): d = 8.13 (d, J = 2.0 Hz, 1 H), 7.45 (dd,
J = 8.3, 2.0 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 1 H), 3.82 (s, 2 H), 2.52
(s, 3 H), 2.27 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 203.0, 142.0, 136.7, 133.6, 129.2,
125.6, 124.6, 47.7, 28.4, 14.6.
electron-rich benzaldehydes.
NMR spectra were recorded using a Bruker 400 MHz spectrometer.
Chemical shifts are reported in ppm and referenced to CDCl3 on the
HRMS: m/z calcd for (M + H): 226.04596; found: 226.05324.
d scale; coupling constants are given in Hz. Column chromatogra-
2-Methylsulfanyl-5-(2-oxopropyl)benzonitrile (5f)
phy was carried out using silica gel (70–230 mesh, E. Merck). High-
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 1.7 Hz, 1 H), 7.37 (dd,
resolution mass spectra were recorded using a Bruker FT ITR MS
4.7T Bio Apex II spectrometer. All solvents, and reagents used were
of technical grade and readily available from multiple suppliers. All
reactions were carried out under N2.
J = 8.3, 2.0 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 3.74 (s, 2 H), 2.58
(s, 3 H), 2.24 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 204.6, 142.3, 134.3, 134.2, 131.4,
126.7, 116.8, 112.0, 49.1, 29.8, 15.9.
Darzens Condensation/a,b-Epoxide Rearrangement of Benzal-
dehydes 3, 7, 10 with Methyl 2-Chloropropionate; General Pro-
cedure
HRMS: m/z calcd for (M + H): 206.05613; found: 206.06341.
1-(4-Methylsulfanyl-3-trifluoromethylphenyl)propan-2-one
(5g)
To a solution of the respective aldehyde 3, 7, or 10 (10 mmol, 1
equiv) in toluene (10 mL) at r.t. was added ( )-2-chloropropionic
acid methyl ester (4; 1.2 equiv) over 10 min. The solution was
cooled to 0–5 °C and a solution of NaOMe in MeOH (1.15 equiv)
was added over 20 min at a rate such that the temperature remained
below 10 °C (mild exotherm). The resulting suspension was stirred
for an additional 30 min at 0–5 °C, and then warmed to r.t. and
stirred until completion of the reaction (3–6 h). The mixture was di-
luted with toluene (5 mL) and warmed to 35–40 °C. Aq 30% NaOH
(1.15 equiv) was added over 45 min to hydrolyze the ester and the
suspension was allowed to stir for 1 h. At completion of the hydro-
lysis, H2O (10 mL) was added, the mixture was cooled to r.t., and
the two phases were separated. The by-products derived from ( )-
2-chloropropionic acid methyl ester (4) and possible remaining al-
dehyde 3, 7, or 10 were removed by extraction with toluene (2 × 10
mL). Additional toluene (20 mL) was added and the resulting mix-
ture was heated to 60 °C. Concd HCl (1.2 equiv) was added over 30
min to reach pH 2.5 (exothermic; CO2 evolution). The mixture was
stirred for 1 h at 60 °C and for an additional 4 h at 95 °C. The bipha-
sic mixture was then cooled to r.t. and the phases were separated.
The organic phase was washed with H2O (10 mL), and concentrated
under vacuum. The residue was purified by flash chromatography
over silica gel (eluent: EtOAc–hexanes).
1H NMR (400 MHz, CDCl3): d = 7.46 (d, J = 1.8 Hz, 1 H), 7.37 (d,
J = 8.3 Hz, 1 H), 7.34 (dd, J = 8.3, 1.8 Hz, 1 H), 3.74 (s, 2 H), 2.58
(s, 3 H), 2.24 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.1, 153.1, 135.7, 133.8, 133.7,
125.6, 116.7, 112.0, 30.7, 15.9.
HRMS: m/z calcd for (M + H): 249.04827; found: 249.05555.
1-(3-Chloro-4-methylsulfanylphenyl)propan-2-one (5h)
1H NMR (400 MHz, CDCl3): d = 7.22 (d, J = 1.8 Hz, 1 H), 7.15 (d,
J = 8.0 Hz, 1 H), 7.09 (dd, J = 8.0, 1.8 Hz, 1 H), 3.66 (s, 2 H), 2.48
(s, 3 H), 2.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.5, 136.5, 132.0, 131.7, 130.3,
128.3, 125.8, 49.7, 29.4, 15.2.
HRMS: m/z calcd for (M + H): 215.02191; found: 215.02919.
1-(3-Bromo-4-methylsulfanylphenyl)propan-2-one (5i)
1H NMR (400 MHz, CDCl3): d = 7.40 (d, J = 1.8 Hz, 1 H), 7.15 (dd,
J = 8.3, 1.8 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 3.66 (s, 2 H), 2.48
(s, 3 H), 2.2 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.6, 138.5, 133.5, 131.7, 128.9,
125.6, 121.9, 49.7, 29.4, 15.8.
1-(3-Fluoro-4-methylsulfanylphenyl)propan-2-one (5b)
1H NMR (400 MHz, CDCl3): d = 7.16 (t, J = 8.0 Hz, 1 H), 6.87 (dd,
J = 8.0, 2.1 Hz, 1 H), 6.83 (dd, J = 10.3, 1.8 Hz, 1 H), 3.60 (s, 2 H),
2.39 (s, 3 H), 2.11 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.5, 159.1–161.5, 134.0, 129.0,
125.6, 124.0, 116.4, 50.0, 29.5, 15.7.
HRMS: m/z calcd for (M + H): 258.97140; found: 258.97867.
1-(3-Methoxy-4-methylsulfanylphenyl)propan-2-one (5j)
1H NMR (400 MHz, CDCl3): d = 7.14 (d, J = 8.0 Hz, 1 H), 6.82 (dd,
J = 8.0, 1.8 Hz, 1 H), 6.69 (d, J = 1.8 Hz, 1 H), 3.90 (s, 3 H), 3.68
(s, 2 H), 2.44 (s, 3 H), 2.17 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.4, 156.5, 132.2, 126.5, 125.7,
HRMS: m/z calcd (M + H): 199.05146; found: 199.05874.
122.2, 111.1, 55.8, 50.8, 29.2, 14.8.
1-(4-Methylsulfanylphenyl)propan-2-one (5c)7
1H NMR (400 MHz, CDCl3): d = 7.22 (d, J = 1.8 Hz, 1 H), 7.15 (d,
J = 8.0 Hz, 1 H), 7.09 (dd, J = 8.0, 1.8 Hz, 1 H), 3.66 (s, 2 H), 2.48
(s, 3 H), 2.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.5, 136.5, 132.0, 131.7, 130.3,
128.3, 125.8, 49.7, 29.4, 15.2.
HRMS: m/z calcd for (M + H): 211.07145; found: 211.07873.
1-(4-Methoxyphenyl)propan-2-one (9a)8
1H NMR (400 MHz, CDCl3): d = 7.14 (dd, J = 6.8, 2.0 Hz, 2 H),
6.90 (dd, J = 6.8, 2.0 Hz, 2 H), 3.82 (s, 3 H), 3.66 (s, 2 H), 2.16 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 207.0, 158.7, 130.4, 129.0, 128.2,
126.3, 114.2, 52.3, 50.1, 29.1.
HRMS: m/z calcd for (M + H): 181.06088; found: 181.06816.
1-(3-Methyl-4-methylsulfanylphenyl)propan-2-one (5d)
1H NMR (400 MHz, CDCl3): d = 7.28–7.01 (m, 5 H), 3.65 (s, 2 H),
2.50 (s, 3 H), 2.39 (s, 3 H), 2.11 (s, 3 H).
HRMS: m/z calcd (M + H): 165.08373; found: 165.09101.
Synthesis 2008, No. 8, 1221–1226 © Thieme Stuttgart · New York

PAPER
Darzens Condensation and a,b-Epoxide Rearrangement
1225
1-Phenylpropan-2-one (9b)9
4-(2-Oxopropyl)benzonitrile (9k)15
1H NMR (400 MHz, CDCl3): d = 7.22–7.29 (m, 5 H), 3.72 (s, 2 H),
2.18 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.64 (d, J = 8.3 Hz, 2 H), 7.32 (d,
J = 8.2 Hz, 2 H), 3.96 (s, 2 H), 2.24 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.5, 134.2, 129.4, 128.8, 127.1,
HRMS: m/z calcd for (M – H): 158.06841; found: 158.06114.
50.1, 29.3.
4-Propionylbenzonitrile (9k¢)14
HRMS: m/z calcd (M + H): 135.07317; found: 135.08044.
1H NMR (400 MHz, CDCl3): d = 8.06 (d, J = 8.5 Hz, 2 H), 7.79 (d,
J = 8.5 Hz, 2 H), 3.04 (q, J = 7.3 Hz, 2 H), 1.26 (t, J = 7.3 Hz, 3 H).
1-p-Tolylpropan-2-one (9c)9
1H NMR (400 MHz, CDCl3): d = 7.14 (dd, J = 8.0, 2.0 Hz, 2 H),
7.08 (dd, J = 8.0, 2.0 Hz, 2 H), 3.68 (s, 2 H), 2.36 (s, 3 H), 2.16 (s,
3 H).
HRMS: m/z calcd for (M – H): 158.06841; found: 158.06114.
1-(2-Methoxyphenyl)propan-2-one (11a)16
1H NMR (400 MHz, CDCl3): d = 7.29 (td, J = 8.0, 1.8 Hz, 1 H), 7.14
(dd, J = 7.3, 1.8 Hz, 1 H), 6.95 (td, J = 7.3, 1.8 Hz, 1 H), 6.91 (d,
J = 8.0 Hz, 1 H), 3.84 (s, 3 H), 3.70 (s, 2 H), 2.16 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 207.0, 136.7, 129.5, 129.3, 128.2,
50.7, 29.2, 21.1.
HRMS: m/z calcd for (M + H): 149.08881; found: 149.08021.
13C NMR (100 MHz, CDCl3): d = 207.0, 157.3, 131.0, 128.6, 123.7,
120.3, 110.2, 55.3, 45.8, 29.3.
1-(4-Fluorophenyl)propan-2-one (9d)10
1H NMR (400 MHz, CDCl3): d = 7.18–7.04 (m, 4 H), 3.70 (s, 2 H),
2.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.1, 160.8, 131.0, 130.9, 129.9,
115.7, 115.5, 52.3, 50.0, 29.3.
HRMS: m/z calcd for (M + H): 165.20594; found: 165.09101.
1-(3-Methoxyphenyl)propan-2-one (11b)17
1H NMR (400 MHz, CDCl3): d = 7.14 (t, J = 7.78 Hz, 1 H), 6.85–
6.77 (m, 3 H), 3.82 (s, 3 H), 3.69 (s, 2 H), 3.18 (s, 3 H).
HRMS: m/z calcd for (M): 152.06374; found: 152.05982.
13C NMR (100 MHz, CDCl3): d = 206.3, 159.7, 135.4, 129.5, 121.5,
114.8, 112.3, 55.0, 50.1, 29.1.
1-Biphenyl-4-ylpropan-2-one (9f)11
1H NMR (400 MHz, CDCl3): d = 7.64–7.56 (m, 4 H), 7.50–7.42 (m,
2 H), 7.40–7.34 (m, 1 H), 7.33–7.26 (m, 2 H), 3.77 (s, 2 H), 2.22 (s,
3 H).
HRMS: m/z calcd for (M + H): 165.20594; found: 165.09101.
1-(2,3-Dimethoxyphenyl)propan-2-one (11c)18
1H NMR (400 MHz, CDCl3): d = 7.02 (t, J = 7.9 Hz, 1 H), 6.86 (d,
J = 7.8 Hz, 1 H), 6.75 (d, J = 7.8 Hz, 1 H), 3.88 (s, 3 H), 3.80 (s, 3
H), 3.72 (s, 3 H), 2.18 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 206.7, 152.7, 147.1, 128.8, 124.1,
122.7, 111.6, 60.4, 55.7, 45.3, 29.4.
13C NMR (100 MHz, CDCl3): d = 206.3, 140.7, 140.1, 133.2, 129.9,
128.8, 127.5, 127.3, 127.1, 50.6, 29.4.
HRMS: m/z calcd for (M + H): 210.10447; found: 211.11174.
1-[4-(2-Oxopropyl)phenyl]propan-2-one (9g)12
1H NMR (400 MHz, CDCl3): d = 7.19 (s, 4 H), 3.70 (s, 4 H), 2.18
(s, 6 H).
13C NMR (100 MHz, CDCl3): d = 206.3, 133.0, 129.8, 50.1, 29.4.
HRMS: m/z calcd for (M + H): 195.09429; found: 195.00356.
1-(3,4-Dimethoxyphenyl)propan-2-one (11d)19
1H NMR (400 MHz, CDCl3): d = 6.74 (dd, J = 8.1, 1.9 Hz, 2 H),
6.66 (d, J = 1.9 Hz, 1 H), 3.81 (s, 6 H), 3.58 (s, 2 H), 2.09 (s, 3 H).
HRMS: m/z calcd for (M + H): 191.09938; found: 191.10666.
HRMS: m/z calcd for (M + H): 195.09429; found: 195.01002.
1-[3-(2-Oxopropyl)phenyl]propan-2-one (9h)13
1H NMR (400 MHz, CDCl3): d = 7.19 (s, 4 H), 3.70 (s, 4 H), 2.18
(s, 6 H).
13C NMR (100 MHz, CDCl3): d = 206.3, 133.0, 129.8, 50.1, 29.4.
References
(1) Current address: University of Neuchâtel, AV. BelleVaux
51, CP 2, 2007 Neuchâtel, Switzerland;
HRMS: m/z calcd for (M + H): 191.09938; found: 191.10666.
jeremy.zimbron@unine.ch.
(2) Hirt H., Haenggi R., Reyes J., Seeger-Weibel M., Gallou F.;
Org. Process Res. Dev. 2008, 12, 111
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1-(3-Methoxyphenyl)propan-2-one (9i)9
1H NMR (400 MHz, CDCl3): d = 7.69 (d, J = 8.3 Hz, 2 H), 7.48 (d,
J = 8.2 Hz, 2 H), 3.86 (s, 2 H), 2.23 (s, 3 H).
1-(4-Trifluoromethylphenyl)propan-1-one (9i¢)14
1H NMR (400 MHz, CDCl3): d = 8.25 (d, J = 8.3 Hz, 2 H), 7.78 (d,
J = 8.3 Hz, 2 H), 3.06 (q, J = 7.3 Hz, 2 H), 1.27 (t, J = 7.3 Hz, 3 H).
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1-(4-Nitrophenyl)propan-2-one (9j)
1H NMR (400 MHz, CDCl3): d = 7.61 (d, J = 8.0 Hz, 2 H), 7.44 (d,
J = 8.0 Hz, 2 H), 3.98 (s, 2 H), 2.19 (s, 3 H).
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HRMS: m/z calcd for (M + H): 180.05824; found: 180.06552.
1-(4-Nitrophenyl)propan-1-one (9j¢)
1H NMR (400 MHz, CDCl3): d = 8.34 (d, J = 8.0 Hz, 2 H), 8.18 (d,
J = 8.0 Hz, 2 H), 3.13 (q, J = 7.3 Hz, 2 H), 1.10 (t, J = 7.3 Hz, 3 H).
HRMS: m/z calcd for (M + H): 180.05824; found: 180.06552.
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Synthesis 2008, No. 8, 1221–1226 © Thieme Stuttgart · New York