Conversion of Benzal Halides to Benzaldehydes in the Presence of Aqueous Dimethylamine

Article abstract of DOI:10.1055/s-2003-44390

Aqueous dimethylamine is an efficient reagent for the conversion of a variety of benzal halides to their corresponding benzaldehydes. Studies indicate that aqueous dimethylamine significantly accelerates aldehyde formation from benzal halide precursors, as compared to the use of water alone. Indeed, these reactions are routinely completed in one hour or less, depending upon substrate substitution. Desired products can be isolated in pure form, and in high yield, but silica gel filtration is often necessary to remove baseline contaminants. The method represents a novel, economical approach to acquire pure, substituted benzaldehydes from commercially available, or easily prepared starting materials.

Full text of DOI:10.1055/s-2003-44390

PAPER
283
Conversion of Benzal Halides to Benzaldehydes in the Presence of Aqueous
Dimethylamine
Conversionof
B
en
o
zal
H
alides
t
n
oBenzalde
h
a
ydes ld Bankston*
Bayer Pharmaceuticals Corporation, Department of Chemistry Research, West Haven, CT 06516, USA
E-mail: donald.bankston.b@bayer.com
Received 8 August 2003; revised 3 November 2003
mono- or disubstitution by triazole 2 did not occur. In-
stead, aldehyde 3 was isolated reproducibly. Repeating
the reaction in the absence of 2 still generated 3. A litera-
ture search indicated that benzal halides could be trans-
Abstract: Aqueous dimethylamine is an efficient reagent for the
conversion of a variety of benzal halides to their corresponding
benzaldehydes. Studies indicate that aqueous dimethylamine signif-
icantly accelerates aldehyde formation from benzal halide precur-
sors, as compared to the use of water alone. Indeed, these reactions formed into aldehydes by sodium iodide in anhydrous
DMF,10 but the yields were poor and sodium iodide was
are routinely completed in one hour or less, depending upon sub-
the documented reagent for the conversion.11 The solvent
strate substitution. Desired products can be isolated in pure form,
and in high yield, but silica gel filtration is often necessary to re-
was clearly responsible for the generation of aldehyde, but
move baseline contaminants. The method represents a novel, eco-
a mechanism was not transparent. 1H NMR displayed an
nomical approach to acquire pure, substituted benzaldehydes from
aldehyde peak after 1 was heated in deuterated N,N-dim-
ethylformamide (DMF-d7) for 6 hours at >140 °C. This
result indicated that an intermolecular formyl transfer did
not occur. Since the reactions in DMF were conducted un-
der anhydrous conditions, water was not considered a vi-
able competitor. Further investigation demonstrated that
these conditions effectively converted other benzal ha-
lides to their corresponding benzaldehydes in good yields
as well (Table 1).
commercially available, or easily prepared starting materials.
Key Words: aqueous dimethylamine, benzal halides, hydrolysis,
benzaldehydes, N,N-dimethylformamide
A variety of methods are available in the literature to syn-
thesize aldehydes.1–9 Common preparations involve oxi-
dation of alcohols (primary, secondary, allylic and
benzylic),2 reduction of acyl halides3 and reduction of
N,N-disubstituted amides.4 Other, more elegant transfor-
mations have also been disclosed. For instance, a recent
publication5 describes a novel, metal-catalyzed conver-
sion of aromatic nitriles to aldehydes in aqueous formic
acid.
Br
O
N
DMF
Br
H
+
O
O
N
>140 ο
C
N
H
O
O
Hydrolysis of gem-dihalides1 has been studied extensive-
ly. Solvolytic displacement formally involves loss of
halogen with successive replacement by hydroxyl, fol-
lowed by loss of water, to generate the corresponding al-
dehyde. The rate of hydrolysis depends upon the
substrate, but the method is most applicable to benzal ha-
lides. In general, hydrolysis of dihalide aliphatics, such as
dichloromethane, is quite slow, which makes the process
less useful for these types of molecules. The explanation
for this is related to resonance stabilization offered by the
aromatics that is not possible with aliphatic systems.1
1
2
3
DMF, >140 ο
C
Scheme 1
Table 1 Reaction of Benzal Bromides with DMF
Entry Sub-
strate
R1
R2
Reaction Yield
Time (h) (%)
Prod-
uct
A new approach, conversion of benzal halides to the cor-
responding benzaldehydes in the presence of aqueous
dimethylamine, is the focus of this report. These transfor-
mations, as well as a mechanism that supports this event,
will be discussed in detail.
1
2
3
4
6
8
H
H
H
H
6
6
6
75
72
70
5
7
9
m-CHBr2
m-Cl
Heating benzal halide 1 in N,N-dimethylformamide
(DMF) in the presence of 1,2,4-triazole (2), or its sodium
salt, afforded unexpected results (Scheme 1). Observed
Additional studies confirmed that aldehyde formation was
extremely slow, or did not occur at all, unless the reaction
temperature was thermostated at or in excess of 140 °C.
Under these conditions, complete reaction occurred with-
in 5–6 hours, but chromatography was normally required
to isolate pure aldehydes.
SYNTHESIS 2004, No. 2, pp 0283–0289
x
x
.
x
x
.2
0
0
3
Advanced online publication: 18.12.2003
DOI: 10.1055/s-2003-44390; Art ID: M03603SS
© Georg Thieme Verlag Stuttgart · New York

284
D. Bankston
PAPER
Br
Br
Based upon all of the information collected, it appeared
that the reactive species might be dimethylamine, a by-
product resulting from the decomposition of DMF at ele-
vated temperatures.11 To test this theory, benzal bromide
1 was heated in the presence of aqueous 40% dimethy-
lamine. Aldehyde 3 was formed in 3 hours (or less) and
was isolated in 86% yield. In general, this reaction, and
others, had a faster rate than those conducted in the pres-
ence of DMF. Quite possibly, this result was due to the in-
duction period required for DMF to decompose slowly to
dimethylamine at elevated temperatures. Inspection of the
reactions of 6 with aqueous dimethylamine shows that
both benzal halide functions were hydrolyzed to afford
1012,13 in at least a third of the time required to afford 7 in
DMF (Scheme 2). The data collected thus far suggested
that the transformation of benzal halides to their corre-
sponding aldehydes might follow a mechanism as out-
lined in Scheme 3. Addition of dimethylamine to I would
provide adduct II, which could rearrange to charged-imi-
ne III. Subsequent addition of water, followed by elimi-
nation of dimethylamine and hydrobromic acid from IV,
effected generation of aldehyde V. This mechanism ratio-
nalized the results observed from these reactions, and the
evidence supported a path based upon ultimate hydrolysis
of a charged imine. Additional benzal bromides and com-
mercially available benzal chlorides were treated with
40% aqueous dimethylamine to better understand the gen-
erality of these conversions (Table 2). Synthesis,14 fol-
lowed by chromatography, delivered pure benzal
bromides in moderate yields (59–62%), albeit, further in-
vestigation indicated that crude benzal halide could be uti-
lized in the hydrolysis step, since tribromide impurity, a
consequence of all of these brominations, did not appear
to react with aqueous dimethylamine. This was demon-
strated by the reaction of 14 and 15 with 40% aqueous
dimethylamine, which delivered aldehyde 16 in 70% yield
(from 13) in 15 minutes or less (Scheme 4). The advan-
tage of this sequence stemmed from the ability to elabo-
rate two sites in tandem in a single stage.
Br
O
O
DMF
6 h
Br
Br
Br
H
7
6
H
aq dimethylamine
2 h
O
H
10
Scheme 2
Br
Br
Br
Me2NH
- HBr
N
R
R
II
I
H
O
H
-
Br
H
O
H
+
H2O
N
- HBr
N
-
Br
R
R
R
- Me2NH
V
IV
III
Scheme 3
24 were completely hydrolyzed to aldehyde 20 in 10 min-
utes in the presence of aqueous dimethylamine. When the
reactions of 19 and 24 were extended to 2 hours, substitu-
tion of the corresponding p-fluoro groups by dimethy-
lamine occurred in good yield (>80%). At least an hour
was required for complete conversions of 25 and 27 to al-
dehydes 2622,23 and 28,13,19,24 respectively. Extending the
reaction time to 8 hours completely converted 27 to 29
(94%)25,26 but substitution of 25 by dimethylamine to give
26a27 was never observed (Scheme 5).
When benzal chloride 24 was stirred at room temperature
in the presence of aqueous dimethylamine for 3 hours,
50% conversion to 20 occurred. This result underscored
the high reactivity of these 4-fluorobenzal halides in the
presence of that reagent. Even under these milder condi-
tions, NMR analysis indicated that a trace of 2128,29
formed as well.
In general, many of the benzal halides investigated (11,
14, 17, 19, 22 and 24) afforded the corresponding alde-
hydes (12,15,16 16, 18,16–19 2013,15,20 and 2316,18,21) in mod-
erate to good yields in 15 minutes or less (Table 2), and
the difference in reaction rates of benzal bromides versus
benzal chlorides was not observed to be significant. In
fact, a mixture of benzal bromide 19 and benzal chloride
Br
CHO
Br
Br
Br
Br
CH3
NBS, CCl4
40% aq Me2NH
CO2CH3
+
CO2CH3
CH3
benzoyl peroxide
CO2CH3
CO2CH3
N
H3C
F
F
F
13
14
15
16
70% (overall yield for both steps)
Scheme 4
Synthesis 2004, No. 2, 283–289 © Thieme Stuttgart · New York

PAPER
Conversion of Benzal Halides to Benzaldehydes
285
Table 2 Reactions of Benzal Halides with Aqueous Dimethylamine
n
Substrate
R1
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
R2
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
R3
R4
Reaction Time Yield (%)
Product
10a
9a
1
2
3
4
5
6
7
8
9
6
m-CHBr2
m-Cl
m-CO2Me
m-NO2
p-F
m-CHO
m-Cl
2 h
80
87
86
87
86
82
68
89
81
80
81
94
8
2 h
11
17
19
19
22
24
24
25
27
27
m-CO2Me
m-NO2
p-F
15 min
10 min
10 min
2 h
12
18
20
p-F
NMe2
m-OMe
p-F
21
m-OMe
p-F
10 min
10 min
2 h
23
20
p-F
NMe2
m-F
21
10
11
12
m-F
1 h
26
o-F
o-F
1 h
28
o-F
NMe2
8 h
29
a Reaction times for 9 and 10 are not optimized/experiments conducted at 60 °C.
A competition experiment, in which 4-fluorobenzal chlo- dence of 26a was observed. This information was derived
ride (24), 3-fluorobenzal chloride (25) and 2-fluorobenzal from a sample that was filtered through a plug of silica
chloride (27) were reacted together with aqueous dimeth- gel. However, when the crude sample was analyzed by 1H
ylamine at 60 °C for an hour, provided interesting results. NMR prior to its contact with silica gel a major aldehyde
The conversion rate of 24 was the fastest, as expected. In- absorption was only observed for 21, along with very
spection of an aliquot after 30 minutes indicated that 24 small absorptions associated with 20, 26 and 28. Further-
was completely converted to 20 (ca. 40%) and 21 (ca. more, two major singlets (and one very minor one) at ca.
60%). In contrast, the reaction rates of 25 and 27 were 2 ppm indicated the intermediacy of precursors that obvi-
considerably slower. NMR data suggested that approxi- ously collapsed to generate 26 and 28 in the presence of
mately 60% of 25 and about 50% of 27 remained unreact- silica gel.
ed. After an hour of reaction time, NMR analysis
Closer scrutiny of the crude mixtures resulting from the
indicated that all of 25 and 27 were consumed. Only a
reactions of 25 and 27 suggested that the major compo-
small amount of 20 persisted, as it continued to react with
nent was 30 (a and b), where the fluorine was essentially
dimethylamine to produce 21. A trace (ca. 10 mol%) of 29
unsubstituted (Scheme 6). The NMR data of this material
indicated the presence of 12 protons (CH3) associated
was also suggested by the analytical results, but no evi-
with complete substitution of the dihalide moiety, as well
as 4 aromatic protons with visible fluorine coupling. The
Cl
Cl
conspicuous absence of a formyl signal confirmed that an
aldehyde was not present. However, when the crude ma-
terial was filtered through a plug of silica gel, the NMR
data of the isolated products only displayed absorptions
associated with 26 and 28. Apparently, the catalytic sur-
face of the silica gel support effected rapid conversion of
that vehicle (in the presence of some moisture) to the de-
sired aldehyde products. The collapse of these intermedi-
ates also occurred in aqueous dimethyl sulfoxide over
time, but the transition was virtually instantaneous in the
presence of silica gel. It appeared that 30 was a transient,
but somewhat stable intermediate, that formed first from
the reactions of these benzal halides with aqueous dimeth-
CHO
40% aq dimethylamine
F
F
25
26
CHO
40% aq dimethylamine
X
CH3
N
CH3
26a
Scheme 5
Synthesis 2004, No. 2, 283–289 © Thieme Stuttgart · New York

286
D. Bankston
PAPER
CH3 CH3
Cl
Cl
N
N
H3C
CH3
CHO
aq dimethylamine
R
R
R
25: R = 3-F
27: R = 2-F
26: R = 3-F
28: R = 2-F
30a: R = 3-F
30b: R = 2-F
Scheme 6
ylamine. The formation of this same type of intermediate
was also observed with many of the other benzal halide
substrates, but not all of them. For instance, even under
carefully controlled conditions, such an intermediate was
never observed during the reactions of highly reactive
substrates such as 4-fluorobenzal halides 19 and 24. The
ramification of this observation was a re-evaluation of the
mechanism to explain the progression of all of these reac-
tions (Scheme 7). Based upon current evidence, benzal
halide I reacted with dimethylamine to form transient in-
termediate VI. Addition of aqueous acid (or silica gel fil-
tration of VI) generated benzaldehyde V.
Table 3 Hydrolysis of Benzal Halides in Water vs Aqueous Dime-
thylamine
Substrate
Reaction Time at 60 °C Reaction Time at 60 °C
in H2O
in Me2NH
14 + 15
24
2.5 h/ca. 10 mol% 16aa
4 h/ca. 50 mol% 20
1 h/ca. 8 mol% 26
1 h/ca. 5 mol% 28
15 min/70% 16
15 min/89% 20
1 h/80% 26
25
27
1 h/81% 28
a Compound 16a is not dimethylamine-substituted.
CH3 CH3
H3C
H
O
Br
Br
N
N
N
H3C
CH3
SiO2 (or aq acid)
- NH(CH3)2
H3C
60 °C for an hour produced only a trace of fluoroaldehyde
16a, but that substrate completely hydrolyzed, and subse-
quently suffered dimethylamine substitution in 15 min-
utes or less in the presence of aqueous dimethylamine to
give 16. Benzal chlorides 25 and 27 likewise hydrolyzed
minimally (ca. 5–8 mol%) under the same conditions in
water, but effectively provided high yields of aldehydes
after an hour in aqueous dimethylamine.
H
NH(CH3)2, H2O
- 2 HBr
R
R
R
VII
VI
I
- NH(CH3)2
O
H
In conclusion, aqueous dimethylamine easily transforms
benzal halides to their corresponding benzaldehydes.
These reactions provide pure materials in good yield after
filtration through a pad of silica gel to remove baseline
contaminants. In general, these conversions are quite rap-
id, and many are complete in 15 minutes or less. The
mechanism of this novel sequence appears to evolve from
a bis(dimethylamine)-substituted intermediate that col-
lapses to the corresponding aldehyde in the presence of
water and/or acidic surfaces such as silica gel.
R
V
Scheme 7
The reaction of 24 with neat N,N′-dimethylethylenedi-
amine also supported this mechanism (Scheme 8). Char-
acterization of the isolated product (31) clearly showed a
disubstitution of nitrogen to provide the imidazolidine.
Treatment of 31 with aqueous acid or filtration through
silica gel afforded 20 cleanly. This result, and others, will
be the subject of a subsequent report.
N
Cl
Cl
N
CHO
H
N
N
A competition study with several of the benzal halides
was conducted to determine their rate of hydrolysis in wa-
ter as compared to aqueous dimethylamine (Table 3). In
each experiment, the benzal halides were converted to
their corresponding benzaldehydes substantially faster in
the presence of aqueous dimethylamine versus water
alone. For instance, heating benzal bromide 14 in water at
hydrolysis
H
F
F
F
31
20
24
Scheme 8
Synthesis 2004, No. 2, 283–289 © Thieme Stuttgart · New York

PAPER
Conversion of Benzal Halides to Benzaldehydes
287
All solvents and reagents were purchased from EM Science, Sigma-
Aldrich Chemicals, Acros or Lancaster, and used without further
purification. Benzal bromides 6, 8, 11, 17, 19 and 22 were prepared
from the corresponding toluene derivatives using N-bromosuccin-
imide in the presence of benzoyl peroxide.14 NMR data was ob-
tained from a Varian 200, 300 or 400 MHz instrument. Mass spectra
were done on a Finnigan LCQ ion-trap mass spectrometer with
electrospray ionization and a Hewlett-Packard 1100 HPLC inter-
face. Electron-impact mass spectra were obtained with a Hewlett
Packard 5989A mass spectrometer equipped with a Hewlett Pack-
ard 5890 gas chromatograph with a J & W DB-5 column (0.25 M
coating; 30 m × 0.25 mm).
GC-MS/EI: m/z = 164 (M+).
3-Nitrobenzaldehyde (18)16–19
Pale-yellow crystals; yield: 87%.
1H NMR (DMSO-d6, 300 MHz): = 7.90 (dd, J = 7.9, 8.3 Hz, 1
arom), 8.33 (ddd, J = 1.2, 1.6, 7.9 Hz, 1 Harom), 8.52 (ddd, J = 1.2,
H
2.2, 8.3 Hz, 1 Harom), 8.68 (dd, J = 1.6, 2.2 Hz, 1 Harom), 10.14 (s, 1
H, CHO).
GC-MS/EI: m/z = 151 (M+).
3-Methoxybenzaldehyde (23)16,18,21
Colorless oil; yield: 68%.
1H NMR (DMSO-d6, 400 MHz): = 3.82 (s, 3 H, OCH3), 7.26 (ddd,
J = 2.6, 2.7, 7.1 Hz, 1 Harom), 7.40 (m, 1 Harom), 7.49 (m, 2 Harom).
Benzaldehydes 3, 9 and 10 from Benzal Halides 1, 8, and 6 by
Aqueous Acidic Workup; General Procedure
A suspension of benzal halide 1, 8, or 6 (0.490–3.52 mmol) in aq
40% dimethylamine (5-30 mL) was heated to 60 °C for 2–3 h under
argon. The contents were then poured into CH2Cl2 (25–60 mL). The
layers were separated, and the organic layer was washed with aq 1
N HCl (50 mL), followed by brine (2 × 50 mL). This solution was
then dried (Na2SO4), concentrated and dried under high vacuum to
afford the aldehyde 3, 9 or 10.
GC-MS/EI: m/z = 136 (M+).
2-Fluorobenzaldehyde (28)13,19,24
Colorless liquid; yield: 81%.
1H NMR (DMSO-d6, 300 MHz): = 7.40 (m, 2 Harom), 7.76 (m, 1
Harom), 7.85 (ddd, J = 2.0, 7.3, 7.9 Hz, 1 Harom), 10.23 (s, 1 H, CHO).
GC-MS/EI or HPLC-MS/ES: inconclusive.
3,3-Dimethyl-1-oxo-3-hydroisobenzofuran-5-carbaldehyde (3)
Yellow crystals; yield: 86%.
1H NMR (CDCl3, 200 MHz): = 1.71 (s, 6 H, CH3), 7.94 (m, 1
Harom), 8.03 (m, 2 Harom), 10.17 (s, 1 H, CHO).
Methyl 2-(Dimethylamino)-5-formylbenzoate (16)
A solution of 13 (2.85 g, 16.95 mmol) in CCl4 (85 mL) was treated
with N-bromosuccinimide (6.60 g, 37.08 mmol) and benzoyl perox-
ide (0.454 g, 1.87 mmol). The contents were refluxed for 10 h under
argon, cooled to r.t. and filtered to remove succinimide. The filtrate
was concentrated to a clear, yellow liquid (a mixture of 14 and 15)
that was added to aq 40% dimethylamine (80 mL). The contents
were slowly heated to 56 °C for 15 min, and the heat was then re-
moved. The dark orange solution was poured into CH2Cl2 (150 mL)
and the layers were separated. The organic layer was concentrated
to a dark yellow oil that was placed onto a column of silica gel (300
cc) equilibrated in hexane. The desired product was eluted with a
gradient ranging from 20–65% EtOAc–hexane to provide 16 (2.46
g, 70%) as a clear, yellow liquid.
GC-MS/EI): m/z = 190 (M+).
Anal. Calcd for C11H10O3·0.10 H2O: C, 68.81; H, 5.35. Found: C,
68.84; H, 5.17.
3-Chlorobenzaldehyde (9)15,20,30
Yellow liquid; yield: 87%.
1H NMR (CDCl3, 400 MHz): = 7.49 (dd, J = 7.8, 8.0 Hz, 1 Harom),
7.61 (ddd, J = 1.3, 1.6, 8.0 Hz, 1 Harom), 7.78 (ddd, J = 1.3, 2.1, 7.8
Hz, 1 Harom), 7.86 (dd, J = 1.6, 2.1 Hz, 1 Harom), 9.98 (s, 1 H, CHO).
GC-MS/EI: m/z = 140 (M+).
1H NMR (DMSO-d6, 300 MHz): = 2.93 [s, 6 H, N(CH3)2], 3.83 (s,
3 H, CO2CH3), 7.05 (d, J = 8.9 Hz, 1 Harom), 7.79 (dd, J = 2.3, 8.9
Hz, 1 Harom), 8.00 (d, J = 2.3 Hz, 1 Harom), 9.73 (s, 1 H, CHO).
Benzene-1,3-dicarbaldehyde (10)12,13
Yellow crystals; yield: 80%.
1H NMR (CDCl3, 400 MHz): = 7.74 (dd, J = 7.6, 7.6 Hz, 1 Harom),
8.17 (dd, J = 1.6, 7.6 Hz, 2 Harom), 8.39 (dd, J = 1.6, 1.6 Hz, 1 Harom),
10.12 (s, 2 H, CHO).
HPLC-MS/ES: m/z = 208 (M + 1).
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.46; H, 6.40; N, 6.50.
GC-MS/EI: m/z = 134 (M+).
4-Fluorobenzaldehyde (20)13,15,20 and 4-Fluorobenzoic Acid
(20a)19
Benzaldehydes 12, 18, 23 and 28 from Benzal-Halides 11, 17, 22
and 27; Silica Gel Workup; General Procedure
A suspension of 19 (0.200 g, 0.746 mmol) in 40% aq dimethy-
lamine (4 mL) was heated to 60 °C under argon for 10 min. The
contents were then poured into CH2Cl2 (25 mL) and the layers were
separated. The organic layer was dried (Na2SO4) and concentrated.
The resultant liquid was placed onto a pad of silica gel (20 cc) equil-
ibrated in hexane, and the desired material was eluted with 20%
hexane–CH2Cl2. The single fraction was concentrated to afford 20
(0.080 g, 86%) as a colorless liquid.
A suspension of benzal halide 11, 17, 22, or 27 (1.79–5.59 mmol)
in 40% aq dimethylamine (5–20 mL) was heated to 60 °C under ar-
gon for 10–15 min. The crude mixture was then poured into CH2Cl2
(15–50 mL) and the layers were separated. The organic layer was
dried (Na2SO4) and concentrated to a pale yellow liquid. The crude
residue was filtered over silica gel (20–200 cc) equilibrated in 50%
EtOAc–hexane, and the desired material was eluted with the same
solvent system. The single fraction was concentrated and dried un-
der high vacuum to afford the aldehyde.
1H NMR (DMSO-d6, 400 MHz): = 7.42 (m, 2 Harom), 7.97 (m, 2
Harom), 9.94 (s, 1 H, OH).
GC-MS/EI: m/z = 124 (M+).
Methyl 3-Formylbenzoate (12)15,16
Upon standing, the liquid auto-oxidized to afford 20a as a white
White solid; yield: 86%.
crystalline solid.
1H NMR (DMSO-d6, 300 MHz): = 3.90 (s, 3 H, CO2CH3), 7.74
(dd, J = 7.5, 7.7 Hz, 1 Harom), 8.14 (ddd, J = 1.6, 1.9, 7.5 Hz, 1
Harom), 8.22 (ddd, J = 1.5, 1.6, 7.7 Hz, 1 Harom), 8.42 (dd, J = 1.5, 1.9
Hz, 1 Harom), 10.06 (s, 1 H, CHO).
1H NMR (DMSO-d6, 400 MHz): = 7.30 (m, 2 Harom), 7.97 (m, 2
Harom), 13.02 (s, 1 H, CO2H).
GC-MS/EI: m/z = 140 (M+).
Synthesis 2004, No. 2, 283–289 © Thieme Stuttgart · New York

288
D. Bankston
PAPER
4-(Dimethylamino)benzaldehyde (21)28,29
Anal. Calcd for C11H15N2F·0.15 H2O: C, 67.08; H, 7.83; N, 14.22.
Found: C, 67.18; H, 8.21; N, 14.39.
GC-MS/EI: m/z = 194 (M+).
A suspension of 19 (1.0 g, 3.73 mmol) in 40% aq dimethylamine
(20 mL) was heated to 60 °C under argon for 2 h. At that time, TLC
(silica gel 60, CH2Cl2, UV detection) analysis indicated complete
reaction. The contents were cooled to r.t., poured into CH2Cl2 (100
mL) and brine (50 mL), and the layers were separated. The organic
layer was washed with brine (50 mL) and concentrated to a dark yel-
low oil. The residue was placed onto a column of silica gel (150 cc)
equilibrated in 30% CH2Cl2–hexane, and the desired material was
eluted with a gradient ranging from 40% CH2Cl2–hexane to 100%
CH2Cl2. The single fraction was concentrated and then vacuum
dried at r.t. for 30 min to afford 21 (0.457 g, 82%) as a yellow solid.
Acknowledgments
I would like to thank Anthony Paiva, Erin Crum and Tim He for
mass spectral support, and Laszlo Musza for NMR data that led to
the structural elucidation of reactive intermediates 30 and 31.
References
1H NMR (DMSO-d6, 300 MHz): = 3.03 [s, 6 H, N(CH3)2], 6.78,
7.68 (AA BB quartet, J = 8.8 Hz, 4 Harom), 9.65 (s, 1 H, CHO).
(1) Salomaa, P. In The Chemistry of the Carbonyl Group, Vol.
1; Patai, S., Ed.; Wiley: New York, 1966, 177–210.
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1978, 34, 1651. (b) Omura, K.; Sharma, A.; Swern, D. J.
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HPLC-MS/ES: m/z = 150 (M + 1).
3-Fluorobenzaldehyde (26)22,23 and 3-Fluorobenzoic Acid
(26a)31
A suspension of 25 (3.0 g, 16.76 mmol) in 40% aq dimethylamine
(60 mL) was heated to 60 °C under argon for 60 min. The contents
were cooled to r.t., poured into CH2Cl2 (50 mL) and the layers were
separated. The organic layer was dried (Na2SO4) and concentrated
to ca. 5 mL. The yellow liquid was placed onto a pad of silica gel
(60 cc) equilibrated in hexane, and desired material was eluted with
10% hexane–CH2Cl2. The single fraction was concentrated to af-
ford 26 (1.67 g, 80%) as a pale yellow liquid.
1H NMR (DMSO-d6, 400 MHz): = 7.55 (m, 1 Harom), 7.65 (m, 2
Harom), 7.76 (ddd, J = 1.2, 2.6, 6.3 Hz, 1 Harom), 9.97 (s, 1 H, CHO).
GC-MS/EI: m/z = 124 (M+).
After several days, the pale yellow liquid partially solidified to a
white, waxy substance. This material was recrystallized from hot
hexane to give 26a (1.11 g, 59%) as white crystals.
1H NMR (DMSO-d6, 400 MHz): = 7.46 (m, 1 Harom), 7.53 (m, 1
(4) Fuson, R. In The Chemistry of the Carbonyl Group, Vol. 1;
Patai, S., Ed.; Wiley: New York, 1966, 211–232.
(5) Xi, F.; Kamal, F.; Schenerman, M. Tetrahedron Lett. 2002,
43, 1395.
Harom), 7.63 (m, 1 Harom), 7.76 (ddd, J = 1.2, 2.4, 6.4 Hz, 1 Harom),
13.26 (s, 1 H, CO2H).
(6) Nace, H.; Monagle, J. J. Org. Chem. 1959, 24, 1792.
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Chem. Soc. 1959, 81, 4113.
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2000, 65, 108.
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(10) Abou-Teim, O.; Jansen, R.; McOmie, J.; Perry, D. J. Chem.
Soc., Perkin Trans. 1 1980, 1841.
(11) Note: These reactions were conducted at temperatures below
70 °C, which are not high enough to promote significant
decomposition of DMF. Decomposition of DMF became
relevant at temperatures around 140 °C.
(12) Nagayama, K.; Shimizu, I.; Yamamoto, A. Chem. Lett.
1998, 1143.
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580.
GC-MS/EI: m/z = 140 (M+).
2-(Dimethylamino)benzaldehyde (29)25,26
A suspension of 27 (2.0 g, 11.17 mmol) in 40% aq dimethylamine
(40 mL) was heated to 60 °C under argon for 8 h. The yellow solu-
tion was cooled to r.t. and poured into CH2Cl2 (200 mL). The layers
were separated and the organic layer was washed with brine (50
mL) and concentrated to a yellow liquid. The liquid was filtered
through a plug of silica gel (200 cc) equilibrated in 50% CH2Cl2–
hexane, and the desired product was eluted with CH2Cl2. The single
fraction (ca. 300 mL) was rotary-evaporated and further concentrat-
ed under a brisk stream of argon to give 29 (1.57 g, 94%) as a yellow
liquid.
1H NMR (DMSO-d6, 300 MHz): = 2.86 [s, 6 H, N(CH3)2], 6.99
(m, 1 Harom), 7.11 (dd, J = 1.0, 8.7 Hz, 1 Harom), 7.51 (ddd, J = 1.7,
7.0, 8.7 Hz, 1 Harom), 7.66 (dd, J = 1.7, 7.6 Hz, 1 Harom), 10.11 (s, 1
H, CHO).
(15) Baillargeon, V.; Stille, J. J. Am. Chem. Soc. 1986, 108, 452.
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Zheng, P.; Ji, X.; Gao, G. Synlett 2002, 2041.
(18) Hajipour, A.; Mallakpour, S.; Baltork, I.; Backnezhad, H.
Synth. Commun. 2002, 32, 771.
2-(4-Fluorophenyl)-1,3-dimethylimidazolidine (31)
A solution of 4-fluorobenzal chloride (24; 0.500 g, 2.79 mmol) in
N,N -dimethylethylenediamine (2 mL) was heated to 70 °C for 14 h
under N2. At that time, the yellow solution was cooled to r.t. and
poured into CH2Cl2 (25 mL) and H2O (40 mL). The layers were sep-
arated and the organic layer was again washed with brine (2 × 20
mL), dried (Na2SO4) and concentrated to afford 31 (0.508 g, 94%)
as a yellow oil.
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28, 3941.
1H NMR (DMSO-d6, 400 MHz): = 2.02 (s, 6 H, NCH3), 2.48 (m,
2 H, CH2), 3.22 (m, 2 H, CH2), 3.22 (s, 1 H, CH), 7.13, 7.38
(AA BB quartet, coupled by fluorine; 4 Harom).
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