Improved Sommelet reaction catalysed by lanthanum triflate

Article abstract of DOI:10.3184/174751914X14175125259964

An improved Sommelet reaction for the synthesis of araldehydes from benzyl halides and hexamethylenetetramine was achieved employing lanthanum triflate (3 mol%) as catalyst in water with sodium dodecyl sulfate (SDS, 2 wt%) as solubiliser. Good to excellent yields were obtained in most of the 18 examples.

Full text of DOI:10.3184/174751914X14175125259964

710 RESEARCH PAPER
VOL. 38 DECEMBER, 710–714
JOURNAL OF CHEMICAL RESEARCH 2014
Improved Sommelet reaction catalysed by lanthanum triflate
Wenhao Xu and Weike Su*
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P.R. China
An improved Sommelet reaction for the synthesis of araldehydes from benzyl halides and hexamethylenetetramine was achieved
employing lanthanum triflate (3 mol%) as catalyst in water with sodium dodecyl sulfate (SDS, 2 wt%) as solubiliser. Good to
excellent yields were obtained in most of the 18 examples.
Keywords: Sommelet reaction, lanthanum triflate, hexamethylenetetramine, benzyl halides, araldehydes
Aldehydes are versatile building blocks for the synthesis of
heterocycles,1–3 and useful functionalised compounds.4–6 They
are frequently used as intermediates in many useful drugs, e.g.
Irbesartan and Valsartan.7 Moreover, a number of aldehydes
possess biological activities8 and their properties have attracted
considerable attention in medicinal chemistry.
hexamethylenetetramine and the Brønsted acid; (ii) some
functional groups are incompatible with Brønsted acid; and
(iii) more than stoichiometric amounts of Brønsted acid24 have
been employed in this reaction. Moreover, these Brønsted acids
cannot be recovered and reused. Therefore, the development
of new eco‑friendly and facile synthetic methods is urgently
needed to overcome the drawbacks of Sommelet reaction.
Metal triflates are a new type of strong Lewis acid. An
outstanding feature of metal triflates lies in their stability
in water. Only catalytic amounts of the metal triflates are
required to complete the reactions in most cases. Furthermore,
metal triflates can be recovered easily after reaction and
reused without loss of activity. Thus many useful reactions
including the aldol reaction25,26 and the Mannich reaction27,28
can be catalysed by them in aqueous medium. To the best of
our knowledge, no uses of metal triflates in the Sommelet
reaction have been published. We now report a novel method
for carrying out the Sommelet reaction catalysed by metal
triflates in water in the presence of a detergent, SDS.
As a ubiquitous synthetic transformation in synthetic
pharmaceuticals9,10 and natural products,11,12 the conversion of
halides to aldehydes has attracted considerable attention and
it has been the subject of considerable research. A common
approach for this transformation can be achieved by two
different routes as shown in Scheme 1. Type (a) is exemplified
by the Sommelet reaction, the Kröhnke reaction,13 and the
Kornblum reaction14 in which halides are transformed into
aldehydes via the formation of ammonium salts or esters prior
to hydrolysis. For example, Moorthy and co‑workers recently
used IBX (2‑iodoxybenzoic acid) in DMSO which allowed the
direct conversion of benzyl halides to aldehydes and ketones
in good yield.15 In type (b), alcohol intermediates generated by
hydrolysis of halides are oxidised in situ by MnO2,16 NaNO3,17
hydrogen peroxide,18 or N‑methyl morpholineoxide.19
Results and discussion
Because hexamethylenetetramine (HMT) is known to be stable
with triflates in water, we aimed at optimising this reaction
by using water alone as solvent. The results of our several
experiments are listed in Table 1. In order to determine the
optimum amount of HMT, we chose as a model the reaction
of benzyl bromide 1b (1 mmol) with varying amounts of HMT
in the presence of zinc triflate (0.03 mmol) stirred in water
(2 mL) at 100 °C (entries 1–4) (Scheme 3). It can be seen that
0.5 mol of 2 giving a yield of 76% is optimal (entry 2). Then
we used the adopted reaction of 1b (1 mmol) and 2 (0.5 mmol)
as a model to study the influence of various metal triflates
on the reaction, and the results are shown in entries 5–10.
Lanthanum triflate was found to be the most suitable catalyst
for this transformation, giving a yield of 84% (entry 10). A
blank experiment without metal triflate afforded 25% yield
(entry 11).
As one of the most important methodologies, the Sommelet
reaction is a well‑established method for converting benzyl
halides into the corresponding aldehydes in excellent yields
(Scheme 2). Since it was first reported in 1913 by Marcel
Sommelet,20 applications of this reaction have been long
associated with a number of disadvantages including: (i)
organic solvents such as chloroform21,22 and acetonitrile23
are needed in order to avoid the interaction between
a
R
A
O
R
X
R
H
R
OH
b
X = Cl, Br, I; A = N+R'3, OR'
Because the solubility of halides and aldehydes in water
is very low, the Sommelet reaction proceeded sluggishly
in water, especially when the reactants were solid. For this
reason we investigated the effect of some surfactants, hoping
Scheme 1 Alternative routes (a, b) from a halide to corresponding aldehyde.
N
O
N
N
N
N
X
H
O
R
R
N
N
1) CHCl3; 2) Acid, H2O
N
H
Br
X = Cl, Br
2
Scheme 2 Typical Sommelet reaction.
M (OTf)n, surfactant, H2O
1b
3a
Scheme 3 Sommelet reaction of benzyl bromide 1b using a metal triflate
as catalyst and a surfactant as a solubiliser.
* Correspondent. E‑mail: pharmlab@zjut.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2014 711
Table 1 Optimisation of the reaction conditions for converting benzyl
bromide 1b to benzaldehyde 3a (Scheme 3)a
N
O
R1
R2
N
R1
R2
Time/h Yield of 3a/%b
2
N
Entry 2/mmol
Catalyst
Surfactant
X
H
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
0.25
0.5
1
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Mg(OTf)2
Cu(OTf)2
Bi(OTf)3
Yb(OTf)3
Y(OTf)3
–
–
–
–
–
–
–
–
–
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1
58
76
72
74
51
48
66
67
79
84
25
74
90
58
65
85
52
75
86
73
R4
R4
La(OTf)3, SDS, H2O
R3
1
R3
3
1.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Scheme 4 Application of the new Sommelet reaction to the preparation
of various benzaldehydes 3 from the corresponding benzyl halides 1 using
lanthanum triflate as catalyst in water with SDS as a solubiliser.
However, after 1.5 h, it was observed that the yield began to
decrease. This was presumably due to the oxidation of the
aldehyde at high temperature over a prolonged period. The
optimal set of conditions were finally obtained as benzyl
bromide 1b (1 mmol) and hexamethylenetetramine (0.5 mmol)
in the presence of lanthanum triflate (0.03 mmol) and sodium
dodecyl sulfate (SDS) (3.4 mg, 2 wt%) in water (2 mL) at reflux
temperature for 1.5 h, which gave benzaldehyde 3a in a very
good yield of 90% (entry 13).
With suitable conditions to hand, we examined a variety of
halides to check the versatility of the new method (Scheme 4).
First, variously substituted benzyl halides with different
halogen groups in the α position were investigated and the
yields are shown in Table 2 (entries 1–3, 6–9, 12–13). In
contrast to benzyl chlorides with/without substituent, the
benzyl bromides and the single benzyl iodide showed positive
activation in the reaction, presumably because Br and I are
better leaving groups than Cl. The results of our limited study
provide some understanding of the electronic/steric factors
governing the performance of the reaction. Electron‑donating
groups favour the reaction. Compared with yields of 52–69%
of those benzyl halides containing strong electron‑withdrawing
groups (entries 11–14), better yields of 72–92% were obtained
for those with electron–donating groups (entries 1–10).
La(OTf)3
–
–
–
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
PEG–400
SDS
CTAB
CAB–35
Triton X–100
SDS
SDS
SDS
SDS
2
2.5
aReaction
conditions:
benzyl
bromide
1b
(1 mmol)
and
hexamethylenetetramine in the presence of a metal triflate (0.03 mmol) and
a surfactant (3.4 mg, 2 wt%) at 100 °C in water (2 mL).
bIsolated yield.
that they would speed up the reaction and increase the yield.
Several kinds of surfactants were tried at 2 wt%): an anionic
surfactant (sodium dodecyl sulfate; SDS), a cationic surfactant
(cetyltrimethyl ammonium bromide; CTAB), a zwitterionic
surfactant (cocoamido–propyl betaine; CAB‑35), and two non‑
ionic surfactants (polyethyleneglycol; PEG and Triton X‑100),29
and the results are shown in entries 12–16. As can be seen,
SDS proved to be superior to the others, giving a yield of 90%
(entry 13).
As an extension of our work, we chose to investigate
three Ang‑II receptor antagonist intermediates 1o–q to
see whether these diphenyl‑4‑methyl bromides would
react under the optimal condition (Scheme 5). The results
showed that all three reactions proceeded successfully
Finally, various reaction times were investigated and the
results are shown as entries 17–20. The optimal reaction time
was found to be 1.5 h which gave a yield of 90% (entry 13).
Table 2 Yields and reaction times for the conversion of various benzyl halides 1a–n to the corresponding benzaldehydes 3a–n by
the new Sommelet reaction (Scheme 4)a
Halides
Entry
Product
Time/h
Yield/%b
R1
R2
R3
R4
X
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
CH3
H
OCH3
OCH3
Br
Br
I
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
H
Cl
Br
I
3a
3a
3a
3d
3e
3f
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
2
78
90
92
84
78
82
84
75
80
72
69
55
61
52
Br
Br
Cl
Br
Cl
Br
Br
Br
Cl
Br
Cl
3f
3h
3h
3j
3k
3l
2
NO2
H
H
2.5
2.5
2.5
4
3l
3n
H
COOH
H
aReaction conditions: benzyl halide 1a–n (1 mmol) and hexamethylenetetramine (0.5 mmol) in the presence of lanthanum triflate
(0.03 mmol) and SDS (3.4 mg, 2 wt%) at 100 °C in water (2 mL).
bIsolated yield.
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712 JOURNAL OF CHEMICAL RESEARCH 2014
N
2
O
N
R5
Br
R5
H
N
N
La(OTf)3, SDS, H2O
Scheme 5 Application of the new Sommelet reaction to the preparation of various biphenyl-
4-carboxaldehydes from the corresponding diphenyl-4-methyl bromides using lanthanum
triflate as catalyst in water with SDS as a solubiliser.
Table 3 Yields and reaction times for the preparation of various biphenyl-
N
2
4-carboxaldehydes 3o–q from the corresponding diphenyl-4-methyl
bromides 1o–q by the new Sommelet reaction (Scheme 5)a
N
N
Entry
Bromide
R5
Product Time/h Yield/%b
N
1
2
1o
1p
CN
3o
3p
4
71
80
O
COO-t-Bu
4.5
R6
Br
R6
H
La(OTf)3, SDS, H2O
3
1q
3q
10
73
Scheme 6 Application of the new Sommelet reaction to the preparation
of various aldehydes from the corresponding bromides using lanthanum
triflate as catalyst in water with SDS as a solubiliser.
aReaction conditions: bromide 1o–q (1 mmol) and hexamethylenetetramine
2 (0.5 mmol) in the presence of lanthanum triflate (0.03 mmol) and SDS
(3.4 mg, 2 wt%) at 100 °C in water (2 mL).
bIsolated yield.
Table 4 Yields and reaction times for the preparation of various aldehydes
3r–t from the corresponding bromides 1r–t by the new Sommelet reaction
(Scheme 6)a
Entry
Bromide
R6
Product Time/h Yield/%a
1
2
3
1r
1s
1t
2-Naphthyl
n-Butyl
Allyl
3r
3s
3t
1.5
4
1.5
94
10b
35b
aReaction conditions: bromide 1r–t (1 mmol) and hexamethylenetetramine
2 (0.5 mmol) in the presence of lanthanum triflate (0.03 mmol) and SDS
(3.4 mg, 2 wt%) at 100 °C in water (2 mL).
bIsolated yield.
and the corresponding biphenyl‑4‑carboxaldehydes 3o–q
were obtained in very good yield (Table 3, entries 1–3).
Finally we hoped to extend the new Sommelet reaction
to nonbenzenoid aromatic, aliphatic and allyl bromides
(Scheme 6). Unfortunately, although an excellent yield of the
correspondingaldehyde3r wasobtainedfrom2‑naphthylmethyl
bromide 1r, low yields of aldehyde 3s, 3t were observed
from butyl 1s and allyl bromide 1t (Table 4, entries 1–3).
The mechanism of the Sommelet reaction has long been known30
to involve three steps, as shown in Scheme 7. The reaction starts
with a SN2 reaction in which hexamethylenetetramine acts as
the nucleophilic moiety displacing the halogen leaving group
of the benzyl halide to give a hexaminium salt I. Then the salt
undergoes a ring‑opening with hydrogen transfer giving an
imide intermediate II. In the aqueous medium, a hydrolysis
process converts the imide into an aminol intermediate III
which breaks down to the aldehyde. Since strong electron‑
withdrawing groups would decrease the electron cloud density
of the benzene ring, such groups would reduce the stability of
the imide intermediate II. This would explain the lower yields
observed for these types of substituent. Substituent groups
on the para position have lower steric hindrance than those
on the ortho position; this would explain why the reaction on
4‑nitrobenzyl bromide 1k gave a higher yield than 2‑nitrobenzyl
bromide 1l (Table 2, entries 11 and 12). Moreover, greater steric
hindrance led to a longer reaction time. For example substrate
1q needed nearly 10 h to give a 73% yield (Table 3).
Scheme 7 Mechanism of the Sommelet reaction.
In summary, we have developed a novel procedure for
carrying out the Sommelet reaction under eco‑friendly
conditions. Advantages of the present process are good yields,
replacement of an organic solvent by water and a decrease in
the amount of Brønsted acid.
Experimental
All solvents and reagents were commercially available and used
without further purification. Deionised water was used as solvent for
the reaction. The flash column chromatography used using silica gel
(200–400 mesh), purchased from Qingdao Haiyang Chemical Co.,
Ltd. Melting points were recorded on a Büchi B‑540 apparatus and
are uncorrected. Mass spectra were obtained on a Finnigan LCQ‑
Advantage. NMR spectra were obtained on a Varian‑400 spectrometer
(1H NMR at 400 Hz, 13C NMR at 100 Hz) in CDCl3 or DMSO‑d6 using
tetramethylsilane as internal standard. Chemical shifts (δ) are given in
ppm and coupling constants (J) in Hz.
Synthesis of 3o; typical procedure
Hexamethylenetetramine 1 (70.1 mg), SDS (3.4 mg) and lanthanum
triflate (17.6 mg) were dissolved in water (0.5 mL). Then 1o (271 mg)
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JOURNAL OF CHEMICAL RESEARCH 2014 713
was added to the flask. The mixture was refluxed for 4 h to complete
the reaction, which was monitored by TLC. The reaction mixture was
extracted with EtOAc three times and the combined organic phases
were distilled under reduced pressure. The crude product was purified
by column chromatography on silica gel using hexane: EtOAc (5:1)
as eluent to give 3o, recrystallisation of which from EtOH gave white
crystals, 147 mg (71%) (Table 3, entry 1).
2‑Naphthaldehyde (3r): White tabular crystals; m.p. 58.1–61.1°C
1
(lit.44 60.5–61.0 °C); H NMR (CDCl3) δ 10.15 (s, 1H, CHO), 8.32 (s,
1H, ArH), 7.99 (d, J=8.0 Hz, 1H, ArH), 7.93 (d, J=1.4 Hz, 1H, ArH),
7.92 (s, 1H, ArH), 7.89 (d, J=8.0 Hz, 1H, ArH), 7.67–7.60 (m, 1H,
ArH), 7.60–7.53 (m, 1H, ArH); 13C NMR (CDCl3) δ 191.8, 136.2, 134.3,
133.9, 132.4, 129.3, 128.9, 127.9, 126.9, 122.5, 119.3; MS(APCI): 156.7,
[M+1]+ (lit.31).
1
1
Benzaldehyde (3a): Colourless oil; H NMR (CDCl3) δ 9.99 (s, 1H,
Butyraldehyde (3s): Colourless oil; H NMR (CDCl3) δ 9.74 (s, 1H,
CHO), 7.86 (d, J=8.0 Hz, 2H, ArH), 7.64–7.58 (m, 1H, ArH), 7.51 (m,
2H, ArH); MS(ESI): 129.2, [M+23]– (lit.18).
CHO), 2.42 (m, 2H, CH2), 1.67 (m, 2H, CH2), 0.96 (t, J=8.0 Hz, 3H,
CH3); MS(ESI): 72.0, [M]+ (lit.38).
4‑Methylbenzaldehyde (3d): Colourless oil; 1H NMR (CDCl3) δ 9.93
(s, 1H, CHO), 7.75 (d, J=8.0 Hz, 2H, ArH), 7.31 (d, J=8.0 Hz, 2H,
ArH), 2.43 (s, 3H, CH3); 13C NMR (CDCl3) δ 191.6, 145.3, 134.0, 129.6,
129.5, 21.9; MS(APCI): 241.1, [2M+1]+ (lit.18).
1
Acrylaldehyde (3t): Light yellow oil; H NMR (CDCl3) δ 9.56 (d,
J=8.0 Hz, 1H, CHO), 6.57–6.45 (m, 1H, CH), 6.44–6.31 (m, 2H, CH2);
MS(ESI): 57.0, [M+1]+ (lit.39).
1
3,5‑Dimethylbenzaldehyde (3e): Colourless oil; H NMR (CDCl3) δ
We thank the National Natural Science Foundation of
China (21176222) and Zhejiang Natural Science Foundation
(Y4090346) for financial support.
9.92 (s, 1H, CHO), 7.47 (s, 2H, ArH), 6.98 (s, 1H, ArH), 2.38 (s, 6H,
CH3); 13C NMR (CDCl3) δ 192.4, 138.5, 136.4, 136.0, 127.4, 21.1;
MS(APCI): 135.8, [M+1]+ (lit.34).
1
4‑Methoxybenzaldehyde (3f): Colourless oil; H NMR (CDCl3) δ
Received 26 October 2014; accepted 5 November 2014
Paper 1402974 doi: 10.3184/174751914X14175125259964
Published online: 19 December 2014
9.85 (s, 1H, CHO), 7.81 (d, J=8.0 Hz, 2H, ArH), 6.98 (d, J=8.0 Hz, 2H,
ArH), 3.86 (s, 3H, CH3); 13C NMR (CDCl3) δ 190.7, 164.6, 132.0, 130.0,
114.4, 55.8; MS(ESI): 136.9, [M+1]+ (lit.31).
4‑Bromobenzaldehyde (3h): White crystal, m.p. 67.0–68.4 °C
(MeOH) (lit.40 66–68°C); H NMR (CDCl3) δ 9.96 (s, 1H, CHO),
1
References
7.74 (d, J=8.0 Hz, 2H, ArH), 7.67 (d, J=8.0 Hz, 2H, ArH); 13C NMR
(CDCl3) δ 190.7, 134.9, 132.3, 130.8, 129.6; MS(ESI): 182.9, 184.9,
[M–1]– (lit.31).
1
2
3
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J=8.0 Hz, 2H, ArH), 7.50 (d, J=8.0 Hz, 2H, ArH). 13C NMR (CDCl3)
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CHO), 8.39 (d, J=8.0 Hz, 2H, ArH), 8.08 (d, J=8.0 Hz, 2H, ArH);
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2‑Nitrobenzaldehyde (3l): Yellow crystals; m.p. 37.6–42.7°C
(MeOH) (lit.42 42–44°C); 1H NMR (CDCl3) δ 10.41 (s, 1H, CHO), 8.11
(m, 1H, ArH), 7.95 (m, 1H, ArH), 7.79 (m, 1H, ArH), 7.77–7.72 (m,
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124.3; MS(APCI): 150.4, [M]+ (lit.33).
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4‑Formylbenzoic acid (3n): Light yellow crystal (water); m.p.
245.1–248.3 °C (MeOH) (lit.43 221–222°C); 1H NMR (DMSO) δ 13.28
(s, 1H, COOH), 10.09 (s, 1H, CHO), 8.12 (d, J=8.0 Hz, 2H, ArH), 8.01
(d, J=8.0 Hz, 2H, ArH); 13C NMR (DMSO) δ 221.0, 194.7, 167.1, 163.9,
158.1, 157.7; MS(ESI): 148.9, [M–1]– (lit.35).
1
2-Cyano-4′-formylbiphenyl (3o): White crystals (EtOH); H NMR
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2010, 49, 6670.
(CDCl3) δ 10.08 (s, 1H, CHO), 8.00 (d, J=8.0 Hz, 2H, ArH), 7.80 (d,
J=8.0 Hz, 1H, ArH), 7.72 (d, J=8.0 Hz, 1H, ArH), 7.68 (d, J=8.0 Hz,
2H, ArH), 7.53 (d, J=8.0 Hz, 1H, ArH), 7.50 (d, J=8.0 Hz, 1H, ArH);
13C NMR (CDCl3) δ 191.4, 143.8, 143.7, 136.0, 133.7, 132.9, 129.9,
129.8, 129.4, 128.3, 118.1, 111.2; MS(ESI): 208.0, [M+1]+ (lit.7).
t-butyl 4′-formylbiphenyl-2-carboxylate (3p): Colourless oil;
1H NMR (CDCl3) δ 10.05 (s, 1H, CHO), 7.91 (d, J=8.0 Hz, 2H,
ArH), 7.84 (d, J=8.0 Hz, 1H, ArH), 7.54–7.40 (m, 4H, ArH), 7.30 (d,
J=8.0 Hz, 1H, ArH), 1.26 (s, 9H, CH3); 13C NMR (CDCl3) δ 191.7,
167.0, 148.2, 140.7, 134.8, 132.3, 130.8, 130.1, 129.9, 129.3, 129.2,
127.8, 81.6, 27.7; MS(APCI): 282.7, [M+1]+ (lit.36).
2′-(2-Trityl-2H-tetrazol-5-yl)biphenyl-4-carboxyaldehyde (3q):
White crystals; m.p. 154.1–156.2°C (EtOH) (lit.37 154–156 °C);
1H NMR (CDCl3) δ 9.88 (s, 1H), 8.04 (m, 1H), 7.59 (d, J=8.0 Hz, 2H,
CHO), 7.54–7.49 (m, 2H, ArH), 7.37 (m, 1H, ArH), 7.33 (s, 1H, ArH),
7.31 (s, 1H, ArH), 7.29 (s, 1H, ArH), 7.27 (s, 1H, ArH), 7.24 (s, 2H,
ArH), 7.22 (s, 3H, ArH), 7.20 (s, 1H, ArH), 6.86 (d, J=8.0 Hz, 7H,
ArH); 13C NMR (CDCl3) δ 191.5, 163.3, 147.3, 140.8, 140.5, 134.6,
130.2, 130.1, 130.0, 129.86, 129.7, 129.1, 128.2, 128.1, 127.5, 126.0,
83.0; MS(APCI): 468.3, [M–24]– (lit.37).
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