Facile, environmentally friendly synthesis of benzaldehyde and phenylacetaldehyde analogs from readily available toluene derivatives

Article abstract of DOI:10.1080/00397911.2010.517366

A facile environmentally friendly synthesis of bezaldehyde and phenylacetaldehyde analogs from readily available toluene derivatives is described. Oxidation of the styrylamines by H₂O2 H₂O2 affords benzaldehydes in moderate yields, while the hydrolysis of styrylamines afforded phenylacetaldehyde analogs in good yields. Copyright

Full text of DOI:10.1080/00397911.2010.517366

This article was downloaded by: [Laurentian University]
On: 04 November 2013, At: 04:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Facile, Environmentally Friendly
Synthesis of Benzaldehyde and
Phenylacetaldehyde Analogs from
Readily Available Toluene Derivatives
Liyan Dai a b , Jie Yu a , Yingqi Chen a & Shichao Yu b
a College of Materials Science and Chemical Engineering , Zhejiang
University , Hangzhou , P. R. China
b Department of Chemistry and Chemical Biology and Department of
Pharmaceutical Chemistry, Rutgers , State University of New Jersey ,
Piscataway , New Jersey , USA
Published online: 11 Jul 2011.
To cite this article: Liyan Dai , Jie Yu , Yingqi Chen & Shichao Yu (2011) Facile, Environmentally
Friendly Synthesis of Benzaldehyde and Phenylacetaldehyde Analogs from Readily Available Toluene
Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:20, 3078-3084, DOI: 10.1080/00397911.2010.517366
To link to this article: http://dx.doi.org/10.1080/00397911.2010.517366
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 41: 3078–3084, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517366
FACILE, ENVIRONMENTALLY FRIENDLY SYNTHESIS
OF BENZALDEHYDE AND PHENYLACETALDEHYDE
ANALOGS FROM READILY AVAILABLE
TOLUENE DERIVATIVES
Liyan Dai,1,2 Jie Yu,1 Yingqi Chen,1 and Shichao Yu2
1College of Materials Science and Chemical Engineering, Zhejiang
University, Hangzhou, P. R. China
2Department of Chemistry and Chemical Biology and Department of
Pharmaceutical Chemistry, Rutgers, State University of New Jersey,
Piscataway, New Jersey, USA
GRAPHICAL ABSTRACT
Abstract A facile environmentally friendly synthesis of bezaldehyde and phenylacetaldehyde
analogs from readily available toluene derivatives is described. Oxidation of the styryla-
mines by H2O2 affords benzaldehydes in moderate yields, while the hydrolysis of styryla-
mines afforded phenylacetaldehyde analogs in good yields.
Keywords Bezaldehyde; hydrolysis; oxidation; phenylacetaldehyde
INTRODUCTION
Aromatic aldehydes constitute an important class of compounds with numer-
ous applications in organic synthesis. They have been employed as building blocks
for a wide variety of heterocyclic and pharmaceutical compounds and as intermedi-
ates for the synthesis of naturally occurring alkaloids. For example, 2-nitrobenzalde-
hyde is a precursor for the synthesis of enantiomerically pure a-amino acids,[1] and
2-aminobenzaldehyde[2] has been used as a key intermediate for preparation of
a-methylamino acids.[3] 2-Nitro-4-chlorobenzaldehyde plays a very important role
Received September 16, 2009.
Address correspondence to Shichao Yu, State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Rd., Shanghai
200032, China (present address). E-mail: shichao@mail.sioc.ac.cn; shichaoyu@gmail.com
3078

BENZALDEHYDE AND PHENYLACETALDEHYDE ANALOGS
3079
in the total synthesis of an anti-HIV agent siamenol.[4] 2-Chloro-4-nitrobenzalde-
hyde also serves as an essential intermediate in the preparation of another anti-HIV
agent, orally active CCR5 antagonist.[5] 4-Nitrobenzaldehyde and 4-cyanobenzalde-
hyde are crucial materials for the production of diarylmethanols, important building
blocks in the synthesis of natural products and pharmacologically active com-
pounds.[6] Phenylacetaldehyde derivatives are extensively used in perfumery.
Traditional synthetic processes for manufacturing benzaldehyde and phenyl-
acetaldehyde analogs with electron-withdrawing substituents often lead to serious
contamination to the environment by releasing large amounts of pollutants to air
and water. For example, the synthesis of 2-nitrobenzaldehyde from 2-nitrotoluene
involved the bromination of 2-nitrotoluene to 2-nitrobenzylidenedibromide followed
by the oxidation of 4-nitrosodimethylaniline to 2-nitrobenzaldehyde.[7] This pro-
cedure required the use of expensive bromine and carcinogenic 4-nitrosodimethylani-
line. Another three-step sequence, consisting of the chlorination of 2- nitrotoluene,
alkaline dimerization to 2,20-dinitrostilbene, and ozonolysis, suffered from poor con-
version rates and poor selectivity.[8] All approaches involving the intermediate
2-nitrobenzyl halides suffer from dangers of explosive decomposition of these
compounds.[9] The synthesis of 2-nitrophenylacetaldehyde by the nitration of
phenylacetaldehyde causes problems separating the other two isomers, 3-nitropheny-
lacetaldehyde and 4-nitrophenylacetaldehyde.[10] Diazotization of 2-nitroaniline to
diazonium salt followed by the Meerwein arylation with an unsaturated acceptor
afforded the desired product with a poor yield.[11] Although different methods are
available for the synthesis of 2-nitrobenzaldehyde and 2-nitrophenylacetaldehyde,
development of another facile, high-yielding, nonpolluting preparation is still of
great importance.[12,13]
In 2007, Naffziger et al. reported an efficient pathway to the 2-nitro-4-chloro-
benzaldehyde starting from 2-nitro-4-chlorotoluene.[4] In his article, the methyl
group was oxidized by N,N-dimethylformamide dimethyl acetal (DMFA) in the
presence of dimethylformamide (DMF) to the styrylamine, which was further
oxidized by NaIO4 to obtain 2-nitro-4-chlorobenzaldehyde in good yield. However,
the high cost of the NaIO4 and the production of inorganic halide waste impeded its
application on a large scale. To facilitate the industrial manufacturing process, we
turned our attention to other economic and environmentally friendly oxidants.
Hydrogen peroxide finally became our choice (Scheme 1).
Initially, we set out to identify the optimal conditions for the new oxidation
system. N,N-Dimethyl-2-(4-chloro-2-nitrophenyl)ethenamine 2a was subjected to
hydrogen peroxide–mediated oxidation in various solvents. Some representative
results are given in Table 1. It was found that the oxidation in CH3CN afforded a
Scheme 1. Synthesis of benzaldehydes using H2O2 as the oxidant.

3080
L. DAI ET AL
a
Table 1. Effect of solvents on oxidation of 2a by H2O2
Entry
Solvent
Yield (%)b
1
2
3
4
5
CH3CN
CH3OH
DMF
37
27
nrc
32
(CH3)2CHOH
(CH3)3COH
34
aReaction conditions: styrylamine 4.4 mmol, H2O2 8.8 mmol, solvent
10 mL, T ¼ rt, t ¼ 5 h.
bOverall yield over two steps of isolated and purified product.
cnr, no reaction.
better yield (entry 1, Table 1). Two other solvents, isobutyl alcohol and tertbutyl
alcohol, also gave comparable results (entries 4 and 5, Table 1).
Then we examined the oxidation of 2a by H2O2 in the presence of CH3CN at
various temperatures (Table 2). The results in Table 2 showed that at 25 ꢀC, a higher
yield was obtained.
With the increased molar ratio of H2O2 to 2a from 1:2 to 1:3, the yield of the
aldehyde was increased to 45% (entry 1, Table 3). Other substrates also afforded the
desired product as described in Table 3.
a
Table 2. Effect of temperatures on oxidation of 2a by H2O2
Entry
Temperature (ꢀC)
Yield (%)b
1
2
3
4
5
15
20
25
30
35
34
35
37
24
16
aReaction conditions: styrylamine 4.4 mmol, H2O2 8.8 mmol,
solvent, CH3CN mL, t ¼ 5 h.
bOverall yield over two steps of isolated and purified product.

BENZALDEHYDE AND PHENYLACETALDEHYDE ANALOGS
3081
Table 3. Synthesis of benzaldehyde analogs using H2O2 as the oxidanta
Entry
X
Y
Z
Time (h)
Product
Yield (%)b
1
2
3
4
5
6
NO2
NO2
H
H
H
H
H
Cl
H
Cl
H
5
4
3a
3b
3c
3d
3e
3f
45
50
39
37
34
43
NO2
NO2
NO2
CN
6
Cl
H
12
7
H
3
aReaction conditions: styrylamine 1 g, molar ratio of H2O2 to styrylamine is 1:3, solvent CH3CN 10 mL,
T ¼ 25ꢀC.
bOverall yield over two steps of isolated and purified product.
Scheme 2. Synthesis of phenylacetaldehyde analogs by hydrolysis of the styrylamines.
Table 4. Synthesis of phenylacetaldehyde analogs by hydrolysisa
Entry
X
Y
Z
Product
Yield (%)b
1
2
3
4
5
6
NO2
NO2
H
H
H
H
H
Cl
H
Cl
H
4a
4b
4c
4d
4e
4f
85
77
68
65
60
70
NO2
NO2
NO2
CN
Cl
H
H
aReaction conditions: styrylamine 1 g, 30% (m=m) sulfuric acid 10 mL, CHCl3 10 mL, rt, t ¼ 2 h.
bOverall yield over two steps.

3082
L. DAI ET AL
The hydrolysis of the styrylamine would afford phenylacetaldehyde, which was
also an important building block for organic synthesis. We then investigated the
reaction of styrylamines in the presence of sulfuric acid in CHCl3 (Scheme 2).
Hydrolysis results are displayed in Table 4. In all the cases, moderate to good yields
of phenylacetaldehyde were obtained.
In summary, we disclosed a facile, environmentally friendly synthesis of benzal-
dehydes and phenylacetaldehydes analogs from the readily available toluene deriva-
tives. The mild reaction condition, low cost, and diversity make our methodology a
valid contribitution to the existing process in the field of aromatic aldehyde sythesis.
CHARACTERIZATION DATA OF REPRESENTATIVE COMPOUNDS 3
2-Nitro-4-chlorobenzaldehyde (3a)
1
Yellow crystal, mp 64–65 ꢀC; H NMR (500 MHz, CDCl3): d ¼ 10.39 (s, 1 H),
8.11 (d, J ¼ 1.95 Hz, 1 H), 7.95 (d, J ¼ 8.25 Hz, 1 H), 7.77 (m, 1 H).
2-Nitrobenzaldehyde (3b)
1
Yellow crystal, mp 42–43 ꢀC; H NMR (500 MHz, CDCl3): d ¼ 10.43 (s, 1 H),
8.13 (m, 1 H), 7.96 (m, 1 H), 7.80 (m, 2 H).
4-Nitrobenzaldehyde (3c)
1
Yellow crystal, mp 101–102 ꢀC; H NMR (500 MHz, CDCl3): d ¼ 10.17 (s, 1
H), 8.41 (m, 2 H), 8.08 (m, 2 H).
2-Chloro-4-nitrobenzaldehyde (3d)
1
Orange crystal, mp 68–69 ꢀC; H NMR (500 MHz, CDCl3): d ¼ 10.55 (s, 1 H),
8.35 (d, J ¼ 2.10 Hz, 1 H), 8.24 (m, 1 H), 8.11 (d, J ¼ 8.55 Hz, 1 H).
3-Chloro-4-nitrobenzaldehyde (3d)
1
Orange crystal, mp 56–57 ꢀC; H NMR (500 MHz, CDCl3): d ¼ 10.07 (s, 1 H),
8.07 (d, J ¼ 1.60 Hz, 1 H), 7.99 (d, J ¼ 8.25 Hz, 1 H), 7.94 (m, 1 H).
4-Cyanobenzaldehyde (3f)
1
Yellow crystal, mp 96–97 ꢀC; H NMR (500 MHz, CDCl3): d ¼ 10.10 (s, 1 H),
8.01 (m, 2 H), 7.86 (m, 2 H).
CHARACTERIZATION DATA OF REPRESENTATIVE COMPOUNDS 4
2-Nitro-4-chlorophenylacetaldehyde (4a)
1
Yellow crystal, mp 65–66 ꢀC; H NMR (500 MHz, CDCl3): d ¼ 9.81 (s, 1 H),
8.12 (d, J ¼ 2.21 Hz, 1 H), 7.59 (m, 1 H), 7.27 (d, J ¼ 8.20 Hz, 1 H), 4.12 (s, 2 H).

BENZALDEHYDE AND PHENYLACETALDEHYDE ANALOGS
3083
2-Nitrophenylacetaldehyde (4b)
1
Yellow liquid; H NMR (500 MHz, CDCl3): d ¼ 9.80 (s, 1 H), 8.08 (m, 1 H),
7.60 (m, 1 H), 7.48 (m, 1 H), 7.31 (m, 1 H), 4.11 (s, 2 H).
4-Nitrophenylacetaldehyde (4c)
Orange crystal, mp: 85–86 ꢀC; 1H NMR (500 MHz, CDCl3): d ¼ 9.82 (m, 1 H),
8.23 (m, 2 H), 7.40 (d, J ¼ 8.60 Hz, 2 H), 3.87 (d, J ¼ 1.40, 2 H).
2-Chloro-4-nitrophenylacetaldehyde (4d)
Yellow crystal, mp 67–68 ꢀC; 1H NMR (500 MHz, CDCl3): d ¼ 9.80 (d,
J ¼ 1.05 Hz, 1 H), 8.28 (d, J ¼ 2.30 Hz, 1 H), 8.11 (m, 1 H), 7.44 (d, J ¼ 8.42 Hz, 1
H), 4.02 (s, 2 H).
3-Chloro-4-nitrophenylacetaldehyde (4e)
Orange viscous liquid, 1H NMR (500 MHz, CDCl3): d ¼ 9.81 (m, 1 H), 7.90 (d,
J ¼ 8.30, 1 H), 7.43 (d, J ¼ 1.59 Hz, 1 H), 7.28 (d, J ¼ 3.29 Hz, 1 H), 3.83 (s, 2 H).
4-Cyanophenylacetaldehyde (4f)
Yellow viscous liquid, 1H NMR (500 MHz, CDCl3): d ¼ 9.79 (m, 1 H), 7.65 (d,
J ¼ 8.20 Hz, 2 H), 7.34 (d, J ¼ 8.16 Hz, 2 H), 3.83 (d, J ¼ 1.41 Hz, 2 H).
ACKNOWLEDGMENT
We sincerely thank the Department of Chemistry of Zhejiang University for
1
providing the H NMR analysis.
REFERENCES
1. Belokon, Y. N. Chiral complexes of nickel(II), copper(II), and copper(I) as reagents,
catalysts, and receptors for asymmetric synthesis and chiral recognition of amino acids.
Pure Appl. Chem. 1992, 64, 1917–1924.
2. (a) Murata, S.; Miura, M.; Nomura, M. Fe3O(OAc)6(Py)3 mediated reduction of aromatic
nitro compounds with 2-mercaptoethanol. Chem. Lett. 1988, 361–362; (b) Murata, S.;
Miura, M.; Nomura, M. Reduction of aromatic nitro compounds with 2-mercaptoethanol
and oxidation of thiophenol with molecular oxygen mediated by trinuclear iron acetate
complexes. J. Chem. Soc., Perkin Trans. 2 1989, 617–621.
3. Belokon, Y. N.; Zeltzer, I. E.; Ryzhov, M. G.; Saporovskaya, M. B.; Bakhmutov, V. I.;
Belikov, V. M. (S)-o-N-(N-benzylprolyl)aminobenzaldehyde and (S)-o-N-(N-benzylprolyl)
aminoacetophenone as reagents for asymmetric synthesis of threonine. J. Chem. Soc.,
Chem. Commun. 1982, 180–181.
4. Naffziger, M. R.; Ashburn, B. O.; Perkins, J. R.; Carter, R. G. DielsꢁAlder approach for
the construction of halogenated, o-nitro biaryl templates and application to the total
synthesis of the anti-HIV agent siamenol. J. Org. Chem. 2007, 72, 9857–9865.

3084
L. DAI ET AL
5. Seto, M.; Aramaki, Y.; Imoto, H.; Aikawa, K.; Oda, T.; Kanzaki, N.; Iizawa, Y.; Baba,
M.; Shiraishi, M. Orally active CCR5 antagonists as anti-HIV-1 agents 2: Synthesis and
biological activities of anilide derivatives containing a pyridine N-oxide moiety. Chem.
Pharm. Bull. 2004, 52, 818–829.
6. Zheng, H. M.; Zhang, Q.; Chen, J. X.; Liu, M. C.; Cheng, S. H.; Ding, J. C.; W, H. Y.; Su,
W. K. Copper(II) acetate–catalyzed addition of arylboronic acids to aromatic aldehydes.
J. Org. Chem. 2009, 74, 943–945.
7. Meyer, H. DE Patent 2,415,062, 1975. Chem. Abstr. 1976, 84, 16962.
8. Neumann, R.; Sasson, Y. The autoxidation of alkylnitroaromatic compounds in
base-catalysed phase transfer catalysis by polythylene glycol under ultrasonic radiation.
J. Chem. Soc. Chem. Commun. 1985, 616–617.
9. Sainz-Diaz, C. I.; Hernandez-Laguna, A. trans-2,20-Dinitrostilbene as a precursor of
o-nitrobenzaldehyde, a key intermediate for pharmaceuticals: Reactivity and molecular
structure studies. J. Chem. Soc., Perkin Trans. 2 1999, 1489–1495.
10. Strazzolini, P.; Giumanini, A. G.; Runcio. A. Nitric acid in dichloromethane solution:
Facile preparation from potassium nitrate and sulfuric acid. Tetrahedron Lett. 2001, 42,
1387–1389.
11. Raucher, S.; Koolpe, G. A. Synthesis of substituted indoles via Meerwein arylation.
J. Org. Chem. 1983, 48, 2066–2069.
12. Mirkhani, V.; Moghadam, M.; Tangestaninejad, S. Catalytic oxidation of olefins with
hydrogen peroxide catalyzed by [Fe(III)(salen)Cl] complex covalently linked to polyoxo-
metalate. Inorg. Chem. Commun. 2007, 10, 1537–1540.
13. Maurya, M. R.; Chandrakar, A. K.; Chand, S. Oxovandium(IV) and copper(II) com-
plexes of 1,2-diaminocyclohexane based ligand encapsulated in zeolite-Y for the catalytic
oxidation of styrene, cyclohexene and cyclohexane. J. Mol. Catal. A: Chem. 2007, 270,
225–235.