Sigmatropic rearrangement of ammonium ylideskey step in the synthesis of methyl 2-formylphenyl acetate

Article abstract of DOI:10.1080/00397911.2010.517891

N-Cyanomethyl-N,N-dimethyl-N-(-methoxycarbonyl)benzylammonium salts 5 were synthesized and treated with different base/solvent systems, giving the products of sigmatropic rearrangements [2,3] 7 and [1,2] 8. In reactions carried out in liquid ammonia, [2,3] rearrangement definitively prevailed. Pure 7(or mixture of 7 and 8) were deprotected to afford methyl 2-formylphenyl acetate (9) in good yield.

Full text of DOI:10.1080/00397911.2010.517891

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Sigmatropic Rearrangement of
Ammonium Ylides—Key Step in the
Synthesis of Methyl 2-Formylphenyl
Acetate
Anna Kowalkowska a & Andrzej Jończyk a
a Faculty of Chemistry, Warsaw University of Technology, Warsaw,
Poland
Version of record first published: 26 Jul 2011
To cite this article: Anna Kowalkowska & Andrzej Jończyk (2011): Sigmatropic Rearrangement
of Ammonium Ylides—Key Step in the Synthesis of Methyl 2-Formylphenyl Acetate, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:22, 3308-3317
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Synthetic Communications1, 41: 3308–3317, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517891
SIGMATROPIC REARRANGEMENT OF AMMONIUM
YLIDES—KEY STEP IN THE SYNTHESIS OF METHYL
2-FORMYLPHENYL ACETATE
´
Anna Kowalkowska and Andrzej Jonczyk
Faculty of Chemistry, Warsaw University of Technology, Warsaw, Poland
GRAPHICAL ABSTRACT
Abstract N-Cyanomethyl-N,N-dimethyl-N-(a-methoxycarbonyl)benzylammonium salts 5
were synthesized and treated with different base=solvent systems, giving the products of sig-
matropic rearrangements [2,3] 7 and [1,2] 8. In reactions carried out in liquid ammonia,
[2,3] rearrangement definitively prevailed. Pure 7(or mixture of 7 and 8) were deprotected
to afford methyl 2-formylphenyl acetate (9) in good yield.
Keywords Ammonium salts; ammonium ylides; methyl 2-formylphenyl acetate; sigma-
tropic rearrangement
INTRODUCTION
Aromatic compounds substituted at two neighboring carbon atoms with a
strong electron-withdrawing group and active methylene one have been recognized
as useful substrates in organic synthesis. Thus, the benzaldehyde, acetophenone,
and benzophenone ortho-substituted with arylsulfonylmethyl group reacted with
electrophilic alkenes in the presence of a base with formation of 1,2-di- or
1,2,3-tri-substituted naphthalenes.[1,2] 2-Cyanomethylbenzaldehyde,[3] under basic
conditions, gave 1,3-di- and 1,2,3-trisubstituted naphthalenes or substituted
1-cyanobenzobicyclo-[2.2.2]octenes depending on the structure of the electrophilic
alkene.[4] The aldehyde reacted also with ammonia and primary and secondary
amines in the presence of a catalytic amount of trifluoroacetic acid, affording
3-aminoisoquinolines.[5]
The present study reports a practical methodology for the synthesis of methyl
2-formylphenylacetate (9).
Received May 5, 2010.
Address correspondence to Andrzej Jonczyk, Warsaw University of Technology, Faculty of
´
Chemistry, Koszykowa St. 75, 00-662, Warszawa, Poland. E-mail: anjon@ch.pw.edu.pl
3308

SYNTHESIS OF METHYL 2-FORMYLPHENYL ACETATE
3309
It has been well known that aldehyde 9 can be prepared by esterification of 2-
formylphenylacetic acid[6,7] or hydrolysis of dimethylacetal of the parent aldehyde
9.[8,9] According to the literature, 2-formylphenylacetic acid can be obtained either
by ozonolysis of indene[1,7] or its derivatives[10,11] or by oxidative decarboxylation of
3-oxoisochromane-1-carboxylic acid.[11] In some cases, the desired acid was
accompanied by other side products[6,7] or synthesized in poor yield.[11] Dimethyl
acetal of 9 was obtained by irradiation of 1,3-bis(diazo)-2-indanone in methanol in
yield of 35%[8] or 69%.[9]
Preliminary experiments revealed that aldehyde 9 is a useful substrate for the prep-
aration of condensed carbocyclic compounds (e.g., the reaction of compound 9 with
electrophilic alkenes under basic conditions gave substituted dihydronaphthalenes).
The synthesis of aldehyde 9 is based on a strategy similar to the synthesis of
cyanomethyl substituted derivative.[3] An initial study was carried out using the
following compounds: methyl a-methylamino- (2),[12,13] methyl a-dimethylamino-
(3),[13,14] and methyl a-bromo-phenylacetate (1).[15] The reaction of 1 with dimethyl-
aminoacetonitrile proceeded to afford crystalline bromide 5a. Aminoester 2 was N-
cyanomethylated with chloroacetonitrile to give 4 and subsequently quaternized with
methylating agent to form 5b,c, whereas in the reaction of dimethylamino derivative
3 with chloroacetonitrile, yellow and viscous quaternary chloride 6 was produced.
Crystalline salt 5d was obtained from chloride 6 by the anion exchange with sodium
tetrafluoroborate (Scheme 1).
As shown in Scheme 2, in the reactions of salts 5, carried out using various
base=solvent systems, cyanomethyl ammonium ylide 5þꢀ was generated, which gave
products 7 and 8[16] by [2,3] and [1,2] sigmatropic rearrangements, respectively.
Scheme 1. Preparation of salts 5a–d.

´
A. KOWALKOWSKA AND A. JONCZYK
3310
Scheme 2. Sigmatropic rearrangements of 5 to 7 and 8.
The required aldehyde 9 was obtained from isolated ester 7 by the deprotection
of formyl group with CuSO4. Aminonitrile 8 reacted with CuSO4 to afford a mixture
of unstable methyl a-formylphenylacetate (10)[17] and methyl phenylglyoxalate
1
(12).[18] The formation of compound 10 was confirmed by H NMR spectral data,
and compound 12 was isolated in poor yield (13–28%) and fully identified by spectral
means and elemental analysis..We assumed that the consecutive elimination of
dimethylamine from 8 occurred to give methyl 2-phenyl-3-cyanoacrylate (11),
followed by its cleavage to ketoester 12 (Scheme 3).
Scheme 3. Cleavage of 7 to ester 9 and ester 8 to 10 and 12.

SYNTHESIS OF METHYL 2-FORMYLPHENYL ACETATE
3311
Therefore, we aimed to find the optimal reaction conditions that provided us
with compounds 7 and 8 in high ratio of 7/8 and in good yield with high purity.
The selected results of the study are reported in Table 1. As shown in Table 1, salt
5d in the reactions carried out with 5% aqueous sodium hydroxide, solid sodium
hydrogen carbonate, or potassium carbonate in dimethylformamide (DMF) afforded
the mixture of 7 and 8 in poor yields (26–48%). The ratio 7=8 ranged from 0.05 to 0.3.
A significant increase of yield (ca. 80%) was achieved by using of potassium carbonate
in dimethylsulfoxide (DMSO) or 25% aqueous ammonia in dichloromethane. Further-
more, the purity of the mixtures obtained under these base=solvent conditions was at
least 95%, but undesired product 8 still prevailed (ratio 7=8 ca 0.5–0.9). Unsatisfied
content of 7 in the reaction mixtures prompted us to examine other basic systems.
Further optimization with various base=solvent systems revealed that salts
5a–d can be efficiently converted into compound 7 in triethylamine=dichloromethane
in good yield (87–98%), high purity (ꢁ96%), and better excess of 7 (7=8 ca 2.6–4.9).
The use of triethylamine in cyclohexane, ethyl ether, or carbon tetrachloride in the
reaction of salts 5a,d gave pure 8 (7=8 ca 0.04), while in DMF or tetrahydrofuran
(THF) ratio of 7=8 increased to 2.3–2.5. In all cases, the yield of rearranged
products exceeded 84%. Greater content of 7 in the reaction mixture was obtained
in the experiment carried out in 1,4-diazabicyclo[2.2.2.]octane (DABCO)=
dichloromethane system (7/8 ca 3.6–5.9).
Being unsatisfied with the poor ratio of 7=8, we continued the screening of
base=solvent systems. Salts 5a–d reacted with triethylamine in liquid ammonia at
ꢀ33 ꢂC to give the mixtures of products 7 and 8 in good yield with high content
of required 7 (ratio of 7/8 ca. 16.1–25.1). The ratio of products 7 and 8 was not
Table 1. Sigmatropic rearrangements of salts 5a–d
Products (%)a
Entry Salt
Base=solvent=temperature
[2,3] 7 (%) [1,2] 8 (%) Ratio of 7=8 Yieldb (%)
1
2
5d 5% aq NaOH
5.5
21.6
93.5
75.4
0.06
0.3
48
26
5d NaHCO3=DMF=ꢀ30 ꢂC
5d K2CO3=DMF=ꢀ35 ꢂC
5d K2CO3=DMSO=rt
3
4.7
35.6
91.0
71.3
0.05
0.5
33
80
4
5
5d 25% NH3=CH2Cl2=ꢀ25 ꢂC
45.0
51.7
0.9
2.6–4.9
80
6
5a-d Et3N=CH2Cl2=rtc
69.3–81.1
3.0–3.5
67.8–69.9
75.7–83.8
89.3–91.8
90.7–91.1
86.7–91.1
16.6–26.5
92.5–93.6
27.6–29.9
14.2–21.2
3.4–6.0
4.4–5.0
2.2–3.0
87–98
91–96
84–87
91–98
82–90d,e
90–92d,e
71–86d,e
7
5a,d Et3N=c-C6H11 or Et2O or CCl4=rt
5d Et3N=DMF or THF=rt
5a-d DABCO=CH2Cl2=rt
5a-d Et3N=NH3 liq=ꢀ33 ꢂC
5a,d NH3 liq=ꢀ33 ꢂC
0.03–0.04
2.3–2.5
3.6–5.9
8
9
10c
11f
12g
16.1–25.1
18.1–20.7
30.4–37.2
5a,d NH3 liq=ꢀ75 ꢂC
aEstimated by GC in crude reactions mixtures.
bYield of a crude mixture of 7 and 8.
cResults obtained in 12–15 experiments.
dUnidentified impurity formed in ca. 1–6% was removed under vacuum (ca. 20 ꢂC=0.05 Torr).
eIn some experiments 2–4% of aldehyde 9 was formed.
fResults obtained in three experiments.
gResults obtained in six experiments.

´
A. KOWALKOWSKA AND A. JONCZYK
3312
dependent on the excess of triethylamine (1–5 equivalents). These results suggest that
liquid ammonia is a sufficiently strong base to deprotonate 5 and to induce the
rearrangement of the corresponding ylide 5þꢀ. Lowering the reaction temperature
to ꢀ33 ꢂC and ꢀ75 ꢂC resulted in very high 7/8 ratios: ca. 20 and ca. 35, respectively.
In the latter case, the yield of crude mixture was lower and the observation has been
reported previously.[19]
As shown in Table 1, the desired product 7 was always accompanied by 8.
However, we found the conditions of sigmatropic rearrangements of ylide 5þ ꢀ gen-
erated from 5 to form 8 as a minor component. The reactions carried out in liquid
ammonia gave 1–6% of unidentified impurity and in some cases 2–4% of aldehyde 9.
Products 7 (yield 60–78%) and 8 (yield 81–83% as a mixture of diastereo-
isomers) were isolated from the reaction mixtures obtained in the experiments car-
ried out in liquid ammonia (entries 10–12, Table 1), in triethylamine=cyclohexane,
in ethyl ether, or in carbon tetrachloride (entry 7, Table 1), respectively. Deprotec-
tion of the formyl group in the isolated compound 7 proceeded to give the expected
aldehyde 9 in 93% yield. On the other hand, because of some difficulties separating
compounds 7 and 8 by crystallization, the deprotection reaction was also carried out
without any separation. All the by-products, especially ketoester 12, were easily
separated by column chromatography, and aldehyde 9 was obtained in yield
44–52% (from salt 5, rearranged in NEt3=CH2Cl2=rt system) or 60–67% (from salt
5, rearranged in liquid ammonia at ꢀ33 ꢂC).
In conclusion, we have developed a simple method for the preparation of the
title aldehyde 9. Further studies on the application of the reaction to the construction
of condensed ring compounds are under investigation.
EXPERIMENTAL
Melting points were measured on a capillary apparatus and were not corrected.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured on a Varian
Mercury 400BB spectrometer in CDCl3 or dimethylsulfoxide (DMSO-d6); chemical
shifts (d) are given in parts per million (ppm) related to tetramethylsilane (TMS),
coupling constants J are given in hertz (Hz). Elemental analyses were performed
on a Perkin-Elmer 2400 Series II CHNS=O microanalyzer. Gas chromatographic
analysis (GC) was performed on an Agilent 6850 Series GC system fitted with
HP-50þ (30 m) column. Column chromatography was performed on Merck silica
gel (240–400 mesh). Commercial methyl a-bromo-phenylacetate (1), obtained
according to literature procedure,[14] was used.
Methyl a-(N-Methylamino)phenylacetate (2)
To a magnetically stirred solution of 1 (11.45 g, 50 mmol) in MeOH (50 mL),
40% aqueous methylamine (19.41 g, 21.6 mL, 250 mmol) was added dropwise at
20–35 ꢂC for ca. 30 min. The mixture was stirred at ambient temperature until GC
analysis indicated total consumption of 1 (ca. 1 h), and then it was diluted with
H2O (70 mL) and extracted with CH2Cl2 (3 ꢃ 40 mL). The combined organic extracts
were washed with H2O (3 ꢃ 40 mL) and dried (MgSO4). The solvent was evaporated,
and the residue was distilled to give 2 (5.74 g, yield 62%).

SYNTHESIS OF METHYL 2-FORMYLPHENYL ACETATE
3313
1
Compound 2: bp 68–69 ꢂC=0.2 Torr (lit.[12] bp 132–134 ꢂC=2 Torr). H NMR
(400 MHz, CDCl3) d ¼ 2.06 (1H, s, NH), 2.39 (3H, s, NH-CH3), 3.69 (3H, s,
OCH3), 4.27 (1H, s, CH-CO2CH3), 7.27–7.37 (5H, m, Ph).
Methyl a-(N,N-Dimethylamino)phenylacetate (3)
To a magnetically stirred solution of 1 (11.45 g, 50 mmol) in MeOH (50 mL),
40% aqueous dimethylamine (28.18 g, 31.66 mL, 0.25 mol) was added dropwise at
20–35 ꢂC for ca 30 min. The mixture was stirred at ambient temperature until GC
analysis indicated total consumption of 1 (ca. 1 h), and then it was diluted with
H2O (70 mL) and extracted with CH2Cl2 (3 ꢃ 40 mL). The combined organic extracts
were washed with H2O (3 ꢃ 40 mL) and dried (MgSO4). The solvent was evaporated
to give crude 3 (9.08 g, yield 94%), purity ca. 97% (by GC), which was used in the
next step without further purification.
Compound 3: 1H NMR (400 MHz, CDCl3) d ¼ 2.24 [6H, s, N(CH3)2], 3.69 (3H,
s, OCH3), 3.86 (1H, s, CH-CO2CH3), 7.28–7.36 (3H, m, Ph), 7.39–7.44 (2H, m, Ph).
Methyl a-(N-Cyanomethyl-N-methylamino)phenylacetate (4)
Chloroacetonitrile (11.33 g, 9.49 mL, 150 mmol) was added dropwise to a vig-
orously stirred mixture of 2 (8.96 g, 50 mmol), MeCN (40 mL), powdered K2CO3
(13.82 g, 100 mmol), and tetrabutylammonium bromide (0.32 g, 1 mmol) for
10 min. The reaction was stirred at 65–70 ꢂC until GC analysis indicated total con-
sumption of 2 (ca. 10 h). The mixture was diluted with CH2Cl2 (60 mL) and filtered;
the solid was washed with CH2Cl2 (2 ꢃ 10 mL). The combined filtrates were washed
with H2O (3 ꢃ 30 mL) and dried (MgSO4). The solvent was evaporated, and the resi-
due was distilled under reduced pressure to give 4 (8.74 g, 80.1%) as yellow oil.
1
Compound 4: bp 115–118 ꢂC=0.2 Torr. H NMR (400 MHz, CDCl3) d ¼ 2.46
(3H, s, N-CH3), 3.40 and 3.57 (2H, ABq, J 17.6, CH2CN), 3.69 (3H, s, OCH3),
4.19 (1H, s, CH-CO2CH3), 7.34–7.40 (3H, m, Ph), 7.43–7.48 (2H, m, Ph). 13C
NMR (100 MHz, CDCl3) d ¼ 40.73, 42.76, 52.41, 71.12, 114.33, 128.60, 129.09,
129.23, 134.63, 171.11. Anal. calcd. for C12H14N2O2 (218.26 g=mol) (%): C, 66.04;
H, 6.47; N, 12.84. Found: C, 65.85; H, 6.64; N, 12.80.
N-Cyanomethyl-N,N-dimethyl-N-(a-methoxycarbonyl)benzyl-
ammonium Bromide (5a)
Dimethylaminoacetonitrile (5.05 g, 5.85 mL, 60 mmol) was added in one
portion to a solution of 1 (11.45 g, 50 mmol) in CH2Cl2 (15 mL) at ambient tempera-
ture. The mixture was left for 10–14 days, the solvent was evaporated, and the solid
residue was ground, washed with Et2O (6 ꢃ 10 mL), and dried in air to give 5a
(11.75–13.78 g, yield 75–88%).
Compound 5a: mp 136–138 ꢂC. 1H NMR (400 MHz, DMSO-d6) d ¼ 3.40 (s, 3H,
Nþ-CH3), 3.41 (s, 3H, Nþ-CH3), 3.76 (s, 3H, OCH3), 5.08 and 5.16 (ABq, 2H, J 16.4,
CH2CN), 6.15 (s, 1H, CH-CO2CH3), 7.56–7.68 (5H, m, Ph). 13C NMR (100 MHz,
DMSO-d6) d ¼ 50.33, 50.74, 51.01, 53.93, 74.29, 111.55, 125.76, 129.77, 131.81,

´
A. KOWALKOWSKA AND A. JONCZYK
3314
132.03, 165.97. Anal. calcd. for C13H17Br.N2O2 (313.20 g=mol) (%): C, 49.86; H,
5.47; N, 8.94. Found: C, 49.91; H, 5.42; N, 8.96.
N-Cyanomethyl-N,N-dimethyl-N-(a-methoxycarbonyl)benzyl-
ammonium Methylsulfate (5b)
Dimethyl sulfate (1.89 g, 1.42 mL, 15 mmol) was added in one portion to a
cooled solution of 4 (2.18 g, 10 mmol) in CH2Cl2 (10 mL), and the mixture was left
overnight in a refrigerator. Next the solvent was evaporated, and the viscous yellow-
ish oil that solidified was ground, washed with Et2O (5 ꢃ 8 mL), and dried on air to
give 5b (3.27 g, yield 95%).
Compound 5b: mp 155–157 ꢂC. 1H NMR (400 MHz, DMSO-d6) d ¼ 3.35 (s, 3H,
Nþ-CH3), 3.37 (s, 3H, CH3SO4), 3.38 (s, 3H, Nþ-CH3), 3.77 (s, 3H, OCH3), 4.94 and
5.07 (ABq, 2H, J 16.4, CH2CN), 5.93 (s, 1H, CH-CO2CH3), 7.55–7.68 (5H, m, Ph).
13C NMR (100 MHz, DMSO-d6) d ¼ 50.56, 50.75, 51.09, 52.89, 53.98, 74.69, 111.58,
125.68, 129.86, 131.86, 132.09, 165.97. Anal. calcd. for C14H20N2O6S (344.39 g=mol)
(%): C, 48.83; H, 5.85; N, 8.13. Found: C, 48.68; H, 5.74; N, 8.12.
N-Cyanomethyl-N,N-dimethyl-N-(a-methoxycarbonyl)benzyl-
ammonium Trifluoromethanesulfonate (5c)
Methyl trifluoromethanesulfonate (2.46 g, 1.70 mL, 15 mmol) was added in one
portion to a cooled solution of 4 (2.18 g, 10 mmol) in CH2Cl2 (10 mL), and the mix-
ture was left overnight in a refrigerator. The crystals were filtered, washed with Et2O
(5 ꢃ 8 mL), and dried on air to give 5c (3.48–3.67 g, yield 91–96%). When the product
did not crystallize in a refrigerator, the solvent was evaporated, and the product 5c
was isolated as in the case of 5b.
Compound 5c: mp 131–132 ꢂC. 1H NMR (400 MHz, DMSO-d6) d ¼ 3.34 (s, 3H,
Nþ-CH3), 3.37 (s, 3H, Nþ-CH3), 3.77 (s, 3H, OCH3), 4.91 and 5.06 (ABq, 2H, J 16.4,
CH2CN), 5.92 (s, 1H, CH-CO2CH3), 7.55–7.69 (5H, m, Ph). 13C NMR (100 MHz,
DMSO-d6) d ¼ 50.59, 50.75, 51.10, 53.98, 74.69, 111.60, 125.64, 129.86, 131.84,
132.09, 165.95. Anal. calcd. for C14H17F3N2O5S (382.36 g=mol) (%): C, 43.98; H,
4.48; N, 7.33. Found: C, 44.00; H, 4.36; N, 7.37.
N-Cyanomethyl-N,N-dimethyl-N-(a-methoxycarbonyl)benzyl-
ammonium Tetrafluoroborate (5d)
The mixture of 3 (9.66 g, 50 mmol) and chloroacetonitrile (5.66 g, 4.75 mL,
75 mmol) was left for 10–14 days. The oil was dissolved in distilled water (ca.
10–20 mL), the organic products were extracted with Et2O (3 ꢃ 10 mL), and the
water phase was treated with NaBF4 (50 mmol, 5.49 g) and left for 48–72 h. The solid
was filtered, washed with H2O (6 ꢃ 5 mL) and Et2O (5 ꢃ 10 mL), and dried in air to
give 5d (8.32–10.56 g, yield 52–66%).
Compound 5d: mp 132–134 ꢂC. 1H NMR (400 MHz, DMSO-d6) d ¼ 3.34 (s, 3H,
Nþ-CH3), 3.37 (s, 3H, Nþ-CH3), 3.77 (s, 3H, OCH3), 4.91 and 5.07 (ABq, 2H, J 16.4,
CH2CN), 5.93 (s, 1H, CH-CO2CH3), 7.55–7.68 (5H, m, Ph). 13C NMR (100 MHz,
DMSO-d6) d ¼ 50.59, 50.75, 51.10, 53.98, 74.68, 111.60, 125.65, 129.86, 131.84,

SYNTHESIS OF METHYL 2-FORMYLPHENYL ACETATE
3315
132.09, 165.95. Anal. calcd. for C13H17BF4N2O2 (320.09 g=mol) (%): C, 48.78; H,
5.35; N, 8.75. Found: C, 48.90; H, 5.25; N, 8.81.
2-(Methoxycarbonymethyl)-a-(dimethylamino)phenylacetonitrile (7)
by Rearrangement of 5
Method 1. To a stirred liquid ammonia (ca. 50 mL), salt 5 (10 mmol) was
added in one portion at ꢀ33 ꢂC. Stirring was continued for 3–5 h, ammonia was
evaporated overnight, and the residue was diluted with CH2Cl2 (70 mL) and H2O
(50 mL). The phases were separated, the water phase was extracted with CH2Cl2
(2 ꢃ 15 mL), and the combined organic extracts were washed with H2O (3 ꢃ 30 mL)
and dried (MgSO4). The solvent was evaporated, and the residue (2.09–2.28 g of yel-
low oil) was analyzed by GC. The crude product was used for preparation of 9.
Alternatively,
2-(methoxycarbonymethyl)-a-(dimethylamino)phenylacetoni-
trile (7) was isolated from the crude reaction mixture by crystallization from hexane
in yield ca. 60–68% (1.39–1.58 g, purity ꢁ98.5% by GC). The filtrate was evaporated,
and the residue was crystallized from MeOH to give pure mixture of 7 and 8. Further
recrystallization of this mixture from hexane afforded 7 (total yield 70–78%,
1.62–1.81 g).
Method 2. Triethylamine (5.06 g, 6.97mL, 50mmol) was added to a stirred mix-
ture of 5 (10 mmol) in CH2Cl2 (25 mL). Stirring was continued at ambient temperature
for 2 h, the mixture was diluted with water (50 mL), the phases were separated, the
water phase was extracted with CH2Cl2 (3 ꢃ 20 mL), and the combined organic
extracts were washed with H2O (3 ꢃ 20 mL) and dried (MgSO4). The solvent was eva-
porated, and the residue (2.03–2.27 g of yellowish oil) was analyzed by GC (Table 1,
entry 6). The crude product (mixture of 7 and 8) was used for preparation of 9.
1
Compound 7: Mp 56–58 ꢂC (hexane). H NMR (400 MHz, CDCl3) d ¼ 2.23
[s, 6H, N(CH3)2], 3.55 and 3.94 (ABq, J 15.6, 2H, CH2CO2CH3), 3.66 (s, 3H,
OCH3), 5.07 (s, 1H, CHCN), 7.25–7.39 (m, 4H, Ph), 7.59–7.62 (m, 1H, Ph). 13C
NMR (100 MHz, CDCl3) d ¼ 38.34, 41.17, 51.98, 61.42, 114.64, 127.49, 128.56,
129.33, 131.93, 132.06, 133.60, 171.43. Anal. calcd. for C13H16N2O2 (232.28 g=
mol) (%): C, 67.22; H, 6.94; N, 12.06. Found: C, 67.01; H, 6.89; N, 11.95.
3-Cyano-3-dimethylamino-2-phenylpropionic Acid Methyl Ester (8) by
Rearrangement of 5a,d
Triethylamine (1.01 g, 1.39 mL, 10 mmol) was added to a stirred mixture of 5a
(0.63 g, 2 mmol) or 5d (0.64 g, 2 mmol) in cyclohexane or diethyl ether or CCl4
(5 mL). Stirring was continued at ambient temperature for 5 h, the mixture was
diluted with water (15 mL), the phases were separated, the water phase was extracted
with CH2Cl2 (3 ꢃ 10 mL), and the combined organic extracts were washed with H2O
(3 ꢃ 10 mL) and dried (MgSO4). The solvent was evaporated, and the residue was
crystallized from MeOH to give 8 (0.37–0.38 g, yield 80–83%) as mixture of diaster-
eoisomers (ratio from 1=1.7 to 1=2.7).
1H NMR (400 MHz, CDCl3) d ¼ 2.26 (s, 6H minor, N(CH3)2), 2.41 [s, 6H
major, N(CH3)2], 3.71 (s, 3H both, OCH3), 3.90 and 4.26 (ABq, J 12.0, 2H major,

´
A. KOWALKOWSKA AND A. JONCZYK
3316
CH-CH), 3.94 and 4.25 ABq, J 11.6, 2H minor, CH-CH), 7.26–7.43 (m, 5H both,
Ph). 13C NMR (100 MHz, CDCl3) d ¼ 41.77, 42.06, 52.57, 52.64, 52.79, 60.29,
62.62, 114.23, 115.40, 127.84, 128.36, 128.39, 128.91, 129.13, 133.01, 133.68,
170.71, 170.94. Anal. calcd. for C13H16N2O2 (232.28 g=mol) (%): C, 67.22; H, 6.94;
N, 12.06. Found: C, 67.01; H, 7.02; N, 11.98.
Methyl 2-Formylphenylacetate (9)
Preparation of 9 from pure 7. A solution of 7 (21.6 g, 93 mmol) (purity ca.
97% by GC) in THF (280 mL) was added in one portion to a vigorously stirred
solution of CuSO4 ꢃ 5H2O (46.44 g, 186 mmol) in H2O (280 mL). The reaction was
stirred, refluxed for 2 h, and cooled; the phases were separated. The water phase
was extracted with CH2Cl2 (3 ꢃ 100 mL), and the combined organic extracts were
washed with H2O (3 ꢃ 100 mL) and dried (MgSO4). The solvent was evaporated to
give 9 (15.38 g, yield 93%, purity ca. 97% by GC) as a yellowish oil. After passing
this oil dissolved in CH2Cl2 (ca. 10 mL) through a short layer of silica gel
(hexane=ethyl acetate 92=8) the product 9 was obtained as a nearly a colorless oil,
solidifying in freezer. The analytical sample was distilled on Kugelrohr apparatus.
Preparation of 9 from Crude Mixture of 7 and 8
Crude rearranged products (4.23 g, containing 89.6% of 7, 5.3% of 8, 1.0% of 9
obtained from 20 mmol of 5a in NEt3=NH3 liq=ꢀ33 ꢂC system) were deprotected as
described previously. The residue was purified by column chromatography (hexane=
ethyl acetate, gradient) giving 2.29 g of 9 (yield 64% from 5a).
Crude rearranged products (4.47 g, containing 71.2% of 7, 26.2% of 8 obtained
from 20mmol of 5a in NEt3=CH2Cl2=rt system) were deprotected as described
previously. The residue was purified by column chromatography (hexane=ethyl acetate,
gradient) giving 0.15 g of 12 (yield 4.6% from 5a) and 1.71g of 9 (yield 48% from 5a).
Compounds 9 and 12
Compound 9: bp 112–115 ꢂC=0.09 Torr (kugelrohr). 1H NMR (400 MHz,
CDCl3) d ¼ 3.69 (s, 3H, OCH3), 4.05 (s, 2H, CH2CO2CH3), 7.27–7.31 (m, 1H,
Ph), 7.47–7.58 (m, 2H, Ph), 7.82–7.85 (m, 1H, Ph), 10.10 (s, 1H, CHO). 13C NMR
(100 MHz, CDCl3) d ¼ 38.82, 52.00, 127.90, 132.26, 133.69, 134.31, 134.36, 135.41,
171.36, 192.96.
Compound 12: 1H NMR (400 MHz, CDCl3) d ¼ 3.98 (s, 3H, OCH3), 7.49–7.54
(m, 2H, Ph), 7.64–7.69 (m, 1H, Ph), 8.00–8.03 (m, 2H, Ph). 13C NMR (100 MHz,
CDCl3) d ¼ 52.75, 128.88, 130.05, 132.39, 134.95, 164.00, 186.02. Anal. calcd. for
C9H8O2 (164.16 g=mol) (%): C, 65.85; H, 4.91. Found: C, 65.71; H, 5.14.
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