Development of a one-pot method for the homologation of aldehydes to carboxylic acids

Article abstract of DOI:10.1016/j.tet.2009.07.032

A highly efficient method is described for the one-carbon homologation of aldehydes to carboxylic acid derivatives employing the reaction of a 1,1-bis-dimethylphosphonate derivative with the aldehyde and controlled acid hydrolysis of the derived α-phosphonoenamine intermediate.

Full text of DOI:10.1016/j.tet.2009.07.032

Tetrahedron 65 (2009) 7794–7800
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of a one-pot method for the homologation of aldehydes
to carboxylic acids
*
James McNulty , Priyabrata Das
Department of Chemistry, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient method is described for the one-carbon homologation of aldehydes to carboxylic acid
derivatives employing the reaction of a 1,1-bis-dimethylphosphonate derivative with the aldehyde and
Received 29 April 2009
Received in revised form 2 July 2009
Accepted 10 July 2009
controlled acid hydrolysis of the derived
a-phosphonoenamine intermediate.
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 16 July 2009
1. Introduction
procedure using readily available reagents for this desirable
transformation, ideally in a single step.
Carbonyl-containing compounds occupy a central role in or-
ganic synthesis by virtue of their participation in a large repertoire
of predictable and controllable chemistry. Carbonyl homologation
strategies are of great importance in the synthesis of reactants and
conversion of the products of reactions (aldol adducts, alkylkation
or Michael addition products) to an expansive array of useful in-
termediates. As a particular example, phenylacetic acid derivatives
are of great interest in view of the wide range of biological activity
displayed by many1 as well as their use as synthetic intermediates.2
Currently, industrial production of such derivatives requires the
synthesis of a benzyl chloride, which is converted to the nitrile and
subsequently hydrolyzed. The method requires several steps and is
noted to suffer from considerable drawbacks.3 Direct methods for
the synthesis of phenylacetic acids through the homologation of
readily available aromatic aldehydes is thus an area of great in-
terest. The conversion of aliphatic aldehydes to their one-carbon
homologated acids is also of interest and has proven to be more
challenging.
Gross and Costisella4b and Degenhardt6a reported methods
involving the intermediacy of a-phosphonoenamines 3 as a route
for this homologation reaction using the anion derived from the bis-
diethylphosphonate ester of 6, Scheme 1. We recently reported4o an
improved method that utilized a Peterson reaction of the a-trime-
thylsilyl derivative 2 in accord with previous studies by Dufrechou
et al.6b (Scheme 1, path i). The major obstacle toward application of
this biphosphonate route to carbonyl homologation is the lack of an
efficient method for the generation of phosphonoenamines 3 from
aldehydes. While the electronic effect demonstrated in the silicon-
directed route allows for better efficiency (70–87% yield4o vs 8–
69%6b) in the conversion to the phosphonoenamine intermediates,
overall these results appear to indicate that steric factors are detri-
mental to the aldehyde addition step. In this paper we report our
complete study on the a-silyl-aminophosphonate homologation route
(Scheme 1, path i) as well as a new very efficient one-pot method in-
volving the use of a lithiated bis-dimethylphosphonate formed by
deprotonation of 6 (Scheme 1, path ii).
Several methods have been developed to achieve the aldehyde
to homologated carboxylic acid transformation, usually requiring
two or three steps.4 The most efficient method to date is the ben-
zotriazole method of Katritzky et al. employing a Peterson reaction
that allowed for the one-pot interconversion of a range of alde-
hydes to homologated carboxylic acids in 45–57% yield.4f Most
other methods are multistep, employ reagents that are not readily
available or suffer from harsh conditions4 and resulting in poor to
moderate overall yields (typically 35–60%). As a result, there is still
a need to develop an operationally simple and efficient synthetic
O
P
O
P
O
P
N
R
N
R'
sec-BuLi, then
R-CHO
N
O
LDA, THF
TMS-Cl
O
( i )
O
SiMe3
O
O
R'
O
3 ( R' = Et )
1
2
HBr
Br -
Br
R-CH2-CO2H
HBr
(MeO)2OP
NMe2
P(OMe)3
THF
LDA, then RCHO
+
N
( ii )
3 ( R' = Me )
4
(MeO)2OP
5
6
Scheme 1. Aldehyde to carboxylic acid homologation strategies via phosphonoen-
amine intermediates 3.
* Corresponding author. Tel.: þ1 905 525 9140x27393; fax: þ1 905 522 2509.
E-mail address: jmcnult@mcmaster.ca (J. McNulty).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.032

J. McNulty, P. Das / Tetrahedron 65 (2009) 7794–7800
7795
2. Results and discussion
The scope of the reaction was investigated with a range of ar-
omatic and aliphatic aldehydes the results of which are summa-
rized in Table 1. Conversions are high in all cases with isolated
yields being only slightly lower. Under these conditions of kinetic
control, aromatic aldehydes provided a mixture of (E)/(Z) olefins
that rapidly isomerize to give exclusively the thermodynamically
more stable (E)-isomers. No significant electronic effect was ob-
served with both electron rich and electron poor derivatives
reacting equally well (entries 16). In the case of aliphatic aldehydes,
dihydro-cinnamaldehyde (entry 7) provided a single (E)-adduct,
most likely as the kinetic product, while other aliphatic aldehydes
gave (E)/(Z) mixtures (entries 8 and 9). These isomers could be
separated and proved to be configurationally stable. The heteroaryl
aldehyde 2-furfural also yielded its corresponding adduct effi-
ciently (entry 10).
In our hands, the direct aldolization of various enolate de-
rivatives of 1 with aromatic aldehydes or ketones to yield the
expected a-phosphonoenamines 3 proved problematic. For exam-
ple, reaction of the anion of 1 (formed with MeLi, THF, ꢀ78 ꢁC) with
4-chlorobenzaldehyde or acetone gave the corresponding
b-hy-
droxyl-
(two diastereomers) and 60%, respectively. Attempts to dehydrate
these intermediates to the -phosphonoenamines were not fruitful
a-aminophosphonate adducts in moderate yields of 67%
a
giving complex mixtures and resulting in poor yields of 3.
The failure to selectively dehydrate these intermediates promp-
ted us to attempt a Peterson variant of the reaction using a func-
tionalized
-trimethylsilyl derivative 2 (Scheme 2) employing a silylation
a
-silyl carbanion.7a To this end, we prepared the
a
strategy first described by Padwa et al. in the silylation of cyanoa-
mines.7b Silylationof1 withchlorotrimethylsilaneproved to berapid
and gave the N-trimethylsilyl ammonium chloride salt. Deprotona-
tion with LDA promoted the desired N to C migration of the trime-
thylsilyl group most likely via a nitrogen ylide intermediate. The
trimethylsilyl intermediate 2 proved to be stable to silica gel and
could be stored underargon for several dayswithout decomposition.
The intermediate was however readily hydrolyzed back to the
starting aminophosphonate 1 when treated with aqueous acid.
Table 1
Peterson reaction of
a
-trimethylsilyl-
a
-dimethylaminophosphonate with aldehydes
O
P
N
O
O
1) sec-BuLi,-78 °C, THF
2) RCHO,-78 °C to 25 °C
O
O
P
O
Si
R
N
2
3
Entry
RCHO
Conversiona (%) 3
Isolated yield
E/Zc
of 3b (%)
O
H
O
O
1
2
3
4
(2a)
>95 3a
>90 3b
>94 3c
>95 3d
87
67
80
85
100:0
100:0
100:0
100:0
O
P
O
P
O
P
N
R
N
N
TMS-Cl
O
O
1) sec-BuLi, THF
2) R-CHO
O
O
H
LDA, THF
SiMe3
O
O
O
(2b)
(2c)
(2d)
3a-3j, 70-87%
isolated yield
1
2 (80%)
O
H
1) MeLi
2) ArCHO
Cl
O
O
(EtO)2P
N
H
MeO
HO
Ar
O
Scheme 2. Direct and silicon-assisted routes to aminophosphonates 3.
H
5
(2e)
>95 3e
82
100:0
Formation of the a-silyl carbanion from the above intermediate 2
O2N
O2N
using s-BuLi in THF (ꢀ78 ꢁC) and addition of piperonal, as outlined in
Scheme 1, to our delight led to the formation of the corresponding
phosphonoenamine 3a with 95% conversion and 87% isolated yield.8
Although the precise mechanism of the Peterson reaction is still unclear
(so-called betaine versus oxasiletanide intermediates)7a the present
intermediate, shown as the betaine (Scheme 3), selected the Peterson
elimination pathway over the Horner–Emmons route. Vinylsilanes are
also possible products from this reaction and this ‘challenge’ un-
ambiguously demonstrates the prominence of the Petersonpathway,6b
O
O
6
7
(2f)
>95 3f
>90 3g
80
75
100:0
100:0
H
H
(2g)
O
8
9
(2h)
(2i)
>90 3h
>90 3i
70
70
60:40
65:35
H
O
reactivity also observed with simple
a
-silylphosphonates.7a
H
O
P
O
O
10
(2j)
>95 3j
75
100:0
N
R
H
Peterson
O
O
P
a
O
Conversion is based on the recovered aldehyde partner.
Isolated yield of the phosphonoeneamine 3 after chromatographic purification.
The (Z)- isomer derived from aromatic aldehydes fully converts to the (E)-iso-
b
c
N
3a-3j
O
mer, see text. Configurational isomers derived from aliphatic aldehydes were
readily separated.
O
SiMe3
Horner-Emmons
-
R
O
Me3Si
N
R
In the previous report on phosphonoenamine hydrolysis, boiling
hydrochloric acid was used in the conversion to the carboxylic
acids. Three examples of this homologation were reported by Gross
and Costisella4b and the route appears to have been applied only
once.6a The hydrolysis mechanism likely involves initial enamine
Betaine
vinyl silane
a-silylated ‘betaine-type’
Scheme 3. Possible pathways for elimination from the
intermediate.
hydrolysis and cleavage of the derived a-ketophosphonate

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J. McNulty, P. Das / Tetrahedron 65 (2009) 7794–7800
intermediate.4b This overall homologation protocol is perhaps
underutilized due to the difficulties in accessing intermediates 3
and the need for optimization of the conditions for enamine hy-
drolysis, which also produces ketophosphonate intermediates and
in 90–98% isolated yield. Although the overall yields of this
two-step route to homologated acids are in the 75% range, the
overall process is less efficient than desired. It appears that the
aldehyde addition step is sluggish, perhaps due to steric con-
straints using the hindered anion derived from 2.
also results in decarboxylation with b
-aryl acids.6a We investigated
the hydrolysis of the adduct 3a under various conditions and de-
termined that heating with hydrobromic acid for a short period of
time was superior to the use of hydrochloric acid. Nonetheless, high
yields of the homologated acid could be obtained only under
a tightly held set of conditions. Treatment of the piperonal-derived
adduct 3a with 48% hydrobromic acid and warming to 100 ꢁC with
a heat-gun led to rapid hydrolysis and isolation of the homologous
acid in 90% yield (Table 2, entry 1). Longer heating time gives very
poor yield of the homologated acid, presumably due to rapid de-
These considerations prompted us to consider an alternative
approach toward the synthesis of the phosphonoenamine (Scheme
1, path ii) intermediate 3 via the diphosphonate 6 (Scheme 4).
Degenhardt previouslyemployed the tetraethyl estercorresponding
to 6 as an alternative route to phosphonoenamines,6a and also
reported their hydrolysis using concentrated hydrochloric acid. This
route provided homologated acids in low yields, typically 35%. As an
extension of this method, we generated the less sterically de-
manding 1,1-bis-dimethylphosphonate intermediate of structural
type6(Scheme4). Theisolatable intermediate 6 was prepared bythe
reaction of commercially available (bromomethylene)-dimethyli-
minium bromide5 5 with 2 equiv of trimethylphosphite. Sequential
treatment of 6 with 1.1 equiv of LDA in THF at ꢀ78 ꢁC followed by
addition of 1 equiv of 4-nitrobenzaldehyde yielded the phospho-
noenamine derivative 3 (Scheme 1, R0¼Me, R¼4-(NO2)C6H4–).
carboxylation, whereas with shorter heating time the
a-keto-
phosphonate was detected. The optimal heating time appeared to
be between 5 and 10 min. The use of HBr under these reaction
conditions proved to be general for both electron rich and electron
deficient aryl derivatives (Table 2, entries 2–5) with high yields of
carboxylic acid being obtained in all cases. Lastly, the hexanal de-
rived a-phosphonoenamine 3f was readily hydrolyzed to heptanoic
acid (Table 2, entry 6) extending the scope to aliphatic derivatives
also.
Br-
P(OMe)3 (MeO)2OP
NMe2
HBr
1) LDA
+
N
R-CH2-CO2H
3
THF
2) RCHO
Br
(MeO)2OP
4
Table 2
6
5
Hydrolysis of
a
-phosphonoenamines to provide the corresponding homologous
Scheme 4. Diphosphonate route toward aminophosphonates 3.
carboxylic acids
O
O
O
48 % HBr
To our surprise, conversion of the aldehyde was complete and
N
P
R
R
OH
the phosphonoenamine 3 could be isolated in 92–93% yield. Steric
factors appear to play a critical role in the overall efficiency of the
carbonyl-addition step to yield the phosphonoenamine. Acidic
hydrolysis of 3 employing 48% HBr yielded the homologated
4-nitrophenylacetic acid 4d in >98% isolated yield.
100 °C, 10 min.
O
3
4
Entry
1
Phosphonoenamine
4 Isolated yield (%)
We next developed a protocol that allowed for all of the chem-
istry described to be conducted efficiently in one flask. A vacuum
strip of solvent was introduced after formation of the bisphospho-
nate 6 to remove traces of bromomethane due to its potential re-
activity with the enamine. Sequential addition of base followed by
aldehyde led to the formation of 3. While the direct introduction of
aqueous HBr after the Horner-type reaction (conversion of 6 to 3)
and conventional heating (100 ꢁC,10 min) completed the hydrolysis
effectively,4o we also determined that microwave irradiation at
100 ꢁC for a short period (3 min) effects rapid hydrolysis. The ho-
mologated acids were isolated efficiently without the need for
chromatographic purification employing a simple base extraction,
separation, and re-acidification work-up protocol.
The scope of this one-pot interconversion was investigated with
a range of aromatic and aliphatic aldehydes the results of which are
presented in Table 3. No major electronic effect was observed as
electron rich and electron deficient aldehydes all yielded the cor-
responding phenylacetic acid derivatives in high isolated yield, al-
though yields appear to be slightly higher with more reactive
aldehydes. In addition, hindered ortho-substituted aldehydes could
be employed (entries 8 and 9) effectively. We also demonstrated
that enolizable aliphatic aldehydes (entries 5 and 10) could be
converted to the homologated acids in good isolated yield follow-
ing the same reaction and work-up protocol.
O
O
O
H
CO2H
N
P
O
O
(3a)
(4a) 90%
O
O
O
P
O
O
CO2H
N
2
3
(3b)
(3c)
(4b) 93%
(4c) 95%
H
O
P
CO2H
O
O
N
H
Cl
Cl
O
P
CO2H
CO2H
CO2H
O
N
O
4
(3d)
(4d) 98%
H
O2N
O2N
O2N
O2N
O
O
O
N
P
5
6
(3e)
(3f)
(4e) 97%
(4f) 90%
H
O
O
O
N
P
The overall results are consistent with lower aldol-type re-
activity of non-activated aromatic aldehydes, hindered aldehydes,
and enolizable aldehydes, and are evidence that the carbonyl-ad-
dition step is still sluggish. Nonetheless, the sterically less de-
manding bis-dimethylphosphonate allows for a very efficient
H
In terms of the overall homologation method (Scheme 1, 1/2
/3/4), the intermediate phosphonoenamines 3 were obtained
in 70–87% isolated yield after silica gel chromatography. Puri-
fication was necessary to remove traces of unreacted aldehyde.
The HBr-mediated hydrolysis gave the homologated acid cleanly
general synthesis of
ethyl ester analog,6a and shows that high yields of phosphonoen-
amines can be attained without recourse to
-silylation.4o,6
a-phosphonoenamines in comparison to its
a

J. McNulty, P. Das / Tetrahedron 65 (2009) 7794–7800
7797
Table 3
derivative 6 and that the anion derived from 6 undergoes a Horner-
type reaction with aldehydes, yielding phosphonoenamines 3.
These same phosphonoenamines can be generated from the
One-pot homologation of aldehydes to carboxylic acids
Entry
RCHO
RCH2CO2H
O H
Yield (%)
82
Peterson reaction of the anion derived of
a-silylated-N,N-dime-
O
thylaminophosphonate 2 with aldehydes. The controlled hydrolysis
of these phosphonoenamine intermediates using hydrobromic acid
provides entry to the homologated carboxylic acid derivatives in
high yield. Overall, the dimethyl-bisphosphonate route is more
efficient than the Peterson route and previous routes using diethyl-
phosphonates6a most likely due to steric effects. A general, one-pot
procedure was developed successfully for the aldehyde-homolo-
gated carboxylic acid conversion employing both aromatic and
enolizable aliphatic aldehydes. This new method allows for the
achievement of this desirable interconversion in the highest yields
reported to date, similar to a recently reported two-step method
employing trichloromethyl carbinols.4p Further developments of
the methodology and synthetic applications are currently under
investigation in our laboratories.
O
O
O
O
1
(4a)
(4b)
H
O
O
O H
2
3
83
80
H
O
O
O H
(4c)
H
O
Cl
Cl
O
O H
H
4
5
6
(4d)
(4f)
(4g)
90
75
80
O
O 2
N
4. Experimental section
4.1. General
O
2N
O
O
4
3
H
O H
O
Reactions were carried out under argon in oven-dried glass-
ware. Diethyl-2-N,N-dimethylaminomethano phosphonate was
obtained from Cytec, all other fine chemicals were obtained from
Aldrich. S-Butyl lithium was obtained from Aldrich as a 1.4 M
solution in cyclohexane. THF was distilled from sodium with ben-
zophenone indicator. CIMS were run on a Micromass Quattro
Ultima spectrometer fitted with a direct injection probe (DIP) with
ionization energy set at 70 eV and HRMS (EI) were performed with
a Micromass Q-Tof Ultima spectrometer. 1H, 13C spectra were
recorded on a Bruker 200 and AV 600 spectrometer in CDCl3 with
O
OH
H
MeO
MeO
O
O H
7
8
(4h)
(4i)
85
79
H
O
F
F
MeO O
OMe
TMS as internal standard, chemical shifts (d) are reported in parts
MeO
OMe
OH
per million downfield of TMS and coupling constants (J) are
expressed in Hertz. The (E) to (Z) ratios were determined from the
relative integration of the 1H spectra for the olefinic protons. Mi-
crowave reactions were performed in crimp-capped vials using
a Biotage Initiator 2.5 reactor. Thin layer chromatography was
performed on Macherey-Nagel SIL-G/UV254 plates and column
chromatography performed over Merck 70–230 mesh silica gel.
H
O
Br
O
H
Br
O H
9
(4j)
90
77
O
O
O
10
(4k)
4.2. Synthesis of diethyl-2-trimethylsilyl-2-N,N-dimethyl-
aminomethanophosphonate 2
9
10
H
O H
Into a 20 mL flame-dried round bottom flask, containing
a magnetic stirring bar, was added diethyl-2-N,N-dimethylamino-
Significant results reported in Table 3 include the direct
conversion of piperonal (entry 1) to its high-value phenylacetate
derivative in 82% yield as well as the conversion of 4-chloro-
benzaldehyde (entry 3) to 4-chlorophenylacetic acid (4-CPA). Chiral
auxiliaries derived from both of these phenylacetate derivatives
have found extensive use in asymmetric synthesis.2 Additionally, 4-
CPA has recently been shown to inhibit estrogen-induced mam-
mary tumor formation directly,1e while other phenylacetate
derivatives are currently employed or are under investigation in
cancer chemotherapy. The direct, general synthesis of phenylacetic
acids, suitable for further elaboration, from readily available aro-
matic aldehydes is thus highly significant and should allow rapid
access to a wide range of structural analogs for further biological
investigation.
methanophosphonate 1 (500 mL, 4.13 mmol) under argon. To this
was added dry THF (8.26 mL). The contents were cooled to ꢀ78 ꢁC
and stirred for 15 min. whereupon TMS-Cl (550 mL, 4.35 mmol) was
added to the reaction flask over 5 min. Upon stirring for 30 min,
a solution of LDA (2.5 mL, 5.0 mmol, 2 M, THF) was added slowly to
the reaction flask maintained at ꢀ78 ꢁC. The flask was kept at
ꢀ78 ꢁC for 2 h and then slowly warmed to room temperature
where it was stirred for a further 6 h. The resulting mixture was
concentrated to remove solvent. Water was added (10 mL) to the
residue, and the resulting mixture was extracted with dichloro-
methane (3ꢂ15 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated. The product, Rf 0.32 (EtOAc,
pink-red to ninhydrin), was purified by silica gel column chroma-
tography (EtOAc). The silica gel was neutralized by adding five
drops of triethylamine into the initial silica gel slurry. The title
compound 2, 882.2 mg (80%), was isolated as a brown oil. 1H NMR
3. Conclusion
In conclusion, we have demonstrated that the commercially
available salt (bromomethylene)-dimethyliminium bromide 5 re-
acts with trimethylphosphite providing the 1,1-bisphosphonate
(200 MHz, CDCl3):
d
0.14 (s, 9H), 1.33 (t, JHH¼6.4 Hz, 6H), 2.38 (d,
JPH¼22.2 Hz, 1H), 2.47 (s, 6H), 4.07 (m, 4H); 13C NMR (50 MHz,
CDCl3):
d
ꢀ0.6 (d, J¼2.5 Hz), 16.5 (dd, J¼6.30, 2.5 Hz), 45.5 (d,

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J. McNulty, P. Das / Tetrahedron 65 (2009) 7794–7800
J¼3.8 Hz), 55.3 (d, J¼112.5 Hz), 60.7 (t, J¼7.8 Hz); 31P NMR (80 MHz,
CDCl3): d
17.2; HRMS (M)þ calculated for C14H21N1O3Cl1P1:
317.0948, found 317.0953.
CDCl3):
d
30.8; HRMS (M)þ calculated for C10H26N1O3SiP: 267.1421,
found: 267.1420.
4.3.4. Synthesis of 3d
4.3. Experimental procedure for the synthesis
of aminophosphonates, Table 1
Into a flame-dried flask containing a magnetic stirring bar was
weighed the a-silylphosphonate 2 (91.6 mg, 0.34 mmol). The flask
was sealed under argon whereupon dry THF (686 mL) was added to
4.3.1. Synthesis of 3a
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
Into a flame-dried flask containing a magnetic stirring bar was
s-BuLi (294 mL, 1.4 M) stock solution was added to the reaction flask
weighed the
a
-silylphosphonate 2 (74 mg, 0.278 mmol). The flask
slowly. After 40 min, a 0.5 M solution (in THF) of 4-methoxy-
benzaldehyde (50 L, 0.41 mmol) was added slowly to the reaction
was sealed under argon whereupon dry THF (556
mL) was added to
m
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC at
flask at ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and then slowly
warmed to room temperature. At the end of the reaction two new
spots were seen (UV–visible and pink-red with ninhydrin). The
product was separated using column chromatography (ethyl ace-
tate as eluant) to give 3d, 85%. Rf (AcOEt): 0.36. 1H NMR (200 MHz,
which time s-BuLi (239 mL, 1.4 M stock solution) was added slowly.
After 40 min, a 0.5 M solution (in THF) of piperonal (50 mg,
0.33 mmol) was added slowly to the reaction flask at ꢀ78 ꢁC. The
flask was kept at ꢀ78 ꢁC for 2 h and then slowly warmed to room
temperature. At the end of the reaction two spots were visible on
TLC (UV–visible and pink-red with ninhydrin). The product was
separated using column chromatography (ethyl acetate as eluant)
to give 3a, 87% (79.1 mg). Rf (AcOEt): 0.36. 1H NMR (200 MHz,
CDCl3):
d
1.36 (t, JHH¼7.2 Hz, 6H), 2.7 (d, JPH¼1.2 Hz, 6H), 3.72 (s,
3H), 4.14 (m, 4H), 6.72 (d, JPH¼14.2 Hz, 1H), 6.86 (d, JHH¼9.1 Hz, 2H),
7.65 (d, JHH¼8.7 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d 16.5 (d,
J¼5.6 Hz), 43.1, 55.2, 61.6 (d, J¼5.5 Hz), 113.6, 128.1 (d, J¼18.2 Hz),
CDCl3):
4H), 5.94 (s, 2H), 6.67 (d, JPH¼14.9 Hz, 1H), 6.75 (d, JHH¼7.8 Hz, 1H),
7.45 (s, 1H); 13C NMR (50 MHz, CDCl3):
d
1.35 (t, JHH¼7.0 Hz, 6H), 2.65 (d, JPH¼2.0 Hz, 6H), 4.13 (m,
130.3 (d, J¼34.2 Hz), 131.5, 137.3 (d, J¼179.1 Hz), 159.3; 31P NMR
(80 MHz, CDCl3):
d
18.3; HRMS (M)þ calculated for C15H25N1O4P1:
d
16.4 (d, J¼6.8 Hz), 43.1 (d,
314.1513, found 314.1521.
J¼2.3 Hz), 61.6 (d, J¼5.6 Hz), 101.1, 107.9, 109.3, 125.0, 129.4 (d,
J¼15.7 Hz), 130.9 (d, J¼31.8 Hz), 137.8 (d, J¼182.1 Hz), 147.3, 147.5;
4.3.5. Synthesis of 3e
31P NMR (80 MHz, CDCl3):
d
18.0; HRMS (M)þ calculated for
Into a flame-dried flask containing a magnetic stirring bar was
C15H22N1O5P1 327.1237, found 327.1236.
weighed the a-silylphosphonate 2 (74 mg, 0.28 mmol). The flask
was sealed under argon whereupon dry THF (555 mL) was added to
4.3.2. Synthesis of 3b
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
Into a flame-dried flask containing a magnetic stirring bar was
s-BuLi (238 mL, 1.4 M) stock solution was added to the reaction
weighed the
a
-silylphosphonate 2 (109.5 mg, 0.41 mmol). The flask
flask slowly. After 40 min, a 0.5 M solution (in THF) of 4-nitro-
benzaldehyde (50 mg, 0.33 mmol) was added slowly to the re-
action flask at ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and
then slowly warmed to room temperature. At the end of the re-
action two new spots were seen (UV–visible and pink-red with
ninhydrin). The product was separated using column chromatog-
raphy (ethyl acetate as eluant) to give 3e, 82% (74.8 mg). Rf
was sealed under argon whereupon dry THF (820 mL) was added to
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
s-BuLi (352 mL, 1.4 M) stock solution was added to the reaction flask
slowly. After 40 min, a 0.5 M solution (in THF) of benzaldehyde
(52 mg, 0.49 mmol) was added slowly to the reaction flask at
ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and then slowly
warmed to room temperature .At the end of the reaction two new
spots were seen (UV–visible and pink-red with ninhydrin). The
product was separated using column chromatography (ethyl ace-
tate as eluant) to give 3b, 67% (77.7 mg). Rf (AcOEt): 0.42. 1H NMR
(AcOEt): 0.29. 1H NMR (200 MHz, CDCl3):
d
1.37 (t, JHH¼7.7 Hz, 6H),
2.75 (s, 6H), 4.14 (m, 4H), 6.52 (d, JPH¼14.9 Hz, 1H), 7.49 (d,
JHH¼9.3 Hz, 2H), 8.15 (d, JHH¼9.3 Hz, 2H); 13C NMR (50 MHz,
CDCl3):
d
16.4 (d, J¼5.4 Hz), 43.6, 62.3 (d, J¼5.5 Hz), 119.1 (d,
(200 MHz, CDCl3):
d
1.37 (t, JHH¼7.4 Hz, 6H), 2.69 (d, JPH¼1.7 Hz,
J¼34.6 Hz), 123.4, 129.3, 142.7 (d, J¼18.5 Hz), 144.3 (d, J¼178.1 Hz),
6H), 4.15 (m, 4H), 6.7 (d, JPH¼15.4 Hz, 1H), 7.29 (m, 3H), 7.57 (d,
147.6; 31P NMR (80 MHz, CDCl3): 15.0; HRMS (Mþ) calculated for
d
JHH¼8.9 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d
16.4 (d, J¼6.4 Hz),
C14H21N2O5P1: 328.1188, found 328.1188.
43.1, 61.8 (d, J¼5.5 Hz), 127.4 (d, J¼32.1 Hz), 127.6, 129.7, 135.3 (d,
J¼14.2 Hz), 139.2 (d, J¼181.6 Hz); 31P NMR (80 MHz, CDCl3):
d
17.5;
4.3.6. Synthesis of 3f
HRMS (M)þ calculated for C14H22N1O3P1: 283.1324, found 283.1337.
Into a flame-dried flask containing a magnetic stirring bar was
weighed the a-silylphosphonate 2 (91.6 mg, 0.34 mmol). The flask
4.3.3. Synthesis of 3c
was sealed under argon whereupon dry THF (686 mL) was added to
Into a flame-dried flask containing a magnetic stirring bar was
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
weighed the
a
-silylphosphonate 2 (38 mg, 0.14 mmol). The flask
s-BuLi (238 mL, 1.4 M) stock solution was added to the reaction
was sealed under argon whereupon dry THF (300
m
L) was added to
flask slowly. After 40 min, a 0.5 M solution (in THF) of 3-nitro-
benzaldehyde (50 mg, 0.33 mmol) was added slowly to the re-
action flask at ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and
then slowly warmed to room temperature .At the end of the re-
action two new spots were seen (UV–visible and pink-red with
ninhydrin). The product was separated using column chromatog-
raphy (ethyl acetate as eluant) to give 3f, 80% (73 mg). Rf (AcOEt):
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
s-BuLi (150 mL, 1.4 M stock) solution was added to the reaction flask
slowly. After 40 min, a 0.5 M solution (in THF) of 4-chloro-
benzaldehyde (24 mg, 0.17 mmol) was added slowly to the reaction
flask at ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and then slowly
warmed to room temperature. At the end of the reaction two new
spots were seen (UV–visible and pink-red with ninhydrin). The
product was separated using column chromatography (ethyl ace-
tate as eluant) to give 3c, 80% (36.1 mg). Rf (AcOEt): 0.34. 1H NMR
0.28. 1H NMR (200 MHz, CDCl3):
d
1.37 (t, JHH¼7.2 Hz, 6H), 2.73 (d,
JPH¼1.6 Hz, 6H), 4.17 (m, 4H), 6.61 (d, JPH¼14.9 Hz, 1H), 7.46 (t,
JHH¼8.5 Hz, 1H), 7.72 (d, JHH¼6.7 Hz, 1H), 8.03 (d, JHH¼6.7 Hz, 1H),
(200 MHz, CDCl3):
d
1.35 (t, JHH¼7.3 Hz, 6H), 2.67 (d, JPH¼0.9 Hz,
8.73 (s, 1H); 13C NMR (50 MHz, CDCl3):
d
16.5 (d, J¼5.5 Hz), 43.4,
6H), 4.14 (m, 4H), 6.61 (d, JPH¼14.5 Hz, 1H), 7.27 (d, JHH¼13.2 Hz,
62.2 (d, J¼5.4 Hz), 120.2, 121.4 (d, J¼33.2 Hz), 123.5, 128.9, 137.4 (d,
2H), 7.5 (d, JHH¼13.2 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d 16.4 (d,
J¼17.2 Hz), 139.2 (d, J¼179.4 Hz), 148.4; 31P NMR (80 MHz, CDCl3):
J¼5.7 Hz), 43.2, 61.9 (d, J¼5.5 Hz), 126.2 (d, J¼35.7 Hz), 128.3, 130.8,
d
15.9 Hz; HRMS (M)þ calculated for C14H22N2O5P1: 329.1266,
133.1, 134.1 (d, J¼19.7 Hz), 140.1 (d, J¼178.6 Hz); 31P NMR (80 MHz,
found 314.1266.

J. McNulty, P. Das / Tetrahedron 65 (2009) 7794–7800
7799
4.3.7. Synthesis of 3g
JHH¼6.5 Hz, 6H), 1.30 (t, JHH¼7.1 Hz, 6H), 2.56 (s, 6H), 3.1 (m, 1H),
4.09 (m, 4H), 5.22 (dd, JPH¼42.2 Hz, JHH¼10.3 Hz, 1H); 13C NMR
Into a flame-dried flask containing a magnetic stirring bar was
weighed the
a
-silylphosphonate 2 (85 mg, 0.32 mmol). The flask
(50 MHz, CDCl3):
d
16.4 (d, J¼6.3 Hz), 23.4, 27.4, 43.8 (d, J¼6.9 Hz),
was sealed under argon whereupon dry THF (636
m
L) was added to
61.6 (d, J¼6.3 Hz), 136.0 (d, J¼24.7 Hz), 147.2 (d, J¼180.5 Hz); 31P
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
NMR (80 MHz, CDCl3) d
16.2; HRMS (M)þ calculated for
s-BuLi (273
mL, 1.4 M) stock solution was added to the reaction flask
C11H25N1O3P1 250.1565, found 250.1572. (E)-isomer: Rf (AcOEt):
slowly. After 40 min,
cinnamaldehyde (50 L, 0.38 mmol) was added slowly to the re-
a
0.5 M solution (in THF) of hydro-
0.47. 1H NMR (200 MHz, CDCl3):
d
0.99 (t, JHH¼7.6 Hz, 6H), 1.33 (t,
m
JHH¼6.9 Hz, 6H), 2.60 (d, JPH¼2.2 Hz, 6H), 2.98 (m, 1H), 4.08 (m, 4H),
action flask at ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and then
slowly warmed to room temperature .At the end of the reaction two
new spots were seen (UV–visible and pink-red with ninhydrin). The
product was separated using column chromatography (ethyl ace-
tate as eluant). The yield of the new product was 75% (74 mg). Rf
6.0 (dd, JPH¼14.2 Hz, JHH¼10.2 Hz, 1H); 13C NMR (50 MHz, CDCl3):
d
16.5 (d, J¼6.25 Hz), 22.3, 26.8 (d, J¼16.3 Hz), 44.4, 61.7 (d,
J¼7.3 Hz), 138.0 (d, J¼181.5 Hz), 148.3 (d, J¼28.9 Hz); 31P NMR
(80 MHz, CDCl3):
d
17.7; HRMS (M)þ calculated for C11H25N1O3P1:
250.1565, found 250.1572.
(AcOEt): 0.4. 1H NMR (200 MHz, CDCl3):
d
1.29 (t, JHH¼6.7 Hz, 6H),
2.55 (d, JPH¼2.1 Hz, 6H), 2.67 (m, 4H), 4.02 (m, 4H), 6.12 (dt,
4.3.10. Synthesis of 3j
Into a flame-dried flask containing a magnetic stirring bar was
weighed the a-silylphosphonate 2 (134.5 mg, 0.50 mmol). The flask
JPH¼14.9 Hz, JHH¼7.3 Hz, 1H), 7.22 (m, 5H); 13C NMR (50 MHz,
CDCl3):
d
16.4 (d, J¼6.6 Hz), 29.3 (d, J¼14.8 Hz), 34.8, 43.8, 61.5 (d,
J¼7.0 Hz), 126.0, 128.4, 138.6 (d, J¼31.1 Hz), 140.1 (d, J¼179 Hz),
was sealed under argon whereupon dry THF (1 mL) was added to
141.5; 31P NMR (80 MHz, CDCl3): 17.3 Hz; HRMS (M)þ calculated
d
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
for C16H27N1O3P1: 312.1718, found 312.1729.
s-BuLi (290 mL, 1.4 M) stock solution was added to the reaction flask
slowly. After 40 min, a 0.5 M solution (in THF) of hexanal (50 mL,
4.3.8. Synthesis of 3h
Into a flame-dried flask containing a magnetic stirring bar was
weighed the a-silylphosphonate 2 (90.5 mg, 0.34 mmol). The flask
0.41 mmol) was added slowly to the reaction flask at ꢀ78 ꢁC. The
flask was kept at ꢀ78 ꢁC for 2 h and then slowly warmed to room
temperature. At the end of the reaction two new spots were seen
(UV–visible and pink-red with ninhydrin). The product was sepa-
rated using column chromatography (ethyl acetate as eluant) to give
was sealed under argon whereupon dry THF (678 mL) was added to
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
s-BuLi (290
mL, 1.4 M) stock solution was added to the reaction
3j, 75% (103 mg). Rf (AcOEt): 0.37. 1H NMR (200 MHz, CDCl3):
(t, JHH¼7.2 Hz, 6H), 2.72 (d, JPH¼2.0 Hz, 6H), 4.13 (m, 4H), 6.45 (m,
1H), 6.73 (m, 2H), 7.41(s, 1H); 13C NMR (50 MHz, CDCl3):
16.5 (d,
d 1.33
flask slowly. After 40 min, a 0.5 M solution (in THF) of hexanal
(50 L, 0.41 mmol) was added slowly to the reaction flask at
m
d
ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and then slowly
warmed to room temperature. At the end of the reaction two new
spots were seen (UV–visible and pink-red with ninhydrin). The
two products were separated using column chromatography (ethyl
acetate as eluting solvent). The total yield was 70% (66 mg). Iso-
lated yield of the (Z)-isomer was 40% (26.3 mg) and that of the (E)-
isomer was 60% (39.7 mg). (Z)-Isomer: Rf (AcOEt): 0.48. 1H NMR
J¼6.9 Hz), 43.2, 61.9 (d, J¼5.8 Hz),112.0 (d, J¼15.1 Hz),112.4,118.7 (d,
J¼33.2 Hz), 142.4 (d, J¼187.2 Hz), 145.7, 151.0; 31P NMR (80 MHz,
CDCl3):
d
17.7; HRMS (M)þ calculated for C12H21N1O4P1: 274.1194,
found 274.1208.
4.4. General experimental procedure for phosphonoenamine
hydrolysis Table 2
(200 MHz, CDCl3):
d
0.87 (t, JHH¼4.5 Hz, 3H), 1.30 (m, 12H), 2.38
(m, 2H), 2.57 (s, 6H), 4.09 (m, 4H), 5.45 (dt, JPH¼41.8 Hz,
4.4.1. Synthesis of 30,40-(methylenedioxy)phenylacetic acid 4a
Into a flame-dried flask was weighed phosphonoenamine 3a
(50 mg, 0.158 mmol) and 3.0 mL of 48% HBr was added to the flask.
The flask was heated with a heat-gun for 10 min. The flask was
cooled immediately. Deposits were seen in the reaction flask, which
was extracted with diethyl ether (3ꢂ15 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated to yield
4a, 26.8 mg, (95%); off-white solid, mp 125–127 ꢁC; CAS registry
number [2861-28-1].9e
JHH¼9.9 Hz, 1H); 13C NMR (50 MHz, CDCl3):
d 14.0, 16.3 (d,
J¼6.0 Hz), 22.2, 28.2, 29.5, 31.5, 43.7 (d, J¼5.2 Hz), 61.6 (d,
J¼5.0 Hz), 128.7 (d, J¼28.4 Hz), 141.0 (d, J¼190 Hz); 31P NMR
(80 MHz, CDCl3):
d
16.0; HRMS (M)þ calculated for C13H29N1O3P1:
278.1885, found 278.1891. (E)-isomer: Rf (AcOEt): 0.52. 1H NMR
(200 MHz, CDCl3):
0.85 (t, JHH¼6.4 Hz, 3H), 1.30 (m, 12H), 2.23
d
(m, 2H), 2.58 (s, 6H), 4.06 (m, 4H), 6.11 (dt, JPH¼13.4 Hz,
JHH¼6.2 Hz, 1H); 13C NMR (50 MHz, CDCl3):
d 13.8, 16.4 (d,
J¼6.7 Hz), 22.4, 27.5 (d, J¼14.6 Hz), 28.3 (d, J¼2.0 Hz), 31.6, 43.8 (d,
J¼2.3 Hz), 61.4 (d, J¼5.8 Hz), 139.7 (d, J¼182.4 Hz), 140.4 (d,
4.5. Experimental procedure for the one-pot synthesis
of homologated carboxylic acid Table 3
J¼29.4 Hz); 31P NMR (80 MHz, CDCl3):
d
17.7; HRMS (M)þ calcu-
lated for C13H29N1O3P1: 278.1885, found 278.1891.
4.5.1. Synthesis of 4-nitrophenylacetic acid 4d
4.3.9. Synthesis of 3i
Into a flame-dried flask containing a magnetic stirring bar was
weighed the a-silylphosphonate 2 (134.5 mg, 0.50 mmol). The flask
Into a flame-dried microwave vial, containing a magnetic stirring
bar, was weighed (bromomethylene)-dimethyliminium bromide
(216.9 mg, 1.0 mmol) under Ar and dry THF (2 mL) added. The flask
was septa-sealed and stirred for 15 min under Ar at room temper-
was sealed under argon whereupon dry THF (1 mL) was added to
make a 0.5 M solution. The flask was stirred for 15 min at ꢀ78 ꢁC.
ature whereupon P(OMe)3 (236 mL, 2.0 mmol) was added slowly.
s-BuLi (429
mL, 1.4 M) stock solution was added to the reaction flask
After 40 min the solvent was removed under argon flow and the
concentratevacuumdriedfor 20 mingiving 6. THF (2 mL)wasadded
and the vial cooled to ꢀ78 ꢁC under Ar for 15 min whereupon LDA
slowly. After 40 min, a 0.5 M solution (in THF) of furfuraldehyde
(50
m
L, 0.60 mmol) was added slowly to the reaction flask at ꢀ78 ꢁC.
The flask was kept at ꢀ78 ꢁC for 2 h and then slowly warmed to
room temperature. At the end of the reaction two new spots were
seen (UV–visible and pink-red with ninhydrin). The two products
were separated using column chromatography (ethyl acetate as
eluant). The total yield was 70% (80 mg). Isolated yield of the (Z)-
isomer was 35% (28 mg) and that of the (E)-isomer was 65% (52 mg).
(550 mL, 1.1 mmol, 2.0 M stock, heptane/THF/ethylbenzene) was
added slowly. After 40 min a 0.5 M solution (in THF) of 4-nitro-
benzaldehyde (159 mg,1.05 mmol) was added slowly to the reaction
flask maintained at ꢀ78 ꢁC. The flask was kept at ꢀ78 ꢁC for 2 h and
then slowly warmed to room temperature where it was stirred for
a further 2 h. The THF was removed under Ar and 3 mL of 48% HBr
was added to the residue. The vial was now crimp-capped and
(Z)-isomer: Rf (AcOEt): 0.42. 1H NMR (200 MHz, CDCl3):
d 0.95 (t,

7800
J. McNulty, P. Das / Tetrahedron 65 (2009) 7794–7800
irradiated in the microwave at 100 ꢁC for 3 min. The resulting mix-
ture was extracted with diethylether (3ꢂ15 mL). The combined or-
ganic layers were partitioned with 10 mL of (10% w/v) aqueous
NaOH allowing clean phase separation (15 min). The ether was
extracted with water (2ꢂ10 mL). The combined aqueous layers were
carefully acidified (10% w/v aqueous HCl) and the resulting mixture
was extracted with diethyl ether (3ꢂ15 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated to yield 4d,
159.4 mg, (88%) as ayellowsolid. Mp 149–150 ꢁC.1HNMR (200 MHz,
1H), 7.58 (d, JHH¼7.8 Hz, 1H); 13C NMR (50 MHz):
d 41.8, 124.1, 127.8,
129.0, 131.8, 132.6, 132.7, 177.7.
4.5.11. Tridecanoic acid (4k)
Yield 77%. 1H NMR (200 MHz, CDCl3):
d 0.90 (m, 3H); 1.20–1.40
(m, 18H), 1.63 (m, 2H), 2.36 (t, JHH¼7.3 Hz, 2H); 13C NMR (50 MHz,
CDCl3):
d
14.1, 22.7, 24.8, 29.3, 29.6, 31.9, 34.1, 177.2; HRCI MS (M)þ
calculated for C13H26O2: 214.1933, found: 214.1929.
CDCl3):
d
3.79 (s, 2H), 7.47 (d, JHH¼8.0 Hz, 2H), 8.20 (d, JHH¼8.0 Hz,
2H); 13C NMR (50 MHz, CDCl3):
d 40.7,123.9,130.5,140.4,147.4,176.1.
Acknowledgements
CAS registry number [104-03-0].9d
We thank NSERC, Cytec Canada Inc. and McMaster University for
financial support of this work.
4.5.2. 3,4-(Methylenedioxy)phenylacetic acid (4a)9e
Mp 125–127 ꢁC (lit.4o 125–127 ꢁC); yield 82%. 1H NMR
(200 MHz, CDCl3): d C
3.57 (s, 2H), 5.91 (s, 2H), 6.71–6.81 (m, 3H); 13
NMR (50 MHz, CDCl3):
177.6.
d 41.4, 107.8, 109.3, 123.2, 127.7, 146.8, 147.9,
References and notes
1. Over 20 marketed pharmaceuticals are phenylacetic acid derivatives including
diclofenac (anti-arthritic), ibufenac (anti-inflammatory), ritalin (anti-ADHD),
homovanillic acid (schizophrenia), propanidid (anesthetic) guanfacine (antihy-
pertensive), and 4-chlorophenylacetic acid (anti-neoplastic). For a selection of
examples see: (a) Failli, A. A.; Kreft, A. F.; Musser, J. H. U.S. Patent 5,021,576, 1991;
(b) Nahar, L.; Russel, W. R.; Middleton, M.; Shoeb, M.; Sarker, S. D. Acta Pharm.
2005, 55, 187–193; (c) Santini, C.; Berger, G. D.; Han, W.; Mosley, R.; MacNaul, K.;
Berger, J.; Doebber, T.; Wu, M.; Moller, D. E.; Tolman, R. L.; Sahoo, S. P. Bioorg.
Med. Chem. Lett. 2003, 13, 1277–1280; (d) Rakowitz, D.; Gmeiner, A.; Schroder, N.;
Matuszczak, B. Eur. J. Pharm. Sci. 2006, 27, 188–193; (e) Sidell, N.; Kirma, N.;
Morgan, E. T.; Nair, H.; Tekmal, R. R. Cancer Lett. 2007, 251, 302–310.
2. For a selection of synthetic applications see: (a) Gore, M. P.; Vederas, J. C. J. Org.
Chem. 1986, 51, 3700–3704; (b) Prashad, M.; Kim, H. Y.; Har, D.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 1998, 39, 9369–9372; (c) Wittenberger, S. J.;
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G.; Key, M. S.; Nicholson, R. L.; Savory, E. D. Chem. Commun. 2000, 1721–1722;
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Prod. 2008, 71, 357–363.
4.5.3. Phenylacetic acid (4b)9a
Mp 75–77 ꢁC (lit.4n 76–78 ꢁC); yield 83%. 1H NMR (200 MHz,
CDCl3): 41.4,
3.61 (s, 3H), 7.18–7.39 (m, 5H); 13C NMR (50 MHz):
d
d
127.0, 128.5, 129.5, 133.0, 177.9.
4.5.4. 4-Chlorophenylacetic acid (4c)9c
Mp 104–105 ꢁC (lit.4n 104–106 ꢁC); yield 80%. 1H NMR
(200 MHz, CDCl3): 3.61 (s, 3H), 7.24–7.30 (m, 4H); 13C NMR
(50 MHz):
d 40.4, 128.9, 130.8, 131.7, 133.5, 177.3.
4.5.5. 3-Nitrophenylacetic acid (4e)
Mp 117–118 ꢁC (lit.4n 118–120 ꢁC); yield 80%. 1H NMR (200 MHz,
CDCl3):
CDCl3):
d
3.51 (s, 2H), 7.43 (m, 2H), 7.98 (m, 2H); 13C NMR (50 MHz,
47.1, 119.7, 125.1, 130.3, 135.6, 140.0, 148.6, 176.9.
d
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4.5.6. Heptanoic acid (4f)9g
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hedron 2005, 61, 5671–5677; (o) McNulty, J.; Das, P.; Gosciniak, D. Tetrahedron
Lett. 2008, 49, 281–285; (p) Cafiero, L. R.; Snowden, T. S. Org. Lett. 2008, 10,
3853–3856.
Yield 75%. 1H NMR (200 MHz, CDCl3):
d 0.89 (m, 3H), 1.20–1.40
(m, 6H), 1.63 (m, 2H), 2.34 (t, JHH¼7.4 Hz, 2H); 13C NMR (50 MHz,
CDCl3):
d 14.0, 22.7, 24.7, 28.7, 31.4, 34.3, 180.5.
4.5.7. 4-Methoxyphenylacetic acid (4g)9f
Mp 84–86 ꢁC (lit.4n 85–87 ꢁC); yield 80%. 1H NMR (200 MHz,
CDCl3):
d
3.63 (s, 2H), 3.77 (s, 3H), 6.83 (d, JHH¼7.7 Hz, 2H), 7.22 (d,
JHH¼7.7 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d 40.1, 56.2, 114.5, 125.6,
130.4, 159.0, 178.2.
4.5.8. 4-Fluorophenylacetic acid (4h)9c
Mp 83–84 ꢁC (lit.4n 82–85 ꢁC); yield 85%. 1H NMR (200 MHz,
d
3.61 (s, 2H), 7.03–7.23 (m, 4H); 13C NMR (50 MHz, CDCl3):
5. This reagent is available from the Aldrich Chemical Company.
CDCl3):
40.1, 115.6, 128.7, 130.9, 160.9, 177.5.
6. (a) Degenhardt, C. R. Synth. Commun. 1982, 12, 415–421; (b) Dufrechou, S.;
Combret, J. C.; Malhiac, C.; Collignon, N. Phosphorus Sulfur Silicon Relat. Elem.
1997, 127, 1–14.
d
7. (a) van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195–200;
(b) Padwa, A.; Eisenbarth, P.; Venkataramana, M. K.; Wong, G. S. K. J. Org. Chem.
1987, 52, 2427–2432.
4.5.9. 2,3-Dimethoxyphenylacetic acid (4i)
Mp 82–83 ꢁC (lit.9h 84 ꢁC); yield 79%. 1H NMR (200 MHz, CDCl3):
d
3.81 (s, 2H), 3.87 (s, 3H), 4.0 (s, 3H), 7.12 (d, JHH¼7.5 Hz, 2H), 7.57
8. Zumstein, F; Klingseisen, F. Ger. Offen DE 4029444 A1, 1990.
(m, 1H); 13C NMR (50 MHz, CDCl3):
d 35.6, 56.7, 60.6, 117.4, 122.6,
9. (a) Zhou, G. B.; Zhang, P. F.; Pan, Y. J. Tetrahedron 2005, 61, 5671–5677;
(b) Adamczyk, M.; Watt, D. S. J. Org. Chem. 1984, 49, 4226–4237; (c) Milne, J. E.;
Murry, J. A.; King, A.; Larsen, R. D. J. Org. Chem. 2009, 74, 445–447; (d) Ando, A.;
Miki, T.; Kumadaki, I. J. Org. Chem. 1988, 53, 3637–3639; (e) Moreira, D. R. M.;
Lima-Leite, A. C.; Pinheiro-Ferreira, P. M.; da Costa, P, M.; Costa-Lotufo, L. V.; de
Moraes, M. O.; Brondani, D. J.; Pessoca, C. O. Eur. J. Med. Chem. 2007, 42, 351–357;
(f) Li, P.; Alper, H. J. Org. Chem. 1986, 51, 4354–4356; (g) Niu, D. F.; Xiao, N. L. P.;
Zhang, A. J.; Zhang, G. R.; Tan, Q. Y.; Lu, J. X. Tetrahedron 2008, 64, 10517–10520;
(h) Chakravarti, S.; Swaminathan, M. Indian J. Chem. 1934, 11, 107–113.
123.5, 124.8, 152.5, 167.1, 177.6; HRCI MS (M)þ calculated for
C10H12O4: 196.0736, found: 196.0745.
4.5.10. 2-Bromophenylacetic acid (4j)9b
9b
Mp 103–105 ꢁC (lit.
103–105 ꢁC); yield 90%. 1H NMR
(200 MHz, CDCl3): 3.81 (s, 3H), 7.12 (m, 2H), 7.29 (d, JHH¼7.8 Hz,