A mild, selective, PyBOP mediated procedure for the conversion of primary Amines into phthalimides

Article abstract of DOI:10.1055/s-1998-2038

A new method for the protection of primary amines or amino alcohols as phthalimides is described. The phthaloyl group is selectively introduced under mild, anhydrous conditions by reacting the amine with 2- (ethoxycarbonyl)benzoic acid activated by PyBOP, followed by the thermally induced cyclization of the resulting phthalamic ester. These reaction conditions are applicable to a variety of primary amines and good yields are obtained in all cases.

Full text of DOI:10.1055/s-1998-2038

March 1998
SYNTHESIS
313
A Mild, Selective, PyBOP Mediated Procedure for the Conversion of Primary Amines
into Phthalimides
Núria Aguilar, Albert Moyano,* Miquel A. Pericàs,* Antoni Riera
Unitat de Recerca en Síntesi Asimètrica (URSA), Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona,
Martí i Franquès 1-11, E-08028 Barcelona, Spain
Fax +34(3)3397878; E-mail: amb@ursa.qo.ub.es; mpb@ursa.qo.ub.es.
Received 30 July 1997; revised 11 September 1997
Abstract: A new method for the protection of primary amines or
amino alcohols as phthalimides is described. The phthaloyl group
is selectively introduced under mild, anhydrous conditions by
reacting the amine with 2-(ethoxycarbonyl)benzoic acid activated
by PyBOP, followed by the thermally induced cyclization of the
resulting phthalamic ester. These reaction conditions are applica-
ble to a variety of primary amines and good yields are obtained in
all cases.
amines, including the aminodiol 1a, were directly con-
verted into the corresponding phthalimides in good to ex-
cellent yields. Although 2-(methoxycarbonyl)benzoic
acid can be also used for this transformation, it gives uni-
formly lower yields, probably due to the diminished sta-
bility of the active benzotriazolyl ester (see below).
BOP (benzotriazol-1-yloxytris(dimethylamino)phospho-
nium hexafluoro phosphate)8 and PyBOP (benzotriazol-
1-yloxytripyrrolidinophosphonium hexafluoro phos-
phate)9 are coupling reagents commonly used in peptide
synthesis. The mild, neutral conditions under which these
reagents promote the formation of amide bonds led us to
think that they could overcome the difficulties encoun-
tered in the reaction of 1a with 2-(alkoxycarbonyl)benzo-
ic acids. In fact, the treatment of a THF suspension of the
aminodiol 1a with a mixture of PyBOP,10 ethyldiisopro-
pylamine and 2-(ethoxycarbonyl)benzoic acid in THF
(which, following the procedure of Kim and Patel,11 had
been previously stirred at room temperature for 40 min-
utes in order to ensure the complete formation of the ac-
tive benzotriazolyl ester) resulted in the conversion of 1a
into the corresponding phthalamic ester 3a after a few
hours of stirring at room temperature, as demonstrated
both by TLC and by 1H NMR of reaction aliquots. Proba-
bly, the completely non-nucleophilic character of the
hexafluorophosphate anion and the totally neutral react-
ing medium avoid the undesired side reactions previously
observed. In addition to that, we were most pleased to find
that the cyclization of the phthalamic ester 3a to the
phthalimide 2a could be effected in situ by heating the
mixture to reflux in the presence of a catalytic amount
of p-toluenesulfonic acid. In this way, after chromato-
graphic purification, pure 2a was obtained in 82% yield
from 1a.
Key words: phthalimides, primary amines, amine alcohols,
PyBOP, 2-(ethoxycarbonyl)benzoic acid
The use of phthalimides as primary amine protecting
groups is extensively documented in the chemical litera-
ture, especially for a-amino acids.1 Recently, in connec-
tion with our work on the synthetic applications of
enantiomerically enriched 3-amino-1,2-diols,2 we wanted
to transform (2S,3S)-3-aminobutane-1,2-diol (1a) into the
corresponding phthalimide 2a, in order to temporarily sup-
press the reactivity of the amine hydrogens (Scheme 1).
Scheme 1
In spite of the apparent simplicity of this process, several
of the described synthetic methods for the protection of
primary amines as phthalimides proved not to be adequate
for our purposes. Those in which phthalic anhydride was
used to introduce the phthalimide function and required
the use of harsh reaction conditions (boiling ethyl acetate,
acetic acid or solid fusion)3 led to complex mixtures of
products in which both the amino and hydroxyl groups
had reacted. Moreover, the insolubility of the aminodiol
1a in relatively nonpolar solvents such as toluene or chlo-
roform interfered with other milder, phthalic anhydride-
based procedures.4 Likewise, the use of 2-(methoxycarbo-
nyl)- and 2-(ethoxycarbonyl)benzoic acids5,6 under many
of the most common activating conditions,7 gave access to
2a only in moderate to low yields, probably due to side re-
actions of the substrate with the activating reagents.
Besides providing a unique solution for the selective pro-
tection of 1a and other related 3-amino-1,2-alkanediols,
this protocol (with slight modifications) proved to be ap-
plicable for the conversion of several primary amines 1 b–
h into their phthalimides 2b–h (Scheme 2). The results are
summarized in the Table.
Whereas several functionalized primary amines were eas-
ily protected as phthalimides in excel]ent yields (entries
1–5) and even in some cases (entries 3 and 4) p-TsOH ca-
ta]ysis was not necessary for the cyclization step (method
A), with other amines (entries 6–8) better results were ob-
tained when the intermediate phthalamic ester was isolat-
ed and submitted to cyclization in a higher boiling point
solvent (toluene, method B). In this way, all phthalimides
were obtained in good to excellent overall yields. Even the
We report in this paper a new method for the preparation
of phthalimides from the corresponding primary amines,
based on the PyBOP-promoted reaction of the amine with
2-(ethoxycarbonyl)benzoic acid, followed by cyclization
of the intermediate phthalamic ester. Under these condi-
tions, a variety of diversely functionalized primary most bulky amine, tert-butylamine, could be converted to

314
Papers
SYNTHESIS
Table. PyBOP-Mediated Conversion of Primary Amines into Phthal-
imides
the corresponding phthalimide in a satisfactory 67% over-
all yield.
Entry
1
Phthalimide
Methoda
A
Yield
(%)
In summary, we have disclosed in this paper a new and ef-
ficient method for the direct synthesis of phthalimides
from primary amines, which takes place under mild con-
ditions and is compatible with several functional groups.
2a
82
Optical rotations were measured at r.t. (23°C) on a Perkin-Elmer 241
MC Polarimeter. IR spectra were recorded on a Perkin-Elmer 681
spectrometer. 1H NMR (200 MHz) and 13C NMR (50.3 MHz) spectra
were recorded in CDCl3, on a Varian Gemini-200 spectrometer with
TMS or CHCl3 as internal standard. J values are given in Hz. Signal
multiplicities in 13C spectra were established by DEPT experiments.
In all cases, chemical shifts are in ppm downfield to TMS. Mass spec-
tra were recorded at 70 eV ionizing voltage; NH3 or CH4 were used
for chemical ionization (CI). THF was distilled from sodium/ben-
zophenone ketyl and toluene was dried over sodium. All reactions
were performed in flame-dried glassware under Ar atmosphere. Re-
action progress was followed by TLC (Merck DC-Alufolien Kiesel-
gel 60 F254). Silica gel (J. T. Baker, 70–230 mesh) was used for
column chromatography. Compounds 2a, 2c, 2g, 3f, 3g and 3h gave
satisfactory combustion analyses.
2
3
2b
2c
A
84
91
Ab
4
5
2d
2e
Ab
A
86
77
6
7
2f
B
87
(2S,3S)-3-(Phthalimido)butane-1,2-diol (2a); Typical Procedure
for Method A:
2g
2h
B
B
80
67
To a suspension of PyBOP (0.513 g, 0.98 mmol, 1.1 equiv) in THF
(1 mL) were sequentially added a solution of 2-(ethoxycarbonyl)ben-
zoic acid (0.200 g, 1.03 mmol, 1.1 equiv) in THF (1 mL) and NEt(Pr-
i)2 (0.23 mL, 1.35 mmol, 1.5 equiv) and the resulting mixture was
stirred for 40 min. at r. t. This solution was subsequently added via
cannula to a suspension of 1a (94 mg, 0.90 mmol) in THF (1 mL) and
the mixture was stirred at r. t. for 2–3 h. At this point, p-TsOH (4–5
mg) was added and the mixture was heated to reflux overnight. After
cooling to r. t„ the mixture was poured into aq sat. NaHCO3 solution
(10 mL) and extracted with EtOAc (2 ´ 20 mL). The combined organ-
ic layers were dried (Na2SO4) and evaporated to give a crude product
which was purified by column chromatography on silica gel (hexane/
EtOAc, 2:1) to afford 0.172 g of 2a (82%) as a white solid; mp 80–
83°C; [a]D –8.4 (c = 1.3, CHCl3).
8
a
Method A: 1.1 equiv of PyBOP, 1.1 equiv of 2-(ethoxycarbon-
yl)benzoic acid and 1.5 equiv of NEt(Pr-i)2 in THF were stirred for
30–40 min. at r.t. The amine (1 equiv) was added and the mixture was
stirred at r.t. for 2–3 h. A catalytic amount (4–5 mg/mmol) ofp-TsOH
was added and the mixture was refluxed overnight. Method B: The in-
termediate phthalamic ester was isolated and submitted to cyclization
in refluxing toluene with a catalytic amount of p-TsOH.
b No p-TsOH was added in this case (see experimental section).
IR (KBr): n = 3580–3480, 2930, 1775, 1700, 1390, 1065, 870,
720 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.47 (d, J = 7 Hz, 3 H), 3.08 (br s,
2 H), 3.58–3.71 (m, 2 H,), 4.02–4.18 (m, 1 H), 4.38–4.48 (m, 1 H),
7.78 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 13.9 (CH3), 48.6 (CH), 63.7 (CH2),
72.7 (CH), 123.3 (CH), 131.5 (Cq), 134.1 (CH), 168.7 (Cq).
MS (CI–CH4): m/z (%) = 276 (M+41+, 10), 264 (M+29+, 15), 236
(M+1+, 100), 218 (M–H2O+1+, 17), 200 (M–2H2O+1+, 1), 174 (M–
C2H5O2+1+, 1).
(R)-2-Phenyl-2-(phthalimido)ethanol (2b):
The typical procedure described above was used with the following
reagents and amounts: PyBOP (0.418 g,0.80 mmol, 1.1 equiv) in THF
(1 mL), 2-(ethoxycarbonyl)benzoic acid (0.156 g, 0.80 mmol, 1.1
equiv) in THF (1 mL), NEt(Pr-i)2 (0.205 mL, 1.204 mmol, 1.5 equiv)
and 1b (0.100 g, 0.73 mmol) in THF (1.5 mL). After purification of
the crude product by column chromatography on silica gel (hexane/
EtOAc, 2:1), 0.164 g of 2b (84%) was obtained as a colorless oil; [a]D
+39.8 (c = 3.9, CHCl3).
IR (film): 4n = 3400 (br), 3050, 2940, 2880, 1770, 1700 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.94 (s, 1 H), 4.19 (dd, JAM
=
11.4 Hz, JAX = 5.2 Hz, 1 H), 4.66 (dd, JMX = 9.2 Hz, JAX = 5.2 Hz, 1
H), 5.46 (dd, JAM = 11.4 Hz, JMX = 9.2 Hz, 1 H), 7.29–7.43 (m, 5
H), 7.71 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 58.0 (CH), 62.4 (CH2), 123.8 (CH),
128.5 (CH), 128.7 (CH), 129.2 (CH), 132.2 (Cq), 134.6 (CH), 137.3
(Cq), 169.4 (Cq).
MS (EI): m/z (%) = 249 (M+–H2O, 1), 236 (M+–CH2OH, 100).
Scheme 2

March 1998
SYNTHESIS
315
13C NMR (50 MHz, CDCl3): d = 14.0 (CH3), 21.7 (CH3), 49.2 (CH),
61.4 (CH2), 126.3 (CH), 128.6 (CH), 129.5 (CH), 129.5 (Cq), 130.0
(CH), 131.6 (CH), 138.0 (Cq), 143.0 (Cq), 166.8 (Cq), 168.2 (Cq,).
MS (CI–NH3): m/z(%) = 298 (M+1+, 100), 315 (M+18+, 79).
(±)-Methyl 3-Phenyl-2-(phthalimido)propionate (2c):
The typical procedure described for 1 was used with the following re-
agents and amounts: PyBOP (0.240 g, 0.46 mmol, 1.1 equiv) in
THF(1 mL), 2-(ethoxycarbonyl)benzoic acid (0.089 g, 0.46 mmol,
1.1 equiv) in THF (1 mL), NEt(Pr-i)2 (0.105 mL, 0.63 mmol, 1.5
equiv) and 1c (0.075 g, 0.42 mmol) in THF (0.5 mL). In this case no
p-TsOH was added before refluxing. Purification of the reaction
crude by column chromatography on silica gel (hexane/EtOAc, 9:1)
gave 0.117 g of 2c (91%) as a white solid; mp 89–91°C.
IR (KBr): n = 3060, 3020, 2910, 2940, 2880, 1770, 1755, 1710, 1390,
720 cm–1.
b) Conversion of 3f to 2f: To a solution of 3f (0.086 g, 0.29 mmol) in
anhyd toluene (15 mL) was added p-TsOH (3–4 mg) and the mixture
was refluxed for 2 h. After cooling to r.t., the mixture was successive-
ly washed with sat. aq NaHCO3 solution (10 mL), brine (2 ´ 10 mL)
and dried (Na2SO4). The solvent was evaporated in vacuo to afford
0.072 g of 2f (99%) as a dense colorless oil (Lit.14 mp 43–44°C). The
overall yield for both steps is 87%.
1H NMR (200 MHz, CDCl3): d = 3.45–3.65 (m, 2 H), 3.79 (s, 3 H),
5.09–5.21 (m, 1 H), 7.17 (s, 5 H), 7.73 (m, 4 H).
IR (film): n = 3480, 3080, 3060, 2950, 1775, 1730, 1620, 1500, 730,
13C NMR (50 MHz, CDCl3): d = 34.6 (CH2), 52.9 (CH), 53.2 (CH3),
123.4 (CH), 126.8 (CH), 128.5 (CH), 128.7 (CH), 131.5 (Cq), 134.0
(CH), 136.6 (Cq), 167.4 (Cq), 169.3 (Cq).
710 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.96 (d, J = 7.2 Hz, 3 H), 5.59 (q, J
= 7.2 Hz, 1 H), 7.30 (m, 3 H), 7.51 (m, 2 H), 7.75 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 17.5 (CH3), 49.6 (CH), 123.1 (CH),
127.4 (CH), 127.6 (CH), 128.4 (CH), 131.9 (Cq), 133.8 (CH), 140.2
(Cq), 168.1 (Cq).
MS (EI): m/z (%) = 309 (M+, 3), 250 (M+–CO2CH3 15), 232 (M+–Ph,
6), 218 (M+–C6H6CH2, 4), 162 (M+–PhthH, 100).
MS (CI–NH3): m/z (%) = 252 (M+1+, 4), 269 (M+18+, 100), 286
(M+35+, 4).
N-(2-Methoxyethyl)phthalimide (2d):
The typical procedure described for 1 was used with the following re-
agents and amounts: PyBOP (0.332 g, 0.64 mmol, 1.1 equiv) in THF
(2 mL), 2-(ethoxycarbonyl)benzoic acid (0.124 g, 0.64 mmol, 1.1
equiv) in THF (2 mL), NEt(Pr-i)2 (0.15 mL, 0.87 mmol, 1.5 equiv)
and freshly distilled 1d (50 mL, 0.58 mmol). In this case no p-TsOH
was added before refluxing. After purification of the reaction crude
by column chromatography on silica gel (hexane/EtOAc, 9:1),
0.103g of 2d (86%) was obtained as a white solid; mp 147–148°C
(Lit.12 mp 147–148°C).
N-Cyclohexylphthalimide (2g):
a) The typical procedure described for the preparation of 2f was used
with the following reagents and amounts: PyBOP (0.25 g, 0.48 mmol,
1.1 equiv) in THF (1.3 mL), 2-(ethoxycarbonyl)benzoic acid
(0.093 g, 0.48 mmol, 1.1 equiv) in THF (1 mL), NEt(Pr-i)2 (0.11 mL,
0.65 mmol, 1.5 equiv) and freshly distilled 1g (50 mL). After purifi-
cation of the crude material by column chromatography on silica gel
(hexane/EtOAc, 4:1), 0.103 g of 3g (86%) was obtained as a white
solid; mp 121–124°C.
1R (KBr): n = 3040, 2950, 2880, 1770, 1705, 1390, 1115, 1030, 730
cm–1.
1H NMR (200 MHz, CDCl3): d = 3.35 (s, 3 H), 3.64 (t, J = 5.6 Hz, 2
H), 3.90 (t, J = 5.6 Hz, 2 H), 7.78 (m, 4 H).
IR (KBr): n = 3270, 3070, 3000, 2920, 2860, 1725, 1640, 1600, 1580,
1550, 1300, 1140, 715 cm–1.
13C NMR (50 MHz, CDCl3): d = 37.2 (CH2), 58.5 (CH3), 69.9 (CH2),
123.2 (CH), 132.0 (Cq), 134.8 (CH), 168.2 (Cq).
1H NMR (200 MHz, CDCl3): d = 1.12–1.82 (m, 13 H), 2.02–2.17 (m,
2 H), 3.87–4.05 (m, 1 H), 4.35 (q, J = 7Hz, 2 H), 5.78 (br d, 1 H),
7.38–7.56 (m, 3 H), 7.80–7.89 (m, 1 H).
EM (CI–NH3): m/z (%) = 206 (M+1+, 13), 223 (M+18+, 100), 240
(M+35+, 8).
13C NMR (50 MHz, CDCl3): d = 14.1 (CH3), 24.8 (CH2), 25.5 (CH2),
32.2 (CH2), 48.7 (CH2), 61.4 (CH2), 127.6 (CH), 129.5 (Cq), 129.9
(CH), 131.7 (CH), 138.5 (Cq), 166.7 (Cq), 168.3 (Cq).
MS (C1–NH3): m/z (%) = 276 (M+1+, 100), 293 (M+18+, 26).
N-Butylphthalimide (2e):
The typical procedure described for 1 was used with the following re-
agents and amounts: PyBOP (0.291 g, 0.55 mmol, 1.1 equiv) in THF
(1.7 mL), 2-(ethoxycarbonyl)benzoic acid (0.108 g, 0.55 mmol, 1.1
equiv) in THF (2 mL), NEt(Pr-i)2 (0.13 mL, 0.76 mmol, 1.5 equiv) and
freshly distilled 1e (50 mL, 0.50 mmol). After purification of the crude
material by column chromatography on silica gel (hexane/EtOAc,
19:1), 79 mg of 2e (77%) was obtained as a colorless oil; Lit.13, oil.
IR (film): n = 3430, 2950, 2880, 1780, 1715, 1400, 1055, 720 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7 Hz), 2.58–2.75 (m, 2
H), 3.69 (t, J = 7.4 Hz, 2 H), 4.39 (m, 2 H), 7.69–7.86 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 20.0 (CH2), 30.6 (CH2),
37.7 (CH2), 123.1 (CH), 132.1 (Cq), 133.8 (CH), 168.4 (Cq).
b) To a solution of 3g (0.076 g, 0.28 mmol) in anhyd toluene (6 mL),
was added p-TsOH (3–4 mg) and the mixture was refluxed for 4 h.
After cooling to r.t., the mixture was successively washed with sat. aq
NaHCO3 solution (10 mL), brine (10 mL) and dried (Na2SO4). The
solvent was evaporated in vacuo to give 0.060 g of 2g (94%); mp
159–161°C. The overall yield for both steps is 80%.
IR (KBr): n = 3410, 2910, 2840, 1765, 1705, 1610, 1465, 1390, 1375,
710 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.22–1.47 (m, 4 H), 1.71–1.93 (m,
4 H), 2.15–2.36 (m, 2 H, J = 5.6 Hz), 4.10 (tt, J = 10, 3 Hz), 7.75 (m,
4 H).
(±)-N-(1-Phenylethyl)phthalimide (2f); Typical Procedure for
Method B:
13C NMR (50 MHz, CDCl3): d = 25.1 (CH2), 26.0 (CH2), 29.8 (CH2),
50.8 (CH), 122.9 (CH), 132.0 (Cq), 133.7 (CH), 168.4 (Cq).
MS (CI–NH3): m/z (%) = 230 (M+1+, 9), 247 (M+18+, 100), 264
(M+35+, 33).
a) Ethyl (±)-2-[N-(1-Phenyl)ethylcarbamoyl]benzoate (3f): To a sus-
pension of PyBOP (0.449 g, 0.86 mmol, 1.1 equiv) in THF (2 mL)
were sequentially added a solution of 2-(ethoxycarbonyl)benzoic acid
(0.167 g, 0.86 mmol, 1.1 equiv) in THF (1 mL) and NEt(Pr-i)2
(0.20 mL, 1.18 mmol, 1.5 equiv) and the resulting mixture was stirred
for 40 min at r.t. Subsequently, freshly distilled 1f (100 mL) was added
and the mixture stirred at r.t. for 30 min. The mixture was then poured
into aq sat. NaHCO3 solution (10 mL) and extracted with CH2Cl2
(3 ´ 20 mL). The combined organic layers were dried (Na2SO4) and
evaporated in vacuo to give the crude product which was purified by
column chromatography on silica gel (hexane/EtOAc, 2:1) to give
0.206 g (88%) of (3f) as a white solid; mp 95–97°C.
N-tert-Butylphthalimide (2h):
a) The procedure described for the preparation of 2f was used with the
following reagents and amounts: PyBOP (0.546 g, 1.05 mmol, 1.1
equiv) in THF (1.3 mL), 2-(ethoxycarbonyl)benzoic acid (0.206 g,
1.05 mmol, 1.1 equiv) in THF (4 mL), NEt(Pr-i)2 and freshly distilled
1h (100 mL, 0.95 mmol). After purification of the crude product by
column chromatography on silica gel (hexane/EtOAc, 4:1), 0.207 g of
3h (87%) was obtained as a white solid; mp 79–81°C.
IR (KBr): n = 3260, 3060, 2970, 1720, 1640, 1600, 1580, 1545, 1300,
1135, 740 cm–1.
IR (KBr): n = 3340, 3080, 2980, 1740, 1635, 1600, 1580, 1560, 1300,
1260, 700 cm–1.
1H NMR (200 MHz, CDCl3):d = 1.26 (t, J = 7 Hz, 3 H), 1.59 (d, J =
7 Hz, 2 H), 4.27 (q, J = 7 Hz, 2 H), 5.32 (q, J = 7 Hz, 1 H), 6.12 (br d,
1 H), 7.25–7.49 (m, 8 H), 7.80–7.89 (m, 1 H).
1H NMR (200 MHz, CDCl3): d = 1.36 (t, J = 7 Hz, 3 H), 1.47 (s, 9 H),
4.35 (q, J = 7 Hz), 5.52 (br d, 1 H), 7.39–7.56 (m, 3 H), 7.81–7.86 (m,
1 H).

316
Papers
SYNTHESIS
13C NMR (50 MHz, CDCl3): d = 14.1 (CH3), 28.7 (CH3), 51.8 (Cq),
61.4 (CH2), 127.5 (CH), 129.2 (CH), 129.5 (Cq), 129.8 (CH), 131.5
(CH), 139.0 (Cq), 166.9 (Cq), 168.5 (Cq).
(3) (a) Chapman, D. W.; Roth, R. W. J. Am. Chem. Soc. 1948, 70,
1473.
(b) Sheehan, J. C.; Frank, V. S. J. Am. Chem. Soc. 1949, 71,
1856.
MS (CI–NH3): m/z(%) = 250 (M+1+, 100), 267 (M+18+, 30).
(c) Sheehan, J. C.; Chapman, D. W.; Roth, R. W. J. Am. Chem.
Soc. 1952, 74, 3822.
(d) Sasaki, S.; Minamoto, T.; 1tock, H. J. Org. Chem. 1978, 43,
2321.
(e) Baker, B. R.; Joseph, J. P.; Schaub, R. E.; Williams, J. H. J.
Org. Chem. 1954, 19, 1786.
(f) Bose, A. K.; Greer, F.; Price, C. C. J. Org. Chem. 1958, 23,
1332.
b) To a solution of 3h (0.083 g, 0.33 mmol) in anhyd toluene (15 mL)
was added p-TsOH (3–4 mg) and the mixture was refluxed for 4 h.
After cooling to r.t., the mixture was washed with sat. aq NaHCO3 so-
lution (10 mL) and brine (2 ´ 10 mL), and dried (Na2SO4). The sol-
vent was evaporated and the crude product was purified by column
chromatography on silica gel (hexane/EtOAc, 19:1) to give 0.052 g of
2h (77% yield) as a white solid. Overall yield 67%; mp 58–59°C
(Lit15 mp 58–59°C).
(g) King, F. E.; Kidd, D. A. A. J. Chem. Soc. 1949, 3315.
(4) Sheehan, J. C.; Guziec, F. S. J. Org. Chem. 1973, 38, 3034.
For a recent related procedure, see:
IR (KBr): n = 3460, 3000, 2940, 1775, 1715, 1470, 1370, 1320, 1105,
1025, 710 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.70 (s, 9 H), 7.75 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 29.0 (CH3), 57.8 (Cq), 122.5 (CH),
132.1 (Cq), 133.7 (CH), 168.4 (Cq).
Reddy, P. Y.; Kondo, S.; Toru, T.; Ueno, Y. J. Org. Chem.
1997, 62, 2652.
(5) Hoogwater, D. A.; Reinhoudt, D. N.; Lie, T. S.; Gunneweg, J.
J.; Beyerman, H. C. Rec. Trav. Chim. Pays-Bas 1973, 92, 819.
(6) 2-(Ethoxycarbonyl)benzoic acid is obtained in essentially quan-
titative yield by refluxing phthalic anhydride in absolute etha-
nol: Beilstein, H 9, 797b.
EM (CI–NH3): m/z (%) = 204 (M+1+, 18), 221 (M+18+, 100), 238
(M+35+, 42).
(7) (a) Vorbrüggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49,
9353.
We thank the “Dirección General de Investigación Científica y Téc-
nica” (PB93-0806) for the financial support, and Dr. F. Albericio for
a generous gift of PyBOP. N. A. is grateful to CIRIT (Generalitat de
Catalunya) for a pre-doctoral fellowship.
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