Microwave-assisted neat procedure for the petasis reaction

Article abstract of DOI:10.1055/s-0029-1218727

A new solvent-free microwave-assisted procedure for the Petasis multicomponent reaction was developed. This method is the first application of the borono-Mannich reaction in solvent-free conditions and proved its applicability to various boronic acids and

Full text of DOI:10.1055/s-0029-1218727

PAPER
2063
Microwave-Assisted Neat Procedure for the Petasis Reaction
M
icrowave-
A
i
ssiste
d
e
Petasis Rea
r
c
tion rick Nun, Jean Martinez, Frédéric Lamaty*
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-Universités Montpellier 1 et 2, Université Montpellier,
2, Place Eugène Bataillon, 34095 Montpellier Cedex 05, France
Fax +33(4)67143847; E-mail: Frederic.lamaty@univ-montp2.fr
Received 26 February 2010; revised 2 March 2010
R2
R1
R3
R4
R2
R3
Abstract: A new solvent-free microwave-assisted procedure for
the Petasis multicomponent reaction was developed. This method is
the first application of the borono-Mannich reaction in solvent-free
conditions and proved its applicability to various boronic acids and
secondary amines. Results are very good in term of yields with
shorter reaction time than the classical methods. Because of the
efficiency of the method, full conversion of the starting materials
towards the expected product was achieved, starting from stoichio-
metric quantities of reactants, avoiding the usual solvent-consum-
ing column chromatography on silica gel. No purification step other
than an aqueous washing was required.
N
R1B(OH)2
R4CHO
+
+
HN
Scheme 1
The two most commonly used aldehydes are glyoxylic
acid and salicylaldehyde, but different hydroxy aldehydes
also proved their applicability,6–8 especially to develop an
asymmetric version of the reaction.9 The presence of an
hydroxy group or other coordinating group is essential to
form a boronate, which can then form the new carbon–
carbon bond after reaction with the in situ prepared
imine.6,8,10
Key words: microwave irradiation, Petasis borono-Mannich reac-
tion, green chemistry, solvent-free
New methods were recently developed in order to im-
prove reaction time, reactivity, and to reduce the environ-
mental impact. We can quote here the use of water,11 ionic
liquids,12 hexafluoroisopropanol,13 organotrifluoro-
borates14 boronates,15 or thioureas.16 Generally, the reac-
tion time needed 24 hours for completion at room
temperature. The use of microwaves was described,17,18
but even if reaction time could be drastically reduced to 10
minutes at 120 °C, isolated yields were low (mostly infe-
rior to 50%).
Microwave activation has emerged as a powerful tech-
nique in organic synthesis to accelerate the preparation of
molecules.1 Many examples have demonstrated that this
technique can be adapted to most organic transformations.
Reactions are generally faster, consequently cleaner, and
sometimes more selective. Furthermore, the focused heat-
ing generated by the microwave enables high temperature
to be reached in a short time.
Because of an increasing interest in developing the use of
environmentally benign reagents and conditions, a possi-
ble approach is to elaborate solvent-free procedures.2
Problems of safety and toxicity could thus be avoided, in
addition to be more economically profitable. Solvent-free
microwave activated procedures have so far mostly in-
volved the use of heterogeneous system: inorganic solid
support such as alumina, silica gel, or montmorillonite.
Nevertheless, when solvent-free procedures are devel-
oped, very often a purification step, expensive in solvent,
is needed.3 Microwave activation of neat equimolar
amounts of reactants leading to a full conversion of the ex-
pected product, thus avoiding a purification step by col-
umn chromatography could provide a valuable approach
to the development of organic reactions. Motivated by our
recent results in the development of solvent-free proce-
dures,4 we present herein our results concerning the devel-
opment of such a procedure for the Petasis reaction.
Petasis or borono-Mannich reaction is a three-component
reaction classically involving a boronic acid, an amine,
and an aldehyde5 (Scheme 1).
Usually, the Petasis borono-Mannich reaction requires a
purification using a preparative TLC and more generally
a solvent-consuming column chromatography. We chose
to develop a solvent-free method for the borono-Mannich
reaction, but without any use of solid support in order to
simplify the purification of the final product. We limited
our investigations to a neat procedure involving an
equimolar amount of the three reactants (amine, aldehyde,
Table 1 Optimization of Reaction Conditions
O
CHO
B(OH)2
N
OH
O
MW
solvent-free
+
+
OH
N
H
Entry
Temp (°C)
90
Time
Conversion (%)a
1
2
3
4
2 h
2 h
87
99
99
84
120
150
45 min
2 h
SYNTHESIS 2010, No. 12, pp 2063–2068
x
x.
x
x
.
2
0
1
0
120 (oil bath)
Advanced online publication: 09.04.2010
DOI: 10.1055/s-0029-1218727; Art ID: Z04910SS
© Georg Thieme Verlag Stuttgart · New York
a Measured by 1H NMR spectroscopy.

2064
P. Nun et al.
PAPER
boronic acid). To our knowledge, there is no example of action is complete after two hours and 45 minutes, respec-
such reaction in solvent-free conditions and especially us- tively. Heating the reaction mixture at 120 °C with a
ing microwave irradiation with a simplified purification classical oil bath led to an appreciable conversion of 84%,
procedure.
but inadequate with our solvent-free procedure.
Our first efforts focused on the optimization of the reac- We finally chose to conduct the reaction at 120 °C for two
tion conditions using the reaction between phenyl boronic hours (Table 1 entry 2) rather than 150 °C for 45 minutes
acid, morpholine, and salicylaldehyde. Results are pre- (Table 1 entry 3), at a temperature more compatible with
sented in Table 1. Reactants are introduced in the micro- most organic structures. These conditions were applied to
wave vial without any addition of solvent. A temperature a wide range of boronic acids and secondary amines to
of 90 °C is not enough to obtain a full conversion in two prove the versatility of our method (Table 2).
hours (Table 1, entry 1) but at 120 °C and 150 °C the re-
Table 2 Reaction of Boronic Acids with Amines and Salicylaldehyde
Boronic acid
Amine
Product
Isolated yield (%)
O
B(OH)2
H
N
N
N
1a
2a
3
78
OH
O
H
N
2b
2c
2a
2b
4
5
6
7
85
85
87
82
OH
Ph
H
N
Ph
N
OH
Ph
Ph
O
B(OH)2
N
1b
OH
N
OH
Ph
N
Ph
2c
2a
8
9
92
78
OH
O
B(OH)2
N
1c
OH
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Microwave-Assisted Petasis Reaction
2065
Table 2 Reaction of Boronic Acids with Amines and Salicylaldehyde (continued)
Boronic acid
Amine
Product
Isolated yield (%)
N
N
N
2b
10
82
OH
OH
O
B(OH)2
1d
2a
2b
11
12
72
87
OH
Ph
N
Ph
2c
2a
13
14
90
92
OH
OMe
B(OH)2
MeO
MeO
O
N
1e
MeO
OMe
OH
OMe
OMe
MeO
MeO
N
2b
2a
2b
15
16
17
89
87
80
OH
NO2
B(OH)2
O
N
1f
OH
NO2
OMe
B(OH)2
N
1g
OH
OMe
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Isolated yield (%)
95
Table 2 Reaction of Boronic Acids with Amines and Salicylaldehyde (continued)
Boronic acid
Amine
Product
O
N
O
1h
2a
18
O
OH
B(OH)2
O
N
1i
2a
2d
19
20
96
44
OH
B(OH)2
H
NH2
N
1a
OH
This method provided a large variety of compounds, al- tion of secondary products, hence providing
a
ways in high yields (>72%). Various secondary amines simplification of the procedure.
could be used. Boronic acids bearing either an electron-
donating or -withdrawing group gave excellent results.
All reagents were purchased from Aldrich Chemical Co. and used
without further purification. NMR analyses were performed on
Bruker Avance DPX 200 (200 MHz for 1H NMR and 50 MHz for
13C NMR) and Bruker Avance AM 300 (300 MHz for 1H NMR and
75 MHz for 13C NMR) spectrometers. Chemical shifts are reported
in ppm and calibrated using residual undeuterated solvents as an in-
ternal reference. Mass spectra (electrospray ionization mode, ESI-
MS) were recorded on a Micromass Q-TOF quadrupole mass spec-
trometer fitted with an electrospray interface. The mass spectrome-
ter was calibrated in the positive- and negative-ion ESI modes. The
samples were dissolved in a mixture H2O–MeCN (50:50 v/v). High-
resolution mass spectra (HRMS) were recorded on a Jeol JMS
DX300-SX 102 in positive mode using NBA (3-nitrobenzylalco-
hol) or GT (mixture of glycerol–thioglycerol, 50:50 v/v) as matrix.
Microwave-assisted reactions were performed in sealed vessels
with a Biotage Initiator 60 EXP® instrument.
We obtained in all cases high conversions with the exclu-
sive formation of the expected product. In order to elimi-
nate salts and the eventual traces of starting reactants, the
crude mixture was washed with an aqueous solution of 0.5
N NaOH. This basic washing eliminates in the aqueous
phase the boron salts as well as traces of boronic acid (for-
mation of boronates) and salicyladehyde. The product can
then be recovered in a pure form and with only few milli-
liters of ethyl acetate as solvent. The use of glyoxylic acid
instead of salicyladehyde gave no conversion in the ex-
pected product. With primary amines such as allylamine
the conversion to the amine 20 was only 44% and mainly
imine was observed. These results are in accordance with
those described by Petasis et al.6 and by McLean et al.17
for primary amines, observing only poor conversions and
the intermediate imine as the main compound.
Reaction of Boronic Acids with Amines; General Procedure
The appropriate boronic acid (0.5 mmol) was introduced in a 2 mL
microwave vial, and then salicylaldehyde (0.5 mmol, 53 mL) and the
respective amine (0.5 mmol) were successively added. The reaction
vessel was sealed and submitted to microwave irradiation at 120 °C
during 2 h in a Biotage Initiator microwave oven. After cooling to
r.t., EtOAc (5 mL) was added and the mixture washed with aq 0.5
M NaOH (5 mL). The organic layer was dried (MgSO4) and concen-
trated in vacuo, to afford the expected product (Table 2).
The practicability and power of the method is well illus-
trated in the synthesis of benzofuran derivative 18. This
compound has been prepared previously using a micro-
wave-assisted Petasis reaction in a low yield of 23% due
to its decomposition during the purification step (column
chromatography on silica gel).17 The same compound
could be prepared in 95% yield using the method de-
scribed herein.
2-[Morpholino(phenyl)methyl]phenol (3)11
Yield: 104.9 mg (78%).
In conclusion, we have developed the first microwave-
assisted neat method for the Petasis reaction. A large
range of compounds could be prepared including fragile
products in two hours at 120 °C and without purification
by column chromatography. The use of microwave irradi-
ation permitted to reduce the reaction time and the forma-
1H NMR (300 MHz, CDCl3): d = 2.42–2.77 (m, 4 H), 3.71–3.88 (m,
2 H), 4.45 (s, 1 H), 6.79 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 8.1 Hz, 1
H), 6.99 (t, J = 7.7 Hz, 1 H), 7.12–7.25 (m, 1 H), 7.27–7.54 (m, 5
H), 11.79 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 52.24, 66.91, 76.68, 117.06,
119.78, 124.82, 127.77, 128.14, 128.32, 128.44, 129.42, 139.30,
156.11.
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Microwave-Assisted Petasis Reaction
2067
MS (ESI): m/z = 270.16 [M + H]+.
J = 8.1 Hz, 1 H), 6.98 (d, J = 7.4 Hz, 1 H), 7.07–7.33 (m, 5 H),
11.79 (s, 1 H).
2-[Phenyl(piperidin-1-yl)methyl]phenol (4)
Yield: 113.4 mg (85%).
1H NMR (300 MHz, CDCl3): d = 1.22–1.59 (m, 7 H), 2.12–2.49 (m,
3 H), 4.39 (s, 1 H), 6.59 (t, J = 7.3 Hz, 1 H), 6.78 (t, J = 7.9 Hz, 2
H), 7.01 (dt, J = 8.8, 1.6 Hz, 1 H), 7.12–7.25 (m, 3 H), 7.27–7.34
(m, 2 H), 12.51 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.55, 52.25, 66.93, 76.91, 117.02,
119.58, 125.56, 128.33, 128.63, 129.11, 129.41, 138.60, 139.27,
156.10.
MS (ESI): m/z = 284.07 [M + H]+.
HRMS: m/z calcd for C18H22NO2: 284.1651; found: 284.1643.
13C NMR (75 MHz, CDCl3): d = 24.13, 26.11, 52.54, 76.48, 116.86,
2-[Piperidin-1-yl(m-tolyl)methyl]phenol (10)
Yield: 115.2 mg (82%).
119.02, 125.57, 127.83, 128.45, 128.81, 129.20, 139.45, 157.15.
MS (ESI): m/z = 268.3 [M + H]+.
1H NMR (300 MHz, CDCl3): d = 1.41–1.69 (m, 6 H), 2.35 (s, 3 H),
2.41–2.50 (m, 4 H), 4.46 (s, 1 H), 6.70 (dt, J = 7.5, 1.2 Hz, 1 H),
6.83–6.94 (m, 2 H), 7.01–7.29 (m, 5 H), 12.57 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.57, 24.15, 26.12, 52.54, 76.21,
116.85, 118.99, 125.66, 128.26, 128.61, 129.21, 129.44, 137.44,
140.00, 157.17.
HRMS: m/z calcd for C18H22NO: 268.1701; found: 298.1697.
2-[(Dibenzylamino)(phenyl)methyl]phenol (5)17
Yield: 161.0 mg (85%).
1H NMR (300 MHz, CDCl3): d = 3.32 (d, J = 13.3 Hz, 2 H), 3.89 (d,
J = 13.3 Hz, 2 H), 5.05 (s, 1 H), 6.78 (t, J = 7.4 Hz, 1 H), 6.72 (d,
J = 7.3 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 7.08 (t, J = 6.8 Hz, 1 H),
7.15–7.45 (m, 15 H), 12.09 (s, 1 H).
MS (ESI): m/z = 282.12 [M + H]+.
HRMS: m/z calcd for C19H24NO: 282.1858; found: 298.1841.
13C NMR (75 MHz, CDCl3): d = 53.76, 68.27, 116.72, 119.04,
124.52, 127.75, 128.55, 128.73, 128.86, 129.40, 129.67, 129.79,
130.61, 131.58, 134.54, 136.92, 157.55.
2-[Morpholino(o-tolyl)methyl]phenol (11)
Yield: 101.8 mg (72%).
1H NMR (300 MHz, CDCl3): d = 2.51–2.59 (m, 5 H), 2.62–2.89 (m,
2 H), 3.71–3.88 (m, 4 H), 4.95 (s, 1 H), 6.77 (dt, J = 7.4, 1.2 Hz, 1
H), 6.92 (dd, J = 8.1, 1.1 Hz, 1 H), 6.97 (dd, J = 7.6, 1.5 Hz, 1 H),
7.12–7.23 (m, 4 H), 7.61–7.68 (m, 1 H), 11.98 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.55, 52.25, 66.93, 76.91, 117.02,
119.58, 125.56, 128.33, 128.63, 129.11, 129.41, 138.60, 139.27,
156.10.
MS (ESI): m/z = 380.2 [M + H]+.
2-[Morpholino(p-tolyl)methyl]phenol (6)11
Yield: 123.1 mg (87%).
1H NMR (300 MHz, CDCl3): d = 2.48–2.50 (m, 4 H), 3.09 (s, 3 H),
3.76–3.79 (m, 4 H), 4.40 (s, 1 H), 6.62 (dt, J = 7.4, 1.2 Hz, 1 H),
6.77 (dd, J = 8.1, 1.1 Hz, 1 H), 6.84 (dd, J = 7.5, 1.6 Hz, 1 H), 6.97–
7.05 (m, 2 H), 7.17–7.24 (m, 2 H), 11.81 (s, 1 H).
MS (ESI): m/z = 284.16 [M + H]+.
13C NMR (75 MHz, CDCl3): d = 21.09, 52.2, 66.93, 76.50, 117.00,
119.61, 125.01, 128.47, 128.62, 129.25, 129.61, 136.27, 137.88,
156.12.
HRMS: m/z calcd for C18H22NO2: 284.1651; found: 284.1647.
2-[Piperidin-1-yl(o-tolyl)methyl]phenol (12)
Yield: 122.2 mg (87%).
1H NMR (300 MHz, CDCl3): d = 1.41–1.69 (m, 6 H), 2.41–2.69 (m,
7 H), 5.01 (s, 1 H), 6.75 (t, J = 7.5 Hz, 1 H), 6.89–6.99 (m, 2 H),
7.09–7.28 (m, 4 H), 7.59–7.70 (m, 1 H), 12.52 (s, 1 H).
MS (ESI): m/z = 284.2 [M + H]+.
2-[Piperidin-1-yl(p-tolyl)methyl]phenol (7)11
Yield: 115.7 mg (82%).
13C NMR (75 MHz, CDCl3): d = 22.04, 25.54, 27.61, 53.35, 71.17,
118.17, 120.06, 126.00, 128.55, 128.78, 129.36, 129.73, 137.74,
139.50, 158.52.
1H NMR (300 MHz, CDCl3): d = 1.04–1.79 (m, 6 H), 2.35 (s, 3 H),
2.41–2.50 (m, 4 H), 4.50 (s, 1 H), 6.73 (t, J = 6.3 Hz, 1 H), 6.91 (t,
J = 8.1 Hz, 2 H), 7.11–7.19 (m, 3 H), 7.29–7.38 (m, 2 H), 12.51 (s,
1 H).
MS (ESI): m/z = 282.18 [M + H]+.
13C NMR (75 MHz, CDCl3): d = 21.12, 24.16, 26.13, 52.43, 76.10,
116.82, 119.01, 125.73, 128.26, 128.78, 129.17, 129.37, 137.53,
140.00, 157.20.
HRMS: m/z calcd for C19H24NO: 282.1858; found: 298.1847.
2-[(Dibenzylamino)(o-tolyl)methyl]phenol (13)
Yield: 176 mg (90%).
MS (ESI): m/z = 282.3 [M + H]+.
1H NMR (300 MHz, CDCl3): d = 2.09 (s, 3 H), 3.79 (d, J = 13.7 Hz,
2 H), 3.99 (d, J = 13.6 Hz, 2 H), 5.48 (s, 1 H), 6.75–6.84 (m, 1 H),
6.98 (d, J = 7.2 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 7.21–7.55 (m,
15 H), 11.98 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.16, 53.01, 53.38, 64.38, 116.85,
119.38, 124.77, 127.68, 128.55, 128.72, 128.91, 129.20, 129.69,
129.89, 130.69, 132.53, 137.13, 138.09, 167.01.
2-[(Dibenzylamino)(p-tolyl)methyl]phenol (8)11
Yield: 180.7 mg (92%).
1H NMR (300 MHz, CDCl3): d = 2.49 (s, 3 H), 3.51 (d, J = 13.2 Hz,
2 H), 4.05 (d, J = 13.2 Hz, 2 H), 5.21 (s, 1 H), 6.75–6.84 (m, 1 H),
6.98 (d, J = 7.2 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 7.21–7.55 (m,
15 H), 12.29 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.30, 53.85, 67.82, 116.66,
119.09, 124.77, 127.68, 128.55, 128.72, 128.91, 129.20, 129.69,
129.89, 130.69, 132.53, 137.13, 138.09, 157.74.
MS (ESI): m/z = 394.21 [M + H]+.
HRMS: m/z calcd for C28H28NO: 394.2171; found: 394.2161.
MS (ESI): m/z = 394.23 [M + H]+.
2-[Morpholino(3,4,5-trimethoxyphenyl)methyl]phenol (14)
Yield: 165.7 mg (92%).
2-[Morpholino(m-tolyl)methyl]phenol (9)
Yield: 110.3 mg (78%).
1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3 H), 2.44–2.71 (m, 4 H),
3.71–3.88 (m, 4 H), 4.40 (s, 1 H), 6.78 (t, J = 7.3 Hz, 1 H), 6.91 (d,
1H NMR (300 MHz, CDCl3): d = 2.38–2.72 (m, 4 H), 3.68–3.89 (m,
13 H), 4.28 (s, 1 H), 6.63–6.71 (m, 1 H), 6.75 (dt, J = 7.3, 1.2 Hz, 1
H), 6.87 (dd, J = 8.1, 1.1 Hz, 1 H), 6.96 (dd, J = 7.6, 1.6 Hz, 1 H),
7.09–7.18 (m, 2 H).
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13C NMR (75 MHz, CDCl3): d = 52.23, 56.11, 60.82, 66.88, 105.22,
117.06, 119.83, 124.83, 128.73, 129.31, 135.19, 137.67, 153.85,
161.56.
13C NMR (75 MHz, CDCl3): d = 31.85, 34.21, 35.04, 51.95, 67.00,
76.55, 116.89, 119.42, 124.96, 125.47, 127.06, 128.54, 129.49,
135.51, 141.65, 144.60, 145.13, 156.42.
MS (ESI): m/z = 360.1 [M + H]+.
MS (ESI): m/z = 380.3 [M + H]+, 293.3.
HRMS: m/z calcd for C20H26NO5: 360.1811; found: 360.1807.
HRMS: m/z calcd for C25H34NO2: 380.2590; found: 380.2585.
2-[Piperidin-1-yl(3,4,5-trimethoxyphenyl)methyl]phenol (15)
Yield: 158.2 mg (89%).
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 1.37–1.72 (m, 6 H), 2.27–2.53 (m,
4 H), 3.79 (s, 3 H), 3.83 (s, 3 H), 4.31 (s, 1 H), 6.61–6.72 (m, 2 H),
6.83 (d, J = 7.2 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 7.05–7.13 (m, 1
H).
We thank the Fondation d’Entreprise EADS for financial support.
References
13C NMR (75 MHz, CDCl3): d = 24.12, 25.81, 52.56, 56.09, 60.82,
105.23, 116.87, 119.08, 125.65, 128.70, 129.08, 135.56, 137.45,
153.05, 153.23, 156.94.
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MS (ESI): m/z = 358.2 [M + H]+.
HRMS: m/z calcd for C21H28NO4: 358.2018; found: 358.2014.
2-[Morpholino(3-nitrophenyl)methyl]phenol (16)
Yield: 136.3 mg (87%).
(2) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.;
Machado, P. Chem. Rev. 2009, 109, 4140.
1H NMR (300 MHz, CDCl3): d = 2.32–2.81 (m, 4 H), 3.69–3.90 (m,
4 H), 4.53 (s, 1 H), 6.68 (t, J = 7.5 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1
H), 6.97 (d, J = 7.5 Hz, 1 H), 7.01–7.18 (m, 1 H), 7.42–7.58 (t,
J = 8.0 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 8.17 (dd, J = 7.2 1.2 Hz,
1 H), 8.28 (s, 1 H), 11.32 (s,1 H).
13C NMR (75 MHz, CDCl3): d = 29.70, 52.36, 66.72, 76.36, 117.52,
120.05, 123.18, 123.44, 123.61, 129.18, 129.39, 130.21, 134.23,
141.65, 148.46, 155.76.
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K. Solvent-Free Organic Synthesis; Wiley-VCH:
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Kumar, D.; Dahiya, R.; Liesen, P. J. J. Microwave Power
Electromagn. Energy 1999, 34, 113.
(4) (a) Colacino, E.; Nun, P.; Colacino, F. M.; Martinez, J.;
Lamaty, F. Tetrahedron 2008, 64, 5569. (b) Declerck, V.;
Nun, P.; Martinez, J.; Lamaty, F. Angew. Chem. Int. Ed.
2009, 48, 9318. (c) Nun, P.; Martinez, J.; Lamaty, F. Synlett
2009, 1761.
MS (ESI): m/z = 314.9 [M + H]+.
HRMS: m/z calcd for C17H19N2O4: 315.1345; found: 315.1330.
(5) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583.
2-[(3-Methoxyphenyl)(piperidin-1-yl)methyl]phenol (17)
(6) Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539.
(7) (a) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 53, 16463. (b) Petasis, N. A.; Zavialov, I. A. J. Am.
Chem. Soc. 1997, 119, 445. (c) Prakash, G. K. S.; Mandal,
M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. Org. Lett.
2000, 2, 3173. (d) Prakash, G. K. S.; Mandal, M.;
Schweizer, S.; Petasis, N. A.; Olah, G. A. J. Org. Chem.
2002, 67, 3718.
Yield: 118.5 mg (80%).
1H NMR (300 MHz, CDCl3): d = 1.31–1.69 (m, 7 H), 2.19–2.37 (m,
3 H), 3.67 (s, 3 H), 4.33 (s, 1 H), 6.59 (dt, J = 7.4, 1.2 Hz, 1 H), 6.69
(dd, J = 8.2, 2.5 Hz, 1 H), 6.75 (dd, J = 8.1, 1.1 Hz, 1 H), 6.80 (dd,
J = 7.6, 1.5 Hz, 1 H), 6.85–6.95 (m, 2 H), 7.00 (dt, J = 7.7, 1.7 Hz,
1 H), 7.12 (t, J = 8.0 Hz, 1 H), 12.31 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.14, 26.11, 52.54, 55.17, 76.50,
112.86, 113.96, 116.86, 118.03, 121.03, 125.48, 128.33, 129.17,
129.69, 141.15, 157.10, 159.75.
(8) Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron
2000, 56, 10023.
(9) (a) Kaiser, P. F.; Churches, Q. I.; Hutton, C. A. Aust. J.
Chem. 2007, 60, 799. (b) Petasis, N. A.; Zavialov, I. A.
J. Am. Chem. Soc. 1998, 120, 11798.
MS (ESI): m/z = 298.11 [M + H]+.
HRMS: m/z calcd for C19H24NO2: 298.1807; found: 298.1794.
(10) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
(11) Candeias, N. R.; Veiros, L. F.; Afonso, C. A. M.; Gois, P. M.
P. Eur. J. Org. Chem. 2009, 1859.
(12) Yadav, P. N.; Reddy, B. V. S.; Lakshmi, P. N. J. Mol. Catal.
A: Chem. 2007, 274, 101.
(13) Nanda, K. K.; Trotter, B. W. Tetrahedron Lett. 2005, 46,
2025.
(14) Tremblay-Morin, J.-P.; Raeppel, S.; Gaudette, F.
Tetrahedron Lett. 2004, 45, 3471.
(15) Jourdan, H.; Gouhier, G.; Van Hijfte, L.; Angibaud, P.;
Piettre, S. R. Tetrahedron Lett. 2005, 46, 8027.
(16) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc.
2007, 129, 6686.
(17) McLean, N. J.; Tye, H.; Whittaker, M. Tetrahedron Lett.
2004, 45, 993.
2-[Benzofuran-2-yl(morpholino)methyl]phenol (18)17
Yield: 146.4 mg (95%).
1H NMR (300 MHz, CDCl3): d = 2.49–2.93 (m, 4 H), 3.62–3.98 (m,
4 H), 4.86 (s, 1 H), 6.71–6.89 (m, 2 H), 6.91–7.01 (m, 2 H), 7.12–
7.45 (m, 3 H), 7.47–7.68 (m, 2 H), 11.19 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 51.37, 66.94, 68.50, 106.44,
111.52, 116.97, 119.59, 121.63, 122.74, 123.06, 124.55, 127.89,
129.25, 129.54, 154.16, 154.93, 156.89.
MS (ESI): m/z = 310.1 [M + H]+.
2-[Morpholino(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphtha-
len-2-yl)methyl]phenol (19)
Yield: 181.9 mg (96%).
(18) Follmann, M.; Graul, F.; Schäfer, T.; Kopec, S.; Hamley, P.
Synlett 2005, 1009.
1H NMR (300 MHz, CDCl3): d = 1.23 (m, 12 H), 1.61–1.71 (m, 4
H), 2.41–2.59 (m, 4 H), 3.70–3.82 (m, 4 H), 4.40 (s, 1 H), 6.73 (t,
J = 7.5 Hz, 1 H), 6.85 (d, J = 7.3 Hz, 1 H), 6.96 (d, J = 7.2 Hz, 1 H),
7.09–7.24 (m, 4 H), 11.79 (s, 1 H).
Synthesis 2010, No. 12, 2063–2068 © Thieme Stuttgart · New York