A Concise Route to 2-Amino-3-aryl-3H-benzofurans and their Use as Precursors to 3-Aryl-3H-benzofuran-2-one and 1H-Benzofuro[2,3-￡]pyridin-2- one Derivatives

Article abstract of DOI:10.1055/s-2003-44389

A concise approach to 2-amino-3-aryl-3H-benzofurans based on the Michael addition of NaCN onto in situ generated substituted o-quinone methides has been developed. Straightforward access to 3-aryl-3H-benzofuran-2-ones was achieved upon acidic hydrolysis whereas JV-Boc-protected 2-amino-3-aryl-3H-benzofurans underwent smooth intramolecular cyclisation to give 1H-benzofuro[2,3-b]pyridin- 2-one derivatives.

Full text of DOI:10.1055/s-2003-44389

PAPER
249
A Concise Route to 2-Amino-3-aryl-3H-benzofurans and their Use as Precur-
sors to 3-Aryl-3H-benzofuran-2-one and 1H-Benzofuro[2,3-b]pyridin-2-one
Derivatives
Synthesis and Use of
2
i
-Amin
c
o-3-aryl-3
H
h
-benzofuran
è
s
le Gerster,* Reto Wicki
Ciba Specialty Chemicals Inc., 4002, Basel, Switzerland
Fax +41(61)6362332; E-mail: michele.gerster@cibasc.com
Received 8 September 2003; revised 24 November 2003
To the memory of Solange Gerster
Herein we report a new and simple approach to 3-aryl-3H-
benzofuran-2-ones 3 (Scheme 2) as well as the further
transformation of the key-intermediate 2-amino-3-aryl-
3H-benzofurans 2 into the new tetracyclic compounds 6
Abstract: A concise approach to 2-amino-3-aryl-3H-benzofurans
based on the Michael addition of NaCN onto in situ generated sub-
stituted o-quinone methides has been developed. Straightforward
access to 3-aryl-3H-benzofuran-2-ones was achieved upon acidic
hydrolysis whereas N-Boc-protected 2-amino-3-aryl-3H-benzo- (Scheme 3).
furans underwent smooth intramolecular cyclisation to give 1H-
benzofuro[2,3-b]pyridin-2-one derivatives.
The key-step in the new synthetic route takes advantage of
the well-established reactivity of quinone methides with
nucleophiles7and emphasizes once more their importance
as intermediates in organic transformations. The ami-
noalkylated phenols6,81 obtained via Mannich reaction of
phenols with an aromatic aldehyde and a secondary amine
were used as precursors to the o-quinone methides. The
reactions were performed in sulfolane, at sufficiently high
temperature (120 °C) to ensure the thermal decomposition
of the Mannich bases to the o-quinone methides, which
then functioned as efficient Michael acceptors towards so-
dium cyanide present in a small excess. The addition
products were not isolated, as spontaneous intramolecular
cyclisation occurred to afford in good yields the 2-amino-
3-aryl-3H-benzofurans 2. The latter were readily hydrol-
ysed under acidic catalysis to afford the 3-aryl-3H-benzo-
furan-2-ones 3 in good yields (Scheme 2). Some typical
results obtained are summarised in Table 1.
Key words: furans, Michael additions, quinones, cyclisations, het-
erocycles
3-Aryl-3H-benzofuran-2-ones are an important class of
excellent heat stabilisers for polymers.1 Therefore consid-
erable effort has been devoted to their preparation
(Scheme 1). One of the earliest synthetic approaches in-
volved the acid2- and thermally3-promoted condensation
of mandelic acid or mandelonitrile with phenols, which
restricted the choice of the 3-aryl-substituent to phenyl, or
phenyl substituted with electron donating groups. The ad-
dition of benzylcyanides to p-benzoquinones afforded in
moderate yields benzofuranones bearing a hydroxy sub-
stituent at position 5 of the phenyl ring.4 Additional versa-
tility in the synthesis of this type of compound was
recently introduced with a two-step synthesis involving an
acid-catalysed cyclocondensation of phenols with glyox-
ylic acid, followed by the alkylation of the intermediate 3-
hydroxy-3H-benzofuran-2-ones with aromatic or het-
eroaromatic hydrocarbons under Friedel–Crafts or acid
catalysis.5 Pd-catalysed CO insertion with o-quinone me-
thides has also been used successfully for the synthesis of
3-aryl-3H-benzofuran-2-ones.6
Scheme 2 Synthesis of 3-aryl-3H-benzofuran-2-one derivatives 3
The new 2-amino-3-aryl-3H-benzofurans 2 are conve-
nient starting materials for new heterocycles otherwise
difficult to obtain. Thus, the N-Boc-protected 2-amino-3-
aryl-3H-benzofuran derivatives 4 and 5 underwent ther-
mal cyclisation to afford the 1H-benzofuro[2,3-b]pyridin-
2-one derivatives 6 as depicted in Scheme 3. The reaction
of 2 with di-tert-butyl dicarbonate gave high yields of the
bis-N-Boc-protected amines 4 which were then selective-
ly deprotected upon treatment with a catalytic amount of
magnesium perchlorate9 in acetonitrile to afford 5. This
two-step approach to the carbamates 5 was chosen, as the
mono-protection of 2 gave unsatisfactory yields. With the
same efficiency, both 4 and 5 underwent thermal ring clo-
sure when heated in decaline. Remarkably, no Friedel–
Scheme 1 Selected synthetic routes to 3-aryl-3H-benzofuran-2-
ones
SYNTHESIS 2004, No. 2, pp 0249–0254
x
x
.
x
x
.2
0
0
3
Advanced online publication: 18.12.2003
DOI: 10.1055/s-2003-44389; Art ID: T09703SS.pdf
© Georg Thieme Verlag Stuttgart · New York

250
M. Gerster, R. Wicki
PAPER
Table 1 Synthesis of 2-Amino-3-aryl-3H-benzofurans 2 and of 3-
Aryl-3H-benzofuran-2-ones 3 (R1 = R2 = t-Bu)
Crafts or Lewis acid catalysis was required for this trans-
formation. The results are summarised in Table 2.
In conclusion, a simple synthetic route to 3-aryl-3H-ben-
zofuran-2-ones has been developed. Its success relied on
the transformation of Mannich bases to 2-amino-3-aryl-
3H-benzofurans upon treatment with sodium cyanide,
which then underwent rapid acidic hydrolysis to afford
good yields of 3-aryl-3H-benzofuran-2-ones. Further util-
ity of the intermediate 2-amino-3-aryl-3H-benzofurans
was demonstrated in the synthesis of novel 1H-benzofu-
ro[2,3-b]pyridin-2-one derivatives obtained upon in-
tramolecular thermally-induced cyclisation of N-Boc-
protected 2-amino-3-aryl-3H-benzofurans.
Ar
2
Yield (%),
Mp (°C)
3
a
b
c
d
e
f
Yield (%),
Mp (°C)
Phenyl
aa
ba
ca
db
eb
fb
99,
176–178
85,
116–119
3,4-Dimethylphenyl
3,4-Dimethoxyphenyl
p-Bromophenyl
p-Thiomethylphenyl
o-Methoxyphenyl
86,
128–130
96,
130–132
95,
172–174
82
–
77,
154–158
87,
135–136
82,
140–141
85,
133–135
The mps were determined on a Büchi 540 capillary apparatus and
are not corrected. IR spectra were registered on a Nicolet–Magna-
IR spectrometer 750. The 1H NMR spectra were recorded in
CDCl3, for 1H in ppm relative to CDCl3 ( = 7.26), for 13C in ppm
relative to CDCl3 ( = 77), on a Bruker ACS 120 spectrometer at
300 MHz for 1H and 75 MHz for 13C, or on a Bruker ACS 60 spec-
83
–
66,
157–159
a Obtained from 1 where NR3R4 = NMe2
1
trometer at 400 MHz for H and 100 MHz for 13C. The EI mass
b Obtained from 1 where NR3R4 = piperidine
spectra were measured by GC-MS (HP-5890 gas chromatograph
with a Finnigan MAT SSQ 710 mass spectrometer) or by direct in-
troduction (DEP). The APCI mass spectra were measured by LC-
MS (Waters-Micromass ZQ). The ESI-HRMS were measured on a
QSTAR XL spectrometer operated in positive ion mode. Mi-
croanalyses were obtained using a LECO-CHNS-932 element anal-
yser and a LECO-RO-478 element analyser.
2,4-Di-tert-butyl-6-(dimethylaminophenylmethyl)phenol (1a);
Typical Procedure
A mixture of 2,4-di-tert-butylphenol (51.5 g, 0.25 mol), benzalde-
hyde (26.5 g, 0.25 mol) and an aq solution of dimethylamine (40%;
42.3 g, 0.38 mol) was heated to 140 °C in a closed vessel for 10 h.
The reaction mixture was cooled down to r.t. The residue was crys-
tallised in i-PrOH to give 1a. Compounds 1b and 1c were also pre-
pared according to this procedure.
Yield: 65.2 g (77%); white solid; mp 120–123 °C.
IR (neat): 3738, 2954, 2865, 1438, 1360, 1247, 884, 759, 668 cm–1.
Scheme 3 Synthesis of 1H-benzofuro[2,3-b]pyridin-2-one derivati-
ves 6
Table 2 Synthesis of 6 from Bis-N-Boc-protected Amines 4
6
Structure
Yield (%),
Mp (°C)
6
Structure
Yield (%),
Mp (°C)
aa
80,
d
72,
>300
>300
b
c
81,
275–279
e
62,
>300
39,
126–131
a 6a was also obtained in 73% from 5
Synthesis 2004, No. 2, 249–254 © Thieme Stuttgart · New York

PAPER
Synthesis and Use of 2-Amino-3-aryl-3H-benzofurans
251
1H NMR (300 MHz, CDCl3): = 12.38 (s, 1 H, OH), 7.50–7.40 (m,
2 H, ArH), 7.35–7.20 (m, 3 H, ArH), 7.14 (d, J = 2.4 Hz, 1 H, ArH),
6.74 (d, J = 2.4 Hz, 1 H, ArH), 4.34 (s, 1 H, CHAr), 2.27 (s, 6 H,
NCH3), 1.45 (s, 9 H, t-Bu), 1.19 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): =152.2 (C), 139.1 (C), 138.9 (C),
134.7 (C), 127.5 (CH), 127.3 (CH), 126.4 (CH), 123.4 (C), 122.4
(CH), 121.3 (CH), 76.6 (CH), 42.0 (CH3), 33.8 (C), 32.9 (C), 30.4
(CH3), 28.4 (CH3).
ArH), 4.30 (s, 1 H, CHAr), 2.45–2.15 (br s, 4 H, NCH2), 1.60–1.50
(br s, 6 H, NCH2CH2CH2), 1.36 (s, 9 H, t-Bu), 1.12 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 153.7 (C), 140.7 (C), 139.6 (C),
136.5 (C), 132.1 (CH), 130.8 (CH), 124.5 (C), 124.1 (CH), 123.0
(CH), 121.8 (C), 77.0 (CH), 52.7 (CH2), 35.4 (C), 34.5 (C), 32.0
(CH3), 30.0 (CH3), 26.3 (CH2), 24.5 (CH2).
MS (EI): m/z (%) = 459, 457 (14) [M+], 374 (14), 371 (15), 359
(23), 357 (25), 294 (20), 293 (100), 171 (15), 84 (43), 57 (22), 41
(11).
HPLC-MS (APCI): m/z (%) = 340 (97) [M + 1+], 295 (100).
Anal. Calcd for C23H33NO: C, 81.37; H, 9.80; N, 4.13; O, 4.71.
Found: C, 81.31; H, 9.64; N, 4.08; O, 4.58.
Anal. Calcd for C26H36BrNO: C, 68.11; H, 7.91; Br, 17.43; N, 3.05;
O, 3.49. Found: C, 68.14; H, 7.98; Br, 17.5; N, 3.02; O, 3.47.
2,4-Di-tert-butyl-6-[dimethylamino-(3,4-dimethylphenyl)meth-
yl]phenol (1b)
2,4-Di-tert-butyl-6-[(4-methylsulfanylphenyl)piperidin-1-ylme-
thyl]phenol (1e)
IR (neat): 2952, 2864, 2779, 1467, 1437, 1360, 1248, 1229, 1183,
IR (neat): 2942, 2866, 2599, 1840, 1478, 1436, 1231, 860, 826, 740
883, 819, 720 cm–1.
cm–1.
1H NMR (300 MHz, CDCl3): = 12.48 (s, 1 H, OH), 7.22–7.10 (m,
3 H, ArH), 7.08–7.00 (m, 1 H, ArH), 6.75 (d, J = 2.1 MHz, 1 H,
ArH), 4.28 (s, 1 H, CHAr), 2.25 (s, 6 H, CH3), 2.22 (s, 6 H, CH3),
1.44 (s, 9 H, t-Bu), 1.19 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 153.9 (C), 140.3 (C), 138.0 (C),
136.9 (C), 136.2 (C), 130.4 (CH), 130.1 (CH), 126.5 (C), 125.3
(CH), 124.1 (CH), 122.7 (CH), 77.9 (CH), 43.6 (CH3), 35.4 (C),
34.5 (C), 32.1 (CH3), 30.0 (CH3), 20.3 (CH3), 19.8 (CH3).
1H NMR (400 MHz, CDCl3): = 12.50 (br s, 1 H, OH), 7.40–7.25
(m, 2 H, ArH), 7.20–7.15 (m, 2 H, ArH), 7.14 (d, J = 2.4 MHz, 1 H,
ArH), 6.72 (d, J = 2.4 MHz, 1 H, ArH), 4.39 (s, 1 H, CHAr), 2.70–
2.20 (m, 4 H, NCH2), 2.46 (s, 3 H, SCH3), 1.70–1.50 (m, 6 H,
NCH2CH2CH2), 1.44 (s, 9 H, t-Bu), 1.19 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 154.2 (C), 140.8 (C), 138.2 (C),
137.5 (C), 136.6 (C), 130.0 (CH), 127.2 (CH), 125.2 (C), 124.5
(CH), 123.1 (CH), 77.3 (CH), 53.0 (CH2), 35.7 (C), 34.8 (C), 32.3
(CH3), 30.3 (CH3), 26.7 (CH2), 24.9 (CH2), 16.3 (CH3).
HPLC-MS (APCI): m/z (%) = 368 (92) [M + 1+], 323 (100).
MS (EI): m/z (%) = 425 (14) [M+], 340 (23), 339 (18), 325 (24), 293
(100), 137 (12), 84 (10), 57 (9).
Anal. Calcd for C25H37NO: C, 81.69; H, 10.15; N, 3.81. Found: C,
81.78; H, 9.95; N, 3.80.
Anal. Calcd for C27H39NOS: C, 76.18; H, 9.23; N, 3.29; O, 3.76; S,
7.53. Found: C, 75.87; H, 8.90; N, 3.13; O, 3.76; S, 7.56.
2,4-Di-tert-butyl-6-[(3,4-dimethoxyphenyl)dimethylaminome-
thyl]phenol (1c)
IR (neat): 2948, 2866, 2656, 1596, 1516, 1456, 1228, 1140, 1034,
2,4-Di-tert-butyl-6-[(2-methoxyphenyl)piperidin-1-ylmeth-
yl]phenol (1f)
883, 823, 766 cm–1.
IR (neat): 2936, 2867, 2811, 1602, 1588, 1475, 1434, 1247, 1089,
1H NMR (400 MHz, CDCl3): = 12.51 (s, 1 H, OH), 7.20–7.10 (m,
2 H, ArH), 6.92–6.88 (m, 1 H, ArH), 6.80–6.72 (m, 2 H, ArH), 4.24
(s, 1 H, CHAr), 3.85 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 2.27 (s, 6
H, NCH3), 1.44 (s, 9 H, t-Bu), 1.20 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 151.9 (C), 147.8 (C), 147.2 (C),
139.0 (C), 134.7 (C), 132.3 (C), 123.8 (C), 122.3 (CH), 121.1 (CH),
119.9 (CH), 109.7 (CH), 109.4 (CH), 76.4 (CH), 54.5 (CH3), 54.4
(CH3), 42.0 (CH3), 33.7 (C), 32.8 (C), 30.4 (CH3), 28.3 (CH3).
1033, 877, 745 cm–1.
1H NMR (400 MHz, CDCl3): = 12.68 (s, 1 H, OH), 7.55–7.45 (m,
1 H, ArH), 7.26–7.15 (m, 1 H, ArH), 7.13 (d, J = 2.0 MHz, 1 H,
ArH), 6.95–6.82 (m, 2 H, ArH), 6.82–6.65 (m, 1 H, ArH), 5.25 (s,
1 H, CHAr), 3.86 (s, 3 H, OCH3), 3.00–2.00 (m, 4 H, NCH2), 1.70–
1.50 (br s, 6 H, NCH2CH2CH2), 1.44 (s, 9 H, t-Bu), 1.19 (s, 9 H, t-
Bu).
13C NMR (100 MHz, CDCl3): = 156.1 (C), 153.2 (C), 138.6 (C),
134.4 (C), 128.6 (CH), 127.1 (CH), 126.7 (C), 123.8 (C), 122.9
(CH), 121.0 (CH), 119.7 (CH), 109.6 (CH), 64.9 (CH), 54.4 (CH3),
32.9 (C), 33.0 (C), 30.6 (CH3), 28.5 (CH3), 25.0 (CH2), 23.2 (CH2).
HPLC-MS (APCI): m/z (%) = 400 (26) [M + 1+], 355 (100).
Anal. Calcd for C25H37NO3: C, 75.15; H, 9.33; N, 3.51; O, 12.01.
Found: C, 75.23; H, 9.33; N, 3.38; O, 11.97.
MS (EI): m/z (%) = 409 (16) [M+], 309 (8), 293 (100), 161 (4), 121
(4), 84 (11), 57 (7).
2-[(4-Bromophenyl)piperidin-1-ylmethyl]-4,6-di-tert-butylphe-
nol (1d); Typical Procedure
Piperidine (17 mL, 173 mmol) was added dropwise at r.t. to a solu-
tion of p-bromobenzaldehyde (14.5 g, 78.6 mmol) in toluene (50
mL). The reaction mixture was heated under reflux for 4 h with con-
comitant removal of H2O. It was then cooled to 90 °C and a solution
of 2,4-di-tert-butylphenol (15.4 g, 74.7 mmol) in toluene (25 mL)
was added slowly. The reaction mixture was heated under reflux for
15 h. After cooling to r.t., the solvent was evaporated. MeOH (70
mL) was added to the oily residue and the solution was stirred at
60 °C for 30 min. A precipitate formed which was filtered off,
washed with cold MeOH (2 × 25 mL) to give 1d. Compounds 1e
and 1f were also prepared according to this procedure.
Anal. Calcd for C27H39NO2: C, 79.19; H, 9.60; N, 3.42; O, 7.81.
Found: C, 79.15; H, 9.65; N, 3.35; O, 7.72.
2-Amino-3-phenyl-5,7-di-tert-butylbenzofuran (2a); Typical
Procedure
Sodium cyanide (0.98 g, 20.0 mmol) dissolved in the minimum
amount of H2O (2.0 mL) was added to 2,4-di-tert-butyl-6-(dimeth-
ylaminophenylmethyl)phenol (1a) (3.39 g, 10.0 mmol) in sulfolane
(10 mL). The mixture was stirred for 1 h at 120 °C under nitrogen.
After cooling to r.t., the yellow–orange mixture was poured into
tert-butyl methyl ether (80 mL) and washed with H2O (80 mL). The
layers were separated and the organic phase repeatedly washed with
H2O. The combined organic phases were dried (MgSO4), filtered
and concentrated to give 2a.
Yield: 30.8 g (90%); white solid; mp 166–168 °C.
IR (neat): 2963, 2935, 2863, 1487, 1436, 1248, 1232, 1010, 875,
827, 722 cm–1.
1H NMR (300 MHz, CDCl3): = 12.30 (s, 1 H, OH), 7.38–7.15 (m,
Yield: 2.80 g (87%); yellow solid; mp 176–178 °C.
IR (KBr): 3344, 2958, 1781, 1640, 1600, 1422, 979, 760, 700 cm–1.
4 H, ArH), 7.07 (d, J = 2.4 Hz, 1 H, ArH), 6.63 (d, J = 2.4 Hz, 1 H,
Synthesis 2004, No. 2, 249–254 © Thieme Stuttgart · New York

252
M. Gerster, R. Wicki
PAPER
5,7-Di-tert-butyl-3-(4-methylsulfanylphenyl)benzofuran-2-
1H NMR (300 MHz, CDCl3): = 7.65–7.50 (m, 4 H, ArH), 7.43 (d,
J = 1.8 Hz, 1 H, ArH), 7.38–7.28 (m, 1 H, ArH), 7.15 (d, J = 1.8 Hz,
1 H, ArH), 4.31 (br s, 2 H, NH2), 1.57 (s, 9 H, t-Bu), 1.42 (s, 9 H, t-
Bu).
ylamine (2e)
IR (neat): 3430, 3348, 2956, 2904, 2867, 1650, 1595, 1500, 1425,
1360, 984, 859, 820 cm–1.
13C NMR (75 MHz, CDCl3): = 153.6 (C), 146.6 (C), 146.4 (C),
134.4 (C), 133.1 (C), 130.4 (C), 129.8 (CH), 128.3 (CH), 126.4
(CH), 116.6 (CH), 112.4 (CH), 95.0 (C), 35.5 (C), 35.0 (C), 32.6
(CH3), 30.6 (CH3).
GCMS (EI): m/z (%) = 322 (17) [M + 1+], 321 (100) [M+], 306 (28),
279 (8), 250 (5), 222 (5), 153 (10), 139 (12), 57 (6).
1H NMR (300 MHz, CDCl3): = 7.58–7.50 (m, 2 H, ArH), 7.48–
7.38 (m, 3 H, ArH), 7.14 (d, J = 2.1 Hz, 1 H, ArH), 4.30 (br s, 2 H,
NH2), 2.58 (s, 3 H, SCH3), 1.56 (s, 9 H, t-Bu), 1.42 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 153.3 (C), 146.4 (C), 146.2 (C),
135.9 (C), 132.9 (C), 131.1 (C), 130.1 (C), 128.6 (CH), 128.1 (CH),
116.4 (CH), 112.1 (CH), 94.3 (C), 35.3 (C), 34.7 (C), 32.4 (CH3),
30.5 (CH3), 16.6 (CH3).
Anal. Calcd for C22H27NO: C, 82.20; H, 8.47; N, 4.36; O, 4.98.
Found: C, 82.05; H, 8.39; N, 4.31; O, 4.92.
GCMS (EI): m/z (%) = 368 (23) [M + 1+], 367 (100) [M+], 352 (16),
176 (17), 162 (15), 57 (7).
5,7-Di-tert-butyl-3-(3,4-dimethylphenyl)benzofuran-2-ylamine
(2b)
Anal. Calcd for C23H29NOS: C, 75.16; H, 7.95; N, 3.81; O, 4.35; S,
8.72. Found: C, 75.10; H, 7.77; N, 3.60; O, 4.37; S, 8.69.
IR (neat): 3321, 2960, 2872, 1650, 1598, 1455, 1362, 1081, 984
cm–1.
5,7-Di-tert-butyl-3-(2-methoxyphenyl)benzofuran-2-ylamine
1H NMR (300 MHz, CDCl3): = 7.15–7.05 (m, 4 H, ArH), 6.88 (d,
J = 1.8 Hz, 1 H, ArH), 4.03 (br s, 2 H, NH2), 2.15 (s, 3 H, CH3), 2.14
(s, 3 H, CH3), 1.32 (s, 9 H, t-Bu), 1.17 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 151.5 (C), 144.8 (C), 144.4 (C),
136.1 (C), 133.0 (C), 131.2 (C), 129.9 (C), 129.2 (CH), 128.8 (C),
127.8 (CH), 124.1 (CH), 114.6 (CH), 110.7 (CH), 93.2 (C), 33.7
(C), 33.1 (C), 30.8 (CH3), 28.9 (CH3), 18.7 (CH3), 18.3 (CH3).
(2f)
IR (KBr): 3345, 2962, 2293, 1424, 1376, 1039 cm–1.
1H NMR (300 MHz, CDCl3): = 7.68–7.62 (m, 1 H, ArH), 7.40–
7.30 (m, 2 H, ArH), 7.20–7.05 (m, 3 H, ArH), 4.46 (br s, 2 H, NH2),
3.95 (s, 3 H, OCH3), 1.57 (s, 9 H, t-Bu), 1.41 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 156.4 (C), 153.9 (C), 146.8 (C),
145.7 (C), 132.6 (C), 131.0 (C), 130.7 (CH), 127.8 (CH), 122.7 (C),
121.9 (CH), 116.0 (CH), 112.6 (CH), 91.1 (C), 56.5 (CH3), 35.3 (C),
34.8 (C), 32.4 (CH3), 30.5 (CH3).
HPLC-MS (APCI): m/z (%) = 350 (100) [M + 1+].
HRMS (ESI): m/z (%) calcd for C24H32NO [M + H+]: 350.2483;
found: 350.2424.
GCMS (EI): m/z (%) = 352 (21) [M + 1+], 351 (100) [M+], 336 (13),
280 (6), 168 (15), 154 (7), 57 (12).
5,7-Di-tert-butyl-3-(3,4-dimethoxyphenyl)benzofuran-2-
ylamine (2c)
Anal. Calcd for C23H29NO2: C, 78.60; H, 8.32; N, 3.98; O, 9.10.
Found: C, 78.32; H, 8.33; N, 3.85; O, 9.14.
IR (neat): 3476, 3350, 2958, 2906, 1656, 1516, 1247, 1026, 996,
856, 815 cm–1.
5,7-Di-tert-butyl-3-phenyl-3H-benzofuran-2-one (3a); Typical
Procedure
1H NMR (300 MHz, CDCl3): = 7.35 (d, J = 2.1 Hz, 1 H, ArH),
7.12–6.95 (m, 4 H, ArH), 4.21 (br s, 2 H, NH2), 3.94 (s, 3 H, OCH3),
3.91 (s, 3 H, OCH3), 1.50 (s, 9 H, t-Bu), 1.35 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 153.0 (C), 149.9 (C), 147.7 (C),
146.3 (C), 146.1 (C), 132.9 (C), 130.4 (C), 126.7 (C), 120.4 (CH),
116.3 (CH), 112.5 (CH), 112.0 (CH), 111.7 (CH), 94.7 (C), 56.4
(CH3), 56.3 (CH3), 35.3 (C), 34.8 (C), 32.4 (CH3), 30.5 (CH3).
HCl (2 N; 4.8 mL, 9.58 mmol) was added at r.t. to 2-amino-3-phe-
nyl-5,7-di-tert-butylbenzofuran (2a) (3.08 g, 9.58 mmol) in i-PrOH
(10 mL). The mixture was stirred for 1.5 h. The precipitate was then
filtered off and washed with i-PrOH. The yellow residue was dried
under high vacuum (10–2 mbar) to give 3a.
Yield: 2.75 g (85%); pale yellow solid; mp 116–119 °C.
IR (neat): 2960, 2871, 1800, 1076, 893, 881, 747, 700 cm–1.
HPLC-MS (APCI): m/z (%) = 382 (100) [M + 1+].
Anal. Calcd for C24H31NO3: C, 75.56; H, 8.19; N, 3.67; O, 12.58.
Found: C, 75.51; H, 8.09; N, 3.57; O, 12.63.
1H NMR (300 MHz, CDCl3): = 7.40–7.25 (m, 4 H, ArH), 7.25–
7.10 (m, 2 H, ArH), 7.10–7.00 (m, 1 H, ArH), 4.83 (s, 1 H, CHAr),
1.44 (s, 9 H, t-Bu), 1.29 (s, 9 H, t-Bu).
3-(4-Bromophenyl)-5,7-di-tert-butylbenzofuran-2-ylamine (2d)
IR (KBr): 3415, 3330, 2962, 2904, 2868, 2383, 1649, 1489, 1427,
988 cm–1.
1H NMR (300 MHz, CDCl3): = 7.75–7.65 (m, 2 H, ArH), 7.55–
7.50 (m, 2 H, ArH), 7.42 (d, J = 2.1 Hz, 1 H, ArH), 7.21 (d, J = 2.1
Hz, 1 H, ArH), 4.37 (br s, 2 H, NH2), 1.65 (s, 9 H, t-Bu), 1.47 (s, 9
H, t-Bu).
13C NMR (75 MHz, CDCl3): = 153.4 (C), 146.4 (C), 133.2 (C),
133.0 (C), 132.7 (CH), 129.8 (C), 129.7 (CH), 119.7 (C), 116.6
(CH), 111.9 (CH), 93.8 (C), 35.3 (C), 34.8 (C), 32.4 (CH3), 30.5
(CH3).
13C NMR (75 MHz, CDCl3): = 173.5 (C), 147.7 (C), 145.3 (C),
133.5 (C), 131.4 (C), 127.0 (CH), 126.3 (CH), 126.0 (CH), 124.7
(C), 121.2 (CH), 117.6 (CH), 47.6 (CH), 32.8 (C), 32.4 (C), 29.5
(CH3), 27.6 (CH3).
HPLC-MS (APCI): m/z (%) = 323 (100) [M + 1+].
Anal. Calcd for C22H26O2: C, 81.95; H, 8.13. Found: C, 81.93; H,
8.13.
5,7-Di-tert-butyl-3-(3,4-dimethylphenyl)-3H-benzofuran-2-one
(3b)
IR (neat): 2958, 2871, 1800, 1483, 1224, 1117, 1070, 902, 878, 813,
MS (EI): m/z (%) = 401, 399 (100) [M+], 386 (26), 384 (26), 193
755 cm–1.
(24), 192 (24), 179 (34), 178 (36), 131 (21), 57 (71), 41 (19).
1H NMR (300 MHz, CDCl3): = 7.35–7.25 (m, 1 H, ArH), 7.15–
7.08 (m, 1 H, ArH), 7.08–6.98 (m, 2 H, ArH), 6.95–6.88 (m, 1 H,
ArH), 4.76 (s, 1 H, CHAr), 2.25 (s, 6 H, CH3), 1.44 (s, 9 H, t-Bu),
1.29 (s, 9 H, t-Bu).
Anal. Calcd for C22H26BrNO: C, 66.00; H, 6.55; Br, 19.96; N, 3.50;
O, 4.00. Found: C, 65.81; H, 6.52; Br, 19.7; N, 3.39; O, 4.16.
13C NMR (75 MHz, CDCl3): = 176.4 (C), 150.2 (C), 147.6 (C),
137.8 (C), 136.9 (C), 133.7 (C), 133.4 (C), 130.7 (CH), 130.1 (CH),
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PAPER
Synthesis and Use of 2-Amino-3-aryl-3H-benzofurans
253
127.5 (C), 126.1 (CH), 123.6 (CH), 120.1 (CH), 49.8 (CH), 35.3
(C), 34.8 (C), 32.0 (CH3), 30.1 (CH3), 20.2 (CH3), 19.8 (CH3).
HPLC-MS (APCI): m/z (%) = 351 (100) [M + 1+].
GCMS (EI): m/z (%) = 353 (21) [M + 1+], 352 (95) [M+], 337 (25),
309 (28), 297 (14), 296 (77), 294 (21), 293 (100), 240 (17), 203
(26), 147 (38), 104 (22), 91 (22), 57 (34), 41 (16).
Anal. Calcd for C23H28O3: C, 78.38; H, 8.01. Found: C, 78.06; H,
8.20.
Anal. Calcd for C24H30O2: C, 82.24; H, 8.63. Found: C, 81.91; H,
8.90.
Compound 4a; Typical Procedure
5,7-Di-tert-butyl-3-(3,4-dimethoxyphenyl)-3H-benzofuran-2-
one (3c)
Et3N (3.3 mL, 24.0 mmol) was added to a solution of 2-amino-3-
phenyl-5,7-di-tert-butylbenzofuran (2a) (7.00 g, 21.8 mmol) in an-
hyd THF (70 mL). The mixture was stirred for 20 min. at r.t. under
nitrogen, whereupon DMAP (266 mg, 21.8 mmol) and di-tert-butyl
dicarbonate (9.52 g, 43.6 mmol) were added. The resulting red mix-
ture was then heated under reflux for 90 min. After cooling to r.t.,
the mixture was poured into H2O (150 mL) and extracted with Et2O
(200 mL). The organic phase was repeatedly washed with H2O. The
combined organic phases were dried (MgSO4), filtered and concen-
trated to give 4a.
IR (neat): 2958, 2871, 1794, 1518, 1234, 1075, 1026, 901, 756 cm–1.
1H NMR (300 MHz, CDCl3): = 7.28–7.20 (m, 1 H, ArH), 7.02–
6.95 (m, 1 H, ArH), 6.80–6.65 (m, 3 H, ArH), 4.71 (s, 1 H, CHAr),
3.80 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 1.37 (s, 9 H, t-Bu), 1.23
(s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 176.2 (C), 150.1 (C), 149.8 (C),
149.3 (C), 147.7 (C), 133.8 (C), 128.2 (C), 127.2 (C), 123.6 (CH),
121.0 (CH), 120.2 (CH), 112.0 (CH), 111.9 (CH), 56.3 (CH3), 56.2
(CH3), 49.5 (CH), 35.2 (C), 34.8 (C), 32.0 (CH3), 30.0 (CH3).
Yield: 11.2 g (99%); light yellow resin.
HPLC-MS (APCI): m/z (%) = 383 (100) [M + 1+].
IR (neat): 2964, 1799, 1759, 1730, 1368, 1242, 1143, 1087, 869,
846, 700 cm–1.
1H NMR (300 MHz, CDCl3): = 7.48–7.15 (m, 7 H, ArH), 1.45 (s,
Anal. Calcd for C24H30O4: C, 75.36; H, 7.91. Found: C, 75.35; H,
7.93.
9 H, t-Bu), 1.30 (s, 9 H, t-Bu), 1.21 (s, 18 H, t-BuO).
3-(4-Bromophenyl)-5,7-di-tert-butyl-3H-benzofuran-2-one (3d)
IR (neat): 2961, 2867, 1810, 1480, 1360, 1071, 1013, 912, 811, 755
cm–1.
1H NMR (300 MHz, CDCl3): = 7.70–7.60 (m, 2 H, ArH), 7.52–
7.48 (m, 1 H, ArH), 7.30–7.22 (m, 2 H, ArH), 7.18–7.15 (m, 1 H,
ArH), 4.94 (s, 1 H, CHAr), 1.58 (s, 9 H, t-Bu), 1.44 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 173.0 (C), 147.7 (C), 145.5 (C),
132.5 (C), 131.6 (C), 130.2 (CH), 128.0 (CH), 124.4 (C), 121.6
(CH), 120.2 (C), 117.5 (CH), 47.1 (CH), 32.8 (C), 32.4 (C), 29.6
(CH3), 27.6 (CH3).
13C NMR (75 MHz, CDCl3): = 150.3 (C), 148.9 (C), 145.9 (C),
142.5 (C), 134.2 (C), 132.1 (C), 129.3 (CH), 128.4 (CH), 127.8
(CH), 119.9 (CH), 114.6 (CH), 83.8 (C), 35.4 (C), 34.9 (C), 32.3
(CH3), 30.3 (CH3), 28.1 (CH3).
MS (EI): m/z (%) = 521 (3) [M+], 421 (3), 365 (100), 321 (34), 306
(17), 57 (71), 41 (11).
8,10-Di-tert-butyl-6H-7-oxa-6-azabenzo[c]fluoren-5-one (6a);
Typical Procedure
A solution of 4a (24.4 g, 46.7 mmol) in decaline (200 mL) was
stirred for 20 h at 200 °C. The reaction mixture was cooled down
and a precipitate formed which was filtered off. The solid was
washed with hexane (2 × 10 mL) and dried under high vacuum
(10–2 mbar) to give 6a.
HPLC-MS (APCI): m/z (%) = 403, 401 (100) [M + 1+].
Anal. Calcd for C22H25BrO2: C, 65.84; H, 6.28; Br, 19.91; O, 7.97.
Found: C, 65.83; H, 6.32; Br, 19.7; O, 7.94.
Yield: 13.0 g (80%); white solid; mp > 300 °C.
IR (KBr): 2957, 2907, 2871, 1642, 1603, 749 cm–1.
1H NMR (400 MHz, CDCl3): = 12.40–11.60 (br s, 1 H, NH), 8.62
(d, J = 8.0 MHz, 1 H, ArH), 8.23 (d, J = 8.0 MHz, 1 H, ArH), 7.90
(s, 1 H, ArH), 7.88 (t, J = 8.0 MHz, 1 H, ArH), 7.53 (t, J = 8.0 MHz,
1 H, ArH), 7.35 (s, 1 H, ArH), 1.60 (s, 9 H, t-Bu), 1.50 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): = 163.9 (C), 150.1 (C), 148.9 (C),
147.5 (C), 134.9 (C), 134.6 (C), 133.9 (CH), 129.7 (CH), 125.2
(CH), 125.1 (C), 123.3 (C), 122.9 (CH), 118.9 (CH), 114.4 (CH),
96.2 (C), 35.5 (C), 35.0 (C), 32.4 (CH3), 30.5 (CH3).
5,7-Di-tert-butyl-3-(4-methylsulfanylphenyl)-3H-benzofuran-2-
one (3e)
IR (neat): 2965, 2871, 1796, 1613, 1477, 1077, 910, 812 cm–1.
1H NMR (300 MHz, CDCl3): = 7.48–7.42 (m, 1 H, ArH), 7.30–
7.23 (m, 2 H, ArH), 7.22–7.15 (m, 2 H, ArH), 7.10–7.05 (m, 1 H,
ArH), 4.82 (s, 1 H, CHAr), 2.50 (s, 3 H, SCH3), 1.53 (s, 9 H, t-Bu),
1.32 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 175.0 (C), 149.2 (C), 146.8 (C),
138.0 (C), 132.9 (C), 131.7 (C), 128.2 (CH), 126.5 (CH), 126.1 (C),
122.8 (CH), 119.0 (CH), 48.6 (CH), 34.3 (C), 33.8 (C), 31.0 (CH3),
29.1 (CH3), 15.2 (CH3).
MS (EI): m/z (%) = 348 (21) [M + 1+], 347 (100) [M+], 332 (50),
304 (58), 276 (64), 152 (14), 57 (10).
HPLC-MS (APCI): m/z (%) = 369 (100) [M + 1+].
Anal. Calcd for C23H28O2S: C, 74.96; H, 7.66; S, 8.70. Found: C,
74.80; H, 7.78; S, 8.75.
Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03; O, 9.21.
Found: C, 79.41; H, 7.35; N, 4.00; O, 9.10.
5,7-Di-tert-butyl-3-(2-methoxyphenyl)-3H-benzofuran-2-one
(3f)
6H-7-Oxa-6-azabenzo[c]fluoren-5-one (6b)
IR (neat): 2730, 1653, 1627, 1452, 880, 855, 761, 735 cm–1.
IR (neat): 2955, 2871, 1799, 1458, 1263, 1117, 1078, 931, 912, 747
1H NMR (300 MHz, THF-d8): = 8.50–8.38 (m, 1 H, ArH), 8.38–
8.25 (m, 1 H, ArH), 8.20–8.10 (m, 1 H, ArH), 7.90–7.75 (m, 1 H,
ArH), 7.65–7.52 (m, 1 H, ArH), 7.52–7.25 (m, 3 H, ArH).
13C NMR (75 MHz, THF-d8): = 159.9 (C), 151.9 (C), 150.7 (C),
132.5 (C), 131.0 (CH), 126.7 (CH), 123.4 (C), 122.9 (CH), 122.2
(CH), 121.6 (CH), 121.0 (CH), 120.6 (C), 118.0 (CH), 109.4 (CH),
94.1 (C).
cm–1.
1H NMR (300 MHz, CDCl3): = 7.38–7.20 (m, 3 H, ArH), 7.05–
6.95 (m, 1 H, ArH), 6.95–6.85 (m, 2 H, ArH), 4.94 (s, 1 H, CHAr),
3.71 (s, 3 H, OCH3), 1.49 (s, 9 H, t-Bu), 1.28 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): = 174.8 (C), 155.5 (C), 148.2 (C),
145.1 (C), 131.2 (C), 128.9 (CH), 127.9 (CH), 126.2 (C), 123.8 (C),
120.9 (CH), 119.4 (CH), 117.0 (CH), 110.2 (CH), 54.1 (CH3), 44.8
(CH), 33.1 (C), 32.7 (C), 30.0 (CH3), 28.0 (CH3).
MS (EI): m/z (%) = 236 (14) [M + 1+], 235 (100) [M+], 206 (17),
178 (5), 152 (11), 117 (7), 76 (11).
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254
M. Gerster, R. Wicki
PAPER
Anal. Calcd for C15H9NO2: C, 76.59; H, 3.86; N, 5.95; O, 13.60.
Found: C, 76.38; H, 4.01; N, 5.92; O, 13.57.
7,9-Di-tert-butyl-5H-6-oxa-1-thia-5-azacyclopenta[c]fluoren-4-
one (6e)
IR (neat): 2957, 1618, 1593, 1485, 1360, 1068, 861, 685 cm–1.
10-Methyl-8-(1-methylheptadecyl)-6H-7-oxa-6-azabenzo[c]flu-
oren-5-one (6c)
1H NMR (400 MHz, CDCl3): = 7.77 (d, J = 5.2 MHz, 1 H, ArH),
7.58 (d, J = 2.0 MHz, 1 H, ArH), 7.31 (d, J = 2.0 MHz, 1 H, ArH),
7.29 (d, J = 5.6 MHz, 1 H, ArH), 1.53 (s, 9 H, t-Bu), 1.41 (s, 9 H, t-
Bu).
IR (neat): 2921, 2851, 1627, 1602, 1434, 1333, 1184, 1134, 838,
751 cm–1.
1H NMR (300 MHz, CDCl3): = 10.65 (br s, 1 H, NH), 8.54 (d,
J = 7.5 MHz, 1 H, ArH), 8.10 (d, J = 8.1 MHz, 1 H, ArH), 7.77 (t,
J = 7.2 MHz, 1 H, ArH), 7.57 (s, 1 H, ArH), 7.43 (t, J = 7.5 MHz, 1
H, ArH), 6.91 (s, 1 H, ArH), 3.35–3.15 (m, 1 H, CHCH3), 2.46 (s, 3
H, ArCH3), 1.80–1.55 (m, 2 H), 1.32 (d, J = 6.9 MHz, 3 H, CHCH3),
1.30–1.00 (m, 28 H), 0.85–0.70 (m, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): = 164.2 (C), 150.5 (C), 149.1 (C),
134.9 (C), 134.3 (C), 133.9 (CH), 131.8 (CH), 129.6 (C), 125.2
(CH), 124.7 (C), 123.2 (C), 122.9 (CH), 117.5 (CH), 96.5 (C), 36.5
(CH2), 34.1 (CH3), 32.3 (CH2), 30.1 (CH2), 30.0 (CH2), 29.8 (CH2),
28.2 (CH2), 23.1 (CH2), 22.2 (CH3), 21.6 (CH3), 14.5 (CH3).
13C NMR (100 MHz, CDCl3): = 159.3 (C), 152.7 (C), 149.4 (C),
147.6 (C), 144.2 (C), 134.8 (C), 125.0 (C), 124.6 (CH), 123.3 (C),
122.7 (CH), 120.0 (CH), 114.2 (CH), 99.4 (C), 35.4 (C), 35.1 (C),
32.3 (CH3), 30.5 (CH3).
MS (EI): m/z (%) = 354 (21) [M + 1+], 353 (100) [M+], 339 (15),
338 (71), 282 (33), 155 (12), 134 (11), 57 (23), 41 (13).
Anal. Calcd for C21H23NO2S: C, 71.36; H, 6.56; N, 3.96; O, 9.05; S,
9.07. Found: C, 71.66; H, 6.48; N, 3.67; O, 8.97; S, 8.88.
Acknowledgment
MS (EI): m/z (%) = 502 (31) [M + 1+], 501 (100) [M+], 277 (31),
We wish to thank P. Nesvadba, S. Evans, P. Dubs and M. Tinkl for
helpful discussions and A. Thomas for useful comments during the
preparation of the manuscript.
276 (50), 262 (33), 130 (11), 43 (14).
HRMS (ESI): m/z (%) calcd for C34H48NO2 [M + H+]: 502.3685;
found: 502.3646.
8,10-Di-tert-butyl-6H-7-oxa-6-azaindeno[1,2-a]phenanthren-5-
one (6d)
References
(1) (a) Hinsken, H.; Mayerhöfer, H.; Müller, W.; Schneider, H.
WO-A-80/01566, 1980; Chem. Abstr. 1981, 94, 16620.
(b) Nesvadba, P.; Evans, S.; Kröhnke, C.; Zingg, J. DE-A-
94/4432732, 1994; Chem. Abstr. 1995, 123, 55685.
(2) Bistrzycki, A.; Flatau, J. Chem. Ber. 1895, 28, 989.
(3) Hewgill, R. F.; Howie, G. B. Aust. J. Chem. 1978, 31, 907.
(4) Smith, L. I.; Dale, W. J. J. Org. Chem. 1950, 15, 832.
(5) Nesvadba, P.; Bugnon, L.; Dubs, P.; Evans, S. Synlett 1999,
S1, 863.
(6) Tinkl, M.; Evans, S.; Nesvadba, P. WO-A2-99/67232,
1999; Chem. Abstr. 1999, 132, 64163.
(7) For a review on quinone methides, see: Grünager, P.
Houben–Weyl, Methoden der organischen Chemie, Vol.
VII/3b; Thieme: Stuttgart, 1979, 395.
IR (neat): 2962, 2479, 1600,1422, 1246, 1209, 1087, 1060, 855, 817
cm–1.
1H NMR (400 MHz, CDCl3): = 12.60 (br s, 1 H, NH), 10.28 (d,
J = 8.4 MHz, 1 H, ArH), 8.37 (d, J = 8.8 MHz, 1 H, ArH), 8.25 (d,
J = 8.8 MHz, 1 H, ArH), 8.05–7.95 (m, 2 H, ArH), 7.85–7.78 (m, 1
H, ArH), 7.68–7.60 (m, 1 H, ArH), 7.39 (d, J = 2.0 MHz, 1 H, ArH),
1.65 (s, 9 H, t-Bu), 1.51 (s, 9 H, t-Bu).
13C NMR (75 MHz, DMSO-d6): = 160.1 (C), 146.5 (C), 144.6 (C),
133.9 (CH), 132.5 (C), 131.4 (C), 129.6 (C), 129.2 (C), 127.0 (CH),
126.4 (CH), 124.5 (CH), 123.8 (CH), 122.3 (C), 119.7 (CH), 116.7
(CH), 113.0 (CH), 33.15 (C), 32.4 (C), 30.0 (CH3), 27.9 (CH3).
MS (EI): m/z (%) = 398 (25) [M + 1+], 397 (100) [M+], 382 (29),
326 (11), 191 (11), 177 (12), 57 (10), 41 (7).
(8) (a) For a review on Mannich bases, see: Tramontini, S.
Synthesis 1973, 703. (b) Van de Water, R. W.; Pettus, T. R.
R. Tetrahedron 2002, 58, 5367.
Anal. Calcd for C27H27NO2: C, 81.58; H, 6.85; N, 3.52; O, 8.05.
Found: C, 81.51; H, 7.08; N, 3.46; O, 8.22.
(9) Stafford, J. A.; Brackeen, M. F.; Karanewsky, D. S.;
Valvano, N. L. Tetrahedron Lett. 1993, 34, 7873.
Synthesis 2004, No. 2, 249–254 © Thieme Stuttgart · New York