A palladium-catalyzed ullmann-ziegler cross-coupling for sterically hindered biaryls

Article abstract of DOI:10.1055/s-0030-1259968

We present a facile and versatile biaryl cross-coupling procedure based on a modified Ullmann coupling that may be applied to a wide range of substrates. This even allows the coupling of sterically hindered substrates under mild reaction conditions. Georg

Full text of DOI:10.1055/s-0030-1259968

PAPER
1249
A Palladium-Catalyzed Ullmann–Ziegler Cross-Coupling for Sterically
Hindered Biaryls
S
tericallyHindered Bi
a
aryls x P. Nüllen, Richard Göttlich*
Institut für Organische Chemie, Justus Liebig Universität Gießen, Heinrich Buff Ring 58, 35392 Gießen, Germany
Fax +49(641)9934349; E-mail: richard.goettlich@org.chemie.uni-giessen.de
Received 12 January 2011; revised 15 February 2011
One of the first reactions to form an aryl–aryl bond was
the reductive copper-mediated coupling reaction between
two aryl halides in the presence of copper powder first de-
scribed in 1901 by Ullmann17 (Scheme 1). Unfortunately,
this procedure leads in most cases to symmetrical biaryl
products and often requires harsh reaction conditions.
Subsequently improved protocols have been developed.
Ziegler18 and co-workers described a modification of the
Ullmann biaryl synthesis allowing the cross-coupling of
aryl halides at ambient temperature.19 It relies on the pre-
formation of an aryl–copper species by lithiation and
transmetalation, but has certain requirements regarding
the substitution pattern of the aromatic substrates, for
example, a coordinating substituent (nitrogen or sulfur)
ortho to the halide.
Abstract: We present a facile and versatile biaryl cross-coupling
procedure based on a modified Ullmann coupling that may be ap-
plied to a wide range of substrates. This even allows the coupling of
sterically hindered substrates under mild reaction conditions.
Key words: biaryls, catalysis, copper, cross-coupling, palladium
The synthesis of functionalized biaryl compounds has re-
ceived much interest due to the importance of the biaryl
moiety in natural products1 and functional molecules.2
Many examples of this scaffold are present in pharmaceu-
tically active compounds3 such as antibiotic,4 antihyper-
tensive,5
anti-inflammatory,6
antimalarial,7
and
anticancer8 agents, and they play an equally important
role in the synthesis of new organic materials such as
organic semiconductors,9 OLEDs,10 and liquid crystals.2a
X
X
R
+
Among this multitude of compounds, ellagic acid (1), and
its higher hydroxylated homologues flavellagic acid (2)
and coruleoellagic acid (3) (Figure 1) triggered our inter-
est, as they possess an interesting range of pharmaceutical
properties,11 for example, against malaria12 and cancer.13
For the synthesis of these compounds, an aryl–aryl cou-
pling is often the key-step.
Cu(0)
+
2 CuX
R
R
R
X = I, Br, Cl
Scheme 1 Classical Ullmann synthesis of symmetrical biaryls
We wish to report herein our efforts in developing an im-
proved variant of the Ullmann–Ziegler cross-coupling re-
action. We particularly focused our attention on biaryls
derived from gallic acid (4) derivatives as these com-
pounds are useful precursors for the synthesis of ellagic
acid derivatives and other compounds based on the 6H-
benzo[c]chromen-6-one scaffold, for example, alternariol
(5) (Figure 2).
R1
O
HO
HO
O
OH
OH
O
R2
O
R1 = R2 = H
R
R
ellagic acid (1):
flavellagic acid (2):
coruleoellagic acid (3):
O
OH
OH
1 = H, R2 = OH
1 = R2 = OH
HO
Figure 1 Ellagic acid (1), flavellagic acid (2), and coruleoellagic
acid (3)
O
HO
OH
OH
OH
O
It is therefore hardly surprising that the development of
efficient protocols for the synthesis of biaryl compounds
has received a great deal of interest, leading to a vast va-
riety of procedures amongst which transition-metal-
catalyzed reactions are the most common ones.14–16
4
5
Figure 2 Gallic acid (4) and alternariol (5)
Similar to the method described by Ziegler, 3,4,5-tri-
methoxybenzoic acid diethylamide (6a) was treated with
s-BuLi/TMEDA at –78 °C to effect ortho-lithiation [di-
rected ortho-metalation (DoM)], followed by transmetala-
tion with a copper(I) salt to give intermediate 7a. To the
thus obtained organocopper solution was added Pd(PPh3)4
SYNTHESIS 2011, No. 8, pp 1249–1254
x
x
.
x
x
.2
0
1
1
Advanced online publication: 24.03.2011
DOI: 10.1055/s-0030-1259968; Art ID: T10911SS
© Georg Thieme Verlag Stuttgart · New York

1250
M. P. Nüllen, R. Göttlich
PAPER
as catalyst and iodobenzene, which after heating under re- could be detected, only small quantities of homocoupling
flux for 12 hours gave the desired cross-coupling product products were found (Table 1, entries 11, 12).
8 in good yield (Table 1, entries 1, 2) with only minor
To determine the scope of the reaction protocol regarding
amounts of homocoupling or dehalogenation products.
the range of substrates, several DoM precursors, as well as
For the reaction, CuBr·SMe2 and CuI proved to be equally
aryl halides were employed. Aryl bromides gave compa-
suitable, while the Liebeskind reagent [copper(I)
rable results (Table 2, entries 1, 5, 6, 7) to iodides while
thiophene 2-carboxylate]20 led to slightly inferior results.
aryl chlorides (entry 2) were unsuitable. Even sterically
We were also able to show that the lithiation additive
demanding coupling partners with ortho substituents (en-
TMEDA seems to play an important role for the outcome
try 3), or with a naphthalene body (entry 5), or heteroaro-
of the reaction by affecting the solubilization of the aryl-
matics (entry 6) gave satisfactory results.
copper intermediate. Upon addition of the copper(I) salt,
On the other hand, the arylcopper compound seemed to
an insoluble precipitate formed when no TMEDA was
require an amide (entries 1–8) or a carbamate (entry 11) in
added. No cross-coupling was observed in these cases.
the ortho-position to the coupling site to achieve satisfac-
As an alternative to conventional heating, the reaction was
tory yields. This is probably due to the coordinating effect
also carried out in a microwave reactor that proved to give
of these functional groups to copper, thereby stabilizing
comparable yields, but speeded up the coupling signifi-
the organocopper intermediate. Substitution of the amide
cantly (30 min compared to 12 h, Table 1, entries 2 vs. 4).
or carbamate for oxygen-containing donors like ethers
Several established palladium catalysts were tested, (entries 9, 10) led to reduced yields.
which all gave satisfactory to good yields (58–81%), ex-
To achieve the efficient coupling of such organocopper
cept PdCl2 which gave only 20% of the desired product.
compounds the solvent was changed from THF to a THF–
Also nickel catalysts may be employed as shown for the
pyridine mixture, with pyridine being able to provide fur-
catalyst system NiCl2(PPh)2/PPh3 (Table 1, entry 10). To
ther stabilization for the arylcopper intermediate and the
verify the necessity of a catalyst, in contrast to the Ziegler
aryllithium to copper ratio was increased to 2:1. By doing
method, control experiments were conducted: In all cases
so, we were able to couple the aryl copper derived from
where the catalyst was omitted, no cross-coupling product
resorcinol dimethyl ether (7c) for which two examples are
shown (Table 2, entries 9, 10).
Table 1 Optimization of Reaction Conditions
O
NEt2
O
NEt2
Cu
O
NEt2
1. s-BuLi, TMEDA
2. CuX
3. catalyst, PhI
THF, Δ
THF, −78 °C
MeO
OMe
MeO
OMe
MeO
OMe
OMe
6a
OMe
OMe
8a
7a
Entry
1
CuX
Catalyst
Conditions
Yield (%)
CuBr·SMe2
7.5 mol% Pd(PPh3)4
7.5 mol% Pd(PPh3)4
7.5 mol% Pd(PPh3)4
7.5 mol% Pd(PPh3)4
7.5 mol% Pd(PPh3)4
80 °C, 12 h
79
78
–
2
CuI
80 °C, 12 h
3a
4
CuI
80 °C, 12 h
CuI
MW,b 110 °C, 30 min
MW,b 110 °C, 30 min
80 °C, 12 h
81
60
78
20
66
58
62
–
5
CuTCc
6
CuBr·SMe2
7.5 mol% PdCl2(dppe)
7.5 mol% PdCl2
7
CuI
80 °C, 12 h
8
CuI
7.5 mol% Pd(PCy3)2
3 mol% PEPPSI-IPr
5 mol% NiCl2(PPh3)2/10 mol% Ph3P
no catalyst
MW,b 110 °C, 30 min
MW,b 110 °C, 30 min
MW,b 110 °C, 30 min
80 °C, 12 h
9
CuI
10
11
12
CuI
CuI
CuI + P(OEt)3 (1 equiv)
no catalyst
80 °C, 12 h
–
a t-BuLi, no TMEDA.
b Pmax = 200 W.
c Copper(I) thiophene-2-carboxylate.
Synthesis 2011, No. 8, 1249–1254 © Thieme Stuttgart · New York

PAPER
Sterically Hindered Biaryls
1251
Table 2 Screening of Substrates
containing ortho substituent on both substrates. Our pro-
tocol allows a facile cross-coupling even of sterically hin-
dered arenes employing easily available reagents.
Entry Ar1–Cu, Methoda
Ar2–X
Product Yield
Ar1–Ar2 (%)
O
NEt2
Cu
All reactions were carried out under inert atmosphere, unless other-
wise mentioned, following standard syringe septa techniques. Sol-
vents were purified by distillation and dried, if necessary, prior to
use. Reactions conducted by heating with microwaves were carried
out in a CEM Discover apparatus (CEM Corp.). Products were pu-
1
8a
76
Br
Cl
MeO
OMe
OMe
rified by flash chromatography on silica gel 60 (Merck). 1H and 13
C
7a, A
7a, A
NMR spectra were recorded on a Bruker Avance II 200 spectrome-
ter (1H at 200 MHz; 13C at 50 MHz), Bruker Avance II 400 spec-
trometer (1H at 400 MHz; 13C at 100 MHz) and Bruker Avance III
600 spectrometer (1H at 600 MHz; 13C at 150 MHz) in CDCl3 using
TMS as internal standard. IR spectra were recorded on a Bruker IFS
25 spectrometer. EI-MS were obtained using a Finnigan MAT 95
mass spectrometer, ESI-MS were obtained using a Bruker Daltonics
MicroTOF spectrometer. Melting points were measured on a Krüss
Optronics melting point apparatus and are uncorrected.
2
3
4
5
–
–
I
7a, A
7a, A
7a, A
8b
8c
8d
76
79
63
MeO
I
NO2
3,4,5-Trimethoxybenzoic Acid Diethylamide (6a)
Br
To a solution of 3,4,5-trimethoxybenzoic acid (6.0 g, 28.3 mmol) in
anhyd CH2Cl2 (50 mL) was added SOCl2 (13.9 g, 115 mmol, 8.5 mL)
and the resulting mixture was heated overnight at 45 °C. After cool-
ing to r.t., the solvent and excess SOCl2 were removed under re-
duced pressure. The obtained residue was dissolved in anhyd THF
(50 mL) and cooled to 0 °C. Et2NH (12.4 g, 170 mmol, 17.5 mL)
was added slowly by syringe and the reaction mixture was stirred
for 1 h at r.t., after which the mixture was diluted with H2O (50 mL)
and extracted with EtOAc (3 × 50 mL). The combined organic lay-
ers were washed with brine (50 mL) and dried (MgSO4). After re-
moval of the solvents in vacuo, the product was purified by flash
chromatography on silica gel [pentane–MTBE (1:1) to MTBE] to
yield 6a (6.1 g, 81%) as colorless oil, which solidified upon stand-
ing; mp 52 °C.
Br
6
7
7a, A
8e
8f
84
65
N
Br
OMe
7a, A
OMe
O
NEt2
Cu
8
8g
53
I
IR (KBr): 2972, 2936, 1629, 1582, 1507, 1473, 1410, 1332, 1276,
1235, 1126, 1003, 855, 824, 764 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.15 (br s, 6 H), 3.37 (br d, 4 H),
7b, A
7c, B
7c, B
3.80 (s, 3 H), 3.82 (s, 6 H), 6.54 (s, 2 H).
OMe
13C NMR (100 MHz, CDCl3): d = 12.9, 14.3, 39.4, 43.4, 56.2, 60.9,
103.6, 132.6, 138.7, 153.2, 171.0.
O
CuLi
9
8h
8i
66
44
Et2N
MS (ESI+): m/z (%) = 290.1 (75, [M + Na]+), 557.3 (100, [2 M +
2
OMe
OMe
Na]+), 824.4 (50, [3 M + Na]+).
I
HRMS (ESI): m/z [M + Na]+ calcd for C14H21NO4 + Na: 290.1368;
found: 290.1369.
Br
Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C,
62.60; H, 7.89; N, 5.23.
CuLi
O
10
2
OMe
Ullmann Cross-Coupling Reactions
General Procedure A
In an oven-dried Schlenk flask, the respective amide and TMEDA
(1.1 equiv) were dissolved in anhyd THF (10 mL) and cooled to
–78 °C. s-BuLi (1.3 M solution in cyclohexane, 1.1 equiv) was added
slowly and the resulting mixture was stirred 30 min. CuBr·SMe2 or
CuI (1.1 equiv) was added as solid, the cooling bath was removed,
and the reaction was allowed to stir for 15 minutes. Pd(PPh3)4
(7.5 mol%) was added, followed by the aryl halide. The reaction
was heated for 12 h at 60 °C and was subsequently quenched by the
addition of sat. aq NH4Cl (10 mL). The layers were separated and
the aqueous layer was extracted with MTBE (3 × 15 mL). The com-
bined organic layers were washed first with a 30% aq solution of
ammonia (15 mL) and then with brine (15 mL). After drying
(MgSO4), the solvent was removed in vacuo and the product was
O
I
NEt2
Cu
O
11
8j
79
Et2N
O
O
EtO
7d, C
a Method A: THF, 60 °C, 12 h; method B: THF–py or DME–py,
60 °C, 12 h; method C: THF, MW, 110 °C, Pmax = 200 W, 30 min.
In conclusion, the procedure described above is a useful
supplement to the Ullmann–Ziegler cross-coupling as it
expands the range of substrates to those without a nitrogen
Synthesis 2011, No. 8, 1249–1254 © Thieme Stuttgart · New York

1252
M. P. Nüllen, R. Göttlich
PAPER
isolated from the residue by flash chromatography on silica gel
(pentane–MTBE).
N,N-Diethyl-4,5,6-trimethoxy-4¢-nitro[1,1¢-biphenyl]-2-carbox-
amide (8c)
Prepared according to general procedure A using amide 6a (260 mg,
0.97 mmol) and 4-iodonitrobenzene (242 mg, 0.97 mmol) yielding
8c (298 mg, 79%) after flash chromatography on silica gel [pen-
tane–MTBE (1:2) to MTBE] as yellow solid; mp 161 °C.
General Procedure B
In an oven-dried Schlenk flask the 1,3-dimethoxybenzene and
TMEDA (2.2 equiv) were dissolved in anhyd DME (3 mL) and
cooled to –78 °C. n-BuLi (1.6 M solution in hexanes, 2.2 equiv) was
added slowly and the resulting mixture was stirred 90 min.
CuBr·SMe2 (1 equiv) was added as solid, the cooling bath was re-
moved and the reaction was allowed to stir for 30 min. Pd(PPh3)4
(7.5 mol%) was added, followed by a solution of aryl halide
(1 equiv) in anhyd pyridine (3 mL). The reaction was heated for 12
h at 60 °C in a sealed vessel and was subsequently quenched by the
addition of sat. aq NH4Cl (10 mL). The layers were separated and
the aqueous layer was extracted with MTBE (3 × 15 mL). The com-
bined organic layers were washed first with a 30% aq solution of
ammonia (15 mL) and then with brine (15 mL). After drying
(MgSO4), the solvent was removed in vacuo and the product was
isolated from the residue by flash chromatography (pentane–
MTBE) (Table 2).
IR (film): 2975, 2936, 1628, 1595, 1513, 1464, 1390, 1342, 1332,
1280, 1192, 1152, 1131, 1092, 1040, 1000, 840, 800, 752, 715 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.75 (t, J = 7.1 Hz, 3 H), 0.85 (t,
J = 7.1 Hz, 3 H), 2.69 (br s, 1 H), 2.90 (br s, 1 H), 3.01 (br s, 1 H),
3.55–3.75 (m, 4 H), 3.90 (s, 3 H), 3.92 (s, 3 H), 6.68 (s, 1 H), 7.57
(d, J = 8.9 Hz, 2 H), 8.19 (d, J = 8.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 12.0, 13.8, 38.4, 42.5, 56.3, 61.2,
61.3, 105.8, 123.0, 123.2, 131.3, 132.7, 142.4, 142.8, 147.0, 151.2,
154.2, 169.1.
MS (EI, 70 eV): m/z (%) = 255 (28), 270 (63), 316 (100, [M –
NEt2]+), 373 (24, [M – CH3]+), 388 (66, [M]+).
HRMS (EI): m/z calcd for C20H24N2O6: 388.1634; found: 343.1632.
Anal. Calcd for C20H24N2O6: C, 61.84; H, 6.23; N, 7.21. Found: C,
62.05; H, 6.19; N, 7.32.
N,N-Diethyl-4,5,6-trimethoxy[1,1¢-biphenyl]-2-carboxamide
(8a)
Prepared according to general procedure A using amide 6a (250 mg,
0.94 mmol) and iodobenzene (380 mg, 1.87 mmol, 0.21 mL) yield-
ing 8a (255 mg, 79%) after flash chromatography on silica gel [pen-
tane–MTBE (1:2) to MTBE] as a white solid; mp 111 °C.
N,N-Diethyl-3,4,5-trimethoxy-2-(naphthalen-2-yl)benzamide
(8d)
Prepared according to general procedure A using amide 6a (275 mg,
1.02 mmol) and 2-bromonaphthalene (213 mg, 1.03 mmol, 0.13
mL) yielding 8d (254 mg, 63%) after flash chromatography on sil-
ica gel (pentane–MTBE, 1:3) as a pale yellow solid; mp 114 °C.
IR (film): 2971, 2934, 1631, 1594, 1471, 1429, 1396, 1333, 1275,
1155, 1127, 1096, 1007, 752, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.70 (t, J = 7.1 Hz, 3 H), 0.83 (t,
J = 7.1 Hz, 3 H), 2.62 (m, 1 H), 2.82 (m, 1 H), 3.06 (m, 1 H), 3.57
(s, 3 H), 3.74 (m, 1 H), 3.90 (s, 3 H), 3.93 (s, 3 H), 6.69 (s, 1 H),
7.24–7.46 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 11.8, 13.7, 38.0, 42.2, 56.2, 61.1,
61.2, 105.6, 125.6, 127.3, 127.9, 130.2, 132.9, 135.2, 142.7, 151.3,
153.2, 169.8.
IR (film): 2972, 2935, 1621, 1463, 1429, 1399, 1332, 1270, 1153,
1121, 1091, 1010, 924, 731 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.51 (t, J = 7.0 Hz, 3 H), 0.79 (t,
J = 7.0 Hz, 3 H), 2.51–2.64 (m, 1 H), 2.69–2.82 (m, 1 H), 3.04–3.16
(m, 1 H), 3.55 (s, 3 H), 3.60–3.72 (m, 1 H), 3.92 (s, 3 H), 3.96 (s, 3
H), 6.74 (s, 1 H), 7.43–7.50 (m, 2 H), 7.54 (d, J = 8.4 Hz, 1 H),
7.80–7.86 (m, 3 H), 7.88 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.8, 13.7, 38.2, 42.4, 56.2, 61.1,
61.2, 105.8, 125.4, 125.9, 126.0, 127.2, 127.6, 128.3, 128.5, 129.1,
132.5, 132.8, 133.1 (2 ×), 142.8, 151.5, 153.3, 169.8.
MS (EI, 70 eV): m/z (%) = 256 (86), 271 (100, [M – NEt2]+), 343
(69, [M]+).
HRMS (EI): m/z calcd for C20H25NO4: 343.1784; found: 343.1791.
MS (EI, 70 eV): m/z (%) = 256 (24), 271 (30), 291 (20), 306 (44),
Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C,
69.83; H, 7.30; N, 3.98.
322 (89, [M – NEt2]+), 343 (20), 393 (74, [M]+).
HRMS (EI): m/z calcd for C24H27NO4: 393.1940; found: 343.1946.
N,N-Diethyl-2¢,4,5,6-tetramethoxy[1,1¢-biphenyl]-2-carboxam-
ide (8b)
Prepared according to general procedure A using amide 6a (250 mg,
0.94 mmol) and 2-iodoanisole (219 mg, 0.94 mmol) yielding 8b
(266 mg, 76%) after flash chromatography on silica gel (pentane–
MTBE, 1:4) as a white solid; mp 97 °C.
Anal. Calcd for C24H27NO4: C, 73.26; H, 6.92; N, 3.56. Found: C,
73.25; H, 6.96; N, 3.32.
N,N-Diethyl-3,4,5-trimethoxy-2-(pyrid-3-yl)benzamide (8e)
Prepared according to general procedure A using amide 6a (250 mg,
0.94 mmol) and 3-bromopyridine (148 mg, 0.94 mmol) yielding 8e
(272 mg, 84%) after flash chromatography on Al2O3 (pentane–
MTBE, 1:3) as a pale yellow solid; mp 85 °C.
IR (film): 2971, 2937, 1632, 1595, 1463, 1430, 1397, 1334, 1242,
1154, 1115, 1089, 1006, 802, 755 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.61 (t, J = 7.1 Hz, 3 H), 0.88 (t,
J = 7.1 Hz, 3 H), 2.93–2.48 (m, 2 H), 3.37–3.13 (m, 2 H), 3.69 (s, 3
H), 3.75 (s, 3 H), 3.89 (s, 6 H), 6.67 (s, 1 H), 6.99–6.82 (m, 2 H),
7.31–7.21 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 11.7, 13.9, 37.7, 41.6, 55.1, 56.0,
60.8, 104.7, 109.8, 120.4, 122.1, 124.4, 128.9, 132.2, 133.1, 141.8,
152.0, 153.2, 156.9, 169.6.
IR (film): 2972, 2936, 1630, 1471, 1430, 1395, 1335, 1281, 1220,
1155, 1128, 1096, 1036, 1002, 793, 716 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.68 (t, J = 7.1 Hz, 3 H), 0.80 (t,
J = 7.1 Hz, 3 H), 2.70–2.56 (m, 1 H), 2.87–2.71 (m, 1 H), 3.06–2.91
(m, 1 H), 3.55 (s, 3 H), 3.71–3.60 (m, 1 H), 3.84 (s, 3 H), 3.86 (s, 3
H), 6.64 (s, 1 H), 7.71–7.65 (m, 1 H), 8.48 (dd, J = 4.8, 1.5 Hz, 1 H),
8.53 (d, J = 1.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 12.0, 13.7, 38.2, 42.3, 56.2, 61.1,
61.2, 105.7, 121.8, 122.9, 131.2, 133.1, 137.7, 142.7, 148.3, 150.7,
151.3, 153.8, 169.2.
MS (EI, 70 eV): m/z (%) = 73 (100), 195 (43, [M – NEt2
–
PhOMe]+), 286 (22), 301 (77, [M – NEt2]+), 342 (21, [M – OMe]+),
373 (28, [M]+).
MS (ESI+): m/z (%) = 345.2 (100, [M + Na]+).
HRMS (EI): m/z calcd for C21H27NO5: 373.1889; found: 373.1887.
HRMS (ESI+): m/z calcd for C19H25N2O4: 345.1814; found:
345.1823.
Synthesis 2011, No. 8, 1249–1254 © Thieme Stuttgart · New York

PAPER
Sterically Hindered Biaryls
2-(2,6-Dimethoxyphenyl)naphthalene (8i)
Prepared according to general procedure B using 1,3-dimethoxy-
benzene (257 mg, 1.86 mmol, 0.24 mL) and 2-bromonaphthalene
(193 mg, 0.93 mmol) yielding 8i (108 mg, 44%) after flash chroma-
tography on silica gel (pentane–MTBE, 3:1 to 1:1) as a colorless oil.
1253
N,N-Diethyl-3¢,4,5,5¢,6-pentamethoxy[1,1¢-biphenyl]-2-carbox-
amide (8f)
Prepared according to general procedure A using amide 6a (250 mg,
0.94 mmol) and 3,5-dimethoxybromobenzene (202 mg, 0.94 mmol)
yielding 8f (242 mg, 65%) after flash chromatography on silica gel
[pentane–MTBE (1:1) to MTBE] as a colorless oil.
IR (film): 3053, 3003, 2937, 2835, 1602, 1587, 1471, 1430, 1246,
1109, 1037, 1025, 858, 819, 783, 749, 728 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.63 (s, 6 H), 6.58 (d, J = 8.4 Hz,
2 H), 7.21 (t, J = 8.4 Hz, 1 H), 7.34–7.39 (m, 3 H), 7.74–7.78 (m, 4
IR (film): 2971, 2937, 1627, 1593, 1460, 1426, 1394, 1329, 1272,
1240, 1204, 1153, 1125, 1100, 1064, 1019, 846, 814, 795 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.76 (t, J = 7.5 Hz, 3 H), 0.85 (t,
J = 7.5 Hz, 3 H), 2.68 (m, 1 H), 2.84 (m, 1 H), 3.07 (m, 1 H), 3.62
(s, 3 H), 3.77 (s, 6 H), 3.82–3.87 (m, 1 H), 3.88 (s, 3 H), 3.90 (s, 3
H), 6.41 (t, J = 2.3 Hz, 1 H), 6.55 (d, J = 2.3 Hz, 2 H), 6.66 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.7, 13.7, 38.0, 42.4, 55.3, 56.1,
61.0, 61.1, 99.8, 105.5, 108.1, 125.3, 132.7, 136.9, 142.6, 151.2,
153.1, 160.1, 169.7.
H).
13C NMR (100 MHz, CDCl3): d = 55.9, 104.2, 119.4, 125.5, 126.9,
127.6, 128.1, 128.8, 129.3, 129.7, 131.7, 132.4, 133.3, 157.8.
MS (ESI+): m/z (%) = 265.1 (100, [M + H]).
HRMS (ESI+): m/z calcd for C18H17NO2: 265.1229; found:
265.1227.
MS (ESI+): m/z (%) = 404.2 (100, [M + H]+), 426.2 (60, [M +
Na]+).
5-[2-(Diethylcarbamoyl)phenyl]-2-ethoxy-2-methylben-
HRMS (ESI+): m/z calcd for C22H30NO6 + Na: 404.2073; found:
zo[d][1,3]dioxol-4-yl Diethylcarbamate (8j)
404.2069.
In an oven-dried flask, 2-ethoxy-5-iodo-2-methylbenzo[d][1,3]di-
oxol-4-yl diethylcarbamate (250 mg, 0.59 mmol) was dissolved in
anhyd THF (10 mL) and cooled to –78 °C. t-BuLi (1.5 M solution
in pentane, 2.3 equiv) was added slowly and the resulting mixture
was stirred 45 min. Copper(I) thiophene-2-carboxylate was added
as solid, the cooling bath was removed, and the reaction mixture
was allowed to stir for 15 min. Pd(PPh3)4 (7.5 mol%) was added,
followed by the aryl halide. The reaction mixture was transferred to
a sealed glass vial and heated in a microwave reactor (110 °C,
Pmax = 220 W, 30 min). The reaction was subsequently quenched by
the addition of sat. aq NH4Cl (10 mL). The layers were separated
and the aqueous layer was extracted with MTBE (3 × 15 mL). The
combined organic layers were washed first with a 30% aq solution
of ammonia (15 mL) and then with brine (15 mL). After drying
(MgSO4), the solvent was removed in vacuo. The product was iso-
lated from the residue by flash chromatography on silica gel (pen-
tane–MTBE, 5:1 to 1:2) as a pale yellow oil (220 mg, 79%).
Anal. Calcd for C22H29NO6: C, 65.49; H, 7.24; N, 3.47. Found: C,
65.47; H, 7.43; N, 3.42.
N,N-Diethyl-4-methyl[1,1¢-biphenyl]-2-carboxamide (8g)
Prepared according to general procedure A using amide 6b (191
mg, 1 mmol) and iodobenzene (204 mg, 0.97 mmol, 0.12 mL) yield-
ing 8g (141 mg, 53%) after flash chromatography on silica gel (pen-
tane–MTBE, 1:1) as a colorless oil.
IR (film): 2973, 2934, 1627, 1458, 1428, 1380, 1315, 1289, 1221,
1093, 840, 822, 779, 766, 735, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.72 (t, J = 7.2 Hz, 3 H), 0.88 (t,
J = 7.2 Hz, 3 H), 2.40 (s, 3 H), 2.56–2.71 (m, 1 H), 2.88–3.05 (m, 2
H), 3.66–3.84 (m, 1 H), 7.17–7.22 (m, 2 H), 7.23–7.28 (m, 1 H),
7.30–7.39 (m, 3 H), 7.47 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 11.9, 13.3, 21.2, 38.2, 42.2,
126.9, 127.3, 128.7, 128.7, 130.0, 133.5, 138.2, 138.6, 139.9, 170.7.
IR (film): 2976, 2934, 1727, 1632, 1484, 1421,1383, 1269, 1252,
1193, 1152, 1097, 1068, 1051, 1021, 919, 872, 833, 803, 785, 754
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.70–0.81 (br m, 3 H), 0.82–0.94
(br m, 6 H), 1.06–1.18 (br m, 3 H), 1.84 (s, 3 H), 2.67–3.17 (br m,
4 H), 3.22–4.00 (br m, 6 H), 6.67 (d, J = 8.1 Hz, 1 H), 6.90 (d,
J = 8.5 Hz, 1 H), 7.29–7.40 (m, 4 H).
13C NMR (150 MHz, CDCl3, 248 K): d = 11.4, 11.7, 13.4, 13.5,
13.6, 14.5, 14.6, 24.6, 24.7, 37.3, 37.7, 41.6, 41.9, 42.1, 42.3, 42.7,
57.6, 58.0, 104.5, 123.2, 126.2, 127.8, 128.0, 128.0, 128.4, 128.5,
129.9, 130.3, 133.1, 136.8, 136.9, 138.6, 147.1, 147.2, 152.5, 169.8.
MS (EI, 70 eV): m/z (%) = 152 (C12H10+, 18), 165 (17), 195 (100,
[M – NEt2]+), 266 (40, [M]+).
HRMS (EI): m/z calcd for C18H21NO: 267.1623; found: 267.1610.
N,N-Diethyl-2¢,6¢-dimethoxy[1,1¢-biphenyl]-2-carboxamide
(8h)
Prepared according to general procedure B using 1,3-dimethoxy-
benzene (257 mg, 0.93 mmol, 0.24 mL) and N,N-diethyl-2-iodoben-
zamide (282 mg, 0.93 mmol) yielding 8h (191 mg, 66%) after flash
chromatography on silica gel (pentane–MTBE, 1:1 to 1:2) as a col-
orless oil.
MS (EI, 70 eV): m/z (%) = 72 (43), 100 (100), 105 (44), 176 (21),
310 (15), 470 (2, M+).
IR (film): 2969, 2934, 1633, 1592, 1471, 1430, 1287, 1246, 1110,
1040, 1003, 785, 760, 742 cm–1.
HRMS (EI): m/z calcd for C26H34N2O6: 470.2412; found: 470.2400.
1H NMR (600 MHz, CDCl3, 248 K): d = 0.75 (t, J = 7.0 Hz, 3 H),
0.98 (t, J = 7.0 Hz, 3 H), 2.73–2.83 (m, 2 H), 3.36–3.44 (m, 1 H),
3.70 (s, 3 H), 3.75 (s, 3 H), 3.79–3.90 (m, 1 H), 6.57 (d, J = 8.4 Hz,
1 H), 6.63 (d, J = 8.4 Hz, 1 H), 7.25–7.33 (m, 2 H), 7.36–7.48 (m,
3 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
13C NMR (150 MHz, CDCl3, 248 K): d = 11.8, 13.9, 37.5, 41.7,
55.2, 55.7, 102.5, 103.6, 116.3, 125.8, 127.0, 128.3, 129.1, 131.4,
131.9, 137.3, 156.7, 158.0, 170.0.
References
(1) Huneck, S. In Fortschritte der Chemie organischer
Naturstoffe /Progress in the Chemistry of Organic Natural
Products, Vol. 81; Herz, W.; Falk, H.; Kirby, G. W.; Moore,
R. E., Eds.; Springer: Wien, 2001.
MS (ESI+): m/z (%) = 314.2 (100, [M + H]+), 336.2 (50, [M +
Na]+), 649.3 (50, [2 M + Na]+).
(2) (a) Pu, L. Chem. Rev. 1998, 98, 2405. (b) Mei, X.; Wolf, C.
HRMS (ESI+): m/z calcd for C19H24NO3: 314.1756; found:
314.1763.
Chem. Commun. 2004, 2078. (c) Mei, X.; Wolf, C. J. Am.
Synthesis 2011, No. 8, 1249–1254 © Thieme Stuttgart · New York

1254
M. P. Nüllen, R. Göttlich
PAPER
5370. (c) Joncour, A.; Liu, J.-M.; Decor, A.; Thoret, S.;
Wdzieczak-Bakala, J.; Bignon, J.; Baudoin, O.
ChemMedChem 2008, 3, 1731. (d) Kozikowski, A. P.;
Chen, Y.; Gaysin, A. M.; Savoy, D. N.; Billadeau, D. D.;
Kim, K. H. ChemMedChem 2008, 3, 487.
Chem. Soc. 2006, 128, 13326. (d) Bao, X.; Snurr, R. Q.;
Broadbelt, L. J. Langmuir 2009, 25, 10730.
(3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893.
(4) (a) Waldmann, H.; He, Y.-P.; Tan, H.; Arve, L.; Arndt, H.-
D. Chem. Commun. 2008, 5562. (b) Zhou, J.; Bhattacharjee,
A.; Chen, S.; Chen, Y.; Duffy, E.; Farmer, J.; Goldberg, J.;
Hanselmann, R.; Ippolito, J. A.; Lou, R.; Orbin, A.; Oyelere,
A.; Salvino, J.; Springer, D.; Tran, J.; Wang, D.; Wu, Y.;
Johnson, G. Bioorg. Med. Chem. Lett. 2008, 18, 6179.
(c) Look, G. C.; Vacin, C.; Dias, T. M.; Ho, S.; Tran, T. H.;
Lee, L. L.; Wiesner, C.; Fang, F.; Marra, A.; Westmacott, D.;
Hromockyj, A. E.; Murphy, M. M.; Schullek, J. R. Bioorg.
Med. Chem. Lett. 2004, 14, 1423. (d) Nicolaou, K. C.;
Boddy, C. N. C.; Braese, S.; Winssinger, N. Angew. Chem.
Int. Ed. 1999, 38, 2096; Angew. Chem. 1999, 111, 2230.
(e) Liu, G.; Fan, Y.; Carlson, J. R.; Zhao, Z.-G.; Lam, K. S.
J. Comb. Chem. 2000, 2, 467.
(9) Elsenbaumer, R. L.; Shacklette, L. W. In Handbook of
Conducting Polymers, Vol. 1; Skotheim, T. A.;
Elsenbaumer, R. L.; Reynolds, J. R., Eds.; Marcel Dekker:
New York, 1987, 213.
(10) Su, S.-J.; Tanaka, D.; Li, Y.-J.; Sasabe, H.; Takeda, T.; Kido,
J. Org. Lett. 2008, 10, 941.
(11) Vattem, D. A.; Shetty, K. J. Food Biochem. 2005, 29, 234.
(12) Sturm, N.; Hu, Y.; Zimmermann, H.; Fritz-Wolf, K.;
Wittlin, S.; Rahlfs, S.; Becker, K. Antimicrob. Agents
Chemother. 2009, 53, 622.
(13) Heber, D. Cancer Lett. 2008, 269, 262.
(14) (a) Iyoda, M. Adv. Synth. Catal. 2009, 351, 984. (b) Fu, G.
C. Acc. Chem. Res. 2008, 41, 1555. (c) Denmark, S. E.;
Regens, C. S. Acc. Chem. Res. 2008, 41, 1486. (d) Corbet,
J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651. (e) Hassan,
J.; Sévingnon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359. (f) Bringmann, G.; Price Mortimer,
A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M.
Angew. Chem. Int. Ed. 2005, 44, 5384; Angew. Chem. 2005,
117, 5518. (g) Miyaura, N.; Buchwald, S. L. Cross-
Coupling Reactions. A Practical Guide; Springer: Berlin,
2002. (h) Metal-Catalysed Cross-Coupling Reactions;
Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1998. (i) Bringmann, G.; Walter, R.; Weirich, R. Angew.
Chem., Int. Ed. Engl. 1990, 29, 977; Angew. Chem. 1990,
102, 1006. (j) Korn, T. J.; Knochel, P. Angew. Chem. Int. Ed.
2005, 44, 2947; Angew. Chem. 2005, 117, 3007.
(15) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem. Int.
Ed. 2009, 48, 9792; Angew. Chem. 2009, 121, 9976.
(16) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M.
Chem. Rev. 2011, 111, 563.
(5) (a) Croom, K. F.; Keating, G. M. Am. J. Cardiovasc. Drugs
2004, 4, 395. (b) Sharpe, M.; Jarvis, B.; Goa, K. L. Drugs
2001, 61, 1501.
(6) (a) Hall, A.; Bit, R. A.; Brown, S. H.; Chaignot, H. M.;
Chessell, I. P.; Coleman, T.; Giblin, G. M. P.; Hurst, D. N.;
Kilford, I. R.; Lewell, X. Q.; Michel, A. D.; Mohamed, S.;
Naylor, A.; Novelli, R.; Skinner, L.; Spalding, D. J.; Tang,
S. P.; Wilson, R. J. Bioorg. Med. Chem. Lett. 2006, 16,
317S. (b) Ducharme, Y.; Blouin, M.; Carriere, M.-C.;
Chateauneuf, A.; Cote, B.; Denis, D.; Frenette, R.; Greig, G.;
Kargman, S.; Lamontagne, S.; Martins, E.; Nantel, F.;
O’Neill, G.; Sawyer, N.; Metters, K. M.; Friesen, R. W.
Bioorg. Med. Chem. Lett. 2005, 15, 1155.
(c) dos Santos Filho, J. M.; de Lima, J. G.; Leite, L. F. C. C.
J. Heterocycl. Chem. 2009, 46, 722. (d) Springer, D. M.;
Luh, B. Y.; Bronson, J. J.; McElhone, K. E.; Mansuri, M. M.;
Gregor, K. R.; Nettleton, D. O.; Stanley, P. L.; Tramposch,
K. M. Bioorg. Med. Chem. 2000, 8, 1087.
(7) (a) Dagne, E.; Steglich, W. Phytochemistry 1984, 23, 1729.
(b) Bringmann, G.; Menche, D.; Bezabih, M.; Abegaz, B.
M.; Kaminsky, R. Planta Med. 1999, 65, 757.
(8) (a) Trova, M. P.; Barnes, K. D.; Barford, C.; Benanti, T.;
Bielaska, M.; Burry, L.; Lehman, J. M.; Murphy, C.;
O’Grady, H.; Peace, D.; Salamone, S.; Smith, J.; Snider, P.;
Toporowski, J.; Tregay, S.; Wilson, A.; Wyle, M.; Zheng,
X.; Friedrich, T. D. Bioorg. Med. Chem. Lett. 2009, 19,
6608. (b) Williams, A. B.; Weiser, P. T.; Hanson, R. N.;
Gunther, J. R.; Katzenellenbogen, J. A. Org. Lett. 2009, 11,
(17) Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34,
2174.
(18) (a) Ziegler, F. E.; Fowler, K. W. J. Org. Chem. 1976, 41,
1564. (b) Ziegler, F. E.; Fowler, K. W.; Kanfer, S. J. Am.
Chem. Soc. 1976, 98, 8282.
(19) Ziegler, F. E.; Fowler, K. W.; Rodgers, W. B.; Wester, R. T.
Org. Synth. 1987, 65, 108.
(20) Zhang, S. J.; Zhang, D. W.; Liebeskind, L. S. J. Org. Chem.
1997, 62, 2312.
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