Preparation of N-aryl compounds by amino acid-promoted Ullmann-type coupling reactions

Article abstract of DOI:10.1055/s-2004-831196

N-Aryl α- or β-amino acids, aryl amines, N-arylpyrroles, N-arylindoles, N-arylimidazoles, N-arylpyrazoles and aryl azides are prepared by CuI-catalyzed coupling reactions of aryl halides with corresponding nitrogen sources using amino acids as the promote

Full text of DOI:10.1055/s-2004-831196

496
PRACTICAL SYNTHETIC PROCEDURES
Preparation of N-Aryl Compounds by Amino Acid-Promoted Ullmann-Type
Coupling Reactions
Preparationof
N
-A
i
ryl Com
a
pounds by
n
U
llmann-Type Co
C
upling Reaction
a
s
i,a Wei Zhu,b Hui Zhang,b Yongda Zhang,b Dawei Ma*a
a
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: madw@mail.sioc.ac.cn
PSP
b
Department of Chemistry, Fudan University, Shanghai 200433, P. R. of China
Received 1 June 2004; revised 30 June 2004
No41
Abstract: N-Aryl a- or b-amino acids, aryl amines, N-arylpyrroles, N-arylindoles, N-arylimidazoles, N-arylpyrazoles and aryl azides are
prepared by CuI-catalyzed coupling reactions of aryl halides with corresponding nitrogen sources using amino acids as the promoters.
Key words: aryl amines, coupling reaction, amino acids, aryl halides
I
H
N
CO2H
OH
L-valine/CuI (10 mol%)
OH
Procedure 1
Procedure 2
K2CO3, DMA, 90 °C, 48 h
81%
1
2
H
allylamine/CuI (10 mol%)
L-proline (20 mol%)
I
N
K2CO3, DMSO, 60 °C, 14 h
84%
MeO
MeO
3
4
indole/CuI (5 mol%)
L-proline (10 mol%)
I
N
Procedure 3
Procedure 4
K2CO3, DMSO, 80 °C, 22 h
78%
O
6
O
5
7
NaN3/CuI (10 mol%)
L-proline (20 mol%)/NaOH (20 mol%)
I
N3
DMSO, 60 °C, 10 h
86%
HO
HO
8
Scheme 1
to occur at relative low temperatures and gave the corre-
sponding N-aryl a-amino acids, aryl amines, N-arylpyr-
roles, N-arylindoles, N-arylimidazoles, N-arylpyrazoles
and aryl azides in good to excellent yields (Scheme 1).
Introduction
Ullmann-type coupling reactions between aryl halides
and N-containing reagents are a traditional method for
preparing N-aryl compounds that are important in the
pharmaceutical and materials science. However, a signif-
icant drawback for these reactions is the requirement of
high reaction temperature, which greatly limits the reac-
tion scopes.1 This short-coming stimulated considerable
efforts to develop relatively mild coupling conditions us-
ing either palladium catalysts2 or some additives in Cu(I)
catalyst system during the past dacade.3–8 We have found
that a-amino acids could promote Ullmann-type coupling
reactions of either themselves or some other N-containing
reagents with aryl halides,5–8 which allow these reactions
Scope and Limitations
For CuI-catalyzed coupling reaction of a-amino acids
with aryl halides, a-amino acids with larger hydrophobic
groups give higher yields in coupling reactions, while
those with smaller hydrophobic groups (L-alanine) deliver
only lower yields and no coupling products were detected
for those with hydrophilic groups (L-serine, L-aspartic
acid and L-glutamic acid). No racemization was observed
except for L-alanine and L-methionine as the substrates.
Both electron-rich and electron-deficient aryl bromides
and aryl iodides worked for this reaction. However, aryl
chlorides and 2,6-disubstituted aryl bromides were not
good substrates. In a control experiment, CuI-catalyzed
reaction of (S)-valinol with iodobenzene at 110 °C gave
SYNTHESIS 2005, No. 3, pp 0496–0499
Advanced online publication: 21.10.2004
DOI: 10.1055/s-2004-831196; Art ID: Z11104SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4

PRACTICAL SYNTHETIC PROCEDURES
N-Aryl Compounds by Ullmann-Type Coupling Reactions
497
less than 5% conversion, which indicated that there is an
accelerating effect induced by the structure of a-amino
acid during the coupling reaction of a-amino acids with
aryl halides.5a Further investigation demonstrated that b-
amino acid also caused this accelerating effect. For exam-
ple, reaction of iodobenzene with (R)-3-aminohexanoic
ethyl ester 9 (being converted to its acid as a potassium
salt at this condition initially) was completed at 100 °C in
48 hours to deliver N-phenyl b-amino acid 10 in 74%
yield (Scheme 2). This reaction proved applicable to an
intramolecular model.6
I
pyrrole/CuI (10 mol%)
L-proline (20 mol%)
N
K2CO3, DMSO, 90 °C, 36 h
80%
Br
Br
16
15
N
I
pyrrole/CuI (10 mol%)
L-proline (20 mol%)
N
K2CO3, DMSO, 80 °C, 34 h
93%
CN
CN
18
17
CO2H
iPr
EtO2C
CuI/K2CO3
+
DMF, 100 °C
48 h, 74%
Scheme 4 Preparation of N-arylpyrroles and N-arylimidazoles
N
H
10
I
H2N
iPr
9
Br
N3
Scheme 2 CuI-catalyzed coupling reaction of iodobenzene with
(R)-3-aminohexanoic ethyl ester
10 mol% CuI, NaN3
30 mol% L-proline
30 mol% NaOH, EtOH/H2O
95 °C, 24 h, 90%
Using L-proline as an additive, CuI-catalyzed coupling re-
action between ordinary amines and aryl halides could be
carried out at 60–90 °C in DMSO.7 A wide range of sub-
strates including primary and secondary aliphatic amines,
primary aryl amines, electron-rich and electron-deficient
aryl bromides and aryl iodides are notably compatible
with this reaction to provide monoaryl or diaryl amines
(see Scheme 3 for two examples). However, no coupling
product was determined even at 100 °C in case of aryl
chlorides as substrates. Furthermore, this reaction condi-
tion could be used for preparation of N-arylpyrroles, N-
arylindoles, N-arylimidazoles, or N-arylpyrazoles by cou-
pling aryl iodides with the corresponding N-containing
heterocycles. This reaction normally gave high yields al-
though longer reaction time was required when electron-
rich aryl iodides was used (see Scheme 4 for two addition-
al examples).8
Cl
19
Cl
20
I
N3
10 mol% CuI, NaN3
20 mol% L-proline
120 mol% NaOH, DMSO
CO2H
NHBoc
CO2H
91%
NHBoc
22
21
10 mol% CuI, NaN3
20 mol% L-proline sodium salt
Ph
I
Ph
N3
DMSO, 70 °C, 2 h
70%
23
24
Scheme 5 Preparation of aryl azides and vinyl azides
substrates (Scheme 5). Noteworthy is that either L-ty-
rosine derived iodide 21 or vinyl iodide 23 produced the
corresponding aryl azide 22 or vinyl azide 24 under these
conditions.
Br
OMe
H
CuI (10 mol%)
L-proline (20 mol%)
H2N
MeO
N
+
K2CO3, DMSO
90 °C, 40 h, 93%
MeO
OH
HO
12
As a summary, we have demonstrated here several exam-
ples for constructing N-aryl compounds using amino acid
promoted Ullmann-type coupling reactions. The inexpen-
sive and easily removable catalytic system and relatively
mild reaction conditions would make these coupling reac-
tions find possible applications in both academic studies
and industry production. Indeed, CuI-catalyzed coupling
of aryl halides and amino acids has found considerable ap-
plications in assembling biologically and synthetically
important compounds.5a,6,11
OMe
11
OMe
OMe
CuI (10 mol%)
L-proline (20 mol%)
K2CO3, DMSO
90 °C, 36 h, 82%
+
I
N
H
NH2
14
13
Scheme 3 Synthesis of monoaryl and diaryl amines
There have appeared few examples for practical prepara-
tion of aryl azides.9 We observed that CuI/L-proline cata-
lytic system could be employed for assembling aryl azides
by coupling aryl halides and sodium azide.10 When aryl
iodides were used, this coupling reaction worked at 40–
70 °C in DMSO using NaOH. Alternative reaction condi-
tions (using EtOH–H2O as the solvents and higher reac-
tion temperature) were needed in case of aryl bromides as
Procedures
We present here four typical synthetic procedures to illustrate the
reaction scope for amino acid-promoted Ullmann-type coupling. In
Procedure 1, we describe the preparation of N-(2¢-hydroxymeth-
ylphenyl)-L-valine (2) in 81% yield by coupling of L-valine and 2-
hydroxymethylphenyl iodide (1). In Procedure 2, CuI/L-proline
catalyzed cross-coupling of 4-iodoanisole (3) with allylamine lead-
Synthesis 2005, No. 3, 496–499 © Thieme Stuttgart · New York

498
Q. Cai et al.
PRACTICAL SYNTHETIC PROCEDURES
ing to N-allyl-p-anisidine (4) is reported. In Procedure 3, assembly
of 1-(4¢-acylphenyl)indole (6) by the reaction of 4¢-iodoacetophe-
none (5) and indole under the catalysis of CuI/L-proline is men-
tioned. In the last procedure (Procedure 4), we report the synthesis
of 4-azidophenol (8) using a CuI/L-proline catalyzed reaction of 4-
iodophenol with sodium azide. Noteworthy is that in all cases com-
mercial available CuI must be washed with THF using a Soxhlet ex-
tractor before it is used to ensure satisfactory catalytic activity! CuI
and L-proline were purchased from Xingxing Chemical Plant of
China, and Baitai chemical company of Shanghai, respectively. All
solvents were used as received. IR spectra were measured on a Schi-
madzu 440 spectrometer. 1H NMR spectra were recorded with
tetramethylsilane as an internal standard on a Brucker AM-300
spectrometer. MS spectra were determined on a HP-5989A spec-
trometer or a Finnigan MAT spectrometer. Optical rotations were
obtained using a Perkin-Elmer 241 Autopol polarimeter.
1-(4-Indol-1-yl-phenyl)ethanone (6); Typical Procedure
In a 250 mL of round-bottom flask equipped with a magnetic stir-
ring bar were placed 4¢-iodoacetophenone (10 g, 40.65 mmol), in-
dole (5.71 g, 48.78 mmol), CuI (0.387 g, 2.03 mmol), L-proline
(0.467 g, 4.07 mmol), K2CO3 (11.24 g, 81.3 mmol) and DMSO (40
mL). After the reaction mixture was degassed and then introduced
under N2 atmosphere with magnetic stirring, it was heated at 80 °C
until reaction completion was observed (monitored by TLC, about
22 h). The reaction mixture was partitioned between water (100
mL) and EtOAc (100 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (2 × 100 mL). The com-
bined organic layers were washed with water and brine, dried over
Na2SO4, and concentrated in vacuo. Chromatography of the residue
eluting with EtOAc–petroleum ether (20:1) provided 6 (7.4 g, 78%
yield) as a white powder; mp 85–86 °C (lit.12 85–87 °C).
IR (KBr): 3399, 3103, 3056, 3001, 1740, 1681 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (m, 2 H), 7.62 (m, 4 H), 7.38
N-(2-Hydroxymethylphenyl)-L-valine (2); Typical Procedure
A 1000 mL round-bottom flask, equipped with a magnetic stirring
bar and a reflux condenser, was charged with 2-hydroxymethylphe-
nyl iodide (46.8 g, 0.2 mol), L-valine (21.4 g, 0.2 mol), K2CO3 (41.4
g, 0.3 mol), CuI (5.73 g, 0.03 mmol). Under N2 atmosphere anhyd
DMA (600 mL) and water (5 mL) were added and then the resultant
mixture was heated at 90 °C. After 2-hydroxymethylphenyl iodide
was consumed, as monitored by TLC (about 48 h), the reaction mix-
ture was concentrated to remove DMA in vacuo. The residue was
diluted with water (300 mL) before it was acidified to pH = 3 with
6 N HCl at 0 °C. The resultant solution was extracted with EtOAc
(4 × 250 mL) and the combined organic layers were washed with
brine, dried over Na2SO4, and concentrated to dryness by rotavapor.
The residual oil was loaded on a silica gel column and eluted with
EtOAc–petroleum ether (1:2) to afford N-(2-hydroxymethylphe-
nyl)-L-valine as a pale yellow oil (36.1 g, 81% yield); [a]D25 –59.7
(c =1.0, CHCl3).
(m, 1 H), 7.24 (m, 2 H), 6.74 (m, 1 H), 2.67 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 196.5, 143.4, 135.1, 134.1, 129.8,
129.6, 127.1, 122.8, 122.7, 121.2, 120.8, 110.4, 104.9, 26.32.
EIMS: m/z = 235 [M+], 220, 191, 165, 140, 110, 89, 43.
HRMS: m/z [M + H]+ calcd for C16H14NO: 236.1070; found:
236.1072.
4-Azidophenol (8);13 Typical Procdure
In a 100 mL of round-bottom flask equipped with a magnetic stir-
ring bar were placed 4-iodophenol (5 g, 23 mmol), NaN3 (1.80 g,
27.6 mmol), CuI (450 mg, 2.3 mmol), L-proline (530 mg, 4.6
mmol), NaOH (184 mg, 4.6 mmol) and DMSO (50 mL). After the
reaction mixture was degassed and then introduced under an Ar at-
mosphere, it was heated at 60 °C until the staring material was con-
sumed indicated by TLC (about 10 h). The mixture was diluted with
water (50 mL) and then extracted with EtOAc (3 × 100 mL). The
combined organic layer was washed with brine (2 × 50 mL), dried
over MgSO4. The solvent was evaporated under vacuo and the res-
idue was purified by flash chromatography eluting with EtOAc–pe-
troleum ether (1:6) to give 8 (2.67 g, 86% yield) as a pale red oil
(due to partial oxidation; 99.2% purity determined by HPLC).
IR (film): 3373, 2114, 2074, 1705, 1596, 1583 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.68 (br s, 1 H), 6.83–6.94 (m, 4
H).
13C NMR (75 MHz, CDCl3): d = 152.40, 132.05, 119.83, 116.32.
MS: m/z = 135 [M+], 107, 93, 79, 65, 52, 39.
HRMS: m/z [M+] calcd for C6H5N3O: 135.0433; found: 135.0456.
IR (KBr): 3328, 1701, 1590 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.21 (t, J = 7.8 Hz, 1 H), 7.07 (dd,
J = 7.7, 1.5 Hz, 1 H), 6.71 (t, J = 7.7 Hz, 1 H), 6.59 (d, J = 7.8 Hz,
1 H), 4.95 (br s, 3 H), 4.72, 4.67 (AB q, d, J = 12.3 Hz, 2 H), 3.86
(d, J = 5.6 Hz, 1 H), 2.23 (m, 1 H), 1.06 (d, J = 7.1 Hz, 6 H).
MS: m/z = 223 [M+], 206, 134, 107, 77, 43.
HRMS: m/z [M+] calcd for C12H17NO3: 223.1209; found: 223.1198.
N-Allyl-p-anisidine (4); Typical Procedure
To a mixture of 4-iodoanisole (10 g, 42.7 mmol), CuI (0.814 g, 4.27
mmol), L-proline (0.983 g, 8.55 mmol) and K2CO3 (11.81 g, 85.5
mmol) in a 250 mL flask, were added allylamine (4.82 mL, 64.10
mmol) and DMSO (85 mL). After the reaction mixture was de-
gassed and then introduced under N2 atmosphere with magnetic stir-
ring , it was heated at 60 °C until 4-iodoanisole disappeared
(monitored by TLC in about 14 h). The mixture was diluted with
water (100 mL) and then extracted with EtOAc (3 × 100 mL). The
combined organic layers were washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. The residual oil was load-
ed on a silica gel column and eluted with EtOAc–petroleum ether
(20:1) to afford 4 (5.8 g, 84% yield) as a pale yellow oil.
Acknowledgment
The authors are grateful to the Chinese Academy of Sciences, Na-
tional Natural Science Foundation of China (grants 20321202 &
20132030), and Science and Technology Commission of Shanghai
Municipality (grants 02JC14032 & 03XD14001) for their financial
support.
IR (KBr): 3399, 2997, 2935, 1845, 1645, 1619, 1590 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.80 (m, 2 H), 6.60 (m, 2 H), 5.91
(m, 1 H), 5.26 (dd, J = 17.1 Hz, 1.2 Hz, 1 H), 5.15 (dd, J = 10.5 Hz,
1.2 Hz, 1 H), 3.78 (s, 3 H), 3.72 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 151.8, 142.1, 135.6, 115.7, 114.5,
114.0, 55.4, 47.2.
References
(1) For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433.
(2) For reviews, see: (a) Hartwig, J. F. Angew. Chem. Int. Ed.
1998, 37, 2046. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
(3) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew.
Chem. Int. Ed. 2003, 42, 5400. (b) Kunz, K.; Scholz, U.;
Ganzer, D. Synlett 2003, 2428.
EIMS: m/z = 163 [M+], 148, 136, 122, 95, 77, 65, 52, 41.
HRMS: m/z [M + H]+ calcd for C10H14NO: 164.1070; found:
164.1064.
Synthesis 2005, No. 3, 496–499 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
N-Aryl Compounds by Ullmann-Type Coupling Reactions
499
(4) For some leading references, see: (a) Antilla, J. C.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
(b) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581. (c) Cristau, H.-J.; Cellier, P. P.; Hamada, S.;
Spindler, J.-F.; Taillefer, M. Org. Lett. 2004, 6, 913.
(d) Han, C.; Shen, R.; Su, S.; Porco, J. A. Jr. Org. Lett. 2004,
6, 27. (e) van Allen, D.; Venkataraman, D. J. Org. Chem.
2003, 68, 4590.
(5) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459. (b) Also see:Ma, D.; Yao, J.
Tetrahedron: Asymmetry 1996, 7, 3075.
(6) Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583.
(7) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
Riper, G. V.; Egger, L. A.; Kidambi, U.; Mumford, R. A.;
Tong, S.; MacCoss, M.; Schmidt, J. A.; Hagmann, W. K.
Bioorg. Med. Chem. Lett. 2002, 12, 2205. (g) Ma, D.; Xia,
C.; Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem. 2003, 68,
442. (h) Reddy, T. J.; Chan, L.; Turcotte, N.; Proulx, M.;
Pereira, O. Z.; Das, S. K.; Siddiqui, A.; Wang, W.; Poisson,
C.; Yannopoulos, C. G.; Bilimoria, D.; L’Heureux, L.;
Alaoui, H. M. A.; Nguyen-Ba, N. Bioorg. Med. Chem. Lett.
2003, 13, 3341. (i) Greenspan, P. D.; Clark, K. L.; Cowen,
S. D.; McQuire, L. W.; Tommasi, R. A.; Farley, D. L.;
Quadros, E.; Coppa, D. E.; Du, Z.; Fang, Z.; Zhou, H.;
Doughty, J.; Toscano, K. T.; Wigg, A. M.; Zhou, S. Bioorg.
Med. Chem. Lett. 2003, 13, 4121. (j) Ding, K.; Flippen-
Anderson, J.; Deschamps, J. R.; Wang, S. Tetrahedron Lett.
2004, 45, 1027. (k) Robichaud, J.; Bayly, C.; Oballa, R.;
Prasit, P.; Mellon, C.; Falgueyret, J.-P.; Percival, M. D.;
Wesolowski, G.; Rodan, S. B. Bioorg. Med. Chem. Lett.
2004, 14, 4291.
(8) Ma, D.; Cai, Q. Synlett 2004, 128.
(9) Liu, Q.; Tor, Y. Org. Lett. 2003, 5, 2571; and references
cited therein.
(10) Zhu, W.; Ma, D. Chem. Commun. 2004, 888.
(11) (a) Hiroi, K.; Suzuki, Y.; Abe, I. Tetrahedron: Asymmetry
1999, 10, 1173. (b) Suzuki, Y.; Abe, I.; Hiroi, K.
Heterocycles 1999, 50, 110. (c) Ma, D.; Xia, C.; Jiang, J.;
Zhang, J. Org. Lett. 2001, 3, 2189. (d) Reynolds, D. J.;
Hermitage, S. A. Tetrahedron 2001, 57, 7765. (e) Clement,
J.-B.; Hayes, J. F.; Sheldrake, H. M.; Sheldrake, P. W.;
Wells, A. S. Synlett 2001, 1423. (f) Kamenecka, T. M.;
Lanza, T. Jr.; de Laszlo, S. E.; Li, B.; McCauley, E. D.;
(12) Polya, K. J. Chem. Soc. C 1970, 85.
(13) Benin, V.; Kaszynski, P.; Radziszewski, J. G. J. Org. Chem.
2002, 67, 1354.
Synthesis 2005, No. 3, 496–499 © Thieme Stuttgart · New York