One-pot synthesis of symmetrical di- and triarylamines using urea as the source of the amino group

Article abstract of DOI:10.1055/s-2005-923596

A simple one-pot palladium-catalyzed reaction for the conversion of aryl halides to aryl amines using urea as an ammonia equivalent is reported. Arylation of urea in the presence of Pd₂dba₃, t-Bu ₃P·HBF₄ and t-BuOK in dioxane gives di- and triarylamines in 65-95% yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-923596

LETTER
235
One-Pot Synthesis of Symmetrical Di- and Triarylamines Using Urea as the
Source of the Amino Group
O
ne-Pot Synthesis
a
of Symm
e
l
D
i
i- and
T
riarylamine
a
s
A. Artamkina, Alexey G. Sergeev, Mikhail M. Stern, Irina P. Beletskaya*
Department of Chemistry, Moscow State University, Leninskie Gory, 119992 Moscow, Russia
Fax +7(95)9393618; E-mail: beletska@org.chem.msu.ru
Received 3 November 2005
Abstract: A simple one-pot palladium-catalyzed reaction for the
Ph
2 P
PPh2
conversion of aryl halides to aryl amines using urea as an ammonia
equivalent is reported. Arylation of urea in the presence of Pd2dba3,
t-Bu3P·HBF4 and t-BuOK in dioxane gives di- and triarylamines in
65–95% yields.
Me2N
O
PCy2
Pt-Bu2
Key words: palladium, arylations, amines, ammonia equivalents,
urea
Xantphos
L1
L2
Figure 1
Palladium-catalyzed arylation of amines, the Buchwald–
Hartwig reaction, is at present widely used for the synthe-
sis of various secondary and tertiary arylamines.1 How-
ever, such reaction has not yet been carried out with
ammonia, and the only procedure allowing one to obtain
symmetrical di- and triarylamines in one step directly
from aryl halides is the arylation of lithium amide.2 With
para- and meta-substituted aryl halides it gives triaryl-
amines (75–82%) and with ortho-substituted aryl halides
diarylamines (64–95%).
system was not efficient for aryl chlorides and electron-
rich aryl bromides.
Electron-rich bulky phosphines, L1, L2 and t-Bu3P, are
widely used as highly efficient ligands in the amination of
electron-rich aryl bromides and aryl chlorides.5,6 We ex-
amined the effect of these ligands in the reaction of p-bro-
motoluene with urea, which in the presence of Xantphos
and Cs2CO3 as a base proceeded to 62% conversion and
gave low yield of N,N¢-diarylurea (7%).3 The couplings
were carried out with 2 mol% of Pd2dba3 (4 mol% Pd) and
6 mol% of L1, L2 or t-Bu3P in dioxane at 100 °C (Table 1).
With the same base (Cs2CO3) these ligands were even less
efficient than Xantphos (entries 1–3), using t-BuONa as a
Here we describe a new convenient method for the
synthesis of symmetrical di- and triarylamines using urea,
a cheap and easily accessible reagent, as an ammonia
equivalent.
In the previous papers we have developed an efficient
method for the synthesis of N,N-diaryl- and N-aryl-N¢-
phenylureas which is based on the reaction of aryl halides
with ureas in the presence of Pd2dba3, Xantphos and
Cs2CO3 in dioxane (Equation 1).
Table 1 Evaluation of Bases and Phosphine Ligands for the Palla-
dium-Catalyzed Reaction of p-Bromotoluene with Ureaa
Entry Ligand
Base
Reaction time Conversion of
(h)
20
18
18
14
14
21
14
14
p-bromotoluene (%)
1
2
3
4
5
6
7
8
Cy3P
t-Bu3P
L1
Cs2CO3
Cs2CO3
Cs2CO3
t-BuONa
t-BuONa
t-BuOK
t-BuOK
t-BuOK
0
9
Pd2dba3,
Xantphos
NHAr(NHPh)
ArHN
H2N
NH2(NHPh)
ArX
+
Cs2CO3,
dioxane,
100 °C
O
O
0
X = I, Br
64–92%
L1
31
Equation 1
L2
39
However, these conditions allow one to carry out the
reaction only with aryl iodides and aryl bromides bearing
electron-withdrawing groups (EWG).3 Modification of
Xantphos by CF3 groups in 3,5-positions of phenyl rings
made it possible to use aryl bromides with a broader range
of substituents.4 Nevertheless the modified catalytic
t-Bu3P
L1
100
100
100
L2
a The reactions were carried out with 1.5 mmol of aryl halide, 0.5
mmol of urea, 2 mol% of Pd2dba3·CHCl3 (4 mol% Pd), 6 mol% of the
ligand, 2.1 mmol of the base in 5 mL of dioxane at 100 °C under argon
to the point when the conversion of the aryl bromide (as shown by
GC) did not increase further.
SYNLETT 2006, No. 2, pp 0235–0238
0
1.
0
2.
2
0
0
6
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923596; Art ID: G34105ST
© Georg Thieme Verlag Stuttgart · New York

236
G. A. Artamkina et al.
LETTER
Me
N
2 mol% Pd2dba3,
6 mol% ligand
Br
H
H2N
NH2
N
+
+
t-BuOK, dioxane,
Me
O
100 °C
Me
Me
Me
Me
Equation 2
base resulted in somewhat better, but still low, conversion N,N¢-ditolylurea, di- and tritolylamines were formed as
of p-bromotoluene (entries 4, 5). Complete consumption the main products (Equation 2).
of the starting aryl halide was achieved only when elec-
Examining the reaction products, we found that in the
tron-rich ligands (L1, L2, Pt-Bu3) were combined with a
presence of 2-(di-tert-butylphosphino)biphenyl L1 as a
strong base t-BuOK (entries 6–8). However, the most sur-
ligand (Figure 1) the coupling of p-bromotoluene with
urea affords the mixture of di- and tri(p-tolyl)amines in
32% and 41% yields correspondingly. In contrast, em-
prising thing was a complete turn of the reaction course
with this new catalytic system: instead of the expected
Table 2 Palladium-Catalyzed Synthesis of Di- and Triarylamines from Aryl Halides and Ureaa
R
N
3
2 mol% Pd2dba3,
R = p-MeO, p-Me, m-Me, H
6 mol% t-Bu3P·HBF4
H2N
NH2
X
+
65–95%
t-BuOK, dioxane
R
O
R
100 °C
X = Br, Cl
NH
2
R = MeO, Me
66–70%
Entry
R
X
Ligand
Reaction time (h) Conversion of aryl halide (%) Isolated yield (%)b
Ar3N
32
Ar2NH
1
2
p-Me
p-Me
p-Me
m-Me
p-MeO
H
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Br
Br
Cl
Cl
L1
21
19
18
21
21
19
44
20
46
8
100
100
100
100
100
100
85
41
7
L2
73
3
t-Bu3Pc
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
80
–
4
85
5
65
6
83
7
p-Me
H
80
8
72
60
5
9
H
100
100
100
78
95
Traces
70
10
11
12
13d
o-Me
o-MeO
20
46
45
66
2,4,6-Me
2,4,6-Me
60
90
87
a The reactions were carried out in sealed vessels with aryl halide (1.65 mmol), urea (0.5 mmol), Pd2dba3·CHCl3 (2 mol%, 4 mol% Pd), ligand
(6 mol%), t-BuOK (2.9 mmol) in dioxane (6 mL) at 100 °C under argon to the point when the conversion of the aryl bromide (as shown by GC)
did not increase further.
b The calculation of the yields was based on urea, taking into account that the only nitrogen in urea is involved in the reaction.
c The ligand was employed as a salt, t-Bu3P·HBF4.
d 5 mol% of Pd2dba3 (10 mol% of Pd) and 15 mol% of the ligand were used.
Synlett 2006, No. 2, 235–238 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Symmetrical Di- and Triarylamines
237
ployment of L2 provides selective formation of tri(p- steric hindrance, and triarylamines bearing ortho-substit-
tolyl)amine (73%) giving only small amount of di(p- uents in each phenyl group cannot be obtained via amina-
tolyl)amine (7%). The best yield of tri(p-tolyl)amine tion of aryl halides under these conditions. A similar
(80%) is obtained using t-Bu3P as a ligand (Table 2, situation was observed in the palladium-catalyzed
entries 1–3).
arylation of lithium amide, where ortho-substituted aryl
halides gave only diarylamines, while para and meta
isomers gave triarylamines.2
New conditions (2 mol% of Pd2dba3·CHCl3, 6 mol% of
t-Bu3P·HBF4, t-BuOK, dioxane) were applied for the syn-
thesis of various triarylamines from unactivated aryl ha- Moreover, double arylation of anilines in the presence
lides and urea.7 The data presented in Table 2 show that Pd2dba3/L1 allows the production of triarylamines con-
under optimized conditions the reactions of several aryl taining only one ortho substituent.9
halides bearing electron-donating substituents in meta-
and para-positions afford triarylamines in high yields. It
should be noted that t-Bu3P can be used as a salt t-
The scope of the described reaction is limited to aryl
halides without an electron-withdrawing group. In case of
activated aryl halides the corresponding aryl-tert-butyl
Bu3P·HBF4, which, in contrast to free phosphine, is an air-
ethers were formed as the main products. For example,
stable solid.8 Amination of bromobenzene, para- and
our attempt of coupling of para-bromobenzotrifluoride
meta-bromotoluenes results in 80–85% yields of triaryl-
with urea resulted in a mixture of para- and meta-trifluo-
amines (entries 3, 4, 6), however, in the reaction with less
romethylphenyl-tert-butyl ethers in 77% overall yield.
Similar result was obtained in a noncatalytic reaction. It is
evident that reaction with electron-poor aryl bromide pro-
active p-bromoanisole a moderate yield is observed (65%,
entry 5).
We have shown that aryl chlorides, including non-activat- ceeds through aryne mechanism of nucleophilic substitu-
ed, also can be aminated under these conditions. In the re- tion, where t-BuOK acts both as a base and a nucleophile
actions of urea with chlorobenzene and p-chlorotoluene (Equation 4).
the yields of triarylamines reach 80–95% (entries 7–9). It
Two pathways can be proposed for the formation of di-
is worth noting that coupling reactions with aryl chlorides
and triarylamines in the reaction of urea with aryl halides.
proceed considerably slower than the reactions with aryl
The first one begins with the arylation of urea, followed
bromides, giving, however, comparable or even higher
by cleavage of resultant arylurea to carbamate and aniline,
product yields (compare entries 3, 7 and 6, 9).
which subsequently undergoes arylation to give di- or tri-
The reactivity of ortho-substituted aryl halides differs arylamines (Scheme 1).
markedly from that of meta- and para-substituted aryl
halides: coupling of ortho-bromotoluene and ortho-
bromoanisole with urea selectively forms diarylamines in
66–70% yield (Table 2, entries 10, 11). Even chloro-
mesitylene, aryl chloride having two substituents in ortho-
positions, was found to be a suitable substrate for amina-
tion (entries 12, 13, Equation 3).
But the catalytic system employed, Pd2dba3–L1–t-BuOK,
was shown to be inefficient for the arylation of amides: we
observed only traces of N-arylated amide (<2%) in the
coupling of p-bromotoluene with p-methylbenzamide
during 19 hours at 100 °C. Therefore, as more probable
we consider the second pathway with the initial dissocia-
tion of urea to ammonia, and subsequent arylation of
Obviously, the subsequent arylation of ortho-substituted ammonia or potassium amide (Scheme 2).
diarylamines under these conditions is hampered due to
Me
Me
Me
5 mol% Pd2dba3,
Cl
H
H2N
NH2
15 mol% t-Bu3P·HBF4
N
+
t-BuOK, dioxane,
100 °C, 45 h
Me
Me
O
Me
Me
Me Me
87%
Equation 3
Ot-Bu
Br
t-BuOK
+
+
dioxane
100 °C, 8 h
F3C
Ot-Bu
F3C
F3C
44%
33%
Equation 4
Scheme 1
ArNH2
+
KHNC(O)Ot-Bu
ArX, [Pd]
ArX, [Pd]
t-BuOK
H2NC(O)NH2
Ar2NH (Ar3N)
ArHNC(O)NH2
t-BuOK
t-BuOK
Synlett 2006, No. 2, 235–238 © Thieme Stuttgart · New York

238
G. A. Artamkina et al.
LETTER
H2N
NH2
H2N
Ot-Bu
KHN
Ot-Bu
+
t-BuOK
+
+
NH3
KNH2
O
O
O
ArX, [Pd]
ArX, [Pd]
ArX, [Pd]
ArX + NH3 (KNH2)
ArNH2
Ar2NH
Ar3N
t-BuOK
t-BuOK
t-BuOK
Scheme 2
(4) (a) Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P.
Tetrahedron Lett. 2003, 44, 4719. (b) Sergeev, A. G.;
Artamkina, G. A.; Beletskaya, I. P. Zh. Org. Khim. 2003, 39,
1814.
Ligands L1 and L2 are known to be very effective for
palladium-catalyzed arylation of amines, even at room
temperature5 and, as it was mentioned previously, have
been used for the arylation of lithium amide.2 It is also
worth pointing out that in aqueous alkali urea acts as
ammonia source giving trialkylamines in the reactions
with alkyl, allyl and benzylchlorides.10
(5) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem. Int. Ed.
1999, 38, 2413. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.;
Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158.
(6) (a) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.;
Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1999, 64, 5575. (b) Stauffer, S. R.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 6977. (c) Stambuli, J. P.; Kuwano,
R.; Hartwig, J. F. Angew. Chem. Int. Ed. 2002, 41, 4746.
(d) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 13978.
(7) Representative Procedure for Tri(m-tolyl)amine.
m-Bromotoluene (282 mg, 1.65 mmol), urea (31 mg, 0.51
mmol), Pd2dba3·CHCl3 (31.5 mg, 0.03 mmol), t-Bu3P·HBF4
(25.2 mg, 0.087 mmol), t-BuOK (325 mg, 2.9 mmol), and
anhydrous dioxane (6 mL) purged with argon were placed
into an argon-filled reactor. The reaction was carried out
with stirring at 100 °C under positive argon pressure. After
the aryl halide was completely consumed (according to GC),
the reaction mixture was cooled to r.t., diluted with EtOAc
(30 mL), filtered through the short plug of Celite® and
evaporated on silica gel. The residue was chromatographed
on silica gel (Merck 60, 40–63 mm), eluting with light PE,
then EtOAc–light PE mixture 1:40 and 1:20 at the end to
give 122 mg (85%) of the product as a white solid. Mp
66 °C (ref. 2: 64–65 °C). 1H NMR (400 MHz, acetone-d6):
d = 7.14 (t, 3 H, 7.7 Hz), 6.77–6.87 (m, 9 H), 2.23 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 287 (100) [M+], 271 (2) [M – CH3
– H+], 257 (4) [M+ – 2 CH3], 180 (5) [C13H10N+].
In summary, a new method for the one-pot preparation of
arylamines from aryl halides and urea is reported.
Arylation of urea in the presence of Pd2dba3, Pt-Bu3 and
t-BuOK gives triarylamines with para- and meta-substi-
tuted aryl halides and diarylamines with ortho-substituted
substrates.
References and Notes
(1) (a) Hartwig, J. F. Synlett 1997, 329. (b) Hartwig, J. F.
Angew. Chem. Int. Ed. 1998, 37, 2046. (c) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. (d) Yang, B.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125. (e) Belfield, A. J.;
Brown, G. R.; Foubister, A. J. Tetrahedron 1999, 55, 11399.
(f) Hartwig, J. F. Pure Appl. Chem. 1999, 71, 1417.
(g) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131. (h) Prim, D.; Campagne, J.; Joseph, D.;
Andrioletti, B. Tetrahedron 2002, 58, 2041. (i) Hartwig, J.
F. In Handbook of Organopalladium Chemistry for Organic
Synthesis, Vol. 2; Negishi, E., Ed.; Wiley-Interscience: New
York, 2002, 1051.
(8) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(9) Harris, M. C.; Buchwald, S. L. J. Org. Chem. 2000, 65,
5327.
(10) Sachinvala, N.; Winsor, D. L.; Maskos, K.; Hamed, G. O.;
Vigo, T. L.; Bertoniere, N. R. J. Org. Chem. 2000, 65, 9234.
(2) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417.
(3) (a) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P.
Tetrahedron Lett. 2001, 42, 4381. (b) Artamkina, G. A.;
Sergeev, A. G.; Beletskaya, I. P. Zh. Org. Khim. 2002, 38,
563.
Synlett 2006, No. 2, 235–238 © Thieme Stuttgart · New York