UFU ('Ullmann-Finkelstein-Ullmann'): a new multicomponent reaction

Article abstract of DOI:10.1016/j.tetlet.2006.04.041

We developed conditions to carry out the first 'one-pot' Ullmann-Finkelstein-Ullmann multicomponent reaction reported. This reaction allows the one-pot synthesis of dissymmetrical para-disubstituted benzene scaffold from 1-bromo-4-iodobenzene and two N-nu

Full text of DOI:10.1016/j.tetlet.2006.04.041

Tetrahedron Letters 47 (2006) 4973–4978
UFU (‘Ullmann–Finkelstein–Ullmann’):
a new multicomponent reaction
`
Patrick Toto, Jean-Claude Gesquiere, Nicolas Cousaert, Benoit Deprez
and Nicolas Willand*
Inserm, U761, Lille F-59006, France
Universite´ de Lille2, Faculte´ de Pharmacie de Lille, 3 rue du Professeur Laguesse, Lille F-59006, France
Institut Pasteur Lille, ‘Biostructures et De´couverte Me´dicament’, Lille F-59019, France
Received 24 January 2006; revised 6 April 2006; accepted 7 April 2006
Available online 26 May 2006
Abstract—We developed conditions to carry out the first ‘one-pot’ Ullmann–Finkelstein–Ullmann multicomponent reaction
reported. This reaction allows the one-pot synthesis of dissymmetrical para-disubstituted benzene scaffold from 1-bromo-4-iodobenz-
ene and two N-nucleophiles. CuI/N,N0-dimethyl-cyclohexane-1,2-diamine was used as a catalyst/ligand couple, K3PO4 as a base and
the reaction was performed in dioxane.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(BAY 59-7939) which prevents thrombin generation in
the coagulation pathway2 (Scheme 2).
Nonsymmetrical para-disubstituted benzene is a com-
mon scaffold found in many biologically active com-
pounds. In particular, acylated or sulphonylated
paraphenylenediamine presented in Scheme 1 are well-
represented in bioactive compounds databases.
These biological data led us to design a simple synthesis
of dissymmetrical acylated or sulfonylated para phenyl-
enediamines, different from reported synthetic routes
that usually involve acylations. We thus developed a
copper-catalysed Ullmann–Finkelstein–Ullmann multi-
component reaction. The copper-catalysed couplings
have been widely studied by Buchwald.5 The ‘Ullmann6’
Antiviral,1 anticoagulant,2 antisclerosis3 or antineoplas-
tic4 activities have been reported for these structures.
Some of them have even entered clinical development
such as Tomeglovir an antiviral, or Rivaroxaban,
7
N-arylation5 of amides and the ‘Finkelstein’ I–Br ex-
change8 have been improved using catalytic amount of
Nu2
Nu2
O
O
S
O
O
O
N
R
N
O
R
N
R
N
N
O
=
H
H
H
O
Nu1
Nu1
Scheme 1. General structure of para-disubstituted benzene scaffold.
*
Corresponding author. Tel.: +33 320964957; fax: +33 0320964709; e-mail: nicolas.willand@univ-lille2.fr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.041

4974
P. Toto et al. / Tetrahedron Letters 47 (2006) 4973–4978
N
O
Cl
O
H
S
N
O
N
H
N
O
O
S
N
O
HO
O
O
N
H
TOMEGLOVIR (antiviral agent)
RIVAROXABAN (anticoagulant)
Scheme 2. Tomeglovir and Rivaroxaban.
CuI and an appropriate ligand. In order to introduce
diversity on a simple benzene scaffold, we designed an
extension of our UF tandem reaction9 by exploring
the possibility to perform a second Ullmann step in a
‘one-pot’ manner. Our aim was to determine the best
conditions and types of nucleophiles for the synthesis
of dissymmetrical products. We postulated that the reac-
tion with one of the nucleophiles had to be faster than
the other to allow a sequential course of the reactions
and yield quantitatively the dissymmetrical compound.
(Scheme 3).
H
i
N
+
R
R'
N
I
R
R'
H
O
NH2
EtOOC
N
O
N
H
H
N
H
N
S
H
O
NH2
O
N
O
N
O
=
R
R'
O
N
O
O
N
H
1
2
3
4
5
6
100
90
80
70
60
50
40
30
20
10
0
In a first approach we determined the reaction rate of six
nucleophiles (two carbamates 1 and 4, three amides 3, 5
and 6 and one sulfonamide 2) in a typical Ullmann N-
arylation. Each nucleophile was reacted with Iodobenz-
ene, a catalytic amount of CuI and N,N0-dimethyl-cyclo-
hexane-1,2-diamine, and K3PO4 as a base in dioxane
following the conditions described by Buchwald.5 The
disappearance of iodobenzene was monitored by HPLC
using a calibration curve based on UV absorbance,
using 1,2,4,5-tetramethylbenzene as an internal stan-
dard. Based on these data (Fig. 1), we could identify
pairs of nucleophiles displaying large differences in reac-
tivity and postulated that they were the best candidates
for a dissymmetrical UFU reaction.
1
2
3
4
5
6
0
50
100
150
200
250
300
time (min)
Figure 1. Iodobenzene conversion by nucleophiles 1 to 6. Reagents
and conditions: (i) 1 equiv of nucleophile, 1 equiv of iodobenzene, 0.1
equiv of CuI,
2
equiv of K3PO4, 0.2 equiv of N,N0-dimethyl-
In the case of oxazolidin-2-one 1 and N-methylbenzene-
sulphonamide 2,10 iodobenzene is more than 70% con-
cyclohexane-1,2-diamine, 0.5 equiv of 1,2,4,5-tetramethylbenzene
(durene), dioxane (0.5 M), 110 ꢁC. Sampling performed under an
argon overpressure. Ratio determined by UV detection at 215 nm.
Nu2
verted after 15 min of reaction. Both reagents can be
considered as fast nucleophiles. The fastest reagent 1
has been engaged in a UFU reaction in the presence
of reagents 3 to 6 and sulfonamide 2, an other fast-react-
ing nucleophile, was engaged with 4, 5 and 6. Though
nucleophile 3 is less reactive (about 50% conversion after
15 min), we mixed it with the slowest reagents 5 and 6 to
determine the limits of the rate difference in a pair of
nucleophiles. Results are reported in Table 1. As we
expected, good selectivity was obtained with pairs
including nucleophiles 1 or 2 as fast nucleophiles.
Six dissymmetrical products were obtained in high
proportion and isolated with good yields. Only nucleo-
phile 3 was not sufficiently reactive to allow a good
selectivity.
Br
"One pot"
UFU reaction
Nu2
+
Nu1
I
Nu1
U
U
I
Br
F
Nu2
+
Nu2
+
Nu1
Nu1
Scheme 3. Sequential course of the UFU ‘one-pot’ reaction U:
Ullmann reaction, F: Finkelstein reaction Nu1, Nu2 = amide, sul-
phonamide, carbamate.
As presented in the introduction, we hypothesised that
the UFU reaction proceeds in three successive steps:

P. Toto et al. / Tetrahedron Letters 47 (2006) 4973–4978
4975
Table 1. UFU reactions between Nu1 (1, 2 and 3) and Nu2 (3 to 6)
tion with the slowest nucleophile to yield the desired dis-
symmetrical compound. To confirm that assumption we
performed a kinetic study with nucleophiles 1 and 6. We
monitored the formation of halogenated intermediates
[1,Br] and [1,I]; the dissymmetrical compound [1,6];
and also the undesired symmetrical compounds [1,1]
and [6,6] (Table 2).
Nu1
Nu2
Nu2
Br
Nu2
i
+
+
+
Nu1
I
Nu2
Nu1
Nu1
After 30 min, reagent 1 was totally converted to the
N-arylated derivatives [1,X]. [1,Br] was converted to
[1,I]. After 18 h, the dissymmetrical product [1,6] was
almost quantitatively formed. Base on this observation
and the catalytic cycles already demonstrated for Ull-
mann and Finkelsein copper-catalysed reactions, we
postulated a mechanism for the UFU reaction, using
the succession of three catalytic cycles U1, F and U2
(Scheme 4).
[Nu2,Nu2]
[Nu1,Nu1]
[Nu1,Nu2]
Compound Structure
[Nu1, Nu2]
Ratioa Yieldb
(%)
(%)
O
80
53
O
[1,3]
O
N
N
N
N
EtOOC
O
H
N
O
O
2. Discussion
N
[1,4]
[1,5]
82
85
60
64
O
O
Through this work, we have identified two families of
N-nucleophiles: cyclic carbamates and alkylated sulfon-
amides that can be used to perform UFU reaction in the
presence of slow-reacting nucleophiles (lactams, amides
and noncyclic carbamates) with a good dissymmetrical
selectivity. According to the kinetic study of the Ull-
mann N-arylation for 1 (pKa = 20.8 in DMSO11), 3
(pKa < 21 in DMSO12) and 4 (pKa = 24.2 in DMSO11),
we observe that the arylation rate is (a) the highest with
the most acidic nucleophiles and (b) lower for sterically
hindered reagents. Both criteria (acidity and steric hin-
drance) shall guide the choice of the candidate pairs of
reagents for a selective UFU reaction.
O
H
N
O
O
N
N
O
[1,6]
95
70
O
N
NH
O
S
H
N
N
[2,4]
[2,5]
92
92
83
70
O
O
O
O
In order to extend the scope of our reaction, we mixed
the nonalkylated benzenesulphonamide 7 with amide 5
using our UFU conditions (Scheme 5). Being less hin-
dered than 1, reagent 7 was thought to react even faster
and give quantitatively the desired compound when
mixed with the slow reagent 5. Unexpectedly, the major
product observed after 48 h was intermediate [7,Br],
while only a trace of the expected product [7,5] could
be detected.
O
S
N
N
N
H
O
O
S
N
O
NH
[2,6]
[3,5]
96
57
81
O
O
O
N
N
N
H
ND
We supposed that the N-arylsulphonamide [7,Br] inter-
mediate could quench all further catalytic cycles. Indeed
with a pKa 2 units lower13 than its unarylated homo-
logue, the resulting conjugated base formed in higher
proportion could trap most of the catalyst as CuL2Nu
copper complex and inhibit the multicomponent reac-
tion. Moreover the high selectivity observed for
the methylated analogue 2 in UFU reaction (Table 1)
confirmed the key role played by the acidic NH of the
sulfonamide [7,Br] in the inhibition phenomena.
N
N
COOEt
COOEt
O
N
O
NH
[3,6]
65
ND
N
N
Reagents and conditions: (i) 1 equiv of each nucleophile, 1 equiv of 1-
bromo-4-iodobenzene, 0.2 equiv of CuI, 4 equiv of K3PO4, 0.4 equiv of
N,N0-dimethyl-cyclohexane-1,2-diamine, dioxane (0.25 M), 110 ꢁC,
22 h.
a Ratio = [Nu1,Nu2] · 100/([Nu1, Nu2] + [Nu1, Nu1] + [Nu2,Nu2])
determined by UV detection at 215 nm.
3. Conclusion
b Isolated yield.
This new UFU multicomponent reaction is a useful tool
for the synthesis of paraphenylenediamine derivatives. It
can be used to prepare large libraries for biomolecular
screening. We describe three structural features that
(1) Ullmann reaction with the most reactive nucleophile,
(2) Finkelstein halogen exchange and (3) Ullmann reac-

4976
P. Toto et al. / Tetrahedron Letters 47 (2006) 4973–4978
Table 2. Conversion rate study of the UFU reaction with nucleophiles 1 and 6
H
N
O
H
N
N
N
NH
O
O
HN
Br
N
6
i
O
O
O
O
N
+
+
+
N
O
H
O
O
N
I
N
N
O
H
[1,6]
[1,1]
[6,6]
1
O
X
O
N
[1, X]
X = I, Br
O
Time
Conversion of 1a (%)
[1,Br]a (%)
[1,I]a (%)
[1,6]a
[1,1] + [6,6]a
15 min
30 min
45 min
60 min
2 h
80
92
84
73
66
54
36
—
8
—
—
—
—
—
—
—
Trace
5%c
100
100
100
100
100
100
16
27
34
46
46
—
Traceb
Trace
Trace
18%
3 h
18 h
95%c
Reagents and conditions: (i) 1 equiv of 1 and 6, 1 equiv of 1-bromo-4-iodobenzene, 0.2 equiv of CuI, 4 equiv of K3PO4, 0.4 equiv of N,N0-dimethyl-
cyclohexane-1,2-diamine, dioxane (0.25 M), 110 ꢁC.
a UV detection at 215 nm. Sampling performed under an argon overpressure.
b Trace means detectable on MS spectrogram but irrelevant by UV detection.
c Relative ratio between dissymmetrical and symmetrical compounds.
Nu2
Br
K3PO4
Nu2H
+
CuI/L
Nu1
Nu1H
I
Br
I
U1
U2
F
Nu1
Nu1
Br
K+
Br
K3PO4
Nu2--
KI
Nu2H
Nu1
I
L
L
Cu
I
L
L
Cu
Nu1
I
U2
L
L
L
U1
L
Cu
L
Cu
Nu2
L
L
Br
Cu
KI
Nu1
I
Nu1--
K+
F
Br
L
K3PO4
Nu1H
Nu2
Cu
I
KBr
Nu1
Nu1
Scheme 4. Supposed mechanism of the UFU reaction.
should be used to select reagent pairs and synthetic
schemes. (1) Acidity, (2) steric hindrance and (3) poten-
tial ligand property of the arylated form of the fastest
nucleophile.

P. Toto et al. / Tetrahedron Letters 47 (2006) 4973–4978
4977
O
O
O
NH2
NH
Br
Br
Br
5
I
NH
i
+
+
+
+
+
O
S
O
S
O
O
S
N
I
I
N
NH2
S
N
Br
H
H
H
O
O
O
O
7
[7,5]
2%a
[7,Br]
72%a
[7,I]
8%a
[5,Br]
3% a
15%a
Scheme 5. UFU reaction between 6 and 7. Reagents and conditions: (i) 1 equiv of 6 and 7, 1 equiv of 1-bromo-4-iodobenzene, 0.2 equiv of CuI, 4
equiv of K3PO4, 0.4 equiv of N,N0-dimethyl-cyclohexane-1,2-diamine, dioxane (0.25 M), 110 ꢁC, 48 h. aUV detection at 215 nm.
4. Experimental
61.9 (N–CH2–CH2–O); 60.6 (CH3–CH2–O); 45.2 (N–
CH2–CH2–O); 40.0 (N–CH3); 22.8 (CH3–C@O); 14.3
(CH3–CH2–O); LCMS (EI): m/z = 373 (base peak).
4.1. General procedure for Ullmann kinetic study
A dried Schlenck tube evacuated and backfilled with
argon (·2) was charged with CuI (10 mg, 0.05 mmol),
K3PO4 (213 mg, 1 mmol), the amide (0.5 mmol) and
1,2,4,5-tetramethylbenzene (33.5 mg, 0.25 mmol) under
argon overpressure. Then dioxane (1 ml), the N,N0-di-
methyl-cyclohexane-1,2-diamine (16 ll, 0.1 mmol) and
iodobenzene (56 ll, 0.5 mmol) were injected in the tube.
The sealed tube was stirred at 110 ꢁC. Samplings were
performed under argon overpressure at 15, 30, 60, 120,
240 min, diluted in MeOH 400 ll and filtered for LCMS
analysis.
4.4. [4-(2-Oxo-oxazolidin-3-yl)-phenyl]-carbamic acid
methyl ester [1,4]
Work-up: the residue was triturated in CH2Cl2 (1.5 ml),
the solid was then filtered and washed with CH2Cl2
(1.5 ml) to give a beige solid (71 mg).
Yield: 60%, mp: 218–223 ꢁC; 1H NMR (300 MHz,
DMSO-d6): d = 7.45 (s, 4 H, CHarom); 4.41 (t, 2H,
JHH = 5 Hz, N–CH2–CH2–O); 4.01 (t, 2H, JHH = 5 Hz,
N–CH2–CH2–O); 3.65 (s, 3H, O–CH3); 13C NMR
(75 MHz, DMSO-d6): d = 155.4 (C@O); 154.5 (C@O);
135.4 (Cqarom); 133.7 (Cqarom) 119.1 (2 · CHarom);
119.0 (2 · CHarom); 61.9 (N–CH2–CH2–O); 52.1 (O–
CH3); 45.4 (N–CH2–CH2–O), LCMS (EI): m/z = 237
(base peak).
4.2. General procedure for Ullmann/Finkelste¨ın/Ullmann
reaction
A dried Schlenck tube evacuated and backfilled with
argon (·2) was charged with CuI (20 mg, 0.1 mmol),
K3PO4 (426 mg, 2 mmol), the 1-bromo-4-iodobenzene
(145 mg, 0.5 mmol), and the two amides (0.5 mmol)
under argon overpressure. Then the dioxane (2 ml)
and the N,N0-dimethyl-cyclohexane-1,2-diamine (32 ll,
0.2 mmol) were injected in the tube. The sealed tube
was stirred at 110 ꢁC for 22 h. A solution of ammonia
(28%, 2 ml) and water (25 ml) was sequentially added
at rt to the reaction mixture. The resulting aqueous layer
was extracted with CH2Cl2 (3 · 25 ml). The combined
organic layers were dried on MgSO4, filtered and evap-
orated under reduced pressure. The residue was tritu-
rated in an appropriate solvent or purified on silica gel.
4.5. Cyclohexanecarboxylic acid [4-(2-oxo-oxazolidin-3-
yl)-phenyl]-amide [1,5]
Work-up: The residue was purified on silica gel (cyclo-
hexane/AcOEt: 6/4) to give a pale yellow solid (93 mg).
Yield: 64%, mp: 190–196 ꢁC; 1H NMR (300 MHz,
DMSO-d6): d = 9.81 (s, 1H, HN–C@O); 7.60 (d, 2H,
JHH = 9 Hz, CHarom); 7.46 (d, 2H, JHH = 9 Hz, CHarom);
4.41 (t, 2H, JHH = 5 Hz, N–CH2–CH2–O); 4.02 (t, 2H,
JHH = 5 Hz,
JHH = 11.1 Hz JHH = 3.6 Hz, CHcyclohexyl); 1.73 (m,
5H, CHcyclohexyl); 1.30 (m, 5H, CHcyclohexyl
13C NMR
N–CH2–CH2–O);
2.30
(Tt,
1H,
)
4.3. 3-{Acetyl-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-amino}-
1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester [1,3]
(75 MHz, DMSO-d6): d = 176.6 (C@O); 155.4 (C@O);
135.8 (Cqarom); 134.0 (Cqarom); 119.9 (2 · CHarom);
118.9 (2 · CHarom); 61.9 (N–CH2–CH2–O); 45.4
(N–CH2–CH2–O); 45.3 (CHcyclohexyl); 29.6 (2 ·
CH2cyclohexyl); 25.9 (CH2cyclohexyl); 25.7 (2 · CH2cyclohexyl),
LCMS (EI): m/z = 287 (base peak).
Work-up: The residue was purified on silica gel (cyclo-
hexane/AcOEt: 5/5) to give a yellowish solid (99 mg).
Yield: 53%, mp: 162–169 ꢁC; 1H NMR (300 MHz,
CDCl3): d = 7.89 (s, 1H, CHpyrazole); 7.50 (m, 4H,
CHarom); 4.48 (t, 2H, JHH = 7.5 Hz, N–CH2–CH2–O);
4.29 (q, 2H, JHH = 7.1 Hz, CH3–CH2–O); 4.06 (t, 2H,
JHH = 7.5 Hz, N–CH2–CH2–O); 3.89 (s, 3H, N–CH3);
2.07 (s, 3H, CH3–C@O); 1.34 (t, 3H, JHH = 7.1 Hz,
CH3–CH2–O); 13C NMR (75 MHz, CDCl3): d = 135.4
(CHpyrazole); 128.9 (2 · CHarom); 118.9 (2 · CHarom);
4.6. 1-[4-(2-Oxo-oxazolidin-3-yl)-phenyl]-piperazin-2-one
[1,6]
Work-up: the aqueous phase (27 ml, ammonia + H2O)
was washed with AcOEt (2 · 5 ml) and then extracted
with CH2Cl2 (3 · 25 ml). The CH2Cl2 fractions

4978
P. Toto et al. / Tetrahedron Letters 47 (2006) 4973–4978
were gathered, dried on MgSO4, filtered and evapo-
rated under reduced pressure to give a greenish solid
(92 mg).
4.9. N-Methyl-N-[4-(2-oxo-piperazin-1-yl)-phenyl]-benz-
enesulfonamide [2,6]
Work-up: The residue was purified on silica gel
(CH2Cl2/MeOH: 9/1) to give a yellow oil (140 mg).
Yield: 70%; mp: 170–180 ꢁC; 1H NMR (300 MHz,
DMSO-d6): d = 7.56 (d, 2H, JHH = 9 Hz, CHarom);
7.32 (d, 2H, JHH = 9 Hz, CHarom); 4.44 (t, 2H,
JHH = 5 Hz, N–CH2–CH2–O); 4.06 (t, 2H, JHH = 5 Hz,
N–CH2–CH2–O); 3.57 (t, 2H, JHH = 5.1 Hz, N–CH2–
CH2–N–C@O); 3.33 (s, 2H, N–CH2–C@O); 3.01 (t,
2H, JHH = 5.1 Hz, N–CH2–CH2–N–C@O) 13C NMR
(75 MHz, DMSO-d6): d = 126.8 (2 · CHarom); 118.9
(2 · CHarom); 61.9 (N–CH2–CH2–O); 51.5 (N–CH2–
CH2–N–C@O); 51.0 (N–CH2–C@O); 45.4 (N–CH2–
CH2–O); 44.9 (N–CH2–CH2–N–C@O), LCMS (EI):
m/z = 262 (base peak).
1
Yield: 81%; H NMR (300 MHz, CDCl3): d = 7.58 (m,
3H, CHarom); 7.47 (m, 3H, CHarom); 7.27 (d, 2H,
JHH = 9 Hz, CHarom); 7.12 (d, 2H, JHH = 9 Hz, CHarom);
3.73 (m, 4H, N–CH2–CH2–N–C@O + N–CH2–C@O);
3.27 (t, 2H, JHH = 5.1 Hz, N–CH2–CH2–N–C@O); 3.15
(s, 3H, N–CH3); 13C NMR (75 MHz, CDCl3): d = 167.7
(C@O); 141.1 (Cq); 139.7 (Cq); 136.4 (Cq); 132.9 (CHarom);
128.9 (CHarom); 127.8 (CHarom); 127.4 (CHarom); 126.2
(CHarom); 51.3 + 50.8 (N–CH2–CH2–N–C@O + N–
CH2–C@O); 43.4 (N–CH2–CH2–N–C@O); 38.1 (N–
CH3); LCMS (EI): m/z = 346 (base peak).
4.7. [4-(Benzenesulfonyl-methyl-amino)-phenyl]-carbamic
acid methyl ester [2,4]
Acknowledgements
The authors would like to thank Pr. Andre Tartar for
helpful discussions. We are grateful to the institutions
Work-up: The residue was purified on silica gel
(CH2Cl2/MeOH: 98/2) to give a colourless oil (133 mg).
´
that support our laboratory (Inserm, Universite de
1
Lille2 and Institut Pasteur de Lille). NMR spectra were
recorded in the ‘Laboratoire d’Application RMN
(LARMN) at U.Lille2’.
Yield: 83%; H NMR (300 MHz, CDCl3): d = 7.57 (m,
3H, CHarom); 7.47 (m, 2H, CHarom) 7.33 (d, 2H,
JHH = 9 Hz, CHarom); 7.01 (d, 2H, JHH = 9 Hz, CHarom);
3.77 (s, 3H, O–CH3); 3.16 (s, 3H, N–CH3); 13C NMR
(75 MHz, CDCl3): d = 153.9 (C@O); 137.2 (Cq); 136.5
(Cq); 136.3 (Cq); 132.8 (CHarom); 128.8 (CHarom);
127.9 (CHarom); 127.5 (CHarom); 118.7 (CHarom); 52.5
(O–CH3); 38.3 (N–CH3); LCMS (EI): m/z = 321 (base
peak).
References and notes
1. Bender, W. Patent Bayer AG WO 9937609; 19990729.
2. Straub, A. Patent Bayer AG WO 0147919; 20010705.
3. Oldham, K. Patent AstraZeneca AB WO 0064866;
20001102.
4. Goldste¨ın, S. Patent Servier US 2003199530; 20031023.
5. (a) Klapars, A.; Antilla, J. C.; Huan, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727–7729; (b) Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421–7428.
6. (a) Ullmann, F. Ber. Dtsh. Chem. Ges. 1903, 36, 2389–
2391; (b) Ullmann, F. Ber. Dtsh. Chem. Ges. 1904, 37,
853–857.
4.8. Cyclohexanecarboxylic acid [4-(benzenesulfonyl-
methyl-amino)-phenyl]-amide [2,5]
Work-up: The residue was purified on silica gel
(CH2Cl2/MeOH: 98/2) to give a white solid (131 mg).
Yield: 70%; mp: 218–223 ꢁC; H NMR (300 MHz,
CDCl3): d = 7.52 (m, 7H, CHarom); 7.01 (d, 2H,
JHH = 9 Hz, CHarom); 3.15 (s, 3H, N–CH3); 2.26 (Tt,
1H, JHH = 11.1 Hz JHH = 3.6 Hz, CHcyclohexyl); 1.87
(m, 4H, CHcyclohexyl); 1.70 (m, 1H, CHcyclohexyl); 1.53
(Qd, 2H, JHH = 12 Hz JHH = 2.7 Hz, CHcyclohexyl);
1.27 (m, 3H, CHcyclohexyl); 13C NMR (75 MHz, CDCl3):
d = 174.8 (C@O); 137.5 (Cq); 136.8 (Cq); 136.2 (Cq);
132.9 (CHarom); 128.9 (CHarom); 127.8 (CHarom); 127.3
(CHarom); 119.9 (CHarom); 46.4 (CHcyclohexyl); 38.3 (N–
CH3); 29.6 (2 · CH2cyclohexyl); 25.6 (3 · CH2cyclohexyl);
LCMS (EI): m/z = 373 (base peak).
7. Finckelstein, H. Ber. 1910, 43, 1528.
8. Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
14844–14845.
`
9. Toto, P.; Gesquiere, J.-C.; Deprez, B.; Willand, N.
Tetrahedron Lett. 2006, 47, 1181–1186.
10. Vigroux, A.; Bergon, M.; Bergonzi, C.; Tisnes, P. J. Am.
Chem. Soc. 1994, 116, 11787–11796.
11. Bordwell, F. G.; Ji, G. Z. J. Am. Chem. Soc. 1991, 113,
8398–8401.
12. Bordwell, F. G.; Fried, H. G. J. Org. Chem. 1991, 56,
4218–4223.
13. Willi, A. V. Helv. Chim. Acta 1956, 39, 46–48.