A Novel Modified Cross-Coupling of Phenols and Amines Using Dichloroimidazolidinedione (DCID)

Article abstract of DOI:10.1055/s-0040-1707224

Phenols are considered as an ideal alternative to aryl halides as coupling partners in cross-coupling reactions. In the present work a copper-catalyzed cross-coupling of phenols with various aromatic and aliphatic amines for the synthesis of secondary aryl amines using dichloroimidazolidinedione (DCID) as a new and efficient activating agent has been developed. Substituted phenols were compatible with the standard reaction conditions. The two proposed mechanisms, which are based on the oxidation addition of copper with Ar-OMCID (MCID: Monochloroimidazolidinedione), are also discussed.

Full text of DOI:10.1055/s-0040-1707224

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
Synlett
K. Madankar et al.
Letter
A Novel Modified Cross-Coupling of Phenols and Amines Using
Dichloroimidazolidinedione (DCID)
Kamelia Madankar
O
O
Javad Mokhtari*
Zohreh Mirjafary
0
0
0
0-0
0
0
1-
8
5
1
2-9
5
1
3
DCID:
N
N
Cy
Cy
Cl Cl
H
OH
CuI (cat.)
N
R
Department of Chemistry, Science and Research
Branch. Islamic Azad University, P.O. Box 14515/775,
Tehran, Iran
+
R NH2
Et3N, MeCN
FG
FG
FG = Cl, MeO, Me
15 examples
j.mokhtari@srbiau.ac.ir
O
O
R = Ar, Bn, Cy, n-Pr
yields: 18–73%
N
N
Cy
Cy
Cl
via
O
FG
Ar–OMCID
Received: 22.05.2020
Accepted after revision: 07.07.2020
Published online: 03.08.2020
such as aryl triflates, tosylates, mesylates, pivalates, and
5–11
even ethers.
Therefore, in addition to the aforemen-
DOI: 10.1055/s-0040-1707224; Art ID: st-2020-r0303-l
tioned, the development of new activated phenol deriva-
tives for cross-coupling reactions has been needed. Herein,
in continuation of our work on cross-coupling reactions,
in this paper we report a general, one-pot cross-coupling of
phenols which are activated by dichloroimidazolidinedione
(DCID) as a new and efficient reagent, with aromatic
amines in the presence of catalytic amount of CuI (Scheme
Abstract Phenols are considered as an ideal alternative to aryl halides
as coupling partners in cross-coupling reactions. In the present work a
copper-catalyzed cross-coupling of phenols with various aromatic and
aliphatic amines for the synthesis of secondary aryl amines using di-
chloroimidazolidinedione (DCID) as a new and efficient activating agent
has been developed. Substituted phenols were compatible with the
standard reaction conditions. The two proposed mechanisms, which
are based on the oxidation addition of copper with Ar-OMCID (MCID:
Monochloroimidazolidinedione), are also discussed.
12
1). Recently, DCID has been used in different organic syn-
theses including a Beckman’s rearrangement of ketoxim-
1
3
14
es, chlorodehydroxylation of alcohols, chemoselective
15
Key words cross-coupling, N-arylation, phenol, amines, dichloroimid-
azolidinedione, diarylamines
amidation from carboxylic acids and amines, multicom-
16
ponent coupling of terminal alkynes, halodehydrating
agent,17 and Suzuki–Miyaura cross-coupling as a new re-
18
Carbon–nitrogen bonds are almost ubiquitously present
in pharmaceuticals, agrochemicals, electronics, and dyes.1
Given the importance of C–N bond formation, numerous ef-
forts have been made to form this bond via transition-met-
al-catalyzed cross-coupling reactions since the 1970s.2
Ullmann and Buchwald–Hartwig condensations are types of
cross-coupling reactions which lead to formation of C–O, C–
agent.
4
2
RNH2
CuI
DCID
H
N
Ar OH
Ar OMCID
Ar
R
NaH, MeCN
base, MeCN
1
3
5
Cy
Cy
O
3
O
O
N
N
N and C–S bond catalyzed by copper and palladium. In the
Cl
Cl
DCID =
MCID =
N
early stages, aryl halides (iodide and bromide) were popu-
lar coupling partners because of their high reactivity. How-
ever, difficulties encountered in accessing aryl halides and
the generation of toxic halogenated waste from the cross-
N
O
Cl
Cy
Cy
Scheme 1 One-pot cross-coupling of phenols and amines using DCID
4
coupling reaction limits their application in industry. To
DCID is readily available from the reaction of DCC with
oxalyl chloride by known reported methods.10 The chemical
structure of the DCID was confirmed by elemental analysis
this end, researchers were trying to find alternate cross-
coupling counterparts with improved generality. Among
these alternatives, phenol derivatives are good candidates
because they are naturally abundant, readily available, non-
toxic, and unique reaction intermediates in organic synthe-
sis. Phenols have a C–O bond with high dissociation energy;
therefore, it is necessary to transform phenols into activat-
ed phenol derivatives possessing rather weak C–O bonds
1
13
and H NMR and C NMR spectra (see the Supporting Infor-
mation). Firstly, to examine the role of DCID in the synthe-
sis of diaryl amines, we used phenol and aniline to optimize
the reaction conditions (Table 1). We found that reaction of
phenol (1 eqiuv) and DCID (1 equiv) in MeCN and in the
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
K. Madankar et al.
Letter
presence of sodium hydride (1 equiv) as base led to Ph-OM-
CID 3a. Upon addition of 1 equivalent of aniline and 20
mol% of CuI, diphenylamine was obtained in good yield.
Cy
Cy Cl
N
O
O
O
O
N
Cl
Cl
Cl
N
N
Cy
Cy
2
a
2
O Na
Table 1 Optimization of the Reaction Conditions
Cy
O
NaCl
N
Cl
O
NH2
a
OH
Cy
O
N
H
N
NH2
4
Cl Cy
N
O
O
O
N
Cl
Cl
Cy
solvent
NaH
CuI
Et3N
N
N
O
base, solvent
Cy
Cy
3
a
4a
1
a
2
3a
5a
O
CuX
Et3NH X
Entry
CuI
Base
Solvent
Time (h) Temp
(°C)
Yield
(%)
A
B
(
mol%)
Cy
Cl
H
N
N
O
CuI
1
2
3
4
5
6
7
10
20
20
20
20
20
20
–
Et
3
N
MeCN
MeCN
MeCN
MeCN
MeCN
THF
24
24
18
12
24
24
24
24
80
80
30
73
65
43
56
65
15
–
O
CuIII
6a
Et
3
N
N
N
N
X
8
a
Cy
O
Cl Cy
N
O
Et
3
3
80
NH2
H
III
Cu
N
N
O
Et
80
Et3N
Cy
O
N
X
3
a
O
K
2
CO
3
3
80
Cy
O
N
X = I, Cl, OMCID
3
Et N
65
Cy
K
2
CO
DMF
150
80
O
7
8
Et
3
N
MeCN
H
N
Et3NH+ Cl–
a
Reaction conditions: 1a (1.0 mmol), 4a (1.6 mmol), DCID (1.0 mmol),
base (1.0 mmol) in MeCN (5 mL) at 80 °C.
5
a
Scheme 2 Two possible pathways for the cross-coupling of phenol and
amines using DCID
Lower amounts of CuI (such as 10 mol%) led to de-
creased yields (Table 1, entry 1), therefore 20 mol% was
chosen. On the other hand, when the reaction was done in
DMF, the yield dropped sharply and formed only 5% of the
product (entry 7). A control experiment for the investiga-
tion of the role of the catalyst was performed. In the ab-
sence of CuI, no conversion to the desired product could be
observed (entry 8).
With the optimized reaction conditions in hand, the
substrate scope was explored. As shown in Table 2, different
aromatic and aliphatic amines reacted efficiently with phe-
nol derivatives. Anilines with an electron-donating group in
para position (Table 2, entries 5 and 6) furnished the prod-
ucts in good yields. An electron-withdrawing group such as
On the basis of the experimental facts and literature re-
ports,1
3,17
initially, the heterolytic cleavage of the C–Cl bond
in DCID 1 occurs by the election donation of two amide ni-
trogen atoms adjacent to the quaternary carbon nucleus, af-
fording 2-chloro-4,5-dioxo-imidazolinium chloride salt 2a.
Subsequently, the attack of phenoxide anion at C2 of 2a
forms the Ph-OMCID 3a. The reaction then proceeds
through two possible oxidative addition/reductive elimina-
tion mechanistic pathways23 (Scheme 2). Cycle B is initiated
by the reaction of aniline with CuI to generate species 6a.
Subsequently, oxidative addition of Ph-OMCID 3a generates
copper(III) intermediate, which undergoes further reduc-
tive elimination to give product 5a. In cycle A the first step
is an oxidative addition of the Ph-OMCID to copper to form
a copper(III) intermediate. Afterwards, the MCID on copper
is exchanged for the aniline and the obtained intermediate,
via a reductive elimination step, releases the product 5a,
and the Cu(I) catalyst is regenerated. Additionally, it is note-
4-nitroaniline, however, led to 18% yield (entry 4), this may
be due to the slow reaction of deactivated aniline with CuI
and formation of copper(III) intermediate (Scheme 2). Also,
1-naphthyl amine and 2-aminopyrimidine (entries 7 and 8)
reacted with phenol to yield the products 5g and 5h in
good yields under identical conditions, respectively. On the
other hand, aliphatic amines such as cyclohexyl amine, n-
propyl amine, and benzylamine were also used in this reac-
tion, generating the desired products with good yields (en-
tries 9–11). Morpholine was also used to evaluate the reac-
tion of the secondary amines in this reaction (entry 12) and
compound 5l was formed in 53% yield.
13
worthy that species 7 was isolated and characterized by
C
NMR and MS analysis (Figures S21 and S22 in the Support-
ing Information). These experimental results suggest that,
under our reaction conditions, DCID-activated phenols and
the resulting Ar-OMCIDs undergo an oxidative addition re-
action.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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Synlett
K. Madankar et al.
Letter
Table 2 Cross-Coupling Reaction of Phenols with Different Amines Using DCIDa
DCID, CuI
H
OH
N
Et3N
R
+
R NH2
FG
MeCN
FG
1
4
5
Entry
1
Phenol 1
RNHR′ 4
Product 5
Yield (%)
73
Mp (°C)
H
N
OH
52–5312c
NH2
5
a
H
N
OH
OH
OH
2
3
4
Cl
NH2
NH2
74
68
18
72–7412c
86–8912c
5
b
Cl
H
N
Br
5
c
Br
H
N
134–13512c
O2N
NH2
NH2
5
d
NO2
H
N
OH
OH
5
6
MeO
Me
61
59
100–10219
86–8912c
OMe
5
e
H
N
NH2
Me
5
f
H
N
NH2
OH
OH
7
67
54
60–6212c
5
g
H
N
N
N
N
8
9
113–11512c
N
NH2
5
h
OH
OH
OH
H
N
NH2
65
62
49
oil20,b
oil20,b
oil21,b
5
i
H
N
1
0
1
NH2
NH2
5
j
H
N
1
5
k
O
O
OH
N
12
53
51–5422
N
H
5
l
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
Synlett
K. Madankar et al.
Letter
Table 2 (continued)
Entry
Phenol 1
RNHR′ 4
Product 5
Yield (%)
62
Mp (°C)
72–7412c
OH
13
14
15
NH2
NH2
NH2
5b
Cl
OH
5e
60
71
100-10219
86–8912c
MeO
OH
5f
Me
a
Reaction conditions: 1 (1.0 mmol), 4 (1.6 mmol), DCID (1.0 mmol), CuI (20 mol%), Et
Structures of compounds 5i, 5j, and 5k were confirmed by NMR spectra (see Supporting Information).
3
N (1.0 mmol) in MeCN (5 mL) at 80 °C.
b
In conclusion, we have developed a novel modified
cross-coupling of phenols with various aromatic and ali-
(7) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem. Eur. J. 2011, 17,
728.
8) So, C. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40, 4963.
1
(
phatic amines using dichloroimidazolidinedione (DCID) as
a new and efficient reagent in the presence of copper(I).24–27
(9) Cornella, J.; Zarate, C.; Martin, R. Chem. Soc. Rev. 2014, 43, 8081.
10) Bisz, E.; Szostak, M. ChemSusChem 2017, 10, 3964.
11) Tobisu, M.; Chatani, N. Top. Curr. Chem. 2016, 374, 41.
12) (a) Panahi, L.; Naimi-Jamal, M. R.; Mokhtari, J.; Morsali, A.
Microporous and Mesoporous Materials 2016, 244, 208.
(b) Tahmasebi, S.; Khosravi, A.; Mokhtari, J.; Naimi-Jamal, M. R.;
Panahi, L. J. Organomet. Chem. 2017, 853, 35. (c) Khosravi, A.;
Tahmasebi, S.; Mokhtari, J.; Naimi-Jamal, M. R.; Panahi, L. RSC
Adv. 2017, 7, 46022.
(
(
(
Various substituted aromatic amines were obtained in good
to excellent yields. The Ph-OMCID intermediate 3 is not iso-
lated in this method and is therefore much more conve-
nient and useful compared to the known reported methods.
Investigations regarding the scope and application of this
reagent (DCID) and further mechanistic studies are current-
ly in progress.
(
13) Gao, Y.; Liu, J.; Li, Z.; Guo, T.; Xu, S.; Zhu, H.; Wei, F.; Chen, S.;
Gebru, H.; Guo, K. J. Org. Chem. 2018, 83, 2040.
(
(
14) Schilter, D.; Bielawski, C. W. Org. Synth. 2016, 93, 413.
15) Li, J.; He, S.; Fu, H.; Chen, X.; Tang, M.; Zhang, D.; Wang, B. Res.
Chem. Intermed. 2018, 44, 2289.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707224.
(16) Zhao, F.; Li, Y.; Wang, Y.; Zhang, W. X.; Xia, Z. Org. Biomol. Chem.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
2014, 12, 3336.
(
(
17) Moerdyk, J. P.; Bielawski, C. W. Chem. Eur. J. 2014, 20, 13487.
18) Madankar, K.; Mokhtari, J.; Mirjafary, Z. Appl. Organomet. Chem.
References and Notes
2020, e5383.
(
1) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359. (b) Stanforth, S. P. Tetrahedron
998, 54, 263. (c) Brown, B. R. The Organic Chemistry of Aliphatic
Nitrogen Compounds; Cambridge University: Cambridge, 2004.
(19) Mallia, C. J.; Burton, P. M.; Smith, A. M. R.; Walter, G. C.;
Baxendale, I. R. Beilstein J. Org. Chem. 2016, 12, 1598.
(20) Xu, H.; Wolf, C. Chem. Commun. 2009, 1715.
(21) Dang, T. T.; Shan, S. P.; Ramalingam, B.; Seayad, A. M. RSC Adv.
2015, 5, 42399.
1
(
(
d) McElroy, W. T.; DeShong, P. Tetrahedron 2006, 62, 6945.
e) Torres, J. C.; Pinto, A. C.; Garden, S. J. Tetrahedron 2004, 60,
(22) Lee, J.-C.; Wang, M.-G.; Hong, F.-E. Eur. J. Inorg. Chem. 2005, 24,
5011.
9889. (f) Lawrence, S. A. Amines: Synthesis, Properties and Appli-
cations; Cambridge University: Cambridge, 2004. (g) Hajduk, P.
J.; Bures, M.; Praestgaard, J.; Fesik, S. W. J. Med. Chem. 2000, 43,
(23) Sperotto, E.; Klink, G. P. M.; Koten, G. V.; de Vries, J. G. Dalton
Trans. 2010, 39, 10338.
3
443.
(24) Synthesis of Dichloroimidazolidinedione (DCID, 2)
Compound 2 was synthesized by following Gao et al.,13 with
minor modifications. To N,N′-dicyclohexylcarbodiimine (DCC, 2
g, 1 mmol) in dry dichloromethane (25 mL) at 0 °C was added
oxalyl chloride (0.9 mL, 1.05 mmol) dropwise. The reaction
mixture was stirred for 1 h at room temperature. The solid
material was separated by filtration and washed with cold
dichloromethane. The recrystallization of white solid in ethanol
(
2) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Ed.; Wiley-VCH: Weinheim, 1998. (b) Cross-Coupling
Reactions. A Practical Guide; Miaura, N., Ed.; Springer: Berlin,
2
002. (c) Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A.; Diederich, F., Ed.; Wiley-VCH: Weinheim, 2004.
3) (a) Fanta, P. E. Synthesis 1974, 9. (b) Castillo, P. R.; Buchwald, S.
L. Chem. Rev. 2016, 116, 12564.
4) (a) Rouhi, A. M. Chem. Eng. News 2004, 82, 49. (b) Corbet, J.-P.;
Mignani, G. Chem. Rev. 2006, 106, 2651.
(
(
(
(
1
yielded DCID (2,5 g, 97%); mp 174–176 °C. HNMR (499.77 MHz,
CDCl ):  = 3.97–4.00 (m, 2 H), 2.02–2.10 (m, 4 H, Cy), 1.73–1.87
3
5) (a) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982,
(m, 4 H, Cy), 1.71–1.75 (m, 4 H, Cy), 1.66–1.69 (m, 2 H, Cy),
1.17–1.36 (m, 6 H, Cy) ppm.
85. (b) Ritter, K. Synthesis 1993, 735.
6) (a) Vorbrüggen, H. Synthesis 2008, 1165. (b) Högermeier, J.;
Reissig, H.-U. Adv. Synth. Catal. 2009, 351, 2747.
Thieme. All rights reserved. Synlett 2020, 31, A–E

E
Synlett
K. Madankar et al.
Letter
(
25) Synthesis of 2-Chloro-1,3-dicyclohexyl-2-phenoxyimidazoli-
mmol) was added. The reaction mixture was stirred for 1 h at
room temperature, and completion of the reaction was moni-
tored by TLC. After completion of the reaction, amines (1.6
dine-4,5-dione (3a)
Typically, to an oven-dried 25 mL round-bottom flask contain-
ing dry MeCN was added phenol (0.047 g 0.5 mmol) and NaH
mmol), Et N (0.101 g, 1 mmol), and CuI (0.038 g, 20 mol%) were
3
(
0.012 g, 0.5 mmol). The reaction mixture stirred for 30 min at
added, and the reaction mixture was stirred at 80 °C for 24 h
(TLC monitoring). For the purification of products, chromatog-
raphy on silica gel was performed (EtOAc–heptane, 1:3). Struc-
ture of the diaryl amines was confirmed by comparison of
melting point and NMR spectra reported in the literature (see
Supporting Information).
room temperature, and then DCID (0.165 g, 0.5 mmol) was
added. The reaction mixture was stirred for 1 h at room tem-
perature and completion of the reaction monitored by TLC.
After completion of the reaction salt was filtered, and the fil-
trate was evaporated under reduced pressure to yield a white
solid (0.1 g, 96%).
Analytical Data of Diphenylamine (5a)
White solid; yield: 0.123 g, 73%; mp 52–53°C. 1H NMR
12c
Analytical Data of 2-Chloro-1,3-dicyclohexyl-2-phenoxyim-
idazolidine-4,5-dione (3a)
(499.70 MHz, CDCl ):  = 7.92 (d, J = 7.2 Hz, 4 H), 7.52 (t, J = 6.9
3
FTIR:  = 2929, 2859, 1742, 1399, 1241, 1060 cm–1. 1HNMR
Hz, 4 H), 7.48 (m, 2 H), 6.85 (s, 1 H, NH) ppm.
(
499.70 MHz, CDCl ):  = 7.16 (t, J = 7.44 Hz, 1 H), 6.82 (t, J = 8.14
(27) Scale-Up Synthesis of Diphenylamine (5a)
3
Hz, 2 H), 6.76 (d, J = 7.59 Hz, 2 H), 3.95 (m, 1 H), 1.79 (m, 6 H),
To an oven-dried 250 mL round-bottom flask containing dry
MeCN (50 mL) were added phenol (4.7 g, 50 mmol) and NaH
(1.2 g, 50 mmol). The reaction mixture was stirred for 30 min at
room temperature, and then DCID (16.5 g, 50 mmol) was added.
The reaction mixture was stirred for 1 h at room temperature,
and completion of the reaction was monitored by TLC. After
1
.71 (m, 4 H), 1.65 (m, 2 H), 1.18 (m, 4 H), 1.15 (m, 4 H) ppm.
13
CNMR (125.66 MHz, CDCl ):  = 156.7, 156.2, 128.9, 121.2,
3
+
116.3, 114.7, 31.8, 28.9, 28.7, 24.4 ppm. EI-MS: m/z = 393 [M +
2], 356, 224, 181, 143, 99, 83, 56.
(
26) General Procedure for the One-Pot Cross-Coupling of
Phenols and Amines Using DCID Catalyzed by CuI
completion of the reaction aniline (7.23 mL, 80 mmol), Et N
3
Typically for the synthesis of 5a, to an oven-dried 25 mL round-
bottom flask containing dry MeCN (5 mL) were added phenol (1
mmol) and NaH (0.024 g, 1 mmol). The reaction mixture stirred
for 30 min at room temperature, and then DCID (0.330 g, 1
(6.97 mL, 50 mmol), and CuI (0.19 g, 20 mol%) were added, and
the reaction mixture was stirred at 80 °C for 24 h (TLC monitor-
ing). Purification of the product by chromatography on silica gel
(EtOAc–heptane, 1:3) yielded compound 5a (6.1 g, 72%).
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E