Electrophilic amination of Cu(I) catalyzed phenylmagnesium bromide with N,O-bis(trimethylsilyl)hydroxylamine in THF:N-donor solvent. Control of C–N and C–O chemoselectivity

Article abstract of DOI:10.1016/j.jorganchem.2019.120884

Reaction of PhMgBr with (Me₃Si)HNO(SiMe₃)[TMSHA] in the presence of CuI or CuCN catalysis (10–20 mol %) in THF:cosolvent (cosolvent = HMPA or TMEDA) at room temperature can provide an atom-economic and step-economic access for arylamine synthesis starting from aryl Grignard reagents. Chemoselectivity to yield C–N or C–O coupling can be controlled by changing reaction parameters. Cu(I) catalyzed reaction of PhMgBr in THF or in THF:HMPA (or TMEDA) affords both C–N and C–O coupling products, i.e. aniline and phenol (mol ratio ≥ 7:3), whereas uncatalyzed reaction of PhMgBr gives phenol. Mechanisms were proposed for the solvent dependence of chemoselectivity in the coupling of both uncatalyzed and Cu(I) catalyzed Grignard reagent with (TMS)HNO(TMS).

Full text of DOI:10.1016/j.jorganchem.2019.120884

Journal of Organometallic Chemistry 899 (2019) 120884
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Electrophilic amination of Cu(I) catalyzed phenylmagnesium bromide
with N,O-bis(trimethylsilyl)hydroxylamine in THF:N-donor solvent.
Control of CeN and CeO chemoselectivity
*
Didem Kahya , Fatma Ero gꢀ lu
Ankara University, Science Faculty, Be s¸ evler, Ankara, 06100, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 January 2019
Received in revised form
Reaction of PhMgBr with (Me Si)HNO(SiMe )[TMSHA] in the presence of CuI or CuCN catalysis (10
3
3
e20 mol %) in THF:cosolvent (cosolvent ¼ HMPA or TMEDA) at room temperature can provide an atom-
economic and step-economic access for arylamine synthesis starting from aryl Grignard reagents. Che-
moselectivity to yield CeN or CeO coupling can be controlled by changing reaction parameters. Cu(I)
catalyzed reaction of PhMgBr in THF or in THF:HMPA (or TMEDA) affords both CeN and CeO coupling
products, i.e. aniline and phenol (mol ratio ꢀ 7:3), whereas uncatalyzed reaction of PhMgBr gives phenol.
Mechanisms were proposed for the solvent dependence of chemoselectivity in the coupling of both
uncatalyzed and Cu(I) catalyzed Grignard reagent with (TMS)HNO(TMS).
25 June 2019
Accepted 30 July 2019
Available online 31 July 2019
Keywords:
Electrophilic amination
N,O-bis(trimethylsilyl)hydroxylamine
Aryl Grignard reagents
Arylamines
©
2019 Elsevier B.V. All rights reserved.
Atom-economy
CeN coupling
1
. Introduction
sulhydroxylamines) [6a, g, h, 7e9] and oxaziridines 7 [7,9] react
with carbanions directly. O-Sulfonyloximes 8, arenediazonium salts
9, azides 10, diazene dicarboxylates 11 and 1-chloro-1-
nitrosocycloalkanes 12 form intermediates which require reduc-
tive work-up to produce amines [7,9].
Over the last twenty years, our research group has been
involved in electrophilic amination of Grignard reagents, dio-
rganocuprates, diorganozincs and triorganozincates with O-meth-
Amines are of much importance due to the amino functionality
in natural products and pharmaceutical compounds as well as
building blocks in organic synthesis [1]. Modern methods are now
available to form CeN bonds and using transition metal catalyzed
amination of C-X bonds [2,3] or CeH bonds [4] provide important
methodologies for the synthesis of arylamines and heteroaryl-
amines. Electrophilic amination of organometallic compounds, that
ylhydroxylamine
(mesitylenesulfonyl)hydroxylamine
Me ) [10f, g] and with acetone O-(mesitylenesulfonyl)oxime
2
(Z ¼ Me) [10e], with N,N-dimethyl O-
1
is coupling of carbanions with electrophilic aminating reagents,
which are synthetic equivalents of NR
6
(R ¼ Y ¼ Me, R ¼ 2,4,6-
4
2
synthons, is also an
3 6 2
C H
1
2
important and potentially valuable methodology for the synthesis
of amines [5e7].
A number of electrophilic aminating reagents and methods have
been developed for nonsymmetric and symmetric amination of
ordinary carbanions [6a-f,h-l], and also for amination of enolates
derived from carbonyl compounds [6g,h].
8 (R ¼ Me, R ¼ 2,4,6-Me
3 6 2
C H ) [10a-d,h].
However, to the best of our knowledge, N,O-bis(trimethylsilyl)
hydroxylamine (TMSHA) 4a [11a] and N-alkyl-O-(trimethylsilyl)
hydroxylamines 4b [11b] did not receive much attention. They have
been used only for high yield amination of aryl and heteroaryl
Lipshutz type cuprates, R
coworkers (Scheme 2a) [11a]. Ferrocene carboxyaldehyde could be
also aminated following -lithiation and reaction of dilithium
2 2
Cu(CN)Li by Ricci, Dembech, Seconi and
3
2
Electrophilic aminating reagents contain either sp N or sp N
(Scheme 1). N-Chloramine 1 [8], O-substituted hydroxylamine 2e6
a
(
O-organyl-,
O-acyl-,
O-silyl-,
O-phosphinyl-
and
O-
mixed cyanocuprate with 4a (Scheme 2b) [11c]. In the amination of
dialkylcyanocuprates and mixed (alkyl)(phenyl)cyanocuprates,
both alkylamine and alkanol formation has been observed due to
the above mentioned nitrenoid/oxenoid equilibrium of the reagent
*
Corresponding author.
E-mail address: kahya@ankara.edu.tr (D. Kahya).
https://doi.org/10.1016/j.jorganchem.2019.120884
022-328X/© 2019 Elsevier B.V. All rights reserved.
0

2
D. Kahya, F. Ero gꢀ lu / Journal of Organometallic Chemistry 899 (2019) 120884
3
2
Scheme 1. sp N and sp N type electrophilic aminating reagents.
Scheme 2. (a) Amination of aryl and heteroaryl cyanocuprates with N,O-bis(trimethylsilyl)-hydroxylamine 4a [11a] and with N-alkyl O-(trimethylsilyl)hydroxylamine 4b [11b]. (b)
Amination of 2-lithioferrocene carboxyaldehyde acetal derivative with 4a [11c]. (c) Amination of dialkylcyanocuprates with 4a [11a].
resulting in CeN and CeO coupling (Scheme 2c) [11c].
applicability of the reaction of uncatalyzed reagents for Caryl-O
coupling. This method provides an atom-economic and step-
economic access for arylamine synthesis using electrophilic
amination.
So, encouraged by these results and essentially in an effort to
broaden the scope of electrophilic amination, we focused our in-
terest on the investigation of utility of TMSHA 4a for amination of
aryl Grignard reagents in the presence of Cu(I) catalysts. We plan-
ned to develop a new method for arylamine synthesis using aryl
Grignard reagent derived catalytic cuprates instead of prepared
2. Results and discussion
2 2
higher order diarylcyanocuprates R Cu(CN)Li . On the other hand,
In the amination of Cu(I) catalyzed Grignard reagents with N,O-
while we are optimizing the reaction parameters for high yield CeN
coupling leading to arylamine synthesis, we observed that CeO
coupling also takes place leading to phenol synthesis due to the
nitrenoid/oxenoid equilibrium of the aminating reagent TMSHA 4a
bis(trimethylsilyl)hydroxylamine (TMSHA) 4a, we began our in-
vestigations by determining the background yields, i.e. the yields of
uncatalyzed Grignard reagents. For these purpose, as model re-
actions, we selected reaction of phenylmagnesium bromide,
PhMgBr 13 and reaction of Cu(I) catalyzed PhMgBr 13 with TMSHA
(Scheme 4). These results prompted us to control the chemo-
selectivity in the reaction for allowing the formation of either
arylamine and phenol.
Herein, we report our successful findings for the development of
a new method for one-pot Caryl-N coupling using reaction of Cu(I)
catalyzed aryl Grignard reagents with TMSHA 4a and also for the
4a in THF (Scheme 3). With the aim of both developing a new
method for CeN coupling and also controlling N- or O- selectivity of
the reactions, we planned to investigate the effect of reaction pa-
rameters, (i) firstly, on the reaction of PhMgBr 13 and (ii) secondly,
on the reaction of Cu(I) catalyzed PhMgBr 13. As reaction

D. Kahya, F. Ero gꢀ lu / Journal of Organometallic Chemistry 899 (2019) 120884
3
Scheme 3. Reaction of TMSHA 4a with uncatalyzed and Cu(I) catalyzed PhMgBr 13 in THF using a cosolvent.
Scheme 4. Reaction of PhMgBr 13 with protonated TMSHA 4a, i.e. 4a-nitreneoid and 4a-oxenoid in THF.
parameters, we screened 13:4a mol ratio, Cu(I) catalysts and N-
the ratio of CeN and CeO coupling products in the reactions
of uncatalyzed and catalyzed aryl Grignard reagents.
(i) The uncatalyzed reactions of PhMgBr 13 were carried out in
THF and in THF:cosolvent with 2:1 and 3:1 mol ratios of
13:4a. The total yield and CeN coupling:CeO coupling ratio
were listed in Table 1. Following the deprotonation of 4a with
an equimolar amount of 13 to give nitrenoid/oxenoid equi-
librium takes place (Scheme 4) [12]. So, both CeN and CeO
coupling reactions might be expected to take place with 4a
in the presence of 2:1 and higher mol ratios of 13:4a (Scheme
3).
donor solvents as organic catalysts. The reaction temperature and
ꢁ
time were optimized to be 25 C and 3.5 h, respectively.
The total yield was found very low with 1:1 mol ratio of 13:4a
and/or in the presence of 5 mol% Cu(I) catalysis. Aiming a successful
atom-economic amination, we tried to carry out the reactions in
2
:1 and 3:1 mol ratios of 13:4a using CuI or CuCN catalyst lower
than 50 mol%. As organic catalysts, N-donor TMEDA and HMPA
were used as cosolvents in mostly 4:1 and 1:1 mol ratios of
THF:cosolvent. The yield of coupled products PhNH
2
14 and PhOH
15 were determined by finding their GC yields. The sum of the
yields of 14 and 15 are given as total yield and the ratio of the yields
of 14 and 15 are evaluated as chemoselectivity, i.e. CeN
coupling:CeO coupling (PhNH :PhOH) ratio.
2
Surprisingly, we observed only, PhOH 15 in THF with 56% and
35% yields in 2:1 and 3:1 mol ratios of 13:4a (Table 1, entries 1 and
4, respectively). N-Donor solvents, monodendate HMPA and
(
iii) We also proposed mechanism to give brief convincing ex-
planations for the solvent dependence of the total yield and
bidendate TMEDA were also tested as coordinating solvents in THF.
As seen, CeN coupling did not take place and the yield decreased in
Table 1
Reaction of phenylmagnesium bromide 13 with TMSHA 4a in THF at room temperature. Effect of 13:4a ratio and N-donor cosolvent on the yield and chemoselectivitya,b
.
ꢁ
PhMgBr ðTMSÞNHOðTMSÞ 1:THF:cosolvent;25 C;3:5h PhNH
PhOH
15
2
þ
ƒƒƒƒƒƒƒƒƒƒƒƒƒ!
þ
13
4a
2:Hydrolysis
14
Entry
Solvent c
Coupling yield, % d
Chemoelectivity 14:15 e
1
3: 4a mol ratio ¼ 2:1
1
THF
56
45
30
0:100
0:100
0:100
2
3
THF:HMPA(1:1)
THF:TMEDA(1:1)
1
3: 4a mol ratio ¼ 3:1
4
5
6
7
8
THF
35
28
24
18
17
0:100
0:100
0:100
13:87
0:100
THF:HMPA(4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
a
b
c
All the data are the average of at least five experiments.
The reactions were carried out on a 1 mmol scale.
THF:cosolvent volume ratio.
The sum of GC yields of 14 and 15.
The ratio of GC yields 14:15.
d
e

4
D. Kahya, F. Ero gꢀ lu / Journal of Organometallic Chemistry 899 (2019) 120884
the presence of coordinating solvents (Table 1, entries 2,3, and
e8). Looking more closely at these results also showed an increase
in the yield of PhOH in the presence of HMPA compared to that in
TMEDA (Table 1, entries 2,3; 5.7 and 6,8).
2
THF:HMPA (Table 2, entries 7, 8). THF led to 75%yield (PhNH :PhOH
5
ratio ¼ 87:13) (Table 2, entry 6). We were delighted to find that the
reaction in THF:HMPA (1:1) takes place with 83% yield and
2
PhNH :PhOH ratio of 95:5 (Table 2, entry 8). These optimized
We also examined the effect of using 4:1 mol ratio of 13:4a for
comparison with the results obtained using 2:1 and 3:1 mol ratio
and we found 53% yield of PhOH in THF, not higher than the
observed maximum yield.
conditions seemed us as an atom economic alternative to electro-
philic amination of diarylcuprates with TMSHA. As a cosolvent,
TMEDA gave quite low yields (Table 2, entries 9 and 10).
We next employed CuCN as a catalysts. In the presence of 10 mol
%
2
CuCN, 59% yield obtained with PhNH :PhOH ratio of 85:15 in THF
(
ii) Next, we turned our attention to the amination of PhMgBr 13
with TMSHA 4a in the presence of CuI or CuCN as catalysts.
(Table 2, entry 11). Using donor solvents resulted in diminished
yields (Table 2, entries 12e15).
Catalytic diorganocuprates “Ph
2
CuMgBr” 16 and “PhCu(CN)
Next, we tried CuCN catalysis in 40 mol% (entries 16e18). In THF,
a quite low yield was obtained again (entry 16). In THF, HMPA (or
TMEDA) (THF:cosolvent ¼ 4:1), the reaction was completed with a
MgBr” 17 and also PhMgBr 13 might deprotanate 4a to form
nitrenoid (Scheme 5). We carried out the experiments at 2:1
and 3:1 mol ratios of 13:4a (Table 2, Table 3 and Table 4,
respectively).
medium yield (57% and 60%), but with a high ratio of PhNH
(96:4 and 85:15), respectively (Table 2, entries 17 and 18).
2
:PhOH
It is also noteworthy that CuI catalyzed reactions lead to
obtaining higher yield and higher PhNH :PhOH ratio in the pres-
ence of HMPA compared to that in the presence of TMEDA (entries
2,3 compared to 4,5; entries 7,8 compared to 9,10). In addition,
increasing the cosolvent generally decreases the total yield (Table 2,
entries 2,3; 4,5; 9,10 and 12, 13).
The effect of Cu(I) catalysis was also examined for the reaction
carried out with 3:1 mol ratio of 13:4a (Table 3). 10 mol% CuI
2
catalysis gave 16e58% yields with quite high PhNH :PhOH ratios
First, we used PhMgBr 13 with 10e40 mol % CuI or CuCN
catalysis in the presence of 2:1 mol ratio of 13:4a (Table 2). 10 mol%
CuI catalysis in THF did not result in a higher yield and
2
PhNH
the reaction gives PhNH
3:7 (Table 2, entries 2 and 3), however the total yield is pretty low
54% and 45%, respectively). Better results were obtained when
using 20 mol% CuI both in THF (Table 2, entry 6) and also in
2
:PhOH ratio (Table 2, entry 1). Surprisingly, in THF:HMPA,
2
with a PhNH :PhOH ratio higher than
2
9
(
2
Scheme 5. Reaction of catalytic Ph CuMgBr 16 and PhCu(CN)MgBr 17 with 4a-nitrenoid and 4a-oxenoid in THF.
Table 2
Reaction of phenylmagnesium bromide 13 with TMSHA 4a (13:4a mol ratio ¼ 2:1) in THF at room temperature. Effect of Cu(I) catalyst and N-donor solvent on the yield and N-
a,b
coupling:O-coupling ratio.
PhMgBr
ðTMSÞNHOðTMSÞ
CuX
PhNH
14
2
PhOH
15
þ
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ!
þ
13 : 4a mol ratio ¼ 2:1
13
4a
ꢁ
1
2
:THF:cosolvent;25 C;3:5h
:Hydrolysis
Entry
CuX (mol%)
Solvent c
Coupling yield, % d
Chemoelectivity
4:15 e
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(20)
CuI(20)
CuI(20)
THF
62
54
45
25
6
75
61
83
22
7
59
23
12
11
21
39
57
60
45:55
96:4
93:7
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
76:24
33:67
87:13
89:11
95:5
0:100
43:57
85:15
91:9
87:13
0:100
24:76
77:23
96:4
CuI(20)
CuI(20)
0
1
2
3
4
5
6
7
8
CuCN(10)
CuCN(10)
CuCN(10)
CuCN(10)
CuCN(10)
CuCN(40)
CuCN(40)
CuCN(40)
THF: HMPA (4:1)
THF:TMEDA(4:1)
85:15
a
b
c
All the data are the average of at least five experiments.
The reactions were carried out on a 1 mmol scale.
THF:cosolvent volume ratio.
The sum of GC yields of 14 and 15.
The ratio of GC yields 14:15.
d
e

D. Kahya, F. Ero gꢀ lu / Journal of Organometallic Chemistry 899 (2019) 120884
5
(
75:25e90:10) in THF and in THF:cosolvent (Table 3, entries 1-5).
The use of 20 mol% CuI increased the total yield in THF and in
THF:HMPA (Table 3, entries 6e8) generating PhNH with 80% yield
Under the optimized conditions, we observed that the results
are consistent. In the reactions carried out with 4:1 mol ratio of
13:4a, 20 mol% CuI catalysis in THF:HMPA (4:1) led to 68% yield of
aniline (Table 4, entry 9). In THF:HMPA (4:1 or 1:1), 40 mol% CuI
catalyzed reactions afforded 72% and 75% yield of aniline, respec-
tively (Table 4, entries 10 and 11). In the presence of 10 mol% and
40 mol% CuCN catalysis, the reaction in THF:TMEDA (4:1) gave 72%
and 77% aniline, respectively (Table 4, entries 12 and 13). We also
2
in THF:HMPA (1:1) (Table 3, entry 8). Meanwhile, 40 mol% CuI
catalyzed reaction was completed with a quantitative yield and 73%
and 76% yield of PhNH in THF:HMPA (4:1) and THF:HMPA (1:1),
2
respectively (Table 3, entries 12 and 13).
CuCN catalysis also resulted in high yields and high
PhNH
2
:PhOH ratios in THF:cosolvent. The yields of anilines were
used a Lewis base additive, Ph
with TMSHA 4a. The reaction at 2:1 mol ratio of 13:4a, the use of
10 mol % Ph P with 10 mol % and 20 mol % CuI and 10 mol % CuCN
catalysis generated 67%, 65% and 96% yield with PhNH :PhOH ratio
of 46:54, 82:18 and 89:11, respectively. At 3:1 mol ratio of 13:4a, we
found that, 10 mol % Ph P with 10 mol %CuI, 20 mol % CuI and
10 mol CuCN afforded 100%, 75% and 100% yield with
PhNH :PhOH ratio of 50:50, 81:19 and 86:14, respectively. How-
ever, it seems that the use of Ph P as a Lewis base catalyst does not
give better results on the yield and PhNH :PhOH ratio compared to
3
P in reactions of PhMgBr 13 reagents
found to be 71% with 10 mol% CuCN, in THF:HMPA (4:1) (Table 3,
entry 17), 69% with 20 mol% CuCN in THF:TMEDA (4:1) (Table 3,
entry 24) and 80% with 40 mol% CuCN in THF:HMPA (4:1) (Table 3,
entry 27) and 84% in THF:TMEDA (4:1) (Table 3, entry 28).
These results obtained using 3:1 mol ratio of 13:4a with CuI or
CuCN catalysis in THF:HMPA and also in THF:TMEDA gratifyingly
bring us a complement for CuI catalyzed reactions in THF:HMPA
carried out in 2:1 mol ratio of 13:4a.
3
2
3
%
2
3
As we noted for the reactions carried out with 2:1 mol ratio of
2
1
3:4a, we observed higher PhNH
2
:PhOH ratio in THF:HMPA
those taken from the reactions obtained in the presence of donor
solvents.
compared to that in THF:TMEDA also in the reactions carried out
with 3:1 mol ratio of 13:4a (Table 3, entries 12, 13 compared to 14,
These results obtained on the uncatalyzed and Cu(I) catalyzed
reactions of PhMgBr 13 with (TMS)NHO(TMS) 4a (Scheme 3) using
2:1, 3:1 and 4:1 mol ratios of 13:4a in THF and in THF:N-donor
solvents are summarized below:
15; entries 22, 23 compared to 24, 25).
This one-pot procedure for amination of catalytic diarylcuprates
and (aryl)(cyano)cuprates was also carried out with 4:1 mol ratio of
PhMgBr: 4a in order to see a probable comparative change in the
outcome of the reactions. Focusing to the atom-economic synthesis
of PhNH , the total yields and chemoselectivities of the reactions
2
with 2:1e4:1 mol ratio resulting more than 68% yield are listed in
(i) The reaction of uncatalyzed PhMgBr in 2:1 mol ratio of 13:4a
in THF yields only CeO coupling product, i.e. PhOH with a
maximum yield of 56% (Table 1, entry 1).
Table 4.
Table 3
Reaction of phenylmagnesium bromide 13 with TMSHA 4a (13:4a mol ratio ¼ 3:1) in THF at room temperature. Effect of Cu(I) catalyst and N-donor solvent on the yield and N-
a,b
coupling
.
PhMgBr
ðTMSÞNHOðTMSÞ
CuX
PhNH
14
2
PhOH
þ
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ!
þ
13 : 4a mol ratio ¼ 3:1
15
13
4a
ꢁ
1
:THF:cosolvent;25 C;3:5h
:Hydrolysis
2
Entry
CuX (mol%)
Solvent c
Coupling yield, % d
Chemoelectivity 14:15 e
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(20)
CuI(20)
CuI(20)
CuI(20)
CuI(20)
CuI(40)
CuI(40)
CuI(40)
CuI(40)
CuI(40)
CuCN(10)
CuCN(10)
CuCN(10)
CuCN(10)
CuCN(10)
CuCN(20)
CuCN(20)
CuCN(20)
CuCN(20)
CuCN(20)
CuCN(40)
CuCN(40)
CuCN(40)
THF
58
41
16
48
35
77
72
88
75
23
51
100
100
48
57
78
87
65
29
34
66
72
65
98
63
54
100
99
90:10
90:10
75:25
83:17
77:23
71:29
89:11
91:9
83:17
26:74
67:33
73:27
76:24
67:33
51:49
71:29
82:18
82:18
50:50
0:100
91:9
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
THF: HMPA (4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
THF
83:17
82:18
70:30
74:26
85:15
80:20
84:16
THF: HMPA (4:1)
THF:TMEDA(4:1)
a
b
c
All the data are the average of at least five experiments.
The reactions were carried out on a 1 mmol scale.
THF:cosolvent volume ratio.
The sum of GC yields of 14 and 15.
The ratio of GC yields 14:15.
d
e

6
D. Kahya, F. Ero gꢀ lu / Journal of Organometallic Chemistry 899 (2019) 120884
Table 4
Optimized conditions for obtaining PhNH
2
14 with medium to high yields (ꢀ68%) in the CuX catalyzed reaction of PhMgBr 13 with 4a in THF or in THF:cosolvent.
PhMgBr ðTMSÞNHOðTMSÞ
Cul or CuCN
PhNH
14
2
PhOH
15
þ
ƒƒƒƒƒƒƒƒƒƒƒ!
þ
13
4a
THF:cosolvent;25
ꢁ
C;3h
Entry
13:4a mol ratio
CuX, (mol%)
Solvent
Coupling yield, %
Chemoelectivity 14:15
2
Yield of PhNH 14, %
1
2
3
4
5
6
7
8
9
1
1
1
1
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
4:1
4:1
4:1
4:1
4:1
CuI (20)
CuI (20)
CuI (40)
CuI (40)
CuCN (10)
CuCN (20)
CuCN (40)
CuCN (40)
CuI (20)
CuI (40)
CuI (40)
CuCN (10)
CuCN (20)
THF:HMPA(4:1)
THF:HMPA(1:1)
THF:HMPA(4:1)
THF:HMPA(1:1)
THF:HMPA(4:1)
THF:TMEDA(4:1)
THF:HMPA(4:1)
THF:TMEDA(4:1)
THF:TMEDA(4:1)
THF:HMPA(4:1)
THF:HMPA(1:1)
THF:TMEDA(4:1)
THF:TMEDA(1:1)
83
88
100
100
87
98
100
99
76
100
99
95:5
91:9
79
80
73
76
71
69
80
84
68
72
75
72
77
73.27
76:24
82:18
70:30
80:20
84:16
90:10
80.20
76.24
72:28
77:23
0
1
2
3
100
100
(
ii) The reaction of CuI or CuCN catalyzed reaction of PhMgBr
allows formation CeN coupling product, PhNH generally
(iii) With these results in hand, we afforded explanations for the
effect of N-donor solvents on the outcome of both uncata-
lyzed and CuI or CuCN catalyzed reaction of PhMgBr 13 with
4a in THF leading to CeN coupling and/or CeO coupling.
2
much more than PhOH. However, chemoselectivity depends
on catalyst and its amount as well as on N-donor solvent and
its amount.
For the reaction of PhMgBr 13 with aminating reagent 4a, we
offered the mechanism given in Scheme 6 written on the attack of
RMgBr to metallated nitrenoid and also attack of PhMgBr to met-
allated oxeneoid. Similar mechanisms were already proposed by
Beak's group for amination reaction of organolithium reagents with
O-substituted hydroxylamines 2e6 [7,13e15]; by Schverdina and
Kotscheshkov for the reaction of alkyl Grignard reagents with
As seen, for an atom-economic amination, reactions carried out
with 4:1 mol ratio of 13:4a do not lead to higher yields compared to
the reactions carried out with 2:1 and 3:1 mol ratio of 13:4a.
Amination using 2:1 or 3:1 mol ratio of 13:4a in THF:HMPA (4:1 or
:1) in the presence of 20 mol% CuI provide aniline with 79% and
0% yield, respectively (Table 4, entry 1 and 2). The use of less
1
8
expensive CuCN (40 mol%) in THF:HMPA (or TMEDA) (4:1) also
gives about the same yields of aniline, i.e. 80% in THF:HMPA (4:1)
MeONH
Grignard reagents with O-(dipenylphosphyl)hydroxylamine 5 [17].
In this mechanism, carbanion of RMgBr(THF) 13 attacks elec-
trophilic N of N(MgBr)(TMS)OTMS 4a-nitrenoid, leading to an S 2-
like transition state to give the product which offers the amine after
hydrolysis (Scheme 6a). Similarly, attack of RMgBr(THF) 13 to
electrophilic O of N(TMS) O(MgBr) 4a-oxeneoid, might form
2
2 [16] and by Boche and coworkers for the reaction of aryl
(Table 4, entry 7) and 84% in THF:TMEDA (4:1) (Table 4, entry 8). So,
2
successful amination of PhMgBr 13 with 4a (13:4a mol ratio ¼ 2:1
or 3:1) in THF:HMPA (4:1 or 1:1) with 20 mol% CuI seems as an
alternative atom-economic and step-economic method to offer for
synthesis of arylamines from Grignard reagents.
N
2
2
2
Scheme 6. Proposed mechanism for the reaction of RMgBr 13 with (a) N(MgBr)(TMS)O(TMS) 4a-Nitrenoid and (b) with N(TMS) O(MgBr) 4a-Oxenoid in THF.

D. Kahya, F. Ero gꢀ lu / Journal of Organometallic Chemistry 899 (2019) 120884
7
another S
N
2-like transition state to give the product which offers
13 are succesful in CeN coupling resulting in high yield of PhNH
Before offering mechanism for CeN and CeO coupling of catalytic
diphenylcuprates, R CuMgBr 16 and RCu(CN)MgBr 17, we first
preferred proposing transition states. We assumed a contact ion
pair (CIP) structure as an heteroaggregate A which is in equilibrium
2
.
the phenol after hydrolysis (Scheme 6b). Reaction of PhMgBr 13
with 4a in THF and in THF:cosolvent generated only PhOH as
product. In order to bring an explanation for the observation of the
observed lower yields of PhOH in the presence of coordinating
solvents, i.e. HMPA and TMEDA, we first thought that in the four-
center intermediate [18,19] coordination of Mg to O occurs by
replacement of donor THF (Scheme 6b). Nucleophilic solvation of
Mg can lead to polarization of the CeMg bond and an increase both
in the nucleophilicity of carbanion and in electrophilicity of O
appear. Then, replacement of donor THF by a coordinating solvent
causes to give a less reactive complex leading to lower reaction
yields, as observed. We can also think that in the coordination with
bidendate TMEDA, RMgBr may have no vacant coordination to
react, i.e. less favorable complex formation takes place compared
with monodendate HMPA and as a cosolvent TMEDA leads to lower
yields compared to HMPA, as expected.
2
2
with a solvent separated ion pair (SSIP) B for R CuMgBr 16 and
homo dimer structure C for RCu(CN)MgBr 17 (Scheme 7) [18e25].
Taking these structures and mechanisms suggested for the re-
actions of cuprates by Nakamura and coworkers [24] and Bertz and
coworkers [25] into consideration, we offered reaction pathways
[10e] for the reaction R CuMgBr 16 and RCu(CN)MgBr 17 with 4a
2
(Scheme 8 and Scheme 9, respectively). For the sake of clarity, we
used monomer structure for RCu(CN)MgBr instead of C.
2
We will propose that in the reaction of R CuMgBr 16-A with 4a,
oxidative addition takes place either to electrophilic N or electro-
philic O (Scheme 8 a and b, respectively) forming the transition
states TS3 or TS4, respectively. In TS3, NeMgBr bonding and CueN
coordination take place and in TS4, OeMgBr bonding and CueO
coordination take place. Reductive elimination gives the CeN
coupling (Scheme 8a) or CeO coupling product (Scheme 8b). The
mechanism for the reaction of RCu(CN)MgBr with 4a leading to
CeN coupling or CeO coupling is analogous to that offered for the
A similar explanation can be given for the reaction of PhMgBr 13
with 4a to produce PhNH (Scheme 6a). As another explanation for
2
the CeO coupling instead of CeN coupling in the reaction of
PhMgBr 13 with 4a, we think to offer the stability of nitrenoid as N-
magnesium complex, 4a-nitrenoid, which might prevent or at
least slow down the CeN coupling of PhMgBr. Then, oxeneoid as O-
magnesium complex, 4a-oxenoid will react with PhMgBr leading
CeO coupling (Scheme 6b).
2
reaction of R CuMgBr (Scheme 9 a and b, respectively). As dio-
rganocuprates are more reactive than Grignard reagents, 16 and 17
give mostly CeN coupling product with the stable N-magnesium
complex of nitrenoid 4a, as expected. In order to bring an expla-
We also supported this mechanism with our work based on the
kinetics and Hammett substituted constants of the reaction of
2
nation for the higher yield and higher PhNH :PhOH ratio in
substituted PhMgBr reagents with MeONH
We also found that catalytic diphenylcuprates Ph
and phenylcyanocuprates PhCu(CN)MgBr 17 derived from PhMgBr,
2
, 2 [10e].
THF:HMPA compared to THF:TMEDA, we think the equilibrium
between CIP and SSIP structures (Scheme 7) [21,24c,26]. Generally
CIP is dominant in weakly solvating solvents and SSIP in solvents
2
CuMgBr 16
Scheme 7. Structures for R
2
CuMgBr, A, B and RCu(CN)MgBr, C.
2 2
Scheme 8. Proposed mechanism for the reaction of R CuMgBr 16-A with (a) N(MgBr)(TMS)O(TMS) 4a-Nitrenoid (b) with N(TMS) O(MgBr) 4a-Oxenoid in THF.

8
D. Kahya, F. Ero gꢀ lu / Journal of Organometallic Chemistry 899 (2019) 120884
2
Scheme 9. Proposed mechanism for the reaction of RCu(CN)MgBr 17 with (a) N(MgBr)(TMS)O(TMS) 4a-Nitrenoid and (b) with N(TMS) O(MgBr) 4a-Oxenoid in THF.
with strong coordination ability [15,19,24b,27]. It is also known that
essentially only CIP structure of a cuprate reacts and reactions can
proceed with a small equilibrium concentration in solution and
SSIP is the much less or even unreactive structure [15,21,24,28,29].
4. Experimental
4.1. General
As expected, in the reactions of R
PhNH :PhOH ratio in THF:HMPA was generally observed higher
than that in THF. However, in THF:TMEDA, the reactions gave
mostly lower PhNH :PhOH ratio than that in THF and in THF:HMPA.
We think that TMEDA can strongly complex with two (MgBr) ions
as a bridging bidentate ligand [21]. In this case, the equilibrium
lying mostly in favor of SSIP structure can much decrease CIP
structure in small equilibrium concentration to react, as in accor-
dance with the observed results.
2
CuMgBr and RCu(CN)MgBr,
All reactions were carried out under a nitrogen atmosphere in
oven dried glassware using standard syring-septum cap techniques
[30]. Quantitative GC analysis were performed on a Thermo Focus
gas chromatograph equipped with a ZB-1 capillary column packed
with phenylpolydimethylsiloxane using the internal standard
technique. THF was distilled from sodium benzophenone dianion.
Grignard reagent was prepared in THF by standard method and its
concentration was found by titration prior to use [31]. (TMS)
HNO(TMS) was distilled and kept under nitrogen. HMPA and
TMEDA were distilled and kept under nitrogen. CuI [32] and CuCN
2
2
4
[33] were purified according to the published procedures.
3
. Conclusions
4.2. Typical procedure for CuI catalyzed reaction of PhMgBr with
(TMS)HNO(TMS) in THF:HMPA
With the aim of developing a new method for synthesis of
arylamines using electrophilic amination of Grignard reagents with
TMS)HNO(TMS);
PhMgBr (2 mmol) was added to CuI (0.0762 g, 0.4 mmol) at
(
room temperature in THF:HMPA (4:1) mixture (5 ml), and after
stirring for 2e3 min (TMS)HNO(TMS) (0,1774 g,1 mmol) was added.
The reaction mixture was stirred for 3.5 h. For hydrolytic work-up
and separation of phenol and aniline, aqueous HCl was used. The
(
i) We have demonstrated that reaction of PhMgBr (2 or 3
equiv) with (TMS)HNO(TMS) (1 equiv) in the presence of
10e20 mol% CuI or CuCN catalysis in THF:cosolvent (cosol-
aqueous phase was washed with Et
NaOH and free amine was extracted with Et
2
O, made basic with aqueous
O. Internal standards
vent ¼ HMPA or TMEDA) at room temperature gives medium
to high yields of aniline. This one-pot procedure can provide
an atom-economic and step-economic access for arylamine
synthesis starting from aryl Grignard reagents.
2
were added to organic phases containing phenol extract, aniline
extract and aliquots were analyzed by GC.
(
ii) Chemoselectivity in the reaction of PhMgBr with (TMS)
HNO(TMS) to give CeN or CeO coupling can be controlled by
changing reaction parameters. Cu(I) catalyzed reaction of
PhMgBr in THF:HMPA (or TMEDA) affords both CeN and CeO
coupling (aniline:phenolꢀ7:3) whereas uncatalyzed PhMgBr
gives CeO coupling yielding phenol. It is obvious that (TMS)
HNO(TMS) is a workable substrate for amination of catalytic
diarylcuprates and arylcyanocuprates.
Acknowledgement
We thank the Ankara University Research Fund, Grant No.
11B424-1 and we appreciate our Ph.D. supervisor Prof. Dr. Ender
Erdik for her help in the preparation of the paper.
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(
iii) Mechanisms were proposed for the solvent dependence of
chemoselectivity in the coupling of both uncatalyzed and
Cu(I) catalyzed Grignard reagent with (TMS)HNO(TMS).
iv) Application of remarkable ability of Cu(I) catalyzed PhMgBr
for CeN coupling with (TMS)HNO(TMS) to other aryl
Grignard reagents are in progress.
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