NH insertion reactions catalyzed by reusable water-soluble ruthenium(II)-hm-phenyloxazoline complex

Article abstract of DOI:10.1016/j.tetlet.2017.10.062

A water-soluble Ru(II)-hm-pheox complex was efficiently catalyzed NH insertion of EDA with a broad class of amine derivatives in water/ether biphasic medium to deliver the biologically active precursors α-aminoester products with excellent yields (up to >99%). The products were separated by decantation and the catalyst was washed and reused several times (at least 8 times) without any specific loss of its catalytic activity. The plausible mechanism of the reaction was explained. Additionally, In case of ethylene diamine, the NH insertion product could be transformed to biological active piperazinone compound in high yield. The asymmetric version of this catalytic reaction is under investigation.

Full text of DOI:10.1016/j.tetlet.2017.10.062

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
NH insertion reactions catalyzed by reusable water-soluble ruthenium
(II)-hm-phenyloxazoline complex
⇑
Abdel-Moneim Abu-Elfotoh
Department of Chemistry, Rabigh College of Science and Arts, King Abdulaziz University, P.O. Box 344, Rabigh 21911, Saudi Arabia
Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A water-soluble Ru(II)-hm-pheox complex was efficiently catalyzed NH insertion of EDA with a broad
Received 19 September 2017
Revised 21 October 2017
Accepted 26 October 2017
Available online xxxx
class of amine derivatives in water/ether biphasic medium to deliver the biologically active precursors
a-aminoester products with excellent yields (up to >99%). The products were separated by decantation
and the catalyst was washed and reused several times (at least 8 times) without any specific loss of its
catalytic activity. The plausible mechanism of the reaction was explained. Additionally, In case of ethy-
lene diamine, the NH insertion product could be transformed to biological active piperazinone compound
in high yield. The asymmetric version of this catalytic reaction is under investigation.
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
NH insertion
Water-soluble catalyst
Ruthenium
Biphasic medium
a-Aminoesters
The N–H insertion of diazo-compounds into primary or sec-
ondary amines have great benefits for formation of different
could be reused five times.9 Encouraged by this results, we selected
the NH-insertion reaction as one of the carbene insertion reaction
to evaluate the catalytic activity of our non-chiral water-soluble
catalyst Ru(II)-hm-pheox 3.
a
-
amino esters, peptide synthesis,1 medicinal chemistry,2,3 and as
precursors for a wide variety of biologically active compounds,
pharmaceuticals,4 and natural products.5 Despite the efforts
devoted in this reaction from the pionering work using copper
bronze6 and the subsequent catalysts to date,7 The potent and reu-
sable catalyst still remain a challenge. Especially, the water-soluble
and reusable catalyst is of great interest as a type of green catalytic
chemistry. And because of the low solubility of most of the organic
compounds in water beside the sensitivity of some organic com-
pounds and intermediates to water, most of the researchers
avoided using water in organic reactions as a solvent. In 2014, J.
Akbari et al. reported the use of acidic ionic liquid [Hmim][BF4]
for EDA insertion into amines,8 Water/CH2Cl2 were added at the
end of reaction to separate the product in CH2Cl2 by decanting
the organic layer and recovering the catalyst in water. Neverthless
the substrate scope was limited and the reusability was unclear.
Recently, we reported the successful use of the novel water-soluble
chiral Ru(II)-hm-Pheox catalyst 1 in intramolecular cyclopropana-
tion of trans-allylic diazoacetates and alkenyl diazoketones that
afforded excellent enantioselectivities and yields and the catalyst
As we mentioned in our pervious report,9 the solubility of the
catalyst in water using hydrophilic pendant was an essential
factor in this biphasic catalytic reaction medium. Thus, we syn-
thesized the insoluble catalyst 2 to compare its catalytic activity
with the water-soluble catalyst 3. Both catalysts 2 and 3 were
synthesized as reported in our previous papers.9,10 Fig. 1 shows
The X-ray crystal structure of catalyst 211 and Fig. 2 Shows the
difference in the solubility of catalysts 2 and 3 in water-phase.
⇑
Address: Department of Chemistry, Rabigh College of Science and Arts, King
Abdulaziz University, P.O. Box 344, Rabigh 21911, Saudi Arabia.
E-mail address: moneim558@hotmail.com
https://doi.org/10.1016/j.tetlet.2017.10.062
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
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2
A.-M. Abu-Elfotoh / Tetrahedron Letters xxx (2017) xxx–xxx
Table 1
Optimization of reaction conditions of NH insertion of EDA into N-methylaniline.a
Entry
Co-solvent
Cat. (mol%)
Time (h)
5a Yield (%)b
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
CH3CN
THF
i-PrOH
H2O
2 (2.5)
3 (2.5)
2 (2.5)
3 (0.01)
3 (0.5)
3 (1.0)
3 (2.5)
3 (3.0)
3 (2.5)
3 (2.5)
3 (2.5)
3 (2.5)
3 (2.5)
24
2.0
24
38
95
40
43
80
91
>99
96
70
85
87
92
23
5.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
9
10c
11c
12c
13c
Fig. 1. The X-ray crystal structure of catalyst 2.
a
Reaction conditions: A solution of N-methylaniline 3a (0.3 mmol in 4.0 mL
solvent) was added to a solution of Ru(II)-catalysts (mol%) in water (1.0 mL), then
EDA 4 (0.3 mmol) was injected and the biphasic reaction mixture was stirred at
room temperature.
b
5a Yield of isolated product.
The reaction is one phase medium.
c
Fig. 2. (a) Ether phase contains amine substrates. (b) Catalyst 3 is completely
soluble in water. (c) catalyst 2 is poor soluble in water.
Initially, we evaluated the catalytic activity of catalysts 2 and 3
in NH insertion of EDA into N-methylaniline in DCM/water or
ether/water biphasic medium and using different catalyst loading
as shown in Table 1 (entries, 1–8). As expected, the catalyst 2
was so sluggish and delivered the product 5a in low yield either
with CH2Cl2 or with Et2O (Table 1, entry 1 and 3) and the reason
of this lower reactivity of catalyst 2 is attributed to the poor solu-
bility of the catalyst in water phase as shown in Fig. 2.
On the other hand, the water-soluble Ru(II)-hm-pheox catalyst
3 showed excellent reactivity and delivered the product 5a in
>99% yield with catalyst loading 2.5 mol% in Et2O/water phase
(Table 1, entry 7). Remarkable yield (95%, Table 1, entry 2) was
obtained when using CH2Cl2 with water. Other catalyst 3 loading
lower or higher than 2.5 mol% showed lower yields (Table 1,
entries 4–6 and 8). Significant decrease in reactivity was detected
by using Toluene/water medium (Table 1, entry 9).
In addition, when using miscible organic solvents with water as
CH3CN, THF, and i-PrOH, good yields were obtained (Table 1,
entries 10–12) but the obstacle of catalyst re-covering was still
there. When using water only as the solvent, 23% yield was
obtained (Table 1, entry 13).
The suggested mechanism for NH insertion of EDA into amine
catalyzed by water-soluble catalyst 3 was shown in Scheme 1.
Where EDA join with Ru(II)-hm-pheox 3 at the interface with evo-
lution of N2 gas. Amine attack the carbene carbon to deliver the
next intermediate at interface which subsequently afforded the
amino ester product in ether phase and the catalyst return back
to the water phase. Hydrogen transfer occurred to deliver the ami-
noester derivatives in Excellent yield. Under the optimized reac-
tion conditions (cat.3 = 2.5 mol%, Et2O/H2O 4:1 v/v, biphasic
Scheme 1. Suggested mechanism for NH-insertion of EDA into various amines
catalyzed by 3 in a water/ether medium.
medium at room temperature), we studied the NH insertion of
EDA into a wide variety of amines as shown in Table 2. EDA was
easily inserted into N-methyl aniline 3a and delivered the N-sub-
stituted glycinate esters 5a and 5b in quantitative yields (Table 2,
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A.-M. Abu-Elfotoh / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 2
NH insertion of EDA into various amine derivatives catalyzed by 3.a
Entry
1
3
5
Time (h)
2.0
Yield (%)b
>99
2
3
2.5
1.6
>99
93
4
5
6
3.0
2.5
3.0
75
95
72
7
3.0
84
8
9
0.7
3.0
98
90
10
3.5
82
11
12
13
4.0
4.0
3.5
76
94
91
14
0.75
85
(continued on next page)
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A.-M. Abu-Elfotoh / Tetrahedron Letters xxx (2017) xxx–xxx
Table 2 (continued)
Entry
15
3
5
Time (h)
1.0
Yield (%)b
88
16
17
18
2.0
2.0
1.0
92
90
89
a
Reaction conditions: A solution of amine 3 (0.3 mmol in 4.0 mL Et2O) was added to a solution of Cat. 3 (4.61 mg, 0.0075 mmol, 2.5 mol%) in water (1.0 mL), then EDA 4
(0.3 mmol) was injected and the biphasic reaction mixture was stirred at room temperature.
b
Yield of isolated product.
Table 3
Reusability of catalyst 3 in NH insertion of EDA into morpholine.a
Cycle
1
2
3
4
5
6
7
8
Yield (%)b
85
86
85
84
88
87
85
85
a
Reaction conditions: A solution of morpholine 3n (26.14 mg, 0.3 mmol in 4.0 mL Et2O) was added to a solution of catalyst 3 (4.61 mg, 0.0075 mmol, 2.5 mol%) in water
(1.0 mL), followed by injection of EDA 4(0.3 mmol) at room temperature and the reaction was stirred for 1–3 h.
b
Yield of isolated product.
entries 1 and 2) without formation of any dimers. It was found that
the high electron withdrawing groups in the para-position of phe-
nyl ring of N-methylaniline will reduce the insertion to give the
product in 75% yield (Table 2, entry 4) while electron donating
groups afforded excellent yields (Table 2, entry 3 and 5).
get of numerous chemists. From this point of view we found that
the water-soluble catalyst 3 could be catalyzed NH insertion of
EDA into ethylene diamine 3s to deliver intermediate 5s which
subsequently afforded 2-piperazinone 6 in 95% yield as shown in
Scheme 2. The Piperazinone ring is considered as valuable scaffold
for constructing common and wide array of biologically active
molecules and natural products like (À)-Agelastatin A,12–14 guaddi-
nomine C2,15 and marcfortine B.16 In addition, the piperazinone
derivatives have been used as peptidomimetic for the discovery
of bioactive molecules. Using our protocol we can reach to piper-
azinone by the easiest method in excellent yield and ability to
reuse the catalyst several times compared with the previously
reported strategies.17
Additionally, as the bulkiness on nitrogen of the aromatic amine
increased as the amino ester products decreased and vice versa
(Table 2, entries 6, 7, and 8). In case of aniline, the mono- and di-
ester product could be easily controlled by the addition of 1 or 2
equivalent of EDA. Aniline itself deliver very good yield compared
with the ortho-substituents either withdrawing or donationg
(Table 2, entries 9, 10, and 11). The para-substituted aniline is quite
similar with aniline reactivity (Table 2, entry 12). Naphthylamine
was as reactive as aniline and reacted with 1 equivalent of EDA
to afford the corresponding product in 91% yield. More basic ali-
cyclic primary and secondary amines such as morpholine, cyclo-
hexyl amine, piperidine and pyrrolidine were also investigated
and their amino ester products were obtained in very good yields
in a short time (Table 2, entries 14, 15, 16, and 17). Dipropylamine
was selected as an example of aliphatic secondary amine and deliv-
ered the insertion product in 89% yield (Table 2, entry 18).
Interestingly, the water-soluble Ru(II)-dm-Pheox (3) could be
easily reused at least eight times without noticeable decrease in
reactivity. Table 3 shows the reusability of catalyst 3 in the inser-
tion of EDA into morpholine since the insertion product could be
easily removed by decantation of the ether layer and the catalyst
was washed 3 times with ether to be ready for the next cycle.
It is noteworthy that the synthesis of an intermediate of biolog-
ical active compounds under very mild conditions and using
water-soluble and reusable catalyst at room temperature is the tar-
O
N2
EtO
H2N
cat. 3 (2.5 mol%)
Et2O/H2O (4:1, v/v), rt
H2N
NH2
+
NH
H
COOEt
3s
4
5s
_
EtOH
H
N
O
N
H
6
Scheme 2. Synthesis of 2-piperazinone via NH-insertion of EDA into Ethylenedi-
amine catalyzed by water-soluble catalyst 3 in biphasic ether-water medium.
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A.-M. Abu-Elfotoh / Tetrahedron Letters xxx (2017) xxx–xxx
5
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effectively catalyzed NH insertion of EDA into a wide array of pri-
mary and secondary amines, cyclic and acyclic in a biphasic water/
ether medium and delivered biologically active precursors ethyl-
glycinate ester derivatives in excellent yields. The products were
obtained by simple decantation in a pure form without necessity
for further purification in most cases and the water-soluble cata-
lyst was readily recycled several times without significant decrease
in reactivity. Additionally, the biological active piperazinone com-
pound could be obtained in 95% yield from the insertion of EDA
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(1.0 mL), then EDA (0.3 mmol, 1.0 equiv.) was injected and the
biphasic reaction mixture was stirred at room temperature. At
the end of reaction, the ether layer was removed by decantation
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(3 Â 5.0 mL). The collected ether phase which contain the aminoe-
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under reduced pressure. The products in most cases were pure
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Acknowledgments
8. Akbari J, Ebrahimi A, Heydari A. Tetrahedron Lett. 2014;55:5417–5419.
9. Abu-Elfotoh A-M, Nguyen DPT, Chanthamath S, Phomkeona K, Shibatomi K,
Iwasa S. Adv Synth Catal. 2012;354:3435–3439.
10. Abu-Elfotoh A-M, Phomkeona K, Shibatomi K, Iwasa S. Angew Chem Int Ed.
2010;49:8439–8443.
11. X-ray analysis of catalyst 2: A single crystal (0.15 Â 0.4 Â 0.7 mm) was obtained
by recrystallization from acetonitrile-toluene. Selected bond lengths [Å] and
angles [°]: Ru1–N1 2.088(3); Ru1–N2 2.147(4); Ru1–N3 2.032(4); Ru1–C1
2.035(4); N1–Ru1–C1 79.4(2); N2–Ru1–C1 176.3(1); C1–C6–C7 112.5(4); Ru1–
This work was supported by the Deanship of Scientific Research
(DSR), King Abdulaziz University, Jeddah, under grant No. (D-038-
662-1438). The author, therefore, gratefully acknowledge the DSR
technical and financial support.
A. Supplementary data
C1–C6 114.3(3). Cystallographic data of catalyst 2:
C19H24F6N5OPRu,
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.10.062.
monoclinic, space group P21/c (#14), a = 8.254(2) Å, b = 22.940(2) Å, c =
13.281(1) Å, b = 94.06(1)°, V = 2508.4(6) Å3, Z = 4, Dcalcd = 1.548 g cmÀ1, R (all
data) = 0.037, Rw (all data) = 0.038, no. of dbsd rflcns 4421 (I > 3a).
Crystallographic data has been deposited in Cambridge Crystallographic Data
Centre as supplementary data with CCDC-no. 648769. Copies of the data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/deposit.
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