Cobalt(II)-catalyzed isocyanide insertion reaction with amines under ultrasonic conditions: A divergent synthesis of ureas, thioureas and azaheterocycles

Article abstract of DOI:10.1002/adsc.201300745

Cobalt(II) acetylacetonate-catalyzed isocyanide insertion reactions with amines utilizing tert-butyl hydroperoxide (TBHP) as an oxidant under ultrasound conditions have been developed, which lead to the synthesis of ureas, thioureas, as well as 2-aminoben

Full text of DOI:10.1002/adsc.201300745

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DOI: 10.1002/adsc.201300745
Cobalt(II)-Catalyzed Isocyanide Insertion Reaction with Amines
under Ultrasonic Conditions: A Divergent Synthesis of Ureas,
Thioureas and Azaheterocycles
Tong-Hao Zhu,a Xiao-Ping Xu,a Jia-Jia Cao,a Tian-Qi Wei,a Shun-Yi Wang,a,*
and Shun-Jun Jia,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
E-mail: shunyi@suda.edu.cn or shunjun@suda.edu.cn
Received: August 17, 2013; Published online: January 10, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300745.
Abstract:
Cobalt(II)
acetylacetonate-catalyzed tions of isocyanides with amines, could be easily
isocyanide insertion reactions with amines utilizing trapped by different nucleophiles such as water,
ACHTUNGTRENNUNG
tert-butyl hydroperoxide (TBHP) as an oxidant sulfur, and intramolecular nucleophilic functional
under ultrasound conditions have been developed, groups. This method provides a simple, general and
which lead to the synthesis of ureas, thioureas, as practical protocol for the divergent synthesis of
well as 2-aminobenzimidazoles, 2-aminobenzothia- ureas, thioureas and azaheterocycles.
zoles, and 2-aminobenzoxazoles under the general
reaction conditions in up to 96% yields, respectively.
The intermediate amino methylidyneaminiums, initi- Keywords: cobalt(II) catalyst; isocyanides; thioureas;
ated by cobalt(II) acetylacetonate-catalyzed reac- ultrasound; ureas
Introduction
cal ureas via palladium-catalyzed cross-coupling reac-
tions of aryl chlorides and triflates with sodium cya-
N,N’-Disubstituted urea derivatives have attracted nate.[9] Although many approaches toward thioureas
a great deal of attention due to their applications in as well as 2-aminobenzoxazoles, 2-aminobenzothia-
agrochemicals, dyes, antioxidants and HIV inhibi- zoles, and 2-aminobenzimidazoles have also been well
tors.[1–3] In addition, they are also used as organocata- studied, general and versatile methodologies to pre-
lysts and precursors for organic synthesis.[4] N,N’-Di- pare ureas, thioureas and azaheterocycles using readi-
ACHTUNGTRENNUNG
also widely applied in organic chemistry, medicinal
Reactions involving isocyanides have received con-
chemistry, as well as materials chemistry.[5] 2-Amino- siderable attention, of which the major focus is on the
benzoxazoles, 2-aminobenzothiazoles, and 2-amino- well-known Ugi reactions.[10,11] Recently, palladium-
benzimidazoles are essential components in numerous catalyzed isocyanide insertion (similar to carbon mon-
potent biologically active compounds and natural oxide insertion) reactions have become increasingly
products.[6] Typically, ureas and thioureas are pre- popular.[12] In addition, since Kharaschꢀs[13] pioneering
pared from isocyanates or isothiocyanates, which are works on the homocoupling reactions of Grignard re-
generated with the requirement of difficult-to-access agents, cobalt catalysts, which are widely available,
precursors and/or hazardous agents such as phosgene not expensive, and have low toxicity, have received
and azides. Recently, transition metal-catalyzed cross- particular attention.[14–17] As a continuation of our
À
coupling reactions allowed for the synthesis of work on the insertion of isocyanides into active N H
ureas.[7] Guanꢀs group reported a palladium-catalyzed bonds under ultrasound irradiation,[18] herein, we
coupling reaction of aromatic amines with CO for the hoped to apply this insertion strategy to construct of
synthesis of symmetrical ureas.[8] Buchwald provided ureas, thioureas, 2-aminobenzoxazoles, 2-aminobenzo-
an efficient protocol for construction of unsymmetri- thiazoles, and 2-aminobenzimidazoles[19] by trapping
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Tong-Hao Zhu et al.
Scheme 1. The direct strategy for synthesis via isocyanide insertion.
the insertion coupling intermediates of isocyanides
with amines.
With the optimized conditions in hand, the scope of
this reaction was investigated and the results are sum-
Our current study has focused on the cobalt(II) marized in Table 1. Wide ranges of anilines and iso-
acetate-catalyzed isocyanide insertion to amine-based cyanides were employed as substrates. The substituted
bisnucleophiles directed towards the formation of 2- anilines (1b–n) reacted well with tert-butyl or cyclo-
aminobenzoxazoles, 2-aminobenzothiazoles, and 2- hexyl isocyanide 2a or 2b (Table 1, entries 2–20),
aminobenzimidazoles.[19] This article is a full account giving the desired products 3b–r in moderate to excel-
of the Co(II)-catalyzed isocyanide insertion reaction lent yields. It is noteworthy that anilines bearing elec-
with amines under ultrasound conditions as a general tron-donating groups (Me, OMe, OBn, OH, NH2)
strategy to the synthesis of ureas, thioureas and aza- could offer the desired products in good yields. How-
heterocycles (Scheme 1), where we disclose (i) the ever, when anilines bearing electron-withdrawing
Co(II)-catalyzed synthesis of ureas from isocyanides groups (NO2 or COMe) were used, no desired prod-
with amines in the presence of water; (ii) the Co(II)- uct was observed (Table 1, entries 21and 22). Further-
catalyzed synthesis of thioureas from isocyanides with more, relatively bulky substrates such as 1d, 1e, 1f
amines in the presence of sublimed sulfur; (iii) the and 1j also efficiently underwent the transformation,
Co(II)-catalyzed synthesis of 2-aminobenzoxazoles generating the desired products 3d, 3e, 3f, and 3j in
from isocyanides with 2-aminophenols; (iv) the 64%, 48%, 75% and 62% yields, respectively
Co(II)-catalyzed synthesis of 2-aminobenzimidazoles (Table 1, entries 4, 5, 6, and 10). Then, several struc-
and 2-aminobenzimidazoles from isocyanides with 2- turally varied isocyanides were also investigated.
aminoanilines and 2-aminobenzenethiol.
When other aliphatic and aromatic isocyanides (2b–e)
were employed, the reactions also proceeded smooth-
ly in moderate yields (52%–93%) (Table 1, en-
tries 15–18). However, the reaction of pyridin-3-
amine 3q could not furnish the desired product
Results and Discussion
Our initial studies focused on developing a more effi- (Table 1, entry 23).
cient catalytic system by investigating isocyanide in-
To evaluate the general performance of our
sertion reactions and we used the reaction of aniline method, we further explored the reactions of other
1a and tert-butyl isocyanide 2a as a model system. amines. The results are listed in Table 2. Aliphatic pri-
After optimization of the reaction conditions (see the mary amines such as tryptamine 4a, 1-phenylethan-
Supporting Information and Table 1 for details), it
was found that the optimal reaction conditions consist were investigated with tert-butyl isocyanide 2a under
of Co(acac)2A(20 mol%), PivONa·H2O (2 equiv.), the optimal conditions, which afforded the corre-
ACHTUNGTRENaNUNG mine 4b, and amino acid methyl esters 4c, 4d, 4e
A
CHTUNGTRENNUNG
TBHP (1 equiv.) and Bu4NBr (1 equiv.) in the solvent sponding products 4aa–ea in up to 96% yields
MeCN: H2O=1:3 under ultrasound irradiation at (Table 2). In addition, secondary amines 5a–d could
758C (HPLC yield 86%). However, when we used the also provide moderate to excellent yields except for
same conditions under the regular heating, even if the diphenylamine 5e.
reaction was prolonged to let it work better, the
Interestingly, the reaction of the tert-butyl isocya-
result was unsatisfactory (for details see the Support- nide 2a with enantiopure amine (S)-4b or (R)-4b pro-
ing Information), and the system was messy. This duced enantiopure carboxamides (S)-(+)-4ba and
result indicated that ultrasound irradiation could (R)-(À)-4ba, respectively, in good yields with reten-
make the reaction run more efficiently.
tion of the chiral configuration (Scheme 2). These re-
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Cobalt(II)-Catalyzed Isocyanide Insertion Reaction with Amines
Table 1. Cobalt-catalyzed insertion reactions of isocyanides 2a–e with substituted anilines 1a–n.[a]
Entry
1
2
Yield of Product [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
R=H
R=4-Me
R=3-Me
R=2-Me
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
R’ =t-Bu
3a
3b
3c
3d
3e
3f
3g
3h
3i
85
96
88
64
48
75
96
73
76
62
34
43
R=2-Et
R=2-Me, 4-Me
R=4-OMe
R=4-OBn
R=4-OH
R=4-OH, 2-Me
9
10
11
12
1j
1k
1k
3j
3k
3kꢀ
13
14
1l
1l
2a
2a
3l
3lꢀ
39
9
15
16
17
18
19
20
21
22
1b
1b
1b
1b
1m
1n
1o
1p
2b
2c
2d
2e
2b
2b
2a
2a
R’ =Cy
3m
3n
3o
3p
3q
3r
89
63
52
93
46
41
trace
trace
R’ =n-Bu
R’ =2,6-Me2C6H3
R’ =Bn
R=4-Cl
R=4-Br
R=4-NO2
R=4-COMe
3s
3t
23
1q
2a
3u
trace
[a]
Reaction conditions: anilines 1a–q (0.5 mmol), isocyanides 2a–e (0.6 mmol), CoACHTNUGTRNEUNG(acac)2 (20 mol%), PivONa·H2O
(2 equiv.), TBHP (1 equiv.), Bn4NBr (1 equiv.), solvent (3 mL), 758C, under ultrasound irradiation for 1 h.
Isolated yield.
[b]
sults show that the cobalt-catalyzed isocyanide inser- obtained by the model reaction of aniline 1a, tert-
tion reactions are also applicable for the preparation butyl isocyanide 2a and sulfur under the ultrasound
of chiral ureas from chiral substrates.
conditions. Fortunately, after the further optimization
As it is well-known, sulfur is a good nucleophile the of reaction conditions (see the Supporting Informa-
same as water. So, we reasoned that thioureas could tion and Table 2 for details), it was found that the
be formed by a similar strategy. Then, we further ex- best reaction conditions comprise CoACHTUNGTRENNUNG(acac)2
plored the Co(II)-catalyzed isocyanide insertion with (20 mol%), Na2CO3 (2 equiv.), and TBHP (1 equiv.)
amines in the presence of sublimed sulfur instead of in the 1,4-dioxane under ultrasound irradiation at
water (Table 3). As expected, thiourea 6a could be
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Table 2. Cobalt-catalyzed isocyanide insertion reactions with other amines 4 and 5.[a,b]
[a]
Reaction conditions: amine 4 or 5 (0.5 mmol), tert-butyl isocyanide 2a (0.6 mmol), CoACHTNUTGRNEUNG(acac)2
(20 mol%), PivONa·H2O (2 equiv.), TBHP (1 equiv.), Bn4NBr (1 equiv.), solvent (3 mL), 758C,
under ultrasound irradiation fo 1 h.
Isolated yield.
[b]
Scheme 2. Cobalt-catalyzed synthesis of chiral amides.
758C. It could produce 1-tert-butyl-3-phenylthiourea action under the optimal conditions. It was found that
6a in 53% isolated yield (61% LC yield).
the functional group on the phenyl ring had a great
With these promising conditions in hand, we inves- effect on this isocyanide insertion reaction. The reac-
tigated the scope of this reaction. As shown in tions of tert-butyl isocyanide 2a and sulfur with substi-
Table 3, different anilines 1a–s were applied to the re- tuted aromatic amines bearing electron-donating
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Cobalt(II)-Catalyzed Isocyanide Insertion Reaction with Amines
Table 3. Cobalt-catalyzed insertion reactions of tert-butyl
isocyanides 2a with substituted anilines 1a–s.[a]
Table 4. Cobalt-catalyzed insertion reactions of isocyanides
2a–e with tryptamine 4a.[a,b]
Entry
Ar-NH2
Yield [%]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1r
R=H
6a
6b
6c
6d
6e
6r
53
45
40
36
46
45
R=4-Me
R=3-Me
R=2-Me
R=2-Et
R=4-Et
7
8
9
10
11
12
1f
1g
1s
1m
1o
1p
R=2-Me, 4-Me
R=4-OMe
R=4-OEt
R=4-Cl
R=4-NO2
R=4-COMe
6f
6g
6s
6m
6o
6p
31
44
42
37
trace
trace
[a]
Reaction conditions: tryptamine 4a (0.5 mmol), isocya-
nides 2a–e (0.6 mmol), Co
AHCTUNGTREG(NNUN 2 equiv.), TBHP (1 equiv.), 1,4-dioxane (3 mL), 758C,
ACHTUNGTRENNUN(G acac)2 (20 mol%), Na2CO3
13
1q
6q
trace
under ultrasound irradiation for 1 h.
Isolated yield.
[a]
[b]
Reaction conditions: anilines 1a–s (0.5 mmol), tert-butyl
isocyanide 2a (0.6 mmol), and sublimed sulfur (2 equiv.)
CoACHTUNGTRENNUNG(acac)2 (20 mol%), Na2CO3 (2 equiv.), TBHP
(1 equiv.), 1,4-dioxane (3 mL), 758C, under ultrasound ir-
radiation for 1 h.
Isolated yield.
was formed. The reaction of diphenylamine 5e could
not afford the desired product 5ea (Scheme 3).
[b]
Recently, we reported a protocol using the cobalt-
catalyzed oxidative isocyanide insertion to amine-
groups such as methyl, ethyl, methoxy, ethoxy could based bis-nucleophiles to synthetize substituted 2-am-
also furnish the desired products in 36%–53% yields
(Table 3, entries 1–9). Unfortunately, when substituted
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
aromatic amines such as 1o and 1p with electron-with- longer times at high temperature. It would be more
drawing groups or pyridin-3-amine 6q were subjected efficient if the cobalt-catalyzed oxidative isocyanide
to the reaction under the identical codntions, no de- insertion to amine-based bis-nucleophiles could be
sired product was observed (Table 3, entries 11–13). achieved under ultrasonic conditions.
Relatively bulky substrates such as 1d, 1e, and 1f also
efficiently underwent the transformation, affording above-optimized conditions [CoAHCUTNGTRENNUNG
Fortunately, the reaction of 9a and 2a under the
(acac)2 (20 mol%),
the desired products 6d, 6e, and 6f in 36%, 46%, and Na2CO3 (2 equiv.), and TBHP (1 equiv.) in the 1,4-di-
31% yields, respectively (Table 2, entries 4, 5, and 7). oxane under ultrasound irradiation at 758C for 1 h]
Subsequently, we explored the reactions of the ali- could proceed well to give the desired product 10a in
phatic amine tryptamine 4a and different isocyanides 77% yield. Subsequently, 2-aminophenols 9a–g and
with sulfur. To our delight, the desired thiourea prod- isocyanides 2a–e were investigated for this reaction
uct 7aa could be obtained in 67% yield (Table 4). We and the results are summarized in Table 5. It was
further investigated the scope of isocyanides and the found that the substituted 2-aminophenols 9a–g per-
generality of the method. When isocyanides 2b– formed well with tert-butyl isocyanide 2a (Table 5, en-
e were applied to the reaction, the thioureas 7ab–ae tries 1–7), affording the desired products 2-
could also be obtained in 53%–65% yields.
aminobenzACTHUGNETRNNUoG xazoles 10a–g in moderate to good yields
Then, we studied the effects of secondary amines (54%–84%). When isocyanides 2b–e were subjected
on the reaction. The reaction of 1,2,3,4-tetrahydroiso- to the reactions with 9a, 10h–k could also be realized
quinoline 5a could also lead to the desired thiourea in 25%–56% yields (Table 5, entries 8–11).
8aa in 21% yield. When 1,2,3,4-tetrahydroquinoline
In addition, our protocol could also be applied to
5b was subjected to the reaction, no thiourea product the synthesis of 2-aminobenzothiazoles and 2-amino-
benzimidazoles from isocyanides. As shown in
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Tong-Hao Zhu et al.
Scheme 3. Cobalt-catalyzed insertion reactions of tert-butyl isocyanides 2a with secondary amines 5a, 5b and 5e.
Table 5. Co(II)-catalyzed insertion reactions of isocyanides 2a–e with substituted 2-aminophenols 9a–g.[a]
Entry
9
2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9a
9a
9a
9a
R1 =H
R2 =t-Bu
R2 =t-Bu
R2 =t-Bu
R2 =t-Bu
R2 =t-Bu
R2 =t-Bu
R2 =t-Bu
R2 =Cy
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
10a
10b
10c
10d
10e
10f
10g
10h
10i
77
74
54
77
84
61
81
56
50
31
25
R1 =5-NO2
R1 =4-NO2
R1 =3-NO2
R1 =4-Cl
R1 =5-CH3
R1 =4-OCH3
R1 =H
9
10
11
R1 =H
R2 =n-Bu
R2 =2,6-Me2C6H3
R2 =Bn
R1 =H
10j
10k
R1 =H
[a]
Reaction conditions: 2-aminophenols 9a–g (0.5 mmol), isocyanides 2a–e (0.6 mmol), Co
(2 equiv.). TBHP (1 equiv.), 1,4-dioxane (3 mL), 758C, under ultrasound irradiation for 1 h.
Isolated yield.
ACHTUNGTRENNUN(G acac)2 (20 mol%), Na2CO3
[b]
Table 6, the reactions of some other bis-nucleophiles furnish cobalt(II)-isonitrile complex B. After addition
11a–d with tert-butyl isocyanide 2a under the optimal of amine to the cobalt(II)-isonitrile complex B under
conditions. proceeded smoothly to furnish the desired basic conditions, cobalt(II)-isonitrile carbene complex
products in 69%–89% yields.
Based on the above results and the chemistry of ide radical originating from the decomposition of
isonitriles, a plausible mechanism was proposed as TBHP[20] to give cobalt
(III) carbene complex D. The
shown in Scheme 4. Co(acac)2 could easy react with radical intermediate E is formed from compelx D
C is formed followed by oxidation by the tert-butox-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
isonitrile to give the cobalt(II)-isonitrile complex A, with the regeneration of complex A. Then, the amino
followed by coordination with another isonitrile to methylidyne aminium intermediate F is formed via an
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Cobalt(II)-Catalyzed Isocyanide Insertion Reaction with Amines
Table 6. Cobalt-catalyzed insertion reactions of isocyanide
2a with bisnucleophiles 11a–d.[a,b]
SET process and subsequently attacked by nucleo-
philes to give intermediate G, followed by isomeriza-
tion to give the target molecules.[21]
Conclusions
In conclusion, the cobalt(II) acetylacetonate-catalyzed
isocyanide insertion to form amino methylidyneamini-
ums utilizing various readily available isocyanides
with amines under ultrasound conditions has been de-
veloped. Amino methylidyneaminiums were success-
fully applied as an important and general intermedi-
ate to be trapped by water, sulfur or intramolecular
nucleophilic functional groups to construct the corre-
sponding ureas, thioureas as well as to prepare of 2-
aminobenzimidazoles, 2-aminobenzothiazoles, and 2-
aminobenzoxazoles. This method not only expands
the scope of cobalt-catalyzed cross-coupling reactions,
but also provides a novel, extensive, efficient and di-
verse approach leading to valuable products. Further
studies to understand the cobalt-catalyzed insertion
reaction mechanism and to extend this strategy to
other synthetic applications are ongoing in our labo-
ratory.
[a]
Reaction conditions: 11a–d (0.5 mmol), tert-butyl isocya-
nide 2a (0.6 mmol), CoACHTUNGRTNEUNG(acac)2 (20 mol%), Na2CO3
(2 equiv.), TBHP (1 equiv.), 1,4-dioxane (3 mL), 758C,
under ultrasound irradiation for 1 h.
Isolated yield.
[b]
Scheme 4. Proposed mechanism.
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Experimental Section
Typical Experimental Procedure (Urea 3a)
To a mixture of aniline 1a (0.5 mmol), tert-butyl isocyanide
2a (0.6 mmol), CoACHTUNGTRENNUNG(acac)2 (20 mol%), PivONa·H2O (2 equiv.,
1 mmol), TBHP (70%, 0.5 mmol, 72 mL), and Bu4NBr
(0.5 mmol) were added 3 mL of mixed solvent acetonitrile:
H2O=1:3. The system was irradiated by ultrasound for an
appropriate time at 758C (for 1 h; checked by TLC, if it
does not show clearly, please immerse it into KMnO4 devel-
oper). Then the reaction mixture was cooled to room tem-
perature, and poured into ice/water (20 mL). The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (3ꢂ20 mL). The combined organic layers were
washed with brine (30 mL), and dried over Na2SO4. Then
the solvent was evaporated under the reduced pressure. The
residue was purified by flash column chromatography with
ethyl acetate and petroleum ether as eluents to afford pure
product.
Typical Experimental Procedure (Thiourea 6a)
To a mixture of aniline 1a (0.5 mmol), tert-butyl isocyanide
2a (0.6 mmol), sublimed sulfur (2 equiv., 1 mmol), CoACHTNUTRGNEUNG(acac)2
(20 mol%), Na2CO3 (2 equiv., 1 mmol), and TBHP (70%,
0.5 mmol, 72 mL), were added 3 mL 1,4-dioxane. The system
was irradiated by ultrasound for an appropriate time at
758C (for 1 h; checked by TLC). Then the solvent was
evaporated under reduced pressure. The residue was puri-
fied by flash column chromatography with ethyl acetate and
petroleum ether as eluents to afford pure product.
Typical Experimental Procedure (2-Aminobenz-
oxazole 10a)
To a mixture of 2-aminophenol 9a (0.5 mmol), tert-butyl iso-
cyanide 2a (0.6 mmol), CoACHTUNGRTNEUNG(acac)2 (20 mol%), Na2CO3
(2 equiv., 1 mmol), and TBHP (70%, 0.5 mmol, 72 mL), were
added 3 mL 1,4-dioxane. The system was irradiated by ultra-
sound for an appropriate time at 758C (for 1 h; checked by
TLC). Then the solvent was evaporated under reduced pres-
sure. The residue was purified by flash column chromatogra-
phy with ethyl acetate and petroleum ether as eluents to
afford pure product.
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Acknowledgements
We gratefully acknowledge the Natural Science Foundation
of China (No. 21172162), the Young National Natural Sci-
ence Foundation of China (No.21202111, 21202113), the
Young Natural Science Foundation of Jiangsu Province
(BK2012174), Key Laboratory of Organic Synthesis of Jiang-
su Province (KJS1211), PAPD, and Soochow University for
financial support.
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