Cobalt(II)-Catalyzed Synthesis of Sulfonyl Guanidines via Nitrene Radical Coupling with Isonitriles: A Combined Experimental and Computational Study

Article abstract of DOI:10.1021/acscatal.7b00798

A Co(II)-catalyzed synthesis of sulfonyl guanidines by using amines, isonitriles, and organic azides as nitrene sources has been developed. This protocol provides an environmentally friendly and simple strategy for the synthesis of sulfonyl guanidine derivatives by employing a range of substrates and will find potential applications in organic synthesis. The computational and EPR studies suggested the formation of guanidine derivatives via a cobalt-nitrene radical intermediate.

Full text of DOI:10.1021/acscatal.7b00798

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Article
Cobalt(II)-Catalyzed Synthesis of Sulfonyl Guanidines via Nitrene Radical
Coupling with Isonitriles: A Combined Experimental and Computational Study
Zheng-Yang Gu, Yuan Liu, Fei Wang, Xiaoguang Bao, Shun-Yi Wang, and Shun-Jun Ji
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Cobalt(II)-Catalyzed Synthesis of Sulfonyl Guanidines via Nitrene
Radical Coupling with Isonitriles: A Combined Experimental and
Computational Study
†,‡
†,‡
ZhengꢀYang Gu,†,‡ Yuan Liu,† Fei Wang,†,‡ Xiaoguang Bao,*,† ShunꢀYi Wang,*, and ShunꢀJun Ji*,
9
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou, 215123, China.
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‡Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, China.
Supporting Information Placeholder
ABSTRACT: A Co(II)ꢀcatalyzed synthesis of sulfonyl guanidines by
using amines, isonitriles, and organic azides as nitrene source has been
developed. This protocol provides an environmentallyꢀfriendly, and
simple strategy for the synthesis of sulfonyl guanidine derivatives by
employing a range of substrates and will find potential applications in
organic synthesis. The computational and EPR studies suggested the
formation of guanidine derivatives via
a cobaltꢀnitrene radical
intermediate.
KEYWORDS: cobalt(II)ꢀcatalyzed, sulfonyl guanidines, amines, isonitriles, organic azides, nitrene, computational study
ꢀ
INTRODUCTION
Substituted guanidine moiety are widely found in biologically
reactivity in various nitrogen transfer reactions such as addition
reactions, radical coupling reactions, as well as CꢀH activation
reactions.10 Furthermore, transition metalꢀcoordinated nitrogenꢀ
centered radicals are generally more stable than free nitrogenꢀ
centered radicals, thus opening the door to potential catalytic
applications.11 In recent years, Zhang’s group made great
contribution to Co(II)ꢀbased metalloradical reactions such as
radical CꢀH alkylation,12 radical CꢀH amination,13 radical olefin
cyclopropanation14 and radical aziridination.15 In addition,
computational studies of the Co(III)–nitrene radical species and
their application in organic synthesis suggested that formation of
the metallanitrenes was the key step in these reactions.16 To the
best of our knowledge, employing cobalt(III)ꢀnitrene radical
approach to produce guanidines has not been studied. Our group
is interested in developing cobaltꢀcatalyzed isocyanide insertion
reactions to construct Nꢀcontaining molecules. Herein, we
describe the synthesis of sulfonyl guanidines by the reaction of
cobaltꢀcatalyzed reaction of azides, isonitriles and various amines
involving cobalt(III)ꢀnitrene radical intermediate (Scheme 1). The
computational and EPR studies provide mechanistic insight into
the formation of guanidine derivatives.
active molecules and natural products, such as Arginine,1
Creatine,2 Guanine,3 Saxitoxin (STX),4 (−)ꢀPalau’amine,5
Sulfaguanidine,6 Pinacidil7 (Figure 1). In view of their importance
and usefulness, synthesis of guanidines has attracted great interest
of organic and medicinal chemists. The reported strategies for
synthesizing the guanidine derivatives can be generally classified
into the following two types, one is solution synthesis8 and
another one is solid phase synthesis.9 However, the traditional
synthetic methodologies suffer from harsh reaction conditions,
multistep synthesis, limited substrate scope, and/or expensive
catalysts. Hence, the development of a broader pallet and efficient
approach to substituted guanidines is highly desired.
Scheme 1. Transition metal-catalyzed nitrile reactions
Figure 1. Guanidine-based bioactive molecules
Nitrene intermediates are among the most promising agents for
selective introduction of nitrogen in molecules. Since the
discovery of practical conditions for the generation of
metallanitrenes, the chemistry of transition metalꢀnitrene radical
intermediates has attracted significant attention due to the high
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diethylamine, dipropylamine, dibutylamine were applied in this
reaction and showed better reactivity than piperidine and
ꢀ
RESULTS AND DISCUSSION
Initially, we tried the reaction of aniline (1a) and isonitrile (2a)
with benzenesulfonyl azide (3a) in MeCN at 80 °C for 12 h. The
desired product (E)ꢀNꢀ(N'ꢀtertꢀbutylꢀNꢀphenylcarbamimidoyl)ꢀ4ꢀ
methylbenzenesulfonamide (4a) could be obtained in 25% LCꢀ
yield (Table 1, entry 1). Some transition metal catalysts such as
Co(OAc)2, Cu(OAc)2, Pd(OAc)2, and FeCl2 were screened as well
and we found that the cobalt salt showed the best catalytic activity
(Table 1, entries 2ꢀ5). Then, more cobalt salts were tested for this
reaction and it was found that the reaction was almost completed
when CoC2O4 (cobalt oxalate) was used (Table 1, entries 6ꢀ8).
Further optimization study indicated that temperature and the
reaction time had great impact on this reaction (Table 1, entries 9ꢀ
15). The threeꢀcomponent reaction showed very low reactivity at
50 °C (Table 1, entry 7), and with the reduction of the time, the
yield of 4a was obviously decreased.
4
5
6
7
8
9
Scheme 2. Substrate scope of arylamines 1a,b
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Table 1. Screening of Reaction Conditionsa
entry
1
2
3
4
5
6
7
8
cat. (5 mol %)
ꢀꢀꢀ
Co(OAc)2
Cu(OAc)2
Pd(OAc)2
FeCl2
Co(acac)2
CoC2O4
CoCl2·6H2O
CoC2O4
CoC2O4
CoC2O4
CoC2O4
CoC2O4
CoC2O4
time (h)
12
12
12
12
12
12
12
12
12
12
6
yield (%)b
T (℃)
80
80
80
80
80
80
80
80
60
50
80
80
80
80
25
91
13
46
17
85
99
86
80
9
10
11
12
13
14
70
99(95)c
90
aReaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), 3a (0.75
mmol), CoC2O4 (5 mol%), MeCN (3 mL) at 80 °C, 6 h under air
atmosphere. bIsolated yield.
4
2
1
81
56
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), 3a (0.75
mmol), catalyst (5 mol%), MeCN (3 mL) under air atmosphere.
bThe yields were determined by LC analysis using diphenyl as an
internal standard. cIsolated yield.
Scheme 3. Substrate scope of secondary amines 1a,b
With the optimized reaction conditions in hand, we first
investigated the scope of various arylamines 1 (Scheme 2). It was
gratifying to observe that paraꢀsubstituted anilines with all kinds
t
of electronꢀdonating groups (Me, OMe, Bu), halogen atoms (F,
Cl, Br, I), and even COOEt group, exhibited a very high reactivity
under optimized reaction condition (4aꢀi, 91ꢀ96%). However,
only trace amount of product 4j could be detected when 4ꢀ
nitroaniline was used in this reaction. Then, some orthoꢀ
substituted anilines were also tested and we found electronꢀ
donating groups (Me, Et, OMe) could give the desired product
4kꢀm in excellent yields (88ꢀ94%). The orthoꢀsubstituted anilines
with halogen atoms (Cl, Br, I) displayed a lower reactivity than
electronꢀdonating groups and the desired product (4nꢀp) could be
isolated in moderate to good yields (77ꢀ81%).
The substrate scope of the secondary amines was then
examined (Scheme 3). We found that piperidine and pyrrolidine
showed poor reactivity, leading to the desired products 5a and 5b
in 38% and 56% yields, respectively. Furthermore, other
secondary amines such as morpholine, diisopropylamine,
aReaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), 3a (0.75
mmol), CoC2O4 (5 mol%), MeCN (3 mL) at 80 °C, 6 h under air
atmosphere. bIsolated yield.
pyrrolidine, which gave 76ꢀ96% yields of products 5cꢀg. Besides,
the expected product 5h could be isolated in 79% yield when Nꢀ
methylaniline was used.
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We next investigated the scope of isocyanides under the
Then, we investigated the scope of organic azides 3 (Scheme 5).
A variety of sulfonyl azides bearing different functional groups
were tested. Various kinds of substituents, such as H, OMe, F, Cl,
optimal conditions (Scheme 4). It was found that
isocyanocyclohexane, 1ꢀadamantyl isocyanide and different aryl
isocyanides worked equally well to furnish the desired product
6aꢀe in >87% yields. Notably, when isocyanide was substituted
by functional groups such as ethyl isocyanoacetate, the
corresponding product 6f could also be obtained in 77% yield.
Unfortunately, some other isocyanides such as 1ꢀisocyanobutane
and pꢀtoluenesulfonylmethyl isocyanide decomposed under the
established conditions and only trace amount of product could be
detected.
3
4
5
6
7
8
9
and
even
Br,
were
well
tolerated.
The
4ꢀ
acetamidobenzenesulfonyl azide and naphthaleneꢀ2ꢀsulfonyl azide
gave the products 7f and 7g in 85% and 93% yields, respectively.
Besides arylsulfonyl azides, alkylsulfonyl azide 3h also exhibited
a good reactivity in this transformation, producing the target
product 7h in 95% yield. However, only trace amount of product
7i could be detected when azidotrimethylsilane was used in this
reaction.
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Scheme 4. Substrate scope of isonitriles 2a,b
R
N
Scheme 6. Gram-scale synthesis of products 4a and 4p.
Ts
NH2
CoC2O4 (5 mol %)
MeCN, 80 oC, 6h
N
NH
H
Ts N3
R
NC
+
+
1a
2
3a
6
N
HN
N
N
Ts
Ts
Ts
Ts
N
H
NH
N
H
NH
N
NH
N
NH
H
H
6a
, 91%
6b
, 89%
6c
, 87%
6d
, 92%
OEt
N
N
N
N
Ts
Scheme 7. Synthetic transformation of product 4p and 6f.
Ts
Ts
O
Ts
Ts
N
H
NH
N
NH
N
H
NH
N
NH
H
H
N
HN
CuCl2 (10 mol %)
Ts
L-Proline (10 mol %)
N
N
H
NH
N
Ts
I
K2CO3 (2.0 equiv)
DMSO, 100 oC, 12 h
6e
, 88%
6f, 77%
6g
, trace
6h, trace
aReaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), 3a (0.75
mmol), CoC2O4 (5 mol%), MeCN (3 mL) at 80 °C, 6 h under air
atmosphere. bIsolated yield.
8, 61%
4p
OEt
NH
N
Scheme 5. Substrate scope of sulfonyl azides 3a,b
Ts
Ts
O
NaOH (2.0 equiv.)
N
NH
N
H
NH
H
EtOH, 60 o
C
6f
9
, 60%
For the reaction to be synthetically useful, we tried two gramꢀ
scale reactions under standard conditions and the products 4a and
4p could be obtained in 98% and 61% yields, respectively
(Scheme 6). To explore the potential application of the prepared
derivatives 4p and 6f (Scheme 7). We first tried the reaction of 4p
in DMSO solvent at 100 °C for 12 h, catalyzed by 10 mol %
CuCl2 and 10 mol % Lꢀproline in the presence of 2 equiv of
K2CO3 and the desired product Nꢀtertꢀbutylꢀ1ꢀtosylꢀ1Hꢀ
benzo[d]imidazolꢀ2ꢀamine
8
was isolated in 61% yield.
Furthermore, the transformation of 6f could easily undergo
reaction with 2 equiv of NaOH in ethanol, providing the
corresponding
4ꢀmethylꢀNꢀ(Nꢀ
phenylcarbamimidoyl)benzenesulfonamide 9 in 60% yield.
Computational studies were carried out to obtain an inꢀdepth
understanding for the mechanism of Co(II)ꢀcatalyzed synthesis of
sulfonyl guanidines (see SI for computational details). According
to the experimental results, the desired product could be formed in
25% yield even in the absence of the Co(II) catalyst. Thus, the
possible pathways leading to the product in the absence and in the
presence of the Co(II) catalyst were computationally considered,
respectively. In the absence of the Co(II) catalyst, the initial step
of dissociation of N2 from sulfonyl azide (3a) to afford the triplet
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), 3 (0.75
mmol), CoC2O4 (5 mol%), MeCN (3 mL) at 80 °C, 6 h under air
atmosphere. bIsolated yield.
3
nitrene intermediate INT2 was calculated to have a free energy
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barrier of 35.6 kcal/mol (Figure 2).17 Subsequently, the formed
3INT2 could attack isocyanide (2a’)18 to yield tripletꢀstate
3
intermediate INT3, which requires an activation energy of 14.2
3
kcal/mol. Afterwards, the tripletꢀstate intermediate INT3 could
5
convert to singlet ground state to form INT4 intermediate via
intersystem crossing (ISC). Alternatively, one may suggest that
the attack of the terminal carbon of isocyanide to the N1 of
sulfonyl azide to release N2 could also afford INT4 in a concerted
fashion. Computational results show that the concerted pathway
has a much higher energy barrier (45.2 kcal/mol) (see SI, Figure
S1), indicating the formation of INT4 in a stepwise manner might
be more feasible. Next, another substrate, PhNH2 (1a), could
undergo nucleophilic attack to the central carbon of INT4, leading
to intermediate INT6 (Figure 2). The predicted ꢁG‡ is 28.9
kcal/mol for this step relative to INT4. From INT6, the
subsequent proton transfer step could be followed to furnish the
desired product. Computational studies suggest that the
intermolecular stepwise proton transfer manner with the
assistance of another PhNH2 molecule would be a favorable
pathway. The additional PhNH2 could form Hꢀbonds with the
added PhNH2 moiety (N4ꢀH…N3) and the sulfonyl group (N4ꢀ
H…O) in INT7. The proton transfer from N3 to N4 was predicted
to have a lower energy barrier (Figure 3). Next, the formed
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Figure 3. Energy profile (in kcal/mol) for the conversion of INT6
to the desired product via proton transfer steps. Bond lengths are
shown in Å.
To consider the catalytic role of Co(II) catalyst, the fourꢀ
coordinated CoC2O4 with two MeCN solvent molecules as ligands
was employed as an initial model. Subsequently, two isocyanide
molecules and one sulfonyl azide molecule may undergo ligand
exchange to afford a sixꢀcoordinated complex INT12. The
dissociation of N2 from the sulfonyl azide in INT12 was
calculated to have an energy barrier of 19.9 kcal/mol, relative to
INT12 (Figure 4). Thus, the presence of the Co(II) catalyst could
efficiently lower the energy barrier of the dissociation of N2 from
the sulfonyl azide to generate the nitrene moiety.20 Subsequently,
the formed Co(III)ꢀnitrene intermediate (INT13) might undergo
coupling reaction between the nitrene moiety with the coordinated
isocyanide ligand to afford the INT14 intermediate, which
requires an energy barrier of 16.9 kcal/mol. Next, another
substrate, PhNH2, could undergo nucleophilic attack to the central
carbon of INT14, leading to intermediate INT16. The formed
INT6 intermediate might dissociate from the Co(II) center after
the ligand exchange step with the isocyanide. As discussed
previously, the energy barriers for the subsequent conversion from
INT6 to the final product are not very high in the absence of the
Co(II) catalyst, which suggests a facile process to occur. The
catalytic role of the Co(II) catalyst in the conversion from INT14
to the final product, if any, should not play a critical role. Overall,
the catalytic role of Co(II) catalyst might attribute to promoting
the dissociation of N2 from the sulfonyl azide to yield the Co(III)ꢀ
nitrene intermediate. In addition, the preference of the
coordination of isocyanides to cobalt center would make the
subsequent coupling reaction with the formed nitrene moiety
ready to occur. The whole catalytic cycle was summarized in
Scheme 8.
+
PhNH3 species could donate the additional proton to N1 to yield
the desired product. The second proton transfer is also a facile
step. Thus, the stepwise intermolecular proton transfer process
was found to be a favorable pathway from INT6 to the desired
product.19 The rateꢀlimiting step for the formation of the desired
product in the absence of the Co(II) catalyst would be the
dissociation of N2 from the sulfonyl azide.
G
N
O
2.11
1.89 N1
(kcal/mol)
Ph
N
S
O
1TS1
35.6
O
1.77
N1
Ph
S
1INT1
O
O
S
N2
Me N2
3TS2
17.5
20.4
1.96
N1
Ph
C
O
ISC
3INT2
3.3
MeNC
O
TsN3
0.0
1.30
1.30
N1
Ph
C
S
Me N2
3INT3
-6.8
O
O
Ph
S
N1
O
1.95
H
PhN3
2.06
H
O
Ph
S
N1
O
C
Me N2
ISC
TS3
INT6
-49.9
-43.6
1.71
H
PhN3
1.56
H
O
INT5
-60.8
PhNH2
Ph
S
O
S
1INT4
-72.5
O
H
PhN3
C
N1
2.13
O
H
N2
Ph
Me
N2
C
N1
1.25
Ph
O
O
1.21
S
Me
N1
C
Me N2
Figure 2. Energy profile (in kcal/mol) for the dissociation of N2
from sulfonyl azide to yield the nitrene intermediate and
subsequent reaction with isocyanide. Bond lengths are shown in Å.
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Figure 4. Energy profile (in kcal/mol) for the formation of the key Co(III)ꢀnitrene intermediate and subsequent coupling reaction with the
coordinated isocyanide ligand. Bond lengths are shown in Å.
Scheme 8. Plausible Mechanism
CoC2O4+Ts-N3+tBu-NC2
g = 1.89
3450
3500
3550
Gauss
Figure 5． EPR spectra of tBuꢀNC 2a (0.5 mmol), TsꢀN3 3a (0.5
mmol), CoC2O4 (0.5 mmol) in MeCN (3 mL) at 298 K
To further confirm the formation of key Co(III)ꢀnitrene
intermediate, electron paramagnetic resonance (EPR) experiments
were also carried out (Figure 5). We found that no EPR signal was
observed when the mixture of CoC2O4 and pꢀtoluenesulfonyl
azide 3a was tested. Following the isonitrile 2a added, a strong
triplet EPR signal was observed (g = 1.89) and the hyperfine
coupling constant aN = 15.47. We also found that the EPR signal
was significantly attenuated after 48 h (More details of the EPR
signals please see Supporting Information).
ꢀ
CONCLUSION
N2 from the sulfonyl azide to generate the Co(III)ꢀnitrene
intermediate, which could be detected by EPR spectroscopy. In
addition, the preference of the coordination of isocyanides to
cobalt center would make the subsequent coupling reaction with
the formed nitrene moiety ready to occur. Further investigations
of the Co(II)ꢀcatalyzed nitrene reactions are currently under study
in our laboratory.
In summary, we have developed a Co(II)ꢀcatalyzed synthesis of
sulfonyl guanidines by using amines, isonitriles, and organic
azides as nitrene source. This protocol provides an
environmentallyꢀfriendly, and simple strategy for the synthesis of
sulfonyl guanidine derivatives with a range of substrates and will
find potential applications in organic synthesis. The catalytic role
of Co(II) catalyst might attribute to promoting the dissociation of
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(11) (a) Suarez, A. I. O.; Lyaskovskyy, V.; Reek, J. N. H.; der Vlugt, J. I.; de Bruin,
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ASSOCIATED CONTENT
B. Angew. Chem. Int. Ed. 2013, 52, 12510. (b) Fumagalli, G.; Rabet, P. T. G.; Boyd,
S.; Greaney, M. F. Angew. Chem. Int. Ed. 2015, 54, 11481. (c) Xie, F.; Qi, Z.ꢀS., Li,
X.ꢀW. Angew. Chem. Int. Ed. 2013, 52, 11862. (d) Alt, I. T.; Plietker; B. Angew.
Chem. Int. Ed. 2016, 55, 1519. (e) Badiei, Y. M.; Dinescu, A.; Dai, X.ꢀL.; Palomino,
R. M.; Heinemann, F. W.; Cundari, T. R., Warren T. H. Angew. Chem. Int. Ed. 2008,
47, 9961. (f) Jung, N.; Brase, S. Angew. Chem. Int. Ed. 2012, 51, 5538. (g) Wiese, S.;
Aguila, M. J. B.; Kogut, E.; Warren, T. H. Organometallics, 2013, 32, 2300.
(12) Cui, X.; Xu, X.; Jin, L.ꢀM.; Wojtas, L.; Zhang, X. P. Chem. Sci. 2015, 6, 1219ꢀ
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(13) (a) Lu, H.ꢀJ.; Subbarayan, V.; Tao, J.ꢀR.; Zhang, X. P. Organometallics 2010,
29, 389. (b) Lu, H.ꢀJ.; Jiang, H.ꢀL.; Wojtas, L.; Zhang, X. P. Angew. Chem. Int. Ed.
2010, 49, 10192. (c) Lu, H.ꢀJ.; Li, C.ꢀQ.; Jiang, H.ꢀL.; Lizardi, C. L.; Zhang, X. P.
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Supporting Information
Detailed experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
ꢀ
AUTHOR INFORMATION
Corresponding Author
9
xgbao@suda.edu.cn;
shunyi@suda.edu.cn;
shunjun@suda.edu.cn
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E. J.; DeBeer, S.; van Schooneveld, M. M.; Pfaff, F. F.; Ray, K.; de Bruin, B. J. Am.
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(17) Intersystem crossing (ISC) could occur to form the triplet ground state of the
nitrene intermediate 3INT2 from the excited singlet state (1INT1).
(18) A smaller isocyanide model, MeNC, was used in the computational study.
(19) The direct intramolecular proton transfer route for INT6 to furnish the final
product, however, has a relatively higher energy barrier (22.9 kcal/mol) compared
with the intermolecular proton pathway assisted by another PhNH2 molecule (see SI,
Figure S2a). In addition, the intramolecular stepwise proton transfer to reach the final
product was also considered, in which an H in the PhNH2 moiety of INT6 migrates
to an O in the sulfonyl group first and subsequently transfers to N1 to afford the final
product (see SI, Figure S2b). However, the predicted energy barrier for this stepwise
intramolecular proton transfer process is also higher (24.4 kcal/mol relative to INT6)
than the intermolecular proton transfer pathway.
Notes
The authors declare no competing financial interests.
ꢀ
ACKNOWLEDGMENT
We gratefully acknowledge the National Natural Science
Foundation of China (21672157, 21542015, 21372174,
21302133), the Ph.D. Programs Foundation of Ministry of
Education of China (2013201130004), the Major Basic Research
Project of the Natural Science Foundation of the Jiangsu Higher
Education Institutions (No. 16KJA150002), PAPD, and Soochow
University for financial support, and State and Local Joint
Engineering Laboratory for Novel Functional Polymeric
Materials.
ꢀ
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