Ruthenium-Catalyzed Urea Synthesis by N–H Activation of Amines

Article pubs.acs.org/IC

Ruthenium-Catalyzed Urea Synthesis by N−H Activation of Amines Varadhan Krishnakumar,† Basujit Chatterjee,† and Chidambaram Gunanathan* School of Chemical Sciences, National Institute of Science Education and Research, Homi Bhabha National Institute, Bhubaneswar 752 050, India S Supporting Information *

ABSTRACT: Activation of the N−H bond of amines by a ruthenium pincer complex operating via “amine−amide” metal−ligand cooperation is demonstrated. Catalytic formyl C−H activation of N,N-dimethylformamide (DMF) is observed in situ, which resulted in the formation of CO and dimethylamine. The scope of this new mode of bond activation is extended to the synthesis of urea derivatives from amines using DMF as a carbon monoxide (CO) surrogate. This catalytic protocol allows the synthesis of simple and functionalized urea derivatives with liberation of hydrogen, devoid of any stoichiometric activating reagents, and avoids the direct use of fatal CO. The catalytic carbonylation occurred at low temperature to provide the formamide; a formamide intermediate was isolated. The consecutive addition of different amines provided unsymmetrical urea compounds. The reactions are proposed to proceed via N−H activation of amines followed by CO insertion from DMF and with liberation of dihydrogen.

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INTRODUCTION The reactivity of the lone pair of electrons available on the nitrogen atom dominates the chemistry of amines, resulting in Lewis acid−base interaction, and thus generally leads to the formation of Werner types of complexes upon treatment with transition metals.1 As a result, activation of the N−H bond, which has enormous potential in catalytic transformation, remains scarce.2 In contrast, a suitable ligand design resulted in activation of the N−H bond of amines on the metal center to provide the “amide”-type ligand. Milstein and co-workers introduced noninnocent ligand-mediated N−H activation of amines in which the metal oxidation state remains the same because of metal−ligand cooperation (MLC).3,4 Although tremendous strides have been made in various bond activation and catalytic applications thereof, the chemistry of N−H activation remains underdeveloped.5 Recently, we demonstrated facile N−H activation of the amine functionality by a monohydrido-bridged dinuclear ruthenium complex, which resulted in the selective α-deuteration of amines and amino acids with excellent catalytic efficiency.6 N,N′-disubstituted urea derivatives have potential applications as efficient organocatalysts,7 green solvents,8 promising nonlinear-optical materials,9 and pharmacological compounds (Figure S1).10−12 Despite notable synthetic advances, the urea derivatives are, in general, obtained using phosgene and isocyanates,13 which generates toxic byproducts. The synthesis of urea compounds using phosgene alternatives requires a multistep synthesis.14 Catalytic carbonylation reactions have a profound influence in the chemical synthesis and are known to employ different compounds as a carbon monoxide (CO) surrogate.15,16 For example, Kim and Hong recently reported the ruthenium-catalyzed efficient urea synthesis directly from © 2017 American Chemical Society

amines using methanol as a CO surrogate, in which methanol was oxidized to formaldehyde, resulting in coupling with amines.16 Although direct carbonylation of amines to urea offers an attractive alternative protocol,17−19 they often suffer from low yield, 17 the requirement of additional and stoichiometric amounts of oxidant,18 the use of toxic pressurized CO gas,19 and chromatographic purifications. Thus, environmentally benign and mild reaction conditions for urea synthesis still remain a challenge. In a continuation of our studies on N−H,6 O−D, and Csp−H bond activation reactions, which resulted in the highly selective deuteration of amines, amino acids, alcohols, and terminal alkynes using D2O,20 we report herein facile N−H bond activation by the ruthenium pincer complex [(PNPPh)RuHCl(CO)] (1; PNP = bis[2-(diphenylphosphino)ethyl]amine) and its direct catalytic application to the synthesis of valuable urea derivatives using N,N′-dimethylformamide (DMF) as a CO alternative (eq 1). The ruthenium pincer complex 1 is an efficient catalyst in oxidative coupling reactions of alcohols and the dehydrogenation and hydrogenation of an assortment of carboxylate derivatives.21 catalyst

2RNH 2 + Me2NCHO ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ RNHCONHR + H 2↑ −HNMMe2

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(1)

RESULTS AND DISCUSSION N−H Activation of Amines. Deprotonation of the ruthenium pincer complex 1 with a base (KOtBu) in the Received: April 24, 2017 Published: May 30, 2017 7278

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1, entries 4−6). When 2 mol % catalyst 1 and 10 equiv of DMF were reacted with benzylamine, N,N′-dibenzylurea was isolated in 91% yield (Table 1, entry 7). Control experiments with no catalyst and base (Table 1, entry 8) and in the presence of only base (Table 1, entry 9) confirmed that the catalyst is essential for this transformation. Further, we have employed the reactive catalyst (PNPPh)RuH(H-BH3)(CO) (Ru-Macho-BH)24 used by Kim and Hong in urea synthesis from methanol and amine,16 which under neutral conditions failed to produce urea from amine and DMF (Table 1, entry 10), indicating that this reaction proceeds via mechanistically different pathways involving N−H activation of amines. Under optimized conditions, an assortment of arylmethylamines was tested for the urea synthesis using catalyst 1 and DMF (Table 2). Benzylamine with electron-donating groups

presence of benzylamine generated complex 3a at room temperature. When 4-fluorobenzylamine and 4-nitroaniline were subjected to the reaction under similar conditions, complexes 3b and 3c were obtained, respectively, as a result of the facile N−H activation of alkyl- and arylamines. Complexes 3a−3c exhibited characteristic 1H, 13C, and 31P NMR signals. Further, the structure of complex 3b was unequivocally corroborated using single-crystal X-ray analysis (Scheme 1).22 Scheme 1. N−H Activation by “Amine−Amide” MLC Operative in Complex 1

Table 2. Synthesis of Arylmethyl- and Arylalkylurea Derivativesa

Catalytic Studies. To explore the catalytic application of N−H activation reactions, direct carbonylation of amines using DMF was planned. DMF is established as a safe alternative to toxic CO.23 At the outset, optimization studies were performed for carbonylation of benzylamine to urea using DMF as a CO surrogate catalyzed by the ruthenium pincer complex 1, and the results are summarized in Table 1. Experiments with 0.5 and 1 mol % ruthenium catalyst 1 and benzylamine (1 mmol) and 3− 5 mmol of DMF resulted in poor yields (12−29%) of N,N′dibenzylurea (Table 1, entries 1−3). The use of 2 mol % catalyst 1 with an excess amount of DMF (3−7 equiv) under open conditions provided enhanced product formation (Table Table 1. Optimization of the Reaction Conditionsa

a

entry 1 2 3 4 5 6 7 8 9c 10

catalyst load (mol %) 0.5 0.5 1.0 2.0 2.0 2.0 2.0

Ru-Macho-BH (2.0)

DMF (equiv)

yield (%)

3 5 3 3 5 7 10 10 10 10

12 22 29 46 67 74 91

Amine (1 mmol), catalyst 1 (2 mol %), KOtBu (4 mol %), DMF (10 mmol), and xylene (1.5 mL) were heated at 165 °C for 24 h in open conditions under an argon atmosphere. Yields correspond to isolated products.

b

provided dialkylurea products in very good yields (Table 2, 4b−4e), while 4-fluorobenzylamine provided the corresponding urea in diminished yield (4f, 76%). The use of 1naphthylmethylamine resulted in 92% dinaphthylmethylurea (Table 2, 4g). Furthermore, reactions of phenethylamine and its derivatives displayed good reactivity (Table 2, 4k−4n). In general, benzylamines and alkylamines provided urea products in good yields. While substitution at the ortho position of benzylamine was tolerated, substitution at the α-amine functionality (4h and 4o) and heteroarylmethylamine (2- and 3-picolylamines) delivered urea products in moderate yields (4i

a Amine (1 mmol), xylene (1.5 mL), and catalyst 1 were heated at 165 °C for 24 h in open conditions under an argon atmosphere. bIsolated yields. cControl experiment in the presence of a base.

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Because formamides can be further used as reagents for the urea synthesis, this observation revealed the possibility for the synthesis of unsymmetrical urea derivatives. Thus, upon the catalytic formation of formamides, different amines were added to the same reaction mixture and heated at elevated temperature, which provided the unsymmetrical urea derivatives in good-to-excellent yield (Table 4, 7a−7i).

and 4j). However, when aniline was subjected to this catalytic transformation, N,N′-diphenylurea was obtained only in 2% yield, implying that nucleophilicity of amines is an essential requirement for the efficient formation of urea. Further, linear n-alkyl- and cycloalkylamines were utilized in the synthesis of N,N′-dialkylurea derivatives. When n-pentylamine was reacted with DMF under optimized conditions, dipentylurea was obtained in 41% yield, perhaps because of the lower boiling point (104 °C) of amines. However, when longchain amines were reacted, the corresponding urea derivatives were isolated in excellent yields. Likewise, cyclohexylmethylamine-, morpholine-, and cyclohexenyl-incorporated amines were subjected to the reaction, which furnished the corresponding dialkylurea products in good yields (Table 3,

Table 4. Synthesis of Unsymmetrical Urea Derivativesa

Table 3. Synthesis of N,N′-Dialkylurea Derivativesa

a

Amine (1 mmol), 1 (2 mol %), KOtBu (4 mol %), DMF (10 mmol), and xylene (1.5 mL) were heated at 135 °C for 12 h in open conditions under an argon atmosphere. Subsequently, a different amine (1 mmol) was added, and the reaction mixture was heated at 150 °C for 16 h. Yields correspond to isolated products.

When benzylamine was subjected to catalysis using the isolated complex 3a as the catalyst, N,N′-dibenzylurea was obtained in 89% yield. Notably, this reaction occurred under neutral conditions (devoid of KOtBu) to provide results similar to those of catalyst 1/KOtBu, indicating that the role of the base in this catalytic process is limited to the generation of active intermediate 2 from 1 (Scheme 3).

a

Scheme 3. Catalytic Synthesis of N,N′-Dibenzylurea by N−H Activation Complex 3a

See the footnote of Table 2.

5f−5i). The cyclohexylamine displayed moderate yield (Table 3, 5j), and in the case of the bulkier adamantylamine, the reaction was sluggish and provided poor yield (Table 3, 5k) because of steric hindrance. Interestingly, the use of 1,3diaminopropane under optimized conditions provided a cyclic urea (5l). Mechanistic Considerations and Synthesis of Unsymmetrical Urea Compounds. To further understand the mechanistic insight of this useful process, the reaction of benzylamine with DMF (4 equiv) catalyzed by 1 (0.5 mol %) was carried out at lower temperature (135 °C), which provided N-benzylformamide in 78% yield, indicating the involvement of formamide as a potential intermediate in the synthesis of urea derivatives (Scheme 2).

Formyl C−H Activation of DMF. The catalytic synthesis of N,N′-dibenzylurea was performed in closed conditions, and after 1 h, the gas phase of the reaction mixture was subjected to gas chromatography (GC) analysis, which allowed us to detect the in situ formed CO and dihydrogen.25 Further, upon reaction of the ruthenium pincer complex 1 with a base in DMF, we observed the formation of complex 8 (31P, 64.28 ppm; IR, 1876 cm−1; Scheme 4). Apparently, complex 8 formed from C−H activation of the formyl functionality of DMF by the in situ formed unsaturated complex 2 at room temperature. However, complex 8 remains elusive to complete characterization, as repeated attempts for its isolation failed. When crystallization of 8 was attempted directly from the above reaction mixture, the dichlororuthenium complex 9 was isolated,24,25 which perhaps resulted from the decomposition of complex 8.

Scheme 2. Catalytic Synthesis of N-Benzylformamide

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activation of DMF by complex 1 (Scheme 4), leads to formation of the intermediate 10. The amide-ligated saturated complex 10 undergoes elimination of the formamide 6 at lower temperature (135 °C, oil bath temperature) and can regenerate complex 2 (Scheme 2). At higher temperature (>150 °C), a second intermolecular nucleophilic attack by amine on a metalcoordinated amide motif occurs, leading to the formation of urea and the saturated ruthenium dihydride complex 11,25 which upon liberation of dihydrogen26 regenerates 2 for further catalysis. Overall, the catalytic carbonylation of amines to urea derivatives proceeds with the liberation of molecular hydrogen. Further, to test the applicability of this catalytic method for the large-scale synthesis of urea derivatives, the reaction of benzylamine with DMF was performed in a 5 mmol scale, which produced the N,N′-dibenzylurea in 82% yield (Scheme 6).

Scheme 4. Observed DMF Activation by In Situ Formed Unsaturated Complex 2

Scheme 6. Large-Scale Synthesis of N,N′-Dibenzylurea

On the basis of the stoichiometric reaction of complex 1 with different amines in the presence of base (Scheme 1), the activation of DMF by complex 1 (Scheme 4), and other experimental observations, a mechanism for the catalytic carbonylation of amines to urea derivatives is proposed in Scheme 5. The reaction of complex 1 with a base, KOtBu,

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SUMMARY In conclusion, a facile N−H activation of amines is demonstrated. The C−H bond activation of the formyl functionality of DMF is observed in situ. These bond activations are further applied for the development of an efficient protocol for the synthesis of urea derivatives catalyzed by the ruthenium catalyst 1. A clean synthetic method using DMF as an effective surrogate for CO is attained and an assortment of symmetrical and unsymmetrical urea derivatives was synthesized by the carbonylation of primary amines. Operating in open conditions and devoid of any deleterious side products make this method highly attractive and advantageous over the related reported procedures for the synthesis of urea derivatives. As these reactions progress with the liberation of hydrogen and without the requirement of any pressure setup, potential applications of this protocol in other organic transformations are currently being explored.

Scheme 5. Proposed Mechanism for the N−H Activation and Catalytic Carbonylation of Amines to Urea Using DMF as a CO Surrogate

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EXPERIMENTAL SECTION

General Procedure for the Synthesis of Complexes 3a−3c. To a screw-cap scintillation vial were added Ru-macho 1 (0.032 mmol, 20 mg), KOtBu (1.1 equiv, 0.035 mmol, 4 mg), and THF (1 mL), and the resulting mixture was allowed to stir at room temperature for 30 min. To the reddish-brown solution was added dropwise amines (2.2 equiv). The solution was then stirred for 5 min at room temperature. The brownish-yellow solution immediately turned red. The resulting solution was reduced under vacuum, and the slow addition of cold hexane (2 mL) provided a yellow precipitate. The solution was decanted, and the precipitate was washed three times with hexane (1 mL). The precipitate was dried under vacuum for 4 h to afford the product as a yellow solid. Ruthenium Benzylamide (3a). Yield: 18.9 mg (87%) as a yellow solid. IR (C6H6): 3026, 2279 (RuH), 1918, 1603, 1495, 1459, 1221, 1081, 1029, 895, 812, 726, 793 cm−1. 1H NMR (C6D6): δ 7.66 (m, 4H, ArCH), 7.36 (m, 4H, ArCH), 6.57 (m, 17H, ArCH), 3.35 (br, 1H, NH), 3.17 (m, 5H, CH2), 2.79 (br, 2H, CH2), 2.49 (t, J = 8 Hz, 1H, NH), 1.95 (br, 2H, CH2), 1.46 (bs, 2H, CH2), −13.77 (t, J = 16 Hz, 1H, RuH). 31P{1H} NMR (C6D6): δ 61.71 (s). Ruthenium 4-Fluorobenzylamide (3b). Yield: 18.2 mg (75%) as a yellow solid. IR (C6H6): 3228, 2192 (RuH), 1915, 1610, 1483, 1216,

generates the unsaturated ruthenium(II) intermediate 2. Formation of the transient intermediate 2 is observed in situ using 1H (δRu−H −5.85) and 31P NMR (δ 48.45) and electrospray ionization mass spectrometry analyses (m/z 572 [(M + H)+]). N−H bond activation of the amine functionality by complex 2 occurs via “amine−amide” MLC4,20 to generate the intermediate 3 (Scheme 1). The insertion of CO (observed in the gas phase of the reaction mixture), generated from the 7281

DOI: 10.1021/acs.inorgchem.7b00962 Inorg. Chem. 2017, 56, 7278−7284

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1176, 1100, 911, 896, 745 cm−1. 1H NMR (C6D6): δ 6.73 (m, 4H, ArCH), 6.30 (m, 4H, ArCH), 5.72 (m, 16H, ArCH), 2.25 (br, 1H NH), 1.53 (br, 1H, NH), 0.98 (br, 1H, CH2), 0.93 (bs, 2H, CH2), 0.88 (bs, 2H, CH2), −13.47 (t, J = 20 Hz, 1H, RuH). 13C NMR: δ 162.42 (quat-C), 159.99 (quat-C), 138.54 (CO), 133.89 (quat-C), 133.81, 133.75, 130.83, 130.78, 130.72, 129.82, 128.82, 128.33, 128.01, 114.30 (CH2), 66.82 (CH2), 24.82 (CH2). 31P{1H} NMR (C6D6): δ 61.93 (s). Crystal data of 3b: C79H80Cl2F2N4O2P4Ru2, crystal dimensions 0.3 × 0.15 × 0.12, triclinic with space group P1̅, a = 13.1153(5) Å, b = 14.6254(5) Å, c = 21.0142(7) Å, α = 83.896(2)°, β = 76.029(2)°, γ = 67.637(2)°, V = 3617.0(2) Å3, Z = 2, T = 100 K, 2θmax = 30.21, ρcalcd = 1.425 g/cm3, μ(Mo Kα) = 0.635 mm−1, min/max transmission factors = 0.6892/0.7460, 21358 reflections collected, 18086 unique (R1 = 0.0427), wR2 = 0.0531 (all data). The structure has been deposited at the CCDC data center and can be retrieved citing CCDC 1526189. Ruthenium 4-Nitrophenylamide (3c). Yield: 13.6 mg (60%) as a light-yellow solid. IR (C6H6): 3197, 2194 (RuH), 1893, 1623, 1478, 1216, 1173, 1156, 941, 887, 746 cm−1. 1H NMR (C6D6): δ 8.12 (m, 4H, ArCH), 8.01 (m, 4H, ArCH), 7.77 (m, 4H, ArCH), 7.48 (m, 4H, ArCH), 6.99 (m, 8H, ArCH), 3.59 (m, 3H, CH2 and NH), 3.36 (s, 1H, NH), 3.28 (br, 2H, CH2), 2.36 (br, 2H, CH2), 2.21 (br, 2H, CH2), −11.97 (t, J = 16 Hz, 1H, RuH). 13C NMR: δ 147.11 (quat-C), 133.88 (quat-C), 133.81 (CO), 130.72, 129.92, 128.87, 128.32, 127.82, 126.82, 124.42, 124.35, 66.82 (CH2), 24.82 (CH2). 31P{1H} NMR (C6D6): δ 58.53 (s). General Procedure for the Synthesis of Symmetrical Urea Derivatives. To an oven-dried Schlenk tube were added catalyst 1 (2 mol %, 0.019 mmol, 12 mg), KOtBu (4 mol %, 0.039 mmol, 4.4 mg), and xylene (1.5 mL), and the reaction mixture was stirred for 10 min at room temperature. After that, amine (1 mmol) and DMF (10 mmol) were added to the reaction mixture, and the Schlenk tube was fitted with a condenser. The Schlenk tube was immediately immersed in a preheated oil bath at 165 °C and heated for 24 h with stirring. Upon completion, the reaction mixture was allowed to cool at room temperature. Hexane (5 mL) was added to the reaction mixture, and the precipitated urea derivative was further washed with hexane (3 mL). The solid obtained was dried under vacuum. General Procedure for the Synthesis of Unsymmetrical Urea Derivatives. To an oven-dried Schlenk tube were added catalyst 1 (2 mol %, 0.019 mmol, 12 mg), KOtBu (4 mol %, 0.039 mmol, 4.4 mg), and xylene (1.5 mL), and the reaction mixture was stirred for 10 min at room temperature. After that, amine (1 mmol) and DMF (10 mmol) were added to the above reaction mixture, and the Schlenk tube was fitted with a condenser under an argon atmosphere. The Schlenk tube was immediately immersed in a preheated oil bath at 135 °C and heated for 12 h with stirring. Further, a different amine (1 mmol) was added to the reaction mixture and heated to 150 °C for 16 h. Upon completion, the reaction mixture was allowed to cool at room temperature. Hexane (5 mL) was added to the reaction mixture, and the precipitated urea derivative was further washed with hexane (3 mL). The solid obtained was dried under vacuum.

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Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chidambaram Gunanathan: 0000-0002-9458-5198 Author Contributions †

V.K. and B.C. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank SERB New Delhi (Grants EMR/2016/002517 and SR/S2/RJN-64/2010), DAE, and NISER for financial support. We thank Prof. S. Muthusamy and Dr. J. V. Yeldho for their kind help in the preparation of this manuscript. V.K. thanks SERB for the National Postdoctoral Fellowship. B.C. thanks UGC for a research fellowship. C.G. is a Ramanujan Fellow.

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DEDICATION Dedicated to Prof. David Milstein on the occasion of his 70th birthday, with our very best wishes. REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b00962. General experimental procedures and spectral data of complexes and urea compounds (PDF) Accession Codes

CCDC 1526189 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 7282

DOI: 10.1021/acs.inorgchem.7b00962 Inorg. Chem. 2017, 56, 7278−7284

Article

Inorganic Chemistry

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DOI: 10.1021/acs.inorgchem.7b00962 Inorg. Chem. 2017, 56, 7278−7284

Article

Inorganic Chemistry (26) Transfer hydrogenation products such as (dimethylamino) methanol were not observed in the 1H NMR and GC analyses of the reaction mixtures.

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DOI: 10.1021/acs.inorgchem.7b00962 Inorg. Chem. 2017, 56, 7278−7284