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Cite this: Chem. Commun., 2014, 50, 3706
PdCl2 catalyzed efficient assembly of organic azides, CO, and alcohols under mild conditions: a direct approach to synthesize carbamates†
Received 21st January 2014, Accepted 11th February 2014
Long Rena and Ning Jiao*ab
DOI: 10.1039/c4cc00538d www.rsc.org/chemcomm
A simple and readily available PdCl2 catalyzed carbamate synthesis method via isocyanate generation and application in situ has been developed. This chemistry provides an efficient and practical approach to synthesize carbamates from simple organic azides, CO atmosphere and alcohols. The broad scope, mild and neutral conditions, and only N2 as the byproduct make this transformation very useful. Moreover, simple examples of modification of bioactive molecules and construction of macrocycles were achieved through this protocol.
Since 1848, when the isocyanate was discovered by Wurtz,1 diverse transformations with nucleophiles, other cumulenes and metal reagents have been widely used in synthetic chemistry,1,2 materials chemistry,1,3 and biological research,4 due to the importance and high reactivity of these kinds of compounds. However, the preparation and application of isocyanates were tedious with a relatively rigorous catalytic system, substrate restriction, unavoidable formation of 1,3-diarylurea as the sole product, or employment of expensive and environmentally unfriendly reagents.5 By employing simple and readily available CO6 and aromatic azides, Bennett et al. first reported the direct synthesis of free isocyanates under harsh conditions (a, Scheme 1).7 However, the application of this strategy has been impeded by the limited scope, the efficiency, under a high CO
Scheme 1
pressure, as well as the expensive catalyst and ligand loading.8 Therefore, it is very desirable to develop an efficient strategy to generate and utilize isocyanates under mild conditions. Herein, we report a practical PdCl2 catalyzed efficient assembly of organic azides, CO, and alcohols for the direct synthesis of carbamates via isocyanate generation and application in situ (b, Scheme 1). The significance of the present finding is fourfold: (1) this chemistry provides an efficient and practical approach to synthesize carbamates, which play very important and also ubiquitous roles in pharmaceutical, agrochemical and material terrains.9 For example, large numbers of molecules with carbamate motifs have been found to possess various bioactive potentials and have been developed into marketed drugs that treat arrhythmias (I, Fig. 1),10 seizures (II),11 asthma (III),12 and AIDS (IV).13 (2) The broad scope, mild and neutral conditions, and only N2 as the byproduct make this transformation very useful. This protocol could also be applied in the modification of bioactive compounds and drugs. (3) This method with CO atmosphere enables this reaction to be very easily handled. (4) A simple and readily available PdCl2 salt (2 mol%) in the absence of any ligand has emerged as an inexpensive and efficient catalyst. The examination of the reaction conditions commenced with the reaction of 1-azido-4-methoxybenzene (1a) and 2-phenylethanol (2a) under 1 atm of CO as the model reaction. To start with
Direct carbonylation of organic azides.
a
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, People’s Republic of China. E-mail: [email protected]; Fax: +86-010-8280-5297; Tel: +86-010-8280-5297 b State Key Laboratory of Elemento-organic Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc00538d
3706 | Chem. Commun., 2014, 50, 3706--3709
Fig. 1
Examples of marketed carbamate drugs.
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Table 1
Examination of reaction conditionsa
Entry
Catalyst
Solvent
Temperature (1C)
Yieldb (%)
1 2c 3 4 5 6 7 8d 9d 10d,e 11d,e 12d–f
5 mol% PdCl2 5 mol% PdCl2 5 mol% Pd(OAc)2 5 mol% PdCl2 5 mol% PdCl2 5 mol% PdCl2 1 mol% PdCl2 1 mol% PdCl2 2 mol% PdCl2 2 mol% PdCl2 No catalyst 2 mol% PdCl2
DMF DMF DMF NMP DMA DMA DMA DMA DMA DMA DMA DMA
80 80 80 70 70 90 70 70 70 70 70 70
52 35 o10 61 90 73 82 76 91 89 0 0
Table 2
The reaction scope of alcoholsa
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol, 1.5 eq.), TEA = triethylamine (0.6 mmol), solvent (2 mL), 24 h with a CO balloon. b Isolated yields. c PPh3 (20 mol%) was added. d 1.2 eq. of 2a was employed in DMA 0.2 M. e Without TEA. f The reaction was carried out under Ar without CO.
searching for a suitable catalyst that could enable this strategy, a series of metal complexes have been tested (see ESI†). Gratifyingly, a moderate yield of the anticipated product phenethyl 4-methoxyphenylcarbamate (3aa) was obtained when 5 mol% of PdCl2 was employed as the catalyst (Table 1, entry 1). The efficiency of a similar reaction decreased in the presence of 20 mol% of PPh3 as the ligand (17%, entry 2). This might be attributed to the occurrence of Staudinger reaction.14 Some other palladium catalysts were then examined, but no better yield was achieved (entry 3, and see the ESI†). Strong polar solvents were found to play a vital role in this reaction producing 3aa in over 40% yields, while no or only a trace of product was detected by using non- or weakly polar solvents (see ESI†). 90% yield was achieved when the reaction was carried out in DMA (dimethylacetamide) at 70 1C (entry 5). There was only a minor decline in yields employing 1 mol% and even 1.2 eq. of 2a (entries 7 and 8). Finally, the standard conditions were simplified to the 2 mol% catalyst in the absence of any base, which produced the desired carbamate product 3aa in 89% yield (entry 10). It is noteworthy that the reaction in the absence of a Pd-catalyst or CO did not work (entries 11 and 12). With the optimized reaction conditions in hand, the scope of alcohols was first explored (Table 2). High yields were obtained with linear alcohols including methanol (3ab), which has a low boiling point relative to the reaction temperature. Moreover, the secondary alcohols also performed well in this transformation leading to the corresponding carbamates in moderate yields (3af–3ai, and 3as). When tertiary alcohols served as the nucleophiles in the reactions, the steric effects decreased the efficiency and afforded the carbamate products in low yields (3aj–3ak). The scope was greatly enlarged by benzyl and allylic alcohols, alcohols containing various terminal alkenyl and alkynyl groups, as well as alcohols with different heterocycles, which underwent a smooth reaction to give desired products in moderate to good yields (3al–3aw). We next investigated the substrate scope of organic azides (Table 3). Aryl azides generally substituted by electron donating
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a
Reactions were carried out under standard conditions: entry 10, Table 1. Isolated yields.
Table 3
The reaction scope of organic azidesa
a Standard conditions: entry 10, Table 1. Isolated yields. was carried out at 90 1C.
b
The reaction
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Table 4
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Investigation of intramolecular reactionsa
a Standard conditions: entry 10, Table 1. Isolated yields. was carried out with PdCl2 (5 mol%) in DMA (6 mL).
b
The reaction
groups produced 3ba, 3ha, and 3ma in about 80% yields, while those substituted by electron-withdrawing groups produced 3ca, 3ga, and 3la in over 90% yields. Interestingly, iodo, nitro or even exposed hydroxyl substituents are tolerated in this transformation leading to the corresponding functionalized carbamates in moderate to good yields (3da, 3ha–3ia, 3la). Moreover, heterocyclic aromatic azides performed well under the standard conditions (3ja and 3ma). It is noteworthy that the alkenyl azide reacted as perfectly as the aryl azide (3ea, 87% yield). Some alkyl azides are also tolerated in this transformation although with low yields (3na and 3oa), which may be due to the low stability of a metal nitrene intermediate without conjugation by an unsaturated bond. With these delightful results above, investigation of intramolecular reactions was taken into account (Table 4). Although phenols were not effective for intermolecular transformation (see ESI†), the intramolecular reaction with the phenol nucleophile worked well and delivered the anticipated product (5a) in 81% yield. In addition, the intramolecular reaction of (2-azidophenyl)methanol (4b) was executed well and afforded the ring closed product 5b in a high yield of up to 99%, which diverted our interest to the synthesis of macrocyclic compounds. Interestingly, 12- and 17-membered rings can also be prepared by this protocol in moderate yields (5c and 5d). Furthermore, by utilizing this protocol, the marketed drugs Chlorzoxazone15 (6a, a centrally acting muscle relaxant) and Chlorpropham16 (6b, an important herbicide and sprout suppressant) were easily prepared from simple and readily available aromatic azides, CO, and alcohols in 84% and 94% yields, respectively (Scheme 2). To demonstrate the applicability of this methodology to bioactive molecule or drug modification, nerol and ergosterol were chosen as the substrates, which provided gratifying results: 6c and 6d were obtained in 84% and 57% yields respectively.
(1)
3aa was obtained in 79% yield directly from the reaction of the isocyanate (7) with alcohol (eqn (1)). Further studies indicate that isocyanate, which was detected as the major product by GC-MS in the absence of a nucleophile, is involved in this process (see ESI†).
3708 | Chem. Commun., 2014, 50, 3706--3709
Scheme 2 Simple applications in drugs synthesis and bioactive compound modification: a Standard conditions: entry 10, Table 1. Isolated yields. b i-PrOH (2.0 eq.) was added. c i-PrOH (10.0 eq.) was added. d Ergosterol (0.25 eq.) was employed, and the yield was calculated based on ergosterol.
Scheme 3
The proposed mechanism.
On the basis of the above results, a plausible mechanism is illustrated in Scheme 3. Initially, a palladium nitrene species A is formed from 1a with the release of N2.17 The subsequent insertion of CO into A affords intermediate B. Then isocyanate C is afforded by the reductive elimination process of intermediate B with the regeneration of the Pd-catalyst. Finally, the nucleophilic attack of 2a on isocyanate C promoted by the Pd-catalyst as a Lewis acid (see Table S5, ESI†)18 occurs and produces the desired product carbamate 3aa. Although some traditional Pd(0) catalysts such as Pd(PPh3)4 did not work in this chemistry (see ESI†), we still do not know the exact Pd-catalyst because of the presence of the azide and CO substrates, which are the potential ligands of Pd-salts. In conclusion, a simple and practical catalytic methodology for the direct formation and application of isocyanates for the synthesis of carbamates has been developed. This chemistry provides an efficient and practical approach using readily available organoazides, CO (1 atm), and alcohols to synthesize highly valuable carbamates. Moreover, the modification of bioactive molecules and the construction of macrocycles could be easily achieved using this method. A simple and ligand-free PdCl2 salt (2 mol%) as the catalyst, ambient pressure, and neutral conditions enable this protocol to be very easily handled. Further studies on the mechanism and the application of this transformation are ongoing in our laboratory.
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Financial support from the National Science Foundation of China (No. 21325206 and 21172006), the National Young Top-notch Talent Support Program, and the PhD Programs Foundation of the Ministry of Education of China (No. 20120001110013) is greatly appreciated. We thank Xiaoyang Wang in this group for reproducing the results of 3am and 6b.
Notes and references 1 E. Delebecq, J.-P. Pascault, B. Boutevin and F. Ganachaud, Chem. Rev., 2013, 113, 80. 2 (a) P. Braunstein and D. Nobel, Chem. Rev., 1989, 89, 1927; (b) J. A. Varela ´, Chem. Rev., 2003, 103, 3787; (c) R. K. Friedman, K. M. Oberg, and C. Saa D. M. Dalton and T. Rovis, Pure Appl. Chem., 2012, 82, 1353; (d) A. D. Allen and T. T. Tidwell, Chem. Rev., 2013, 113, 7287; (e) C. Wentrup, J. J. Finnerty and R. Koch, Curr. Org. Chem., 2011, 15, 1745; ( f ) M.-W. Ding and G.-F. Yang, Trends Heterocycl. Chem., 2006, 11, 87. 3 For a review, see: Z. Wang and S. M. Cohen, Chem. Soc. Rev., 2009, 38, 1315, and references therein. 4 (a) D. Liu, K. Xia and R. Yang, Curr. Org. Chem., 2012, 16, 1838; (b) K. V. Srinivasan, P. K. Chaskar, S. N. Dighe, D. S. Rane, P. V. Khade and K. S. Jain, Heterocycles, 2011, 83, 2451; (c) T. Choshi and S. Hibino, Heterocycles, 2011, 83, 1205; (d) P. Spanu and F. Ulgheri, Curr. Org. Chem., 2008, 12, 1071; (e) J. H. Rigby, Synlett, 2000, 1; ( f ) I. Gallou, Org. Prep. Proced. Int., 2007, 39, 55. 5 For Curtius rearrangement, see: (a) J. H. Saunders and R. J. Slocombe, Chem. Rev., 1948, 43, 203; (b) J. Weinstock, J. Org. Chem., 1961, 26, 3511; (c) T. L. Capson and C. D. Poulter, Tetrahedron Lett., 1984, 25, 3515; (d) H. Lebel and O. Leogane, Org. Lett., 2006, 8, 5717. For other selected examples, see: (e) Z.-H. Guan, H. Lei, M. Chen, Z.-H. Ren, Y. Bai and Y.-Y. Wang, Adv. Synth. Catal., 2012, 354, 489; ( f ) B. Gabriele, R. Mancuso, G. Salerno and M. Costa, J. Org. Chem., 2003, 68, 601; (g) E. V. Vinogradova, N. H. Park, B. P. Fors and S. L. Buchwald, Org. Lett., 2013, 15, 1394; (h) X. Yang, Y. Zhang and D. Ma, Adv. Synth. Catal., 2012, 354, 2443; (i) C. Mollar, C. R. ´n and G. Asensio, J. Org. Chem., 2012, de Arellano, M. Medio-Simo 77, 9693; ( j) F. Ragaini, M. Gasperini, S. Cenini, L. Arnera, A. Caselli, P. Macchi and N. Casati, Chem.–Eur. J., 2009, 15, 8064; (k) D. J. Dı´az, A. K. Darko and L. McElwee-White, Eur. J. Org. Chem., 2007, 4453; (l ) Y. Zhang, M. Anderson, J. L. Weisman, M. Lu, C. J. Choy, V. A. Boyd, J. Price, M. Sigal, J. Clark, M. Connelly, F. Zhu, W. A. Guiguemde, C. Jeffries, L. Yang, A. Lemoff, A. P. Liou, T. R. Webb, J. L. DeRisi and R. K. Guy, ACS Med. Chem. Lett., 2010, 1, 460; (m) J. In, S. Hwang, C. Kim, J. H. Seo and S. Kim, Eur. J. Org. Chem., 2013, 965; (n) C. Ma, K. Jin, J. Cao, L. Zhang, X. Li and W. Xu, Bioorg. Med. Chem., 2013, 21, 1621; (o) H. Lebel and O. Leogane, Org. Lett., 2005, 7, 4107. 6 For some reviews, see: (a) D. Milstein, Acc. Chem. Res., 1988, 21, 428; (b) K. Khumtaveeporn and H. Alper, Acc. Chem. Res., 1995, 28, 414; (c) R. Skoda-Foldes and L. Kollar, Curr. Org. Chem., 2002, 6, 1097; ¨hrer, H. Neumann and M. Beller, Angew. Chem., Int. (d) A. Brennfu Ed., 2009, 48, 4114. 7 R. P. Bennett and W. B. Hardy, J. Am. Chem. Soc., 1968, 90, 3295. 8 (a) G. L. La Monica and S. Cenini, J. Organomet. Chem., 1981, 216, C35; (b) G. L. La Monica and G. Ardizzoia, J. Mol. Catal., 1986, 38, 327; (c) H. Doi, J. Barletta, M. Suzuki, R. Noyori, ¨m, Org. Biomol. Chem., 2004, 2, 3063. Y. Watanabe and B. Långstro 9 (a) N. Pendem, Y. R. Nelli, C. Douat, L. Fischer, M. Laguerre, E. Ennifar, B. Kauffmann and G. Guichard, Angew. Chem., Int. Ed., 2013, 52, 4147; (b) K. M. Patil, R. J. Naik, M. Fernandes, M. Ganguli and V. A. Kumar, J. Am. Chem. Soc., 2012, 134, 7196; (c) G. H. Jin, H. J. Lee, H. J. Gim, J.-H. Ryu and R. Jeon, Bioorg. Med. Chem. Lett.,
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2012, 22, 3301; (d) A. L. Wolfe, K. K. Duncan, N. K. Parelkar, S. J. Weir, G. A. Vielhauer and D. L. Boger, J. Med. Chem., 2012, 55, 5878; (e) R. C. Gupta, Toxicology of Organophosphate & Carbamate Compounds, Academic, St Louis, 1st edn, 2005; ( f ) C. Timchalk, Biomonitoring of Pesticides: Pharmacokinetics of Organophosphorus and Carbamate Insecticides, in Anticholinesterase Pesticides: Metabolism, Neurotoxicity, and Epidemiology, ed. T. Satoh and R. C. Gupta, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2011, and references therein. (a) S. A. Mahler and R. M. Borland, Am. J. Cardiol., 1990, 65, 11D; (b) H. J. Mann, Clin. Pharmacol., 1990, 9, 842; (c) A. Fitton and M. T. Buckley, Drugs, 1990, 40, 138; (d) L. D. Anna, M. M. John and E. T. James, Drugs, 2008, 68, 607. (a) E. S. Carl, G. Seden and K. Peter, Nature Rev. Drug Discovery, 2011, 10, 729; (b) J. G. Martin, H. L. Charles and S. Raman, Epilepsia, 2012, 53, 412; (c) D. Tikoo and M. Gupta, Int. J. Pharmacol. Clin. Sci., 2012, 1, 85; (d) R. Konrad, J. L. Jarogniew, B. Barbara, C. Roman and J. C. Stanislaw, Ther. Clin. Risk Manage., 2012, 8, 7. (a) J. C. Adkins and R. N. Brogden, Drugs, 1998, 55, 121; (b) C. J. Dunn and K. L. Goa, Drugs, 2001, 61, 285; (c) S. D. Anderson, Treat. Respir. Med., 2004, 3, 365; (d) C. M. Bonuccelli, Clin. Exp. Allergy Rev., 2001, 1, 274. (a) F. Claude and J. Veronique, Expert Rev. Anti-Infect. Ther., 2004, 2, 671; (b) Y. R. Natella, Expert Opin. Drug Metab. Toxicol., 2010, 6, 95; (c) S. M. Clarke and F. M. Mulcahy, HIV Med., 2000, 1, 15; (d) E. Martı´nez, M. A. Garcı´a-Viejo, J. L. Blanco, L. Bianchi, E. Buira, I. Conget, R. Casamitjana, J. Mallolas and J. M. Gatell, Clin. Infect. Dis., 2000, 31, 1266. J. E. Leffler and R. D. Temple, J. Am. Chem. Soc., 1967, 89, 5235. (a) A. A. Izzo and E. Ernst, Drugs, 2009, 69, 1777; (b) D. F. Marsh and L. Hill, US Pat., 2890985, 1959. ¨ zhan, S. O ¨ zden and B. Alpertunga, J. Environ. Sci. Health, (a) G. O Part B, 2005, 40, 827; (b) C. Lentza-Rizos and A. Balokas, J. Agric. Food Chem., 2001, 49, 710. Metal-nitrene can be generated from orginic azides with Mn, Fe, Ni, Zr, Ta, Ru, Rh, Ir, but Pd-nitrene has not been reported. For metal nitrene, see: (a) P. Mueller, C. Baud and I. Naegeli, J. Phys. Org. Chem., 1998, 11, 597; (b) M. M. Abu-Omar, C. E. Shields, N. Y. Edwards and R. A. Eikey, Angew. Chem., Int. Ed., 2005, 44, 6203; (c) H. M. L. Davies and M. S. Long, Angew. Chem., Int. ¨ller and J. C. Peters, Ed., 2005, 44, 3518; (d) N. P. Mankad, P. Mu J. Am. Chem. Soc., 2010, 132, 4083; (e) A. I. Nguyen, R. A. Zarkesh, D. C. Lacy, M. K. Thorson and A. F. Heyduk, Chem. Sci., 2011, 2, 166; ( f ) A. F. Heyduk, R. A. Zarkesh and A. I. Nguyen, Inorg. Chem., 2011, 50, 9849; ( g) S. Wiese, M. J. B. Aguila, E. Kogut and T. H. Warren, Organometallics, 2013, 32, 2300; (h) Q. Zhang, C. Wu, L. Zhou and J. Li, Organometallics, 2013, 32, 415; (i) R. E. Cowley, N. A. Eckert, J. Elhaık and P. L. Holland, Chem. Commun., 2009, 1760. For some reviews, see: ( j) T. G. Driver, Org. Biomol. Chem., 2010, 8, 3831; (k) J. F. Berry, Dalton Trans., 2012, 41, 700, For metal carbene, see: (l ) Z. Qu, W. Shi and J. Wang, J. Org. Chem., 2001, 66, 8139; (m) C. Peng, Y. Wang and J. Wang, J. Am. Chem. Soc., 2008, 130, 1566; (n) F. Ye, X. Ma, Q. Xiao, H. Li, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2012, 134, 5742, For some reviews, see: ´s, Angew. Chem., Int. Ed., 2011, (o) J. Barluenga and C. Valde 50, 7486; (p) Z. Shao and H. Zhang, Chem. Soc. Rev., 2012, 41, 560; (q) Y. Zhang and J. Wang, Eur. J. Org. Chem., 2011, 1015; (r) Q. Xiao, Y. Zhang and J. Wang, Acc. Chem. Res., 2013, 46, 236. (a) Z. Zhang, Y. Liu, L. Ling, Y. Li, Y. Dong, M. Gong, X. Zhao, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2011, 133, 4330, For review, see: (b) Z. Zhang, Y. Zhang and J. Wang, ACS Catal., 2011, 1, 1621; (c) N. Asao, T. Nogami, K. Takahashi and Y. Yammamoto, J. Am. Chem. Soc., 2002, 124, 764; (d) Y. Xiao and J. Zhang, Angew. Chem., Int. Ed., 2008, 47, 1903.
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Cite this: Chem. Commun., 2014, 50, 3706
PdCl2 catalyzed efficient assembly of organic azides, CO, and alcohols under mild conditions: a direct approach to synthesize carbamates†
Received 21st January 2014, Accepted 11th February 2014
Long Rena and Ning Jiao*ab
DOI: 10.1039/c4cc00538d www.rsc.org/chemcomm
A simple and readily available PdCl2 catalyzed carbamate synthesis method via isocyanate generation and application in situ has been developed. This chemistry provides an efficient and practical approach to synthesize carbamates from simple organic azides, CO atmosphere and alcohols. The broad scope, mild and neutral conditions, and only N2 as the byproduct make this transformation very useful. Moreover, simple examples of modification of bioactive molecules and construction of macrocycles were achieved through this protocol.
Since 1848, when the isocyanate was discovered by Wurtz,1 diverse transformations with nucleophiles, other cumulenes and metal reagents have been widely used in synthetic chemistry,1,2 materials chemistry,1,3 and biological research,4 due to the importance and high reactivity of these kinds of compounds. However, the preparation and application of isocyanates were tedious with a relatively rigorous catalytic system, substrate restriction, unavoidable formation of 1,3-diarylurea as the sole product, or employment of expensive and environmentally unfriendly reagents.5 By employing simple and readily available CO6 and aromatic azides, Bennett et al. first reported the direct synthesis of free isocyanates under harsh conditions (a, Scheme 1).7 However, the application of this strategy has been impeded by the limited scope, the efficiency, under a high CO
Scheme 1
pressure, as well as the expensive catalyst and ligand loading.8 Therefore, it is very desirable to develop an efficient strategy to generate and utilize isocyanates under mild conditions. Herein, we report a practical PdCl2 catalyzed efficient assembly of organic azides, CO, and alcohols for the direct synthesis of carbamates via isocyanate generation and application in situ (b, Scheme 1). The significance of the present finding is fourfold: (1) this chemistry provides an efficient and practical approach to synthesize carbamates, which play very important and also ubiquitous roles in pharmaceutical, agrochemical and material terrains.9 For example, large numbers of molecules with carbamate motifs have been found to possess various bioactive potentials and have been developed into marketed drugs that treat arrhythmias (I, Fig. 1),10 seizures (II),11 asthma (III),12 and AIDS (IV).13 (2) The broad scope, mild and neutral conditions, and only N2 as the byproduct make this transformation very useful. This protocol could also be applied in the modification of bioactive compounds and drugs. (3) This method with CO atmosphere enables this reaction to be very easily handled. (4) A simple and readily available PdCl2 salt (2 mol%) in the absence of any ligand has emerged as an inexpensive and efficient catalyst. The examination of the reaction conditions commenced with the reaction of 1-azido-4-methoxybenzene (1a) and 2-phenylethanol (2a) under 1 atm of CO as the model reaction. To start with
Direct carbonylation of organic azides.
a
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, People’s Republic of China. E-mail: [email protected]; Fax: +86-010-8280-5297; Tel: +86-010-8280-5297 b State Key Laboratory of Elemento-organic Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc00538d
3706 | Chem. Commun., 2014, 50, 3706--3709
Fig. 1
Examples of marketed carbamate drugs.
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Table 1
Examination of reaction conditionsa
Entry
Catalyst
Solvent
Temperature (1C)
Yieldb (%)
1 2c 3 4 5 6 7 8d 9d 10d,e 11d,e 12d–f
5 mol% PdCl2 5 mol% PdCl2 5 mol% Pd(OAc)2 5 mol% PdCl2 5 mol% PdCl2 5 mol% PdCl2 1 mol% PdCl2 1 mol% PdCl2 2 mol% PdCl2 2 mol% PdCl2 No catalyst 2 mol% PdCl2
DMF DMF DMF NMP DMA DMA DMA DMA DMA DMA DMA DMA
80 80 80 70 70 90 70 70 70 70 70 70
52 35 o10 61 90 73 82 76 91 89 0 0
Table 2
The reaction scope of alcoholsa
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol, 1.5 eq.), TEA = triethylamine (0.6 mmol), solvent (2 mL), 24 h with a CO balloon. b Isolated yields. c PPh3 (20 mol%) was added. d 1.2 eq. of 2a was employed in DMA 0.2 M. e Without TEA. f The reaction was carried out under Ar without CO.
searching for a suitable catalyst that could enable this strategy, a series of metal complexes have been tested (see ESI†). Gratifyingly, a moderate yield of the anticipated product phenethyl 4-methoxyphenylcarbamate (3aa) was obtained when 5 mol% of PdCl2 was employed as the catalyst (Table 1, entry 1). The efficiency of a similar reaction decreased in the presence of 20 mol% of PPh3 as the ligand (17%, entry 2). This might be attributed to the occurrence of Staudinger reaction.14 Some other palladium catalysts were then examined, but no better yield was achieved (entry 3, and see the ESI†). Strong polar solvents were found to play a vital role in this reaction producing 3aa in over 40% yields, while no or only a trace of product was detected by using non- or weakly polar solvents (see ESI†). 90% yield was achieved when the reaction was carried out in DMA (dimethylacetamide) at 70 1C (entry 5). There was only a minor decline in yields employing 1 mol% and even 1.2 eq. of 2a (entries 7 and 8). Finally, the standard conditions were simplified to the 2 mol% catalyst in the absence of any base, which produced the desired carbamate product 3aa in 89% yield (entry 10). It is noteworthy that the reaction in the absence of a Pd-catalyst or CO did not work (entries 11 and 12). With the optimized reaction conditions in hand, the scope of alcohols was first explored (Table 2). High yields were obtained with linear alcohols including methanol (3ab), which has a low boiling point relative to the reaction temperature. Moreover, the secondary alcohols also performed well in this transformation leading to the corresponding carbamates in moderate yields (3af–3ai, and 3as). When tertiary alcohols served as the nucleophiles in the reactions, the steric effects decreased the efficiency and afforded the carbamate products in low yields (3aj–3ak). The scope was greatly enlarged by benzyl and allylic alcohols, alcohols containing various terminal alkenyl and alkynyl groups, as well as alcohols with different heterocycles, which underwent a smooth reaction to give desired products in moderate to good yields (3al–3aw). We next investigated the substrate scope of organic azides (Table 3). Aryl azides generally substituted by electron donating
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a
Reactions were carried out under standard conditions: entry 10, Table 1. Isolated yields.
Table 3
The reaction scope of organic azidesa
a Standard conditions: entry 10, Table 1. Isolated yields. was carried out at 90 1C.
b
The reaction
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Table 4
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Investigation of intramolecular reactionsa
a Standard conditions: entry 10, Table 1. Isolated yields. was carried out with PdCl2 (5 mol%) in DMA (6 mL).
b
The reaction
groups produced 3ba, 3ha, and 3ma in about 80% yields, while those substituted by electron-withdrawing groups produced 3ca, 3ga, and 3la in over 90% yields. Interestingly, iodo, nitro or even exposed hydroxyl substituents are tolerated in this transformation leading to the corresponding functionalized carbamates in moderate to good yields (3da, 3ha–3ia, 3la). Moreover, heterocyclic aromatic azides performed well under the standard conditions (3ja and 3ma). It is noteworthy that the alkenyl azide reacted as perfectly as the aryl azide (3ea, 87% yield). Some alkyl azides are also tolerated in this transformation although with low yields (3na and 3oa), which may be due to the low stability of a metal nitrene intermediate without conjugation by an unsaturated bond. With these delightful results above, investigation of intramolecular reactions was taken into account (Table 4). Although phenols were not effective for intermolecular transformation (see ESI†), the intramolecular reaction with the phenol nucleophile worked well and delivered the anticipated product (5a) in 81% yield. In addition, the intramolecular reaction of (2-azidophenyl)methanol (4b) was executed well and afforded the ring closed product 5b in a high yield of up to 99%, which diverted our interest to the synthesis of macrocyclic compounds. Interestingly, 12- and 17-membered rings can also be prepared by this protocol in moderate yields (5c and 5d). Furthermore, by utilizing this protocol, the marketed drugs Chlorzoxazone15 (6a, a centrally acting muscle relaxant) and Chlorpropham16 (6b, an important herbicide and sprout suppressant) were easily prepared from simple and readily available aromatic azides, CO, and alcohols in 84% and 94% yields, respectively (Scheme 2). To demonstrate the applicability of this methodology to bioactive molecule or drug modification, nerol and ergosterol were chosen as the substrates, which provided gratifying results: 6c and 6d were obtained in 84% and 57% yields respectively.
(1)
3aa was obtained in 79% yield directly from the reaction of the isocyanate (7) with alcohol (eqn (1)). Further studies indicate that isocyanate, which was detected as the major product by GC-MS in the absence of a nucleophile, is involved in this process (see ESI†).
3708 | Chem. Commun., 2014, 50, 3706--3709
Scheme 2 Simple applications in drugs synthesis and bioactive compound modification: a Standard conditions: entry 10, Table 1. Isolated yields. b i-PrOH (2.0 eq.) was added. c i-PrOH (10.0 eq.) was added. d Ergosterol (0.25 eq.) was employed, and the yield was calculated based on ergosterol.
Scheme 3
The proposed mechanism.
On the basis of the above results, a plausible mechanism is illustrated in Scheme 3. Initially, a palladium nitrene species A is formed from 1a with the release of N2.17 The subsequent insertion of CO into A affords intermediate B. Then isocyanate C is afforded by the reductive elimination process of intermediate B with the regeneration of the Pd-catalyst. Finally, the nucleophilic attack of 2a on isocyanate C promoted by the Pd-catalyst as a Lewis acid (see Table S5, ESI†)18 occurs and produces the desired product carbamate 3aa. Although some traditional Pd(0) catalysts such as Pd(PPh3)4 did not work in this chemistry (see ESI†), we still do not know the exact Pd-catalyst because of the presence of the azide and CO substrates, which are the potential ligands of Pd-salts. In conclusion, a simple and practical catalytic methodology for the direct formation and application of isocyanates for the synthesis of carbamates has been developed. This chemistry provides an efficient and practical approach using readily available organoazides, CO (1 atm), and alcohols to synthesize highly valuable carbamates. Moreover, the modification of bioactive molecules and the construction of macrocycles could be easily achieved using this method. A simple and ligand-free PdCl2 salt (2 mol%) as the catalyst, ambient pressure, and neutral conditions enable this protocol to be very easily handled. Further studies on the mechanism and the application of this transformation are ongoing in our laboratory.
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Financial support from the National Science Foundation of China (No. 21325206 and 21172006), the National Young Top-notch Talent Support Program, and the PhD Programs Foundation of the Ministry of Education of China (No. 20120001110013) is greatly appreciated. We thank Xiaoyang Wang in this group for reproducing the results of 3am and 6b.
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