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An efficient method for the synthesis of substituted 5-aminotetrazoles from selenoureas using PhI(OAc)2
Accepted Manuscript An efficient method for the synthesis of substituted 5-aminotetrazoles from selenoureas using PhI(OAc)2 Yuanyuan Xie, Dongyan Guo, Xiaoying Jiang, Haixuan Pan, Wenhui Wang, Tingting Jin, Zhisheng Mi PII: DOI: Reference:
S0040-4039(15)00598-5 http://dx.doi.org/10.1016/j.tetlet.2015.03.128 TETL 46131
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
16 February 2015 24 March 2015 30 March 2015
Please cite this article as: Xie, Y., Guo, D., Jiang, X., Pan, H., Wang, W., Jin, T., Mi, Z., An efficient method for the synthesis of substituted 5-aminotetrazoles from selenoureas using PhI(OAc)2, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.03.128
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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An efficient method for the synthesis of substituted 5-aminotetrazoles from selenoureas using PhI(OAc)2
Yuanyuan Xie∗ , Dongyan Guo, Xiaoying Jiang, Haixuan Pan, Wenhui Wang, Tingting Jin, Zhisheng Mi
Leave this area blank for abstract info.
1
Tetrahedron Letters j o ur n al h om e p a g e : w w w . e l s e v i er . c o m
An efficient method for the synthesis of substituted 5-aminotetrazoles from 5 selenoureas using PhI(OAc)2 4
Yuanyuan Xiea,b,∗ Dongyan Guob, Xiaoying Jianga, Haixuan Panc, Wenhui Wangb, Tingting Jinb, Zhisheng b 7 Mi 6
8 a Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R. China 9 b College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P.R. China 10 c Zhengjiang Jingxin Pharmaceutical Co., LTD. Shaoxing, P.R. China 11
A R T IC LE IN F O
A B S TR A C T
Article history: Received Received in revised form Accepted Available online
An efficient method to access 5-aminotetrazoles starting from readily accessible 1,3-disubtituted selenoureas has been discovered. This is the first example of the synthesis of 5-aminot etrazoles involving the use of diacetoxyiodobenzene (DIB). The reaction is in line with the requirements of green chemistry by virtue of mild conditions, environmental benign, short reaction time and good selectivity. 2009 Elsevier Ltd. All rights reserved.
Keywords: Selenourea Sodium azide Diacetoxyiodobenzene 5-Aminotetrazoles Electrocyclization
12 Introduction 13 14 15 16 17 18 19 20 21 22 23 24
Tetrazoles are a representative class of heterocyclic compound with high nitrogen content and good stability. They are considered as bioisosteres of cis amides and carboxylic acids in medicinal chemistry with higher liphophilicity.1 Although tetrazoles and their derivatives rarely occur in nature,2 the vast majority of all show the biological activity. 3 Among them, 5aminotetrazoles (Figure 1) show anti-allergic and antiasthmatic,4 antiviral and anti-inflammatory, 5 antineoplastic,6 and cognition disorder activities.7 Related compounds such as 3'-(5-amino-1,2,3,4-tetrazol-1-yl)-3'-deoxythymidines and its derivatives were developed as anti-HIV drug (Figure 1) by Bayer. 8
25 26 27 28 29 30 31 32 33 34 35 36 37 38
Some methods are available to synthesize 5-aminotetrazoles. In 1922, Stollé9 described a method to synthesize l-phenyl-5anilinotetrazole employing diphenylcarbodiimide with sodium azide in dry ethanol for 5h. In 1979, Svĕtlík10 et al studied the way to access 1,5-disubstituted tetrazoles, in which freshly prepared carbodiimide in benzene was chosen as a starting material, a solution of azoimide was added and the resulting mixture was allowed to stir at room temperature, with the reaction time being 1 to 12 hours according to different substrates. In 2000, Batey and Powell11 reported the mercury(II)-promoted attack of azide anion on a thiourea to synthesize 5aminotetrazoles. Additionally, trimethylsilyl azide (TMSA)12 is also a good reagent in the synthesis of aminotetrazole. TMSA was added to isolated cyanamide or carbodiimide and after a ———
39 few steps aminotetrazole was obtained. These methods require 40 harsh reaction conditions, toxic reagents, and long reaction 41 time. 42 43 44 45 46 47 48 49 50
In the past few years, hypervalent iodine reagents have emerged as versatile reagents for organic transformations. According to recent literature, hypervalent iodine reagents have been used for desulfurization purposes and synthesis of 5aminotetrazoles.13 However, the deselenization ability of diacetoxyiodobenzene (DIB), in particular, has been rarely explored. Thus we envisaged that selenoureas could serve as versatile intermediates for the synthesis of substituted 5aminotetrazoles promoted by DIB.
51 Figure 1. Structure of 5-aminotetrazoles and related com52 pounds
53
∗ Corresponding author. Tel.& fax: +86-571-8832-0878; E-mail: [email protected]
2 54 Results and discussion 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 89
Tetrahedron Letters 72 was not improved (Table 1, entry 11). Furthermore, we in73 creased the dosage of PhI(OAc)2, as we expected, the more NTo initiate the study, 1,3-diphenylselenourea was chosen as 74 acetylated byproduct 3a was produced (Table 1, entry 12). a model substrate to optimize the reaction conditions. The 75 Other trial such as increasing temperature to 50°C was useless screening of different parameters was summarized in Table 1. 76 for the yield of 2a (Table 1, entry 13). To achieve better selecWe examined various solvents such as DMF, CH3CN, THF, 77 tivity of the reaction, bases were added to neutralize HOAc. DMSO, toluene, dioxane and acetone (Table 1, entries 1-7), 78 NaOH was proved to be superior to NaH, Na2CO3, NaHCO3 and DMF was found to be the best choice for this transfor79 and Et3N (Table 1, entries 14–18). In order to improve the solmation. The conversion rate of 1a was 100%. But only 50% of 80 ubility of NaOH and NaN3, water was added to the reaction the desired product 2a was obtained and the remaining 45% is 81 mixture (Table 1, entry 19). Surprisingly, the N-acetylated the N-acetylated byproduct 3a. Besides, a trace amount (≤5%) 82 byproduct 3a was not observed when inorganic base NaOH (2 of unidentified impurity existed. For this reason, we reduced 83 equiv.) and water (0.5mL) were used.
the reaction time and found that the required product 2a could 84 The effort of reaction optimization revealed that the best be obtained in 10 minutes (Table 1, entry 8). Then the quanti85 conditions for the conversion of 1,3-diphenylselenourea ties of NaN3 and PhI(OAc)2 were also studied. It is noteworthy 86 (0.5mmol) into diphenyl-5-aminotetrazole is PhI(OAc)2 that the yield of diphenyl-5-aminotetrazole (Table 1, entries 887 (0.5mmol), NaN3 (1.5mmol), and NaOH pellets (1mmol), wa11) markedly increased with the increase of NaN3 and the yield 88 ter (0.5 mL) in DMF(5mL) at room temperature for 10 minutes. of 2a reached 90% when 3 equivalent of NaN3 was used. With further increase of NaN3 quantity (4 equiv.), the yield of 2a Table 1. Optimization for the conversion of 1,3-diphenylselenourea into diphenyl-5-aminotetrazole
90 NaN3
PhI(OAc)2
Water
(equiv.)
(equiv.)
(mL)
1 2 3
1 1 1
1 1 1
----
4
1
1
--
Toluene
rt
60
--
0:100
50
5
1
1
--
Acetone
rt
60
--
0:100
30
6 7 8
1 1 1
1 1 1
----
Dioxane DMF DMF
rt rt rt
60 60 10
----
0:100 50:45 52:48
30 b 100 100
9 10
2 3
1 1
---
DMF DMF
rt rt
10 10
---
60:40 90:10
100 100
11 12 13
4 3 3
1 1.2 1
----
DMF DMF DMF
rt rt 50
10 10 10
----
90:10 80:20 76:24
100 100 100
14 15 16
3 3 3
1 1 1
----
DMF DMF DMF
rt rt rt
10 10 10
NaH (2) NaOH (2) Na2 CO3 (1)
80:20 92:8 85:15
100 100 100
17 18
3 3
1 1
---
DMF DMF
rt rt
10 10
NaHCO3 (2) Et 3N (2)
60:40 75:25
100 100
19
3
1
0.5
DMF
rt
10
NaOH (2)
100:0
100
Entry
Solvent MeCN THF DMSO
Temp
Time
Base
(oC)
(min)
(equiv.)
rt rt rt
60 60 60
----
Tetrazole(2a):N-aceylurea(3a)
Convert ratio(%)a
0:100 0:100 0:100
10 15 10
91 a Conversion (%) of 1,3-diphenylselenourea (1a) b 5% Unknown impurity 92 93 94 95 96 97 98 99 100 101
Subsequently, various 1,3-disubstituted selenoureas (1) were investigated under the optimized conditions to study the scope of the system (Table 2). Symmetrical selenoureas bearing electron-donating substituents viz. o-Et (1b), m-Me (1c), p-Me (1d), p-OMe (1e), 2,4,6-tri-Me (1f) were very fast to give the corresponding 5-aminotetrazoles (2b-f) in good to excellent yields. However, the electron-withdrawing ones viz. p-F (1g) and p-Cl (1h) provided the corresponding 5-aminotetrazoles in modest yields. Also aliphatic selenoureas (1i) afforded good yield of aminotriazoles (2i).
102 After successfully synthesized various symmetrical 5103 aminotetrazoles, we focused our attention on the regioselective 104 electrocyclization of unsymmetrical selenoureas. Our earlier
105 106 107 108 109 110 111 112 113 114 115 116 117
report14 on regioselective N-acylation of unsymmetrical 1,3disubstituted selenoureas disclosed that the difference of pKa between the precursor amines has important influence on the regioselectivity of N-acetylation. We reasoned that, similarly, unsymmetrical 1,3-disubstituted selenoureas generated regioselectively 5-aminotetrazoles (2j-2l, 2n) due to the difference in the pKa values of the precursor amines attached to the selenoureas. To our great delight they all obtained single product. This has been confirmed by 2D NMR i.e. homonuclear correlation spectroscopy (H, H COSY). For example, we observed that the CNH proton (δ 4.53ppm) shows correlation with the CHN proton (δ3.43ppm) in 5-aminotetrazole 2j. But the pKa of p-methylaniline is similar to aniline, selenoureas
3 118 (1m) obtained a mixture of aminotetrazoles (2m) and (2m'). 119 This result can be explained by the reaction mechanism. 120 Table 2. Synthesis of 5-aminotetrazoles from 1,3-disubstituted selenoureas
R1
H N
H N Se
Entry
123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151
R1
NaN3 /PhI(OAc)2
R1
N N N N R2 2a-2o
2 + R
N H
DMF/NaOH/H2O
1a-1o
121
122
R2
R2
Product
N N N N N H R1 2a'-2o'
a
Time
Yield
(min)
(%)
1
Ph
Ph
2a
10
95
2
o-EtC6H4
o-EtC6 H4
2b
10
92
3
m-MeC6 H4
m-MeC6H4
2c
10
89
4
p-MeC6 H4
p-MeC6 H4
2d
10
87
5
p-OMeC6H4
p-OMeC6H4
2e
10
87
6
2,4,6-triMeC6H2
2,4,6-triMeC6H2
2f
10
82
b
7
p-FC6 H4
p-FC6H4
2g
20
69
8
p-ClC6H4
p-ClC6 H4
2h
20
65
9
Benzyl
Benzyl
2i
15
85
10
n-Butyl
Ph
2j
15
90
11
cyclohexyl
Ph
2k
15
92
12
Ph
1-naphthyl
2l
10
85
13
p-MeC6 H4
Ph
2m:2m'
10
86(75:25)c
14
H
Ph
2n
15
71
a
Confirmed by IR and 1H and 13 C NMR. b Isolated yield based on 1. c Ratio of regioisomers determined by 1H NMR
The proposed mechanism for the formation of diphenyl-5aminotetrazole and N-acetylated byproduct is shown in Scheme 1. The precipitation of selenium power further supports the mechanism. The selenium atom of 1,3-disubstituted selenourea 1a attacks the iodine atom of DIB in place of one of the AcO− giving intermediate 6. The deselenization of DIBactivated selenourea generates an intermediate carbodiimide (7). The attack of azide ion (N3-) on carbodiimide generates guanyl azide (8), which subsequently affords the 5aminotetrazole 2 via electrocyclization. The attack of azide ion (N3-) on unsymmetrical carbodiimide would lead to the protonation toward the amine having higher pKa. The measured pKa values of both n-butylamine (pKa=10.77) and cyclohexylamine (pKa=10.66) are higher than aniline (pKa=4.61), 2j and 2k are the major product in excellent yields because the protonation toward n-butyl- and cyclohexyl-side in substrates 1j and 1k were preference. The pKa of naphthylamine (4.21) and p-methylaniline (5.04) are similar to aniline (4.61), but the 2l was the exclusive regioselective product mainly due to the steric factor of naphthyl group. Unsymmetrical selenoureas (1m) reacted with sodium azide and DIB, obtaining a mixture of aminotetrazoles (2m) and (2m') in the ratio of 75:25. Additionally, 1-phenyl-5-aminotetrazole from the terminal phenylselenourea 1n was obtained 2n in good yield. Inorganic acid scavenger viz. NaOH introduced in the system decreased the concentration of AcOH and increased the opportunity of attacking carbodiimide by azide ion (N3-), generating the regioselective 5-aminotetrazole (2a). Thus, the formation of N-acetylated byproduct 3a was significantly avoided.
152 Scheme1. The proposed mechanism for the formation of 153 diphenyl-5-aminotetrazole and N-acetylated byproduct
154 155 156 157 158 159 160 161 162
In conclusion, we have developed an efficient system of PhI(OAc)2 and NaN3 for the synthesis of symmetrical and unsymmetrical 5-aminotetrazoles starting from the corresponding 1,3-disubstituted selenoureas. This novel reaction possesses the advantages of metal-free conditions, short reaction time, good selectivity, and environmental acceptability. The results of experiment suggest that the reaction has general applicability for the substrates.
4 163 Acknowkedgment
Tetrahedron Letters
164 We are grateful to the Qianjiang Talent Project of Scicence 165 Technology Deparment of Zhejiang Province (No.2013R10059) 166 for financial support. We also thank Prof. Tao Zhou and Prof. 167 Weihui Zhong for helpful discussions. 168 References and notes 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235
1.
2.
3. 4.
5.
6.
7. 8.
9. 10. 11. 12.
13. 14. 15.
(a) Roh, J.; Vávrová, K.; Hrabálek, A. Eur. J. Org. Chem. 2012, 31, 6101–6118; (b) Biot, C.; Bauer, H.; Schirmer, R. H.; Davioud-Charvet, E. J. Med. Chem. 2004, 47, 5972-5983; (c) Yella, R.; Khatun, N.; Rout, S. K. and Patel, B. K. Org. Biomol. Chem. 2011, 9, 3235–3245. (a) Sathishkumar, M.; Shanmugavelan, P.; Nagarajan, S.; Dinesh , M.; Ponnuswamy, A. New J. Chem. 2013, 37, 488-493; (b) Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem. Heterocycl. Compd. 2007, 43, 1-9. Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26, 499-531. (a) Toney, J. H.; Fitzgerald, P. M. D.; Grover-Sharma, N.; Olson, S. H.; May, W. J.; Sundelof, J. G.; Vanderwall, D. E.; Cleary, K. A.; Grant, S. K.; Wu, J. K.; Kozarich, J. W.; Pompliano, D. L.; Hammond, G. G. Chem. Biol. 1998, 5, 185196; (b) Ford, R. E.; Knowles, P.; Lunt, E.; Marshall, S. M.; Penrose, A. J.; Ramsden, C. A.; Summers, A. J. H.; Walker, J. L.; Wright, D. E. J. Med. Chem. 1986, 29, 538-549. (c) Peet, N. P.; Baugh, L. E.; Sundler, S.; Lewis, J. E.; Matthews, E. H.; Olberding, E. L.; Shah, D. N. J. Med. Chem. 1986, 29, 24032409. (a) Poonian, M. S.; Nowoswiat, E. F.; Blount, J. F.; Kramer, M. J. J. Med. Chem. 1976, 19, 1017-1020; (b) De Clercq, E. J. Clin. Virol. 2004, 30, 115-133; (c) Navidpour, L.; Shadnia, H.; Shafaroodi, H.; Amini, M.; Dehpour, A. R.; Shafiee, A. Bioorg. Med. Chem. 2007, 15. 1976-1982; (d) Lebouvier, N.; Giraud, F.; Corbin, T.; Na, Y. M.; Le Baut, G.; Marchand, P.; Le Borgne, M. Tetrahedron Lett. 2006, 47, 6479-6483. (a) Akimoto, H.; Ootsu, K.; Itoh, F. Eur. Patent EP 530537, 1993; (b) Taveras, A. G.; Mallams, A. K.; Afonso, A. Int. Patent WO 9811093, 1998. Mitch, C. H.; Quimby, S. J. Int. Patent WO 9851312, 1998. (a) Habich, D. Synthesis, 1992, 4, 358-360; (b) Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem. Hetero. Com. 2007, 43, 1-9. Stollé, R. Chem. Ber. 1922, 55, 1289-1297. Svĕtlík, J.; Martvonň, A. and Leško, J. Chem. zvesti. 1979, 33, 4, 521-527. Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237-3240. (a) Tsuge, Y.; Satoshi, O. U. and Oe, K. J. Org. Chem. 1980, 45, 5130-5136. (b) Nishiyama, K.; Watanabe, A. Chem. Lett. 1984, 13, 455-458; (c) Nishiyama, K.; Oba, M.; Watanabe, A. Tetrahedron, 1987, 43, 693-700. Chaudhari, P. S.; Pathare, S. P.; Akamanchi, K. G. J. Org. Chem. 2012, 77, 3716−3723. Xie, Y. Y.; Pan, H. X. Phosphorus, Sulfur, and Silicon, 2014, 189, 98–105. General experimental procedure to synthesize 5-aminotetrazoles: A mixture of 1,3-diphenylselenourea (0.5 mmol), iodobenzene diacetate (0.5 mmol) and NaN3 (1.5 mmol) in DMF(5mL) followed by the addition of NaOH (1 mmol) and H2 O (0.5mL), then stirred at room temperature for 10 min. The progress of the reaction was monitored by TLC. Precipitation of selenium powder was observed during this period. After completion, the reaction mixture was filtered. The filtrate was poured into a saturated NaCl solution (50 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and evaporated to afford the crude product, which was purified by flash chromatography on silica gel using hexane/EtOAc 4:1 as eluent. N,1-Diphenyl-1H-tetrazol-5-amine 2a: white solid, mp 158-160 °C (Lit.9 158-159 °C); IR (KBr) ν max 3433, 1612, 1571, 1496, 1454, 1090, 746cm-1 ; 1 H NMR (400 MHz, CDCl 3) δ 7.64-7.58 (m, 3H), 7.53-7.51 (m, 4H), 7.33 (t, J = 7.6Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.42 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 151.5, 138.0, 132.7, 130.4, 130.3, 129.2, 124.7, 123.4, 118.2; ESI-MS m/z calc. 237.10, found 260.4 (M+Na)+.
S0040-4039(15)00598-5 http://dx.doi.org/10.1016/j.tetlet.2015.03.128 TETL 46131
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
16 February 2015 24 March 2015 30 March 2015
Please cite this article as: Xie, Y., Guo, D., Jiang, X., Pan, H., Wang, W., Jin, T., Mi, Z., An efficient method for the synthesis of substituted 5-aminotetrazoles from selenoureas using PhI(OAc)2, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.03.128
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 2 3
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
An efficient method for the synthesis of substituted 5-aminotetrazoles from selenoureas using PhI(OAc)2
Yuanyuan Xie∗ , Dongyan Guo, Xiaoying Jiang, Haixuan Pan, Wenhui Wang, Tingting Jin, Zhisheng Mi
Leave this area blank for abstract info.
1
Tetrahedron Letters j o ur n al h om e p a g e : w w w . e l s e v i er . c o m
An efficient method for the synthesis of substituted 5-aminotetrazoles from 5 selenoureas using PhI(OAc)2 4
Yuanyuan Xiea,b,∗ Dongyan Guob, Xiaoying Jianga, Haixuan Panc, Wenhui Wangb, Tingting Jinb, Zhisheng b 7 Mi 6
8 a Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, P.R. China 9 b College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P.R. China 10 c Zhengjiang Jingxin Pharmaceutical Co., LTD. Shaoxing, P.R. China 11
A R T IC LE IN F O
A B S TR A C T
Article history: Received Received in revised form Accepted Available online
An efficient method to access 5-aminotetrazoles starting from readily accessible 1,3-disubtituted selenoureas has been discovered. This is the first example of the synthesis of 5-aminot etrazoles involving the use of diacetoxyiodobenzene (DIB). The reaction is in line with the requirements of green chemistry by virtue of mild conditions, environmental benign, short reaction time and good selectivity. 2009 Elsevier Ltd. All rights reserved.
Keywords: Selenourea Sodium azide Diacetoxyiodobenzene 5-Aminotetrazoles Electrocyclization
12 Introduction 13 14 15 16 17 18 19 20 21 22 23 24
Tetrazoles are a representative class of heterocyclic compound with high nitrogen content and good stability. They are considered as bioisosteres of cis amides and carboxylic acids in medicinal chemistry with higher liphophilicity.1 Although tetrazoles and their derivatives rarely occur in nature,2 the vast majority of all show the biological activity. 3 Among them, 5aminotetrazoles (Figure 1) show anti-allergic and antiasthmatic,4 antiviral and anti-inflammatory, 5 antineoplastic,6 and cognition disorder activities.7 Related compounds such as 3'-(5-amino-1,2,3,4-tetrazol-1-yl)-3'-deoxythymidines and its derivatives were developed as anti-HIV drug (Figure 1) by Bayer. 8
25 26 27 28 29 30 31 32 33 34 35 36 37 38
Some methods are available to synthesize 5-aminotetrazoles. In 1922, Stollé9 described a method to synthesize l-phenyl-5anilinotetrazole employing diphenylcarbodiimide with sodium azide in dry ethanol for 5h. In 1979, Svĕtlík10 et al studied the way to access 1,5-disubstituted tetrazoles, in which freshly prepared carbodiimide in benzene was chosen as a starting material, a solution of azoimide was added and the resulting mixture was allowed to stir at room temperature, with the reaction time being 1 to 12 hours according to different substrates. In 2000, Batey and Powell11 reported the mercury(II)-promoted attack of azide anion on a thiourea to synthesize 5aminotetrazoles. Additionally, trimethylsilyl azide (TMSA)12 is also a good reagent in the synthesis of aminotetrazole. TMSA was added to isolated cyanamide or carbodiimide and after a ———
39 few steps aminotetrazole was obtained. These methods require 40 harsh reaction conditions, toxic reagents, and long reaction 41 time. 42 43 44 45 46 47 48 49 50
In the past few years, hypervalent iodine reagents have emerged as versatile reagents for organic transformations. According to recent literature, hypervalent iodine reagents have been used for desulfurization purposes and synthesis of 5aminotetrazoles.13 However, the deselenization ability of diacetoxyiodobenzene (DIB), in particular, has been rarely explored. Thus we envisaged that selenoureas could serve as versatile intermediates for the synthesis of substituted 5aminotetrazoles promoted by DIB.
51 Figure 1. Structure of 5-aminotetrazoles and related com52 pounds
53
∗ Corresponding author. Tel.& fax: +86-571-8832-0878; E-mail: [email protected]
2 54 Results and discussion 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 89
Tetrahedron Letters 72 was not improved (Table 1, entry 11). Furthermore, we in73 creased the dosage of PhI(OAc)2, as we expected, the more NTo initiate the study, 1,3-diphenylselenourea was chosen as 74 acetylated byproduct 3a was produced (Table 1, entry 12). a model substrate to optimize the reaction conditions. The 75 Other trial such as increasing temperature to 50°C was useless screening of different parameters was summarized in Table 1. 76 for the yield of 2a (Table 1, entry 13). To achieve better selecWe examined various solvents such as DMF, CH3CN, THF, 77 tivity of the reaction, bases were added to neutralize HOAc. DMSO, toluene, dioxane and acetone (Table 1, entries 1-7), 78 NaOH was proved to be superior to NaH, Na2CO3, NaHCO3 and DMF was found to be the best choice for this transfor79 and Et3N (Table 1, entries 14–18). In order to improve the solmation. The conversion rate of 1a was 100%. But only 50% of 80 ubility of NaOH and NaN3, water was added to the reaction the desired product 2a was obtained and the remaining 45% is 81 mixture (Table 1, entry 19). Surprisingly, the N-acetylated the N-acetylated byproduct 3a. Besides, a trace amount (≤5%) 82 byproduct 3a was not observed when inorganic base NaOH (2 of unidentified impurity existed. For this reason, we reduced 83 equiv.) and water (0.5mL) were used.
the reaction time and found that the required product 2a could 84 The effort of reaction optimization revealed that the best be obtained in 10 minutes (Table 1, entry 8). Then the quanti85 conditions for the conversion of 1,3-diphenylselenourea ties of NaN3 and PhI(OAc)2 were also studied. It is noteworthy 86 (0.5mmol) into diphenyl-5-aminotetrazole is PhI(OAc)2 that the yield of diphenyl-5-aminotetrazole (Table 1, entries 887 (0.5mmol), NaN3 (1.5mmol), and NaOH pellets (1mmol), wa11) markedly increased with the increase of NaN3 and the yield 88 ter (0.5 mL) in DMF(5mL) at room temperature for 10 minutes. of 2a reached 90% when 3 equivalent of NaN3 was used. With further increase of NaN3 quantity (4 equiv.), the yield of 2a Table 1. Optimization for the conversion of 1,3-diphenylselenourea into diphenyl-5-aminotetrazole
90 NaN3
PhI(OAc)2
Water
(equiv.)
(equiv.)
(mL)
1 2 3
1 1 1
1 1 1
----
4
1
1
--
Toluene
rt
60
--
0:100
50
5
1
1
--
Acetone
rt
60
--
0:100
30
6 7 8
1 1 1
1 1 1
----
Dioxane DMF DMF
rt rt rt
60 60 10
----
0:100 50:45 52:48
30 b 100 100
9 10
2 3
1 1
---
DMF DMF
rt rt
10 10
---
60:40 90:10
100 100
11 12 13
4 3 3
1 1.2 1
----
DMF DMF DMF
rt rt 50
10 10 10
----
90:10 80:20 76:24
100 100 100
14 15 16
3 3 3
1 1 1
----
DMF DMF DMF
rt rt rt
10 10 10
NaH (2) NaOH (2) Na2 CO3 (1)
80:20 92:8 85:15
100 100 100
17 18
3 3
1 1
---
DMF DMF
rt rt
10 10
NaHCO3 (2) Et 3N (2)
60:40 75:25
100 100
19
3
1
0.5
DMF
rt
10
NaOH (2)
100:0
100
Entry
Solvent MeCN THF DMSO
Temp
Time
Base
(oC)
(min)
(equiv.)
rt rt rt
60 60 60
----
Tetrazole(2a):N-aceylurea(3a)
Convert ratio(%)a
0:100 0:100 0:100
10 15 10
91 a Conversion (%) of 1,3-diphenylselenourea (1a) b 5% Unknown impurity 92 93 94 95 96 97 98 99 100 101
Subsequently, various 1,3-disubstituted selenoureas (1) were investigated under the optimized conditions to study the scope of the system (Table 2). Symmetrical selenoureas bearing electron-donating substituents viz. o-Et (1b), m-Me (1c), p-Me (1d), p-OMe (1e), 2,4,6-tri-Me (1f) were very fast to give the corresponding 5-aminotetrazoles (2b-f) in good to excellent yields. However, the electron-withdrawing ones viz. p-F (1g) and p-Cl (1h) provided the corresponding 5-aminotetrazoles in modest yields. Also aliphatic selenoureas (1i) afforded good yield of aminotriazoles (2i).
102 After successfully synthesized various symmetrical 5103 aminotetrazoles, we focused our attention on the regioselective 104 electrocyclization of unsymmetrical selenoureas. Our earlier
105 106 107 108 109 110 111 112 113 114 115 116 117
report14 on regioselective N-acylation of unsymmetrical 1,3disubstituted selenoureas disclosed that the difference of pKa between the precursor amines has important influence on the regioselectivity of N-acetylation. We reasoned that, similarly, unsymmetrical 1,3-disubstituted selenoureas generated regioselectively 5-aminotetrazoles (2j-2l, 2n) due to the difference in the pKa values of the precursor amines attached to the selenoureas. To our great delight they all obtained single product. This has been confirmed by 2D NMR i.e. homonuclear correlation spectroscopy (H, H COSY). For example, we observed that the CNH proton (δ 4.53ppm) shows correlation with the CHN proton (δ3.43ppm) in 5-aminotetrazole 2j. But the pKa of p-methylaniline is similar to aniline, selenoureas
3 118 (1m) obtained a mixture of aminotetrazoles (2m) and (2m'). 119 This result can be explained by the reaction mechanism. 120 Table 2. Synthesis of 5-aminotetrazoles from 1,3-disubstituted selenoureas
R1
H N
H N Se
Entry
123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151
R1
NaN3 /PhI(OAc)2
R1
N N N N R2 2a-2o
2 + R
N H
DMF/NaOH/H2O
1a-1o
121
122
R2
R2
Product
N N N N N H R1 2a'-2o'
a
Time
Yield
(min)
(%)
1
Ph
Ph
2a
10
95
2
o-EtC6H4
o-EtC6 H4
2b
10
92
3
m-MeC6 H4
m-MeC6H4
2c
10
89
4
p-MeC6 H4
p-MeC6 H4
2d
10
87
5
p-OMeC6H4
p-OMeC6H4
2e
10
87
6
2,4,6-triMeC6H2
2,4,6-triMeC6H2
2f
10
82
b
7
p-FC6 H4
p-FC6H4
2g
20
69
8
p-ClC6H4
p-ClC6 H4
2h
20
65
9
Benzyl
Benzyl
2i
15
85
10
n-Butyl
Ph
2j
15
90
11
cyclohexyl
Ph
2k
15
92
12
Ph
1-naphthyl
2l
10
85
13
p-MeC6 H4
Ph
2m:2m'
10
86(75:25)c
14
H
Ph
2n
15
71
a
Confirmed by IR and 1H and 13 C NMR. b Isolated yield based on 1. c Ratio of regioisomers determined by 1H NMR
The proposed mechanism for the formation of diphenyl-5aminotetrazole and N-acetylated byproduct is shown in Scheme 1. The precipitation of selenium power further supports the mechanism. The selenium atom of 1,3-disubstituted selenourea 1a attacks the iodine atom of DIB in place of one of the AcO− giving intermediate 6. The deselenization of DIBactivated selenourea generates an intermediate carbodiimide (7). The attack of azide ion (N3-) on carbodiimide generates guanyl azide (8), which subsequently affords the 5aminotetrazole 2 via electrocyclization. The attack of azide ion (N3-) on unsymmetrical carbodiimide would lead to the protonation toward the amine having higher pKa. The measured pKa values of both n-butylamine (pKa=10.77) and cyclohexylamine (pKa=10.66) are higher than aniline (pKa=4.61), 2j and 2k are the major product in excellent yields because the protonation toward n-butyl- and cyclohexyl-side in substrates 1j and 1k were preference. The pKa of naphthylamine (4.21) and p-methylaniline (5.04) are similar to aniline (4.61), but the 2l was the exclusive regioselective product mainly due to the steric factor of naphthyl group. Unsymmetrical selenoureas (1m) reacted with sodium azide and DIB, obtaining a mixture of aminotetrazoles (2m) and (2m') in the ratio of 75:25. Additionally, 1-phenyl-5-aminotetrazole from the terminal phenylselenourea 1n was obtained 2n in good yield. Inorganic acid scavenger viz. NaOH introduced in the system decreased the concentration of AcOH and increased the opportunity of attacking carbodiimide by azide ion (N3-), generating the regioselective 5-aminotetrazole (2a). Thus, the formation of N-acetylated byproduct 3a was significantly avoided.
152 Scheme1. The proposed mechanism for the formation of 153 diphenyl-5-aminotetrazole and N-acetylated byproduct
154 155 156 157 158 159 160 161 162
In conclusion, we have developed an efficient system of PhI(OAc)2 and NaN3 for the synthesis of symmetrical and unsymmetrical 5-aminotetrazoles starting from the corresponding 1,3-disubstituted selenoureas. This novel reaction possesses the advantages of metal-free conditions, short reaction time, good selectivity, and environmental acceptability. The results of experiment suggest that the reaction has general applicability for the substrates.
4 163 Acknowkedgment
Tetrahedron Letters
164 We are grateful to the Qianjiang Talent Project of Scicence 165 Technology Deparment of Zhejiang Province (No.2013R10059) 166 for financial support. We also thank Prof. Tao Zhou and Prof. 167 Weihui Zhong for helpful discussions. 168 References and notes 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235
1.
2.
3. 4.
5.
6.
7. 8.
9. 10. 11. 12.
13. 14. 15.
(a) Roh, J.; Vávrová, K.; Hrabálek, A. Eur. J. Org. Chem. 2012, 31, 6101–6118; (b) Biot, C.; Bauer, H.; Schirmer, R. H.; Davioud-Charvet, E. J. Med. Chem. 2004, 47, 5972-5983; (c) Yella, R.; Khatun, N.; Rout, S. K. and Patel, B. K. Org. Biomol. Chem. 2011, 9, 3235–3245. (a) Sathishkumar, M.; Shanmugavelan, P.; Nagarajan, S.; Dinesh , M.; Ponnuswamy, A. New J. Chem. 2013, 37, 488-493; (b) Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem. Heterocycl. Compd. 2007, 43, 1-9. Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26, 499-531. (a) Toney, J. H.; Fitzgerald, P. M. D.; Grover-Sharma, N.; Olson, S. H.; May, W. J.; Sundelof, J. G.; Vanderwall, D. E.; Cleary, K. A.; Grant, S. K.; Wu, J. K.; Kozarich, J. W.; Pompliano, D. L.; Hammond, G. G. Chem. Biol. 1998, 5, 185196; (b) Ford, R. E.; Knowles, P.; Lunt, E.; Marshall, S. M.; Penrose, A. J.; Ramsden, C. A.; Summers, A. J. H.; Walker, J. L.; Wright, D. E. J. Med. Chem. 1986, 29, 538-549. (c) Peet, N. P.; Baugh, L. E.; Sundler, S.; Lewis, J. E.; Matthews, E. H.; Olberding, E. L.; Shah, D. N. J. Med. Chem. 1986, 29, 24032409. (a) Poonian, M. S.; Nowoswiat, E. F.; Blount, J. F.; Kramer, M. J. J. Med. Chem. 1976, 19, 1017-1020; (b) De Clercq, E. J. Clin. Virol. 2004, 30, 115-133; (c) Navidpour, L.; Shadnia, H.; Shafaroodi, H.; Amini, M.; Dehpour, A. R.; Shafiee, A. Bioorg. Med. Chem. 2007, 15. 1976-1982; (d) Lebouvier, N.; Giraud, F.; Corbin, T.; Na, Y. M.; Le Baut, G.; Marchand, P.; Le Borgne, M. Tetrahedron Lett. 2006, 47, 6479-6483. (a) Akimoto, H.; Ootsu, K.; Itoh, F. Eur. Patent EP 530537, 1993; (b) Taveras, A. G.; Mallams, A. K.; Afonso, A. Int. Patent WO 9811093, 1998. Mitch, C. H.; Quimby, S. J. Int. Patent WO 9851312, 1998. (a) Habich, D. Synthesis, 1992, 4, 358-360; (b) Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem. Hetero. Com. 2007, 43, 1-9. Stollé, R. Chem. Ber. 1922, 55, 1289-1297. Svĕtlík, J.; Martvonň, A. and Leško, J. Chem. zvesti. 1979, 33, 4, 521-527. Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237-3240. (a) Tsuge, Y.; Satoshi, O. U. and Oe, K. J. Org. Chem. 1980, 45, 5130-5136. (b) Nishiyama, K.; Watanabe, A. Chem. Lett. 1984, 13, 455-458; (c) Nishiyama, K.; Oba, M.; Watanabe, A. Tetrahedron, 1987, 43, 693-700. Chaudhari, P. S.; Pathare, S. P.; Akamanchi, K. G. J. Org. Chem. 2012, 77, 3716−3723. Xie, Y. Y.; Pan, H. X. Phosphorus, Sulfur, and Silicon, 2014, 189, 98–105. General experimental procedure to synthesize 5-aminotetrazoles: A mixture of 1,3-diphenylselenourea (0.5 mmol), iodobenzene diacetate (0.5 mmol) and NaN3 (1.5 mmol) in DMF(5mL) followed by the addition of NaOH (1 mmol) and H2 O (0.5mL), then stirred at room temperature for 10 min. The progress of the reaction was monitored by TLC. Precipitation of selenium powder was observed during this period. After completion, the reaction mixture was filtered. The filtrate was poured into a saturated NaCl solution (50 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and evaporated to afford the crude product, which was purified by flash chromatography on silica gel using hexane/EtOAc 4:1 as eluent. N,1-Diphenyl-1H-tetrazol-5-amine 2a: white solid, mp 158-160 °C (Lit.9 158-159 °C); IR (KBr) ν max 3433, 1612, 1571, 1496, 1454, 1090, 746cm-1 ; 1 H NMR (400 MHz, CDCl 3) δ 7.64-7.58 (m, 3H), 7.53-7.51 (m, 4H), 7.33 (t, J = 7.6Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.42 (s, 1H); 13 C NMR (100 MHz, CDCl3) δ 151.5, 138.0, 132.7, 130.4, 130.3, 129.2, 124.7, 123.4, 118.2; ESI-MS m/z calc. 237.10, found 260.4 (M+Na)+.