Mild, Efficient, and Highly Regioselective Synthesis of 2,6-Diiodobenzaldehyde Derivatives

Raed M. Al-Zoubi; Khaled T. Jaradat; Walid K. Al-Jammal; Robert McDonald

doi:10.1055/s-0040-1708004

Synlett, Table of Contents

Synlett 2020; 31(10): 953-958
DOI: 10.1055/s-0040-1708004

letter

Mild, Efficient, and Highly Regioselective Synthesis of 2,6-Diiodobenzaldehyde Derivatives

Raed M. Al-Zoubi∗

^aDepartment of Chemistry, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan Email: rmzoubi@just.edu.jo

,

Khaled T. Jaradat

^aDepartment of Chemistry, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan Email: rmzoubi@just.edu.jo

,

Walid K. Al-Jammal

^aDepartment of Chemistry, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan Email: rmzoubi@just.edu.jo

,

Robert McDonald

^bDepartment of Chemistry, Gunning-Lemieux Chemistry Centre, University of Alberta, Edmonton, AB, T6G 2G2, Canada

› Author Affiliations

Abstract

All articles of this category

Abstract

An efficient and versatile synthesis of 2,6-diiodobenzaldehydes via highly regioselective metal–iodine exchange (MIE) of 5-substituted 1,2,3-triiodobenzenes is reported. The nature of substituents (R) on the phenyl has a large influence on the reactivity of reaction but not on the regioselectivity. The regioselectivity of the MIE can be controlled by the use of ethyl formate as a formylating agent providing only the internal benzaldehyde derivatives in excellent site-selectivity. The best reactivity and the highest isolated yields were furnished with products bearing electron-rich substituents. Several chemical transformations of the target compound as a valuable precursor in synthesis were also demonstrated providing the desired derivatives in good isolated yields. This report discloses a protocol for the synthesis of 2,6-diiodobenzaldehyde derivatives that is scalable, general in scope, and indeed difficult to be made by other means.

Keywords

2,6-diiodobenzaldehydes - Grignard reactions - regioselectivity - metal–iodine exchange - substituent effect - Suzuki–Miyaura cross-coupling - nucleophilic addition

Full Text

References

References and Notes
1 More SS, Vince R. US 20180230105A1, 2018
2 Dreher MR, Lewis AL, Willis SL. WO 2017158482A1, 2017
3 Hohn S, Lewis AL, Willis SL, Dreher MR, Ahrafi K, Tang Y. WO 2015033093A1, 2015
4 Zech SG, Kohlmann A, Zhou T, Li F, Squillace RM, Parillon LE, Greenfield MT, Miller DP, Qi J, Thomas RM, Wang Y, Xu Y, Miret JJ, Shakespeare WC, Zhu X, Dalgarno DC. J. Med. Chem. 2016; 59: 671

5a Balaji B, Ramanathan M. J. Enzyme Inhib. Med. Chem. 2012; 27: 832
5b Yang C, Edsall R, Harris HA, Zhang X, Manas ES, Mewshaw RE. Bioorg. Med. Chem. 2004; 12: 2553
5c Mewshaw RE, Yang C. WO 2004099122A2, 2004
5d Edsall RJ, Harris HA, Manas ES, Mewshaw RE. Bioorg. Med. Chem. 2003; 11: 3457

6a Tsuchiya T, Wasnaire P, Hoffmann S, Seitz T, Hillebrand S, Benting J, Schmidt JP, Cristau P. WO 2013098229A2, 2013
6b Ek F, Almen T, Gardner R. WO 2000066544A1, 2000
6c Fouda AM, Assiri MA, Mora A, Ali TE, Afifi TH, El-Agrody AM. Bioorg. Chem. 2019; 93: 103289

7 Scifinder: 1 g/USD 4998 for CAS 1806389-59-2; 1 g/USD 5988 for CAS 21693922-49-6; 1 g/USD 4998 for CAS 1804422-78-3.

8a Hu P, Tan M, Cheng L, Zhao H, Feng R, Gu W.-J, Han W. Nat. Commun. 2019; 10: 1
8b Waheed M, Ahmed N, Alsharif MA, Alahmdi MI, Mukhtar S. ChemistrySelect 2019; 4: 7572
8c Li F, Zhou Y, Yang H, Wang Z, Yu Q, Zhang F.-L. Org. Lett. 2019; 21: 3692
8d Khenkin AM, Somekh M, Carmieli R, Neumann R. Angew. Chem. Int. Ed. 2018; 57: 5403
8e Rathore PS, Patidar R, Thakore S. RSC Adv. 2014; 4: 41111
8f Faraji AR, Ashouri F, Hekmatian Z, Heydari S, Mosazadeh S. Polyhedron 2019; 157: 90
8g Huang S, Feng Q, Chen D, Zhang Y. CN 108314612A, 2018
8h Muthumari S, Ramesh R. ChemistrySelect 2018; 3: 3036
8i Zhang L, Liu J, Zhang F, Zhang X.-M. J. Catal. 2017; 354: 78
8j Xiao P, Tang Z, Wang K, Chen H, Guo Q, Chu Y, Gao L, Song Z. J. Org. Chem. 2018; 83: 1687
8k Han W, Zhao H. CN 107216242A, 2017
8l Karimi B, Vahdati S, Vali H. RSC Adv. 2016; 6: 63717
8m Giovani S, Singh R, Fasan R. Chem. Sci. 2016; 7: 234
8n Liu C, Fang Z, Yang Z, Li Q, Guo S, Guo K. Org. Biomol. Chem. 2016; 14: 577
8o Hajipour AR, Karimi H. J. Chem. Sci. 2015; 127: 1945
8p Karimi B, Farhangi E, Vali H, Vahdati S. ChemSusChem 2014; 7: 2735
8q Montazerozohori M, Nasr-Esfahani M, Joohari S, Akhlaghi P, Dehghani A. Asian J. Chem. 2011; 23: 1081
8r Zheng P, Yan L, Ji X, Duan X. Synth. Commun. 2011; 41: 16
8s Yang W, Hou Y, Zhu R. CN 109384723A, 2019
8t Goswami M, Geuijen P, Reek JN. H, de Bruin B. Eur. J. Inorg. Chem. 2018; 617
8u Liu X.-H, Park H, Hu J.-H, Hu Y, Zhang Q.-L, Wang B.-L, Sun B, Yeung K.-S, Zhang F.-L, Yu J.-Q. J. Am. Chem. Soc. 2017; 139: 888
8v Krzeszewski M, Kodama T, Espinoza EM, Vullev VI, Kubo T, Gryko DT. Chem. Eur. J. 2016; 22: 16326
8w Miller MT, Anderson C, Arumugam V, Bear BR, Binch HM, Clemens JJ, Cleveland T, Conroy E, Coon TR, Frieman BA, Grootenhuis PD. J, Gross RS, Hadida-Ruah SS, Haripada K, Joshi PV, Krenitsky PJ, Lin C.-C, Marelius GE, Melillo V, McCartney J, Nicholls GM, Pierre FJ. D, Silina A, Termin AP, Uy J, Zhou J. US 20160095858A1, 2016
8x Hong K.-I, Yoon H, Jang W.-D. Chem. Commun. 2015; 51: 7486
8y Meng L, Cheng Q, Kim C, Gao W.-Y, Wojtas L, Chen Y.-S, Zaworotko MJ, Zhang XP, Ma S. Angew. Chem. Int. Ed. 2012; 51: 10082
8z Nigel-Etinger I, Mahammed A, Gross Z. Catal. Sci. Technol. 2011; 1: 578

9a Rawal RK, Tripathi R, Katti SB, Pannecouque C, De Clercq E. Eur. J. Med. Chem. 2008; 43: 2800
9b Lulinski S, Serwatowski J. J. Org. Chem. 2003; 68: 5384
9c Chen X.-Y, Sorensen EJ. J. Am. Chem. Soc. 2018; 140: 2789
9d Liu J, Jiang X, Zhang Y, Yan S, Shen J, Ma X, Chen D, Gu S, Ni F, Li Y, Wang Q, Chen M. CN 106748681A, 2017
9e Ganiek MA, Becker MR, Berionni G, Zipse H, Knochel P. Chem. Eur. J. 2017; 23: 10280
9f Pratt D, Moehring H. WO 2016102207A1, 2016
9g Toriumi T. JP 2015214503A, 2015
9h Liu K, Xu Y, Yao Z, Miras HN, Song Y.-F. ChemCatChem 2016; 8: 929
9i Guan M, Wang C, Zhang J, Zhao Y. RSC Adv. 2014; 4: 48777
9j Gonzalez-de-Castro A, Xiao J. J. Am. Chem. Soc. 2015; 137: 8206
9k Oslob J, Anderson R, Aubele D, Evanchik M, Fox JC, Kane B, Lu P, McDowell R, Rodriguez H, Song Y, Sran A. WO 2014205223A1, 2014
9l Sun H, DiMagno SG. Angew. Chem. Int. Ed. 2006; 45: 2720

10 Cvengroš J, Stolz D, Togni A. Synthesis 2009; 2818

11a Al-Zoubi RM, Al-Mughaid H, Al-Zoubi MA, Jaradat KT, McDonald R. Eur. J. Org. Chem. 2015; 5501
11b Al-Zoubi RM, Al-Zoubi MS, Jaradat KT, McDonald R. Eur. J. Org. Chem. 2017; 5800
11c Al-Zoubi RM, Al-Mughaid H, McDonald R. Aust. J. Chem. 2015; 68: 912
11d Al-Zoubi RM, Al-Zoubi MS, Abazid AH, McDonald R. Asian J. Org. Chem. 2015; 4: 359
11e Al-Zoubi RM, Futouh HA, McDonald R. Aust. J. Chem. 2013; 66: 1570
11f Al-Zoubi RM, Ibdah A, Al-Jammal WK, Al-Zoubi MS, Almasalma AA, McDonald R. Synthesis 2018; 50: 384

12a DiMichele L, Menzel K, Mills P, Frantz D, Nelson T. Magn. Reson. Chem. 2006; 44: 1041
12b Menzel K, Dimichele L, Mills P, Frantz DE, Nelson TD, Kress MH. Synlett 2006; 1948
12c Menzel K, Mills PM, Frantz DE, Nelson TD, Kress MH. Tetrahedron Lett. 2008; 49: 415
12d Sämann C, Haag B, Knochel P. Chem. Eur. J. 2012; 18: 16145
12e Al-Zoubi RM, Al-Jammal WK, McDonald R. New J. Chem. 2020; 44: 3612
12f Du CJ. F, Hart H, Ng KK. D. J. Org. Chem. 1986; 51: 3162
12g Liu Y, Kim J, Seo H, Park S, Chae J. Adv. Synth. Catal. 2015; 357: 2205
12h Wang D, Cai Q, Ding K. Adv. Synth. Catal. 2009; 351: 1722

13 CCDC 1965598 and 1965599 contain the supplementary crystallographic data for compounds 10_A and 19, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

14a Boehm VP. W, Schulze V, Broenstrup M, Mueller M, Hoffmann RW. Organometallics 2003; 22: 2925
14b Hoffmann RW, Broenstrup M, Mueller M. Org. Lett. 2003; 5: 313
14c Mueller M, Broenstrup M, Knopff O, Schulze V, Hoffmann RW. Organometallics 2003; 22: 2931
14d Schulze V, Bronstrup M, Bohm VP. W, Schwerdtfeger P, Schimeczek M, Hoffmann RW. Angew. Chem. Int. Ed. 1998; 37: 824

15 Schnuerch M, Spina M, Khan AF, Mihovilovic MD, Stanetty P. Chem. Soc. Rev. 2007; 36: 1046
16 General Procedure for the MIE Reaction between 5-Substituted 1,2,3-Triiodobenzenes and Ethyl FormateA flame-dried round-bottom flask was charged with 5-substituted 1,2,3-triiodobenzene (1.02 mmol, 1.0 equiv.) and 10 mL of freshly dried THF. The mixture was cooled down under argon gas to –78 °C. 2 M solution of isopropylmagnesium chloride (1.15 mmol, 1.1 equiv.) was added dropewise over 1 h. The solution was stirred for 30 min at the same temperature. Ethyl formate (1.53 mmol, 1.50 equiv.) was added and the mixture left to warm up overnight. Saturated NH₄Cl (20 mL) was added, and the reaction mixture was extracted with diethyl ether (2 × 50 mL). Organic layers were combined, washed with brine, dried with Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography (5% EtOAc/hexane) to yield the pure desired product.2,6-Diiodobenzaldehyde (6_A)Yellow solid (261 mg, 71% yield). Mp 58–60 °C. IR (cast film): 3026, 3008, 2913, 2887, 1715, 1613, 1598, 983, 864 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.78 (s, 1 H), 8.01 (d, 2 H, J = 7.8 Hz), 6.86 (t, 1 H, J = 7.8 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 195.7, 141.6, 135.6, 134.6, 97.5. HRMS (ESI): m/z calcd for C₇H₅I₂O [M + H]⁺: 358.8430; found: 358.8425.4-Fluoro-2,6-diiodobenzaldehyde (7_A)Yellow solid (192 mg, 50% yield). Mp 91–93 °C. IR (cast film): 3028, 3004, 2979, 2846, 1719, 1642, 1599, 976, 817, 688, 524 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.73 (s, 1 H), 7.80 (d, 2 H, J = 7.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 194.5, 164.5, 161.8, 131.3 131.29, 129.2 129.0, 97.7, 97.6. HRMS (ESI): m/z calcd for C₇H₄FI₂O [M + H]⁺: 376.8336; found: 376.8331.4-Chloro-2,6-diiodobenzaldehyde (8_A)Yellow solid (312 mg, 78% yield). Mp 65–67 °C. IR (cast film): 3012, 3004, 2941, 2876, 1709, 1621, 1587, 1008, 867, 726, 553 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.72 (s, 1 H), 8.05 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.7, 141.1, 139.7, 133.5, 97.4. HRMS (ESI): m/z calcd for C₇H₄ClI₂O [M + H]⁺: 392.8040; found: 392.8033.4-Bromo-2,6-diiodobenzaldehyde (9_A)Yellow solid (201 mg, 45% yield). Mp 101–103 °C. IR (cast film): 3024, 3004, 2943, 2869, 1706, 1607, 1587, 943, 634 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.70 (s, 1 H), 8.19 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.8, 143.8, 134.0, 128.3, 97.6. HRMS (ESI): m/z calcd for C₇H₄BrI₂O [M + H]⁺: 436.7535; found: 436.7528.2,6-Diiodo-4-methylbenzaldehyde (10_A)Yellow solid (288 mg, 76% yield). Mp 130–132 °C. IR (cast film): 3031, 3010, 3004, 2953, 2896, 1713, 1621, 1589, 981, 736 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.76 (s, 1 H), 7.86 (s, 2 H), 2.31 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.5, 146.1, 142.5, 132.2, 98.0, 20.5. HRMS (ESI): m/z calcd for C₈H₇I₂O [M + H]⁺: 372.8586; found: 372.8584.2,6-Diiodo-4-methoxybenzaldehyde (11_A)Yellow solid (317 mg, 80% yield). Mp 83–85 °C. IR (cast film): 3027, 3011, 2945, 2879, 1713, 1621, 1587, 1207, 1186, 873, 736 cm^–1. ¹H NMR (400MHz, CDCl₃): δ = 9.71 (s, 1 H), 7.59 (s, 2 H), 3.86 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.8, 162.6, 127.8, 126.7, 99.4, 56.2. HRMS (ESI): m/z calcd for C₈H₇I₂O₂ [M + H]⁺: 388.8535; found: 388.8529.Methyl 4-formyl-3,5-diiodobenzoate (12_A)Yellow solid (280 mg, 66% yield). Mp 76–78 °C. IR (cast film): 3031, 3015, 2983, 2907, 1741, 1716, 1627, 1583, 1207, 1131, 867, 627 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.78 (s, 1 H), 8.61 (s, 2 H), 3.96 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.2, 163.5, 142.1, 139.4, 134.9, 96.1, 53.2. HRMS (ESI): m/z calcd for C₉H₇I₂O₃ [M + H]⁺: 416.8485; found: 416.8477.2-Chloro-6-iodobenzaldehyde (13_A)Yellow solid (209 mg, 77% yield). Mp 80–82 °C. IR (cast film): 3021, 3002, 2937, 2889, 1719, 1641, 1599, 867, 764, 537 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.19 (s, 1 H), 7.94 (d, 1 H, J = 8.0 Hz), 7.48 (d, 1 H, J = 8.0 Hz), 7.13 (t, 1 H, J = 7.9 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 191.7, 140.1, 136.9, 134.1, 133.1, 131.2, 96.4. HRMS (ESI): m/z for C₇H₅ClIO [M + H]⁺: 266.9074; found: 266.9067.2-Bromo-6-iodobenzaldehyde (14_A)Yellow solid (238 mg, 75% yield). Mp 87–89 °C. IR (cast film): 3019, 3004, 2983, 2876, 1714, 1607, 1596, 861, 584 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.05 (s, 1 H), 7.98 (d, 1 H, J = 8.0 Hz), 7.68 (d, 1 H, J = 8.0 Hz), 7.03 (t, 1 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 193.1, 140.9, 134.6, 134.4, 134.4, 125.4, 96.5. HRMS (ESI): m/z for C₇H₅BrIO [M + H]⁺: 310.8568; found: 310.8564.

Supplementary Material