Oxidative β-Halogenation of Alcohols: A Concise and Diastereoselective Approach to Halohydrins

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

β-Halohydrins bearing transformable halo- and hydroxyl groups, are easily converted into various valuable blocks in organic and pharmaceutical synthesis. A diastereoselective β-halogenation of benzylic alcohols was achieved under simple and low-cost conditions, which provided a direct synthesis of β-halohydrins. The simple reaction conditions, easily available reagents, high diastereoselectivities, and additional oxidant-free make this reaction very attractive and practical.

Key words

halogenation - alcohols - dimethyl sulfoxide - halohydrins - oxidation

Organohalides are one of the most widespread and important chemicals and are present in more than 4500 natural products,[1] as well as a great number of industrially valuable products such as pharmaceuticals, fire retardants, agrochemicals, and some new materials.[2] In addition, it is no doubt that organohalides with their general reactivity make the chemical synthesis more simple, accessible, and valuable. β-Halohydrins, bearing a hydroxyl and halide functional group, are privileged building blocks in organic synthesis and could be conveniently converted into other significant organic intermediates such as azido alcohols, amino alcohols, and epoxides, all of which are widely used in the synthesis of many highly value-added chemicals.[3] Up to date, halohydrins could be prepared by halohydroxylation of olefins,[4] reduction of haloketones,[5] ring-opening reaction of epoxides,[6] and nucleophilic substitution of benzyl halides[7] (Scheme [1], A). In most cases, the halo atom of halohydrins was introduced by the halo cation such as N-halosuccinimides and their analogues which are not good choices for large-scale halogenations because of expensive price and low atomic economy. Inspired by the enzyme-catalyzed aerobic oxidative halogenation in nature,[8] a sophisticated approach by in situ generating the halogenating reagent from oxidant and halide salts is widely applied in halogenations[9] [10] especially in the oxidative halohydroxylation of olefins which provided a direct approach to halohydrins,[10] although solvent, halide source, acid, oxygen source, and oxidant were required in these approaches.

Scheme 1 The synthesis of halohydrins

The β-halogenation of alcohols[11] provides another direct approach to halohydrins. However, the reported β-halogenation of alcohols with halo cations always delivered mixtures of products (Scheme [1], B).[12] As our continuous development of DMSO-based reactions,[13] we herein reported our success in β-halogenation of alcohols with in situ generation of halo cation from sodium halides and DMSO (Scheme [1], C). The magic multiple role of DMSO[14] as solvent, oxidant,[15] stabilizer of halo cations,[10j] and nucleophile[16] successfully enabled this novel transformation. Very importantly and interestingly, the diastereoselectivities of this transformation were very high (>25:1)

This reaction began with an unexpected bromination. As reported,[12a] [17] the combination of aqueous HBr and DMSO showed high efficiency in the aromatic bromination of 2-naphthol 1 to deliver aryl bromide 2 in 79% yield (Scheme [2], eq 1). To our surprise, when changing the substituent of naphthalene from –OH (1) to –CH(OH)CH₃(3a), the aromatic bromination was totally supressed, and aliphatic bromination at the methyl group occurred to afford bromohydrin 4a in 33% yield (Scheme [2], eq 2).[18] Due to the importance of the halohydrins, this bromination drew our great interest.

Scheme 2

We then optimized the bromination conditions (Table [1]). The reaction did not work when changing aqueous HBr to KBr (Table [1], entry 1). This experiment revealed the acidic conditions were essential for this reaction. When HBr was generated by KBr and H₂SO₄ in situ, 4a could be obtained in 38% yield (Table [1], entry 2). The yield increased to 44% using NaBr instead of KBr (Table [1], entry 3). Other organic acids such as TsOH, MsOH, or TfOH showed lower efficiency than that of H₂SO₄ (Table [1], entries 3–6). The amount of acidic additive influenced the yield strongly. Compound 4a was obtained in 73% yield when 4 equiv of H₂SO₄were employed (Table [1], entry 9). When the reaction preformed with 1.2 equiv of NaBr, only 46% yield of 4a was obtained (Table [1], entry 11). Compound 4a was not detected when the reaction was carried out in other solvents (Table [1], entries 12 and 13). These results indicated that DMSO was indispensable in this bromination.

Table 1 Optimization of the Reaction Conditions^a

Entry	[Br] (equiv)	Additive (equiv)	Solvent	T (°C)	Yield (%)b
1	KBr (2)	–	DMSO	60	0
2	KBr (2)	H2SO4 (2)	DMSO	60	38
3	NaBr (2)	H2SO4 (2)	DMSO	60	44
4	NaBr (2)	TsOH (2)	DMSO	60	25
5	NaBr (2)	MsOH (2)	DMSO	60	27
6	NaBr (2)	TfOH (2)	DMSO	60	44
7	NaBr (2)	H2SO4 (2)	DMSO	40	trace
8	NaBr (2)	H2SO4 (4)	DMSO	80	mess
9	NaBr (2)	H2SO4 (4)	DMSO	60	73
10	NaBr (2)	H2SO4 (8)	DMSO	60	45
11	NaBr (1.2)	H2SO4 (4)	DMSO	60	46
12	NaBr (2)	H2SO4 (4)	DCE	60	0
13	NaBr (2)	H2SO4 (4)	THF	60	0

^a Reaction conditions: The solution of 3a (0.5 mmol), bromide source, and additive in solvent (1 mL) was stirred under air for 24 h.

^b Isolated yields.

We then investigated the substrate scope of this novel bromination (Scheme [3]). Various benzylic alcohols worked well under the standard conditions. It was noteworthy that when an electron-donating group such as methoxy, tert-butyl, or methyl was contained at the aryl ring, the corresponding bromohydrins 4d,e and 4g were highly selectively obtained in good yields, respectively. The reported bromination on the electron-rich arenes was not detected in this protocol. In addition, heteroarenes such as benzothiophenyl- and benzofuranyl-substituted alcohols were well tolerated in this transformation and converted into bromohydrins 4m,n in moderate yields. Furthermore, the gram-scale reaction of 3a with 69% yield shows the potential application of this low-cost protocol. However, no bromohydrin was detected when alcohols without benzylic substituent was exposed under the standard conditions.

Scheme 3 Substrate scope of benzylic alcohols.^{a a}Reaction conditions: The solution of 3a (0.5 mmol), NaBr (1 mmol), and H₂SO₄(2 mmol) in DMSO (1 mL) was stirred under air at 60 °C for 24 h. Isolated yields. ^bH₂SO₄(4 mmol) was used. ^cH₂SO₄(1.2 mmol) was used.

It is very challenging to control the diastereoselectivity of β-functionalization of alcohols. To our delight, the six-membered cyclic alcohols 3o,p produced trans-bromohydrins 4o,p as the sole product in high efficiency (Scheme [4]). Although the five-membered and seven-membered cyclic alcohols 3q,r afforded the target bromohydrins 4q,r in moderate yields, the diastereoselectivities of these brominations were also very high (>25:1).[18] The substituents on the phenyl ring had little influence on the efficiency and diastereoselectivity.

Scheme 4 Diastereoselective bromination of alcohols.^{a a} Reaction conditions: The solution of 3 (0.5 mmol), NaBr (1 mmol), and H₂SO₄(2 mmol) in DMSO (1 mL) was stirred under air at 60 °C for 24 h. Isolated yields. ^b H₂SO₄(4 mmol) was used.

When mixture of cis/trans (1.4:1) alcohol 3u was subjected to the standard conditions, bromohydrin 4u was produced with only one diastereoselective isomer in 52% yield (Scheme [5], eq 3). This experiment demonstrates the excellent diastereoselectivity of present bromination reaction. Compared to C–Br bond, the C–I bonds are more reactive but hard to construct. To our delight, the β-iodination of alcohol 3a also underwent smoothly and produced the desired iodohydrin 6 in 53% yield using NaI and H₂SO₄ as the simple reagents (Scheme [5], eq 4).

Scheme 5

The bromohydrin 4a was conveniently converted into other valuable products (Scheme [6]). Azido alcohol 7, the key intermediate of β-blocker pronethalol[19a] and other bioactive molecules,[19b] was synthesized in 98% yield by stirring 4a with NaN₃ at 60 °C in DMSO. Exposure of 4a with aqueous NaOH solvent in THF afforded epoxide 8 in 95% yield, which could easily react with amines to produce amino alcohol drugs.[19c] Amino alcohol 9 also could be synthesized by treating 4a with ammonium hydroxide in MeOH. The reaction of 4a and CO₂ in the presence of NMe₄HCO₃ provided carbonic ester 10 in 97% yield.

Scheme 6 Transformation of bromohydrin 4a. Reaction conditions: a) NaN₃ (2 equiv), DMSO, 60 °C, 12 h. b) Aqueous NaOH (4 equiv), THF, 0 °C, 1 h. c) NH₃·H₂O (28%), MeOH, 25 °C, 4 h, then Boc₂O (2 equiv), NEt₃ (2 equiv), DCM, 25 °C, 4 h. d) NH₄HCO₃ (2 equiv), CO₂ (1 atm), MeCN, 25 °C, 0.5 h.

To investigate the mechanism of this bromination, control experiments were performed. Ethyl naphthalene 11 could not be brominated under the standard conditions, indicating the hydroxyl was indispensable for present bromination (Scheme [7], eq 5). Treatment of alcohol 3a under standard conditions in the absence of NaBr afforded alkene 12 in 39% yield (Scheme [7], eq 6). Subjecting the obtained alkene 12 back to the standard conditions led to 4a in 76% yield, which indicated that alkene 12 might be the key intermediate of this transformation (Scheme [7], eq 7).

Scheme 7

Previous studies reported that the hydrobromic acids could be oxidized by DMSO to molecular bromine (Scheme [7], eq 8).[17] If Br₂ was generated, it would readily react with the in situ generated alkene 12 to afford a trans-dibrominated product 13.[13d] However, exposure of trans-13 under the conditions for 24 h provided the product 4p only in 27% yield and showed much lower diastereoselectivity (trans/cis = 9:1, Scheme [7], eq 9). This experiment demonstrated that the corresponding dibromination was not involved in this process. We therefore suspected that the HBr was oxidized to bromo cation (Br⁺) which was stabilized by DMSO through coordination (Scheme [7], eq 10).[10j]

On the basis of the above experimental results and previous reports,[18] [20] we proposed the mechanism of this halogenation of alcohols in Scheme [8]. Under acidic conditions, alkene 12u is generated by the hydroxyl elimination process. Meanwhile, Br⁺ is generated and immediately coordinated by DMSO to give (DMSO)_nBr⁺DMS (n = 1–3).[10j] The electrophilic addition of Br⁺ to alkene 12u preferentially affords bromonium A rather than B because of the steric hindrance of the methyl group. Further nucleophilic attack of DMSO to A delivers the alkoxysulfonium C which quickly decomposes to produce trans-bromohydrin 4u.[10j] [16a] [i]

Scheme 8 Proposed mechanism

In conclusion, we have developed a novel β-halogenation of benzylic alcohols for the efficient synthesis of high-value halohydrins. The simple reaction conditions, easily available reagents, and high diastereoselectivity control make this protocol very attractive and practical. Mechanistic studies reveal that halo cation (X⁺) rather than molecular halogen is involved in the transformation. This reaction demonstrates a new application of DMSO and HX in organic synthesis and would promote the application of the alkene in situ generation strategy.

• References

• 1 Gribble GW. J. Chem. Educ. 2004; 81: 1441
• 2 Dagani MJ, Barda HJ, Benya TJ, Sanders DC. Bromine Compounds in Ullmann’s Encyclopedia of Industrial Chemistry . Wiley-VCH; Weinheim: 2002
• 3 Organic Bromine and Iodine Compounds in The Handbook of Environmental Chemistry. Neilson AH. Springer; Berlin, Heidelberg: 2003
• 4 Buckles RE, Maurer JE. J. Org. Chem. 1953; 18: 1585
• 5 Naimi-Jamal MR, Mokhtari J, Dekamin MG, Kaupp G. Eur. J. Org. Chem. 2009; 3567
• 6a Ren WM, Liu Y, Lu XB. J. Org. Chem. 2014; 79: 9771
• 6b Naeimi H. J. Chin. Chem. Soc. 2008; 55: 1156
• 7 Bhosale SS, Joshi PL, Rao AS. Org. Prep. Proced. Int. 1992; 24: 695

For selected reviews on enzyme-catalyzed oxidative halogenations, see:
• 8a Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT. Chem. Rev. 2006; 106: 3364
• 8b Lewis JC, Coelho PS, Arnold FH. Chem. Soc. Rev. 2011; 40: 2003
• 9a Podgoršek A, Zupan M, Iskra J. Angew. Chem. Int. Ed. 2009; 48: 8424
• 9b Yonehara K, Kamata K, Yamaguchi K, Mizuno N. Chem. Commun. 2011; 47: 1692
• 9c Yang L, Lu Z, Stahl SS. Chem. Commun. 2009; 45: 6460
• 9d Podgorsek A, Eissen M, Fleckenstein J, Stavber S, Zupan M, Iskra J. Green Chem. 2009; 11: 120
• 9e Zhang GF, Liu RH, Xu Q, Ma LX, Liang XM. Adv. Synth. Catal. 2006; 348: 862
• 9f Yu T.-Y, Wang Y, Hu X.-Q, Xu P.-F. Chem. Commun. 2014; 50: 7817
• 9g Wang G.-W, Gao J. Green Chem. 2012; 14: 1125
• 9h Adimurthy S, Ghosh S, Patoliya PU, Ramachandraiah G, Agrawal M, Gandhi MR, Upadhyay SC, Ghosh PK, Ranu BC. Green Chem. 2008; 10: 232
• 9i Rana S, Bag S, Patra T, Maiti D. Adv. Synth. Catal. 2014; 356: 2453
• 9j Bedrač L, Iskra J. Adv. Synth. Catal. 2013; 355: 1243
• 10a Sels BF, De Vos DE, Jacobs PA. J. Am. Chem. Soc. 2001; 123: 8350
• 10b Pandit P, Gayen KS, Khamarui S, Chatterjee N, Maiti DK. Chem. Commun. 2011; 47: 6933
• 10c Dewkar GK, Narina SV, Sudalai A. Org. Lett. 2003; 5: 4501
• 10d Yang X, Wu J, Mao X, Jamison TF, Hatton TA. Chem. Commun. 2014; 50: 3245
• 10e Darensbourg DJ, Wilson SJ. J. Am. Chem. Soc. 2011; 133: 18610
• 10f Kozhushkov SI, Yufit DS, de Meijere A. Adv. Synth. Catal. 2005; 347: 255
• 10g Sels B, De Vos D, Buntinx M, Pierard F, Kirsch-De Mesmaeker A, Jacobs P. Nature 1999; 400: 855
• 10h Barluenga J, Gonzalez JM, Campos PJ, Asensio G. Angew. Chem. 1985; 97: 341
• 10i Rao DS, Reddy TR, Babachary K, Kashyap S. Org. Biomol. Chem. 2016; 14: 7529
• 10j Ashikari Y, Shimizu A, Nokami T, Yoshida J. J. Am. Chem. Soc. 2013; 135: 16070

For α-functionalization of alcohols, see:
• 11a Jeffrey JL, Terrett JA, MacMillan DW. Science 2015; 349: 1532
• 11b Shi L, Tu Y.-Q, Wang M, Zhang F.-M, Fan C.-A, Zhao Y.-M, Xia W.-J. J. Am. Chem. Soc. 2005; 127: 10836
• 11c Zhang S.-Y, Tu Y.-Q, Fan C.-A, Zhang F.-M, Shi L. Angew. Chem. Int. Ed. 2009; 48: 8761

For β-functionalization of alcohols, see:
• 11d Espino CG, Du Bois J. Angew. Chem. Int. Ed. 2001; 40: 598
• 11e Ren Z, Mo F, Dong G. J. Am. Chem. Soc. 2012; 134: 16991
• 11f Wappes EA, Nakafuku KM, Nagib DA. J. Am. Chem. Soc. 2017; 139: 10204
• 11g Bunescu A, Butcher TW, Hartwig JF. J. Am. Chem. Soc. 2018; 140: 1502

For γ-functionalization of alcohols, see:
• 11h Simmons EM, Hartwig JF. Nature 2012; 483: 70
• 11i Alderson JM, Phelps AM, Scamp RJ, Dolan NS, Schomaker JM. J. Am. Chem. Soc. 2014; 136: 16720
• 11j Espino CG, Wehn PM, Chow J, Du Bois J. J. Am. Chem. Soc. 2001; 123: 6935
• 11k Chen K, Richter JM, Baran PS. J. Am. Chem. Soc. 2008; 130: 7247
• 11l Zalatan DN, Du Bois J. J. Am. Chem. Soc. 2008; 130: 9220

For δ-functionalization of alcohols, see:
• 11m Hu A, Guo J.-J, Pan H, Tang H, Gao Z, Zuo Z. J. Am. Chem. Soc. 2018; 140: 1612
• 11n Wu X, Wang M, Huan L, Wang D, Wang J, Zhu C. Angew. Chem. Int. Ed. 2018; 57: 1640
• 11o Zhang J, Li Y, Zhang F, Hu C, Chen Y. Angew. Chem. Int. Ed. 2016; 55: 1872
• 11p Wang CY, Harms K, Meggers E. Angew. Chem. Int. Ed. 2016; 55: 13495
• 12a Cami-Kobeci G, Williams JM. J. Synlett 2003; 124
• 12b Ajvazi N, Stavber S. Molecules 2016; 21: 1325
• 12c Klimczyk S, Huang X, Farès C, Maulide N. Org. Biomol. Chem. 2012; 10: 4327
• 13a Song S, Sun X, Li X, Yuan Y, Jiao N. Org. Lett. 2015; 17: 2886
• 13b Liang Y.-F, Li X, Wang X, Zou M, Tang C, Liang Y, Song S, Jiao N. J. Am. Chem. Soc. 2016; 138: 12271
• 13c Liang Y.-F, Wu K, Song S, Li X, Huang X, Jiao N. Org. Lett. 2015; 17: 876
• 13d Song S, Li X, Sun X, Yuan Y, Jiao N. Green Chem. 2015; 17: 3285
• 13e Song S, Zhang Y, Yeerlan A, Zhu B, Liu J, Jiao N. Angew. Chem. Int. Ed. 2017; 56: 2487

For reviews on DMSO as the reagent in organic synthesis, see:
• 14a Wu X.-F, Natte K. Adv. Synth. Catal. 2016; 358: 336
• 14b Jones-Mensah E, Karki M, Magolan J. Synthesis 2016; 48: 1421
• 15a Huang H, Tang L, Liu Q, Xi Y, He G, Zhu H. Chem. Commun. 2016; 52: 5605
• 15b Kawaguchi T, Miyata H, Ataka K, Mae K, Yoshida J. Angew. Chem. Int. Ed. 2005; 44: 2413
• 15c Ge W, Wei Y. Green Chem. 2012; 14: 2066
• 15d Chen J, Li G, Xie Y, Liao Y, Xiao F, Deng G.-J. Org. Lett. 2015; 17: 5870
• 15e Mal K, Kaur A, Haque F, Das I. J. Org. Chem. 2015; 80: 6400
• 15f Sun J.-G, Weng W.-Z, Li P, Zhang B. Green Chem. 2017; 19: 1128
• 15g Liang Y.-F, Yuan Y, Shen T, Song S, Jiao N. Chin. J. Chem. 2018; 36: 233
• 15h Mupparapu N, Khan S, Battula S, Kushwaha M, Gupta AP, Ahmed QN, Vishwakarma RA. Org. Lett. 2014; 16: 1152
• 15i Kohmoto S, Kobayashi T, Minami J, Ying X, Yamaguchi K, Karatsu T, Kitamura A, Kishikawa K, Yamamoto A. J. Org. Chem. 2001; 66: 66
• 15j Khenkin AM, Neumann R. J. Org. Chem. 2002; 67: 7075
• 15k Saba S, Rafique J, Braga AL. Adv. Synth. Catal. 2015; 357: 1446
• 16a Tomita R, Yasu Y, Koike T, Akita M. Angew. Chem. Int. Ed. 2014; 53: 7144
• 16b Ashikari Y, Nokami T, Yoshida J. J. Am. Chem. Soc. 2011; 133: 11840
• 16c Ashikari Y, Nokami T, Yoshida J. Org. Lett. 2012; 14: 938
• 16d Xu R, Wan J.-P, Mao H, Pan Y. J. Am. Chem. Soc. 2010; 132: 15531
• 16e Wu X, Gao Q, Geng X, Zhang J, Wu YD, Wu A. Org. Lett. 2016; 18: 2507
• 16f Xiang JC, Cheng Y, Wang M, Wu Y, Wu A. Org. Lett. 2016; 18: 4360
• 16g Deshidi R, Kumar M, Devari S, Shah BA. Chem. Commun. 2014; 50: 9533
• 16h Li X, Song S, Jiao N. Acta Chim. Sin. 2017; 75: 1202
• 16i Reddi RN, Prasad PK, Sudalai A. Angew. Chem. Int. Ed. 2015; 54: 14150
• 16j Wu X, Gao Q, Liu S. Wu A. 2014; 16: 2888
• 16k Song S, Huang X, Liang Y.-F, Tang C, Li X, Jiao N. Green Chem. 2015; 17: 2727
• 16l Gao Q, Wu X, Liu S, Wu A. Org. Lett. 2014; 16: 1732
• 16m Gao Q, Zhang J, Wu X, Liu S, Wu A. Org. Lett. 2015; 17: 134
• 17 Majetich G, Hicks R, Reister S. J. Org. Chem. 13
• 18 Karki M, Magolan J. J. Org. Chem. 2015; 80: 3701
• 19a Sayer JR, Wallden K, Pesnot T, Campbell F, Gane PJ, Simone M, Koss H, Buelens F, Boyle TP, Selwood DL, Waksman G, Tabor AB. Bioorg. Med. Chem. 2014; 22: 6459
• 19b Neyyappadath RM, Chisholm R, Greenhalgh MD, Rodríguez-Escrich C, Pericàs MA, Hähner G, Smith AD. ACS Catal. 2018; 8: 1067
• 19c Wei S, Messerer R, Tsogoeva SB. Chem. Eur. J. 2011; 17: 14380
• 20a Mislow K, Simmons T, Melillo J, Ternay A. J. Am. Chem. Soc. 1964; 86: 1452
• 20b Floyd M, Du MT, Fabio PF, Jacob LA, Johnson BD. J. Org. Chem. 1984; 50: 5022