CC BY ND NC 4.0 · Synlett 2019; 30(04): 437-441
DOI: 10.1055/s-0037-1610385
letter
Copyright with the author

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

Lingsheng Ai
a  State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: ssong@bjmu.edu.cn   Email: jiaoning@pku.edu.cn
,
Weijin Wang
a  State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: ssong@bjmu.edu.cn   Email: jiaoning@pku.edu.cn
,
Jialiang Wei
a  State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: ssong@bjmu.edu.cn   Email: jiaoning@pku.edu.cn
,
Qing Li
a  State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: ssong@bjmu.edu.cn   Email: jiaoning@pku.edu.cn
,
Song Song*
a  State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: ssong@bjmu.edu.cn   Email: jiaoning@pku.edu.cn
b  State Key Laboratory of Drug Research Shanghai Institute of Materia Medical Chinese Academy of Sciences, Shanghai 201203, P. R. of China
,
a  State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: ssong@bjmu.edu.cn   Email: jiaoning@pku.edu.cn
b  State Key Laboratory of Drug Research Shanghai Institute of Materia Medical Chinese Academy of Sciences, Shanghai 201203, P. R. of China
› Author Affiliations
Financial support from the National Basic Research Program of China (973 Program) (grant No. 2015CB856600), the National Natural Science Foundation of China (Nos. 21602005, 21632001, 21772002), and the State Key Laboratory of Drug Research are greatly appreciated.
Further Information

Publication History

Received: 26 August 2018

Accepted after revision: 23 October 2018

Publication Date:
21 November 2018 (eFirst)

 

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.


#

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.

Zoom Image
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.

Zoom Image
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 Conditionsa

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.

Zoom Image
Scheme 3 Substrate scope of benzylic alcohols.a aReaction 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.

Zoom Image
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).

Zoom Image
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.

Zoom Image
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).

Zoom Image
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]

Zoom Image
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.


#

Supporting Information

  • 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

  • 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

 
Zoom Image
Scheme 1 The synthesis of halohydrins
Zoom Image
Scheme 2
Zoom Image
Scheme 3 Substrate scope of benzylic alcohols.a aReaction 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.
Zoom Image
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.
Zoom Image
Scheme 5
Zoom Image
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.
Zoom Image
Scheme 7
Zoom Image
Scheme 8 Proposed mechanism