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Highly Chemo- and Regioselective Vinylation of N-Heteroarenes with Vinylsulfonium Salts Mingwei Zhou, Xuefei Tan, Yimin Hu, Hong C Shen, and Xuhong Qian J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00682 • Publication Date (Web): 25 May 2018 Downloaded from http://pubs.acs.org on May 25, 2018
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The Journal of Organic Chemistry
Highly Chemo- and Regioselective Vinylation of N-Heteroarenes with Vinylsulfonium Salts Mingwei Zhou,a,b Xuefei Tan,b Yimin Hu,b Hong C. Shen,*b Xuhong Qian*a a
Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, Shanghai 200237, China
b
Roche Innovation Center Shanghai, Roche Pharmaceutical Research and Early Development, Shanghai 201203, China Supporting Information Placeholder
R2 Ar
Y X N H
R1
+
Ar
+
S - BPh
R1
Y
R2 Ar
DBU
X N
DMSO
4
Ar E-isomer up to 96%
ABSTRACT: An efficient chemo- and regioselective N-vinylation of N-heteroarenes has been developed using vinylsulfonium salts. The reaction proceeded under mild and transition-metal-free conditions and consistently provided moderate to high yields of vinylation products with 100% E-stereoselectivity. This reaction is also highly chemoselective, and compatible with a variety of functional groups, such as -NHR, -NH2, -OH, -COOH, ester, etc.
Nitrogen-containing heterocyclic compounds are common structural motifs of natural products, agrochemicals, and pharmaceuticals, and they are also useful intermediates in a number of industrial processes.1 Diverse vinylation derivatives of N-heteroarenes are widely incorporated in materials for potentially medicinal use (Figure 1),2 information recording and storage,3 construction of molecular muscle fiber mimics,4 and fluorescence labels.5 The E/Z configuration of the vinyl group can often result in different biological activity,6 photochromic properties and applications.7 As such, it is important to develop stereo- and chemoselective synthesis of alkenes which are present in natural products and molecules of particular biological significance in medicinal chemistry.8 In literature several methodologies have been developed for vinylation of N-heteroarenes (Scheme 1). In 1999, Knochel and colleagues published the first example of the addition of heterocyclic amines to alkynes using CsOH·H2O (eq 1).9 Later the Kondo group reported the addition of pyrrole to diphenylacetylene employing the phosphazene superbase P4-t-Bu.10 Verma et al. disclosed the regio- and stereoselective addition of N-heteroarenes to alkynes using KOH, and founded that the ratio of Z/E products was dependent upon time as well as the choice of base.11 Trofimov and co-workers found that regioselectivity was also dependent upon the structures of substrates.12 Recently, Mao reported that a high selectivity of Z-products could be obtained by heating the reaction mixture in DMSO with potassium phosphate.13 Other approaches include the use of trimethylsilylacetylene derivatives (eq 2)14 and 3-arylpropiolic acid (eq 3)15 as vinylation reagents. However, the regioselectivity of reaction is poor. Beside alkynes, vinyl halides are always used as the vinylation reagent for Nheteroarene substrates applying the Cu/Pd catalyst with good yields and excellent selectivity of the corresponding E-isomer products (eq 4).16 Since the nucleophilic groups like phenols,
N H
N N
O
O Cl
OH HO
HO
N HO
O
HO
NH
N
Cl
OH
N
N N
OH O O N H
O
N
OH
OH
b
a Serum/Glucocorticoid-Regulated Kinase 1 Inhibitors, SI-113
.CF
NH
N
N
3 CO2 H
N
N
N N
c
Chemopreventive Agents Lipoprotein Drugs Targeting Beta-Amyloid Disorders, Betanin
N
O
N O F N H
O
HN
F
ONa
F
OH
O
O
N
d Proto-Oncogene tyrosine-Protein Kinase Src Inhibitors; Abl Kinase Inhibitors, AP-24226
e DNA Topoisomerase II Inhibitors, Makaluvamine E
f PPARgamma Partial Agonists
Figure 1. N-heterocyclic vinyl arene compounds of medicinal interests.
amines, etc., could also react with vinyl halides, apparently this method may present the functional group compatibility issue.16 On the other hand, electrophiles such as bromides and iodides may be incompatible with conditions involving Cu or Pd catalysts. Therefore, the previously described procedures are rather limited in scope and selectivity, especially for the formation of E-isomers.17 A new method of highly chemo- and regio-selectivity transitionmetal-free vinylation of N-heteroarene to form pure E-isomers could be an attractive alternative approach to interesting natural products or compounds of medicinal chemistry interest, as described in scheme 1.
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Scheme 1. Vinylation of N-Heteroarenes Previous work:
Y
R2 Ar
X
Ar
R1
X
Base
Ar
R1
Y
Y
Si
R2 Ar
X
[Cu]
Ar
R1
OH
X N H
R2 Ar
Y
R2 Ar
X
R1
N H
eq 3 (Ref. 15)
Ar
Z/E
X
Ar
R1
X N
Base
Y
eq 2 (Ref. 14)
Ar
Z/E O
Y
R1
N
N H
eq 1 (Ref. 9~13)
Ar
Z/E
X
R2 Ar
R1
N
N H
R2 Ar
Y
R2 Ar
R2 Ar
Y X
R1
N
eq 4 (Ref. 16)
[Cu] or [Pd] E
Ar
This work: Ar
R2
S
+
BPh4-
R1
Y
R2 Ar
X
Ar
R1
Y X N
N H
1. High chemo-selectivity 2. High regio-selectivity 3. Broad group tolerance
Page 2 of 10
on the reaction yields (Table 1, entries 5-9). The use of DMSO and 3 equiv. of DBU provided the best yield (Table 1, entry 5). Similar to our previous report,18 the byproduct such as N-alkyl sulfonium (see Scheme 5) was observed if DBU was insufficient (e.g., < 3 equiv.) particularly for indole substrates containing an electrondonating group. A weaker base such as TEA gave a very poor yield of the desirable product primarily due to the formation of the N-alkyl sulfonium species, which failed to undergo further elimination (Table 1, entry 7). The 1H NMR of the isolated product showed that the coupling constant between the two hydrogen atoms on the double bond is 14.5 Hz. By comparing with the literature data,14 it can be confirmed that the product is solely the Eisomer. In addition, no Z-isomer product was observed by examining the crude reaction mixture in DMSO-d6 at different reaction time intervals (i.e. at every 30 min from time zero of the reaction up to 6 h, when the reaction was complete) via 1H NMR and LC/MS. Scheme 2. Vinylation of N-Heteroarenes Substratesa, c
DBU E
Ar +
S
Recently, we have developed a cyclopropanation method for oxindoles, and found that the vinylation byproduct of unprotected “N” could be obtained without the addition of zinc triflate under the reaction condition.18 This finding prompted us to explore the vinylation of N-heteroarene with various vinylsulfonium salts. In 2003, Mukaiyama and co-workers reported the synthesis of αimidostyrenes and 2-arylaziridines with β-phenylvinylsulfonium salts.19 In 2014 and 2015, the Aggarwal group reported the synthesis of 6- and 7-membered N-heterocycles, epoxide- and cyclopropane-fused heterocycles with α-phenylvinylsulfonium salts.20 However, the vinylation reaction of N-heteroarenes with αphenylvinylsulfonium salts has not been disclosed. Herein, we explored the chemo- and regio-selectivity of the vinylation of Nheteroarenes with α-vinylsulfonium salts.
R2
BPh4 -
R1
R1 R2
Ar N
Ar N H
DBU, DMSO 2b~2r
1b~1r
O Cl
O
HO
N
O
N
2b, 93%
N
2d, 61%
2c, 74% O
N
2e, 93%
OH O
O OH
N
N H
O2N
N
N
N
N
a
Table 1. Optimization of the Vinylation of Indole 1a
2f, 96%
+
2g, 92%
BPh4 N H
N Cl N
N
Base
N
1a
Entry 1 2 3 4 5 6 7 8 9 10
Base (equiv.) DBU (2.0) DBU (2.0) DBU (2.0) DBU (2.0) DBU (3.0) Cs2CO3 (2.0) TEA (3.0) K3PO4(3.0) NaOH (3.0) DBU (3.0)
N
N
N Cl
2a
Solvent DCM MeCN DMF DMSO DMSO DMF DMSO DMSO DMSO DMSO-d6
2i, 92%
2h, 86%
S
Yield (%)b 70 73 76 81 83 76
