Insertion of N-Tosylacetimidates/Acetimidamides onto Arynes via [2 + 2] Cycloaddition

Article abstract of DOI:10.1021/acs.joc.5b02907

A novel insertion reaction of N-tosylacetimidates and N-tosylacetimidamides onto arynes via a benzocyclobutene intermediate followed by ring cleavage is developed to afford o-benzylbenzoic acid derivatives in good yields. Interestingly, the use of cyclic

Full text of DOI:10.1021/acs.joc.5b02907

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Article
Insertion of N-tosylacetimidates/acetimidamides
onto arynes via [2+2] cycloaddition
Ramagonolla Kranthikumar, Rambabu Chegondi, and Srivari Chandrasekhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02907 • Publication Date (Web): 01 Mar 2016
Downloaded from http://pubs.acs.org on March 3, 2016
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Insertion of N-tosylacetimidates/acetimidamides onto arynes
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via [2+2] cycloaddition
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Ramagonolla Kranthikumar, Rambabu Chegondi and Srivari Chandrasekhar*
CSIRꢀIndian Institute of Chemical Technology, Division of Natural Product Chemistry,
Hyderabad 500007, India
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Eꢀmail: srivaric@iict.res.in
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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ABSTRACT: A novel insertion reaction of Nꢀtosylacetimidates and Nꢀtosylacetimidamides onto aryne
via benzocyclobutene intermediate followed by ring cleavage is developed to afford oꢀbenzyl benzoic
acid derivatives in good yields. Interestingly, the use of cyclic 2ꢀsulfonyliminoindolines provided two
distinct products such as azepanimines via [2+2] cycloaddtion and indolamines via protonation based on
solvent medium.
KEYWORDS: Insertion, aryne, Nꢀtosylacetimidates/acetimidamides, [2+2] cycloaddtion
INTRODUCTION
The alkyne functionality is one of the perfect backbones to organic chemistry.1 The diverse
behavior of this functionality is well utilized in both symmetrical and unsymmetrical environments in
aliphatic chemistry. The transient and highly reactive alkyne present in ‘aryne’ has provided new avenue
to this linear group. The highly strained acetylenic unit in aryne provides enormous opportunities for
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further derivatization.2 These arynes act as excellent dienophiles in DielsꢀAlder reaction,3 [2+2] and [3+2]
cycloadditions,2f insertion reactions,4 multiꢀcomponent coupling reactions (MCRs),5 and many more.2
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Scheme 1: Insertion reaction of arynes into CꢀC sigmaꢀbond cleavage reaction.
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A direct insertion of aryne (in situ preparation under mild condition using fluorideꢀinduced 1,2ꢀ
elimination of oꢀsilyl aryltriflates)6 into a CꢀC sigmaꢀbond generated variety of aromatic compounds.
Stoltz research group has successfully achieved insertion of βꢀketoesters into benzyne to form acylꢀalkyl
arenes (Scheme 1a).7 In their protocol, the products are generally classified as oꢀacyl phenylacetic acid
derivatives. Yoshida and coꢀworkers succeeded in acylfluorenylation of arynes.8a This group was also
prudent in addition of trifluoromethyl ketones into benzynes to furnish oꢀbenzyl trifluoroacylarenes
(Scheme 1b).8b Inspired by these results, we aimed at the synthesis of benzoic acid derivatives through
the CꢀC bond insertion on to aryne. However, initial attempts using 2ꢀaryl acetates as the CꢀC insertion
partners on to aryne were unfruitful (Scheme 1c). Many unsuccessful attempts using 2ꢀarylacetates
finally culminate in identifying Nꢀtosylacetamidate of aryl acetic acid as an ideal partner (Scheme 1c)
probably due to its lower pKa value of αꢀprotons compare to 2ꢀaryl acetates (ethyl 2ꢀphenylacetate pKa
23).9 The results are documented herein.
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RESULTS AND DISCUSSION
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Initially, direct installation of imidate and benzyl functionalities on insitu generated benzyne from 1a
using Nꢀtosylacetamidate 2a (prepared by an easy threeꢀcomponent coupling of terminal alkynes, sulfonyl
azide and alcohols or amines in presence of a copper catalyst and an amine base)10 was attempted under
mild conditions. To our utmost satisfaction, the insertion reaction was perfect with CsF and MeCN in less
than 5 h to generate the desired oꢀbenzyl benzimidate 3a in 81% yield (Scheme 2). We believe this
transformation operates through the cyclobutane intermediate A as postulated by earlier workers.7,8
Scheme 2: Initial result.
Among the tested reaction conditions varying fluoride sources and solvents (Table 1), the reaction in
presence of CsF in CH3CN at room temperature provided the best result. Other fluoride source such as
TBAF, KF/18ꢀCꢀ6 also gave 65% and 61% yields, respectively (table 1, entries 2 and 4). Further
screening of other solvents revealed that the insertion reaction gave moderate to good yields in the
presence of THF, CH2Cl2 and diethyl ether (table 1, entries 6ꢀ8). In case of CsF, decreasing the reaction
time did not show any significant variation on yields (table 1, entries 1 and 10).
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Table 1 Screening Optimal Conditions
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Standard reaction conditions: (a) The reaction was carried out with 1a (0.15 mmol), 2a (0.1 mmol), fluride source (0.25 mmol)
in solvent (0.2 M) at room temperature. [b] Yield of the isolated product. [c] 0.25 mmol of 18ꢀcrownꢀ6 was used as an addition
Synthetic utility of benzimidate 3a is shown in Scheme 3. The products thus obtained in insertion reaction
is distinctly unique with imidate group and is sensitive to DBU in DMFꢀwater to provide ethyl ester 4 in
90% yield, whereas exposure to harsh acid provided Nꢀtosylbenzamide 5 in 85% yield.9a The benzylic
methylene group in ester 4 (not accessible with other insertion protocols) is functionalized to ketone using
I2/tꢀBuOOH oxidation which gave benzophenone 6 in 75% yield.11 Controlled reduction of 3a with Redꢀ
Al at ꢀ78 oC furnished aldehyde 7 in 68% yield.9a
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Scheme 3: Further transformations of oꢀbenzyl benzimidate 3a.
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Next, we surveyed various substrates to determine the scope of the reaction under aforementioned optimal
conditions. We began our studies on insertion reaction using simple benzyne precursor 1a with various
Nꢀtosylacetamidates and Nꢀtosylacetimidamides 2 (Table 2). Substrates with both electronꢀdonating and
electronꢀwithdrawing groups on aryl groups of imidates participated in this reaction; electronꢀrich
substrates 2bꢀc as well as electronꢀdeficient ones 2dꢀf including orthoꢀsubstituted Nꢀtosylacetamidates
gave products 3bꢀf in comparable yields in the range of 72ꢀ80% (Table 2, entries 2ꢀ6). Similarly, Nꢀ
tosylacetimidamides substituted with natural amino acids 2gꢀj efficiently underwent the insertion reaction
to furnish corresponding oꢀbenzylation products 3gꢀj in good yields (Table 2, entries 7ꢀ10).
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Table 2: Scope for imidatesa
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Standard reaction conditions: (a) The reaction was carried out with 1a (0.15 mmol),
(0.25 mmol) in CH3CN (0.2M) at room temperature. [b] Yield of the isolated product.
2 (0.1 mmol), CsF
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After investigation of the scope of acetamidates and acetimidamides, different symmetrical and
unsymmetrical substituents on the benzyne precursors 1bꢀd were tested in insertion reaction with a variety
of Nꢀtosylacetamidates 2 (Table 3). The electronꢀrich methylenedioxy aryne precursor 1b inserted
smoothly onto imidates 2d and 2e to furnish oꢀbenzylated products 3k and 3l, respectively in good yields
(Table 3, entries 1 & 2). Next, we observed the coupling of unsymmetrical aryne precursor 1c with
imidates 2aꢀe to produce the benzimidates 3mꢀq in 65ꢀ75% yields (Table 3, entries 3ꢀ7). This reaction
furnished all insertion adducts 3mꢀq as single regioisomers as claimed by earlier workers.12 Singleꢀcrystal
Xꢀray analysis of compound 3q unambiguously established its regioselective structure (see the Supporting
Information).13 Another symmetrical aryne precursor 1d also afforded oꢀbenzyl benzimidates 3r and 3s
in excellent yields (Table 3, entries 8 & 9). Disappointingly, aliphatic imidate failed to participate the
insertion reaction under the present conditions (see the experimental section).
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Table 3: Scope for arynesa.
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Standard reaction conditions: (a) The reaction was carried out with 1 (0.15 mmol), 2 (0.1 mmol), CsF (0.25 mmol)
in CH3CN (0.2M) at room temperature. [b] Yield of the isolated product
.
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Table 4: Tunable reactivity of 2ꢀsulfonyliminoindolinesa
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Standard reaction conditions: (a)The reaction was carried out with 1a (0.2 mmol), 8 (0.1 mmol), fluride source (0.25 mmol) in
solvent (0.2 M) at room temperature. [b] Yield of the isolated product.
Enticed by these results, we investigated the reactivity of cyclic imidamides14 in insertion reaction (Table
4). At first, we performed the reaction of simple benzyne precursor 1a (2 equiv) with 2ꢀ
sulfonyliminoindolines 8a (1 equiv) under standard reaction conditions in CH3CN using CsF and TBAF
independently, as fluoride sources (entry 1 & 2). Surprisingly, we observed diphenyl substituted
indolamine 9a as major product along with trace amount of ring expansion product 10a (≤5%). We
hypothesized that the reaction proceeded through αꢀarylation and subsequent protonation with CH3CN
followed by Nꢀarylation with benzyne to give 9a as major product. Formation of the minor product 10a
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was due to the expected benzocyclobutene intermediate. The structure of 9a was fully characterized by
NMR spectroscopy, IR, and HRMS data. Singleꢀcrystal Xꢀray analysis of compound 9a has also
established the indole structure (Scheme 4).13 Interestingly, the same reaction with both CsF and TBAF
in THF as solvent at room temperature gave major ring expansion product 10a and minor amount of
diarylation product 9a (Table 4, entries 3 & 4). The starting material 8b also gave corresponding products
9b and 10b with similar kind of ratios in two different solvents. To probe the reaction mechanism in
acetonitrile solvent, the reaction was conducted with 1a and 8a in the presence of CsF in CD3CN to
produce compound 11 with deuterium incorporation at orthoꢀposition of two phenyl rings (Scheme 4).
This clearly indicates the formation of 11 was proceeded via protonation with solvent. We also observed
the reaction with equimolar ratio of starting materials 1a and 8a in the presence of CsF/CH3CN as well
as TBAF/THF conditions. In this case, the insertion reaction produced similar kind of product ratios with
lower yields and starting material recovery.10
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Scheme 4: Mechanistic study
In summary, insertion of Nꢀtosylacetimidates and Nꢀtosylacetimidamides onto various substituted
benzynes is demonstrated. The products thus obtained could be diversified to building blocks with various
functionalities. The cyclic 2ꢀsulfonyliminoindolines also were inserted onto benzyne to provide ring
expansion products via benzocyclobutene intermediate and diphenyl substituted indolamines via
protonation based on solvent medium.
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EXPERIMENTAL SECTION
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General information: Unless otherwise noted, all reagents were used as received from commercial
suppliers without further purification. All reactions were performed under nitrogen atmosphere and in a
flameꢀdried or ovenꢀdried glassware with magnetic stirring. Acetonitrile was dried in the presence of
calcium chloride and distilled prior to use. THF was dried in the presence of sodium metal using
benzophenone as indicator and distilled prior to use. Reactions were monitored using thinꢀlayer
chromatography (SiO2). TLC plates were visualized with UV light (254 nm), iodine treatment or using
pꢀanisaldehyde stain. Column chromatography was carried out using silica gel (60ꢀ120 mesh & 100ꢀ200
mesh) packed in glass columns. NMR spectra were recorded at 300, 400, 500 MHz (H) and at 75, 101,
126 MHz (C), respectively. Chemical shifts (δ) are reported in ppm, using the residual solvent peak in
CDCl3 (H: δ = 7.26 and C: δ = 77.1 ppm) as internal standard, and coupling constants (J) are given in Hz.
HRMS were recorded using ESIꢀTOF techniques.
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a. Representative procedure for the preparation of imidates and acetimidamides:
General procedure: To a vigorously stirred solution alkyne (1 equiv), pꢀtoluenesulfonylazide (1.2 equiv),
alcohol or amine (1.2 equiv) and CuI (0.1 equiv) in CH2Cl2 (0.5 M) was slowly added Et3N (2.5 equiv,
0.084 mL, 0.6 mmol) at room temperature under nitrogen atmosphere and stirred for 12 h. Later, the
reaction mixture was diluted with CH2Cl2 and then extracted with aqueous NH4Cl solution. The combined
organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified
by silica gel column chromatography (EtOAc/hexanes) to give the desired imidate or imidamide 2 in good
yields.
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Ethyl (Z)-2-phenyl-N-tosylacetimidate (2a)10: Prepared according to the general procedure as described
above in 85% yield (2.0 g). It was purified by flash chromatography (6% EtOAc/hexanes) to afford a
yellow semisolid; 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.35 – 7.13 (m, 7H), 4.18 (s,
2H), 4.08 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.1,
143.2, 139.1, 133.7, 129.6, 129.4, 128.6, 127.2, 126.7, 64.9, 39.7, 21.6, 13.6; IR (neat) υmax 3230, 3040,
2921, 1718, 1540, 1460, 1380, 1168, 1086, 760; HRMS (ESI) calcd for C17H20NO3S [M+H]+: 318.1158
; found: 318.1149.
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Ethyl (Z)-2-(o-tolyl)-N-tosylacetimidate (2b): Prepared according to the general procedure as described
above in 82% yield (2.3 g). It was purified by flash chromatography (6% EtOAc/hexanes) to afford an
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yellow oil; H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.19 – 7.09
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(m, 4H), 4.26 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); C
NMR (75 MHz, CDCl3) δ 173.6, 143.2, 139.1, 136.8, 132.5, 130.2, 129.8, 129.4, 127.3, 126.7, 126.0,
64.9, 37.6, 21.6, 19.7, 13.5; IR (neat) υmax 3244, 3068, 2923, 2853, 1919, 1715, 1597, 1444, 1344, 1086,
881, 815, 750, 664; HRMS (ESI) calcd for C18H21NNaO3S [M+Na]+: 354.1134; found: 354.1155
Ethyl (Z)-2-(3,4-dimethoxyphenyl)-N-tosylacetimidate (2c): Prepared according to the general
procedure as described above in 76% yield (1.7 g). It was purified by flash chromatography (10%
EtOAc/hexanes) to afford a yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.29 (d, J
= 8.0 Hz, 2H), 6.97 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.2, 2.0 Hz, 1H), 6.81 (dd, J = 8.2, 4.1 Hz, 1H), 4.16
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(s, 2H), 4.13 (q, J = 7.08 Hz, 2H), 3.87(s, 3H), 3.86 (s, 3H), 2.42 (s, 3H), 1.21 (t, J = 8.3 Hz, 3H); C
NMR (75 MHz, CDCl3) δ 173.3, 148.8, 148.2, 143.2, 139.2, 129.4, 126.6, 126.0, 121.9, 112.8, 111.1,
64.8, 55.9, 39.8, 21.5, 13.6; IR (neat) υmax3250, 2924, 2851, 1725, 1594, 1515, 1457, 1306, 1264, 1156,
1090, 1027, 854, 769, 688; HRMS (ESI) calcd for C19H23NNaO5S [M+Na]+: 400.1189; found: 400.1207.
Ethyl (Z)-2-([1,1'-biphenyl]-4-yl)-N-tosylacetimidate (2d): Prepared according to the general
procedure as described above in 85% yield (1.9 g). It was purified by flash chromatography (6%
EtOAc/hexanes) to afford a pale yellow solid; m.p = 180 oC, 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J =
8.4 Hz, 2H), 7.43 (ddd, J = 4.1, 3.3, 1.8 Hz, 2H), 7.41 – 7.36 (m, 2H), 7.31 – 7.25 (m, 4H), 7.22 – 7.16
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(m, 1H), 7.16 – 7.10 (m, 2H), 4.12 (s, 2H), 4.01 (q, J = 7.12 Hz, 2H), 2.26 (s, 3H), 1.07 (q, J = 7.02 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 173.1, 143.4, 140.9, 140.2, 139.2, 132.8, 130.1, 129.5, 128.9, 127.4,
127.2, 126.8, 65.0, 39.5, 21.7, 13.7; IR (neat) υmax3249, 3031, 2923, 1718, 1598, 1446, 1342, 1168,
1086, 815, 755, 699; HRMS (ESI) calcd for C23H24NO3S [M+H]+: 394.1471; found: 394.1502.
Ethyl (E)-2-(3-chlorophenyl)-N-tosylacetimidate (2e): Prepared according to the general procedure as
described above in 80% yield (2.0 g). It was purified by flash chromatography (8% EtOAc/hexanes) to
afford a pale yellow semisolid; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.34 – 7.20 (m,
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6H), 4.22 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); C NMR (75 MHz,
CDCl3) δ 172.2, 143.4, 138.9, 135.5, 134.3, 129.8, 129.6, 129.4, 127.9, 127.5, 126.7, 65.0, 39.2, 21.6,
13.5; IR (neat) υmax 3240, 2924, 2855, 1718, 1597, 1575, 1441, 1347, 1170, 1121, 1086, 840, 792, 683;
HRMS (ESI) calcd for C17H18ClNNaO3S [M+Na]+: 374.0588; found: 374.0593.
Ethyl (E)-2-(2-bromophenyl)-N-tosylacetimidate (2f): Prepared according to the general procedure as
described above in 80% yield (1.7 g). It was purified by flash chromatography (7% EtOAc/hexanes) to
afford a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.36 Hz, 2H), 7.54 (dd, J = 6.2, 2.2
Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.28 – 7.20 (m, 2H), 7.16 – 7.10 (m, 1H), 4.40 (s, 2H), 4.16 (q, J = 7.13
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Hz, 2H), 2.43 (s, 3H), 1.13 (t, J = 7.09 Hz, 3H); C NMR (101 MHz, CDCl3) δ 172.3, 143.3, 138.9,
134.1, 132.7, 131.2, 129.4, 128.9, 127.5, 126.8, 125.1, 65.1, 40.6, 21.6, 13.4; IR (neat) υmax 3062, 2985,
1919, 1598, 1472, 1371, 1306, 1157, 1093, 1026, 893, 749, 689; HRMS (ESI) calcd for C17H19BrNO3S
[M+H]+: 396.0264; found: 396.0297.
Methyl (Z)-4-phenyl-3-(tosylimino)butanoate (2g): Prepared according to the general procedure as
described above in 82% yield (2.8 g). It was purified by flash chromatography (15% EtOAc/hexanes) to
afford a pale yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.43 – 7.35 (m, 3H), 7.28
(d, J = 8.0 Hz, 2H), 7.26 – 7.23 (m, 2H), 5.86 (s, 1H), 4.31 (s, 2H), 3.98 (d, J = 4.7 Hz, 2H), 3.66 (s, 3H),
2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.1, 166.5, 142.5, 140.4, 132.6, 130.2, 129.5, 129.2, 128.3,
126.5, 52.6, 43.4, 39.5, 21.5; IR (neat) υmax, 3354, 2955, 2925, 1749, 1560, 1275, 1145, 1091, 813, 759,
694; HRMS (ESI) calcd for C18H21N2O4S [M+H]+: 361.1217; found: 361.1239.
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Methyl (Z)-(2-phenyl-1-(tosylimino)ethyl)-L-alaninate (2h): Prepared according to the general
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EtOAc/hexanes) to afford a pale yellow oil; [α]D ꢀ7.64 (c 1.5, CHCl3), H NMR (300 MHz, CDCl3) δ
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7.83 (d, J = 8.2 Hz, 2H), 7.46 – 7.34 (m, 3H), 7.32 – 7.20 (m, 4H), 5.98 (d, J = 6.0 Hz, 1H), 4.53 (p, J =
7.0 Hz, 1H), 4.30 (s, 2H), 3.64 (s, 3H), 2.43 (s, 3H), 1.31 (d, J = 7.08 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 172.3, 165.7, 142.3, 140.5, 132.8, 130.0, 129.4, 129.2, 128.2, 126.4, 52.6, 50.1, 39.5, 21.5, 17.3; IR
(neat) υmax 3306, 3065, 2926, 2855, 2423, 1914, 1744, 1558, 1453, 1360, 1277, 1147, 1023, 814, 763,
700; HRMS (ESI) calcd for C19H23N2O4S [M+H]+: 375.1373; found: 375.1404.
Methyl (Z)-(2-phenyl-1-(tosylimino)ethyl)valinate (2i): Prepared according to the general procedure as
described above in 82% yield (3.2 g). It was purified by flash chromatography (12% EtOAc/hexanes) to
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afford a yellow oil; [α]D ꢀ22.30 (c 0.9, CHCl3), H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H),
7.41 (t, J = 7.3 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.30 – 7.24 (m, 4H), 5.71 (d, J = 7.0 Hz, 1H), 4.47 (dd,
J = 7.8, 4.7 Hz, 1H), 4.40 (d, J = 17.5 Hz, 1H), 4.25 (d, J = 17.5 Hz, 1H), 3.61 (s, 3H), 2.42 (s, 3H), 2.13
– 1.98 (m, 1H), 0.75 (d, J = 6.9 Hz, 3H), 0.67 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.1,
166.4, 142.3, 140.5, 132.8, 130.1, 129.5, 129.2, 128.3, 126.3, 59.0, 52.2, 39.8, 30.7, 21.5, 18.7, 17.7; IR
(neat) υmax 3230, 2960, 2926, 2855, 1743, 1551, 1455, 1369, 1274, 1211, 1146, 1090, 1032, 812, 759,
697; HRMS (ESI) calcd for C21H26N2NaO4S [M+Na]+: 425.1505; found: 425.1536.
Methyl (R,Z)-2-phenyl-2-(2-phenyl-N'-tosylacetimidamido)acetate (2j): Prepared according to the
general procedure as described above in 86% yield (3.2 g). It was purified by flash chromatography (12%
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EtOAc/hexanes) to afford a pale yellow semisolid; [α]D +26.82 (c 0.3, CHCl3), H NMR (400 MHz,
CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.45 – 7.36 (m, 3H), 7.33 – 7.26 (m, 4H), 7.25 (dd, J = 3.3, 1.7 Hz,
1H), 7.20 (d, J = 8.0 Hz, 2H), 7.09 (dt, J = 3.7, 2.2 Hz, 2H), 6.35 (d, J = 5.7 Hz, 1H), 5.40 (d, J = 6.1 Hz,
1H), 4.31 (q, J = 17.5 Hz, 2H), 3.58 (s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.3, 165.3,
142.2, 140.3, 135.2, 132.7, 130.0, 129.5, 129.0, 128.9, 128.8, 128.3, 127.3, 126.3, 58.3, 53.0, 39.6, 21.5;
IR (neat) υmax 3320, 2925, 2855, 1746, 1547, 1273, 1219, 1147, 1092, 773, 698; HRMS (ESI) calcd for
C24H24N2NaO4S [M+Na]+: 459.1349; found: 459.1372.
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Ethyl (Z)-N-tosylhexanimidate (S1): Prepared according to the general procedure as described above in
88% yield (3.0 g). It was purified by flash chromatography (5% EtOAc/hexanes) to afford a colourless
oil; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 4.14 (q, J = 7.0 Hz,
2H), 2.86 (t, J = 7.64 Hz, 2H), 2.43 (s, 3H), 1.69 (ddd, J = 15.2, 8.9, 6.6 Hz, 2H), 1.42 – 1.30 (m, 4H),
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1.26 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H); C NMR (101 MHz, CDCl3) δ 176.4, 143.1, 139.4,
129.4, 126.6, 64.5, 34.0, 31.5, 25.7, 22.3, 21.5, 13.9, 13.7; IR (neat) υmax 2958, 2933, 1601, 1463, 1374,
1311, 1158, 1094, 1022, 889, 815, 690; HRMS (ESI) calcd for C15H23NNaO3S [M+Na]+: 320.1291;
found: 320.1303.
b. General Optimal Reaction Procedure for the Insertion Reaction: A oven dried roundꢀbottom flask
equipped with a magnetic stirring bar was charged with aryne precursor 1 (0.3 mmol), imidate or
imidamide 2 (0.2 mmol) and CsF (0.5 mmol) in CH3CN (0.2 M) under nitrogen atmosphere. The resulting
mixture was stirred at room temperature for 4 hours. After the reaction was finished, the solvent was
evaporated and the residue was purified by flash column chromatography (hexanes/ethyl acetate) to give
the corresponding product.
Ethyl (Z)-2-benzyl-N-tosylbenzimidate (3a): Prepared according to the general procedure as described
above in 81% yield (100 mg). It was purified by flash chromatography (7% EtOAc/hexanes) to afford a
pale yellow semisolid, 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.40 – 7.32 (m, 2H), 7.27
(d, J = 3.2 Hz, 1H), 7.25 – 7.16 (m, 5H), 7.14 – 7.07 (m, 3H), 4.24 (q, J = 7.1 Hz, 2H), 3.89 (s, 2H), 2.41
(s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.7, 143.3, 139.9, 138.9, 138.3, 132.5,
130.7, 130.2, 129.4, 128.5, 128.0, 127.2, 126.4, 125.9, 65.5, 39.3, 21.7, 13.7; IR (neat) υmax 2925, 2854,
1608, 1592, 1304, 1155, 1091, 940, 736; HRMS (ESI) calcd for C23H24NO3S [M+H]+: 394.1471; found:
394.1474.
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Ethyl (Z)-2-(2-methylbenzyl)-N-tosylbenzimidate (3b): Prepared according to the general procedure as
described above in 75% yield (91 mg). It was purified by flash chromatography (7% EtOAc/hexanes) to
afford a yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.3 Hz, 2H), 7.38 – 7.29 (m, 2H), 7.24 (dd,
J = 11.5, 4.4 Hz, 3H), 7.18 – 7.08 (m, 3H), 7.00 (d, J = 6.9 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 4.28 (q, J =
7.1 Hz, 2H), 3.84 (s, 2H), 2.42 (s, 3H), 2.18 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 171.9, 143.3, 138.9, 137.8, 137.6, 136.9, 132.5, 130.7, 130.5, 130.3, 129.4, 129.2, 127.9, 127.2, 126.8,
126.1, 125.8, 65.5, 36.7, 21.7, 19.8, 13.7; IR (neat) υmax 2981, 2925, 1608, 1450, 1303, 1156, 1091,
1014, 939, 814, 745, 686; HRMS (ESI) calcd for C24H26NO3S [M+H]+: 408.1628; found: 408.1646.
Ethyl (Z)-2-(3,4-dimethoxybenzyl)-N-tosylbenzimidate (3c): Prepared according to the general
procedure as described above in 72% yield (86 mg). It was purified by flash chromatography (6%
EtOAc/hexanes) to afford a yellow oil Yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 8.3 Hz, 2H),
7.33 – 7.27 (m, 2H), 7.20 (d, J = 3.7 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 7.6 Hz, 1H), 6.69 (d,
J = 8.1 Hz, 1H), 6.65 – 6.59 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.77 (s, 3H), 3.72 (s, 3H),
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2.34 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 170.5, 147.8, 146.4, 142.1, 137.5,
131.3, 129.6, 128.9, 128.2, 126.8, 125.9, 124.8, 120.2, 111.5, 109.8, 64.3, 54.8, 54.7, 37.7, 20.5, 12.6; IR
(neat) υmax 2925, 2854, 1785, 1744, 1593, 1514, 1464, 1304, 1261, 1155, 1090, 1027, 940, 771, 686;
HRMS (ESI) calcd for C25H28NO5S [M+H]+: 454.1683; found: 454.1705.
Ethyl (Z)-2-([1,1'-biphenyl]-4-ylmethyl)-N-tosylbenzimidate (3d): Prepared according to the general
procedure as described above in 80% yield (95 mg). It was purified by flash chromatography (8%
EtOAc/hexanes) to afford a pale yellow solid (80%); m.p = 220 oC; 1H NMR (300 MHz, CDCl3) δ 7.55
(d, J = 8.3 Hz, 2H), 7.51 – 7.45 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.6 Hz, 3H), 7.26 – 7.16
(m, 3H), 7.15 – 7.07 (m, 5H), 4.16 (q, J = 7.1 Hz, 2H), 3.88 (s, 2H), 2.31 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 171.6, 143.2, 141.0, 139.3, 139.0, 138.9, 138.3, 132.6, 130.8, 130.3, 129.8,
129.3, 128.9, 128.5, 128.2, 127.3, 127.2, 127.1, 126.1, 65.5, 39.1, 21.7, 13.7; IR (neat) υmax 3027, 2923,
2405, 1593, 1487, 1304, 1155, 1091, 1010, 940, 761, 686; HRMS (ESI) calcd for C29H28NO3S [M+H]+:
470.1784; found: 470.1794.
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Ethyl (Z)-2-(3-chlorobenzyl)-N-tosylbenzimidate (3e): Prepared according to the general procedure as
described above in 72% yield (87 mg). It was purified by flash chromatography (6% EtOAc/hexanes) to
afford a colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.42 – 7.33 (m, 2H), 7.28
(t, J = 6.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.19 – 7.15 (m, 2H), 7.13 – 7.07 (m, 2H), 7.02 (d, J = 6.6
Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 2.42 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.5, 143.4, 142.0, 138.8, 137.4, 134.3, 132.6, 130.9, 130.1, 129.8, 129.4, 128.2, 127.6, 127.1,
126.6, 126.3, 65.5, 39.0, 21.7, 13.6; IR (neat) υmax 2925, 2854, 1738, 1592, 1448, 1304, 1155, 1091,
1014, 1014, 941, 708, 685; HRMS (ESI) calcd for C23H23ClNO3S [M+H]+: 428.1082; found: 428.1084.
Ethyl (Z)-2-(2-bromobenzyl)-N-tosylbenzimidate (3f): Prepared according to the general procedure as
described above in 75% yield (89 mg). It was purified by flash chromatography (5% EtOAc/hexanes) to
afford a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.54 (dt, J = 7.8, 3.9 Hz, 1H),
7.47 – 7.35 (m, 2H), 7.34 – 7.28 (m, 1H), 7.24 – 7.16 (m, 3H), 7.10 – 7.00 (m, 3H), 4.26 (q, J = 7.1 Hz,
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2H), 3.93 (s, 2H), 2.40 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H); C NMR (126 MHz, CDCl3) δ 171.5, 143.2,
139.2, 138.6, 136.6, 132.5, 132.5, 131.4, 130.8, 129.9, 129.2, 128.3, 128.0, 127.5, 127.0, 126.1, 124.7,
65.4, 39.1, 21.6, 13.5; IR (neat) υmax 2984, 1591, 1469, 1444, 1370, 1307, 1219, 1156, 1091, 1022, 939,
814, 769, 708, 686; HRMS (ESI) calcd for C23H23BrNO3S [M+H]+: 472.0577; found: 472.0597.
Methyl (Z)-((2-benzylphenyl)(tosylimino)methyl)glycinate (3g): Prepared according to the general
procedure as described above in 83% yield (100 mg). It was purified by flash chromatography (16%
EtOAc/hexanes) to afford a brown oil; 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.29 (dt,
J = 4.2, 1.7 Hz, 1H), 7.24 (d, J= 8.7 Hz, 2H), 7.22 – 7.19 (m, 1H), 7.13 – 7.08 (m, 3H), 7.03 – 6.98 (m,
2H), 6.86 (dd, J = 7.1, 2.2 Hz, 2H), 4.35 (s, 2H), 4.27 (s, 2H), 3.60 (s, 3H), 2.41 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 168.6, 166.5, 142.2, 141.8, 140.5, 134.2, 129.6, 129.1, 128.9, 128.5, 128.2, 127.9, 126.5,
54.5, 52.2, 37.1, 21.5; IR (neat) υmax 3320, 2925, 2850, 1750, 1543, 1495, 1283, 1216, 1147, 1090, 773,
701; HRMS (ESI) calcd for C24H25N2O4S [M+H]+: 437.1530; found: 437.1510.
Methyl (Z)-((2-benzylphenyl)(tosylimino)methyl)-D-alaninate (3h): Prepared according to the general
procedure as described above in 80% yield (96 mg). It was purified by flash chromatography (15%
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EtOAc/hexanes) to afford a brown oill; [α]D ꢀ49.92 (c 0.4, CHCl3), 1H NMR (300 MHz, CDCl3) δ 7.81
(d, J = 8.2 Hz, 2H), 7.38 – 7.27 (m, 3H), 7.25 – 7.17 (m, 2H), 7.15 – 7.08 (m, 3H), 6.93 – 6.79 (m, 3H),
4.73 (q, J = 7.3 Hz, 1H), 4.22 (q, J = 15.3 Hz, 2H), 3.57 (s, 3H), 2.41 (s, 3H), 1.20 (d, J = 7.3 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 171.6, 165.6, 142.2, 140.6, 139.0, 134.4, 129.4, 129.3, 129.1, 129.1, 128.9,
128.5, 128.4, 128.2, 126.5, 126.5, 59.0, 52.2, 38.0, 21.5, 15.2; IR (neat) υmax 3320, 2925, 2856, 2881,
1746, 1541, 1495, 1455, 1377, 1283, 1208, 1149, 1090, 1016, 809, 760, 703; HRMS (ESI) calcd for
C25H26N2NaO4S [M+Na]+: 473.1505; found: 473.1531.
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Methyl (Z)-((2-benzylphenyl)(tosylimino)methyl)valinate (3i): Prepared according to the general
procedure as described above in 78% yield (92 mg). It was purified by flash chromatography (16%
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EtOAc/hexanes) to afford a colourless oil; [α]D ꢀ113.28 (c 0.2, CHCl3); H NMR (500 MHz, CDCl3) δ
7.83 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.8 Hz, 3H), 7.19 (t, J = 7.2 Hz, 2H), 7.13 – 7.03 (m, 4H), 6.98 (s,
1H), 6.81 – 6.76 (m, 2H), 4.33 (d, J = 8.6 Hz, 1H), 4.30 (d, J = 15.3 Hz, 1H), 4.18 (d, J = 15.2 Hz, 1H),
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3.56 (s, 3H), 2.43 (s, 3H), 2.19 – 2.28 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H); C
NMR (126 MHz, CDCl3) δ 170.3, 166.0, 142.2, 140.5, 134.3, 129.1, 128.7, 128.6, 128.1, 126.5, 126.5,
70.3, 51.8, 38.1, 28.1, 21.5, 20.7; IR (neat) υmax 3306, 2966, 1744, 1540, 1494, 1284, 1205, 1149, 1091,
1013, 771, 704; HRMS (ESI) calcd for C27H31N2O4S [M+H]+: 479.1999 ; found: 479.1999.
Methyl (S,Z)-2-(2-benzyl-N'-tosylbenzimidamido)-2-phenylacetate (3j): Prepared according to the
general procedure as described above in 79% yield (92 mg). It was purified by flash chromatography
(16% EtOAc/hexanes) to afford an orange oil; [α]D +2.16 (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.85 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.25 – 7.21 (m, 1H), 7.13 – 7.09 (m, 4H), 7.04 (t, J =
7.3 Hz, 4H), 6.92 – 6.88 (m, 2H), 6.86 (dd, J = 6.5, 2.9 Hz, 2H), 6.79 (dd, J = 10.8, 5.9 Hz, 1H), 6.16 (d,
J = 7.6 Hz, 1H), 6.14 (s, 1H), 4.31 – 4.19 (m, 2H), 3.55 (s, 3H), 2.42 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 170.3, 166.2, 142.3, 137.7, 134.5, 132.3, 130.7, 130.5, 130.4, 129.1, 128.6, 128.5, 128.4, 128.3, 128.2,
126.6, 126.4, 66.7, 52.3, 38.2, 21.5; IR (neat) υmax 3306, 2923, 1747, 1536, 1283, 1216, 1148, 1091, 772,
701; HRMS (ESI) calcd for C30H29N2O4S [M+H]+: 513.1843; found: 513.1821.
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Ethyl (Z)-6-([1,1'-biphenyl]-4-ylmethyl)-N-tosylbenzo[d][1,3]dioxole-5-carbimidate (3k): Prepared
according to the general procedure as described above in 68% yield (88 mg). It was purified by flash
chromatography (8% EtOAc/hexanes) to afford a brown semisolid; 1H NMR (500 MHz, CDCl3) δ 7.67
(d, J = 8.3 Hz, 2H), 7.57 – 7.53 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.4
Hz, 1H), 7.21 (dd, J = 8.2, 3.3 Hz, 4H), 6.84 (s, 1H), 6.60 (s, 1H), 5.98 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H),
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3.85 (s, 2H), 2.40 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 170.9, 149.6, 145.7,
143.1, 140.9, 139.0, 138.9, 133.2, 129.5, 129.2, 128.7, 128.3, 127.1, 127.0, 125.2,110.3, 108.3, 101.7,
65.4, 38.7, 21.5, 13.6; IR (neat) υmax 3027, 2958, 2923, 1594, 1485, 1374, 1305, 1158, 1091, 1038, 924,
759, 694; HRMS (ESI) calcd for C30H28NO5S [M+H]+: 514.1683 ; found: 514.1681.
Ethyl (Z)-6-(3-chlorobenzyl)-N-tosylbenzo[d][1,3]dioxole-5-carbimidate (3l): Prepared according to
the general procedure as described above in 68% yield (91 mg). It was purified by flash chromatography
(10% EtOAc/hexanes) to afford a colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.71 – 7.66 (m, 2H), 7.26
– 7.23 (m, 2H), 7.20 – 7.16 (m, 2H), 7.11 (t, J = 3.6 Hz, 1H), 7.06 – 7.00 (m, 1H), 6.81 (s, 1H), 6.52 (s,
1H), 5.98 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.77 (s, 2H), 2.42 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 170.7, 149.7, 145.8, 143.3, 142.0, 138.8, 134.2, 132.2, 129.7, 129.3, 129.2, 127.3,
127.0, 126.5, 125.3, 110.1, 108.3, 101.7, 65.5, 38.7, 21.6, 13.5; IR (neat) υmax 2925, 2854, 1606, 1462,
1321, 1204, 1159, 1089, 933, 754, 686; HRMS (ESI) calcd for C24H23ClNO5S [M+H]+: 472.0980; found:
472.1014.
Ethyl (Z)-2-benzyl-4,6-dimethoxy-N-tosylbenzimidate (3m): Prepared according to the general
procedure as described above in 75% yield (107 mg). It was purified by flash chromatography (8%
EtOAc/hexanes) to afford a yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.24 (d, J
= 7.56 Hz, 2H), 7.22 – 7.13 (m, 5H), 6.23 f– 6.20 (m, 2H), 4.36 – 4.13 (m, 2H), 3.86 (s, 2H), 3.72 (s, 3H),
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3.62 (s, 3H), 2.40 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 170.0, 162.2, 157.4,
142.9, 141.0, 139.8, 138.8, 129.3, 129.1, 128.5, 127.4, 126.3, 115.2, 106.6, 96.1, 65.3, 55.6, 55.4, 39.5,
21.7, 13.7; IR (neat) υmax 2929, 1606, 1460, 1322, 1159, 1089, 936, 772, 686; HRMS (ESI) calcd for
C25H28NO5S [M+H]+: 454.1683; found: 454.1673.
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Ethyl (Z)-2,4-dimethoxy-6-(2-methylbenzyl)-N-tosylbenzimidate (3n): Prepared according to the
general procedure as described above in 70% yield (98 mg). It was purified by flash chromatography
(10% EtOAc/hexanes) to afford a colourless oil; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H),
7.14 (d, J = 8.1 Hz, 2H), 7.09 – 6.94 (m, 4H), 6.15 (d, J = 2.0 Hz, 1H), 5.96 (d, J = 2.0 Hz, 1H), 4.21 (q,
J = 6.9 Hz, 2H), 3.75 (s, 2H), 3.61 (s, 3H), 3.57 (s, 3H), 2.34 (s, 3H), 2.13 (s, 3H), 1.12 (t, J = 7.1 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 170.0, 162.1, 157.3, 142.9, 140.5, 138.7, 137.4, 136.8, 130.3, 130.1,
129.0, 127.2, 126.6, 125.9, 106.0, 95.7, 65.2, 55.5, 55.2, 36.7, 21.5, 19.7, 13.6; IR (neat) υmax 2924,
2852, 1606, 1462, 1322, 1204, 1159, 1089, 933, 753, 685; HRMS (ESI) calcd for C26H29NNaO5S
[M+Na]+: 490.1659; found: 490.1659.
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Ethyl (Z)-2-(3,4-dimethoxybenzyl)-4,6-dimethoxy-N-tosylbenzimidate (3o): Prepared according to
the general procedure as described above in 65% yield (88 mg). It was purified by flash chromatography
(10% EtOAc/hexanes) to afford a yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.20
(d, J = 8.0 Hz, 2H), 6.79 – 6.67 (m, 3H), 6.21 (t, J = 1.9 Hz, 2H), 4.35 – 4.20 (br.m, 2H), 3.85 (s, 3H),
3.81 (s, 3H), 3.80 (d, J = 3.9 Hz, 1H), 3.77 (d, J = 3.9 Hz, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 2.40 (s, 3H),
1.23 (t, J = 5.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.0, 162.2, 157.4, 149.0, 147.6, 142.9, 141.4,
138.8, 132.3, 129.1, 127.3, 121.4, 112.8, 111.1, 106.4, 96.1, 65.7, 56.0, 55.6, 55.4, 39.0, 21.7, 13.8; IR
(neat) υmax 3010, 2933, 2847, 2278, 1735, 1606, 1513, 1463, 1320, 1303, 1206, 1158, 1089, 1027, 936,
814, 758, 684; HRMS (ESI) calcd for C27H31NNaO7S [M+Na]+: 536.1713; found: 536.1744.
Ethyl (Z)-2-([1,1'-biphenyl]-4-ylmethyl)-4,6-dimethoxy-N-tosylbenzimidate (3p): Prepared according
to the general procedure as described above in 74% yield (99 mg). It was purified by flash chromatography
(8% EtOAc/hexanes) to afford a brown oil; 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.51
– 7.45 (m, 2H), 7.44 – 7.30 (m, 4H), 7.26 (dd, J = 13.2, 5.9 Hz, 1H), 7.14 (dd, J = 12.3, 8.1 Hz, 4H), 6.18
(dd, J = 15.6, 2.0 Hz, 2H), 4.30 – 4.05 (br.m, 2H), 3.85 (s, 2H), 3.68 (s, 3H), 3.55 (s, 3H), 2.31 (s, 3H),
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1.10 (t, J = 7.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 169.9, 162.2, 157.6, 142.9, 141.1, 140.9, 139.3,
138.9, 138.8, 129.7, 129.1, 128.8, 127.3, 127.2, 127.2, 127.1, 115.3, 106.8, 96.2, 65.4, 55.7, 55.5, 39.2,
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21.6, 13.7; IR (neat) υmax 3024, 2937, 1735, 1605, 1462, 1303, 1205, 1158, 1089, 1049, 936, 757, 686;
HRMS (ESI) calcd for C31H32NO5S [M+H]+: 530.1996; found: 530.1995
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Ethyl (Z)-2-(3-chlorobenzyl)-4,6-dimethoxy-N-tosylbenzimidate (3q): Prepared according to the
general procedure as described above in 68% yield (94 mg). It was purified by flash chromatography
(10% EtOAc/hexanes) to afford a yellow solid (72%); m.p = 138 oC; 1H NMR (500 MHz, CDCl3) δ 7.56
(d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.11 – 7.05 (m, 3H), 6.98 (d, J = 6.8 Hz, 1H), 6.15 (dd, J =
9.8, 2.1 Hz, 2H), 4.28 – 4.08 (m, 2H), 3.77 (s, 2H), 3.68 (s, 3H), 3.55 (s, 3H), 2.33 (s, 3H), 1.11 (t, J = 7.1
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Hz, 3H); C NMR (75 MHz, CDCl3) δ 169.9, 162.3, 157.6, 143.0, 141.9, 140.0, 138.7, 134.3, 129.7,
129.3, 129.1, 127.5, 127.3, 126.6, 106.7, 96.3, 65.4, 55.7, 55.5, 39.2, 21.7, 13.7; IR (neat) υmax 2926,
2850, 1606, 1465, 1320, 1206, 1158, 1089, 937, 758, 685; HRMS (ESI) calcd for C25H27ClNO5S [M+H]+:
488.1293; found: 488.1293.
Ethyl (Z)-2-benzyl-4,5-dimethyl-N-tosylbenzimidate (3r): Prepared according to the general procedure
as described above in 75% yield (99 mg). It was purified by flash chromatography (6% EtOAc/hexanes)
to afford a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 7.25 – 7.16 (m, 5H),
7.13 (d, J = 7.4 Hz, 2H), 7.01 (s, 1H), 6.88 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.86 (s, 2H), 2.41 (s, 3H),
2.19 (s, 6H), 1.17 (t, J = 7.1 Hz, 3H).; 13C NMR (126 MHz, CDCl3) δ 172.0, 143.0, 140.3, 139.5, 138.9,
135.6, 134.2, 131.4, 129.2, 129.1, 128.8, 128.3, 127.3, 127.1, 126.1, 65.2, 38.9, 21.6, 19.9, 19.3, 13.6; IR
(neat) υmax 2924, 1736, 1596, 1473, 1322, 1302, 1158, 1092, 1017, 921, 773, 686; HRMS (ESI) calcd for
C25H28NO3S [M+H]+: 422.1784; found: 422.1781.
Ethyl (Z)-2-(3-chlorobenzyl)-4,5-dimethyl-N-tosylbenzimidate (3s): Prepared according to the general
procedure as described above in 78% yield (101 mg). It was purified by flash chromatography (7%
EtOAc/hexanes) to afford a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.59 (m, 2H), 7.24 – 7.19
(m, 2H), 7.18 – 7.09 (m, 3H), 7.04 (dd, J = 7.6, 5.8 Hz, 2H), 6.90 – 6.83 (m, 1H), 4.21 (q, J = 7.1 Hz,
2H), 3.84 (d, J = 3.6 Hz, 2H), 2.41 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 171.8, 143.0, 142.4, 139.6, 134.6, 134.1, 131.4, 129.6, 129.16, 129.0, 127.4, 127.3,
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127.1, 127.0, 126.3, 65.3, 38.6, 21.6, 19.9, 19.3, 13.5; IR (neat) υmax 2924, 1596, 1473, 1322, 1220, 1156,
1092, 921, 773; HRMS (ESI) calcd for C25H27ClNO3S [M+H]+: 456.1395; found: 456.1399.
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Ethyl 2-benzylbenzoate (4)15: A solution of imidate 3a (100 mg, 0.254 mmol) in DMF and H2O (95/5, 1
ml) was added DBU (10 mol%, 6.2 µl). The reaction mixture was stirred at room temperature for 30 h,
and then diluted with water, extracted with cold Et2O (3 x 10 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel
column chromatography (EtOAc/hexanes = 2:98) to give the desired ester 4 in 90% yield (55 mg) as a
colourless oil; 1H NMR (300 MHz, CDCl3) δ 7.92 – 7.85 (m, 1H), 7.41 (dt, J = 7.5, 3.8 Hz, 1H), 7.33 –
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7.26 (m, 2H), 7.25 – 7.11 (m, 5H), 4.38 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); C
NMR (75 MHz, CDCl3) δ 167.8, 141.9, 141.0, 131.8, 131.5, 130.5, 128.9, 128.3, 126.2, 125.9, 60.9, 39.6,
14.2; IR (neat) υmax 2926, 2854, 1720, 1451, 1260, 1130, 1079, 773, 741; HRMS (ESI) calcd for
C16H16NaO2 [M+Na]+: 263.1043; found: 263.1045.
2-Benzyl-N-tosylbenzamide (5): To a solution of sulfonylimidate 3a (100 mg, 0.254 mmol) in
EtOH/H2O (95/5, 1 ml) was added conc. H2SO4 (95 µl, 7.0 equiv). The reaction mixture was stirred at
100 °C for 3 h. After cooling to room temperature, the mixture was diluted by addition of CH2Cl2. A
saturated aqueous solution of NaHCO3 was added, and the reaction mixture was extracted with CH2Cl2
(3 x 10 mL).The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo.
The crude residue was purified by silica gel column chromatography (EtOAc/hexanes = 20:80) to give
the desired amide 5 in 85% yield (79 mg) as a yellow solid. m.p = 140 oC,1H NMR (400 MHz, CDCl3) δ
8.19 (bs, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.45 – 7.38 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 11.9
Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.17 – 7.12 (m, 3H), 6.96 (dd, J = 7.0, 2.5 Hz, 2H), 4.07 (s, 2H), 2.46
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(s, 3H).; C NMR (75 MHz, CDCl3) δ 140.0, 131.9, 131.6, 129.6, 128.7, 128.6, 128.5, 127.6, 126.6,
126.3, 38.4, 21.7 ;IR (neat) υmax 3239, 3063, 2924, 1700, 1598, 1493, 1432, 1344, 1241, 1168, 1091,
1060, 890, 813, 745, 701.; HRMS (ESI) calcd for C21H19NNaO3S [M+Na]+: 388.0978; found: 388.0998.
Ethyl 2-benzoylbenzoate (6)16: A mixture of ester 4 (100mg, 0.416mmol), iodine (10.5mg,
0.0416mmol), pyridine (4.2µl, 0.0416mmol), aqueous tertꢀbutylhydroperoxide (70% in H2O, 1.0mL)
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were placed into a 15 mL sealed tube, and heated at 80 oC with vigorous stirring for 24 h. The reaction
mixture was cooled to room temperature and directly subjected to purification by flash column
chromatography (EtOAc/hexanes = 5:95) to afford the desired benzophenone 6 in 75% yield (78 mg) as
an yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.06 (dd, J = 1.2, 7.8 Hz, 1H), 7.78 – 7.75 (m, 2H), 7.66 –
7.62 (m, 1H), 7.59 – 7.53 (m, 2H), 7.45 – 7.39 (m, 3H), 4.07 (q, J = 7.1 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H);
13C NMR (126 MHz, CDCl3) δ 197.1, 152.6, 137.4, 133.2, 132.5, 130.3, 129.7, 129.6, 129.5, 128.6, 128.5,
127.8, 61.6, 13.8; IR (neat) υmax 2940, 2863, 1760, 1680, 1520, 1352, 1195, 980, 720, 699; HRMS (ESI)
calcd for C16H14NaO3 [M+Na]+: 277.0835 ; found: 277.0856.
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2-Benzylbenzaldehyde (7)17: To a stirred solution of imidate 3a (100 mg, 0.254mmol) in THF (0.1 M)
was added slowly RedꢀAl (65% w/w toluene solution, 554 µl, 7.0 equiv) at –78 °C. The reaction was
continued at –78 °C for 18 h, and then quenched by addition of MeOH (0.1 ml) at same temperature. The
mixture was stirred for 5 min at that temperature, and H2O (5 mL) was added. The temperature was
allowed to increase to room temperature; extracted with ethyl acetate (2 x 10 mL) and a saturated aqueous
solution of NH4Cl (10 mL). The combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The crude residue was purified by flash column chromatography (EtOAc/hexanes
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= 2:98) to afford the desired aldehyde 7 in 68% yield (30 mg) as a colorless oil; H NMR (500 MHz,
CDCl3) δ 10.24 (s, 1H), 7.85 (dd, J = 7.6, 1.1 Hz, 1H), 7.51 (td, J = 7.5, 1.3 Hz, 1H), 7.40 (t, J = 7.3 Hz,
1H), 7.28 (dd, J = 11.6, 4.8 Hz, 1H), 7.24 (s, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 7.3 Hz, 2H), 4.44
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(s, 2H); C NMR (126 MHz, CDCl3) δ 192.4, 143.0, 140.3, 133.9, 132.1, 131.7, 128.8, 128.6, 127.0,
126.3, 38.1; IR (neat) υmax 2923, 2820, 1698, 1599, 1452, 1203, 756, 699; HRMS (ESI) calcd for C14H13O
[M+Na]+: 197.0961; found: 197.0957.
c. Reactivity of 2-sulfonyliminoindolines in insertion reaction with CsF in CH3CN or THF:
General procedure: An oven dried roundꢀbottom flask equipped with a magnetic stirring bar was charged
with aryne precursor 1a (2equiv), 2ꢀsulfonyliminoindolines 814 (1 equiv) and CsF (2.5 equiv) in CH3CN
or THF (0.2 M) under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5
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hours. After the reaction was finished, the solvent was evaporated and the residue was purified by flash
column chromatography (hexanes/ethyl acetate) to give corresponding major and minor products.
d. Reactivity of 2-sulfonyliminoindolines in insertion reaction with TBAF in CH3CN or THF:
General procedure: An oven dried roundꢀbottom flask equipped with a magnetic stirring bar was charged
with aryne precursor 1a (2 equiv) and 2ꢀsulfonyliminoindolines 8 (1 equiv) in THF or CH3CN (0.2 M)
under nitrogen atmosphere. The resulting reaction mixture was added TBAF (1.0 M in THF solution, 2.5
equiv) and stirred at room temperature for 3 hours. After the reaction was finished, the solvent was
evaporated and the residue was purified by flash column chromatography (hexanes/ethyl acetate) to give
corresponding major and minor products.
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N-(1-Allyl-3-phenyl-1H-indol-2-yl)-4-methyl-N-phenylbenzenesulfonamide (9a): Prepared according
to the general procedure as described above in 85% yield (124 mg) as major isomer. It was purified by
flash chromatography (2% EtOAc/hexanes) to afford a white solid; m.p = 152 oC; 1H NMR (500 MHz,
CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.37 – 7.33 (m, 2H), 7.32 – 7.26 (m, 3H),
7.25 – 7.20 (m, 5H), 7.20 – 7.15 (m, 3H), 7.09 (ddd, J = 8.4, 2.6, 1.3 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H),
5.93 (ddt, J = 17.1, 10.4, 5.7 Hz, 1H), 5.22 (ddd, J = 13.7, 11.6, 1.3 Hz, 2H), 4.88 (qdt, J = 16.6, 5.3, 1.6
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Hz, 2H), 2.31 (s, 3H); C NMR (126 MHz, CDCl3) δ 143.9, 142.1, 136.3, 134.9, 133.6, 133.2, 129.6,
129.2, 129.2, 128.4, 128.0, 126.6, 126.2, 124.9, 123.4, 121.4, 120.4, 120.4, 117.8, 115.5, 111.1, 46.4,
21.5; IR (neat) υmax 3060, 2330, 1598, 1492, 1461, 1357, 1217, 1165, 1090, 927, 814, 771, 700; HRMS
(ESI) calcd for C30H26N2NaO2S [M+Na]+: 501.1607; found: 501.1610.
4-Methyl-N-(1-methyl-3-phenyl-1H-indol-2-yl)-N-phenylbenzenesulfonamide
(9b):
Prepared
according to the general procedure as described above in 82% yield (123 mg) as major isomer. It was
purified by flash chromatography (2% EtOAc/hexanes) to afford a white solid; m.p = 191 oC; 1H NMR
(500 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 1H), 7.27 – 7.38 (m, 4H), 7.25 – 7.23 (m, 2H), 7.22 – 7.17 (m,
6H), 7.14 – 7.08 (m, 3H), 6.96 (d, J = 8.1 Hz, 2H), 3.85 (s, 3H), 2.32 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 143.9, 142.5, 136.7, 135.3, 133.6, 129.9, 129.4, 129.3, 129.3, 128.4, 127.8, 126.4, 125.7, 124.8, 123.5,
120.9, 120.5, 120.4, 114.9, 110.0, 30.0, 21.5; IR (neat) υmax3060, 2926, 2854, 1596, 1491, 1470, 1358,
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1166, 1091, 964, 928, 814, 752, 697; HRMS (ESI) calcd for C28H25N2O2S [M+H]+: 453.1631; found:
453.1640.
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(Z)-N-(5-Allyl-5,11-dihydro-6H-dibenzo[b,e]azepin-6-ylidene)-4-methylbenzenesulfonamide (10a):
Prepared according to the general procedure as described above in 61% yield (78 mg). It was purified by
flash chromatography (8% EtOAc/hexanes) to afford as a red colour oil; 1H NMR (400 MHz, CDCl3) δ
8.00 (dd, J = 7.7, 1.2 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.39 – 7.27 (m, 3H), 7.23 – 7.10 (m, 6H), 5.99 (ddt, J
= 16.5, 10.3, 5.9 Hz, 1H), 5.19 – 5.10 (m, 2H), 4.79 – 4.62 (m, 2H), 3.90 (d, J = 13.2 Hz, 1H), 3.48 (d, J
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= 13.2 Hz, 1H), 2.39 (s, 3H); C NMR (126 MHz, CDCl3) δ 163.6, 142.8, 141.7, 141.5, 140.3, 139.4,
132.4, 132.33, 132.29, 129.0, 127.6, 127.3, 126.9, 126.3, 126.2, 125.4, 124.2, 118.5, 56.5, 38.5, 21.5; IR
(neat) υmax3018, 2924, 2854, 1733, 1582, 1519, 1478, 1402, 1286, 1146, 1089, 1023, 909, 821, 766;
HRMS (ESI) calcd for C24H22N2NaO2S [M+Na]+: 425.1294; found: 425.1295.
(Z)-4-methyl-N-(5-methyl-5,11-dihydro-6H-dibenzo[b,e]azepin-6-ylidene)benzenesulfonamide
(10b): Prepared according to the general procedure as described above in 66% yield (82 mg). It was
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purified by flash chromatography (8% EtOAc/hexanes) to afford as a brown semisolid, H NMR (500
MHz, CDCl3) δ 8.05 (dd, J = 7.8, 1.2 Hz, 1H), 7.81 – 7.78 (m, 2H), 7.38 (tt, J = 5.3, 2.6 Hz, 1H), 7.33 –
7.27 (m, 2H), 7.24 – 7.20 (m, 4H), 7.19 – 7.13 (m, 2H), 3.92 (d, J = 13.1 Hz, 1H), 3.65 (s, 3H), 3.52 (d, J
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= 13.2 Hz, 1H), 2.39 (s, 3H); C NMR (101 MHz, CDCl3) δ 164.1, 142.8, 142.0, 141.8, 140.4, 139.7,
132.8, 132.6, 129.8, 129.2, 128.9, 127.7, 127.3, 127.1, 126.6, 126.4, 126.3, 125.6, 124.2, 41.7, 38.6, 21.6;
IR (neat) υmax 2950, 1730, 1517, 1388, 1281, 1145, 1089, 772; HRMS (ESI) calcd for C22H20N2NaO2S
[M+Na]+: 399.1138; found: 399.1118.
N-(1-Allyl-3-(phenyl-2-d)-1H-indol-2-yl)-4-methyl-N-(phenyl-2-d)benzenesulfonamide
(11):
Prepared according to the general procedure as described above in 78% yield (51 mg). It was purified by
flash chromatography (2% EtOAc/hexanes) to afford as a white semisolid; 1H NMR (500 MHz, CDCl3)
δ 7.68 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.29 (ddd, J = 7.5, 6.4, 4.5
Hz, 2H), 7.25 – 7.15 (m, 7H), 7.10 (dd, J = 10.9, 3.7 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 5.93 (ddd, J =
22.8, 10.7, 5.6 Hz, 1H), 5.23 (ddd, J = 13.7, 11.4, 1.2 Hz, 2H), 4.89 (qd, J = 16.6, 5.6 Hz, 2H), 2.32 (s,
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3H); 13C NMR (75 MHz, CDCl3) δ 144.0, 142.2, 136.4, 135.0, 133.6, 133.3, 129.7, 129.3, 129.3, 129.2,
128.5, 128.4, 128.1, 126.7, 126.3, 125.0, 123.5, 121.5, 120.5, 117.9, 115.6, 111.3, 46.5, 21.6; HRMS
(ESI) calcd for C30H24D2N2NaO2S [M+Na]+: 503.1733; found: 503.171.
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e. Reactivity of aliphatic imidate S1 in insertion reaction.
Acknowledgement
RK thanks University Grants Commission (UGC), New Delhi for a research fellowship. RC thanks CSIRꢀ
Senior Research Associateship (Scientists' Pool Scheme) for financial assistance. We thank Council of
Scientific and Industrial Research (CSIR)ꢀNew Delhi for financial support as part of XII fiveꢀyear
programme project under ORIGIN (CSCꢀ108). We gratefully acknowledge Dr. Balasubramanian Sridhar,
Laboratory of Xꢀray Crystallography, CSIRꢀIICT for Xꢀray analysis. The authors thank one of referees
for providing useful clues in understanding the mechanistic pathway.
Supporting Information
Copies of 1H and 13C spectra for all new compounds; Xꢀray crystallographic data (CIF file) of compounds
3q and 9a. This material is available free of charge via the Internet at http://pubs.acs.org.
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