α-N-Heteroarylation and α-Azidation of Ketones via Enolonium Species

Article abstract of DOI:10.1021/acs.joc.7b03058

Enolonium species, resulting from the umpolung of ketone enolates by Koser's hypervalent iodine reagents activated by boron trifluoride, react with a variety of nitrogen heterocycles to form α-aminated ketones. The reactions are mild and complete in 4-5 h. Additionally, α-azidation of the enolonium species takes place using trimethylsilyl azide as a convenient source of azide nucleophile.

Full text of DOI:10.1021/acs.joc.7b03058

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#-N-Heteroarylation and #-Azidation of Ketones via Enolonium Species
Atul More, Gulab K. Pathe, Keshaba N. Parida, Shimon
Maksymenko, Yuriy B. Lipisa, and Alex Martin Szpilman
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 15 Jan 2018
Downloaded from http://pubs.acs.org on January 15, 2018
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The Journal of Organic Chemistry
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αꢀNꢀHeteroarylation and αꢀAzidation of Ketones via Enolonium Speꢀ
cies
Atul A. More,‡ Gulab K. Pathe,‡ Keshaba N. Parida, Shimon Maksymenko, Yuriy B. Lipisa, and Alex
M. Szpilman*
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Department of Chemical Sciences, Ariel University, 4070000 Ariel, Israel
Supporting Information Placeholder
ABSTRACT: Enolonium Species, resulting from the umpolung of ketone enolates by Koser’s hypervaꢀ
lent iodine reagents activated by boron trifluoride, react with a variety of nitrogen heterocycles to form
αꢀaminated ketones. The reactions are mild and complete in 4ꢀ5 hours. Additionally, αꢀazidation of the
enolonium species takes place using trimethylsilyl azide as a convenient source of azide nucleophile.
Introduction of nitrogen at the α position of ketones is an important reaction due to the ubiquity of this
structural theme in biologically active compounds. Classically, it relies on the nucleophilic displacement
of a halide by a nitrogen nucleophile (Scheme 1a). In the case of azoles (with the exception of simple
pyrazoles) alkylation typically requires long reaction times and/or elevated temperatures.1 Indeed, αꢀ
triazolo ketones are often preferentially prepared by [2+3] (click) cycloaddition reactions.2
Alternatively, amination of ketones may be carried out by attack of the corresponding enolates on elecꢀ
trophilic nitrogen donors. Hypervalent iodine reagents3 containing iodine bound electrophilic nitrogen
has been used in the amination of ketone enolates. However, this method is generally limited to sulꢀ
fonated amines or ammonia and does not extend to azoles.
Recently, the α functionalization of carbonyl compounds via umpolung4 of carbonyl enolates has reꢀ
ceived much attention. Maulide has reported extensively on the umpolung functionalization of amide
enolates5 including amination.6 Wirth, Waser, our group, and others have reported on the amination,3b,7
azidation,8 alkylation,9 and alkynylation,10 of ketone enolates.
Earlier this year we reported the characterization of enolonium species derived from ketones and hyperꢀ
valent iodine reagents.11 A seminal part of this study was the development of conditions to produce the
otherwise unstable enolonium species 4 as discrete entities (Scheme 1b). This in turn led us to develop a
twoꢀstep strategy in which the lower oxidizing power of the enolonium species 4 compared to the parent
hypervalent iodine reagent 2 would make it possible to use a much larger variety of nucleophiles
(Scheme 1b). We have reported the use of this strategy in arylation12 and allylation of ketones as well as
in chlorination, tosylation and enolate dimerization.11 In our mechanistic study we also reported the
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coupling of triazole with acetophenone in 58% yield.11 In this paper we report the successful coupling of
ketone enolates with a variety of azoles under mild conditions and short reaction times. In addition, we
show that αꢀazidation may be carried out under similar conditions.
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Scheme 1. Selected examples of αꢀAmination and – azidation of ketones.
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In optimizing the conditions for coupling of enolonium species with triazole, we specifically targeted
minimizing the amounts of reagents necessary to achieve an optimum yield. Unlike in the case of arylaꢀ
tion,12 it was found that as little as 1.25 equivalent of Koser’s reagent (2) and 1.2ꢀ1.6 equivalent of BF3
(4) gave similar yields those achieved using higher amounts. An excess of azole was used as nucleoꢀ
philes since these are inexpensive commodity chemicals. The scope with respect to different parent azꢀ
oles were first tested in the reaction with the enolonium species derived from acetophenone (Scheme 2).
Pyrazole afforded the desired coupling product 9 in 72% yield. The influence of a nucleophilicity reducꢀ
ing nitro group was also tested in the reaction with nitroꢀpyrazole. The expected product 10 was formed
in 65% yield. The indazole analogue reacted to give 11 in 66% yield. Imidazole afforded the coupling
product 12 in 63% yield. As previously reported triazole was coupled to give 13 in 58% yield. The benꢀ
zotriazole congener afforded the coupling product in 45% yield, mainly due to issues with low solubility
of the benztriazole leading to competing formation of tosylated product. In the case of tetrazole this solꢀ
ubility issue, led us to modify the procedure. Thus, tetrazole substrates were dissolved in acetonitrile at
room temperature and the solution slowly added to the ꢀ55 °C solution of enolonium species. This modiꢀ
fication prevented precipitation and the tetrazole acetophenone coupling product 15 was produced in
78% yield. Methylꢀtetrazole gave the coupling product 16 in 88% yield. We also tested orthoꢀ and paraꢀ
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DMAP in the reaction. These led to formation of the fluoride salts 17 and 18 in 55% and 65% isolated
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yield respectively.
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We then examined the scope of the coupling reaction with respect to enolonium species using tetrazole
as the azole component. Both electronꢀpoor (pꢀchloro) and electron donating (pꢀmethoxy) substituents
on the phenyl group were tolerated, giving products 19 and 20 in 74% and 72% yield respectively. The
reaction is not limited to methylketones as both tetralone and dihydroꢀindenone afforded the coupling
products in 63% and 62% yield. Our previous studies have shown that these enolonium species are
compatible with a range of other functionalities such and substituents patterns including alkenes.11ꢀ12
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Scheme 2, Direct αꢀamination of ketones with azoles.a
step 1
step 2
Z
OH
Ph
O
HO
5
N
2.5-
5 equiv
Q
1.25-
1.5 equiv
Z
Ph
I
2
I
O
OTMS
R2
Q
OTs
4
N
R2
P
H
R1
R1
R1
BF3 OEt2(3)
1.6 equiv
-78 to -55 °C
CH2Cl2 or MeCN
R2
7
1
Enolonium
Species
O
N
O
N
N
N
NO2
O
N
N
N
Ph
Ph
N
N
N
9, 72%
10, 65%
MeO
19, 74%
N
N
O
N
O
N
N
N
N
O
N
N
N
Ph
Ph
Ph
Ph
Ph
11, 66%
12, 63%
Cl
O
N
N
N
N
20
, 72%
O
N
N
O
N
N
13, 58%
14, 45%
O
N
N
O
N
N
N
21, 63%
N
N
Ph
Ph
O
N
N
15, 78%
16, 88%
Me
N
F-
O
F-
O
N
N
N
22, 62%
Ph
17, 55%
18, 65%
N
aThe blue bond indicates the bond formed. All yields are isolated yields.
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Primary alkyl amines and secondary alkyl amines are not suitable nucleophiles for enolonium species
under these conditions. It was found that the former generally did not afford product. This is presumably
due to the ability of primary amines to displace the enolꢀoxygen from the I(III) atom in preference to
attack on the α carbon of the enolonium species. Secondary amines did form the desired amines in up to
65% yield but the yields were capricious and the source of the variable yields could not be identified. As
an alternative to amination, we therefore pursued the synthesis of azido ketones. Azido ketones are easiꢀ
ly reduced and acylated or alkylated. There are numerous methods, for the azidation via nucleophilic
displacement of αꢀhalo or αꢀsulfonyloxy ketones with azide anion.13,14 Many of these methods involve
in situ formation of the αꢀhalo or αꢀsulfonyloxy ketone. However, there are relatively few methods for
direct umpolung azidation of ketone enolates and most of these are restricted to βꢀketo esters.15,16 In a
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seminal contribution Moriarty reported the use of TMSꢀazide for the umpolung azidation of βꢀketoꢀ
esters however this procedure was not amenable for simple ketones. Waser reported an elegant direct
azidation of TMSꢀenolates of simple ketones using azidoꢀbenziodoxoles as electrophilic azide equivaꢀ
lents,8 but such azidation reagents must be prepared before use and are potentially explosive.18 We inꢀ
vestigated the αꢀazidation of ketone derived enolonium species with commercially available TMSꢀazide
as the source of nucleophilic azide (Scheme 3).
Scheme 3. Direct azidation of ketones.a
aThe blue bond indicates the bond formed. All yields are isolated yields.
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It was found that TMSꢀazide reacts readily with enolonium species 4 to afford the corresponding azidoꢀ
ketones in 69ꢀ88% yield (Scheme 3). A variety of ketones were tested. Acetophenone enolate afforded
the corresponding azide 23 in 88% yield. Propiophenone adduct 24 was formed in 73% yield. Cyclic
ketones 2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀone and cyclohexanone were azidated via their enolonium species to
afford 31 and 32 in 74% and 77% yield respectively. The latter is an example of a dialkyl ketone. Furꢀ
ther the electron rich methoxy substituted azido ketone 25 was prepared in 78% yield with no observaꢀ
ble overꢀoxidation. Electron poor nitro compound 26 was likewise prepared in 69% yield. The series of
αꢀazido halogenated (F, Cl, Br, and I) acetophenones 27 to 30 were also formed successfully. Especially
remarkable is paraꢀiodo product 30 formed in 77% yield with no observable oxidation of the iodine atꢀ
om.
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In conclusion, we report a convenient procedure for the coupling of azoles with ketones. The conditions
are mild and a variety of azoles participate efficiently in the reaction. Both electron rich and electron
poor ketones may be used in the reaction. We have previously shown that these conditions are compatiꢀ
ble with an even wider array of functional groups including alkenes and dialkyl ketones.11ꢀ12 These conꢀ
ditions are preferable to the classical twoꢀstep halogenationꢀSN2 displacement technique in terms of
ease, reaction time, and mildness. These conditions were also extended to azidation and the scope of this
reaction with respect to ketone was outlined. We believe that these azole and azido introducing reactions
may find wide use in medicinal chemistry research.
Experimental section
General Methods: Airꢀ and/or moistureꢀsensitive reactions were carried out in anhydrous solvents unꢀ
der Ar atmosphere in ovenꢀdried glassware. All anhydrous solvents were distilled prior to use: CH2Cl2
and CH3CN from CaH2. All commercial reagents were used without purification. Column chromatogꢀ
raphy was carried out by using silica gel (100−200 mesh). NMR spectra were recorded on Bruker
Avance III 400 spectrometers operating at 400 MHz (1H) and 101 MHz (13C). 1H and 13C NMR chemiꢀ
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cal shifts are reported in ppm relative to chloroformꢀD (δ = 7.26 for H and 77.16 for C) or TMS (0.0
ppm) and coupling constants (J) are reported in Hertz (Hz). The following abbreviations have been used
to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad. IR spectra were recorded as films on a Bruker FTꢀIR. TOFꢀESIꢀHSMS (m/z): was recorded on a
Waters Micromass LCT premier instrument at 70eV in the positive or negative mode. APCIꢀHRMS was
recorded on a Bruker Maxis Impact QTOF instrument using the APCI solid probe.
General procedure for preparation of αꢀamination of ketones with various azoles
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At –78 °C, BF3·OEt2 (1.6 equiv.) was added to a suspension of hydroxy(tosyloxy)iodobenzene (1.25
equiv.) in anhydrous CH2Cl2 (8 mL) under positive argon pressure. The mixture was stirred at room
temperature for 10 min. and the resulting yellow solution was cooled to –78 °C. To the reaction mixture
was added dropwise trimethylsilyl enolate (1.0 equiv.) in CH2Cl2 (4 mL). After 10 min. Nꢀheterocycle
(2.5 to 5.0 equiv.) in CH2Cl2 (5 mL) was added. The reaction mixture was stirred for 15 min at –78 °C
and then at –55 °C for 4–5 h. The reaction mixture was quenched by addition of H2O (5 mL) and then
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL),
dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by column
chromatography (20 → 60% EtOAc in hexane) to afford the corresponding products.
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1ꢀPhenylꢀ2ꢀ(1Hꢀpyrazolꢀ1ꢀyl)ethenone (9): Umpolung addition of 1Hꢀpyrazole (4.95 equiv., 420 mg,
6.176 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the general
procedure gave 9 (168 mg, 72%) as a colorless solid; Rf 0.2 (1:3 v/v EtOAc/hexane); mp 66ꢀ71 °C; FTꢀ
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IR: Ѵmax 2962, 1699, 1220, 960, 750 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.96−7.98 (m, 2H),
7.58−7.64 (m, 2H), 7.46−7.52 (m, 3H), 6.37 (t, J = 2.1 Hz, 1H), 5.61 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 192.5, 140.0, 134.4, 134.2, 131.0, 129.0, 128.2, 106.6, 57.7 ppm; HRMS (ESI+) m/z calculated
for C11H11N2O 187.0871 [M+H]+; found 187.0871.
2ꢀ(4ꢀNitroꢀ1Hꢀpyrazolꢀ1ꢀyl)ꢀ1ꢀphenylethanone (10): Umpolung addition of 4ꢀnitro pyrazole (5 equiv.,
776 mg, 6.24 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the
general procedure gave 10 (188 mg, 65%) as a white solid; Rf 0.2 (2:3 v/v EtOAc/hexane); mp 109ꢀ111
°C; FTꢀIR: Ѵmax 3412, 2916, 1729, 1691, 1517, 1345, 735 cmꢀ1; 1H NMR: (400 MHz, DMSOꢀd6) δ
8.85 (d, J = 0.6 Hz, 1H), 8.33 (d, J = 0.6 Hz, 1H), 8.05 (dd, J = 8.3, 1.2 Hz, 2H), 7.73 (d, J = 7.4 Hz,
1H), 7.62 (dd, J = 10.9, 4.5 Hz, 2H), 5.99 (s, 2H); 13C NMR: (101 MHz, DMSOꢀd6) δ 192.1, 135.6,
134.3, 133.7, 132.1, 129.0, 128.1, 79.1, 58.9 ppm; HRMS (APCI+): m/z calcd for C11H10N3O3 232.0717
[M+H]+; found 232.0746.
2ꢀ(1HꢀIndazolꢀ1ꢀyl)ꢀ1ꢀphenylethanone (11): Umpolung addition of 1Hꢀindazole (5 equiv., 739 mg,
6.25 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following the general
procedure gave compound 11 (195 mg, 66%) as a thick liquid; Rf 0.2 (2:3 v/v EtOAc/hexane); FTꢀIR:
Ѵmax 3123, 2981, 2937, 2871, 1690, 1586, 1509, 1405, 1302, 1221, 991, 817, 755, 642, 468 cmꢀ1; 1H
NMR: (400 MHz, CDCl3) δ 8.00 ꢀ 7.97 (m, 3H), 7.75 – 7.57 (m, 3H), 7.48 (t, J = 7.7 Hz, 2H), 7.31 –
13
7.24 (m, 1H), 7.13 – 7.02 (m, 1H), 5.85 (s, 2H); C NMR: (101 MHz, CDCl3) δ 191.6, 149.2, 134.5,
134.4, 129.1, 128.3, 126.5, 124.9, 122.5, 122.1, 120.5, 117.6, 59.1 ppm; HRMS (APCI+): m/z calcd for
C15H13N2O 237.1028 [M+H]+; found 237.1056.
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2ꢀ(1HꢀImidazolꢀ1ꢀyl)ꢀ1ꢀphenylethanone19 (12): Umpolung addition of 1Hꢀimidazole (4.95 equiv., 5
equiv., 420 mg, 6.176 mmol) on trimethyl((1ꢀphenylvinyl)oxy)silane (0.24 g, 1.247 mmol) following
the general procedure gave compound 12 (146 mg, 63%) as a colorless solid; Rf 0.3 (1:99 v/v
EtOH/hexane); mp 72ꢀ76 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (dt, J = 8.0, 1.2 Hz, 2H), 7.64 (tt, J =
7.3, 1.2 Hz, 1H), 7.51 (t, 7.7 Hz, 3H,), 7.10 (s, 1H), 6.92 (s, 1H), 5.38 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 191.7, 138.2, 134.4, 134.2, 129.4, 129.2, 128.0, 120.5, 52.6 ppm.
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1ꢀphenylꢀ2ꢀ(1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)ethanone11 (13): Umpolung addition of 1Hꢀ1,2,3ꢀtriazole (2.5
equiv., 180 mg, 2.60 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (200 mg, 1.04 mmol) following
the general procedure gave 13 (113 mg, 58%) as a white solid; Rf 0.6 (1:5 v/v EtOAc/hexane); mp 82ꢀ84
°C; 1H NMR (400 MHz, CDCl3): δ 8.00 (dd, J = 8.3, 1.2 Hz, 2H), 7.80 (d, J = 0.5 Hz, 1H), 7.74 (d, J =
0.5 Hz, 1H), 7.67 (tt, J = 14.9, 7.4 Hz, 1H), 7.54 (t, J = 7.9 Hz, 2H), 5.89 (s, 2H); 13C NMR (101 MHz,
CDCl3): δ 190.4, 134.8, 134.3, 134.1, 129.3, 128.3, 125.5, 55.4 ppm.
2ꢀ(1HꢀBenzo[d][1,2,3]triazolꢀ1ꢀyl)ꢀ1ꢀphenylethanone (14): Umpolung addition of 1Hꢀbenzotriazole (3
equiv., 560 mg, 4.70 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (300 g, 1.56 mmol) following the
general procedure gave 14 (165 mg, 45%) as a pale yellow solid; Rf 0.6 (1:1 v/v EtOAc/hexane); mp
114ꢀ115 °C; FTꢀIR: Ѵmax 1681.46, 1265.17, 745.38 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.05−8.10 (m,
13
3H), 7.65−7.69 (m, 1H), 7.53−7.57 (m, 2H), 7.46−7.50 (m, 1H), 7.36−7.42 (m, 2H), 6.10 (s, 2H); C
NMR (101 MHz, CDCl3) δ 190.4, 146.1, 134.6, 134.1, 133.8, 129.2, 128.3, 127.8, 124.0, 120.2, 109.5,
53.9 ppm; HRMS (APCI+) m/z calculated for C14H12N3O 238.0980 [M+H]+ found 238.1007.
2ꢀ(Dimethylamino)ꢀ1ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)pyridinꢀ1ꢀium fluoride (17): Umpolung addition of 2ꢀ
dimethylaminopyridine (5 equiv., 760 mg, 6.23 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (0.24
o
g, 1.247 mmol) following the general procedure (reaction time 20 h at ꢀ55 C) gave 17 (179 mg, 55%)
as a colorless solid; Rf 0.3 (1:99 v/v MeOH/CH2Cl2); mp 120ꢀ125 °C; FTꢀIR: Ѵmax 687, 1597, 1025,
747 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.37 (ddd, J = 4.7, 1.8, 0.7 Hz, 1H), 8.05 (qd, J = 7.0, 1.8 Hz,
1H), 7.93 (m, 3H), 7.59 (tt, J = 7.4, 1.2 Hz, 1H), 7.42−7.47 (m, 3H), 5.83 (s, 2H), 3.80 (s, 6H). 13C
NMR (101 MHz, CDCl3) δ 190.0, 156.5, 148.6, 141.3, 135.1, 133.5, 129.2, 128.3, 125.7, 114.7, 68.9,
54.8 (2C) ppm. HRMS (ESI+) m/z calculated for C15H17N2O+ 241.1341 [MꢀF]+; found 241.1359.
4ꢀ(Dimethylamino)ꢀ1ꢀ(2ꢀoxoꢀ2ꢀphenylethyl)pyridinꢀ1ꢀium fluoride (18): Umpolung addition of 4ꢀ
dimethylaminopyridine (5 equiv., 760 mg, 6.23 mmol) on trimethyl((1ꢀphenylvinyl)oxy)silane (0.24g,
1.247 mmol) following the general procedure (reaction time 20 h at –55 oC) gave 18 (211 mg, 65%) as a
colorless solid; Rf 0.2 (1:99 v/v MeOH/CH2Cl2); mp 133ꢀ135 °C; FTꢀIR: Ѵmax 1652, 1577, 996, 761
cmꢀ1; 1H NMR (400 MHz, CD3OD) δ 7.98−8.04 (m, 4H), 7.68 (tt, J = 7.5, 1.2 Hz, 1H), 7.54 (m, 2H),
13
6.98 (dt, J = 8.1, 3.1 Hz, 2H), 5.85 (m, 2H) 3.23 (s, 6H); C NMR (101 MHz, CD3OD) δ 194.1, 158.8,
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145.2, 136.4, 136.0, 130.9, 130.1, 109.3, 64.4, 41.2 (2C) ppm; HRMS (ESI+) m/z calculated for
C15H17N2O+ 241.1341 [MꢀF]+; found 241.1309.
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General procedure for the preparation of αꢀtetrazoleꢀketones
At –78 °C, BF3·OEt2 (1.6 equiv.) was added to a suspension of hydroxy(tosyloxy)iodobenzene (1.5
equiv.) in anhydrous CH2Cl2 (5 mL) under positive argon pressure. The mixture was stirred at room
temperature for 10 min. and the resulting yellow solution was cooled to –78 °C. To the reaction mixture
was added dropwise trimethylsilyl enolate (1.0 equiv.) in CH2Cl2 (5 mL). After 10 min. 1Hꢀtetrazol
(3.95 to 5.0 equiv.) in CH3CN (10 mL) was added dropwise. The reaction mixture was stirred for 15
min at –78 °C and then at –55 °C for overnight . The reaction mixture was stirred at rt for 2–3 h before
it was quenched by addition of H2O (5 mL). The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (5 × 30 mL). The combined organic layers were dried (Na2SO4), and concentratꢀ
ed under reduced pressure. The crude product was purified by column chromatography (20 → 70%
EtOAc in hexane) to afford the corresponding tetrazol product.
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1ꢀPhenylꢀ2ꢀ(1Hꢀtetrazolꢀ1ꢀyl)ethanꢀ1ꢀone (15): Umpolung addition of 1Hꢀtetrazole (4.9equiv., 17 mL,
0.45 M, 7.65 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (300 mg, 1.56 mmol) following the
general procedure gave 15 (229 mg, 78%) as a white solid: Rf 0.3 (1:1 v/v EtOAc/hexane); mp 122ꢀ124
1
°C; FTꢀIR: Ѵmax 3141, 2936, 2869, 2115, 1695, 1596, 1449, 1351, 1228, 1173 cmꢀ1; H NMR (400
MHz, CDCl3): δ 8.86 (s, 1H), 7.99 (dd, J = 8.5, 1.2 Hz, 2H), 7.70 (tt, J = 7.5, 2.9 Hz, 1H), 7.56 (t, J =
7.8 Hz, 2H), 5.98 (s, 2H); 13C NMR (101 MHz, CDCl3): δ 189.0, 144.2, 135.2, 133.5, 129.5, 128.3, 53.5
ppm; HRMS (ESI+): m/z calcd for C9H9N4O 189.0776 [M+H]+; found 189.0745.
2ꢀ(5ꢀmethylꢀ1Hꢀtetrazolꢀ1ꢀyl)ꢀ1ꢀphenylethanꢀ1ꢀone (16): Umpolung addition of 5ꢀMethylꢀ1Hꢀ
tetrazole (5 equiv., 655 mg, 7.80 mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (300 mg, 1.56 mmol)
following the general procedure gave 16 (277 mg, 88%) as a white solid: Rf 0.3 (1:1 v/v EtOAc/hexane);
1
mp 111ꢀ113 °C; FTꢀIR: Ѵmax 3008, 2938, 2874, 1694, 1594, 1562, 1452, 1357, 1227, 1181 cmꢀ1; H
NMR (400 MHz, CDCl3): δ 8.00 (dd, J = 8.3, 1.1 Hz, 2H), 7.71 (tt, J = 7.4, 1.1 Hz, 1H), 7.57 (t, J = 7.8
13
Hz, 2H), 5.81 (s, 2H), 2.50 (s, 3H); C NMR (101 MHz, CDCl3): δ 188.8, 153.3, 135.1, 133.6, 129.5,
128.4, 52.7, 9.0 ppm; HRMS (ESI+): m/z calcd for C10H11N4O 203.0933 [M+H]+; found 203.0922.
1ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀ(1Hꢀtetrazolꢀ1ꢀyl)ethenone (19): Umpolung addition of 1Hꢀtetrazole (5
equiv. 13.6 mL, 0.45 M, 6.12 mmol) over ((1ꢀ(4ꢀmethoxyphenyl)vinyl)oxy)trimethylsilane (280 mg,
1.26 mmol) following the general procedure gave 19 (203 mg, 74 %) as an yellow solid; Rf 0.15 (1:4 v/v
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EtOAc/hexane); mp 115ꢀ116 °C; FTꢀIR: Ѵmax 3114, 2977, 2943, 2845, 1722, 1698, 1598, 1349, 1264,
972, 720, 590, 567 cmꢀ1; 1H NMR: (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.04 – 7.91 (m, 2H), 7.03 (d, J =
9.0 Hz, 2H), 5.90 (s, 2H), 3.92 (s, 3H); 13C NMR: (101 MHz, CDCl3) δ 187.0, 165.1, 144.1, 130.7,
126.4, 114.7, 55.8, 53.0 ppm; HRMS (ESI+): m/z calcd for C10H11N4O2 219.0882 [M+H]+; found
219.0871.
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1ꢀ(4ꢀChlorophenyl)ꢀ2ꢀ(1Hꢀtetrazolꢀ1ꢀyl)ethenone (20): Umpolung addition of 1Hꢀtetrazole (5 equiv.,
350 mg, 5.0 mmol) over ((1ꢀ(4ꢀchlorophenyl)vinyl)oxy)trimethylsilane (226 mg, 1.0 mmol) following
the general procedure gave 20 (159 mg, 72%) as a colorless solid; Rf 0.4 (1:1 v/v EtOAc/hexane); mp
164ꢀ169 °C; FTꢀIR: Ѵmax 1691, 1518, 1245, 894 cmꢀ1; 1H NMR (400 MHz, DMSOꢀd6) δ 9.36 (s, 1H),
8.09 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 6.36 (s, 2H); 13C NMR (101 MHz, DMSOꢀd6) δ
190.4, 145.2, 139.4, 132.5, 130.2, 129.2, 53.9 ppm; HRMS (ESI+) m/z calculated for C9H8ClN4O
223.0387; [M+H]+ found 223.0372.
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2ꢀ(1Hꢀtetrazolꢀ1ꢀyl)ꢀ3,4ꢀdihydronaphthalenꢀ1(2H)ꢀone (21): Umpolung addition of 1Hꢀtetrazole
(3.95 equiv., 380 mg, 5.42 mmol,) on (3,4ꢀdihydronaphthalenꢀ1ꢀyloxy)trimethylsilane (300 mg, 1.37
mmol) following the general procedure gave 21 (185 mg, 63%) as an yellow solid; Rf 0.2 (1:9 v/v
MeOH/CH2Cl2); mp 108ꢀ113 °C; FTꢀIR: Ѵmax 3119, 1697, 1596, 1273, 814 cmꢀ1; 1H NMR (400 MHz,
CDCl3) δ 8.84 (s, 1H), 8.08 (dd, J = 7.9, 1.2 Hz, 1H), 7.62 (td, J = 7.5, 1.4 Hz, 1H), 7.36−7.43 (m, 2H),
5.54 (dd, J = 12.6, 5.8 Hz, 1H), 3.24−3.43 (m, 2H), 2.80−2.89 (m, 2H); 13C NMR (101 MHz, CDCl3) δ
189.7, 143.1, 143.1, 135.1, 130.6, 129.1, 128.4, 127.6, 63.9, 30.1, 28.3 ppm; HRMS (ESI+) m/z
calculated for C11H10N4O 214.0855 [M]+ ;found 214.0843.
2ꢀ(1HꢀTetrazolꢀ1ꢀyl)ꢀ2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀone (22): Umpolung addition of 1Hꢀtetrazole (5 equiv.,
350 mg, 5.0 mmol) over ((1Hꢀindenꢀ3ꢀyl)oxy)trimethylsilane (204 mg, 1.0 mmol) following the general
procedure gave 22 (124 mg, 62%) as a colorless solid; Rf 0.4 (1:1 v/v EtOAc/hexane); mp 147ꢀ152 °C;
FTꢀIR: Ѵmax 1721, 1597, 1097, 757 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 7.87 (d, J = 7.7
Hz, 1H), 7.77 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 5.45 (dd, J = 8.4, 5.5
13
Hz, 1H), 4.01 (dd, 1 H, J = 17.2, 8.5 Hz, 1H), 3.87 (dd, J = 17.2, 5.4 Hz, 1H); C NMR (101 MHz,
CDCl3) δ 196.6, 150.8, 142.8, 137.2, 133.5, 129.1, 126.9, 125.5, 61.7, 33.2 ppm; HRMS (ESI+) m/z calꢀ
culated for C10H9N4O 201.0776; [M+H]+ found 201.0775.
General procedure for preparation of αꢀketo azides
Caution: Azides are energetic compounds and often unstable. Care to avoid static electricity, shock and
heat is advised when preparing such compounds.
At –78 °C, BF3·OEt2 (1.6 equiv.) was added to a suspension of hydroxy(tosyloxy)iodobenzene (1.5
equiv.) in anhydrous CH2Cl2 (5 mL) under positive argon pressure. The mixture was stirred at room
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temperature for 10 min. and the resulting yellow solution was cooled to –78 °C. To the reaction mixture
was added dropwise trimethylsilyl enolate (1.0 equiv.) in CH2Cl2 (5 mL). After 10 min. azidotrimeꢀ
thylsilane (2.5 equiv. to 3.66 equiv.) was added dropwise. The reaction mixture was stirred for 15 min at
–78 °C and then at –55 °C for 2–3 h . The reaction mixture was quenched by addition of H2O (5 mL)
and then extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with brine (2 ×
20 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by
column chromatography to afford the corresponding phenacyl azide product.
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2ꢀAzidoꢀ1ꢀphenylethanꢀ1ꢀone20 (23): Umpolung addition of azidotrimethylsilane (0.35 mL, 2.60
mmol) over trimethyl((1ꢀphenylvinyl)oxy)silane (200 mg, 1.04 mmol) following the general procedure
gave 23 (148 mg, 88%) as a white solid: Rf 0.6 (1:5 v/v EtOAc/hexane); 1H NMR (400 MHz, CDCl3): δ
13
7.91 (dt, J = 8.4, 1.6 Hz, 2H), 7.70 – 7.59 (m, 1H), 7.54 – 7.44 (m, 2H), 4.56 (s, 2H); C NMR (101
MHz, CDCl3): δ 193.3, 134.5, 134.3, 129.1, 128.1, 55.0 ppm.
2ꢀAzidoꢀ1ꢀphenylpropanꢀ1ꢀone8 (24): Umpolung addition of azidotrimethylsilane (0.41 mL, 3.12
mmol) on trimethyl((1ꢀphenylpropꢀ1ꢀenꢀ1ꢀyl)oxy)silane (255 mg, 1.238 mmol) following the general
procedure gave 24 (158 mg, 73%) as a colourless liquid; Rf 0.4 (1:19 v/v EtOAc/hexane); 1H NMR (400
MHz, CDCl3) δ 7.94 (dt, J = 7.2, 1.6 Hz, 2H), 7.61 (tt, J = 7.4, 1.2 Hz, 1H), 7.49 (tt, J = 7.4, 1.6 Hz,
13
2H), 4.71 (q, J = 7.0 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H); C NMR (101 MHz, CDCl3) δ 196.8, 134.4,
134.0, 129.0, 128.7, 58.5, 16.5 ppm.
2ꢀAzidoꢀ1ꢀ(4ꢀmethoxyphenyl)ethenone20 (25): Umpolung addition of azidotrimethylsilane (0.35 mL,
2.60 mmol) over ((1ꢀ(4ꢀmethoxyphenyl)vinyl)oxy)trimethylsilane (231 mg, 1.04 mmol) following the
1
general procedure gave 25 (155 mg, 78 %) as a white solid; Rf 0.6 (1:5 v/v EtOAc/hexane); H NMR:
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(400 MHz, CDCl3) δ 7.92 – 7.83 (m, 2H), 7.01 – 6.91 (m, 2H), 4.50 (s, 2H), 3.88 (s, 3H); C NMR:
(101 MHz, CDCl3) δ 191.8, 164.4, 130.4, 127.5, 114.3, 55.7, 54.7 ppm.
2ꢀAzidoꢀ1ꢀ(4ꢀnitrophenyl)ethenone21 (26): Umpolung addition of azidotrimethylsilane (0.35 mL, 2.60
mmol) over trimethyl((1ꢀ(4ꢀnitrophenyl)vinyl)oxy)silane (247 mg, 1.04 mmol) following the general
1
procedure gave 26 (147 mg, 69%) as a yellow solid; Rf 0.6 (1:5 v/v EtOAc/hexane); H NMR: (400
13
MHz, CDCl3) δ 8.43 – 8.28 (m, 2H), 8.11 – 8.02 (m, 2H), 4.61 (s, 2H); C NMR: (101 MHz, CDCl3) δ
192.2, 151.0, 138.9, 129.3, 124.3, 55.4 ppm.
2ꢀAzidoꢀ1ꢀ(4ꢀfluorophenyl)ethanꢀ1ꢀone22 (27): Umpolung addition of azidotrimethylsilane (0.35 mL,
2.60 mmol) over ((1ꢀ(4ꢀfluorophenyl)vinyl)oxy)trimethylsilane (150 mg, 0.71 mmol) following the genꢀ
1
eral procedure gave 27 (98 mg, 77%) as a white solid: Rf 0.5 (1:20 v/v EtOAc/hexane); H NMR (400
MHz, CDCl3): δ 8.01 – 7.88 (m, 2H), 7.23 – 7.12 (m, 2H), 4.53 (s, 2H).; 13C NMR (101 MHz, CDCl3) δ
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192.9, 167.5 (d, J = 256.7 Hz), 132.1 (d, J = 3.1 Hz), 131.95 (d, J = 9.5 Hz), 129.7 (d, J = 106.6 Hz),
117.5 (d, J = 22.1 Hz), 56.0 ppm.
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2ꢀAzidoꢀ1ꢀ(4ꢀchlorophenyl)ethenone20 (28): Umpolung addition of azidotrimethylsilane (0.41mL, 3.12
mmol) over ((1ꢀ(4ꢀchlorophenyl)vinyl)oxy)trimethylsilane (282 mg, 1.25 mmol) following the general
procedure gave 28 (196 mg, 80%) as a white solid; Rf 0.4 (1:9 v/v EtOAc/hexane); 1H NMR (400 MHz,
CDCl3) δ 7.83 (dt, J = 8.7, 2.2 Hz, 2H), 7.45 (dt, J = 8.7, 2.2 Hz, 2H), 4.52 (s, 2H); 13C NMR (101
MHz, CDCl3) δ 192.2, 140.8, 132.8, 129.44, 129.43, 54.9 ppm.
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2ꢀAzidoꢀ1ꢀ(4ꢀbromophenyl)ethanꢀ1ꢀone23 (29): Umpolung addition of azidotrimethylsilane (0.35 mL,
2.60 mmol) over ((1ꢀ(4ꢀbromoophenyl)vinyl)oxy)trimethylsilane (270 mg, 1 mmol) following the genꢀ
eral procedure gave 29 (172 mg, 72%) as a white solid: Rf 0.5 (1:20 v/v EtOAc/hexane); 1H NMR (400
MHz, CDCl3): δ 7.83 – 7.71 (m, 2H), 7.69 – 7.58 (m, 2H), 4.53 (s, 2H); 13C NMR (101 MHz, CDCl3): δ
192.5, 133.2, 132.4, 129.52, 129.47, 54.9 ppm.
2ꢀazidoꢀ1ꢀ(4ꢀiodophenyl)ethenone (30): Umpolung addition of azidotrimethylsilane (0.17 mL, 1.30
mmol) over ((1ꢀ(4ꢀiodophenyl)vinyl)oxy)trimethylsilane (166 mg, 0.52 mmol) following the general
procedure gave 30 (115 mg 77%) as a white solid; Rf 0.5 (1:20 v/v EtOAc/hexane); FTꢀIR: Ѵmax 3083,
1
3031, 2891, 2091, 1686, 1578, 1277, 1217 cmꢀ1; H NMR: (400 MHz, CDCl3) δ 7.91 – 7.83 (m, 2H),
13
7.67 – 7.56 (m, 2H), 4.51 (s, 2H); C NMR: (101 MHz, CDCl3) δ 192.7, 138.4, 133.7, 129.3, 102.4,
54.8 ppm; HRMS : The compound decomposed under all conditions tested. This compound is
commercially available.
2ꢀAzidoꢀ2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀone8 (31): Umpolung addition of azidotrimethylsilane (0.41 mL,
3.12 mmol) over ((1Hꢀindenꢀ3ꢀyl)oxy)trimethylsilane (255 mg, 1.25 mmol) following the general proꢀ
1
cedure gave 31 (161 mg, 74%) as a yellow liquid; Rf 0.4 (1:9 v/v EtOAc/hexane); H NMR (400 MHz,
CDCl3) δ 7.77 (d, J = 7.7 Hz, 1H), 7.64 (td, J = 7.9, 1.0 Hz, 1H), 7.39–7.45 (m, 2H), 4.31 (dd, J = 8.1,
4.6 Hz, 1H), 3.50 (dd, J = 17.1, 8.2 Hz, 1H), 2.92 (dd, J = 17.1, 4.6 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ 201.8, 151.3, 136.2, 134.3, 128.3, 126.7, 124.7, 62.1, 33.1 ppm.
2ꢀAzidocyclohexanone14 (32): Umpolung addition of azidotrimethylsilane (0.45 mL, 3.38 mmol) over
(cyclohexꢀ1ꢀenꢀ1ꢀyloxy)trimethylsilane (230 mg, 1.35 mmol) following the general procedure gave 32
1
(145 mg, 77%) as a pale orange liquid; Rf 0.3 (1:10 v/v EtOAc/hexane); H NMR (400 MHz, CDCl3) δ
3.93 (dd, J = 11.0, 6.0 Hz, 1H), 2.51–2.57 (m, 1H), 2.26–2.37 (m, 2H), 2.02ꢀ2.09 (m, 1H), 1.93–2.09
(m, 1H), 1.66–1.73 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 205.7, 66.6, 40.9, 33.7, 27.2, 23.9 ppm.
ASSOCIATED CONTENT
Supporting Information
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Reproductions of H and C NMR spectra for all compounds. The Supporting Information is available
free of charge on the ACS Publications website.
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AUTHOR INFORMATION
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Corresponding Author
*amszpilman@gmail.com
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Notes
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The authors declare no competing financial interests.
‡ These Authors contributed equally to this work
ACKNOWLEDGMENT
This research was supported by Ariel University. Support by the Israel Science Foundation (grant no.
1914/15) is gratefully acknowledged.
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