Unprecedented regiochemical control in the formation of aryl[1,2-a]imidazopyridines from alkynyliodonium salts: Mechanistic insights

Article abstract of DOI:10.1039/c3ob41112e

Aryl(alkynyl)iodonium salts have been demonstrated to be valuable precursors to a diverse range of heteroaromatic ring systems including aryl[1,2-a]imidazopyridines. Successful application, using the recently described aryl(alkynyl)iodonium trifluoroacetate salts, is described, highlighting for the first time that the regioselectivity of this process is both counter-ion and concentration dependent. Studies with a carbon-13 labelled substrate established that the reactions of alkynyliodonium salts are highly complex and that multiple mechanistic processes appear to be underway simultaneously.

Full text of DOI:10.1039/c3ob41112e

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Organic & Biomolecular Chemistry
Unprecedented Regiochemical Control in the Formation of Aryl[1,2-
a]imidazopyridines from Alkynyliodonium Salts: Mechanistic Insights**
Luke I. Dixon,a Michael A. Carroll,a* Thomas J. Gregson,b George J. Ellames,b Ross W. Harringtona and
William Clegga
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Aryl(alkynyl)iodonium salts have been demonstrated to be valuable precursors to a diverse range of
heteroaromatic ring systems including aryl[1,2-a]imidazopyridines. Successful application, using the
recently described aryl(alkynyl)iodonium trifluoroacetate salts, is described, highlighting for the first time
10 that the regioselectivity of this process is both counter-ion and concentration dependent. Studies with a
carbon-13 labelled substrate established that the reactions of alkynyliodonium salts are highly complex
and that multiple mechanistic processes appear to be underway simultaneously.
40 addition of the anion to the β-acetylenic position was still
observed.30 As such the development of alkynyliodonium salts
with an intramolecular anion has been an area of continuing
interest as a means of restraining the addition reaction.30-36 In
contrast, alkynyliodonium trifluoroacetates (TFA) have received
45 little attention,3, 37 though it was recently shown by us that they
are not only readily prepared38 but also available on a large scale
(>0.5 mol).39
Introduction
Alkynyliodonium salts, first discovered in 1965 by Beringer and
15 Galton,1 are a highly versatile class of compounds and have
found widespread application in both organic and inorganic
syntheses and as such have been the subject of numerous
reviews.2-10
As
highly
electron-deficient
acetylenic
species,
Despite the wealth of alkynyliodonium salts reported to date,
very little is known about the effects of the counter-ion used or
50 their solution state behaviour. A novel comparison is presented
herein between the TFA salts and some of the more common
alkynyliodonium salts, demonstrating for the first time that the
anion used imparts a profound effect on the regioselectivity of
arylimidazo[1,2-a]pyridine formation; it was also found that the
55 outcome of the reaction could be manipulated through substrate
concentration. This study highlights a dynamic solution state for
alkynyliodonium salt derivatives and that, through control of
experimental conditions, access to a plethora of substituted
heteroaromatics may be achieved, with alternative regioisomers
60 possible from the same starting material.
20 alkynyliodonium salts are reactive partners in cycloaddition
reactions3 including 1,3-dipolar cycloadditions11-14 and Diels-
Alder chemistry.15-17 The hypernucleofuge nature of the
iodoarene in alkynyliodonium salts also makes them excellent
sources of carbenes,10 providing access to a wealth of cyclic
25 species such as cyclopentenes18, 19 and pyrroles;20 recently highly
synthetically challenging cyanocarbenes have also been
generated.21, 22
In 2004 Liu and co-workers reported the synthesis of a range
of 2-arylimidazo[1,2-a]pyridines (cf. 3a) from the reaction of
alkynyliodonium tosylates and 2-aminopyridine.40 Surprisingly,
the analogous reaction of 1a afforded both 2- and 3-substituted
65 imidazo[1,2-a]pyridines in roughly equal amounts (Scheme 2), as
confirmed by X-ray crystallography (ESI and Figure 1).
Scheme 1. Heteroaromatics from alkynyliodonium salts 2, 4
30 In the same fashion, indoles, furopyridines, indenes,
Scheme 2. Synthesis of imidazo[1,2-a]pyridines from 1a
imidazopyridines,
imidazopyrimidines,
furotropones,
furonaphthoquinones, thiazoles, selenazoles and benzofurans
This intriguing production of two regioisomers led us to repeat
70 the procedure reported by Liu and co-workers40 using the
tosylate, 5, to confirm that just one regioisomer had indeed been
produced. In our hands, the experiment showed that the major
product of the reaction was in fact 4a and that, although this was
dominant, trace amounts of 3a were also present (2%, 3a : 44%,
4
(Scheme 1) may also be formed.2, Cumulatively, these ring
systems account for a wide range of known pharmacophores, yet
35 the potential for alkynyliodonium salts in the preparation of
heterocycles remains to be exploited.
Commonly used anions in alkynyliodonium salts include
mesylates,23 tosylates,24, 25 triflates26, 27 and tetrafluoroborates28, 29
due to their low nucleophilicity, though in many of these cases
1
75 4a); comparison of the H-NMR data with other reports supports
this regiochemical assignment.41-44 Having optimized the reaction
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[1a] (molL-1)
Ratio (3a) : (4a)
Total Yield (%)[a][b][c]
shown in Scheme 2 for a range of solvents and bases (see
supporting information, ESI), fluorobenzene (PhF) (to minimise
intermolecular insertion) and K2CO3 were chosen respectively,
and at room temperature to minimize decomposition of the
alkynyliodonium salts.
0.01
0.02
0.11
0.50
1.00
90 : 10
73 : 27
39 : 61
26 : 74
17 : 83
49
49
50
34
38
5
40 [a] Isolated yields; [b] mean of 3 syntheses; [c] 5 mmol scale
It should be noted that 1a was soluble in DCM and CHCl3 at all
the concentrations tested, though not in PhF; however, in all three
solvents, rapid dissolution of 1a was observed on addition of 2.
Under the reaction conditions outlined in Scheme 1 the K2CO3
45 remained as a solid throughout. This suggests that the key
reactive species is generated in situ as the same concentration
dependence was observed for all three solvents (see ESI).
Figure 1. Structures of the cations of 3a·HCl·H2O (left) and
4a·HCl·2H2O (right), with 40% probability displacement ellipsoids; N
atoms are shown with shading.
10 Heterogeneous bases and aprotic,45 non-coordinating solvents
gave the best results. Despite slightly lower yields, PhF was
chosen as it resulted in a 'cleaner' reaction facilitating isolation of
the products. Comparison with other alkynyliodonium salts
showed that 3a was undetectable using the triflate (6), whereas
15 the cyclic iodane, 7 (see ESI), produced a ratio of products
between that observed for the trifluoroacetate and tosylate salts
(Table 1). Only the phenyliodonium derivatives were investigated
since variation of the second aromatic ring was previously found
to have no effect in the preparation of 2-arylfuro[3,2-
20 c]pyridines.38
Table 1. Counter-ion dependence for the reaction of phenyl(phenyl-
ethynyl)iodonium salts and 2
Figure 2. Concentration dependence for the reaction of 1a and 2
50 Although some increase in yield was observed at higher dilutions,
far more noticeable was the concentration-dependent
regioselectivity favouring the 2-substituted regioisomer, 3a. To
confirm this unexpected dependence, reactions were conducted
using five different iodonium salt concentrations (Table 2 and
55 Figure 2). This ‘tuning’ of the reaction conditions has potential
value, for example in drug discovery, where both regioisomers
are accessible from a single set of reagents.
Ar, X
Ratio 3a : 4a Total Yield (%)[a]
Ph, TFA (1a)
Ph, OTs (5)
Ph, OTf (6)
73 : 27
7 : 93
49[b]
62
0 : 100
37 : 63
58
54

C6H4-2-CO2 , – (7)[c]
Table 3. Concentration dependence for the reaction of 1b–1d and 2
[a] Isolated yields; [b] mean of 3 syntheses; [c] Temp. raised to reflux
25 after 14 h
Such a dependence on the anion used has never been reported
previously in the formation of heteroaromatics from
alkynyliodonium salts, though the literature suggests that the
conversion of alkynyliodonium salts to alkenyliodonium salts
30 appears to demonstrate stereoselectivity for the E- or Z-isomer
depending on the counter-ion used.45-55 The influence of solvent
on ion pair separation, and hence choice of counter-ion, has also
been shown to affect the reactions of diaryliodonium salts.56
In addition to the counter-ion dependence of the reaction it was
35 found that the concentration of the reactants also exerted an
unexpected degree of control over the product distribution (Table
2 and Figure 2).
Ratio
3 : 4 [a]
74 : 26
44 : 54
84 : 16
57 : 43
81 : 19
53 : 47
Total Yield
Ar
[1] (molL-1)
(%)[b]
66
4-Methylphenyl (1b)
4-Methylphenyl (1b)
3′-Thienyl (1c)
3′-Thienyl (1c)
4-Bromophenyl (1d)
4-Bromophenyl (1d)
0.02
0.10
0.02
0.14
0.02
0.14
63
60
58
78
55
60 [a] 2.5 mmol scale; [b] Isolated yields
To establish whether the observed concentration dependence was
restricted to the production of phenylimidazo[1,2-a]pyridines (3a
and 4a) several alternative alkynyliodonium salts were also
studied (1b–1d) and it was pleasing to note that a similar trend
65 was found (Table 3).
Table 2. Concentration dependence for the reaction of 1a and 2
The mechanism of imidazopyridine formation presented by Liu40
follows that previously reported by Wipf57 (and later Togo30) for
2
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Scheme 3. Distribution of products from the reaction of [7′-13C]-1
the formation of thiazoles. An alternative route to the observed
product has also been proposed by Ochiai.58 All of these options
invoke a monomeric form of the aryl(alkynyl)iodonium salt as
the starting species even though kinetic and spectroscopic
As the acetylenic products of 1,2-migration have been reported to
63
5
be highly reactive,58,
especially within a basic environment,
they may prove difficult to observe and as such we prepared the
isotopically labelled [7′-13C]-1a to investigate the process.
evidence for other hypervalent iodine compounds has been 35 This preliminary 13C-labelling study generated [2-13C]-3a and [3-
reported that indicates the presence, in solution, not only of
13C]-4a as expected (Scheme 3); however, the isotopomer [3-
13C]-3a was also isolated, highlighting that a competitive 1,2-
migration was occurring (Scheme 4) and suggesting that at least
three reaction pathways are in operation.
10 associated counter-ions, but also of higher-order structures
(dimers, oligomers etc.).59-61 Such species have also been shown
61
to be highly concentration-dependent60,
and therefore
contributions from these structures cannot be ruled out.
In addition these proposals rapidly result in loss of the counter-
15 ion. However, to retain the influence of this component, and
taking into account these prior mechanistic studies, we propose
that intermediates such as 9 and 14 (Figure 2) and 8 and 13
(Figure 3) should also be considered in the mechanistic rationale
since both the amino- and pyridinyl-nitrogen atoms of 2-
20 aminopyridine are viable nucleophiles62 (Scheme 3: there may
also be influence of the counter-ion in the subsequent steps due to
the charged nature of the proposed intermediates).
40
Scheme 4. Mechanism of isotopomer formation; [3-13C]-3a
Conclusions
In summary, we have presented the first example of
regiochemical control in the synthesis of heteroaromatics from
45 alkynyliodonium salts. A protocol based on the counter-ion and
concentration dependence of the process has been identified for
the selective formation of 2-arylimidazo[1,2-a]pyridines and 3-
arylimidazo[1,2-a]pyridines. In addition, initial studies using
carbon-13 labelled substrates have demonstrated that, even
50 though well studied, the reactions of alkynyliodonium salts are
highly complex and that multiple mechanistic processes appear to
be underway simultaneously.
This new-found understanding is being applied to the
preparation of a diverse range of heterocyclic ring systems which
55 are of interest to our drug discovery programmes. Further work to
resolve and differentiate the many mechanistic options is on-
going.
Figure 2. Proposed [10-I-4] intermediates, 14 and 18
25 Further complexity is introduced following alkylidene carbene
formation (the carbene can either cyclize directly or undergo 1,2-
migration prior to cyclization), resulting in the formation of 3a or
4a via several different pathways.
Experimental
Reactions requiring anhydrous conditions were performed using
60 oven- or flame-dried glassware and conducted under a positive
30 Figure 3. Potential intermediates of Michael addition
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pressure of nitrogen. Anhydrous solvents were prepared thus:
DCM and MeCN were refluxed over CaH2; THF, ether and 60 1296, 1272, 1262, 1175, 1148, 1134, 1074, 1009; δH (400 MHz,
νmax/cm1 (neat) 1634, 1603, 1540, 1499, 1480, 1450, 1442, 1352,
hexane were refluxed over sodium/benzophenone; toluene was
refluxed over sodium; and dibromomethane, chloroform, 1,4-
dioxane and fluorobenzene were stored over 3Å molecular sieves.
d6-DMSO; Me4Si) 8.45 (1H, d, H5 J 6.9), 7.72 (1H, s, H2), 7.61
(1H, d, H8 J 8.7), 7.57 (2H, d, H2′/H6′ J 7.3), 7.46 (2H, tapp.
H3′/H5′ J 7.8), 7.34 (1H, t, H4′ J 7.4), 7.21 (1H, tapp., H7 J 7.8),
6.86 (1H, tapp., H6 J 6.6); δC (100 MHz, d6-DMSO; Me4Si) 146.06
,
5
Infrared spectra were recorded on a Varian Scimitar Series 800
1
FT-IR with internal calibration. H and 13C-NMR spectra were 65 (C9), 133.07 (C2), 129.74 (C3′/C5′), 129.42 (C1′), 128.37 (C4′),
recorded on a Bruker Advance 300 MHz spectrometer, a Jeol
ECS 400 MHz spectrometer or a Jeol Lamda 500 MHz
127.97 (C2′/C6′), 125.58 (C3), 125.00 (C7), 124.45 (C5), 118.09
(C8), 113.30 (C6); m/z (ESI) 195 ([M+H]+, 100%). Found:
10 spectrometer with residual tetramethylsilane solvent as the
[M+H]+, 195.0905. C13H11N2 requires 195.0922.
1
72
reference for H and 13C. All coupling constants are given in Hz.
2-(4′-Methylphenyl)imidazo[1,2-a]pyridine (3b):69,
Using
Elemental analyses were carried out at London Metropolitan 70 K2CO3 (1.09 g, 7.89 mmol), 2 (0.32 g, 3.39 mmol), PhF (113 mL)
University. Mass spectrometry was recorded at the EPSRC Mass
Spectrometry Service, Swansea or on a Waters LCT Premier
15 (TOF-MS) operating in ‘W’ mode. Melting points were recorded
on a Gallenkamp MF-370 melting point apparatus and are
and 1b (1.11 g, 2.56 mmol). White crystalline solid (0.26 g, 1.25
mmol, 49%)(as well as 4b (17%)). mp 138-140 °C (from acetone)
(lit.,72 145-146 °C); Rf 0.23 (4:1 ether/petrol); Found: C, 80.9; H,
5.7; N, 13.4. Calc. for C14H12N2: C, 80.7 ; H, 5.8; N, 13.5%.; IR
uncorrected. Automated flash chromatography was performed 75 νmax/cm-1 (neat) 3132, 1633, 1506, 1483, 1372, 1349, 1268, 1245,
using
a
Varian IntelliFlash 971-FP discovery scale flash
1202, 1139; δH (500 MHz, CDCl3; Me4Si) 8.05 (1H, dtapp, H5 J
6.8, J 1.2), 7.84 (2H, d, H3′/H5′ J 8.1), 7.77 (1H, s, H3), 7.60
(1H, dd, H8 J 9.1, J 0.8), 7.23 (2H, d, H2′/H6′ J 8.1), 7.12 (1H,
ddd, H7 J 9.1, J 6.8, J 1.3), 6.71 (1H, dtapp, H6 J 6.8, J 1.1), 2.38
purification system. The terms ‘ether’ and ‘petrol’ refer to diethyl
20 ether and the fractions boiling between 40 and 60 °C (unless
otherwise specified) respectively. X-ray crystallographic data
were measured on an Agilent Technologies Gemini A Ultra 80 (3H, s, Me); δC (125 MHz, CDCl3; Me4Si) 145.86, 145.55,
diffractometers at 150 K, using Mo or CuK radiation; full
details are in the ESI and deposited with CCDC.
137.72, 130.89, 129.36, 125.90, 125.45, 124.41, 117.36, 112.21,
107.69, 21.22; m/z (ESI) 209 ([M+H]+, 100%). Found: [M+H]+,
209.1071. C14H13N2 requires 209.1073.
3-(4′-Methylphenyl)imidazo[1,2-a]pyridine (4b): Using K2CO3
85 (1.06 g, 7.65 mmol), 2 (0.31 g, 3.29 mmol), PhF (24 mL) and 1b
(1.07 g, 2.47 mmol). White crystalline solid (0.18 g, 0.88 mmol,
36%)(as well as 3b (27%)). mp 84-86 °C (from DCM-ether); Rf
0.09 (4:1 ether/petrol); Found: C, 80.9; H, 5.7; N, 13.4. Calc. for
C14H12N2: C, 80.7; H, 5.8; N, 13.5%; IR νmax/cm-1 (neat) 2981,
25 CAUTION: Some hypervalent iodanes are potentially explosive
and should be handled taking appropriate precautions.64-67
68, 69
2-Phenylimidazo[1,2-a]pyridine (3a):40,
K2CO3 (1.05 g,
7.62 mmol) and 2 (0.31 g, 3.27 mmol) were stirred together in
30 dry PhF (250 mL) for 45 min before the addition of 1a (1.05 g,
2.51 mmol) by powder funnel. The solution was then stirred in
darkness, at RT, under nitrogen overnight before being washed 90 1634, 1545, 1490, 1353, 1295, 1255, 1166, 1148, 1013; δH (500
with water (300 mL) and extracted into DCM (2 × 75 mL). The
organic fractions were dried (MgSO4) and concentrated in vacuo
35 to give a brown oil. The crude product was purified by column
chromatography (SiO2, Grace Resolve™ 80 g cartridge;§ sample
MHz, CDCl3; Me4Si) 8.30 (1H, dtapp, H5 J 6.9, J 1.2), 7.66 (1H,
overlapped s, H2), 7.65 (1H, overlapped d, H8 J 8.0), 7.44 (2H, d,
H3′/H5′ J 8.0), 7.32 (2H, dd, H2′/H6′ J 8.0, J 0.6), 7.17 (1H, ddd,
H6 J 9.1, J 6.9, J 1.3), 6.78 (1H, tdapp , H7 J 6.9, J 1.2), 2.43 (3H,
loaded in DCM, 1:0 hexane/ether for 5 min then increasing to 3:7 95 s, Me); δC (125 MHz, CDCl3; Me4Si) 145.99, 138.13, 132.28,
over 120 min and holding at this solvent mixture until elution was
complete) to give the product as a white crystalline solid (0.24 g,
40 1.22 mmol, 49%). mp 132–133 °C (from DCM–petrol) (lit.,70
136–137 °C from cyclohexane); Rf 0.55 (4:1 ether/petrol); Found:
129.88, 128.00, 126.36, 125.73, 123.94, 123.34, 118.21, 112.34,
21.27. m/z (ESI) 209 ([M+H]+, 100%). Found: [M+H]+,
209.1072. C14H13N2 requires 209.1073.
2-(3′-Thienyl)imidazo[1,2-a]pyridine (3c): Using K2CO3 (1.06
C, 80.4; H, 5.3; N, 14.4. Calc. for C13H10N2: C, 80.4; H, 5.2; N, 100 g, 7.64 mmol), 2 (0.32 g, 3.36 mmol), PhF (113 mL) and 1c (1.03
14.4%; IR νmax/cm1 (neat) 3130, 1632, 1502, 1475, 1447, 1369,
1353, 1304, 1273, 1246, 1203, 1145, 1077, 1027; δH (300 MHz,
45 CDCl3; Me4Si) 8.10 (1H, d, H5 J 6.9), 7.97 (2H, d, H2′/H6′ J
g, 2.43 mmol). White crystalline solid (0.25 g, 1.21 mmol,
50%)(as well as 4c (10%)). mp 163-165 °C (from acetone); Rf
0.12 (4:1 ether/petrol); Found: C, 66.1; H, 3.9; N, 13.8. Calc. for
C11H8N2S: C, 66.0 ; H, 4.0; N, 14.0%; IR νmax/cm-1 (neat) 3124,
7.2), 7.85 (1H, s, H3), 7.65 (1H, d, H8 J 9.0), 7.45 (2H, tapp.
,
H3′/H5′ J 7.5), 7.34 (1H, t, H4′ J 7.5), 7.17 (1H, tapp., H7 J 6.9), 105 1632, 1508, 1476, 1338, 1306, 1272, 1242, 1144, 1090; δH (500
6.77 (1H, tapp., H6 J 6.0); δC (75 MHz, CDCl3; Me4Si) 146.41
(C2), 146.09 (C9), 134.27 (C1′), 128.99 (C3′/C5′), 128.27 (C4′),
50 126.55 C2′/C6′), 125.86 (C5), 124.79 (C7), 118.00 (C8), 112.66
(C6), 108.38 (C3); m/z (CI) 195 ([M+H]+, 100%), 95 (3), 80 (2),
52 (4). Found: [M+H]+, 195.0917. C13H11N2 requires 195.0917.
3-Phenylimidazo[1,2-a]pyridine (4a):43, 71 Using K2CO3 (2.15 g,
15.55 mmol), 2-aminopyridine (0.61 g, 6.50 mmol), PhF (5 mL)
55 and 1a (2.07 g, 4.95 mmol). White crystalline solid (0.36 g, 1.84
mmol, 37%). mp 95–97 °C (from MeOH–H2O) (lit.,71 97–98 °C
MHz, d6-DMSO; Me4Si) 8.49 (1H, d, H5 J 6.7), 8.23 (1H, s, H3),
7.89 (1H, d, H2′ J 2.8), 7.61-7.55 (2H, m, H4′/H5′), 7.54 (1H, d,
H8 J 9.0), 7.21 (1H, tapp, H7 J 6.6), 6.86 (1H, tapp, H6 J 6.7); δC
(125 MHz, d6-DMSO; Me4Si) 144.94, 141.44, 136.38, 127.16,
110 127.07, 126.46, 125.15, 121.43, 116.76, 112.46, 109.31; m/z
(ESI) 201 ([M+H]+, 100%). Found: [M+H]+, 201.0480. C11H9N2S
requires 201.0481.
3-(3′-Thienyl)imidazo[1,2-a]pyridine (4c): Using K2CO3 (1.07
g, 7.76 mmol), 2 (0.32 g, 3.36 mmol), PhF (24 mL) and 1c (1.05
from petroleum ether); Rf 0.13 (4:1 ether/petrol); Found: C, 80.3; 115 g, 2.48 mmol). White crystalline solid (0.12 g, 0.62 mmol,
H, 5.1; N, 14.3. Calc. for C13H10N2: C, 80.4; H, 5.2; N, 14.4%; IR
25%)(as well as 3c (33%)). mp 54-57 °C (from DCM); Rf 0.06
4
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(4:1 ether/petrol); IR νmax/cm-1 (neat) 3090, 1690, 1637, 1576,
([79Br,79Br]M+, 8%), 184 (18), 182 (18), 103 (100). Found: M+,
1501, 1483, 1343, 1330, 1299, 1264, 1225, 1169, 1154, 1128, 60 260.8868. C713C1 H679Br2 requires 260.8864.
1087, 1019; δH (500 MHz, d6-DMSO; Me4Si) 8.61 (1H, d, H5 J
7.0), 7.93 (1H, dd, H2′ J 1.7, J 1.3), 7.85 (1H, s, H2), 7.76 (1H,
dd, H5′ J 5.0, J 2.1), 7.64 (1H, d, H8 J 8.5), 7.54 (1H, dd, H4′ J
Phenyl-α-[13C]acetylene ([13C]-20):74 1′,1′-Dibromo-2′-[13C]-
styrene ([13C]-20) (1.21 g, 4.60 mmol) was dissolved in dry ether
(30 mL) and cooled to -78 °C under an atmosphere of nitrogen. n-
Butyllithium (2.17M in hexanes, 5.41 mL, 11.75 mmol) was
5
5.0, J 1.3), 7.29 (1H, ddd, H7 J 8.5, J 6.7, J 1.7), 6.99 (1H, tdapp
,
H6 J 6.8, J 1.1); δC (125 MHz, d6-DMSO; Me4Si) 145.18, 65 added dropwise over 10 minutes and the solution stirred for a
132.58, 128.97, 127.20, 127.08, 124.57, 124.27, 121.18, 121.06,
further 30 minutes then for 1 hour at room temperature. The
reaction was quenched with water (50 mL), washed with water
(50 mL) and extracted into ether (3 × 50 mL). The organic layers
were combined, dried (MgSO4) and concentrated in vacuo to give
117.40, 112.88; m/z (ESI) 201 ([M+H]+, 100%). Found: [M+H]+,
10 201.0479. C11H9N2S requires 201.0481.
2-(4′-Bromophenyl)imidazo[1,2-a]pyridine
(3d):73
Using
K2CO3 (0.96 g, 6.91 mmol), 2 (0.28 g, 2.95 mmol), PhF (102 mL) 70 the product as a pale yellow oil (0.46 g, 4.43 mmol, 96%)‡ with
and 1d (1.13 g, 2.27 mmol). White crystalline solid (0.29 g, 1.47
mmol, 65%)(as well as 4d (13%)). mp 196-198 °C (from acetone)
15 (lit.,73 215-216 °C from heptane); Rf 0.34 (4:1 ether/petrol);
Found: C, 57.3; H, 3.2; N, 10.1. Calc. for C13H9BrN2: C, 57.2; H,
sufficient purity to be used in subsequent reactions. δH (300 MHz,
CDCl3; Me4Si) 7.54-7.49 (2H, m), 7.37-7.34 (3H, m), 3.09 (1H,
d, J 49.52); δC (75 MHz, CDCl3; Me4Si) 84.05 (C1′-label). m/z
(EI) 103 ([M]+, 100%). Found: M+, 103.0496. C713C1H6 requires
3.3; N, 10.3%; IR νmax/cm-1 (neat) 2955, 2924, 1679, 1635, 1428, 75 103.0498.
1401, 1371, 1321, 1203, 1065, 1006; δH (500 MHz, d6-DMSO;
Me4Si) 8.51 (1H, dtapp, H5 J 6.8, J 1.2), 8.42 (1H, s, H3), 7.91
20 (2H, d, H3′/H5′ J 8.7), 7.61 (2H, d, H2′/H6′ J 8.7), 7.56 (1H, dd,
H8 J 9.1, J 1.0), 7.24 (1H, ddd, H7, J 9.1, J 6.8, J 1.3), 6.89 (1H,
Phenyl(phenyl-β-[13C]-ethynyl)iodonium
trifluoroacetate
([13C]-1a): Trifluoroacetic acid (1.01 g, 8.82 mmol) was added
dropwise at -30 °C to a stirred solution of phenyliodonium
bis(acetate) (1.35 g, 4.20 mmol) in dry DCM (25 mL) over a
tdapp, H6 J 6.8, J 1.0); δC (125 MHz, d6-DMSO; Me4Si) 144.82, 80 period of 10 minutes. After a further 30 minutes the solution was
143.13, 133.16, 131.55, 127.47, 126.87, 125.11, 120.59, 116.61,
112.34, 109.42; m/z (ESI) 275 ([81Br][M+H]+ , 97%), 273
25 ([79Br][M+H]+, 100%). Found: [M+H]+, 273.0026. C13H10BrN2
requires 273.0022.
allowed to warm to room temperature and stirred for 1 hour
before being re-cooled to -30 °C for the injection of a solution of
phenyl[α-13C]acetylene, [13C]-20, (0.46 g, 4.43 mmol) in dry
DCM (5 mL) over 5 minutes. The resulting mixture was then
3-(4′-Bromophenyl)imidazo[1,2-a]pyridine
(4d):69
Using 85 allowed to reach room temperature over 3.5 hours in darkness
K2CO3 (1.04 g, 7.55 mmol), 2 (0.31 g, 3.29 mmol), PhF (24 mL)
and 1d (1.23 g, 2.48 mmol). White crystalline solid (0.18 g, 0.65
30 mmol, 26%)(as well as 3d (29%)). mp 89-92 °C (from acetone);
Rf 0.25 (4:1 ether/petrol); Found: C, 57.1; H, 3.2; N, 10.2. Calc.
before concentration in vacuo (to about 5 mL) followed by
crystallization to give the product as a white, crystalline solid
(0.63 g, 1.50 mmol, 36%). M.p. 79-81 °C (dec.)(from DCM-
ether-petrol) δH (400 MHz, CDCl3; Me4Si) 8.14 (2H, d, H2/H6, J
for C13H9BrN2: C, 57.2; H, 3.3; N, 10.3%; IR νmax/cm-1 (neat) 90 8.7), 7.58 (1H, dt, H4, J 7.8, J 0.9), 7.49-7.39 (5H, m), 7.34 (2H,
3023, 1537, 1499, 1478, 1398, 1351, 1303, 1291, 1264, 1174,
1151, 1101, 1074, 1007; δH (500 MHz, CDCl3; Me4Si) 8.25 (1H,
35 dtapp, H5 J 7.0, J 1.2), 7.67 (1H, s, H2), 7.66 (1H, d, H8 J 9.1, J
1.1), 7.62 (2H, d, H2′/H6′ J 8.6), 7.40 (2H, d, H3′/H5′ J 8.6), 7.19
t, H3/H5 J 7.3); δC (100 MHz, CDCl3; Me4Si) 162.55 (q, (CO) J
36.2), 133.55 (s, C2/C6), 132.90 (d, C3′/C5′, J 2.4), 132.14 (s,
C3/C5), 131.96 (s, C4), 130.86 (d, C4′, J 1.4), 128.72 (d, C2′/C6′,
J 5.5), 120.67 (s, C1), 120.40 (d, C1′, J 86.2), 104.10 (s, C7′-
(1H, ddd, H7 J 9.1, J 6.7, J 1.3), 6.80 (1H, tdapp, H6 J 6.8, J 1.1); 95 label), 45.14 (d, C8′, J 160.6); m/z (ESI) 306 ([M-TFA]+, 100%),
δC (125 MHz, CDCl3; Me4Si) 146.24, 132.68, 132.38, 129.35,
128.15, 124.49, 124.39, 123.06, 122.05, 118.29, 112.76; m/z
40 (ESI) 275 ([81Br][M+H]+ , 98%), 273 ([79Br][M+H]+, 100%).
Found: [M+H]+, 273.0026. C13H10BrN2 requires 273.0022.
294 (14), 179 (19). Found: [M-TFA]+, 305.9861. C1313C1 H10I
requires 305.9855.
2-Phenyl-2/3-[13C]-imidazo[1,2-a]pyridine ([13C]-3a) and 3-
Phenyl-3-[13C]-imidazo[1,2-a]pyridine ([13C]-4a): Potassium
1′,1′-Dibromo-2′-[13C]-styrene
([13C]-19):74 100 carbonate (0.30 g, 2.18 mmol) and 2-aminopyridine (0.09 g, 0.97
Triphenylphosphine (5.04 g, 19.22 mmol) and dry carbon
tetrabromide (3.10 g, 9.34 mmol) were dissolved in dry DCM (30
45 mL) at 0 °C under an atmosphere of nitrogen. The solution was
stirred for 30 minutes before the dropwise addition of
mmol) were stirred together in dry fluorobenzene (6.3 mL) for 45
minutes under an atmosphere of nitrogen before the addition of
phenyl(phenyl[β-13C]ethynyl)iodonium trifluoroacetate (0.30 g,
0.70 mmol) by powder funnel. The solution was then stirred in
benzaldehyde [13C]-carbonyl (0.50 g, 4.67 mmol) over 5 minutes. 105 darkness, at room temperature, overnight before being washed
The solution was stirred at 0 °C for 1 hour before washing with
an aqueous 5M solution of CuSO4 (300 mL) followed by
50 extraction into DCM (3 × 50 mL). The organic layers were
combined, dried (MgSO4) and concentrated in vacuo. The
with water (150 mL) and extracted into DCM (4 × 30 mL). The
organic fractions were combined, dried (NaSO4), filtered and
concentrated in vacuo to a brown oil. The crude product was
purified by column chromatography (Grace Resolve™ 80g, 150
resulting orange oily solid was dry loaded onto silica and purified 110 mL silica cartridge; 1:0 hexane/ether for 5 min then to 3:7 over
by column chromatography (silica) to give the product as a pale
orange clear oil which crystallized on standing (1.21 g, 4.60
55 mmol, 98%). Rf 0.74 (petrol 40/60); δH (300 MHz, CD2Cl2;
Me4Si) 7.50-7.39 (2H, m), 7.44 (1H, d, J 159.07), 7.33-7.23 (3H,
120 min and holding at this solvent mixture until elution was
complete), loading the sample in DCM, to give the products as a
white, crystalline solids; 2-Phenyl-2/3-[13C]-imidazo[1,2-
a]pyridine ([13C]-3a) (0.03 g, 0.14 mmol, 20%) and 3-Phenyl-3-
m); δC (75 MHz, CD2Cl2; Me4Si) 137.86 (C1′-label). m/z (EI) 265 115 [13C]-imidazo[1,2-a]pyridine ([13C]-4a) (0.04 g, 0.21 mmol,
([81Br,81Br]M+, 8%), 263 ([81Br,79Br]M+, 18%), 261
30%).
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DOI: 10.1039/C3OB41112E
Organic & Biomolecular Chemistry
Page 6 of 7
2-Phenyl-2/3-[13C]-imidazo[1,2-a]pyridine ([13C]-3a): Rf 0.55
60 3. P. J. Stang, Angew. Chem., Int. Ed. Engl., 1992, 31, 274-285.
(4:1 ether/petrol); δH (400 MHz, CDCl3; Me4Si) 8.09 (1H, dt, H5
J 6.8, J 1.2), 7.97-7.93 (2H, m, H2′/H6′), 7.84 (0.82H, dd, H3 J
8.4, J 0.8), 7.84 (0.18H, d, H3 J 190.7) 7.63 (1H, d, H8 J 9.2),
7.43 (2H, tapp., H3′/H5′ J 8.0), 7.32 (1H, t, H4′ J 7.6), 7.15 (1H,
ddd., H7 J 9.2, J 6.6, J 1.2), 6.75 (1H, dtapp., H6 J 6.6, J 0.8); δC
(100 MHz, CDCl3; Me4Si) 145.82 (C2-label), 145.47 (d, C9 J
4.5), 133.76 (d, C1′ J 67.9), 133.76 (s, C1'), 128.82 (d, C3′/C5′ J
4.4), 128.82 (s, C3′/C5′), 128.08 (s, C4′), 126.14 (d, C2′/C6′ J
10 2.5), 125.66 (d, C5 J 7.9), 125.66 (s, C5), 124.79 (C7), 117.62 (d,
C8 J 6.1), 117.62 (s, C8) 112.55 (C6), 108.21 (C3-label); m/z (CI)
196 ([M+H]+, 100%), 184 (12). Found: [M+H]+, 196.0947.
C1213C1H11N2 requires 196.0950.
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3-Phenyl-3-[13C]-imidazo[1,2-a]pyridine ([13C]-4a): Rf 0.13
15 (4:1 ether/petrol); δH (400 MHz, CDCl3; Me4Si) 8.31 (1H, dd, H5
J 6.8, J 1.2), 7.68 (1H, od, H2 J 12.4), 7.65 (1H, od, H8 J 8.8),
7.55-7.52 (2H, m, H2′/H6′), 7.49 (2H, tapp., H3′/H5′ J 8.0), 7.39
(1H, tt, H4′ J 7.2, J 1.2), 7.17 (1H, ddd., H7 J 9.2, J 6.4, J 1.2),
6.86 (1H, tapp., H6 J 6.8); δC (100 MHz, CDCl3; Me4Si) 146.21 (d,
20 C9 J 9.1), 132.57 (d, C2 J 69.0), 132.52 (s, C9), 129.40 (d, C1' J
67.4), 129.33 (d, C3′/C5' J 4.2), 129.33 (s, C3'/C5'), 128.27 (s,
C4′), 128.11 (d, C2′/C6′ J 2.7), 125.84 (C3-label), 124.34 (s, C7),
123.43 (s, C5), 118.09 (C8), 113.30 (C6); m/z (CI) 196 ([M+H]+,
100%). Found: [M+H]+, 196.0945. C1213C1H11N2 requires
25 196.0950.
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907274 contain the supplementary crystallographic data for this
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We thank sanofi-aventis, Newcastle University and the EPSRC
(equipment grant EP/F03637X/1) for funding. We also thank
35 Prof. W. McFarlane and Dr C. Wills for contributions in the field
of NMR and the EPSRC National Mass Spectrometry Service
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Notes and references
a
School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1
40 7RU (UK); Fax: (+44) 191 222 6929; E-mail: m.a.carroll@ncl.ac.uk
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b
Department of Isotope Chemistry and Metabolite Synthesis, sanofi-
aventis, Alnwick, Northumberland, NE66 2JH (UK). Current address:-
Department of Isotope Chemistry, Covance Laboratories, Alnwick,
Northumberland, NE66 2JH (UK).
45 † Electronic Supplementary Information (ESI) available:full experimental
details and spectra, tables of X-ray crystallographic data and results. See
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