Metal-Free [2+2+1] annulation of alkynes, nitriles and nitrogen atoms from iminoiodanes for synthesis of highly substituted imidazoles

Article abstract of DOI:10.1002/adsc.201500032

Boron trifluoride nitrile complexes promote oxidative [2+2+1] annulations of alkynes, nitriles and N-atoms from iminoiodanes to give the corresponding 2,4-disubstituted and 2,4,5-trisubstituted N-tosylimidazoles in moderate to good yields with high regios

Full text of DOI:10.1002/adsc.201500032

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DOI: 10.1002/adsc.201500032
Metal-Free [2+2+1]Annulation of Alkynes, Nitriles and Nitrogen
Atoms from Iminoiodanes for Synthesis of Highly Substituted
Imidazoles
Akio Saito,a,* Yui Kambara,a Takuma Yagyu,a Keiichi Noguchi,b
Akira Yoshimura,c and Viktor V. Zhdankinc
a
Division of Applied Chemistry, Institute of Engineering Tokyo University of Agriculture and Technology, Koganei, Tokyo
184-8588, Japan
E-mail: akio-sai@cc.tuat.ac.jp
Instrumentation Analysis Center, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, USA
b
c
Received: January 15, 2015; Revised: February 10, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500032.
Abstract: Boron trifluoride nitrile complexes pro-
mote oxidative [2+2+1]annulations of alkynes, ni-
triles and N-atoms from iminoiodanes to give the
corresponding 2,4-disubstituted and 2,4,5-trisubsti-
tuted N-tosylimidazoles in moderate to good yields
with high regioselectivities.
We have been engaged in the synthesis of heterocy-
clic systems through the activation of alkynes by iod-
AHCTUNGTRENNUNG
ine(III) reagents,[9] which have gained much attention
as eco-friendly oxidants.[10] As a part of our studies,
an oxidative [2+2+1]annulation of alkynes, nitriles
and oxygen atoms from iodosylbenzene (PhIO) was
recently reported for the facile, metal-free and regio-
selective construction of 2,4-disubstituted and 2,4,5-
trisubstituted oxazoles.[11] The oxazole formation was
achieved by using PhI(OH)X, which is generated in
situ from iodosylbenzene (PhIO) and a Brønsted acid
(HX). Therefore, we envisaged that the iodine(III)-
mediated oxidative annulation could be extended to
Keywords: alkynes; annulation; iminoiodanes;
metal-free conditions; nitriles
The imidazole nucleus represents an important struc- a metal-free approach to the synthesis of highly sub-
tural motif in a large number of natural and synthetic stituted imidazoles by the use of N-sulfonyliminophe-
molecules with a wide range of applications in medici- nyliodane (PhINSO2R) and an acid additive instead
nal chemistry[1] and material science.[2] In addition, of PhI(OH)X (Scheme 1b). Under transition metal-
imidazole derivatives have been utilized as ionic liq- catalyzed conditions, PhINSO2R[12] has been well
uids[3] and N-heterocyclic carbene (NHC) ligands for known to serve as an excellent nitrenoid precursor in
various metal complexes.[4] Therefore, the wide ap- the aziridination of alkenes,[13] the C H amidation of
À
plicability of this heterocycle has still encouraged the alkanes, arenes and aldehydes,[14] and so on.[15] Very
development of efficient and versatile approaches to recently, it has been reported that ArINSO2R medi-
functionalized imidazoles.[5,6] As one of attractive syn-
thetic methods for a diversity of target molecules, the
metal-catalyzed [2+2+1]annulation of alkynes, ni-
triles and nitrogen atoms from azides was known
(Scheme 1a).[7] The method, however, can stand fur-
ther improvement due to the requirements of high re-
action temperature and tedious procedures, and the
limitation of the substrate generality (terminal alkynes
only). Although a metal-free multicomponent ap-
proach to highly substituted imidazoles from internal
alkynes, aldehydes, and ammonium acetate with or
without anilines has been reported very recently, this
procedure was demonstrated only for the synthesis of
4,5-diarylimidazoles.[8]
Scheme 1. Imidazole synthesis via [2+2+1]annulations.
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Akio Saito et al.
Table 1. Evaluation of additives for the formation of 2a.
Table 2. Reaction scope of alkynes and nitriles.
Entry PhI=NTs (equiv.) Additive (equiv.) Yield [%][a]
2a
3
Entry
1
R1
R2
R3CN
Yield [%][a]
1[b]
2
3
4
5
1.5
1.5
1.5
1.5
1.8
1.8
1.8
1.8
1.5
TfOH (1.2)
Tf2NH (1.2)
Tf2NH (2.0)
38
44
39
6
9
42
6
0
1
2
3
4
1a
1b
1c
1d
1e
1f
Ph
H
H
H
Me
Me
MeCN
MeCN
MeCN
MeCN
MeCN
2a
2b
2c
61
71
70
54
43
72
54
68
63
38
50
23
49
(CH2)2Ph
(CH2)5Me
Ph
i-Pr
n-Pr
BF3·MeCN (2.0) 60
BF3·MeCN (2.4) 84
2d
2e
2f
5
6
7
BF3·OEt2 (2.4)
BF3·2H2O (2.4)
8
0
0
6
n-Pr MeCN
D
H
n-Pr EtCN
H
n-Pr i-BuCN 5f
H
n-Pr PhCN
16
21
4
7[b]
8
d-1a Ph
MeCN
EtCN
d-2a
4b
4f
8
HBF4·OEt2 (2.4) 20
BF3·MeCN (2.0) 34
9[c,d]
1b
1f
1a
1f
1b
1f
(CH2)2Ph
n-Pr
Ph
n-Pr
(CH2)2Ph
n-Pr
9
[a]
1
The yield was determined by H NMR analysis using tol-
uene as internal standard.
10
11
12
13
i-BuCN 5a
[b]
[c]
Reaction conditions: 808C, 4 h.
PhCN
6b
6f
10 equiv. of MeCN were employed in CH2Cl2 instead of
MeCN solvent.
Reaction conditions: room temperature, 18 h.
[a]
[d]
Isolated yields of products.
The deuteration rate of d-2a was more than 99% D.
[b]
ates the aziridination of alkenes[16] and C H amida-
À
tion of aldehydes and 1,3-dicarbonyl compounds[17] PhINTs and MeCN to give the corresponding 2,4-di-
without any metal catalyst. To the best of our knowl-
ACHTUNGTRENsNUGN ubstituted and 2,4,5-trisubstituted N-tosylimidazoles
edge, however, multicomponent reactions with 2 in 38–72% yields (entries 1–6). Unfortunately, di-
PhINSO2R have not been achieved. We herein de- phenylacetylene was not converted to the 4,5-
scribe a metal-free procedure for the [2+2+1]annula- diphenyl
tion of alkynes, nitriles and N-atoms from N-tosylimi- for 20 h. On the other hand, the present reaction con-
nophenyliodane (PhINTs, Scheme 1b). ditions have a tolerance for deuterium and d-2a was
ACHTUNGTRENUNiNG midazole in a similar manner, even at 808C
Our initial effort was focused on the evaluation of obtained with a high deuteration rate (>99% D,
acid additives (1.2 equiv.) in the reaction of ethynyl- entry 7). Furthermore, by the use of other BF3·nitrile
benzene (1a) and acetonitrile (MeCN) as a solvent complexes (BF3·R3CN),[18] the reactions with various
with PhINTs (1.5 equiv., Table 1). At the outset, the nitriles (propionitrile, isovaleronitrile, benzonitrile) in
use of triflic acid (TfOH) and triflic imide (Tf2NH), the place of MeCN proceeded smoothly giving rise to
which were effective additives for the iodine(III)- the functionalized imidazoles 4–6 (entries 8–13). In all
mediated oxazole synthesis,[11] was found to produce cases shown in Table 1 and Table 2, imidazoles 2 and
the 2,4-disubstituted imidazole 2a in moderate yields 4–6 were obtained as a single isomer with the illus-
(entries 1 and 2). Although an increase in the amount trated structures. The regiochemistry of 2a was deter-
of TfNH2 to 2 equiv. did not improve the yield of 2a mined by X-ray structure analysis (Figure 1),[19] and
due to formation of oxazole 3 in a considerable yield those of other products were determined by the ob-
(entry 3), 2 equiv. BF3·MeCN brought about superior
results (2a: 60%, entry 4). When 2.4 equiv.
BF3·MeCN were employed with 1.8 equiv. PhINTs,
the yield of 2a was improved up to 84% at room tem-
perature for 4 h (entry 5). It should be mentioned that
other BF3 complexes and HBF4·OEt2 were ineffective
(entries 6–8). Unfortunately, the use of 10 equiv. of
MeCN in CH2Cl2 instead of MeCN solvent reduced
the yield of 2a (34%), even for 18 h (entry 8).
With the optimal conditions in hand, the reaction
scope of various alkynes and nitriles was next investi-
gated as shown in Table 2. Thus, in the presence of
BF3·MeCN, not only terminal alkynes 1a–c but also
internal alkynes 1d–f successfully reacted with Figure 1. X-ray structure of N-tosylimidazole 2a.
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Metal-Free [2+2+1]Annulation of Alkynes, Nitriles and Nitrogen Atoms
by the reductive elimination of PhI in intermediate C
give the target imidazoles 2 and 4–6. As an alternative
route from trans-B to imidazoles, the ligand coupling
of trans-B giving rise to enamine trans-E is possibly
involved. It has been reported that the ligand cou-
pling of alkenyliodanes proceeds through partially po-
larized transition states such as D.[24] After trans-E
has isomerized to cis-E via enamine-imine tautomeri-
zation, the cyclization of cis-E yields the imidazoles.
Therefore, the regiochemistry of imidazoles depends
on the outcome of the Ritter-type addition step, in
which the bulky iodonium ion would bind to the less
sterically hindered R2 side of the alkyne carbon in
1a–e (Table 2, entries 1–5, 7, 8, 10, 12). A similar re-
giochemistry of products was observed in the PhIO/
acid-mediated oxidative [2+2+1]annulation of al-
kynes, nitriles and O-atoms.[11]
Scheme 2. Detosylation of N-tosylimidazole 5a.
In conclusion, we have developed a metal-free and
regioselective synthesis of 2,4-disubstituted or 2,4,5-
trisubstituted N-tosylimidazoles from terminal or in-
ternal alkynes and nitriles with PhINTs and
BF3·nitrile complexes. The present procedure could
be regarded as a useful alternative method for the
synthesis of 4,5-dialkylimidazoles,[25] albeit not appli-
cable to the synthesis of 4,5-diarylimidazoles. Since
multicomponent reactions with PhINSO2R were not
previously achieved, our findings provide not only an
attractive procedure for access to highly substituted
imidazoles, but also a new reactivity pattern of the io-
dine(III) reagent. Further investigations will focus on
the mechanism studies and extending this strategy
beyond intermolecular reactions of alkynylamines.
Scheme 3. Proposed major reaction pathway.
served NOE or chemical shift values (see the Sup- Experimental Section
porting Information).
The product 5a can be easily converted to the N- Representative Procedure for the Formation of
unsubstituted imidazole 7, which is catharsitoxin E Imidazole 2a from Alkyne 1a with MeCN and
isolated from the Chinese remedy qiung laug,[20] by PhINTs
treatment with trifluoroacetic anhydride and pyridine
BF3·MeCN (0.43 mL, 0.96 mmol) was added to a suspension
of 1a (44 mL, 0.40 mmol) and PhINTs (269 mg, 0.72 mmol)
(Scheme 2).[21]
On the basis of these results and our previous re-
ports about the PhIO/acid-mediated oxidative
in MeCN (4.0 mL) at 08C under an argon atmosphere.
After being stirred at ambient temperature for 4 h, the mix-
ture was quenched with saturated NaHCO3 solution
(0.5 mL), diluted with ether and filtered through a short alu-
mina column. Concentration of the filtrate to dryness and
the subsequent purification of the residue by silica gel
column chromatography (hexane/AcOEt=85/15) gave 2a;
yield: 76.2 mg (61%).
[2+2+1]annulation of alkynes, nitriles and
O
atoms,[11] the proposed major reaction pathway for
the present imidazole formation is shown in
Scheme 3. That is, intermediates trans-B and/or cis-B
would be formed through the activation of alkyne
1 by iodonium species A (and/or A’) and then the
Ritter-type addition of R3CN.[22] Since alkenyliodanes
bearing a leaving group at the b-position have been
known to undergo a nucleophilic vinylic substitu-
tion,[23] considering the presence of the large excess
amount of nitrile and leaving ability of a unilateral ni-
trile of bis-nitrilium intermediate, trans-B may be con-
verted to cis-B by the addition and elimination of
Detosylation of N-Tosylimidazole 5a
To a solution of 5a (130 mg, 0.37 mmol) in CH2Cl2 (0.5 mL)
was added trifluoroacetic anhydride (1.5 mL, 10.8 mmol)
and pyridine (65 mL, 0.81 mmol) at ambient temperature.
After being stirred for 4 h, the mixture was concentrated
under reduced pressure and then the residue was stirred in
R3CN. Subsequently, the cyclization of cis-B followed methanol (1.0 mL) for 1 h. After evaporation of the solvent,
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water was added and the pH adjusted to about 8 with solid
Jiang, P. Lu, Y. Wang, Org. Lett. 2012, 14, 6266; f) S. K.
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sodium carbonate. The aqueous layer was extracted with
chloroform and the combined organic layers were dried
over sodium sulfate. Concentration of the filtrate to dryness
and the subsequent purification of the residue by silica gel
column chromatography (hexane/AcOEt=50/50) gave 7;
yield: 42.2 mg (57%).
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Acknowledgements
This work was partially supported by JSPS Grants-in-Aid for
Young Scientists (B) Grant No 24790024, and by the Asahi
Glass Foundation.
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6 Metal-Free [2+2+1]Annulation of Alkynes, Nitriles and
Nitrogen Atoms from Iminoiodanes for Synthesis of Highly
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Adv. Synth. Catal. 2015, 357, 1 – 6
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