Au(I)-catalyzed intramolecular hydroamination of the fluorinated N′-aryl-N-propargyl amidines: Mild conditions for the synthesis of 2-fluoroalkyl imidazole derivatives

Article abstract of DOI:10.1021/ol3000525

The gold(I)-catalyzed synthesis of 2-fluoroalkyl imidazole derivatives was developed. Catalyzed by gold(I), propargyl amidines underwent a 5-exo-dig cyclization to afford 2-fluoroalkyl-5-methyl imidazoles. Also, 2-fluoroalkyl imidazole-5-carbaldehydes wer

Full text of DOI:10.1021/ol3000525

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1130–1133
Au(I)-Catalyzed Intramolecular
Hydroamination of the Fluorinated
N0-Aryl-N-Propargyl Amidines: Mild
Conditions for the Synthesis of
2-Fluoroalkyl Imidazole Derivatives
Shan Li,† Zhengke Li,† Yafen Yuan,† Dongjie Peng,† Yajun Li,†,‡ Lisi Zhang,† and
Yongming Wu*,†
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, and School of
Chemistry and Chemical Engineering, Huazhong University of Science and Technology,
1037 Luoyu Road, Wuhan, Hubei 430074, China
ymwu@sioc.ac.cn
Received January 11, 2012
ABSTRACT
The gold(I)-catalyzed synthesis of 2-fluoroalkyl imidazole derivatives was developed. Catalyzed by gold(I), propargyl amidines underwent a
5-exo-dig cyclization to afford 2-fluoroalkyl-5-methyl imidazoles. Also, 2-fluoroalkyl imidazole-5-carbaldehydes were obtained in the presence
of NIS. A mechanism investigation manifested the probable process and the carbonyl oxygen derived from O2.
Reactions catalyzed by gold have attracted much
attention.1ꢀ3 Compared to other transition-metal catal-
yzed reactions, these reactions are more economical and
mild. Among them, the most important reaction pattern is
the addition of nucleophiles to CꢀC multiple bonds.4 In
1987, Utimoto reported the first evidence of intramolecu-
lar hydroamination of 5-yn-1-amine, which delivered tet-
rahydropyridines by isomerization from enamine.5 Since
then, investigation in this areahas been growing rapidly. In
2000, Hashmi demonstrated that even carbonyl oxygen
can serve as a nucleophile.6 Based on these findings, we
wish to report our work on cyclization of fluorinated
N0-aryl-N-propargyl amidines catalyzed by gold(I) to syn-
thesize 2-fluoroalkyl imidazole derivatives.
Hacksell reported that when bases were used as a
catalyst, propargyl amides might be cyclized to the
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J. A. D.; Toste, F. D. J. Am. Chem. Soc. 2010, 132, 8885–8887. (h)
Zhang, G.; Luo, Y.; Wang, Y.; Zhang, L. Angew. Chem., Int. Ed. 2011,
50, 4450–4454. (i) Tkatchouk, E.; Mankad, N. P.; Benitez, D.; Goddard,
W. A.; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 14293–14300.
† Shanghai Institute of Organic Chemistry, Chinese Academy of Science.
‡ Huazhong University of Science and Technology.
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A. Chem. Rev. 2008, 108, 3266–3325. (c) Li, Z.; Brown, C.; He, C. Chem.
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Rev. 2008, 108, 3239–3265. (d) Jimenez-Nunez, E.; Echavarren, E.
Chem. Rev. 2008, 108, 3326–3350. (e) Gorin, D. J.; Sherry, B. D.; Toste,
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r
10.1021/ol3000525
Published on Web 02/03/2012
2012 American Chemical Society

corresponding oxazoles.7 However, fluorinated propargyl
amidines were unstable under strong basic conditions,
which often resulted in low yield. This cyclization also
could be accomplished by using a Brønsted acid;8 the yield
of 2-fluoroalkyl imidazoles was only 30%, but both long
reaction times and high temperatures were required. To
our delight, an excellent yield was obtained under mild
conditions by gold(I) catalysis via 5-exo-dig cyclization.
We envisioned that 2-fluoroalkyl imidazoles can be ob-
tainedinonepotfromfluorinatedimidoyl chlorides.9 With
Ph3PAuCl/AgSbF6 as the catalyst and CH3CN as the
solvent, an optimized yield of 87% was obtained when
the reaction was carried out at 60 °C (see Table S1 in the
Supporting Information (SI)).
of them offered the expected products in good yields.
Substrates with electron-donating groups on the benzene
ring gave good yields (Table 1, entry 2). Electron-
withdrawing groups would lead to lower yields (Table 1,
entries 4, 5, 7). Compared to the electronic effect, steric
hindrance of the substituents had little influence on the
yield (Table 1, entries 3, 6, 8). The effect of fluoroalkyl
(Rf) was also examined; substrates with ꢀCF2Br often
had lower yields, and the corresponding products decom-
posed easily (Table 1, entries 9ꢀ15). With 3-phenyl pro-
pargyl amine as the starting material, the reaction inter-
mediate of propargyl amidine underwent a 6-endo-dig
cyclization to generate 1,4-dihydropyrimidine 3r in 73%
yield (Table 1, entry 18). As we expected, nonfluorinated
imidazole 2s was obtained in moderate yield when a non-
fluorinated substrate was used (Table 1, entry 19).
In this reaction, cationic Au(I) is thought to be coordi-
nated with CꢀC triple bonds to form a vinyl-gold inter-
mediate. We tried to prepare this intermediate, and an
alkylgold(I) species 3t that differed from Hashmi’s work
was obtained.10,11 Treated 3t with protontic acid solvent
failed to generate imidazole 3b, but decomposed.
Table 1. Au(I)-Catalyzed the Formation of 2-Fluoroalkyl
Imidazolesa
We speculated that a gold(I) intermediate in the reaction
may be a zwitterionic species. Coordinated with cationic
Au(I), CꢀC triple bonds accept the attack of amidinonyl
nitrogen to afford intermediate A. Affected by Rf, A
isomerizes to the more stable imidazole B by an H-1,3
shift first. In this process, the nitrogen atom in imidazole is
protonated all the way, which favors HꢀAu (I) exchange
to give the final product imidazole 3 which is accomplished
in one pot (Scheme 1).
entry
R
R1
R2
yield/%b
1
-CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
3a/78
3b/87
3c/89
3d/72
3e/68
3f/85
3g/68
3h/85
3i/74
3j/79
3k/79
3l/65
3m/63
3n/60
3o/76
3p/87
3q/62
3r/73c
3s/67
3t
2
-CF3
p-OCH3
o-CH3
p-NO2
p-COOEt
Naphthyl
m-CF3
o-Cl
3
-CF3
4
-CF3
5
-CF3
6
-CF3
7
-CF3
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297–300. (b) Fukuda, Y.; Utimoto, K. Synthesis 1991, 975–978.
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Angew. Chem., Int. Ed. 2000, 39, 2285–2288. (b) Hashmi, A. S. K.
Angew. Chem., Int. Ed. 2000, 39, 3590–3593.
8
-CF3
9
-CF2Br
-CF2Br
-CF2Br
-CF2Br
-CF2Br
-CF2Br
-CF2Br
-CF2H
-CF2CF3
-CF3
p-CH3
m-CH3
o-CH3
p-CF3
p-CN
p-Cl
10
11
12
13
14
15
16
17
18
19
20
o-Br
H
H
p-OCH3
H
-COOEt
-CF3
p-OCH3
AuPPh3
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269–275. (b) Nilsson, B. M.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J.
J. Med. Chem. 1992, 35, 285.
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R.; Castro, J. L.; Chambers, M. S.; Guiblin, A. R.; Hobbs, S. C.;
Matassa, V. G.; Reeve, A. J.; Beer, M. S. J. Med. Chem. 1993, 36,
1529. (c) Pan, Y. M.; Zheng, F. J.; Lin, H. X.; Zhan, Z. P. J. Org. Chem.
2009, 74, 3148–3151. (d) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin,
T. Chem. Commun. 2009, 5075–5087.
a Reaction conditions: Ph3PAuCl (5 mol %)/AgSbF6 (10 mol %),
fluoronated imidoyl chlorides (1.0 mmol), propargyl imine (2.5 mmol),
CH3CN (3.5 mL), 60 °C. b Isolated yield. c The product is 1,4-
dihydropyrimidine.
Under the optimized conditions, a variety of fluorinated
imidoyl chlorides were tested (Table 1). This reaction has
good compatibility to various functional groups, and most
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K. J. Org. Chem. 1993, 58 (1), 32–35.
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Schuster, A.; Hengst, T.; Schetter, S.; Littmann, A.; Rudoiph, M.;
Hamzic, M.; Visus, J.; Rominger, F.; Frey, W.; Bats, J. W. Chem.;
Eur. J. 2010, 16, 956–963.
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Giuffredi, G. T.; Gee, A. D.; Gouverneur, V. Synlett 2010, 18, 2737–
2742. (c) de Haro, T.; Nevado, C. Adv. Synth. Catal. 2010, 352, 2767. (d)
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Chem., Int. Ed. 2009, 48, 8243–8246.
Org. Lett., Vol. 14, No. 4, 2012
1131

Table 2. Au (I)-Catalyzed Synthesis of Imidazole-5-
carbaldehydea
Scheme 1. Proposed Mechanism for the Formation of
2-Fluoroalkyl Imidazoles
entry
R
R1
R2
yield/%b
1
-CF3
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
4a/98
4b/94
4c/82
4d/89
4e/87
4f/95
4g/90
4h/57
4i/60
4j/81
2
-CF3
p-OCH3
p-Cl
3
-CF3
4
-CF3
o-CH3
o-I
5
-CF3
6
-CF3
p-COOEt
o-Ph
p-CN
o-CF3
H
7
-CF3
In order to functionalize 2-fluoroalkyl imidazoles, we
next investigated the possibility of coupling fluorinated
propargyl amidines with electrophiles.12 In the presence of
Ph3PAuCl/AgBF4, propargyl amidine 2b was treated with
NIS. To our surprise, imidazole-5-carbaldehyde formed
instead of the expected product 5-iodomethyl imidazole.
An excellent yield of 98% was obtained with 1.0 equiv of
K2CO3 added in acetone at room temperature (see Table
S2 in the SI).
8
-CF2Br
-CF2Br
-CF2H
-CF2CF3
-COOEt
-CF3
9
10
11
12
13
H
4k/93
4l/86
4m/74c
H
p-OCH3
a Reaction conditions: Ph3PAuCl (5 mol %)/AgBF4 (10 mol %),
fluorinated propargyl amidines (1.0 mmol), NIS (2.5 mmol), K2CO3
(1.0 mmol), acetone (10 mL), rt, in the absence of light. b Isolated yield.
c The product is 5-iodo-1,4-dihydropyrimidine.
The transformations with NIS proceeded without any
difficultytoaffordthedesired productsingood toexcellent
yields (Table 2). Both electron-rich and -poor propargyl
amidines are reactive. Functional groups, including ester
and cyano (Table 2, entries 6, 8), as well as sterically
hindered ones (Table 2, entries 4, 5, 7) are tolerated.
However, substrates with ꢀCF2Br were found to be
inefficient because of its instability (Table 2, entries 8, 9).
This method is also suitable for nonfluorinated substrates.
Nonfluorinated aldehyde 4l was obtained in good yield
under similar conditions (Table 2, entry 12). Unfortu-
nately, our method is only suitable for substrates with a
terminal alkyne group. The substrate that possesses a
group of Ph at an alkyne terminus converted to 5-iodo-
1,4-dihydropyrimidine 4m in moderate yield (Table 2,
entry 13).
Scheme 2. Reactions without Au(I) Catalyst
Studies were undertaken to explore a feasible mechan-
ism. When 3t was treated with NIS in acetone, no aldehyde
4b was detected. When the reaction was carried out in
anhydrous acetonitrile under a nitrogen atmosphere,
5-iodomethyl imidazole 4n, the probable intermediate, was
not detected, but 4b formed in lower yield.
Gold(I) catalyst was considered to just act as a Lewis
acid to active CꢀC triple bonds promoting the reaction
with NIS; no gold(I) intermediate formed in the reaction.
Further investigation revealedthatthistransformation can
take place in the absence of gold(I) catalyst with a low
yield. 4n was found to convert to 4b in excellent yield
(Scheme 2). Based on these above-mentioned observa-
tions, we understood the plausible pathway for this
transformation.
Both O2 and H2O could be the source of carbonyl
oxygen. In order to determine which one deserves the
credit, we carried out parallel experiments as follows: 4n
was prepared first and then divided into two portions; the
first portion with distilled water added was inactive, while
the second portion of 4n was converted to 4b when exposed
to dry air. Moreover, acetal 4owas obtained when CH3OH
was added to the standard system, no 5-methoxylmethyl
imidazole was detected (Scheme 3). On the basis of these
results, the carbonyl oxygen was considered to come
from O2.
(12) (a) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147–2150.
(b) Hashmi, A. S. K.; Ramamurthi, T. D.; Rominger, F. J. Organomet.
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1132
Org. Lett., Vol. 14, No. 4, 2012

Scheme 4. Proposed Mechanism for Carbonylation
Scheme 3. Effect of O2 and H2O on Carbonylation
Scheme 5. Another Proposed Mechanism for Carbonylation
Light plays another significant role, when the reaction
was carried out in nonpolar solvent. When exposed to light
and air, 4n was converted to 4b efficiently in toluene.
Under N2, only a 19% yield of 4b was formed (which
might have resulted from the residual O2 mixed in N2), and
60% of 4n was recovered after 24 h. In both experiments, I2
was formed in the reaction. In the absence of light, 4n was a
relatively stable compound under N2 in nonpolar solvent
(Scheme 4).
Based on these results, a possible mechanism is proposed
in Scheme 5. Two steps were involved in this transforma-
tion. The first step: propargyl amidine 2 activated by
[Ph3PAuþ] reacts with NIS to afford 5-iodomethyl imida-
zole N. The second step may be a radical process.13 The
CꢀI bond in N dissociates into radical intermediate A and
an iodine radical. In the presence of O2, A converts to
peroxy-intermediate B. Aldehyde 4 forms by means of
removal of ahydroxyl radicalfrom B. Thehydroxyl radical
combines with the iodine radical to afford HIO, which
decomposes into O2, I2, and H2O.
In summary, we have developed a simple but efficient
method for the synthesis of 2-fluoroalkyl imidazole deri-
vatives. Catalyzed by Au(I), the substrates with a terminal
alkyne group undergo a 5-exo-dig cyclization to afford
imidazole derivatives. It is worth mentioning that this meth-
od is also suitable for nonfluorinated substrates. Also, 1,4-
dihydropyrimidine was obtained from the substrates with a
substituent at the alkyne terminus by 6-endo-dig cyclization.
Research carried out on the reaction mechanism revealed the
general process of these transformations and confirmed that
carbonyl oxygen is derived from O2.
Acknowledgment. This work was supported by the
National Science Foundation of China (No. 21172239)
Supporting Information Available. Full experimental
procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Wang, H. H.; Wang, Y.; Liang, D.; Liu, L.; Zhang, J.; Zhu, Q.
Angew. Chem., Int. Ed. 2011, 50, 5678–5681.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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