Gold(I)-catalyzed aminohalogenation of fluorinated N′-aryl-N- propargyl amidines for the synthesis of imidazole derivatives under mild conditions

Article abstract of DOI:10.1002/chem.201202402

A procedure for the synthesis of fluorinated imidazole derivatives from propargyl amidines has been developed. Under gold(I) catalysis, propargyl amidines were converted into 5-fluoromethyl imidazoles in the presence of Selectfluor through a cascade cyclization/fluorination process. In contrast, imidazole-5-carbaldehydes were obtained in high yields when N-iodosuccinimide (NIS) was used as the halogenating reagent. The polarity of the solvent and light had significant impact on the formation of the carbaldehydes. These transformations showed excellent functional-group tolerance. An unfluorinated substrate with an electron-withdrawing group also underwent aminohalogenation to give the corresponding product in good yield. Mechanistic investigation revealed the general pathways of these transformations. Copyright

Full text of DOI:10.1002/chem.201202402

FULL PAPER
DOI: 10.1002/chem.201202402
Gold(I)-Catalyzed Aminohalogenation of Fluorinated N’-Aryl-N-Propargyl
Amidines for the Synthesis of Imidazole Derivatives under Mild Conditions
Shan Li,[a] Zhengke Li,[a] Yafen Yuan,[a] Yajun Li,[a, b] Lisi Zhang,[a] and Yongming Wu*[a]
Abstract: A procedure for the synthe-
sis of fluorinated imidazole derivatives
from propargyl amidines has been de-
veloped. Under gold(I) catalysis, pro-
succinimide (NIS) was used as the hal-
ogenating reagent. The polarity of the
solvent and light had significant impact
on the formation of the carbaldehydes.
These transformations showed excel-
lent functional-group tolerance. An un-
fluorinated substrate with an electron-
withdrawing group also underwent
aminohalogenation to give the corre-
sponding product in good yield. Mech-
anistic investigation revealed the gener-
al pathways of these transformations.
ACHTUNGTRENNUNGpargyl amidines were converted into 5-
fluoromethyl imidazoles in the pres-
ence of Selectfluor through a cascade
cyclization/fluorination process. In con-
trast, imidazole-5-carbaldehydes were
obtained in high yields when N-iodo-
Keywords: aminohalogenation
·
cyclization · gold · homogeneous
catalysis · imidazoles
Introduction
fluorination of alkynes by using an electrophilic source of
fluorine, Selectfluor.[10] Based on this strategy, Gouverneur
and co-workers[11a] and de Haro and Nevado[11b,e] indepen-
The physiochemical properties of organic compounds that
contain fluorinated substituents often exhibit significant dif-
ferences compared to those without such substituents.[1,2]
Recently, imidazoles that feature fluorine-containing func-
tional groups have attracted much attention owing to their
interesting behavior as pharmaceuticals and agrochemicals.[3]
However, the introduction of fluorinated groups into organ-
ic molecules represents a major challenge because such
methods for the preparation of complex fluorinated com-
pounds are often based on fluorinated building blocks.[4,5,6]
Homogeneous gold catalysis has made significant progress
in the last decade. Most of the processes that use gold catal-
ysis rely on the p-acidic nature of the cationic gold species
to activate alkynes or alkenes towards nucleophilic addi-
tion.[7,8] Following this line of research, in 2007, Sadighi and
co-workers reported the direct gold-catalyzed hydrofluorina-
tion of alkynes with Et3N·3HF as the nucleophilic fluorine
source.[9] In the following year, Gouverneur and co-workers
developed an alternative procedure for the gold-catalyzed
AHCTUNGTREGdNNNU ently reported the preparation of a-fluoroenones from
propargyl acetates through a gold-catalyzed rearrangement/
fluorination cascade, whilst Xu and co-workers[11c,d] applied
the gold-catalyzed aminofluorination of alkynes to synthe-
size fluorinated pyrazoles. These studies have laid the foun-
I
À
dation for efficient Csp2 F bond formation by using a Au /
AuIII cycle.[12] Hashmi et al. reported a synthetic route to al-
kylidenoxazolines and -oxazoles through a gold-catalyzed in-
tramolecular hydroamination of alkynes.[13] Our group has
demonstrated that propargyl amidines could be converted
into imidACTHNUTRGENUGaN zoles by gold-catalyzed 5-exo-dig cyclization
[15]
(Scheme 1).[14] In these reactions, vinyl gold species were
À
Scheme 1. Gold(I)-catalyzed aminohydrogenation.
[a] Dr S. Li, Z. Li, Y. Yuan, Y. Li, L. Zhang, Prof. Dr. Y. Wu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Science
proposed as the intermediates that effectively underwent
[10,12a,16]
À
Csp2 X bonds formation.
on the gold-catalyzed aminofluorination reaction to give 5-
Herein, we report our work
345 Lingling Road, Shanghai 200032 (P. R. China)
Fax : (+86)021-54925190
fluoromethyl imidazoles through a cyclization/fluorination
E-mail: ymwu@sioc.ac.cn
À
cascade process that involves the construction of new Csp3
bonds. Similarly, the analogous aminoiodination afforded 5-
iodomethyl imidazoles, which were converted into imid-
F
[b] Y. Li
School of Chemistry and Chemical Engineering
Huazhong University of Science and Technology
1037 Luoyu Road, Wuhan, Hubei, 430074 (P. R. China)
AHCTUNGTERGaNNUN zole-5-carbaldehydes in air.
Supporting information for this article, including experimental details,
is available on the WWW under http://dx.doi.org/10.1002/
chem.201202402.
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Table 2. Gold(I)-catalyzed aminofluorination of fluorinated propargyl
amidines.
Results and Discussion
We selected 2-trifluoromethyl-N-p-tolyl-N-propargyl ami-
dine (1b) as the model substrate to optimize the reaction
conditions. Preliminary studies showed that both the catalyst
and the base played important roles in the reaction: Pro-
ACHTUNGTRENNUNGpargyl amidine 1b decomposed on treatment with Select-
fluor in the absence of catalyst or base (Table 1, entries 1
Entry
Rf
R1
R2
2
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF2Br
CF2H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
–
78
82
77
70
74
71
60
68
55
49
31
42
57
–
Table 1. Optimization of the aminofluorination of N-tolyl propargyl ami-
dine 1b.
p-CH3
m-CH3
m-Cl
p-I
p-COOEt
P-NO2
p-CN
p-CF3
naphthyl
o-Ph
o-OCH3
o-F
p-OCH3
p-OCH3
H
Entry
Catalyst
–
Base
Solvent
T [oC]
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
NaHCO3
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
80
80
80
100
60
45
80
80
80
60
80
80
RT
80
60
60
60
60
60
–
–
ACHTUNGTRENNUNG
G
NaHCO3
NaHCO3
NaHCO3
NaHCO3
CH3COOK
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
55
32
53
41
30
15
73
82
–
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
–
2n
–
65
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Yield of isolated product.
ACHTUNGTRENNUNG
T
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
patibility: Propargyl amidines with substituents at the para
or meta positions of the phenyl ring all gave good yields of
their corresponding products (Table 2, entries 2, 3, and 5).
Propargyl amidines with strongly electron-withdrawing
groups gave lower yields (Table 2, entries 7–9) and steric
hindrance was also found to have a significant influence on
the yield of the products. N-naphthyl propargyl amidine 1j
or substrates that contained a substituent at the ortho posi-
tion of the phenyl ring afforded very low yields (Table 2, en-
tries 10–13). A substrate with a phenyl group on the alkyne
terminus was not suitable in this transformation (Table 2,
entry 14). The effect of fluoroalkyl groups was also exam-
ined. Propargyl amidines with a CF3 group effectively under-
went cyclization/fluorination to give the product in moder-
ate-to-good yield. However, no product was obtained when
a substrate with a CF2Br group was used, presumably owing
to its poor stability (Table 2 entry 15). On the contrary, a
substrate with a CF2H group reacted smoothly to give the
desired product in moderate yield (Table 2, entry 16).
G
toluene
CH2Cl2
DCE
–
G
87[b]
75[b]
–
ACHTUNGTRENNUNG
R
THF
G
acetone
acetone
CH3CN
CH3CN
40
70
59
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[c]
G
–
[a] Yield of isolated product. [b] The product was 2-trifluoromethyl-5-
methyl imidazole. [c] NFSI was used as the fluorinating reagent. p-tol=
p-toluene, DCE=1,2-dichloroethane.
and 2). When the reaction was carried out in the presence
of [Ph3PAuCl] (5 mol%), Selectfluor (2.5 equiv), and
NaHCO3 (1.5 equiv) in CH3CN at 808C for 2 h, 5-fluoro-
methyl imidazole 2b was observed as the sole product in
55% yield (Table 1, entry 3). Optimization studies were car-
ried out to determine the best general conditions. CH3CN
and Na2CO3 were identified as the best solvent and base for
this transformation, respectively, and compound 2b was ob-
tained in 82% yield when the reaction was carried out at
608C (Table 1, entry 10). When a halogenated solvent was
used in place of CH3CN, only the protonated product was
obtained, owing to the decomposing of Selectfluor (Table 1,
entries 13 and 14). [IPrAuCl] was less efficient for this trans-
formation compared to [Ph3PAuCl] (Table 1, entries 17 and
18). None of the desired product was detected when N-fluo-
robenzenesulfonimide (NFSI), another electrophilic fluori-
nating reagent, was used (Table 1, entry 19).
Next, we investigated the reaction of fluorinated N-pro-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
chlorosuccinimide (NCS) in acetone was unsuccessful. With
N-bromosuccinimide (NBS) as the halogenating reagent,
5,5-dibromomethyl imidazole 3b was obtained in 47% yield
under the same conditions, whilst a byproduct, imidazole-5-
carbaldehyde 4b, was also isolated in 19% yield (see
Scheme 2). Surprisingly, imidazole-5-carbaldehyde 4b was
formed as the sole product in excellent yield (94%) when
N-propargyl amidine was treated with NIS (Scheme 2). This
With the optimized conditions in hand, we proceeded to
investigate the scope of this transformation. As summarized
in Table 2, our results showed broad functional-group com-
product is most likely formed from 5-monohalomethyl imACHTUNGTRENNUNGid-
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Gold(I)-Catalyzed Aminohalogenation of Fluorinated Amidines
FULL PAPER
periments revealed that this transformation could take place
without a gold(I) catalyst, but in very low yield. Raising the
temperature of the reaction improved the yield of the im
azole-5-carbaldehyde (Table 3, entries 12 and 13).
With the standard reaction conditions in hand, we set out
ACHTUNGTRENNUNGid-
AHCTUNGTRENNUNG
to explore the scope of the propargyl amidines. Unlike ami-
nofluorination, neither the electronic properties nor the
steric bulk of the substituents on the phenyl ring had much
impact on the transformations (Table 4, entries 2 versus 7
Table 4. Gold(I)-catalyzed synthesis of imidazole-5-carbaldehydes.
Scheme 2. Reaction of fluorinated propargyl amidine 1o with electrophil-
ic reagents such as NCS, NBS, or NIS.
ACHTUNGTRENNUNGazole through halogen-atom elimination. The elimination of
bromine is more difficult than iodine. Meanwhile, the in-
creased acidity of the hydrogen atom in the bromomethyl
group, owing to the presence of the electron-withdrawing
Entry
R1
R2
R3
4
Yield [%][a]
CF3 group, led to the formation of 5,5-dibromomethyl im
ACHTUNGTRENNUNG
ACHTUNGERTNiNUNG d-
1
2
3
4
5
6
7
8
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
4a
4b
4c
4d
4e
4 f
4g
4h
4i[b]
4j
4k
4l
4m
4n
4o
98
94
82
91
89
87
95
90
74
69
57
46
81
93
86
p-OCH3
p-Cl
m-CF3
o-CH3
o-I
p-CO2Et
o-Ph
p-OCH3
p-CH3
p-CN
o-Br
H
tions. Control experiments indicate that 5,5-dibromomethyl
imidazole 3b is stable at room temperature and does not un-
dergo hydrolysis.
Studies were undertaken to identify general reaction con-
ditions in the presence of NIS. The reaction of the gold pre-
cursor with a Ag salt formed the cationic gold(I) catalyst.
Base was desirable to promote the formation of the carbal-
dehyde; K2CO3 appeared to be particularly suitable and an
excellent yield of 98% was obtained when 1.0 equivalent of
K2CO3 was added (Table 3, entries 1 and 2). Lowering the
amount of NIS resulted in a lower yield of the product
(Table 3, entry 3). Solvent was essential for this transforma-
tion. A higher yield was obtained when the reactions were
carried out in polar solvents, except for water, owing to the
poor solubility of NIS in water. Acetone was the best sol-
vent for this reaction (Table 3, entries 2, 4–7). Control ex-
9
CF3
10
11
12
13
14
15
CF2Br
CF2Br
CF2Br
CF2H
CF2CF3
CO2Et
H
H
[a] Yield of isolated product. [b] The product was 5-iodo-1,4-dihydropyri-
midine.
and entries 1 versus 8). Lower yields were obtained for sub-
strates that contained a CF2Br substituent, presumably
owing to their instability under the reaction conditions
(Table 4, entries 10–12). Moreover, imidazole-5-carbalde-
hydes were obtained as the sole products from substrates
with a terminal alkyne group. A substrate that contained a
Ph group at the propargylic position could be converted into
5-iodo-1,4-dihydropyrimidine in moderate yield, but the
product was very instable, even at low temperatures
(Table 4, entry 9). Gratifyingly, unfluorinated propargyl ami-
dine also reacted effectively to give the corresponding prod-
uct in good yield (Table 4, entry 15).
Table 3. Optimization of the synthesis of imidazole-5-carbaldehyde 4a.
Entry
Catalyst
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgBF4
[Ph3PAuCl]/AgSbF6
[Ph3PAuCl]/AgClO4
Base
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
G
–
acetone
acetone
acetone
water
CH3CN
CH2Cl2
toluene
acetone
acetone
acetone
acetone
acetone
acetone
65
E
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
98
To investigate the mechanism of the aminofluorination re-
E
46[b]
50
À
action, a gold(I) alkyl species (3a) was prepared by the re-
ACHTUNGTRENNUNG
action of [Ph3PAuCl] with KOtBu. However, no monofluori-
nated product was obtained from the treatment of com-
pound 3a with Selectfluor (Scheme 3). This result suggests
that the monofluorinated product is most likely formed di-
R
76
58
42
77
70
75
50
R
N
G
N
À
rectly from vinyl gold species. The proposed mechanism is
U
shown in Scheme 4. First, the propargyl amidine interacts
with the gold center to form a p complex (A). This inter-
mediate undergoes nucleophilic attack in a 5-exo-dig mode
N
–
–
47
30[c]
À
[a] Yield of isolated product. [b] NIS (1.0 equiv). [c] 608C.
to form the vinyl gold species (B), which has a tautomerism
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Y. Wu et al.
Naturally, the carbonyl oxygen atom was supposed to be
taken from air. Under a N2 atmoACTHNUGRTNEUNGsphere and in darkness, 5-
iodomethyl imidazole 3c could be stored for a long time in
non-polar solvent. When it was exposed to dry air, 5-iodo-
methyl imidazole 3c was gradually converted into imida-
zole-5-carbaldehyde 4b. However, compound 3c was stable
in water. These results indicated that the carbonyl oxygen
atom was most likely obtained from air.
Further study indicated that light had a significant impact
on the formation of imidazole-5-carbaldehydes when the re-
action was performed in non-polar solvent. As noted above,
5-iodomethyl imidazole 3c could be stored for a long time
when the system was kept in the dark under a N2 atmos-
phere. However, in the presence of air and light, 5-iodo-
methyl imidazole 3c was quickly converted into imidazole-
5-carbaldehyde. In this experiment, the color of the solution
gradually turned red, owing to the generation of iodine.
When exposed to light under a N2 atmosphere, only a 19%
yield of carbaldehyde 4b was detected. It is possible the re-
sidual O2 in the N2 gas reacted with compound 3c to form
compound 4b (Scheme 6).
Scheme 3. Substrates for the mechanism investigation.
Scheme 4. Proposed mechanism for the gold(I)-catalyzed aminofluorina-
tion reaction.
À
À
equilibrium with imidazole gold species 3a. Then, vinyl
gold intermediate B reacts with Selectfluor to generate the
À
vinyl fluoride product (C), which is aromatized to afford
the final product (2).
Scheme 6. Effect of light on the formation of imidazole-5-carbaldehydes.
These aforementioned control experiments demonstrated
that the formation of imidazole-5-carbaldehydes could take
place without a gold(I) catalyst, although the yield was very
low. With CH2Cl2 as the solvent, 5-iodomethyl imidazole 3c
was prepared in 38% yield in the absence of a catalyst
under a N2 atmosphere (Scheme 5).[17e,18] We also found that
Our proposed pathway for the formation of imidazole-5-
carbaldehydes is shown in Scheme 7. Catalyzed by the cat-
AHCTUNGTRENNUNG
ionic AuI species, propargyl amidine 1 is converted into 5-
iodoACTHUNRTGNEUNGmethyl imidazole, as in the formation of 5-fluoromethyl
imidazole (Scheme 4). A radical intermediate (M) and an
À
iodine radical are created by homolytic cleavage of the C I
Scheme 5. Reactions without a gold(I) catalyst.
5-iodomethyl imidazole could be efficiently converted into
imACHTUNGTRENNUNGidACHTUNGTRENNUNGazole-5-carbaldehyde 4b in air. However, the treatment
of compound 3a with NIS showed no formation of com-
pound 4b, but, instead, resulted in the decomposition of
compound 3a (Scheme 5). Based on these observations, we
inferred that imidazole-5-carbaldehyde 4b originated direct-
ly from 5-iodomethyl imidazole 3c and that this process did
not involve the gold(I) catalyst.
Scheme 7. Proposed mechanism for the formation of imidazole-5-carbal-
dehydes.
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Gold(I)-Catalyzed Aminohalogenation of Fluorinated Amidines
FULL PAPER
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M then combines with O2 to give a peroxy-radical species
(N).[20] In a concerted reaction, species N releases a hydroxyl
radical to afford carbaldehyde 4. I2 is most likely generated
through the decomposition of HIO, which was formed from
the combination of iodine radicals with hydroxyl radicals.
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Conclusion
In conclusion, we have presented a simple, mild, and effi-
cient method for the preparation of 2-fluoroalkyl-imidazole
derivatives from fluorinated propargyl amidines. Under
gold(I) catalysis, fluorinated propargyl amidines underwent
a 5-exo-dig-cyclization/fluorination cascade reaction in the
À
presence of Selectfluor with the construction of new Csp3
F
bonds. Treatment with NIS afforded the conversion of fluo-
rinated and unfluorinated propargyl amidines into imid-
azole-5-carbaldehydes in good-to-excellent yields. Our
mechanistic investigation revealed that both transformations
involved a vinyl gold intermediate (B; Scheme 4), which
underwent halogenation to form 5-halogenmethyl imidazole.
5-Iodomethyl imidazoles were converted into imidazole-5-
carbaldehydes through a radical mechanism.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
À
Acknowledgements
This work was supported by the National Science Foundation of China
(No. 21172239).
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Received: July 6, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Gold(I)-Catalyzed Aminohalogenation of Fluorinated Amidines
FULL PAPER
Gold(I) Catalysis
S. Li, Z. Li, Y. Yuan, Y. Li, L. Zhang,
Y. Wu* ......................... &&&& — &&&&
Gold(I)-Catalyzed Aminohalogenation
of Fluorinated N’-Aryl-N-Propargyl
Amidines for the Synthesis of Imida-
zole Derivatives under Mild Condi-
tions
Golden(I): Under gold(I) catalysis,
propargyl amidines were converted
into 5-fluoromethyl imidazoles in the
presence of Selectfluor. Treatment
with N-iodosuccinimide afforded imi-
dazole-5-carbaldehydes as the final
product (see scheme).
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!