Fluorination-Oxidation of 2-Hydroxymethylindole Using Selectfluor

Article abstract of DOI:10.1002/adsc.201600786

An unexpected fluorination-oxidation of 2-hydroxymethylindole using selectfluor under mild condi-tions without a catalyst is described. This new chemistry allows for efficient and rapid synthesis of various 3-fluoroindole-2-aldehydes and novel quaternary

Full text of DOI:10.1002/adsc.201600786

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DOI: 10.1002/adsc.201600786
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Fluorination-Oxidation of 2-Hydroxymethylindole Using
Selectfluor
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Xiaojian Jiang,a,* Feng Zhang,a Junjie Yang,a Pei Yu,a Peng Yi,a Yewei Sun,a,* and
Yuqiang Wanga
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a
Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-
cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou 510632, People’s Republic of China
Fax: +(86)-(0)-20-8522-5030
Phone: (+86)-(0)-20-8522-6152; e-mail: chemjxj2015@jnu.edu.cn yxy0723@163.com
Received: November 23, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600786
the 3-fluoro-indole compound is useful for both
organic and medicinal chemistry.
Abstract: An unexpected fluorination-oxidation of
2-hydroxymethylindole using selectfluor under mild
condi-tions without a catalyst is described. This new
We have previously reported a facile pathway to
synthesize diverse 3-chloro/bromoindole-2-aldehyde
chemistry allows for efficient and rapid synthesis of
compounds from 2-hydroxymethylindole via the halo-
various 3-fluoroindole-2-aldehydes and novel qua-
genation-oxidation process (Scheme 2, eq 1).[5] We
ternary 3-fluoro-3-hydroxymethyl-2-oxindoles with
expected that fluorination-oxidation of 2-hydroxyme-
up to 86% isolated yield.
thylindole might lead to the formation of the 3-
fluoroindole-2-aldehyde compound 2b in a similar
Keywords: Fluorination; Oxidation; 2-Hydroxyme-
fashion (Scheme 2, eq 2). A fluorine source, such as
thylindole; Selectfluor
selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane bis(t-etrafluoroborate), is a versatile
mediator or catalyst in organic synthesis.[6-8] It serves
33 Indole scaffolds cover a large range of natural and as a strong oxidant for diverse “fluorine-free” func-
34 bioactive molecules, which are important in both tionalizations.[7] Selectfluor is widely used as a media-
35 organic and medicinal chemistry.[1] The incorporation tor in transformations of oxidizable functional groups.
36 of a fluorine atom into the indole skeleton offers Selectfluor can oxidize a hydroxymethyl group to
37 significant potential in medicinal applications. The form an aldehyde group. As such, when combined
38 fluorine substituent affects nearly all of the physical with the fluorination and oxidation properties of
39 properties of a lead compound, including its absorp- selectfluor, the desired product 3-fluoroindole-2-alde-
40 tion, distribution, metabolism and excretion.[2] hyde 2b can be formed from the corresponding 2-
41 Although the fluorination strategies in recent develop-
42 ments have been diverse, the incorporation of a
43 fluorine atom into the C3 position of an indole moiety
44 remains a challenging task.[3] For instance, 3-fluoroin-
45 dole-2-aldehyde compound 2a was obtained with less
46 than a 24% overall yield because the final fluorination
47 process returned only a 33% yield (Scheme 1).[4]
48 Therefore, development of novel strategy to produce
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Scheme 1. Formation of 2a.
Scheme 2. Reactions of Halogenation-Oxidation.
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hydroxymethylindole 1b in
(Scheme 2, eq 2).
a
one-pot reaction presence of 2.5 equiv. of selectfluor and K2CO3 when
acetonitrile was used as a solvent at room temperature
We also discovered that novel quaternary 3,3- (Table 1, entry 4). The absence of a base (Table 1,
disubstituted 2-oxindole 5a was formed when 3- entry 2) returned a comparable yield. The yield
bromo-2-hydroxymethylindole 4a was used in the significantly decreased when the temperature was
presence of fluorine source (Scheme 2, eq 3). This decreased (Table 1, entry 3). Only 26% of the desired
process might occur due to the rearrangement proper- product was detected when 1.2 equiv. of selectfluor
ties of selectfluor.[6,9]
(Table 1, entry 1) were applied, suggesting that the
Herein, we report an unexpected fluorination- mechanistic pathway consumed two equiv. of the
10 oxidation of 2-hydroxymethylindole to produce vari- fluorine source. Replacement of selectfluor with N-
11 ous 3-fluoroindole-2-aldehyde compounds and novel fluorobenzenesulfonimide (F2) (Table 1) produced 2b
12 quaternary
13 compounds.
3-fluoro-3-hydroxymethyl-2-oxin-dole with inferior yields (Table 1, entries 5–7). Alterations
to other fluorine sources such as 1-fluoro-2, 4, 6-
14
As demonstrated in Table 1, a yield of up to 70% trimethylpyridinium triflate (F3) (Table 1, entry 8), 4-
15 of 3-fluoroindole-2-aldehyde 2b was achieved in the tert-butyl-2, 6-dimethyl-phenylsulfur (F4) (Table 1,
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entry 9) and diethylaminosulfur trifluoride (F5) (Ta-
ble 1, entry 10) failed to produce the desired product.
Changing K2CO3 to other bases, such as Na2CO3,
CsCO3, and Na3PO4 (Table 1, entries 11–13), could not
Table 1. Optimization of Substrate 1b.
produce 2b with
a superior yield. Acetonitrile
appeared to be a suitable solvent for this reaction
because other solvent systems, such as acetone, THF,
and 1, 4-dioxane, had negative effects on this reaction
(Table 1, entries 14–16). In addition, we obtained
product 2b in similar yields when performed control
experiments under nitrogen and oxygen respectively,
suggesting that oxygen might not involve in the
oxidation process (Table 1, entries 17 and 18).
Entrya) Solvent Baseb)
Fluorine Temp Yield (%)e)
source
(oC)
With the optimized conditions chosen, we pro-
ceeded to study the effect of the substrate on this
transformation. As illustrated in Table 2, substrate 1a
produced the desired product 2a with up to a 72%
yield in a one-pot procedure (Table 2, entry 3).
Diverse N-substituents of indole were compatible with
this reaction, including the ones with alkyne and
alkene moieties (Table 2, entries 8–12). Other N-
substituents, such as alkyl and aryl groups produced
good yields (Table 2, entries 2, 4, 7 and 13). Addition-
ally, the reactive indolic hydrogen had a slight effect
on this reaction, increasing the yield up to 61%
(Table 2, entry 1). Functional groups such as F and CN
in the alkyl chain were well-suited to these reaction
conditions and delivered good yields (Table 2, en-
tries 5 and 6). Acceptable yields could be achieved
when the Ar system of the indole ring was electron-
deficient (Table 2, entries 14, 15 and 18). A high yield
was successfully obtained when the Ar system was
substituted with an alkyl group (Table 2, entry 16) as
well. Unfortunately, we could not detect any of the
desired product when the electron-donating system of
the indole ring was applied (Table 2, entry 17). We
suspected that the electron-rich Ar ring, for example,
a 5-OMeÀAr system of 1q, probably triggered the
substitution reaction in the benzene ring rather than
triggering the oxidation process in the alcoholic
moiety.
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
–
–
–
F1c)
F1d)
F1d)
rt
rt
0
26
70
44
70
12
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49
<5
<5
<5
63
62
66
50
47
38
69
70
2f)
3
4
5
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7
K2CO3 F1d)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
–
F2d)
K2CO3 F2d)
Me2CO K2CO3 F2d)
8
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
K2CO3 F3d)
K2CO3 F4d)
K2CO3 F5d)
Na2CO3 F1d)
CsCO3 F1d)
Na3PO4 F1d)
10
11
12
13
14
15
16
17g)
18h)
Me2CO K2CO3 F1d)
THF
K2CO3 F1d)
Dioxane K2CO3 F1d)
MeCN
MeCN
–
–
F1d)
F1d)
[a] Reactions were carried out at 0.2 mmol scale in 8 mL of
solvent under air.
[b] Base used were 2.5 equiv.
[c] Fluorine source used were 1.2 equiv.
[d] Fluorine source used were 2.5 equiv.
[e] Isolated yield.
[f] Reaction conditions of using 2.5 equiv. of F1(selectfluor) in
MeCN at room temperature under air was the “optimized
conditions”.
[g] Reaction was conducted under oxygen atmosphere.
[h] Reaction was conducted under nitrogen atmosphere.
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the fluorination-oxidation process might involve a
stepwise mechanism.
Table 2. Substrate Scope of 2.
3
4
5
Entrya) Substrate R1
R2
Product Yield (%)b)
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9
1
2
3
4
5
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7
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1c
1b
1a
1d
1e
1f
1g
1h
1i
H
CH3
H
H
H
H
H
H
H
H
H
2c
2b
2a
2d
2e
2f
2g
2h
2i
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70
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83
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CH3CH2
isopropyl
F(CH2)2
NC(CH2)3
Bn
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propargyl
allyl
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12
1j
1k
1l
H
H
H
2j
2k
2l
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65
82
Scheme 3. Reactions of 1 s, 4e and 6.
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1m
1n
1o
1p
1q
1r
Ph
H
H
H
H
H
H
F
2m
2n
2o
2p
79
66
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76
<5
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We found that the 1,2-rearrangement oxidation
process proceeded well when 1.2 equiv. of selectfluor
were applied and when acetonitrile was used as the
solvent at room temperature.[10] Versatile N-substitu-
ents of indole, such as alkyl, aryl, allyl, and propargyl,
were well-suited to this reaction and allowed for up to
an 86% isolated yield to be obtained (5j) (Scheme 4).
However, the presence of indolic hydrogen, such as in
substrate 4k, was an exception. We suspected that the
reactive indolic hydrogen might cause side reactions,
Br
Me
OMe –
Cl 2q
[a] All reactions were carried out at 0.2 mmol scale with
0.5 mmol of F1 in MeCN (8 mL) under air.
[b] Isolated yield.
We discovered that the substituent at the C3
34 position has a fundamental effect on the fluorination-
35 oxidation process developed herein. As previously
36 discussed, the fluorination-oxidation process proceed-
37 ed smoothly to generate the 3-fluoroindole-2-aldehyde
38 product 2 when a 3-hydrogen-2-hydroxy-methylindole
39 substrate was used. However, 3-chloroindole-2-alde-
40 hyde 3 was formed under the optimized conditions if
41 the C3 position processed a chloride group (Scheme 3,
42 eq 1). Given this result, selectfluor only served as an
43 oxidizing reagent.[7] Compared to a chloride group, a
44 bromide group is a better leaving group. The incorpo-
45 ration of a bromide group into the C3 position may
46 trigger a 1,2-rearrangement process. As shown in
47 Scheme 3, 3-bromo-2-hydroxymethyl-indole substrate
48 4e, which bears a bromide group in the C3 position,
49 was replaced by a fluorine substituent in the presence
50 of selectfluor. Subsequent 1,2-rearrangement followed
51 by oxidation produced the desired 3-fluoro-3-hydrox-
52 ymethyl-2-oxindole product 5e with a moder-ate yield
53 (Scheme 3, eq 2). We also found that 3-fluoro-2-
54 hydroxymethyl-indole substrate 6 was oxidized to give
55 aldehyde product 2i under the identical conditions
56 (selectfluor 1.2 equiv., Scheme 3, eq 3), implying that
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Scheme 4. Substrate Scope of 5.a a)All reactions were carried
out at 0.2 mmol scale of 4 in MeCN (8 mL) with 1.2 equiv. of
selectfluor under air. b) Isolated yield.
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resulting in the negative formation of 5k (Scheme 4).
These novel quaternary 3-fluoro-3-hydroxymethyl-2-
oxindole pr-oducts supplement the quaternary 3-
hydroxymethyl-2-oxindole
compounds.
Previous
methods for quaternary 3-hydroxymethyl-2-oxindole
compounds were lengthy and required air-sensitive
transition metals as catalysts.[11–16] Quaternary 3-
hydroxy-methyl-2-oxindole compounds are useful in-
termedi-ates in total synthesis. This successful syn-
10 thesis of quaternary 3-fluoro-3-hydroxymethyl-2-oxin-
11 dole co-mpounds under mild conditions without a
12 catalyst is beneficial to organic and medicinal applica-
13 tions.
14
It is noteworthy to mention that the free alcohol
15 group probably has certain important influence on the
16 reactivity in the formation of 3-fluoro-2-aldehyde
17 product 2 and 3-fluoro-3-hydroxymethyl-2-oxin-dole
18 5. As illustrated in Scheme 5, alcohol protected
19 substrate 7 returned product 2b with a low yield under
20 optimized conditions (Scheme 5, eq 1). The fluorina-
21 tion-oxidation reaction of 3-bromo-2-methoxymethyl-
22 indole substrate 8 resulted in a complicated mixture
Scheme 6. Proposed Mechanism.
23 (Scheme 5, eq 2). In this case, we could only isolate a
24 small amount of 3-fluoroindole-2-aldehyde 2b instead
25 of the 3-fluoro-2-oxindole rearrangement product.
Subsequent oxidation with extra equiv. of selectfluor
might offer a hypofluoride[18] which may lead to the
generation of 3-fluoroindole-2-aldehyde 2.
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In the case of 3-bromo-substrate 4, the 3-fluoroin-
dolenium ion II preferred to initiate the 1,2-rearrange-
ment process with concomitant loss of bromide to
form an intermediate V (Scheme 6, route b). In the
course of this oxidative 1,2-rearrangement, a trace
amount of water in the media might attack C2 position
to offer an intermediate III. Because bromide is a
good leaving group, then a carbocation IV could be
produced. This carbocation intermediate could be-
come a driving force for the adjacent hydroxymethyl
group to migrate to C3 position. Subsequently, the
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Scheme 5. Reactions of 7 and 8.
For the formation of 3-fluoroindole-2-aldehyde resultant oxonium ion intermediate V furnished the
40 compounds, a two-step mechanism may be required oxidative rearrangement product 5. This 1,2-rear-
41 because we recovered a certain amount of the initial rangement process was further supported by the
42 material and fluorinated 2-hydroxymethylindole when rearrangement of indolyl acetates and carbonates,[19]
43 1.2 equiv. of selectfluor were applied. We suggested as well as the recent discovery of 1,2-rearrangement
44 that the nitrogen atom in substrates 1 and 4 could oxidation of 2,3-disubstituted indole using select-
45 contribute to the fluorination to give an iminium ion fluor.[9]
46 intermediate I (Scheme 6). Subsequent fluorination of
In conclusion, a facile method to produce diverse
47 C3 position might offer a 3-fluoroindolenium ion 3-fluoroindole-2-aldehyde compounds from the corre-
48 intermedate II which served as a common intermedi- sponding 2-hydroxymethylindole has been established.
49 ate for both route a and route b pathways.
The method also allows for the efficient and rapid
50
For the formation of 3-fluoroindole-2-aldehyde synthesis of novel quaternary 3-fluoro-3-hydroxymeth-
51 compounds 2, a two-step mechanism was probably yl-2-oxindole compounds. Various 3-fluoroindoles or
52 involved when the C3 position contained a hydride 3-fluorooxindoles are now prod-ucible with good
53 group because the fluorination of the C3 position was yields under mild conditions without a catalyst, which
54 likely to result in the formation of intermediate II. is beneficial for synthetic and medicinal applications.
55 This step was supported by significant work demon-
56 strating that 3-hydrogen-indoles react with selectfluor
57 to introduce a CÀF bond in the C3 position.[17]
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Experimental Section
General Procedure for Fluorination-oxidation.
To a solution of alcohol 1 (0.2 mmol, 1.0 equiv.) in MeCN
(8 mL) was added selectfluor (177.1 mg, 0.50 mmol,
2.5 equiv.) in one portion under air. The resultant mixture
was stirred at room temperature and monitored by TLC.
After removing the solvent in vacuo. The residue was
purified by flash column chromatography (Hexanes/EtOAc
9:1) to yield the corresponding 3-fluoro-indole-2-aldehyde
compounds 2.
[6] Review: S. Stavber, Molecules 2011, 16, 6432.
[7] Recent progress for selectfluor mediated oxidation:
a) Y. Lin, L. Zhu, Y. Lan, Y. Rao, Chem. Eur. J. 2015,
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Su, RCS. Adv. 2015, 5, 7232; d) C. A. Dannenberg, V.
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Lett. 2011, 52, 3086; h) Z. Jin, B. Xu, G. B. Hammond,
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General Procedure for fluorination,
1,2-Rearrangeme-nt Oxidation.
To a solution of alcohol 4 (0.2 mmol, 1.0 equiv.) in MeCN
(8 mL) was added selectfluor (85 mg, 0.24 mmol, 1.2 equiv.)
in one portion under air. The resultant mixture was stirred at
room temperature and monitored by TLC. After removing
the solvent in vacuo. The residue was purified by flash
column chromatography (Hexanes/EtOAc 3:1) to yield the
corresponding 3-fluoro-3-hydroxymethyl-2-oxindole com-
pounds 5.
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Acknowledgements
This work was supported in part by the National Natural
Science Foundation of China (Grant No. 21502068). We
thank Prof. Ying-Yeung Yeung (The Chinese University of
Hong Kong), Prof. Xiaodan Zhao (Sun Yat-sen University),
Prof. Ling Zhou (Northwest University) and Prof. Jackson
D. Leow (National Tsing Hua University) for their valuable
advice.
[9] X. Jiang, J. Yang, F. Zhang, P. Yu, P. Yi, Y. Sun, Y.
Wang, Org. Lett. 2016, 18, 3154.
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