Zinc-catalyzed direct cyanation of indoles and pyrroles: Nitromethane as a source of a cyano group

Article abstract of DOI:10.1002/adsc.201301073

With nitromethane and diphenylsilane (Ph₂SiH₂), zinc triflate behaves as a Lewis acid catalyst for the cyanation of nitrogen-containing heteroarenes such as indoles and pyrroles. This is the first realization of the Lewis acid-catalyzed direct cyanation of a C(aryl)-H bond with no CN group-containing cyanating agent.

Full text of DOI:10.1002/adsc.201301073

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DOI: 10.1002/adsc.201301073
Zinc-Catalyzed Direct Cyanation of Indoles and Pyrroles:
Nitromethane as a Source of a Cyano Group
Yuta Nagase,a Tetsuya Sugiyama,a Shota Nomiyama,a Kyohei Yonekura,a
and Teruhisa Tsuchimotoa,*
a
Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashimita, Tama-ku,
Kawasaki 214-8571, Japan
Fax : (+81)-44-934-7228; e-mail: tsuchimo@isc.meiji.ac.jp
Received: December 2, 2013; Published online: January 13, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301073.
Abstract: With nitromethane and diphenylsilane
(Ph2SiH2), zinc triflate behaves as a Lewis acid cata-
lyst for the cyanation of nitrogen-containing hetero-
arenes such as indoles and pyrroles. This is the first
realization of the Lewis acid-catalyzed direct cyana-
À
emerged also in succession recently, but, here again,
as transition metal-based systems: Pd catalysts–Cu co-
oxidants or a stoichiometric amount of Cu salts.[5j,16]
In sharp contrast, we have found for the first time
that a Lewis acid can participate as a catalyst in this
reaction category.[17] We disclose herein a conceptually
new cyanation reaction using a nitromethane–hydrosi-
lane system under zinc catalysis.
tion of a CACHTUNGTRENNUNG(aryl) H bond with no CN group-con-
taining cyanating agent.
Keywords: heteroarenes; heterocycles; Lewis acids;
nitriles; zinc
We first examined suitable reaction conditions for
the cyanation of indole (1a) (Table 1). Treating 1a
with 10 mol% of ZnACHTUNGTRNEGNU(OTf)2 (Tf=SO2CF3) at 908C for
10 h in MeNO2, which was used not only as a reagent
but also as a reaction medium, resulted in no cyana-
tion of 1a (entry 1). Although the addition of mono-
Aryl and heteroaryl nitriles represent an important hydrosilanes 2a–2c provided no improvement, 3-cya-
class of core structures found in natural products, noindole (3a) was formed by using di- and trihydrosi-
pharmaceuticals, agrochemicals, and functional mate- lanes 2d–2f (entries 2–7). Among them, Ph2SiH2 (2e)
rials.[1] The CN group has also been recognized as is the most preferable, giving 3a in 76% yield
a versatile scaffold for elaboration of functional (entry 6). Reducing the amount of 2e from 3 to 2.5
groups, for instance, CHO, CO2H, CO2R, CONH2, molar equiv. lowered the yield, and its higher loading
CH2NH2, and others.[2] The most common way to con- was unnecessary (entries 8 and 9). Investigating the
À
struct (hetero)aryl CN linkages is likely to be treat- effect of other Lewis acids clearly showed that only
ment of pre-activated (hetero)arenes with metal cya- zinc salts are valid as catalysts, and Zn
N
nides under transition metal catalysis,[3,4,5] which has most promising for the cyanation (entries 6 and 10–
developed since the advent of Sandmeyer[6] and Rose- 20). No cyanation occurred without
a catalyst
nmund–von Braun[7] reactions. However, due to (entry 21). The use of a co-solvent had no positive
recent trends towards reducing our dependence on effect, and the simple reduction of the quantity of
pre-activation and toxic metal reagents,[8] a major in- MeNO2 resulted in a poor yield (entries 22–26).
terest has been rapidly shifting to direct (hetero)aryl
With the suitable reaction conditions in hand, we
C H cyanation[9] with inexpensive, harmless and read- explored the scope of the indole substrate (Table 2).
ily available non-metallic reagents.[10] Of particular in- Besides N-unsubstituted indole 1a, N-methyl- and N-
terest is the use of cyanating agents that have no CN benzylindoles participated in the cyanation reaction
group but act as CN sources. In this regard, the pio- (see 3a–3c). Indoles 1 with alkyl, alkoxy and bromo
neering research by Yu and colleagues has disclosed groups on the carbon atom were also cyanated to
that nitromethane is able to cyanate 2-phenylpyridine afford 3d–3j in moderate to good yields. The acid-
À
with the aid of a stoichiometric amount of CuACTHNUTRGNEUNG
(OAc)2, labile benzyloxy moiety was retained here (see 3h).[18]
based on a chelation-assisted strategy.[11] Approaches In contrast to the preceding copper-based sys-
DMF,[12]
DMF–NH
(NH4I),[13]
DMSO– tems,[4,11–15] the aryl boron bond that is useful for fur-
À
with
NH4HCO3
and t-BuNC[15] as CN suppliers have ther transformations also remained intact (see 3k).
[14]
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Yuta Nagase et al.
Table 1. Lewis acid-catalyzed cyanation of indole.[a]
Table 2. Zinc-catalyzed cyanation of indoles with MeNO2
and Ph2SiH2.[a]
Entry Lewis
acid
RnSiH4Àn
AHCTUNGTRENN(GUN equiv.)
Co-sol-
vent
Yield
[%][b]
1
2
3
4
5
6
7
8
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Cu
N
none
Et3SiH 2a (6)
none
none
<1
1
<1
<1
35
76
40
66
63
<1
<1
<1
<1
<1
<1
51
10
2
25
20
Me2PhSiH 2b (6) none
MePh2SiH 2c (6) none
MePhSiH2 2d (3) none
Ph2SiH2 2e (3)
PhSiH3 2f (2)
2e (2.5)
2e (3.5)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
2e (3)
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
toluene
Bu2O
dioxane[e]
EtCN
none
9
10
11
12
13
14
15
16
17
18
19
20
21
22[d]
23[d]
24[d]
25[d]
26[f]
AgOTf
In(OTf)3
Bi(OTf)3
Fe(OTf)3
Sc(OTf)3
T
N
N
E
[c]
Zn
Zn
ZnI2
ZnBr2
ZnCl2
none
Zn
Zn
Zn
Zn
Zn
<1
72
47
6
40
2e (3)
2e (3)
2e (3)
2e (3)
11
[a]
Reagents: 1a (0.80 mmol), MeNO2 (7.4 mmol, 0.40 mL), 2
(1.6–4.8 mmol), Lewis acid (80 mmol).
Determined by GC.
[b]
[c]
[d]
Nf=SO2C4F9.
Performed in MeNO2 (0.30 mL) and the co-solvent
(0.10 mL).
Dioxane=1,4-dioxane.
[e]
[f]
Performed in MeNO2 (0.20 mL).
[a]
Yields of isolated 3 based on 1 are shown here. Further
details on the reaction conditions for each reaction are
given in the Supporting Information.
ZnACHTNURTGNE(UNG OTf)2 (15 mol%) was used.
[b]
This is an advantage of the present zinc catalysis.[19]
Despite the fact that a series of 1- and 2-(hetero)aryl-
ACHTUNGTRENNUNGindoles have multiple possible reaction sites, only nated with MeNO2 and 2e under zinc catalysis to
mono-cyanation at the indolyl C-3 atom occurred to afford 5a as a separable mixture of a- and b-isomers.
provide 3l–3r, thus showing remarkable chemo- and Pyrroles with other alkyl and aryl groups on the nitro-
regioselectivity. This should be because the indolyl C- gen atom also participated in this protocol (see 5b–
3 site is the most nucleophilic among the aromatic 5d), whereas the size of the substituent did not affect
carbons,[20] and the electron-withdrawing character of significantly the a/b ratio. Here again, no extra cyana-
the CN group decreases the nucleophilicity of the tion on and except on the pyrrole ring was observed.
products so as to retard extra cyanation. The less nu- In contrast, other aromatic substrates such as 3,4-
cleophilic C-2, compared to a C-3, also worked as a re- ethy
action site (see 3s and 3t).
This zinc process is also applicable to the cyanation nucleophilicity. However, such a reactivity would
of pyrroles (Table 3). Thus, 1-hexylpyrrole was cya- have contributed to the selective mono-cyanation.
ACHTUNGRTENNlUNG enedioxythiophene and PhNMe2 were not cya-
nated successfully (ꢀ5%), due probably to their low
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Zinc-Catalyzed Direct Cyanation of Indoles and Pyrroles
Table 3. Zinc-catalyzed cyanation of pyrroles with MeNO2
and Ph2SiH2.[a]
[a]
Yields of isolated 5 based on 4 are shown here. Further
details on the reaction conditions for each reaction are
provided in the Supporting Information.
Scheme 2. Mechanistic studies.
Importantly, a practical application is accomplished
by the synthesis on a preparative scale. For example,
cyanation of 1a on a 10-mmol scale provided us with
1.03 g (72% yield) of 3a.
clusively into the CN group of the product (13C-3a),
The utility of the present reaction can be demon- thus showing that the CN group comes from MeNO2.
strated by transforming the product into a biologically In order to clarify the role of Zn(OTf)2, we next tried
important structure, an indolo
[3,2-c]quinoline,[21] its recovery after the cyanation reaction and then
which is found, for instance, in natural isocryptole- used the recovered solid for other reaction in which
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
pine[22] showing antimalarial activity (Scheme 1). Zn
ACTHUNTRGNE(UGN OTf)2 has been found to act as a Lewis acid cata-
Thus, nucleophilic attack of p-tolylMgBr to the CN lyst.[24] Thus, a solid recovered with 97% efficiency
group of 3n followed by protonation with MeOH and after the cyanation of 1a nicely catalyzed the transfor-
À
Cu-catalyzed oxidative N C bond-forming annulation mation of benzhydrol to diphenylacetonitrile in 85%
gave 6a in 90% yield.[23] This one-pot reaction is also NMR yield, which is fully comparable to that ob-
effective for 3q, thus indicating its good flexibility.
tained with fresh ZnACHTGUNRTEN(NUG OTf)2. Accordingly, ZnACHTUNGTRENNUNG(OTf)2
Some experimental observations might be useful would exist without changing its form during the cy-
for the mechanistic studies (Scheme 2). We first ad- anation process, and its role in the cyanation would
dressed the role of MeNO2. When 13C-labeled nitro- be that of a Lewis acid catalyst. We successively ex-
methane was used, the 13C atom was incorporated ex- amined the role of silicon reagent 2e and carried out
the reaction of 1a with Ph2SiMe2 having no hydrogen
atom, instead of 2e, which, however, led to no cyana-
À
tion. This result clearly shows that the Si H moiety is
essential for the cyanation reaction. The hydride char-
À
acter of Si H might thus play an important role in
this reaction. A final observation is that the reaction
of N-methylindole (1b) (Table 2, 3b) provided a non-
negligible amount of 3,3’-diindolylmethane 7a as a by-
product in addition to 3b.[25] Based on the literature,
where MeNO2 activated by a Lewis acid reacts with
1,3-dicarbonyl compounds as nucleophiles to be
incorporated as a methylene unit into products,[26]
7a might be formed via a similar type of process
triggered
by
activation
of
MeNO2
by
Zn
AHCTUNGTRENNUNG
Although further studies are required to verify the
reaction mechanism, its tentative interpretation is
Scheme 1. One-pot annulation of 3-cyano-2-(hetero)aryl-
ACHTUNGTRENNUNGindoles.
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349

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Yuta Nagase et al.
Experimental Section
General Procedure Exemplified by the Synthesis of
3a on a 10-mmol Scale
ZnACTHNUTRGEN(UGN OTf)2 (364 mg, 1.00 mmol) was placed in a 100-mL
Schlenk tube, which was heated at 1508C under vacuum for
2 h. The tube was cooled down to room temperature and
filled with argon. Nitromethane (5.0 mL) was added to the
tube, and the mixture was stirred at room temperature for
3 min. To this were added indole (1.17 g, 10.0 mmol) and
Ph2SiH2 (5.53 g, 30.0 mmol) successively. After stirring at
908C for 10 h, a saturated aqueous NaHCO3 solution
(3 mL) was added and the resulting mixture was stirred and
filtered through a cotton plug, which was then flushed with
EtOAc (10 mL). The aqueous phase was extracted with
EtOAc (30 mLꢁ2), and the combined organic layer was
washed with brine and dried over anhydrous Na2SO4. Filtra-
tion and evaporation of the solvent followed by column
chromatography on silica gel (n-hexane/EtOAc=2/1) gave
3-cyanoindole (3a); yield: 1.03 g (72%).
Scheme 3. A proposed reaction mechanism. ZnII =Zn
Si=SiR3.
ACHTUNGERTN(NUNG OTf)2.
Acknowledgements
proposed in Scheme 3, where substituents of 1 are
omitted for clarity. The first should be nucleophilic
attack of 1 to aci-nitromethane 8 activated by ZnII,
just like the attack of water occurring in the Nef reac-
tion.[28] In the present reaction, generation of 12 and
13 as non-polymeric siloxanes, which would be de-
rived from self-dehydration of the corresponding
Y. N. thanks the JSPS for a Research Fellowship for Young
Scientists.
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Adv. Synth. Catal. 2014, 356, 347 – 352