Synthesis of N-Hydroxyindole Derivatives via Pd-Catalyzed Electrophilic Cyclization

Full text of DOI:10.1002/bkcs.12285

Communication
DOI: 10.1002/bkcs.12285
BULLETIN OF THE
S. M. Oh and S. Shin
KOREAN CHEMICAL SOCIETY
Synthesis of N-Hydroxyindole Derivatives via Pd-Catalyzed
Electrophilic Cyclization
*
Soo Min Oh and Seunghoon Shin
Department of Chemistry, Institute for Natural Sciences and Center for New Directions in Organic
Synthesis (CNOS), Hanyang University, Seoul 04763, South Korea. *E-mail: sshin@hanyang.ac.kr
Received March 24, 2021, Accepted April 15, 2021
Keywords: N-hydroxyindoles, Umpolung, Hydroxylamine, Electrophilic cyclization
Heterobiaryl compounds are important building blocks that
are frequently found in pharmaceuticals, natural products,
organic functional materials, and chiral ligands.1 In this
regard, C H/C H aryl coupling reactions have received
intense attention recently,2 as they obviate the need for pre-
functionalization of coupling partners (C-M or C-X). For
the coupling of two nucleophilic (hetero)arenes, methods
based on internal oxidants, i.e., pre-functionalization of
substrates with oxidizing groups, may provide an enhanced
level of selectivity over external-oxidant-based approaches
(Scheme 1(a) vs. 1(b)). For example, Proctor and
coworkers have utilized benzothiophene S-oxides that can
function as an electrophilically modified thiophene for
heterobiarylation.3a or electrophilic activators of phenols
for subsequent homo- and heterocoupling.3b,c
In contrast to the facile oxidation of benzothiophenes,
the oxidation of indoles has been difficult. Conventional
oxidation of indoles involves cumbersome reduction–
reoxidation sequence, or condensation of ortho-methyl
nitroarenes followed by reductive cyclization which suffer
from limited commercial availability of ortho-methyl
nitroarenes (Scheme 2(a)).4 Therefore, an efficient and gen-
eral synthetic access to N-oxidized indoles may prove use-
ful for the selective functionalization of indoles.4b Inspired
by the Larock cyclization of ortho-alkynyl anilines,5 we
posited that ortho-alkynyl hydroxylamines would furnish
N-hydroxyindoles (Scheme 2(b)). Wide availability of
ortho-halonitrobenzenes and the reliable Sonogashira reac-
tion would ensure the generality of the method.
At the outset, ortho-alkynylnitrobenzenes were prepared
via Sonogashira reaction of ortho-iodo (or bromo) nitroben-
zene derivatives.6 Among a number of conditions tested for
the reduction of 1,7 we found that a combination of Ni
powder (1.2 equiv.) and hydrazine hydrate (6.5 equiv.) in
1,2-DCE:EtOH (1:1) smoothly transformed 1 into their
hydroxylamine derivatives 2 in a general fashion. Subse-
quently, we tested conditions for electrophilic cyclization
of N-(2-alkynylaryl)hydroxylamines 2a employing various
transition metal catalysts (Table 1). Lewis acids, such as
Ag, Zn, Sc, In, Yb, and Cu complexes produced unknown
byproducts, but 3a was not observed (entries 1–11).
Au(I) and Au(III) complex produced 3a (entries 12–13),
but to find a cheaper alternative, we kept on screening vari-
ous Pd(II) complexes (entries 14–17). Among them, PdCl2
showed promising results (entry 17). Interestingly, the yield
of 3a was highly dependent on the solvent, and CH3CN
turned out to be the best medium furnishing 3a in 84% iso-
lated yield after 30 min at ambient temperature (entry 18).
With these optimized conditions in hand, we next dem-
onstrated the generality of N-hydroxyindoles (Table 2).
(a)
(b)
Scheme 1. Comparison of external- vs. internal-oxidant approaches for C H/C H cross-coupling reaction.
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(a)
(b)
Scheme 2. Synthesis of N-hydroxyidoles.
Table 1. Electrophilic cyclization of 2a.
Entry
Catalyst
Conditions
Conv (%)
Yield (%)a
b
1
2
3
4
5
6
7
8
Ag(OCOCF3)
AgNO3
RT, 1 h, CH2Cl2
RT, 24 h, CH2Cl2
RT, 24 h, CH2Cl2
>99
70
—
b
—
b
AgOTf
>99
>99
>99
>59
>99
>99
>99
66
—
b
AgOTf, HOTf (10% mol each)
RT, 2 h, CH2Cl2
RT, 24 h, CH2Cl2
RT, 36 h, CH2Cl2
RT, 30 h, CH2Cl2
RT, 10 h, CH2Cl2
RT, 24 h, CH2Cl2
RT, 36 h, CH2Cl2
RT, 0.5 h, CH2Cl2
RT, 12 h, CH2Cl2
RT, 0.5 h, CH2Cl2
RT, 18 h, CH2Cl2
RT, 8 h, CH2Cl2
RT, 2 h, CH2Cl2
—
b
AgSbF6
Zn(OTf)2
ZnI2
Sc(OTf)3
In(OTf)3
—
b
—
b
—
b
—
b
9
—
b
10
11
12
13
14
15
16
Yb(OTf)3
Cu(OTf)2
—
b
>99
>99
>99
—
AuCl(PPh3), AgOTf (10% mol each)
AuCl3
59
64
c
c
PdCl2(PPh3)2
Pd(OAc)2
Pd(TFA)2
—
—
>99
>99
5
34
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Table 1 (continued)
Entry
Catalyst
Conditions
Conv (%)
Yield (%)a
17
18
19
20
21
22
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
RT, 12 h, CH2Cl2
RT, 0.5 h, CH3CN
RT, 3 h, THF
RT, 7 h, 1,4-dioxane
RT, 7 h, C6H6
>99
>99
>99
>99
>99
>99
39
84
80
79
44
62
RT, 2 h, MeOH
a Isolated yield after chromatography.
b Desired 3a was not observed; a mixture of unknown byproducts were obtained.
c No reaction.
Table 2. Synthesis of N-acyloxyindole derivatives.a
Entry
R1,b
R2,b
2 (%)
4 (%)c
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
2a, 89
—
4a, 84
4a, 78d
4b, 77
4c, 55
4d, 54
4e, 68
4f, 18
4g, 64
4h, 82
4i, 66
4-Me-C6H4
2b, 94
2c, 99
2d, 99
2e, 93
2f, 99e
2g, 99
2h, 89
2i, 99
2j, 92
2k, 99
2l, 99f
2m, 97
2n, 94
2o, 85
—
4-MeO-C6H4
4-CF3-C6H4
4-Cl-C6H4
4-NC-C6H4
2-Naph
1-Naph
n-Pr
c-propyl
c-hexyl
tert-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4j, 90
4k, 71
4l, 53
H
3-Me
5-Me
5-CF3
4-F
5-F
6-F
5-CO2Me
3-Me
3-Me
4m, 79
4n, 84
4o, 78
4p, 72g
4q, 67
4r, 47g
4s, 42
4t, 37
4u, 45
2q, 99
—
2s, 74
2t, 92
2u, 91
4-MeO-C6H4
4-CF3-C6H4
a 1 (1.5 ~ 2.1 mmol) scale; isolated yield after chromatography.
b The numbering refers the position of indole 4.
c Yields over two steps from 2.
d Overall yield from 1a, without isolation of intermediates 2a.
e Zn was used instead of Ni powder.
f PdCl2 (20 mol%) was used.
g 2p and 2r was unstable and were used in-situ in the next step; overall yield from 1p and 1r, respectively.
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Some of the N-hydroxyindole derivatives showed limited
stability and was protected in-situ into O-activated 4. The
presence of O-4-CF3Àbenzoyl group would form
electrophilically more activated N-hydroxyindole deriva-
tives. For 1a, reduction, cyclization, and O-acylation
sequence could be conducted without purification of inter-
mediates, with similar overall yields from 1a (entries 1 and
2). Due to the generality of Sonogashira coupling, various
Ar (entries 3–9) as well as alkyl groups (entries 10–13)
could be accommodated at the C2-position of the indole 4.
The reaction was remarkably general, except the nitrile
derivative 4f. For the reduction of 1f, standard condition
gave no product, and changing the reducing agents into Zn
and hydrazine produced 2f in an excellent yield (entry 7).
Cyclization into 3f was also problematic and gave modest
yield of 4f after O-acylation. Substituents at the indole core
were also widely tolerated (entries 14–22). Hydroxylamines
2p and 2r were unstable: in this case, the crude intermedi-
ates after workup were directly transformed into 3, furnish-
ing the corresponding 4 after acylation in good yields
(entries 17 and 19). Using the current method, synthesis of
C2-unsubstituted N-hydroxyindoles (R2 = H) has been
tested, but Pd(II)-catalyzed cyclization of 2 having a termi-
nal acetylene (R2 = H) did not occur, which is the limita-
tion of the current protocol. We also compared the
synthesis of 4a under conventional protocol (reduction–
reoxidation)4b to afford overall 52% of 4a, which clearly
illustrates the merit of the current protocol (cf. entry
1, Table 2).
Acknowledgments.
The authors thank the National
Research Foundation of Korea (grant numbers NRF-
2014-011165, NRF-2021R1A5A6002803, and NRF-2021
R1A2C3010552) for generous financial support.
Supporting Information. Additional supporting informa-
tion may be found online in the Supporting Information
section at the end of the article.
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ꢀ
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In summary, we reported herein a novel synthesis of N-
hydroxyindole derivatives that could function as an electro-
philic partner in a cross-coupling reaction. This protocol con-
sisting of Sonogashira coupling, partial reduction of the nitro
group, and Pd-catalyzed cyclization turned out to be highly
general, accommodating a wide variety of substituents in the
resulting indole. Cross-coupling chemistry based on 4 is under-
way in the laboratory and will be reported in due course.
Bull. Korean Chem. Soc. 2021
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