Synthesis of N-Alkyl and N-H-Carbazoles through SNAr-Based Aminations of Dibenzothiophene Dioxides

Article abstract of DOI:10.1002/chem.201903916

Alkyl amines have become available for the synthesis of diverse N-alkyl carbazoles through twofold S_NAr aminations of dibenzothiophene dioxides by using alkali metal bases. Of particular importance is the choice of counter cations on alkali metal bases, that is, i) the use of Li base for the efficient intermolecular reaction and ii) the sequential addition of heavier alkali metal bases (Na, K, or Cs) to promote intramolecular cyclization in a one-pot manner. This protocol also enables the cascade synthesis of N-H-carbazoles by using 2-phenylethylamine by removal of the 2-phenethyl group from N-(2-phenethyl) carbazoles in a single operation.

Full text of DOI:10.1002/chem.201903916

DOI: 10.1002/chem.201903916
Communication
&
Organic Synthesis
Synthesis of N-Alkyl and N-H-Carbazoles through SNAr-Based
Aminations of Dibenzothiophene Dioxides
Atsushi Kaga, Keisuke Nogi, and Hideki Yorimitsu*[a]
Abstract: Alkyl amines have become available for the syn-
thesis of diverse N-alkyl carbazoles through twofold SNAr
aminations of dibenzothiophene dioxides by using alkali
metal bases. Of particular importance is the choice of
counter cations on alkali metal bases, that is, i) the use of
Li base for the efficient intermolecular reaction and ii) the
sequential addition of heavier alkali metal bases (Na, K, or
Cs) to promote intramolecular cyclization in a one-pot
manner. This protocol also enables the cascade synthesis
of N-H-carbazoles by using 2-phenylethylamine by remov-
al of the 2-phenethyl group from N-(2-phenethyl) carba-
zoles in a single operation.
Scheme 1. Syntheses of N-alkyl carbazoles.
Carbazoles represent an important class of nitrogen-containing
heteroaromatics in the field of medicinal and material scien-
ces.[1,2] Of particular interest is N-alkyl carbazoles which possess
potent bioactivities[3] and unique photophysical and electro-
chemical properties.[4] The syntheses of N-alkyl carbazoles gen-
erally rely on the nucleophilic substitution reaction of N-H-car-
bazoles with alkyl halides by the SN2 pathway (Scheme 1,
path A).[5] However, the process is sensitive to the steric hin-
drance of alkyl halides, primary and activated secondary alkyl
halides being only applicable to the reaction.[6] Another ap-
proach is the transition-metal-catalyzed double N-arylation of
primary amines with 2,2’-di(pseudo)halobiaryls (path B), which
typically requires a precious palladium catalyst.[7] In addition,
the benzannulation of N-alkyl indoles with various four-carbon
synthons, such as two molecules of alkynes, has proven to be
a successful strategy to give N-alkyl carbazoles (path C)[8,9]
while installable N-alkyl chains are not diverse. The oxidative
resents a transformation of a heteroaromatic skeleton to an-
other ring system through the partial disassembly of the start-
ing aromatic core.[12–14] Particularly, we have developed the
transition-metal-free transformation of dibenzothiophenes into
N-aryl carbazoles through twofold SNAr reactions of dibenzo-
thiophene dioxides[15] with anilines in the presence of
KN(SiMe3)2, the potassium cation of which played a key role to
promote SNAr aminations (Scheme 2).[13b] However, the reaction
of dibenzothiophene dioxides with alkyl amines by using
KN(SiMe3)2 was sluggish. We thus investigated the effect of
Brønsted bases in more detail to achieve the efficient synthesis
of N-alkyl carbazoles from dibenzothiophene dioxides and alkyl
amines.
cyclization of N,N-diarylalkylamines (path D) or 2-alkylamino-
[10,11]
biaryls (path E) has also been developed
while these
methods suffer from the poor regioselectivity in the case of
multisubstituted aromatic substrates. Therefore, the develop-
ment of novel methods for the synthesis of diverse N-alkyl car-
bazoles is still desirable.
Recently, we have been interested in ‘aromatic metamorpho-
sis’ of heteroatom-containing aromatic compounds, which rep-
Scheme 2. Our previous transformation of dibenzothiophenes into carba-
zoles and its limitation.
[a] Dr. A. Kaga, Dr. K. Nogi, Prof. Dr. H. Yorimitsu
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo-ku, Kyoto 606-8502 (Japan)
E-mail: yori@kuchem.kyoto-u.ac.jp
We commenced our studies with the reaction of dibenzo-
thiophene dioxide (1a) with n-hexylamine (2a) in 1,4-dioxane
at 1008C (Table 1). Extensive screening of Brønsted bases re-
vealed that the use of KN(SiMe3)2 or NaN(SiMe3)2 resulted in
poor yields of desired carbazole 3aa along with a complex
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201903916.
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other hand, the reaction with KI, a neutral potassium salt, af-
forded a low yield of 3aa with a complex mixture of unidenti-
fied products (entry 6). In fact, the use of Cs2CO3 or Na2CO3 in-
stead of potassium bases also provided comparable yields of
carbazole 3aa (entries 7 and 8) albeit a longer reaction time
(7 h) was required for the reaction using Na2CO3 (entry 8). In
contrast, Li2CO3 proved to be ineffective (entry 9), which sup-
ports the importance of heavier alkali metal ion (Na+, K+, or
Cs+) for the efficient cyclization process. From the screening
study, we decided to evaluate the two sets of reaction condi-
tions that utilize KN(SiMe3)2 (entry 1) or K2CO3 (entry 5) for the
investigation of the reaction scope.[19]
Table 1. Screening of alkali metal bases.
Entry
M
t [h]
Yield of 3aa [%][a]
Yield of 4aa [%][b]
1
2
3
4
K
Na
Li
3
3
3
17
37
2
0
0
61
42
Li
24
17
[a] 1H NMR yields. [b] Isolated yields.
The scope with respect to alkyl amines 2 is depicted in
Scheme 3A. A variety of a-primary and secondary alkyl amines
were applicable under the optimal reaction conditions for the
synthesis of N-alkyl carbazoles 3ab–3aj in good yields. Nota-
bly, our method is capable of using sterically hindered neopen-
mixture of unidentified products (Table 1, entries 1 and 2).[16]
We expected that the formation of a strongly basic K or Na
amide generated from amine 2a in situ leads to the decompo-
sition of 1a as the predominant pathway. Hence, we next ex-
amined LiN(SiMe3)2 as the weaker base, which rendered the re-
action process cleaner to provide zwitterionic intermediate
4aa in 61% yield as an isolable solid (entry 3). The zwitterion
4aa should be formed upon protonation of dianion A (see
Table 2), which was generated through the intermolecular SNAr
reaction of 1a with amine 2a in the presence of LiN(SiMe3)2.
On the other hand, the prolonged reaction time (24 h) for the
same reaction in the presence of LiN(SiMe3)2 did not improve
the yield of carbazole 3aa satisfactorily (entry 4).
Table 2. One-pot reactions of dianion A with alkali metal bases.
Entry
Alkali metal base
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
9
KN(SiMe3)2
KOt-Bu
KOH
K3PO4
K2CO3
KI
Cs2CO3
Na2CO3
Li2CO3
2
2
2
2
2
24
2
7
91 (86)[b]
87
88
91
91
19
90
90
24
20
[a] 1H NMR yields. [b] Isolated yield.
Considering the fact that KN(SiMe3)2 is the irreplaceable base
in our previous report for the synthesis of N-aryl carbazoles,[13b]
we envisioned that the salt metathesis reaction of dianion A
with additional KN(SiMe3)2 promotes the intramolecular SNAr
cyclization to deliver carbazole 3aa.[17,18] We thus performed
the reaction of 1a with amine 2a in the presence of LiN-
(SiMe3)2 to form dianion A, followed by treatment with
KN(SiMe3)2 at 1008C as a one-pot procedure. Indeed, the one-
pot reaction furnished carbazole 3aa in excellent yield
(Table 2, entry 1). Additions of different potassium bases also
resulted in similar reaction efficiencies (entries 2–5). On the
Scheme 3. Scope of the synthesis of N-alkyl carbazoles 3. [a] K2CO3 was used
instead of KN(SiMe3)2. [b] 1.5 equiv of neopentylamine (2e) was used. [c] At
1208C for the first step.
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tylamine (2e) to furnish carbazole 3ae, which is difficult to
synthesize by the SN2 reaction of carbazole with neopentyl hal-
ides.[20] Furthermore, the reaction of 1a with trans-4-methylcy-
clohexylamine (2h) resulted in the stereoretentive synthesis of
carbazole 3ah, which demonstrates the stereochemical com-
plementarity between our protocol and the conventional SN2
alkylation of carbazoles. In the case of p-methoxybenzylamine
(2k) as a starting amine, a slightly lower yield of carbazole 3ak
was obtained possibly owing to the undesired fragmentation
of amine 2k bearing the benzylic protons under the basic con-
ditions.[21] Unfortunately, the reaction of 1a with sterically hin-
dered 1-adamantylamine did not provide the desired product
at all.
of N-H-carbazole 5a in 79% yield (Scheme 4ii). We suppose
that N-H-carbazole 5a was formed by a sequence of 1) SNAr
aminations of 1a with amine 2l, 2) elimination reaction of 3al
with the concomitant extrusion of styrene, and 3) protonation
of the resulting carbazolide anion B.[24,25]
This cascade reaction successfully provided a series of N-H-
carbazoles 5 including phenyl-substituted 5b and 5c as well
as p-extended 5d and 5e (Scheme 5). When sterically hindered
1 f was used, harsh reaction conditions (6.0 equivalents of
KN(SiMe3)2 for 42 h as the second step) were required to deliv-
er a good yield of N-H-carbazole 5 f.
We next turned our attention to the generality of dibenzo-
thiophene dioxides 1 (Scheme 3B). Our protocol afforded 9-
hexyl-3,6- and 2,7-diphenyl-9H-carbazoles 3ba and 3ca with
retention of the original substitution pattern of dibenzothio-
phene dioxides 1b and 1c, respectively. This method also ena-
bled the efficient syntheses of p-extended carbazoles 3da and
3ea and sterically hindered 3 fa. Furthermore, benzothiophene
dioxide 1g was a suitable substrate under our reaction condi-
tions to give 2,3-diaryl substituted indole 3ga in 46% yield. On
the other hand, the current process can not tolerate a 2,7-di-
chloro- or dibromo-dibenzothiophene dioxide probably due to
the formation of aryne intermediates under the basic condi-
tions.
This protocol was found capable in the divergent synthesis
of N-alkyl and N-H-carbazoles when 2-phenylethylamine (2l)
was used as a starting amine (Scheme 4). The reaction of 1a
with amine 2l with the aid of LiN(SiMe3)2 followed by treat-
ment with Na2CO3 at 1008C produced 9-phenethyl-9H-carba-
zole (3al) in 78% yield as a sole product (Scheme 4i). In con-
trast, the use of K2CO3, Cs2CO3 or KN(SiMe3)2 instead of Na2CO3
as the second Brønsted base provided a mixture of N-alkyl cab-
azole 3al and 9H-carbazole (5a).[22,23] A modification of the re-
action conditions identified that employment of KN(SiMe3)2 at
1208C for the second step resulted in the exclusive formation
Scheme 5. Scope of the synthesis of N-H carbazoles 5. [a] At 1208C for the
first step. With 6.0 equiv of KN(SiMe3)2 for the second step. Isolated as the
N-Boc carbazole after the N-protection with Boc2O.
By taking advantage of the generation of carbazolide anion
in situ, we also demonstrated the one-pot conversion of carba-
zolide anion C toward various carbazoles containing different
N-substituents from 2,7-diphenyldibenzothiophene dioxide 1c
(Scheme 6). Carbazolide anion C was prepared by the reaction
of 1c with amine 2l under the same LiN(SiMe3)2/KN(SiMe3)2
system in Scheme 5. Treatment of carbazolide anion C with 2-
fluoropyridine in the same pot induced an intermolecular SNAr
reaction, providing N-(2-pyridyl) carbazole 6 which is an attrac-
tive scaffold as organic light emitting diodes.[26] Of note is that
the synthesis of carbazole 6 has not been achieved by means
of our previous synthesis of N-aryl carbazoles from the reaction
Scheme 4. Divergent synthesis of (i) 9-phenethyl-9H-carbazole (3al) and
(ii) 9H-carbazole (5a).
Scheme 6. One-pot syntheses of carbazoles 6 and 7 from 1c with amine 2l.
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of dibenzothiophene dioxides with anilines using KN(SiMe3)2
because of the low nucleophilicity of 2-aminopyridine.[13b] Fur-
thermore, a one-pot addition of Boc2O to carbazolide anion C
successfully gave N-Boc carbazole 7 in 86% yield.
In conclusion, we have developed a practical method to pre-
pare structurally diverse N-alkyl carbazoles from dibenzothio-
phene dioxides with alkyl amines by twofold SNAr aminations.
The substitution process begins with intermolecular SNAr reac-
tion of dibenzothiophene dioxides with alkyl amines in the
presence of LiN(SiMe3)2, which is followed by intramolecular
SNAr cyclization promoted by KN(SiMe3)2 in a one-pot manner.
The method is also applicable to the cascade synthesis of N-H-
carbazoles by the one-pot removal of 2-phenethyl group from
N-(2-phenethyl) carbazoles. Further extensions of this SNAr-
based amination toward the synthesis of new p-conjugated
compounds are currently being studied in our group.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP16H04109, JP18H04254, JP18H04409, JP19H00895 and
JP18K14212. H.Y. thanks The Asahi Glass Foundation for finan-
cial support.
Conflict of interest
[11] J. A. Jordan-Hore, C. C. C. Johansson, M. Gulias, E. M. Beck, M. J. Gaunt,
J. Am. Chem. Soc. 2008, 130, 16184.
The authors declare no conflict of interest.
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Keywords: alkali metals
dibenzothiophene dioxides · nucleophilic aromatic substitution
·
amination
·
carbazoles
·
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[19] Comparison of two sets of reaction conditions [LiN(SiMe3)2/KN(SiMe3)2
or LiN(SiMe3)2/K2CO3] revealed that comparable yields of desired carba-
zoles 3ab, 3ac, 3ae, 3af, 3aj, 3ak, and 3ca were obtained by using
two different systems. On the other hand, the LiN(SiMe3)2/KN(SiMe3)2
system is superior to the LiN(SiMe3)2/K2CO3 one in terms of the reaction
efficiency for the intramolecular SNAr cyclization (LiN(SiMe3)2/KN(SiMe3)2:
2–3 h, LiN(SiMe3)2/K2CO3: 2–6 h). Hence, we mainly applied the LiN(-
SiMe3)2/KN(SiMe3)2 system to the investigation of the substrate scope.
See Schemes S2–S3 in the Supporting Information for the overview of
reaction outcomes.
[20] T. H. Lowry, K. S. Richardson in Mechanism and Theory in Organic
Chemistry, Harpercollins, New York 1987, pp. 377.
[21] H. G. Richey Jr., W. F. Erickson, J. Org. Chem. 1983, 48, 4349.
[22] See Table S3 in the Supporting Information for the detailed optimiza-
tion for the synthesis of 5a.
[23] The reaction of 1a with LiNH2 instead of amine 2l as a starting material
resulted in 25% yield of 5a probably owing to the low reactivity and
Manuscript received: August 27, 2019
Revised manuscript received: September 24, 2019
Accepted manuscript online: September 25, 2019
Version of record online: && &&, 0000
Chem. Eur. J. 2019, 25, 1 – 6
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ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
COMMUNICATION
&
Organic Synthesis
A. Kaga, K. Nogi, H. Yorimitsu*
&& – &&
Synthesis of N-Alkyl and N-H-
Carbazoles through SNAr-Based
Aminations of Dibenzothiophene
Dioxides
One-pot, two-fold SNAr aminations of
dibenzothiophene dioxides with alkyl
amines by using a LiN(SiMe3)2/
cascade synthesis of N-H-carbazoles
through concomitant removal of the 2-
phenethyl group from N-(2-phenethyl)-
carbazoles in a single operation (see
scheme).
KN(SiMe3)2 system have been developed
for the synthesis of diverse N-alkyl car-
bazoles. This protocol also enables the
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Chem. Eur. J. 2019, 25, 1 – 6
www.chemeurj.org
6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!