Indium-Catalyzed Formal N-Arylation and N-Alkylation of Pyrroles with Amines

Article abstract of DOI:10.1002/adsc.201600656

Under indium Lewis acid catalysis, a nitrogen atom of N-unsubstituted pyrroles was replaced with a nitrogen atom of primary amines, thereby producing N-aryl- and N-alkylpyrroles. This system formally introducing such carbon frameworks to the pyrrole nitrogen atom shows unique selectivity: only the H?N(pyrrolyl) unit undergoes the N-arylation and N-alkylation even in the coexistence of a similar H?N(indolyl) part; and an aryl–halogen bond remains intact. These are clearly different from the typical method depending on the C?N(pyrrolyl) bond-forming reaction with organic halides as substrates. From a viewpoint of pyrrole N-protection–deprotection chemistry, worth noting is that a methyl group on the pyrrole nitrogen atom can be removed, albeit in a formal way. (Figure presented.).

Full text of DOI:10.1002/adsc.201600656

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DOI: 10.1002/adsc.201600656
Indium-Catalyzed Formal N-Arylation and N-Alkylation of
Pyrroles with Amines
Kyohei Yonekura,a Kenji Oki,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@meiji.ac.jp
Received: June 22, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600656.
Abstract: Under indium Lewis acid catalysis, a nitro-
gen atom of N-unsubstituted pyrroles was replaced
with a nitrogen atom of primary amines, thereby
producing N-aryl- and N-alkylpyrroles. This system
formally introducing such carbon frameworks to the
pyrrole nitrogen atom shows unique selectivity:
by transition metal (T.M.) catalysis[5] or by nucleophil-
ic substitution under strongly basic conditions
(SNAr).[6] Alkyl halides are the prime candidates used
for the base-promoted SN2-based N-alkylation.[7]
ꢀ
Other N(pyrrolyl) C bond-forming protocols are also
used occasionally for preparing N-alkylpyrroles.[8,9,10]
Recently, we have disclosed that an indium salt can
activate a heteroaryl ring via forming an indium–het-
eroaryl p-complex, in which the heteroaryl unit
changes its electronic character from originally nucle-
ophilic to electrophilic to react with other heteroaryls
for heteroaryl–heteroaryl bond formation.[11] We envi-
sioned that the indium–heteroaryl p-complex would
be the seed to develop a new strategy for synthesizing
N-aryl- and N-alkylpyrroles. Our working hypothesis
is thus the following: the pyrrole ring coordinating to
an indium salt might have electrophilicity capable of
ꢀ
only the H N(pyrrolyl) unit undergoes the N-aryla-
tion and N-alkylation even in the coexistence of
ꢀ
a similar H N(indolyl) part; and an aryl–halogen
bond remains intact. These are clearly different
ꢀ
from the typical method depending on the C
N(pyrrolyl) bond-forming reaction with organic hal-
ides as substrates. From a viewpoint of pyrrole N-
protection–deprotection chemistry, worth noting is
that a methyl group on the pyrrole nitrogen atom
can be removed, albeit in a formal way.
Keywords: amines; chemoselectivity; heterocycles;
indium; Lewis acids
Pyrroles with carbon frameworks of aryl and alkyl
groups on the nitrogen atom represent key structural
motifs in natural products,[1] biologically and pharma-
cologically active molecules,[2] functional materials,[3]
and ligands for transition metal catalysis.[4] Such im-
portance has consistently stimulated the development
of new synthetic methods for N-aryl- and N-alkylpyr-
roles. Among the strategies disclosed so far, synthesis
of the N-substituted pyrrole starting from a pyrrole
appears to be the most straightforward and, in fact,
a large number of relevant reports have emerged in
the literature. However, the focus of their studies is
exclusively on introducing the aryl and alkyl units to
ꢀ
the pyrrole nitrogen atom, thus being an N(pyrrolyl)
C bond-forming reaction (Scheme 1). For example,
aryl halides and aryl metals have been used most fre-
Scheme 1. Synthesis of N-aryl- and N-alkylpyrroles from N-
unsubstituted pyrroles: previous approach vs. our approach.
quently for the N-arylation, which is achieved mainly In=an indium salt.
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Table 1. Lewis acid-catalyzed formal N-4-butylphenylation
accepting nucleophilic attack of amines, and the N-
substituted pyrrole might be formed through a se-
quence of opening and closing of the pyrrole ring, just
like a retro-version of the well-known Paal–Knorr
pyrrole synthesis (Scheme 1).[12,13] This approach in-
cludes the process of exchanging each nitrogen atom
between pyrroles and amines, and is thus distinctly
different from the previous strategies to utilize the
carbon atom as a reaction site. The superior aspect of
this nitrogen–nitrogen exchange reaction is that the
molecular weight of the by-product is 17 of NH3,
which is smaller than those of hydrogen halides and
metal salts co-produced in the previous systems.
Herein, we disclose a new synthetic protocol for N-
aryl- and N-alkylpyrroles from pyrroles and amines,
on the basis of the nitrogen–nitrogen exchange strat-
egy. To the best of our knowledge, only one study
probably via the same route has been reported, but
its substrate scope is narrow.[14]
Initially, we examined suitable reaction conditions
for the reaction of pyrrole (1a) with 4-butylaniline
(2a) (Table 1). Treating a 1:2 mixture of 1a and 2a
with In(OTf)3 (30 mol%, Tf=SO2CF3) in 1,4-dioxane
at 1208C for 24 h gave N-(4-butylphenyl)pyrrole (3aa)
in 42% yield (entry 1). The use of other metal triflates
lowered the reaction rate and thus resulted in no im-
provements of the yield (entries 2–9). Replacing OTf
on the indium metal with NTf2 delivered 3aa in
a higher yield, while ONf (Nf=SO2C4F9) and Cl were
unsuitable ligands (entries 10–12). With a Brønsted
acid, HNTf2, as a catalyst, a significantly lower reac-
tion efficiency based on the yield/conversion ratio was
observed, due to the formation of considerable
amounts of unidentified products,[15] indicating that
a Lewis acid is a superior catalyst for this reaction
(entry 13). Switching the solvent 1,4-dioxane to other
ethereal and aromatic solvents afforded 3aa in com-
parable yields, but slightly decreased the reaction effi-
ciency (entries 14–17). The prolonged reaction time
increased the yield to 57% with complete consump-
tion of 1a (entry 18). Other than the conditions in 1,4-
dioxane, the solvent-free system with 6 molar equiva-
lents of 2a is also available, and was found to be more
effective, giving 3aa in 70% yield (entry 19). Here
again, extending the reaction period from 24 to 36 h
of pyrrole with 4-butylaniline.[a]
En-
try
Lewis
acid
Solvent
Conv. of
Yield of
1a [%][b]
3a [%][c]
1
2
3
4
5
6
7
8
In(OTf)3
Y(OTf)3
Nd(OTf)3
Sm(OTf)3
Fe(OTf)3
Cu(OTf)2
AgOTf
Zn(OTf)2
Bi(OTf)3
In(NTf2)3
In(ONf)3
InCl3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Bu2O
89
29
21
42
76
74
51
22
73
85
76
9
94
96
90
94
97
>99
89
98
98
>99
82
79
8
42
17
10
26
34
31
24
3
31
53
33
<1
29
50
48
54
52
57
70
86
73
21
42
52
<1
9
10
11
12
13
14
15
16
17
18
19
20
21[e]
22[f]
23
24
25
HNTf2
In(NTf2)3
In(NTf2)3
In(NTf2)3
In(NTf2)3
In(NTf2)3
In(NTf2)3
In(NTf2)3
In(NTf2)3
In(NTf2)3[g]
In(NTf2)3[g]
In(NTf2)3
none
DEE[d]
p-xylene
PhCl
1,4-dioxane
none
none
none
none
none
none
1,4-dioxane
[a]
Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol for
entries 1–18 and 25, 1.2 mmol for entries 19–24), Lewis
acid (60 mmol), solvent (0.20 mL), reaction time (24 h for
entries 1–17, 19 and 25, 36 h for entries 18 and 20–23,
48 h for entry 24).
[b]
[c]
[d]
[e]
[f]
Determined by GC.
1
Determined by H NMR.
DEE=1,2-diethoxyethane.
Performed in the presence of 3ꢁ MS (20 mg).
Performed in the presence of TsOH (0.20 mmol).
20 mol% of In(NTf2)3 were used.
[g]
raised the yield to 86% (entry 20). With the intention Besides simple pyrrole (1a), the nitrogen atoms of
of trapping NH3 as a possible by-product, which may Me-, Ph-, 4-FC6H4-, and 3-MeSO2C6H4-substituted
deactivate the Lewis acid In(NTf2)3, the process was pyrroles 1b–1g were successfully replaced with the ni-
performed in the presence of 3ꢁ molecular sieves trogen atom of 2a, giving N-4-butylphenylated pyr-
(3ꢁ MS) and TsOH (p-CH3C6H4SO3H), but no posi- roles 3ba–3ga in moderate to high yields. Different
tive effects were observed (entries 21 and 22). Lower- from the reaction of 1a, there were no significant gaps
ing the loading of In(NTf2)3 to 20 mol% made the re- in the yields of products by using methods A and B
action sluggish (entries 23 and 24). No 3aa was (3ba and 3ca). Accordingly, method A which allows
formed without a catalyst (entry 25).
the use of a smaller amount of 2 than that of method
With the conditions performed in 1,4-dioxane as B was primarily selected hereafter. Simple and other
method A and the solvent-free conditions as method substituted anilines also participated well in this strat-
B, we explored the scope of the reaction (Table 2). egy. In the reaction of phenylenediamines with two
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Table 2. Indium-catalyzed formal N-arylation of pyrroles
with arylamines.[a]
Scheme 2. Indium-catalyzed formal N-arylation of 2,5-dime-
thylpyrrole with p-phenylenediamine.
1208C for 48 h to give mono-pyrrolylarene 3ce in
91% yield exclusively. On the other hand, the solvent-
free reaction with higher loadings of 1c and In(NTf2)3
provided dipyrrolylbenzene 3ce’ as a major product.
The results obtained with ortho-substituted anilines
2d and 2f in Table 2 imply that our method is likely
to be sensitive to steric demands (3cd and 3bf). The
hydroxyethyl moiety caused no troublesome side re-
actions of dehydration[16] and condensation[17] (3cg).
Importantly, the C(sp2)–halogen bonds remained
intact under the conditions, thus 3ch and 3ci were
produced safely.[18] Worthy of note is that the chemo-
selective introduction of the aryl unit onto the pyrrole
ring is achievable under the coexistence of the indole
ring (3cj and 3hc).[19] The compatibility of the C(sp2)–
halogen bond and the pyrrole-selective N-arylation
are unique aspects which are distinctly different from
ꢀ
the general C N(pyrrolyl) bond-forming reac-
tion.[5,6b–e]
This indium process is equally applicable to the cor-
responding N-alkylation with alkylamines (Table 3).
Thus, linear and branched alkylamines reacted with
methyl-substituted pyrroles to afford the correspond-
ing N-alkylpyrroles 3ck and 3bl. With benzyl-type
amines (2m and 2n), no N-debenzylation of products
3am, 3cm and 3bn occurred even under the heating
Lewis acidic conditions.[20] With respect to (S)-3bn,
the configuration of the chiral center was retained
without any loss of the optical purity. The alkenyl
moiety is capable of surviving without undergoing hy-
droamination under Lewis acid catalysis (3co).[21]
Here again, the alkyl group is formally installed only
to the pyrrole ring (3cp).
[a]
Reagents for method A:
0.80 mmol), In(NTf2)3
1
(0.20 mmol),
2
(0.40–
(10–60 mmol),
1,4-dioxane
(0.20 mL). Reagents for method B: 1 (0.20 mmol), 2
(1.2 mmol), In(NTf2)3 (20 or 60 mmol). Yields of isolated
3 based on 1 are shown here. The methods used are
shown in parentheses. Further details on reaction condi-
tions for each reaction are given in the Supporting Infor-
mation.
amino groups, the single pyrrole ring formation pro-
This system is practically carried out on a prepara-
ceeded selectively (3ae, 3ce and 3bf), and then the re- tive scale. For example, under the conditions shown in
maining amino groups can be favorably utilized for Scheme 2, treating 1c with 2e on a 10 mmol scale pro-
further transformations as discussed later (see vided us with 1.80 g of 3ce in 95% yield.
Scheme 4). As shown separately in Scheme 2, the
To date, the Clauson–Kaas reaction has been uti-
preferential double pyrrole ring construction is also lized as one of the reliable methods for the synthesis
feasible by the appropriate choice of reaction condi- of N-aryl- and N-alkylpyrroles from primary amines
tions. Thus, 1c and 2e mixed in a 1:2.5 ratio were as nucleophiles, but is limited actually to preparing
treated with In(NTf2)3 (5 mol%) in 1,4-dioxane at the N-substituted pyrrole without any substituent on
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Table 3. Indium-catalyzed formal N-alkylation of pyrroles
with alkylamines.[a]
Scheme 3. Indium-catalyzed formal N-demethylation of
1,2,5-trimethylpyrrole.
proceeded with a relatively high reaction efficiency
(21% yield of 1c/29% conversion of 1c–Me), albeit
slowly (Scheme 3). The reaction rate must be im-
proved, but this is the first example showing that the
methyl group can be removed from the pyrrole nitro-
gen atom, to the best of our knowledge.
The utility of this reaction can be enhanced by
transforming the products synthesized here into other
structural motifs.
We first focused on synthetic applications of the re-
maining NH2 group of 3ce and 3bf (Scheme 4). For
example, the aerobic oxidative homocoupling of 3ce
under copper catalysis led to the formation of an azo
structure,[23] which is of importance as dyes[24] and
photoswitching materials.[25] In fact, product 4 was ob-
tained as an orange solid absorbing visible light with
a wavelength of around 450 nm. Moreover, treating
3bf with benzaldehyde in the presence of AcOH gave
a 70% yield of 5, consisting of a tricyclic 4,5-dihydro-
pyrrolo[1,2-a]quinoxaline,[26,27] the framework of
which is, for instance, found in an anti-obesity
agent,[28] an agent for reducing the size of cysts,[29] and
also serves as a tunable and regenerable biomimetic
[a]
Reagents: 1 (0.20 mmol), 2 (0.40 mmol), In(NTf2)3 (20 or
40 mmol), 1,4-dioxane (0.20 mL). Yields of isolated 3
based on 1 are shown here. Further details on the reac-
tion conditions for each reaction are given in the Sup-
porting Information.
Performed using method B with 1a (15 equiv.) to 2m
(0.20 mmol). Isolated yield of 3am based on 2m is shown
[b]
here.
the carbon atom of the pyrrole ring, due to the use of, hydrogen source.[30]
albeit inexpensive, 2,5-dimethoxytetrahydrofuran as
ꢀ
The C Br bond of 3ci is also available for further
an electrophile.[22] Our protocol which is capable of C N bond elongation, based on the Ullmann–Gold-
ꢀ
offering both the C-substituted and C-unsubstituted berg
reaction
as
improved
by
Buchwald
pyrroles would thus be advantageous over the con- (Scheme 5).[31] Thus, 6a with the C N(indolyl) bond
ꢀ
ꢀ
ventional reaction.
or 6b with the C N(pyrrolidonyl) bond was prepared
In pyrrole chemistry, the proper choice of a protect-
ing group on the nitrogen atom is one of the signifi-
cant aspects of performing subsequent transforma-
tions successfully.[20] Although there are a number of
options, an electron-donating protecting group will be
required when using the pyrrole ring itself as a nucleo-
phile, as in the electrophilic aromatic substitution
(SEAr). In this context, if the methyl group is avail-
able, it will be the smallest electron-donating protect-
ing group, thus being able to minimize the mass quan-
tity of deprotected waste. However, such treatment
ꢀ
has no precedent since no method for cleaving Me
N(pyrrolyl) bonds is available. Accordingly, we pre-
liminarily tried to apply our nitrogen–nitrogen ex-
change strategy to the N-demethylation. Thus, 1,2,5-
trimethylpyrrole (1c–Me) as a model substrate was
treated with ammonium acetate (NH4OAc) as an am-
monia source under the conditions of method A and,
Scheme 4. Synthetic applications of N-(aminophenyl)pyr-
to our delight, we found that the reaction to give 1c roles.
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Scheme 7. A trapping experiment for evolved NH3 gas.
XPhos=2-(dicyclohexylphosphino)-2’,4’,6’-triisopropyl-1,1’-
biphenyl.
Scheme 5. Copper-catalyzed Ullmann–Goldberg reaction of
3ci.
Scheme 8 shows possible routes, based on some exper-
imental results and information demonstrated here
and previously by us and others. First up is the coordi-
under the conditions [a] or [b], respectively.[32] There- nation of pyrrole 1 to the indium Lewis acid (In) to
fore, combining our strategy and T.M. catalysis ena- afford p-complex 9,[11] the a-carbon of which can be
bles the stepwise installation of different nitrogen het- electrophilic to react with amine 2. After protonation
ꢀ
erocycles onto one aromatic ring, since our strategy is of the resulting C In bond to give enamine 10 that
independent of activating the C–halogen bond when isomerizes to the more stable imine form 11,[35] path
ꢀ
making the C N(pyrrolyl) bond.
a and b might be possible. In path a, indium-induced
Some pieces of experimental evidence are available ring-opening of 11 and ring-closing of 12a, both of
for the mechanistic understanding. First, in order to which are accompanied by proton migration, give 13
confirm whether the present reaction involves the ex- (R=H in path a). The last stage is the elimination of
change of each nitrogen atom between pyrroles and ammonia from 13 to afford 3. On the other hand,
amines, the formal N-phenylation using 15N labeled path b includes the attack of another molecule of 2 to
aniline (15N-2b) was performed. On treatment of 1c 11, as the difference from path a. The resulting 14
with 15N-2b under the standard reaction conditions, leads to 13 and then 3 via the ring-opening and ring-
the corresponding 15N labeled N-phenylpyrrole (15N- closing sequence, as similar to path a (R¼H in path
3cb) was obtained (Scheme 6). From a mechanistic b). Importantly, the reaction pathway proposed here
point of view, this result importantly indicates that
the a-carbon atoms of the pyrrole substrate partici-
ꢀ
pate as reaction sites in the stage of the N C bond
formation. Moreover, a trapping experiment of NH3
was conducted (Scheme 7). Thus, the palladium-cata-
lyzed Buchwald–Hartwig amination of 2-bromonaph-
thalene (7) was carried out for capturing the NH3 gas
that could be evolved from the reaction of 1c with
2a.[33] As expected, tris(2-naphthyl)amine (8) was ob-
tained in 35% yield. The rather low yield is due in
part to competitive etherification of 7 reacting with
NaO-t-Bu used as a base,[34] but this result clearly
shows that NH3 is generated in situ in our system.
Although further investigation should be necessary
to clarify the mechanistic aspects of this reaction,
Scheme 8. Proposed reaction mechanisms. In=In(NTf2)3. R
(italic)=H in path a. R (italic)¼H in path b.
Scheme 6. An 15N labeled experiment.
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The combined organic layer was washed with brine (5 mL)
and then dried over anhydrous Na2SO4. Filtration and evap-
oration of the solvent followed by column chromatography
on silica gel (n-hexane/EtOAc=4/1) gave 4-(2,5-dimethyl-
1H-pyrrol-1-yl)benzenamine (3ce); yield: 1.80 g (95%).
appears to closely resemble that of the Zincke reac-
tion, where the nitrogen–nitrogen exchange reaction
between the Zincke salt [N-(2,4-dinitrophenyl)pyridi-
nium chloride] and amines through the ring-opening
and ring-closing sequence is involved as the key
stage.[36] Accordingly, considering that p-complex 9 in
the present reaction behaves like the Zincke salt in
the Zincke reaction, the proposed mechanism should
be rationally understood. The proposed mechanism
should also support the experimental observation that
the indole ring undergoes no nitrogen–nitrogen ex-
change reaction, probably because, in the indole case,
hypothetical intermediate 12c corresponding to 12a in
the pyrrole case has an unfavorable form of dearoma-
tization (Scheme 9).
Acknowledgements
We greatly appreciate Dr. Motonari Sakai, Dr. Go Hirai, and
Prof. Dr. Mikiko Sodeoka at RIKEN, Japan, for their helpful
support in measurement of optical rotations.
References
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Scheme 9. An unfavorable indole case.
In summary, we have developed the formal N-ary-
lation and N-alkylation of pyrroles with amines with
the aid of the Lewis acid catalyst of indium. Since the
concept of this reaction depending on the nitrogen–
nitrogen exchange strategy is totally different from
ꢀ
the general strategy adopting the C N(pyrrolyl) bond
formation, unique reaction site selectivity was ob-
ꢀ
ꢀ
served: an H N(indolyl) bond and a C halogen bond
are compatible with this system. The N-demethylation
of the N-methylpyrrole should be also remarkable. In
terms of the promotion of sustainable chemistry, the
lower molecular weight of the by-product is also an
advantage of this method. Further studies on the
mechanistic details are in progress in our laboratory.
Experimental Section
Synthesis of 3ce on a 10 mmol Scale
In(NTf2)3 (479 mg, 0.501 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. 1,4-Dioxane (5.0 mL) was added, and the
mixture was stirred at room temperature for 3 min. To this
were added 2,5-dimethylpyrrole (964 mg, 10.1 mmol) and p-
phenylenediamine (2.70 g, 25.0 mmol) in that order, and the
resulting mixture was then stirred at 1208C for 48 h. A satu-
rated NaHCO3 aqueous solution (2.5 mL) was added, and
the aqueous phase was extracted with EtOAc (50 mLꢂ3).
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X.-T. Li, R.-H. Hu, S.-Q. Han, Synthesis 2015, 47, 1913–
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lyzed coupling reaction of aryl halides with nitrogen
nucleophiles including pyrroles. Under the reaction
conditions [a] and [b], the coupling reactions of 2,5-di-
methylpyrrole (1c) with 1,3-dibromobenzene (15a) or
3-bromoiodobenzene (15b) were conducted, but 3ci
was not produced in a reasonable yield in any of the
cases, thus showing that our strategy would be superior
for the synthesis of N-(haloaryl)pyrroles. These compa-
rative experiments were carried out on the basis of the
literature methods. For the reaction conditions [a]:
a) J. C. Antilla, J. M. Baskin, T. E. Barder, S. L. Buch-
wald, J. Org. Chem. 2004, 69, 5578–5587; for the reac-
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[18] In accordance with the comment of one reviewer, the
ꢀ
synthesis of 3ci based on the N(pyrrolyl) C bond-form-
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ing strategy was attempted, and thus carried out under
the conditions of the Ullmann–Goldberg reaction
which has been known traditionally as the copper-cata-
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Indium-Catalyzed Formal N-Arylation and N-Alkylation of
Pyrroles with Amines
9
Adv. Synth. Catal. 2016, 358, 1 – 9
Kyohei Yonekura, Kenji Oki, Teruhisa Tsuchimoto*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!