NH4PF6-promoted cyclodehydration of α-amino carbonyl compounds: Efficient synthesis of pyrrolo[3,2,1-ij]quinoline and indole derivatives

Article abstract of DOI:10.1039/c4ra11168k

NH₄PF₆ is an inexpensive, safe, and low-toxicity inorganic salt; it was found to promote the cyclodehydration of α-amino carbonyl compounds in the absence of metal reagents. This simple cyclodehydration strategy enables highly atom-e

Full text of DOI:10.1039/c4ra11168k

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NH4PF6-promoted cyclodehydration of a-amino
carbonyl compounds: efficient synthesis of pyrrolo-
[3,2,1-ij]quinoline and indole derivatives†
Cite this: RSC Adv., 2014, 4, 53837
Received 25th September 2014
Accepted 17th October 2014
*
*
Xiao-Ming Ji, Shu-Juan Zhou, Chen-Liang Deng, Fan Chen and Ri-Yuan Tang
DOI: 10.1039/c4ra11168k
www.rsc.org/advances
NH4PF6 is an inexpensive, safe, and low-toxicity inorganic salt; it was synthetic methods for pyrrolo[3,2,1-ij]quinolines preparation is
found to promote the cyclodehydration of a-amino carbonyl therefore urgent.
compounds in the absence of metal reagents. This simple cyclo-
Indoles, because of their wide-ranging biological activity,
dehydration strategy enables highly atom-economic formation of continue to promote numerous researchers to focus on efficient
pyrrolo[3,2,1-ij]quinoline and indole derivatives, which are significant synthetic methodologies.2a,13 Among indole synthesis, an
pharmacophores.
intriguing approach would start from an ortho-unsubstituted
anilines or mono-substituted arene, followed by direct cycliza-
tion with C–C or C–N bond formation to a C–H bond.13b This
type of approach includes Fischer indole synthesis,14 Bischler
indole synthesis,15 Hemetsberger indole synthesis,16 Nenitzescu
indole synthesis,17 Bartoli indole synthesis18 and et al. We
hypothesized that the Bischler reaction15 would provide a suit-
able pathway for the preparation of pyrrolo[3,2,1-ij]quinolines
and indoles, because the sole by-product is water, and a-amino
carbonyl compounds are readily prepared.19 An improved Bis-
chler reaction involves a microwave-assisted approach, which
allows one-pot synthesis of 2-arylindoles under solvent-free and
metal-free conditions, albeit with moderate yields.20 Metal
catalysts such as rhodium carbenoids,21 cationic iridium
complexes,22 Ru3(CO)12 (ref. 23) and Zn(TfO)2 (ref. 24) give
efficient indole synthesis via the Bischler reaction. However,
most of these metal reagents are expensive, which has limited
synthetic applications. Recently, a modied Bischler reaction
was developed for the preparation of N-aryl-2,3-disubstituted
indoles, although expensive and unstable arynes are used as
reaction partners.25 Based on previous reports of Bischler indole
synthesis,15,20–25 we strive to use eco-friendly reagents to
synthesize pyrrolo[3,2,1-ij]quinolines and indoles via the Bis-
chler reaction; this will contribute to sustainable development
in chemistry (Scheme 1). Here, we report a NH4PF6-promoted
Pyrrolo[3,2,1-ij]quinolines1 and indoles2 are important struc-
tural units, and are found in numerous pharmaceuticals and
natural products. Extensive studies have demonstrated that
pyrrolo[3,2,1-ij]quinolines are lead candidates for fungicides
active against rice blast disease,1d and in potential treatments
for asthma,1e epilepsy, and obesity.1f In addition, it has been
reported in numerous patents that pyrrolo[3,2,1-ij]quinoline is a
promising skeleton in drug development.3 Considerable efforts
have been devoted to the synthesis of pyrroloquinolines.4–12
Early reported methods generally suffer from drawbacks such as
harsh reaction conditions, limited substrate scope or low
yields.4 In the past decade, synthetic methodologies including
Michael-type annulations,5 free radical cyclizations,6 sigma-
tropic rearrangements7 and multicomponent reactions8 have
been used for pyrroloquinolines synthesis, albeit with narrow
substrate scope. Broader substrate scope can be achieved by
transition metal-catalyzed reaction. For instance, palladium- or
copper-catalyzed intramolecular cyclization of 8-alkynylated
tetrahydroquinolines,9,10 indium-catalyzed intramolecular Frie-
del–Cras annulations of modicated indoles,11 and zirconium-
catalyzed cycloaddition of tetrahydroquinoline hydrazines with
internal alkynes.12 However, these substrates require compli-
cated pre-functionalization. The development of efficient
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
Zhejiang, 325035, China. E-mail: try@wzu.edu.cn; fanchen@wzu.edu.cn; Tel:
+86-577-86689615
† Electronic supplementary information (ESI) available: Detailed condition
screening table, experimental details, and 1H and 13C NMR spectra of the
products. See DOI: 10.1039/c4ra11168k
Scheme 1 Green synthesis of pyrrolo[3,2,1-ij]quinolines.
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efficient method for the synthesis of pyrrolo[3,2,1-ij]quinolines dissolve NH4PF6, leading to amplifying the reactivity. In
and indoles by cyclodehydration of a-amino carbonyl contrast, other solvents, e.g., toluene, DCE, and DMF, did not
compounds in the absence of metals.
affect the reaction (Table 1, entries 7–9); while EtOH gave a
Major limitations in scaling up reactions arise from the use rather low yield (Table 1, entry 10). To further test the effect of
of corrosive acids and metal pollution, therefore we focused on HFIP, the reaction with NH4Cl or NH4OAc in HFIP was con-
using inorganic salts that are eco-friendly, readily post-treated, ducted, respectively; to our delight, both yields were enhanced
and compatible with functional groups to achieve the cyclo- to 75% (Table 1, entries 12 and 13). It was showed that addition
dehydration of a-amino carbonyl compounds. We reasoned that of 2 equiv. of H2O would slightly decrease the yield to 87%
ammonium salts would promote cyclodehydration because the (Table 1, entry 14). We next reduced the NH4PF6 loading and
+
NH4 cation can activate the carbonyl group.26,27 Based on this lowered the reaction temperature, respectively. Decreasing the
supposition, we used the cyclodehydration of 1a as the model NH4PF6 loading gave a lower yield (Table 1, entry 15), and the
reaction. NH4Cl, NH4OAc, and NH4PF6 were used to explore the yield at 90 ꢀC decreased to 69% (Table 1, entry 16). Several Lewis
reaction in CH3CN at 110 ꢀC (Table 1, entries 1–3). As expected, acids (FeCl3, ZnCl2, AlCl3, and AgOTf) and Brønsted acids (HCl,
the reaction occurred in the presence of NH4Cl or NH4OAc, H2SO4, AcOH, F3CCOOH, TsOH, and HPF6) were evaluated (see
giving the desired products in 8% and 10% yields, respectively the ESI†). In comparison with NH4PF6, these reagents showed
(Table 1, entries 1 and 2). Under the NH4PF6-promoted reaction poor reactivity and gave low yields. Control reactions, in the
conditions, the yield increased to 56% (Table 1, entry 3). We absence of NH4PF6, were conducted in CH3CN and HFIP,
then attempted to improve the reactivity by using the more respectively. No reaction occurred in CH3CN, which suggested
soluble (n-Bu)4NPF6. However, only a 12% yield was obtained that ammonium salts were crucial for the reaction (Table 1,
À
(Table 1, entry 4). We speculated that the PF6 anion may be entries 1–3 and 17); interestingly, a 48% yield was obtained in
crucial for the reaction, therefore we investigated KPF6 and HFIP without NH4PF6 (Table 1, entry 18), which demonstrated
AgPF6 in the reaction, respectively. No target product was that the unique solvent effect of HFIP may decrease the reaction
obtained in the reaction with KPF6 or AgPF6 (Table 1, entries 5 energy barrier, thus facilitating the cyclodehydration under
and 6). In terms of the solvent effect, 1,1,1,3,3,3- 110 ꢀC. Moreover, HFIP can act as an acid to promote the
hexauoropropan-2-ol (HFIP) signicantly enhanced the reac- reaction. Finally, we found that a combination of NH4PF6 as the
tivity of NH4PF6, affording the target product in 95% yield promoter and HFIP as the solvent, at 110 ꢀC, gave the best yield.
(Table 1, entry 11). HFIP, as a strong polar solvent, may help to
With this new Bischler reaction procedure in hand, the scope
of a-amino carbonyl compounds tolerated was investigated
(Table 2). Substituents such as Me, MeO, Br, Cl, F, CN, and CF3
groups on the aromatic ring of the 1-arylethanone moiety are
tolerated well under the standard conditions (products 2b–2i);
for example, substrate 1b, which has a methyl group, gave a
high yield of 2b (92%). The presence of a MeO group on
substrate 1c was tolerated, providing the corresponding product
2c in 78% yield. Halo-substituted substrates also gave good
yields, these are synthetically useful for further modications,
because of the diverse reactivities of halo groups (products 2d–
2g). These results showed that different halo-substituted
substrates had similar reactivity (products 2d–2g). For
example, the para- and meta-uoro-substituted substrates
almost had the same yields (products 2f and 2g). Reactions of
substrates with electron-withdrawing groups such as cyano and
triuoromethyl were also carried out, affording the corre-
sponding products 2h and 2i in 53% and 78% yields, respec-
tively. A diuoro-substituted substrate had better reactivity,
giving the desired product 2j in 92% yield. Despite the steric
hindrance effect of the naphthalene, substrate 1k underwent
cyclodehydration smoothly to afford the target product 2k in
72% yield. The benzofuran moiety, which is a useful pharma-
cophore, was tolerated, providing the corresponding product 2l
in 72% yield. An alkyl ketone showed excellent reactivity in the
reaction, affording the desired product 2m in 92%. An a-amino
ester performed smoothly under the optimal conditions
(product 2n), enabling further modications that are important
for the preparation of diverse pyrrolo[3,2,1-ij]quinolines.
Substituted tetrahydroquinolines were also investigated to test
the scope (products 2o–2q). 2-Methyl and 6-methyl substituted
Table 1 Screening of optimal conditionsa
Entry
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
NH4Cl
NH4OAc
NH4PF6
(n-Bu)4NPF6
KPF6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DCE
DMF
EtOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
CH3CN
HFIP
8
10
56
12
0
AgPF6
0
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4Cl
NH4OAc
NH4PF6
NH4PF6
NH4PF6
—
Trace
Trace
0
9
10
11
12
13
14c
15d
16e
17
18
24
95
75
75
87
72
69
0
—
48
a
Reaction conditions: 1a (0.2 mmol), additive (0.4 mmol, 2 equiv.) in
b
c
solvent (2 mL) at 110 ꢀC for 24 h. Isolated yields. H2O (2 equiv.)
was added. d NH4PF6 (0.2 mmol, 1 equiv.). e At 90 ꢀC.
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Table 2 NH4PF6-promoted synthesis of pyrrolo[3,2,1-ij]quinolinesa
Table 3 NH4PF6-promoted synthesis of indolesa
a
a
Reaction conditions: 1 (0.2 mmol), NH4PF6 (0.4 mmol, 2 equiv.) in
Reaction conditions: 1 (0.2 mmol), NH4PF6 (0.4 mmol, 2 equiv.) in
HFIP (2 mL) at 110 ꢀC for 24 h.
HFIP (2 mL) at 110 ꢀC for 24 h.
yield. The poor yield resulted from partial decomposition and
low conversion rate of substrate 3h. It is worth noting that a
yield of 71% was obtained in the reaction of substrate 3i, which
has an ester group. To further test the scope of this protocol,
compounds with Me, MeO, Cl, and Br substituents on the
aromatic ring of aniline were evaluated for the reaction; and the
corresponding products were obtained in yields of 65–87% (4j–
4n). Finally, the effect of protecting group on nitrogen atom was
examined. Benzyl protected aniline gave a good yield of 85%
(product 4o). Unfortunately, unprotected aniline 3p was
decomposed under standard conditions, only a large amounts
of N-methylaniline was observed on GC-MS (product 4p).
To test their potential in large scale synthesis, the reactions
of 1a and 3a were conducted at 0.502 g (2 mmol) and 0.45 g (2
mmol) scales, respectively, giving 2a and 4a in 85% and 84%
yields, respectively (Scheme 2). Additionally, HFIP is readily
recovered by distillation, because its boiling point is 59 ꢀC.
These results suggest that the newly established reaction system
has potential for industrial applications.
tetrahydroquinolines proceeded smoothly to give the target
product in good yields (products 2o and 2p). To our delight,
substrate 1q with two methyl group at the 2-position of tetra-
hydroquinoline also performed well, giving the target product
in 76% yield (product 2q).
Having demonstrated the efficiency of NH4PF6 in the
synthesis of pyrrolo[3,2,1-ij]quinolines, we investigated whether
this approach was generally applicable to the synthesis of
indoles. A wide range of a-amino carbonyl compounds 3 (Table
3, products 4a–4p) were subjected to the optimal conditions.
The cyclodehydration of 3a in HFIP gave product 4a in 93%
yield. Substituents such as Me, MeO, Cl, Br, and CF3 were
compatible with the optimal conditions, providing the corre-
sponding products 4b–4f in moderate to high yields. Impor-
tantly, chlorinated and bromated arenes on a-amino carbonyl
compounds 3 were well tolerated, facilitating possible further
modications at the halogenated positions (4d and 4e). Cyclo-
dehydration of the diuoro-substituted substrate 3g proceeded
smoothly to afford the expected product 4g in 73% yield.
Substrate 3h, which has a benzofuran motif, also underwent
cyclodehydration to yield the corresponding product 4h in 47%
According to the classical Bischler reaction mechanism15
and the present results, possible reaction pathways were
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Notes and references
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Scheme 2 Reaction scale up.
Scheme 3 Possible reaction pathways.
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+
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vate the carbonyl that facilitates the Friedel–Cras cyclization to
produce an intermediate A and NH3$H2O.26,27 The intermediate
A undergoes a dehydration process to give an intermediate C,
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Acknowledgements
We gratefully acknowledge the NSFC (no. 21202121 and
21272178) and Wenzhou University (no. wzucy034) for nancial
support.
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¨
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