Construction of CF3-containing tetrahydropyrano[3,2- b]indoles through DMAP-catalyzed [4+1]/[3+3] domino sequential annulation

Article abstract of DOI:10.1021/acs.orglett.0c02164

A [4+1]/[3+3] domino sequential annulation reaction of o-aminotrifluoroacetophenone derivatives and β′-acetoxy allenoates enabled by DMAP has been reported. A variety of CF3-containing tetrahydropyrano[3,2-b]indoles were obtained as a single diastereomer in high yields (≤98%) under mild conditions. The reaction can build one C-N bond, one C-C bond, and one C-O bond sequentially in a single step. The synthetic utility was demonstrated with gram-scale reactions and various transformations of the products.

Full text of DOI:10.1021/acs.orglett.0c02164

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Letter
Construction of CF3‑Containing Tetrahydropyrano[3,2‑b]indoles
through DMAP-Catalyzed [4+1]/[3+3] Domino Sequential
Annulation
Yannan Zhu and You Huang*
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ABSTRACT: A [4+1]/[3+3] domino sequential annulation reaction of o-aminotrifluoroacetophenone derivatives and β′-acetoxy
allenoates enabled by DMAP has been reported. A variety of CF3-containing tetrahydropyrano[3,2-b]indoles were obtained as a
single diastereomer in high yields (≤98%) under mild conditions. The reaction can build one C−N bond, one C−C bond, and one
C−O bond sequentially in a single step. The synthetic utility was demonstrated with gram-scale reactions and various
transformations of the products.
he pyranoindole skeletons are of great importance
because of their wide distribution in classic human
drugs that have diverse pharmacological properties (Figure 1).
of simple and efficient synthetic methods for the synthesis of
heterocycles containing CF3 is important.
T
Since the pioneering work of Lu,5 Lewis base-catalyzed
annulation reactions of allenes have shown their capability in
the construction of different ring system carbo- and hetero-
cycles.6 Among these cyclization reactions, nucleophilic
phosphine catalysis has proven to be one of the most practical
and powerful in domino annulation reactions,7 and multiple
rings can be constructed in a one-step reaction to generate
molecules that are structurally diverse and complex.8 In
contrast, amines are generally less nucleophilic than similarly
substituted phosphines;9 therefore, tertiary amine-catalyzed
domino annulations are relatively rare,10 and most of them can
construct only a single ring in one step. In 2010, β′-acetoxy
allenoate 2a was disclosed by Tong;11 after the phosphine
attack, the acetate group at the β′ position undergoes SN2′
displacement, creating electrophilic phosphonium diene A,
whose γ and β′ positions can be attacked by nucleophiles and
complete the subsequent cyclization reactions (Scheme 1a).12
Similarly, under the catalysis of tertiary amines, the
Figure 1. Examples of pharmaceuticals featuring pyranoindoles and
CF3-containing heterocyclic scaffolds.
For example, as a best-selling anti-inflammatory drug, Etodolac
containing a pyranoindole core is widely used in the clinical
treatment of arthritis and acute pain.1 On the contrary, the
introduction of fluorine-containing groups into drug molecules
can improve molecular properties,2 such as metabolic stability,
lipophilicity, and permeability, and their interaction with
biological targets, which has gradually become a common
method for drug screening. Among them, CF3-containing
heterocycles have become some of the most promising
fragments for drug molecules.3 For example, Efavirenz, a
molecule with a trifluoromethyl group in a heteroaliphatic ring,
is a non-nucleoside reverse transcriptase inhibitor used in the
treatment of patients with HIV.4 Therefore, the development
Received: June 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02164
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Design Plan for the Lewis Base-Catalyzed
Domino Annulation
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
base (equiv)
solvent
yield (%)
dr
1
2
3
4
5
6
7
8
PPh3
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Na2CO3 (1.2)
K2CO3 (1.2)
Et3N (1.2)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
acetone
THF
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
0
0
44
0
−
−
>20:1
−
DABCO
DMAP
−
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
57
61
48
trace
45
28
35
11
64
73
68
58
48
71
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
CH3ONa (1.2)
−
9
10
11
12
13
14
15
16
17
18
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
d
e
d
d
d
,
,
,
f
g
h
corresponding electrophilic diene intermediate B can be
generated, but to date, all nucleophiles are additions to its β′
position (Scheme 1a).13 There has been no report on the
addition of nucleophiles to the γ position of intermediate B, for
there is no empty orbital in the ammonium ion of intermediate
B to stabilize the carbon anion in the subsequently generated
ammonium ylide (Scheme 1b).14 To overcome the limitations,
and on the basis of our group’s previous work in the
exploration of novel reaction modes of β′-acetoxy allenoate15
and sequential annulations in organocatalysis to construct the
polycycles,16 we envisioned that the DMAP (4-dimethylami-
nopyridine) would provide a π-system and make it a more
stable corresponding ylide intermediate through a p-π
conjugation between the carbon anion and the aromatic ring
of DMAP. Herein, we sought to use o-aminotrifluoroaceto-
phenone derivatives as electron donor−acceptor compounds
to realize a DMAP-catalyzed [4+1]/[3+3] domino annulation
for the efficient formation of a CF3-containing
tetrahydropyrano[3,2-b]indole system (Scheme 1c). One C−
N bond, one C−C bond, and one C−O bond were
sequentially built in a single step. To the best of our
knowledge, the introduction of CF3 unit into pyranoindoles
remains a blank field.
To examine the feasibility of the envisaged domino reaction,
we chose o-aminotrifluoroacetophenone derivative 1a and
allenoate 2a as the model substrates to optimize this reaction
in chloroform at room temperature in the presence of Cs2CO3.
We initiated our research by examining various Lewis bases as
catalysts (30 mol %). In the presence of PPh3 or tertiary amine
DABCO, no desired product 3aa was observed (Table 1,
entries 1 and 2). To our delight, DMAP was found to be an
effective catalyst, furnishing product 3aa in 44% yield with
>20:1 dr (Table 1, entry 3). The blank control experiment
showed that without DMAP as a catalyst, the desired
cyclization process could not be achieved (Table 1, entry 4).
We further investigated a range of inorganic and organic bases
(entries 5−8). It was established that the utility of K2CO3
enhanced the yield of 3aa to 61% (entry 6), and the yield was
also lower in the absence of a base (entry 9). The examination
of the solvent effect revealed that chloroform was the suitable
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol, 2.0 equiv),
catalyst (30 mol %), and base in 1.0 mL of the indicated solvent at
b
c
room temperature for 18 h. Isolated yield. Diastereoselectivity was
d
1
determined by H NMR spectroscopy. Solvent volume of 2.0 mL.
e
f
g
Solvent volume of 4.0 mL. With 1.5 equiv of 2a. Reaction carried
h
out at 0 °C. Reaction carried out at 40 °C.
medium for this transformation (Table 1, entries 10−12).
Then, the use of a lower base loading can slightly increase the
yield to 64% (Table 1, entry 13). Surprisingly, decreasing the
concentration of the system to 0.05 M provided a much
cleaner reaction, and the yield of 3aa was further improved to
73% (Table 1, entry 14). Finally, further decreasing the
reaction concentration, decreasing the amount of 2a, and
changing the reaction temperature did not provide better
results (Table 1, entries 15−18).
With the optimized reaction conditions in hand, the
substrate scope of allenoates was then tested (Scheme 2). In
addition to 3aa, electron-withdrawing (3ab) or electron-
donating (3ac) substituents at the ortho position of the phenyl
ring and heteroaryls such as 9-anthryl (3ah) and 1-naphthyl
(3ai) were all suitable for the reaction, and the corresponding
products were obtained as a single diastereomer (>20:1 dr) in
good to high yields (61−73%). The R substituent can also be a
diphenylmethyl group, delivering the desired product 3ak in
good yield. Apart from benzyl allenoates, allenoates containing
alkyl substituents were also suitable. The alkyl groups can be
linear (3ad and 3ae), branched (3af and 3ag), or aryl-bearing
(3aj and 3al), and the corresponding products were obtained
in good to excellent yields (64−98%) with excellent
diastereoselectivity (>20:1 dr). In addition, this methodology
is also amenable to the use of diphenylphosphine oxide 2m,
providing the corresponding product 3am in high yield. The
structure and stereochemistry of 3ag were unambiguously
characterized by single-crystal X-ray analysis.17
Subsequently, the scope of o-aminotrifluoroacetophenone
derivatives 1 was investigated (Scheme 3). Both electron-
donating and -withdrawing substituents could be installed at
the para position of the amino group of substrates 1, with the
B
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a
such as SMe, NMe2, and L-menthyl did not interfere with the
reaction efficiency (3ja−3la). Finally, variation of the phenyl
ring of the arylsulfone moiety and methanesulfonyl on the
amino group can also be tolerated, and products (3ma−3pa)
were obtained in 51−72% yields. Notably, only a single
diastereomer was observed in all cases.
Scheme 2. Substrate Scope for Reactions of 2 with 1a
To demonstrate the practical applicability of this domino
annulation, a gram-scale reaction of 1a was performed under
standard reaction conditions (Scheme 4). The reaction still
Scheme 4. Gram-Scale Synthesis and Further
Transformation of the Product
a
The reactions were carried out with 1a (0.1 mmol), 2 (0.2 mmol),
DMAP (30 mol %), and K2CO3 (0.1 mmol) in 2.0 mL of CHCl3 at
1
room temperature. Diastereoselectivity was determined by H NMR
spectroscopy.
a
Scheme 3. Substrate Scope for Reactions of 1 with 2a
smoothly proceeded to afford 3aa with an improved yield
(83%) and excellent diastereoselectivity. Subsequently, syn-
thetic transformations of product 3aa were conducted. As
shown in Scheme 4, epoxidation and dihydroxylation readily
converted 3aa into 4a and 4b in 46% and 80% yields,
respectively, with excellent diastereoselectivity. The structure
and stereochemistry of 4b were determined by single-crystal X-
ray analysis.18 Moreover, consequent hydrolysis/amidation of
3aa enabled the construction of amide 4c in 46% total yield.
Facile reduction of the ester moiety with LiAlH4 at room
temperature furnished 4d in high yield. In addition, treating
3aa with PhMgBr afforded 4e with a tertiary alcohol group.
To study the reaction mechanism, we conducted the domino
reaction with 1a and 2a in the presence of 20 equiv of D2O
under the optimized reaction conditions (Scheme 5). The
Scheme 5. Deuterium Labeling Experiment
a
The reactions were carried out with 1 (0.1 mmol), 2a (0.2 mmol),
DMAP (30 mol %), and K2CO3 (0.1 mmol) in 2.0 mL of CHCl3 at
room temperature. Diastereoselectivity was determined by H NMR
spectroscopy.
deuterated product d-3aa was obtained in 46% yield, and H/D
exchange was observed at the β and γ positions of allenoate 2a,
indicating the possibility of the involved carbanion at position
2 of the allene intermediate.
1
corresponding products afforded in good to high yields (68−
90%) (3ba−3ha). Further investigation showed that substrates
1 bearing an aryl group (3ia) were also efficient for the
transformation. Moreover, the aromatic rings of substrates 1
bearing other heteroatom substituents at the para position
On the basis of the control experimental (Table 1, entries 4
and 9) and the experimental result with deuterium, a plausible
reaction pathway for this domino annulation is proposed in
Scheme 6. The reaction is triggered by the addition of DMAP
to allenoate 2a and subsequent 1,2-elimination of the acetate
C
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Accession Codes
Scheme 6. Plausible Reaction Mechanism
CCDC 1934884 and 1951502 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
You Huang − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; Collaborative Innovation Center of
Chemical Science and Engineering, Tianjin 300071, China;
orcid.org/0000-0002-9430-4034; Email: hyou@
nankai.edu.cn
Author
group to generate electrophilic diene intermediate I. Then,
ammonium ylide III was formed by a γ-addition between
intermediate I and intermediate II (deprotonated 1a), induced
by the electron-withdrawing ability of the ammonium in
intermediate I and the p-π conjugation between the carbon
anion and the aromatic ring moiety of the ammonium in
ammonium ylide III. The subsequent 1,2-proton shift of III
followed by intramolecular 1,2-addition in intermediate IV
gives intermediate V (path a). Finally, intramolecular SN2′
substitution in intermediate V yields product 3aa with DMAP
catalyst regeneration. On the contrary, we thought that the 1,2-
proton shift from intermediate III to IV lacks a certain driving
force, so another plausible pathway was proposed. On the basis
of intermediate IV, DMAP is removed by 1,2-elimination to
form intermediate VI (path b), and then an intramolecular
Diels−Alder reaction in intermediate VI occurs, affording
product 3aa directly. However, we failed to isolate
intermediate VI during the whole reaction. The observed
excellent diastereoselectivity of the reaction indicated that the
concerted Diels−Alder reaction pathway would be more
possible.
In summary, we have developed a novel [4+1]/[3+3]
domino sequential annulation reaction between o-amino-
trifluoroacetophenone derivatives and β′-acetoxy allenoates
by employing the DMAP catalyst, and a series of CF3-
containing tetrahydropyrano[3,2-b]indole products were syn-
thesized in high to excellent yields with a single diaster-
eoselectivity under mild reaction conditions. Moreover, the
mechanistic studies revealed that the reaction proceeds
through an ammonium ylide intermediate. The gram-scale
reactions and the various transformations of the products may
have broad applications in the synthesis of valuable
pharmaceuticals with trifluoromethyl-substituted heterocycles.
Further investigations of the reaction mechanism and the
enantioselective version of this reaction are currently underway
in our laboratory.
Yannan Zhu − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02164
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21871148, 21672109, and 21472097) for financial
support.
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F
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Org. Lett. XXXX, XXX, XXX−XXX