Tandem Rh-Catalyzed [4 + 2] Vinylic C-H O-Annulation of Exocyclic Enones with Alkynes and 1,5-H Shift

Article abstract of DOI:10.1021/acs.orglett.7b04042

Active pyrylium intermediates are in situ generated by a Rh-catalyzed vinylic C-H annulation reaction between exocyclic α,β-enones and alkynes, which undergo a base-promoted rearrangement via 1,5-H shift to form 1H-benzo[f]chromene derivatives.

Full text of DOI:10.1021/acs.orglett.7b04042

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tandem Rh-Catalyzed [4 + 2] Vinylic C−H O‑Annulation of Exocyclic
Enones with Alkynes and 1,5‑H Shift
Yinsong Zhao, Chuangui Yu, Tianbao Wang, Zhijie She, Xuesong Zheng, Jingsong You, and Ge Gao*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29
Wangjiang Road, Chengdu 610064, P. R. China
S
* Supporting Information
ABSTRACT: Active pyrylium intermediates are in situ
generated by a Rh-catalyzed vinylic C−H annulation reaction
between exocyclic α,β-enones and alkynes, which undergo a
base-promoted rearrangement via 1,5-H shift to form 1H-
benzo[f ]chromene derivatives.
Scheme 1. Transformations of in Situ Generated Pyrylium
Species via C−H Annulation of α,β-Enones with Alkynes
(Benzo)pyrylium salts, a unique class of cationic aromatic
compounds with nonuniform electron density distribution
property, have drawn much attention since the 1950s due to
their high reactivity toward various nucleophiles.1 Their recent
renaissance focuses on the chemistry of zwitterionic metal-
pyrylium intermediates, which are mostly in situ generated by
transition-metal-catalyzed intramolecular cyclizations of enynals
and undergo successive Diels−Alder, nucleophilic addition and
hydrogenation reactions for the construction of synthetically
useful compounds.2 New methods to more easily generate
active pyrylium species from simple, readily available reagents,
as well as new transformations, are still in high demand.
Over the past decades, transition-metal-catalyzed chelation-
directed C−H activation/annulation reactions have emerged as
a straightforward and efficient strategy to construct carbocycles
and N-heterocycles.3,4 In this context, pyridine and pyridinium
derivatives are synthesized by the one-step [4 + 2] vinylic C−H
N-annulation of α,β-unsaturated imines or oximes with alkynes
under the catalysis of [Rh] and [Ru].5 Nevertheless, the
corresponding α,β-unsaturated ketones (α,β-enones) could not
be annulated with alkynes in a similar manner to give the
corresponding O-heterocycles, i.e. pyrylium salts, but mostly
underwent vinylic C−H additions to alkynes.6 Recently, we
showcased the first example of an intermolecular [4 + 2] vinylic
C−H O-annulation of acyclic α-aryl enones with alkynes to
synthesize multisubstituted furans (Scheme 1, eq 1).7 We
recognized that this is a very convenient method to generate
pyrylium salts and were interested in harnessing this highly
active species for novel transformation into other useful organic
skeletons. Our attention then turned to possible vinylic C−H
activation/annulation of more challenging exocyclic α,β-enones
1 with alkynes. Besides easy side reactions such as polymer-
ization8 and conjugate additions9 under oxidative conditions,
exocyclic α,β-enones might also suffer from weak and instable
cyclometalation for effective C−H bond activation due to the
twisted conformation caused by the steric hindrance of the
substituents at both the α,β-positions.4b,6 We report herein a
tandem rhodium and copper mediated reaction of exocyclic
α,β-enones with alkynes to deliver 1H-benzo[f ]chromene
derivatives (Scheme 1, eq 2). The mechanism study verified
that the reaction combines the expected Rh-catalyzed [4 + 2]
O-annulation to generate the active pyrylium intermediates and
an unprecedented rearrangement via a 1,5-H shift.
The model reaction of (E)-1-(p-methylbenzylidene)-3,4-
dihydronaphthalen-2(1H)-one 1a and diphenylacetylene 2a
under the optimal reaction conditions for acyclic α,β-enones7
gave 1H-benzo[f]chromene 3a in less than 5% yield (Table 1,
entry 1). The structure of 3a was unambiguously confirmed by
NMR spectra, HRMS spectrometry, and X-ray diffraction
analysis. The reaction is characteristic of aromatization of the
tetrahydronaphthalene ring and conversion of the vinylic sp2
carbon into a benzylic sp3 carbon. 1H-Benzo[f ]chromene
derivatives represent an important class of polyheterocyclic
compounds that are frequently found in many pharmaceutical
and natural products.10 Systematic optimization of the reaction
conditions was then conducted, and 3a was obtained in a
highest yield of 75% in the presence of [Cp*Rh(CH3CN)3]-
(SbF6)2 (10 mol %), Cu(OAc)2·H2O (2.0 equiv), and Cu2O
(0.5 equiv) in DCM (1 mL) at 100 °C for 24 h in air (Table 1,
entry 2).11 Control experiments showed that the reaction did
not occur without the rhodium catalyst, yet gave a trace amount
of 3a in the absence of Cu(OAc)2·H2O (Table 1, entries 3−4).
The combination of [Cp*RhCl2]2 and AgSbF6 only gave a
Received: December 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b04042
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Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scopes of Exocyclic α,β-Enoens and Alkynes
b
entry
variation from optimal conditions
yield (%)
c
1
[Cp*RhCl2]2/AgSbF6
none
<5%
75
2
3
4
without [Rh]
n.d.
trace
55
no Cu(OAc)2·H2O
[Cp*RhCl2]2/AgSbF6
[(p-cymene)Ru(CH3CN)3](SbF6)2
[Cp*Ir] or [Cp*Co]/AgSbF6
without Cu2O
d
5
e
6
45
d
7
n.d.
57
8
f
9
CuO instead of Cu2O
59
f
10
11
12
13
14
NaOAc instead of Cu2O
48
f
Et3N instead of Cu2O
n.d.
30
f
extra NaOAc
DCE as solvent
PhCl as solvent
49
13
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Cp*Rh-
(CH3CN)3](SbF6)2 (10 mol %), Cu(OAc)2·H2O (0.4 mmol), and
b
Cu2O (0.1 mmol) in DCM (1 mL) in air at 100 °C for 24 h. Isolated
c
yield. [Cp*RhCl2]2/AgSbF6 (5/20 mol %), without Cu2O, DME as
the solvent at 90 °C for 24 h (see ref 7). [M]/[Ag]: [Cp*RhCl2]2 (5
d
a
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), [Cp*Rh-
(CH3CN)3](SbF6)2 (10 mol %), Cu(OAc)2·H2O (0.4 mmol), and
Cu2O (0.1 mmol) in DCM (1 mL) in air at 100 °C for the indicated
mol %), [Cp*IrCl2]2 (5 mol %) or [Cp*Co(CO)I2] (10 mol
e
f
%)/AgSbF6 (20 mol %). [Ru] complex (10 mol %). 0.2 mmol. n.d. =
b
c
no detected. p-tol = p-methylphenyl.
time. Isolated yield. 1 mmol scale. TMP = 3,4,5-trimethoxyphenyl.
ities were achieved when unsymmetrical phenyl alkyl alkynes
such as 1-phenylpropyne and 4-phenylbut-3-yn-1-yl pivalate
were employed, exclusively giving 3w−3y with the phenyl ring
installed adjacent to the oxygen atom of the 1H-benzo[f ]-
chromene core.
moderate yield (Table 1, entry 5). For other catalysts, [Ru]
gave a lower yield, while [Ir] and [Co] were ineffective (Table
1, entries 6−7). Cu2O played a crucial role to achieve a high
yield, while both CuO and NaOAc gave lowered yields and
Et3N ceased the reaction (Table 1, entries 8−11). The addition
of an extra equivalent of NaOAc resulted in a complicated
mixture, and 3a was isolated in 30% yield (Table 1, entry 12). It
is also interesting that other halogenated solvents such as DCE
and PhCl were significantly inferior to DCM (Table 1, entries
13−14).
To gain insight into the reaction mechanism, the reaction of
D6-1b with 2a was conducted under the standard conditions
1
(Scheme 3, eq 1). The H NMR analysis of the product 3b
Scheme 3. Experiments to Verify Pyrylium Intermediate via
Vinylic C−H Bond Cleavage
With the optimal conditions in hand, the generality of this
reaction was investigated (Scheme 2). A variety of (E)-1-
(arylmethylene)-3,4-dihydronaphthalen-2(1H)-ones containing
both electron-donating groups, such as methoxyl, phenyl, and
vinyl, and electron-withdrawing groups, including choloro,
bromo, iodo, and trifluoromethyl, on different positions of the
phenyl ring could smoothly react with 2a to yield the desired
multisubstituted 1H-benzo[f ]chromenes 3b−3m in moderate
to good yields. The strong steric hindrance effect of the 3,4,5-
trimethoxyphenyl group (TMP) in 1l rendered the reaction
sluggish. 3l was obtained in 57% yield after 48 h with a small
amount of 1l recovered. The aryl group in 1 could be extended
to bulky naphthalen-2-yl 1n and heteroaryls including 2-furyl,
2-thienyl, and 3-thienyl 1o−1q, affording the corresponding
(naphthalen-2-yl)- and heroaryl-containing 1H-benzo[f ]-
chromene derivatives 3n−3q in moderate yields. In addition,
enones 1r and 1s bearing functional groups such as methoxyl
and bromo on the 3,4-dihydronaphthalen-2(1H)-one core
worked well with 2a to yield 3r and 3s in good yields. The
scope of alkynes was also examined. A series of symmetrical
alkynes bearing common functional groups were successfully
annulated with 1b to provide the corresponding 3t−3v in
satisfactory yields. It is noteworthy that complete regioselectiv-
a
Reaction conditions: 4 (0.2 mmol), [Cp*Rh(CH3CN)3](SbF6)2 (10
mol %), Cu(OAc)2·H2O (0.4 mmol), and Cu2O (0.1 mmol) in DCM.
showed no benzylic deuterium, indicating that this reaction
underwent a vinylic C(sp2)−H bond cleavage. The H/D
exchange experiment between 1b and D2O showed that the
initial vinylic C−H bond cleavage was irreversible. The kinetic
isotope effect (KIE) was calculated to be 1.5 from the reaction
of a mixture of 1b and D6-1b with 2a (see the Supporting
Information, SI), suggesting that the vinylic C−H bond
cleavage was not involved in the turnover-limiting step. An
B
DOI: 10.1021/acs.orglett.7b04042
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Letter
analogue of the pyrylium intermediate 4 was then synthesized
by a traditional method. 4 successfully converted into 5 in 32%
yield under the optimal conditions (Scheme 3, eq 2),
confirming the pyrylium species generated by the Rh-catalyzed
direct [4 + 2] O-annulation of exocyclic α,β-enones with
alkynes as the key intermediate.
Scheme 5. A Plausible Mechanism
By using 0.5 equiv of Cu2O alone, 5 was obtained in 30%
yield.12 Surprisingly, Cu(OAc)2·H2O was ineffective. NaOAc
and Et3N were more beneficial for this transformation to offer 5
in high yields than Cu2O (Scheme 3, eq 2). These control
experiments for the conversion of 4 to 5 suggested that this
process is probably promoted by a base. However, it is worth
noting that the overall performances of NaOAc and Et3N for
the tandem reaction of exocyclic α,β-enones with alkynes were
inferior (Table 1, entries 10−11), implying that the [4 + 2]
annulation process is less tolerant of a basic environment.
Therefore, the role of Cu2O could possibly be to provide a
compatible environment for the two inconsistent processes.
To clarify the subsequent process, it is critical to know the
source of the benzylic hydrogen in 3b. H/D exchange was not
observed in the reaction of either 1b with 2a or product 3b
itself in the presence of 10 equiv of D2O (see SI), suggesting
the benzylic hydrogen was transferred intramolecularly. The
reaction between C3-D2-1b and 2a yielded 3b without any
benzylic deuterium (Scheme 4, eq 1), which indicated that it
Scheme 6. Conversion of 1H-Benzo[f ]chromene 3 into
Cationic O-Containing PHAs
Scheme 4. Experiments to Clarify the Benzylic H Source
a
Reaction conditions: 3 (0.2 mmol), Br2 (0.22 mmol) in AcOH at 100
b
°C for 1 h. Reaction conditions: 6 (0.05 mmol) and HBF4 (0.05
mmol) in AcOH under irradiation (254 nm) at rt in air for 24 h.
chromen-3-iums salts 7 in almost quantitative yields. These
cationic O-containing polycyclic heteroaromatics (PHAs) may
find applications in photochemistry, spintronics, and materials
science.13
In summary, we have developed a Rh-catalyzed C−H
annulation reaction between exocyclic α,β-enones and alkynes
to provide 1H-benzo[f ]chromene derivatives. The preliminary
mechanism studies confirmed the active pyrylium salts as the
key intermediates, which underwent the subsequent rearrange-
ment via a 1,5-hydrogen shift. The 1H-benzo[f ]chromene
products could be easily converted into O-containing PHAs for
further investigation as functional materials.
was the C4−H in 1b that was transferred to the benzylic
position in 3b. To confirm this result, C3,4-D4-1b (containing
60% C4-D) was reacted with 2a under the standard conditions.
As expected, 46% of benzyl-D was detected in 3b (Scheme 4,
eq 2).
On the basis of the preliminary experimental results and our
previous research,3,5,7 a plausible mechanism was depicted in
Scheme 5. The reaction started with an irreversible vinylic C−
H bond activation of 1 by [Rh(III)] to give the five-membered
rhodacycle A, followed by the alkyne insertion to generate the
seven-membered rhodacycle B. Direct reductive elimination
delivered the key pyrylium intermediate C and released the
[Rh(I)] species, which was oxidized by [Cu(II)] to regenerate
the [Rh(III)] catalyst. The highly active C was then
deprotonated at the benzylic position of the pyrylium ring by
a base (not identified), giving a conjugated triene D, which was
further aromatized into the more stable 1H-benzo[f ]chromene
3 through 1,5-H shift.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b04042.
1
Experimental procedures, characterization data, and H,
13C, and 19F NMR spectra of products (PDF)
Accession Codes
CCDC 1510670 and 1558651 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.
The 1H-benzo[f ]chromene products 3 could be easily
oxidized into naphthoflavylium salts 6 by bromine (Scheme
6). Further site selective photooxidation reaction in air at room
temperature provided π-extended phenanthro[9,10,1-def ]-
C
DOI: 10.1021/acs.orglett.7b04042
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) A similar yield of 73% was obtained when the reaction was
conducted in a N2 atmosphere. Therefore, an inert atmosphere was
not necessary.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gg2b@scu.edu.cn.
ORCID
(12) 5 was obtained in 66% yield when 4.0 equiv of Cu2O were used.
(13) For selected reviews, see: (a) Romero, N. A.; Nicewicz, D. A.
̇
́ ́
, M.; Gonka, E.; Z yła, M.;
Chem. Rev. 2016, 116, 10075. (b) Stępien
Sprutta, N. Chem. Rev. 2017, 117, 3479. For selected recent examples,
Jingsong You: 0000-0002-0493-2388
Ge Gao: 0000-0001-9980-7311
see: (c) Wu, D.; Pisula, W.; Haberecht, M. C.; Feng, X.; Mullen, K.
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Org. Lett. 2009, 11, 5686. (d) Anamimoghadam, O.; Symes, M. D.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the financial support from the National NSF of
China (Nos. 21472127, 21772134, and 21432005).
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DOI: 10.1021/acs.orglett.7b04042
Org. Lett. XXXX, XXX, XXX−XXX