Ti(OiPr)4-Facilitated Formal Deoxygenative Annulation of Alkynyl 1,2-Diketones for the Synthesis of Highly Functionalized Furans

Article abstract of DOI:10.1021/acs.orglett.1c00291

A unique deoxygenative cyclodimerization of alkynyl 1,2-diketones facilitated by Ti(OiPr)4 is achieved, affording a series of highly functionalized furan products. An unusual C-C bond and CO bond cleavage of the substrates is observed, and Ti(OiPr)4 plays triplicate roles in the reaction. Furthermore, the products show uncommon fluorescent emission in the solid state, indicating the potential practical applications of this work.

Full text of DOI:10.1021/acs.orglett.1c00291

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Letter
Ti(OiPr)4‑Facilitated Formal Deoxygenative Annulation of Alkynyl
1,2-Diketones for the Synthesis of Highly Functionalized Furans
Shouang Lan,∥ Rui Liu,∥ Xiangwen Kong, Jinggong Liu, Benlong Luo, Shuang Yang,*
and Xinqiang Fang*
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ABSTRACT: A unique deoxygenative cyclodimerization of
alkynyl 1,2-diketones facilitated by Ti(OiPr)4 is achieved, affording
a series of highly functionalized furan products. An unusual C−C
bond and CO bond cleavage of the substrates is observed, and
Ti(OiPr)4 plays triplicate roles in the reaction. Furthermore, the
products show uncommon fluorescent emission in the solid state,
indicating the potential practical applications of this work.
Scheme 1. Background Introduction
he exploitation of novel transformations using earth-
Tabundant transition metals via unprecedented mecha-
nisms has attracted the research interest of chemists for many
years because of the possibility of expanding the application
scope of the metals and facilitating previously inconvenient
transformations.1 For instance, titanium reagents have proven
to be vital in a variety of transformations through diverse
activation modes of substrates, acting either as catalysts or as
stoichiometric reagents.2 A recent important development is
the field of titanium-mediated redox processes,3 and the
corresponding reactions include Sharpless epoxidation,
McMurry reaction, pinacol coupling, Barbier reaction,
Kulinkovich reaction, the de Meijere and Szymoniak
modifications, Pauson−Khand reaction, alkyne cyclotrimeriza-
tion (Scheme 1a),3f−h and the recently developed [2+2+1]
pyrrole synthesis by Tonks (Scheme 1b).3i−m Among them,
the latter two protocols are powerful in the rapid construction
of substituted benzene and pyrrole rings, which are highly
useful in diverse fields. Despite these great achievements,
titanium-facilitated rapid construction of aromatic rings from
easily available starting materials is still underdeveloped, and
new methods are left to be disclosed.
On the other side, furans make up a class of valuable fine
chemicals and have been widely used as synthetic inter-
mediates to access useful compounds such as natural products,
pharmaceuticals, and polymers.4 Although a variety of
approaches have been developed to afford differently
substituted furans,5 the rapid synthesis of fully substituted
furans with multiple functional groups is still a challenging
topic, and new protocols for addressing the issue are still highly
desirable.
enones and ynones6 and reported furan synthesis via a formal
[3+2] annulation between alkynyl diketones and cyano
ketones (Scheme 1c).6e Here we describe a formal
deoxygenative cyclodimerization reaction of alkynyl 1,2-
diketones facilitated by Ti(OiPr)4 (Scheme 1d). The reaction
undergoes a unique C−C and CO bond cleavage of the
substrate and a C−C/CC/C−O bond formation process;
Received: January 25, 2021
Published: February 3, 2021
We have been interested in α-diketone chemistry and have
disclosed a series of new reactivities concerning conjugated
diketones that are thoroughly distinct from those of common
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© 2021 American Chemical Society
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unique triplicate roles of Ti(OiPr)4 are involved, which is
thoroughly different from the known modes. Furthermore, the
furan products display promising fluorescence, which repre-
sents an uncommon outcome in the field of material chemistry.
Herein, we report the results.
Our initial test of the annulation of 1a under a
stoichiometric amount of Ti(OiPr)4 in CH2Cl2 resulted in
no product (Table 1, entry 1). However, increasing the
Having identified the optimal conditions for the formation
of highly functionalized furan, we then focused on the survey
of the substrate scope. The variation of the R1 groups by
introducing electron-rich phenyl rings showed better effects on
the yields, releasing 2b−2d in ≤91% yield (Scheme 2, 2b−2d).
When R1 was a fluoro-substituted phenyl or naphthyl group,
the reaction proceeded well to give the corresponding
products, albeit in relatively lower yields (Scheme 2, 2e and
2f). In addition, heterocyclic furan and thiophene substituents
showed little impact on the reactions (Scheme 2, 2g and 2h),
and the aliphatic cyclopropyl group proved to be suitable for
the protocol (Scheme 2, 2i). Subsequently, we evaluated a
series of R2 groups on the substrates and found that an
electron-rich OMe group installed on a phenyl ring showed
little effect on the reaction under the optimal conditions
(Scheme 2, 2j), but a lower concentration of 0.5 M and rt have
to be used to suppress side reactions when the R2 groups were
electron-deficient phenyl rings (Scheme 2, 2k and 2l).
Additionally, when R2 was a thienyl group, a 63% yield of
2m was produced (Scheme 2, 2m), and the furan product with
a cyclopropyl substituent was also obtained, albeit in a poor
yield (Scheme 2, 2n). Furthermore, the simultaneous variation
of both R1 and R2 groups also proved to be possible, and
substrates having different substitution patterns such as
electron-rich and electron-poor (Scheme 2, 2o and 2p), both
electron-rich (Scheme 2, 2q and 2r), and electron-poor
(Scheme 2, 2s) could all produce the corresponding products.
Finally, a substrate with a camphor unit was tested and allowed
access to 2t in 67% yield (Scheme 2, 2t). The structure of the
products was confirmed unambiguously by the single-crystal X-
ray analysis of 2j, and other compounds were assigned by
analogy.
The scale-up reaction can be easily achieved using 1.17 g of
1a, which could afford 0.975 g of 2a in 83% yield (Scheme 3,
eq 1). Then further transformations on 2a were also
conducted, and we found that the alkyne moiety could be
readily transferred to ketone 3a in 91% yield under gold
catalysis (Scheme 3, eq 2). Then the hydrogenation of 2a
released 3b in good yield (Scheme 3, eq 3), and the 1,4-
diketone unit of 2a was found to undergo the condensation
with hydrazine to yield 3c in 76% yield (Scheme 3, eq 4).
To our delight, we found that the solid furan products
showed fluorescence emission under ultraviolet irradiation at
365 nm. As shown in Figure 1a, 2j, 2a, 2t, 2f, 2o, and 2d show
a gradient color change from green to yellow according to the
substitution patterns. Fluorescent materials have found wide
applications in organic OLEDs, semiconductor lasers, and
fluorescent sensors.8 However, troubles caused by aggregation-
caused quenching (ACQ) have greatly restricted the
corresponding applications because fluorescent materials are
usually used in the aggregated or solid state.9 Furthermore,
furan compounds have been conventionally considered inferior
in displaying photochemical properties.10 In this context, our
work provides an uncommon exception. As shown in panels b
and c of Figure 1, obvious red shifts can be observed from the
emission spectra of the six products, which range from 434 to
494 nm (see the Supporting Information for more details).
The origin of the unusual fluorescent emission could be
deduced from the molecular packing arrangement in the crystal
of 2j (Figure 1d). One can see that close π−π stacking exists
between the alkynyl 4-OMe-phenyl unit of one molecule of 2j
and the 4-OMe-phenyl moiety of another molecule of 2j,
which is essential for the regular arrangement and the
a
Table 1. Condition Optimizations
concn
(M)
yield
(%)
entry Ti reagent
solvent
temp
rt
rt
rt
rt
rt
rt
rt
rt
additive
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
TiCl4
CH2Cl2
CH2Cl2
DMF
CH3CN
THF
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
0.2
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
2.0
2.0
2.0
1.0
1.0
2.0
2.0
−
−
−
−
−
−
−
−
0
33
trace
0
15
0
41
46
53
53
79
77
75
13
0
b
rt
−
−
−
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
c
Zn(OTf)2
AlCl3
−
−
−
c
d
e
Ti(OtBu)4
Al(OiPr)3
0
0
e
−
a
Reaction conditions: 1a (1 mmol), under an argon atmosphere, 12 h.
b
All isolated yields were based on 1a. With 2 equiv of Ti(OiPr)4
c
d
added. With 20 mol % additive added. With 20 mol % Ti(OiPr)4
e
added. A complicated reaction mixture was obtained.
concentration to 0.5 M led to a 33% yield of 2a (Table 1, entry
2). The formation of the product undergoes a formal scission
of the CO−CO bond and the internal CO bond, and then
recombination with the second alkynyl diketone molecule. The
process is in accordance with the “cut and sew” strategy
proposed by Dong and co-workers.7 Other solvents such as
DMF, CH3CN, THF, and MeOH were also surveyed but
proved to be less suitable (Table 1, entries 3−6, respectively).
To our delight, toluene increased the yield to 41% (Table 1,
entry 7), and a concentration of 1.0 M could further improve
the yield (Table 1, entry 8). Then, 2.0 equiv of Ti(OiPr)4 or 40
°C can promote the yield to 53% (Table 1, entry 9 or 10,
respectively). A further modification of the reaction concen-
tration to 2.0 M resulted in 2a at an acceptable level (Table 1,
entry 11). The addition of a Lewis acid such as Zn(OTf)2 and
AlCl3 as the additives showed almost no influence on the yield
(Table 1, entries 12 and 13, respectively). Catalytic Ti(OiPr)4
liberated 2a in only 13% yield (Table 1, entry 14), and another
titanium reagent such as TiCl4 was also studied but produced
only a complicated reaction mixture (Table 1, entry 15). In
sharp contrast, the use of Ti(OtBu)4 led to no conversion of 1a
(Table 1, entry 16), and Al(OiPr)3 resulted in a messy mixture
despite the full consumption of the starting material (Table 1,
entry 17).
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a
Scheme 2. Scope of Furan Synthesis
Scheme 3. Scale-up Reaction and Product Derivatizations
Figure 1. (a) Selected illuminant compounds under visible light and
ultraviolet irradiation at 365 nm. (b) Ultraviolet−visible absorption
spectra of selected 2 as amorphous powders (T = 298 K). (c)
Emission spectra of selected 2 as amorphous powders (T = 298 K,
excited at the respective λmax). (d) Molecular packing arrangement in
the crystal of 2j.
a
Reaction conditions: 1 (1 mmol), Ti(OiPr)4 (1 mmol), toluene (0.5
mL), 40 °C, 12 h, under an argon atmosphere. All yields were of
the production of the corresponding unique photochemical
property.
b
isolated products. The reaction was conducted at rt for 24 h at a
To gain more mechanistic insights into the reaction, we
conducted a series of control experiments. First, the reaction of
common ynone 1aa under the standard conditions cannot
occur, indicating the unique chemistry of alkynyl diketones
compared to common yones (Scheme 4a). Second, the
reaction using a 1:1 ratio of 1j and 1k at rt afforded both
homoannulation and cross-annulation products in different
concentration of 0.5 M.
induction of emission. To further prove this conclusion, we
also tested the possible emission of 3a and 3b but observed no
fluorescence, indicating the importance of the alkyne moiety in
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Scheme 4. Control Experiments
Scheme 5. Postulated Mechanism
intermediate I, which has a resonance structure of II. Then the
valence tautomery between Ti(IV) and the enolate leads to
Ti(III) and III.13 The regioselective attack of III to 1a
produces IV, and the corresponding cleavage generates alkynyl
formal radical V and olefin VI. The following radical addition
of V to VI generates VII, and during the process, Ti(III) to
Ti(IV) is also involved. An intramolecular addition of an
oxygen anion to the ynone moiety gives VIII, and after
deoxygenation, IX is formed, followed by the formation of
oxonium X. Finally, an elimination furnishes 2a together with
acetone. The chemistry of acyl radicals has been well
documented, and one of the featured properties is to attack
activated alkenes.14 The failure in trapping III or V is possibly
caused by the high reactivity of 1a and VI. In the whole
process, Ti(OiPr)4 plays at least three different roles: (1)
acting as a Lewis acid to activate the substrate, (2) releasing an
isopropoxy anion to undergo the following Michael addition,
which triggers the following radical reactions, and (3) the
titanium oxygen anion acting as a base to grab the proton of X,
which finally completes the reaction. To the best of our
knowledge, such triplicate roles of Ti(OiPr)4 have not been
disclosed.
In summary, the formal deoxygenative cyclodimerization
reaction of alkynyl 1,2-diketones facilitated by Ti(OiPr)4 has
been achieved for the first time, affording a series of highly
functionalized furans in a one-step fashion. The reaction
undergoes a unique C−C and CO bond cleavage of the
substrate and a C−C/CC/C−O bond formation process. A
TiIV/TiIII redox mechanism is proposed, and triplicate roles of
Ti(OiPr)4 are involved, which has been not observed in known
reports. Moreover, the furan products show promising
fluorescent properties in the solid state, which also provides
a useful hint for solving the challenging topic in materials
chemistry.
yields, indicating that the reaction happens in a two-molecule
fashion (Scheme 4b). Then we found that the reaction of 1a
using 20 mol % Ti(OiPr)4 and 1 equiv of NaOiPr failed to give
2a, and only 4a was detected (Scheme 4c). This shows that
stoichiometric Ti(OiPr)4 is necessary for the reaction. More
importantly, the addition of freshly prepared phenyl Grignard
reagent to the reaction mixture of 1a under the standard
conditions resulted in a 77% yield of 2-phenylpropan-2-ol (4d)
together with 4b and 4c,11 clearly illustrating that acetone is
produced in the reaction (Scheme 4d). We have observed that
TiCl4 could not facilitate the reaction (Table 1, entry 15),
showing that the OiPr anion is also vital for the reaction. The
addition of TEMPO retarded the reaction with the formation
of 4e (Scheme 4e), but in the absence of Ti(OiPr)4, no
12
reaction occurred (Scheme 4f). The use of P(OEt)3 as the
additive quenched the reaction, with a 69% yield of 1a
recovered. Our efforts to trap the possible intermediates of the
reaction using 5a−5c were not successful, and only 2a and
recovered 1a were isolated (Scheme 4h).
Although more evidence is needed to fully understand the
mechanistic details, at present we propose a probable
mechanism (Scheme 5). The coordination of Ti(OiPr)4 with
1a produces a certain amount of free isopropoxy anion, and the
Michael addition of the anion to activated 1a results in enolate
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00291.
■
sı
Experimental procedures, spectroscopic data for all new
compounds, and crystallographic data for 2j (PDF)
FAIR data, including the primary NMR FID files, for
compounds 2a−t, 3a−c, 4a, and 4b (ZIP)
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Accession Codes
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Letter
Natural Science Foundation (2018J05035), the China
Postdoctoral Science Foundation (2018M630734), and the
Science and Technology Research Program of the Education
Department of Jiangxi Province (GJJ1991151).
CCDC 2041198 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Xinqiang Fang − State Key Laboratory of Structural
Chemistry and Key Laboratory of Coal to Ethylene Glycol
and Its Related Technology, Center for Excellence in
Molecular Synthesis, Fujian Institute of Research on the
Structure of Matter, University of Chinese Academy of
Sciences, Fuzhou 350100, China; orcid.org/0000-0001-
8217-7106; Email: xqfang@fjirsm.ac.cn
Shuang Yang − State Key Laboratory of Structural Chemistry
and Key Laboratory of Coal to Ethylene Glycol and Its
Related Technology, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of
Matter, University of Chinese Academy of Sciences, Fuzhou
350100, China; Email: yangshuang@fjirsm.ac.cn
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Authors
Shouang Lan − State Key Laboratory of Structural Chemistry
and Key Laboratory of Coal to Ethylene Glycol and Its
Related Technology, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of
Matter, University of Chinese Academy of Sciences, Fuzhou
350100, China
Rui Liu − State Key Laboratory of Structural Chemistry and
Key Laboratory of Coal to Ethylene Glycol and Its Related
Technology, Center for Excellence in Molecular Synthesis,
Fujian Institute of Research on the Structure of Matter,
University of Chinese Academy of Sciences, Fuzhou 350100,
China
Xiangwen Kong − State Key Laboratory of Structural
Chemistry and Key Laboratory of Coal to Ethylene Glycol
and Its Related Technology, Center for Excellence in
Molecular Synthesis, Fujian Institute of Research on the
Structure of Matter, University of Chinese Academy of
Sciences, Fuzhou 350100, China
Jinggong Liu − Orthopedics Department, Guangdong
Provincial Hospital of Traditional Chinese Medicine, The
Second Affiliated Hospital of Guangzhou University of
Chinese Medicine, Guangzhou 510120, China
Benlong Luo − Pingxiang University, Pingxiang 337055,
China
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Complete contact information is available at:
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Author Contributions
∥S.L. and R.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21871260 and
22071242), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB20000000), the Fujian
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