Formal [5+1] annulation reactions of dielectrophilic peroxides: Facile access to functionalized dihydropyrans

Article abstract of DOI:10.1039/d0cc05565d

A general [5+1] annulation reaction, which utilized 4-bromo- or 4-mesyloxy-but-2-enyl peroxides as unique five-atom bielectrophilic synthons to participate in the C-C and the subsequent umpolung C-O bond-forming reactions with C1 nucleophiles, has been developed for the facile synthesis of 2,2-disubstituted dihydropyrans in high yields under mild basic conditions. The dihydropyrans, which are readily prepared on a gram scale by this new method, can be flexibly transformed into the biologically important tetrahydropyrans and pyranones in 1-2 steps.

Full text of DOI:10.1039/d0cc05565d

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Formal [5+1] annulation reactions of
dielectrophilic peroxides: facile access
Cite this:DOI: 10.1039/d0cc05565d
to functionalized dihydropyrans†
Received 15th August 2020,
Accepted 21st September 2020
Chen Zhong, Qi Yin, Yukun Zhao, Qinfeng Li and Lin Hu
*
DOI: 10.1039/d0cc05565d
rsc.li/chemcomm
A general [5+1] annulation reaction, which utilized 4-bromo- or
4-mesyloxy-but-2-enyl peroxides as unique five-atom bielectrophilic
synthons to participate in the C–C and the subsequent umpolung
C–O bond-forming reactions with C1 nucleophiles, has been devel-
oped for the facile synthesis of 2,2-disubstituted dihydropyrans in high
yields under mild basic conditions. The dihydropyrans, which are
readily prepared on a gram scale by this new method, can be flexibly
transformed into the biologically important tetrahydropyrans and
pyranones in 1–2 steps.
Dihydropyrans are the core structural units of many biologically
and pharmaceutically active compounds (Scheme 1A).1 They
also serve as versatile starting materials toward many other
biologically important six-membered oxygenated heterocycles
such as tetrahydropyrans and pyranones, since the olefin
functional group provides a convenient handle for structural
variations.2 Due to the synthetic and medicinal importance of
these molecules, their preparation methods have been actively
pursued by the community. While many approaches have been
developed for the synthesis of dihydropyrans,3,4 highly efficient
and attractive one-step annulation protocols remain limited.
Currently, such annulation strategies primarily rely on the [4+2]
hetero-Diels–Alder reactions5 of carbonyl compounds with
1,3-dienes or the [5+1] Prins-type annulation reactions6 of carbonyl
Scheme 1 Background and our synthetic strategy.
compounds with 4-hydroxyl-vinylsilanes (Scheme 1B). None- 3,6-dihydro-2H-pyrans in high yields by using 4-bromo- or
theless, both methods generally require the use of activated 4-mesyloxy-but-2-enyl peroxides as unique five-atom bielectro-
aldehydes, glyoxylates or ketomalonates as substrates, which philic synthons to react with a variety of one carbon nucleo-
substantially restrains the scope of the reactions. In this regard, philes, such as b-keto esters, b-keto phosphonates, and simple
the development of a more general annulation strategy for the ketones, under very mild basic conditions (Scheme 1C). Unlike
facile synthesis of such oxygenated heterocycles is still in high previous strategies, this new annulation approach involves a
demand.
tandem C–C and C–O bond-forming process, wherein the critical
Herein, we report a highly efficient and formal [5+1] annulation ring-closing C–O bond was constructed via an unconventional
approach to access a broad range of functionalized 2,2-disubstituted umpolung method.7
Previously, dialkyl peroxides have been exploited for the C–O
bond-forming reactions with highly reactive carbon nucleophiles
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research,
such as organolithium and Grignard reagents.8 With this
School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331,
approach, ethers were generated via the attack of carbanion
China. E-mail: lhu@cqu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0cc05565d species onto the electrophilic oxygen reagents. Such an umpolung
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Table 1 Optimization of the reaction conditionsa
C–O bond-forming strategy, however, has long been underutilized
for the synthesis of oxygen heterocycles,9 in spite of its great
potential in developing new transformations that may be
difficult to access from conventional strategies. Recently, we
developed a highly efficient [4+1] annulation reaction to access
functionalized tetrahydrofurans under mild basic conditions.7a
The key feature of this reaction relied on the use of peroxides
as bifunctional electrophilic oxygen and carbon synthons to
engage in the tandem C–C and C–O bond-forming reactions
with one carbon nucleophiles. As part of our ongoing research
aimed at developing new cyclization reactions from functiona-
lized peroxides, we were particularly interested in examining
whether such an annulation strategy could be applied to
the synthesis of six-membered oxacycles. To the best of our
knowledge, the general [5+1] annulation10 reaction utilizing a
[C1] gem-dianion and a [O1–C5] dielectrophile coupling strategy
has not been realized to date.
We commenced the investigation by selecting ethyl benzoyl-
acetate 1a as the model nucleophile and peroxides 2a–f as
possible five-atom electrophiles. Our primary concern was the
competitive double intermolecular C-alkylation or O-alkylation
pathways, as they would terminate the desired cyclization
process. Meanwhile, we were also quite uncertain whether per-
oxides 2a–f were sufficiently stable under the basic conditions,
as these compounds might undergo Kornblum–DeLaMare type
decomposition11 or double bond isomerization in the presence
of bases. Actually, we found that the structure of peroxides had
a significant impact on the outcomes of the reaction (Table 1,
entries 1–6). Peroxides 2b and 2d bearing alkyl iodide and allyl
chloride functionalities were sufficiently stable but less reactive.
Only a trace amount of the desired product was detected under
various basic conditions.12 Peroxide 2f with an allyl iodide group
was highly reactive but less stable. The double bond in this
compound was readily isomerized to the trans geometry, which
made the subsequent ring-closing C–O bond formation more
difficult. Fortunately, peroxides 2a and 2e bearing mesyloxy and
bromo groups were found to be highly reactive and sufficiently
stable in the presence of the Cs2CO3 base. Both of them
successfully provided product 3a in 77% and 75% yields,
respectively. Further optimization revealed that the base and
temperature also had significant impacts on the reaction
(Table 1, entries 7–13). A weaker base (K2CO3) or a lower
temperature (25 1C) resulted in sluggish reactions, and the
C-alkylation intermediate was generated as the major product.
A stronger base (KOH) or a higher temperature (90 1C) led to the
severe decomposition of the peroxide. Similarly, the screening of
Entry
Variation from standard conditions
Yieldb (%)
1
2
None
2b
77
0
3
4
2c
2d
50
12
75
0c
5
6
2e
2f
7
8
25 1C
90 1C
0d
27
35
58
27
54
0d
9
Cs2CO3 (3.0 equiv.)
Cs2CO3 (10.0 equiv.)
KOH (5.0 equiv.)
K3PO4 (5.0 equiv.)
K2C03 (5.0 equiv.)
DMF
10
11
12
13
14
15
16
0e
CH3CN, THF, or DCM
2a (2.0 equiv.)
16–46
73
a
Standard conditions: 1a (0.12 mmol), 2a (0.1 mmol), and Cs2CO3
b
c
(0.50 mmol) in EtOAc, 50 1C for 6 h. Isolated yield. Isomerization of
the double bond was observed. The C-alkylation intermediate was
formed. Peroxide was decomposed.
d
e
Table 2 Substrate scope for nucleophilesa
a
Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), and Cs2CO3
(1.0 mmol) in EtOAc (2 mL) at 50 1C for 6–12 h.
other reaction parameters such as solvents and reactant ratios (Table 2, 3a–e). Similarly, bicyclic naphthalene as well as
also failed to improve the yield (Table 1, entries 14–16). Thus, we heteroaromatic furan and thiophene substrates were also
finally established the optimal conditions by using peroxide 2a tolerated under the current conditions, affording the products
or 2e as a suitable electrophile and Cs2CO3 (5.0 equiv.) as the in 76–82% yields (Table 2, 3f–h). In addition, a range of
base in ethyl acetate at 50 1C (Table 1, entries 1 and 5).
aliphatic b-keto esters were also examined for the annulation
With the optimized reaction conditions in hand, we next reactions. Substrates 1i–o consistently provided the dihydropyrans
evaluated the scope of the nucleophiles. As shown in Table 2, in about 80% yields, regardless of the structural variation on
a range of aromatic b-ketoesters bearing electron-donating both ester and carbonyl side groups (Table 2, 3i–o). Meanwhile,
or electron-withdrawing groups on the phenyl ring were other active methylene compounds, such as 1,3-dicarbonyl,
well tolerated and delivered dihydropyrans in 73–83% yields diethyl malonate, ethyl cyanoacetate, and b-keto phosphonate
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Table 4 Substrate scope for other common nucleophilesa
compounds, were also good substrates for this annulation. All of
them smoothly furnished the products in 70–81% yields (Table 2,
3p–t). Notably, product 3t bearing a rare phosphonate-containing
dihydropyran framework, has not been prepared previously.
To further expand the reaction scope, we next examined the
structural tolerance of peroxides. As shown in Table 3, a range
of 2- and 3-substituted as well as 2,3-disubstituted peroxides 4
smoothly cyclized with ethyl benzoylacetate 1a and acetoacetate 1i
under standard conditions. A series of 2,2,4-/2,2,5-trisubstituted or
2,2,4,5-tetrasubstituted dihydropyrans, including the structurally
complicated bicyclic compounds 5q–t, were conveniently prepared
in high yields (Table 3, 5a–t). It should be noted that 4-bromo-but-
2-enyl peroxides were used in these cases because they provided
slightly better yields compared to 4-mesyloxy-but-2-enyl peroxides.
In addition to active methylene compounds, other common
nucleophiles such as phenyl ester, cyanide, cyclic and acyclic
ketones were also tested for the reaction (Table 4). Bearing less
a
Reaction conditions: 6 (0.24 mmol), 2a or 4g (0.2 mmol), and KOtBu
b
(0.4 mmol) in THF (2 mL), À20 1C for 10 min. The reaction was
c
acidic a-protons, these nucleophiles were more challenging carried out at À40 1C. 3.0 equiv. of 6 and KOtBu were used.
substrates for the [5+1] annulation, as peroxides may be
incompatible with the stronger basic conditions required for
Bearing the versatile olefin and carbonyl functionalities, the
the deprotonation step. Fortunately, after careful screening, we
dihydropyrans prepared using the current method are highly
found that dihydropyrans 7a–j, including those spirocyclic
valuable building blocks for the synthesis of other six-
membered oxygenated heterocycles. As shown in Scheme 2,
compound 3i was readily converted into dihydropyranone 8 in
72% yield after a single step of chemoselective oxidation with
CrO3–pyridine reagents. Similarly, the treatment of 3i with
m-CPBA selectively produced the active ketal compound 9 in
62% yield via Baeyer–Villiger oxidation. Also, the treatment of
dihydropyran 3k with OsO4 (5 mol%) and NMO afforded diol 10
products 7d–g, were successfully generated in good yields by
using KOtBu as the base at a lower temperature. These results
indicated that the current annulation strategy was quite general
in terms of both nucleophiles and peroxides.
To explore the practicality of this new transformation, the
gram-scale synthesis of dihydropyrans was carried out under
the standard conditions. As shown in Scheme 2, [5+1] annula-
tion reactions still proceeded well on a 5 or 9 mmol scale of
peroxides and smoothly afforded products 3a, 3i, and 7g in
63–78% yields.
in 85% yield and 5 : 1 dr. Impressively, tetrahydropyran 12
could be obtained in 92% yield and with excellent diastereo-
selectivity (420 : 1 dr) via the hydrogenation of compound 7b.
Moreover, the carbonyl functionalities in dihydropyran molecules
could also be utilized for further transformation. For example,
Table 3 Substrate scope for peroxidesa
compound 3i was smoothly transformed into b-lactone 14 in 67%
a
Reaction conditions: 1a or 1i (0.24 mmol), 4 (0.2 mmol), and Cs2CO3
Scheme 2 Gram-scale synthesis and synthetic applications.
(1.0 mmol) in EtOAc (2 mL), r.t. for 6–12 h.
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G. Faita and P. Quadrelli, Chem. Rev., 2018, 118, 2080; (d) M. D. Delost,
D. T. Smith, B. J. Anderson and J. T. Njardarson, J. Med. Chem., 2018,
61, 10996.
2 (a) W. Song, S. Wang and W. Tang, Chem. – Asian J., 2017, 12, 1027;
(b) Y. Yang and B. Yu, Chem. Rev., 2017, 117, 12281.
3 For reviews, see: (a) A. Deiters and S. F. Martin, Chem. Rev., 2004,
104, 2199; (b) J. A. Marco, M. Carda, J. Murgab and E. Falomir,
Scheme 3 Control experiments.
˜
´
Tetrahedron, 2007, 63, 2929; (c) M. G. Nu´nez, P. Garcıa, R. F. Moro
´
and D. Dıez, Tetrahedron, 2010, 66, 2089; (d) V. Eschenbrenner-Lux,
overall yield and 5 : 1 dr after two steps of reduction and cycliza-
tion operations. Again, this rigid spirocyclic compound is struc-
turally new, and was prepared for the first time. The relative
configurations of the above products were unequivocally
assigned by the nuclear Overhauser effect analysis.12
Finally, to gain insights into this annulation process, we
conducted the following control experiments (Scheme 3). When
carrying out the reaction of 1a and 2a at room temperature,
we isolated the C-alkylation intermediate 15 in 85% yield. After
resubmitting this intermediate to the standard conditions, the
final product 3a was obtained in 83% yield. Furthermore,
adding a stoichiometric amount of TEMPO to the above con-
ditions did not significantly affect the reaction yields. These
results indicated that the tandem process probably proceeded
via a C–C - C–O bond-forming sequence, wherein both bonds
were more likely formed via a nucleophilic substitution
mechanism instead of a radical pathway.8,9
In conclusion, we have developed a highly efficient and
general [5+1] annulation reaction of 4-bromo- or 4-mesyloxy-
but-2-enyl peroxides with various carbon nucleophiles for the
facile synthesis of a wide range of 2,2-disubstituted dihydro-
pyrans in high yields. Unlike previous strategies, this new
approach utilized the peroxides as unique five-atom bielectro-
philic synthons to participate in the C–C and subsequent
umpolung C–O bond-forming reactions with C1 nucleophiles,
thus providing a distinct strategy to access the target dihydro-
pyrans under operationally simple conditions. We also
demonstrated that these dihydropyran products were readily
synthesized on a gram-scale and could be flexibly transformed
into other biologically important six-membered oxacycles such
as tetrahydropyran, pyranone, structurally novel spirocyclic
b-lactone, and active ketal products in 1–2 steps.
K. Kumar and H. Waldmann, Angew. Chem., Int. Ed., 2014, 53, 11146;
(e) R. Jacques, R. Pal, N. A. Parker, C. E. Sear, P. W. Smith,
A. Ribaucourt and D. M. Hodgson, Org. Biomol. Chem., 2016,
14, 5875.
4 For representative examples, see: (a) S. D. Burke, R. A. Ng,
J. A. Morrison and M. J. Alberti, J. Org. Chem., 1998, 63, 3160;
(b) S. Ma and W. Gao, J. Org. Chem., 2002, 67, 6104; (c) B. Schmidt
´
˜
and S. Nave, J. Org. Chem., 2006, 71, 7364; (d) S. Catalan-Munoz,
C. A. Mu¨ller and S. V. Ley, Eur. J. Org. Chem., 2010, 183;
(e) D. K. Mohapatra, P. P. Das, M. R. Pattanayak and J. S. Yadav,
Chem. – Eur. J., 2010, 16, 2072; ( f ) K.-G. Ji, H.-T. Zhu, F. Yang,
A. Shaukat, X.-F. Xia, Y.-F. Yang, X.-Y. Liu and Y.-M. Liang, J. Org.
Chem., 2010, 75, 5670; (g) B. Guo, G. Schwarzwalder and J. T.
Njardarson, Angew. Chem., Int. Ed., 2012, 51, 5675; (h) A. Zhdanko
and M. E. Maier, Eur. J. Org. Chem., 2014, 3411.
5 (a) H. Robert, B. Garrigues and J. Dubac, Tetrahedron Lett., 1998,
´
39, 1161; (b) C. Bolm and O. Simic, J. Am. Chem. Soc., 2001,
´
`
123, 3830; (c) C. Bataille, G. Begin, A. Guillam, L. Lemiegre, C. Lys,
J. Maddaluno and L. Toupet, J. Org. Chem., 2002, 67, 8054;
(d) C. Bolm, M. Verrucci, O. Simi´c, P. G. Cozzi, G. Raabe and
´
H. Okamura, Chem. Commun., 2003, 2826; (e) A. Chretien,
I. Chataigner and S. R. Piettre, Tetrahedron, 2005, 61, 7907;
( f ) N. Momiyama, H. Tabuse and M. Terada, J. Am. Chem. Soc.,
2009, 131, 12882; (g) K. Fujiwara, T. Kurahashi and S. Matsubara,
`
J. Am. Chem. Soc., 2012, 134, 5512; (h) L. Liu, H. Kim, Y. Xie, C. Fares,
P. S. J. Kaib, R. Goddard and B. List, J. Am. Chem. Soc., 2017,
139, 13656.
6 (a) G. S. Viswanathan, J. Yang and C.-J. Li, Org. Lett., 1999, 1, 993;
´
(b) A. P. Dobbs and S. Martinovic, Tetrahedron Lett., 2002, 43, 7055;
´
´
(c) P. O. Miranda, D. D. Dıaz, J. I. Padron, J. Bermejo and
´
V. S. Martın, Org. Lett., 2003, 5, 1979; (d) S. P. Fearnley and
P. Lory, Org. Lett., 2007, 9, 3507; (e) M. P. Castaldi, D. M. Troast
and J. A. Porco, Org. Lett., 2009, 11, 3362; ( f ) R. F. Lambert,
R. J. Hinkle, S. E. Ammann, Y. Lian, J. Liu, S. E. Lewis and
R. D. Pike, J. Org. Chem., 2011, 76, 9269; (g) V. Weidmann,
J. Ploog, S. Kliewer, M. Schaffrath and W. Maison, J. Org. Chem.,
2014, 79, 10123.
7 (a) M. Gao, Y. Zhao, C. Zhong, S. Liu, P. Liu, Q. Yin and L. Hu, Org.
Lett., 2019, 21, 5679; (b) B. Wu, J. Yang, M. Gao and L. Hu, Org. Lett.,
2020, 22, 5561.
8 (a) T. W. Campbell, W. Burney and T. L. Jacobs, J. Am. Chem. Soc.,
¨
1950, 72, 2735; (b) R. E. Ziegert and S. Brase, Synlett, 2006, 2119;
We are grateful for the financial support from the NSFC
(21871032), the Fundamental Research Funds for the Central
Universities (2018CDQYYX0041, 2020CDJ-LHZZ-007), the Natural
Science Foundation of Chongqing (cstc2020jcyj-msxmX0520),
and the Venture & Innovation Support Program for Chongqing
Overseas Returnees (cx2017013).
(c) Y. Hou, C. Y. Meyers and M. Akomeah, J. Org. Chem., 2009,
74, 6362; (d) S. Kyasa and P. H. Dussault, Org. Lett., 2014, 16, 5235;
(e) S. Kyasa, R. N. Meier, R. A. Pardini, T. K. Truttmann, K. T. Kuwata
and P. H. Dussault, J. Org. Chem., 2015, 80, 12100.
9 (a) R. Willand-Charnley, B. W. Puffer and P. H. Dussault,
J. Am. Chem. Soc., 2014, 136, 5821; (b) A. Horn and P. H. Dussault,
J. Org. Chem., 2019, 84, 14611.
10 For reviews of [5+1] reactions, see: (a) X.-F. Fu and Z.-X. Yu, in
Methods and Applications of Cycloaddition Reactions in Organic Syntheses,
ed. N. Nishiwaki, Wiley-VCH, Weinheim, 1st edn, 2014, vol. 17,
pp. 551–564; (b) Y. Gao, X.-F. Fu and Z.-X. Yu, in Transition Metal-
Catalyzed Cycloadditions of Cyclopropanes for the Synthesis of Carbo-
cycles: C–C Activation in Cyclopropanes, ed. G.-B. Dong, Springer-
Verlag, Berlin Heidelberg, 1st edn, 2014, vol. 7, 195–231.
11 (a) N. Kornblum and H. E. DeLaMare, J. Am. Chem. Soc., 1951,
73, 880; (b) S. T. Staben, X. Linghu and F. D. Toste, J. Am. Chem. Soc.,
2006, 128, 12658.
Conflicts of interest
There are no conflicts of interest to declare.
Notes and references
¨
1 (a) J. Mulzer and E. Ohler, Chem. Rev., 2003, 103, 3753; (b) T. C.
Johnson and D. Siegel, Chem. Rev., 2017, 117, 12052; (c) G. Desimoni, 12 See the ESI,† for details.
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