Highly diastereoselective synthesis of 3-methylenetetrahydropyrans by palladium-catalyzed oxa-[4 + 2] cycloaddition of 2-alkenylbenzothiazoles

Article abstract of DOI:10.1039/d0ob01434f

A highly diastereoselective synthesis of 3-methylenetetrahydropyrans via palladium-catalyzed oxa-[4 + 2] cycloaddition of 2-alkenylbenzothiazoles with allyl carbonates bearing a nucleophilic alcohol side chain is presented. This synthetic methodology tolerates a wide variety of 2-alkenylbenzothiazoles and afforded the desired 3-methylenetetrahydropyrans in good yields and excellent dr. In addition, further derivatizations resulted in new scaffolds, making them useful synthetic precursors.

Full text of DOI:10.1039/d0ob01434f

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DOI: 10.1039/D0OB01434F
COMMUNICATION
Highly Diastereoselective Synthesis of 3-
Methylenetetrahydropyrans by Palladium-Catalyzed Oxa-[4+2]
Cycloaddition of 2-Alkenylbenzothiazoles
Xiaoxiao Song,*a Lei Xu a and Qijian Ni *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A
highly
diastereoselective
synthesis
of
3- to access functional heterocycles.3 Various allyl precursors
methylenetetrahydropyrans via palladium-catalyzed oxa-[4+2] were introduced to generate allylpalladium species under
cycloaddition of 2-alkenylbenzothiazoles with allyl carbonates palladium(0) catalyst. For instance, trimethylenemethane,4
bearing a nucleophilic alcohol side chain is presented. This vinyl cyclopropanes,5 vinyl epoxides6 or vinylethylene
synthetic methodology tolerates
a
wide variety of 2- carbonates7 have been widely used as C3 synthons to conduct
alkenylbenzothiazoles and afforded
the
desired
3- [3+n] cycloaddition reactions. Moreover, the approaches
methylenetetrahydropyrans in good yields and excellent dr. In involved [4+n] cycloadditions with vinyl benzoxazinones8 or γ-
addition, further derivatizations resulted in new scaffolds, making methylidene-δ-valerolactones9 have been well studied to
them useful synthetic precursors.
Functionalized 3-methylenetetrahydropyrans
synthesize diverse functionalized heterocyclic compounds.
In view of the six-member ring of 3-methylenetetra-
hydropyrans, the intermolecular [3+3] or [4+2] cycloadditions
through palladium-stabilized zwitterions enabled a facile and
straightforward tool for the formation of this intriguing
scaffold. In this context, Klumpp and co-workers reported the
pioneering work on palladium-catalyzed regioselective [3+3]
cycloadditions of 2-(chloromagnesiomethyl)-2-alkenyl ethers
with epoxides to provide synthetic important 1,3-oxazolidines
in high yields (Scheme 1a).10 Guo described a palladium-
catalyzed decarboxylative [4+2] cycloaddition of 2-
methylidenetrimethylene carbonate with alkenes to construct
chiral tetrapyran-fused spirocyclic scaffolds (Scheme 1b).11
However, rarely have allyl carbonates bearing a nucleophilic
alcohol been used for intermolecular cycloaddition, and to our
knowledge, only two examples of [4+2] cycloadditions were
reported to generate 3-methylenetetrahydropyrans. In 2016,
the group of You developed palladium catalyzed [4+2]
cycloaddition of indole with allyl carbonates bearing a nucleophilic
alcohol via dearomatization strategy to synthesize polycyclic
constitute
synthetically valuable building blocks in organic synthesis and
are characteristic structural motifs in numerous biologically
active natural products and pharmaceuticals.1 Thus,
considerable effort has been directed towards the
development of new methods for the rapid construction of
diversely substituted 3-methylenetetrahydropyrans.2 These
methods include intramolecular radical cycloaddition,2i Claisen
rearrangement,2f
palladium-catalyzed
umpolung
cycloaddition,2h and Ni-catalyzed reductive coupling.2g
However, most of these transformations involved substrate
limitation or harsh condition that are difficult to handle, thus
leaving us much room for exploring.
Fig.
1 Typical examples of 3-methylenetetrahydropyran-containing natural
indoline with 3-methylenetetrahydropyran moiety (Scheme 1c,
products and pharmaceuticals.
12
left).
Later, Yao and co-workers employed electrophilic para-
quinone methides as reaction partner and obtained spirocyclic
framework containing 3-methylenetetrahydropyran ring through
palladium-catalyzed [4+2] cycloaddition (Scheme 1c, right).13 In aim
to develop new methods for the efficient synthesis of 3-
methylenetetrahydropyran scaffolds, we report herein a formal
[4+2] cycloaddition of activated alkene with allyl carbonates
bearing a nucleophilic alcohol for the quick access of
In the past decades, the cycloaddition reactions utilizing
palladium-stabilized zwitterions provided a powerful strategy
a.College of Chemistry and Materials Science, Key Laboratory of Functionalized
Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based
Materials, Anhui Normal University, Wuhu, Anhui 241002, P. R. China. E-mail:
qijianni@ahnu.edu.cn, xsong@ahnu.edu.cn.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Journal Name
Table 1 Optimization of the reaction conditions.a
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DOI: 10.1039/D0OB01434F
Entry
[M]
(mol %)
Ligand
(mol %)
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
Xantphos
DPEPhos
dppp
Solvent
t
dr
Yield
(%)b
95
(h)
15
24
24
24
24
24
12
24
24
24
24
12
72
12
12
24
24
(%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(OAc)2
Pd2(dba)3
Pd(dba)2
THF
THF
>20:1
-
NR
NR
NR
NR
NR
85
THF
-
Pd2(dba)3·CHCl3
Pd(MeCN)2Cl2
[IrCl(cod)2]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
THF
-
THF
-
THF
-
Scheme
1 Palladium-catalyzed cycloaddition reaction for the synthesis of 3-
methylenetetrahydropyran skeleton.
Et2O
>20:1
Dioxane
Toluene
DCM
MeCN
THF
-
NR
NR
NR
NR
90
functionalized
3-methylenetetrahydropyrans
with
our
-
prolonged interest on cycloaddition.14
-
-
Initially, the reaction of 2-alkenylbenzothiazole with allyl
carbonates bearing a nucleophilic alcohol side chain was
chosen as a model reaction and commenced our study in the
presence of Pd(OAc)2 (5 mol%) and BINAP (5 mol%). The
results of condition optimization were collected in Table 1. To
our delight, the reaction proceeded smoothly in THF at room
>20:1
>20:1
>20:1
>20:1
-
THF
88
THF
95
dppe
THF
90
PPh3
THF
NR
NR
17
TMPhth
THF
-
temperature for 15
h
and produced the desired 3-
a
General conditions: 1a (0.1 mmol), 2 (0.15 mmol), [Pd] (5 mol %), and L (5 mol %) in
b
c
methylenetetrahydropyran 3a in 95% yield and excellent
diasteroselectivity (entry 1). Intriguely, other palladium salts or
iridium complex resulted in no reaction (entries 2-6). Changing
to Et2O as solvent gave inferior result in terms of yield (entry 7).
While a quick screening of other solvents such as toluene,
MeCN, DCM or dioxane (entries 8-11) did not afford the
cycloadduct 3a. We then moved our attention toward the
phosphine ligands. Bidentate phosphines such as Xantphos,
DPEPhos, dppe and dppp led to similar catalytic results to that
of BINAP (entries 12-15). The dppp emerged as the optimal
candidate delivering the target cycloadduct 3a in 95% yield
and >20:1 dr within 12 h (entry 14). However, the switch of
monodentate triphenylphosphine or bidentate nitrogen ligand
exhibited no reactivity (entries 16-17). Finally, the optimal
conditions were identified by using Pd(OAc)2 (5 mol%) and
dppp (5 mol%) as the catalyst in THF at room temperature for
12 h, with the desired 3-methylenetetrahydropyrans 3a
formed in 95% yield (entry 14).
solvent (1.0 mL) at room temperature. All yields refer to the isolated yields. The dr
values were determined by 1H NMR spectroscopy. NR = No reaction.
excellent yields and excellent diastereoselectivities.
Introduction of electron-donating groups (-OMe, -Me) and
electron-withdrawing groups (-F, -Cl, -Br, -NO2) at the para-
position of phenyl ring of 2-alkenylbenzothiazoles led to the
corresponding 3-methylenetetrahydropyrans 3b-g in good to
excellent yields. In addition, cycloadducts 3h-l with meta-
substituted phenyl substitution were obtained in 65-92% yields.
Moreover, the presence of a substituent at the ortho-position was
well tolerated to afford good yields of 3m and 3n . 2-Naphthyl or
1-naphthyl group could also be used as the substituent on R,
giving the desired 3o and 3p in 76-85% yields at 50 °C for 24 h.
Pleasingly, heteroaryl groups, such as 2-pyridyl and 2-quininyl were
also worked well under the standard reaction conditions or at 50 °C.
The desired cycloadducts 3q-s were obtained in 87-92% yields.
Variation of R on 2-alkenylbenzothiazoles
1 to alkenyl group
Under the optimized conditions, we next investigated the
substrate scope of this palladium-catalyzed oxa-[4+2]
cycloaddition and the results are summarized in Table 2. In
most cases, the reaction proceeded smoothly for a variety of
2-alkenylbenzothiazoles bearing either electron-withdrawing
or electron-donating groups on the aromatic group (R) and
afforded the corresponding cycloadducts 3a-j with good to
displayed lower reactivity and resulted in the desired 3u in
31% yield. Moreover, 2-alkenylbenzothiazoles with aliphatic
substitutes on R successfully provided the desired 3v, albeit
with a low yield (26%). Finally, substrate 1w bearing a chloro
substituent on the benzothiazole ring also reacted with allyl
carbonates
2 smoothly, giving the expected products 3w with
95% yield. The relative configuration of the substituted 3-
methylenetetrahydropyrans was confirmed by single crystal X-
ray analysis of the product 3a (Fig. 2).15
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
Table 2 Screening of Substrate Scope.a
Pd(OAc)2 (5 mol%)
L* (5 mol%)
View Article Online
DOI: 10.S1039/D0OB01434F
Ph
N
OCO2Bn
O
+
S
CN
OH
MTBE, rt
Ph
NC
3a
N
1a
2
O
Me
O
O
PPh2
PPh2
PPh2
PPh2
PAr2
Ar =
PAr2
Me
O
L3
L2
L1
no reaction
95% yield, >20:1 dr, 12% ee
92% yield, >20:1 dr, 3% ee
O
Me
Me
O
O
PAr2
Ar =
PAr2
Me
N
O
P
Ph2P
NH HN
PPh2
O
Me
O
O
O
L4
L5
L6
no reaction
95% yield, >20:1 dr, 37% ee
no reaction
Scheme 2 Enantioselective studies of this methodology.
chiral bidentate ligands was examined (Scheme 2).
Unfortunately, only axially chiral bisphosphine ligand realized
the enantioselectivity and gave 3a in 95% yield and up to 37%
ee. when employing (R)-DM-SEGphos L4 as chiral ligand. Trost
ligand L5 and monodentate phosphoramidite ligand L6 were
also tested, however, the reactions failed to afford the desired
3a
.
To demonstrate the potential utility of 3-methylenetetra-
hydropyrans, further synthetic transformation of 3a was
performed. As shown in Scheme 3, hydrogenation of 3a in the
presence of H2 and 10 mol% Pd/C selectively reduced the C=C
double bond, forming
4 in 90% yield and >20:1 dr. The
oxidation of exocylic double bond was also achieved by using
m-CPBA, which provided 61% yield of spirocyclic epoxide
single diasteromer.
5 in
a
Standard conditions: 1a (0.1 mmol), 2 (0.15 mmol), Pd(OAc)2 (5 mol%), and dppp (5
mol%) in THF (1.0 mL) at room temperature for 12 h. All dr values were >20 : 1 as
determined from the crude 1H NMR spectra. b All yields refer to the isolated yields.
c
50 °C , 24 h. d rt, 24 h. e 50 °C .
Scheme 3 Derivatization of the product 3a. Reaction conditions: (a) 10 mol%
Pd/C, H2 (balloon), MeOH, 50 °C, 12 h; (b) m-CPBA (1.8 equiv.), DCE, reflux, 24 h.
Conclusions
In summary, we have developed an efficient strategy for the
highly diastereoselective synthesis of 3-methylenetetrahydro-
pyrans via palladium catalyzed oxa-[4+2] cycloaddition of 2-
alkenylbenzothiazoles with allyl carbonates bearing a nucleophilic
alcohol side chain. The reaction features good functional group
tolerance, allowing efficient access to a wide variety of highly
substituted 3-methylenetetrahydropyrans under mild conditions.
Further transformations of the cycloadducts demonstrated the
synthetic utility of this process and provided useful tetrahydropyran
derivatives. Investigations concerning the asymmetric study, as
well as the use of this methodology are currently underway in
our laboratory.
Fig. 2 Single-crystal X-ray diffraction analysis of 3a
.
To further investigate this transformation, we then turn
our attention to the asymmetric oxa-[4+2] cycloaddition
reaction. First, we performed the above model reaction in the
presence of Pd(OAc)2 and (R)-BINAP with the ether-type
solvent of THF and MTBE, respectively. As a result, MTBE was
proved to be better for the improvement of enantioselectivity
(12% ee vs 5% ee). Subsequently, an extensive screening of
Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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11600-11604; (e) H.-W. Zhao, L.-R. Wang, J.-M. Guo, W.-Q.
Acknowledgements
We are grateful for the financial support from the Anhui
Provincial Natural Science Foundation (1908085QB55) and the
Scientific Research Foundation of the Higher
Institutions of Anhui Province (KJ2019A0499).
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0OB01434F
A highly diastereoselective synthesis of 3-methylenetetrahydropyrans via
palladium-catalyzed oxa-[4+2] cycloaddition of 2-alkenylbenzothiazoles with
allyl carbonates bearing a nucleophilic alcohol side chain is described
Ar
N
S
OCO2R
OH
EWG
S
Pd(OAc)2 / dppp
+
Ar
EWG
THF, rt - 50 C
Ar
O
N
Ar
23 examples
26-96% yield
>20:1 dr