Asymmetric Intramolecular Hydroalkoxylation of Unactivated Alkenes Catalyzed by Chiral N-Triflyl Phosphoramide and TiCl4?

Article abstract of DOI:10.1002/cjoc.201900544

By using a combination of a chiral N-triflyl phosphoramide and TiCl₄ as the catalyst, a new process for asymmetric intramolecular hydroalkoxylation of unactivated alkenes was developed, producing various chiral tetrahydrofuran derivatives in 51%—99% yields with 30%—71% ee's.

Full text of DOI:10.1002/cjoc.201900544

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Asymmetric Intramolecular Hydroalkoxylation of Unactivated Alkenes
Catalyzed by Chiral N-Triflyl Phosphoramide and TiCl4
Pengyuan Zhao, Aolin Cheng, Xinxu Wang, Jiguo Ma, Guoqing Zhao,* Yingkun Li, Yi Zhang, Baoguo Zhao*
†The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University,
Shanghai 200234, P. R. China
Summary of main observation and conclusion By using a combination of a chiral N-triflyl phosphoramide and TiCl4 as the catalyst, a new process for
asymmetric intramolecular hydroalkoxylation of unactivated alkenes was developed, producing various chiral tetrahydrofuran derivatives in 51-99% yields
with 30-71% ee’s.
Scheme
unactivated alkenes.
1 Catalytic asymmetric intramolecular hydroalkoxylation of
Background and Originality Content
Hydroalkoxylation of alkenes is defined as addition of an
alcohol group to a C-C double bond, which provides an atom-
economical and highly straightforward way for the synthesis of
ethers with increased value from readily available olefins.1
Although non-asymmetric hydroalkoxylation of unactivated
olefins has been achieved by using strong Lewis acids,2 Brønsted
acids,3 or transition metals4 as the catalyst, development of
asymmetric processes still remains a formidable challenge in
organic chemistry. Recently, asymmetric hydroalkoxylation of
unactivated alkenes has been sporadically reported.5-9 For
example, in 2015 Sawamura and co-workers used
(R)-DTBM-SEGPHOS-Cu(I) complex as the catalyst for asymmetric
intramolecular hydroalkoxylation of an alkenol to give the
corresponding chiral tetrahydrofuran in a 39% yield with 71% ee
(Scheme 1a).5 At the same time, Hintermann and co-workers
developed asymmetric intramolecular hydroalkoxylation of
allylphenols to chiral 2-methylcoumarans in the presence of 5 mol%
of Ti(OiPr)4-L2 under microwave irradiation, affording chiral
2-methylcoumarans in 56-93% yields with 71-87% ee’s (Scheme
1b).6 Very recently, List and co-workers developed chiral Brønsted
acid catalyzed asymmetric intramolecular hydroalkoxylation of
1,1-disubstituted alkenes by using chiral imidodiphosphorimidate
L3 as the catalyst to produce various chiral tetrahydrofurans and
tetrahydropyrans with yields of up to 94% and ee’s of up to 97%
(Scheme 1c).7 In addition, chiral salen-Co catalyzed and enzymatic
asymmetric intramolecular hydroalkoxylations also were
respectively developed by Shigehisa and coworkers,8 and Yang and
coworkers.9 Chiral phosphoric acids and N-triflyl phosphoramides
have been widely used as acid-base cooperative organocatalysts
for various asymmetric catalysis.10 However, their Brønsted acidity
is generally not strong enough to promote hydroalkoxylation of
unactivated olefins. By combining a chiral N-triflyl phosphoramide
and strong Lewis acid TiCl4, we achieved catalytic asymmetric
hydroalkoxylation of alkenols to produce chiral tetrahydrofurans11
under mild conditions (Scheme 1d). Herein, we report our results
on the project.
2a in 99% yield in the presence of 50 mol% of TiCl4, whereas HCl3b
did not promote the hydroalkoxylation under otherwise the same
conditions (Table 1, entry 2 vs 3). This demonstrated that the
active catalyst for the reaction likely was the strong Lewis acid
TiCl4, not its “hidden Brønsted acid” HCl.12 A decrease in the
amount of TiCl4 to 10 mol% almost completely eliminated the
transformation probably due to hydrolysis of TiCl4 by the moisture
Results and Discussion
Studies started with the investigation of the hydroalkoxylation
of alkenol 1a [Table 1 and Table S1 in Supporting Information (SI)].
The reaction went smoothly to form substituted tetrahydrofuran
*E-mail: gqzhao@shnu.edu.cn, zhaobg2006@shnu.edu.cn
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First author et al.
Report
in the reaction
system (Table 1, entry 1). However, the reaction became active
again when introducing additional 10 mol% of chiral N-triflyl
phosphoramide (R)-3a (Table 1, entry 5). But the phosphoramide
(R)-3a itself couldn’t promote the hydroalkoxylation (Table 1,
entry 6), implying that (R)-3a likely served as a ligand to stabilize
TiCl4 and also contribute the enantiocontrol during the catalysis.
The additive trimethylsilyl chloride (TMSCl) could eliminate the
moisture and thus protected the TiCl4 species from hydrolysis,
making the reaction much more reproducible without any loss of
yield and enantioselectivity (Table 1, entry 9 vs 8). Further studies
showed that phosphoramide (R)-3f exhibited the highest
enantioselectivity for the reaction, to give the corresponding
chiral tetrahydrofuran 2a in a 92% yield with 59% ee (Table 1,
entry 12 vs entries 5, 7-11, and 13, and Scheme 2). The absolute
configuration of 2a was determined as S by X-ray analysis (see SI).
The ee value can be further improved to 71% when
tetrachloromethane (CCl4) was chosen as the solvent for the
reaction (Table 1, entry 14). Lowering reaction temperature from
40 ℃ to 25 ℃ resulted in a similar ee but a much lower
isolated yield (SI, Table S1, entry 15 vs 14). An increase in the
amount of phosphoramide (R)-3f led to an obvious decrease of
enantioselectivity (SI, Table S1, entry 14 vs 18-19). The
replacement of TiCl4 with other strong Lewis acids (AlCl3, SnCl4, or
FeCl3) or of phosphoramide (R)-3f with BINOL resulted in
disappearance of enantioselectivity or conversion (Table 1, entries
15-18 and 4). Control experiments showed that the AlCl3, SnCl4,
and FeCl3 catalytic systems could not promote racemization of
enantioenriched tetrahydrofuran 2a (see SI), implying these
corresponding catalytic systems did not have stereoselective
induction for the hydroalkoxylation.
Table 1 Investigation of reaction conditionsa
Under the optimized reaction conditions, the substrate scope
was then examined for the asymmetric hydroalkoxylation with 10
mol% TiCl4 and 10 mol% chiral N-triflyl phosphoramide (R)-3f as
the catalyst (Table 2). Various 2,2-disubstituted terminal alkenols
1a-h underwent asymmetric intramolecular hydroalkoxylation to
give the corresponding chiral tetrahydrofuran derivatives 2a-h in
63-99% yields with 42-71 ee’s (Table 2, entries 1-8). The
electronic property of the 2,2-substituents seems to have little
impact on the reaction in terms of reactivity and
enantioselectivity (Table 2, entries 1-4 vs entry 5). Alkenol
substrates bearing an internal double bond such as compounds 1i
and 1j displayed obviously lower reactivity for the transformation
(Table 2, entries 9 and 10). The corresponding hydroalkoxylations
were carried out at an increased temperature (60 ℃ vs 40 ℃),
forming chiral tetrahydrofurans 2i and 2j in lower yields and with
decreased ee’s. No six-membered products were observed for the
two substrates although the corresponding 6-endo-trig cyclization
was also allowed by Baldwin’s rules. Alkenol 1k having a phenyl
substituent at the internal carbon of the double bond underwent
intramolecular hydroalkoxylation to produce 2k in 85% yield but
without any enantioselectivity (Table 2, entry 11). The substrate
was even active for the hydroalkoxylation with N-triflyl
phosphoramide (R)-3f as the catalyst without TiCl4, but resulting
in similar reaction results (90% yield, 0% ee). Alkenols with one
carbon longer chain between the hydroxyl group and the C-C
double bond such as 2,2-diphenylhex-5-en-1-ol were ineffective
for the reaction.
aAll reactions were performed with 1a (0.91 mmol), MXn (0.091 mmol,
10 mol%), (R)-3 (0.091 mmol, 10 mol%), TMSCl (0.0273 mmol, 30 mol%) in
solvent (1.5 mL) at 40 °C for 22 h unless otherwise stated. The absolute
configuration of 2a was determined as
S by X-ray crystallography.
c
bIsolated yields based on 1a. Enantiomeric excesses were determined by
d
chiral HPLC analysis. 50 mol% of TiCl4 was used. e82 mol% of dry HCl was
used. fThe reaction was performed with 1a (0.25 mmol), TiCl4 (0.025 mmol,
10 mol%), (R)-3g (0.025 mmol, 10 mol%), TMSCl (0.075 mmol, 30 mol%)
in CCl4 (0.45 mL) at 40 °C for 22 h.
Scheme 2 Phosphoramides 3 examined.
The two phenyl substituents of 1a was crucial for its
intramolecular hydroalkoxylation activity. Replacement of the
phenyl substituents with methyl groups (1l) or hydrogens (1m) led
to a dramatic decrease in the yield of cyclization product 2l or
even a complete deactivation for the formation of 2m (Scheme
3a). These results demonstrated that the phenyl substituents had
an obvious Thorpe-Ingold effect on the intramolecular
hydroalkoxylation.13 Reaction of 2-allylphenol (1n) under the
standard conditions did not give the corresponding cyclized
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Running title
Chin. J. Chem.
hydroalkoxylation product, but produced hydrochlorination
product 4 (Scheme 3b). No isomerization of the C-C double bond
of 1n was observed during the reaction and TiCl4 catalyst was
necessary for the chlorination, implying the transformation likely
proceeded via a Lewis acid catalyzed process.
stated. The absolute configuration of 2a was determined as S by
X-ray crystallography and those of 2b-j were tentatively assigned
as S by analogy. bIsolated yields based on 1. cEnantiomeric
d
excesses were determined by chiral HPLC analysis. The reaction
was carried out with 1 (0.455 mmol), TiCl4 (0.091 mmol), (R)-3f
(0.091 mmol), TMSCl (0.273 mmol) in CCl4 (1.0 mL) at 60 ℃ for
22 h. eNo 6-membered cyclized products were observed as judged
by 1H NMR analysis of the crude reaction mixtures, so
regioselectivities were greater than 20:1. fReaction time was 12 h.
gThe reaction was carried out with 1 (0.91 mmol, 10 mol%), (R)-3f
(0.091 mmol, 10 mol%) in CCl4 (1.5 mL) at 40 °C for 22 h.
Table 2 Investigation of the substrate scope for the catalytic asymmetric
hydroalkoxylation of olefinsa
Scheme 3 Control experiments.
In the absence of TiCl4, the N-triflyl phosphoramides (R)-3
alone could not promote the hydroalkoxylation of 1a (Table 1,
entry 6). This implied that the active catalytic species likely be a
complex formed between (R)-3 and TiCl4 (Scheme 4).14 The
Ti(IV)-(R)-3 complex may serve either as a chiral Lewis acid or as a
chiral super strong Brønsted acid to catalyze the asymmetric
hydroalkoxylation. We preferred the Lewis acid-catalyzed process
based on the following considerations. (1) The combination of
TiCl4 and N-mesyl phosphoramide (R)-3g also displayed catalytic
activity for the reaction (Table 1, entry 13), despite the much
lower Brønsted acidity as compared to N-triflyl phosphoramide
(R)-3f. (2) A possible carbon cation intermediate generated during
a Brønsted acid catalyzed process may trigger the isomerization of
the double bond to a more stable one, but no isomerization
occurred in the treatment of 1n with (R)-3f and TiCl4 as judged by
1H NMR analysis of the crude reaction mixture (Scheme 3b).
On the other hand, the formation of the Ti(IV)-(R)-3 complex
can greatly increase in the Brønsted acity of N-triflyl
phosphoramide (R)-3.14-16 So it is also possible that the complex
acted as a chiral super strong Brønsted acid catalyst for the
hydroalkoxylation.14-16 At this point we have not been able to
completely eliminate this mechanistic possibility.
Scheme 4 The Proposed complex formed between 3 and TiCl4.
Conclusions
In summary, we have developed
a new process for
asymmetric intramolecular hydroalkoxylation of unactivated
olefins by using a combination of N-triflyl phosphoramide (R)-3
and TiCl4 as catalyst. Although the enantioselectivity is moderate,
this work has provided a new catalytic strategy for asymmetric
hydroalkoxylation of challenging unactivated olefins.
aAll reactions were performed with 1 (0.91 mmol), TiCl4 (0.091
mmol, 10 mol%), (R)-3f (0.091 mmol, 10 mol%), TMSCl (0.273
mmol, 30 mol%) in CCl4 (1.5 mL) at 40 °C for 22 h unless otherwise
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.
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3

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Hydroalkoxylation of Non-activated Olefins Catalysed by Lewis
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Supporting Information
The Supporting Information is available free of charge on the
WWW under https://doi.org/10.1002/cjoc.2019xxxxx. Synthetic
procedure, characterization data, spectroscopic spectra, and
chromatograms for ee determination (pdf), Crystallographic data
for 2a (CIF).
Tetrahydrofurans
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Accession Codes
CCDC 1863034 contains the supplementary crystallographic
data for compound 2a. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
re-quest@ccdc.cam.ac.uk, or by contacting the Cambridge
Crystallo-graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033.
Acknowledgement
We are grateful for the generous financial support from the
National Natural Science Foundation of China (21672148,
21871181), the Shanghai Municipal Education Commission
(2019-01-07-00-02-E00029), the Science and Technology
Commission of Shanghai Municipality (19XD1402700), and the
Shanghai Engineering Research Center of Green Energy Chemical
Engineering.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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Entry for the Table of Contents
Page No.
Asymmetric Intramolecular Hydroalkoxylation
of Unactivated Alkenes Catalyzed by Chiral
N-Triflyl Phosphoramide and TiCl4
A combination of N-triflyl phosphoramide and TiCl4 challenges asymmetric hydroalkoxylation of
unactivated alkenes.
Pengyuan Zhao, Aolin Cheng, Xinxu Wang, Jiguo
Ma, Guoqing Zhao,* Yingkun Li, Yi Zhang,
Baoguo Zhao*
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.
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