Mild C–C Bond Formation via Lewis Acid Catalyzed Oxetane Ring Opening with Soft Carbon Nucleophiles

Article abstract of DOI:10.1002/anie.202013062

Mild oxetane opening by soft carbon nucleophiles has been developed for efficient C?C bond formation. In the presence of LiNTf₂ or TBSNTf₂ as catalyst, silyl ketene acetals were found to be effective nucleophiles to generate a wide range of highly oxygenated molecules, which are key substructure in natural products like polyketides. Furthermore, intramolecular oxetane opening by a styrene-based carbon nucleophile via a Prins-type process was also achieved with Sc(OTf)₃ as catalyst, leading to efficient formation of the useful 2,3-dihydrobenzo[b]oxepine skeleton.

Full text of DOI:10.1002/anie.202013062

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Accepted Article
Title: Mild C–C Bond Formation via Lewis Acid Catalyzed Oxetane
Ring Opening with Soft Carbon Nucleophiles
Authors: Hai Huang, Tianyu Zhang, and Jianwei Sun
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Mild C–C Bond Formation via Lewis Acid Catalyzed Oxetane Ring
Opening with Soft Carbon Nucleophiles
Hai Huang, Tianyu Zhang, and Jianwei Sun*
[
8]
Abstract: Mild oxetane opening by soft carbon nucleophiles has been
developed for efficient C–C bond formation. In the presence of LiNTf
or TBSNTf as catalyst, silyl ketene acetals were found to be effective
nucleophiles to generate wide range of highly oxygenated
chemistry. On the other hand, its chemical inertness (relative to
[
9]
2
carbonyl and epoxides) toward nucleophiles has resulted in a
substantial paucity of transformations with broad applications in
organic synthesis (Scheme 1C). Indeed, among their ring-opening
reactions, the vast majority employed heteroatom-based
2
a
molecules, which are key substructure in natural products like
polyketides. Furthermore, intramolecular oxetane opening by a
styrene-based carbon nucleophile via a Prins-type process was also
[
10,11]
nucleophiles.
In contrast, the use of a carbon nucleophile for C–
C bond formation has been much less explored. Current success has
been limited to the use of strong organometallic reagents (e.g., RLi,
RMgX), typically in combination with strong Lewis acid activation (e.g,
3
achieved with Sc(OTf) as catalyst, leading to efficient formation of the
useful 2,3-dihydrobenzo[b]oxepine skeleton.
[
12]
3
BF ). Consequently, these strong conditions led to poor functional
group tolerance and limited applications in organic synthesis. In this
context, a mild catalytic protocol using soft carbon nucleophiles
remains highly desirable.
Carbon–carbon (C–C) bond-forming reactions are of paramount
importance in organic synthesis, as they play a pivotal role in the
[
1]
elaboration and extension of organic molecule frameworks. Among
3
3
them, C(sp )–C(sp ) cross-couplings are generally more challenging
2
[1b]
than those involving C(sp ) or C(sp) atoms.
Therefore, the
3
development of efficient, selective, and mild protocols for C(sp )–
3
C(sp ) bond formation has been a longstanding pursuit of organic
[
2]
chemists. Of particular note is enolate alkylation, a power strategy
for the access to various synthetically valuable oxygenated molecules
that are key subunits of numerous natural products, such as
[
3]
polyketides.
The aldol reaction, employing simple carbonyl
compounds as electrophile, represents the most versatile access to
[
4]
1
,3-oxygenated molecules (Scheme 1A). Along this line, the use of
[
5]
epoxides leads to 1,4-oxygenation. Furthermore, the Michael
[
6]
addition to enones provides 1,5-oxygenated molecules. In addition
to these relatively reactive electrohpiles, it is important to note that the
search for additional electrophiles for mild C–C bond formation would
not only enrich the enolate chemistry, but also provide complementary
access to such valuable oxygenated molecules. Herein we disclose a
new mild catalytic approach for the efficient synthesis of 1,5-
oxygenated molecules by direct intermolecular C–C bond formation
from silyl enolates and oxetanes (Scheme 1B). Oxtanes can
accommodate additional functional groups in the 3-position, thus
allowing more diversified functionalization/oxygenation patterns in the
product framework. Further extension to the use of styrene as another
type of soft carbon nucleophiles has also been achieved, providing
access to the important heterocycle, 2,3-dihydrobenzo[b]oxepine.
Oxetane is an important functional group in organic synthesis and
[
7,8]
medicinal chemistry.
Notably, its resemblance to a carbonyl group
Scheme 1. Synthesis of 1,n-oxygenated molecules from enolates.
in dipole moments combined with the metabolic stability has enabled
oxetane to serve as a unique carbonyl surrogate in medicinal
We began our study with 1a as substrate. Different silyl enolates
were evaluated as potential nucleophiles with HNTf
2
as catalyst (see
[
13,14]
the SI for details).
The preliminary results indicated that silyl
[]
Dr. H. Huang, T. Zhang, Prof. J. Sun
ketene acetal (SKA) 2a showed the best reactivity toward C–C bond
formation. We next screened different Lewis acid catalysts (Table 1).
Jiangsu Key Laboratory of Advanced Catalytic Materials &
Technology, School of Petrochemical Engineering, Changzhou
University, Changzhou (China)
–
It was found that those bearing weakly coordinating anions (e.g.,
–
OTf and NTf
2
) were generally better, likely due to higher Lewis
Prof. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (China)
E-mail: sunjw@ust.hk
[15]
acidity than those having a stronger anion (see the SI for details).
LiNTf
formation of the desired product 3a (88% yield, entry 8). Notably,
replacing either the metal ion (e.g., NaNTf , KNTf ) or the counter
anion (e.g., LiOTf, LiBr, LiOAc) resulted in completely no reaction.
2
was identified as a superior catalyst, leading to clean
2
2
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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COMMUNICATION
We believe that this unique combination of the most Lewis acidic alkali
We were interested to know whether LiNTf
2
serves as a pre-catalyst
+
–
metal ion Li and a weak anion NTf
increasing the loading of SKA further improved the efficiency (entry
2).
2
is critically important. Finally,
of silyl triflimide, since in-situ generation of the latter has been known
[
4g,14]
in the related Mukaiyama aldol reactions.
amounts of substrate 2a and LiNTf . However, no trace of TBSNTf
was observed based on F NMR spectra (Eq. 1). Indeed, the reverse
reaction between the lithium enolate and TBSNTf should be a very
Thus, we mixed equal
1
2
2
19
Table 1. Screening of Lewis acid catalysts.[a]
2
[
18]
facile reaction.
The above results could be inconclusive. If the above equilibrium is
fast and substantially favors the left side, a small amount of TBSNTf
2
19
can still be present without noticeable shift of the F NMR signal. Next,
[
19]
we separately prepared TBSNTf
2
and examined its catalytic activity.
, the reaction
Entry
X
Conv. (%)
Yield[b]
To our surprise, in the presence of 2.5 mol% of TBSNTf
2
1
2
3
4
5
6
7
8
9
Sc(OTf)
3
52
0
7
between 1a and 2a proceeded to form product 4a in quantitative yield
(Scheme 3). This product might result from a second nucleophilic
attack onto the initial product 3a (or its analogue, vide infra). It is worth
AgOTf
0
Sn(OTf)
2
58
50
100
0
23
2
noting that, in the standard protocol with LiNTf as catalyst, the
In(OTf)
3
22
formation of 4a was essentially not observed (Scheme 3). The
Yb(OTf)
3
66
observation of orthogonal products is indirect evidence of involving
Zn(OTf)
2
0
+
+
different catalytic species in these two systems (Li vs. TBS ).
AgNTf
2
31
90
0
29
Moreover, the complete incapability of NaNTf
2
+
and KNTf
2
for this
LiNTf
LiOTf
NaNTf
2
88
reaction is also consistent with the key role of Li for activation.
0
The special performance of TBSNTf
2
prompted us to briefly
1
0
1
2
0
0
0
examine this cascade double C–C bond formation process. Indeed,
after acidic work-up, the protected ζ,ε-dihydroxy β-ketoesters 5 could
be obtained. This cascade protocol provides new access to diversely-
functionalized carbonyl compounds with remarkable C–C bond-
forming efficiency. Moreover, the substitution of a 3-alkoxyl group in
the oxetane allowed formation of 1,2,5,7-tetraoxygenated carbon
frameworks.
1
KNTf
2
0
1
2[c]
LiNTf
2
100
93 (80)[d]
[
[
a] Reaction scale: 1a (0.20 mmol), 2a (0.3 mmol), LA (10 mol%), DCE (2.0 mL).
b] Determined by H NMR analysis of the crude mixture using (CH
internal standard. [c] 2.5 equiv of 2a. [d] Isolated yield in parentheses.
1
2
Br)
2
as an
A range of oxetanes and SKAs smoothly participated in this process
(Scheme 2). Oxetanes with various 3-substituents led to diverse γ-
functionalized-δ-siloxy esters 3. The mild conditions tolerated a broad
range of functional groups. Different heterocycles and a steroid
substructure were also incorporated into the products. However,
oxetanes with a substituent in the 2-position did not provide a clean
reaction. The low yields of 3p-q were due to low conversion. However,
in the case of 3v-y, some unknown byproducts were observed.
Increasing catalyst loading or temperature did not improve the results.
An α-substituted SKA led to clean formation of the α-branched ester
product 3ae, albeit with slow conversion. A gram-scale synthesis of 3l
was also demonstrated. Notably, γ-iodo and related products 3m-o
are known intermediates in the synthesis of biologically important
molecules, but their conventional synthesis typically entailed a
[
16]
multistep sequence.
Moreover, the protected γ,δ-dihydroxy
carbonyl compounds are also valuable intermediates in complex
[
17]
molecule synthesis. An enantioenriched SKA with (+)-menthol as
chiral auxiliary afforded the corresponding product 3af in 62% yield.
Unfortunately, the diastereoselectivity was moderate, likely due to the
remote position of the new stereogenic center relative to the chiral
auxiliary.
2
Scheme 3. Cascade bond formation with TBSNTf .
Possible mechanisms are proposed in Scheme 4. The reaction
begins with oxetane activation by catalyst MNTf (M = Li or TBS). The
resulting oxonium I undergoes nucleophilic substitution by the silyl
ketene acetal, leading to oxocarbenium II. With LiNTf as catalyst, this
2
2
intermediate can proceed to product 3 via two possible pathways. In
path a, direct silyl 1,7-migration affords the observed product 3.
Alternatively, the silyl transfer can be stepwise via ester III by forming
TBSNTf
2
followed by silylation on the alkoxide motif (path b). In
as catalyst (path c), there is no driving force
contrast, with TBSNTf
2
for silyl migration in intermediate II (M = TBS), since there is no
alkoxide nucleophile in this case. This allows another molecule of silyl
ketene acetal to attack the electrophilic oxocarbenium, forming the
second C–C bond. The resulting intermediate IV finally leads to the
2
observed product 4 and regenerates TBSNTf .
2
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2
Scheme 2. Reaction scope. 1 (2.0 mmol), 2 (5.0 mmol), LiNTf (10 mol%), DCE (20 mL); Isolated yields. [a] Yield based on recovered starting material.
yield. It was believed that the reaction initially generated the benzylic
[
21]
carbcation V followed by deprotonation.
Scheme 4. Proposed mechanisms.
Scheme 5. Intramolecular opening by styrene. Conditions: LA (10 mol%),
PhBox (20 mol%), 5Å MS, PhCl, RT.
The success with silyl enolates as nucleophile promopted us to
extend the C–C bond formation to other types of soft carbon
This process is general for the synthesis of 2,3-
dihydrobenzo[b]oxepines. The oxetane-tethered styrenes bearing
various substituents on the arene or the double bond reacted with
good to excellent efficiency (Scheme 6). It is worth noting that
benzoxepine is a core structure of a wide range of natural products
[
20]
nucelophiles. Inspired by the Prins reaction, which employs olefin
as the nucleophile to form C–C bond with a carbonyl electrophile, we
attempted an intramolecular version with styrene as the nucleophile.
The model compound 6a was treated with catalyst LiNTf
). Unfortunately, no desired C–C bond formation was observed. We
next examined other Lewis acid catalysts (see the SI for details). With
Sc(OTf) alone, there was still no desired product formation. However,
2
(Scheme
[
22]
5
and biologically active molecules.
3
the use of PhBox ligand smoothly promoted the desired C–C bond
formation to form the 2,3-dihydrobenzo[b]oxepine product 7a in 89%
3
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Scheme 6. Scope for the synthesis of 2,3-dihydrobenzo[b]oxepines. Scale: 6
3
(0.50 mmol), Sc(OTf) (10 mol%), PhBox (20 mol%), 5Å MS (100 mg), PhCl (6.0
mL); Isolated yields.
The products obtained from our reaction could be precursors to
other highly oxygenated molecules (Scheme 7). For example, after
simple silyl deprotection of product 3a with TBAF, free δ-hydroxy ester
Scheme 7. Product transformations. (a) TBAF, THF, RT, 1 h. (b) LiAlH
4
, THF,
o
6
0 C, 1 h. (c) PhC≡CLi, BF
3
•OEt
, THF, RT, 2 h, 1:1 dr. (f) NaH, BnBr, THF, RT, 6 h. (g) HCl (conc.),
•OEt , HSi(Et) , CH CN, >20:1 dr. (h) Pd/C, H , MeOH, 12
6 5 3
F ) (5 mol%), DCM, RT, 12 h.
2
, THF, RT, 5 h. (d) HCl (conc.), DCM, RT, 48
h. (e) NaBH
4
DCM, RT, 48 h; BF
h. (i) B(C
3
2
3
3
2
8
was afforded in high yield. The ester group could also be reduced
to primary alcohol 9. Direct conversion to ynone 10 was also feasible
using lithium acetylide as the nucleophile. Furthermore, under acidic
conditions, the δ-silyl deprotection could be coupled with one-pot
transesterification to form the δ-lactone 11 in excellent yield. Some
derivatizations of the cascade product 5a were also demonstrated.
The ketoester could be selectively reduced to ζ-siloxy-ε-aryloxy-β-
hydroxy ester 12. Moreover, facile double α-alkylation of the ketoester
furnished 13. Finally, acidic deprotection of the silyl group in 5a
In conclusion, we have demonstrated that oxetane can serve as a
useful electrophile for the mild efficient C–C bond formation with soft
carbon nucleophiles, despite the low reactivity of both reaction
partners. With silyl ketene acetals, the process provided expedient
access to a wide range of 1,5-oxygenated molecules, an attractive
complement to the Michael addition of enolates. The uniquely
3 2 3
followed by one-pot treatment with BF •OEt and Et SiH resulted in
effective catalyst LiNTf
extremely mild conditions, thus compatible with a diverse range of
functional groups. With TBSNTf as catalyst, this process was further
2
enabled this reaction to proceed under
formation of tetrahydropyran 14, likely via a cyclic oxocarbenium
intermediate. These densely-oxygenated carbon frameworks are
highly useful in polyketide synthesis, but their assembly by
2
extended to cascade C–C bond formation leading to 1,3,7-
oxygenated products. These highly oxygenated organic frameworks
are substructures of useful complex molecules including polyketides.
[
23]
conventional approaches was not as straightforward. Additionally,
the 2,3-dihydrobenzo[b]oxepine product 7a could undergo
hydrogenation to form 2,3,4,5-tetrahydrobenzo[b]oxepine 15 with high
Mechanistically, the orthogonal catalytic activity of LiNTf
2
and
6 5 3
efficiency. Interestingly, a catalytic amount of B(C F ) catalyzed
TBSNTf is evident to rule out the possibility of in-situ generation of
2
intramolecular cyclization of 7a to form bicyclic compound 16.
the latter as true catalyst in the former case. Furthermore,
intramolecular C–C bond formation by styrene was also achieve with
Sc(OTf)
3
as catalyst, which provided mild access to 2,3-
dihydrobenzo[b]oxepines.
Acknowledgements
Financial support was provided by NSFC (91956114), Hong Kong
RGC (16302318), Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology (BM2012110), Changzhou Sci&Tech
Program (CJ20200082), and Jiangsu specially appointed professors
program. We also thank Dr. Xin Li for initial study.
Keywords: strained molecules • C–C bond formation • Lewis acids
•
oxetane • ring opening
4
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[
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Angewandte Chemie International Edition
10.1002/anie.202013062
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Herein we describe mild C–C bond formation processes via ring-opening of oxetanes by soft carbon nucleophiles to access the useful 1,n-
oxygenated molecules and heterocycles.
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