Gold-Catalyzed Silyl-Migrative Cyclization of Homopropargylic Alcohols Enabled by Bifunctional Biphenyl-2-ylphosphine and DFT Studies

Article abstract of DOI:10.1021/acs.orglett.9b02735

The development of novel ligands specifically tailored for homogeneous gold catalysis permits the development of new gold catalysis. In this work, we report that a remotely functionalized biphenyl-2-ylphosphine ligand enables gold-catalyzed cyclization of homopropargylic alcohols accompanied by an unusual silyl migration, which provides efficient access to 3-silyl-4,5-dihydrofurans. DFT studies of the mechanism of this novel transformation suggest the synergy between the steric bulk of the ligand and its properly positioned remote tertiary amino group in facilitating a concerted silyl migration and cyclative C-O bond formation step.

Full text of DOI:10.1021/acs.orglett.9b02735

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed Silyl-Migrative Cyclization of Homopropargylic
Alcohols Enabled by Bifunctional Biphenyl-2-ylphosphine and DFT
Studies
Ting Li,*,†,‡ Yuhan Yang,† Bo Li,† Xiaoguang Bao,*,§ and Liming Zhang*,‡
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan 473061, China
‡Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
§College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park,
Suzhou, Jiangsu 215123, China
S
* Supporting Information
ABSTRACT: The development of novel ligands specifically
tailored for homogeneous gold catalysis permits the develop-
ment of new gold catalysis. In this work, we report that a
remotely functionalized biphenyl-2-ylphosphine ligand enables
gold-catalyzed cyclization of homopropargylic alcohols
accompanied by an unusual silyl migration, which provides
efficient access to 3-silyl-4,5-dihydrofurans. DFT studies of the
mechanism of this novel transformation suggest the synergy
between the steric bulk of the ligand and its properly
positioned remote tertiary amino group in facilitating a
concerted silyl migration and cyclative C−O bond formation step.
cyclization to deliver 4,5-dihydrofuran products. To our
surprise, there is an apparent silyl migration4 in the cyclization
step that has limited precedents.5 It is important to understand
the underpinning mechanism and, moreover, the role, if any, of
the bifunctional phosphine ligand in such an unusual migration.
In this work, we report a much broader scope of this cyclization
by directly employing silylated homopropargylic alcohol
substrates and reveal via DFT calculations the essential roles
of the steric bulk and the properly positioned remote tertiary
amino group of the bifunctional phosphine ligand in facilitating
a concerted silyl migration and cyclative C−O bond formation
step.
The scope of the homopropargylic alcohol 1 in our previous
work is limited by the prerequisite of its in situ generation, i.e.,
the gold-catalyzed propargylation of aldehyde, which has to be
activated by the presence of an electron-deficient aryl or an
ester group and the alkyne propargylic position must be
substituted with a π system (Scheme 1). Moreover, these
alcohol intermediates were generated with low to moderate
syn/anti selectivities, which in turn led to mixtures of product
diastereomers. With homopropargylic alcohols generated from
conventional methods and their syn/anti isomers potentially
separable, we could probe the generality of this surprising silyl-
migrating cyclization and develop a general approach to 3-
silylated 4,5-dihydrofurans with excellent stereochemistry
ecently, we reported the development of designed
1
Rbiphenyl-2-ylphosphine ligands featuring a remote basic
functional group for homogeneous gold catalysis.2 These
ligands possessing an amide,1b,e,f an aniline,1d or a tertiary
amine1a,c can dramatically accelerate gold catalysis or enable
reactions that could not be achieved in the presence of typical
phosphine or NHC ligands. A recent study of ours1g details the
in situ generation of σ-allenylgold species3 and their
nucleophilic reactions with activated aldehydes (Scheme 1).1g
This reaction could not be achieved with other gold ligands and
represents for the first time the catalytic deprotonative
generation of nucleophilic σ-allenylmetal species. The antici-
pated homopropargylic alcohol products further undergo
Scheme 1. Our Previous Work on the Reaction of
Catalytically Generated σ-Allenylgold Intermediates
Received: August 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02735
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Organic Letters
Letter
control. This type of dihydrofurans, however, has only been
accessed via the reaction of allenylsilanes in a limited scope.6,7
Initially, we examined the reaction by using 1aa as the
substrate. It could not be generated using our previously
reported σ-allenylgold chemistry but was prepared in 90% yield
from deprotonated TBS-terminated 3-phenylprop-1-yne and
acetone.8 The optimal conditions of the cyclization entail
L1AuCl (5 mol %), NaBArF4 (10 mol %), DCE as the solvent,
90 °C, and 2 h. Under these conditions, the desired silyl-
migrated 4,5-dihydrofuran product 2aa was formed in 92%
isolated yield while the nonmigrated counterpart 2aa′ was
barely detectable (Table 1, entry 1). Not to our surprise, in the
the transformation as PhCF3, and THF led to much slower
reactions (entries 11 and 12).
With the optimized conditions in hand, we next examined the
reaction scope. First, the substrates prepared from tert-
butyldimethyl(3-phenylprop-1-yn-1-yl)silane and various alde-
hydes were studied. As shown in Scheme 2, the dihydrofuran
Scheme 2. Reaction Scope with Substrates Derived from tert-
a
Butyldimethyl(3-phenylprop-1-yn-1-yl)silane
a
Table 1. Conditions Optimization
b
deviation from the optimized
conditions
conversion
(%)
2aa yield
(2aa/2aa′)
b
c
entry
1
2
3
4
5
6
7
8
none
>99
0
<20
>99
30
<10
<10
<5
92 (>50/1)
0
15 (0/1)
JohnPhos as Au ligand
JohnPhos as Au ligand, 10% Et3N
L2 as Au ligand
L3 as Au ligand
L4 as Au ligand
55% (<1/10)
20% (>50/1)
<5
L5 as Au ligand
<5
<5
<5
a
AgNTf2 instead of NaBArF
Reactions run in vials; the substrate initial concentration was 0.1 M;
4
AgOTf instead of NaBArF
<5
isolated yields are reported. The ratio of the silyl-migrated product vs
9
4
the silyl-unmigrated product is mostly >50:1 unless otherwise noted
10
11
12
20 °C and 48 h
PhCF3 as solvent
THF as solvent
85
62
57
72 (>50/1)
52 (>50/1)
50 (>50/1)
b
as the rr (regioisomeric ratio) value. Yield based on the portion of
c
d
the syn-substrate used (67%). Syn-substrate used. The reaction was
performed at 60 °C for 4 h.
a
All reactions were run in sealed vials with the initial [1a] = 0.1 M.
b
c
DCE = 1,2-dichloroethane. Isolated yield. Determined by 1H NMR.
products 2ab−2af were formed smoothly in moderate to good
yields. It is worth noting that low silyl regioselectivity was
observed in the case of 2af, where the substrate is a primary
alcohol. In the cases of 2ac−2ae, the syn-homopropargylic
alcohol substrates were readily prepared pure. Consequently,
the cis-products were obtained. The substrates derived from
various ketones reacted with high efficiencies, affording 2ah−
2ak in mostly >80% yields.
Next, the scope of the substrates prepared from various
silylated alkynes was examined. As shown in Scheme 3,
dihydrofuran products 2ba−2ga with various substituted
phenyl groups at C4 were isolated in moderate to good yields.
Other π-systems such as 2-naphthyl (2ha), 2-thiophene-yl
(2ia), and alkenyl (2ja and 2ka) are readily allowed at the 4-
position. To substantially expand the scope, we also examined
reactions employing substrates prepared from aliphatic alkynes.
The products 2la and 2ma possessing a nonfunctionalized and
an oxygenated alkyl group at the 4-position, respectively, were
formed in good yields. Moreover, the 4,5-dihydrofurans
without such a substitution such as 2o and 2p were accessed
without event. Unlike the other cases where the silyl
regioselectivities are >50:1, the selectivities are 10/1 in the
case of 2o and an even worse 4:1 in the case of 2p. The poor
regioselectivities in these cases and that of 2af revealed a
positive correlation between substrate steric congestion and the
preference for silyl migration. The reaction can also be run on a
2 mmol scale without event. As shown in eq 1, 2aa was isolated
in 495 mg and 86% yield.
absence of the ligand remote amino group, the related biphenyl-
2-ylphosphine JohnPhos led to no reaction, while 15% yield of
the nonmigrated 2aa′5 was formed when 10 mol % of Et3N was
added (entries 2 and 3). The congener of L1 featuring a
sterically smaller secondary amine, i.e., L2, that could facilitate
the cyclization to completion and with moderate efficiency
(entry 4), but surprisingly, 2aa′ was favored by >10:1 over the
silyl-migrated product 2aa. The much bulkier congener L3 with
a 3-pentyl group at the remote nitrogen1a led to a much slower
reaction, although the silyl group regioselectivity was similar to
that of L1 (entry 5). These results reveal the role of ligand steric
bulk in promoting the silyl migration. Other bifunctional
ligands1a with the tertiary amino moiety positioned differently
from L1, such as L4 (entry 6) and L5 (entry 7), were mostly
ineffective, reflecting the critical importance of a properly
positioned ligand remote basic group in this catalysis. Further
studies indicated that NaBARF is essential as the chloride
4
abstractor. With AgNTf2 or AgOTf instead, only trace product
could be observed (entries 8 and 9). It was also found that a
slower reaction could be observed when it was performed at
room temperature (entry 10). The solvent DCE was optimal for
B
DOI: 10.1021/acs.orglett.9b02735
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Organic Letters
Letter
the ligand L1 in the reaction, DFT calculations were performed,
and the energy profiles are shown in Figure 1. Initially, the
substrate 1aa and the catalyst L1Au+ form a complex with two
conformations, i.e., INT1 and INT1′, via the coordination of
the C≡C of 1aa with Au(I) in two different orientations. For
INT1, an H-bonding interaction between the hydroxyl group of
1aa and the amino moiety of L1 ligand (O−H···N) is formed to
stabilize the complex. Remarkably, the Si−C1−C2 angle of
137° in INT1 significantly deviates from linearity in 1aa due to
the pronounced steric congestion between one of the bulky Ad
groups of L1 and the TBS group of 1aa. For INT1′, such steric
crowdedness is less significant, which is reflected is less
significant, which is reflected by the less distorted angle of
the Si−C1−C2 angle of 1aa (163°); on the other hand, the
stabilizing O−H···N H-bond interaction is absent in this
complex. Computational results show that INT1 and INT1′ are
very close in energy, suggesting that both of these conformers
are possible. From INT1, driven by the steric repulsive
interaction between the Ad group and the TBS group, a
transition state (i.e., TS1) was located for the concerted
cyclization, 1,2-silyl migration, and proton transfer to N of L1,
in which the Si···C1 and Si···C2 distances are 2.23 and 2.10 Å,
respectively, and the O···C1 distance is 3.04 Å. The predicted
free energy barrier is 10.4 kcal/mol relative to INT1. This step
affords the cyclized intermediate INT5. The involvement of a
water molecule in the 1,2-silyl migration process (TS2) was also
considered but unlikely as the energy barrier is 7 kcal/mol
higher than that of TS1. Afterward, the protodeauration step via
internal proton transfer (TS3) could occur to furnish the final
product 2aa. Alternatively, the Au(I)-catalyzed 5-endo cycliza-
tion from INT1′ was also considered, which leads to the
formation of 2aa′. The optimized TS was shown as TS4, in
which the O···C1 distance is shortened to 2.03 Å. The Au(I)-
Scheme 3. Reaction Scope with Substrates Prepared from
Various Silylated Alkynes
a
a
Reactions run in vials; [1] = 0.1 M; isolated yields are reported; the
ratio of the silyl-migrated product vs the silyl-unmigrated product is
mostly >50:1 unless otherwise noted.
To understand the unexpected 1,2-silyl migration in this
cyclization reaction and to elucidate the impact of substrate
steric bulk on product regioselectivity and the essential role of
Figure 1. Energy profiles for the pathways of Au(I)-catalyzed 1,2-silyl group migration and 5-endo cyclization of 1aa leading to 2aa and 2aa′,
respectively. Bond distances are shown in Å.
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02735.
Experimental procedures, characterization data for all
products, NMR spectra, and DFT-optimized Cartesian
coordinates and energies (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chemlt2015@nynu.edu.cn.
*E-mail: xgbao@suda.edu.cn.
*E-mail: zhang@chem.ucsb.edu.
ORCID
Xiaoguang Bao: 0000-0001-7190-8866
Liming Zhang: 0000-0002-5306-1515
Notes
The authors declare no competing financial interest.
́
́
(5) Fernandez, S.; Gonzalez, J.; Santamaría, J.; Ballesteros, A.
Propargylsilanes as Reagents for Synergistic Gold(I)-Catalyzed
Propargylation of Carbonyl Compounds: Isolation and Character-
ization of Σ-Gold(I) Allenyl Intermediates. Angew. Chem., Int. Ed.
2019, 58, 10703−10817.
ACKNOWLEDGMENTS
■
We thank NSF CHE 1800525 for financial support and NIH
shared instrument grant S10OD012077 for the purchase of a
400 MHz NMR spectrometer. T.L. acknowledges financial
support from the NSFC (21602120).
(6) Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y. M. Application of
Allenylsilanes in [3 + 2] Annulation Approaches to Oxygen and
Nitrogen Heterocycles. J. Am. Chem. Soc. 1985, 107, 7233−7235.
(7) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. Highly
Enantioselective Syntheses of Homopropargylic Alcohols and
Dihydrofurans Catalyzed by a Bis(Oxazolinyl)Pyridine−Scandium
Triflate Complex. J. Am. Chem. Soc. 2001, 123, 12095−12096.
(8) For details, see the Supporting Information.
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