Bifunctional Ligand Enables Efficient Gold-Catalyzed Hydroalkenylation of Propargylic Alcohol

Article abstract of DOI:10.1002/anie.201802533

Using the previously designed biphenyl-2-ylphosphine ligand, featuring a remote tertiary amino group, the first gold-catalyzed intermolecular hydroalkenylation of alkynes has been developed. Synthetically valuable conjugated dienyl alcohols are formed in moderate to good yields. A range of alkenyltrifluoroborates are allowed as the alkenyl donor, and no erosion of alkene geometry and/or the propargylic configuration are detected. DFT calculations confirm the critical role of the remote basic group in the ligand as a general-base catalyst for promoting this novel gold catalysis with good efficiency.

Full text of DOI:10.1002/anie.201802533

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Accepted Article
Title: Bifunctional Ligand Enables Efficient Gold-Catalyzed
Hydroalkenylation of Propargylic Alcohol
Authors: shengrong liao, Alessio Porta, Xinpeng Cheng, xu ma,
Giuseppe zanoni, and Liming Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802533
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10.1002/anie.201802533
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COMMUNICATION
Bifunctional Ligand Enables Efficient Gold-Catalyzed
Hydroalkenylation of Propargylic Alcohol
Shengrong Liao,[a,b] Alessio Porta,[c] Xinpeng Cheng,[b] Xu Ma,[b] Giuseppe Zanoni[c]* and Liming
Zhang[b]*
Abstract: Using our previously designed biphenyl-2-ylphosphine L2
‘relay’ fashion enhance the nucleophilicity of the alkenyl moiety
and achieve intramolecularity of the alkene attack at the C-C triple
bond. As such, the reaction would constitute a novel bimolecular
synthesis of dienols and conceptually achieve a gold-catalyzed
intermolecular hydroalkenylation of C-C triple bond. Notably,
intermolecular[4] hydroalkenylation[5],[6] has not been reported in
gold catalysis.
featuring a remote tertiary amino group as an enabling ligand, we
have
developed
the
first
gold-catalyzed
intermolecular
hydroalkenylation of alkynes. Synthetically valuable conjugated dienyl
alcohols are formed in moderate to good yields. A range of
alkenyltrifluoroborates are allowed as the alkenyl donor, and no
erosion of alkene geometry and/or the propargylic configuration are
detected. DFT calculations confirm the critical role of the remote basic
group as a general base catalyst in promoting this novel gold catalysis
in good efficiency.
For the past several years we have developed several new
phosphine ligands[1] for homogeneous gold catalysis.[2] These
ligands, as shown in Figure 1, share the privileged biphenyl-2-
ylphosphine framework[3] but are unique and hence novel in their
featured basic functional groups at the lower half of the pendant
benzene ring. They are designed to achieve beneficial
interactions between such a basic group and the substrate or
incoming nucleophiles by harnessing the rather unique and robust
linear structure of ligand-gold(I)-substrate complexes (Figure 1A).
With the amine-based ligands including L1-L4, several gold
catalyses are enabled by engaging interactions between the basic
nitrogen with alkyne/allene substrates.[1a, 1c, 1e] With WangPhos
featuring a remote amide group as ligand, nucleophilic additions
to alkynes are accelerated owing to H-bonding between its
remote amide group and incoming nucleophiles in the form of
general base catalysis.[1b, 1d, 1f] This phenomenon has recently
been harnessed to achieve highly enantioselective allenol
cyclizations.[1g] However, the nucleophiles are so far limited to
heteronucleophiles due to the necessity of H-bonding.
Figure 1: Development of gold-specific biphenyl-2-ylphosphines featuring
remote basic groups: A) design; B) selected examples.
The dienol motif of 3 can be found as key structural
components of natural products[7] or in key intermediates in
natural product synthesis[8] and, due to its densely packed
functionalities, are rich with reactivities.[8b, 9] As summarized in
Scheme 2B, it can be mainly assembled in the following manners
but with limitations: i) the Suzuki-Miyaura coupling,[10] which is
straightforward but requires often difficult-to-access chiral α-
haloallylic alcohols in order to prepare chiral 3; ii) the additions of
buta-2,3-dien-1-ylmetal species to aldehydes, which are mostly
explored without substitution (i.e., R = H) [9e, 11] or lead selectively
to the formation of products possessing a (Z)-double bond distal
to the hydroxy group when R ≠ H[12] and hence display limited
It is envisioned, however, that a ligand-enabled relay strategy
could enable the use of alkenyl-based nucleophiles. As shown in
Scheme 1A, with a propargylic alcohol as the substrate, the H-
bonding between the hydroxy group and the remote basic site
should
form
the
structure
A
and
enhance
the
basicity/nucleophilicity of the oxygen atom, which would in turn
exhibit increased tendency to recruit an alkenylboron reactant via
the formation of a Lewis pair in B. Such an interaction would in a
product
scope;
iii)
transition
metal-catalyzed
hydroalkenylations[6b-d, 6f, 13] of propargylic alcohols using boronic
acids, which has examples using only internal propargyl alcohol
substrates[13c-e] and exhibiting opposite[13c] or poor[13d]
regiochemistry; iv) intermolecular enyne metathesis, which
displays low/moderate E/Z selectivities;[9d, 14] v) one related case
of oxidative Heck (57% yield, not shown).[15]
[a] Dr. Shengrong Liao
Key Laboratory of Tropical Marine Bio-resources and Ecology, South
China Sea Institute of Oceanology, CAS, Guangzhou, P. R. China
[b] Dr. Shengrong Liao, Mr. Xinpeng Cheng, Mr. Xu Ma, and Prof. Dr.
Liming Zhang
Department of Chemistry and Biochemistry, UCSB, CA 93106, USA
E-mail: zhang@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
[c] Dr. Alessio Porta and Prof. Dr. Giuseppe Zanoni
Dept of Chem., Univ. of Pavia, Viale Taramelli, 10, 27100 Pavia – Italy
E-mail: gz@unipv.it
Herein, we report that the implementation of our design
(Scheme 1A), which permits for the first time gold-catalyzed
intermolecular additions of alkenyltrifluoroborates to C-C triple
bonds and, moreover, provides a broadly applicable and
expedient access to 2-methylene-3-buten-1-ol derivatives with
well-defined regio- and stereochemistry.
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201802533
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COMMUNICATION
protodeboronation appeared to be more facile than that of (E)-1a
and is the major process for its decomposition (entry 15).
Table 1. Reaction conditions optimization.[a]
Entry
Deviation from the optimized conditions
Yield(%)[b]
1
2
3
4
5
6
7
8
9
-
77
69
67
0
DCE/H2O (4:1) as reaction media
PhCF3/H2O (4:1) as reaction media
PhCH3/H2O (4:1) as reaction media
NaBARF instead of AgNTf2 as chloride abstractor
AgOTf instead of AgNTf2 as chloride abstractor
AgBF4 instead of AgNTf2 as chloride abstractor
2 equiv of 1a; DCE/H2O (4:1) as reaction media
70
70
61
56
Ph3P, IPr, JohnPhos or MorDalPhos as Au ligand; 2 equiv of 1a; ≤6
Scheme 1: Synthesis of dienols: a) our design, a relay strategy based on ligand-
enabled gold catalysis. b) prior arts and their limitations.
DCE/H2O (4:1) as reaction media
10
JohnPhos as Au ligand, 2 equiv of 1a; DCE/H2O (4:1) as
16
reaction media; 5% Et3N
11 L3 as Au ligand; 2 equiv of 1a; DCE/H2O (4:1) as reaction media 37
12 L4 as Au ligand; 2 equiv of 1a; DCE/H2O (4:1) as reaction media 18
At the outset, we chose the terminal secondary propargylic
alcohol 1-hexyn-3-ol (2) as the substrate and trans-styryl-based
trifluoroborate (E)-1a as the nucleophilic alkenyl species for
reaction discovery and optimization (Table 1). Extensive
exploration of ligands and reaction conditions revealed that the
optimal conditions are: (E)-1a : 2 = 3:1, L2AuCl (5 mol%), AgNTf2
(4.8 mol %), DCM/H2O = 4:1, 24 h, ambient temperature. As
shown in entry 1, under these conditions, the desired dienol
product 3a was formed in 77% yield. The organic phase could be
replaced by DCE (entry 2) or PhCF3 with only minor impact on
yield but not by toluene (entry 4) due to its poor solubility of (E)-
1a. Besides AgNTf2, other typically employed chloride abstractors
including NaBARF (entry 5), AgOTf (entry 6) and AgBF4 (entry 7)
were effective but led to slightly lower yields. Decreasing the
amount of (E)-1a to 2 equiv resulted a notable drop of yield (56%
in entry 8 vs. 69% in entry 2). With 2 equiv of (E)-1a and DCE/H2O
(4:1) as reaction media, the performance of various other ligands
are shown in entries 9-12. Not surprisingly, commercially
available and typically employed ligands such as Ph3P, IPr,
JohnPhos and MorDalPhos were largely ineffective (entry 9); in
the presence of exogeneous Et3N (1 eq to Au), the yield was
notably improved but still poor (entry 10). These results highlight
the enabling role of the basic tertiary amino group in L2. Notably,
the other tertiary amine-functionalized ligands L3 (entry 11) and
L4 (entry 12) we previously developed[1c] along with L2 are inferior
to L2, and L4 is only marginally better than the JohnPhos/Et3N
combination (cf. entry 10). These results reveal the importance of
properly positioning the basic group in this catalysis and affirm the
advantage of our designed bifunctional ligands in achieving it.
Without adding H2O, no desired product was observed (entry 13),
which suggests that that the trifluoroborate salt need to undergo
(partial) hydrolysis during the reaction.[16] When the
corresponding boronic acid was used in place of (E)-1a, the
reaction did occur, but was contaminated by competing hydration
and afforded a lower yield (entry 14). In entries 9-12 and 14,
protodeboronation leading to styrene is a significant side reaction
and responsible for the low yields. When (Z)-1a was used, no
dienol 3a or its double isomer was detected, and its
13
14
15
dry DCM used as solvent
0
35[c]
0[d]
(E)-styrylboronic acid instead of 1a
(Z)-1a instead
[a]
[b]
0.1 mmol of 1-hexyn-3-ol (2) were used. NMR yields. [c] 27% 2 remained
along with 22% of hydration product. [d] Mostly protodeboronation.
The reaction scope is shown in Scheme 2. Firstly, a range of
the terminal secondary propargylic alcohols 2 was examined.
Various R3 groups of 2 are allowed, including H, sterically
demanding cyclohexyl (in the case of 3d), O-/N-functionalized
alkyl groups (in the cases of 3e-3f) and a phenyl (in the case of
3h). Fairly good to excellent yields of 3b-3g were realized. In the
series of 3b-3d, it is clear that the reaction efficiency correlates
inversely with the steric size of the R3 group. On the other hand,
terminal tertiary or internal propargylic alcohols do not lead to
observable reaction. The scope of the (E)-styryltrifluoroborates
was then examined. As shown in the cases of 3h-3m,
substitutions on the benzene ring such as halides, electron-
donating MeO, electron-withdrawing ester and a sterically
congesting 2-methyl group were all tolerated. Of note are the
cases of 3h and 3i, the C-Br bonds of which should be a liability
in relevant Ph/Rh catalysis. The scope of the alkenylborate 1 can
be substantially broadened beyond styryl ones to include those
substituted by a heteroarene, a cyclohexyl, and another alkenyl to
afford highly functionalized 3n-3p in serviceably yields.
Furthermore, the conjugative substituents on the alkenylborate 1
featured in the cases discussed so far are not prerequisites for
this gold catalysis. As shown with the cases of 3q-3w, monoalkyl
substitutions (3u-3w) and bisalkyl substitutions in cyclic forms
(3q-3s) and an acyclic one (3t) were all smoothly accommodated,
and in some cases (e.g., 3q and 3t) the yields were excellent. Of
note is that the alkyl substitutions ipso to boron in the cases of 3q-
3t could hinder the reaction but quite to contrary appear to be
somewhat beneficiary. For the cases of 3o and 3u-3w, 6.0 equiv
of the corresponding borates were needed for full conversion,
which is attributed to their susceptibility to protodeboration. In all
these cases, the double bond geometries of the borates 1 were
completely maintained in the dienol products.
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10.1002/anie.201802533
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calculations, the 1-adamantyl groups of L2 were replaced by
methyl groups. As alluded above, the trifluoroborates should
undergo hydrolysis[16] at the beginning. We have examined both
of the hydrolyzed boron species, RB(OH)F and RB(OH)2. In the
case of RB(OH)F, the two diastereomers of the initially formed
ternary complexes (e.g., B-F-OH in Scheme 3) differing by the
orientation of the boron F and HO substituents are separately
calculated. Among the three reaction paths, the one shown in
Scheme 3 is energetically most favorable and has the lowest free
energy barrier in the critical first step [10.0 kcal/mol vs. 15.3
kcal/mol for RB(OH)2 and 15.2 kcal/mol for the other RB(OH)F
path, DCM, for details, see SI]. This finding is consistent with
RB(OH)2 leading to a lower yield (see Table 1, entry 14). The initial
ternary complex B-F-OH in Scheme 3 exhibits an expected H-
bond between L2 amino nitrogen and propargylic hydroxy proton
and some electrostatic attraction between propargylic oxygen and
the boron center. The early transition state, B-F-OH-TS1, is only
10.0 kcal/mol higher in free energy and reveals the migration of
the hydroxy proton from O to N in an early stage and the
significant shortening of the nascent B-O bond. The subsequently
formed cyclopropyl gold carbene intermediate B-F-OH-Int1 is
21.4 kcal/mol (DCM) more stable than B-F-OH and has the
original propargyl hydroxy proton completely migrated to the
ligand amino nitrogen while maintaining a H-bond with its initially
bonded oxygen. The next step, i.e., the fragmentation of the C-B
bond, has an even lower barrier of ∆G = 5.4 kcal/mol, and
throughout the H-bond between the protonated ammonium and
the original propargylic oxygen is maintained. Subsequent
protodeauration of the resulting intermediate B-F-OH-Int2 by the
ammonium proton (not calculated) should afford the final product.
These theoretical studies largely support our original design and
confirm that the properly positioned remote tertiary amino group
plays an intimate role of a general base catalyst in proton shuttling.
The reaction energetics corresponding to Scheme 3 but with L3
or L4 as ligand (the Ad groups are again replaced by methyl
groups, see SI) was also calculated. The first step barrier in DCM
is 17.4 kcal/mol and 16.3 kcal/mol for L3 and L4, respectively,
which is in line with the observed lower efficiencies in Table 1,
entries 11 and 12.
Scheme 2. The reaction scope. Isolated yields reported. [a] 8% cat. and 6.0
equiv. of borates were used in 3e-g. [b] 6.0 equiv. of borates were used.
To understand the reaction mechanism and substantiate the
essential role of the remote tertiary amino group of L2 in
facilitating the reaction, we performed DFT-B3LYP[17] calculations
on the energetics of the reaction up to the step resulting in the
formation of the dienylgold intermediate. To simplify the
Scheme 3. B3LYP/6-31+G(d,p)/LANL2DZ(Au) energetics of the reaction with alkenyl(fluoro)(hydroxy)borane as nucleophilic reagent in gas phase and in DCM
(number in parenthesis, calculated with PCM as single point and with def2-TZVP for Au).
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To establish the synthetic utility of this chemistry, we first
examined whether the reaction would erode the e.e. of a chiral
propargylic center. As shown in Eq. 1, essentially no racemization
is detected in the formation of (R)-3h. Combined with readily
available chiral propargylic alcohols, this chemistry offers valuable
access to chiral dienols. A Diels-Alder cycloaddition was
performed by using compound 3k and N-phenylmaleimide as the
substrates, and only the endo-cycloadduct was obtained with an
excellent yield (Eq. 2). Finally, a selective epoxidation of the allylic
C-C double bond was achieved. The epoxy alcohol product 5 is
not stable on silica gel column and hence isolated crude yet
mostly pure due to the high reaction efficiency (Eq. 3). Only one
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diastereoisomer of
5
was detected, and the relative
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In summary, we have developed the first gold-catalyzed
intermolecular hydroalkenylation of propargylic alcohols.
A
designed biphenyl-2-ylphosphine ligand featuring a remote basic
tertiary amine is experimentally proven as critical in enabling this
novel gold catalysis with high efficiency. DFT calculations reveal
the role of the amino group as a general base catalyst.
Synthetically valuable conjugated dienyl alcohols are formed in
moderate to good yields. A range of alkenyltrifluoroborates are
allowed as the alkenyl donor, and the reaction is highly
regioselective with regard to the propargylic alcohol,
stereospecific with regard to the alkene geometry, and does not
erode the propargylic configuration.
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S Liao thanks China Scholarship Council for scholarship. LZ thank
NIGMS R01GM123342 for financial support and NIH shared
instrument grant S10OD012077 for the acquisition of a 400 MHz
NMR spectrometer. GZ thanks Regione Lombardia – Cariplo
Foundation Grant (Sottomisura B/2016), POR FESR 2014-
2020/Innovazione e competitività, progetto VIPCAT for financial
support.
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Keywords: gold • ligand • catalysis • dienol • calculations
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Author(s), Corresponding Author(s)*
Page No. – Page No.
Bifunctional Ligand Enables Efficient
Gold-Catalyzed Hydroalkenylation of
Propargylic Alcohol
Efficient gold-catalyzed intermolecular hydroalkenylation of propargylic alcohol is
enabled by a previously designed biphenyl-2-ylphosphine featuring a remote
tertiary amino group. Conjugated dinenol are formed with high regioselectivity at the
propargylic alcohols and stereospecificity with regard to alkenyltrifluoroborates and
without erosion at the propargylic configuration.
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