Regioselectivity Influences in Platinum-Catalyzed Intramolecular Alkyne O-H and N-H Additions

Article abstract of DOI:10.1021/acs.orglett.9b03557

The steric and electronic drivers of regioselectivity in platinum-catalyzed intramolecular hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly observed.

Full text of DOI:10.1021/acs.orglett.9b03557

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselectivity Influences in Platinum-Catalyzed Intramolecular
Alkyne O−H and N−H Additions
Jeff P. Costello and Eric M. Ferreira*
Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
S
* Supporting Information
ABSTRACT: The steric and electronic drivers of regioselectivity in platinum-catalyzed intramolecular hydroalkoxylation are
elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can
be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne
substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient
carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar
trends in directionality are predominant although not uniformly observed.
nol ethers are highly useful functional groups because of
the electron-rich nature of the π-bond, which enables
manifold is initiated by Pt catalyst coordination to an alkyne
(Scheme 1A), followed by intramolecular 5-endo nucleophilic
attack by a pendant alcohol. Loss of the ethereal group then
leads to carbene formation. Rearranging the propargylic unit
E
unique reactivity across a range of transformations.1 There are
several methods available for the synthesis of enol ethers,2
including a variety of metal-catalyzed processes such as
alcohol/alkenyl halide cross coupling,3 allylic ether isomer-
ization,4 and alkyne hydroalkoxylation.5 This latter reaction
class can be direct and convenient, although a primary
consideration in this process is the regioselectivity of the
addition.6 Given the prevalence of enol ethers in natural
products and bioactive molecules7 that could arise from either
selective endo or exo intramolecular cyclizations (Figure 1),
methods that can achieve these processes selectively would be
of high potential value.
Scheme 1. Regioselectivity in Pt-Catalyzed
Hydroalkoxylation
We and others have been investigating the use of platinum
catalysis to generate α,β-unsaturated carbene intermediates
from propargylic ethers;8 these carbenes have been demon-
strated to undergo cycloadditions,8a−e hydrogen migrations,8f−i
and vinylogous nucleophilic additions.8j−l Reactivity in this
Figure 1. Enol-ether-containing natural products and bioactive
molecules.
Received: October 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Bidirectional Cyclization Optimization
a
a
entry
R
ligand
additive (equiv)
time (h)
% yield 5
% yield 6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
H (4a)
OAc (4b)
OBoc (4c)
OMe (4d)
OBoc
OBoc
OBoc
OBoc
OBoc
OBoc
OBoc
OBoc
OBoc
OBoc
OBoc
OBoc
OMe





16
16
16
16
16
2
54
30
43
5
20
8
8
31
7
11
10
14
18
8



PPh3

22
52
37
63
71
20
32
75
85
60
<5
88 (86)
27
21
45
(S)-BINAP
dppp


5
P(OPh)3
P(C6F5)


1.5
0.5
16
16
0.5
0.5
1
17
0.5
0.5
0.5
0.5

Sc(OTf)3 (0.1)
MgCl2 (1.0)
Na2CO3 (0.5)
Na2CO3 (1.0)
K3PO4 (1.0)
i-Pr2NEt (1.2)
Na2CO3 (1.0)
Na2CO3 (1.0)


5

13
10
11
<5
7
49
75 (72)
52


P(C6F5)
P(C6F5)

OMe
OMe
P(C6F5)
P(C6F5)
Na2CO3 (1.0)
a
1
Yield determined by H NMR using vanillin as a standard. Isolated yields in parentheses.
presents a challenge, as 6-endo cyclization could potentially
compete with 5-exo cyclization (Scheme 1B). Thus, the
regioselectivity of the initial nucleophile attack on the alkyne
would potentially influence successful carbene formation, in
that the 6-endo process may not be productive in catalysis. As
an example, we found that the initial hydroalkoxylation toward
carbene formation was not straightforward; substrate 1 was
found to form both compounds 2 and 3 (Scheme 1C). In an
effort to expand our understanding of carbene generation, we
believed it necessary to investigate this hydroalkoxylation
cyclization process in a more singular and methodical context.
Herein, we ascertain the primary impact of electronic biasing in
intramolecular alkyne hydroalkoxylation regioselectivity, dem-
onstrating that high levels can be achieved to generate
products of either 5-exo or 6-endo cyclizations.
Regioselectivity in metal-catalyzed intramolecular alkyne
hydroalkoxylation has been observed, but the determinants
have been difficult to parse.6 Mechanistic discrepancies (e.g., π-
activation vs metal alkoxide alkyne insertion9) can dictate
different outcomes. Within π-activation, terminal alkynes
typically adhere to the propensity of the metal catalyst to
reside on the unsubstituted carbon in a vinyl metal
intermediate.10 Internal alkynes appear more nuanced. The
process will be governed in part by the inherent preference of
the substrate to form a desired ring size (generally 5/6), but
other factors could also be influential. For example, Liu and De
Brabander showed that regioselectivity in nonbiased alkyl
systems can be modulated by pendant Lewis basic groups that
stabilize specific catalyst intermediates.11 Other aspects such as
catalyst choice and steric environment should also be taken
into consideration. Selectivities have been reported in other
nonmetal12 and metal-catalyzed hydroalkoxylations (Au,13
Pd14) that pointed to electronic biasing. Isolated cases in Pt-
catalyzed cyclizations suggested that this attribute could be
consequential,15 although the degree to which was unclear.
With the backdrop of our α,β-unsaturated Pt-carbene studies,
we believed that a hydroalkoxylation analysis of aryl alkynes
would be most informative, and we set out to directly address
this question in this context.
We conducted a preliminary scan of 3-alkyn-1-ols with four
differentially substituted arenes, using Zeise’s dimer in toluene
as baseline conditions (Table 1, entries 1−4). We observed a
notable separation of cyclization directionality in this scan.
Based on this initial data, we sought to further optimize
conditions of exo/endo selectivity using the two ends of the
spectrum, the p-OBoc aryl compound (4c) and the p-OMe aryl
compound (4d). For compound 4c, although added ligands
had minor impacts on regioselectivity, it appeared that
electron-deficient ligands (P(OPh)3, P(C6F5)3) gave a
measurable boost in yield (entries 8 and 9). Added Lewis
acids suppressed reactivity, while inorganic bases gave a
moderate increase in regioselectivity, with the combination of
P(C6F5)3 (1:1 P/Pt ratio) and 1 equiv of Na2CO3 providing
the optimal yield and selectivity for exo product 5c (entry 16).
In the endo-selective direction with compound 4d, the base
was counterproductive to enriched regioselectivity. The added
electron-deficient phosphine, however, still proved beneficial to
overall yield, and the endo product (6d) could be obtained in
72% isolated yield (entry 18).16
The enol ether products from substrates that are selective for
5-exo cyclization are depicted in Chart 1A. As illustrated,
arenes substituted with electron-withdrawing groups are highly
reactive and selective for the formation of the furanyl
compound. This observation appears rather consistent across
electron-withdrawing substituents, whether in a para, meta, or
ortho relationship to the alkyne. Less inductively withdrawing
groups, such as p-NHBoc, m-NHBoc, and m-OMe, begin to
erode the exo/endo selectivity (5n−5p). If the arene is
B
DOI: 10.1021/acs.orglett.9b03557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Chart 1. Pt-Catalyzed Regioselectivities in Enol Ether Formation
a
1
Exo:endo selectivity is of crude reaction analysis by H NMR. Yield and Z/E ratio are of isolated material, major isomer only unless otherwise
b
c
noted. Reaction performed at 40 °C with 2 mol % of [(C2H4)PtCl2]2 and 4 mol % of P(C6F5)3. Yield is of 12.5:1 mixture of 5m/6m. Isomers
were chromatographically inseparable. Yield is of 7.0:1 mixture of 5o/6o. Isomers were chromatographically inseparable. Reaction performed at
40 °C. Yield is of 1.2:1 mixture of 6r/5r. Isomers were chromatographically inseparable.
d
e
f
electronically neutral, then exo/endo selectivity is more
diminished (3:1), although synthetically useful yields can still
be achieved. The predominance of the Z-isomer indicates an
anti-selective addition process, although measurable formation
of the E-enol ether was frequently observed. It has been
reported that isomerization of this type of enol ether can occur
under mild conditions,17 which may be leading to this minor
isomer.
Dihydrofurans arising from selective 6-endo cyclizations are
shown in Chart 1B. Here, two main effects drive selectivity in
this direction. Particularly, electron-rich arenes (e.g., (p-
OMe)C6H4) were rather selective for the 6-endo product. A
p-NMe2 group shut down reactivity, however, likely due to its
enhanced Lewis basicity disrupting catalysis. A substituent in
the ortho position, if sufficiently nonwithdrawing, will also
force the formation of the 6-endo products. This observation
would be consistent with a steric destabilization of an
intermediate arising from 5-exo cyclization (vide infra). An
aliphatic alkyne substituent also drove 6-endo selectivity (6y),
likely owing to its electron-rich nature.18,19
drivers, but the pronounced formation of the latter relative to
5k (Chart 1A) indicates that electronic effects must continue
to be accounted for in these expectations. In both cases, the
presence or absence of Na2CO3 was less consequential on
regioselection than what was observed in the cases in Table
1.20
The most straightforward rationalization for the observed
regioselectivities across these substrates is depicted in Figure 2.
Looking strictly at electronic effects, the arene induces a
polarization of the alkyne. For an electron-poor arene (i.e.,
4e,f,h), the alkyne β-carbon is more electron-deficient, and
thus the electrophilic metal association favors the α-carbon.
This leads to nucleophilic attack on the β-carbon and 5-exo
To interrogate different and potentially opposing electronic
and other effects within this class, we performed two tests
(Chart 1C). In the first case, substrate 4z features a p-NO2,
electronically favoring 5-exo cyclization (see 5f) and an o-Me
sterically favoring 6-endo cyclization (see 6w). In this example,
the 5-exo cyclization dominates (4z → 5z). The second test
examines different effects. The p-OMe should electronically
bias the reaction toward 6-endo cyclization, while the o-OBoc
will promote 5-exo cyclization due to electronic and/or
potential directing effects (vide infra). The 1.9:1 mixture of
5aa and 6aa reflects more of an equal combination of the two
Figure 2. Rationales for observed regioselectivities.
C
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cyclization. The reverse occurs with electron-rich arenes (i.e.,
4d), promoting 6-endo cyclizations. Electronic impacts
correlate well with either Hammett sigma values21 or 13C
NMR β-carbon chemical shifts.22 Predictive tools for ortho-
substituted arenes are not as clear-cut, as steric and/or
directing effects can affect selectivity, and electronic effects are
not as readily measured.23 When present, an ortho substituent
can sterically interfere with α-carbon metal association,
steering the cyclization in the 6-endo direction (Figure 2),
while a coordinative group would direct an exo cyclization if
the alternative leads to an unfavorable ring size. The variations
in cyclization preference based on an ortho-substituent track
decently with this rationale (−Me endo-selective (6w);
−OBoc, −OAc exo-selective (5k,l)), although an endo-
selective outlier such as o-NHAc (6v) suggests there are
more nuanced effects. The overall trend of electronic
correlation aligns well with the aforementioned other metal-
and nonmetal-catalyzed reactions.12−15
Scheme 3. Regioselectivity Analysis with Alternative
Nucleophiles
When examining larger rings (i.e., the competition between
6-exo and 7-endo cyclizations), electronics induce only a mild
perturbation (Scheme 2). Formation of the 6-membered rings
Scheme 2. Larger Rings: 6-exo/7-endo Competition
earlier cases, but this substrate class is different in that exo
represents nucleophilic attack at Cα and endo at Cβ. 13C NMR
analysis suggested nothing extraordinary regarding the
electronic effects on Cβ, raising questions about what else
could be dictating regioselectivity in this family. The
positioning of the nucleophile is different, which would explain
different product distributions relative to the other groups of
substrates, but certainly not the inverted trend. Although
presently unclear, the underlying message is that substrate
classes are subject to multiple effects including but not limited
to electronic induction, and each class should be evaluated
along these lines.27
was substantially more preferred.24 An electron-rich arene
shifted the endo selectivity a minor amount only, even when
using the base-free conditions that enhance this endo
directionality. (The major product dihydropyran 8d′ is also
indicative of an exo cyclization.)
These regioselective cyclizations can also be linked to
cascade transformations (Scheme 4). Cheng and co-workers
have reported the combination of alkynyl alcohols and indoles
to produce tetrahydrofurans and tetrahydropyrans.28 In this
study, selectivity for oxygen ring size was not analyzed in
general. When alcohol 4a is subjected to the cyclization
conditions in the presence of N-methylindole, tetrahydrofuran
20 is afforded as the major product. Alternatively, alcohol 4d
Both carbamate and carboxylic acid nucleophiles are subject
to the same electronic principles in this chemistry. Three
substrates in each class were evaluated (Scheme 3). Consistent
with the analysis of the alcohol systems, the electronic effects
of the arene directly impacted the 5-exo/6-endo competition.25
For enamide formation, an electron-withdrawing group favored
5-exo cyclization (11g), while an electron-donating group
promoted 6-endo cyclization (11d). As anticipated, the more
neutral arene was in between on this spectrum, affording a
mixture of the exo and endo products.26 In the case of lactone
formation, a “phase-shifted” trend was observed, where 5-exo
cyclization was predominant regardless of arene substitution
but to different degrees of selectivity based on the consistent
electronic effects.
Scheme 4. Tandem Hydroalkoxylation/Heteroarylation
Inasmuch as it may be preferable toward our understanding
for this electronic trend to be consistent across all substrate
classes, curiously this was not the case. Benzylic alcohols
16a,d,f were evaluated toward the synthesis of isochromenes
(Scheme 3C). Interestingly, here the electronic effect was
inverted. Methoxy-substituted isochromene 18d was formed
exclusively, while the nitro-substituted variant was observed
with a small but measurable amount of the 5-exo isomer. We
note the exo/endo directionality trend is the same as the
D
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Organic Letters
Letter
Maity, P.; Ranu, B. C. Copper-Assisted Nickel Catalyzed Ligand-Free
C(sp2)−O Cross-Coupling of Vinyl Halides and Phenols. Org. Lett.
2014, 16, 1040−1043.
will prefer endo cyclization, and the related tetrahydropyran
(21) is produced as the major compound.29 These experi-
ments illustrate how the selectivity can be leveraged in
convergent processes to form decorated heterocyclic com-
pounds.
Catalytic transition metal hydroalkoxylation processes have
been proven to be an important fixture in synthetic chemistry
due to their capacity to promote the formation of a variety of
oxygen-containing heterocycles. The results described here
highlight the ability to generate these heterocycles regiose-
lectively under mild, platinum-catalyzed conditions. We
anticipate that the studies herein may prove beneficial to
their integration in the development of the platinum carbene
manifold. Future studies toward application of these methods
in the capture of α,β-unsaturated carbenes are ongoing, and
their results will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
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for Efficient and Highly Selective Hydroalkoxylation and Hydro-
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03557.
Experimental procedures, compound characterization
data, and spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: emferr@uga.edu.
ORCID
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Eric M. Ferreira: 0000-0001-9412-0713
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The National Institutes of Health (NIGMS, R01GM110560)
is gratefully acknowledged. Mass spectrometry data were
acquired on an instrument supported by the NIH
(S10RR028859).
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modest yield, we cannot rule out nonspecific decomposition of an exo
product under these conditions. No keto alcohol products were
detected, but when base was added to the reaction, minor quantities
of the exo products were observed.
(20) The 5z/6z ratio was 16.4:1 without Na2CO3 added. The 5aa/
6aa ratio was 1.3:1 without Na2CO3 added.
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(22) All chemical shifts are reported in CDCl3. See the Supporting
Information. From our observations, if the Cβ chemical shift was >91
ppm, then exo selectivity was highly favored (>18:1). From 89 to 91
ppm, mixtures favoring exo cyclization were observed, but the direct
correlation was not perfectly linear.
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(24) MS4A was added to the reaction mixture to suppress observed
ketone formation, presumably arising from hydrolysis of the enol
ether.
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of Na2CO3 was found to be less impactful in magnitude than for that
represented in Table 1.
(26) The switch from Z- to E-selectivity using these nitrogen
nucleophiles is curious but likely attributable to a postcyclization Z-to-
E isomerization. Compound 11g was photoisomerized to a 1.2:1 E/Z
mixture and when subjected to the catalytic reaction conditions was
found to convert back to the E-isomer only (>19:1). The enol ether
products were less prone to isomerization. See the Supporting
Information for details. We thank a referee for this suggestion.
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́ ́
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́
́
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F
DOI: 10.1021/acs.orglett.9b03557
Org. Lett. XXXX, XXX, XXX−XXX