Trans-Hydroboration of Propiolamides: Access to Primary and Secondary (E)-β-Borylacrylamides

Article abstract of DOI:10.1021/acs.orglett.9b02408

A base-mediated trans-hydroboration of propiolamides that provides access to previously elusive primary and secondary (E)-β-borylacrylamide products has been developed. In the presence of n-butyllithium and pinacolborane, complete regioselectivity and ste

Full text of DOI:10.1021/acs.orglett.9b02408

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
trans-Hydroboration of Propiolamides: Access to Primary and
Secondary (E)-β-Borylacrylamides
R. Justin Grams,† Russell G. Fritzemeier,† Carla Slebodnick, and Webster L. Santos*
Department of Chemistry, Virginia Tech, 900 West Campus Drive, Blacksburg, Virginia 24061, United States
S
* Supporting Information
ABSTRACT: A base-mediated trans-hydroboration of pro-
piolamides that provides access to previously elusive primary
and secondary (E)-β-borylacrylamide products has been
developed. In the presence of n-butyllithium and pinacolbor-
ane, complete regioselectivity and stereoselectivity is observed,
affording the corresponding vinylboronate products in up to 91% yield. A wide variety of primary and secondary amides served
as efficient substrates for this transformation. A plausible reaction mechanism that involves substrate-assisted activation and a
key intramolecular cyclization is discussed.
he boronic acid moiety has emerged as one of the most
versatile functional groups in modern organic synthesis,
Scheme 1. Strategies for the Transition Metal-Free trans-
Hydroboration of Internal Alkynes
T
because of its versatility in many chemical transformations.
Most notable is their use as substrates in Suzuki−Miyaura
cross-coupling reactions.1 Notwithstanding their importance in
complex molecule synthesis, boron-containing compounds are
also valuable in medicinal chemistry, as five small molecule
organoboron drugs have been approved by the FDA.2 Thus,
methods for their synthesis are needed. Classical hydro-
boration of CC bonds using trivalent borane reagents
generate organoboron compounds with cis configuration;3 the
resulting alkenylboronates are particularly advantageous,
because of their desirable stability and reactivity profiles.4
More recently, reports of hydroboration of terminal alkynes
provide access to previously elusive (Z)-vinylboronates.5 The
more challenging transformation includes the corresponding
hydroboration reactions of internal alkynes affording the trans-
addition products (see Scheme 1). Toward this end, a handful
of transition-metal-catalyzed protocols using Ru,6 Pd,7 and Au8
have been developed. However, the corresponding transition
metal-free trans-hydroboration reactions are scarce. In seminal
work, Wang and Yamaguchi developed an elegant transition
metal-free protocol utilizing a 2-pyridyl group as an intra-
molecular directing group (Scheme 1a).9 Complete regiose-
lectivity and stereoselectivity was observed, but the substrate
scope was limited to dialkylboranes such as 9-BBN and
instability of the products lead to decreased yield during
isolation. An alternative approach by Ingleson and co-workers
involved an N-heterocyclic carbene (NHC)/9-BBN complex
that transfers a hydride to B(C6F5)3 forming a borenium ion
that coordinates to the alkyne facilitating the hydride transfer
to afford the desired product (Scheme 1b).10 Subsequently,
Taniguchi et al. reported a radical-mediated reaction of
internal alkynes with NHC-activated borane, which is catalyzed
by di-tert-butyl peroxide (Scheme 1c).11 Excellent regioselec-
tivity and stereoselectivity was observed across a broad range
of substrates, although terminal alkynes and alkynoates
suffered from reduced yields. More recently, a phosphine-
catalyzed method was independently reported by our group, as
well as groups led by Sawamura and Vilotijevic (Scheme 1d).12
The hydroboration reaction proceeded under mild conditions
with <10% catalyst loading and a wide variety of alkynoate
esters and tertiary propiolamides served as effective substrates
affording hydroborated product in good to excellent yields.
Drawbacks from these methods include limited scope with
Received: July 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02408
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Organic Letters
Letter
electron-deficient arenes and incomplete stereoselectivity with
alkyl substrates.12 Most notably, primary and secondary
propiolamides are inert under these reaction conditions.
However, the hydroboration of unsaturated amides is not
unprecedented. For example, Li and co-workers recently
reported the rhodium-catalyzed reversed hydroboration of
substituted acrylamides, which were subsequently oxidized
before isolation. The transformation proceeded efficiently with
excellent regioselectivity and stereoselectivity.13 Intramolecular
coordination of the amide to rhodium in the reduced
organorhodium species provided the necessary conformation
for stereoselective borylation; this highlights the utility of
amide coordination in substrate-driven stereoselectivity.
Inspired by these previous reports, we sought to develop a
method to previously inaccessible primary and secondary (E)-
β-borylacrylamides. We envisioned a Brønsted base-mediated
deprotonation that facilitates the formation of a tetrahedral
borohydride intermediate similar to the diboration14 and
silaboration15 protocols recently reported by our group as well
as alkynylboration methodology reported by Uchiyama16
(Scheme 1e). We hypothesize that the borohydride complex
is sufficiently activated to deliver a hydride to the α-carbon and
subsequent β-borylation generates the desired product with E
configuration.14,16
(Table 1, entry 2). The role of the crown ether is to chelate
with the Li cation and generate a naked alkoxide of 1a, thereby
increasing its Lewis basicity toward HBpin. Reducing the
equivalency of reagents resulted in a minor increase in yield
(Table 1, entry 3), but diluting the reaction mixture further
increased the product yield (Table 1, entry 4). We presume
that dilute conditions allow for more-efficient solvation of ion
aggregates.17 Excitingly, a similar yield was obtained in the
absence of crown ether (Table 1, entry 5).18 This is
advantageous as crown ether coelutes with the product and
is difficult to remove. Reducing the equivalency of base and
pinacolborane to 1.0 had minimal impact on product yield
(Table 1, entry 6). Alternative bases such as phenyllithium also
efficiently mediated the transformation, albeit in slightly lower
yield (Table 1, entry 7). The use of a Grignard reagent such as
EtMgBr resulted in an unsatisfactory yield (Table 1, entry 8).
Unfortunately, metal hydrides such as LiH do not mediate the
hydroboration reaction, although the reason for this is unclear
(Table 1, entry 9). We found that LiTMP and LDA also
afforded 2a, but at the cost off a modest reduction in yield
(Table 1, entries 10 and 11). Weaker bases such as t-BuOLi or
TEA were ineffective (Table 1, entries 12 and 13). We next
determined the effect of solvents. Replacing THF with toluene
or CPME resulted in poor yields that are likely due to reduced
solubility of ionic intermediates (Table 1, entries 14 and 15).
Dichloromethane as a solvent afforded 2a in only a modest
yield (Table 1, entry 16). We thus chose n-butyllithium as the
base with THF as solvent as the optimized reaction condition
(Table 1, entry 5). Characterization of 2a by 11B NMR
spectroscopy suggested internal coordination between B and
carbonyl oxygen (13 ppm). Following X-ray crystallographic
studies, we unambiguously confirmed the E configuration of
the alkene and internal coordination, as suggested by the B−O
bond length of 1.61 Å (Figure 1, see CCDC Accession No.
1907779).
We initiated our studies by first confirming that the
phosphine-catalyzed protocol was incompatible with propiola-
mide substrates. Thus, treating propiolamide 1a with tri-n-
butyl phosphine afforded no product, and starting materials
were recovered (Table 1, entry 1). Next, we employed a strong
base such as n-butyllithium (1.4 equiv) in the presence of 12-
crown-4 and HBpin at −78 °C to afford 2a in good yield
a
Table 1. Optimization of Reaction Conditions
e
entry
solvent
base/catalyst (equiv) temperature (°C) yield (%)
b
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
CPME
DCM
n-Bu3P (0.5)
n-BuLi (1.4)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.0)
PhLi (1.1)
EtMgBr (1.1)
LiH (1.1)
LiTMP (1.1)
LDA (1.1)
t-BuOLi (1.1)
TEA (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
60
−78
−78
−78
−78
−78
−78
−78
0
0
71
73
94
90
85
78
34
0
c
2
c
3
d
4
5
6
7
8
9
10
11
12
13
14
15
16
Figure 1. X-ray crystal structure of compound 2a (CCDC Accession
No. 1907779; see the Supporting Information).
−78
−78
0
68
52
0
With the optimal reaction conditions in hand, we sought to
determine the substrate scope and limitations (Scheme 2).
Increasing the steric constraint on nitrogen was well-tolerated.
For example, N-propyl (1b), N-isopropyl (1c), and N-tert-
butyl (1d) propiolamides efficiently afforded products 2b−2d
in good yields. Furthermore, an N-allyl substituted propiola-
mide (1e) was chemoselectively transformed to 2e in the
presence of a competing alkene. When the N-phenyl
substituted propiolamide (1f) was treated with n-BuLi and
HBpin, 2f was obtained in good yield but with contamination
of inseparable impurities. However, switching the base to PhLi
allowed the reaction to proceed smoothly in good yield.
Substitutions on the aryl moiety were also well-tolerated. Aryl
substituents with electron-donating groups such as 4-
methoxyphenyl (1g)- and 2-methoxyphenyl (1h)-substituted
0
0
−78
−78
−78
25
30
64
a
General procedure: propiolamide (0.2 mmol) was diluted in solvent
(0.1 M); base (0.22 mmol) was added at −78 °C; pinacolborane
(0.22 mmol) was added dropwise then the reaction was warmed to
b
room temperature (rt). 1.1 equiv of pinacolborane was used and the
reaction was run for 4 h at 0.6 M. Reaction performed at 0.2 M with
12-crown-4 (same equiv as n-BuLi). Reaction performed at 0.1 M
with 12-crown-4 (1.1 equiv). Isolated yield. CPME = cyclo-
c
d
e
pentylmethyl ether; DCM = dichloromethane.
B
DOI: 10.1021/acs.orglett.9b02408
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
reduction in yield. Propiolamides with electron-withdrawing
groups such as trifluoromethyl (1l) and 3,5-difluoro (1m) were
effective substrates for this transformation and afforded
products 2l−2m in good yields. Bromine at the ortho- or
para-position of the aryl ring provided 2n and 2o; however,
LiTMP as a base was utilized to avoid the problematic lithium-
halogen exchange with n-butyllithium. The reaction was also
compatible with protecting groups such as benzyl and MOM,
generating 2p and 2q, respectively. Larger rings such as
naphthalene (1r) and heteroaryl ring systems, such as
quinoline (1s), as well as thiophenes (1t and 1u), served as
good substrates generating the corresponding borylated
products 2r−2u. We surmised that the reduced yield for 2t
may be due to the acidic 2-H on the thiophene unit. We
confirmed this by performing hydroboration on the 5-
methylthiophene derivative (1u) and observed an increase in
product yield (2u). Finally, we confirmed the amenability of
the transformation to scale up with a 1 mmol reaction of 1a,
affording 89% isolated product (Scheme 2).
Scheme 2. Substrate Scope of Secondary Propiolamides
With the substrate scope of aryl substituents established, we
determined the tolerance of the reaction with nonaromatic
substituents (Scheme 3). In the presence of enyne 3a, the
Scheme 3. Substrate Scope of Enyne and Aliphatic
a
Secondary Propiolamides
a
General procedure: Same as in Scheme 1. After reaching rt, these
reactions were heated to 66 °C for 1.5 h.
triple bond was chemoselectively hydroborated (4a) in good
yield. Under our reaction conditions, aliphatic substituted
propiolamides 3b and 3c exclusively afforded single E isomers
4b and 4c in fair to good yields. However, the phosphine-
catalyzed hydroboration of propiolates with cyclic alkane
substituents, such as cyclohexyl and cyclopropyl, resulted in a
mixture of E and Z isomers.12a,b
Primary amides are especially challenging for alkyne
reduction since, to date, limited examples exist for this
transformation.14,15 Utilizing the developed method with 2
equiv of n-BuLi and pinacolborane, 3-phenylpropiolamide (5a)
was borylated in excellent yield (Scheme 4). Other functional
groups on the phenyl ring such as electron-donating methyl
(6b) and electron-withdrawing trifluoromethyl (6c) were
similarly generated in good yields. Whereas 5-methylthiophene
(6d) was achieved in 61% yield, the linear alkyl-substituted 6e
was afforded in modest yield. Steric encumbrance around the
β-carbon and the lack of resonance stabilization of the
intermediate carbanion may reduce borylation efficiency
(vide infra).
A plausible mechanistic route to explain the reactivity and
stereoselectivity observed is shown in Scheme 5, similar to a
previously reported mechanism for the diboration of
propiolamides.14 Deprotonation of 1a, followed by the
addition of pinacolborane, likely leads to borate complex 2I,
which, upon intramolecular hydride transfer, would yield the
high-energy vinyl anion 2II. Intramolecular ring closure in a
stereochemical determining step affords 2III. Subsequent
workup affords product 2a. To demonstrate that the hydrogen
a
General procedure: propiolamide (0.25 mmol) was diluted in THF
(0.1 M) and cooled to −78 °C; n-butyllithium (0.275 mmol, 2.5 M in
hexanes) was added at −78 °C, followed by pinacolborane (0.275
b
mmol); then, the reaction was warmed to rt. Performed with PhLi.
cPerformed with LiTMP.
propiolamides efficiently afforded 2g and 2h in excellent yields.
Alkyl substituents on the ring (1i−1k) were efficient
substrates, although increasing the steric bulk, such as that
observed in the mesityl group, was accompanied by a modest
C
DOI: 10.1021/acs.orglett.9b02408
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Organic Letters
Letter
a
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +
44 1223 336033.
Scheme 4. Substrate Scope of Primary Propiolamides
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: santosw@vt.edu.
ORCID
R. Justin Grams: 0000-0001-7306-3473
Webster L. Santos: 0000-0002-4731-8548
a
Author Contributions
General procedure: propiolamide (0.11 mmol) was diluted in THF
(0.1 M); n-butyllithium (0.24 mmol, 2.5 M in hexanes) was added at
−78 °C; pinacolborane (0.24 mmol) was added dropwise, and then
†These authors contributed equally to this work.
Notes
b
the reaction was warmed to rt. After reaching rt, the reaction was
heated to 66 °C for 1.5 h.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 5. Plausible Mechanism and Deuterium
Incorporation Study
■
We acknowledge financial support by the National Science
Foundation under Grant Nos. CHE-1414458 and CHE-
1726077 for X-ray crystallography experiments. We also
thank the Virginia Tech graduate school for fellowship funding
for R.J.G. and R.G.F.
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borane (see Scheme 5B). Compound 7a indicated 75%
deuterium incorporation, suggesting mechanistically that a
formal hydroboration is occurring.
In conclusion, we have developed an efficient and stereo-
selective transition metal-free trans-hydroboration of primary
and secondary propiolamides affording the corresponding (E)-
β-borylacrylamides. A wide substrate scope was demonstrated
with a variety of aromatic, heteroaromatic, and aliphatic
propiolamides. This protocol provides a method for these
otherwise inaccessible commodity materials. Further inves-
tigations into the synthetic and medicinal applications of the
borylated products is an ongoing area of research, which will
be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
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Experimental procedures and NMR data (PDF)
Accession Codes
CCDC 1907775, 1907776, 1907777, 1907778, and 1907779
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.
ac.uk/data_request/cif, or by emailing data_request@ccdc.
D
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