Catalytic, transition-metal-free semireduction of propiolamide derivatives: Scope and mechanistic investigation

Article abstract of DOI:10.1021/acs.orglett.0c02567

We report a transition-metal-free trans-selective semireduction of alkynes with pinacolborane and catalytic potassium tert-butoxide. A variety of 3-substituted primary and secondary propiolamides, including an analog of FK866, a potent nicotinamide mononucleotide adenyltransferase (NMNAT) inhibitor, are reduced to the corresponding (E)-3-substituted acrylamide derivatives in up to 99% yield with >99:1 E/Z selectivity. Mechanistic studies suggest that an activated Lewis acid-base complex transfers a hydride to the α-carbon followed by rapid protonation in a trans fashion.

Full text of DOI:10.1021/acs.orglett.0c02567

pubs.acs.org/OrgLett
Letter
Catalytic, Transition-Metal-Free Semireduction of Propiolamide
Derivatives: Scope and Mechanistic Investigation
R. Justin Grams, Christopher J. Garcia, Connor Szwetkowski, and Webster L. Santos*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02567
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report a transition-metal-free trans-selective semi-
reduction of alkynes with pinacolborane and catalytic potassium tert-
butoxide. A variety of 3-substituted primary and secondary propiolamides,
including an analog of FK866, a potent nicotinamide mononucleotide
adenyltransferase (NMNAT) inhibitor, are reduced to the corresponding (E)-3-substituted acrylamide derivatives in up to 99% yield
with >99:1 E/Z selectivity. Mechanistic studies suggest that an activated Lewis acid−base complex transfers a hydride to the α-
carbon followed by rapid protonation in a trans fashion.
Scheme 1. Methods toward E-Selective Semireduction of
Alkynes and Cinnamamide Synthesis
he semireduction of an alkyne to a (Z)- or (E)-alkene is
fundamental in organic synthesis. Methods toward the
T
(Z)-selective semireduction of alkynes are well established,1
with the most popular being semihydrogenation mediated by
Lindlar’s catalyst (Pd/CaCO3/Pb/quinoline).2 The comple-
mentary reduction methods affording (E)-alkenes are limited.
Early work involved treating alkynes with dissolved metals,3
low-valent chromium salts,4 or metal hydrides;5 however, these
methods are harsh and highly substrate-dependent. Trost and
coworkers later developed a general method for the (E)-
selective semireduction of alkynes via a ruthenium-mediated
hydrosilylation, which is subsequently protodesilylated with
TBAF, affording (E)-alkenes in high yield with excellent
stereoselectivity.6 Similarly, Fu
̈
rstner developed a one-step,
stereoselective semireduction of alkynes using a similar
ruthenium catalyst.7 Beyond these two examples, various
transition-metal-catalyzed methods toward the (E)-selective
semireduction of alkynes have been developed, such as Pd,1i,n,8
Rh,9 Ru,1q,10 In,11 Ir,1ab,12 Co,1ac,13 Ni,1ad,14 and Fe15 (Scheme
1A).
The transition-metal-free semireduction of alkynes to (E)-
alkenes is limited to a few examples. Koide treated γ-hydroxy-
α,β-alkynoic esters with Red-Al or NaBH4 and obtained
alkenoic esters in good yield with good stereoselectivity,
although the substrate scope is limited by the necessity of the
directing ability of the γ-hydroxyl moiety (Scheme 1B).16 Chen
and Liu employed sodium sulfide nonahydrate as a reducing
reagent to facilitate the stereoselective semihydrogenation of
diarylalkynes to (E)-alkenes (Scheme 1C). This method
successfully reduced a broad scope of diarylalkynes in good
to excellent yield with high stereoselectivity (98:2 E/Z).17
Similarly, Zhou and Liu demonstrated the semireduction of
diarylalkynes utilizing H2Se, which was generated in situ from
Se/DMF/H2O (Scheme 1C), to obtain alkenes in good yield
with high stereoselectivity (>95:5 E/Z).18 However, both
aforementioned methods were limited to diarylalkynes, and the
reaction conditions were fairly harsh. Recently, our group
Received: July 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02567
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
reported the α-boronation−protodeboronation of propiolic
acids (Scheme 1D). After boryl transfer to the α-carbon, the α-
boryl cinnamic acid is readily protodeboronated upon workup,
furnishing (E)-cinnamic acids in good yield with good
stereoselectivity.19 (E)-Cinnamic acids are commonly used as
precursors to (E)-cinnamamides, which are omnipresent
pharmacophores in synthetic pharmaceuticals and natural
products.20
These studies also demonstrated that the reaction is finished
within 10 min. KOH (entry 6) and NaOMe (entry 7)
mediated the semireduction to 2a, albeit in reduced yields.
However, the use of a weaker carbonate base such as K2CO3
was nonproductive (entry 8). With the optimal base conditions
in hand (entry 5), we screened a variety of different solvents.
Switching to 1,4-dioxane (entry 9) afforded 2a in modest yield.
Acetonitrile (entry 10) and dichloromethane (entry 11) were
sufficient solvents, although the yield was lower. DMF was also
a useful solvent for the semireduction of 1a (entry 12), but the
reaction time was considerably longer.
Only one method has been disclosed for the (E)-selective
semireduction of propiolamides, which requires a Pd catalyst
and superstoichiometric Mn to reduce 3-phenylpropiolamide
as well as tertiary propiolamides to the corresponding (E)-
cinnamamides. Typically, the (E)-configuration of cinnama-
mides is derived from E-cinnamic acid, a precursor commonly
synthesized by the condensation of aryl aldehydes with acetic
anhydride (Perkin reaction)21 or malonic acid (Knoevenagel−
Doebner condensation).22 The corresponding (E)-cinnama-
mides are synthesized by coupling (E)-cinnamic acid using
activating agents and the desired amine (Scheme 1E), the
synthesis of which remains widely used today but is nonideal.
More recently, Zacuto designed a direct synthesis of (E)-
acrylamides via the Knoevenagel−Doebner condensation of β-
imido acids with aldehydes (Scheme 1F).23 The paucity of
methods and the shortcomings of the current protocols
(including over-reduction) motivated us to develop an E-
selective method toward the semireduction of propiolamides.24
We initiated our investigation by treating N-methyl-3-
phenylpropiolamide (1a) with stoichiometric pinacolborane
and LiOtBu. To our delight, this afforded methyl (E)-
cinnamamide 2a with excellent stereoselectivity (>99:1 E/Z)
in 82% yield (Table 1, entry 1). A stoichiometric base was
unnecessary, as catalytic amounts of base efficiently produced
2a in good yield (entry 2). Upon increasing the size of the tert-
butoxide counterion from Li to K (entries 2−4), a remarkable
increase in the reaction efficiency was observed with KOtBu,
delivering a near-quantitative yield and >99% (E)-stereo-
selectivity, even at higher concentrations (0.5 M, entry 5).
With the optimal conditions in hand (Table 1, entry 5), we
investigated the substrate scope against a wide variety of
secondary propiolamides (Scheme 2). Sterically encumbered
a
Scheme 2. Secondary Propiolamide Scope
a
Table 1. Optimization of Reaction Conditions
b
entry
c d
base (equiv)
solvent
THF
THF
THF
THF
THF
THF
THF
THF
1,4-dioxane
MeCN
CH2Cl2
DMF
time
4 h
7 h
yield
,
1
2
3
4
5
6
7
8
9
LiOtBu (1.1)
LiOtBu (0.1)
NaOtBu (0.1)
KOtBu (0.1)
KOtBu (0.1)
KOH (0.1)
NaOMe (0.1)
K2CO3 (0.1)
KOtBu (0.1)
KOtBu (0.1)
KOtBu (0.1)
KOtBu (0.1)
82
62
75
95
96
39
58
0
47
85
78
52
e f
,
f
f
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
2 h
a
General procedure: Same as in Table 1, entry 5. >99:1 E/Z unless
otherwise specified. Isolated yields reported.
N-substitutions such as N-isopropyl (1b) and N-phenyl (1c)
were well-tolerated under these conditions, as cinnamamides
2b and 2c were produced in good yield. The Boc-protected
glycine derivative 1d was chemoselectively reduced to
cinnamamide 2d, with no ester reduction products observed.
Substrate 1e bearing a propargyl group was chemoselectively
reduced to cinnamamide 2e in excellent yield. Likewise,
electron-donating substituents (1f−h) and alkyl substitutions
such as m-methyl (1i) and p-tert-butyl (1j) afforded 2f−j in
good to excellent yields with near-exclusive E-selectivity.
Substrates bearing halogens such as o-Cl (1k), p-trifluorome-
10
11
12
a
General procedure: 1a (0.2 mmol), THF (0.5 M), base (0.02
b
c
mmol), and HBpin (0.22 mmol). Isolated yield (>99:1 E/Z). Base
and HBpin added at −78 °C, then heated to 40 °C for 4 h.
d
e
Propiolamide diluted to 0.1 M. Base and HBpin added at 25 °C,
f
then heated to 60 °C for 7 h. 0.2 M.
B
https://dx.doi.org/10.1021/acs.orglett.0c02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
thoxy (1l), and 3,5-difluoro (1m) were reduced to the
corresponding cinnamamides (2k−m) in high yield. Propio-
lamides with strong electron-withdrawing groups on the aryl
ring such as p-cyano (1n) were also suitable substrates,
although with a slight reduction in stereoselectivity. Hetero-
aromatics such as thiophene (1o) or pyridyl (1p) substitutions
were also efficient substrates. We were pleased to find that the
reaction was amenable to scale-up, as 3.5 mmol of 1a was
readily converted to 2a without a loss in yield or stereo-
selectivity (Scheme 2).
Scheme 4. Primary Propiolamide Scope
To further explore the substrate scope, we investigated
nonaromatic systems (Scheme 3). For example, enyne 3a was
Scheme 3. Enyne and Aliphatic Secondary Propiolamide
c
Scope
a
General procedure: 1a (0.2 mmol), THF (0.2 M), base (0.2 mmol),
and HBpin (0.22 mmol). >99:1 E/Z unless otherwise specified.
Isolated yields reported.
5-thiophen-2-yl substrate 5f was reduced in good yield. We
were also pleased to find that 2- and 3-pyridyl substitutions in
5g and 5h, respectively, did not affect the reaction, as they
were reduced in high to near-quantitative yield with excellent
chemo- and stereoselectivity (6g,h). On the contrary, an
aliphatic 3-cyclohexyl substitution (5i) resulted in a reduction
in yield and stereoselectivity similar to the related trans
diboration.
a
b
THF (0.2 M), KOtBu (1.0 equiv). Order of addition: HBpin
c
followed by KOtBu. Isolated yields reported. General procedure:
Same as in Table 1, entry 5. Stereochemistry is >99:1 E/Z unless
otherwise specified.
reduced to 4a in high yield with high E-stereoselectivity and
chemoselectivity for the alkyne. However, alkyl-substituted
propiolamides required a stoichiometric base and diluted
reaction conditions to afford satisfactory yields. Under these
conditions, substrates 3b,c were reduced to 4b,c in good yield
with good stereoselectivity. Fortunately, the 3-cyclopropyl
propiolamide 3d enhanced the reactivity and (E)-stereo-
selectivity compared with other aliphatic substrates, which we
also observed in the hydroboration of propiolamides.24c
Additionally, we found that the unsubstituted substrate N-
methyl propiolamide (3e) and dimethyl(phenyl)silyl derivative
3f could be converted to cinnamamides 4e and 4f, respectively,
in good yield when first treated with pinacolborane then base,
as treatment with base alone results in rapid degradation of the
starting material.
We next set out to apply this boron-mediated semireduction
protocol to the more challenging primary propiolamides.
Similar to most nonaryl secondary propiolamides in Scheme 3,
we observed that the stoichiometric addition of KOtBu and
pinacolborane was optimal. Thus 3-phenylpropiolamide (5a)
was reduced to 6a in excellent yield with high stereoselectivity
for the (E)-isomer, and this conversion was achieved in a near-
quantitative yield upon scale-up (Scheme 4). t-Butyl (5b) and
trifluoromethyl (5c) as well as trifluoromethoxy (5d)
substitutions were effectively converted to (E)-cinnamamides
6b−d. Strong electron-withdrawing p-nitro substitution (5e)
caused a minor reduction in (E)-stereoselectivity (6e).
Heterocyclic primary propiolamides were well-tolerated, as a
We then turned our attention toward the application of this
protocol. Cinnamamides are important structural features in
medicinal chemistry. For example, peptide 7 is an inhibitor of
the main protease in coronaviruses, including picomolar
activity against the Middle East Respiratory Syndrome
(MERS) coronavirus.25 FK866 is a potent inhibitor of the
nicotinamide mononucleotide adenyltransferase (NMNAT)
pathway26 that completed clinical trials as a potential
chemotherapeutic agent.27 Furthermore, recent research
suggests that FK886 is a promising treatment for various
diseases.28 Thus we decided that FK866 was a suitable
substrate for late-stage modification. We augmented the initial
portion of a previously described total synthesis of FK86629
and eventually installed the propiolamide via amide formation
by DCC/DMAP coupling to 3-phenylpropiolic acid (Scheme
5). Once installed, propiolamide 8 was stereoselectively
reduced to 9 in 76% yield, resulting in a 20% overall yield of
FK866 analog 9 in seven steps In comparison, previous
syntheses have an overall 8−12% yield.29,30 An advantage of
the method is the potential for rapid structure−activity
relationship studies and the control of olefin geometry, as
commercially available cinnamic acid derivatives are sold as a
mixture of cis/trans isomers.
To understand the origin of the trans selectivity of the
semireduction, we performed a mechanistic investigation.
Under the reaction conditions using deuterated 10, compound
11 was isolated in 40% yield with the deuterium atom installed
on the β carbon almost quantitatively (Scheme 6A). This result
C
https://dx.doi.org/10.1021/acs.orglett.0c02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 5. Structures of Medicinally Relevant
Cinnamamides and Synthesis of FK866 Analog
Scheme 7. Proposed Mechanism
Scheme 6. Mechanistic Studies
(i.e., transition state 14). The deuteration occurs on the
opposite side of the alkyne by coordination of t-BuOD with the
potassium of t-butoxide, which establishes the trans alkene
geometry in intermediate 15; upon workup, 11 is generated.
In conclusion, we have developed a transition-metal-free
semireduction reaction of primary and secondary propiola-
mides that selectively affords (E)-cinnamamides in good to
excellent yields. The reaction is tolerant of a wide variety of
substrates and is a facile process that uses inexpensive,
commercially available reagents. The utility of the reaction is
demonstrated in the late-stage alkyne reduction to achieve the
cinnamamide-containing drug candidate FK866. Lastly,
mechanistic studies suggest that the role of t-BuOK is to act
as a Brønsted base to activate the propiolamide for Lewis
acid−base complexation with pinacolborane, inducing an
intramolecular hydride transfer.
suggests that (i) hydride is adding on the α-carbon, (ii)
protonation occurs on the β-carbon, and (iii) a 1,4-conjugate
addition pathway is unlikely via hydride addition to the β-
carbon (i.e., from a Lewis base t-BuO−pinacolborane
complex). Alternatively, β-borylation can occur followed by
rapid protodeboration.31 However, the reaction of 12 under
the same conditions afforded only unreacted starting materials
(Scheme 6B). Recently, Thomas32 and Chang33 reported that
pinacolborane can decompose to BH3 in the presence of
catalysts such as t-BuOK. We thus treated 1a with t-BuOK and
BH3 (Scheme 6C). When we used borane as the reducing
agent, a significant loss in yield and a deterioration of
stereoselectivity was observed (77:23 E/Z), suggesting that
in situ formed BH3 is unlikely mediating the transformation.
Likewise, the addition of a catalytic amount of BH3 under
standard conditions afforded 2a in excellent yield and with E
selectivity. The BH3-mediated reduction of alkynes affords the
Z-alkene product, which is the opposite of what is observed
here. Taken together, a proposed mechanism is shown in
Scheme 7. The role of t-BuOK is to deprotonate propiolamide
10, which is in equilibrium with t-BuOD and its conjugate base
13. The Lewis-basic oxygen in 13 then complexes with
pinacolborane, activating the B−H bond24b,34 for an intra-
molecular pseudo-5-exo-dig24c hydride transfer to the α-carbon
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02567.
■
sı
Experimental procedures and NMR data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Webster L. Santos − Department of Chemistry, Virginia Tech,
Blacksburg, Virginia 24061, United States; orcid.org/0000-
0002-4731-8548; Email: santosw@vt.edu
Authors
R. Justin Grams − Department of Chemistry, Virginia Tech,
Blacksburg, Virginia 24061, United States; orcid.org/0000-
0001-7306-3473
Christopher J. Garcia − Department of Chemistry, Virginia
Tech, Blacksburg, Virginia 24061, United States
Connor Szwetkowski − Department of Chemistry, Virginia
Tech, Blacksburg, Virginia 24061, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02567
D
https://dx.doi.org/10.1021/acs.orglett.0c02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Cohen, N.; De Noble, J. P.; Specian, A. C.; Saucy, G. J. Org. Chem.
1976, 41, 3497−3505.
(4) (a) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117,
8106−8125. (b) Smith, A. B., III; Levenberg, P. A.; Suits, J. Z.
Synthesis 1986, 3, 184−189. (c) Hanson, J. R. Synthesis 1974, 1, 1−8.
(d) Castro, C. E.; Stephens, R. D. J. Am. Chem. Soc. 1964, 86, 4358−
4363.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
(5) (a) Tsuda, T.; Yoshida, T.; Kawamoto, T. J.; Saegusa, T. J. Org.
Chem. 1987, 52, 1624−1627. (b) Jones, T. K.; Denmark, S. E. Organic
Syntheses; Wiley & Sons: New York, 1985; Vol. 7. (c) Dabdoub, M. J.;
Dabdoub, V. B.; Comasseto, J. V. Tetrahedron Lett. 1992, 33, 2261−
2264.
ACKNOWLEDGMENTS
■
We acknowledge financial support by the National Science
Foundation (CHE-1414458) and the Virginia Tech Chemistry
Department.
(6) (a) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726−
̈
12727. (b) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002,
124, 7922−7923.
REFERENCES
■
(7) (a) Fu
̈
rstner, A. J. Am. Chem. Soc. 2019, 141, 11−24.
rstner, A. Angew. Chem., Int.
(1) Palladium-catalyzed: (a) Li, J.; Hua, R.; Liu, T. J. Org. Chem.
2010, 75, 2966−2970. (b) Drost, R. M.; Bouwens, T.; van Leest, N.
P.; de Bruin, B.; Elsevier, C. J. ACS Catal. 2014, 4, 1349−1357.
(c) van Laren, M. W.; Elsevier, C. J. Angew. Chem., Int. Ed. 1999, 38,
3715−3717. (d) Hauwert, P.; Maestri, G.; Sprengers, J. W.; Catellani,
M.; Elsevier, C. J. Angew. Chem., Int. Ed. 2008, 47, 3223−3226.
(e) Mitsudome, T.; Takahashi, Y.; Ichikawa, S.; Mizugaki, T.;
Jitsukawa, K.; Kaneda, K. Angew. Chem., Int. Ed. 2013, 52, 1481−
1485. (f) Sajiki, H.; Mori, S.; Ohkubo, T.; Ikawa, T.; Kume, A.;
Maegawa, T.; Monguchi, Y. Chem. - Eur. J. 2008, 14, 5109−5111.
(g) Fukazawa, A.; Minoshima, J.; Tanaka, K.; Hashimoto, Y.; Kobori,
Y.; Sato, Y.; Atobe, M. ACS Sustainable Chem. Eng. 2019, 7, 11050−
11055. (h) Iwasaki, R.; Tanaka, E.; Ichihashi, T.; Idemoto, Y.; Endo,
K. J. Org. Chem. 2018, 83, 13574−13579. (i) Shen, R.; Chen, T.;
Zhao, Y.; Qiu, R.; Zhou, Y.; Yin, S.; Wang, X.; Goto, M.; Han, L.-B. J.
(b) Radkowski, K.; Sundararaju, B.; Fu
Ed. 2013, 52, 355−360.
̈
(8) (a) Luo, F.; Pan, C.; Wang, W.; Ye, Z.; Cheng, J. Tetrahedron
2010, 66, 1399−1403. (b) Maazaoui, R.; Abderrahim, R.; Chemla, F.;
Ferreira, F.; Perez-Luna, A.; Jackowski, O. Org. Lett. 2018, 20, 7544−
7549. (c) Shirakawa, E.; Otsuka, H.; Hayashi, T. Chem. Commun.
2005, 5885−5886.
(9) Burch, R. R.; Muetterties, E. L.; Teller, R. G.; Williams, J. M. J.
Am. Chem. Soc. 1982, 104, 4257−4258.
(10) (a) Schabel, T.; Belger, C.; Plietker, B. Org. Lett. 2013, 15,
2858−2861. (b) Michaelides, I. N.; Dixon, D. J. Angew. Chem., Int. Ed.
2013, 52, 806−808. (c) Cho, C. S.; Kim, D. T.; Shim, S. C. Bull.
Korean Chem. Soc. 2009, 30, 1931−1932.
(11) Hayashi, N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981−
4983.
̈
̈
Am. Chem. Soc. 2011, 133, 17037−17044. (j) Masing, F.; Nusse, H.;
Klingauf, J.; Studer, A. Org. Lett. 2017, 19, 2658−2661.
(k) Nishibayashi, R.; Kurahashi, T.; Matsubara, S. Synlett 2014, 25,
(12) Tani, K.; Iseki, A.; Yamagata, T. Chem. Commun. 1999, 1821−
1822.
(13) Qi, X.; Liu, X.; Qu, L.-B.; Liu, Q.; Lan, Y. J. Catal. 2018, 362,
25−34.
̀
1287−1290. (l) Monfredini, A.; Santacroce, V.; Marchio, L.; Maggi,
R.; Bigi, F.; Maestri, G.; Malacria, M. ACS Sustainable Chem. Eng.
2017, 5, 8205−8212. (m) Mohamed, Y. M. A.; Hansen, T. V.
Tetrahedron 2013, 69, 3872−3877. (n) Zhao, C.-Q.; Chen, Y.-G.;
Qiu, H.; Wei, L.; Fang, P.; Mei, T.-S. Org. Lett. 2019, 21, 1412−1416.
(o) Gellrich, U.; Wech, F.; Hasenbeck, M. Chem. - Eur. J. 2020,
DOI: 10.1002/chem.202001276. (p) Belger, C.; Neisius, N. M.;
Plietker, B. Chem. - Eur. J. 2010, 16, 12214−12220. (q) Kusy, R.;
Grela, K. Org. Lett. 2016, 18, 6196−6199. Copper-catalyzed:
(r) Whittaker, A. M.; Lalic, G. Org. Lett. 2013, 15, 1112−1115.
(s) Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Adv. Synth.
Catal. 2012, 354, 1542−1550. (t) Semba, K.; Kameyama, R.; Nakao,
Y. Synlett 2015, 26, 318−322. (u) Bao, H.; Zhou, B.; Jin, H.; Liu, Y. J.
Org. Chem. 2019, 84, 3579−3589. Gold-catalyzed: (v) Yan, M.; Jin,
T.; Ishikawa, Y.; Minato, T.; Fujita, T.; Chen, L.-Y.; Bao, M.; Asao,
N.; Chen, M.-W.; Yamamoto, Y. J. Am. Chem. Soc. 2012, 134, 17536−
17542. (w) Wagh, Y. S.; Asao, N. J. Org. Chem. 2015, 80, 847−851.
(x) Vasilikogiannaki, E.; Titilas, I.; Vassilikogiannakis, G.; Stratakis, M.
Chem. Commun. 2015, 51, 2384−2387. Niobium-catalyzed:
(y) Gianetti, T. L.; Tomson, N. C.; Arnold, J.; Bergman, R. G. J.
Am. Chem. Soc. 2011, 133, 14904−14907. Vanadium-catalyzed:
(z) La Pierre, H. S. L.; Arnold, J.; Toste, F. D. Angew. Chem., Int. Ed.
2011, 50, 3900−3903. Iron-catalyzed: (aa) Enthaler, S.; Haberberger,
M.; Irran, E. Chem. - Asian J. 2011, 6, 1613−1623. Iridium-catalyzed:
(ab) Yang, J.; Wang, C.; Sun, Y.; Man, X.; Li, J.; Sun, F. Chem.
Commun. 2019, 55, 1903−1906. Cobalt-catalyzed: (ac) Fu, S.; Chen,
N.-Y.; Liu, X.; Shao, Z.; Luo, S.-P.; Liu, Q. J. Am. Chem. Soc. 2016,
138, 8588−8594. Nickel-catalyzed: (ad) Richmond, E.; Moran, J. J.
Org. Chem. 2015, 80, 6922−6929.
́
(14) (a) Reyes-Sanchez, A.; Canavera-Buelvas, F.; Barrios-Francisco,
̃
R.; Cifuentes-Vaca, O. L.; Flores-Alamo, M.; García, J. J. Organo-
metallics 2011, 30, 3340−3345. (b) Chen, T.; Xiao, J.; Zhou, Y.; Yin,
S.; Han, L.-B. J. Organomet. Chem. 2014, 749, 51−54.
(15) Srimani, D.; Diskin-Posner, Y.; Ben-David, Y.; Milstein, D.
Angew. Chem., Int. Ed. 2013, 52, 14131−14134.
(16) Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785−1787.
(17) Chen, Z.; Luo, M.; Wen, Y.; Luo, G.; Liu, L. Org. Lett. 2014, 16,
3020−3023.
(18) Li, H.-C.; An, C.; Wu, G.; Li, G.-X.; Huang, X.-B.; Gao, W.-X.;
Ding, J.-C.; Zhou, Y.-B.; Liu, M.-C.; Wu, H.-Y. Org. Lett. 2018, 20,
5573−5577.
(19) Verma, A.; Grams, R. J.; Rastatter, B. P.; Santos, W. L.
Tetrahedron 2019, 75, 2113−2117.
(20) (a) Gaikwad, N.; Nanduri, S.; Madhavi, Y. V. Eur. J. Med. Chem.
2019, 181, 111561. (b) De, P.; Baltas, M.; Bedos-Belval, F. Curr. Med.
́
Chem. 2011, 18, 1672−1703. (c) Gunia-Krzyzak, A.; Panczyk, K.;
̇
Waszkielewicz, A. M.; Marona, H. ChemMedChem 2015, 10, 1302−
1325.
(21) Perkin, W. H. J. Chem. Soc. 1868, 21, 53−63.
(22) (a) Doebner, O. Ber. Dtsch. Chem. Ges. 1900, 33, 2140−2142.
(b) Verley. Bull. Soc. Chim. Fr. 1899, 21, 414. (c) Knoevenagel, E. Ber.
Dtsch. Chem. Ges. 1898, 31, 2596−2619.
(23) Zacuto, M. J. J. Org. Chem. 2019, 84, 6465−6474.
(24) (a) Fritzemeier, R.; Santos, W. L. Chem. - Eur. J. 2017, 23,
15534−15537. (b) Verma, A.; Snead, R. F.; Dai, Y.; Slebodnick, C.;
Yang, Y.; Yu, H.; Yao, F.; Santos, W. L. Angew. Chem. 2017, 129,
5193−5197. (c) Grams, R. J.; Fritzemeier, R. G.; Slebodnick, C.;
Santos, W. L. Org. Lett. 2019, 21, 6795−6799.
(2) (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 446−450. (b) Lindlar,
H.; Dubuis, R. Org. Synth. 1966, 46, 89. (c) Chandrasekhar, S.;
Narsihmulu, C.; Chandrashekar, G.; Shyamsunder, T. Tetrahedron
Lett. 2004, 45, 2421−2423. (d) Crombie, L.; Jarrett, S. R. M. J. Chem.
Soc., Perkin Trans. 1 1992, 1, 3179−3183.
(3) (a) Brandsma, L.; Nieuwenhuizen, W. F.; Zwikker, J. W.;
Maeorg, U. Eur. J. Org. Chem. 1999, 1999, 775−779. (b) Chan, K.-K.;
(25) Zhang, L.; Lin, D.; Kusov, Y.; Nian, Y.; Ma, Q.; Wang, J.; von
Brunn, A.; Leyssen, P.; Lanko, K.; Neyts, J.; de Wilde, A.; Snijder, E.
J.; Liu, H.; Hilgenfeld, R. J. Med. Chem. 2020, 63, 4562−4578.
(26) Khan, J. A.; Forouhar, F.; Tao, X.; Tong, L. Expert Opin. Ther.
Targets 2007, 11, 695−705.
̈
E
https://dx.doi.org/10.1021/acs.orglett.0c02567
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(27) For current information, see: http://clinicaltrials.gov.
(28) (a) Esposito, E.; Impellizzeri, D.; Mazzon, E.; Fakhfouri, G.;
Rahimian, R.; Travelli, C.; Tron, G. C.; Genazzani, A. A.; Cuzzocrea,
S. J. Neuroinflammation 2012, 9, 66. (b) Lee, J.; Kim, H.; Lee, J. E.;
Shin, S.-J.; Oh, S.; Kwon, G.; Kim, H.; Choi, Y. Y.; White, M. A.; Paik,
S.; Cheong, J.-H.; Kim, H. S. Gastroenterology 2018, 155, 799.
(c) Guo, E.; Li, R.; Yang, J.; Zhang, J.; Li, A.; Yang, Y.; Liu, S.; Liu, A.;
Jiang, X. Sci. Rep. 2017, 7, 2206. (d) Desautels, D. N.; Bourrier, M.;
Peltier, C.; Banerji, V.; Banerji, S. O. J. Clin. Oncol. 2015, 33, e18562−
e18562. (e) Nacarelli, T.; Fukumoto, T.; Zundell, J. A.; Fatkhutdinov,
N.; Jean, S.; Cadungog, M. G.; Borowsky, M. E.; Zhang, R. Cancer Res.
2020, 80, 890−900. (f) Gerner, R. R.; Macheiner, S.; Reider, S.;
Siegmund, K.; Grabherr, F.; Mayr, L.; Texler, B.; Moser, P.;
Effenberger, M.; Schwaighofer, H.; Moschen, A. R.; Kircher, B.;
Oberacher, H.; Zeiser, R.; Tilg, H.; Nachbaur, D. Leukemia 2020, 34,
1885−1897.
(29) Galli, U.; Ercolano, E.; Carraro, L.; Blasi Roman, C. R.; Sorba,
G.; Canonico, P. L.; Genazzani, A. A.; Tron, G. C.; Billington, R. A.
ChemMedChem 2008, 3, 771−779.
(30) Klinge Pharma, WO 97/48397, 1997.
(31) Nagao, K.; Yamazaki, A.; Ohmiya, H.; Sawamura, M. Org. Lett.
2018, 20, 1861−1865.
(32) (a) Bage, A. D.; Hunt, T. A.; Thomas, S. P. Org. Lett. 2020, 22,
4107. (b) Ang, N. W. J.; Buettner, C. S.; Docherty, S.; Bismuto, A.;
Carney, J. R.; Docherty, J. H.; Cowley, M. J.; Thomas, S. P. Synthesis
2018, 50, 803−808.
(33) Jeong, E.; Heo, J.; Park, S.; Chang, S. Chem. - Eur. J. 2019, 25,
6320−6325.
(34) Query, I. P.; Squier, P. A.; Larson, E. M.; Isley, N. A.; Clark, T.
B. J. Org. Chem. 2011, 76, 6452−6456.
F
https://dx.doi.org/10.1021/acs.orglett.0c02567
Org. Lett. XXXX, XXX, XXX−XXX