Tetrahydrobenzochromene Synthesis Enabled by a Deconjugative Alkylation/Tsuji-Saegusa-Ito Oxidation on Knoevenagel Adducts

Article abstract of DOI:10.1021/acs.orglett.8b01857

A modular and practical route to versatile cyano-1,3-dienes by a sequence involving deconjugative alkylation and "Tsuji-Saegusa-Ito oxidation" is reported. In this letter, the versatility of the products is also explored, including a route to benzochromene scaffolds common to many natural products.

Full text of DOI:10.1021/acs.orglett.8b01857

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tetrahydrobenzochromene Synthesis Enabled by a Deconjugative
Alkylation/Tsuji−Saegusa−Ito Oxidation on Knoevenagel Adducts
Primali V. Navaratne and Alexander J. Grenning*
Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611-7200, United States
S
* Supporting Information
ABSTRACT: A modular and practical route to versatile cyano-1,3-dienes by a sequence involving deconjugative alkylation and
“Tsuji−Saegusa−Ito oxidation” is reported. In this letter, the versatility of the products is also explored, including a route to
benzochromene scaffolds common to many natural products.
he tetrahydro- and hexahydrobenzochromene scaffold is
Though photocannabinoid synthesis has been studied since the
1960s, the routes have many similarities. It is common to
prepare the tetrahydrobenzochromene by the addition of a
nucleophilic arene to the monoterpene or monoterpene
derivative.10 An allylic alkylation (or Ireland−Claisen rear-
rangement)/ring-closing metathesis sequence has also been
examined by numerous research groups.11 Related to this
report, the intramolecular Diels−Alder reaction has also been
examined.12 Regarding medicinal chemistry centered on THC
and the benzochromene scaffold, the biomimetic route is most
commonly utilized (Figure 2).14
T
common to many biologically active molecules (Figure
1). For example, the natural product Δ9-tetrahydrocannabinol1
(THC) bears this core, as well as many other natural products,
including machaeriol A,2 conicol,3 salvidorol,4 sauchinone,5
alfileramine,6 exotiacetal A,7 and palodesangren E.8
Δ9-THC and its synthetic and semisynthetic analogs (e.g.,
nabilone, levonantradol, and 1-desoxy-Δ9-THC) are by far the
most synthetically targeted tetrahydrobenzochromenes.1,9−16
Figure 2. Summary of strategies toward tetrahydrobenzochromene
scaffolds.
Inspired by cannabinoids, we wished to devise a new route
to tetrahydrobenzochromene scaffolds that would be concise,
operationally simple, and convergent from the abundant
starting material classes.17 This would allow for diverse target
and target-analog synthesis. With this goal in mind, we
proposed the following sequence: allyl cyanoacetate and
ketone-derived Knoevenagel adducts 1 and 2-allyloxybenzyl
electrophiles 2 can undergo (i) deconjugative alkylation to 3,18
(ii) the Tsuji-variant of the Saegusa−Ito oxidation (“Tsuji−
Saegusa−Ito oxidation”) yielding the diene/dienophile-paired
substrate 4,19 and (iii) intramolecular [4 + 2] cycloaddition
Figure 1. Representative natural and unnatural tetrahydro- and
hexahydro-benzochromenes.
Received: June 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01857
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yielding the target scaffolds 5.20 The scaffolds can have high
structural diversity considering their synthetic origins (ketones,
allyl cyanoacetate, salicylaldehydes, and allylic electrophiles)
and would contain a nitrile, which themselves have beneficial
medicinal properties and are excellent functional handles.21
From the perspective of cannabinoid structure−activity
relationship studies, nitrile-containing analogs have never
been evaluated.1,9−16 Furthermore, the nitrile has the potential
to stabilize the Δ9-alkene configuration on the tetrahydro-
benzochromene, potentially improving its physical properties.
The proposed sequence has the potential to be operationally
simple, as the key C−C bond forming reactions require mild
bases (step i) or are thermal (step iii). The major synthetic
liability was the proposed Tsuji−Saegusa−Ito oxidation to
yield cyano-1,3-dienes 4 (step ii). Although ketone and nitrile
dehydrogenation catalyzed by Pd(0) using allyl acetate as a
stoichiometric oxidant has been known for decades,19 it has
not been explored for preparing 2-cyano-1,3-dienes. It should
also be noted that Newhouse and co-workers are making
related advancements to Pd-catalyzed Tsuji-type dehydrogen-
ation.22 It is also possible that the targeted 2-cyano-1,3-dienes
could be prepared by Horner−Wadsworth−Emmons (HWE)
reactions between aldehydes and α-cyano vinyl phosphonates.
However, this transformation yields preferentially 1-cyano-1,3-
dienes via vinylogous-HWE reaction, isomeric connectivity to
our targeted 2-cyano-1,3-dienes.23 Herein, we report the
development of the sequence outlined in Scheme 1.
imentation, we uncovered that high yields of the desired
product 7a could be accessed using 10 mol % Pd(OAc)2, 8 mol
% PPh3, and 2 equiv of allyl acetate in acetonitrile at 80 °C.
The Pd-precatalyst to PPh3 ratio is very important. Pd(PPh3)4
and other Pd(0) precatalysts/PPh3 yielded primarily the
decarboxylative allylation product 9a. To varying degrees, the
desired product was observed with Pd(II) precatalysts and
phosphine in roughly equimolar ratios. These results are in line
with Tsuji’s original report: the phosphine likely serves as a
sacrificial reductant, and Pd(0)·PR3 complexes promote
decarboxylative allylation.19 Thus, it is important to ensure
no additional phosphine is present.
With the optimized conditions in hand, we systematically
explored the coupling partners and found that good yields of
the 2-cyano-1,3-dienes 7 could be prepared when Knoevenagel
adducts were derived from methyl ketones and various 1° alkyl
halides (Scheme 2). Also noteworthy, in all cases, single diene
Scheme 2. Scope of 2-Cyano-1,3-diene Synthesis
Scheme 1. New Diene Synthesis and Application in
Benzochromene Synthesis
a
b
5 mol % Pd(OAc)2, 4 mol % PPh3 [gram scale]. 10 mol % White
c
catalyst used in lieu of Pd(OAc)2. Distilled over CaH2 MeCN used in
lieu of commercial-anhydrous (over molecular sieves) MeCN.
diastereomers were observed. For example, products 7a and 7b
were prepared from benzyl bromide or ethyl iodide,
respectively. Products 7c and 7d were prepared from different
ketone-derived starting materials (acetone or acetopheone,
respectively). Products 7e−7g have various electronic and
steric patterns about the arene. The 2-cyano-1,3-diene
synthesis was also scalable (up to gram-scale) without
significant changes in yield (Scheme 2, footnote a). In this
study, the catalyst loading was also reduced to 5 mol %
Pd(OAc)2. In a few cases, we observed unacceptable amounts
of protonation byproducts (10−20%) that were inseparable
from the desired product. We found that repurified acetonitrile
(distilled of CaH2) seemed to perform better than the
commercial anhydrous solvent (obtained over molecular
sieves, footnote c).
To begin our studies, we wished to examine the proposed
Tsuji−Saegusa−Ito oxidation separately. Test substrate 6a was
prepared from pyruvaldehyde dimethyl acetate, allyl cyanoa-
cetate, and benzyl bromide (Table 1). After some exper-
Table 1. Optimization of 2-Cyano-1,3-diene Synthesis
We also examined the substrate 10a derived from cyclo-
hexanone, allyl cyanoacetate, and benzyl bromide (eq 1). This
catalyst
(10 mol % Pd)
allyl
acetate
7a
(%)
8a
(%)
9a
(%)
entry
Pd/P
1
2
3
4
5
6
7
Pd(PPh3)4
1:4
1:1
0 equiv
0 equiv
0 equiv
0 equiv
0 equiv
2 equiv
2 equiv
−
−
67
40
78
95
95
−
86
41
−
21
−
Pd2dba3:PPh3
Pd(OAc)2:PPh3
Pd(OAc)2:dppe
Pd(OAc)2:PPh3
Pd(OAc)2:PPh3
White cat.:PPh3
trace
trace
trace
trace
−
1:0.5
1:0.5
1:0.8
1:0.8
1:0.8
−
−
substrate has two potential sites for β-hydrogen elimination. In
this case, the regioselectivity opposite to that observed from
−
B
DOI: 10.1021/acs.orglett.8b01857
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
methyl ketone-derived Knoevenagel adducts was observed (eq
1 vs Scheme 2). In this case, a 1-cyano-1,3-diene 10b was
prepared.
Scheme 4. Modular Route to Tetrahydrobenzochromene
Scaffolds
We next examined the reactivity of these cross-conjugated 2-
cyano-1,3-dienes 7 (Scheme 3). The electron-rich olefin could
Scheme 3. Reactivity of 2-Cyano-1,3-dienes 7a/b
a
b
3 mol % OsO4, 1.5 equiv of NMO, acetone/H2O (4:1). 1.5 equiv of
c
mCPBA, 3.5 equiv of NaHCO3, CH2Cl2. 10 equiv of dimethly
acetylenedicarboxylate, neat, 150 °C.
be dihydroxylated with a subsequent Pinner reaction to yield
an α,β-unsaturated cyclic imidate 11 in excellent yield.
Similarly, this olefin can also be selectively epoxidized to 12
using mCPBA. 1,3-Dienes are commonly utilized in cyclo-
addition reactions. Although they bear a 2-cyano group, the 1-
aryl-3-alkyl groups electronically dominate, and this diene
reacts with electron-deficient dieneophiles to yield cyclo-
adducts such as 13.
We next turned to our original goal, targeting diverse
tetrahydrobenzochromene scaffolds by a Tsuji−Saegusa−Ito
oxidation/intramolecular [4 + 2] cycloaddition strategy
(Scheme 4). Under the standard conditions for decarboxylative
oxidation, dienes 4a−4i could be prepared and were
competent cycloaddition substrates (to 5a−5i). Regarding
the [4 + 2] cycloaddition, there was a slight preference for the
cis-fused ring system in most cases. However, 5b slightly
favored the trans-fused ring system (2:1 dr), likely due to a
secondary orbital overlap between the phenyl group and the
diene. Surprisingly 5d was prepared as a single diastereomer
and is the result of an exo-cycloaddition. Although in most
cases diastereomeric mixtures were observed due to competing
endo-/exocycloadditions, stereochemistry can converge to the
trans-product by acetal deprotection/isomerization (Scheme
5). Diversity can easily be achieved by simple modification of
the starting materials; we explored a variety of allylic and arene
substitution patterns. For example, scaffolds 5a−5e are
systematically diversified based on the allylic electrophile
where allyl (5a), cinnamyl (E-olefin, 5b), cis-buten-1−4-diol
(Z-olefin, 5c), cyclohexenyl (5d), and prenyl (5e) electrophiles
were utilized. These changes result in benzochromenes that are
“palodesangren-like (5b),” “sauchinone-like (5d),” and “salvi-
dorol-like (5e)” (Scheme 4 compared to Figure 1). Scaffolds
5f−5h were prepared respectively from 4-bromo- (5f), 5-
bromo- (5g), and 5-nitro- (5h) salicylaldehyde. In the course
of our studies, 5i was prepared multiple times on gram scale
(Scheme 4B). Scheme 4B also reiterates the significance of this
route: all starting materials, reagents, and catalysts are
inexpensive, the synthesis is operationally simple, and the
target scaffold has orthogonal functional groups distributed
about the core. This is ideal for drug discovery applications.
Regarding the latter point, 5i is decorated with bromoarene,
nitrile, acetal, and protected alcohol functional groups.
a
10 mol % Pd (OAc)2, 8 mol % PPh3, 2 equiv of allyl acetate, MeCN
b
c
(0.3 M), 80 °C, 30 min. Toluene (0.1 M), 12 h, reflux. Inseparable
from protonation byproduct. 10% White catalyst in lieu of
Pd(OAc)2.
d
coupling conditions with phenylboronic acid, 14a was
prepared. Acetal deprotection/isomerization can occur under
a variety of acidic conditions to yield either 14b or 14c with
concomitant alcohol deprotection. By design, the aldehyde
incorporated on the scaffold is a useful functional handle; in
this regard the imidate-containing product 14d was prepared
by a reduction/intramolecular Pinner reaction. Finally, the
protected alcohol could selectively be deprotected using
DIBAL−H to yield 14e.
In conclusion, we have developed a modular two-step route
to 2-cyano-1,3-dienes from Knoevenagel adducts and alkyl
electrophiles. These dienes are versatile and can be converted
to a variety of unique scaffolds. We also utilized this report’s
development in conjunction with intramolecular cycloaddition
to modularly assemble benzochromene scaffolds. In addition to
the pursuits of target/target-analog synthesis and biological
evaluation, for which we are seeking collaborators, the
In preparation for target- and target-analog synthesis, our
final studies in this initial letter are potential ways 5i can be
manipulated (Scheme 4). Under standard Suzuki cross-
C
DOI: 10.1021/acs.orglett.8b01857
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Letter
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Scheme 5. Functional Group Interconversion of
Tetrahydrobenzochromene Scaffold 5i
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a
10 mol % PdCl2(PPh3)2, 3 equiv of PhB(OH)2, 3 equiv of K2CO3
b
dioxane (0.5 M), 120 °C. 0.5 equiv of CBr4, MeCN/H2O (1:2), 80
c
d
°C. 0.5 equiv of TsOH, acetone/H2O (4:1), 40 °C. NaBH4, MeOH
e
(0.5 M) 0 °C. 2 equiv of DIBALH, CH2CL2 (0.25 M), diastereomers
separable by chromatography; major diasteromer reported.
discoveries reported herein will lead to significant future
synthetic developments related to improving the scope and
stereoselectivity.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01857.
Experimental procedures, characterization data (1H, 13C
NMR and HRMS) (PDF)
(14) (a) Kulkarni, S.; Nikas, S. P.; Sharma, R.; Jiang, S.; Paronis, C.
A.; Leonard, M. Z.; Zhang, B.; Honrao, C.; Mallipeddi, S.; Raghav, J.
AUTHOR INFORMATION
̈
G.; Benchama, O.; Jarbe, T. U. C.; Bergman, J.; Makriyannis, A. J.
■
Med. Chem. 2016, 59, 6903. (b) Thakur, G. A.; Bajaj, S.; Paronis, C.;
Peng, Y.; Bowman, A. L.; Barak, L. S.; Caron, M. G.; Parrish, D.;
Deschamps, J. R.; Makriyannis, A. J. Med. Chem. 2013, 56, 3904.
(c) Drake, D. J.; Jensen, R. S.; Busch-Petersen, J.; Kawakami, J. K.;
Concepcion Fernandez-Garcia, M.; Fan, P.; Makriyannis, A.; Tius, M.
A. J. Med. Chem. 1998, 41, 3596.
Corresponding Author
*E-mail: grenning@ufl.edu.
ORCID
Alexander J. Grenning: 0000-0002-8182-9464
Notes
(15) Xiong, W.; Cheng, K.-J.; Cui, T.-X.; Godlewski, G.; Rice, K. C.;
Xu, Y.; Zhang, L. Nat. Chem. Biol. 2011, 7, 296.
The authors declare no competing financial interest.
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(b) Huffman, J. W.; Yu, S.; Showalter, V.; Abood, M. E.; Wiley, J. L.;
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(17) Our research group focuses on developing an operationally
simple and convergent/tunable polycycle synthesis. For other
examples, see: (a) Lahtigui, O.; Emmetiere, F.; Zhang, W.; Jirmo,
L.; Toledo-Roy, S.; Hershberger, J. C.; Macho, J. M.; Grenning, A. J.
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ACKNOWLEDGMENTS
■
We thank the College of Liberal Arts and Sciences and the
Department of Chemistry at the University of Florida for start-
up funds. We thank the Mass Spectrometry Research and
Education Center and their funding source: NIH S10
OD021758-01A1.
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