Synthesis of Highly Substituted Phenols and Benzenes with Complete Regiochemical Control

Article abstract of DOI:10.1021/acs.orglett.0c02157

Substituted phenols are requisite molecules for human health, agriculture, and diverse synthetic materials. We report a chemical synthesis of phenols, including penta-substituted phenols, that accommodates programmable substitution at any position. This method uses a one-step conversion of readily available hydroxypyrone and nitroalkene starting materials to give phenols with complete regiochemical control and in high chemical yield. Additionally, the phenols can be converted into highly and even fully substituted benzenes.

Full text of DOI:10.1021/acs.orglett.0c02157

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Letter
Synthesis of Highly Substituted Phenols and Benzenes with
Complete Regiochemical Control
Xiaojie Zhang and Christopher M. Beaudry*
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ABSTRACT: Substituted phenols are requisite molecules for
human health, agriculture, and diverse synthetic materials. We
report a chemical synthesis of phenols, including penta-substituted
phenols, that accommodates programmable substitution at any
position. This method uses a one-step conversion of readily
available hydroxypyrone and nitroalkene starting materials to give
phenols with complete regiochemical control and in high chemical
yield. Additionally, the phenols can be converted into highly and
even fully substituted benzenes.
henols are indispensable molecules. Substituted phenols
represent essential pharmaceuticals, such as the analgesic
When regioselective phenol synthesis is required, a common
strategy features rearrangement of O-bound groups to the
adjacent ortho-position. In a classic example, allyl phenyl ethers
(1) undergo Claisen rearrangements to reliably give ortho-
substituted products 2 and 3 (Scheme 1a). When both ortho-
positions are unsubstituted, selectivities (2 vs 3) tend to be
low.5 Other classic reactions (e.g., the Fries rearrangement)
also follow this trend.6
P
morphine, the leukemia drug ecteinascidin, and the hormonal
birth control estrogen (Figure 1).1 Substituted phenols are also
There has been a flurry of recent activity directed at C−H
bond functionalization of phenol derivatives.7 As one example,
phenol derivative 4 contains a suitable directing group, which
facilitates Pd-catalyzed bond formation at the ortho-position
(Scheme 1b).8 In substrates such as 4 with two available ortho-
positions, the contra-steric product 5 is obtained, and the
product of vicinal substitution (6) is not observed. To
summarize decades of work on substitution of phenol
derivatives: such reactions produce limited regiochemical
outcomes that disfavor vicinal substitution, making highly
substituted phenols inaccessible by these routes.
Limitations associated with substitution-based strategies for
phenol syntheses have spawned a variety of alternatives. One
strategy is to oxidize a corresponding six-membered carbocycle
to a phenol. For example, Stahl reported that cyclohexenone 7
undergoes oxidative aromatization to give substituted phenol 8
(Scheme 1c).9 The challenge of preparing the substituted
phenol now becomes a challenge of preparing the substituted
starting material, and very few phenols with vicinal substitution
Figure 1. Pharmaceutical phenols.
common agrochemicals (e.g., the citrus fungicide 2-phenyl-
phenol and the food additive butylated hydroxytoluene); many
are important substructures of biological polymers (e.g., lignin,
tyrosine) and are used in human-made polymers such as the
ubiquitous phenolic resin plastics.2 The properties of phenolic
molecules are substantially influenced by the substitution on
the phenolic ring.3 For these reasons, the synthesis of phenols
with control of substituent regiochemistry is of paramount
interest to organic, medicinal, and polymer chemists.
The chemical synthesis of phenols with complex substitution
patterns is an enduring challenge, and multiple strategies have
emerged for this task. However, current methods have
substantial limitations. For example, classic alkylations (e.g.,
Friedel−Crafts alkylations) of unprotected phenols give phenyl
ethers, rather than substituted phenols.4 Substitution of phenyl
ethers gives multiple products as a result of limited
regioselectivity (ortho- vs para-substitution) accompanied by
overalkylation products.4
Received: June 29, 2020
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reactions is the lack of regioselectivity; both the diene and
dienophile lack strong electronic polarization, and the reaction
gives either symmetric products or regiochemical mixtures that
require tedious separations.12 Nonetheless, these cycloaddi-
tions display tantalizing reactivity: they represent single-step
transformations that bring together highly substituted coupling
partners to deliver benzenes with substitution at all six carbons.
We sought to address the long-standing gap in the
controlled synthesis of highly substituted phenols. Our
research in this area is directed at identifying a strategy for
substituted phenol and benzene synthesis that overcomes the
inherent regiochemical limitations associated with substitution
strategies and delivers multiple substituents on the product
benzenoid ring (Scheme 1e).
Scheme 1. Synthesis of Substituted Phenols
We hypothesized that the reactivity and regioselectivity
limitations of the Diels−Alder-based strategies discussed above
could be overcome if both coupling partners are electronically
polarized. Specifically, starting materials 14 and 15 would show
both enhanced reactivity and give programmable regioselec-
tivity in the products. An alkyne-equivalent14−16 dienophile
(15) would need to be identified that facilitates the initial
Diels−Alder cycloaddition at lower temperatures and provides
regioselectivity in the cycloaddition giving 16. The activating
group would have to double as a leaving group, undergoing
elimination, prior to the final retro-cycloaddition that liberates
CO2 and delivers the product 17.
Initial experimentation focused on combining a hydroxypyr-
one diene 18 with a vinyl sulfone dienophile (29, Table 1).17
Table 1. Development of the Phenol Synthesis
temp
(°C)
yield
(%)
entry alkene
reagent
have been reported using this method. Siegel also discovered
that substituted benzenes can be oxidized to phenols by direct
oxidation;10 however, oxidation regiochemistry is based on C−
H bond strength, and regioselectivities can be moderate. These
oxidative methods provide useful access to phenol products
from the corresponding benzene; however, the above methods
have not resulted in a phenol synthesis that produces highly
substituted (i.e., penta-substituted) phenols with control of
substitution patterns.
1
2
3
4
5
6
7
8
19
21
21
21
21
21
21
21
none
none
LiClO4 (1 equiv)
SiO2 (1 equiv)
FeCl3 (10 mol %)
ZnCl2 (10 mol %)
Zn(OTf)2 (10 mol %)
1-phenyl-3-(2-pyridyl)urea
(10 mol %)
170
150
80
150
150
150
150
150
7
56
35
65
65
54
52
27
A final strategy is to use a cycloaddition cascade to prepare
the phenol. The Diels−Alder reaction is commonly featured in
such cascades. A substituted diene, such as pyrone 9 (Scheme
1d), or other weakly aromatic heterocycle, reacts with a
dienophile, most often an alkyne, to give the phenyl ether 10.11
This reaction proceeds by a Diels−Alder−retro-Diels−Alder
sequence. Nonsymmetric internal alkynes are not particularly
polarized, and low regioselectivities are observed in the initial
Diels−Alder event. Regioselectivities aside, these reactions are
predominantly used to prepare simple mono- and disubstituted
phenols.
Diels−Alder reactions of highly reactive dienes are well-
known to undergo cycloaddition with alkynes to give benzenes
with high levels of substitution,12 including hexa-substituted
benzenes. For example, heating 2,3,4,5-tetraphenyl cyclo-
pentadiene (11) with diphenylacetylene (12) gives hexaphenyl
benzene (13, Scheme 1d).13 The limitation with these
9
10
11
21
21
21
quinidine (1 equiv)
AlCl3 (10 mol %)
AlCl3 (10 mol %), BHT (10 mol %)
150
150
150
0
76
85
Both coupling partners are suitably polarized such that single
regioisomeric phenol 20 is formed. However, initial experi-
ments revealed that successful cycloadditions required high
temperatures, and substantial decomposition of the reactants
was observed. The requirement of forcing conditions was
attributed to sluggish reactivity of the vinyl sulfone, and we
sought a more reactive dienophile.
Nitroalkenes are potent dienophiles,18,19 and we investigated
the cycloaddition cascade with nitroalkene 21 (Table 1, entry
2).20 Gratifyingly, the cycloaddition cascade was successful,
and it occurred at relatively mild temperatures. Phenol 20 was
observed as the major product as a single regioisomer, albeit in
B
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Scheme 2. Substituted Phenol Synthesis
moderate yield. To the best of our knowledge this represents
the first reaction of a pyrone and a nitroalkene to give a
benzene product.
presence of a radical inhibitor, butylated hydroxytoluene
(BHT), which likely prevents decomposition of the reagents
at elevated temperatures (entry 11). The reaction delivered
one observable phenol isomer by NMR. Analysis by gas
chromatography indicated that the regioisomer ratio (rr) was
33:1. Activation appears to involve deprotonation of the
hydroxyl group, and the related dienes 3-methylpyrone, 3-
methoxypyrone, and 3-dibutylaminopyrone did not react with
21 under identical conditions with AlCl3.
Diels−Alder reactions can be accelerated through catalysis.21
One common paradigm involves Lewis acid (LUMO lowering)
activation of the dienophile. Conditions known to activate
nitroalkenes gave little rate acceleration (Table 1, entries 3−8).
Alternatively, Diels−Alder reactions of hydroxypyrone dienes
can also be accelerated by activation of the diene. Partial or full
deprotonation of the hydroxyl group increases the reactivity of
the diene, possibly through an alkoxide anion or by promoting
a stepwise Diels−Alder process.22 For example, cinchona-
based alkaloids, such as quinidine, are known to catalyze
hydroxypyrone Diels−Alder reactions.22 However, little
improvement in the reaction of 18 and 21 was observed in
the presence of quinidine (entry 9). We surveyed additional
Lewis acids that could complex and activate the hydroxypyr-
one. It was discovered that AlCl3 promoted the reaction such
that it occurred on useful time scales and in high yield (entry
10). Finally, the best chemical yields were obtained in the
The regioisomeric nitroalkene (23, R4 = H, R5 = Pr) was
then subjected to our optimal reaction conditions (Scheme 2).
The regioisomeric ortho-substituted phenol 25 was obtained as
a single observable product (rr = 125:1, GC). This result
demonstrated that a regiospecific synthesis of phenols could be
realized through a cascade Diels−Alder/elimination/retro-
Diels−Alder process.
The phenol synthesis was further investigated using an
expanded set of coupling partners.23 Our general reaction
conditions (150 °C, 16 h, 0.1 equiv of BHT) were used in
most cases. Less hindered phenols were often formed with
C
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shorter reaction times, and more hindered phenols occasionally
required slightly elevated temperatures (i.e., 180 °C) or longer
reaction times (e.g., 24 h). See Supporting Information for
details.
pattern. As such, this represents a major advance in the
preparation of highly substituted benzenoid molecules.
A major reason for the interest in phenols is their ability to
participate in bond formations using the hydroxy functional
group. This allows for the conversion of phenols into
substituted benzenes of interest (Scheme 3). We evaluated
Simple nitroalkenes bearing a single alkyl group readily
participated in the reaction, and the same regiospecificity was
observed. Isomeric nitroalkenes bearing alkyl groups gave
regioisomeric pairs of products (26 and 27; 28 and 29). Bulky
substituents were tolerated on the nitroalkene (30), as well as
silyl ethers (31), and unactivated alkenes (32). When the
nitroalkene dienophile contains an additional electron-with-
drawing group that competes for polarization of the
dieneophile, the nitro group still controls the regioselectivity,
but the reaction occasionally showed decreased regioselectivity
(33, rr = 2:1).24
Scheme 3. Synthesis of Substituted Benzenes
Nitroalkenes with increased substitution (23, R4 and R5 ≠
H) also participated in the reaction to give 2,3-disubstituted
phenols. Disubstituted phenol 34 was obtained as a single
observable (NMR) isomer. As above, the reaction was
regiospecific, and regioisomeric phenol 35 was produced
selectively. Note that such 2,3-disubstituted phenols are not
products obtained from substitution of either 2-alkylphenols or
3-alkylphenols. Phenol 34 was previously prepared in six steps
featuring a ring-closing metathesis to construct the six-
membered ring,25 and isomer 35 has not been prepared
previously. Other nitroalkenes bearing two substituents
participated in the phenol synthesis, and aromatic (36) and
ester (37, 38, and 39) groups are well tolerated. As above,
when the nitroalkene bears an ester group, the nitro functional
group dictates the major regioisomer; however, when the ester
competes for alkene polarization (38), the regioisomer ratio
can be lower. When the ester and nitro groups are located on
the same carbon, the regioselectivity is high (39); however, the
dienophile was very reactive and prone to decomposition.
Higher substitution on the pyrone was also well tolerated. 3-
Hydroxypyrone (18) could be regioselectively transformed to
4-alkyl-3-hydroxy-2-pyrones in two steps (22, R1 = alkyl; see
Supporting Information). These substrates also underwent the
pericyclic cascade reaction to give phenols in good yields (40−
59). As above, the reaction was regiospecific with respect to
the nitroalkene dienophile and regioisomeric pairs could be
prepared with nitroalkenes bearing one alkyl group (42 and
43; 44 and 45; 47 and 48), or with two alkyl groups (49 and
50; 54 and 55; 57 and 58). The reaction successfully prepared
a variety of other 2,5-disubstituted, 2,6-disubtituted, and 2,5,6-
trisubstituted phenols with control of substituent regiochem-
istry.
Matsuda’s one-step Rh-catalyzed synthesis of pyrones was
used to prepare 5,6-disubstituted 3-hydroxypyrones (22, R2
and R3 ≠ H).26 These pyrones reacted to give 3,4,5-
trisubstituted or 3,4,6-trisubstituted phenols (60−69). As
before the reaction gives pairs of phenols with regiospecificity
(61 and 62; 65 and 66) based on the choice of nitroalkene
starting material. Reaction with more substituted nitroalkenes
gave tetrasubstituted phenols 70 and 71. Finally, fully
substituted pyrones were prepared (22, R1, R2, and R3 ≠ H;
see Supporting Information), and they reacted with nitro-
alkenes to give tetrasubstituted phenols (72−74) and
pentasubstituted (i.e., fully substituted) phenols 75−79 with
complete control of regiochemistry. This method represents a
direct synthesis of substituted benzene rings with up to six
different substituents with complete control of substitution
the ability of our highly substituted phenols to couple with
organometallic reagents to give highly substituted benzenes.
Phenol 55 underwent Stille cross-coupling27 to give allyl
benzene 80, and it participated in a Suzuki−Miyaura
coupling28 to give 81. The ester-containing phenol 56 also
reacted under the same conditions to give high yields of
benzenes 82, and 83, respectively. Finally, fully substituted
phenol 76 was converted by Stille and Suzuki couplings to give
84 and 85, respectively.
D
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T.; Hiyama, T. Dehydrogenative Carbon−Carbon Bond Formation
Using Alkynyloxy Moieties as Hydrogen-Accepting Directing Groups.
Angew. Chem., Int. Ed. 2015, 54, 11813−11816.
In conclusion, we have developed a direct synthesis of
substituted phenols from 3-hydroxypyrones and nitroalkenes
that is regiospecific with respect to the alkene. Moreover, high
levels of substitution are tolerated and fully substituted phenols
are prepared by our method. Yields are synthetically useful and
compare favorably with classic and modern phenol syntheses.
The programmable nature of the reaction allows noncanonical
substitution patterns to be constructed. Finally, conversion of
the phenols to the corresponding benzenes allows synthesis of
highly substituted benzenes with full control of substituent
location.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02157.
Full experimental details and depicted 1H and 13C NMR
spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Christopher M. Beaudry − Department of Chemistry, Oregon
State University, Oregon 97331, United States; orcid.org/
0000-0002-4261-2596; Email: christopher.beaudry@
oregonstate.edu
Author
Xiaojie Zhang − Department of Chemistry, Oregon State
University, Oregon 97331, United States
(17) Zhao, P.; Beaudry, C. M. Enantioselective and regioselective
pyrone Diels−Alder reactions of vinyl sulfones: Total synthesis of
(+)-cavicularin. Angew. Chem., Int. Ed. 2014, 53, 10500−10503.
(18) Holmes, H. L. The Diels−Alder reaction: Ethylenic and
acetylenic dienophiles. Org. React. 2011, 4, 60−173.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02157
(19) Bartelson, K. J.; Singh, R. P.; Foxman, B. M.; Deng, L. Catalytic
asymmetric [4 + 2] additions with aliphatic nitroalkenes. Chem. Sci.
2011, 2, 1940−1944.
Notes
The authors declare no competing financial interest.
(20) Elimination of nitrous acid from nitroalkanes is well known.
ACKNOWLEDGMENTS
■
See: Fritzsche, K.; Beckhaus, H.-D.; Ruchardt, C. Termischer Zerfall
̈
von β-Phenyl- und β,β-Diphenyl-nitroalkanen. Tetrahedron Lett. 1988,
29, 2805−2808.
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reactions − a review. Org. Prep. Proced. Int. 1994, 26, 129−158.
(22) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L.
Enantioselective Diels−Alder reaction of simple α,β-unsaturated
ketones with a cinchona alkaloid catalyst. J. Am. Chem. Soc. 2008,
130, 2422−2423.
(23) All nitroalkenes used in this study were prepared using the
Henry reaction. For review, see: Luzzio, F. A. The Henry reaction:
recent examples. Tetrahedron 2001, 57, 915−945.
(24) Reported yields are the combined chemical yield of both
regioisomers.
Financial support from Oregon State University and the U.S.
National Science Foundation (CHE-1465287 and CHE-
1956401) is gratefully acknowledged.
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