Multicomponent Condensation Reactions via ortho-Quinone Methides

Article abstract of DOI:10.1021/acs.orglett.7b00647

Iron(III) salts promote the condensation of aldehydes or acetals with electron-rich phenols to generate ortho-quinone methides that undergo Diels - Alder condensations with alkenes. The reaction sequence occurs in a single vessel to afford benzopyrans in up to 95% yield. The reaction was discovered while investigating a two-component strategy using 2-(hydroxy(phenyl)methyl)phenols to access the desired ortho-quinone methide in a Diels - Alder condensation. The two-component condensation also afforded the corresponding benzopyran products in yields up to 97%. Taken together, the two- and three-component strategies using ortho-quinone methide intermediates provide efficient access to benzopyrans in good yields and selectivities.

Full text of DOI:10.1021/acs.orglett.7b00647

Letter
pubs.acs.org/OrgLett
Multicomponent Condensation Reactions via ortho-Quinone
Methides
Emily E. Allen, Calvin Zhu, James S. Panek, and Scott E. Schaus*
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Life Science and Engineering Building, Boston University, 24
Cummington Mall, Boston, Massachusetts 02215, United States
S
* Supporting Information
ABSTRACT: Iron(III) salts promote the condensation of aldehydes
or acetals with electron-rich phenols to generate ortho-quinone
methides that undergo DielsAlder condensations with alkenes. The
reaction sequence occurs in a single vessel to afford benzopyrans in
up to 95% yield. The reaction was discovered while investigating a
two-component strategy using 2-(hydroxy(phenyl)methyl)phenols to
access the desired ortho-quinone methide in a DielsAlder
condensation. The two-component condensation also afforded the
corresponding benzopyran products in yields up to 97%. Taken
together, the two- and three-component strategies using ortho-quinone methide intermediates provide efficient access to
benzopyrans in good yields and selectivities.
ortho-Quinone Methides (oQMs) are reactive synthetic
building blocks useful for the synthesis of natural products
and pharmaceutical compounds (Figure 1).1 They are short-
multicomponent reaction (MCR) strategy, enabling convergent
approaches in the synthesis of benzopyrans using oQMs as
reactive intermediates.6
Condensation reactions between hydroxybenzyl alcohols and
olefins affording benzopyrans have featured specific dienophile
reaction partners catalyzed by chiral phosphoric acid (PA)
catalysts.7 Schneider reported the chiral PA-catalyzed reactions
with electron-rich enamines and diones,8 and Rueping
described the asymmetric synthesis of chromans in the reaction
of hydroxybenzyl alcohols with diones and styrene derivatives.9
Similarly, Shi examined reactions with vinyl indoles and
enamides catalyzed by chiral PA catalysts.10 These two-
component approaches are advantageous when the o-
hydroxybenzyl alcohols are easily prepared and react well in
the cycloaddition reaction. However, we wished to determine if
metals could promote the reaction of hydroxybenzyl alcohols
with olefins and investigated the multicomponent strategy to
access oQMs in situ.
We initially designed experiments to evaluate the reactivity of
o-hydroxybenzyl alcohols and p-methoxy styrene with Lewis
acids (Table 1). Magnesium chloride led to a trace amount of
product after 1 h (Table 1, entry 1), and Pd(TFA)2 (entry 2)
resulted in a 22% yield. The reaction promoted by FeCl3·6H2O
(Table 1, entry 3) afforded a 36% yield of the desired product
in a 6:1 dr. Anhydrous FeCl3 afforded a 57% yield and 4:1 dr
(Table 1, entry 4) after 1 h in CH2Cl2. The addition of
molecular sieves slowed the reaction; FeCl3 with 4 Å MS (200
mg) in CH2Cl2 gave a 28% yield and 1:1 dr (Table 1, entry 5).
Dry HCl was generated from TMSCl and MeOH and
promoted the reaction in 26% yield and 4:1 dr (Table 1,
Figure 1. Representative natural products and pharmaceuticals bearing
substituted benzopyrans.
lived intermediates, and their reactivity is understood by two
canonical forms: a biradical species or a polarized zwitterion.2
These resonance structures highlight the susceptibility of oQMs
to undergo nucleophilic attack at the methide carbon, with
rearomatization as the thermodynamic driving force.3 In
addition, oQMs react with electron-rich dienophiles in
inverse-electron demand hetero-DielsAlder reactions.4 We
reported a DielsAlder reaction of oQMs and dienophiles
promoted by Fe salts.5 We postulated that we would be able to
develop a multicomponent approach using oQMs as reactive
intermediates in DielsAlder reactions using phenols and
aldehydes as oQM precursors. Herein we report a one-pot,
Received: March 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00647
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Table 1. Catalyzed Hetero-Diels−Alder of o-Quinone
a
Methides
b
c
entry
catalyst
MgCl2
solvent
time (h)
yield (%)
dr
1
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1
<5
22
36
57
28
26
82

Pd(TFA)2
FeCl3·6H2O
FeCl3
5
2:1
6:1
4:1
1:1
4:1
4:1
6
1
d
5
FeCl3, 4 Å MS
TMSCl/MeOH
FeCl3
1
6
1
e
7
1.3
a
Reaction conditions: diol (0.5 mmol, 1 equiv), p-methoxystyrene (2
equiv), catalyst (10 mol % with respect to diol) and 0.5 M with respect
b
c
to diol, 0 °C to rt. Isolated yields. diastereomeric ratio determined by
d
e
1H NMR 4 Å MS (200 mg), CHCl3 stabilized with amylenes.
entry 6). Anhydrous FeCl3 proved the most efficient at
mediating the reaction, and after evaluating additional solvents,
CHCl3 afforded a higher yield than CH2Cl2 (82% yield, entry
7).
The optimized reaction conditions were used to explore the
scope of the two-component hetero-Diels−Alder reaction
(Figure 2). We evaluated diols featuring both electron-rich
and -deficient substituents. Diols with pendant aryl rings at the
methide carbon performed better than those with alkyl groups,
likely due to the increased stability of the oQM from
conjugation (3b vs 3l). Styrene worked well in the reaction
(3g). The reaction conditions also tolerated geminal methyl
substituents at the methide carbon (3m). Indene was effective,
and although it does not bear electron-donating substituents,
the rigidity of the fused bicycle and ring strain may have
contributed to its reactivity (3d−f, 3h, 3k, 3m). 1,1′-
Disubstituted olefins underwent the cycloaddition condensa-
tion reaction in good yields (3i, 3j, 3n, 3o). The geminal
substitution renders the dienophile more electron-rich, which is
represented in the higher isolated yields. Additionally, α-pinene
underwent the condensation and was determined to proceed
with exo selectivity (3n, 3o). The use of this dienophile affords
a trisubstituted benzopyran with the cyclobutane intact.
We sought to expand the type of condensation reaction that
could undergo the Fe salt catalyzed process by using stabilized
enolates (Scheme 1). Wang and co-workers described the
reaction of oQM precursors with β-ketoesters and diones under
reflux conditions to afford the corresponding 4H-chromenes in
high yields.11 Under FeCl3 catalyzed conditions, the reaction
between o-hydroxybenzyl alcohol 1a and methyl acetoacetate
4a afforded the trisubstituted benzopyran 5 featuring an
adjacent hemiketal and ester. The hemiketal can be isolated
and further functionalized. Reduction of the chroman hemiketal
with a triethylsilane and BF3·OEt2 reduction to afford
benzopyran 6 in 67% yield as a single diastereomer.12 In
addition, 4H-chromene 8 was accessed by an acid catalyzed
dehydration of hemiketal 7 in 91% yield in two steps from the
o-hydroxybenzyl alcohol 1a and 2,4-pentanedione 4c.
Figure 2. FeCl3 mediated cycloaddition of o-hydroxybenzyl alcohols
and olefins.a a Reaction conditions: 1 (1.0 mmol), 2 (2 equiv), FeCl3
(10 mol % with respect to diol) and 0.5 M with respect to diol;
1
diastereomeric ratio determined by H NMR. b Diol (0.5 mmol, 1
equiv), p-methoxystyrene (2 equiv), FeCl3 (20 mol % with respect to
diol). Detailed experimental conditions are provided in the Supporting
Information.
Scheme 1. FeCl3 Mediated Cycloaddition of Diones and β-
Ketoesters To Afford Benzopyrans and 4H-Chromenes
There are a limited number of stable oQMs; most reactions
that use oQMs employ precursors that undergo in situ
formation of the reactive oQM.13,14 We sought to test the
limits of oQM generation and reactivity and postulated a
multicomponent condensation to generate oQM in situ from
aldehydes and phenols. We envisaged a metal-mediated
B
DOI: 10.1021/acs.orglett.7b00647
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Letter
condensation reaction as a route to an oQM that would
undergo a subsequent HDA reaction (Figure 3).
Figure 3. Multicomponent condensation reaction with aldehydes,
phenols, and olefins.a a Reaction conditions: 2.0 mmol of phenol, 2.0
mmol of aldehdye, and 1.0 mmol of dienophile, 0.5 M with respect to
dienophile and 10 mol % FeCl3·6H2O with respect to phenol; isolated
yields; diastereomeric ratio determined by 1H NMR; detailed
experimental conditions are provided in the Supporting Information.
b Yield and dr after trituration with hot hexanes.
Figure 4. Multicomponent condensation reaction with acetals,
phenols, and olefins.a a Reaction conditions: 2.0 mmol of phenol, 2.0
mmol of acetal, and 1.0 mmol of dienophile, 0.5 M with respect to and
10 mol % FeCl3·6H2O with respect to phenol unless otherwise stated;
1
isolated yields; diastereomeric ratio determined by H NMR; detailed
The reaction of 3,4-dimethoxyphenol with benzaldehyde and
styrene afforded 11a in 90% yield and 3:1 dr. p-Chloro-
benzaldehyde was used to afford 11b in good yields and
diastereoselectivities. Cyclohexanecarboxaldehyde also under-
went condensation to afford chroman 11c in good yields but in
only 2:1 dr. Heteroatom-containing aldehydes underwent the
transformation, albeit in modest yields (11d−f). The electron-
deficient aryl aldehyde, p-(trifluoromethyl)benzaldehyde, af-
forded 11g in 43% yield, 5:1 dr. The reaction of sesamol with
benzaldehyde and indene afforded 11h in 48% yield and 3:1 dr.
While the multicomponent reaction proceeded with
aldehydes, the yields tended to be less than 70%. We
hypothesized that acetals may be better electrophiles for the
Friedel−Crafts reaction. Acetals react through an oxonium ion
which has a lower π* than that of an aldehyde. For comparison,
the reaction of benzaldehyde dimethyl acetal with sesamol and
indene afforded the corresponding product 13a in 86% yield
and 6:1 dr. The same product was isolated from the reaction of
benzaldehyde in 48% yield and 3:1 dr (11h), providing
evidence that the electrophilicity of the second component has
a significant outcome on the reaction yield (Figure 4).
experimental conditions are provided in the Supporting Information.
b Yield and dr after trituration with hot hexanes.
the MCR. 1,1-Disubstituted dieneophiles were effective at
trapping the oQM and generating a benzopyran. 1,1′-Diphenyl-
ethylene and α-methylstyrene were high yielding (13b, 13c,
13j). Indene proceeded with good diastereoselectivity, most
likely due to the rigidity of the fused bicycle (13a, 13i). Styrene
performed better than p-methoxy styrene, despite being less
electron-rich (13d).
Interestingly, benzofuran afforded a fused pentacycle 13f in
good diastereoselectivity (17:1 dr) but low yields. The best
yields were obtained with 5 mol % FeCl3; the product
undergoes further decomposition under the reaction con-
ditions. Norborene afforded the corresponding condensation
product 13g in low yield and selectivity (29% yield, 14:1 dr).
The reaction conditions also tolerated substituted benzalde-
hyde acetals. 2-Bromobenzaldehyde dimethyl acetal proceeded
in lower yield, likely due to the steric hindrance of the ortho-Br,
but still afforded 13h in 44% yield and 4:1 dr. p-
Methoxybenzaldehyde dimethyl acetal performed well under
the general reaction conditions (13i−k); the acetal is less
electrophilic than benzaldehyde dimethyl acetal, but can
Sesamol and benzaldehdye dimethyl acetal were excellent
reaction partners for generating the reactive oQM to be used in
C
DOI: 10.1021/acs.orglett.7b00647
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In conclusion, we have developed two strategies to access
benzopyrans using Fe(III) salts as catalysts. The two-
component approach to access benzopyrans and 4H-chromenes
from o-hydroxybenzyl alcohols and olefins proceeds well under
Fe-catalysis. Moreover, Fe(III) salts will also mediate the one-
pot MCR via an in situ generated oQM from the condensation
of a phenol and an aldehyde or acetal. The MCR features the
use of readily available starting materials and performs well on
gram scale. Future studies will focus on the development of an
asymmetric catalytic approach and use in natural product
syntheses.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00647.
Optimization, experimental procedures, compound char-
acterization, and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: seschaus@bu.edu.
ORCID
Scott E. Schaus: 0000-0002-5877-6587
Notes
The authors declare no competing financial interest.
(14) Robust leaving groups: (a) Chambers, J. D.; Crawford, J.;
Williams, H. W. R.; Dufresne, C.; Scheigetz, J.; Bernstein, M. A.; Lau,
C. K. Can. J. Chem. 1992, 70 (6), 1717−1732. (b) Huang, Y.; Pettus,
T. R. R. Synlett 2008, 2008, 1353−1356. (b) Marsini, M. A.; Huang,
Y.; Lindsey, C. C.; Wu, K.-L.; Pettus, T. R. R. Org. Lett. 2008, 10,
1477−1480.
ACKNOWLEDGMENTS
This research was supported by the NIH (R01 GM078240 and
P50 GM067041).
■
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