Microwave-Assisted Generation and Capture by Azoles of ortho-Quinone Methide Intermediates under Aqueous Conditions

Article abstract of DOI:10.1002/ejoc.201701183

An efficient activator-free protocol for the coupling of o-hydroxybenzyl alcohols and azoles in water has been developed. This C–N bond-formation process is supposed to proceed through an ortho-quinone methide intermediate. A broad range of o-hydroxybenzy

Full text of DOI:10.1002/ejoc.201701183

A Journal of
Accepted Article
Title: Microwave-Assisted Generation and Capture by Azoles of ortho-
Quinone Methide Intermediates under Aqueous Conditions
Authors: Silvia González-Pelayo and Luis A. López
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10.1002/ejoc.201701183
European Journal of Organic Chemistry
COMMUNICATION
Microwave-Assisted Generation and Capture by Azoles of ortho-
Quinone Methide Intermediates under Aqueous Conditions
Silvia González-Pelayo,[a] and Luis A. López*[a]
Dedication ((optional))
Abstract: An efficient activator-free protocol for the coupling of o-
hydroxybenzyl alcohols and azoles in water has been developed.
This C-N bond formation process is supposed to proceed through an
ortho-quinone methide intermediate.
A
broad range of o-
hydroxybenzyl alcohols including those having alkenyl and alkynyl
functionalities is compatible with this protocol. In most cases, the
products are isolated in good to excellent yields without
chromatographic purification. Preliminary results demonstrated that
this methodology can be also used for the generation and trapping of
the isomeric para-quinone methide intermediates.
Scheme 1. General structure of ortho-quinone methide intermediates and
elimination methods for their in situ generation
Introduction
Taking into account the obvious multiple advantages of water as
reaction medium in the context of the development of
environmentally benign synthetic procedures, we embarked on a
study of the feasibility to generate o-QMs in water.[10] Herein, we
report the realization of this appealing goal; specifically, we
describe the microwave-assisted generation of these valuable
intermediates and their capture by azoles leading to synthetically
useful N-functionalized azole derivatives in good to excellent
yields. Interestingly, this process does not require the presence
of an activator to proceed. In general, the reactions are very
clean and do not require chromatographic purification. The
feasibility of this protocol for the generation of isomeric para-
quinone methides is also advanced.
ortho-Quinone methides (o-QMs) are highly reactive
intermediates, that have found a vast array of applications not
only in organic synthesis but also in medicinal chemistry.[1] As a
result,
a plethora of successful approaches have been
established for their in situ generation from suitable substrates.
Most existing methods rely on acid-, base- or fluoride-mediated
elimination reactions of substrates substituted at the benzylic
position with good leaving groups (Scheme 1).[2] Other
methodologies for the in situ generation of o-QMs include
oxidation[3] or isomerisation[4] reactions of appropriate starting
materials. Finally, in the last few years transition-metal mediated
procedures have also emerged as powerful alternatives for the
generation of o-QMs.[5]
The reactivity of o-QMs mimics that of ,-unsaturated ketones
and, consequently, they react easily with nucleophiles including
those of biological relevance to provide the corresponding 1,4-
addition products.[6] Additionally, o-QMs undergo extremely
facile [4+2] cycloaddition reactions with several electron-rich
dienophiles[7] as well as other [4+n] cycloaddition reactions.[8]
Remarkable levels of stereoselectivity have been accomplished
in some of these transformations by using transition-metal
catalysts or organocatalysts.[9]
Results and Discussion
Initial studies focused on the generation of parent ortho-quinone
methide from o-hydroxybenzyl alcohol (1a). In these exploratory
experiments, we selected pyrazole (2a) as trapping reagent
because this heterocyclic nucleus is present in several
biologically relevant compounds.[11] Pleasingly, we found that
microwave heating at 120 ⁰C for 10 hours a mixture of 1a and 2a
(6 equiv) in water afforded the N-substituted pyrazole derivative
3aa in excellent yield (90%) after extraction with ethyl acetate
and removal of the excess of pyrazole by sublimation under
reduced pressure at 60 ⁰C (Scheme 2). The reaction also
proceeded under conventional oil-bath thermal conditions.
However, under these conditions an extended reaction time was
required to reach a comparable yield.
Salient features of this C-N bond forming transformation include:
a) it does not require the presence of an activator; b) all the
solvents involved in this process (water and ethyl acetate used
in the extraction step) are classified as “recommended” in terms
of greenness evaluation in most common solvent selection
guides;[12] c) the leftover pyrazole could be recovered in pure
form almost quantitatively by sublimation allowing its reutilization,
thus resulting in minimal waste generation; d) compound 3aa
[a]
S. González-Pelayo, Dr. L. A. López
Departmento de Química Orgánica e Inorgánica and Instituto
Universitario de Química Organometálica “Enrique Moles”
Universidad de Oviedo
Julián Clavería 8, 33006-Oviedo, Spain
E-mail: lalg@uniovi.es
http://personales.uniovi.es/web/sos
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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was isolated in high purity and excellent yield without
chromatographic purification.
The reaction could be extended to substrates with additional
substitution at the aryl backbone (substrate 1k; R1 = R2 = H, R3
= 4-MeO). Thereby, the expected product 3ka was obtained in
85% yield.
Finally, substituted pyrazoles are also suitable reagents in this
C-N bond forming process. Indeed, reaction of 3,5-
dimethylpyrazole (2b) with 2-(hydroxy(phenyl)methyl)phenol
(1b) afforded compound 3bb in good yield (91%).
Table 1. Reaction of o-hydroxybenzyl alcohols 1 wit pyrazole derivaties 2:
Scope[a]
Scheme 2. Initial finding on the generation and trapping of ortho-quinone
methide intermediates in water.
For the sake of comparison it is worth noting that compound 3aa,
a valuable intermediate in the synthesis of compounds with
antiarrhythmic activity, had previously been obtained in 56%
yield after chromatographic purification by reaction between o-
hydroxybenzyl alcohol and thionyldipyrazole (prepared in situ
from
pyrazole
and
harmful
thionyl
chloride)
in
dichloromethane.[13,14]
Encouraged by this promising initial result, next the substrate
scope of this C-N bond forming process was assessed using a
range of substituted o-hydroxybenzyl alcohols 1 (Table 1).
Owing to the relevance of triarylmethanes (TRAMs) in a number
of important areas,[15] initially we questioned whether our
protocol could be applied to the synthesis of triarylmethane
derivatives containing a pyrazolyl group. For that purpose, first
we investigated the reaction of phenyl-substituted o-
hydroxybenzyl alcohol 1b (R1 = Ph, R2 = R3 = H) with pyrazole
(2a) under the above conditions. To our delight, we found that
1b performed perfectly well, delivering the targeted
triarylmethane derivative 3ba in excellent yield. Aryl-substituted
substrates 1c-e (R1 = tolyl, R2 = R3 = H) were found to be also
viable substrates in this transformation. Interestingly, all three
isomeric substrates furnished the desired TRAMs 3ca-ea in
nearly quantitative yield regardless of the position of the methyl
substituent. As in the model reaction, TRAMs 3ba-ea could be
isolated in pure form without the need of chromatography after
standard extraction and sublimation under reduced pressure.
To further expand the scope of this process we extended the
study to substrates bearing alkyl groups at the benzylic position.
Indeed, we found that o-hydroxybenzyl alcohols 1f-h bearing a
primary alkyl group at the benzylic position are suitable
substrates affording the corresponding phenol derivatives 3fa-ha
in good to excellent yields. Similarly, a substrate bearing an
isopropyl group at this position (1i; R1 = isopropyl, R2 = R3 = H)
posed no problems affording alkylated pyrazole derivative 3ia in
82% yield.[16]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (1.2 mmol, 6 equiv.), water (2mL), 120
⁰C (microwave heating), 10 h. Unless otherwise stated all products were
isolated by initial extraction with ethyl acetate, subsequent removal of solvent
and final sublimation of excess pyrazole under reduced pressure at 60 ⁰C.
Reaction performed on a 1.0 mmol scale
[b]
A substrate having two alkyl groups at the benzylic position (1j;
R1 = R2 = Me, R3 = H) was also well suited to this transformation
affording the desired product 3ja, albeit in lower yield (58%).
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Next, in order to further expand the scope of this C-N bond
forming reaction and evaluate the feasibility of an eventual
cascade process we extended the study to substrates featuring
additional functionalities at the benzylic position (Scheme 3).
First, we found that alkenyl functions do not interfere with the
To demonstrate further the potential of this process, we
extended the study to other azole derivatives. Gratifyingly, upon
treating o-hydroxybenzyl alcohol 1b with imidazole (2c) under
the above reaction conditions we obtained the corresponding
coupling product 3bc in nearly quantitative yield (Scheme 4).[19]
reaction course. Indeed,
a
completely chemoselective
transformation was observed with substrates 1l and 1m bearing
vinyl and allyl groups, respectively. Under the applied reaction
conditions, we did not observe any product resulting from the
participation of the unsaturated moiety.
The reactivity of substrates containing alkynyl groups at the
benzylic position towards pyrazole (2a) was also investigated.
Thus, we found that treatment of substrates 1n-p bearing an
internal alkyne with pyrazole (2a) in water at 90 ⁰C led to the
formation of the expected pyrazole-containing products. Both
aryl and alkyl groups at the alkyne terminus were well tolerated
as illustrated by the formation of adducts 3na-3pa in good yields
(77-96%). In contrast, reaction with terminal acetylenic substrate
1q yielded a chromatographically separable mixture of 3qa
(41%) and 4 (45%). The formation of benzofuran derivative 4
could be explained in terms of a 5-exo-dig addition of phenolate
oxygen to the substituted sp-hybridized carbon atom of 3qa.[17,18]
Scheme 4. Extension to imidazole.
Next, we conducted some control experiments aimed at gaining
insight into the mechanism of this reaction (Scheme 5). Thus,
when benzyl alcohol (1r) and pyrazole (2a) were heated in water
under microwave irradiation at 120 ⁰C for 10 hours no reaction
was observed at all. A similar result was obtained when using
diphenylmethanol (1s). Besides, we found that, under otherwise
similar conditions, reaction of pyrazole (2a) with phenol
derivative 1t bearing the hydroxymethyl group at the meta
possition did not proceed and the starting materials were
recovered unchanged. Taken collectively, these observations
would rule out a direct displacement of the hydroxyl group, thus
supporting the participation of an ortho-quinone methide
intermediate.
Scheme 5. Control experiments aimed at demonstrating the participation of
ortho-quinone methide intermediates.
Although our focus has been on the generation of ortho-quinone
methide intermediates, it should be noted that isomeric para
intermediates[20] can also be efficiently generated in water, as
illustrated by the formation of phenol derivative 6aa when p-
hydroxybenzyl alcohol (5a) and pyrazole (2a) were subjected to
the above reaction conditions (Scheme 6).[21] The high-yielding
preparation of compound 6aa clearly exemplifies the potential of
the reported methodology. Interestingly, the use of toluene as
Scheme 3. Reaction of alkenyl- and alkynyl-substituted substrates with
pyrazole in water.
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10.1002/ejoc.201701183
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COMMUNICATION
solvent in this transformation under otherwise identical
conditions (microwave irradiation at 120 ⁰C for 10 hours) failed
to provide phenol derivative 6aa with comparable efficacy
evidencing the unique features of water in this process.
Acknowledgements
Financial support from Ministerio de Economía y Competitividad
(MINECO, grant CTQ2013-41511-P), Agencia Estatal de
Investigación (AEI) and Fondo Europeo de Desarrollo Regional
(FEDER) (Grant CTQ2016-76840-R) and Principado de Asturias
(grant GRUPIN14-013) is gratefully acknowledged. We thank
Prof. J. M. González for interesting discussions.
Keywords: Azoles • Quinone methides • C-N bond formation •
Microwave-assisted • Water
[1]
Selected recent reviews on the chemistry of o-QM intermediates: a) A. A.
Jaworski, K. A. Scheidt, J. Org. Chem. 2016, 81, 10145-10153; b) M. S. Singh,
A. Nagaraju, N. Anand, S. Chowdhury, RSC Adv. 2014, 4, 55924-55959; c)
W.-J. Bai, J. G. David, Z.-G. Feng, M. G. Weaver, K.-L. Wu, T. R. R. Pettus,
Acc. Chem. Res. 2014, 47, 3655-3664; d) N. J. Willis, C. D. Bray, Chem. Eur.
J. 2012, 18, 9160-9173; e) R. W. van de Watter, T. R. R. Pettus, Tetrahedron
2002, 58, 5367-5405.
Scheme 6. Preliminary study on the extension to p-hydroxybenzyl alcohols.
Conclusions
In summary, we have demonstrated that ortho-quinone methide
intermediates can be efficiently generated under thermal
conditions in water. In contrast to most current methodologies
for the generation of these synthetically valuable intermediates,
our protocol does not require the use of any activator. Once
generated, these reactive species can be efficiently and
irreversibly trapped by azoles to furnish the corresponding N-
alkylated azole derivatives in good to excellent yields. In most
cases, the isolation of the products does not require a
chromatographic purification, which makes our protocol
particularly well suited for large-scale synthesis. Preliminary
studies demonstrated that this protocol could be also
implemented for the generation and trapping of para-quinone
methide intermediates. Further applications of this protocol are
currently investigated in our research group.
[2]
For selected examples of generation of ortho-quinone methides through
elimination reactions, see: a) (fluoride-mediated elimination) T. B.
Samarakoon, M. Y. Hur, R. D. Kurtz, P. R. Hanson, Org. Lett. 2010, 12, 2182–
2185; b) (acid-catalyzed elimination) S. Saha, C. Schneider, Org. Lett. 2015,
17, 648–651; c) (base-promoted elimination) C. D. Bray, Org. Biomol. Chem.
2008, 6, 2815-2819.
[3]
[4]
For a representative example, see: L. M. Bishop, M. Winkler, K. N. Houk, R.
G. Bergman, D. Trauner, Chem. Eur. J. 2008, 14, 5405-5408.
For the generation of ortho-quinone methides through Pd-catalyzed
isomerization of vinylphenols, see: M. J. Schultz, M. S. Sigman, J. Am. Chem.
Soc. 2006, 128, 1460-1461. For additional examples, see ref. 5a
[5]
[6]
For a review on applications of ortho-quinone methides in transition metal
catalysis, see: a) T. P. Pathak, M. S. Sigman, J. Org. Chem. 2011, 76, 9210-
9215. For a recent contribution involving proton/metal dual catalysis, see: b) J.
Ma, K. Chen, H. Fu, L. Zhang, W. Wu, H. Jiang, S. Zhu, Org. Lett. 2016, 18,
1322-1325.
For a recent contribution on the catalytic asymmetric substitution of ortho-
hydroxybenzyl alcohols with enamines, see: M.-M. Xu, H.-Q. Wang, Y. Wan,
J. Yan, S. Zhang, S.-L. Wang, F. Shi, Org. Chem. Front. 2017, 4, 358-368. For
the 1,4-addition reaction of deoxycytidine to ortho-quinone methide
intermediates, see: M. P. McCrane, E. E. Weinert, Y. Lin, E. P. Mazzola, Y.-F.
Lam, P. F. Scholl, S. E. Rokita, Org. Lett. 2011, 13, 1186-1189. For the use of
binol quinone methides as DNA alkylating reagents, see: S. N. Richter, S.
Maggi, S. C. Mels, M. Palumbo, M. Freccero, J. Am. Chem. Soc. 2004, 126,
13973-13979. For a study of the substituent effect on the reactivity of ortho-
quinone methide intermediates with biological nucleophiles, see: E. E. Weinert,
R. Dondi, S. Colloredo-Melz, K. N. Frankenfield, C. H. Mitchell, M. Freccero,
S. E. Rokita, J. Am. Chem. Soc. 2006, 128, 11940-11947.
Experimental Section
Representative Procedure (3aa)
A 2-5 mL microwave vial was charged with o-hydroxybenzyl alcohol 1a
(24.8 mg, 0.2 mmol), pyrazole 2a (81.7 mg, 1.2 mmol), H2O (2 mL) and a
triangular stirring bar. The vessel was sealed with a septum, placed into
the microwave cavity and irradiated to maintain the reaction at 120 ⁰C
during 10 hours in a Biotage Initiator microwave apparatus. Then, the
reaction mixture was allowed to reach room temperature and extracted
with ethyl acetate (3 x 3 mL). The solvent was removed under reduced
pressure (rotary evaporator). Then, the flask is fitted with a cold finger
and placed into a preheated 60 ⁰C oil bath and stirred in vacuum. After
30 min, the excess of pyrazole is recovered nearly quantitatively and the
pyrazole derivative 3aa was isolated (31.4 mg, 90%) as a white solid (m.
p. 123-125 ºC). 1H-NMR (300 MHz, CDCl3): 5.25 (s, 2H), 6.27 (t, J = 2.1
Hz, 1H), 6.89 (td, J = 7.4 and 0.9 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.20
(dd, J = 7.5 and 1.4 Hz, 1H), 7.25 (td, J = 7.5 and 1.4 Hz, 1H), 7.51 (d, J
= 2.1 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 10.32 (s, 1H); 13C-NMR (75 MHz,
CDCl3): 53.4, 105.6, 118.9, 120.2, 123.3, 129.5, 130.1, 130.6, 139.2,
156.6; HR-MS (EI) calculated for [C10H10N2O]+ (M+): 174.0788, found
174.0788.
[7]
[8]
For selected applications of [4+2] cycloadditions of ortho-quinone methide
intermediates in total synthesis, see: a) J.-P. Lumb, K. C. Choong, D. Trauner,
J. Am. Chem. Soc. 2008, 130, 9230-9231; b) L. Xu, F. Liu, L.-W. Xu, Z. Gao,
Y.-M. Zhao, Org. Lett. 2016, 18, 3698-3701. For additional examples, see ref.
1.
For [4+1] cycloaddition reactions, see: a) N. Meisinger, L. Roiser, U.
Monkowius, M. Himmelsbach, R. Robiette, M. Wasser, Chem. Eur. J. 2017,
23, 5137-5142 and references cited therein. For a recent [4+3] cycloaddition
reaction of ortho-quinone methide intermediates, see: G.-J. Mei, Z.-Q. Zhu, J.-
J. Zhao, C.-Y. Bian, J. Chen, R.-W. Chen, F. Shi, Chem. Commun. 2017, 53,
2768-2771. For a formal [4+4] cycloaddition reaction, see: T. B. Samarakoon,
M. Y. Hur, R. D. Kurtz, P. R. Hanson, Org. Lett. 2010, 12, 2182-2185.
For a review covering advances in catalytic asymmetric reactions of ortho-
quinone methides, see: Z. Wang, J. Sun, Synthesis 2015, 47, 3629-3644. For a
review on the applications of quinone methides in asymmetric organocatalysis,
see: L. Caruana, M. Fochi, L. Bernardi, Molecules, 2015, 20, 11733-11764.
[9]
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COMMUNICATION
For a catalytic asymmetric oxa-Diels-Alder reaction of ortho-quinone methides
generated in situ from ortho-hydroxybenzyl alcohols, see: J.-J. Zhao, S.-B. Sun,
S.-H. He, Q. Wu, F. Shi, Angew. Chem. Int. Ed. 2015, 54, 5460-5464. For an
enantioselective cyclization of ortho-hydroxybenzyl alcohols with enaminones,
see: J.-J. Zhao, Y.-C. Zhang, M.-M. Xu, M. Tang, F. Shi, J. Org. Chem. 2015,
80, 10016-1024. For a recent organocatalytic asymmetric intramolecular [4+2]
cycloaddition reaction of ortho-quinone methide intermediates, see: Y. Xie, B.
List, Angew. Chem. Int. Ed. 2017, 56, 4936-4940.
isolated in 57% yield by reaction of 1-hydroxymethylpyrazole with an excess
(9 equiv) of phenol: H. S. Attaryan, V. I. Rstakyan, S. S. Hayotsyan, G. V.
Asratyan, Russ. J. Gen. Chem. 2012, 82, 1319-1321.
[15] For a recent review on the synthesis and pharmaceutical uses of di- and
triarylmethane derivatives, see: S. Mondal and G. Panda, RSC Adv., 2014, 4,
28317–28358. For a review on the synthesis of triarylmethanes by transition
metal catalysts, see: M. Nambo, C. M. Crudden, ACS Catal. 2015, 5, 4734-
4742.
[10] The photochemical generation and reactivity of ortho-naphthoquinone
methides in aqueous solutions has been reported: a) S. Arumugam, V. V. Popik,
J. Am. Chem. Soc. 2009, 131, 11892-11899; b) S. Arumugam, V. V. Popik, J.
Am. Chem. Soc. 2011, 133, 5573-5579. For a related example involving
hydroarylation of o-QMs generated in situ from 4-hydroxycoumarin, see: A.
Kumar, M. Kumar, M. Kumar Gupta, Green Chem. 2012, 14, 2677-2681. The
TFA-mediated generation of ortho-quinone methides in water and subsequent
trapping with lactams and styrenes has been recently reported: R. Sharma, S.
Abbat, R. Mudududdla, R. A. Vishwakarma, P. V. Bharatam, S. B. Bharate,
Tetrahedron Lett. 2015, 56, 4057-4059.
[16] In contrast, the reaction was completely inhibited when a bulky tert-butyl
group was installed at the benzylic position (R1 = tert-butyl, R2 = R3 = H).
[17] For related intramolecular additions of phenolate to unactivated double and
triple bonds, see: C. M. Evans, A. J. Kirby, J. Chem. Soc. Perkin Trans. II,
1984, 1269-1275.
[18] The reaction of compound 1q with pyrazole (2a) in D2O under otherwise
identical conditions provided a mixture of 3qa and the =CD2 product 4-d2.This
result would suggest that the cyclization is slower than the exchange of the
acetylenic proton.
[19] In contrast, under otherwise identical conditions, reactions with indole and
pyrrole did not proceed and the starting materials were recovered unchanged.
[20] For a review on the synthetic applications of para-quinone methides, see: A.
Parra, M. Tortosa, ChemCatChem, 2015, 7, 1524-1526. Selected recent
examples: a) P. Goswami, G. Singh, R. V. Anand, Org. Lett. 2017, 19, 1982-
1985; b) C. Jarava-Barrera, A. Parra, A. López, F. Cruz-Acosta, D. Collado-
Sanz, D. J. Cárdenas, M. Tortosa, ACS Catal. 2016, 6, 442-446.
[11] For a recent review on biologically active pyrazole derivatives, see: A. Ansari,
A. Ali, M. Asif, Shamsuzzaman, New. J. Chem., 2017, 41, 16-41.
[12] D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S. Abou-Shedada, P.
J. Dunn, Green Chem. 2016, 18, 288-296.
[13] M. Ogata, H. Matsumoto, K. Takahashi, S. Shimizu, S. Kida, M. Ueda, S.
Kimoto, M. Haruna, J. Med. Chem. 1984, 27, 1142-1149.
[14] Compound 3aa was also prepared in 88% yield from 2-(bromomethyl)phenyl
acetate and pyrazole in the presence of 3 equiv. of NaH (a pyrophoric
chemical): Y. L. Choi, H. Lee, B. T. Kim, K. Choi, J.-N Heo, Adv. Synth.
Catal. 2010, 352, 2041-2049. In a different approach, compound 3aa was
[21] Compound 6aa was previously obtained in 47% yield by heating 4-
hydroxybenzyl alcohol and pyrazole at 160 ⁰C: P. J. Machin, D. N. Hurst, R.
M. Bradshaw, L. C. Blaber, D. T. Burden, R. A. Melarange, J. Med. Chem.
1984, 27, 503-509.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
ortho-Quinone methides can be
efficiently generated in water. Their
trapping with azoles provides a
convenient route to alkylated azole
derivatives, a class of heterocyclic
compounds with potential
applications in medicinal chemistry.
This protocol does not require any
activator for the generation of the
reactive intermediate. Besides, no
chromatographic purification is
required in most cases.
Sustainable Chemistry*
S. González-Pelayo and L. A. López*
Page No. – Page No.
Microwave-Assisted Generation and
Capture by Azoles of ortho-Quinone
Methide Intermediates under
Aqueous Conditions
*one or two words that highlight the emphasis of the paper or the field of the study
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