Zinc-catalyzed synthesis of functionalized furans and triarylmethanes from enynones and alcohols or azoles: Dual X-H bond activation by zinc

Article abstract of DOI:10.1002/anie.201301625

Ba'zinc'ga! A zinc-catalyzed sequence involving a cyclization with a subsequent C-O, C-N, or C-C bond formation enables the preparation of a variety of valuable furfuryl ethers (with alcohols) and unsymmetrically substituted triarylmethane derivatives (wi

Full text of DOI:10.1002/anie.201301625

Angewandte
Chemie
DOI: 10.1002/anie.201301625
Zinc Catalysis
Zinc-Catalyzed Synthesis of Functionalized Furans and
Triarylmethanes from Enynones and Alcohols or Azoles:
ꢀ
Dual X H Bond Activation by Zinc**
Jesffls Gonzµlez, Javier Gonzµlez, Carmela PØrez-Calleja, Luis A. López,* and RubØn Vicente*
ꢀ
Research on transition-metal-catalyzed processes has allowed
the development of highly efficient and selective synthetic
procedures. Thus, transition-metal catalysis certainly consti-
tutes one of the most-employed approaches towards the
preparation of highly valuable organic compounds used in
relevant research areas, ranging from medicine or biology to
materials science.[1] Nevertheless, most of the transformations
are based on the use of rather expensive, scarce, and toxic
metals as palladium, rhodium, iridium, gold, or paltinum,
among others. Considering sustainability and environmental
criteria, the use of abundant, cheap, and nontoxic metal
catalysts has nowadays become one of the most relevant goals
in chemistry and catalysis.[2] Among these metals, the use of
zinc in catalysis has been less exploited in comparison to iron,
copper, or cobalt.[3] Because of our interest in the use of
economical and low-toxic zinc-based catalysts, we have
recently developed various zinc-catalyzed transformations.[4]
In particular, we reported a catalytic version of the Simmons–
Smith cyclopropanation using alkynes as a zinc carbene
source (Scheme 1). In the same manner, we also described the
first zinc-catalyzed carbene Si H bond insertion reactions.
Theoretical studies suggested a zinc carbene intermediate as
the key species in both reactions. Additionally, the overall
outcome of these transformations enabled the synthesis of
highly functionalized furan derivatives. This class of hetero-
cycles is important since furan derivatives are valuable
building blocks in synthesis[5] and are present in compounds
with properties of relevance in medicinal or materials
chemistry, among others.[6]
As a part of our studies on the cyclopropanation reactions
with in situ generated zinc carbenes through alkyne activa-
tion,[7] we found an unexpected reaction outcome when using
a prototypical substrate, such as allyl alcohol (2a), for the
Simmons–Smith reaction.[8] Thus, under the previously estab-
lished reaction conditions (10 mol% ZnCl2, CH2Cl2, 258C),
we observed the formation of the furan derivative 3a,
ꢀ
a product derived from a formal zinc carbene O H bond
insertion, along with the dimeric tetrasubstituted alkene 4a
(Scheme 2). In contrast, the formation of the cyclopropane 5a
was not detected.
Scheme 1. Zinc-catalyzed furan syntheses through cyclization/cyclopro-
ꢀ
panation or Si H bond insertion sequences.
Scheme 2. Zinc-catalyzed reaction of 1a with allyl alcohol (2a): Initial
finding. Yields of isolated product within parentheses.
[*] J. Gonzꢀlez, Dr. J. Gonzꢀlez, C. Pꢁrez-Calleja, Dr. L. A. Lꢂpez,
Dr. R. Vicente
To our knowledge, this type of transformation has not
been reported to date for zinc catalysis and consequently we
decided to study it in more detail. We disclose herein our
findings, which describe the zinc-catalyzed synthesis of
valuable compounds such as functionalized furfuryl alcohol
derivatives[9] and unsymmetrically substituted triarylmethane
derivatives. A mechanistic rationale based on computational
Departamento de Quꢃmica Orgꢀnica e Inorgꢀnica e Instituto
Universitario de Quꢃmica Organometꢀlica “Enrique Moles”
Universidad de Oviedo
c/Juliꢀn Claverꢃa 8, 33007 Oviedo (Spain)
E-mail: lalg@uniovi.es
vicenteruben@uniovi.es
[**] Financial support from the Ministerio de Economꢃa y Competitivi-
dad of Spain (Grant CTQ2012-20517-C02-01 and predoctoral grant
for J.G.) is gratefully acknowledged. Calculations were carried out at
the “Cluster de Modelizaciꢂn Cientꢃfica” (Universidad de Oviedo).
R.V. is a Ramꢂn y Cajal Fellow.
ꢀ
studies involving a zinc-promoted dual activation of X H
bonds is also discussed.
Stimulated by the results depicted in Scheme 2, we
evaluated a range of reaction conditions to achieve an
efficient and selective access to benzyl ether 3a. Optimization
studies (see the Supporting Information for details) revealed
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301625.
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that the use of ZnCl2 (20 mol%) as the catalyst at room
temperature in n-hexane resulted in the formation of the
desired furan derivative 3a in 74% after chromatographic
purification. Interestingly, under these optimized reaction
conditions, the formation of the dimer 4a was completely
suppressed. With the optimized reaction conditions in hand,
we next explored the scope of this transformation (Scheme 3).
Various simple primary alcohols were first probed, thus
affording the furan derivatives 3b–e in reasonable yields.
Cyclopentylmethanol was also employed to obtain the furan
3 f, although a slightly higher reaction temperature was
required (Scheme 3).[10] Moreover, propargyl alcohol proved
suitable for this transformation, thus giving rise to the furan
3g in good yield, even on large scale. Electron-rich alkynes
participated in this transformation as well, thus leading to the
furans 3h,i in useful yields. Further modifications on the
substituents of the furan ring were also accomplished to
furnish compounds 3j–l. Interestingly, the use of secondary
alcohols for this reaction also proved feasible, although
0.5 equivalents of ZnCl2 were required. Thus, the furans
3m,n, derived from isopropanol and cyclohexanol, respec-
tively, were obtained in moderate yields. Interestingly,
industrially relevant (+)-menthol was employed to prepare
the furan derivative 3o (d.r. = 1:1). As a limitation of this
transformation, we found that alkynes bearing alkyl groups or
electron-poor arenes either did not give rise to the expected
furans or proceeded in low yield (3p, 12%). Tertiary alcohols
led to unsatisfactory results as well.
Next, we also tried substrates bearing an additional
alkenyl moiety as the alkyne substituent (Scheme 4).
Remarkably, under otherwise identical reaction conditions,
the alcohol partner was coupled at the vinylogous position. As
Scheme 4. Zinc-catalyzed synthesis of allyl ether derivatives 6. Yields
of isolated product within parentheses.
a result, the allyl ether derivatives 6a–e were obtained in
moderate to good yields and with complete E stereoselectiv-
ity.
Our attention then turned towards amines or amides,
which could be suitable substrates in this zinc-catalyzed
ꢀ
process to afford products resulting from a formal N H bond
insertion. In this regard, we did not observe the formation of
the desired furfuryl amines when piperidine or tosylamide
were reacted with 1a under various reaction conditions. On
the contrary, when using 1H-pyrazole (7a) under mild
reaction conditions (10 mol% ZnCl2, CH2Cl2, 25–408C), we
were pleased to observe the formation in low yields of the
desired compound 8a (ca. 30%), which is a triarylmethane
(TRAM) derivative. Since these compounds are relevant in
different areas such as medicinal chemistry or materials
science,[11,12] we subsequently optimized the reaction condi-
tions and evaluated the scope. Thus, we found that the use
ZnCl2 (20 mol%) in 1,2-dichloroethane (DCE) at 808C gave
rise to 8a in almost quantitative yield (Scheme 5). A larger
scale reaction was again practical, thus providing 8a in good
yield. Modifications in the enynone component were then
accomplished and found to afford the corresponding TRAMs
ꢀ
8b–e in good yields. This zinc-catalyzed cyclization/C N bond
Scheme 3. Zinc-catalyzed synthesis of furfuryl ether derivatives 3.
Reaction conditions: 1 (0.2–0.3 mmol), 2 (6 equiv), ZnCl2 (20 mol%),
n-hexane (0.1m), 258C. Yields of isolated product within parentheses.
[a] Along with small amounts of a isomeric product (see Ref. [10]).
[b] At 358C. [c] Used 0.5 equiv of ZnCl2. n.d.=not detected.
formation sequence proved feasible with other azoles
(Scheme 5). Thus, in addition to pyrazole, monocyclic azoles
such as imidazole, 1,2,4- and 1,2,3-triazole could be success-
fully used in this process, thus affording the compounds 8 f–h
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Scheme 6. Mechanistic proposal. a) Dual activation mode. b) Catalytic
cycle (applicable for azoles as well).
A computational study at the B3LYP/6-31G* level of
theory on the reaction of 1a with 2a,[16] showed that this
pathway is energetically favored over a either concerted zinc
ꢀ
carbene O H bond insertion or an addition/elimination
stepwise process. While the highest energy barrier required
for the alcohol activation mechanism was + 8.7 kcalmolꢀ1
ꢀ
(found for the transition state of B!C), zinc carbene O H
bond insertions require + 38.4 kcalmolꢀ1 (concerted) or
+ 35.6 kcalmolꢀ1 (stepwise), thus making the latter mecha-
nisms less likely (see the Supporting Information). An
analogous reaction pathway was found for the reaction with
7a, and it showed a higher barrier of + 17.5 kcalmolꢀ1, which
is in agreement with the experimental observations.[17] The
formation of isomers (3d’, 3 f’)[10] and the formation of the
allyl ethers 6 (and 8m) might arise from the intermediate C
through nucleophilic attack on other positions.
Finally, taking into account the ability of zinc to promote
Friedel–Crafts alkylations with benzylic substrates,[18] we
envisioned that other unsymmetrical TRAMs could be
prepared in a one-pot cascade sequence involving the in situ
generation of the benzyl ether 3 and a subsequent Friedel–
Crafts reaction in the presence of an appropriate arene. As
shown in Scheme 7a, preliminary studies demonstrated that
the activated arenes 9 were able to participate in this one-pot
transformation to afford the TRAMs 10a–c in moderate
yields. Interestingly, this zinc-catalyzed reaction proved
applicable to other electron-rich heteroarenes. Thus, the
treatment of N-methoxycarbonylindole with substrate 1a
(R1 = Ph) afforded the indole derivative 10d in a respectful
overall yield (58%). This strategy was further extended to
another nucleophile, pentane-2,4-dione (11), which led to the
compound 12 in 64% yield (Scheme 7b). Notably, in both
Scheme 5. Zinc-catalyzed synthesis of unsymmetrical triarylmethane
derivatives 8a–k and compounds 8l–m. Reaction conditions: 1 (0.2–
0.3 mmol), 7 (6 equiv), ZnCl2 (20 mol%), DCE (0.1m), 808C. Yields of
isolated product within parentheses.
in good yields. Benzofused derivatives were also suitable
partners and efficiently provided the TRAMs 8i–k. In
addition, an alkyl-substituted alkyne proved applicable to
this reaction, thus leading to 8l, albeit in modest yield.
Furthermore, the use of an enynone bearing an alkenyl
substituent (R3 = 1-cyclopentenyl) led to compound 8m,
which was obtained along with minor amounts of other
isomers (see the Supporting Information for details).
As for our previous report,[4] a generation of the zinc
ꢀ
ꢀ
carbene and subsequent O H (or N H) bond insertion might
account for the present reaction, although there are no
ꢀ
reports on zinc carbene O H bond insertion to our knowl-
edge. However, considering the ability of zinc metalloen-
zymes to activate nucleophiles (H2O or alcohol residues like
serine or threonine), an alternative mechanistic scenario,
where the zinc catalyst plays a double role, might also be
possible (Scheme 6a).[13] Thus, zinc coordination to the
alcohol (A) might first translate into an increase of its acidity,
and thus triggers the cyclization from the intermediate B to C
(Scheme 6b).[14] Then, the attack of the more nucleophilic
zinc alkoxide D would lead to compounds 3 or 6 (R3 =
alkenyl).[15] An analogous proposal could account for the
formation of 8, wherein zinc coordination to one of the
N atoms activates the azole.
cases the overall transformation comprised
a cascade
sequence involving an initial cyclization and final formation
ꢀ
of a new C C bond, which was performed with the single
simple catalyst ZnCl2.[19]
In summary, we have reported a novel zinc-catalyzed
ꢀ
ꢀ
sequence, cyclization/C O or C N bond formation. This
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Beller, Angew. Chem. 2008, 120, 3363; Angew. Chem. Int. Ed.
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[3] Selected recent reviews on zinc catalysis: a) S. Enthaler, ACS
Catal. 2013, 3, 150; b) X.-F. Wu, Chem. Asian J. 2012, 7, 2502;
c) X.-F. Wu, H. Neumann, Adv. Synth. Catal. 2012, 354, 3141.
[4] R. Vicente, J. Gonzꢀlez, L. Riesgo, J. Gonzꢀlez, L. A. Lꢁpez,
Angew. Chem. 2012, 124, 8187; Angew. Chem. Int. Ed. 2012, 51,
8063.
[5] For reviews on furans, see: a) H. N. C. Wong, X.-L. Hou, K.-S.
Yeung, H. Huang in Modern Heterocyclic Chemistry (Eds.: J.
ꢂlvarez-Builla, J.-J. Vaquero, J. Barluenga), Wiley-VCH, Wein-
heim, 2011; b) A. Boto, L. ꢂlvarez in Heterocycles in Natural
Products Syntheis (Eds.: K. C. Majumdar, S. K. Chattopdahyay),
Wiley-VCH, Weinheim, 2011; c) R. C. D. Brown, Angew. Chem.
2005, 117, 872; Angew. Chem. Int. Ed. 2005, 44, 850; d) B. A.
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Vol. 2 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven),
Elsevier, Oxford, 1997, p. 395.
[6] Selected examples: a) X. Cui, X. Xu, L. Wojtas, M. M. Kim, X. P.
Zhang, J. Am. Chem. Soc. 2012, 134, 19981; b) C. H. Woo, P. M.
Beaujuge, T. W. Holcombe, O. P. Lee, J. M. J. Frꢃchet, J. Am.
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Brzezniska, T. Iwasaki, T. Ohshima, K. Mashima, R. Dembinski,
J. Org. Chem. 2008, 73, 5881.
[7] For selected examples on the alkyne activation with zinc
compounds, see: a) A. Zulys, M. Dochnahl, D. Hollmann, K.
Lçhnwitz, J.-S. Herrmann, P. W. Roesky, S. Blechert, Angew.
Chem. 2005, 117, 7972; Angew. Chem. Int. Ed. 2005, 44, 7794;
b) A. Sniady, A. Durham, M. S. Morreale, K. A. Wheeler, R.
Dembinsky, Org. Lett. 2007, 9, 1175; c) K. Alex, A. Tillack, N.
Schwarz, M. Beller, Angew. Chem. 2008, 120, 2337; Angew.
Chem. Int. Ed. 2008, 47, 2304; d) C.-L. Deng, R.-J. Song, Y.-L.
Liu, J.-H. Li, Adv. Synth. Catal. 2009, 351, 3096; e) T. Sugiishi, H.
Nakamura, J. Am. Chem. Soc. 2012, 134, 2504.
ꢀ
Scheme 7. Zinc-catalyzed cyclization/C C bond formation sequence.
Yields of isolated product within parentheses. [a] At 608C.
methodology allowed the synthesis of valuable functionalized
furfuryl ether derivatives when using alcohols. Analogously,
the use of azoles enabled a straightforward preparation of
relevant unsymmetrical triarylmethane derivatives. Besides,
zinc chloride proved capable to catalyze a cascade comprising
ꢀ
a cyclization/C C bond formation, to afford different triaryl-
methanes. Computational studies point out a mechanism
involving an activation of the alcohol (or the azole) by zinc,
which mimics the function of zinc metalloenzymes. Consid-
ering the current demands for sustainable catalysis, our work
presented herein, using ZnCl2 is a remarkable example for the
application of a simple, inexpensive, and low-toxic metal
catalyst. We believe that this work contributes to establish
zinc compounds as valuable tools for organic synthesis.
[8] H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev.
2003, 103, 977.
[9] For conceptually different approaches to furfuryl alcohol
derivatives, see: a) J. S. Clark, A. Boyer, A. Aimon, P. E.
Garcꢄa, D. M. Lindsay, A. D. F. Symington, Y. Danoy, Angew.
Chem. 2012, 124, 12294; Angew. Chem. Int. Ed. 2012, 51, 12128;
b) L. Albrecht, L. K. Ransborg, B. Gschwend, K. A. Jørgensen,
J. Am. Chem. Soc. 2010, 132, 17886.
[10] When using butanol and cyclopentanemethanol, variable
amounts (ca. 5%) of isomeric acetals were isolated. See the
Supporting Information for details.
Experimental Section
Representative procedure for the synthesis of 3a: ZnCl2 (5.4 mg,
0.04 mmol, 20 mol%) was added to a solution of 1a (42 mg,
0.2 mmol) and 2a (70 mg, 1.2 mmol, 6.0 equiv) in n-hexane (2 mL).
The mixture was stirred for 6 h at 258C (disappearance of 1a checked
by TLC). The solvent was removed under reduced pressure and the
resulting residue was purified by flash chromatography (SiO2,
n-hexane/EtOAc = 10:1) to yield 3a (40 mg, 74%) as a pale-yellow
oil.
Received: February 25, 2013
Published online: April 22, 2013
[11] Selected reviews on TRAMs: a) M. S. Shchepinov, V. A. Kor-
shun, Chem. Soc. Rev. 2003, 32, 170; b) D. F. Duxbury, Chem.
Rev. 1993, 93, 381. Selected examples of relevant TRAMs: c) J.
Doiron, A.-H. Soultan, R. Richard, M. M. Tourꢃ, N. Picot, R.
Richard, M. Cuperlovic-Culf, G. A. Robichaud, M. Touaibia,
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Am. Chem. Soc. 1983, 105, 2078.
Keywords: alkynes · carbenes · cyclization · furans · zinc
.
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[17] See the Supporting Information for further details on the
mechanism.
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