C-H bond functionalization via hydride transfer: synthesis of dihydrobenzopyrans from ortho-vinylaryl akyl ethers

Article abstract of DOI:10.1021/ol900915p

The hydride transfer initiated cyclization ("HT-cyclization") of aryl alkyl ethers, which leads to direct coupling of sp³ C-H bonds and activated alkenes, is reported. Readily available salicylaldehyde derived ethers are converted in one step to dihydrobenzopyrans, an important class of heteroarenes frequently found in biologically active compounds. This process has not been previously reported, in contrast to known HTcyclizations of the corresponding fert-amines ("tert-amino effect" reactions).

Full text of DOI:10.1021/ol900915p

ORGANIC
LETTERS
2009
Vol. 11, No. 14
2972-2975
C-H Bond Functionalization via Hydride
Transfer: Synthesis of
Dihydrobenzopyrans from
ortho-Vinylaryl Akyl Ethers
Kevin M. McQuaid, Jonathan Z. Long, and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway, New York, New York 10027
sames@chem.columbia.edu
Received April 27, 2009
ABSTRACT
The hydride transfer initiated cyclization (“HT-cyclization”) of aryl alkyl ethers, which leads to direct coupling of sp3 C-H bonds and activated
alkenes, is reported. Readily available salicylaldehyde derived ethers are converted in one step to dihydrobenzopyrans, an important class of
heteroarenes frequently found in biologically active compounds. This process has not been previously reported, in contrast to known HT-
cyclizations of the corresponding tert-amines (“tert-amino effect” reactions).
In the context of a broad research program in the area of
C-H bond functionalization,1 we have been interested in
direct coupling of sp3 C-H bonds and alkenes, to afford
R-alkylation of ethers and amines under catalytic, nonbasic
conditions. As an alternative to the transition metal catalyzed
process, where the coupling is initiated by the metal-mediated
cleavage of the C-H bond,2,3 we have been developing a
different approach based on intramolecular hydride transfer
(Scheme 1).4 In this process, activation of an electron-
deficient alkene by a Lewis acid triggers a 1,5-hydride
transfer and formation of a zwitterionic intermediate (in-
tramolecular redox event), which is followed by cyclization
via ionic C-C bond formation.
This overall cyclization is initiated by an intramolecular
redox process and thus does not require a stoichiometric
oxidant.5 For example, we previously reported that the
relatively reactive benzyl ethers undergo facile cyclization
in the presence of boron trifluoride etherate (Scheme 2A).4a
(4) (a) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc.
2005, 127, 12180–12181. (b) Pastine, S. J.; Sames, D. Org. Lett. 2005, 7,
5429–5431. (c) McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131,
402–403. For a commentary on this area of research, see: (d) Tobisu, M.;
Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683–1684. For a recent
example from other laboratories, see: (e) Shikanai, D.; Murase, H.; Hata,
T.; Urabe, H. J. Am. Chem. Soc. 2009, 131, 3166–3167.
(1) Godula, K.; Sames, D. Science 2006, 312, 67–72.
(2) Some recent examples: (a) Chatani, N.; Asaumi, T.; Yorimitsu, S.;
Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935–
10941. (b) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004,
126, 6556–6557. (c) Shi, L.; Tu, Y. -Q.; Wang, M.; Zhang, F. -M.; Fan, C.
-A.; Zhao, Y. -M.; Xia, W. -J. J. Am. Chem. Soc. 2005, 127, 10836–10837.
(d) Kubiak, R.; Prochnow, I.; Doye, S. Angew. Chem., Int. Ed. 2009, 48,
1153–1156. (e) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.;
(5) For recent examples of R-alkylation of ethers using an external
oxidant, see: (a) Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed.
2008, 47, 4184–4187. (b) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed.
2008, 47, 7497–7500. (c) Cao, K.; Jiang, Y. -J.; Zhang, S. -Y.; Fan, C. -A.;
Tu, Y. -Q.; Pan, Y. -J. Tetrahedron. Lett. 2008, 49, 4652–4654.
(6) Selected examples of chroman synthesis: (a) Yamamoto, Y.; Itonaga,
K. Org. Lett. 2009, 11, 717–720. (b) Youn, S. W. Synlett 2007, 19, 3050–
3054. (c) Marsini, M. A.; Huang, Y.; Lindsey, C. C.; Wu, K. -L.; Pettus,
T. R. R. Org. Lett. 2008, 10, 1477–1480. (d) Hajra, S.; Maji, B.; Karmakar,
A. Tetrahedron Lett. 2005, 46, 8599–8603. (e) Youn, S. W.; Pastine, S. J.;
Sames, D. Org. Lett. 2004, 6, 581–584. (f) Shi, Z.; He, C. J. Am. Chem.
Soc. 2004, 126, 5964–5965. (g) Lu, G.; Malinakova, H. C. J. Org. Chem.
2004, 69, 8266–8279.
Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 2116–2118
.
(3) C-C bond formation at the R-position of ethers and carbamates can
be achieved under neutral conditions via catalytic carbene insertion reactions.
(a) Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W. J. Am.
Chem. Soc. 2003, 125, 6462–6468. (b) Davies, H. M. L.; Beckwith, R. E. J.;
Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126–6132
.
10.1021/ol900915p CCC: $40.75
Published on Web 06/23/2009
 2009 American Chemical Society

Scheme 1
.
Mechanistic Concept for the R-Alkylation of Ethers
Scheme 3. Activation of Aryl Ethers and Aryl Amines
and Amines via Hydride Transfer
Scheme 2
.
Development of Different Activation Protocols for
HT-Cyclization Reactions
zopyrans (or chromans),6 an important structural class found
in many natural products and biologically active compounds.7
As expected, the aryl alkyl ethers were less reactive in
comparison to the dialkyl ethers, owing to the electron-
withdrawing nature of the arene ring (and thus lower
carbocation stabilizing ability of the aryl ether oxygen). The
benzyl ether-enone 9 gave no reaction even under the highly
activating conditions using BF3·Et2O and ethylene glycol
(Scheme 3A). Thus, we examined alkenes with two electron-
withdrawing groups (compounds of type I, Scheme 3B) and
found that these substrates underwent the desired HT-
cyclization in the presence of Sc(OTf)3. The corresponding
N-arylamines (compounds of type II) are much more reactive
in comparison and are known to undergo HT-cyclization
either thermally or in the presence of acid catalysts (these
reactions are often referred to as the “tert-amino effect”).8,9
To the best of our knowledge, the HT-cyclization has not
been previously reported with phenol-derived substrates.10
The desired substrates were synthesized in short order by
the alkylation of the phenol, followed by the Knoevenagel
The less reactive substrates, such as pyrrolidine carbamate
3, however, require stronger activation with PtCl4, to give
the cyclization product 4 in good yield (Scheme 2B).
The higher hydridophilicity of the double bond may also be
accomplished by using doubly activated alkenes and a
suitable Lewis acid capable of chelating the diester unit, as
illustrated by the R,ꢀ-unsaturated malonate ester 5 and
Sc(OTf)3 (Scheme 2C). More recently, we showed that even
primary ethers could be induced to undergo the HT-
cyclization, by the action of a simple yet powerful activation
protocol employing BF3·Et2O and ethylene glycol, which
generates highly reactive alkenyl-oxocarbenium intermediates
from the corresponding enones in situ (Scheme 2D).4c
Increasing the hydridophilicity of the alkene led to expansion
of the scope of the HT-cyclization reactions, and it appears
that the boron trifluoride/ethylene glycol activation of enones
and the scandium triflate activation of R,ꢀ-unsaturated
malonates are the most effective systems in this regard
(Scheme 2).
(7) (a) Koufaki, M.; Theodorou, E.; Galaris, D.; Nousis, L.; Katsanou,
E. S.; Alexis, M. N. J. Med. Chem. 2006, 49, 300–306. (b) Lee, S. B.; Lin,
C. Y. L.; Gill, P. M. W.; Webster, R. D. J. Org. Chem. 2005, 70, 10466–
10473. (c) Toyota, M.; Omatsu, I.; Asakawa, Y. Chem. Pharm. Bull. 2001,
49, 924–926.
(8) Reviews: (a) Meth-Cohn, O.; Suschitzky, H. AdV. Heterocycl. Chem.
1972, 14, 211–278. (b) Meth-Cohn, O. AdV. Heterocycl. Chem. 1996, 65,
´
1–37. (c) Ma´tyus, P.; Elia´s, O.; Tapolcsa´nyi, P.; Polonka-Ba´lint, A.; Hala´sz-
Dajka, B. Synthesis 2006, 16, 2625–2639.
(9) For interesting recent developments in the area of HT-cyclization
of tert-amines, see: (a) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel,
D. Org. Lett. 2009, 11, 129–132. (b) Zhang, C; Murarka, S.; Seidel, D. J.
Org. Chem. 2009, 74, 419–422. (c) Ruble, J. C.; Hurd, A. R.; Johnson,
T. A.; Sherry, D. A.; Barbachyn, M. R.; Toogood, P. L.; Bundy, G. L.;
Graber, D. R.; Kamilar, G. M. J. Am. Chem. Soc. 2009, 131, 3991–3997.
(d) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130,
416–417. (e) Barluenga, J.; Fan˜ana´s-Mastral, M.; Anzar, F.; Valde´s, C.
Angew. Chem., Int. Ed. 2008, 47, 6594–6597. (f) Polonka-Ba´lint, A.;
Saraceno, C.; Luda´nyi, K.; Benyei, A.; Ma´tyus, P. Synlett 2008, 18, 2846–
2850. (g) Parjapati, D.; Borah, K. J. Beilstein J. Org. Chem. 2007, 3, 1–4,
No. 43.
In this study, we examined the reactivity of aryl alkyl
ethers (Scheme 3). These compounds are attractive substrates
as they are prepared in two steps from readily available
salicylaldehydes and in one step would furnish dihydroben-
(10) A related HT-cyclization of aromatic acetals and thioacetals has
been reported, see: Alajar´ın, M.; Bonillo, B.; Ortin, M.-M.; Sa´nchez-
Andrada, P.; Vidal, A. Org. Lett. 2006, 8, 5645–5648, and references therein.
Org. Lett., Vol. 11, No. 14, 2009
2973

Scheme 4
.
Synthesis of Substrates from Salicylaldehydes
Table 2. Variation in Hydride Donor/Acceptor Groupsa
condensation with the selected carbonyl partner (Scheme 4).
We chose substrate 13 to examine an array of Lewis acids
and to optimize the reaction conditions (Table 1).
Table 1. Screen for Catalyst Activitya
a All reactions were performed at 0.025 M concentration with dodecane
as an internal standard and monitored by GC. b Percentage of starting
material remaining relative to internal standard. c Product formed relative
to internal standard. d Isolated yield.
a All reactions were performed on a 0.2-0.4 mmol scale in CH2Cl2
(0.025 M substrate) at 80 °C with indicated amount of Sc(OTf)3 catalyst.
b Isolated yields as an average of three runs.
loading, which is likely due to the cleavage of the benzyl
ether bond. The low efficiency of the HT-cyclization of the
allyl ether substrate 19 is in part due to a competing Claisen
rearrangement.11
As noted above, the aryl ether substrates are quite
unreactive as seen from low or no conversion with many
Lewis acids. Importantly, complete conversion of the starting
material and excellent isolated yield of the desired product
was accomplished by heating with Sc(OTf)3 as the catalyst.
It should be noted that no reaction was observed in the
absence of catalyst under these conditions (Table 1, entry
1), which stands in contrast to the corresponding tert-amine
substrates that are known to undergo the HT-cyclization upon
heating.8,9
We next focused our efforts on exploring the substrate
scope with respect to the hydride donor and acceptor
components of the substrate. The HT-cyclization occurred
readily with cyclic and acyclic aliphatic ethers to afford
excellent yields of the dihydrobenzopyran products (Table
2, entries 1 and 2). The benzyl ether 17 (Table 2, entry 3),
however, gave lower yield and required increased catalyst
In regard to the hydride acceptor component, the best
results were obtained with the diester substrates such as
compounds 13 and 15 or the keto-ester substrates such as
21. The diketone substrates with acyclic and cyclic hydride
donor moieties did undergo the HT-cyclization (Table 2,
entries 6 and 7), but in these cases a significant amount of
the product was lost to competing side reactions (see
Supporting Information). The keto-sulfone 27 was also
converted to the expected product 28, albeit in modest yield
due to lower reactivity under these reaction conditions (Table
2, entry 8).
We next examined the substitution of the arene ring, which
revealed its strong effect on the reactivity. For instance,
compound 29 with the methoxy group in the C-4 position is
2974
Org. Lett., Vol. 11, No. 14, 2009

an excellent substrate providing high yield of the desired
dihydrobenzopyran 30 (Table 3, entry 1). This is consistent
hydridophilicity of the alkene by the electron-donating
resonance effect of the methoxy group (in the para-position
with respect to the alkene), as well as by reducing the hydride
donor ability of the iso-propoxy group by the σ-effect of
the methoxyl oxygen atom. The deactivating bromine sub-
stituent was well tolerated at the C-4 position, although it
significantly reduced the reactivity of substrate 33 as longer
reaction time was required to reach completion, affording
high yield of dihydrobenzopyran 34 (Table 3, entry 3).
However, bromine at the C-5 position completely shut down
the cyclization reaction (Table 3, entry 4). We rationalize
this result by the σ-electron withdrawing effect of the
bromine atom, which severely decreases the hydride donor
ability of the iso-propoxy group when the bromine substituent
is situated closer. Similar to compound 31, substrate 37
containing the diethylamino group at the C-5 position was
deactivated and required excess Lewis acid to achieve 60%
conversion in 48 h. Lastly, we were pleased to find that 39
was converted to product 40 in high yield (Table 3, entry
6), illustrating the compatibility of this method with relatively
complex substrates.
Table 3. Substitution of the Aromatic Ringa
In summary, we developed a new and concise synthetic
approach to highly substituted dihydrobenzopyrans via the
HT-cyclization of ortho-vinylaryl alkyl ethers. Applying this
method, widely available salicylaldehydes can be converted
in three steps to the desired dihydrobenzopyrans, an impor-
tant class of heterocycles frequently found in biologically
active compounds. The ortho-vinylaryl alkyl ethers are
significantly less reactive, which limits the scope of the HT-
cyclization of these substrates, compared to the analogous
tert-amines. Nevertheless, guided by the results of this study,
a wide spectrum of interesting structures can be accessed in
a three-step synthetic sequence.
a All reactions were performed on a 0.2-0.4 mmol scale in CH2Cl2
(0.025 M substrate) at 80 °C with indicated amount of Sc(OTf)3 catalyst.
b Isolated yields as an average of three runs. c No reaction. Recovered only
starting material. d 40% of the starting material was recovered.
Acknowledgment. This work was supported by the
National Institute of General Medical Sciences (NIGMS).
J.Z.L. is the recepient of the Pfizer Summer Undergraduate
Research Fellowship.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for starting materials and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
with the ability of the methoxy group to stabilize the
developing oxocarbenium ion in the para-position through
the resonance effect. In contrast, the regioisomer 31 contain-
ing the methoxy group at the C-5 position was much less
reactive, providing the corresponding product in modest
yield, requiring higher catalyst loading and longer reaction
time. This observation can be rationalized by decreasing the
OL900915P
(11) Castro, A. M. M. Chem. ReV. 2004, 104, 2939–3002.
Org. Lett., Vol. 11, No. 14, 2009
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