Cyclic Ether Synthesis via Palladium-Catalyzed Directed Dehydrogenative Annulation at Unactivated Terminal Positions

Article abstract of DOI:10.1021/jacs.5b07384

Here, a palladium-catalyzed functionalization of unactivated sp³ C-H bonds with internal alcohol nucleophiles is described. Directed by an oxime-masked alcohol, annulation chemoselectively occurs at the β position, leading to a range of aliphatic cyclic ethers with four- to seven-membered rings. Tethered primary, secondary, and tertiary free hydroxyl groups can all react to give the corresponding cyclized products. In addition, benzyl and silyl protected alcohols can also be directly coupled. An sp³ C-H activation/intramolecular S_N2 pathway was proposed.

Full text of DOI:10.1021/jacs.5b07384

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Communication
Cyclic Ether Synthesis via Palladium-catalyzed Directed De-
hydrogenative Annulation at Unactivated Terminal Positions
Samuel J. Thompson, Danny Q. Thach, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07384 • Publication Date (Web): 31 Aug 2015
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Cyclic Ether Synthesis via Palladium-catalyzed Directed De-
hydrogenative Annulation at Unactivated Terminal Positions
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Samuel J. Thompson, Danny Q. Thach and Guangbin Dong*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
Supporting Information Placeholder
and site-selective breaking of stronger terminal (unacti-
vated) C−H bonds is generally nontrivial. Recently,
White and coworkers reported an elegant method for the
efficient preparation of six-membered cyclic ethers
through allylic C−H oxidation (Scheme 1b).4 During the
past decade, C−O bond formation via activation of inert
sp3 C−H bonds has been greatly advanced by palladium
catalysis.5 While ether synthesis through directed activa-
tion of aromatic C−H bonds has been extensively stud-
ied by Sanford,5a,6 Yu,7 Liu,8 Yoshikai,9 Wang,10 and oth-
ers,11 sp3 C−H alkoxylation with alcohols remains a sig-
nificant challenge.12,13 The Chen group reported the first
intermolecular alkoxylation of unactivated sp3 C−H
bonds using a picolinamide directing group (DG).14 Lat-
er, Shi and Rao independently reported amide-directed
linear ether syntheses through activation of methyl and
methylene groups.15 To the best of our knowledge, in-
tramolecular sp3 C−H alkoxylation at unactivated ter-
minal positions has yet been developed. Herein, we de-
scribe a Pd-catalyzed masked-alcohol-directed method
for preparing various sized cyclic ethers through activa-
tion of a methyl group.
ABSTRACT: Here, a palladium-catalyzed functionaliza-
tion of unactivated sp3 C−H bonds with internal alcohol
nucleophiles is described. Directed by an oxime-masked
alcohol, annulation chemoselectively occurs at the β
position, leading to a range of aliphatic cyclic ethers
with 4 to 7-membered rings. Tethered primary, second-
ary and tertiary free hydroxyl groups can all react to give
the corresponding cyclized products. In addition, benzyl
and silyl protected alcohols can also be directly coupled.
An sp3 C−H activation/intramolecular SN2 pathway was
proposed.
Cyclic ethers are commonly found in a variety of bio-
logically important molecules (Fig. 1).1 While numerous
efficient methods (e.g., various SN2 reactions) have been
introduced to synthesize this moiety from an alcohol
nucleophile with a tethered electrophile,2 the dehydro-
genative coupling between an O−H bond and an unacti-
vated sp3 C−H bond arguably represents the most attrac-
tive approach since pre-activation can be avoided at the
position to be cyclized (eq 1).
Scheme 1. Dehydrogenative Annulation for Cyclic Ether
Synthesis
O
MeO
H
O
N
N
O
O
OH
CF3
N
O
N
N
Me
O
PF-4634817
O
O
NH
dual CCR2/CCR5 antagonist
H
O
O
O
OH
OH
O
OH
O
H
O
O
N
N
S
O
O
paclitaxel
anti-cancer
O
amprenavir
HIV protease inhibitor
H2N
Figure 1. Examples of Bioactive Compounds Containing
Cyclic Ether Moieties
Preparation of aliphatic cyclic ethers via dehydrogena-
tive annulation can first be traced back to a hydrogen-
atom-transfer strategy mediated by a highly reactive
oxygen-centered radical (Scheme 1a);3 however, chemo-
Our laboratory has been interested in masked alcohol-
directed C−H functionalization due to the prevalence of
hydroxyl groups in organic molecules.16 Oximes, first
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demonstrated by Sanford and coworkers in directed sluggish reactions (entries 8-10). Replacing PhI(OAc)2
catalytic C−H activation,17 are employed here as alcohol
surrogates and DGs for β sp3-C−H functionalization in-
volving an exo-metallocycle. Instead of relying on at-
tacks by external reagents, a strategy of using a pendant
alcohol as an internal nucleophile was conceived for
cyclic ether formation via sp3 C−H alkoxylation. This
approach would allow for a new disconnection strategy
to construct cyclic ethers. While the proximity effect in
an intramolecular setting should accelerate the reaction
rate, three challenges can nevertheless exist: 1) Pd-
mediated alcohol dehydrogenation to aldehydes/ketones
is well known,18 thus substrate stability represents a ma-
jor concern; 2) intermolecular reactions, such as β-
acetoxylation16 and esterification with the free −OH (vi-
de infra), can compete; 3) compared to the intermolecu-
lar reaction14,15 that can possibly use excess alcohols,
only a stoichiometric quantity of alcohol is available in
an intramolecular setting, thus any side reactions afore-
mentioned with the free −OH would lead to a lower
yield.
with oxone was also effective; however, a significant
amount of 2,6-dimethoxylbenzaldehyde was formed as
the byproduct, indicating more decomposition of the
oxime substrate (entry 11). Finally, lowering the reaction
temperature to 80 °C gave a lower conversion but still
provided the desired product (entry 12).
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8
Scheme 2. Substrate Scopea
9
DG
DG
O
O
10 mol% Pd(OAc)2
1.3 equiv. PhI(OAc)2
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R
R
n
H
AcOH (0.2 M), 100 C, 3h
1a-w
2a-w
O
n
OH
DG
DG
DG
DG
O
O
O
O
Me
O
O
O
O
Me
Me
2c (83%)
2d (57%)
2a (58%)
2b (66%)
DG
O
DG
DG
O
DG
O
O
O
O
O
O
Me Me
2e (90%)
Me
Me
2h (19%)
2f (21%)
2g (52%)
Table 1. Optimization with Substrate 1aa
DG
DG
DG
DG
O
O
O
O
Me
O
Me
O
O
O
Me
Br
2k (70%)
2l (79%)
2j (31%)
2i (56%)
DG
O
DG
DG
DG
O
O
O
Me
O
Me
O
O
O
F
EtO2C
2m (86%)
2n (81%)
2o (70%)
2p (79%)
DG
DG
DG
O
DG
O
O
O
O
O
O
O
N
Ph
a
N
N
All the reactions were run on a 0.1 mmol scale. The
N
HN
Ph
2q (84%)
(x-ray obtained)
Boc
EtO2C
O
yield was determined by 1H-NMR using 1,1,2,2-
tetrachloroethane as the internal standard. b Isolated yield.
2s (84%)
2r (79%)
2t (78%)
O
DG
DG
O
Stimulated by these challenges, we started with mono-
protected diol (2,6-dimethoxybenzaldoxime) 1a as the
initial substrate. After optimizing the reaction condi-
tions, to our delight, the tetrahydrofuran product (2a)
was formed in 64% yield simply with 10 mol%
O
iPr
OH
C
Me
O
O
H
O
O
D
N
O
O
N
H
Me
OAc
DG
O
paclitaxel C/D ring
O
2w (35%)
2u (52%)
(+31% 1u recovered)
2v (64%)
o
Pd(OAc)2 and 1.3 equiv PhI(OAc)2 in HOAc at 100 C
for 3h (Table 1, entry 1). Interestingly, oxidation of the
alcohol to the corresponding aldehyde was not ob-
served.19 Control experiments showed that in the ab-
sence of either the palladium catalyst or oxidant, no cy-
clized product was observed (entries 2 and 3). Use of
acetic anhydride led to more acylation of the free alco-
hol (entry 4). Addition of molecular sieves or water re-
duced the yield to 39% and 54% respectively (entries 5
and 6). The reaction also proceeded in TFA albeit in a
lower yield (entry 7). Attempts to use less acetic acid
with other organic co-solvents were unfruitful, causing
a
Isolated yields. Product consists of a mixture of oxime
E/Z stereoisomers (for details, see Supporting Information).
The substrate scope was then explored (Scheme 2, for
details of substrate preparation, see Supporting Infor-
mation). Gratifyingly, substrates possessing a primary,
secondary, or tertiary hydroxyl group all cyclized to give
the corresponding cyclic ethers under the standard con-
ditions in moderate to high yields. It is interesting to
note that the yield increased significantly in the order of
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primary < secondary < tertiary alcohol nucleophiles (e.g. To gain insight into this transformation, a control exper-
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2a-c), despite increasing steric congestion. It is likely
that tertiary alcohols are less prone to undergo esterifica-
tion with HOAc, and the Thorpe−Ingold effect20 should
also help the annulation. Besides 5-membered rings, a
number of 6- and 7-membered cyclic ethers were also
formed in moderate to high yields.21
iment showed that a regular benzyl ether (e.g. 5) was not
deprotected under these reaction conditions. In addition,
a significant amount of benzyl acetate was isolated dur-
ing the C−H activation/cyclization reaction (see Support-
ing Information). These observations indicated that the
ether oxygen may have acted as a nucleophile for the
annulation reaction, instead of a free hydroxyl group.
It is not surprising to note that the efficiency of the
dehydrogenative annulation reaction is closely related to
the relative stereochemistry of the substrates. For exam-
ple, the anti diol derivative (2i) resulted in 56% yield,
while its syn diastereomer (2h) only gave 19% yield.
This trend was further confirmed in a pair of tertiary
hydroxyl substrates (2j versus 2k). While the reaction
mechanism remains to be better understood, these ob-
servations are consistent with the proposed C−H activa-
tion/intramolecular SN2 pathway22 (for a mechanistic
discussion, vide infra). In addition, similar substrates
with bromide and fluoride substitution on the arene gave
satisfactory yields (2l and 2m).
DG
DG
O
O
9
Pd(OAc)2
PhI(OAc)2
R
R
n
H
+
R'OAc
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AcOH
O
n
OR'
R' = H or Bn
n=0, 1, 2, 3
OMe
[PdII]
PhI(OAc)2
-[PdII]
DG=
OMe N
DG
DG
O
O
[PdII]
OAc
[Pdx]
R
OAc
R
n
n
O
O
R'
R'
x =3 or 4
Figure 2. Plausible Reaction Pathway.
While the exact mechanism remains to be defined, a
plausible reaction pathway is proposed (Fig. 2). After a
directed C−H palladation followed by oxidation of the
palladium to a high oxidation state (e.g. PdIV), an intra-
molecular SN2 reaction26 can occur to give an oxonium
intermediate, and meanwhile reduce the palladium to
PdII. Subsequently, an acetate ion would undergo a net
deprotonation or de-benzylation to afford the cyclic
ether product.
With the success of tertiary alcohols participating in
the cyclization, forming spirocyclic ethers was next in-
vestigated. Indeed, 6,5-, 5,5- and 4,5- spiroethers can be
efficiently accessed (2o-2v). Moreover, protected piperi-
dine (2r-2v) was also found compatible under the reac-
tion conditions. Besides aryl bromides and fluorides, a
number of functional groups were found compatible
under the reaction conditions, such as ester (2n), carba-
mates (2r and 2s), urea (2t), amide (2u) and aryl alde-
hyde (2v). Furthermore, this dehydrogenative annulation
approach can also be applied to synthesize oxetane
rings. Oxetanes, four-membered cyclic ethers, are wide-
ly found in pharmaceutically interesting compounds, e.g.
paclitaxel (Taxol).23,24 Using this approach, a 6/4-fused
oxetane product (2w), exhibiting a structural motif mim-
icking the Taxol D-ring, can be successfully afforded in
a moderate yield.25
Scheme 4. Cyclization of Silyl Protected Alcohols
Scheme 3. Cyclization with a Benzyl-Protected Alcohol
Besides benzyl-protected alcohols, silyl-protected al-
cohol substrate 6, available in two steps from commer-
cially available 1,3-buta-diol,27 also successfully cy-
clized to tetrahydrofuran 2a albeit through a different
mechanism (Scheme 4). Control experiments have
shown that the TBS group was deprotected in situ under
the reaction conditions. Hence, the yield was compara-
ble to the reaction of unprotected alcohol 1a (vide supra,
Scheme 2). Addition of a fluoride source slightly im-
proved the yield to 62%. Given the ready availability of
1,3-diols, this approach is expected to be useful for
streamlining synthesis of functionalized tetrahydrofu-
For the substrate containing a tertiary DG and a ben-
zyl-protected alcohol (3), an unexpected transformation
was observed (Scheme 3). Under the standard reaction
conditions, a highly functionalized tetrahydrofuran com-
pound (4) was isolated, and the yield can be improved to
71% simply by employing two equivalent of PhI(OAc)2.
Two interesting aspects can be noted: 1) the gem-
dimethyl groups can both be functionalized and differen-
tiated via double C−H activation; 2) benzyl-protected
alcohols can be directly used as the annulation precursor.
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rans.28 Finally, the DG in the products can be easily re-
moved through zinc-mediated N−O bond cleavage (Eqs
2 and 3).16
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. (c) Giri, R.; Liang,
J.; Lei, J. G.; Li, J. J.; Wang, D. H.; Chen, X.; Naggar, I. C.; Guo, C.;
Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 7420.
(6) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8,
1141.
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In summary, we developed a Pd-catalyzed masked al-
cohol-directed site-selective C−H annulation approach,
which provides rapid access to a variety of cyclic ethers
of different ring sizes. The oxidative cyclization
chemoselectively occurs at an inert terminal position,
thus complementary to other existing ether-synthesis
methods. The reaction can tolerate air and moisture, and
is operationally simple. Free primary, secondary, tertiary
alcohols, and even protected alcohols, can be employed
as the internal nucleophile, suggesting a promising sub-
strate scope. In particular, the feasibility of directly us-
ing benzyl ethers as the coupling partner should have a
broad implication (e.g. use of masked nucleophiles) be-
yond this work. Detailed mechanistic study and expan-
sion of the reaction scope to methylene C−H bonds and
other internal nucleophiles are under investigation in our
laboratory.
(7) (a) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 12203; (b) Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.;
Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6774.
(8) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-F.; Xu, J.;
Liu, L. J. Am. Chem. Soc. 2011, 133, 9250.
(9) Wei, Y.; Yoshikai, N. Org. Lett. 2011, 13, 5504.
(10) (a) Wang, G.-W.; Yuan, T.-T. J. Org. Chem. 2010, 75, 476;
(b) Jiang, T.-S.; Wang, G.-W. J. Org. Chem. 2012, 77, 9504.
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56, 15.
(13) For alkoxylation of benzylic C−H bonds, see: ref 5b and (a)
Bhadra, S.; Matheis, C.; Katayev, D.; Gooßen, L. J. Angew. Chem.,
Int. Ed. 2013, 52, 9279. (b) Takemura, N.; Kuninobu, Y.; Kanai, M.
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(14) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.;
Chen, G. J. Am. Chem. Soc. 2012, 134, 7313.
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S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 4187. (b) Shan, G.; Yang, X.;
Zong, Y.; Rao, Y. Angew. Chem. Int. Ed. 2013, 52, 13606.
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43, 264.
(17) ref 5b and Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12,
532.
(18) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681.
(19) The reaction was accompanied by 13% byproduct through
esterification of the alcohol with HOAc.
(20) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc.,
Trans. 1915, 107, 1080; (b) Jung, M. E.; Piizzi, G. Chem. Rev. 2005,
105, 1735.
(21) Attempts to form 8-membered cyclic ethers using similar
substrates were unsuccessful under these reaction conditions.
(22) The syn diol substrate is expected to have a lower activation
energy than the anti one. For a proposed model, see:
ASSOCIATED CONTENT
Supporting Information. Experimental procedures; spec-
tral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*gbdong@cm.utexas.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We would like to thank CPRIT for start-up funding, the
Welch Foundation (F-1781), and ACS PRF for research
grants. G.D. is a Searle Scholar and Sloan Fellow. Dr.
Lynch and Ms. Spangenberg are acknowledged respective-
ly for X-ray crystallography and NMR advice. Mr. Yan Xu
is acknowledged for the discovery of benzyl ether nucleo-
phile. Mr. Zhongxing Huang is thanked for checking the
experiments. We also thank Johnson Matthey for a gener-
ous donation of palladium salts.
(23) For recent reviews see: (a) Burkhard, J. A.; Wuitschik, G.;
Rogers-Evans, M.; Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed.
2010, 49, 9052; (b) Wuitschik, G.; Carreira, E. M.; Wagner, B.;
Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K. J.
Med. Chem. 2010, 53, 3227.
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T.; Inoue, M. Chem. Rev. 2015 DOI: 10.1021/cr500716f.
(25) Other diastereomers of the alcohol substrate were unsuccessful
in the cyclization reaction.
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Pd(IV) intermediates, see: (a) Liu, G.; Stahl, S. S. J. Am. Chem. Soc.
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Angew. Chem. Int. Ed. 2012, 51, 3412; (c) Camasso, N. M.; Pérez-
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(27) Choong, I. C.; Ellman, J. A. J. Org. Chem. 1999, 64, 6528.
(28) (a) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261; (b)
Synthesis of Saturated Oxygenated Heterocycles I; 1 ed.; Springer-
Verlag Berlin Heidelberg, 2014.
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