Mild synthesis of sterically congested alkyl aryl ethers

Article abstract of DOI:10.1021/acs.orglett.6b01975

An efficient and transition-metal-free method is presented to access tertiary alkyl aryl ethers by arylation of tertiary alcohols with ortho-substituted diaryliodonium salts. The scope covers cyclic and acyclic aliphatic, benzylic, allylic, and propargyli

Full text of DOI:10.1021/acs.orglett.6b01975

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Letter
pubs.acs.org/OrgLett
Mild Synthesis of Sterically Congested Alkyl Aryl Ethers
Erik Lindstedt, Elin Stridfeldt, and Berit Olofsson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: An efficient and transition-metal-free method is
presented to access tertiary alkyl aryl ethers by arylation of tertiary
alcohols with ortho-substituted diaryliodonium salts. The scope
covers cyclic and acyclic aliphatic, benzylic, allylic, and propargylic
tertiary alcohols as well as primary and secondary fluorinated
alcohols. The methodology gives access to alkyl aryl ethers of
previously unprecedented steric congestion. Furthermore, the
versatility of the developed procedure was demonstrated by arylation of the pro-drug mestranol.
he synthesis of ethers and functionalization of alcohols are
broad research areas due to the prevalent occurrence of
waste.5 Addition to alkenes is another strategy to obtain sterically
hindered alkyl aryl ethers. Such reactions require transition
metals or acidic conditions and are usually intramolecular.1a,6
Development of new methodologies is hence required to obtain
highly sterically congested aryl ethers.
T
these compound classes as both starting materials and products
in Nature and pharmaceuticals. However, traditional methods for
synthesis of alkyl aryl ethers are all associated with difficulties,
and the arylation of tertiary alcohols with electron-rich or
sterically hindered arenes to obtain highly sterically hindered
ethers is severely limited (Scheme 1a).1 Among the methods
Diaryliodonium salts are reactive, electrophilic arylation
reagents that have been utilized to arylate a wide range of
nucleophiles in recent years.7 Many developed methodologies
for O-arylation with these hypervalent iodine reagents have a
broad scope, both in terms of nucleophiles and aryl groups.7
However, the formation of alkyl aryl ethers from aliphatic
alcohols has proved problematic and sensitive to steric
hindrance.8 While primary alcohols react well, and secondary
alcohols with some limitations, there are only two reported
examples with tertiary alcohols, using an electron-withdrawing
nitro group on the diaryliodonium salt to facilitate the
reaction.8d,e Arylation of aliphatic alcohols with electron-
donating diaryliodonium salts has also been challenging and
often results in complex mixtures due to aryne formation.9
Our research group has had a long-term interest in the
synthesis and applications of diaryliodonium salts,10 and we set
out to develop a methodology that enables synthesis of sterically
congested alkyl aryl ethers by arylation of tertiary alcohols with
ortho-substituted diaryliodonium salts (Scheme 1b).
Scheme 1. Synthesis of Sterically Hindered Alkyl Aryl Ethers
As a model reaction, the arylation of tert-butoxides (t-BuOZ)
with dimesityliodonium salts (Mes2IX, 1a) to reach mesitylated
ether 2a was initially screened (Table 1). To our delight, 2a was
formed in good yield at room temperature.11 Such an electron-
rich and sterically hindered aryl group has not previously been
transferred to an aliphatic alcohol using diaryliodonium salts.12
The cation Z markedly influenced the outcome, and t-BuOLi was
considerably inferior to t-BuOK and t-BuONa (entries 1−3).
The solvent had a major impact on the reaction (entries 1, 4−7),
and the nonpolar solvent pentane was selected for further
screening (entries 7−15).
based on arylation of alcohols, SNAr reactions can be used.2 The
method tolerates sterically congested alcohols as well as ortho-
substituted arenes, but the scope is limited to arenes activated by
electron-withdrawing groups. Another approach is via aryne-type
intermediates, which generally suffer from regioselectivity issues
and the lack of bis-ortho substituent patterns.3 While some
transition-metal-catalyzed methodologies are compatible with
tertiary alcohols, the combination of such substrates with ortho-
substituted aryl groups remains difficult, and examples with bis-
ortho-substituted aryl groups are lacking.4 Furthermore, these
methods usually require high temperatures and have problems
associated with remaining traces of transition metals.
Alternatively, Mitsunobu-type reactions can be applied, which
are limited by steric bulk on the alcohol and by the formation of
Received: July 7, 2016
© XXXX American Chemical Society
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a
Table 1. Investigation of the Counterion Effect
Scheme 3. Arylation Scope
a
entry anion X t-BuOZ (equiv)
solvent
time (h) yield (%)
1
2
3
4
5
6
7
8
9
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
K, 1
toluene
toluene
toluene
TBME
THF
24
24
24
24
24
24
24
24
24
24
1
62
53
10
53
9
Na, 1
Li, 1
K, 1
K, 1
K, 1
MeCN
pentane
pentane
heptane
pentane
pentane
pentane
pentane
pentane
pentane
0
K, 1
71
62
56
73
91
85
79
60
76
Na, 1
Li, 1
Na, 1
Na, 2
Na, 2
Na, 2
Na, 2
K, 2
b
10
11
12
13
14
15
BF4
a
Conditions: Ar2IX 1 (0.5 mmol), t-BuONa (2 equiv), pentane (2.5
Br
1
b
c
mL). 5 mmol scale. Toluene, 24 h, crude NMR ratio 2.8:1 of 2e:2a.
OTs
OTf
OTf
1
d
In toluene, see ref 8d.
1
1
a
0.2 mmol scale, 0.2 M; 1H NMR yields with 1,3,5-trimethoxybenzene
b
as internal standard. at 110 °C, 0.05 M.
chemoselectively transferred the more electron-deficient aryl
group in high yield.
The same cation trend was observed in pentane (entries 7 and
8), and product formation in reactions with t-BuOLi was enabled
by increasing the temperature and decreasing the concentration
(entry 9).11 The tetrafluoroborate salt 1a-BF4 proved as efficient
with t-BuONa, providing 2a in 73% yield (entries 7 and 10).
Ether 2a was obtained in 91% yield within 1 h when 2 equiv of t-
BuONa was employed (entry 11). This efficiency was also
observed with other anions X (entries 12−13), although the
triflate salt worked best with t-BuOK (entries 14 and 15).
Presently, we have no explanation for the observed ion effects.
The chemoselectivity in reactions with unsymmetric diary-
liodonium salts was investigated with salt 1b having a
trimethoxyphenyl (TMP) ligand as “dummy group“ (Scheme
2). The reaction was performed on a 5 mmol scale without
Likewise, the 2,6-dichloro-substituted product 2d was formed
in excellent yield. To show the versatility of the reaction, we
synthesized ether 2e, carrying three different halides suitable for
further transformations, using an unsymmetric salt with a mesityl
dummy group. While Stuart and co-workers have used the
mesityl group as a dummy ligand for the arylation of secondary
alcohols,8e we obtained a separable mixture of ethers under our
reaction conditions.11 Nitro-substituted ether 2f was formed in
higher yield than with our previous methodology,8d illustrating
that the present conditions are preferable also with reactive,
electron-deficient diaryliodonium triflates.
The arylation of a range of tertiary alcohols 3 was subsequently
investigated (Scheme 4a). 2-Phenylpropan-2-ol was selected as
model substrate, and a brief screening of bases revealed that
NaHMDS was best. With this base, the mesitylated product 4a
was easily isolated in high yield, without the need for excess
reagents.11 The dichloro-substituted ether 4b was formed in
equally good yield, despite the acid-sensitive nature of this
compound. The unsymmetric, bromo-substituted salt 1c
displayed the same high degree of chemoselectivity as before,
delivering ether 4c in high yield.
Scheme 2. Large-Scale, Chemoselective Arylation
Several different alcohols were then screened. To our delight,
the highly sterically hindered substrate 1,1-diphenylethan-1-ol
smoothly delivered the ether product 4d. Reactions with
triphenylmethanol, with further increased steric congestion,
failed to give any desired product. 1-Methylcyclohexanol was
mesitylated to 4e in moderate yield with salt 1b; the isolated yield
increased to 59% using salt 1a. Furthermore, severely sterically
hindered acyclic alcohols underwent the reaction with ease,
delivering 4f,g in good yields. A tertiary allylic alcohol was also
well tolerated, delivering the mesitylated product 4h.
Propargylic alcohols are an interesting class of alcohols that
can undergo a large set of transformations. Propargyl aryl ethers
are usually synthesized by substitution reactions using a phenol
as the nucleophile.15 The formed ethers can be ring-closed to
give chromenes, which are precursors to biologically active
coumarins.16 Primary propargylic alcohols were recently arylated
with diaryliodonium salts.17
detectable transfer of the TMP group, delivering 2a in high yield
with TMP-I as the easily isolable iodoarene. Salts with the TMP
dummy group are efficiently synthesized and have previously
been reported as highly chemoselective.13 In the present
reaction, the advantage of using 1b over mesityl salt 1a resides
in the facile separation of TMP-I from the product.
The arylation scope was screened with various ortho-
substituted symmetric and unsymmetric diaryliodonium salts
with 3 h reaction time to ensure full conversion into the tert-butyl
aryl ethers 2 (Scheme 3).14 The mesitylated product 2a was
synthesized using either salt 1a or 1b, with 1b proving slightly
better. 2,6-Dimethyl product 2b was formed with similar efficacy.
Halide substituents were well tolerated, and bromo ether 2c was
efficiently obtained using an unsymmetric TMP salt (1c) that
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a
and the nitro-substituted 4n were obtained with complete
regioselectivity, highlighting that electron-deficient, unhindered
diaryliodonium salts are suitable for arylation of tertiary alcohols.
Internal alkyne substrates derived from alkynylation of ketones
were also suitable substrates, delivering 4o,p.
Scheme 4. Alcohol Scope
Having achieved the goal of developing methodology for
arylation of tertiary alcohols, we applied the optimized
conditions to primary and secondary alcohols. While benzyl
alcohol and 1-phenylethanol performed poorly, alcohols with
lower pKa were well tolerated (Scheme 4b). Trifluoroethanol was
mesitylated to give 4q and bromomesitylated to give 4r in good
yield with excellent chemoselectivity. Likewise, 2-hexafluoropro-
panol underwent the reaction smoothly, allowing efficient access
to ether 4s. Facile functionalization of this fluorinated substrate
class could be of high interest, for example, in the pharmaceutical
industry.
Derivatization of complex alcohols provides novel products
with potentially interesting biological properties. Arylation of the
pro-drug mestranol was hence undertaken as a proof of concept
of the sterical bulk tolerated in the methodology. Under the
standard reaction conditions, the mesitylated ether 4t was
isolated in 64% yield (Scheme 5).
Scheme 5. Arylation of the Pro-drug Mestranol
To conclude, transition-metal-free methodology to access
sterically hindered alkyl aryl ethers by arylation of tertiary
alcohols with ortho-substituted diaryliodonium salts has been
developed. The substrate scope includes cyclic, acyclic,
propargylic, and allylic alcohols. The methodology has been
extended to arylation of fluorinated primary and secondary
alcohols and to arylations with electron-deficient para-
substituted diaryliodonium salts. The straightforward derivatiza-
tion of the pro-drug mestranol illustrates the utility of the
presented methodology. A detailed mechanistic study of O-
arylations with diaryliodonium salts is currently ongoing in our
laboratory to understand the limitations in reactions with ortho-
unsubstituted electron-rich diaryliodonium salts.
a
Conditions: Ar2IX 1 (0.5 mmol), alcohol 3 (1 equiv), NaHMDS (1
b
equiv), pentane (2.5 mL). 1 mmol scale.
When tertiary propargylic alcohols were subjected to our
optimized conditions, the arylated products 4i−l were obtained
in high yields. The reaction could easily be scaled up to 2 mmol
with maintained yield and excellent chemoselectivity (4k).
Notably, even the highly sterically congested triisopropylphenyl
group was efficiently transferred to give product 4l in good yield.
This further demonstrates the usefulness of diaryliodonium salts
as group-transfer reagents of highly sterically hindered aryl
moieties. Protection of the alkyne was not necessary, hence
allowing for further transformations in a straightforward fashion.
Another advantage with this methodology to obtain propargyl
aryl ethers, compared to substitution reactions, is that the
stereochemistry is retained.8d,10b
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01975.
Experimental details and spectral data for novel
compounds, as well as NMR spectra of all products
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
We briefly investigated the arylation of the propargylic
alcohols with unhindered, para-substituted diaryliodonium
salts. Reactions with p-Br- and p-t-Bu-substituted salts afforded
regioisomeric mixtures, indicating that arynes were formed as
intermediates.9a,d To our delight, the CF3-substituted ether 4m
*E-mail: berit.olofsson@su.se.
Notes
The authors declare no competing financial interest.
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(12) The mesityl group has previously been used as a “dummy” ligand
(i.e., not been transferred) in arylation of alcohols; see ref 8e. In parallel
with this study, we developed the O-arylation of carbohydrates, which
chould also be mesitylated: Tolnai, G. L.; Nilsson, U. J.; Olofsson, B.
Angew. Chem., Int. Ed. 2016, DOI: 10.1002/anie.201605999.
ACKNOWLEDGMENTS
■
The Swedish Research Council (621-2011-3608 and 2015-
04404) is kindly acknowledged for financial support.
(13) (a) Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.; Olofsson, B.
Chem. - Eur. J. 2013, 19, 10334−10342. (b) Seidl, T. L.; Sundalam, S. K.;
McCullough, B.; Stuart, D. R. J. Org. Chem. 2016, 81, 1998−2009.
(14) The salts were synthesized according to: (a) Zhu, M.; Jalalian, N.;
Olofsson, B. Synlett 2008, 2008, 592−596. (b) Bielawski, M.; Aili, D.;
Olofsson, B. J. Org. Chem. 2008, 73, 4602−4607. (c) Bielawski, M.; Zhu,
M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610−2618. Bromide
salts were avoided, as competing formation of bromoarene can
complicate recycling of the formed iodoarene.
(15) (a) Banday, A. H.; Shameem, S. A.; Gupta, B. D.; Kumar, H. M. S.
Steroids 2010, 75, 801−804. (b) Nishibayashi, Y.; Milton, M. D.; Inada,
Y.; Yoshikawa, M.; Wakiji, I.; Hidai, M.; Uemura, S. Chem. - Eur. J. 2005,
11, 1433−1451. (c) Anderson, J. C.; McCarthy, R. A.; Paulin, S.; Taylor,
P. W. Bioorg. Med. Chem. Lett. 2011, 21, 6996−7000. (d) Godfrey, J. D.,
Jr; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.; Colandrea, V. J.
Tetrahedron Lett. 1994, 35, 6405−6408.
REFERENCES
■
(1) Steric hindrance is tolerated on the arene or on the alcohol, but few
reports tolerate a combination of the two: (a) Hu, N.; Li, K.; Wang, Z.;
Tang, W. Angew. Chem., Int. Ed. 2016, 55, 5044−5048. Addition of
RMgX to o-quinol acetates delivers sterically hindered ethers in
moderate yields: (b) Miller, B. J. Org. Chem. 1977, 42, 1402−1408.
(2) (a) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998,
63, 9594−9596. (b) Henderson, A. S.; Medina, S.; Bower, J. F.; Galan,
M. C. Org. Lett. 2015, 17, 4846−4849. (c) Engle, K. M.; Luo, S.-X.;
Grubbs, R. H. J. Org. Chem. 2015, 80, 4213−4220.
(3) Dong, Y.; Lipschutz, M. I.; Tilley, T. D. Org. Lett. 2016, 18, 1530−
1533.
(4) (a) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011,
50, 9943−9947. (b) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 3490−3491. (c) Altman, R. A.; Shafir, A.; Choi, A.;
Lichtor, P. A.; Buchwald, S. L. J. Org. Chem. 2008, 73, 284−286.
(d) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973−976. (e) Gowrisankar, S.; Sergeev, A. G.; Anbarasan, P.;
Spannenberg, A.; Neumann, H.; Beller, M. J. Am. Chem. Soc. 2010, 132,
11592−11598. (f) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am.
Chem. Soc. 2000, 122, 10718−10719. (g) Parrish, C. A.; Buchwald, S. L.
J. Org. Chem. 2001, 66, 2498−2500. (h) Wang, H.; Li, G.; Engle, K. M.;
Yu, J.-Q.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6774−6777.
(i) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
12203−12205.
(16) (a) Majumdar, N.; Paul, N. D.; Mandal, S.; de Bruin, B.; Wulff, W.
D. ACS Catal. 2015, 5, 2329−2366. (b) Tahtaoui, C.; Demailly, A.;
Guidemann, C.; Joyeux, C.; Schneider, P. J. Org. Chem. 2010, 75, 3781−
3785. (c) Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A.-L.; Tillequin,
́ ́
F.; Koch, M.; Pierre, A.; Guilbaud, N.; Leonce, S.; Kraus-Berthier, L.;
Rolland, Y.; Atassi, G. J. Med. Chem. 1996, 39, 4762−4766. (d) Yan, K.;
Yang, D.; Wei, W.; Wang, F.; Shuai, Y.; Li, Q.; Wang, H. J. Org. Chem.
2015, 80, 1550−1556.
(17) Sasaki, T.; Miyagi, K.; Moriyama, K.; Togo, H. Org. Lett. 2016, 18,
944−947.
(5) (a) Liu, D.; Sanow, L. P.; Zhang, C. Tetrahedron Lett. 2014, 55,
3090−3092. (b) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.;
Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551−2651. (c) Lepore, S. D.;
He, Y. J. Org. Chem. 2003, 68, 8261−8263.
(6) (a) Li, W.; Zhang, J., 4.05 Addition of HX Reagents to Alkenes,
Alkynes, and Allenes without Transition Metal. In Comprehensive
Organic Synthesis, 2nd ed.; Molander, G. A., Knochel, P., Eds.; Elsevier:
Amsterdam, 2014; Vol. 4, pp 342−391. (b) Yang, C.-G.; He, C. J. Am.
Chem. Soc. 2005, 127, 6966−6967.
(7) (a) Olofsson, B. Top. Curr. Chem. 2016, 373, 135−166. (b) Aradi,
K.; Toth, B. L.; Tolnai, G. L.; Novak, Z. Synlett 2016, 27, 1456−1485.
́ ́
(c) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052−
9070. (d) Yusubov, M. S.; Maskaev, A. V.; Zhdankin, V. V. ARKIVOC
2011, i, 370−409.
(8) (a) Lubinkowski, J. J.; Gimenez Arrieche, C.; McEwen, W. E. J. Org.
Chem. 1980, 45, 2076−2079. (b) Lubinkowski, J. J.; Knapczyk, J. W.;
Calderon, J. L.; Petit, L. R.; McEwen, W. E. J. Org. Chem. 1975, 40,
3010−3015. (c) Lindstedt, E.; Ghosh, R.; Olofsson, B. Org. Lett. 2013,
15, 6070−6073. (d) Ghosh, R.; Lindstedt, E.; Jalalian, N.; Olofsson, B.
ChemistryOpen 2014, 3, 54−57. (e) Sundalam, S. K.; Stuart, D. R. J. Org.
Chem. 2015, 80, 6456−6466.
(9) Formation of arynes from diaryliodonium salts is known; see:
(a) Wang, B.; Graskemper, J. W.; Qin, L.; DiMagno, S. G. Angew. Chem.,
Int. Ed. 2010, 49, 4079−4083. (b) Graskemper, J. W.; Wang, B.; Qin, L.;
Neumann, K. D.; DiMagno, S. G. Org. Lett. 2011, 13, 3158−3161.
(c) Ghosh, R.; Olofsson, B. Org. Lett. 2014, 16, 1830−1832. During the
preparation of this paper, the synthetic use of these aryne intermediates
was reported; see: (d) Sundalam, S. K.; Nilova, A.; Seidl, T. L.; Stuart, D.
R. Angew. Chem., Int. Ed. 2016, 55, 8431−8434. We have performed a
detailed mechanistic study of aryne formation, the results of which will
be reported shortly.
(10) (a) Ghosh, R.; Stridfeldt, E.; Olofsson, B. Chem. - Eur. J. 2014, 20,
8888−8892. (b) Jalalian, N.; Petersen, T. B.; Olofsson, B. Chem. - Eur. J.
2012, 18, 14140−14149. (c) Reitti, M.; Villo, P.; Olofsson, B. Angew.
Chem., Int. Ed. 2016, 55, 8928−8932. (d) Tinnis, F.; Stridfeldt, E.;
Lundberg, H.; Adolfsson, H.; Olofsson, B. Org. Lett. 2015, 17, 2688−
2691.
(11) See the Supporting Information for more details.
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