Copper-Catalyzed Synthesis of Hindered Ethers from α-Bromo Carbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.8b02371

A catalytic method for the synthesis of sterically hindered ethers and thioethers from α-bromo carbonyl compounds and the corresponding nucleophiles using an inexpensive Cu(I) catalytic system is reported. This facile transformation takes place at ambient temperature and does not require the exclusion of air or moisture; thus, it is well-suited for the functionalization and derivatization of complex organic molecules.

Full text of DOI:10.1021/acs.orglett.8b02371

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Synthesis of Hindered Ethers from α‑Bromo
Carbonyl Compounds
‡
Zhe Zhou,‡ Nicole Erin Behnke, and Laszlo Kurti*
́
́
̈
Department of Chemistry, Rice University BioScience Research Collaborative, 6500 Main Street, Room 380, Houston, Texas 77030,
United States
S
* Supporting Information
ABSTRACT: A catalytic method for the synthesis of
sterically hindered ethers and thioethers from α-bromo
carbonyl compounds and the corresponding nucleophiles
using an inexpensive Cu(I) catalytic system is reported. This
facile transformation takes place at ambient temperature and
does not require the exclusion of air or moisture; thus, it is
well-suited for the functionalization and derivatization of
complex organic molecules.
respectively) generally can only make ethers with at least one
he ether linkage is a ubiquitous structural motif in natural
Tproducts and active pharmaceutical ingredients. Because aryl group;5 and (D) the hydroalkoxylation of alkenes also
1
suffers from the limitation caused by steric hindrance, and most
examples of tertiary ether formation with this strategy are limited
to intramolecular examples.6
of ether’s importance and frequent occurrence, synthetic
methodologies that target ethers have seen significant advance-
ments in recent years.2 However, currently, there are still
challenges in the syntheses of certain classes of ethers, especially
those with hindered (3° or 2°) alkyl groups. A survey of the
existing synthetic strategies for ethers reveals their inadequacies
(Figure 1): (A) the Williamson ether synthesis suffers when
hindered nucleophiles or electrophiles are involved;3 (B) the
Ullmann coupling is only applicable for the synthesis of biaryl
ethers;4 (C) copper(II)- and palladium-catalyzed ether syn-
thesis (Chan−Lam coupling and Buchwald−Hartwig coupling,
Synthesizing tertiary alkyl ethers is especially difficult, and
generally requires either strongly acidic conditions or the
prolonged heating of substrates in the presence of a strong base.
Neither condition is ideal for delicate substrates that are often
found as intermediates in natural product total synthesis and
medicinal chemistry. Barton pioneered the use of aryl bismuth
reagents to form aryl ethers under Cu(II) catalysis,7 and
Mukaiyama later optimized this methodology to form aryl/
tertiary alkyl ethers using bismuth(V) reagents.8 However, the
substrate scope for these types of reactions is still quite limited
and the required aryl bismuth reagents are often difficult to
obtain. The use of diaryliodonium salts in the syntheses of
hindered ethers has also been reported,9 although currently the
transferable aryl groups are limited to either electron-deficient or
sterically hindered aromatic rings. Recently, a C−H ether-
ification reaction reported by the Warren group demonstrated a
promising new strategy in this research area.10 However, the
requirement for a large excess (20 equiv) of the alkyl coupling
partner could potentially hinder its efficient utilization. The
formation of bis-tertiary alkyl ethers remains one of the most
difficult challenges, for which no general methods are currently
available. Starting our investigation, we quickly realized that the
steric bulkiness of the tertiary alkyl groups creates a major
obstacle.
To overcome this issue, we considered the use of radicals, as
steric effects tend to have less impact on their reactivity when
compared to other reactive intermediates.11 We started our
investigation with a search for a catalytic system that can readily
Figure 1. Existing etherification methods and the initial design for
radical etherification.
Received: July 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02371
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Organic Letters
Letter
a
Table 1. Reaction Conditions Optimization for the Etherification of α-Bromo Carbonyl Compounds
entry
RBr
catalyst
additive/ligand
base
solvent
yield (%)
b
b
b
1
2
3
4
5
6
7
8
6
7
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
Co(acac)3
Fe(acac)3
PMDETA (1 equiv)
PMDETA (1 equiv)
PMDETA (1 equiv)
PMDETA (1 equiv)
PPh3 (10 mol %)
PPh3 (10 mol %)
PPh3 (10 mol %)
PPh3 (10 mol %)
PPh3 (10 mol %)
P(2-furyl)3 (10 mol %)
DPPF (10 mol %)
PCy3 (10 mol %)
none
TBABr
TBABr
TBABr
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
toluene
toluene
toluene
toluene
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
NR
NR
NR
5
24
48
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
7
b
<10
30
trace
44
9
none
10
11
12
13
14
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
CuBr·SMe2
22
87
NR
NR
c
c
PCy3 (10 mol %)
a
Reactions were conducted on a 0.2 mmol scale. Amide (1 equiv), phenol (3 equiv), catalyst (7.5 mol %), base (1.2 equiv), and ligand/additive
were mixed in 0.5 mL of solvent and stirred at rt for 4 h. Abbrevations: PMDETA = N,N,N′,N″,N″-pentamethyldiethylenetriamine, TBABr =
b
c
tetrabutylammonium bromide, DPPF = 1,1′-ferrocenediyl-bis(diphenylphosphine). The reactions were carried out at 40 °C. Significant amount
of elimination was observed.
generate tertiary alkyl radicals. In polymer science, a commonly
employed strategy is the atom transfer radical addition
polymerization (ATRAP), which generates radicals from alkyl
bromides with transition metal catalysts.12 Since its discovery in
1995, successful attempts have been made by organic chemists
to exploit this strategy in the syntheses of small molecules.13 To
the best of our knowledge, this strategy has not been used in
etherification. Herein, we report the results of our investigation.
We carried out the initial trials with fully substituted α-bromo
carboxylates (Table 1, entries 1 and 2). No ether products were
observed. We rationalized this result with the apparent lower
reactivity of alcohols and phenols compared to styrenes.13a,e
However, a small amount of the ether was obtained when amide
8a was used (Table 1, entry 4). Encouraged by this initial result,
further optimizations were carried out (Table 1).
A milder base (K3PO4) effectively promoted the nucleophilic
attack while minimizing side reactions caused by elimination
(Table 1, entry 4). A phosphine ligand drastically improved the
reaction outcome, albeit with a relatively low turnover number
(Table 1, entry 5). The reaction occurs in both polar and
nonpolar solvents, with acetonitrile being the best to achieve a
fast reaction rate at ambient temperature (Table 1, entry 6; also
see Supporting Information). Other metals (i.e., cobalt and
iron) also catalyzed the reaction, although not as efficiently as
Cu(I) (Table 1, entries 7−8). While several phosphines can
facilitate the reaction, PCy3 was found to be the most effective
(Table 1, entry 10−12). The reaction does not yield an ether
product in the absence of a ligand, and the acrylamide 8g
resulting from the elimination was observed as the only major
product (Table 1, entry 13). In the absence of copper, only a
trace amount of the ether product was detected (Table 1, entry
9). Reactions generally reached completion after 4 h, and were
conducted without the exclusion of moisture or air. A control
experiment under argon gave virtually the same results.
Interestingly, even with the optimized conditions, the reaction
still did not proceed in the absence of a secondary amide (Table
1, entry 14). These observations were generally consistent with
reports by Nishikata et al. in the context of amine synthesis.13c
Next, we explored the reaction scope with various phenols and
alcohols (Scheme 1). The conditions worked well with primary
alcohols and electron-rich phenols, and the corresponding
ethers were obtained in good to excellent yields at room
temperature. Interestingly, styrenyl olefins were unaffected
under the reaction conditions (Scheme 1, 15 and 20), which
is unexpected for the radical-based mechanism. Electron-rich
phenols worked as well as primary alcohols. Electron-neutral and
electron-deficient phenols generally gave lower yields of the
corresponding ethers (Scheme 1, 23 and 24) and very electron-
deficient phenols such as 4-nitrophenol failed to participate in
the reaction. For the amide portion of the substrates, various
arylamines were tolerated, and the electronic properties of the
aryl group did not have a significant influence on the reaction
outcomes (Scheme 1, 15a vs 15b; 17a vs 17d). Dialkyl
substitutions in the α-position of the amides were also well-
tolerated. Aside from α-bis-methyl substitution, the reaction also
worked well with carboxamides containing cyclohexane and
cyclopentane substituents. The conditions tolerated various
functional groups, and even a densely functionalized phenol
such as estrone participated in the reaction and furnished the
desired ether in an excellent isolated yield (Scheme 1, 31). It was
observed that for phenols with an ortho substituent, PPh3 is a
superior ligand (Scheme 1, 10a, 10c, and 22). For primary
alcohols, similar yields were obtained when the amount of the
alcohol coupling partner was reduced to two equivalents.
However, a significant drop in yields occurred when the number
of equivalents of phenols was reduced (see Suppporting
B
DOI: 10.1021/acs.orglett.8b02371
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secondary alcohols participated in the reaction and gave good
to excellent yields of the corresponding ethers (Scheme 1, 13−
14, 26−27, 30, and 32). Tertiary alcohols did not react at room
temperature. However, upon elevating the reaction temperature,
synthetically useful yields of the bis-tert-alkyl ethers were
obtained after 24 h (Scheme 1, 16 and 28−29). The yields
are lower than those of the less hindered nucleophiles, although
it should be noted that such transformations were unprece-
dented, and to the best of our knowledge, none of the resulting
ethers have ever been reported. Heterocyclic rings were also
well-tolerated in this reaction (Scheme 1, 25−26). The reaction
conditions’ mildness was further demonstrated with the
successful etherification of a furanose derivative bearing acid-
labile functionalities (Scheme 1, 30).
Scheme 1. Formation of Hindered Ethers from α-Bromo
Carboxamides
a
The reaction conditions’ tolerance toward a wide range of
functional groups enables the development of more efficient
routes toward medicinal chemistry targets, as demonstrated in
Scheme 2. Phosphonate 36 can be synthesized via this new route
Scheme 2. Synthesis of an Analogue of Protease Activated
Receptor-1 (PAR-1) Antagonist
to serve as a common intermediate for a series of PAR-1
antagonists, while previously, the alkene building blocks had to
be synthesized individually due to the harsh conditions required
for etherification.14
Despite being important building blocks in organic synthesis,
amides are not always ideal for further functionalization. In our
attempts, amides resisted reduction even with strong reductants
such as LiAlH4, and the reaction yields were low even after
prolonged reaction time (see SI). Therefore, this method will be
much more advantageous if it can be extended to other carbonyl
compounds. To achieve this goal, we took a closer look at the
mechanism.
Although we started this study with the assumption of a
radical-based mechanism, several of our observations do not
lend support to it. As mentioned before, no C−C bond
formation with styrenes or phenols was observed in these
reactions, whereas such side reactions should be expected from a
process that involves carbon-centered radicals.15 To probe the
reaction mechanism, further investigations were carried out
(Scheme 3). In the presence of 3 equiv of isobutylene, the
reaction proceeded normally and gave a nearly identical yield of
the ether without generating any product from isobutylene
trapping (Scheme 3, I vs II). In the presence of 3 equiv of KCN,
the reaction was greatly inhibited and only 12% yield of the ether
was obtained (Scheme 3, III). Most importantly, the reaction
a
[a] Reaction conditions: carboxamide (0.2 mmol), CuBr·SMe2 (7.5
mol %), PCy3 (10 mol %), K3PO4 (1.2 equiv), and alcohol/phenol (3
equiv) were mixed in MeCN at room temperature. [b] Reaction
performed with PPh3 instead of PCy3. [c] Reaction performed at 50
°C for 24 h. [d] Reaction performed at 80 °C for 24 h.
Information). The reaction also scaled up nicely without a
significant drop in efficiency and, in one instance, the isolated
yield increased slightly (see Scheme 1, 9a and 11a).
Next, we attempted more challenging etherifications with
sterically hindered secondary and tertiary alcohols. Most
C
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Driven by this hypothesis, we anticipated that a structurally
similar intermediate E (Scheme 3, IV) generated from
carbocyclic acids should also facilitate the etherification. This
prediction came to fruition, as initial trials yielded positive
results. After further optimization, moderate to good yields were
obtained for a variety of nucleophiles (Scheme 4).
Scheme 3. Investigation of the Mechanism
Scheme 4. Formation of Hindered (Thio)ethers from α-
a
Bromo Carboxylic Acids
did not proceed when the amide functionality was absent, an
observation that cannot be adequately explained by a
mechanistic hypothesis based on a radical process.
On the basis of these results, we propose a different
mechanism for these reactions: upon deprotonation of the
amide N−H bond, the copper(I) first coordinates to the oxygen
atom of the resulting imino-carboxylate anion (Scheme 3, IV−
A), followed by an intramolecular oxidative addition into the
tertiary C−Br bond (Scheme 3, IV−B). Ligand exchange
followed by reductive elimination generates the ether product
and completes the catalytic cycle (Scheme 3, IV−D). We
propose that the initial coordination between copper and the
amide lowers the activation barrier for oxidative addition and is
essential for the success of this reaction; therefore, a secondary
amide is required for this reaction. Indeed, etherification did not
proceed when tertiary amides were used. A cyanide anion slows
down the oxidative addition step upon coordination to copper,
thus inhibiting the reaction.16 Although it is possible that the
oxidative addition step involves a radical species (i.e., radical
oxidative insertion),17 it is unlikely that a free radical exists in a
significant concentration, given that isobutylene failed to trap
the hypothetical radical intermediate. It is noted that in one of
their latest reports, the Nishikata group also proposed an
oxidative addition/reductive elimination mechanism, although
it did not take into consideration the participation of the imino-
carboxylate.13c
a
[a] Reaction conditions A: Carboxylic acids (0.4 mmol), CuBr·SMe2
(2.5 mol %), PCy3 (3.5 mol %), K3PO4 (1.2 equiv), and alcohol/
phenol (3 equiv) were reacted in 2 mL of DCM at room temperature
for 16 h. [b] Reaction conditions B: Carboxylic acids (0.4 mmol),
CuBr·SMe2 (7.5 mol %), PCy3 (10 mol %), K3PO4 (1.2 equiv), and
alcohol/phenol (3 equiv) were reacted in a mixed solvent of 1 mL of
DCM and 1 mL of hexafluoroisopropanol (HFIP) at room
temperature for 16 h. [c] Reaction was ran according to condition
A but without Cu and ligand.
DCM was a better solvent for carboxylic acid substrates, and
lower catalyst loading to 2.5 mol % improved the reaction yields
for phenol and thiophenol nucleophiles (Scheme 4, condition
A). Initially, we experienced great difficulties attempting to
extend the scope of nucleophiles to include simple aliphatic
alcohols, as decomposition of the α-bromo acids outcompeted
the etherification under the reaction conditions. However, upon
the addition of HFIP, the side reactions were suppressed and the
yields for the ethers greatly improved. The scope of nucleophiles
was comparable to that of the amide substrates. Phenols
(Scheme 4, 41−44), primary and secondary alcohols (Scheme
4. 45−51 and 56−59) and thiophenols (Scheme 4, 52−55)
D
DOI: 10.1021/acs.orglett.8b02371
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were successfully coupled with the α-bromo acids. It was
observed that the uncatalyzed reactions between thiophenols
and α-bromo acids could proceed, albeit with much lower yields
(Scheme 4, 55). Because of the accelerated decomposition of
the carboxylic acids upon heating, we were unable to make bis-
tertiary ethers with satisfactory yields. The carboxylic acid
products provide ample opportunities for further modification,
as they can be easily converted to esters, amides, aldehydes, and
alcohols. Furthermore, these functionalized carboxylic acids can
potentially serve as coupling partners in various decarboxylative
coupling reactions.18
In conclusion, we have developed an efficient method for the
synthesis of sterically congested ethers and thioethers. This
scalable transformation proceeds at ambient temperature and is
tolerant toward air and moisture. We anticipate that this method
will benefit the field of medicinal chemistry and chemical
biology, where hindered ethers are commonly found as
structural motifs in biologically active molecules and small
molecule probes, yet no general synthetic tools have been
available for their synthesis. Currently, studies are underway to
further probe the reaction mechanism and expand the reaction
scope.
(7) Barton, D. H. R.; Bhatnagar, N. Y.; Blazejewski, J.-C.; Charpiot, B.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02371.
(9) Lindstedt, E.; Stridfeldt, E.; Olofsson, B. Org. Lett. 2016, 18,
4234−4237.
Experimental details, characterizations of compounds,
and NMR spectra (PDF)
(10) Salvador, T. K.; Arnett, C. H.; Kundu, S.; Sapiezynski, N. G.;
Bertke, J. A.; Raghibi Boroujeni, M.; Warren, T. H. J. Am. Chem. Soc.
2016, 138, 16580−16583.
AUTHOR INFORMATION
■
(11) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc.
2016, 138, 12692−12714.
Corresponding Author
*E-mail: kurti.laszlo@rice.edu.
ORCID
(12) (a) Kato, M.; Kamigaito, M.; Sawamoto, M.; Higashimura, T.
Macromolecules 1995, 28, 1721−1723. (b) Wang, J.-S.; Matyjaszewski,
K. J. Am. Chem. Soc. 1995, 117, 5614−5615.
Zhe Zhou: 0000-0003-1194-4026
(13) (a) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am.
Chem. Soc. 2013, 135, 16372−16375. (b) Nishikata, T.; Ishida, S.;
Fujimoto, R. Angew. Chem., Int. Ed. 2016, 55, 10008−10012. (c) Ishida,
S.; Takeuchi, K.; Taniyama, N.; Sunada, Y.; Nishikata, T. Angew. Chem.,
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Commun. 2017, 53, 5017−5019. (e) Gockel, S. N.; Buchanan, T. L.;
Hull, K. L. J. Am. Chem. Soc. 2018, 140, 58−61. (f) Murata, Y.;
Nishikata, T. Chem. - Eur. J. 2018, 24, 6354−6357.
́
́
Laszlo Kurti: 0000-0002-3412-5894
̈
Author Contributions
‡Z.Z. and N.E.B. contributed equally.
Funding
Rice University, National Institutes of Health (R01 GM-
114609-01), National Science Foundation (CAREER:Su-
sChEM CHE- 1546097), Robert A. Welch Foundation (Grant
C-1764), and ACS-PRF (Grant 51707-DNI1).
(14) Clasby, M. C.; Chackalamannil, S.; Czarniecki, M.; Doller, D.;
Eagen, K.; Greenlee, W. J.; Lin, Y.; Tsai, H.; Xia, Y.; Ahn, H. S.; Agans-
Fantuzzi, J.; Boykow, G.; Chintala, M.; Foster, C.; Bryant, M.; Lau, J.
Bioorg. Med. Chem. Lett. 2006, 16, 1544−8.
(15) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.;
Lei, A. Chem. Rev. 2017, 117, 9016−9085.
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(17) Jahn, U. Radicals in Transition Metal Catalyzed Reactions?
Transition Metal Catalyzed Radical Reactions? A Fruitful Interplay
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Dr. Andras Toro (Rice University & Baylor
College of Medicine) for helpful discussions.
■
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Anyway. In Radicals in Synthesis III; Heinrich, M., Gansauer, A., Eds.;
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