A mild and versatile method for the synthesis of alkyl ethers from methoxymethyl ethers and application to the preparation of sterically crowded ethers

Article abstract of DOI:10.1002/adsc.201200290

A mild and divergent route for the synthesis of alkyl ethers from methoxymethyl (MOM) and methoxyethyl (ME) ether derivatives via pyridinium-type salt intermediates has been developed. The addition of organocuprates to the salts afforded the corresponding alkyl ethers, including highly crowded ones, in high yields even in the presence of acid- or base-sensitive functional groups. Copyright

Full text of DOI:10.1002/adsc.201200290

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DOI: 10.1002/adsc.201200290
A Mild and Versatile Method for the Synthesis of Alkyl Ethers
from Methoxymethyl Ethers and Application to the Preparation
of Sterically Crowded Ethers
Yutaka Minamitsuji,a Atsuhisa Kawaguchi,a Ozora Kubo,a Yoshifumi Ueyama,a
Tomohiro Maegawa,a and Hiromichi Fujiokaa,*
a
Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamada-oka, Suita, Osaka 565-0871, Japan
Fax : (+81)-6-6879-8229; e-mail: fujioka@phs.osaka-u.ac.jp
Received: April 7, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200290.
Abstract: A mild and divergent route for the syn-
thesis of alkyl ethers from methoxymethyl (MOM)
and methoxyethyl (ME) ether derivatives via pyri-
dinium-type salt intermediates has been developed.
The addition of organocuprates to the salts afforded
the corresponding alkyl ethers, including highly
crowded ones, in high yields even in the presence of
acid- or base-sensitive functional groups.
rates as C-nucleophiles.[7,8] Bode and co-workers have
developed an efficient method for the preparation of
alkyl ethers that utilizes methoxymethyl (MOM)
ethers or their derivatives, exemplified by hydroxamic
acid-derived acetals.[7] However, sp3 C-nucleophiles
(e.g., alkyl groups) cannot be employed in this pro-
cess. Molander and co-workers have devised a direct
route for alkyl ether formation in heterocyclic sub-
strates that involves treatment of alkoxytrifluorobo-
Keywords: alkyl ethers; alkylation; crowded ethers;
nucleophilic substitution; organocuprates; pyridini-
um-type salts
rates in the presence of Mn
amounts of the Mn(III) reagent are needed and sub-
(OTf)3.[8] However, excess
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
strate limitations exist in this process. Therefore, the
discovery of new, versatile and efficient procedures
for alkyl ether synthesis remains a worthy goal in or-
ganic chemistry. Below, we describe the results of an
investigation that led to the development of a mild
Alkyl ethers are fundamentally important compounds and divergent route for the synthesis of alkyl ethers.
in organic chemistry that are often chemically and In a prior effort, we devised a mild and efficient
metabolically stable.[1] Ether moieties are also found method for the deprotection of MOM ethers.[9] This
in many pharmaceutical agents and biologically active reaction [Scheme 1, Eq. (1)], which proceeds under
compounds.[2] Therefore, the development of efficient mild conditions via a substituted pyridinium salt inter-
methods to prepare ethers is of general interest. The mediate, is promoted by treatment of the ethers with
Williamson ether synthesis protocol, involving reac- TMSOTf and 2,2’-bipyridyl. The key feature of the re-
tions between an alkoxide and alkyl halide, is perhaps action is its high chemoselectivity, which enables the
the best known of the traditional methods used for survival of various functional groups including halo-
this purpose.[3,4] However, this protocol has critical gens, esters, amides, and acid-labile trityl (Tr) and
limitations associated with the use of strongly basic tert-butyldimethylsilyl (TBS) ethers.
nucleophiles. Furthermore, Williamson ether synthe-
An analysis of the mechanistic route followed in
ses are sensitive to steric hindrance in alkyl halide the MOM ether deprotection reaction led to the pro-
substrates and, as a result, cannot be applied to prep- posal that appropriate C-nucleophiles might partici-
aration of the crowded ethers. In order to overcome pate in reactions with the pyridinium salt intermedi-
these drawbacks, various alternative methods for the ate and, if so, the overall process would serve as
preparation of alkyl ethers have been developed.[5,6] a mild and highly general method for the preparation
However, many of these methods often involve harsh of alkyl ethers [Scheme 1, Eq. (2)]. In order to ex-
conditions, have severe substrate limitations, or re- plore this proposal, we treated MOM ether 1a in
quire the use of complicated procedures. Recently, CH2Cl2 with a combination of TMSOTf and 2,2’-bi-
a few alkyl ether-forming reactions have been de- pyridyl under the conditions that were optimized in
scribed which utilize potassium organotrifluorobo- previous studies of the MOM ether deprotection pro-
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Scheme 1. The previously developed mild and chemoselective method for deprotection of MOM ethers [Eq. (1)] and the
new strategy for synthesis of alkyl ethers [Eq. (2)].
Table 1. Optimization of reaction conditions for the alkyl ether-forming reaction.[a]
Entry
Pyridine derivative
Reaction time [h]
Yield [%][b]
1
2
3
4
2,2’-bipyridyl
5
24
3
trace
n.r.[c]
52
2-methoxypyridine
2-(dimethylamino)pyridine
2-bromopyridine
1
58
5
2-chloropyridine
1
62
6
2-chloro-4-picoline
2-chloro-4-picoline
1
1
72
92
7[d]
[a]
Reaction conditions: MOM ether 1a was treated with pyridine derivative and TMSOTf in CH2Cl2 (0.2M) at 08C for
30 min. The C-nucleophile was then added and the resulting mixture was stirred at 08C.
Isolated yield.
No reaction.
THF was used as solvent instead of CH2Cl2.
[b]
[c]
[d]
cess. The in situ generated pyridinium salt was then Grignard reagents and CuI (Table 2). Reactions em-
reacted with 3.0 equivalents of Ph2CuMgBr (from ploying phenyl and p-tolyl cuprate were observed to
PhMgBr and stoichiometric CuI).[10] Indeed this two- produce the corresponding benzyl ethers in high
step, one-pot reaction was found to generate a trace yields (entries 1 and 2). The aryl organocuprate bear-
amount of the desired benzyl ether 2aa (Table 1, ing an electron-withdrawing fluoride substituent also
entry 1). Studies probing the efficiencies of the ether- underwent this reaction efficiently to afford the corre-
forming reaction taking place via salts derived from sponding ether (entry 3) and electron-donating group
a variety of 2-substituted pyridines[11] showed that the substituted (4-methoxy and 2,4-dimethoxy) aryl cup-
electron-donating substituted 2-methoxypyridine did rates also reacted to form the respective ethers in ex-
not promote alkyl ether formation and the process cellent yields (entries 4 and 5). Moreover, the bulky
using 2-dimethylaminopyridine gave 2aa in only mesityl, the further conjugated naphthyl, and a variety
a moderate yield (entries 2 and 3). In contrast, 2- of heteroaromatic cuprates also reacted with the pyri-
bromo- and 2-chloropyridines, both of which contain dinium salt intermediate to produce ethers in excel-
weak electron-withdrawing groups, were suitable re- lent yields (entries 6–10). The scope of this process
agents for this reaction, which yielded 2aa in better was found to include vinyl, 2-methyl-1-propenyl, and
yields (entries 4 and 5). 2-Chloro-4-picoline was found phenylethynyl cuprates, which all added to the salt to
to be the optimal pyridine for the alkyl ether-forming form the corresponding products in moderate yields
process (2aa formed in 72% yield, entry 6). Further- (entries 11–13). In order to extend the range of this
more, replacement of CH2Cl2 by THF as solvent was process, we explored reactions of sp3 carbon-bonded
found to lead to a further increase in the efficiency of organocuprates, such as ethyl, trimethylsilylmethyl,
this process (entry 7).[12,13]
benzyl, isopropyl, cyclohexyl, and tert-butyl cuprates.
The generality of the ether-forming reaction, car- The results demonstrated that, in each case, a reaction
ried out under the optimized conditions described occurred to form the alkyl ether product in an excel-
above, was explored using several different cuprates lent yield (entries 14–19). This observation contrasts
(R2CuMgX) derived from the corresponding with those made earlier, which showed that Bodeꢁs
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A Mild and Versatile Method for the Synthesis of Alkyl Ethers from Methoxymethyl Ethers
Table 2. Reactions of the pyridinium salt formed from MOM ether 1a with various organocuprates.[a]
Entry
R
2a
Reaction time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Ph
p-MeC6H4
p-FC6H4
p-MeOC6H4
2,4-(MeO)2C6H3
2,4,6-Me3C6H2
2-naphthyl
2-thienyl
2-benzothienyl
2-furyl
2aa
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
2aj
2ak
2al
2am
2an
2ao
2ap
2aq
2ar
2as
1
1
1
3
2
2
1
1
1
1
2
2
2
3
2
2
1
2
1
92
90
92
88
84
87
62
94
91
92
73
68
68
75
82
73
81
75
90
9
10
11
12
13
14
15
16
17
18
19
vinyl
À
A
ꢀ À
Ph-C C
Et
TMSCH2
Bn
i-Pr
cyclohexyl
t-Bu
[a]
Reaction conditions: MOM ether 1a was treated with 2-chloro-4-picoline (3.0 equiv.) and TMSOTf (2.0 equiv.) in THF
(0.2M) at 08C for 30 min. Organocuprate (3.0 equiv.) was then added and the resulting mixture was stirred at 08C.
Isolated yield.
[b]
method could not be applied to sp3 C-nucleophiles. It dary or primary MOM ethers, 1j or 1k, respectively
should be emphasized that bulky tert-butyl ethers that (entries 9–11).
are typically difficult to generate by using other meth-
ods could be prepared in excellent yields using the or- context of more crowded a,a’-disubstituted and multi-
ganocuprate-pyridinium salt protocol (entry 19). substituted ethers, which are difficult to synthesize by
The new ether-forming process was next probed in
Further investigations revealed that various types using the Williamson ether synthesis method. For ex-
of MOM ethers served as starting materials in the ample, the highly substituted ether 4a, which could
new ether-forming process (Table 3). For example, re- not be generated using the classical method owing to
action of (t-Bu)2CuMgCl with the terminal olefin con- steric hindrance encountered in reactions between the
taining MOM ether 1b-derived salt took place appropriate alkoxide and halides or triflates
smoothly to produce the corresponding ether product [Scheme 2, Eq. (4)], was efficiently generated by reac-
2b (entry 2). The results of this effort also showed tion of the methoxyethyl (ME) ether 3a utilizing
that the process displayed a high chemoselectivity in 2,4,6-collidine in place of 2-chloro-4-picoline followed
that a host of functional groups, such as methyl ester, by treatment with (t-Bu)2CuMgCl [Scheme 2, Eq.
acetoxy (AcO), benzoyloxy (BzO), benzyloxy (BnO), (3)].[14]
tert-butyldimethylsilyloxy (TBSO), and trityloxy
Table 4 contains a summary of results obtained in
(TrO) groups, were unreactive under the reaction con- the effort of exploring applications of the new
ditions (entries 3–8). It is especially noteworthy that method to the synthesis of several crowded ethers. In
base-labile ester moieties were not affected in this all processes, the desired alkyl ethers 4 were obtained
process (entries 3–5) because they are typically sensi- in excellent yields. In addition, tert-butyl cuprate
tive to conditions employed in the Williamson ether could also be used in these processes to generate the
synthesis protocol. Furthermore, Lewis and Brønsted desired alkyl ethers (entries 1, 4, and 5).[15]
acid sensitive TBS and Tr ethers tolerated the condi-
Further investigations revealed that catalytic
tions used in new ether-forming reaction (entries 7 amounts of CuI were as effective as stoichiometric
and 8). Finally, this study showed that the method amounts in promoting reactions that afforded alkyl
could be used to prepare the bulky ethers 2i–k, start- ethers 2c, 2h, and 4c in high yields, even in cases (e.g.,
ing with the 1-adamantanol derivative 1i and secon- 2c, 2h) where methyl ether and trityl ether moieties
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Table 3. Reactions of various MOM ethers 1 with (t-Bu)2CuMgCl.[a]
Entry
MOM ether (1)
Alkyl ether (2)
Yield [%][b]
1
2
1a
1b
2as
2b
90
90
3
1c
2c
93
4
5
6
7
8
1d
1e
1f
1g
1h
R=Ac
R=Bz
R=Bn
R=TBS
R=Tr
2d
2e
2f
2g
2h
R=Ac
R=Bz
R=Bn
R=TBS
R=Tr
89
90
86
81
85
9
1i
2i
81
10
1j
2j
82
81
11
1k
2k
[a]
Reaction conditions: MOM ethers 1 were treated with 2-chloro-4-picoline (3.0 equiv.) and TMSOTf (2.0 equiv.) in THF
(0.2m) at 08C for 30 min. (t-Bu)2CuMgCl (3.0 equiv.) was then added and the resulting mixture was stirred at 08C.
Isolated yield.
[b]
Scheme 2. Synthesis of crowded ether 4a using the new method and the Williamson ether synthesis protocol.
were present in the substrates. Moreover, utilization proceeding through addition of organocuprate to the
of substrate 1c on a gram-scale was successful in this corresponding pyridinium salt, take place efficiently
reaction to afford the corresponding alkyl ether 2c in to produce sterically crowded alkyl ethers bearing
high yield (Scheme 3).
various functional groups. Significantly, these ether
In summary, the current work has led to the devel- targets could not be generated using the classical Wil-
opment of a mild and versatile method for the synthe- liamson ether synthesis or the Bode or Molander pro-
sis of alkyl ethers. The observations made in this tocols.
study show that reactions of MOM and ME ethers,
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A Mild and Versatile Method for the Synthesis of Alkyl Ethers from Methoxymethyl Ethers
Table 4. Synthesis of crowded ethers 4 using several ME ethers 3 and organocuprates.[a]
Entry
1
ME ether (3)
R
Alkyl ether (4)
Yield [%][b]
83
3a
3a
t-Bu
4a
4b
2
3
4
Cy
Ph
84
88
3a
4c
3b
3c
t-Bu
t-Bu
4d
4e
83
84
5[c]
[a]
Reaction conditions: acetals 3 were treated with 2,4,6-collidine (3.0 equiv.) and TMSOTf (2.0 equiv.) in THF (0.2M) at
08C for 30 min. Organocuprate (3.0 equiv.) was then added and the resulting mixture was stirred at 08C.
Isolated yield.
The reaction was carried out at À308C to À208C.
[b]
[c]
Scheme 3. Alkyl ether-forming reactions by use of a catalytic amount of CuI.
Experimental Section
CuI (149.7 mg, 0.786 mmol) in THF (2.8 mL), was added to
the mixture by cannula, and the resulting mixture was vigo-
rously stirred at 08C until all polar components had disap-
peared by TLC. The reaction mixture was then diluted with
saturated aqueous NH4Cl, stirred for 20 min at 08C, and ex-
tracted with CH2Cl2. The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated
under vacuum, giving a residue that was subjected to flash
SiO2 column chromatography (n-hexane/benzene=1/1) to
give alkyl ether 2aa as a colorless oil; yield: 61.0 mg (92%).
See the Supporting Information for characterization details.
Representative Procedure for the Conversion of
MOM Ether 1a to Ether 2aa
TMSOTf (95 mL, 0.524 mmol) was added dropwise to a solu-
tion of MOM ether 1a (54.5 mg, 0.262 mmol) and 2-chloro-
4-picoline (86 mL, 0.786 mmol) in THF (1.2 mL, 0.2M) at
08C under argon. The reaction mixture was stirred at 08C
for 30 min, at which time 1a had disappeared (by TLC). A
solution of Ph2CuMgBr, prepared by reaction of phenylmag-
nesium bromide (1.10M in THF, 1.43 mL, 1.57 mmol) and
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Acknowledgements
[7] a) T. A. Mitchell, J. W. Bode, J. Am. Chem. Soc. 2009,
131, 18057–18058; b) C.-V. T. Vo, T. A. Mitchell, J. W.
Bode, J. Am. Chem. Soc. 2011, 133, 14082–14089.
[8] G. A. Molander, V. Colombel, V. A. Braz, Org. Lett.
2011, 13, 1852–1855.
[9] a) H. Fujioka, O. Kubo, K. Senami, Y. Minamitsuji, T.
Maegawa, Chem. Commun. 2009, 4429–4431; b) H. Fu-
jioka, Y. Minamitsuji, O. Kubo, K. Senami, T. Maega-
wa, Tetrahedron 2011, 67, 2949–2960.
[10] In our previous work, direct alkylation to acetals, orga-
nocuprates derived from Grignard reagents was effec-
tive, see: H. Fujioka, T. Okitsu, Y. Sawama, T. Ohnaka,
Y. Kita, Synlett 2006, 3077–3080.
This work was financially supported by the Hoansha Foun-
dation, the Uehara Memorial Foundation, and a Grant-in-
Aid for scientific research from the Ministry of Education,
Culture, Sports, Sciences and Technology of Japan.
References
[1] P. G. M. Wuts, T. W. Greene, Protective Groups in Or-
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[2] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54,
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[11] In the deprotection of MOM ethers, the salt from 2-
substituted pyridines was subjected to hydrolysis, but
the salt from 2,4,6-collidine did not undergo the hydrol-
ysis, see ref.[9]
[12] PhLi or PhMgBr caused decomposition of pyridinium
salt intermediate and no reaction occurred under treat-
ment with Ph2Zn.
[3] a) J. March, Marchꢀs Advanced Organic Chemistry, Re-
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cited therein.
[13] As described later (Scheme 3), the reaction with a cata-
lytic amount of CuI produced an about 10% lower
yield than the stoichiometric reaction. Therefore, we
decided to use the stoichiometric reaction as our opti-
mized conditions. Reduction of organocuprate also de-
creased the yield of 2aa (89% with 2.0 equiv. of
Ph2CuMgBr; 83% with 1.5 equiv. of Ph2CuMgBr).
[14] In our previous work, we have disclosed that 2,4,6-colli-
dine was an efficient base in the mild deprotection of
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[15] When the reaction of 3c was conducted at 08C, b-elimi-
nation occurred as a side reaction and a decreased
yield of 4e (62%) was obtained.
[6] For a review of acetal-based ether synthesis, see: T.
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A Mild and Versatile Method for the Synthesis of Alkyl
Ethers from Methoxymethyl Ethers and Application to the
Preparation of Sterically Crowded Ethers
7
Adv. Synth. Catal. 2012, 354, 1 – 7
Yutaka Minamitsuji, Atsuhisa Kawaguchi, Ozora Kubo,
Yoshifumi Ueyama, Tomohiro Maegawa,
Hiromichi Fujioka*
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