Enantioselective allylic etherification: Selective coupling of two unactivated alcohols

Article abstract of DOI:10.1002/anie.201007716

An Ir(P,alkene) complex catalyzes the enantioselective allylic etherification of unactivated secondary allylic alcohols. Useful levels of enantioselectivity and yield were achieved with this operationally easy and robust protocol. Initial kinetic studies indicate a significant rate difference for the substrate enantiomers, allowing for a resolution process. cod=1,5-cyclooctadiene Copyright

Full text of DOI:10.1002/anie.201007716

Communications
DOI: 10.1002/anie.201007716
Allylic Etherification
Enantioselective Allylic Etherification: Selective Coupling of Two
Unactivated Alcohols**
Markus Roggen and Erick M. Carreira*
Enantioselective allylic etherification reactions provide effi-
cient methods for the synthesis of enantiomerically enriched,
value-added building blocks.[1] Palladium,[2] ruthenium,[3] and
iridium[4] catalysts have been developed for this transforma-
tion. Iridium and rhodium catalysts are particularly promising
because they enable the synthesis of enantioenriched
branched products incorporating monosubstituted olefins.
The enantioselective approach employing Ir has been docu-
mented by the groups of Alexakis, Hartwig, and Helmchen,
and the Rh-catalyzed enantiospecific substitution of optically
enriched, branched allylic carbonates has been developed by
the group of Evans.[5] For the preparation of ethers, all of the
methods to date have employed activated electrophiles, for
example carbonates or esters, and activated nucleophiles in
the form of alkoxides. Optically active allylic ethers may also
be prepared through Ir-catalyzed kinetic resolution of race-
mic allylic alcohol derivatives.[6] Herein, we report the direct,
enantioselective substitution of unactivated, branched allylic
alcohols to afford branched allylic ethers by a dynamic kinetic
resolution process (DKR; Scheme 1).[7] We also document
kinetic data on the relative rates of substitution for two
enantiomeric alcohols, which also permits kinetic resolution
of the substrate in a divergent fashion to provide access to
alcohol and ether in enantiopure form. The process is robust,
as it can be conducted with technical-grade solvent, with an
open flask, employing in situ formed catalyst. To the best of
our knowledge, no enantioselective iridium-catalyzed allylic
etherification, employing branched substrates, has been
reported to date.[6b,8]
In previous work we disclosed the Ir-catalyzed enantio-
specific allylic substitution of branched allylic alcohols with
sulfamic acid (NH3SO3) to form primary allylic amines with
high stereospecificity.[9] We have subsequently become inter-
ested in expanding the salient features of this process to other
nucleophiles. Specifically, we sought the development of a
process that would enable direct substitution of the allylic
alcohol substrate by an alcohol nucleophile. It is important to
note that the processes reported in the literature for the
metal-catalyzed preparation of ethers require activated allylic
electrophiles (carbonates, esters, and chlorides) and prescribe
the use of alcohols as nucleophiles when subjected to
prior[4b–d] (ROM: M = Li, Na, Cu, and (RO)2Zn) or in
situ[4e–g] (ROH + K3PO4 or guanidine or Et3N) activation
as the corresponding alkoxides.
The basis of our investigation was the observation of a
side reaction involving condensation of phenyl vinyl carbinol
(1a) to the corresponding symmetrical ether in the presence
of Brønsted acids and Ir complexes incorporating the P,alkene
ligand 3. This suggested the possibility of fashioning a process
for the preparation of unsymmetrical ethers derived from the
condensation of allylic and aliphatic alcohols. We then
proceeded to screen a range of acid additives for activation
of the allylic alcohol substrate in the presence of a second
alcohol. The results indicate that Brønsted acids with pKa
values in the range of 3.4 to 3.9 (aq) were found to be
competent promoters for a range of aliphatic alcohols. The
use of weaker acids, such as acetic and benzoic acid, led to
negligible conversion (Table 1, entries 1 and 2), and the use of
stronger acids, such as camphorsulfonic acid, resulted in
decomposition of starting material (entry 3).
For Brønsted acids within the acceptable pKa window,
subtle structural effects on reaction yield and enantioselec-
tivity were observed. Thus, formic acid (pKa 3.8) performed
less effectively than m-chlorobenzoic acid (pKa 3.8) although
both have the same pKa (entries 6 and 8). In this respect, p-
nitrobenzoic acid (pKa 3.4), a stronger acid than formic acid,
performed almost identically (entry 7). 1,2-Dichloroethane
was identified as superior to toluene or tetrahydrofuran
(entries 4–6) and optimal as the solvent for the allylic
etherification. We have noted that the use of 5 equivalents
of aliphatic alcohol co-reactant precludes the formation of the
symmetrical diallyl ether and, consequently, provides good
yields of the corresponding unsymmetrical allyl alkyl ethers.
Interestingly, the use of more than 10 equivalents of alcohol
Scheme 1. Direct, enantioselective substitution of unactivated,
branched allylic alcohols.
[*] M. Roggen, Prof. Dr. E. M. Carreira
ETH Zꢀrich, HCI H335
8093 Zꢀrich (Switzerland)
Fax: (+41)44-632-1328
E-mail: carreira@org.chem.ethz
[**] We thank Dr. Marc-Olivier Ebert and Dr. Martin Klussmann for help
with the kinetic studies. M.R. acknowledges a Stipendienfonds
Schweizerische Chemische Industrie (SSCI) fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007716.
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Angew. Chem. Int. Ed. 2011, 50, 5568 –5571

Table 1: Optimization of allylic etherification[a]
(Table 2, 2a), other common alcohols, such as methanol (2b),
ethanol (2c), and 2-propanol (2d), serve as nucleophiles in
the reaction of rac-1a. The corresponding ether derived from
Table 2: Stereoselective allylic etherification.[a]
Entry
Acid
Solvent
Conv (%)[b]
e.r.
1
2
3
4
5
6
7
8
9
MeCO2H
toluene
toluene
toluene
toluene
THF
<10
0
0
60
50
73
74
>95
0
–
–
–
PhCO2H
CSA[c]
HCO2H
HCO2H
HCO2H
p-NO2C6H4CO2H
m-ClC6H4CO2H
m-ClC6H4CO2H
92.5:7.5
81.5:18.5
87.0:13.0
89.5:10.5
98.5:1.5
–
DCE
DCE
DCE
BnOH, DCE[d]
[a] General procedure: 1a (0.10 mmol, 1.0 equiv), BnOH (5.0 equiv),
[{Ir(cod)Cl}2] (2.5 mol%), 3 (10 mol%), acid (0.50 equiv), solvent
1
(0.20 mL). [b] Determined by H NMR spectroscopy. [c] CSA=camphor
sulfonic acid. [d] BnOH (0.2 mL, 20 equiv) and DCE as cosolvent
(0.05 mL). DCE=1,2-dichloroethane.
co-reactant inhibits the reaction (entry 9). The product of
1
linear substitution was not observed, as assayed by H NMR
spectroscopy. It is important to note that the allylic ether-
ification could be performed under ambient atmosphere with
technical-grade solvents with minimal loss in enantioselectiv-
ity (Scheme 2), which is a testament to the robustness of the
iridium catalyst.[9a]
[a] Yield of isolated product after full consumption of starting material 1;
e.r. values determined by SFC on a chiral phase; absolute configuration
determined by comparison with [a]D of known compounds.[10]
p-methoxy benzyl alcohol was obtained in 97% yield and an
e.r. of 99.0:1.0 (2e). It is important to note that the yields
listed in Table 2 correspond to the yields of products isolated
at full consumption, or conversion, of starting material. Thus,
the reaction that leads to the formation of product 2k was
allowed to proceed until all alcohol starting material had been
observed to be consumed.
Using benzyl alcohol as the common nucleophile, it was
found that aromatic (2 f, 2g), heteroaromatic (2j, 2k), and
electron-deficient (2l) allylic alcohols were competent sub-
strates. In general, however, the highest yields and enantio-
selectivities were achieved in reactions utilizing arene vinyl
carbinols. Interestingly, rac-ethyl 3-hydroxypent-4-enoate
serves as a substrate and affords ether 2p. To the best of
our knowledge such allylic alcohols have not been inves-
tigated as substrates before and their use in the allylic
etherification reaction provides an alternate direct route to
protected acetate aldol adducts of acrolein.
Scheme 2. Substitution reactions in techical-grade solvent with catalyst
prepared in situ (top) and with preformed and purified catalyst
[Ir(3)2Cl] (bottom).
Moreover, the Ir(3)2Cl complex prepared and crystallized
beforehand was found to be catalytically competent: its use in
the allylic etherification provided product in identical yield
and enantioselectivity, as that of reactions in which
[{Ir(cod)Cl}2] (cod = 1,5-cyclooctadiene) and ligand (3) were
added sequentially to the reaction vessel prior to addition of
substrates (Scheme 2; compare Table 1, entry 8). This result
also suggests that the cod ligand is not a participant in the
active catalyst. The reaction time can be shortened by heating
the reaction mixture to 808C, which leads to completion of
the reaction in 5 hours but with decreased enantioselectivity
(e.r.: 80:20).[10]
In order to demonstrate that both substrate enantiomers
are transformed to the same ether enantiomer, highly
enantioenriched samples of either (R)- or (S)-1a were
separately subjected to the catalytic etherification reaction
conditions as described above. (S)-2a was formed in
> 99.5:0.5 e.r. from (S)-1a and in 97.0:3.0 e.r. from (R)-1a
With the optimal conditions at hand (Table 1, entry 9) the
substrate scope of the allylic etherification reaction was
investigated. A variety of both aliphatic and allylic alcohol
substrates were evaluated. In addition to benzyl alcohol
1
(Figure 1). When the reactions were monitored by H NMR
spectroscopy, it was found that the rate for the reaction of (S)-
1a exceeds that for the reaction using (R)-1a.
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Communications
Additional studies are underway, and results will be reported
as they become available.
Experimental Section
A round-bottom flask under argon was charged with [{Ir(cod)Cl}2]
(8.40 mg, 13.0 mmol, 2.50 mol%), ligand
3 (25.4 mg, 50.0 mmol,
10.0 mol%), and m-chlorobenzoic acid (39.1 mg, 250 mmol,
0.50 equiv). Dichloroethane (1.00 mL, 0.5m with respect to allylic
alcohol) was added, and the reaction mixture was stirred at 238C for
15 min. Benzyl alcohol (260 mL, 2.50 mmol, 5.00 equiv) was added by
syringe, followed by allylic alcohol 1a (67.1 mg, 0.500 mmol,
1.00 equiv). The resulting reaction mixture was stirred at 508C for
1 day. The reaction mixture was washed with sodium carbonate
(10.0 mL). The aqueous layer was extracted with dichloromethane
(2 ꢀ 5.00 mL), and the combined organic fractions dried with magne-
sium sulfate. The solvent was removed in vacuo, and purification of
the residue by flash chromatography on silica gel using hexanes/ethyl
acetate as eluent afforded allylic ether 2a as a clear oil in 98% yield
Figure 1. Profile for the allylic etherification for both substrate enantio-
1
*
mers, (S)-1a (+) and (R)-1a ( ), monitored by H NMR spectroscopy
at 528C. Full conversion of (R)-1a was observed after 1 day.[10]
(110 mg, 0.49 mmol). e.r.: 98.5:1.5 (OJ-H; flow: 3.00 mLminꢀ1
;
24.5 min (major), 26.4 min (minor); 100% CO2 at 100 bar, 258C)
22:9
½aꢁD ¼ꢀ2.19 (c = 0.1 in CHCl3).
The observed rate difference prompted us to investigate
the possible kinetic resolution of the allylic alcohol substra-
te.[8c] At room temperature the allylic alcohol rac-1a was
successfully resolved to its R enantiomer by selective allylic
etherification of (S)-1a with benzyl alcohol following the
(P,alkene)Ir-catalyzed allylic etherification protocol de-
scribed (Scheme 3). The use of 5 equivalents of benzyl alcohol
as the nucleophile posed no problem to the resolution and
both products were recovered in good yield (46–48%) and
excellent enantioselectivity (e.r.: 99.5:0.5 or better).
Received: December 8, 2010
Published online: May 13, 2011
Keywords: alcohols · allylic substitution · asymmetric synthesis ·
.
homogeneous catalysis · iridium
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Scheme 3. Kinetic resolution at room temperature.
In summary, we have developed a robust enantioselective
allylic etherification reaction that employs two alcohols, with
allylic alcohols as electrophiles and commercially available
aliphatic alcohols as nucleophiles. As part of a preliminary
mechanistic study, we have noted a difference involving the
rate of the reaction of the enantiomeric substrates, as
1
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resolution of an allylic alcohol, allowing isolation of
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ability of a Brønsted acid to serve as co-catalyst. This
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