Ir(I)-catalyzed enantioselective decarboxylative allylic etherification: A general method for the asymmetric synthesis of aryl allyl ethers

Article abstract of DOI:10.1021/ol3033237

Ir(I)-catalyzed enantioselective decarboxylative allylic etherification of aryl allyl carbonates provides aryl allyl ethers. Key to the generality and high stereoselection of the reaction is the use of the intramolecular decarboxylative allylation process

Full text of DOI:10.1021/ol3033237

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ir(I)-Catalyzed Enantioselective
Decarboxylative Allylic Etherification:
A General Method for the Asymmetric
Synthesis of Aryl Allyl Ethers
Dongeun Kim, Srinivasa Reddy, Om V. Singh, Jae Seung Lee, Suk Bin Kong, and
Hyunsoo Han*
Department of Chemistry, University of Texas at San Antonio, San Antonio,
Texas 78249, United States
Hyunsoo.han@utsa.edu
Received December 4, 2012
ABSTRACT
Ir(I)-catalyzed enantioselective decarboxylative allylic etherification of aryl allyl carbonates provides aryl allyl ethers. Key to the generality and
high stereoselection of the reaction is the use of the intramolecular decarboxylative allylation process and [Ir(dbcot)Cl]2 as an Ir(I) source. Ir(I)-
catalyzed diastereoselective decarboxylative allylic etherification, combined with asymmetric aldehyde crotylation and cross metathesis, can
furnish monoprotected 2-methyl-1,3-diols (starting from simple aldehydes) with high diastereoselectivities.
Enantiomerically enriched aryl allyl ethers are valuable
in organic synthesis.1 Numerous biologically important
compounds can be accessed through aryl allyl ethers.2 Aryl
allyl ethers, particularly p-methoxylphenyl (PMP-) allyl
ethers, can also serve as an alcohol protection group.3
Moreover, the recent demonstrations of aryl-Claisen [3,3]-
sigmatropic rearrangements4 and FriedelÀCrafts type
cyclizations5 of aryl allyl ethers further attest to the im-
portance of aryl allyl ethers in organic synthesis.
transition metals such as Pd,6 Rh,7 Ru,8 and Ir.2c,9
Although these methods sometimes provided aryl allyl
ethers at synthetically useful levels of reaction yield and
stereoselectivity, they suffered from their own draw-
backs requiring (a) preformation of phenoxide anions
and proper choice of the counterions for the phenoxide
anions,2c,7,9b,9d (b) the use of nucleophiles or allylic elec-
trophiles in excess,6f,8b,9aÀ9d and/or (c) the use of optically
pure allylic electrophiles (eq 1).7,8d Furthermore, when
Despite such diverse synthetic utility, methods for the
asymmetric synthesis of aryl allyl ethers have been spor-
adically reported, and all reported asymmetric method-
ologies are based on allylation reactions catalyzed by
(6) (a) Trost, B. M.; Crawley, M. L. Chem.;Eur. J. 2004, 10, 2237.
(b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545. (c)
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815. (d) Goux,
C.; Massacret, M.; Lhoste, P.; Sinou, D. Organometallics 1995, 14, 4585.
(e) Cannon, J. S.; Olson, A. C.; Overman, L. E.; Solomon, N. S. J. Org.
Chem. 2012, 77, 1961. (f) Kirsch, S. F.; Overman, L. E.; White, N. S. Org.
Lett. 2007, 9, 911.
(7) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012.
(8) (a) Austeri, M.; Linder, D.; Lacour, J. Chem.;Eur. J. 2008, 14,
5737. (b) Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem., Int. Ed.
2008, 47, 1454. (c) Mbaye, M. D.; Renaud, J.-L.; Demerseman, B.;
Bruneau, C. Chem. Commun. 2004, 1870. (d) Trost, B. M.; Fraisse, P. L.;
Ball, Z. T. Angew. Chem., Int. Ed. 2002, 41, 1059.
(1) (a) Trost, B. M.; Crawley, M. L. Top. Organomet. Chem. 2011, 38,
321. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(2) (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(b) Clive, D. L. J.; Stoffman, E. J. L. Org. Biol. Chem. 2008, 6, 1831. (c)
He, H.; Ye, K.-Y.; Wu, Q.-F.; Dai, L.-X.; You, S. L. Adv. Synth. Catal.
2012, 354, 1084. (d) Kompis, I. M.; Islam, K.; Then, R. L. Chem. Rev.
2005, 105, 593.
(3) Qin, D.; Byun, H.-S.; Bittman, R. J. Am. Chem. Soc. 1999, 121,
662.
(4) Ramadhar, T. R.; Kawakami, J.-I.; Lough, A. J.; Batey, R. A.
Org. Lett. 2010, 12, 4446.
(5) Medeiros, M. R.; Narayan, R. S.; McDougal, N. T.; Schaus, S. E.;
(9) (a) Stanley, L. M.; Bai, C.; Ueda, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2010, 132, 8918. (b) Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett.
2005, 7, 1093. (c) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M.
J. Am. Chem. Soc. 2004, 126, 1628. (d) Lopez, F.; Ohmura, T.; Hartwig,
J. F. J. Am. Chem. Soc. 2003, 125, 3426.
Porco, J. A., Jr. Org. Lett. 2010, 12, 3222.
r
10.1021/ol3033237
XXXX American Chemical Society

linear allylic electrophiles were used, relatively modest regio-
and enantioselectivities were often observed,6b,6d,8a,8c and the
scope of allylic electrophiles was limited.6f,8a,8c Particularly
notable in the context of the current work was that only one
straight chain aliphatic allylic substrate was used in Ir(I)-
catalyzed intermolecular allylic etherification of linear
allylic carbonates with phenoxides, and more synthetically
useful aliphatic substrates with branched alkyl groups were
not reported.2c,9d Thus, a general methodology for the
asymmetric synthesis of aryl allyl ethers has not been
developed. Herein, we describe Ir-catalyzed enantioselective
decarboxylative allylic etherification as a general method for
the asymmetric synthesis of aryl allyl ethers, eliminating all
the previous limitations (eqs 1 and 2).8a,10,11
Table 1. Ir(I)-Catalyzed Enantioselective Decarboxylative
Allylic Etherification of Aryl Allyl Carbonates 1a
yield
ee of
entry
RÀ
R1À
2:3c
[%]b
2 [%]d
1
n-Pr
Ph
H (a)
H (b)
70
72
80
85
78
80
84
85
72
70
70
70
75
80
70
70
80
78
92:08
>99:01
94:06
86
94
92
>99
93
97
95
nd
89
98
93
>99
94
96
74
80
75
76
2
3
n-Pr
Ph
4-OMe (c)
4-OMe (d)
2-OMe (e)
2-OMe (f)
3,4-(OMe)2 (g)
3,4-(OMe)2 (h)
4-Me (i)
4
>99:01
95:05
5
n-Pr
Ph
6
>99:01
97:03
7
n-Pr
Ph
8
>99:01
94:06
9
n-Pr
Ph
10
11
12
13
14
15
16
17
18
4-Me (j)
>99:01
94:06
n-Pr
Ph
2-Me (k)
2-Me (I)
>99:01
98:02
n-Pr
Ph
2,6-(Me)2 (m)
2,6-(Me)2 (n)
4-CI (o)
>99:01
89:11
n-Pr
Ph
4-CI (p)
97:03
n-Pr
Ph
4-Br (q)
89:11
We recently reported the first Ir(I)-catalyzed enantiose-
lective decarboxylative allylic amidation of benzyl allyl
imidodicarboxylates by employing a catalytic system in-
volving [Ir(COD)Cl]2, phosphoramidite ligand L*, DBU,
and PS (proton sponge) in THF12 and wondered if similar
catalytic conditions would enable the corresponding en-
antioselective decarboxylative allylic etherification of aryl
allyl carbonates. Initial optimization studies were conducted
with phenyl cinnamyl carbonate and phenyl trans-2-butenyl
carbonate as a representative of aliphatic and aromatic
carbonates, respectively. After a variety of bases, phosphor-
amidite ligands, additives, and solvents were screened, the
catalytic conditions employing [Ir(COD)Cl]2 (2 mol %),
phosphoramidite ligand L* (4 mol %), and DBU (1 equiv)
in THF were determined to be optimal, and PS was not
necessary.
4-Br (r)
96:04
a All reactions were performed at 0.2 mmol scale using 2 mol %
[Ir(COD)Cl]2, 4 mol % L*, and DBU (1 equiv) in 1.5 mL of THF.
1
b Isolated yields. c Regioselectivities determined by the H NMR spec-
trum of reaction mixtures. d Enantiomeric excesses determined by chiral
HPLC.
good to excellent regio- and enantioselectivities, (b) the
position of substituents on the phenyl ring exhibited little
effect on reaction yield and stereoselectivity, and (c) electron-
donating groups showed better regio- and enantio-
selectivities than electron-withdrawing groups.13 In general,
cinnamyl (R=aromatic) carbonates gave better reac-
tion yields and stereoselectivities than trans-2-butenyl
(R=aliphatic) carbonates.
Noting that electron-donating substituents gave rise to
higher reaction yields and stereoselectivities in the above
allylation reactions and that the p-methoxyphenyl (PMP)
group can serve as a good alcohol protection group,5
the reaction scope was further explored by employing a
wide range of R-groups for the allyl part of aryl allyl
carbonates and fixing the aryl part as PMP. As shown in
Table 2, synthetically useful levels of reaction yield and
The scope of Ir-catalyzed enantioselective decarboxyla-
tive allylic etherification was studied by varying the aryl
part of aryl cinnamyl/trans-2-butenyl carbonates, and the
results are described in Table 1. It is evident that (a) both
electron-donating and -withdrawing groups worked well
to give rise to the desired branched allylation products with
(10) (a) Hartwig, J. F.; Pouy, M. J. Top. Organomet. Chem. 2011, 34,
€
169. (b) Helmchen, G.; Dahnz, A.; Duebon, P.; Schelwies, M.; Weiho-
fen, R. Chem. Commun. 2007, 675.
(11) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem.
Rev. 2011, 111, 1846.
(12) (a) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774. (b)
Singh, O. V.; Han, H. Org. Lett. 2007, 9, 4801.
(13) Strongly electron-withdrawing groups did not work well: with
4-CF3, the allylic etherification reaction proceeded with modest reaction
yield (48%) and regioselectivity (7:3), and with 4-NO2, the desired
etherification product did not form, instead cleavage of the carbonate
occurred.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Ir(I)-Catalyzed Enantioselective Decarboxylative
Allylic Etherification of PMP Allyl Carbonates 4a
Scheme 1. Ir(I)-Catalyzed Enantioselective Decarboxylative
Allylic Etherification Reactions of Allyl Carbonates 7 and 9
with a Bulky Alkyl Side Chain as well as the Corresponding
Intermolecular Versions
the active catalyst generated from [Ir(COD)Cl]2 might not
survive under elevated temperatures for prolonged reaction
times and that [Ir(dbcot)Cl]2 would generate the more robust
catalysts,14 the catalytic conditions using [Ir(dbcot)Cl]2
instead of [Ir(COD)Cl]2 were attempted for the allylic
etherification of 7. Gratifyingly, the reaction proceeded
cleanly at 60 °C to give the desired branched allylation
product 8 in 6 h with excellent reaction yield and stereo-
selectivities (Scheme 1). Remarkably, the modified cata-
lytic conditions employing [Ir(dbcot)Cl]2 enabled the
enantioselective allylic etherification of even bulkier car-
bonate 9 with the allyl part bearing a t-Bu group in 24 h.
To our knowledge, enantioselective installation of a CÀO
bond at such a neopentyl carbon by transition metal
catalyzed allylation of linear allylic substrates has never
been accomplished before.15
To assess the advantages of decarboxylative allylic
etherification over traditional intermolecular allylic etherifi-
cation, the corresponding intermolecular versions of the
above two reactions were studied under otherwise identical
conditions except that 1.5 equiv of PMPOH were externally
added to ethyl allyl carbonates 11 and 12 (Scheme 1). Similar
levels of enantio- and diastereoselectivities were observed
from these reactions, but reaction yields dropped signifi-
cantly to 32% and 20%, respectively, even after heating at
a All reactions were performed at 0.2 mmol scale using 2 mol %
[Ir(COD)Cl]2, 4 mol % L*, and DBU (1 equiv) in 1.5 mL of THF.
1
b Isolated yields. c Regioselectivities determined by the H NMR spec-
trum of reaction mixtures. d Enantiomeric excesses determined by chiral
HPLC.
stereoselectivity were obtained in all cases studied. Linear
alkyl (entry 1), branched alkyl (entry 2), and cyclic alkyl
(entry 3) groups proceeded with good to excellent regio-
and enantioselectivities, as did functionalized alkyl groups
with ether, halide, double bond, and triple bond function-
alities (entries 4À8). A variety of aryl groups with an electron-
donating or -withdrawing group (entries 9 and 11À13) also
worked well. The position of those substituents had little
effect on reaction yield and stereoselectivity, except one case
(R=2-Br-C6H4) that required elevated temperature and
proceeded with relatively modest enantioselectivity (entry
10, ee = 75%).
Encouraged by the excellent enantioselectivities ob-
served with branched aliphatic alkyl groups (entries 2
and 3 in Table 2), Ir(I)-catalyzed enantioselective decar-
boxylative allylic etherification reactions of PMP allyl
carbonates 7 and 9 with the bulkier branched alkyl groups
were studied. As shown in Scheme 1, when 7 was subjected
to the catalytic conditions, the desired allylic etherification
reaction did not occur and the starting material remained
unreacted up to 85 °C for 25 h. Based on the reasoning that
(14) Spiess, S.; Welter, C.; Frank, G.; Taquet, J.-P.; Helmchen, G.
Angew. Chem., Int. Ed. 2008, 47, 7652.
(15) In ref 9a, the Hartwig group reported that an Ir-catalyzed
intermolecular allylic etherification reaction between NaOPh and a
branched allylic benzoate in which the allyl unit is substituted with a
t-Bu group occurred at 50 °C to give the desired allyl aryl ether product.
However, when the corresponding linear allylic benzoate (which is
known to be less reactive than the branched isomer) was used, the allylic
etherification reaction did not occur.
Org. Lett., Vol. XX, No. XX, XXXX
C

higher temperatures for 24 h. These results, taken together
with those in Tables 1 and 2, demonstrate the clear adven-
tage of Ir-catalyzed enantioselective decarboxylative allylic
etherification over the intermolecular counterpart.16
Scheme 2. Asymmetric Synthesis of Monoprotected
2-Methyl-1,3-diols 18 and 19
To highlight a synthetic utility of the Ir(I)-catalyzed
decarboxylative allylic etherification, we chose to synthe-
size monoprotected2-methyl-1,3-diols, which are common
structural motifs in natural products.17,18 Asymmetric
crotylation of hydrocinnamaldehyde (13) by (R,R)-1419
followed by cross-metathesis (CM) of the resulting alkene
with 15 in the presence of HoveydaÀGrubbs secondÀ
generation catalyst 16 delivered PMP allyl carbonate 17
in 83% yield and with >25:1 E/Z selectivity (Scheme 2).20
When 17 was subjected to the catalytic conditions employing
L*, aryl allyl ether 18 was obtained in 91% yield and with
13:1 diastereoselectivity. On the other hand, the use of ent-L*
in otherwise identical conditions gave rise to the correspond-
ing diastereomer 19 in 88% yield and with >25:1 dia-
stereoselectivity. These results clearly indicate that the
stereochemical outcome of the Ir(I)-catalyzed decarboxy-
lative allylic etherification is predominantly governed by
the stereochemistry of a phosphoramidite ligand used
(reagent-controlled), and the existing chiral center has
little effect on reaction stereochemistry.
of alkyl allyl ethers,21 allylic alcohols,22 and allylic esters,23
should be able to provide a convenient synthetic tool box
for the enantioselective introduction of an allylic CÀO
bond. Also developed is a very efficient synthetic strategy
consisted of asymmetric aldehyde crotylation, CM, and
the Ir(I)-catalyzed decarboxylative allylic etherification for
the asymmetric synthesis of monoprotected 2-methyl-1,3-
diol motifs.
In summary, we have developed the Ir-catalyzed enan-
tioselective decarboxylative allylic etherification as a gen-
eralmethod for theasymmetricsynthesisof arylallylethers
and demonstrated that the substrate scope of the reaction
is greatly expanded by using [Ir(dbcot)Cl]2 as an Ir(I)
source. The method, combined with other transition metal
catalyzed allylation reactions for the asymmetric synthesis
Acknowledgment. Support by the National Science
Foundation (CHE 0911134) is greatly acknowledged.
(16) Similar advantages were observed in Pd-catalyzed allylation: (a)
€
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Trost, B. M.; Schaffner, B.; Osipov, M.; Wilton, D. A. A. Angew. Chem.,
Int. Ed. 2011, 50, 3548. (b) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem.
Soc. 2009, 131, 18343.
(17) (a) Paterson, I.; Paquet, T.; Dalby, S. M. Org. Lett. 2011, 13,
4398. (b) Paterson, I.; Razzak, M.; Anderson, E. A. Org. Lett. 2008, 10,
3295. (c) Lanners, S.; Norouzi-Arasi, H.; Salom-Roig, X. J.; Hanquet,
G. Angew. Chem., Int. Ed. 2007, 46, 7086.
(21) (a) Roggen, M.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50,
5568. (b) Ueno, S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 1928.
(c) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124, 7882.
(18) For recent synthetic approaches, see: (a) Gao, X.; Han, H.;
Krische, M. J. J. Am. Chem. Soc. 2011, 133, 12795. (b) Ichibakase, T.;
Nakajima, M. Org. Lett. 2011, 13, 1579. (c) Dorgan, P. D.; Durrani, J.;
Cases-Thomas, M. J.; Hulme, A. N. J. Org. Chem. 2010, 75, 7475. (d)
Rohr, K.; Herre, R.; Mahrwald, R. J. Org. Chem. 2009, 74, 3744. (e)
€
(22) (a) Gartner, M.; Mader, S.; Seehafer, K.; Helmchen, G. J. Am.
Chem. Soc. 2011, 133, 2072. (b) Kanbayashi, N.; Onitsuka, K. Angew.
Chem., Int. Ed. 2011, 50, 5197.
(23) (a) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1628. (b) Cannon, J. S.; Kirsch, S. F.; Overman,
L. E. J. Am. Chem. Soc. 2010, 132, 15185. (c) Takii, K.; Kanbayashi, N.;
Onitsuka, K. Chem. Commun. 2012, 48, 3872. (d) Geurts, K.; Fletcher,
S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 15572. (e) Koschker,
P.; Lumbroso, A.; Breit, B. J. Am. Chem. Soc. 2011, 133, 20746. (f)
Lumbroso, A.; Koschker, P.; Vautravers, N. R.; Breit, B. J. Am. Chem.
Soc. 2011, 133, 2386. (g) Kanbayashi, N.; Onitsuka, K. J. Am. Chem.
Soc. 2010, 132, 1206.
ꢀ
Mlynarski, J.; Rakiel, B.; Stodulski, M.; Suszczynska, A.; Frelek, J.
Chem.;Eur. J. 2006, 12, 8158. (f) Gnanadesikan, V.; Horiuchi, Y.;
Oshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7782. (g)
Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken, J. P. Angew.
Chem., Int. Ed. 2001, 40, 601.
(19) (a) Leighton, J. L. Aldrichimica Acta 2010, 43, 3. (b) Kim, H.;
Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 6517.
(20) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) Hoveyda, A. H.;
Lombardi, P. J.; O’Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc.
2009, 131, 8378. (b) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev.
2010, 110, 1746.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX