Palladium-Catalyzed Enantioselective Intermolecular Coupling of Phenols and Allylic Alcohols

Article abstract of DOI:10.1021/jacs.6b11486

An enantioselective intermolecular coupling of oxygen nucleophiles and allylic alcohols to give β-aryloxycarbonyl compounds is disclosed using a chiral pyridine oxazoline-ligated palladium catalyst under mild conditions. As opposed to the formation of traditional Wacker-type products, enantioselective migratory insertion is followed by β-hydride elimination toward the adjacent alcohol. Deuterium labeling experiments suggest a syn-migratory insertion of the alkene into the Pd-O bond. A broad scope of phenols, various allylic alcohols, and an alkyl hydroperoxide are viable coupling partners in this process.

Full text of DOI:10.1021/jacs.6b11486

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Communication
Palladium-Catalyzed Enantioselective Intermolecular
Cou-pling of Phenols and Allylic Alcohols
Nicholas J. Race, Cristiane Schwalm, Takayuki Nakamuro, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11486 • Publication Date (Web): 23 Nov 2016
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Palladium-Catalyzed Enantioselective Intermolecular Cou-
pling of Phenols and Allylic Alcohols
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Nicholas J. Race, Cristiane S. Schwalm, Takayuki Nakamuro and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 S 1400 E, Salt Lake City, Utah, 84112
Supporting Information Placeholder
enantioselective nucleopalladation wherein the resulting
Pd-alkyl intermediate readily undergoes decomposition
ABSTRACT: An enantioselective intermolecular
coupling of oxygen nucleophiles and allylic alcohols
to an ortho-quinone methide in lieu of β-hydride elimina-
to give β-aryloxycarbonyl compounds is disclosed
tion. Diastereoselective intermolecular addition of a se-
using a chiral pyridine oxazoline-ligated palladium
catalyst under mild conditions. As opposed to the
formation of traditional Wacker-type products, en-
antioselective migratory insertion is followed by β-
cond nucleophile then occurs to deliver the product.
Scheme 1. Wacker-type Alkene Functionaliza-
tion
hydride elimination towards the adjacent alcohol. Deu-
R1
R2
A. Pd(II)-catalyzed functionalization of alkenes
terium labeling experiments suggest
a
syn-
[Pd]
RO OR
B, Wacker process
[PdII]
Ha
R1
R2
R1
R2
+
migratory insertion of the alkene into the Pd–O
bond. A broad scope of phenols, various allylic al-
cohols, and an alkyl hydroperoxide are viable cou-
pling partners in this process.
ROH
R1 R2
OR Hb
A
Key questions: • syn or anti addition? • enantioselectivity?
• regioselectivity of β-hydride elimination?
OR
C, chiral alcohol
B. Enantioselective functionalization of alkenes with oxygen nucleophiles
(Hosokawa/Murahashi,ref 5 Hayashi/Uozumi,ref 6 Stoltzref 7
)
R2
R2
R2
H
Pd(II)/L*
oxidant
R1
HO
O
O
The addition of heteroatom nucleophiles to alkenes is
an area of great interest to the synthetic community.1
Perhaps the most extensively investigated process of
this type is the Pd(II)-catalyzed coupling of water and
alkenes, known as the Wacker reaction.2 In general, ad-
dition of oxygen nucleophiles to alkenes can proceed
through either nucleophilic addition (anti) or migratory
insertion (syn) to deliver a Pd-alkyl intermediate (A). De-
spite recent advances in Pd(II)-catalyzed alkene func-
tionalization reactions, the enantioselective coupling of
oxygen nucleophiles and alkenes remains underdevel-
oped, especially in an intermolecular setting.3,4 This is
because at the stage of A β-hydride elimination of Ha
occurs to ultimately deliver an achiral product (B,
Scheme 1A).2 In order to circumvent this innate selectivi-
ty, several strategies have been reported in which the
stereochemical information generated after nucleophilic
addition is retained in the product (Scheme 1B). The
first, described by Hosokawa and Murahashi, is an enan-
[PdII]
R1 ≠ H
R1
R1
no β-H α to oxygen
up to 98:2 er
OH Nuc
Sigmanref 10
OH
Pd0L*
O
Pd(II)/L*
oxidant
Nuc
O
O
Nuc
base
HO
up to 99:1 er
up to 10:1 dr
formation of quinone methide
C. Intermolecular enantioselective coupling of phenols and disubstituted alkenes
O
O
OH
OH
Pd(II)/PyrOx
*
+
H
R
R
1
2
3
[Pd]
Ha
favored?
O
R
OH
acidic phenol OH
promotes syn addition?
selective β-hydride
elimination of Hb?
Hb
4
In all, the two approaches described above utilize de-
signed substrates to avoid the propensity of the Pd in-
termediate to eliminate the C–H bond at the site of nu-
cleopalladation in intermediate A. To the best of our
knowledge, there have been no reports of processes,
after initial oxypalladation, where β-hydride elimination of
Hb occurs in the presence of Ha. Thus, we questioned
whether it would be possible to develop an enantioselec-
tive Pd-catalyzed intermolecular addition of an appropri-
ate oxygen nucleophile to a simple disubstituted alkene,
which avoids deleterious β-hydride elimination of Ha and
provides an enantioenriched product (C, Scheme 1A).11
tioselective
Wacker-type
cyclization
of
ortho-
(trisubstituted)allyl phenol derivatives.5 Chiral dihydrofu-
rans are generated in this reaction as the Pd-alkyl inter-
mediate, generated upon cyclization, cannot undergo β-
hydride elimination towards the oxygen by virtue of no
available C–H bonds. The enantioselectivity of this reac-
tion was significantly improved by both Hayashi and Uo-
zumi6 as well as Stoltz and coworkers who also applied
aerobic reaction conditions.7,8,9 A second, distinctly dif-
ferent, approach has been reported by our group in the
enantioselective difunctionalization of styrenes contain-
ing an ortho-phenol.10 This reaction is also initiated by
At the outset of this study, we were cognizant of two
underlying mechanistic challenges: 1) how can a site
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Journal of the American Chemical Society
Page 2 of 5
selective, mechanistically distinct oxypalladation step be trace product (<1%). Additionally, the use of other polar
1
facilitated, and as articulated above, 2) can the resultant
Pd-intermediate avoid β-hydride elimination at the newly
established C–O stereocenter? In terms of the first ques-
tion, the use of a disubstituted allylic alcohol should pro-
ceed under the requisite reaction conditions in high site
selectivity as established in both the Wacker12 and Heck
literature.13 Likely of more importance is whether the
oxy-palladation occurs via either a syn (Heck-type) or
anti (Wacker-type) addition. If both mechanisms are op-
erative, it is difficult to imagine that a chiral ligand can
impart enantioselectivity during the key C–O forming
step. Both Stoltz7a and Hayashi14 have shown that their
respective cyclization reactions occur via syn insertion of
the alkene into the Pd–O bond. However, it should be
noted that these are both intramolecular processes and
most intermolecular additions of oxygen nucleophiles are
thought to proceed through a Wacker-type anti addition.2
Therefore, in our initial evaluation of oxygen nucleo-
philes, we focused on more acidic variants to bias the
system towards a possible syn-oxypalladation.
solvents provided <5% of the desired product. A signifi-
cant increase to 20% yield occurred when the solvent
was changed to 1,2-dichloroethane and benzoquinone
(BQ) was employed as the terminal oxidant. Further im-
provements were found upon switching from cis- to
trans-2-penten-1-ol (2a), leading to desired product 3a in
41% yield and 60:40 er (entry 1, Table 1). Surprisingly, a
significant increase in enantioselectivity occurred (87:13
er) when the less bulky 2-i-PrPyrOx L-2 was employed
(entry 2) in contrast to our previous reports.15d A variety
of bases and oxidants were then examined to presuma-
bly enhance the formation of the Pd-phenoxide complex
required for a Heck-type addition (entries 2-5). As a re-
sult, Ca(OH)2 and BQ were selected for further ligand
optimization. A range of differentially substituted PyrOx
ligands were examined, which ultimately revealed 2-
PhPyrOx (L-3) furnishing product 3a in 68% yield and
93:7 er (entry 6). Decreasing the reaction temperature
resulted in a significantly reduced yield (34%) without a
commensurate increase in enantioselectivity (entry 7).
Ultimately, changing the solvent to trifluorotoluene led to
an improved 76% isolated yield and 94:6 er (entry 8).
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Concerning the second challenge, assuming the C–O
bond formation could be rendered enantioselective, it
was reasoned that the direction of β-hydride elimination
could be again influenced by the use of an allylic alcohol
as the alkene coupling partner. Specifically, after oxy-
palladation, intermediate 4 should be formed (Scheme
1C). We hypothesized that the terminal OH should ren-
der Hb in 4 more hydridic than Ha, since the phenol oxy-
gen’s lone pair is in conjugation with the aromatic ring. β-
Hydride elimination should, therefore, occur preferential-
ly with Hb akin to our efforts in relay Heck-type
reactions.15 Herein, we report the successful develop-
ment of the addition of phenols and an alkylperoxide to
allylic alcohols to form β-alkoxyaldehyde and ketone
derivatives.
Table 2. Evaluation of Allylic Alcoholsa
Pd(OTs)2(MeCN)2 (8 mol %)
OH
L-3 (10 mol %)
OH
+
R1
O
O
BQ (3 equiv), Ca(OH)2 (1 equiv)
R2
R2
3 Å MS, PhCF3 , 22 °C
1a
2 equiv
2
R1
1 equiv
3
O
O
O
O
O
O
O
O
H
Me
H
Me
H
Me
H
Me
4
3a, 76% yield
3b, 65% yield
93:7 er
3c, 71% yield
94:6 er
3d, 56% yield
90.5:9.5 er
94:6 erb
Table 1. Reaction Optimizationa
O
O
O
O
O
O
O
O
Pd(OTs)2(MeCN)2 (8 mol %)
PyrOx ligand (10 mol %)
Me
Me
H
H
TsO
H
NC
H
OH
3
3
OH
+
Me
O
O
base, oxidant
3e, 58% yield
3f, 71% yield
3g, 43% yield
3h, 48% yield
3 Å MS, solvent, rt
1a
2 equiv
2a
1 equiv
H
90.5:9.5 er
91:9 er
92:8 er
92:8 er
Me
3a
entry
ligand
base (equiv)
oxidant (equiv)
solvent
yield (%)
er
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
PhCF3
1
2
3b
4
5
6
7c
8
DTBMP (2)
DTBMP (2)
DTBMP (2)
Ca(OH)2 (1)
Ca(OH)2 (1)
Ca(OH)2 (1)
Ca(OH)2 (1)
Ca(OH)2 (1)
BQ (3)
BQ (3)
Cu(OTf)2/O2
DDQ (3)
BQ (3)
BQ (3)
BQ (3)
BQ (3)
41
53
40
0
50
68
34
79 (76)d
60:40
87:13
84:16
- -
87:13
93:7
L-1
L-2
L-2
L-2
L-2
L-3
L-3
L-3
O
O
O
O
O
O
O
O
PhthN
H
Cl
H
Me
Ph
Me Ph
3
3
3i, 33% yield
3j, 41% yield
3k, 63% yield
3l, 49% yield
93:7 er
93.5:6.5 er
96:4 er
95.5:4.5 er
a Each entry represents the isolated yield on 0.25 mmol scale. Er values were
determined by SFC and HPLC after aldehyde reduction. b 2 mmol: 50% yield, 94:6 er
93.5:6.5
94:6
With the optimal reaction conditions in hand, the scope
of allylic alcohols using phenol as the standard nucleo-
phile was examined. Increasing the length of the alkyl
group did not significantly alter the yield and er of the
corresponding aldehyde (3b-c). However, when trans-
crotyl alcohol (2d) was subjected to the reaction condi-
tions, a decrease in er was observed (3d, 90.5:9.5 er).
Methyl branching and incorporation of a phenyl group on
the alkyl chain resulted in a decrease in enantioselectivi-
ty (3e and 3f, respectively). Functional groups such as a
tosyl-protected alcohol (3g), nitrile (3h), phthalimide (3i)
and primary chloride (3j) are tolerated in this reaction
and provide the desired aldehydes in modest yield and
ligands
O
N
O
O
F3C
F3C
F3C
N
N
N
N
N
t-Bu
i-Pr
Ph
L-1
L-2
L-3
a Reaction optimization was performed on 0.2 mmol scale. Yields were determined by 1
H
NMR using an internal standard. Er values were determined by HPLC after reduction to
the corresponding alcohol. b 50 °C. c 10 °C. d Isolated yield in parentheses.
To initiate our studies, phenol (1a) and cis-2-penten-1-
ol (not shown) were selected as model substrates for
reaction discovery and optimization. Employing reaction
conditions similar to our previously reported oxidative
relay-Heck reaction (Pd(OTs)2(MeCN)2, pyridine oxazo-
line (PyrOx) ligand L-1, Cu(OTf)2, O2 and DMF)15c gave
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Journal of the American Chemical Society
good er. Two secondary allylic alcohols were also sub- oxygen nucleophiles add is highly dependent on the re-
action conditions employed.1 In order to establish the
mode of insertion (syn or anti), deuterated alkenol 2a-d2
was prepared and subjected to the standard reaction
conditions (Scheme 2). Assuming the alkene does not
dissociate during the reaction, the initially generated Pd–
C stereocenter is retained in the migration sequence.15a-b
As a result, the relative stereochemistry between the site
of phenol addition and the α-deuterium in the aldehyde
product would allow the insertion mechanism to be ra-
tionalized as either syn (cis relationship) or anti (trans
relationship, Scheme 2A). In the event, aldehyde 3a-d2
was isolated with complete diastereoselective migration
of one deuterium atom to the α-carbon (Scheme 2B). In
order to determine the relative stereochemistry between
the phenol and the α-deuterium, aldehyde 3a-d2 was
converted to chromanone 5, a common pharmacophore,
through a Pinnick oxidation/Friedel-Crafts sequence.16
Subsequent 1D nOe experiments confirmed a cis rela-
tionship, as shown on the structure 5 in Scheme 1B. This
provides strong evidence for a syn migratory insertion
pathway occurring in this reaction. Direct evidence for
syn migratory insertion into Pd–O bonds has been re-
1
2
3
4
5
6
7
8
jected to the reaction and afforded the corresponding β-
phenoxyketones 3k and 3l in good yield and excellent er
(96:4 and 95.5:4.5 respectively). Unfortunately, the anal-
ogous homo-allylic alcohols do not react effectively un-
der these conditions and only recovered phenol was
observed.
Table 3. Evaluation of Phenolsa
9
R
3
Pd(OTs)2(MeCN)2 (8 mol %)
OH
L-3 (10 mol %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
+
Me
O
O
BQ (3 equiv), Ca(OH)2 (1 equiv)
3 Å MS, PhCF3 , rt
R
1
H
2a
1 equiv
Me
2 equiv
Me
F
Cl
Br
O
O
O
O
O
O
O
O
H
H
H
H
Me
Me
Me
Me
3m, 60% yield
93.5:6.5 er
CF3
3n, 63% yield
94:6 er
3o, 57% yield
94:6 er
3p, 75% yield
94:6 er
OCF3
OBn
F
ported
by
several
groups
for
intramolecular
processes.8a,14,17 However, such evidence is compara-
tively lacking for intermolecular processes. The mecha-
nistic features of this reaction closely resemble those of
an oxidative Heck reaction but with an oxygen nucleo-
phile. The absolute stereochemistry of 5 was determined
to be (S) through [α]D comparison with the reported non-
deuterated analogue (see Supporting Information). This
is consistent with the stereochemical models proposed in
our previously reported redox-relay Heck reaction.15b
O
O
O
O
O
O
O
O
H
H
H
H
Me
Me
Me
Me
3s, 76% yieldb
3q, 61% yield
3r, 38% yield
3t, 41% yield
90.5:9.5 er
93:7 er
94:6 er
93:7 er
Me
Me
Me
t-Bu
O
O
O
O
O
O
O
O
O
H
H
H
H
Me
Me
Me
Me
3x, 55% yieldb
3u, 63% yield
3v, 89% yieldb
3w, 82% yield
Scheme 2. Mechanistic Analysis
96:4 er
94:6 er
95:5 er
90:10 er
a Each entry represents the isolated yield on 0.25 mmol scale. Er values were determined
by SFC and HPLC after aldehyde reduction. b 1,2-Dichloroethane as solvent.
A. Rationalization of different insertion mechanisms
[Pd]
[Pd]
[Pd]
[Pd]
PhOH
PhOH
Et
PhO
OH
Et
PhO
OH
Et
OH
The enantioselectivity of this reaction is, for the most
part, unaffected by differentially substituted phenols,
containing both electron-withdrawing and donating
groups. Fluoride-, chloride- and bromide-substituted
phenols afford the corresponding aldehydes (3n-p) in
good yield (57 – 75%) and enantioselectivity (94:6 er.).
Additionally, electron-deficient 4-(CF3)-phenol (1q) deliv-
ered aldehyde 3p in 53% yield and 93:7 er, while 4-
(OCF3)-phenol (1r) produced aldehyde 3r in 94:6 er,
albeit in 38% yield. Electron-donating 4-benzyl ether 1s
also works well under these reaction conditions, provid-
ing product 3s in 76% yield and 93:7 er. The reaction
endures ortho-substituted phenols (1t) with a moderate
decrease in yield and enantioselectivity (3t, 41% yield,
91:9 er). A variety of differentially alkyl substituted phe-
nols were also evaluated and afforded the desired prod-
ucts in excellent yields and er (3u-w). Finally, 3-
acetylphenol (1x) furnished product 3x in 55% yield and
90:10 er. It should be noted that phenols that were not
soluble in trifluorotoluene (1s, 1v, 1x) performed well in
anti
insertion
D
syn
insertion
D
D
D
D
D
D
2a-d2
D
Et
O
Et
O
PhO
D
PhO
D
trans-3a-d2
cis-3a-d2
B. Determination of absolute and relative stereochemistry
D
>95%
O
O
O
see
Table 2
1. Pinnick
2. TFAA/TFA
nOe
Et
H
D
2a-d2
+
PhOH
O
D
65% yield
94:6 er
65% yield
(two steps)
>95%
cis-3a-d2
Et
H
5
As alluded to in the introduction, the pKa of the oxygen
nucleophile would likely be critical for effective syn oxy-
palladation of internal alkenes. Indeed, simple aliphatic
alcohols do not undergo this reaction, but on the basis of
our previously reported use of alkyl peroxides in Wacker
oxidations,18 we reasoned that such nucleophiles would
be applicable to this reaction manifold. Indeed, cumene
hydroperoxide 6 was found to effectively participate, al-
lowing access to β-hydroxycarbonyl products (Table
4).19,20 The scope was briefly examined, using (R)-L-3 as
ligand, and 7a-c were afforded in good yield and enanti-
oselectivity. Unfortunately, use of primary allylic alcohols
with cumene hydroperoxide resulted in low product
yields, potentially due to decomposition of the aldehyde
product in the presence of excess hydroperoxide. Lastly,
1,2-dichloroethane.
The
hydroquinone
byproduct
generated in these reactions was not observed to
undergo competive addition to the allylic alcohols for the
reactions reported in Tables 2 and 3.
Unlike Heck arylations and alkenylations, which un-
dergo syn-migratory insertion, the mechanism by which
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(1) (a) Kočovský, P.; Bäckvall, J.-E. Chem.—Eur. J. 2015, 21,
it has previously been demonstrated that the O–O bond
in these molecules can be reduced to afford formal
cross-aldol products.20
36. (b) Doháňošová, J.; Gracza, T. Molecules 2013, 18, 6173.
(c) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111,
2981.
(2) Michel, B. M.; Steffens, L. D.; Sigman, M. S. “The Wacker
Oxidation” In Organic Reactions; Vol 84; Denmark, S. E. Ed.,
John Wiley & Sons, Inc.: 2014; pp 75-414.
(3) Kawamura, Y.; Kawano, Y.; Matsuda, T.; Ishitobi, Y.;
Hosokawa, T. J. Org. Chem. 2009, 74, 3048.
(4) (a) El-Qisairi, A.; Henry, P. M. J. Organomet. Chem. 2000,
603, 50. This process has been reinvestigated and revealed to
exhibit no enantioselectivity, see (b) Denmark, S. E.; Carson,
N. Org. Lett., 2015, 17, 5728.
1
2
3
4
5
6
7
8
Table 4. Evaluation of Cumene Hydroperoxidea
R1
O
Pd(OTs)2(MeCN)2 (8 mol %)
R1
OH
(R)-L-3 (10 mol %)
Ph
O
O
R2
OH
+
O
Me
R2
BQ (3 equiv), Ca(OH)2 (1 equiv)
3 Å MS, PhCF3 , rt
Me
Me
Me
6
2
Ph
7
2 equiv
1 equiv
9
O
Me
O
Me
O
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
Me
O
Ph
O
Ph
O
O
(5) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S. J. Am.
Chem. Soc. 1981, 103, 2318.
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
(6) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc.
1997, 119, 5063.
(7) (a) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am.
Chem. Soc. 2005, 127, 17778. (b) Trend, R. M.; Ramtohul, Y.
K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003,
42, 2892.
(8) (a) Takenaka, K.; Mohanta, S. C.; Patil, M. L.; Rao, C. V.
L.; Takizawa, S.; Suzuki, T.; Sasai, H. Org. Lett. 2010, 12,
3480. (b) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am.
Chem. Soc. 2001, 123, 2907.
(9) (a) Kapitán, P. Gracza, T. ARKIVOC 2008, viii, 8. (b)
Tietze, L. F; Zinnegrebe, J.; Spiegl, D. A; Stecker, F.
Heterocycles 2007, 74, 473. (c) Tietze, L. F.; Sommer, K. M.;
Zinngrebe, J.; Stecker, F. Angew. Chem. Int. Ed. 2005, 44, 257.
(10) (a) Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am.
Chem. Soc. 2010, 132, 17471. (b) Pathak, T. P.; Gligorich, K.
M.; Welm, B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132,
7870. (c) Jensen, K. H.; Pathak, T. P.; Zhang, Y.; Sigman, M.
S. J. Am. Chem. Soc. 2009, 131, 17074.
(11) For intermolecular (racemic) hydroetherification of
alkenes with phenols, see (a) Haibach, M. C.; Guan, C.; Wang,
D. Y.; Li, B.; Lease, N.; Steffens, A. M.; Krogh-Jespersen, K.;
Goldman, A. S. J. Am. Chem. Soc. 2013, 135, 15062. (b)
Sevov, C. S.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135,
9303. (c) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N.
W.; He, C. Org. Lett. 2006, 8, 4175. (d) Yang, C.-G.; He, C. J.
Am. Chem. Soc. 2005, 127, 6966. (e) Utsunomiya, M.; Kawa-
tsura, M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2003, 42, 5865.
(12) DeLuca, R. J.; Edwards, J. L.; Steffens, L. D.; Michel, B.
W.; Qiao, X.; Zhu, C.; Cook, S. P.; Sigman, M. S. J. Org. Chem.
2013, 78, 1682.
7a, 71% yield
96:4 er
7b, 69% yield
92:8 er
7c, 70% yield
96:4 er
a Each entry represents the isolated yield on 0.20 mmol scale. Er values were determined
by SFC.
In conclusion, we have developed the first enantiose-
lective, intermolecular ‘oxa-Heck’ reaction between
commercially available oxygen nucleophiles (phenols
and cumene hydroperoxide) and allylic alcohols. Mecha-
nistic studies provide evidence for a syn migratory inser-
tion in the C–O bond forming event; a mechanism that is
underdeveloped in intermolecular, asymmetric process-
es. The strategic use of allylic alcohols promotes the
direction of β-hydride elimination ‘away’ from the newly
formed C–O stereocenter to ultimately deliver β-aryloxy-
and β-peroxycarbonyl products. The carbonyls formed
from this reaction are formal conjugate addition adducts.
However, there are few reports of enantioselective oxa-
Michael reaction of phenols with α,β-unsaturated cou-
pling partners.21 This new methodology thus provides a
complementary approach for the synthesis of these
products. Future studies in our laboratory will focus on
expanding the scope of this new reaction by exploring
new heteroatom nucleophiles compatible with this strat-
egy.
AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu
(13) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009.
(14) Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J.
Am. Chem. Soc. 2004, 126, 3036.
ACKNOWLEDGMENTS
(15) (a) Hilton, M. J.; Xu, L.-P.; Norrby, P.-O.; Wu, Y.-D.;
Wiest, O.; Sigman, M. S. J. Org. Chem. 2014, 79, 11841. (b)
Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P.-O.; Wu, Y.-D.;
Sigman, M. S.; Wiest, O. J. Am. Chem. Soc. 2014, 136, 1960.
(c) Mei, T.-S.; Werner, E. W.; Burckle, A. J.; Sigman, M. S. J.
Am. Chem. Soc. 2013, 135, 6830. (d) Werner, E. W.; Mei, T.-
S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455.
(16) (a) Zhao, D.; Beiring, B.; Glorius, F. Angew. Chem. Int.
Ed. 2013, 52, 8454. (b) Vila, C.; Hornillos, V.; Fañanás-Mastral,
M.; Feringa, B. L. Chem. Commun. 2013, 49, 5933.
(17) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127,
16468.
The work was supported by National Institute of Health
(NIGMS R01GM063540). We thank Dr. Peter Flynn
(D.M. Grant NMR Center) for assistance with NMR ex-
perimentation. C.S.S acknowledges CNPq for a postdoc-
toral fellowship. T.N. acknowledges the JSPS fellowship
for young scientists.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information
is available free of charge on the ACS Publications
website. Experimental procedures and characteriza-
tion data for new compounds (PDF)
(18) Michel, B. W.; Steffens, L. D.; Sigman, M. S. J. Am.
Chem. Soc. 2011, 133, 8317.
(19) Harris, J. R.; Waetzig, S. R.; Woerpel, K. A. Org. Lett.
2009, 11, 3290.
REFERENCES
(20) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am.
Chem. Soc. 2008, 130, 8134.
(21) Nising, C. F.; Bräse, S. Chem. Soc. Rev. 2012, 41, 988.
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[Pd]
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[PdII]
Db
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selective β-H elimination of Db
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• enantioselective, intermolecular coupling of phenols and alkenes
• evidence for syn migratory insertion of alkene into Pd-O bond
• 27 examples, 35 - 89% yield and 90:10 - 96:4 er
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