Highly regio- and stereoselective synthesis of Z and E enol esters by an amine-catalyzed conjugate addition-rearrangement reaction of ynals with carboxylic acids

Article abstract of DOI:10.1021/acscatal.6b02206

The broad synthetic utility of labile enol esters demands efficient methods for the stereo- and regioselective synthesis of both Z and E isomers. The available synthetic methods dominated by metal catalysis cannot meet the challenge. We wish to report a metal-free organocatalytic divergent approach to both E and Z isomers of enol esters from the same reactant pools with the same catalytic system. A process involves an amine-catalyzed conjugate addition of carboxylic acids to ynals, which triggers a rearrangement leading to enol esters. The reaction proceeds highly regio- and stereoselectively. Simple manipulation of reaction temperatures enabled us to produce Z isomers at 0 °C (Z:E (15-20):1), whereas E isomers were produced at 30 °C (E:Z (15-20):1). Furthermore, the mild reaction conditions accommodate a broad array of densely functionalized carboxylic acids for the process, including complex biologically relevant structures and ynals. Therefore, synthetically valued, structurally diverse enol esters are efficiently synthesized. Preliminary mechanistic studies suggest an amine-promoted conjugate addition-rearrangement pathway to be responsible for the formation of the enol esters. (Chemical Equation Presented).

Full text of DOI:10.1021/acscatal.6b02206

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Article
Highly Regio- and Stereoselective Synthesis of Z and E
Enol Esters by an Amine Catalyzed Conjugate Addition-
rearrangement Reaction of Ynals with Carboxylic Acids
He Huang, Xinshuai Zhang, Chenguang Yu, Xiangmin Li, Yueteng Zhang, and Wei Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02206 • Publication Date (Web): 24 Oct 2016
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Page 1 of 8
ACS Catalysis
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Highly Regio- and Stereoselective Synthesis of Z and E Enol
Esters by an Amine Catalyzed Conjugate Addition-
rearrangement Reaction of Ynals with Carboxylic Acids
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He Huang,†,≠ Xinshuai Zhang,†,≠ Chenguang Yu,† Xiangmin Li,†,‡ Yueteng Zhang,† and Wei
Wang†,‡,
*
† Department of Chemistry & Chemical Biology, University of New Mexico, Albuquerque, NM 87131‐0001, USA
‡ State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, Shanghai Key
Laboratory of Chemical Biology, and School of Pharmacy, East China University of Science & Technology, Shanghai
200237, China
ABSTRACT: The broad synthetic utility of labile enol esters demands efficient methods for the stereo‐ and regio‐selective syn‐
thesis of both Z and E isomers. The available synthetic methods dominated by metal catalysis cannot meet the challenge. We
wish to report a metal free organocatalytic divergent approach to both E and Z isomers of enol esters from the same reactant
pools with the same catalytic system. A process involves an amine catalyzed conjugate addition of carboxylic acids to ynals,
which triggers a rearrangement leading to enol esters. The reaction proceeds highly regio‐ and stereoselectivley. Simple mani‐
pulation of reaction temperatures enables to produce Z‐isomers at 0 °C (Z:E 15:1 ‐ >20:1), whereas at higher 30 °C to give E‐
isomers (E:Z 15:1 ‐ >20:1). Furthermore, the mild reaction conditions accommodate a broad array of densely functionalized car‐
boxylic acids including complex biologically relevant structures and ynals for the process. Therefore, synthetically valued, struc‐
turally diverse enol esters are efficiently synthesized. Preliminary mechanistic studies suggest an amine promoted conjugate
addition‐rearrangement pathway responsible for the formation of the enol esters.
KEYWORDS: Enol esters / Organocatalysis / Ynals / Carboxylic Acids / Michael additions.
Previous works: Ru and Rh-catalyzed direct additions of carboxylic acid to alkynes:
Introduction
O
R2
Ru or Rh
R3
R1CO2H
Despite the lability of enol esters, the functionality is
featured in a number of natural products with intriguing
biological properties such as anti‐cancer, inhibitory BACE1,
and anti‐viral activities.1 Moreover, the lability endows high
activity as versatile building blocks in organic synthesis.
They have been widely used for a variety of transformations
such as aldol and Mannich,2 asymmetric hydrogenation,3
cyclization,4 and cross‐coupling5 reactions. The configura‐
tion of products produced highly depend on the geometry of
E and Z isomers of the enol esters employed. Therefore the
stereoselective synthesis of E and Z isomers is critically im‐
portant for their synthetic applications. The state‐of‐the‐art
technologies for their syntheses are dominated by transition
metal catalysis.6‐11 One of the attractive approaches involves
the direct addition of simple carboxylic acids to alkynes in
the presence of transition metal promoters. The pioneering
study of Ru promoted addition of carboxylic acids to alkynes
by Rotem and Shvo8a has triggered significant interests on
the development of effective Ru,8 or Rh9 complexes as
catalysts aimed at improving E and Z selectivity and/or
regioselectivity (Scheme 1, Eq. 1 and 2). However, only a
handful of approaches are disclosed for the preparation of E
by Dixneuf,8d Itoh8j Cramer9d or Z by Dixneuf,8b Gooßen,8e
Leong,8f Inoue,8k and Breit9b,9c isomers. In principle, E and Z
isomers can be accessed from the same pool of reactants.
Nonetheless, to the best of our knowledge, a strategy capable
+
R2
R3
R1
O
ref. 8d, 8j and 9d
(1)
E isomers
Ru or Rh
R2
R3
internal alkynes: difficult
HO2CR1to control regioselectivity
O
Ru or Rh
R1
O
R1CO2H
R2
R3
(2)
+
R3
ref. 8b, 8e, 8f,
8k, 9b and 9c
R2
Z isomers
This work: metral free amine catalyzed divergent synthesis of E and Z isomers from
carboxylic acids and ynals
high regio- and stereoselectivity
divergent access both E and Z isomers
operational simplicity: without requring air and moisture free conditions
R1CO2H
N
O
N
H
H
O
1
amine
0 o
R1
O
amine
+
COR2 (3)
E isomers
R1
O
COR2
30 o
C
R2
CHO
C
Z isomers
2
rearrangement
rearrangement
N
H
N
O
N
R1
HO
O
H
N
R1
H
R1
H
H
O
R2
O
O
R2
R2
Scheme 1. Methods for Synthesis of Enol Esters.
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Page 2 of 8
of producing E and Z isomers in an efficient divergent fa‐
1
shion remains elusive. Furthermore, it is difficult for the Ru
and Rh activation mode to achieve good regioselectivity for
internal alkynes (Scheme 1). Finally, in addition to toxicity
and cost concerns and the lability of ligand‐metal complexes,
these transition metals catalyzed reactions are generally
performed under restricted air and moisture free conditions.
Herein we wish to report a new alternative catalytic
approach to enol esters using amine as a catalyst for the first
time under operationally simple ambient conditions.11 We
found that an amine catalyzed conjugate addition of
carboxylic acids to ynals triggered an unexpected subsequent
rearrangement leading to highly regio‐ and stereo‐controlled
Z and E enol ester products in a divergent manner (Scheme 1,
Eq. 3). At lower temperature (0 °C), Z‐isomers are formed
highly stereoselectively (> 15:1 Z:E), while at higher
temperature (30 °C), thermodynamic control E products are
produced dominantly (> 15:1 E:Z). The strategy reported in
this study is distinct from that of widely studied transition
metal Ru and Rh catalysis. An unprecedented amine cata‐
lyzed the conjugate addition of carboxylic acid to C≡C triple
bonds leads to an unexpected rearrangement process for the
enol ester formation.
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Figure 1. X‐ray single crystal structure.
Table 1. Optimization of Amine Catalyzed Synthesis
of Enol Estersa
Ph
O
Cat
.(30 mol%)
Ph COOH
+
Ph
CHO
O
Results and Discussion
DCM, rt
Ph
1a
2a
3
Exploration and optimization Iminium catalysis has
enjoyed great success.12 A diverse array of nucleophiles can
participate in conjugate addition processes to form new C‐C
and C‐X bonds. Nonetheless, to the best of our knowledge,
carboxylic acids as nucleophiles for the amine promoted
conjugate addition reactions with enals have not been
developed. We believe that weak nucleophilicity and high
leaving tendency of carboxylic acids are difficult to be added
into an iminium ion in the reversible process. Inspired by
our and other groups’ studies with ynals in organocatalysis,13‐
15 we proposed the use of ynals instead of enals because of the
formation of irreversible adduct due to p‐ conjugation of
the lone pair electrons with the C=C double bond and higher
reactivity of ynals than that of enals (Scheme 2, Eq. 1).
O
Cat.
Ar
Ar
OTMS
Ph
Ph
R
N
H
N
N
N
H
H
H
C8
C6 Ar=3,5-dimethylphenyl
C7 Ar=3,5-bis(trifluoro
methyl)phenyl
C1 R = OTMS C4 R = OH
C2 R = OTBS C5 R = H
C3 R = OTES
C9
Entry
Cat.
t (h)
Yield (%)b
1
2
C1
C2
C3
C4
C5
C6
C7
C8
C9
C7
C7
C7
C7
24
24
24
24
48
24
24
48
48
24
24
24
96
29
16
24
36
-
3
4
O
R2
O
R1CO2H
+
amine
Ph
(1)
R1
O
H
R2
CHO
5
6
32
76
-
Ph
N
ArCO2H
+
H
OTMS
7
O
Ar
O
O
O
30 mol%
CHO
(2)
Ar
Ar
O
H
CH2Cl2, 48 h
Ar
O
8
Ar
Ar = p-BrC6H4
not formed
obtained product
27% yield
9
-
Scheme 2. Amine Catalyzed Conjugate Addition of
Carboxylic Acids to Ynals
10c
11d
12d,e
13d,f
60
72
80
72
To validate the feasibility, we performed an exploratory
investigation of reacting of 4‐bromobenzolic acid with (4‐
bromophenyl)propynal in the presence of Jorgensen‐Hayashi
diphenyl prolinol TMS ether (30 mol%) in CH2Cl2 (Eq. 2). To
our delight but unexpectedly, an E‐enol ester rather than a
conjugate addition adduct was obtained, verified by X‐ray
single crystal structure (Figure. 1).16
a
Reaction conditions: unless specified, the reaction was
carried out with 0.24 mmol of 1a and 0.2 mmol of 2a in 0.8
mL of CH2Cl2 with 30 mol% catalyst was stirred at rt for a
specified time. Unless specified, see the Experimental Section
b
c
for reaction conditions. Isolated yields with both isomers.
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d
20% catalyst was used. 20% catalyst was added in three
times, each time 1/3 of the total amount catalyst was used,
see Methods for details. e 0 oC, Z/E > 20/1. f 30 oC, E/Z > 20/1.
product and direct conjugate unrearrangement adduct in
25% yield. It appears that aliphatic acid adducts are difficult
to undergo the subsequent rearrangement process.
1
2
3
4
5
6
7
8
9
Synthesis of E isomers Having established an efficient
protocol for the synthesis of Z‐enol esters, we then turned
our attention on the construction of E‐enol esters. Since the
more stable E‐enol esters are thermodynamically controlled
products, we conducted studies by raising the reaction
temperature and/or extending the reaction time. To our
delight, the desired E‐enol esters were obtained when the
reaction was performed at 30 °C and longer reaction time
(96‐120 h) (Scheme 4).
The unexpected outcomes prompted us to investigate the
interesting process in details. In the initial effort, we at‐
tempted to optimize the reaction conditions to improve the
reaction yields using benzoic acid 1a and phenylpropiolalde‐
hyde 2a as substrates in the present of an amine catalyst (Ta‐
ble 1). Screening of catalysts (entries 1‐9) revealed C7 giving
the best results (76% yield, entry 7). It seems that the steric
hindrance and side chain acidity of catalysts can facilitate the
process by enhancing the formation of iminium ion and fa‐
cial selectivity and minimizing 1,2‐addition reaction. De‐
creasing the catalyst loading to 20 mol % furnished lower
yield (60%, entry 10). We found that the addition of the
catalyst in three portions led to improved yield by reducing
the catalyst decomposition under the acidic reaction condi‐
tions (72%, entry 11). We also noticed that after 24 h at rt the
Z/E ratio of the product 3a was 5/1 based on 1H NMR analysis
of the reaction mixture. This suggests that the process could
involve a kinetic/thermodynamic control. Indeed, at lower
temperature (0 °C, entry 12), a kinetic control product Z iso‐
mer (> 20:1 Z/E) was obtained in 80% yield. Higher tempera‐
ture was favored for the thermodynamic control E isomer.
Only E isomer was produced in 72% yield at 30 °C after 96 h
(entry 13). To the best of our knowledge, this study
represents the first example, enabling synthesis of both E and
Z enol esters using the same catalytic system and the same
reactants.
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O
CHO
C7 (10-20 mol %)
R1 CO2H
+
R1
Cl
O
CH2Cl2, 0 o
C
R2
COR2
1
2
Z-3
O
O
O
O
O
O
O
Cl
O
O
Z-3aa
24 h, 80% yieldb
Z : E > 20:1c
Z-3ca
Z-3ba
6 h, 88% yieldb
Z : E = 16:1c
O
27 h, 71% yieldb
Z : E > 20:1c
I
O
Br
O
MeO
O
O
O
O
O
Z-3fa
24 h, 71% yieldb
Z : E = 17:1c
O
Z
-3ea,d
Z-3da,d
6 h, 93% yieldb
Z : E > 20:1c
6 h, 91% yieldb
Z : E = 16:1c
O
O
O
O
O
O
O
O
O
N
O
Z-3ga,d
12 h, 86% yieldb
Z : E > 20:1c
O
Z-3ia
Z-3ha
20 h, 83% yieldb
Z : E = 18:1c
O
36 h, 63% yieldb
Z : E > 20:1c
O
Synthesis of Z isomers We first probe the scope of the
process for the formation of Z isomer products. As shown in
Scheme 3, clean Z‐enol esters are produced (Z/E > 15/1). It
appears that the reactions have significant tolerance toward
structural variations of both reactants, carboxylic acids 1 and
ynals 2. Therefore, structurally diverse Z‐enol esters are
obtained under the mild reaction conditions. First, the elec‐
tronic and steric effects of different functional groups on the
phenyl ring in acids 1 were examined (Z‐3a ‐ Z‐3f). It was
found that regardless of the electron‐neutral, ‐donating or ‐
withdrawing groups installed on the substrates, all afford the
desired products in good to high yields. In addition to substi‐
tuted phenyl systems, fused aromatic (e.g., 9‐anthracenyl, Z‐
3g) and heteroaromatic structures including 3‐pyridinyl, 3‐
furanyl and 2‐indolyl (Z‐3h ‐ Z‐3j) can effectively engage in
the processes. It is interestingly observed that for 2‐indolyl
carboxylic acid, the CO2H rather than C3 position, which is
considered more nucleophilic, participated in the reaction
(Z‐3j). We also found that α, β‐unsaturated acids such as
methacrylic acid (Z‐3k) and trans‐cinnamic acid (Z‐3l) could
be tolerated by the process in good yields. Examination of
the structural alternation of ynals reveals a similar trend (Z‐
3m ‐ Z‐3q). Furthermore, heteroaromatic and aliphatic
systems could be applied (Z‐3r ‐ Z‐3t). It is also realized the
limitation of the process. Aliphatic acids can participate in
the process, but the reactivity is lower than that of aromatics
ones. It takes longer reaction time and it produces a mixture
of Z and E isomers and unrearrangement product. For ex‐
ample, reaction of 3‐phenylpropionic acid with phenylpropi‐
olaldehyde 2a even with 30 mol% C7 gave 18% enol ester
O
Ph
O
O
NH
O
O
Z-3la
36 h, 63% yieldb
Z : E > 20:1c
O
Z-3ka
36 h, 63% yieldb
Z : E = 16:1c
Z-3ja
24 h, 69% yieldb
Z : E > 20:1c
O
O
O
O
O
O
Cl
O
O
O
Z-3ma
Z-3oa
Z-3na
24 h, 63% yieldb
Z : E > 20:1c
24 h, 74% yieldb
Z : E > 20:1c
24 h, 70% yieldb
Z : E > 20:1c
Cl
F
O
O
O
O
O
O
O
Z-3ra
O
O
Z-3pa
Z-3qa
S
24 h, 63% yieldb
Z : E > 20:1c
24 h, 81% yieldb
Z : E > 20:1c
24 h, 72% yieldb
CN
OMe
Z : E > 20:1c
O
O
O
Cl
O
O
O
O
Z-3ta
O
O
Z-3sa
Z-3ua
N
24 h, 70% yieldb
Z : E > 20:1c
36 h, 62% yieldb
18 h, 86% yieldb
Z : E = 17:1c
Ts
Z : E > 20:1c
O
O
O
O
O
O
MeO
O
NC
O
F
O
Z-3wa
Z-3xa
Z-3va
36 h, 52% yieldb
Z : E > 20:1c
36 h, 72% yieldb
Z : E > 20:1c
24 h, 84% yieldb
Z : E = 17:1c
O
O
O
O
O
O
OMe
O
O
O
Z-3ya
Z-3aaa
Z-3za
36 h, 62% yieldb
Z : E > 20:1c
Me
24 h, 70% yieldb
Z : E > 20:1c
NO2
24 h, 85% yieldb
Z : E > 20:1c
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a
Unless stated otherwise, see SI Methods for detail of the
Derivatization of complex carboxylic acids In addition to
the relative simple acids, we also demonstrated that the mild
b
c
1
1
2
3
4
5
6
7
8
reaction conditions. isolated yields. Determined by H
NMR. d 10 mol % C7 used.
reaction conditions enable biologically relevant, more com‐
plex carboxylic acids to selectively react with ynals using
phenyl propynal as example (Scheme 5). It was found that
under the thermodynamically controlled reaction conditions,
heavily functionalized acids can effectively participate in the
reactions chem‐, regio‐ and stereo‐selectively to deliver in‐
teresting E‐enol ester derivatives 4‐6 in high yields. They
include retinoic acid,17 mycophenolic acid,18 an immunosup‐
pressant drug and others (Scheme 5). It is noteworthy that
the reaction conditions can tolerate highly acid sensitive
polyene and nucleophilic phenol moieties in retinoic acid
and mycophenolic acid. Finally, we chose therapeutic pro‐
benecid19 to show divergent synthesis of its Z and E enol es‐
ters. Both cases offered good yields and excellent Z and E
selectivity. Furthermore, this protocol can be conveniently
scaled up, as shown in the use of probenecid (5.0 mmol) and
phenylpropiolaldehyde (3.6 mmol) with 10 mol% catalyst C7,
delivering E‐6 in 85% yield (Scheme 5).
Scheme 3. Substrate scope of C7‐catalyzed synthesis of
Z‐enol esters.
Notably under the reaction conditions, again clean E‐
isomers (15:1 ‐ > 20:1 E : Z ratio) were attended in good to
high yields (62‐92%). Again, a variety of acids and ynals as
reactants can be applied for this process with a broad
substrate scope and therefore this offers a viable approach to
E‐enol esters with various structure features.
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O
C7 (20 mol %)
CH2Cl2, 30 o
CHO
COR2
R
1 CO2H
+
R1
O
R2
C
1
2
E-3
O
O
O
O
Cl
O
O
O
Ph
O
O
E-3ca
E-3ba
E-3aa
Cl
96 h, 70% yieldb
96 h, 72% yieldb
96 h, 72% yieldb
E : Z = 19:1c
E : Z > 20:1c
E : Z > 20:1c
O
O
O
O
O
O
O
Ph
CHO
C7 (20 mol %)
O
O
O
Ph
COPh
2a
R
O
O
E-3fa
120 h, 66% yieldb
E : Z > 20:1c
+
CH2Cl2, 30 o
C
NH
E-3ja
O
E-3ia
nature products or drugs
bearing carboxylic acid group
E-enol esters
96 h, 71% yieldb
96 h, 80% yieldb
E : Z > 20:1c
O
OMe
E : Z = 16:1c
OH
O
O
O
O
O
O
Me
Me
O
Ph
COPh
O
Me Me
Ph
O
Ph
Ph
Ph
O
Ph
O
O
O
O
E-3na
E-3la
O
E-3ma
Cl
96 h, 70% yieldb
120 h, 71% yieldb
Cl
Me
O
120 h, 66% yieldb
E : Z > 20:1c
retinoic acid enol ester (4)a
mycophenolic acid enol ester (5)a
E : Z > 20:1c
E : Z > 20:1c
51% yieldb
60% yieldb
O
O
Cl
O
O
O
O
O
O
COPh
O
Ph
O
O
S
N
O
E-3qa
CN
E-3ra
COPh
E-3pa
OMe
108 h, 76% yieldb
E : Z > 20:1c
96 h, 74% yieldb
96 h, 73% yieldb
E : Z > 20:1c
Ph
O
O
E : Z > 20:1c
MeO
F
O
O
O
O
O
indometacin enol esteraa
61% yieldb
COPh flurbiprofen enol estera
65% yieldb
ibuprofen enol estera
60% yieldb
O
O
O
O
O
E-3sa
O
E-3ta
O
O
E-3ua
N
Ts
96 h, 68% yieldb
120 h, 72% yieldb
COPh
96 h, 62% yieldb
Cl
O
E : Z > 20:1c
E : Z > 20:1c
E : Z > 20:1c
(n-C3H7)2N
(n-C3H7)2N
COPh
82% yieldb
S
O
O
S
84% yieldb
at 0 o
O
O
O
O
O
O
O
O
gram scale: 85% yield with 10 mol% C1
probenecid E-enol ester (E-6)a
O
C
O
O
Ph
probenecid Z-enol ester (Z-6)a
E-3va
F
E-3wa
E-3ya
MeO
96 h, 71% yieldb
120 h, 66% yieldb
E : Z > 20:1c
b OMe
a
120 h, 62% yield
E : Z > 20:1c
E : Z > 20:1c
Unless stated otherwise, see SI Methods for detail of the
reaction conditions. b Isolated yield.
O
O
OMe O
O
O
O
Ph
O
Ph
O
O
Scheme 5. Synthesis of enol esters derived from natural
products and therapeutics.
E-3za
E-3aaa
E-3aba
NO2
Me
120 h, 67% yieldb
E : Z > 20:1c
108 h, 73% yieldb
E : Z > 20:1c
96 h, 87% yieldb
E : Z > 20:1c
Preliminary mechanistic studies The unexpected enol
ester formation from carboxylic acids and ynals prompted us
to conduct preliminary studies of the interesting reaction
mechanism. We found that the process involving the
Meyer−Schuster type rearrangement20 was ruled out because
the formation of the hemiacetal or hemiaminal was not ob‐
served (Scheme 6, Eq. 1), which is an essential precursor for
the rearrangement. Instead, a Michael adduct 7 was formed
1
initially, observed by in situ H NMR (Figure 2). Further‐
a
Unless stated otherwise, see SI Methods for detail of the
reaction conditions. Isolated yield. Determined by H
NMR.
more, we isolated and characterized the product by reaction
of benzoic acid 1a with ynal 2a. It was found that only in the
presence of C7, the adduct was able to converted into enol
ester Z‐3a (Eq. 2). Without the catalyst, no reaction oc‐
curred. These results suggest that the catalyst is necessary
for the initial Michael and subsequent rearrangement reac‐
tions.
b
c
1
Scheme 4. Scope of C7‐catalyzed synthesis of E‐enol es‐
ters.
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Ph CO2H
OH
O
N
O
1
2
3
C7 (20 mol%)
1a
+
(1)
O
Ph or
Ph
CDCl3, rt
O
Ph
Ph
CHO
Ph
hemiacetal
hemiaminal
2a
Not observed
4
Not observed
5
C7 (20 mol%)
6
7
8
9
Ph CO2H
1a
Z-3a
Ph
CDCl3, rt
65% yield
C7 (20 mol%)
O
CHO
+
(2)
No reaction
O
Ph
CHO
CDCl3, rt
Ph
without C7
2a
7
CDCl3, rt
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
O
Ph
30 o
C
Ph
O
(3)
Ph
O
Ph
O
CH2Cl2
96 h
E-3a
100% Yield
Z-3a
Scheme 6. Reactions designed for study of reaction me‐
chanism.
a The in situ 1H NMR analysis was carried out with 0.12 mmol of 1a and 0.1 mmol of 2a in 2 mL of CDCl3 with 30 mol% catalyst C7.
Figure 2. Reaction progress of C7 catalyzed reaction of 1a with 3a.
Based on the above studies, we proposed a catalytic cycle for
the formation of enol esters 3 (Scheme 7). Nucleophilic
attack of benzoic acid from less hindered side of the iminium
ion 8 is followed by protonation of α‐carbon gives cis‐
iminium ion 9. Nucleophilic addition H2O to the iminium
ion leads to hemiaminal 11 after proton transfer with 10.
Hydroxyl group triggers an interesting rearrangement via
intramolecular transesterification to gives rise to a Z‐enol
ester Z‐3 with concomitant release of the catalyst. Under
thermodynamic control condition, the kinetic control Z‐3
undergoes isomerization via intermediated 12 to furnish
more stable E‐3, which is confirmed by the transformation of
Z‐3 to E‐3 experiment (Scheme 6, Eq. 3).
Scheme 7. Proposed catalytic cycle.
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Chem., Int. Ed. 2006, 45, 2176‐2203. (c) Dragutan, V.; Dragutan, I.;
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C.; Zimmermann, B. Pure Appl. Chem. 2008, 80, 1725‐1733.
1
2
3
4
5
6
7
8
Conclusions
In conclusion, we have established a new divergent
(8) (a) Rotem, M.; Shvo, Y. Organometallics 1983, 2, 1689‐1691. (b)
Doucet, H.; Martin‐Vaca, B.; Bruneau, C.; Dixneuf, P. H. J. Org.
Chem. 1995, 60, 7247‐7255. (c) Melis, K.; Samulkiewicz, P.; Rynkows‐
ki, J.; Verpoort, F. Tetrahedron Lett. 2002, 43, 2713‐2716. (d) Le Paih,
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D.; Muller, G.; Demonceau, A. Eur. J. Org. Chem. 2009, 5020‐5027.
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Chem. Eur. J. 2013, 19, 12067‐12076. (d) Pham, M. V.; Cramer, N. An‐
gew. Chem., Int. Ed. 2014, 53, 14575‐14579.
(10) Other metals: Cu: (a) Yoo, W.‐J.; Li, C.‐J. J. Org. Chem. 2006,
71, 6266‐6268. (b) Huang, F.; Quach, T. D.; Batey, R. A. Org. Lett.
2013, 15, 3150‐3153. Au: (c) Marion, N.; Nolan, S. P. Angew. Chem., Int.
Ed. 2007, 46, 2750‐2752. (d) Peng, Y.; Cui, L.; Zhang, G.; Zhang, L. J.
Am. Chem. Soc. 2009, 131, 5062‐5063. Zr: (e) DeBergh, J. R.; Spivey,
K. M.; Ready, J. M. J. Am. Chem. Soc. 2008, 130, 7828‐7829. Pd: (f)
Mamone, P.; Gruenberg, M. F.; Fromm, A.; Khan, B. A.; Gooβen, L. J.
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Alsabeh, P. G.; Stradiotto, M.; Beller, M. Chem.‐Eur. J. 2012, 18, 15592‐
15597.
(11) To our knowledge, so far only one organocatalyzed enol ester
formation has been reported by Schaefer and Fu using a nucleophilic
DMAP derivative as catalyst: Schaefer, C.; Fu, G.C. Angew. Chem. Int.
Ed. 2005, 44, 4606‐4608.
(12) (a) Lelais, G.; MacMillan, D.W. Aldrichim Acta. 2006, 39, 79‐
87. (b) Erkkilä, A.; Majander, I.; Pihko, P.M. Chem. Rev. 2007, 107,
5416‐5470.
(13) Compared with enals, ynals are underdeveloped in iminium
catalysis, for reviews, see: (a) Fraile, A.; Parra, A.; Tortosa, M.;
Alemán, J. Tetrahedron 2014, 70, 9145‐9173. (b) Salvio, R.; Moliterno,
M.; Bella, M. Asian J. Org. Chem. 2014, 3, 340‐351.
(14) From our groups: (a) Zhang, X. S.; Zhang, S. L.; Wang, W. An‐
gew. Chem., Int. Ed. 2010, 49, 1481‐1484. (b) Liu, C.‐L.; Zhang, X.‐S.;
Wang, R.; Wang, W. Org. Lett. 2010, 12, 4948‐4951. (c) Zhang, X. S.;
Song, X. X.; Li, H.; Zhang, S. L.; Chen, X. B.; Yu, X. H.; Wang, W.
Angew. Chem., Int. Ed. 2012, 51, 7282‐7286. (d) Song, A.‐G.; Chen, X.‐
B.; Song, S.‐S.; Zhang, X.‐S.; Zhang, S.‐L.; Wang, W. Org. Lett. 2013,
15, 2510‐2513.
organocalytic protocol for the preparation of both E‐ and Z‐
enol esters from a diverse array of simple carboxylic acids
and ynals. Under kinetic control conditions, Z‐enol esters
are produced highly stereoselectively while E‐isomers are
selectively formed by thermodynamic control. Preliminary
mechanistic studies suggest an amine catalyzed
unprecedented Michael‐rearrangement pathway for the
formation of the enol esters. Different from transition metal
9
10
11
12
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catalysis of carboxylic acids with alkynes,
a
novel
organocatalytic catalysis strategy is implemented for the
conjugate addition of carboxylic acid to polarized C≡C triple
bonds. Further investigation of the reaction mechanism in
detail and the exploration of the chemistry for new
transformations are currently pursued in our laboratories.
ASSOCIATED CONTENT
Experiment details and spectroscopic data. This material is
available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
wwang@unm.edu.
Author Contributions
≠These authors contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support of this research from the National Science
Foundation of China (21572055), and the NSF (CHE‐1565085)
is gratefully acknowledged.
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1
2
3
TOC:
O
cat.
(10-20 mol %)
4
5
6
7
8
9
R1
O
CH2Cl2, 0 oC
COR2
cat.
Z-3
R1 CO2H
F3C
CF3
Z/E > 15/1
up to 93% yield
27 examples
CF3
CF3
+
R2
CHO
N
H
cat.
(20 mol %)
OTMS
O
10
11
12
13
14
15
16
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21
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COR2
CH2Cl2, 30 oC
R1
O
E-3
E/Z > 15/1
up to 87% yield
25 examples
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