1,4-Bis-Dipp/Mes-1,2,4-Triazolylidenes: Carbene Catalysts That Efficiently Overcome Steric Hindrance in the Redox Esterification of α- And β-Substituted α,β-Enals

Article abstract of DOI:10.1021/jacs.5b11796

As reported by Scheidt and Bode in 2005, sterically nonencumbered α,β-enals are readily converted to saturated esters in the presence of alcohols and N-heterocyclic carbene catalysts, e.g., benzimidazolylidenes or triazolylidenes. However, substituents at the α- or β-position of the α,β-enal substrate are typically not tolerated, thus severely limiting the substrate spectrum. On the basis of our earlier mechanistic studies, a set of N-Mes- or N-Dipp-substituted 1,2,4-triazolium salts were synthesized and evaluated as (pre)catalysts in the redox esterification of various α- or β-substituted enals. In particular the 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes overcome the above limitations and efficiently catalyze the redox esterification of a whole series of α/β-substituted enals hitherto not amenable to NHC-catalyzed transformations. The synthetic value of 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes is further demonstrated by the one-step bicyclization of 10-oxocitral to (racemic) nepetalactone in diastereomerically pure form.

Full text of DOI:10.1021/jacs.5b11796

Subscriber access provided by GAZI UNIV
Article
1,4-Bis-Dipp/Mes-1,2,4-Triazolylidenes: Carbene Catalysts
that Efficiently Overcome Steric Hindrance in the
Redox Esterification of #- and #-Substituted #,#-Enals
Veera Reddy Yatham, Wacharee Harnying, Darius Kootz, Jörg-
Martin Neudörfl, Nils E. Schlörer, and Albrecht Berkessel
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11796 • Publication Date (Web): 21 Jan 2016
Downloaded from http://pubs.acs.org on January 27, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
1,4-Bis-Dipp/Mes-1,2,4-Triazolylidenes: Carbene Catalysts
that Efficiently Overcome Steric Hindrance in the Redox Es-
terification of α- and β-Substituted α,β-Enals
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
Veera Reddy Yatham,a Wacharee Harnying,a Darius Kootz,a Jörg-M. Neudörfl,a,b
Nils E. Schlörer,a,c and Albrecht Berkessela*
aDepartment of Chemistry (Organic Chemistry), University of Cologne, Greinstrasse 4, 50939 Cologne, Germany
bX-Ray crystallography; cNMR-spectroscopy
KEYWORDS: Carbenes, umpolung, Breslow intermediate, homoenolate, redox esterification, natural products
ABSTRACT: As reported by Scheidt and Bode in 2005, sterically non-encumbered α,β-enals are readily converted to satu-
rated esters in the presence of alcohols and N-heterocyclic carbene catalysts, e.g. benzimidazolylidenes, or triazolylidenes.
However, substituents in the α- or-β-position of the α,β-enal substrate are typically not tolerated, thus severely limiting
the substrate spectrum. Based on our earlier mechanistic studies, a set of N-Mes or N-Dipp substituted 1,24-triazolium
salts were synthesized and evaluated as (pre)catalysts in the redox esterification of various α- or β-substituted enals. In
particular the 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes overcome the above limitations, and efficiently catalyze the redox
esterification of a whole series of α/β-substituted enals hitherto not amenable to NHC-catalyzed transformations. The
synthetic value of 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes is further demonstrated by the one-step bicyclization of 10-oxo-
citral to (racemic) nepetalactone in diastereomerically pure form.
Beyond the generation of acyl anion equivalents, the
I. INTRODUCTION
“conjugate Umpolung” of α,β-unsaturated aldehydes (a3-
d3 Umpolung), discovered by Bode and Glorius in 2004,4
N-Heterocyclic carbenes (NHCs) have emerged as highly
efficient organocatalysts for a wide range of transformat-
has recently become a most fascinating and proliferative
field in NHC catalysis. In this process, the NHC catalyst
ions.1 The most intriguing use of NHCs is based on their
ability to render the electrophilic carbonyl unit of alde-
and the enal substrate first combine to the diamino
hydes nucleophilic, thus converting them to acyl anion
dienol II (Scheme 1, b). In the latter, the β-position of the
equivalents (a1-d1 Umpolung to the Breslow intermediate
substrate α,β-unsaturated carbonyl compound (a3) is
I, Scheme 1, a).2 Important applications of a1-d1 Umpolung
rendered nucleophilic, too. Therefore, the diamino di-
are the benzoin condensation and the Stetter reaction.3
enols II can act as homoenolate equivalents (d3) (Scheme
1, b).5 A subsequent OH-Cγ proton shift may convert the
Scheme 1. NHC-catalyzed Umpolung of (a) simple al-
dehydes and (b) α,β-enals
diamino dienol II to the azolium enolate III (Scheme 1),
an enolate equivalent (d2).
O
O
δ+
δ+
R'
R
N
Both the homoenolate and the azolium enolate path-
ways have, in virtuosic manner, been exploited for the
synthesis of complex target structures,1b and in many
cases in an enantioselective fashion.6,7 Among the ho-
moenolate reactions, the internal redox esterification of
enals catalyzed by NHCs provides a new and fully atom-
economic approach to saturated esters, under redox neu-
tral conditions and without the use of coupling reagents
(Scheme 2).8,9 Scheidt and Chan first reported the reac-
tion conditions using a benzimidazolium derived NHC
(catalyst 30, vide infra) in combination with excess phe-
nol, effecting β-protonation/esterification of enals to
saturated ester in 56-90% yield.8 Shortly thereafter, Bode
and Sohn demonstrated the use of a mesityl (Mes: 2,4,6-
trimethylphenyl) substituted triazolium salt as a highly
α
δ+
H
H
R'
N
R
(a)
(b)
a1ꢀd1 Umpolung
a3ꢀd3 Umpolung
of simple aldehydes
of α,βꢀenals
R
N
R
N
R
OHꢀCγ
proton
shift
OH
δꢀ
O
E
OH
α
N
δꢀ
α
α
β
δꢀ
γ
R'
N
R
δꢀ
R'
R'
E
N
R
N
R
γ
β
E
diamino enol I
Breslow intermediate
diamino dienol II
azolium enolate III
acyl anion
chemistry
enolate
chemistry
homoenolate
chemistry
e.g. benzoin condensaꢀ
tion, Stetter reaction
e.g. chiral βꢀlactones,
γ,δꢀunsaturated δꢀlactones,
γ,δꢀunsaturated δꢀlactams
e.g. chiral γꢀlactones,
γꢀlactams, spiroꢀlactones,
cyclopentenes,
saturated esters
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 24
from α-methylcinnamic aldehyde was found to be re-
effective catalyst for the redox esterification, with no
additional proton source needed.9 Mechanistically, the
redox esterification of α,β-enals is believed to result from
γ-protonation of the diamino dienol II (Scheme 2) to the
azolium enol IV, followed by tautomerization of the latter
to the acyl azolium cation V. Deacylation of the latter by
the alcohol nucleophile furnishes the product ester and
regenerates the NHC catalyst.
1
2
3
4
5
6
7
8
versible, and the latter diamino dienol readily tautomer-
ized to the more stable azolium enolate (X-ray).10,11 The
solid state structures of the Breslow intermediates point
to a stabilizing dispersive effect12,13 of the ancillary iso-
propyl groups of SIPr (1) - presumably the molecular basis
of the "N-mesityl effect" mentioned earlier.5c,9 Taken to-
gether, we sought to employ triazolylidenes carrying effi-
cient dispersion energy donors (DEDs), such as 2,6-bis(2-
propyl)phenyl (Dipp), to effect the problematically redox
esterifications of α-substituted enals. We anticipated that
the diamino dienol intermediates of type II (Scheme 2)
would be stabilized by dispersion interactions as well,
hence promoting the overall catalytic transformation.
Scheme 2. Mechanism proposed for the NHC-catalyz-
9
ed redox esterification of α,β-enals
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
II.2 Catalyst design - undesired side reactions of α-
substituted enals with the saturated N-heterocyclic
carbene SIPr (1). In our NMR studies on the interaction
of SIPr (1) with α,β-enals other than α-methylcinnamic
aldehyde, we observed several reaction modes that do not
afford diamino dienol, and thus no ester product [sum-
marized in Scheme 3 (see SI for NMR data)].
Inspection of the α,β-enal substrates employed reveals,
however, that in all a3-d3 Umpolung reactions, exclusively
Scheme 3. Reaction of SIPr (1) with α-substituted
enals in THF-d8
α-unsubstituted α,β-enals have found application, includ-
ing NHC-catalyzed redox esterifications (i.e. R1 = H
Scheme 2).5 The only exception may be seen in α-
methylcinnamic aldehyde which was reported by Scheidt
et al. to be converted to the corresponding ester, but
again proved recalcitrant under Bode's conditions.8a,9a
With this in mind, we engaged on a study aiming at (i)
elucidating the mechanistic reasons for the recalcitrance
of α-substituted α,β-enals in redox esterifications, and (ii)
at the design, synthesis and application of a new genera-
tion of NHC catalysts that overcomes the mechanistic
hurdles. As the touchstone reaction, the redox esterifica-
tion of α-substituted α,β-enals (such as hexahydro α-
methylcinnamic aldehyde) that are completely unreactive
in the presence of known NHC catalysts was envisaged.
9
CHO
CHO
Dipp
CHO
Dipp
R
H3C
8
7
N
2
N
CHO
N
2
N
N
2a,b
R
R
4a,b
7
Dipp
Dipp
R
6
6
(i)
(ii)
CH3
N
1 (SIPr)
Dipp
Dipp
5a, R = Me
5b, R = Et
3a, R = Me
3b, R = Et
CHO
R1
Ph
CHO
6a, R = R1 = Me
6b, R = R1 = Et
CH3
9
R
(iii)
(iv)
Dipp
N
Dipp
CHO
Dipp
CHO
R
N
N
CHO
CH3
R
R1
N
Dipp
R1
N
N
Dipp
Ph
Dipp
10
Dipp=2,6ꢀbis(2ꢀpropyl)phenyl
7a, R = R1 = Me
7b, R = R1 = Et
8a, R = R1 = Me
8b, R = R1 = Et
1H NMR monitoring at room temperature revealed that
for methacrolein (2a) and ethacrolein (2b) as substrates,
clean Michael addition to the deoxy Breslow intermedi-
ates14 3a and 3b occured [Scheme 3, (i); see SI for X-ray
crystal structure of 3b]. On the other hand, the interac-
tion of SIPr with E-2-methyl-2-butenal (4a) afforded ex-
clusively the formal γ-C-H insertion adduct 5a [Scheme 3,
(ii)]. The latter most likely results from allylic deprotona-
tion of the enal by the NHC, and subsequent recombina-
tion of the allyl anion with the imidazolidinium cation.
II. RESULTS AND DISCUSSION
II.1 Catalyst design - the importance of N-Mes/N-Dipp
substituents. Earlier studies9 by Bode et al. had led to
the conclusion that the formation of the diamino dienol
II from cinnamic aldehyde and the NHC catalyst is irre-
versible, thereby promoting the ester formation (R1=H,
R2=Ph; Scheme 2). On the other hand, the analogous
transformation of α-methylcinnamic aldehyde (R1=CH3,
R2=Ph) was assumed to be reversible, resulting in an inef-
ficient overall process. The presence of an N-mesityl
group on triazolium NHCs was found to be essential for
reactions of α,β-enals involving the conjugated Breslow
intermediate (diamino dienol II, Scheme 2).5c,9 This “N-
mesityl effect” was proposed to promote the formation of
the key Breslow intermediate.
1
Characteristic H NMR signals of 5a are a multiplet at δ =
2.43-2.41 ppm (2H, H6), a triplet at δ = 5.0 ppm (3JHH = 5.0
Hz, 1H, H2), a triplet at δ = 5.88 ppm (3JHH = 6.5 Hz, 1H,
13
H7), a singlet at δ = 8.78 ppm (1H, H9), and C NMR res-
onances are at δ = 80.4 (C2), 35.8 (C6), 149.4 (C7), 192.5
(C9) ppm. Similar NMR features for the formation of 5b
were observed when E-2-ethyl-2-butenal (4b) was ex-
posed to SIPr (1). Note that the analogous reaction of α-
unsubstituted 2-butenal (E-crotonaldehyde) with SIPr (1)
gave exclusively the 1,2-addition adduct, the azolium
enolate in this case.10a
Our earlier work had supported the above assump-
tions, in the sense that the imidazolidinylidene SIPr (1)
forms a stable diamino dienol with cinnamic aldehyde,
amenable to X-ray crystallography.10 In contrast, the for-
mation of the analogous conjugated Breslow intermediate
ACS Paragon Plus Environment

Page 3 of 24
Journal of the American Chemical Society
The interaction of the enals 6 with SIPr (1) gave a mix- substituted triazolium salts 15a,b, we further explored the
1
2
3
4
5
6
7
8
synthesis of the bis-Mes/Dipp precatalysts (Scheme 5).
The key step was the coupling reaction of the hydrochlo-
rides 18a,b20 (of the corresponding Mes/Dipp-hydrazines
17a,b) with the corresponding imidoylchloride 16.21 We
found that the addition of mesityl hydrazine (17a, pre-
pared ex situ from the salt 18a by treatment with tBuOK)
to a solution of the N-mesityl imidoylchlorid 16a in THF
at room temperature resulted in the formation of 19, a 2:1
adduct, as the major product. The structure of 19 was
unambiguously established by X-ray analysis (see SI).
ture of 7 (Michael addition) and 8 [formal γ-C-H inser-
tion; Scheme 3, (iii)]. With E-2-methyl-2-pentenal (6a), 7a
and 8a were obtained in a ratio of 5:3. When E-2-ethyl-2-
hexenal (6b) reacted with SIPr (1), 7b was obtained along
with just trace amounts of 8b. Unexpectedly, the reaction
of SIPr (1) with 9, the β-methyl derivative of α-methylcin-
namic aldehyde (used as pure E-isomer or E/Z mixture),
gave only the formal C-H insertion adduct 10 [Scheme 3
(iv)]; see SI for X-ray analysis of 10). In contrast to the
reactivity of α-methylcinnamic aldehyde,10a no 1,2-addit-
ion affording the diamino dienol/azolium enolate was
observed for the enal 9.
9
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
Scheme 4. Synthesis and X-ray crystal structures of
the mono-Mes/Dipp triazolium salts 15a,b•HCl.
The above mentioned observations reveal a major com-
petitive reaction pathway: when the addition of the NHC
catalyst to the enal's carbonyl C-atom is sterically imped-
ed, allylic proton abstraction may occur. To suppress this
side reaction, low basicity NHCs must be employed. 1,2,4-
Triazol-5-ylidenes are significantly less basic (aqueous
pKa~16-18)15a than imidazolidin-2-ylidenes such as SIPr (1)
[aqueous pKa of SIPr (1) ~21.5].15b Additionally, in redox
esterification, 1,2,4-triazol-5-ylidenes have already been
shown to be catalytically superior to imidazol-2-ylidenes
and thiazol-2-ylidenes.9a Accordingly, we focused on the
synthesis of new NHCs based on the 1,2,4-triazole core, by
exchanging the N-phenyl substituents of the well-known
Enders-Teles carbene 1116 for 2,6-di(2-propyl)phenyl
(Dipp) or 2,4,6-trimethylphenyl (Mes) groups. Note that
based on calculations, the additional phenyl group at the
3-position of 11 is believed to support its higher Lewis bas-
icity, hence higher reactivity, compared to 3-unsubstitut-
ed analogues.17
Ph
Ph
Ph
100 °C,
12 h
NH
NH
N
N
N
CH(OEt)3, HCl
PhCl, 120 °C
N
• HCl
Ar NH2
Cl
+
Ph
NH
Ar
N
Ph
Cl
Ph
13a, Ar = Mes
13b, Ar = Dipp
Ar
12
14a, 60%
14b, 68%
15a•HCl, Ar = Mes, 65%
15b•HCl, Ar = Dipp, 77%
Mes = 2,4,6ꢀtrimethylphenyl; Dipp = 2,6ꢀbis(2ꢀpropyl)phenyl
15a•HCl
15b•HCl
8.4°
C1ꢀN1ꢀC9ꢀC14
C1ꢀN3ꢀC18ꢀC23
N2ꢀC2ꢀC3ꢀC8
159.7°
–98.4°
40.4°
–96.8°
43.0°
Scheme 5. Synthesis and X-ray crystal structures of
the bis-Mes/Dipp triazolium salts 21a,b•HCl.
Mes
N
THF, tꢀBuOK
Mes
HN Mes + 1:1 adduct
20a or tautomer)
r.t.
N
Ar = Mes
(
Ph
N
Ar
Cl
Ph
N
NH2
+
HN
19 (2:1 adduct)
• HCl
Ar
NH
Ph
16a
Ar
Ar
18a
THF, NMM
0οC to r.t.
CH(OEt)3, HCl
PhCl, 120 °C
N
N
,
b
,b
N
• HCl
NH
Ar
Cl
N
16,18,20
16,18,20
,
,
21a: Ar = Mes
21b: Ar = Dipp
Ph
20a,b
Ph
II.3 Synthesis of new mono-Mes/Dipp 1,2,4-triazolium
salts. For the later comparison in reactivities, we aimed at
synthesizing a series of mon0/bis-Mes/Dipp- and bis-
Ipp/Bph-substituted triazolium salts [Ipp: 2-(2-propyl)-
phenyl, BPh: (o-biphenylyl)]. Condensation of N-phenyl-
benzohydrazonoyl chloride (12)18 with the Mes/Dipp-
amines 13 gave the desired isomer of the hydrazonea-
mides 14. After ring closure with triethyl orthoformate,19
the desired triazolium salts 15a•HCl and 15b•HCl were
obtained in good yields after precipitation from ethyl
acetate. Recrystallization from hot ethyl acetate and DCM
(3:1) afforded crystalline samples of 15a•HCl and 15b•HCl,
suitable for X-ray structural analysis (Scheme 4). Both
crystal structures reveal similarity, in the sense that the
phenyl ring at N1 is virtually coplanar with the triazolium
ring, while the phenyl group at C3 is twisted out of the
plane. Most interestingly, the Mes/Dipp-group at N3 is
almost perpendicular to the triazolium ring, with a dihe-
dral angle of C1-N3-C18-C23 of -98.4° and -96.8° for
15a•HCl and 15b•HCl, respectively.
Ar
21a•HCl, 39%
21b•HCl, 32%
Mes = 2,4,6ꢀtrimethylphenyl; Dipp = 2,6ꢀbis(2ꢀpropyl)phenyl
21a•HCl
21b•HCl
75.7°
C1ꢀN1ꢀC9ꢀC14
C1ꢀN3ꢀC18ꢀC23
N2ꢀC2ꢀC3ꢀC8
66.7°
–103.8°
40.4°
–90.4°
18.5°
Gratifyingly, upon modification of the reaction condi-
tions [in situ treatment of the hydrazinium salts 18a,b
with N-methylmorpholine (NMM), 0oC reaction tempera-
ture], the formation of the desired hydrazoneamides 20
was achieved, which could be used in the next step with-
out prior purification. The final ring closure of 20a,b was
effected by treatment with triethyl orthoformate, and
II.4 Synthesis of bis-Mes/Dipp 1,2,4-triazolium salts.
After the successful preparation of the mon0-Mes/Dipp-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 24
furnished the desired bis-Mes/Dipp precatalysts 21a•HCl II.6 Spectroscopic properties, X-ray crystal struc-
1
2
3
4
5
6
7
8
and 21b•HCl in moderate yields. The X-ray crystal struc-
tures of 21a•HCl and 21b•HCl are shown in Scheme 5 (bot-
tom). In the solid state, the phenyl groups at C2 of both
21a•HCl and 21b•HCl are twisted out of the plane of the
triazolium ring, with dihedral angles of N2-C2-C3-C8 of
40.4° and 18.7°, respectively. The two Mes/Dipp groups at
N1 and N3 of the heterocyclic ring (C1-N1-C9-C14 and C1-
N3-C18-C23 dihedral angles) in 21a•HCl and 21b•HCl are
arranged in an almost perpendicular fashion, the two
Dipp groups of 21b•HCl more so than the two mesityl
groups of 21a•HCl. Notably, one of the Dipp groups of
21b•HCl is perfectly arranged perpendicular (C1-N3-C18-
C23 dihedral angle = -90.4°) to the triazolium ring.
tures, and catalytic activities of the free carbenes. For
NMR spectroscopic analysis (THF-d8), the free carbenes
15a,b and 21a-d were generated by in situ deprotonation
of the corresponding triazolium salts with tBuOK or NaH.
The carbene C-atoms of 15a, 15b, 21a, 21b, 21c and 21d
resonate at δ = 216.4, 216.7, 218.1, 219.0, 217.7, and 218.2
ppm, respectively. Their 13C NMR signals are thus in a
range similar to the triphenyl triazolylidene 11, the car-
bene C-atom of which has its resonance at δ = 214.8
ppm.22
9
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
Single crystals of the free carbenes 21a and 21b suitable
for X-ray structural analysis were obtained by crystalliza-
tion from a 3:1 mixture of n-pentane and THF. The mo-
lecular structure of 21b is shown in Figure 2 (see SI for the
structure of 21a). Comparison of the solid structures of
the carbene 21b (two independent molecules per unit
cell) and the azolium salt 21b•HCl (cf. Scheme 5) revealed
significant differences. The bond angle at the carbene
carbon C1 of 21b is significantly smaller than that of
21b•HCl. For 21b, N1-C1-N3 of 100.6° (99.4°) is typical for
singlet carbenes,23 whereas N1-C1-N3 amounts to 106.9°
for 21b•HCl. The C1-N1 and C1-N3 bonds of 21b are elon-
gated to 1.35-1.38 Å from the value of 1.32-1.33 Å found in
the triazolium salt 21b•HCl. However, the N1-C9 and N3-
C18 bonds are shorter (1.442-1.444 Å) than the corre-
sponding bond lengths in the triazolium salt 21b•HCl
(1.459-1.460 Å). Upon moving from the triazolium salt
21b•HCl to the carbene 21b, the largest structural changes
occur around the carbene center of 21b. These changes
II.5 Synthesis of bis-Ipp/bis-BPh 1,2,4-triazolium
salts. Our third line of syntheses aimed at the bis-Ipp/
bis-BPh (Ipp: 2-(2-propyl)phenyl; BPh: 2-biphenylyl) tria-
zolium carbenes/azolium salts 21c,d. The Ipp/Bph groups
were hoped to still induce a perpendicular arrangement of
the N-substituents, relative to the triazolium core. At the
same time, they were expected to be of a less shielding
effect with regard to the reactive carbene site. The bis-
Ipp/BPh triazolium salts of 21c,d were prepared by a pro-
cedure analogous to the one summarized in Scheme 5
(see SI for complete experimental details). Attempts to
crystallize the hydrochlorides of 21c and 21d were unsuc-
cessful. However, upon anion exchange to the corre-
sponding tetraphenylborates, we obtained crystalline
samples of 21c•HBPh4 and 21d•HBPh4 suitable for X-ray
structural analysis (Figure 1).
reflect a diminished π-delocalization in 21b as compared
to triazolium salts 21b•HCl. In the carbene 21b, the phenyl
group at C2 is virtually coplanar with the heterocyclic
ring, while the Dipp groups at N1 and N3 are perpendicu-
lar to the plane of the heterocyclic ring.
21c•HBPh4
89.6°
21d•HBPh4
C1ꢀN1ꢀC9ꢀC14
C1ꢀN3ꢀC18ꢀC23
N2ꢀC2ꢀC3ꢀC8
87.5° (74.0°)
–114.8 (–97.7°)
24.0° (38.3°)
–98.7°
43.3°
C1ꢀN1ꢀC9ꢀC14 90.3° (100.0°)
C1ꢀN3ꢀC18ꢀC23 –88.8° (–101.4°)
Figure 1. X-ray crystal structures of 21c•HBPh4 and
21d•HBPh4 (two independent molecules per unit cell: dihe-
dral angles of the second form are given in brackets); the
tetraphenylborate anion is omitted for clarity.
N2ꢀC2ꢀC3ꢀC8
0.7° (23.1°)
No reaction of 21b with O2, H2O, MeOH and PhCHO over 5 days!
Figure 2. Left: X-ray crystal structures of the bis-Dipp tria-
zolylidene 21b (two independent molecules per unit cell:
bond angles of the second form are given in brackets). Right:
Reactivity comparison of the 1,2,4-triazolylidenes 11 and 21b.
In fact, both N-substituents, especially those of
21c•HBPh4, are almost perpendicular to the heterocyclic
core, particularly at N1, less pronounced at N3. In the case
of 21d•HBPh4, we found two independent molecules per
unit cell. It is striking that both ortho-substituents of the
aromatic substituents at N1 and N3 point to the same side
of the triazolium ring. In the case of 21c•HBPh4, this con-
formation exists also in CDCl3 solution, as evidenced by
NOE-signals between the two iPr-groups (see SI for NMR
data).
We next examined the stability of the new triazolyli-
denes 15 and 21 towards MeOH. At room temperature, the
Enders-Teles carbene 11 inserts within minutes into the
O-H bond, and affords the methanol adduct 23 quantita-
tively (Figure 2). In contrast, mono-Mes 15a and mono-
Dipp 15b reached equilibrium after ca. 1 day, with ca. 90
% and 67 % of the methanol adduct being formed, respec-
tively. Similarly, equilibrium is reached at ca. 60 % con-
ACS Paragon Plus Environment

Page 5 of 24
Journal of the American Chemical Society
With 28, we observed the pronounced formation of un-
version for the bis-Ipp 21c. In contrast, the bis-BPh car-
1
2
3
4
5
6
7
8
bene 21d was completely converted to the methanol ad-
duct within 1h. Remarkably, for the bis-Mes and bis-Dipp
carbenes 21a and 21b, no reaction with methanol could be
observed over 5 days. Furthermore, solutions of 21b
showed no reaction with atmospheric oxygen, water or
benzaldehyde over 5 days, while the triphenyl triazolyli-
dene 11 reacts instantaneously with water (to 23, R = H,
Figure 2) and oxygen (to the urea 22), and adds stoichio-
metric benzaldehyde to the ketone 24 (Figure 2).16a,22 The-
se results clearly indicate a strong shielding of the car-
bene center by the two Mes/Dipp groups. Note, however,
that 21b effected the condensation of more reactive alde-
hydes, such as propionaldehyde, 3-phenyl propionalde-
hyde, and 2,4-bis(trifluoromethyl)benzaldehyde, to give
benzoin product.
saturated ester (~17%) as by-product. Note that the thia-
zolium 29, which was successfully applied to the redox
esterification of α,β-epoxy aldehydes,25 as well as the ben-
zimidazolium 308a gave no product formation with the
enal 25a as substrate (entries 10-11).
Table 1. Optimization of the reaction conditions for
redox esterification
O
O
9
NHC (10 mol%)
Base (15 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
H
OR
ROH (1.2 eq),
100οC
25a
26a, 31a-33a
Ph
N
Ph
N
ClO4
Ar
N
N
N
N
Cl
X
N
Ar
N
21a—HCl
21b—HCl
21c—HBPh4
21d—HBPh4
,
,
Ar = Mes
Ar = Dipp
Ph
Ph
N
Ar
Ph
Ph
11—HClO4
,
Ar = Ipp
15a—HCl
15b—HCl
,
,
Ar = Mes
Ar = Dipp
,
Ar = BPh
II.7 Redox esterification of α-substituted enals -
identification of suitable NHC catalysts. With the new
triazolium precatalysts in hand, we proceeded to investi-
Me
N
I
Me
Me
Me
Dipp
S
N
S
N
N
N
Cl
Ph
ClO4
N
Dipp
Cl
Me
N
Me
gate their activity in the redox esterification of
α-
27
28
29
30
substituted α,β-unsaturated aldehydes. As reported by
Scheidt et al.,8a the redox esterification of α-methyl-
cinnamic aldehyde could be performed under NHC catal-
ysis when using the benzimidazolium precatalyst 30.
More demanding substrates, such as hexahydro α-methyl-
cinnamic aldehyde (25a) or the enals 25e and 25j (see
Table 2) gave no reaction at all under the conditions de-
scribed by Scheidt. We chose 25a as the model substrate
for our study, and various NHCs were tested under stand-
ard conditions [10 mol % of NHC, 15 mol % of base and 1.2
equiv of alcohol (ROH) at 100 °C]. The results are summa-
rized in Table 1.
entry catalyst
Base
ROH
time
[h]
relative
yield [%]a
1b
2
11•HClO4
15a•HCl
15b•HCl
21a•HCl
21b•HCl
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
BnOH
40
40
40
40
40
40
40
40
40
40
40
120
30
40
40
30
30
30
0
26a, 33
26a, 60
26a, 75
26a, 97
26a, 18
26a, 20
26a, 15
26a, 51
0
3
4
5
6
21c•HBPh4 DIPEA
21d•HBPh4 DIPEA
7
To our delight, all new triazolium-based catalysts 15a,b
and 21a-d provided the desired saturated ester 26a, while
the parent triphenyl triazolium catalyst 11 gave no conver-
sion at all (entries 1-7). Among the new triazolium precat-
alysts, the bis-Dipp salt 21b•HCl gave the best results
(entry 5). It can be seen clearly that the reactivity of the
N-Dipp-substituted azolium is superior to its mesityl
analogue [21b•HCl > 21a•HCl (entries 4-5) and 15b•HCl >
15a•HCl (entries 2-3)]. Furthermore, triazoles with two-
fold N-Dipp/Mes substitution are more efficient than
their mono-N-Dipp/Mes analogues [21b•HCl > 15b•HCl
(entries 3, 5) and 21a•HCl > 15a•HCl (entries 2, 4)]. On the
other hand, the azolium salts with bis ortho-mono-sub-
stitution (21c•HBPh4 and 21d•HBPh4) were catalytically
less active than the mono N-Mes substituted salt 15a•HCl
(compare entries 6-7 with 2). This is in line with previous
reports that reactions of α,β-enals are more effectively
catalyzed by NHCs carrying ortho,ortho′-disubstituted
aromatic groups on the triazolium ring ("mesityl effect").5
8
27
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DBU
9
28
10b
11b
12c
13b
14
15
16
17
18
29
30
0
21b•HCl
21b•HCl
21b•HCl
21b•HCl
21b•HCl
21b•HCl
21b•HCl
26a, 97
26a, trace
26a, 90
26a, 33
31a, 90
32a, 90
33a, 90
Et3N
NMM
DIPEA
DIPEA
DIPEA
MeOH
EtOH
H2O
1
aDetermined by H NMR analysis of the crude reaction mix-
tures. bDetermined by GC-MS. c5 mol % of catalyst and 8 mol
% of DIPEA were used.
Lowering the loading of the pre-catalyst 21b•HCl to 5
mol% did not affect the excellent yield of 26a obtained,
however, longer reaction time was necessary (entry 12).
We also examined the effect of different bases. Et3N prov-
ed to be almost as effective as DIPEA (entry 14), but DBU
led to trace amounts of product only (entry 13). Much
lower reaction rates resulted from the use of weaker ba-
ses, such as N-methylmorpholine (entry 15). This result is
consistent with observations by Bode et al.9a that DIPEA
We furthermore examined the N-Dipp analogue 27 (see
SI for the synthesis and X-ray crystal structure of 27) of
the N-Mes catalyst described by Bode et al.,9 and the N-
Dipp thiazolium salt 28, previously described by Glorius
et al..24 The thiazolium salt 28 was found to be more effec-
tive than 27 (entries 8-9), albeit lower in reactivity com-
pared to our mono-Dipp 15b•HCl and bis-Dipp 21b•HCl.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 24
and NEt3 are the most effective bases, presumably acting smoothly under our catalytic conditions, affording the
1
2
3
4
5
6
7
8
as proton shuttles. Variation of the alcohol component
from benzyl alcohol to methanol or ethanol resulted in
similarly high ester yields (entries 16-17). Remarkable,
even water can serve as the nucleophilic component, and
affords the carboxylic acid (entry 18).
corresponding esters 26a-l in very good isolated yields of
70-82%. Notably, only with the enals 25i,m as substrates,
trace amounts of unsaturated ester were detected as by-
product. In the case of the α-fluoroenal 25m, dihydro-
fluorinated product was obtained together with the satu-
rated fluoroester 26m. For the β,β-disubstituted enals
25n-q, 5 mol% of 21b•HCl was sufficient to complete the
redox esterification within 10-12h. In line with this result,
the transformation of the less hindered β-mono-
substituted enals 25r-v proceeded even more rapidly, and
reached completion within 6-8h. Note that 25p was pre-
viously reported by Scheidt et al. to be recalcitrant to
redox esterification under their conditions, with benzim-
idazole 30 as catalyst.8a
II.8 Substrate scope of the bis-Dipp triazolium
(pre)catalyst 21b•HCl. With the newly developed cata-
lytic system [bis-Dipp triazolium salt 21b•HCl (5-10
mol%), DIPEA (1.5 equivalents relative to 21b•HCl)] in
hand, we set out to study the substrate scope with regard
to various α-substituted enals (Table 2). To our delight,
the redox esterification of a variety of α-methyl-, α-ethyl-
and even α-iso-propyl-substituted enals proceeded
9
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
Table 2. Substrate scope of the (pre)catalyst 21b•HCla
Under our standard conditions, the α,β-trisubstituted
enals 9, 25w-y remained unchanged and did not yield the
desired ester product, most likely due to excessive steric
hindrance. Interestingly, no formal γ-C-H insertion oc-
cured as side reaction, as it was the case with SIPr (1) as
carbene (cf. Scheme 3). We attribute this result to the
lower basicity of 21b compared to SIPr (1). In the cases of
the α-methylene aldehydes 25aa and 25ab, no ester for-
mation was observed. As ESI-MS analysis of the reaction
mixtures indicated formation of 1:1 adducts of the carbene
catalyst with the substrates, we assume that Michael addi-
tion to the deoxy Breslow intermediates had occured [cf.
Scheme 3 for the analogous cases of methacrolein (2a)
and ethacrolein (2b)].
R2
O
R2
O
21b—HCl (5ꢀ10 mol%)
R1
O
H
R1
OBn
DIPEA (8ꢀ15 mol %),
BnOH (1.2 eq),
100 °C
R3
R3
25
26
O
O
O
nꢀPr
O
OBn
OBn
OBn
OBn
CH3
CH3
CH3
CH3
26a
26bb
12 h, 80%
26cb
12 h, 80%
26d
50 h, 72%
30 h, 82%
O
O
O
O
nꢀHex
OBn
CH3
OBn
OBn
CH3
Ph
OBn
CH3
F
CH3
26eb
26g
55 h, 71%
26h
60 h, 70%
26f
48 h, 78%
27 h, 76%
O
O
O
O
nꢀBu
O
S
II.9 Application of NHC catalysis to the one-step
synthesis of nepetalactone (rac-35). The naturally
occuring monoterpene nepetalactone (35, Table 3) was
first isolated in 1941 by distillation from catnip oil.26 Re-
cently, it has been used as the starting material in the
synthesis of biological highly active Englerin A by Christ-
mann and coworkers.27 A literature survey revealed a few
enantioselective preparations of nepetalactone from 10-
oxocitral (34) or citronellal, requiring several synthetic
steps.28 Here we disclose the first one-step synthesis of
nepetalactone from 10-oxocitral (34) by NHC catalysis.
OBn
CH3
OBn
OBn
OBn
H3C
CH3
26l
30 h, 72% (dr 2:1)
CH3
H3C
26k
CH3
26i
72 h, 75%
26j
168 h, 60%
72 h, 80%
O
CH3
O
CH3
CH3
O
OBn
OBn
H3C
OBn
F
MeO
H3C
26mb,c
12 h, 85%
26nb
12 h, 80%
26ob
10 h, 65%
O
Ph
O
O
CH3
O
EtO
nꢀBu
OBn
OBn
Ph
OBn
26rb
6 h, 71%
OBn
26pb
10 h, 72%
26qb
15 h, 62%
26sb
O
6 h, 76%
O
O
O
As shown in Table 3, both of the bis-Mes/Dipp triazoli-
um salts 21a•HCl and 21b•HCl were similarly effective
catalysts for the bicyclization of linear 10-oxocitral (34) to
nepetalactone (rac-35, entries 4,5). The bis-Mes (pre)-
catalyst 21a•HCl proved somewhat superior, and afforded
nepetalactone (rac-35) in 60% isolated yield (entry 4).
Remarkable, the product rac-35 was obtained as one sin-
gle diastereomer, with cis-junction of the five-membered
rings, and exo-orientation of the methyl substituent, as
shown in Table 3. This diastereomer has previously been
shown to be the thermodynamically most stable one.29
The mono-Dipp triazolium salt 15b•HCl gave moderate
yields (entry 3). In contrast, both the triphenyl triazolyli-
dene 11 and its perchlorate salt, as well as the mono-Dipp
precursors 27, 28 (see Table 1 for structures), and IMes
(36) were catalytically inactive (entries 1-2, 9-11). It is wor-
thy of note that the conversion of 10-oxocitral (34) to
nepetalactone (rac-35) also proceeded when the triazoli-
OBn
OBn
H3C
OBn
MeO
26vb
6 h, 60%
Cl
26tb
8 h, 73%
26ub
8 h, 75%
No ester formation:
CH3
CH3
O
H3C
Ph
O
Ph
O
O
H
Ph
H
Ph
H
CH3
CH3
H
CH3
CH3
CH3
25w
9
25x
25y
O
CH3
CH3 O
Ph
H
H3C
H
25aa
25ab
a10 mol% of catalyst and 15 mol% of DIPEA were used, isolat-
ed yields are given. b5 mol % of catalyst and 8 mol % of
c
DIPEA were used. 1:1-mixture of 26m and dehydrofluorinat-
ed cinnamic ester was obtained.
ACS Paragon Plus Environment

Page 7 of 24
Journal of the American Chemical Society
yl group effects the ring closure to nepetalactone, and the
um salt 21b•HCl was used in the absence of base (compare
entries 5 and 6), albeit at much lower rate.30
regeneration of the cabene catalyst 21a,b.
1
2
3
4
Table 3. Catalyst screening for the one-step synthesis
of rac-nepetalactone (rac-35)
III. CONCLUSIONS
Based on the results of our mechanistic studies, we have
designed and synthesized 1,2,4-triazolium salts and their
corresponding triazolylidene carbenes carrying mesityl
(Mes) and 2,6-di(2-propyl)phenyl (Dipp) groups at N-1
and N-4. These novel N-heterocyclic carbenes efficiently
catalyze the redox esterification of α- and β-substituted
α,β-enals hitherto recalcitrant to this type of transfor-
mation. We interpret the superior catalytic activity of this
new class of NHCs by (i) enhanced formation of the Bres-
low intermediate, due to stabilizing interaction with the
dipersion energy donors (DEDs) at N-1,4, and (ii) by their
superior stability under the reaction conditions. Compu-
tational studies, addressing inter alia the dispersive effects
of Mes/Dipp substitution, will be published elsewhere.
Overall, the bis-Mes/Dipp triazolium salts 21a,b•HCl
emerged from our study as a novel NHC (pre)catalyst
with significant potential for other, thus far impossible,
Umpolung reactions of α- or β-substituted α,β-enals.
Work addressing the latter aspect is in progress in our
laboratory.
CH3
O
5
6
7
8
O
Mes
H3C
H
H
NHC (5 mol%)
DIPEA (8 mol%)
N
H
O
BF4
N
toluene, 60oC
Mes
CH3
H3C
CHO
34
9
rac-35
36
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
entry catalyst
t [h]
20
12
yield [%]a
T [°C]
60
1
11•HClO4
0
2b
11
60
0
3
15b•HCl
21a•HCl
21b•HCl
21b•HCl
21c•HBPh4
21d•HBPh4
27
60
18
34
4
60
6
66 (60)
60 (55)
63
5
6c
60
6
60
50
24
24
20
12
7
60
trace
trace
0
8
9
10
11
60
60
28
60
0
IV. ASSOCIATED CONTENT
36
60
24
0
aThe reaction was performed until completion and the prod-
uct yield was determined by GC using dodecane as an inter-
nal standard. The isolated yield is shown in brackets. b10 mol
% of phenol was added. cNo base was added.
Supporting Information. Synthesis of all new triazolium
salts, catalytic redox esterification of enals, one-step synthe-
sis of nepetalactone (rac-35), 1D, 2D NMR of the products
resulting from SIPr (1) and α-alkyl substituted enals, spectral
data and X-ray data of 3b, 10, 19, 15a,b•HCl, 21a,b•HCl,
21c,d•HBPh4, 21a,b and 27. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 6. Proposed mechanism for the one-step
synthesis of nepetalactone
21a: Ar = Mes
21b: Ar = Dipp
21a,b—HCl
V. AUTHOR INFORMATION
+ Base
O
H3C
H
ꢀ Base.HX
O
CH3
O
Corresponding Author
Ar
H
*berkessel@uni-koeln.de
H
N
34
N
CH3
rac-35
N
Ph
Author Contributions
OHC
CH3
Ar
21a,b
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
Ar
Ar
N
N
N
CH3
OH
O
Ph
N
CH3
N
N
O
Ar
Ph
γ
Ar
CHO
CH3
Ar
O
N
Funding Sources
N
CH3
V
II
CH3
Financial support by the Deutsche Forschungsgemeinschaft
(DFG), priority program "Control of London dispersion in-
teraction in molecular chemistry" (SPP 1807, grant no. BE
998/14-1) is gratefully acknowledged.
N
β
Ph
Ar
OHC
III
CH3
The mechanism proposed for the formation of nepata-
lactone (rac-35) by NHC catalysis is shown in Scheme 6.
First, deprotonation of the triazolium salt 21a,b•HCl by
the base generates the carbene 21a,b. The sterically less
hindered enal function of 34 is first attacked by the nu-
cleophilic carbene 21a,b, furnishing the diamino dienol II.
Intra- or intermolecular proton transfer to the γ-position
of II provides the azolium enolate III, now nucleophilic at
the β-position. Subsequent intramolecular Michael addi-
tion of the latter enolate III to the α-methyl enal gener-
ates the acyl azolium intermediate V. Finally, intramolec-
ular attack of the enolate oxygen atom of V at the carbon-
VI. ACKNOWLEDGMENT
This work was supported by the Fonds der Chemischen In-
dustrie and by BASF SE.
VII. REFERENCES
(1) For selected reviews on NHC catalysis, see: (a) Grossmann,
A.; Enders, D. Angew. Chem. 2012, 124, 320–332; Angew. Chem.
Int. Ed. 2012, 51, 314–325. (b) Izquierdo, J.; Hutson, G. E.; Cohen,
D. T.; Scheidt, K. A. Angew. Chem. 2012, 124, 11854-11866; Angew.
Chem. Int. Ed. 2012, 51, 11686−11698. (c) Bugaut, X.; Glorius, F.
Chem. Soc. Rev. 2012, 41, 3511–3522. (d) Douglas, J.; Churchill, G.;
Smith, A. D. Synthesis 2012, 2295–2309. (e) Ryan, S. J.; Candish,
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 24
L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906−4917. (f) Sarkar,
Weber, B. Angew. Chem. 1970, 82, 394‒395; Angew. Chem. Int.
1
2
3
4
5
6
7
8
S. D.; Biswas, A.; Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19,
4664−4678. (g) Hopkinson, M. N.; Richter, C.; Schedler, M.;
Glorius, F. Nature 2014, 510, 485–496. (h) D. M. Flanigan, F.
Romanov-Michailidis, N. A. White, T. Rovis, Chem. Rev. 2015, 115,
9307-9387.
(2) (a) Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762–1763. (b)
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726. (c) Berkessel,
A.; Elfert, S.; Yatham, V. R.; Neudörfl, J.-M.; Schlörer, N. E.;
Teles, J. H. Angew. Chem. 2012, 124, 12537–12541; Angew. Chem.,
Int. Ed. 2012, 51, 12370–12374.
(3) For selected examples of the benzoin reaction, see: (a)
Enders, D.; Kallfass, U. Angew. Chem. 2002, 114, 1822–1824;
Angew. Chem. Int. Ed. 2002, 41, 1743–1745. (b) Enders, D.;
Niemeier, O.; Balensiefer, T. Angew. Chem. 2006, 118, 1491–1495;
Angew. Chem. Int. Ed. 2006, 45, 1463–1467. (c) Takikawa, H.;
Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew. Chem. 2006, 118,
3572–3574; Angew. Chem. Int. Ed. 2006, 45, 3492–3494. For se-
lected Stetter reactions, see: (d) Stetter, H.; Kuhlmann, H. Org.
React. 1991, 40, 407–496. (e) Stetter, H.; Schreckenberg, M.
Angew. Chem., Int. Ed. Engl. 1973, 12, 81. (f) Enders, D.; Breuer,
K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta. 1996, 79, 1899–1902.
(4) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 14370–14371. (b) Burstein, C.; Glorius, F. Angew.Chem.
2004, 116, 6331–6334; Angew. Chem. Int. Ed. 2004, 43, 6205–6208.
(c) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006,
2418-2439.
(5) For reviews, see: (a) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu,
C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40,
5336−5346. (b) Chiang, P.-C.; Bode, J. W. TCI MAIL, 2011, 149, 2–
17. (c) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47,
696–707.
(6) Examples of asymmetric homoenolate chemistry: (a) He,
M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418–
8420. (b) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 418–
419. (c) Kaeobamrung, J.; Bode, J. W. Org. Lett. 2009, 11, 677–680.
(d) Chiang, P.-C.; Kaeobamrung, J.;.Bode, J. W.; J. Am. Chem.
Soc. 2007, 129, 3520–3521. (e) Fang, X.; Jiang, K.; Xing, C.; Hao, L.;
Chi, Y. R. Angew. Chem. Int. Ed. 2011, 50, 1910–1913. (f) Fu, Z.; Xu,
X.; Zhu, X.; Leong, W. W. Y.; Chi, Y. R. Nat. Chem. 2013, 5, 835–
839. (g) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860–
2861.
(7) Examples of asymmetric azolium enolate chemistry: (a)
He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088−15089. (b) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett.
2008, 10, 3817–3820. (c) Kaeobamrung, J.; Kozlowski, M. C.;
Bode, J. W. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20661−20665.
(d) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. An-
gew. Chem., Int. Ed. 2007, 46, 3107−3110. (e) Kobayashi, S.; Ki-
noshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Org. Lett. 2009, 11,
3934−3937. (f) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye , S.
Org. Lett. 2008, 10, 277–280.
(8) (a) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905–908. For
further studies on β-protonation of homoenolate equivalents,
see: (b) Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 1306–
1315. (c) Maki, B. E.; Patterson, E. V.; Cramer, C. J.; Scheidt, K. A.
Org. Lett. 2009, 11, 3942–3945. (d) Wang, M. H.; Cohen, D. T.;
Schwamb, B.; Mishra, R. K.; Scheidt, K. A. J. Am. Chem. Soc.
2015, 137, 5891–5894.
Ed. Engl. 1970, 9, 375. (b) Weber, L.; Lassahn, U.; Stammler, H.-
G.; Neumann, B. Eur. J. Inorg. Chem. 2005, 4590‒4597. (c) Lee,
Y.-G.; Moerdyk, J. P.; Bielawski, C. W. J. Phys. Org. Chem. 2012,
25, 1027‒1032. (d) Hans, M.; Wouters, J.; Demonceau, A.;
Delaude, L. Chem. Eur. J. 2013, 19, 9668-9676. (e) Maji, B.; Mayr,
H. Angew. Chem. 2013, 125, 11370–11374; Angew. Chem., Int. Ed.,
2013, 52, 11163–11167. (f) Hans, M.; Wouters, J.; Demonceau, A.;
Delaude, L. Chem. Eur. J. 2015, 21, 10870-10877. (g) Davies, A. T.;
Taylor, J. E.; Douglas, J.; Collett, C. J.; Morrill, L. C.; Fallan, C.;
Slawin, A. M. Z.; Churchill, G.; Smith, A. D. J. Org. Chem. 2013,
78, 9243-9257.
(12) (a) Grimme, S. Dispersion Interaction and Chemical Bond-
ing, in The Chemical Bond: Chemical Bonding Across the Periodic
Table; Frenking, G.; Shaik, S., Eds.; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, 2014. (b) Wagner, J. P.; Schreiner, P. R.
Angew. Chem. 2015, 127, 12446-12471; Angew. Chem. Int. Ed. 2015,
54, 12274–12296.
9
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
(13) Grimme, S.; Huenerbein, R.; Ehrlich, S. ChemPhysChem
2011, 12, 1258–1261.
(14) For selected examples of deoxy-Breslow intermediates de-
rived from NHCs and acrylic acid derivatives, see: (a) Biju, A. T.;
Padmanaban, M.; Wurz, N. E.; Glorius, F. Angew. Chem. Int. Ed.
2011, 50, 8412−8415. (b) Matsuoka, S.; Ota, Y.; Washio, A.;
Katada, A.; Ichioka, K.; Takagi, K.; Suzuki, M. Org. Lett. 2011, 13,
3722−3725.(c) Kato, T.; Ota, Y.; Matsuoka, S.; Takagi, K.; Suzuki,
M. J. Org. Chem. 2013, 78, 8739−8747. (d) Kato, T.; Matsuoka, S.;
Suzuki, M. J. Org. Chem. 2014, 79, 4484−4491. (e) Rajachan, O.-
a.; Paul, M.; Yatham, V. R.; Neudörfl, J.-M.; Kanokmedhakul, K.;
Kanokmedhakul, S.; Berkessel, A. Tetrahedron Lett. 2015, 56,
6537–6540.
(15) (a) Massey, R. S.; Collett, C. J.; Lindsay, A. G.; Smith, A. D.;
O’Donoghue, A. C. J. Am. Chem. Soc. 2012, 134, 20421−20432. (b)
Higgins, E. M.; Sherwodd, J. A.; Lindsay, A. G.; Armstrong, J.;
Massey, R. S.; Alder, R. W.; O’Donoghue, A. C. Chem. Commun.
2011, 47, 1559–1561.
(16) (a) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J.
H.; Melder, J.-P.; Ebel, K.; Brode, S. Angew. Chem. 1995, 107, 1119–
1122; Angew. Chem. Int. Ed. Engl. 1995, 34, 1021–1023. (b) Teles, J.
H.; Melder, J.-P.; Ebel, K.; Schneider, R.; Gehrer, E.; Harder, W.;
Brode, S.; Enders, D.; Breuer, K.; Raabe, G. Helv. Chim. Acta
1996, 79, 61–83. (c) Enders, D.; Breuer, K.; Kallfass, U.;
Balensiefer, T. Synthesis 2003, 1292–1295.
(17) Maji, B.; Breugst, M.; Mayr, H. Angew. Chem. 2011, 123,
7047–7052; Angew. Chem. Int. Ed. 2011, 50, 6915–6919.
(18) Sibi, M. P.; Stanley, L. M.; Jasperse, C. P. J. Am. Chem. Soc.
2005, 127, 8276−8277.
(19) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362–376.
(20) Ling, K. B.; Smith, A. D. Chem. Commun. 2011, 47,
373−375.
(21) (a) Dijk, T. V.; Burck, S.; Rong, M. K.; Rosenthal, A. J.;
Nieger, M.; Slootweg, J. C.; Lammertsma, K. Angew. Chem. Int.
Ed. 2014, 53, 9068–9071. (b) Frøseth, M.; Netland, K. A.; Røm-
ming, C.; Tilset, M. J. Organomet. Chem. 2005, 690, 6125–6132.
(22) Berkessel, A.; Elfert, S.; Etzenbach-Effers, K.; Teles, J. H.
Angew. Chem. 2010, 122, 7275–7279; Angew. Chem. Int. Ed. 2010,
49, 7120–7124.
(23) (a) Bauschlicher Jr, C. W.; Schaefer III, H. F.; Bagus, P. S.
J. Am. Chem. Soc. 1977, 99, 7106–7110. (b) Dixon, D. A. J. phy.
Chem. 1986, 90, 54. (c) Dixon, D. A.; Arduengo III, A. J. J. Am.
Chem. Soc. 1991, 95, 4180–4182.
(24) Piel, I.; Pawelczyk, M. D.; Hirano, K.; Fröhlich, R.;
Glorius, F. Eur. J. Org. Chem. 2011, 5475–5484.
(9) (a) Sohn, S. S.; Bode, J.W. Org. Lett. 2005, 7, 3873–3876. (b)
Mahatthanachai, J.; Bode, J.W. Chem. Sci.2012, 3, 192–197.
(10) (a) Berkessel, A.; Yatham, V. R.; Elfert, S.; Neudörfl, J.-M.
Angew. Chem. 2013, 125, 11364–11369; Angew. Chem., Int. Ed. 2013,
52, 11158–11162. (b) Yatham, V. R.; Neudörfl, J.-M.; Schlörer, N. E.;
Berkessel, A. Chem. Sci. 2015, 6, 3706−3711.
(25) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
8126–8127.
(26) (a) McElvain, S. M.; Bright, R. D.; Johnson, P. R. J. Am.
Chem. Soc. 1941, 63, 1558–1563. For structure determination, see:
(11) Examples for the generation and characterization of
azolium enolates from ketenes/NHCs: (a) Regitz, M.; Hocker, J.;
ACS Paragon Plus Environment

Page 9 of 24
Journal of the American Chemical Society
(b) Bates, R. B.; Eisenbraun, E. J.; McElvain, S. M. J. Am. Chem.
(30) The free carbene may be generated by deprotonation of
1
2
3
4
5
6
7
8
Soc. 1958, 80, 3420–3424.
the triazolium cation by the chloride counterion, as observed
earlier by Bode et al.: Kaeobamrung, J.; Mahatthananchai, J.;
Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010, 132, 8810–8812.
(31) CCDC 1422406 (10), 1422407 (21b), 1422408 (21a•HCl),
1422409 (21b•HCl), 1422410 (19), 1422411 (27), 1422412 (15a•HCl),
1422413 (15b•HCl), 1422415 (3b), 1422416 (21d•HBPh4), 1422417
(27) Willot, M.; Radtke, L.; Könning, D.; Fröhlich, R.; Gessner,
V. H.; Strohmann, C.; Christmann, M. Angew. Chem., Int. Ed.
2009, 48, 9105–9108.
(28) (a) Schreiber, S. L.; Meyers, H V.; Wiberg, K. B. J. Am.
Chem. Soc. 1986, 108, 8274–8277. (b) Santangelo, E. M.; Rotticci,
D.; Liblikas, I.; Norin, T.; Unelius, C. R. J. Org. Chem. 2001, 66,
5384–5387.
(29) Liblikas, I.; Santangelo, E. M.; Sandell, J.; Baeckström, P.;
Svensson, M.; Jacobsson, U.; Unelius, C. R. J. Nat. Prod. 2005, 68,
886–890.
(21c•HBPh4),
1447520
(21a)
contain
supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/ cif.
9
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
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 24
TOC graphics:
1
2
3
4
5
6
1,4-bis-Dipp/Mes
triazolylidene catalysts
redox
esterification
α
,
β
-substitution
tolerated
O
R2
O
R2
Ph
N
R1
H
R1
alkyl + RꢀOH
RO
N
N
R
alkyl
R
7
8
9
CH3
O
azolium
enolate
chemistry
O
H3C
single-step
bicyclization
H
H
H
O
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
CH3
H3C
CHO
R = Dipp
racꢀnepetalactone
10
ACS Paragon Plus Environment

Page 11 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
127x69mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 24
1
2
3
4
5
6
7
8
9
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
140x80mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 13 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
27x5mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 24
1
2
3
4
5
6
7
8
9
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
22x4mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 15 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
82x55mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 24
1
2
3
4
5
6
7
8
9
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
33x8mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 17 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
107x80mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 18 of 24
1
2
3
4
5
6
7
8
9
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
68x54mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 19 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
76x41mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 20 of 24
1
2
3
4
5
6
7
8
9
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
24x4mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 21 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
40x11mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 22 of 24
1
2
3
4
5
6
7
8
9
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
59x25mm (300 x 300 DPI)
ACS Paragon Plus Environment

Page 23 of 24
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
Revised version of "Table 2" graphics
255x472mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 24 of 24
1
2
3
4
5
6
7
8
9
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
160x69mm (300 x 300 DPI)
ACS Paragon Plus Environment