Dynamic Kinetic Resolution Enabled by Intramolecular Benzoin Reaction: Synthetic Applications and Mechanistic Insights

Article abstract of DOI:10.1021/jacs.6b02929

The highly enantio-, diastereo-, and regioselective dynamic kinetic resolution of β-ketoesters and 1,3-diketones was achieved via a chiral N-heterocyclic carbene catalyzed intramolecular cross-benzoin reaction. A variety of tetralone derivatives bearing two contiguous stereocenters and multiple functionalities were liberated in moderate to excellent yields and with high levels of stereoselectivity (>95% ee and >20:1 dr in most cases). In addition, the excellent regioselectivity control for aryl/alkyl 1,3-diketones, and the superior electronic differentiation of 1,3-diarylketones were highlighted. Moreover, a set of new mechanistic rationale that differs with the currently widely accepted understanding of intramolecular benzoin reactions was established to demonstrate the superior preference of benzoin over aldol transformation: (1) A coexistence of competitive aldol and benzoin reactions was detected, but a retro-aldol-irreversible benzoin process performs a vital role in the generation of predominant benzoin products. (2) The most essential role of an N-electron-withdrawing substituent in triazolium catalysts was revealed to be accelerating the rate of the benzoin transformation, rather than suppressing the aldol process through reducing the inherent basicity of the catalyst.

Full text of DOI:10.1021/jacs.6b02929

Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Article
Dynamic Kinetic Resolution Enabled by Intramolecular Benzoin
Reaction: Synthetic Applications and Mechanistic Insights
Guoxiang Zhang, Shuang Yang, Xiaoyan Zhang, Qiqiao Lin, Deb K. Das, Jian Liu, and Xinqiang Fang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02929 • Publication Date (Web): 07 Jun 2016
Downloaded from http://pubs.acs.org on June 7, 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 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Dynamic Kinetic Resolution Enabled by Intramolecular Benzoin Reꢀ
action: Synthetic Applications and Mechanistic Insights
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
Guoxiang Zhang, Shuang Yang, Xiaoyan Zhang, Qiqiao Lin, Deb. K. Das, Jian Liu, and Xinqiang
Fang∗
†State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, University of Chinese
Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
‡Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of
Matter, University of Chinese Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
Supporting Information Placeholder
reactions to well address the above issue. In 2009, Ema and coꢀ
workers reported the asymmetric desymmetrization of cyclic 1,3ꢀ
diketones affording bicyclic tertiary alcohols through an intramoꢀ
lecular crossꢀbenzoin reaction.3 In 2014, Johnson group disclosed
a graceful intermolecular two stereocenters forming benzoin
transformation through the dynamic kinetic resolution (DKR)5 of
βꢀstereogenic αꢀketo esters.4 An asymmetric desymmetrization of
acyclic 1,3ꢀdiketones was also achieved by our group recently.6
Based on these pioneering reports, we envisioned that the introꢀ
duction of an electronꢀwithdrawing group (EWG) into a ketoneꢀ
aldehyde substrate (e.g., βꢀketo ester 1a and 1,3ꢀdiketone 3 in
Scheme 1a and 1c respectively) should provide a new opportunity
in achieving a DKR through an NHC catalyzed intramolecular
benzoin reaction, wherein enantioenriched tetralone products with
two stereocenters and multiple functional groups will also be built
simultaneously.
ABSTRACT: The highly enantioꢀ, diastereoꢀ, and regioselective
dynamic kinetic resolution of βꢀketoesters and 1,3ꢀdiketones was
achieved via a chiral Nꢀheterocyclic carbene catalyzed intramoꢀ
lecular crossꢀbenzoin reaction. A variety of tetralone derivatives
bearing two contiguous stereocenters and multiple functionalities
were liberated in moderate to excellent yields and with high levels
of stereoselectivity (> 95% ee and > 20:1 dr in most cases). In
addition, the excellent regioselectivity control for aryl/alkyl 1,3ꢀ
diketones, and the superior electronic differentiation of 1,3ꢀ
diarylketones were highlighted. Moreover, a set of new mechaꢀ
nistic rationale that differs with the currently widely accepted
understanding of intramolecular benzoin reactions was established
to demonstrate the superior preference of benzoin over aldol
transformation: (1) a coꢀexistence of competitive aldol and benꢀ
zoin reactions was detected, but a retroꢀaldolꢀirreversible benzoin
process performs a vital role in the generation of predominant
benzoin products; (2) the most essential role of an Nꢀelectronꢀ
withdrawing substituent in triazolium catalysts was revealed to be
accelerating the rate of the benzoin transformation, rather than
suppressing the aldol process through reducing the inherent basicꢀ
ity of the catalyst.
Scheme 1. Key Challenges in Achieving DKR through
NHC Catalyzed Intramolecular Benzoin Reaction
INTRODUCTION
The asymmetric benzoin reaction enabled by chiral Nꢀ
heterocyclic carbenes (NHCs) has been a longstanding research
focus since 1966.1 The Enders, Rovis, Suzuki, Leeper, You, Canꢀ
non, Gravel, and Johnson groups, etc. have made great contribuꢀ
tions in this arena through exploiting novel chiral NHC catalysts
and discovering innovative benzoin reaction patterns, therefore
promoted significantly the development of this named reaction.2
Since there has been an increasing demand in assembling moleꢀ
cules with stereoꢀdiversity and structural complexity in a highly
selective and efficient manner both in basic organic research and
practical chemical industry, the discovery of protocols allowing
access to optically enriched substances with two or more stereoꢀ
centers via oneꢀstep benzoin reaction is thus urgent and indispenꢀ
sable. However, despite the enormous progress being made, it still
remains a significant challenge for the current stage of benzoin
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
1
2
3
4
5
6
7
8
9
However, comparing with the previous reports especially those
gation of the intramolecular benzoin reaction at a fundamental
level. Herein we report our results.
from the Suzuki2gꢀh, Enders2f and You2i,2l groups, at least two forꢀ
midable challenges (Scheme 1) must be addressed to achieve an
ideal outcome: (1) the competing aldolꢀtype side reactions must
be suppressed. In Suzuki, Ender, and You’s early studies, two
main strategies were utilized to suppress an aldol process: first,
the amounts of bases were controlled accurately to be equal to or
less than those of the catalysts to minimize aldol side reactions;2fꢀ
Scheme 2. Natural Products Containing Tetralone Units
i,2l,7
second, because the inherent basicity of a free carbene can
also promote an aldol process,2h,8 Suzuki and coꢀworkers modified
the NHC catalyst through replacing Nꢀphenyl group with an Nꢀ
electronꢀwithdrawing 3,5ꢀ(CF3)2C6H3 group, thereby reduced the
capability of the catalyst in enolizing substrates.2h This approach
proved successful, but when substrates with relatively strong acidꢀ
ic protons adjacent to carbonyl groups were utilized, aldol prodꢀ
ucts were still unavoidable (Scheme 1b). For example, in Suzuki’s
report,2h the treatment of S1 or S2 with phenyl substituted Rovis
catalyst C1 afforded aldolꢀtype products in 82% and 37% yields
respectively; although the side reactions can be significantly supꢀ
pressed by using electronꢀpoor Nꢀ3,5ꢀ(CF3)2C6H3 catalyst C2, a
27% combing yield of the byproducts was still obtained when S1
was tested (Scheme 1b). Thus, considering that the substrates used
in this study (e.g., 1a and 3 in Scheme 1) contain more acidic
protons than those in S1/S2 (the Ka value of 1a is about 4ꢀ5 orders
of magnitude greater than that of S1 according to the Bordwell’s
pKa table9), it can be reasoned that an aldol process should be
inevitable and even be predominant.10 Also to be noted, in all the
known successful NHC catalysis mediated DKR reports, such as
those from the Scheidt,11a Johnson4,11b and Wang11cꢀd groups, exꢀ
cess amounts of bases relative to the catalysts were utilized to
achieve efficient DKRs, so this contradiction also increases the
difficulty of reducing aldolꢀtype byproducts to get an ideal outꢀ
come. (2) furthermore, when 1,3ꢀdiketone 3 was employed as the
substrate, new challenge of regioselectivity control during the
benzoin reaction arises and must be well handled besides the diaꢀ
stereoꢀ and enantioselectivity, otherwise a mixture of maximal
eight stereoisomers could be obtained from the benzoin process,
thereby making this methodology synthetically useless (Scheme
1c). However, the regiochemistry of the intramolecular benzoin
reaction remains an underexploited field thus far, therefore differꢀ
ent to the first challenge, no readily available approaches or even
hints can be drawn from the currently known reports1,2 regarding
the question that which ketone moiety will be attacked preferenꢀ
tially.
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
RESULT AND DISCUSSION
As illustrated in Table 1, we commenced by selecting readily
available βꢀketoester 1a and a series of aminoindanolꢀderived
carbene catalysts developed initially by the Rovis group to test
our hypothesis. Unsurprisingly, aldol product 2a’ was produced
predominantly in 76% yield when triazolium A13 (15 mol%) was
used as the catalyst and K2CO3 (1.0 eq.) as the base, and only 10%
yield of benzoin product 2a was obtained, albeit with an excellent
diastereoselectivity and a promising 84% ee (Table 1, entry 1).
Mesitylꢀsubstituted catalyst B14, first reported by the Bode group,
was also tested but no better result than that of A was obtained
(Table 1, entry 2). Catalyst C, bearing a 4ꢀbromoꢀphenyl group,
induced an excellent ee of 99%, however, the aldol product was
still predominant (Table 1, entry 3). The strong electronꢀ
withdrawing C6F5 group in catalyst D15 was proved to be essential
in tuning the distribution of products, with benzoin adduct 2a
isolated in 66% yield, but with a low 61% ee (Table 1, entry 4). A
variety of chiral catalysts F−I with diverse skeletons were further
examined, and different ratios of benzoin to aldol products were
observed with varying degrees of enantioselectivity (Table 1,
entries 5−8). To our delight, a search for alternative electronꢀ
withdrawing substituents in Rovis type catalysts revealed that
triazolium E16, with an Nꢀtrichlorophenyl group, was optimal
regarding both the yield (88%) and ee (99%) (Table 1, entry 9).
Further effort to suppress the aldol byproduct by evaluating other
reaction parameters such as bases and solvents didn’t lead to betꢀ
ter results (Table 1, entries 10−13). Cheerfully, we found that
lowering the reaction temperature to 0 °C was beneficial to diminꢀ
ish the aldol adduct (Table 1, entry 14). Thus finally, the optimal
result was established by setting the temperature at −20 °C and
benzoin product 2a was produced in almost quantitative yield and
with 99% ee (Table 1, entry 15). To be noted, the use of subꢀ
stoichiometric K2CO3 retarded the reaction and led to an increased
amount of 2a’ significantly (Table 1, entries 16).
To address all the above challenges, we recently conducted the
DKR of ketones with αꢀEWGs via an intramolecular benzoin
reaction. To our delight, through the elaborate screening of reacꢀ
tion conditions, aldolꢀtype side reactions were completely “supꢀ
pressed”, furnishing 1ꢀtetralone products with two contiguous
stereocenters in moderate to high yields and with high degrees of
stereoselectivity. To be noted, the enantioenriched tetralone prodꢀ
ucts are useful building blocks in organic synthesis and privileged
structural motifs in a broad range of natural products and pharmaꢀ
ceuticals (Scheme 2).12 What’s more, in contrast to the wellꢀ
known strategy of trying to suppress aldol reactions to guarantee a
smooth benzoin process,2fꢀh,7 the mechanistic study of this protoꢀ
col revealed a competitive aldol process occurring together with
the benzoin one, but the reversible aldol and irreversible benzoin
processes jointly enabled the formation of the desired products in
high yields. Moreover, different to the widely accepted viewꢀ
point,2h,i,l,n the most important role of Nꢀelectronꢀwithdrawing
groups in catalysts was proved to be not reducing the basicities of
catalysts but accelerating the rates of benzoin transformations. All
these findings provided a number of new insights into the investiꢀ
With the optimal conditions in hand, we set on exploring the
generality and limitations of this NHC catalyzed DKR process
(Table 2). A variety of aromatic ketones with αꢀethoxycarbonyl
group performed very well, and both electronꢀdonating and withꢀ
drawing substituents on the aryl rings were tolerated, with exꢀ
tremely excellent 99% ee observed in most cases (Table 2, 2a−2h).
Replacement of the phenyl ring at the ketone moiety with a hetꢀ
eroꢀaromatic thienyl group had little effect on the yield (89%) and
enantioselectivity (99% ee) (Table 2, 2i). Introduction of a fluoro
substituent into the formylphenyl ring did not encumber the reacꢀ
tion considering both the yield and ee (Table 2, 2j). The change of
electronꢀwithdrawing CO2Et group to a phenyl group allowed
access to the benzoin product with excellent ee (95%), albeit in a
moderate yield (Table 2, 2k). We also surveyed the aliphatic meꢀ
thyl and ethyl ketone substrates and moderate ee (75% and 65%,
respectively) was detected (Table 2, 2l and 2m). Unfortunately,
efforts to expand this protocol to substrates with aliphatic formal
groups were not successful; mixtures of two diastereomers were
obtained in low yields (< 20%) and with low ee (< 30%).
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
1
2
Table 1. Initial Studies and Reaction Optimizationa
Table 2. Scope of αꢀKetoestersa
3
4
5
6
7
8
9
O
CHO
O
HO
R1
O
O
CHO
R3
HO
E
NHC (15 mol %)
(15 mol %)
R1
HO
Ph
PhOC
Ph
R3
+
K2CO3 (1 eq.), THF
argon, -20 °C
CO2Et
1a
base (1 eq.)
conditions
EWG
EtO2C
EWG
H
2
EtO2C
(> 20:1 dr )
EWG = CO2Et or Ph
(racemic)
(single diastereomer)
X-ray of 2f
2a' (aldol)
BF4
2a
(cross-benzoin)
rac-1
O
O
O
HO
O
BF4
N
O
product
2b
R
yield (%) ee (%)
Ph
BF4
N
N
N
HO
Me
2c OMe
92
82
85
94
98
90
89
99
99
99
99
99
N
N
O
N
Ph
N
HO
Ph
Bn
Ph
Mes
BF4
G
2d
2e
2f
F
Br
F
Cl
Ph
N
R
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
Me
EtO2C
H
EtO2C
H
2a
Ar
Ar = Ph; Ar = Mes
C Ar = 4-BrC6H4;
Ar = C6F5
E Ar = 2,4,6-Cl3C6H2
2h
95% yield
99% ee
A
B
BF4
EtO2C
H
HO
Ph
99% yield
99% ee
2g
N
N
N
N
N
Ph
D
Ph
Ph
N
I
H
O
O
O
HO
Ph
O
O
HO
F
HO
Ph
HO
HO
Me
Et
Ph
S
entry
1
conditions
yield (2a/2a’, %)b
10/76
6/53
ee (2a, %)c
EtO2C
H
EtO2C
H
MeO2C
H
2mb
EtO2C
H
2l
Ph
H
2i
2j
2k
A, K2CO3, THF, 23 °C
B, K2CO3, THF, 23 °C
C, K2CO3, THF, 23 °C
D, K2CO3, THF, 23 °C
F, K2CO3, THF, 23 °C
G, K2CO3, THF, 23 °C
H, K2CO3, THF, 23 °C
I, K2CO3, THF, 23 °C
E, K2CO3, THF, 23 °C
E, DIPEA, THF, 23 °C
E, Cs2CO3, THF, 23 °C
84
68
99
61
49
24% yield
65% ee
95% yield
97% ee
60% yield
95% ee
39% yield
75% ee
89% yield
99% ee
aAll reactions were run on a 0.2 mmol scale; all yields were of isolated prodꢀ
ucts; in all cases, only one diastereomer was observed via 1H NMR analysis; ee
values were determined via HPLC analysis on a chiral stationary phase. The
absolute configuration was determined via the Xꢀray single crystal structure
analysis of 2g17. bCH2Cl2 was used as the solvent.
2
3
8/81
4
66/23
29/51
42/20
25/46
1/84
5
the possibility of achieving the efficient DKR of 1,3ꢀdiketones via
an intramolecular benzoin reaction, we first examined the reactiviꢀ
ty of 3a under the standard conditions utilized in Table 2. Cheerꢀ
fully, an excellent regioselectivity was detected, with 4a as the
single benzoin product among eight possible stereomers, albeit
with moderate ee; no any other possible isomers such as 4a’ were
observed from the 1H NMR analysis of the reaction mixture
(Scheme 3a). Moreover, further evaluation of propionyl substitutꢀ
ed 3b showed somewhat surprising outcome because 4b was isoꢀ
lated as the only product, with the phenyl ketone moiety attacked
by the acyl anion equivalent (Scheme 3b). It’s worthwhile to menꢀ
tion that 4b was furnished with a high degree of enantioselectivity
(99% ee). From the observed results, the regioselectivity sequence
in this DKR mediated intramolecular benzoin reaction can be
defined as Me>Ph>Et with respect to the reactivities of ketone
units. At the current stage, we speculate that the superposition of
both electronic and steric factors of different ketone substituents is
responsible for the excellent regioselectivity observed, and the
powerfulness of NHC catalysts in distinguishing minute reactivity
differences (such as Me and Et) was distinctly illustrated.20 More
insights into this regioselectivity preference will be one of the
focuses in our ongoing investigation.
6
−98
−8
99
99
99
92
97
99
99
99
99
7
8
9
88/7
10
11
12
13
14
15
16d
65/22
72/4
E, K2CO3, Toluene, 23 °C
E, K2CO3, CH2Cl2, 23 °C
E, K2CO3, THF, 0 °C
74/6
81/5
90/3
E, K2CO3, THF, −20 °C
99/0
E, K2CO3, THF, −20 °C
68/16
aReaction conditions: 1a (0.2 mmol), NHC (15 mol %), solvent (2 mL), base
(0.2 mmol), argon protection, 12h. Diastereomeric ratios were determined via
1H NMR analysis of reaction mixtures. bIsolated yields based on 1a. cDeterꢀ
mined via HPLC analysis on a chiral stationary phase; the absolute configuraꢀ
tion was assigned by analogy to the Xꢀray single crystal structure of 2f17.
dK2CO3 (0.75 eq.) was used.
Scheme 3. Reactions of Me/Ph and Et/Ph 1,3ꢀDiketones
O
HO
O
HO
Me
Ph
4a
(a)
83% yield
> 20:1 dr
63% ee
Having achieved an efficient DKR of βꢀketoesters through the
highly selective intramolecular benzoin reaction, we wondered
whether this methodology can be extended to 1,3ꢀdiketone subꢀ
strates such as 3a (Scheme 3). As has been illustrated in Scheme
1c, it’s more challenging because besides the resolution efficiency,
the regioselectivity control is also an arduous mission to be acꢀ
complished. It’s wellꢀknown that regioselective transformations
play a vital role in organic synthesis,18 but to the best of our
knowledge, even in the whole domain of asymmetric catalysis,
there are very limited successful DKR reports using 1,3ꢀdiketones
as substrates, most probably owning to the enormous difficulties
in controlling the regioselectivity of two similar ketone moieties.19
Additionally, although regioselectivity study is one of the fundaꢀ
mental aspects in the research field of the intramolecular benzoin
reaction, hitherto the related reports are scarcely seen. So, to test
Ph
H
O
Me
4a'
H
O
O
O
CHO
e
M
not observed
=
R
standard
Ph
conditions
O
HO
Ph
O
R
R
=
E
HO
Et
t
(b)
3a, R = Me
3b
4b
, R = Et
Et
92% yield
> 20:1 dr
99% ee
Ph
4b'
H
H
O
O
not observed
The scope of this NHC catalyzed DKR of 1,3ꢀdiketones proved
very general. First, product 4a can be gotten with 83% ee under
slightly modified conditions using CH2Cl2 as the solvent (Table 3,
4a). Second, variations on the substitution pattern at the aryl keꢀ
tone moiety of 2b were possible. For example, electronꢀdonating
Me or OMe groups had little effect on the enantioselectivities
(Table 3, 4c−4d); introduction of a phenyl substituent was also
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
1
2
Table 3. Scope of 1,3ꢀDiketonesa
alities congested 1,2ꢀdiol 7a in 89% yield and with 99% ee
(Scheme 5a).21 Moreover, the ethyl ketone moiety of 4b underꢀ
went the chemoselective reaction with hydroxylamine to form the
oxime, and then after the Beckmann rearrangement, chiral amide
7b was delivered without any erosion in enantioselectivity
(Scheme 5b).22
3
4
5
6
7
8
9
O
HO
R3
O
O
CHO
R3
R1
E
(15 mol%)
R1
R2
K2CO3 (1 eq.), THF, argon, -20 °C
H
R2
4
O
rac-3
(single diastereomer)
Scheme 5. Derivatization of Benzoin Products
O
HO
product
R
yield (%) ee (%)
4b
4c
4d
4e
4f
H
Me
OMe
Ph
F
92
59
54
55
59
82
66
99
99
99
98
99
98
97
Me
O
HO
HO
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
MgBr
HO
Ph
H
R
2a
89% yield
> 20:1 dr
99% ee
Ph
O
4a
THF, argon
(a)
(b)
99% ee
7a
7b
83% yield 28% yieldb
63% ee 83% eeb
EtO2C
HO
Et
H
4g
4h
Cl
Br
H
O
4h
X-ray of
O
O
1) NH2OH HCl
O
4b
O
O
Ph
O
61% yield
> 20:1 dr
99% ee
F
HO
2) TsCl, Et3N,
then SiO2
HO
HO
HO
O
99% ee
N
H
H
Et
Et
H
4i
Et
H
4j
H
H
O
59% yield
99% ee
4k
4l
O
O
O
MECHANISTIC STUDIES
44% yield
96% ee
63% yield
> 99% ee
60% yield
99% ee
Control Experiments. As has been speculated in the first
challenge (Scheme 1a–b), and based on the current understanding
of the intramolecular benzoin reaction, an aldol side reaction in
this methodology should be inevitable owning to the easily enolizꢀ
ing feature of the substrates under basic conditions. Thus it is
really puzzling since an excellent outcome was obtained in view
of the preference of benzoin over aldol transformations. To clarify
this perplexity and gain more insights into this highly selective
process, we conducted the control experiments depicted in
Scheme 6. First, despite the wellꢀknown reversible feature of benꢀ
zoin reactions,23 the exposure of compound 2a to the standard
conditions with catalysts entꢀE or A did not resulted in any eroꢀ
sion of the ee value or the formation of aldol products, indicating
an irreversible benzoin process24 in this protocol (Scheme 6, eq 1
and 2). However, the treatment of aldol product 2a’ with trichloꢀ
roꢀcatalyst E led to a full conversion of 2a’ to the benzoin product
2a under the standard conditions, presumably through a retroꢀ
aldolꢀbenzoin process (Scheme 6, eq 3). This result also suggests
the possibility of using aldol adducts as aldehyde surrogates to
undergo NHC catalyzed reactions. In contrast to catalyst E, pheꢀ
nylꢀcatalyst A cannot facilitate an aldol to benzoin transformation
within 12h at room temperature, but we did observe the forꢀ
mations of small amounts of benzoin product 2a and starting maꢀ
terial 1a in an extended reaction time (48h), which unambiguousꢀ
ly demonstrated the existence of a retroꢀaldol process25 (Scheme 6,
eq 4).
aSee footnote a in Table 2. The absolute configuration was determined via the
Xꢀray single crystal structure analysis of 4h17. bCH2Cl2 was used as the solvent.
amenable, affording 4e in 55% yield and with excellent 98% ee
(Table 3, 4e); substrates equipped with electronꢀwithdrawing F,
Cl or Br groups at the paraꢀposition of the aryl ring were tolerated,
releasing the annulation products in moderate to good yields (59%
−82%) and with excellent enantioselectivities (97−99% ee, Table
3, 4f−4h). The substrate diversity was further evaluated by introꢀ
ducing a fluoro group into the formyl aromatic ring and no any
erosion in enantioselectivity was detected (Table 3, 4i). A hetꢀ
eroaromatic furyl group substituted ketone was compatible under
the standard conditions (Table 3, 4j). The replacement of the proꢀ
pionyl moiety with a butyryl or cyclopropanecarbonyl group had
no significant influence on the regioꢀ and enantioselectivities (99%
ee in both cases, Table 3, 4k and 4l). It’s noteworthy that in all
cases the benzoin products were obtained with excellent > 20:1 dr
and no any other possible benzoin adducts were perceived.
The substrate scope of this methodology was further expanded
to 1,3ꢀdiaryketones such as 5a. To our delight, the subjection of
5a to the standard conditions exhibited excellent electronic differꢀ
entiation, with the electronꢀpoor aryl ketone unit being attacked
preferentially. However, two diastereomers of 6a (35% yield, 99%
ee) and 6b (53% yield, 14% ee) were generated, and their strucꢀ
tures were confirmed unambiguously via the Xꢀray crystal analyꢀ
sis17 (Scheme 4). Disappointingly, attempts to explore the reaction
of 1,3ꢀdialkylketones (e.g., Me/Et or Et/cyclopropyl substituted
1,3ꢀdiketones) was not successful; complicated reaction mixtures
were obtained and no possible benzoin products were identified.
Anyway, we have provided useful information for the first time
with respect to the regiochemistry of the intramolecular benzoin
reaction.
Scheme 6. Control Experiments
O
ent-E (15 mol %)
A
(15 mol %)
HO
2a
2a
(1)
(3)
(2)
(4)
Ph
K2CO3 (1 eq.), THF
-20 °C, 12h, argon
K2CO3 (1 eq.), THF
-20 °C, 12h, argon
99% yield
99% ee
99% yield
99% ee
2a
(99% ee)
EtO2C
HO
E
(15 mol %)
PhOC
A (15 mol %)
2a' + 2a + 1a
2a
99% yield
99% ee
Scheme 4. Reaction of Diaryl Substituted 1,3ꢀDiketone
K2CO3 (1 eq.), THF
23 °C, 48h, argon
K2CO3 (1 eq.), THF
-20 °C, 12h, argon
EtO2C
14
: 1 : 1
2a'
Cl
NMR Monitoring Experiments. Furthermore, to get an intuꢀ
CHO
itive understanding of the reaction profile, we performed NMR
tracking experiments through detecting the concentrations of the
starting material and the benzoin/aldol products (Figures 1−2).
The reaction diagram of 1a with trichloroꢀcatalyst E (Figure 1)
reveals a competitive aldol process against the benzoin one occurꢀ
ring at the initial stage, and then aldol product 2a’ even predomiꢀ
nates over benzoin adduct 2a at the point of the 30th minute.
Thereafter, 2a’ gradually diminishes accompanied by an increasꢀ
ing amount of 2a, therefore confirming that part of 2a is produced
through a retroꢀaldolꢀbenzoin process (Figure 1).26 In contrast, the
standard conditions
+
O
O
6a
35% yield
99% ee
6b
5a
MeO
53% yield
14% ee
To showcase the synthetic applications of this protocol, further
transformations based on the enantioenriched benzoin products
were performed in highly chemoꢀ and stereoselective manners
(Scheme 3). For instance, the diastereoselective nucleophilic atꢀ
tack of chiral 2a by vinylmagnesium bromide furnished functionꢀ
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
reaction profile of 1a under the catalysis of phenylꢀcatalyst A
and sterically more hindered Nꢀsubstituents were considered to be
beneficial for the reactivity promotion in acyl anion related reacꢀ
tions.30,31 Based on these important reports and the data depicted
in Figures 1−2, we concluded that the most important role of an
NꢀEWG in catalysts such as E is to enhance the rate of benzoin
process to be capable of competing with, rather than suppressing
the aldol reactions. In contrast, phenyl catalyst A acts on the benꢀ
zoin reaction in a much slower fashion, caused probably by both
the relatively slow Breslow intermediate formation and the slugꢀ
gish catalyst turnover in the final benzoin product formation
step,30,31 therefore no remarkable benzoin product can be isolated
within the reaction time (12h). However, it can be reasoned that,
given enough time, the full conversion of 1a to 2a can be realized.
1H NMR analysis of the reaction in Scheme 7 confirmed this deꢀ
duction: 1H NMR analysis of the reaction mixture showed that the
ratio of 2a versus 2a’ increased from 1:7 to 1:3 when the reaction
time was extended to 48 h. As a whole, this new finding—an Nꢀ
EWG in catalyst is to accelerate the benzoin reaction, not to supꢀ
press the aldol one—is another sharpest contrast to the intramoꢀ
lecular benzoin reaction related early reports.2fꢀI,7
(Figure 2) shows a continuous formation of aldol product 2a’
together with a slow generation of 2a in the initial several hours.
But to be noted, the amount of 2a’ slightly decreases in the 6th
hour, accompanied by a small increase in the amount of benzoin
product 2a (Figure 2). Hence in both cases, the aldol reactions are
absolutely not suppressed, and the main difference between them
lies in the rates of the benzoin products formation, with a superior
one from catalyst E than that from A. Therefore, entirely distinct
from the presently widely accepted and utilized aldolꢀsuppression
strategy,2fꢀI a retroꢀaldolꢀbenzoin process lays the foundation of
the success of this intramolecular benzoin reaction.27
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 7. Reaction of 1a Under the Catalysis of A in Difꢀ
ferent Times
O
BF4
N
N
N
HO
O
O
CHO
A
Ph
PhOC
(15 mol %)
HO
Ph
Ph
+
K2CO3 (1 eq.), THF
23 °C, argon
EtO2C
CO2Et
EtO2C
2a'
2a
Figure 1. Reaction profile of 1a under the catalysis of E at −20 ºC. All
conditions were the same as that in Table 2.
1a
12h: 2a/2a' = 1:7 (> 95% conversion)
2a 2a' 1:3
(> 95% conversion)
48h:
/
=
Proposed Mechanism. On the basis of the above analysis, the
mechanistic profile of the whole reaction system can be briefly
described in the following Scheme 8. At the initial stage, enoalte
Intꢀ1 is formed in a fast and reversible way from both enantioꢀ
mers of 1a under basic conditions, followed by the rapid release
of aldol product 2a’. Simultaneously, the Breslow intermediate
Intꢀ2 is also generated quickly and reversibly30 from (S)ꢀ1a and
finally afford 2a via an irreversible benzoin reaction. In contrast,
(R)ꢀ1a acts on the NHC catalyst much more slowly, hence the
minor isomer 2a’’ was not perceived. To be noted, although the
retroꢀaldol step occurs in a slow fashion, it exists throughout the
entire dynamic reaction system since the formation of aldol prodꢀ
uct 2a’.
Scheme 8. Mechanistic Profile
Figure 2. Reaction profile of 1a under the catalysis of A at 23 ºC. Other
conditions were the same as that in Table 2.
O
Ph
C
HO
H
N
N
EtO2C
t
s
a
f
Evaluation of the Role of NꢀEWG in the Catalyst. Smith
et al. have reported a range of 16.5‒18.5 for the pKa values of
triazolium salts with different Nꢀsubstituents in aqueous solution
(the pKa of triazolium A is 16.5; pKa of D is 18.5).28 However,
the pKa values of acetylacetone and ethyl acetoacetate in water
are 9.0 and 10.7 respectively.29 These data indicate that the free
carbenes derived from both catalysts A and E have stronger basicꢀ
ities than that from deprotonated 1a; plus with the stoichiometric
K2CO3 employed in the reaction, we reason that the distinction
between A and E in suppressing aldol processes caused by their
different basicities should be unconspicuous, thereby not decisive
for the formation of benzoin products in this work. The Smith
group has revealed markedly superior rates performed by Nꢀ
electronꢀdeficient aryl triazolium precatalysts than those with Nꢀ
electronꢀrich substituents in intramolecular Stetter reactions.30
Bode et al. have also studies comprehensively the reactivity disꢀ
tinction of differently substituted triazoliums.31 Electron deficient
N
N
O
CHO
NHC
f
a
s
t
Ph
Int-2
CO2Et
(S)-1a
O
fast
HO
Ph
HO
PhOC
2a
(major)
O
CHO
EtO2C
fast
Ph
Int-1
O
EtO2C
2a'
slow
CO2Et
HO
Ph
(aldol)
fast
2a''
EtO2C
(not observed)
O
CHO
w
o
l
NHC
Ph
s
N
N
HO
CO2Et
O
(R)-1a
N
s
l
o
w
Ph
EtO2C
N
H
C
Int-3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
1
2
3
4
5
6
7
8
(2) For selected reports on chiral NHC catalyzed benzoin type homoꢀ
CONCLUSION
couplings, see: (a) Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta.
1996, 79, 1217. (b) Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin
Trans. 1 1998, 1891. (c) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed.
2002, 41, 1743. (d) Ma, Y.; Wei, S.; Wu, J.; Yang, F.; Liu, B.; Lan, J.;
Yang, S.; You, J. Adv. Synth. Catal. 2008, 350, 2645. (e) Baragwanath, L.;
Rose, C. A.; Zeitler, K.; Connon S. J. J. Org. Chem. 2009, 74, 9214. For
selected reports on chiral NHC catalyzed crossꢀbenzoin reactions, see: (f)
Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed. 2006, 45,
1463. (g) Takikawa, H.; Hachisu,Y.; Bode, J. W.; Suzuki, K. Angew.
Chem., Int. Ed. 2006, 45, 3492. (h) Takikawa, H.; Suzuki, K. Org. Lett.
2007, 9, 2713. (i) Li, Y.; Feng, Z.; You, S.ꢀL. Chem. Commun. 2008, 2263.
(j) Enders, D.; Grossmann, A.; Fronert, J.; Raabe, G. Chem. Commun.
2010, 46, 6282. (k) DiRocco, D. A.; Rovis, T. Angew. Chem., Int. Ed.
2012, 51, 5904. (l) Jia, M.ꢀQ.; You, S.ꢀL. ACS Catal. 2013, 3, 622. (m)
Thai, K.; Langdon, S. M.; Bilodeau, F.; Gravel, M. Org. Lett. 2013, 15,
2214. (n) Rafiński, Z.; Kozakiewicz, A. J. Org. Chem. 2015, 80, 7468. (o)
SánchezꢀDíez, E.; Fernández, M.; Uria, U.; Reyes, E.; Carrillo, L.; Vicario,
J. L. Chem. Eur. J. 2015, 21, 8384.
(3) (a) Ema, T.; Oue, Y.; Akihara, K.; Miyazaki, Y.; Sakai, T. Org. Lett.
2009, 11, 4866. (b) Ema, T.; Akihara, K.; Obayashi, R.; Sakaia, T. Adv.
Synth. Catal. 2012, 354, 3283.
(4) Goodman, C. G.; Johnson, J. S. J. Am. Chem. Soc. 2014, 136,
14698.
(5) For selected reviews on DKR processes, see: (a) Noyori, R.; Toꢀ
kunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36. (b) Ward, R.
S. Tetrahedron: Asymmetry 1995, 6, 1475. (c) Huerta, F. F.; Minidis, A.
B.; Bäckvall, J.ꢀE. Chem. Soc. Rev. 2001, 30, 321. (d) Kim, M.ꢀJ.; Ahn, Y.;
Park, J. Curr. Opin. Biotechnol. 2002, 13, 578. (e) Pellissier, H. Tetraheꢀ
dron 2003, 59, 8291. (f) Pellissier, H. Tetrahedron 2008, 64, 1563. (g)
Steinreiber, J.; Faber, K.; Griengl, H. Chem. Eur. J. 2008, 14, 8060. (h)
Pellissier, H. Tetrahedron 2011, 67, 3769.
In summary, we have demonstrated both the synthetic applicaꢀ
tions and mechanistic insights of the challenging DKR of αꢀ
EWGs substituted ketones enabled by the highly selective intraꢀ
molecular crossꢀbenzoin reaction for the first time. A variety of
enantioenriched tetralones bearing two contiguous stereocenters
and multiple functionalities were assembled with high diastereoꢀ
and enantioselectivities. In addition, this work shed light on the
excellent regioselectivity control for aryl/alkyl 1,3ꢀdiketones, and
the superior electronic differentiation of 1,3ꢀdiarylketones. Furꢀ
thermore, a set of new mechanistic rationale was established to
clarify the preference of the benzoin over aldol process: (1) deꢀ
spite the widely accepted aldolꢀsuppression strategy, a coꢀ
existence of both aldol and benzoin reactions was revealed and a
retroꢀaldolꢀbenzoin mechanism enables the generation of benzoin
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
products in
a predominant manner; (2) the Nꢀelectronꢀ
withdrawing substituents in NHC catalysts play a vital role in
accelerating the transformation of aldehydeꢀketone substrates to
benzoin products, rather than diminishing aldol products through
reducing the basicities of carbene catalysts. Overall, despite the
wellꢀknown investigations established almost ten years ago, we
provided herein a number of new insights into the fundamental
research of the intramolecular benzoin reaction. Further study
focusing on the regiochemistry and new reaction modes discovery
of the benzoin reaction is ongoing.
ASSOCIATED CONTENT
Supporting Information
(6) Li, Y.; Yang, S.; Wen, G.; Lin, Q.; Zhang, G.; Qiu, L.; Zhang, X.;
Du, G.; Fang, X. J. Org. Chem. 2016, 81, 2763.
Experimental procedures, spectral data, and crystallographic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(7) (a) Hachisu, Y.; Bode, J. W.; Suzuki, K. Adv. Synth. Catal. 2004,
346, 1097. (b) Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2431.
(8) (a) Kim, Y.ꢀJ.; Streitwieser, A. J. Am. Chem. Soc. 2002, 124, 5757.
(b) Higgins, E. M.; Sherwood, J. A.; Lindsay, A. G.; Armstrong, J.; Masꢀ
sey, R. S.; Alder, R. W.; O’Donoghue, A. C. Chem. Commun. 2011, 1559.
(c) Massey, R. S.; Collett, C. J.; Lindsay, A. G.; Smith, A. D.;
O’Donoghue, A. C. J. Am. Chem. Soc. 2012, 134, 20421.
AUTHOR INFORMATION
Corresponding Author
∗xqfang@fjirsm.ac.cn
Notes
(9) (a) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327. (b)
Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(10) For selected reports on intramolecular aldol reactions under basic
conditions, see: (a) Grigg, R.; Reimer, G. J.; Wade, A. R. J. Chem. Soc.
Perkin Trans. 1 1983, 1929. (b) Thorimbert, S.; Taillier, C.; Bareyt, S.;
Humiliere, D.; Malacria, M. Tetrahedron Lett. 2004, 45, 9123. (c) Nicoꢀ
laou; M., Tamsyn; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem.
Soc. 2005, 127, 8872.
(11) For reports on NHC catalysis mediated DKRs via enolate, hoꢀ
moenolate and vinyl enolate intermediates, see: (a) Cohen, D. T.; Eichman,
C. C.; Phillips, E. M.; Zarefsky, E. R.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2012, 51, 7309. (b) Goodman, C. G.; Walker, M. M.; Johnson, J. S. J.
Am. Chem. Soc. 2015, 137, 122. (c) Wu, Z.; Li, F.; Wang, J. Angew.
Chem., Int. Ed. 2015, 54, 1629. (d) Zhao, C.; Li, F.; Wang, J. Angew.
Chem., Int. Ed. 2015, 54, 1820.
(12) For selected examples, see: (a) Asai, M. Chem. Pharm.
Bull. 1970, 18, 1699. (b) Martin, R.; Sterner, O.; Alvarez, M. A.; De
Clercq, E.; Bailey, J. E.; Minas, W. J. Antibiot. 2001, 54, 239. (c) Shaaban,
K. A.; Shaaban, M.; GruenꢀWollny, I.; Maier, A.; Fiebig, H. H.; Laatsch,
H. J. Nat. Prod. 2007, 70, 1545.
(13) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002,
124, 10298.
(14) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
15088.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by National Science Foundation of Chiꢀ
na (21402199 and 21450110), the Chinese Recruitment Program
of Global Experts and Fujian Institute of Research on the Strucꢀ
ture of Matter (FJIRSM). We thank Professor Daqiang Yuan,
Professor Qingfu Sun, Mingli Liang, Yinghua Yu and Meiyan
Gao in FJIRSM for the help of Xꢀray structures determination and
data analysis.
REFERENCES
(1) For the first report of asymmetric benzoin reaction, see: (a) Sheehan,
J.; Hunneman, D. H. J. Am. Chem. Soc. 1966, 88, 3666. For selected reꢀ
views of NHC catalysis including benzoin reactions, see: (b) Enders, D.;
Balensiefer T. Acc. Chem. Res. 2004, 37, 534. (c) Johnson, J. S. Angew.
Chem., Int. Ed. 2004, 43, 1326. (d) Zeitler, K. Angew. Chem., Int. Ed.
2005, 44, 7506. (e) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev.
2007, 107, 5606. (f) Marion, N.; DiezꢀGonzález,S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988. (g) Moore, J.; Rovis, T. Top. Curr. Chem.
2010, 291, 77; (h) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011,
44, 1182. (i) Vora, H. U.; Rovis, T. Aldrichimica Acta 2011, 44, 3. (j)
Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511. (k) Hopkinson, M.
N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485. (l) Flaniꢀ
gan, D. M.; RomanovꢀMichailidis, F.; White, N. A.; Rovis T. Chem. Rev.
2015, 115, 9307.
(15) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876.
(16) DiRocco, D. A.; Rovis T. J. Am. Chem. Soc. 2012, 134, 8094.
(17) CCDC 1435672 (2f), CCDC 1435673 (4h), CCDC 1435674 (6a)
and CCDC 1435675 (6b) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Camꢀ
bridge Crystallographic Centre via www.ccdc.cam.ac.uk/data_request/cif.
(18) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure John Wiley & Sons, Inc., Hoboken,
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
New Jersey, 2007. (b) Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E.
Chem. Rev. 1999, 99, 665.
(19) For DKRs mediated by enzyme catalyzed regioselective reduction
of 2ꢀsubstitutedꢀ1,3ꢀdiketones, see: (a) Lüdeke, S.; Richter, M.; Müller, M.
Adv. Synth. Catal. 2009, 351, 253. (b) Kalaitzakis, D.; Rozzell, J. D.;
Kambourakis, S.; Smonou, I. Org. Lett. 2005, 7, 4799. For DKR mediated
by transition metal catalyzed regioselective reduction of 2ꢀsubstitutedꢀ1,3ꢀ
diketones, see: (c) Eustache, F.; Dalko, P. I.; Cossy. J. Org. Lett. 2002, 4,
1263.
9
(20) For an example of NHC catalyzed highly regioselective homoenoꢀ
late reaction, see: Fang, X.; Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R. Angew.
Chem., Int. Ed. 2011, 50, 1910.
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
(21) The absolute configuration of the newly formed stereogenic center
was assigned by analogy to the similar report, see: Yamamoto, K.;
Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Chem. Eur. J. 2003, 9,
3242.
(22) For similar reports, see: (a) Paquette, L. A.; Varadarajan, A.; Bay,
E. J. Am. Chem. Soc. 1984, 106, 6702. (b) Paquette, L. A.; Varadarajan,
A.; Burke, L. D. J. Am. Chem. Soc. 1986, 108, 8032. (c) Frutos, R. P.;
Denice, D. M. Tetrahedron Lett. 1998, 39, 2475. (d) Diedrichs, N.; Krelaꢀ
us, R.; Gedrath, I.; Westermann, B. Can. J. Chem. 2002, 80, 686.
(23) For selected reports on retroꢀbenzoin reactions, see: (a) Stetter, H.;
Angew. Chem., Int. Ed. 1976, 15, 639; (b) Dünkelmann, P.; KolterꢀJung,
D.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen, B.; Baumann, M.; Pohl,
M.; Müller, M. J. Am. Chem. Soc. 2002, 124, 12084. (c) Li, G.ꢀQ.; Dai,
L.ꢀX.; You, S.ꢀL. Chem. Commun. 2007, 852. (d) Liu, Q.; Perreault, S.;
Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066. (e) Chiang, P.ꢀC.; Rommel,
M.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 8714. (f) Wilde, M. M. D.;
Gravel, M. Org. Lett. 2014, 16, 5308. (g) Collett, C. J.; Massey, R. S.;
Taylor, J. E.; Maguire, O. R.; O’Donoghue, A. C.; Smith, A. D. Angew.
Chem., Int. Ed. 2015, 54, 6887. (h) Langdon, S. M.; Legault, C. Y.; Gravel,
M. J. Org. Chem. 2015, 80, 3597.
(24) A survey of literature reports indicates that the reaction conditions
are probably responsible for the irreversibility of the benzoin reaction
depicted in this work. For selected examples of irreversible benzoin reacꢀ
tions, see: (a) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.;
Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696. (b)
Ramanjaneyulu, B. T.; Mahesh, S.; Anand R. V. Org. Lett. 2015, 17, 6.
(25) For selected reports on retroꢀaldol reactions, see: (a) Flanagan, M.
E.; Jacobsen, J. R.; Sweet, E.; Schultz, P. G. J. Am. Chem. Soc. 1996, 118,
6078. (b) Zhong, G.; Shabat, D.; List, B.; Anderson, J.; Sinha, S. C.; Lerꢀ
ner, R. A.; Barbas III, C. F. Angew. Chem., Int. Ed. 1998, 37, 2481. (c)
Carlier, P. R.; W.ꢀS. Lo, C.; M.ꢀC. Lo, M.; Wan, N. C.; Williams, lan D.
Org. Lett. 2000, 2, 2443. (d) Clerici, F.; Gelmi, M. L.; Pellegrino, S.;
Pilati, T. J. Org. Chem. 2003, 68, 5286. (e) Flock, A. M.; Reucher, C. M.
M.; Bolm, C. Chem. Eur. J. 2010, 16, 3918. (f) Jung, M. E.; Chang, J. J.
Org. Lett. 2012, 14, 4898. (g) Zhang, S.ꢀL.; Yu, Z.ꢀL. J. Org. Chem. 2016,
81, 57.
(26) At the current time, we can’t clarify that all or only part of the
benzoin products are derived from the retroꢀaldolꢀbenzoin process.
1
(27) H NMR analysis of the following reaction did not show a retroꢀ
aldolꢀbenzoin process (see the supporting information for more details):
(28) Massey, R. S.; Collett, C. J.; Lindsay, A. G.; Smith, A. D.;
O’Donoghue, A. C. J. Am. Chem. Soc. 2012, 134, 20421. The pKa value
of triazolium E utilized in this work is hitherto unknown.
(29) (a) Jones, J. R.; Patel. S. P. J. Am. Chem. Soc. 1974, 96, 574. (b)
Data from both the Bordwell’s pKa table and Wikipedia.
(30) (a) Collett, C. J.; Massey, R. S.; Maguire, O. R.; Batsanov, A. S.;
O’Donoghue, A. C.; Smith, A. D. Chem. Sci. 2013, 4, 1514. (b) Collett, C.
J.; Massey, R. S.; Taylor, J. E.; Maguire, O. R.; O’Donoghue, A. C.;
Smith, A. D. Angew. Chem. Int. Ed. 2015, 54, 6887.
(31) (a) Mahatthananchai, J.; Bode, J. W. Chem. Sci. 2012, 3, 192. (b)
Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
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
8
ACS Paragon Plus Environment