Divergent Roles of Urea and Phosphoric Acid Derived Catalysts in Reactions of Diazo Compounds

Article abstract of DOI:10.1055/s-0035-1561061

Hydrogen-bond-donor catalysts enable a variety of formal insertion reactions of diazo compounds. The role of the catalyst in the reaction system may vary depending on several factors, including the nucleophilicity of the diazo compound and the acidity of the insertion partner. Ureas and phosphoric acid derivatives can offer complementary reactivity patterns when selected as catalysts for selected O-H and S-H insertion reactions of aryl- and diazo-substituted esters.

Full text of DOI:10.1055/s-0035-1561061

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 677–686
feature
677
B. Bernardim et al.
Feature
Synthesis
Divergent Roles of Urea and Phosphoric Acid Derived Catalysts in
Reactions of Diazo Compounds
Barbara Bernardima
Erica D. Couchb
Andrea M. Hardman-Baldwinb
Antonio C. B. Burtoloso*a
Anita E. Mattson*b
O
H
N
nucleophilic
diazo compound
R1O
Ar2
Ar1
O
N–H insertion/
arylation
O
O
Ar
R1O
Ar2
F
F
R1O
N2
B
O
P
Ar1
Ar
double
arylation
O
RO
RO
or
a Instituto de Química de São Carlos, Universidade de São Paulo,
CEP 13560-970, São Carlos, SP, Brazil
or
Ar
OH
N
H
N
O
H
S
R1O
R2
R2
antonio@iqsc.usp.br
O
NO2
R1O
boronate urea
phosphate
b Department of Chemistry and Biochemistry, The Ohio State
University, 100 W. 18th Ave., Columbus, OH 43210, USA
mattson@chemistry.ohio-state.edu
O
R1O
S–H
N2
insertion
Ar
O–H insertion
electrophilic
diazo compound
Received: 24.09.2015
Accepted after revision: 20.11.2015
Published online: 11.01.2016
abilities of ureas (e.g., A) and phosphates (e.g., B) to catalyze
formal insertion reactions and multicomponent coupling
reactions of both electrophilic and nucleophilic diazo com-
pounds (Scheme 1).
DOI: 10.1055/s-0035-1561061; Art ID: ss-2015-e0559-fa
Abstract Hydrogen-bond-donor catalysts enable a variety of formal
insertion reactions of diazo compounds. The role of the catalyst in the
reaction system may vary depending on several factors, including the
nucleophilicity of the diazo compound and the acidity of the insertion
partner. Ureas and phosphoric acid derivatives can offer complementa-
ry reactivity patterns when selected as catalysts for selected O–H and
S–H insertion reactions of aryl- and diazo-substituted esters.
Urea-Catalyzed Multicomponent Coupling
Reactions of α-Nitro-α-diazo Esters
Early on, our investigations led us to the unanticipated
finding that difluoroboronate urea 1 enabled the N–H in-
sertion/arylation of α-nitro-α-diazo esters 2, giving rise to
glycines 3 in good to excellent yields (53–91%, Scheme 2).4
The well-documented observation that ureas can hy-
drogen bond and co-crystallize with a number of functional
groups, including the nitro group, was the inspiration of our
initial attempt to control reactions of nitrodiazo com-
pounds with urea catalysis.5 In the context of α-nitro-α-di-
azo ester 2, it was initially hypothesized that hydrogen
bonding of the urea functionality to the nitro group would
lead to activation of the diazo compound through interme-
diate 4 (Figure 1). Further investigations, both experimental
Key words diazo compounds, substituent effects, homogeneous ca-
talysis, insertion reactions, urea catalysts, phosphate catalysts
Diazo compounds participate in a variety of attractive
bond-forming reactions.1 Conventionally, the useful reac-
tivity patterns of diazo compounds are often accessed with
the aid of transition metal catalysis.2 Recent advances in
hydrogen-bond-donor catalysis have demonstrated the po-
tential to develop new and useful reactivity patterns that
are difficult and/or inaccessible with transition metal catal-
ysis.3 To this end, we have been interested in the divergent
O
H
O
nucleophilic
S
electrophilic
diazo compound
N
R1O
Ar2
diazo compound
O
R1O
R2
Ar1
Ar
O
Ar
N–H insertion/
arylation
NO2
R1O
S–H insertion
R1O
N2
N2
O
O
Ar2
O
F
F
R1O
R1O
R2
B
O
O
Ar1
double
arylation
Ar
O–H insertion
RO
RO
P
Ar
OH
N
H
N
H
B
A
phosphate
boronate urea
Scheme 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

678
B. Bernardim et al.
Feature
Synthesis
Biographical Sketches
Antonio C. B. Burtoloso
the Federal University of Rio de
Janeiro (2002) and his Ph.D. in
Chemistry at the State Universi-
ty of Campinas (2006). In 2007,
he was a postdoctoral fellow at
the Scripps Research Institute
under the supervision of Prof. K.
C. Nicolaou. Since 2008, he has
been Professor at the Institute
of Chemistry of São Carlos, Uni-
graduated with a technological
degree in chemistry at the Fed-
eral University of Rio de Janeiro
(2001). He performed his M.Sc.
in natural products chemistry at
versity of São Paulo (IQSC
USP).
-
Barbara Bernardim was born
in Guarapuava-PR, Brazil, in
1989. She received her degree
in chemistry from Midwest
State University (UNICENTRO)
in 2010. In 2011, she moved to
Sao Carlos-SP to start her M.Sc.
in organic chemistry in the
group of Prof. Dr. Antonio
Burtoloso at the University of
Sao Paulo. In 2013, she started
her Ph.D in the same group
working on the chemistry of
α,β-unsaturated diazo ketones.
Anita Mattson received her
B.Sc. degree from Northern
Michigan University in 2002,
where she studied polarity re-
versal catalysis in the context of
radical reactions with Professor
Frankie Ann McCormick. As a
graduate student at Northwest-
ern University, she joined the
group of Professor Karl Scheidt
and developed new thiazolium-
based strategies for acyl anion
addition reactions. In 2007, she
completed her Ph.D. and be-
came a National Institutes of
Health postdoctoral fellow in
Professor Michael Crimmins’s
group at the University of North
Carolina at Chapel Hill, where
she investigated a highly con-
vergent approach toward hemi-
brevetoxin B. Mattson joined
the faculty in the Department
of Chemistry and Biochemistry
at The Ohio State University in
2009. Her current research pro-
gram centers on the design of
new families of organic cata-
lysts, the development of met-
al-free methodologies, and the
synthesis of naturally occurring
molecules.
Erica Couch received her B.Sc.
degree from Butler University in
2012, where she worked with
Professor LuAnne McNulty in
the development of new strate-
gies towards the synthesis of di-
hydropyran-containing natural
products by tandem reactions
of cyclic boronic half acids.
Upon graduation, she joined
Professor Anita Mattson’s group
at The Ohio State University,
where she investigated boro-
nate ureas as catalysts for
metal-free
diazo
insertion
chemistry. Graduating with her
M.Sc in 2014, she is currently
working at PPG in Texas.
Andrea Hardman-Baldwin
was born in 1989 in Harrison,
Arkansas. She received her B.Sc.
degree in chemistry from Hard-
ing University in 2011 while
working under the mentorship
of Professor Carl B. Holland-
sworth. In June of 2011, she
moved to The Ohio State Uni-
versity to begin graduate stud-
ies with Professor Anita E.
Mattson. Her graduate research
is centered on the synthesis and
functionalization of heterocy-
cles by utilizing new classes of
hydrogen-bond-donor organo-
catalysts.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

679
B. Bernardim et al.
Feature
Synthesis
Ar
CF3
F
F
O
N
B
H
O
O
O
urea
recognition
O
O
N
N
NO2
Ar
H
(eq 1)
(eq 2)
RO
N
H
N
CF3
O
RO
O
H
N2
H
2
4
O
N2
N
Ar2
OR
1 (20 mol%)
NO2
EtO
no urea recognition
observed by
1H NMR spectroscopy
Ar1
53–91%
Ar
NH2Ar2, HAr1
toluene
N2
3
RO
2
N2
5
Scheme 3
iPr
Me
Ar1
=
H2N
H2N
Et2N
MeO
H2N
tron-rich α-aryl-α-diazo esters 5 to afford 6 in high yields.
The substrate scope was even more broad with respect to
the S–H insertion: arenethiols, alkanethiols, and thioacids
all reacted well with electron-rich α-aryl-α-diazo esters 5.
MeN
iPr
Me
NH2
Me
NH2
NH2
NH2Ar2
=
F
Scheme 2
O–H insertion
O
1 (2.5 mol%)
PhMe, 23 °C, 24 h
Ar
O
53–92%
MeO
and computational, were conducted and supported the
likelihood of the urea activating the diazo compound
through hydrogen bonding.6 More specifically, 1H NMR
spectroscopic studies detected an observable binding inter-
action between boronate urea 1 and the α-nitro-α-diazo es-
ter 2. DFT calculations also supported the likelihood of this
interaction.
O
Ar
O
R
H
MeO
6
O
R
OH
N2
5
O
S–H insertion
Ar
1 (2.5 mol%)
PhCF3, 23 °C,12 h
42–91%
MeO
RS
H
O
7
SH
or
R
R
SH
R = alkyl or aryl
F
F
F
F
B
B
Scheme 4
O
O
N
N
H
H
CF3
CF3
As mentioned above, the experiments in our laboratory
suggested that direct urea activation of the α-aryl-α-diazo
ester 5 was unlikely, and prompted us to consider a reaction
pathway in which the urea was activating the insertion
partner, the thiol or carboxylic acid, as opposed to the diazo
compound (Scheme 5, intermediate 8). Indeed several re-
cent reports by Jacobsen, Seidel, and others describe the
potential involvement of urea–Brønsted acid co-catalytic
systems.8 Moreover, a recent report by Cheng and co-work-
ers provided support that the acidity of Brønsted acids
could be enhanced up to 9 pKa units in the presence of a
urea.9 Adding further support to the urea acid activation
was Smith’s evidence demonstrating the excellent molecu-
lar recognition of boronate ureas for acetate ions.10
N
N
O
O
N
O
O
N
H
H
EtO
O
EtO
O
4a
4b
N2
N
N
CF3
CF3
Figure 1
Urea-Catalyzed Formal Insertion Reactions of
α-Aryl-α-diazo Esters
Whereas good evidence supporting urea recognition of
the nitro group exists (Scheme 3, eq. 1), it was not obvious
if or how a urea catalyst would interact with and/or activate
an α-aryl-α-diazo ester. Indeed, our efforts to observe any
binding between these two species by NMR spectroscopy
were fruitless (Scheme 3, eq. 2).
Despite the unclear mode of action of urea catalysis in
the context of α-aryl-α-diazo ester activation, excellent
yields of both O–H and S–H insertion products were fre-
quently isolated when α-aryl-α-diazo esters were treated
with appropriate insertion partners in the presence of just
2.5 mol% of boronate urea catalyst 1 (Scheme 4).7 Impor-
tantly, no reaction was observed if the boronate urea cata-
lyst was omitted while otherwise keeping the reaction con-
ditions identical. In our initial study, a variety of carboxylic
acids were found to operate as insertion partners with elec-
F
F
O
B
O
Ar
MeO
O
Ar
N
H
N
H
5
N2
O
Ar
urea 1
MeO
O
H
R
OH
O
O
O
H
8
R
urea-induced acid
amplification
6
R
Scheme 5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

680
B. Bernardim et al.
Feature
Synthesis
in the first step of the reaction system. Control experiments
also ruled out the direct protonation of the diazo com-
pound with the boronate urea.
R1
R1
O
PhSH
1 (2.5 mol%)
O
OR
OR
12 h, 23 °C
PhCF3
H
S
5
7
With the hypothesis that the reaction is proceeding
with urea activation of the insertion partner, we set out to
first explore the tolerance of the reaction to the nucleo-
philicity of the α-aryl-α-diazo ester 5 (Scheme 6). Several
diazo compounds were prepared and subjected to an inser-
tion reaction with thiophenol catalyzed by 1. As a general
trend, the more nucleophilic diazo compounds afforded
higher yields of product. The most electron-rich dimethyl-
amino-substituted diazo ester 5a gave the highest yield of
insertion product 7a (92%). The methoxy-subsituted diazo
ester 5b also operated well in the formal S–H insertion
event, giving rise to 7b in 90% yield. The less electron-rich
diazo compounds 5c and 5d also participated in the desired
bond-forming reactions, although the yields of isolated
products 7c and 7d were somewhat lower (72% and 65%, re-
spectively).
N2
Ph
Me2N
Me2N
O
O
O
O
7a: 92%a
5a
OEt
OEt
H
SPh
O
N2
MeO
MeO
7b: 90%
7c: 72%
7d: 65%
5b
OMe
OEt
OMe
N2
H
SPh
O
Br
Br
OEt
5c
H
H
SPh
N2
H
H
O
O
5d
OEt
OEt
SPh
N2
The investigations next turned to probe the effect of in-
sertion partner acidity on the outcome of the reaction
(Scheme 7). Several alcohols and thiols, with pKa values in
dimethyl sulfoxide ranging from 5 to 30, were selected as
reactants with methoxy-substituted diazo ester 5b. The
most reactive partner for this reaction turned out to be
thiophenol [pKa ~10 (DMSO)] giving rise to product 7b in
90% yield after 12 hours at 23 °C. Acetic acid also gave rise
to high yields of product, although a longer reaction time
was required (6d, 91% after 24 h). The less acidic dodec-
anethiol and phenol also participated in the insertion
event, giving, however, lower yields of product after extend-
ed reaction times.11 The two alcohols ethanol and trifluo-
roethanol afforded minimal amounts of desired products 6a
and 6b. The most acidic species tested in this study, thio-
a isolated yield
Scheme 6
In addition to the literature precedent, a variety of ex-
periments suggested urea activation of the insertion part-
ner as the proposed mode of action. First, no reaction was
observed when base was added to the reaction mixture
[Et3N (1 equiv) in addition to the optimized reaction condi-
tions]. Moreover, removal of the acidic X–H bond from the
reaction, for instance, sodium acetate used in place of acetic
acid, resulted in no reaction. These data provided us with
two theories: (a) the X–H bond is essential for the reaction
to occur, and (b) nucleophilic attack is likely not occurring
MeO
MeO
MeO
RO–H
O
RS–H
1 (2.5 mol%)
O
O
1 (2.5 mol%)
OMe
O
OMe
HO
OMe
toluene
PhCF3
H
S
6
5b
7
H
O
N2
R
R
O
Me
HO
HS
CF3
HS
HO
Me
10
Ph
Ph
HO
Me
HS
Ph
30
24
18
17
O
13
O
10
5
decreasing insertion partner pKa (DMSO)
O
O
O
O
O
Ar
Ar
Ar
Ar
Ar
O
Ar
Ar
OMe
OMe
OMe
6c
OMe
OMe
OMe
7b
OMe
H
O
H
O
H
O
H
S
H
O
H
S
H S
6a
6b
7e
6d
7f
Ph
Ph
O
Et
CF3
Me
Ph
10
Me
69%
yielda
<5%
<5%
72 h
65%
48 h
91%
24 h
90%
12 h
54%
12 h
reaction
time
72 h
80 h
a isolated yield
Scheme 7
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

681
B. Bernardim et al.
Feature
Synthesis
benzoic acid, was tolerated and gave rise to a modest yield
of 7f after a reaction time of 12 hours (54%).
background reactions (7–10%) by using nitromethane as
the solvent and three equivalents of the insertion partner
(Scheme 8, method B).
At the conclusion of this short study, it appeared that
boronate urea 1 was most successful facilitating the cou-
pling of more nucleophilic diazo compounds (5a and 5b)
with O–H and S–H partners having a pKa (DMSO) between
10 and 13.
Divergent Roles of Ureas and Phosphates in
Reactions of Diazo Compounds
The role of urea and phosphate catalysts in reactions of
diazo compounds may vary depending upon the nature of
the diazo substrate and the insertion partner. Several
modes of action by which the catalysts may be operating
are considered in Scheme 9. Plausible catalytic cycles are
also described.
Select electrophilic diazo compounds, such as α-nitro-
α-diazo esters, may experience direct activation by a hydro-
gen-bond-donor catalyst. For example, in the case of urea-
catalyzed reactions of α-nitro-α-diazo compounds, the ini-
tial hydrogen bonding of the urea catalyst to the nitro group
is proposed to prime the α-nitro-α-diazo ester for reaction
with aniline (4, Scheme 9). Our investigations into the
mechanism suggest that the α-nitro-α-diazo ester operates
as an electrophile while aniline undergoes addition to even-
tually give rise to the N–H insertion product 11. The subse-
quent formation of an iminium ion from 11 yields a species
that reacts in a Friedel–Crafts-type process to give rise to
glycine 3, which is isolable if the reaction is conducted un-
der mild temperatures (23 °C or lower).
Phosphate-Catalyzed Formal Insertion Reac-
tions of α-Aryl-α-diazo Esters
While urea 1 was only an effective catalyst with moder-
ately acidic insertion partners, we were curious to know if
less acidic alcohols would insert into diazo compounds
with a different type of hydrogen bond donor. Specifically,
we were interested in analyzing phosphates as catalysts in
diazo insertion reactions. Our studies were inspired by the
recent success of phosphoric acid-derived catalysts in a va-
riety of reaction platforms.12,13
Early on in our studies, we were delighted to find that
diphenyl phosphate 9 proved to be a suitable catalyst for in-
sertion reactions of the less acidic alcohols [pKa ~30
(DMSO), Scheme 8]. Under the best conditions found to ef-
fect these formal insertions, namely neat alcohol or thiol
(10 equiv) with diphenyl phosphate 9 (30 mol%; method A),
excellent yields of products 6a and 6e were obtained by in-
sertion reactions of ethanol and benzyl alcohol into diazo
ester 5b (87% and 90%, respectively). Importantly, if no cata-
lyst was included, the yields dropped to between 2–6%. The
reaction system also tolerated moderately acidic, strongly
nucleophilic species, like alkanethiols. For example, 7e was
prepared in 80% yield by the phosphate-catalyzed insertion
reaction. As an alternative for expensive or solid alcohols/
thiols, the reaction can also be performed with minimal
The role of the urea catalyst is likely significantly differ-
ent in the reaction of α-aryl-α-diazo esters and O–H or S–H
insertion partners. In this case, the proposed reaction path-
way begins with urea coordination to the insertion partner
to yield hydrogen-bonded complex 12 (Scheme 9). It is
thought that this interaction serves to acidify the insertion
partner to enable its deprotonation by the diazo-substitut-
R3O–H or R4S-H
O
O
O
R1
R1
R1
or
O
P
OR2
OR2
OR2
HO
OPh
OPh
9 (30 mol%)
H
O
R3
H
S
R4
6
7
N2
Me
HO
HO
HO
CF3
HS
HO
Me
10
Ph
18
30
decreasing insertion partner pKa (DMSO)
24
29
17
MeO
O
6a
6e
6b
6c
7e
OMe
method A: 80%
method B: 80%
method A: -
method B: <5%
method A: 90%
method B: 55%
method A: 10%
method B: <5%
method A: 87%
method B: 63%
5b
5c
N2
Br
O
6f
6g
6h
6i
7g
OEt
method A: <5%
method B: <5%
method A: -
method B: <5%
method A: 12%
method B: <5%
method A: 25%
method B: 11%
method A: 42%
method B: 14%
N2
method A: neat, 10 equiv diazo ester; method B: 3 equiv diazo ester in 1 M solution of MeNO2
yields are of isolated product
Scheme 8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

682
B. Bernardim et al.
Feature
Synthesis
direct activation of diazo compound
insertion partner activation
R2
diazo protonation
R2
N
R2
N
O
P
R2
N
O
O
N
O
O
O
HO
OPh
OPh
H
H
H
O
O
O
Ar
O
O
N
O
N
H
N
R1
1
1
N
R1
9
OMe
R1
N
N
R1
H
H
H
O
H
X
Ar
H
EtO
R3
H
H
EtO
O
N
N
O
P
OMe
X
N2
R3
N
N
N2
OPh
OPh
4
12
5
14
2
plausible catalytic cycles:
2
1
9
R3X-H
5
6 or 7
6 or 7
4
1
HNO3
HAr1
R2
3
NH2Ar2
O
P
O
R2
R4
O
O
O
OPh
OPh
O
H
N2
R2
O
Ar
H
N
OMe
R1
N
OMe
H
Ar
H
H
O
O
N
H
R1
N2
N
R3
OMe
O
O
X
O
H
N
H
R3
O
H
X
R1
H
O
O
N
N
N
H
X
R3
N
N
P
R1
EtO
OPh
OPh
H
N
H
EtO
O
HN
N
R2
O
Ar2
R3X-H
10
11
12
13
14
15
5
H2N
N2
Ar2
Scheme 9
ed ester to generate ion pair 13. The addition of the conju-
gate base produced in the deprotonation event completes
the formal insertion reaction and reintroduces the urea
back in the catalytic cycle.
CH2Cl2, THF, DMF, and MeCN were purified by passage through a bed
of activated alumina.14 Purification of reaction products was carried
out by flash chromatography over Aldrich 60 Å (40–63 μm) silica gel.
Analytical TLC was performed on EMD Chemicals 0.25 μm silica gel
60-F254 plates. Visualization was accomplished with UV light and ceric
ammonium molybdate stains followed by heating. Melting points
were obtained on a Thermo Scientific Mel-temp apparatus and are
uncorrected. IR spectra were obtained on a Perkin Elmer Spectrum
100R spectrophotometer; liquid products were prepared as thin films
on a NaCl disk and solid products were prepared as NaBr pellets. 1H
NMR spectra of samples in deuterated solvents were recorded on a
Bruker Avance AVIII 400 (400 MHz) spectrometer. Chemical shifts are
reported in ppm relative to the solvent as internal standard (CHCl3,
δ = 7.26 and DMSO, δ = 2.50). Proton-decoupled 13C NMR spectra
were recorded on a Bruker Avance AVIII 400 (100 MHz) spectrometer
and are reported in ppm relative to the solvent as internal standard
(CHCl3, δ = 77.16; DMSO, δ = 39.52). Proton-decoupled 19F NMR spec-
tra were recorded on a Bruker Avance AVIII 400 (376 MHz) spectrom-
eter and are reported in ppm relative to CF3C6H5 as an external stan-
dard (δ = –63.72). 11B NMR spectra were recorded on a Bruker Avance
DPX 500 (160 MHz) or Bruker Avance AVIII 400 (128 MHz) spectrom-
eter and are reported in ppm relative to BF3·OEt2 as an external stan-
dard (δ = 0.00). Electrospray mass spectra (ESI-MS) were obtained by
using a Bruker MicrOTOF mass spectrometer. Unless otherwise noted,
all other commercially available reagents and solvents were pur-
chased and used without further purification. CAUTION: While we
have not experienced any problems handling α-nitro-α-diazo esters,
aryldiazoacetates, or 4-acetamidobenzenesulfonyl azide (p-ABSA),
appropriate care should be exercised when handling any diazo com-
pound or azide.
In the phosphate-catalyzed reaction, it is proposed that
diphenyl phosphate initially protonates diazo-substituted
ester 5, leading to the diazonium 14. Nucleophilic displace-
ment of molecular nitrogen by the alcohol or thiol, followed
by hydrogen abstraction by the conjugate base of the cata-
lyst, leads to the product and regenerates the catalyst. Al-
though less probable due to the presence of an ester, forma-
tion of the benzylic carbocation from 14 when nucleophilic
diazo-substituted esters are employed (R1 = OMe, NR2) may
compete with the SN2 mechanism. Investigations are ongo-
ing to learn more about the reaction pathway.
Conclusion
Useful formal insertion and multicomponent coupling
reactions are accessible when diazo compounds are sub-
jected to the influence of hydrogen-bond-donor catalysis.
Urea and phosphate catalysts can provide complementary
reactivity of diazo compound insertion reactions with alco-
hols and thiols. The difference in reactivity is plausibly due
to their divergent roles in the presence of the diazo com-
pound and insertion partner. Studies that more fully relate
the boundaries of the substrate scope to the type of hydro-
gen-bond donor or Brønsted acid catalyst are current topics
of interest.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

683
B. Bernardim et al.
Feature
Synthesis
Preparation of Boronate Urea Catalyst 115
HRMS (ESI): m/z [M + Na]+ calcd for C21H20BF6N2O3Na: 419.0572;
found: 419.0580.
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl]urea
Synthesis of Reagent 5a
A flame-dried round-bottom flask under N2 was charged with 2-
aminophenylboronic acid pinacol ester (600 mg, 2.74 mmol). Freshly
distilled MeCN (30 mL) was added to create a colorless solution. Last,
3,5-bis-trifluoromethylphenyl isocyanate (473 μL, 2.74 mmol) was
introduced to the reaction flask dropwise by syringe. Shortly after ad-
dition of the isocyanate, a white precipitate began to form. The reac-
tion mixture was allowed to stir at 23 °C for 4 h. The pure boronate
urea pinacol ester was isolated as a white solid after vacuum filtration
followed by washing with hexanes. The solid was dried under vacu-
um.
Ethyl 2-[4-(Dimethylamino)phenyl]-2-oxoacetate
A modified version of a previously reported procedure was used.17
A
flame-dried 100 mL round-bottom flask was charged with 4-bromo-
N,N-dimethylaniline (3.00 g, 15.0 mmol), dissolved in THF (25 mL),
and placed under an atmosphere of N2. The reaction mixture was
cooled to –78 °C and 1.3 M n-BuLi in hexanes (11.65 mL, 15.15 mmol)
was added dropwise over 15 min. The reaction mixture was stirred at
–78 °C for an additional 15 min. The resulting suspension was then
transferred dropwise via cannula at –78 °C to a separate 250 mL
flame-dried round-bottom flask containing a solution of diethyl oxa-
late (3.26 mL, 24 mmol) in THF (25 mL) at –78 °C. The reaction mix-
ture was stirred at –78 °C for 20 min and then allowed to warm to 0
°C. H2O (40 mL) was slowly added to quench the reaction. The reac-
tion mixture was then extracted with Et2O (3 × 75 mL), washed with
H2O (3 × 75 mL), dried (MgSO4), and concentrated to afford a viscous
yellow oil. The residue was recrystallized from benzene to afford ethyl
2-[4-(dimethylamino)phenyl]-2-oxoacetate as bright yellow flakes;
yield: 2.23 g (67%).
Yield: 1.08 g (83%); Rf = 0.94 (EtOAc–hexanes–MeOH, 4:4:1); mp
215.2–216.9 °C.
IR (NaBr): 3415, 3132, 2985, 1640, 1600, 1581, 1476, 1184, 1129 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.93 (br s, 1 H), 9.19 (br s, 1 H), 8.16
(s, 2 H), 7.69 (s, 1 H), 7.52–7.50 (m, 1 H), 7.42–7.34 (m, 2 H), 7.08–
7.04 (m, 1 H), 1.24 (s, 12 H).
13C NMR (100 MHz, DMSO-d6): δ = 154.0, 142.2, 141.7, 134.7, 131.2
(q, J = 33 Hz, CCF3), 130.8, 123.8 (q, J = 271 Hz, CF3), 123.4, 119.7,
119.4, 115.6, 83.0, 25.5. The carbon bonded to boron was not seen
due to broadening.16
IR (film): 3056, 2986, 2917, 1729, 1650, 1591, 1549, 1443, 1375, 1229
cm–1
.
11B NMR (160 MHz, DMSO-d6): δ = 26.0 (br s).
HRMS (ESI): m/z [M + H]+ calcd for C21H21BF6N2O3: 475.1622; found:
1H NMR (400 MHz, CDCl3): δ = 7.90 (app d, J = 9.2 Hz, 2 H), 6.66 (app
d, J = 9.2 Hz, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.09 (s, 6 H), 1.40 (t, J = 7.2
Hz, 3 H).
475.1614.
13C NMR (100 MHz, CDCl3): δ = 184.0, 165.1, 154.6, 132.6, 120.4,
111.0, 61.9, 40.1, 14.3.
HRMS (ESI): m/z [M + Na]+ calcd for C12H15NNaO3: 244.0944; found:
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(difluoroboryl)phe-
nyl]urea (1)
A flame-dried round-bottom flask under N2 was charged with the
above-described boronate urea pinacol ester (2.18 g, 4.6 mmol) and
freshly distilled MeOH (30 mL). A 4.5 M solution of KHF2 in H2O (4 mL,
18.4 mmol) was introduced to the reaction flask dropwise by syringe,
resulting in a white heterogeneous mixture, and the reaction mixture
was heated to 50 °C. Shortly after heating, the reaction mixture be-
came a colorless solution. After 2 h at 50 °C, the reaction mixture was
cooled to 23 °C and concentrated. The white solid was filtered and
washed several times with H2O to afford the potassium trifluoroboryl
urea salt (92%). The urea salt (1.95 g, 4.29 mmol) was dissolved in
EtOAc (15 mL) and extracted with H2O (2 × 5 mL). The organic layer
was dried and concentrated in a 500 mL round-bottom flask. To the
flask was added CH2Cl2 (250 mL) and the mixture was allowed to stir
rapidly at r.t. for 1 h, after which the solid was filtered and washed
with CH2Cl2 to afford difluoroboryl urea 1 as a white powder.
244.0945.
Ethyl 2-Diazo-2-[4-(dimethylamino)phenyl]acetate (5a)
A solution of hydrazine hydrate (5.77 mL, 117.52 mmol, 52 equiv) in
an AcOH–H2O mixture (1:1; 18 mL) was added to ethyl 2-[4-(dime-
thylamino)phenyl]-2-oxoacetate (500 mg, 2.26 mmol, 1 equiv) in
MeOH (31 mL) at r.t. The reaction mixture was stirred for 72 h and
then the solvent was removed under reduced pressure. CH2Cl2 (25
mL) was added and the mixture was washed with H2O (25 mL), 10%
aq HCl (25 mL), and sat. aq NaHCO3 (25 mL). The organic layer was
dried with Na2SO4 and concentrated to provide the hydrazone as a
yellow solid; yield: 505.2 mg (95%).
1H NMR (400 MHz, CDCl3): δ = 7.21 (app d, J = 14.4 Hz, 2 H), 6.78 (app
d, J = 14.4 Hz, 2 H), 6.16 (br s, 2 H), 4.31 (q, J = 11.6 Hz, 2 H), 3.00 (s, 6
H), 1.35 (t, J = 11.2 Hz, 3 H).
Yield: 1.55 g (3.11 mmol, 85%); mp 205.3–205.9 °C.
The hydrazone (387 mg, 1.528 mmol, 1 equiv) was dissolved in CH2Cl2
(55 mL) and MnO2 (1.5 g, 17.3 mmol, 11 equiv) was added in one por-
tion. After stirring at r.t. for 2 h, the mixture was filtered through
Celite, concentrated, and purified by chromatography (silica gel,
EtOAc–hexanes, 5:95 to 10:90) to afford pure 5a.
IR (NaBr): 3628, 3345, 2986, 1741, 1671, 1585, 1479, 1187, 1128 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.27 (br s, 1 H), 10.65 (br s, 1 H),
8.11 (s, 2 H), 7.96 (s, 1 H), 7.42–7.40 (m, 1 H), 7.32–7.28 (m, 1 H),
7.15–7.10 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 154.4, 138.1, 137.5, 131.0 (q, J = 33
Hz, CCF3), 130.6, 128.2, 124.6, 123.0, 123.0 (q, J = 271 Hz, CF3), 118.4,
115.4, (the carbon bonded to boron was not seen due to broaden-
ing).16
Yield: 256 mg (67%); Rf = 0.72 (EtOAc–hexanes, 30:70).
IR (film): 2980, 2802, 2076, 1703, 1613, 1520, 1338, 1253, 1152, 1049
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.31 (app d, J = 8.8 Hz, 2 H), 6.77 (app
d, J = 8.8 Hz, 2 H), 4.31 (q, J = 7.2 Hz, 2 H), 2.95 (s, 6 H), 1.33 (t, J = 6.8
Hz, 3 H).
11B NMR (160 MHz, DMSO-d6): δ = 3.63 (br s).
19F NMR (376 MHz, DMSO-d6): δ = –61.7 (s, 6 F), –132.8 (s, 1 F),
–132.9 (s, 1 F)
13C NMR (100 MHz, CDCl3): δ = 166.3, 149.1, 126.1, 113.1, 111.7, 60.8,
40.5, 14.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

684
B. Bernardim et al.
Feature
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C12H16N3O2: 234.1237; found:
234.1238.
Yield: 140.5 mg (92%); Rf = 0.20 (Et2O–hexanes, 5:95).
IR (film): 3051, 2984, 2925, 2805, 1735, 1610, 1522, 1477, 1356,
1144, 1026 cm–1
.
O–H Insertion Catalyzed by 1a; General Procedure
1H NMR (400 MHz, CDCl3): δ = 7.44–7.38 (m, 2 H), 7.34 (d, J = 8.4 Hz, 2
H), 7.30–7.21 (m, 3 H), 6.68 (app d, J = 8.4 Hz, 2 H), 4.88 (s, 1 H), 4.11
(AB dq, Jab = 10.8, 7.2 Hz, Δδ = 0.02, 2 H), 2.96 (s, 6 H), 1.16 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 150.6, 134.7, 132.4, 129.4,
129.0, 127.7, 122.7, 112.5, 61.6, 55.9, 40.6, 14.2.
A dry, screw-capped reaction vial, equipped with a magnetic stir bar,
was charged with 5 (0.364 mmol) and catalyst (0.0091 mmol, 2.5
mol%), and placed under a N2 atmosphere. Toluene (1.45 mL) was
added and the reaction mixture was degassed by bubbling N2 through
the solution for 5 min at 23 °C. The appropriate insertion partner
(0.437 mmol, 1.2 equiv) was added in one portion and the reaction
mixture was allowed to stir for the appropriate amount of time at 23
°C and then immediately purified by flash column chromatography
(silica gel) to afford 6.
HRMS (ESI): m/z [M + H]+ calcd for C18H22SNO2: 316.1366; found:
316.1362.
Methyl 2-(4-Methoxyphenyl)-2-(phenylsulfanyl)acetate (7b)
Methyl 2-(4-Methoxyphenyl)-2-phenoxyacetate (6c)
The compound was isolated as a white solid by flash column chroma-
tography (silica gel, Et2O–hexanes, 5:95 to 15:85).
The compound was isolated after 48 h at 23 °C as a white solid by
flash column chromatography (silica gel, EtOAc–hexanes, 5:95 to
20:80).
Yield: 125.7 mg (90%); Rf = 0.15 (EtOAc–hexanes, 5:95).
IR (film): 3003, 2951, 2838, 1737, 1607, 1509, 1443, 1251, 1154, 1027
cm–1
.
Yield: 43 mg (65%); Rf = 0.4 (EtOAc–hexanes, 20:80).
1H NMR (400 MHz, CDCl3): δ = 7.41–7.33 (m, 4 H), 7.29–7.24 (m, 3 H),
6.85 (app d, J = 8.8 Hz, 2 H), 4.88 (s, 1 H), 3.80 (s, 3 H), 3.67 (s, 3 H).
IR (film): 2953, 2838, 1756, 1610, 1588, 1513, 1494, 1458, 1437,
1304, 1235, 1175, 1062, 1031 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.47 (app d, J = 8.4 Hz, 2 H), 7.29–
13C NMR (100 MHz, CDCl3): δ = 171.2, 159.8, 134.0, 132.7, 129.9,
7.23 (2 H), 7.00–6.90 (5 H), 5.59 (s, 1 H), 3.81 (s, 3 H), 3.74 (s, 3 H).
129.1, 128.1, 127.7, 114.2, 55.8, 55.4, 52.8.
13C NMR (100 MHz, CDCl3): δ = 170.8, 160.3, 157.5, 129.7, 128.7,
HRMS (ESI): m/z [M + Na]+ calcd for C16H16SNaO3: 311.0712; found:
127.7, 121.9, 115.6, 114.4, 78.4, 55.5, 52.7.
311.0714.
HRMS (ESI): m/z [M + Na]+ calcd for C16H16O4Na: 295.0941; found:
295.0940.
Ethyl 2-(4-Bromophenyl)-2-(phenylsulfanyl)acetate (7c)
The compound was isolated as a colorless oil by flash column chro-
matography (silica gel, Et2O–hexanes, 5:95).
Methyl 2-Acetoxy-2-(4-methoxyphenyl)acetate (6d)
The compound was isolated as a clear solid by flash column chroma-
tography (silica gel, EtOAc–hexanes, 5:95 to 20:80).
Yield: 123.4 mg (72%); Rf = 0.24 (EtOAc–hexanes, 5:95).
IR (film): 3058, 2980, 2935, 1738, 1585, 1487, 1439, 1271, 1148, 1072
cm–1
.
Yield: 79 mg (91%); Rf = 0.42 (EtOAc–hexanes, 20:80).
1H NMR (400 MHz, CDCl3): δ = 7.44 (app d, J = 8.4 Hz, 2 H), 7.40–7.34
(m, 2 H), 7.31 (app d, J = 8.4 Hz, 2 H), 7.27 (app d, J = 2.8 Hz, 2 H), 4.83
(s, 1 H), 4.13 (AB dq, Jab = 10.8, 7.2 Hz, Δδ = 0.02, 2 H), 1.17 (t, J = 7.2
Hz, 3 H).
IR (film): 3057, 2957, 2840, 1751, 1612, 1515, 1458, 1438, 1428,
1374, 1235, 1179, 1034 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38 (app d, J = 8.4 Hz, 2 H), 6.91 (app
d, J = 8.8 Hz, 2 H), 5.88 (s, 1 H), 3.81 (s, 3 H), 3.719 (s, 3 H), 2.18 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 170.1, 135.0, 133.4, 133.1, 131.9,
13C NMR (100 MHz, CDCl3): δ = 170.5, 169.7, 160.5 129.3, 126.0,
130.4, 129.2, 128.4, 122.5, 62.0, 56.0, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C16H15NaBrSO2: 372.9868; found:
114.4, 74.3, 55.5, 52.7, 20.9.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14NaO5: 261.0733; found:
372.9866.
261.0726.
Ethyl 2-Phenyl-2-(phenylsulfanyl)acetate (7d)
S–H Insertion Catalyzed by 1a; General Procedure
The compound was isolated as a colorless oil by flash column chro-
matography (silica gel, Et2O–hexanes, 5:95 to 10:90).
A dry, screw-capped reaction vial, equipped with a magnetic stir bar,
was charged with 5 (0.485 mmol) and catalyst (0.012 mmol, 2.5
mol%), and placed under a N2 atmosphere. PhCF3 (0.97 mL) was added
and the reaction mixture was degassed by bubbling N2 through the
solution for 5 min at 23 °C. The appropriate thiol (0.533 mmol, 1.1
equiv) was added in one portion and the reaction mixture was al-
lowed to stir for the appropriate amount of time at 23 °C and then im-
mediately purified by flash column chromatography (silica gel) to af-
ford 7.
Yield: 86.4 mg (65%); Rf = 0.26 (EtOAc–hexanes, 5:95).
1H NMR (400 MHz, CDCl3): δ = 7.47–7.43 (m, 2 H), 7.40–7.36 (m, 2 H),
7.34–7.28 (m, 3 H), 7.28–7.25 (m, 3 H), 4.90 (s, 1 H), 4.12 (m, 2 H),
1.17 (t, J = 7.1 Hz, 3 H). All spectral data match those previously re-
ported.18
Methyl 2-(4-Methoxyphenyl)-2-(dodecanylsulfanyl)acetate (7e)
The compound was isolated after 80 h at 23 °C as a colorless oil by
flash column chromatography (silica gel, EtOAc–hexanes, 5:95 to
10:90).
Ethyl 2-[4-(Dimethylamino)phenyl]-2-(phenylsulfanyl)acetate
(7a)
Yield: 64 mg (69%); Rf = 0.7 (EtOAc–hexanes, 20:80).
The compound was isolated as a yellow oil by flash column chroma-
tography (silica gel, Et2O–hexanes, 5:95 to 20:80).
IR (film): 2918, 1747, 1732, 1614, 1584, 1504, 1470, 1434 1336, 1248,
1148, 1035 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

685
B. Bernardim et al.
Feature
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.39 (app d, J = 8.8 Hz, 2 H), 6.87 (app
d, J = 8.8 Hz, 2 H), 4.55 (s, 1 H), 3.80 (s, 3 H), 3.73 (s, 3 H), 2.49 (m, 2
H), 1.56 (m, 2 H), 1.35–1.20 (m, 18 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.8, 159.6, 129.8, 128.3, 114.2, 55.4,
52.7, 51.7, 32.11, 32.06, 29.78, 29.77, 29.72, 29.6, 29.5, 29.3, 29.1,
29.0, 22.8, 14.3.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.27 (m, 7 H), 6.93–6.88 (m, 2 H),
4.88 (s, 1 H), 4.56 (q, J = 12.0 Hz, 2 H), 3.81 (s, 3 H), 3.71 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.6, 160.1, 137.3, 128.9, 128.6,
128.5, 128.2, 128.0, 114.2, 79.2, 71.0, 55.4, 52.4.
HRMS (ESI): m/z [M + Na]+ calcd for C17H18NaO4: 309.1097; found:
309.1087.
HRMS (ESI): m/z [M + Na]+ calcd for C22H36NaO3S: 403.2277; found:
403.2274.
Ethyl 2-(4-Bromophenyl)-2-ethoxyacetate (6f)
The compound was isolated as a pale yellow oil by flash column chro-
matography (silica gel, EtOAc–hexanes, 5:95 to 20:80).
Methyl 2-(Benzoylsulfanyl)-2-(4-methoxyphenyl)acetate (7f)
The compound was isolated as a colorless oil by flash column chro-
matography (silica gel, Et2O–hexanes, 5:95 to 15:85).
Yield: 26 mg (0.089 mmol, 42%); Rf = 0.34 (EtOAc–hexanes, 10:90).
IR (film): 2980, 2899, 1751, 1487, 1400, 1206, 1179, 1113, 1013 cm–1
1H NMR (500 MHz, CDCl3); δ = 7.50–7.46 (m, 2 H), 7.36–7.32 (m, 2 H),
4.81 (s, 1 H), 4.25–4.10 (m, 2 H), 3.64–3.45 (m, 2 H), 1.27 (t, J = 7.0 Hz,
3 H), 1.21 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.7, 136.0, 131.8, 128.9, 122.7, 80.4,
65.6, 61.5, 15.2, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C12H15BrNaO3: 309.0097; found:
309.0085.
.
Yield: 83.6 mg (54%); Rf = 0.15 (Et2O–hexanes, 5:95).
1H NMR (400 MHz, CDCl3): δ = 7.96–7.92 (m, 2 H), 7.60–7.54 (m, 1 H),
7.47–7.38 (m, 4 H), 6.89 (app d, J = 8.8 Hz, 2 H), 5.45 (s, 1 H), 3.80 (s, 3
H), 3.78 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 190.5, 170.9, 159.9, 136.2, 133.9,
129.9, 128.8, 127.5, 126.7, 114.5, 55.4, 53.2, 50.7. All spectral data
match those previously reported.
Insertion Reactions Catalyzed by 9; General Procedure
Ethyl 2-(Benzyloxy)-2-(4-bromophenyl)acetate (6g)
Method A: To a dry screw-capped reaction vial charged with 5 (0.186
mmol) under a N2 atmosphere was added the appropriate alcohol or
thiol (1.860 mmol, 10 equiv). The catalyst (0.0558 mmol, 30 mol%)
was then added in one portion and the reaction mixture was allowed
to stir at r.t. for 24 h (for larger scales, adding a needle to the cap to
vent the nitrogen gas formed during the reaction is recommended).
After this period, the reaction mixture was purified by flash column
chromatography (silica gel) to afford 6 or 7.
The compound was isolated as a pale yellow oil by flash column chro-
matography (silica gel, EtOAc–hexanes, 5:95 to 20:80).
Yield: 16 mg (0.0465 mmol, 25%); Rf = 0.30 (EtOAc–hexanes, 10:90).
IR (film): 2980, 2928, 1748, 1487, 1206, 1179, 1096 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.47 (m, 2 H), 7.37–7.28 (m, 7 H),
4.87 (s, 1 H), 4.59 (d, J = 1.3 Hz, 2 H), 4.24–4.11 (m, 2 H), 1.21 (t, J = 7.1
Hz, 3 H).
Method B: To a 1.0 M solution of 5 (0.186 mmol) in MeNO2 under a N2
atmosphere was added the appropriate alcohol or thiol (0.558 mmol,
3.0 equiv). Catalyst (0.058 mmol, 30 mol%) was then added in one
portion. The reaction mixture was allowed to stir for 24 h at r.t. and
then purified by flash column chromatography on silica gel to afford
6 or 7 (for larger scales, adding a needle to the cap to vent the nitro-
gen gas formed during the reaction is recommended).
13C NMR (100 MHz, CDCl3): δ = 170.5, 137.1, 135.6, 131.9, 129.1,
128.7, 128.2, 128.2, 122.9, 79.2, 71.5, 61.6, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H17BrNaO3: 371.0253; found:
371.0244.
Ethyl 2-(4-Bromophenyl)-2-(dodecylsulfanyl)acetate (7g)
The compound was isolated as a pale yellow oil by flash column chro-
matography (silica gel, EtOAc–hexanes, 5:95 to 20:80).
Methyl 2-Ethoxy-2-(4-methoxyphenyl)acetate (6a)
The compound was isolated as a pale yellow oil by flash column chro-
matography (silica gel, EtOAc–hexanes, 5:95 to 20:80).
Yield: 12%; Rf = 0.60 (EtOAc–hexanes, 10:90).
IR (film): 2955, 2926, 2855, 1738, 1487, 1271, 1146, 1013 cm–1
.
Yield: 36 mg (0.162 mmol, 87%); Rf = 0.20 (EtOAc–hexanes, 10:90).
1H NMR (400 MHz, CDCl3): δ = 7.50–7.44 (m, 2 H), 7.39–7.32 (m, 2 H),
4.50 (s, 1 H), 4.30–4.08 (m, 2 H), 2.65–2.35 (m, 2 H), 1.67–1.44 (m, 3
H), 1.44–1.16 (m, 20 H), 0.88 (t, J = 6.9 Hz, 3 H).
IR (film): 3063, 3032, 2953, 2837, 1751, 1611, 1585, 1512, 1437,
1248, 1173, 1097, 1030 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.34 (m, 2 H), 6.91–6.86 (m, 2 H),
4.83 (s, 1 H), 3.79 (s, 3 H), 3.70 (s, 3 H), 3.60–3.45 (m, 2 H), 1.26 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.7, 135.6, 131.9, 130.3, 122.2, 61.9,
51.8, 32.2, 32.0, 29.7, 29.7, 29.6, 29.4, 29.9, 29.2, 29.1, 28.9, 22.8, 14.3,
14.2.
13C NMR (125 MHz, CDCl3): δ = 171.7, 159.8, 128.6, 128.5, 114.0, 80.4,
HRMS (ESI): m/z [M – 28 + Na]+ calcd for C20H31BrNaO2S: 437.1126;
65.0, 55.2, 52.1, 15.1
found: 437.1117.
HRMS (ESI): m/z [M + Na]+ calcd for C12H16NaO4: 247.0940; found:
247.0934.
Acknowledgment
Methyl 2-(Benzyloxy)-2-(4-methoxyphenyl)acetate (6e)
A.E.M. and A.B. gratefully acknowledge joint support from The Ohio
State University and FAPESP for an international collaboration to un-
dertake these studies. We would like to thank FAPESP (Research Sup-
porting Foundation of the State of Sao Paulo) for financial support
(2013/18009-4, 2013/25504-1 and 2013/50312-9) and a fellowship
to B.B. (2012/22274-2). A.E.M. is also grateful to Donors of the Ameri-
The compound was isolated as a pale yellow oil by flash column chro-
matography (silica gel, EtOAc–hexanes, 5:95 to 20:80).
Yield: 48 mg (0.167 mmol, 90%); Rf = 0.17 (EtOAc–hexanes, 10:90).
IR (film): 3003, 2953, 2837, 1751, 1611, 1512, 1248, 1173, 1097, 1030
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686

686
B. Bernardim et al.
Feature
Synthesis
can Chemical Society Petroleum Research Fund for partial support of
investigations used to collect data reported herein.
2013, 52, 14084; Angew. Chem. 2013, 125, 14334. (c) Burns, N.
Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133,
14578. (d) Lee, Y.; Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2011,
13, 5564. (e) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E.
N. Science 2010, 327, 986.
Supporting Information
(9) For a computational study on hydrogen-bond-donor-induced
acidity enhancement of proline, see: (a) Xue, X.-S.; Yang, C.; Li,
X.; Cheng, J.-P. J. Org. Chem. 2014, 79, 1166. (b) Yang, C.; Xue, Z.-
S.; Li, X.; Cheng, J.-P. J. Org. Chem. 2014, 79, 4340.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561061.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(10) For pioneering work on boronate ureas in anion recognition,
see: (a) Hughes, M. P.; Shang, M. Y.; Smith, B. D. J. Org. Chem.
1996, 61, 4510. (b) Hughes, M. P.; Smith, B. D. J. Org. Chem.
1997, 62, 4492.
References
(1) For reviews on diazo chemistry, see: (a) Morton, D.; Davies, H.
Chem. Soc. Rev. 2011, 40, 1857. (b) Slattery, C.; Ford, A.; Maguire,
A. Tetrahedron 2010, 66, 6681. (c) Moody, C. Angew. Chem. Int.
Ed. 2007, 46, 9148. (d) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthe-
sis 2001, 2203. (e) List, B.; Castello, C. Synlett 2001, 1687.
(2) For selected examples of rhodium-catalyzed diazo chemistry,
see: (a) Qin, C.; Davis, H. M. J. Am. Chem. Soc. 2014, 136, 9792.
(b) Smith, A. G.; Davis, H. M. J. Am. Chem. Soc. 2012, 134, 18241.
(c) Ju, L.; Liu, P.; Song, C.; Wang, J.; Wang, M.; Xu, Z.; Zhang, Y.
Chem. Eur. J. 2013, 19, 3584. (d) Hrdina, R.; Lacour, J.; Moraleda,
D.; Guenee, L. Organometallics 2013, 32, 473. For recent exam-
ples of copper-catalyzed diazo chemistry, see: (e) Lee, E. C.; Fu,
G. C. J. Am. Chem. Soc. 2007, 129, 12066. (f) Zhu, S.; Xu, B.; Wang,
G.; Zhou, Q. J. Am. Chem. Soc. 2013, 134, 436.
(3) For a review on Brønsted acid catalyzed C–C bond formation of
diazoalkanes, see: Johnston, J. N.; Muchalski, H.; Troyer, T.
Angew. Chem. Int. Ed. 2010, 49, 2290.
(4) So, S. S.; Mattson, A. E. J. Am. Chem. Soc. 2012, 134, 8798.
(5) (a) Etter, M. C.; Urbanczyklipkowska, Z.; Ziaebrahimi, M.;
Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415. (b) Etter, M. C.;
Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 8415. (c) Etter, M. C.
Acc. Chem. Res. 1990, 23, 120.
(11) Evidence of sulfur hydrogen bonding with even weak hydrogen
bond donors has been observed: (a) Bhattacharyya, S.;
Bhattacherjee, A.; Shirhatti, P. R.; Wategaonkar, S. J. Phys. Chem.
A. 2013, 117, 8238. (b) Howard, D. L.; Kjaergaard, H. G. Phys.
Chem. Chem. Phys. 2008, 10, 4113. (c) Wierzejewska, M.; Sadyka,
M. J. Mol. Struct. 2006, 786, 33. (d) Nordstrand, K.; Åslund, F.;
Meunier, S.; Holmgren, A.; Otting, G.; Berndt, K. D. FEBS Lett.
1999, 449, 196. (e) Ueyama, N.; Nishikawa, N.; Yamada, Y.;
Okamura, T.-A.; Nakamura, A. J. Am. Chem. Soc. 1996, 118,
12826. (f) Sherry, A. D.; Purcell, K. F. J. Am. Chem. Soc. 1972, 94,
1848.
(12) For reviews on Brønsted acid catalysis, see: (a) Rueping, M.;
Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539.
(b) Akiyama, T. Chem. Rev. 2007, 107, 5744. (c) Akiyama, T.; Itoh,
J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
(13) For an early example of phosphoric acid derived catalysis with
diazo compounds, see: Uraguchi, D.; Sorimachi, K.; Terada, M.
J. Am. Chem. Soc. 2005, 127, 9360.
(14) Pangborn, A.; Giardello, M.; Grubbs, R.; Rosen, R.; Timmers, F.
Organometallics 1996, 15, 1518.
(15) So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. Org. Lett. 2012, 14,
444.
(16) Wrackmeyer, B. Modern Magnetic Resonance, Part 1; Webb, G.
A., Ed.; Springer: Dordrecht, 2006, 455.
(17) Creary, X. J. Org. Chem. 1987, 52, 5026.
(6) So, S. S.; Oottikkal, S.; Badjic, J. D.; Hadad, C. M.; Mattson, A. E.
J. Org. Chem. 2014, 79, 4832.
(7) Couch, E. D.; Auvil, T. J.; Mattson, A. E. Chem. Eur. J. 2014, 20,
8283.
(8) For examples of proposed urea–Brønsted acid co-catalysis, see:
(a) Mittal, N.; Sun, D. X.; Seidel, D. Org. Lett. 2014, 16, 1012.
(b) Min, C.; Mittal, N.; Sun, D. X.; Seidel, D. Angew. Chem. Int. Ed.
(18) Davies, P. W.; Albrecht, S. J. C.; Assanelli, G. Org. Biomol. Chem.
2009, 7, 1276.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 677–686