Practical Synthesis of Chiral N-Heterocyclic Carbene Triazolium Salts Containing a Hydroxy Functional Handle

Article abstract of DOI:10.1055/s-0037-1611786

A library of functionalized chiral pyrrolidine-based N-heterocyclic carbene triazolium salts containing a hydroxy handle is prepared from readily accessible chiral (S)-pyroglutamic acid in eight steps. This improved synthetic protocol affords increased yields for known structures and 18 new NHCs are prepared by this method. The presence of a hydroxy handle offers potential for further functionalization and for non-covalent control over catalytic reactions in which the NHCs can serve as organocatalysts or ligands for organometallic catalysis.

Full text of DOI:10.1055/s-0037-1611786

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–T
paper
A
en
V. Dhayalan et al.
Paper
Synthesis
Practical Synthesis of Chiral N-Heterocyclic Carbene Triazolium
Salts Containing a Hydroxy Functional Handle
Vasudevan Dhayalan
Kanchan Mal
0
0
0
0-0
0
0
3-
4
5
4
8-2
8
9
4
1) Me3OBF4, DCM
2) ArylNHNH2, DCM
N
N
BF4
O
R
N
R
N
Anat Milo*
0
0
0
0-
0
0
0
3-1
5
5
2-8
1
9
3
R
H
3) (EtO)3CH, DCM
4) (EtO)3CH, PhCl
5) TMSBr, CH3OH
or
OH
R
FG
OR'
Department of Chemistry, Ben-Gurion University of the Negev,
Beer-Sheva 84105, Israel
anatmilo@bgu.ac.il
One pot reaction
Examples: 22
Yield: up to 96%
FG = EWG/EDG
R = H, Ar
R' = TMS, TIPS, TBS
HBF4·OEt2, PhCl
Published as part of the Bürgenstock Special Section 2018 Future Stars
in Organic Chemistry
Received: 04.02.2019
Accepted after revision: 19.03.2019
Published online: 02.04.2019
versatility, while introducing a hydroxy unit that adds a
non-covalent component for controlling catalysis. The re-
sulting NHCs can be further functionalized at the hydroxy
handle to extend the library of catalysts by covalent and
non-covalent modifiers.
DOI: 10.1055/s-0037-1611786; Art ID: ss-2019-z0072-op
Abstract A library of functionalized chiral pyrrolidine-based N-hetero-
cyclic carbene triazolium salts containing a hydroxy handle is prepared
from readily accessible chiral (S)-pyroglutamic acid in eight steps. This
improved synthetic protocol affords increased yields for known struc-
tures and 18 new NHCs are prepared by this method. The presence of a
hydroxy handle offers potential for further functionalization and for
non-covalent control over catalytic reactions in which the NHCs can
serve as organocatalysts or ligands for organometallic catalysis.
Our synthetic protocol is based on previous literature
reports with several modifications described below, which
enabled the improvement of yields and the introduction of
several new NHC scaffolds.4 The protocol starts with com-
mercially available (S)-pyroglutamic acid (1), which is con-
verted into ester 2 in the presence of thionyl chloride
(SOCl2). By increasing the number of equivalents of SOCl2,
the time required for the reaction decreased to 4 hours
compared to previous reports and the formation of by-
products was mitigated.5 In the subsequent Grignard reac-
tion, the order of addition of phenylmagnesium bromide in-
fluenced the yield of the reaction and adding the ester to
the Grignard reagent improved our yields by 10–15% for
compound 3a. The corresponding tertiary benzylic alcohol
derivatives 3a–d were obtained in up to 69% yield (Scheme
Key words N-heterocyclic carbenes, triazolium salts, organocatalysis,
organomagnesium reagents, arylhydrazines, benzyl alcohol, protecting
groups, desilylation
The introduction of functional groups capable of non-
covalent interactions into the structure of organocatalysts
is often beneficial for their selectivity.1 For example, the
highest enantioselectivity in the benzoin reaction afforded
by an N-heterocyclic carbene (NHC) organocatalyst was the
result of installing a hydroxy group in proximity to the cat-
alytic center.2 We have recently become interested in such
motifs as secondary sphere non-covalent modifiers for or-
ganocatalysts; therefore, we sought to improve the synthet-
ic protocol for the preparation of triazolium NHCs contain-
ing a hydroxy handle. In this article, we report a practical
method for the preparation of functionalized chiral NHC
triazolium salts in moderate to high yields. These chiral
NHC salts are synthesized from readily accessible chiral (S)-
pyroglutamic acid in eight steps. The described protocol en-
ables the functionalization of pyrrolidine-based NHCs on
either side of the carbene moiety using Grignard reagents
and arylhydrazines. Synthetic protocols to modify the steric
and electronic properties of NHC structures serve to tune
selectivity, catalytic activity and basicity in organocatalytic
reactions.3 The presented synthetic protocol conserves this
O
O
SOCl2 (1.5 equiv)
HO
MeO
N
N
CH3OH, 0 °C, 4 h
90%
H
H
O
O
1
2
3a) Ar = C6H5, 69%
Ar
Ar
3b) Ar = 4-F3CC6H4, 23%
3c) Ar = 4-MeC6H4, 53%
3d) Ar = 4-n-BuC6H4, 56%
ArMgBr (3.2 equiv)
THF, 0–20 °C, 24 h
HO
N
O
H
3a–d
2,6-Lutidine (3 equiv)
TBSOTf (2.5 equiv)
Ar
4a) Ar = C6H5, 96%
Ar
4b) Ar = 4-F3CC6H4, 76%
4c) Ar = 4-MeC6H4, 90%
4d) Ar = 4-n-BuC6H4, 94%
TBSO
N
H
DCM, 0–20 °C,15 h
O
4a–d
Scheme 1 Synthesis of functionalized pyrrolidinones 4a–d via the ad-
dition of arylmagnesium reagents to pyroglutamic ester 2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

B
V. Dhayalan et al.
Paper
Synthesis
1). Selective silyl protection of the hydroxy functional
group of 3a–d with tert-butyldimethylsilyl triflate led to
the corresponding silyl ethers 4a–d in up to 96% yield.
These silyl ethers were purified and subjected to a previ-
ously reported three-step, one-pot reaction affording chiral
triazolium salts 5a–e in up to 78% yield (Scheme 2).5 It is
noted that functionalized Grignard reagents were used,
leading to three new chiral NHC triazolium salts.
1) Me3OBF4 (1.1 equiv)
DCM, 20 °C, 15 h
2) Arylhydrazine (1.1 equiv)
DCM, 20 °C, 2–8 h
N
Ph
Ph
N
Ar
N
3) (EtO)3CH, DCM
40 °C, 1 h
4) (EtO)3CH, PhCl
130 °C, 24 h
5) TMSBr (2.5 equiv), CH3OH
20 °C, 5–12 h
O
N
H
Ph
Ph OH
OTMS
6a–k Br
6l BF4
4a′
F
BF4
N
1) Me3OBF4 (1.1 equiv)
DCM, 20 °C, 24 h
Ar =
Ar =
N
Ar
Ar =
N
4a–d
2) Arylhydrazine (1.1 equiv)
DCM, 20 °C, 24 h
3) (EtO)3CH, 120 °C, 24 h
F
Ar
Ar OTBS
5a–e
6a (96%)
6b (55%)
6c (76%)
5a) Ar = C6H5; Ar = C6H5, 56%
5b) Ar = C6H5; Ar = C6F5, 44%
5c) Ar = 4-F3CC6H4; Ar = C6H5, 78%
5d) Ar = 4-MeC6H4; Ar = C6H5, 59%
5e) Ar = 4-n-BuC6H4; Ar = C6H5, 70%
F
F
F
F
Ar =
Ar =
Ar =
F
F3C
F
F
Scheme 2 Synthesis of chiral NHC triazolium salts 5a–e by one-pot
reactions of pyrrolidinones 4a–d functionalized by Grignard reagents
6d (73%)
6e (66%)
6f (50%)
Cl
NO2
Ar =
In order to obtain NHC salts with deprotected hydroxy
groups, we opted for a more labile silyl protecting group
following literature reports.2b,4b Trimethylsilyl (TMS)-pro-
tected pyrrolidinone 4a′ was prepared according the same
procedure used for TBS protection (Scheme 1). Following
the literature report, methylation of the TMS protected am-
ide 4a′ was performed using Meerwein’s reagent (trimethy-
Ar =
Ar =
CF3
Cl
6h (94%)
6g (69%)
6i (69%)
Me
Me
Ar =
Ar =
Ar =
–
loxonium tetrafluoroborate, Me3O+BF4 ) to afford an imine
Me
OMe
Me
Me
intermediate (step 1), which was treated in situ with func-
tionalized arylhydrazines to generate the corresponding
coupled imine precursor (step 2). Serendipitously, we had
started the next step by using DCM as the solvent instead of
PhCl and obtained overall increased yields, therefore, we
added one hour of reflux in DCM to the literature proce-
dure. Following our modified protocol, triethyl orthofor-
mate [(EtO)3CH] was added in two batches, the first 8
equivalents were added in DCM (step 3), then DCM was re-
moved by rotary evaporation, and the second batch was
added in PhCl (step 4). Finally, deprotection of the TMS
group (step 5) was performed according to the literature
procedure using TMSBr (Scheme 3).
To ensure that the modified conditions (Scheme 3) us-
ing DCM in the third step of the reaction were improving
the yields across the substrate scope, we selected several
electron-donating and electron-withdrawing examples and
performed the reaction in the absence of this step (Scheme
4). For all of these examples, the yields were improved by
adding the DCM step (Scheme 3, step 3). The modified con-
ditions afforded the chiral NHC salts in improved yields
compared to previous reports and several new examples
were prepared. We note that the improvement in yields was
most remarkable for electron-withdrawing substituents on
6j (80%)
6k (51%)
6l (84%)
Scheme 3 Synthesis of chiral NHC triazolium salts 6a–l by a one-pot,
five-step reaction sequence
the aryl ring compared to previous reports.3a,4,5 Overall, flu-
orinated aryl substituents led to reduced yields compared
to other substrates, even under our improved conditions.
Br
Ar
1) Me3OBF4 (1.1 equiv)
DCM, 20 °C, 24 h
N
Ph
Ph
N
O
N
2) Arylhydrazine (1.1 equiv)
DCM, 20 °C, 2–8 h
3) (EtO)3CH, PhCl
130 °C, 24 h
4) TMSBr (2.5 equiv)
CH3OH, 20 °C
5–12 h
N
H
OTMS
Ph
Ph
OH
4a′
6
6a) Ar = C6H5; 82%
6e) Ar = C6F5; 30%
6h) Ar = 2,6-ClC6H3; 62%
6l) Ar = 2,4,6-(Me)3C6H2; 71%
Scheme 4 Synthesis of chiral NHC triazolium salts 6 by a one-pot, four-
step reaction sequence
The silyl deprotection (step 5) was performed under
similar conditions to previous literature reports, however,
in these reports it was assumed that the counterion re-
mained non-coordinating tetrafluoroborate (BF4 ).2b By flu-
–
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

C
V. Dhayalan et al.
Paper
Synthesis
orine NMR analysis we noticed that in fact the characteris-
tic BF4 peak does not appear; therefore, we assume that
Table 1 Substrate Scope of NHC Triazolium Salts 10a–jPrepared from 9a–c
–
Entry
1
R
ArNHNH2
Product
10
Yield
69%
6a–k were obtained as bromine salts. As the counterion can
influence catalytic properties, we tested whether it would
be possible to exchange the counterion. The reaction of
compounds 6a–b, e, k with tetrafluoroboric acid diethyl
ether complex (HBF4·OEt2) in DCM afforded the desired chi-
ral NHC BF4– salts 7a–d in excellent yields (Scheme 5).4f
N
N
N
9a C6H5
10a
OTIPS
N
N
N
2
3
4
9b C6H5
10a′
10b
10c
70%
77%
84%
Br
BF4
Ar
N
N
OTBS
HBF4·OEt2 (1.5 equiv)
DCM, 20 °C, 3 h
N
Ar
N
N
N
N
F
Ph
Ph
Ph
Ph
7a–d
N
N
7a) Ar = C6H5; 99%
7b) Ar = 2-FC6H4; 98%
7c) Ar = C6F5; 98%
9a 3-FC6H4
9a 4-FC6H4
OH
OH
6
OTIPS
7d) Ar = 4-MeOC6H4; 98%
N
Scheme 5 NHC triazolium counterion exchange
N
N
F
F
OTIPS
Hydroxy-functionalized pyrrolidinone 8 was prepared
from commercially available (S)-pyroglutamic acid (1) in a
one-pot reaction by esterification followed by reduction
with NaBH4 (Scheme 6). Following this reduction, a new
family of chiral NHC triazolium salts with less steric hin-
drance near the hydroxy handle was prepared. Selective
protection of the alcohol group was performed with differ-
ent silylating reagents (RCl: TBSCl, TIPSCl, TBDPSCl, TMSCl)
in excellent yields using a literature procedure.6 The isolat-
ed silylated compounds 9a–c were subjected to a three-
step, one-pot procedure to afford the protected chiral NHC
salts 10a–j according to the literature (Scheme 6 and Table
1).7
F
F
F
N
F
F
F
N
N
5
6
9a C6F5
10d
56%
40%
OTIPS
F
F
F
F
F
F
N
N
N
9b C6F5
10d′
F
OTBS
N
N
N
7
8
9
9c
C6F5
10d′′ 48%
F
OTBDPS
HO
1) SOCl2 (1.5 equiv)
CH3OH, 0 °C, 4 h
Imidazole (2.5 equiv)
RCl (1.2 equiv)
N
O
HO
N
H
N
N
9a 4-F3CC6H4
10e
10f
67%
66%
HN
2) NaBH4 (2 equiv)
EtOH, 0–20 °C, 24 h
84%
DMF, 20 °C, 24 h
CF3
O
O
OTIPS
8
1
N
CF3
N
N
1) Me3OBF4 (1.1 equiv)
DCM, 20 °C, 24 h
BF4
N
9b 3,5-(F3C)2C6H3
RO
N
N
OTBS
Ar
2) Arylhydrazine (1.1 equiv)
DCM, 20 °C, 24 h
3) (EtO)3CH, PhCl
130 °C, 24 h
N
CF3
O
H
10a–j
(40–87%)
OR
9a–c
N
N
N
10
11
12
13
9a 4-F3COC6H4
9a 4-i-PrC6H4
10g
10h
10i
61%
73%
73%
87%
9a) R = TIPS, 97%
9b) R = TBS, 99%
9c) R = TBDPS, 98%
9d) R = TMS, 0%
OCF3
OTIPS
N
Scheme 6 Synthesis of NHC triazolium salts 10a–j from (S)-pyroglu-
tamic acid (1)
N
N
OTIPS
Because we had obtained improved yields for the previ-
ous set of substrates by adding a step, we tried our modified
protocol for this new set. (EtO)3CH was added in two batch-
es, the first 8 equivalents in DCM (according to Scheme 3,
step 3) and the second batch was added in PhCl (according
to Scheme 3, step 4). However, in this case, the yields were
diminished using the modified protocol. Finally, the depro-
tection of the silyl groups on compounds 10a–j (TIPS and
TBS) efficiently proceeded with HBF4·OEt2 in dry PhCl, af-
N
N
N
9a 2,6-(Me)2C6H3
9a 2,4,6-(Me)3C6H2
OTIPS
N
N
N
10j
OTIPS
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

D
V. Dhayalan et al.
Paper
Synthesis
fording the desired chiral NHC triazolium salts 11a–j in up
to 95% yield (Scheme 7). By applying this protocol, nine
new NHC scaffolds with hydroxy handles were prepared.
We noticed that under the acidic conditions of the depro-
tection reaction and under column chromatography, NHC
triazolium salts 11a–j were prone to elimination; therefore,
short reaction times and a purification process based on
washing off impurities and recrystallization were opted for.
This effect is most pronounced for electron-withdrawing
substituents on the aryl ring.
To unravel the effect of DCM in our modified protocol
for the synthesis of triazolium salts 6a–l, we carried out
several control experiments (Table 2). Based on plausible
mechanisms for the one-pot NHC cyclization and previous
literature reports, HBF4 is a probable by-product of this re-
action.4f,p Therefore, NHC catalyst 5a′ was subjected to this
proposed by-product in the presence of different solvents
to reveal potential side reactions. The labile TMS protecting
group of 5a′ underwent smooth deprotection in the pres-
ence of HBF4·OEt2 in DCM, affording 7a (Table 2, entry 1).
Under similar reaction conditions with PhCl as the solvent,
7a underwent further elimination to afford a 41% yield of
7a′ (Table 2, entry 3), and over a longer reaction time 7a′
was isolated in 95% yield (Table 2, entry 5). In the presence
of 8 equivalents of (EtO)3CH in DCM, 5a′ remained stable for
1 hour and could be recovered in quantitative yield. Under
similar reaction conditions with PhCl as the solvent, a mix-
ture of products was observed including a 1:3 ratio of 5a′ to
7a along with additional unidentified by-products (Table 2,
entry 4). From these control experiments, we conclude that
using DCM as the solvent in the first hour of the reaction in
the presence of (EtO)3CH can mitigate the cleavage of the
TMS protecting group, the subsequent elimination process
and additional side reactions. In contrast, due to the in-
creased stability of the protecting groups used in the syn-
thesis of 10a–j (TIPS and TBS), DCM did not improve the ob-
served yields for this new family of NHC triazolium salts.
In conclusion, a library of functionalized chiral pyrroli-
dine-based NHC triazolium salts containing a hydroxy han-
dle has been prepared from readily accessible (S)-pyroglu-
tamic acid in eight steps and with moderate to high reac-
tion yields. These NHCs can serve as organocatalysts or
ligands for organometallic catalysis, while the presence of a
hydroxy handle could allow further functionalization and
control of reactivity and selectivity through non-covalent
interactions.
BF4
BF4
Ar
N
N
HBF4·OEt2 (1.1 equiv), PhCl
20–80 °C, 1–3 h
N
N
N
N
Ar
OR
OH
10a–j
11a–j (56–95%)
F
Ar =
Ar =
Ar =
F
11a (95%) from 10a
11a (92%) from 10a′
11b (93%)
11c (89%)
F
CF3
F
Ar =
Ar =
Ar =
CF3
F
F
CF3
F
11d (74%) from 10d
11d (83%) from 10d′
11e (87%)
11f (82%) from 10f
R1
Ar =
Ar =
Ar =
OCF3
i-Pr
R2
R1
11g (56%)
11h (94%)
11i R1 = Me, R2 = H (68%)
11j R1, R2 = Me (94%)
Scheme 7 Deprotection of NHC salts 10a–j to afford 11a–j with a free
hydroxy group
Table 2 Control Experimentsa
BF4
N
BF4
Ph
BF4
Ph
N
N
N
Ph
N
N
N
N
N
HBF4·OEt2 (1.0 equiv)
Ph
Ph
+
Ph
Ph
(EtO)3CH
OTMS
Ph
OH
Ph
(0 or 8 equiv)
7a
5a′
7a′
Entry
(EtO)3CH (equiv)
Solvent
Temp (°C)
Time (h)
5a′ (%)b
7a (%)b
7a′ (%)b
Yield (%)c
1
2
3
4
5
–
8
–
8
–
DCM
DCM
PhCl
PhCl
PhCl
40
1
0
100
0
0
92 (7a)
97 (5a′)
–
40
1
100
0
0
110
110
110
1
59
75
0
41
0
1
25
0
–
15
100
95 (7a′)
a Unless otherwise stated, reactions were performed under a nitrogen atmosphere as follows: 5a′ (0.38 mmol, 1 equiv), HBF4·OEt2 (0.38 mmol, 1 equiv), dry
solvent (10 mL).
b The ratios of the three products were determined by 1H NMR integration (see the Supporting Information).
c Yield of isolated product after recrystallization.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

E
V. Dhayalan et al.
Paper
Synthesis
solution (600 mL). The organic layer was removed and the aqueous
layer was washed with DCM (5 × 50 mL). The organic extracts were
combined, dried over Na2SO4 and concentrated under reduced pres-
sure. The product was purified by recrystallization with Et2O (2 × 200
mL) to give pure 3a (14.30 g, 69%).
Reagents were purchased from commercial suppliers and used with-
out further purification. (EtO)3CH was distilled before use. Anhydrous
THF was prepared by adding molecular sieves (3 Å), that had been ac-
tivated by microwave irradiation under vacuum (20% m/v), to com-
mercial grade (AR) THF, which was used after 24–48 h. Similarly, acti-
vated molecular sieves (3 Å) were used for preparing the different an-
hydrous solvents used in this work: CH3OH, DCM, Et2O, DMF and
PhCl. Unless otherwise stated, all operations were performed using
high-vacuum standard Schlenk techniques under nitrogen/argon
atmospheres. Thin-layer chromatography (TLC) analysis of reaction
mixtures was performed using Merck silica gel 60 F254 TLC plates
and samples were visualized under UV light or by staining with
KMnO4. Column chromatography was performed on Merck Silica Gel
60 Å (230–400 mesh). IR spectra were obtained using a Bruker Tensor
II spectrophotometer equipped with a platinum attenuated total re-
flectance (ATR) accessory. Nuclear magnetic resonance (NMR) spectra
were recorded using Bruker DPX400 or DMX500 instruments. The 1H
and 13C chemical shifts are reported in ppm downfield of tetramethyl-
silane and referenced to the residual solvent peaks (CHCl3: H = 7.26
ppm, C = 77.0 ppm; DMSO: H = 2.50 ppm, C = 39.52 ppm; CH3CN:
4-(Trifluoromethyl)phenylmagnesium Bromide
4-(Trifluoromethyl)phenylmagnesium bromide was prepared using a
modified procedure based on a previous report.10 A dry, argon-
flushed, two-neck Schlenk flask equipped with a magnetic stir bar
and a septum was charged with magnesium turnings (11.70 g, 481
mmol, 2.5 equiv) and heated with a heat gun under high vacuum for 5
min. After cooling to 0 °C, anhydrous THF (100 mL) was added and the
magnesium turnings were activated using iodine (50 mg). The sus-
pension was cooled to 0 °C followed by the dropwise addition of 4-
(trifluoromethyl)phenyl bromide (44 g, 195 mmol, 1.0 equiv) in THF
(80 mL). The reaction mixture was stirred at 0 °C for 30 min, warmed
to 20 °C over 1 h and then heated at reflux for 2 h. The solids were
allowed to settle and the yield of the insertion reaction was deter-
mined by iodometric titration of the supernatant solution (0.6 M in
THF, 56%).

H = 1.94 ppm, C = 1.32, 118.26 ppm). Multiplicities are reported us-
ing standard abbreviations. HRMS data were obtained using a Ther-
moscientific LTQU XL Orbitrap HRMS utilizing APCI (atmospheric-
pressure chemical ionization).
(S)-5-{Hydroxy-bis[4-(trifluoromethyl)phenyl]methyl}pyrrolidin-
2-one (3b)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with methyl pyroglutamate 2
(5.5 g, 38.4 mmol, 1 equiv) in anhydrous THF (50 mL). 4-(trifluoro-
methyl)phenylmagnesium bromide (192.0 mL, 115 mmol, 0.6 M in
THF, 3.0 equiv) was added dropwise at 0 °C and the mixture warmed
to 20 °C and left to stir for 24 h. The reaction mixture was quenched
with 3% aqueous HCl solution (300 mL). The organic layer was re-
moved and the aqueous layer was washed with DCM (5 × 50 mL). The
organic extracts were combined, dried over Na2SO4 and concentrated
under reduced pressure. The obtained crude residue was purified by
flash column chromatography (silica gel pre-neutralized with tri-
ethylamine, n-hexane/EtOAc, 1:9) to furnish compound 3b.
(S)-Methyl 5-Oxopyrrolidine-2-carboxylate (2)
Precursor 2 was prepared according to a modified literature proce-
dure.5 A dry, argon-flushed, two-neck Schlenk flask equipped with a
magnetic stir bar and a septum was charged with L-pyroglutamic acid
(1) (10.00 g, 77 mmol, 1 equiv) in anhydrous CH3OH (250 mL). SOCl2
(8.30 mL, 116 mmol, 1.5 equiv) was added dropwise at 0 °C and the
mixture then slowly warmed to 20 °C over 4 h. After full consumption
of the starting material (TLC monitoring), CH3OH was removed under
reduced pressure and 2 was dried under high vacuum for 12 h. The
crude product was used without further purification.
Phenylmagnesium Bromide
Yield: 3.50 g (23%); white solid.
Phenylmagnesium bromide was prepared using a modified procedure
based on a previous report.8 A dry, argon-flushed, two-neck Schlenk
flask equipped with a magnetic stir bar and a septum was charged
with magnesium turnings (23.70 g, 975 mmol, 2.5 equiv) and heated
with a heat gun under high vacuum for 5 min. After cooling to 0 °C,
anhydrous THF (200 mL) was added and the magnesium turnings
were activated using iodine (50 mg). The resulting suspension was
cooled to 0 °C followed by the dropwise addition of bromobenzene
(41.50 mL, 395 mmol, 1.0 equiv) in THF (50 mL). The reaction mixture
was stirred at 0 °C for 30 min, warmed to 20 °C over 1 h and then
heated at reflux for 2 h. The solids were allowed to settle and the yield
of the insertion reaction was determined by iodometric titration of
the supernatant solution (1.35 M in THF, 85%).9
1H NMR (400 MHz, DMSO-d6):  = 1.73–1.82 (m, 1 H), 1.90–2.07 (m, 3
H), 4.88–4.90 (m, 1 H), 6.21 (s, 1 H), 7.40 (s, 1 H), 7.64–7.73 (m, 8 H).
13C NMR (100 MHz, DMSO-d6):  = 21.8, 29.9, 59.4, 78.8, 120.2 (q, J =
13.0 Hz), 124.3 (q, J = 270.0 Hz), 125.0 (q, J = 3.0 Hz), 127.0, 127.2,
127.3, 127.5 (q, J = 4.0 Hz), 128.1 (q, J = 40.0 Hz), 149.6, 177.7.
19F NMR (376 MHz, DMSO-d6):  = –60.98 (s, 3 F), –60.91 (s, 3 F).
4-Methylphenylmagnesium Bromide
4-Methylphenylmagnesium bromide was prepared using a modified
procedure based on a previous report.11 A dry, argon-flushed, two-
neck Schlenk flask equipped with a magnetic stir bar and a septum
was charged with magnesium turnings (11.7 g, 481 mmol, 2.5 equiv)
and heated with a heat gun under high vacuum for 5 min. After cool-
ing to 0 °C, anhydrous THF (200 mL) was added and the magnesium
turnings were activated using iodine (50 mg). The resulting suspen-
sion was cooled to 0 °C followed by the dropwise addition of p-tolyl
bromide (33.4 g, 195 mmol, 1.0 equiv) in THF (30 mL). The reaction
mixture was stirred at 0 °C for 30 min, warmed to 20 °C over 1 h and
then heated at reflux for 2 h. The solids were allowed to settle and the
yield of the insertion reaction was determined by iodometric titration
of the supernatant solution (0.66 M in THF, 77%).
(S)-5-(Hydroxydiphenylmethyl)pyrrolidin-2-one (3a)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with phenylmagnesium bro-
mide (183.00 mL, 248 mmol, 1.35 M in THF, 3.2 equiv). Methyl pyro-
glutamate 2 (11.10 g, 77.4 mmol, 1 equiv) in anhydrous THF (100 mL)
was added dropwise at 0 °C and the mixture warmed to 20 °C and left
to stir for 24 h (the duration of the reaction was initially determined
by GC analysis until full consumption of the starting material was ob-
served).5 The reaction mixture was quenched with 3% aqueous HCl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

F
V. Dhayalan et al.
Paper
Synthesis
(S)-5-(Hydroxydi-p-tolylmethyl)pyrrolidin-2-one (3c)
(S)-5-{[(tert-Butyldimethylsilyl)oxy]diphenylmethyl}pyrrolidin-
2-one (4a)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with methyl pyroglutamate 2
(5.5 g, 38.4 mmol, 1 equiv) in anhydrous THF (50 mL). 4-Methylmag-
nesium bromide (204.0 mL, 134 mmol, 0.66 M in THF, 3.5 equiv) was
added dropwise at 0 °C and the mixture warmed to 20 °C and left to
stir for 24 h. The reaction mixture was quenched with 3% aqueous HCl
solution (300 mL). The organic layer was removed and the aqueous
layer was washed with DCM (5 × 50 mL). The organic extracts were
combined, dried over Na2SO4 and concentrated under reduced pres-
sure. The obtained crude residue was purified by flash column chro-
matography (silica gel was pre-neutralized with triethylamine, n-
hexane/EtOAc, 1:9) to furnish compound 3c.
Precursor 4a was prepared using a previous literature report.5 A dry,
argon-flushed, two-neck Schlenk flask equipped with a magnetic stir
bar and a septum was charged with alcohol 3a (2.7 g, 10.2 mmol, 1
equiv) in anhydrous DCM (80 mL). 2,6-Lutidine (3.3 g, 31 mmol, 3
equiv) was slowly added at 0 °C and the mixture stirred for 5 min fol-
lowed by the slow addition of tert-butyldimethylsilyl triflate (6.72 g,
26 mmol 2.5 equiv) at 0 °C. The reaction mixture was then stirred at
20 °C for 15 h, quenched with 0.5% aqueous HCl (100 mL) and extract-
ed with DCM (5 × 30 mL). The combined organic phases were dried
over Na2SO4 and concentrated in vacuo. The obtained crude residue
was purified by flash column chromatography (silica gel was pre-neu-
tralized with triethylamine, n-hexane/EtOAc, 2:1) to furnish com-
pound 4a as a colorless solid (3.72 g, 96%).
Yield: 6.05 g (53%); white solid.
1H NMR (400 MHz, DMSO-d6):  = 1.76–1.93 (m, 4 H), 2.23 (s, 3 H),
2.25 (s, 3 H), 4.65–4.67 (m, 1 H), 5.58 (s, 1 H), 6.95 (s, 1 H), 7.07 (t, J =
8.0 Hz, 4 H), 7.31 (dd, J = 12.0, 8.0 Hz, 4 H).
(S)-5-[Diphenyl(trimethylsilyloxy)methyl]pyrrolidin-2-one (4a′)
Precursor 4a′ was prepared using a previous literature report.5 A dry,
argon-flushed, two-neck Schlenk flask equipped with a magnetic stir
bar and a septum was charged with alcohol 3a (14.00 g, 53 mmol, 1
equiv) in anhydrous DCM (400 mL). 2,6-Lutidine (18.40 mL, 159
mmol, 3 equiv) was slowly added at 0 °C and the mixture stirred for 5
min followed by the slow addition of trimethylsilyl triflate (24.00 mL,
133 mmol 2.5 equiv) at 0 °C. The reaction mixture was then stirred at
20 °C for 15 h, quenched with 0.5% aqueous HCl (200 mL) and extract-
ed with DCM (5 × 60 mL). The combined organic phases were dried
over Na2SO4 and concentrated in vacuo. The obtained crude residue
was purified by flash column chromatography (silica gel was pre-neu-
tralized with triethylamine, n-hexane/EtOAc, 2:1) to furnish com-
pound 4a′ as a colorless solid (16.50 g, 92%).
13C NMR (100 MHz, DMSO-d6):  = 20.5, 20.6, 22.0, 29.9, 59.6, 78.4,
126.1, 126.4, 128.3, 128.4, 135.3, 142.8, 143.0, 177.4.
4-n-Butylphenylmagnesium Bromide
4-n-Butylphenylmagnesium bromide was prepared using a modified
procedure based on a previous report.12 A dry, argon-flushed, two-
neck Schlenk flask equipped with a magnetic stir bar and a septum
was charged with magnesium turnings (6.07 g, 250 mmol, 2.5 equiv)
and heated with a heat gun under high vacuum for 5 min. After cool-
ing to 0 °C, anhydrous THF (100 mL) was added and the magnesium
turnings were activated using iodine (50 mg). The suspension was
cooled to 0 °C followed by the dropwise addition of 4-(n-butyl)bro-
mobenzene (21.3 g, 100 mmol, 1.0 equiv) in THF (20 mL). The reac-
tion mixture was stirred at 0 °C for 30 min, warmed to 20 °C over 1 h
and heated at reflux for 2 h. The solids were allowed to settle and the
yield of the insertion reaction was determined by iodometric titration
of the supernatant solution (0.67 M in THF, 80%).
(S)-5-{[(tert-Butyldimethylsilyl)oxy]bis[4-(trifluoromethyl)phe-
nyl]methyl}pyrrolidin-2-one (4b)
Precursor 4b was prepared using a modified procedure based on pre-
vious reports. A dry, argon-flushed, two-neck Schlenk flask equipped
with a magnetic stir bar and a septum was charged with alcohol 3b
(1.0 g, 2.5 mmol, 1 equiv) in anhydrous DCM (60 mL). 2,6-Lutidine
(797 mg, 7.5 mmol, 3 equiv) was slowly added at 0 °C and the mixture
stirred for 5 min followed by the slow addition of tert-butyldimethyl-
silyl triflate (1.63 g, 6.2 mmol, 2.5 equiv) at 0 °C. The reaction mixture
was then stirred at 20 °C for 15 h, quenched with 0.5% aqueous HCl
(60 mL) and extracted with DCM (5 × 20 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The ob-
tained crude residue was purified by flash column chromatography
(silica gel was pre-neutralized with triethylamine, n-hexane/EtOAc,
8:2) to furnish compound 4b.
(S)-5-[Bis(4-butylphenyl)(hydroxy)methyl]pyrrolidin-2-one (3d)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with methyl pyroglutamate 2
(3.5 g, 24.5 mmol, 1 equiv) in anhydrous THF (50 mL). 4-n-Butyl-
phenylmagnesium bromide (110.0 mL, 73 mmol, 0.67 M in THF, 3.0
equiv) was added dropwise at 0 °C and the mixture warmed to 20 °C
and left to stir for 24 h. The reaction mixture was quenched with 3%
aqueous HCl solution (300 mL). The organic layer was removed, and
the aqueous layer was washed with DCM (5 × 50 mL). The organic ex-
tracts were combined, dried over Na2SO4 and concentrated under re-
duced pressure. The obtained crude residue was purified by flash col-
umn chromatography (silica gel was pre-neutralized with triethyl-
amine, n-hexane/EtOAc, 1:9) to furnish compound 3d.
Yield: 970 mg (76%); white solid.
1H NMR (400 MHz, DMSO-d6):  = –0.46 (s, 3 H), –0.25 (s, 3 H), 0.76–
0.89 (m, 1 H), 0.92 (s, 9 H), 1.75–1.92 (m, 2 H), 2.00–2.11 (m, 1 H),
4.75–4.78 (m, 1 H), 7.53 (t, J = 8.0 Hz, 4 H), 7.73 (t, J = 8.0 Hz, 4 H), 8.03
(s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = –3.6, –3.2, 18.5, 21.5, 25.9, 28.8,
58.2, 81.9, 120.0 (q, J = 13 Hz), 124.2, 124.2 (q, J = 270 Hz), 124.9 (q, J =
4 Hz), 128.3 (q, J = 32 Hz), 128.9, 129.6, 146.9, 147.5, 177.6.
Yield: 4.05 g (56%); white solid.
1H NMR (400 MHz, CD3OD):  = 0.89–0.94 (m, 6 H), 1.28–1.39 (m, 4
H), 1.52–1.61 (m, 4 H), 1.96–2.12 (m, 4 H), 2.54–2.60 (m, 4 H), 4.76–
4.79 (m, 1 H), 4.85 (s, 1 H), 7.09–7.16 (m, 4 H), 7.31–7.34 (m, 2 H),
7.38–7.41 (m, 2 H).
13C NMR (100 MHz, CD3OD):  = 14.3, 23.2, 23.3, 31.1, 34.8, 36.1, 62.4,
80.1, 127.6, 129.0, 129.3, 142.7, 142.9, 143.1, 143.9, 181.9.
19F NMR (376 MHz, DMSO-d6):  = –61.03 (s, 3 F), –60.85 (s, 3 F).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

G
V. Dhayalan et al.
Paper
Synthesis
(S)-5-{[(tert-Butyldimethylsilyl)oxy]di-p-tolylmethyl}pyrrolidin-
TBS-Protected Pre-Catalysts 5 (Scheme 2); Typical Procedure 1
2-one (4c)
(TP1)
Precursor 4c was prepared using a modified procedure based on pre-
vious reports. A dry, argon-flushed, two-neck Schlenk flask equipped
with a magnetic stir bar and a septum was charged with alcohol 3c
(2.4 g, 8.2 mmol, 1 equiv) in anhydrous DCM (80 mL). 2,6-Lutidine
(2.6 g, 24.4 mmol, 3 equiv) was slowly added at 0 °C and the mixture
stirred for 5 min followed by the slow addition of tert-butyldimethyl-
silyl triflate (5.3 g, 20 mmol, 2.5 equiv) at 0 °C. The reaction mixture
was then stirred at 20 °C for 15 h, quenched with 0.5% aqueous HCl
(60 mL) and extracted with DCM (5 × 30 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The ob-
tained crude residue was purified by flash column chromatography
(silica gel was pre-neutralized with triethylamine, n-hexane/EtOAc,
1:1) to furnish compound 4c.
Catalysts 5a–e were prepared based on previous reports.3a,5
(1) A dry, argon-flushed Schlenk flask equipped with a magnetic stir
bar and a septum was charged with 4a–d (10.0 mmol, 1 equiv) in an-
hydrous DCM (100 mL). Me3O+BF4– (11.0 mmol, 1.1 equiv) was added
and the reaction mixture was stirred at 20 °C for 24 h.
(2) The arylhydrazine (11.0 mmol, 1.1 equiv) was added to the solu-
tion and the mixture was stirred at 20 °C for 24 h. The solvent was
removed in vacuo and the solid residue dried under high vacuum for
12 h. This product was then used in the next step without further pu-
rification.
(3) The solid from step 2 was dissolved in anhydrous (EtO)3CH (100
mL) and then stirred at 120 °C for 24 h under an argon atmosphere.
The solvent was removed in vacuo and the residue dried under high
vacuum for 3 h at 80 °C. The crude product was purified by flash col-
umn chromatography (silica gel, acetone/DCM) or by recrystallization
from CH3OH or Et2O to give pure compounds 5a–e.
Yield: 3.01 g (90%); white solid.
1H NMR (400 MHz, CDCl3):  = –0.40 (s, 3 H), –0.34 (s, 3 H), 0.93 (s, 9
H), 1.00–1.07 (m, 1 H), 1.82–1.88 (m, 1 H), 2.04–2.18 (m, 2 H), 2.34 (s,
3 H), 2.35 (s, 3 H), 4.58–4.60 (m, 1 H), 5.74 (s, 1 H), 7.12 (t, J = 8.0 Hz, 4
H), 7.17–7.18 (m, 2 H), 7.23 (d, J = 4.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = –3.1, –3.0, 18.9, 21.2, 22.5, 26.2, 29.3,
60.2, 82.3, 128.5, 128.7, 128.8, 128.9, 137.6, 137.9, 139.5, 140.0, 178.8.
(S)-5-{[(tert-Butyldimethylsilyl)oxy]diphenylmethyl}-2-phenyl-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluorobo-
rate (5a)
NHC 5a5 was prepared according to TP1. (1) Compound 4a (3.8 g, 10
mmol, 1 equiv), anhydrous DCM (100 mL) and Me3O+BF4– (1.63 g, 11
mmol, 1.1 equiv). (2) Phenylhydrazine (1.3 g, 11 mmol, 1.1 equiv). (3)
Anhydrous (EtO)3CH (100 mL). The crude product was recrystallized
from CH3OH to give the pure NHC compound 5a.
(S)-5-{[(tert-Butyldimethylsilyl)oxy]bis(4-butylphenyl)meth-
yl}pyrrolidin-2-one (4d)
Precursor 4d was prepared using a modified procedure based on pre-
vious reports. A dry, argon-flushed, two-neck Schlenk flask equipped
with a magnetic stir bar and a septum was charged with alcohol 3d
(2.3 g, 6.1 mmol, 1 equiv) in anhydrous DCM (80 mL). 2,6-Lutidine
(1.94 g, 18.2 mmol, 3 equiv) was slowly added at 0 °C and the mixture
stirred for 5 min followed by the slow addition of tert-butyldimethyl-
silyl triflate (4.0 g, 15.1 mmol, 2.5 equiv) at 0 °C. The reaction mixture
was then stirred at 20 °C for 15 h, quenched with 0.5% aqueous HCl
(60 mL) and extracted with DCM (5 × 30 mL). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The ob-
tained crude residue was purified by flash column chromatography
(silica gel was pre-neutralized with triethylamine, n-hexane/EtOAc,
2:1) to furnish compound 4d.
Yield: 3.20 g (56%); white solid.
1H NMR (400 MHz, DMSO-d6):  = –0.37 (s, 3 H), –0.26 (s, 3 H), 0.91 (s,
9 H), 1.54–1.63 (m, 1 H), 2.77–2.94 (m, 2 H), 3.01–3.11 (m, 1 H), 6.00–
6.02 (m, 1 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.38–7.47 (m, 8 H), 7.62–7.71
(m, 3 H), 7.81–7.86 (m, 2 H), 10.14 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = –3.6, –3.4, 18.5, 20.1, 26.0, 29.5,
65.6, 81.8, 121.9, 128.1, 128.3, 128.7, 128.7, 129.0, 129.1, 130.0, 130.8,
135.4, 138.5, 139.9, 140.0, 163.3.
(S)-5-{[(tert-Butyldimethylsilyl)oxy]diphenylmethyl}-2-(perfluo-
rophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium
Tetrafluoroborate (5b)
NHC 5b4c was prepared according to TP1. (1) Compound 4a (3.8 g, 10
mmol, 1 equiv), anhydrous DCM (100 mL) and Me3O+BF4– (1.63 g, 11
mmol, 1.1 equiv). (2) Pentafluorophenylhydrazine (2.18 g, 11 mmol,
1.1 equiv). (3) Anhydrous (EtO)3CH (100 mL). The crude product was
recrystallized from EtOAc to give the pure NHC compound 5b.
Yield: 2.80 g (94%); white solid.
1H NMR (400 MHz, CDCl3):  = –0.42 (s, 3 H), –0.36 (s, 3 H), 0.90–1.01
(m, 7 H), 0.92 (s, 9 H), 1.29–1.40 (m, 4 H), 1.55–1.64 (m, 4 H), 1.80–
1.87 (m, 1 H), 2.03–2.21 (m, 2 H), 2.58–2.63 (m, 4 H), 4.58–4.61 (m, 1
H), 5.74 (s, 1 H), 7.10–7.13 (m, 4 H), 7.18–7.20 (m, 2 H), 7.24 (d, J = 8.0
Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = –3.2, –3.1, 14.1, 18.9, 22.4, 22.5, 26.2,
29.0, 33.6, 33.7, 35.3, 35.3, 60.2, 77.4, 82.2, 127.8, 128.2, 128.7, 128.9,
139.5, 140.1, 142.6, 143.0, 178.8.
Yield: 2.90 g (44%); white solid.
1H NMR (400 MHz, DMSO-d6):  = –0.41 (s, 3 H), –0.25 (s, 3 H), 0.90 (s,
9 H), 1.72–1.80 (m, 1 H), 2.81–2.87 (m, 1 H), 2.97–3.15 (m, 2 H), 6.11–
6.13 (m, 1 H), 7.16–7.29 (m, 2 H), 7.40–7.52 (m, 8 H), 10.25 (s, 1 H).
Arylhydrazines from Arylhydrazine Salts (HCl); General Procedure
13C NMR (100 MHz, DMSO-d6):  = –3.6, –3.5, 18.4, 20.4, 25.9, 29.2,
66.5, 81.9, 110.0 (m), 128.0, 128.4, 128.6, 128.9, 129.2, 136.2 (m),
138.7 (m), 139.8, 139.8, 141.7 (m), 144.0 (m), 144.3, 164.4.
A 250 mL, single-neck, round-bottomed flask equipped with a mag-
netic stir bar and a septum was charged with the arylhydrazine salt
(1.0 g) in Et2O (50 mL) and 1 M aq NaOH (50 mL) was added at 0 °C.
The reaction mixture was stirred at 0 °C for 1–2 h and then extracted
with Et2O (2 × 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The obtained residue was dried
under high vacuum for 2–3 h to furnish the desired arylhydrazines.4p
(S)-5-{[(tert-Butyldimethylsilyl)oxy]bis[4-(trifluoromethyl)phe-
nyl]methyl}-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]-tri-
azol-2-ium Tetrafluoroborate (5c)
NHC 5c was prepared according to TP1. (1) Compound 4b (518 mg,
1.0 mmol, 1 equiv), anhydrous DCM (10 mL) and Me3O+BF4– (163 mg,
1.1 mmol, 1.1 equiv). (2) Phenylhydrazine (119 mg, 1.1 mmol, 1.1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

H
V. Dhayalan et al.
Paper
Synthesis
equiv). (3) Anhydrous (EtO)3CH (10 mL). The crude product was puri-
fied by flash column chromatography (silica gel, acetone/DCM, 20:80)
and washed with Et2O to give the pure NHC compound 5c.
1H NMR (400 MHz, DMSO-d6):  = –0.37 (s, 3 H), –0.28 (s, 3 H), 0.86–
0.91 (m, 15 H), 1.25–1.35 (m, 4 H), 1.52–1.64 (m, 5 H), 2.25–2.57 (m, 4
H), 2.75 (t, J = 8.0 Hz, 1 H), 2.85–2.92 (m, 1 H), 2.99–3.09 (m, 1 H), 5.94
(dd, J = 8.0, 4.0 Hz, 1 H), 7.18–7.35 (m, 8 H), 7.65–7.71 (m, 3 H), 7.81
(d, J = 8.0 Hz, 2 H), 10.06 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = –3.6, –3.5, 13.7, 18.4, 20.1, 21.5,
21.6, 25.9, 29.5, 32.8, 32.9, 34.3, 66.0, 81.6, 121.9, 128.1, 128.6, 128.7,
130.0, 130.8, 135.3, 137.1, 138.3, 142.9, 143.2, 163.2.
Yield: 550 mg (78%); white solid.
IR (diamond-ATR, neat): 610, 717, 775, 837, 875, 1015, 1069, 1124,
1166, 1324, 2858, 2933 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = –0.40 (s, 3 H), –0.21 (s, 3 H), 0.92 (s,
9 H), 1.62–1.70 (m, 1 H), 2.80 (t, J = 12.0 Hz, 1 H), 2.92–3.11 (m, 2 H),
6.12 (dd, J = 8.0, 4.0 Hz, 1 H), 7.54–7.55 (m, 2 H), 7.65–7.73 (m, 5 H),
7.80 (d, J = 8.0 Hz, 2 H), 7.87 (t, J = 8.0 Hz, 4 H), 10.25 (s, 1 H).
HRMS (ESI): m/z [M – BF4]+ calcd for C38H52N3OSi: 594.3874; found:
594.3857.
13C NMR (100 MHz, DMSO-d6):  = –3.7, –3.4, 18.5, 20.2, 25.9, 29.4,
64.9, 81.3, 121.3 (q, J = 270 Hz), 122.0, 125.4 (q, J = 3 Hz), 126.2 (q, J =
3 Hz), 128.0, 129.0, 129.4 (q, J = 32 Hz), 129.8, 129.9, 129.9, 130.9,
135.4, 138.8, 144.1, 144.3, 163.2.
Deprotected Pre-Catalysts 6 (Scheme 3); Typical Procedure 2 (TP2)
NHCs 6a–l were prepared using a modified procedure based on previ-
ous reports.2b,4b
19F NMR (376 MHz, DMSO-d6):  = –148.33 (s, 4 F), –61.18 (s, 3 F),
–61.05 (s, 3 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C32H34F6N3OSi: 618.2370; found:
618.2331.
(1) A dry, argon-flushed Schlenk flask equipped with a magnetic stir
bar and a septum was charged with 4a′ (9.3 mmol, 1 equiv) in anhy-
drous DCM (60 mL). Me3O+BF4– (10.2 mmol, 1.1 equiv) was added and
the reaction mixture was stirred at 20 °C for 15 h.
(2) Arylhydrazine (10.2 mmol, 1.1 equiv) was added to the solution
and the reaction mixture was stirred at 20 °C for 2–8 h. The solvent
was removed in vacuo and the residue dried under high vacuum for
12 h. This product was used without further purification.
(S)-5-{[(tert-Butyldimethylsilyl)oxy]di-p-tolylmethyl}-2-phenyl-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluorobo-
rate (5d)
(3) The reaction mixture was dissolved in anhydrous DCM (80 mL)
and (EtO)3CH (74 mmol, 8 equiv) was added. After refluxing this mix-
ture for 1 h, the solvent was removed in vacuo and dried under high
vacuum for 60 min.
NHC 5d was prepared according to TP1. (1) Compound 4c (1.23 g, 3.0
mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4– (488 mg, 3.3
mmol, 1.1 equiv). (2) Phenylhydrazine (357 mg, 3.3 mmol, 1.1 equiv).
(3) Anhydrous (EtO)3CH (30 mL). The crude product was purified by
flash column chromatography (silica gel, acetone/DCM, 20:80) and
washed with Et2O to give the pure NHC compound 5d.
(4) Anhydrous PhCl (80 mL) and (EtO)3CH (74 mmol, 8 equiv) were
added and the reaction mixture was heated at reflux for 24 h under
an argon atmosphere. The solvent was removed in vacuo and the resi-
due dried under high vacuum for 12 h. The product was used without
further purification.
Yield: 1.05 g (59%); white solid.
IR (diamond-ATR, neat): 518, 584, 777, 834, 877, 1029, 1071, 1510,
1590, 2851, 2926 cm–1
.
(5) Anhydrous CH3OH (300 mL) was added to the reaction flask fol-
lowed by the addition of bromotrimethylsilane (TMSBr) (3.1 mL, 23
mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The reaction mixture
was stirred at 20 °C for 5–12 h. The solvent was removed in vacuo and
the residue dried under high vacuum for 3 h at 80 °C. The crude prod-
uct was recrystallized from EtOAc/CH3OH or was purified by column
chromatography and washed with Et2O to give the pure NHC com-
pound 6a–l. Care must be taken in running these columns as the
products easily stick to the silica gel and decompose, thus they cannot
be left on the column for prolonged periods of time and the chroma-
tography should be performed expeditiously.
1H NMR (400 MHz, DMSO-d6):  = –0.37 (s, 3 H), –0.29 (s, 3 H), 0.90 (s,
9 H), 1.61–1.69 (m, 1 H), 2.33 (s, 3 H), 2.35 (s, 3 H), 2.77 (t, J = 12.0 Hz,
1 H), 2.86–2.92 (m, 1 H), 2.97–3.07 (m, 1 H), 5.94 (dd, J = 12.0, 4.0 Hz,
1 H), 7.14–7.21 (m, 4 H), 7.26–7.34 (m, 4 H), 7.64–7.70 (m, 3 H), 7.82
(d, J = 8.0 Hz, 2 H), 10.09 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = –3.5, –3.4, 18.4, 20.2, 20.6, 20.7,
25.9, 29.5, 65.7, 81.4, 121.9, 128.0, 128.7, 128.7, 129.4, 129.9, 130.8,
135.3, 136.9, 137.1, 138.0, 138.4, 163.3.
HRMS (ESI): m/z [M – BF4]+ calcd for C32H40N3OSi: 510.2935; found:
510.2913.
(S)-5-[Hydroxy(diphenyl)methyl]-2-phenyl-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium Bromide (6a)
(S)-5-{[(tert-Butyldimethylsilyl)oxy]bis(4-butylphenyl)methyl}-2-
phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetra-
fluoroborate (5e)
NHC 6a2b was prepared according to TP2. (1) Compound 4a′ (3.2 g, 9.3
–
mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g, 10.2
NHC 5e was prepared according to TP1. (1) Compound 4d (494 mg,
1.0 mmol, 1 equiv), anhydrous DCM (10 mL) and Me3O+BF4– (163 mg,
1.1 mmol, 1.1 equiv). (2) Phenylhydrazine (119 mg, 1.1 mmol, 1.1
equiv). (3) Anhydrous (EtO)3CH (10 mL). The crude product was puri-
fied by flash column chromatography (silica gel, acetone/DCM, 10:90)
to give the pure NHC compound 5e.
mmol, 1.1 equiv). (2) Phenylhydrazine (1.1 g, 10.2 mmol, 1.1 equiv).
(3) Anhydrous DCM (80 mL) and (EtO)3CH (12.3 mL, 74 mmol, 8
equiv). (4) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL, 74 mmol,
8 equiv). (5) Anhydrous CH3OH (300 mL) and TMSBr (3.0 mL, 23
mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude product was
recrystallized from CH3OH/Et2O (1:9) to give the pure NHC compound
6a.
Yield: 480 mg (70%); white solid.
IR (diamond-ATR, neat): 520, 687, 762, 777, 835, 881, 1018, 1055,
Yield: 4.0 g (96%); white solid.
1253, 1465, 1511, 1592, 1698, 2857, 2928, 2955 cm–1
.
IR (diamond-ATR, neat): 500, 617, 644, 685, 702, 755, 975, 1002,
1065, 1173, 1206, 1378, 1448, 1519, 1590, 2961, 3067, 3153 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

I
V. Dhayalan et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6):  = 2.57–2.62 (m, 1 H), 2.90–3.02 (m, 2
H), 3.10–3.18 (m, 1 H), 6.18 (d, J = 8.0 Hz, 1 H), 6.55 (s, 1 H), 7.28 (t, J =
8.0 Hz, 1 H), 7.34–7.38 (m, 3 H), 7.44 (t, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0
Hz, 2 H), 7.59–7.68 (m, 5 H), 7.79 (d, J = 8.0 Hz, 2 H), 9.60 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.3, 29.9, 67.1, 79.0, 121.4, 126.0,
126.1, 127.5, 127.8, 128.4, 128.9, 130.1, 130.6, 135.3, 137.7, 143.3,
143.5, 163.6.
was purified by flash column chromatography (silica gel, ace-
tone/CH3OH, 200:20), recrystallized from CH3OH/EtOAc (1:9) and
washed with Et2O to give the pure NHC compound 6c.
Yield: 1.12 g (76%); white solid
IR (diamond-ATR, neat): 521, 615, 640, 705, 734, 752, 839, 1151,
1204, 1238, 1382, 1449, 1501, 1522, 1583, 2964, 3060, 3175, 3272
cm–1
.
HRMS (ESI): m/z [M – Br]+ calcd for C24H22N3O: 368.1757; found:
368.1750.
1H NMR (400 MHz, DMSO-d6):  = 2.54–2.61 (m, 1 H), 2.89–3.00 (m, 2
H), 3.09–3.17 (m, 1 H), 6.18 (d, J = 4.0 Hz), 6.54 (s, 1 H), 7.28 (t, J = 8.0
Hz, 1 H), 7.34–7.38 (m, 3 H), 7.44 (t, J = 8.0 Hz, 2 H), 7.51–7.60 (m, 6
H), 7.83–7.87 (m, 2 H), 9.34 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.2, 29.9, 67.1, 79.0, 117.1 (d, J =
24.0 Hz), 124.3 (d, J = 9.0 Hz), 126.1 (d, J = 15.0 Hz), 127.4, 127.8,
128.4, 128.9, 131.8 (d, J = 2.0 Hz), 138.0, 143.3, 143.5, 161.4, 163.6,
163.9.
(S)-5-[Hydroxy(diphenyl)methyl]-2-phenyl-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium Bromide(6a); Alternative Protocol
without DCM Treatment
NHC 6a was prepared according to TP2 but without treatment with
DCM and (EtO)3CH (8 equiv) (see Scheme 4). (1) Compound 4a′ (3.2 g,
–
9.3 mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g,
19F NMR (376 MHz, DMSO-d6):  = –109.92 (s, 1 F).
HRMS (ESI): m/z [M – Br]+ calcd for C24H21FN3O: 386.1663; found:
10.2 mmol, 1.1 equiv). (2) Phenylhydrazine (1.1 g, 10.2 mmol, 1.1
equiv). (3) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL, 74 mmol,
8 equiv). (4) Anhydrous CH3OH (300 mL) and TMSBr (3.0 mL, 23
mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude product was
recrystallized from CH3OH/Et2O (1:9) to give the pure NHC compound
6a.
386.1644.
(S)-2-(3,5-Difluorophenyl)-5-(hydroxydiphenylmethyl)-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6d)
NHC 6d was prepared according to TP2. (1) Compound 4a′ (1.05 g, 3.1
mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4– (503 mg, 3.4
mmol, 1.1 equiv). (2) 3,5-Difluorophenylhydrazine (490 mg, 3.4
mmol, 1.1 equiv). (3) Anhydrous DCM (30 mL) and (EtO)3CH (4.0 mL,
25 mmol, 8 equiv). (4) Anhydrous PhCl (30 mL) and (EtO)3CH (4.0 mL,
25 mmol, 8 equiv). (5) Anhydrous CH3OH (100 mL) and TMSBr (1.0
mL, 8.0 mmol, 2.5 equiv) dissolved in CH3OH (10 mL). The crude prod-
uct was recrystallized from EtOAc and washed with Et2O to give the
pure NHC compound 6d.
Yield: 3.53 g (82%); white solid.
(S)-2-(2-Fluorophenyl)-5-(hydroxydiphenylmethyl)-6,7-dihydro-
5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6b)
NHC 6b was prepared according to TP2. (1) Compound 4a′ (3.2 g, 9.3
–
mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g, 10.2
mmol, 1.1 equiv). (2) 2-Fluorophenylhydrazine (1.28 g, 10.2 mmol,
1.1 equiv). (3) Anhydrous DCM (80 mL) and (EtO)3CH (12.3 mL, 74
mmol, 8 equiv). (4) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL,
74 mmol, 8 equiv). (5) Anhydrous CH3OH (300 mL) and TMSBr (3.0
mL, 23 mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude prod-
uct was recrystallized from CH3OH/EtOAc (1:9) and washed with Et2O
to give the pure NHC compound 6b.
Yield: 1.10 g (73%); white solid.
IR (diamond-ATR, neat): 505, 615, 618, 625, 641, 655, 672, 694, 704,
732, 748, 849, 864, 882, 984, 1128, 1175, 1438, 1589, 1615, 2954,
3060, 3178, 3230, 3331 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.55–2.61 (m, 1 H), 2.80–2.88 (m, 1
H), 2.93–3.02 (m, 1 H), 3.09–3.15 (m, 1 H), 6.16 (d, J = 8.0 Hz, 1 H),
6.58 (s, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.33–7.38 (m, 3 H), 7.42–7.50 (m,
4 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.63 (tt, J = 8.0, 4.0 Hz, 1 H), 7.79 (d, J =
4.0 Hz, 2 H), 9.89 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.2, 30.0, 67.4, 79.0, 105.6 (d, J =
11.0 Hz), 105.7 (d, J = 30.0 Hz), 106.2 (t, J = 25.0 Hz), 126.2 (d, J = 14.0
Hz), 127.5, 127.9, 128.4, 129.0, 137.0 (t, J = 14.0 Hz), 138.8, 143.3 (d,
J = 14.0 Hz), 161.3, 163.7 (d, J = 14.0 Hz), 163.8.
Yield: 2.40 g (55%); white solid.
IR (diamond-ATR, neat): 621, 640, 660, 697, 751, 764, 779, 968, 1034,
1067, 1111, 1201, 1232, 1522, 1599, 3057, 3175, 3197, 3247 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.62–2.67 (m, 1 H), 2.93–3.04 (m, 2
H), 3.14–3.20 (m, 1 H), 6.23 (dd, J = 8.0, 4.0 Hz, 1 H), 6.64 (s, 1 H), 7.29
(t, J = 8.0 Hz, 1 H), 7.33–7.39 (m, 3 H), 7.43 (t, J = 8.0 Hz, 2 H), 7.48–
7.54 (m, 3 H), 7.58–7.64 (m, 3 H), 7.69–7.73 (m, 1 H), 7.77 (td, J = 8.0,
2 Hz, 1 H), 9.34 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.3, 29.6, 67.5, 78.9, 117.2 (d, J =
14.0 Hz), 123.4 (d, J = 7.0 Hz), 125.7, 126.0, 126.5, 127.5, 127.8, 128.4,
128.8, 133.1 (d, J = 7.0 Hz), 140.7, 143.2, 143.4, 153.3, 155.3, 163.5.
19F NMR (376 MHz, DMSO-d6):  = –106.25 (s, 2 F).
HRMS (ESI): m/z [M – Br]+ calcd for C24H20F2N3O: 404.1569; found:
19F NMR (376 MHz, DMSO-d6):  = –123.19 (s, 1 F).
404.1551.
HRMS (ESI): m/z [M – Br]+ calcd for C24H21FN3O: 386.1663; found:
386.1649.
(S)-5-(Hydroxydiphenylmethyl)-2-pentafluorophenyl-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6e)
NHC 6e2b was prepared according to TP2. (1) Compound 4a′ (3.2 g, 9.3
(S)-2-(4-Fluorophenyl)-5-(hydroxydiphenylmethyl)-6,7-dihydro-
5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6c)
–
mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g, 10.2
mmol, 1.1 equiv). (2) Pentafluorophenylhydrazine (2.00 g, 10.2 mmol,
1.1 equiv). (3) Anhydrous DCM (80 mL) and (EtO)3CH (12.3 mL, 74
mmol, 8 equiv). (4) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL,
74 mmol, 8 equiv). (5) Anhydrous CH3OH (300 mL) and TMSBr (3.0
mL, 23 mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude prod-
uct was recrystallized from EtOAc and washed with Et2O. We noted
that the catalyst contained EtOAc in most cases, which was removed
NHC 6c was prepared according to TP2. (1) Compound 4a′ (1.05 g, 3.1
mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4– (503 mg, 3.4
mmol, 1.1 equiv). (2) 4-Fluorophenylhydrazine (428 mg, 3.4 mmol,
1.1 equiv). (3) Anhydrous DCM (30 mL) and (EtO)3CH (4.0 mL, 25
mmol, 8 equiv). (4) Anhydrous PhCl (30 mL) and (EtO)3CH (4.0 mL, 25
mmol, 8 equiv). (5) Anhydrous CH3OH (100 mL) and TMSBr (1.0 mL,
8.0 mmol, 2.5 equiv) dissolved in CH3OH (10 mL). The crude product
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

J
V. Dhayalan et al.
Paper
Synthesis
by dissolving the product in distilled THF and removing the solvent in
vacuo. Finally, the product was washed with Et2O to give the pure
NHC compound 6e.
(S)-5-(Hydroxydiphenylmethyl)-2-[4-(trifluoromethyl)phenyl]-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6g)
NHC 6g was prepared according to TP2. (1) Compound 4a′ (1.05 g, 3.1
mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4– (503 mg, 3.4
mmol, 1.1 equiv). (2) 4-(Trifluoromethyl)phenylhydrazine (598 mg,
3.4 mmol, 1.1 equiv). (3) Anhydrous DCM (30 mL) and (EtO)3CH (4.0
mL, 25 mmol, 8 equiv). (4) Anhydrous PhCl (30 mL) and (EtO)3CH (4.0
mL, 25 mmol, 8 equiv). (5) Anhydrous CH3OH (100 mL) and TMSBr
(1.0 mL, 8.0 mmol, 2.5 equiv) dissolved in CH3OH (10 mL). The crude
product was purified by flash column chromatography (silica gel, ace-
tone/CH3OH, 200:20), recrystallized from EtOAc and washed with
Et2O to give the pure NHC compound 6g.
Yield: 3.30 g (66%); white solid.
IR (diamond-ATR, neat): 610, 635, 678, 697, 739, 871, 972, 1002,
1069, 1375, 1448, 1510, 1522, 1542, 1595, 2954, 3142 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.64–2.70 (m, 1 H), 2.87–2.92 (m, 1
H), 2.99–3.09 (m, 1 H), 3.16–3.23 (m, 1 H), 6.19 (dd, J = 12.0, 4.0 Hz, 1
H), 6.80 (m, 1 H), 7.29–7.39 (m, 4 H), 7.42–7.48 (m, 4 H), 7.56 (d, J =
8.0 Hz, 2 H), 9.64 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.5, 29.7, 68.1, 78.8, 111.1 (m),
126.1, 127.7, 128.0, 128.5, 128.9, 136.2 (m), 138.7 (m), 141.2 (m),
142.9, 143.2, 143.5, 143.9 (m), 164.7.
Yield: 1.10 g (69%); white solid.
IR (diamond-ATR, neat): 597, 640, 705, 845, 1068, 1111, 1131, 1169,
HRMS (ESI): m/z [M – Br]+ calcd for C24H17F5N3O: 458.1286; found:
458.1289.
1321, 1589, 1615, 3068, 3170, 3190, 3411 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.57–2.62 (m, 1 H), 2.89–3.01 (m, 2
H), 3.11–3.19 (m, 1 H), 6.21 (d, J = 4.0 Hz, 1 H), 6.56 (s, 1 H), 7.28 (t, J =
8.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 3 H), 7.44 (t, J = 8.0 Hz, 2 H), 7.52 (d, J =
8.0 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 8.04–8.07 (m, 4 H), 9.85 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.2, 29.9, 67.3, 79.0, 122.3, 123.5
(q, J = 271.0 Hz), 126.0, 126.2, 127.3 (q, J = 3.0 Hz), 127.5, 127.8, 128.4,
128.9, 130.4 (q, J = 32.0 Hz), 138.2, 138.7, 143.3, 143.4, 163.9.
(S)-5-(Hydroxydiphenylmethyl)-2-pentafluorophenyl-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4] triazol-2-ium Bromide (6e); Alterna-
tive Protocol without DCM Treatment
NHC 6e was prepared according to TP2 but without treatment with
DCM and (EtO)3CH (8 equiv) (see Scheme 4). (1) Compound 4a′ (3.2 g,
–
9.3 mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g,
19F NMR (376 MHz, DMSO-d6):  = –61.25 (s, 3 F).
HRMS (ESI): m/z [M – Br]+ calcd for C25H21F3N3O: 436.1631; found:
10.2 mmol, 1.1 equiv). (2) Pentafluorophenylhydrazine (2.00 g, 10.2
mmol, 1.1 equiv). (3) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL,
74 mmol, 8 equiv). (4) Anhydrous CH3OH (300 mL) and TMSBr (3.0
mL, 23 mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude prod-
uct was recrystallized from EtOAc and washed with Et2O. We noted
that the catalyst contained EtOAc in most cases, which was removed
by dissolving the product in distilled THF and removing the solvent in
vacuo. Finally, the product was washed with Et2O to give the pure
NHC compound 6e.
436.1611.
(S)-2-(2,6-Dichlorophenyl)-5-(hydroxydiphenylmethyl)-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6h)
NHC 6h was prepared according to TP2. (1) Compound 4a′ (1.05 g, 3.1
mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4– (503 mg, 3.4
mmol, 1.1 equiv). (2) 2,6-Dichlorophenylhydrazine (602 mg, 3.4
mmol, 1.1 equiv). (3) Anhydrous DCM (30 mL) and (EtO)3CH (4.0 mL,
25 mmol, 8 equiv). (4) Anhydrous PhCl (30 mL) and (EtO)3CH (4.0 mL,
25 mmol, 8 equiv). (5) Anhydrous CH3OH (100 mL) and TMSBr (1.0
mL, 8.0 mmol, 2.5 equiv) dissolved in CH3OH (10 mL). The crude prod-
uct was purified by flash column chromatography (silica gel, ace-
tone/CH3OH, 200:20), recrystallized from EtOAc and washed with
Et2O to give the pure NHC compound 6h.
Yield: 1.51 g (30%); white solid.
(S)-5-(Hydroxydiphenylmethyl)-2-[2-(trifluoromethyl)phenyl]-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6f)
NHC 6f was prepared according to TP2. (1) Compound 4a′ (3.2 g, 9.3
–
mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g, 10.2
mmol, 1.1 equiv). (2) 2-(Trifluoromethyl)phenylhydrazine (1.8 g, 10.2
mmol, 1.1 equiv). (3) Anhydrous DCM (80 mL) and (EtO)3CH (12.3 mL,
74 mmol, 8 equiv). (4) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3
mL, 74 mmol, 8 equiv). (5) Anhydrous CH3OH (300 mL) and TMSBr
(3.0 mL, 23 mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude
product was recrystallized from CH3OH/acetone (1:9) and washed
with Et2O to give the pure NHC compound 6f.
Yield: 1.50 g (94%); white solid.
IR (diamond-ATR, neat): 605, 629, 652, 699, 749, 755, 764, 795, 1066,
1194, 1411, 1443, 1572, 1593, 3055, 3138 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.67–2.76 (m, 1 H), 2.81–2.90 (m, 1
H), 3.12–3.24 (m, 2 H), 6.23 (d, J = 8.0 Hz, 1 H), 6.82 (s, 1 H), 7.32–7.49
(m, 10 H), 7.75–7.85 (m, 3 H), 9.59 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.4, 29.9, 68.0, 78.8, 126.1, 126.4,
127.8, 128.0, 128.5, 128.8, 129.4, 131.0, 132.6, 134.4, 142.8, 142.9,
143.0, 164.2.
Yield: 2.40 g (50%); white solid.
IR (diamond-ATR, neat): 503, 627, 699, 758, 779, 1065, 1074, 1116,
1132, 1178, 1316, 1446, 1599, 2998, 3187 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.65–2.70 (m, 1 H), 2.79–2.85 (m, 1
H), 3.05–3.12 (m, 2 H), 6.16 (d, J = 8.0 Hz, 1 H), 6.72 (s, 1 H), 7.30–7.41
(m, 6 H), 7.47 (d, J = 4.0 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.0
Hz, 1 H), 7.93–8.01 (m, 2 H), 8.08 (d, J = 8.0 Hz, 1 H), 9.62 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.1, 29.9, 67.5, 78.7, 122.4 (q, J =
272.0 Hz), 125.0 (q, J = 31.0 Hz), 126.0, 126.3, 127.6 (q, J = 4.0 Hz),
127.8, 128.4, 128.7, 130.1, 132.4, 132.8, 134.3, 141.9, 143.1, 143.3,
163.2.
HRMS (ESI): m/z [M – Br]+ calcd for C24H20Cl2N3O: 436.0978; found:
436.0963.
(S)-2-(2,6-Dichlorophenyl)-5-(hydroxydiphenylmethyl)-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6h); Alterna-
tive Protocol without DCM Treatment
NHC 6h was prepared according to TP2 but without treatment with
DCM and (EtO)3CH (8 equiv) (see Scheme 4). (1) Compound 4a′ (1.05
19F NMR (376 MHz, DMSO-d6):  = –57.76 (s, 3 F).
HRMS (ESI): m/z [M – Br]+ calcd for C25H21F3N3O: 436.1631; found:
–
g, 3.1 mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4 (503
mg, 3.4 mmol, 1.1 equiv). (2) 2,6-Dichlorophenylhydrazine (602 mg,
3.4 mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (4.0
436.1631.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

K
V. Dhayalan et al.
Paper
Synthesis
mL, 25 mmol, 8 equiv). (4) Anhydrous CH3OH (100 mL) and TMSBr
(1.0 mL, 8.0 mmol, 2.5 equiv) dissolved in CH3OH (10 mL). The crude
product was purified by flash column chromatography (silica gel, ace-
tone/CH3OH, 200:20), recrystallized from EtOAc and washed with
Et2O to give the pure NHC compound 6h.
(S)-5-(Hydroxydiphenylmethyl)-2-(4-methoxyphenyl)-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6k)
NHC 6k4f was prepared according to TP2. (1) Compound 4a′ (3.2 g, 9.3
–
mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g, 10.2
mmol, 1.1 equiv). (2) 4-Methoxyphenylhydrazine (1.4 g, 10.2 mmol,
1.1 equiv). (3) Anhydrous DCM (80 mL) and (EtO)3CH (12.3 mL, 74
mmol, 8 equiv). (4) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL,
74 mmol, 8 equiv). (5) Anhydrous CH3OH (300 mL) and TMSBr (3.0
mL, 23 mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude prod-
uct was purified by flash column chromatography (silica gel, DCM/ac-
etone, 80:20) and recrystallized from Et2O to give the pure NHC com-
pound 6k.
Yield: 1.0 g (62%); white solid.
(S)-5-(Hydroxydiphenylmethyl)-2-(3-nitrophenyl)-6,7-dihydro-
5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6i)
NHC 6i was prepared according to TP2. (1) Compound 4a′ (1.05 g, 3.1
mmol, 1 equiv), in anhydrous DCM (20 mL) and Me3O+BF4 (503 mg,
–
3.4 mmol, 1.1 equiv). (2) 3-Nitrophenylhydrazine (524 mg, 3.4 mmol,
1.1 equiv). (3) anhydrous DCM (30 mL) and (EtO)3CH (4.0 mL, 25
mmol, 8 equiv). (4) Anhydrous PhCl (30 mL) and (EtO)3CH (4.0 mL, 25
mmol, 8 equiv). (5) Anhydrous CH3OH (100 mL) and TMSBr (1.0 mL,
8.0 mmol, 2.5 equiv) dissolved in CH3OH (10 mL). The crude product
was purified by flash column chromatography (silica gel, ace-
tone/CH3OH, 200:20), recrystallized from EtOAc and washed with
Et2O to give the pure NHC compound 6i.
Yield: 2.25 g (51%); white solid.
IR (diamond-ATR, neat): 500, 564, 609, 632, 649, 702, 744, 801, 834,
971, 1023, 1038, 1172, 1199, 1259, 1442, 1506, 1532, 1586, 2957,
3201 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.57–2.61 (m, 1 H), 2.90–3.00 (m, 2
H), 3.08–3.15 (m, 1 H), 3.84 (s, 3 H), 6.16 (d, J = 8.0 Hz, 1 H), 6.54 (s, 1
H), 7.18 (d, J = 8.0 Hz, 2 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.34–7.38 (m, 3 H),
7.44 (t, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H),
7.70 (d, J = 8.0 Hz, 2 H), 9.48 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.3, 29.8, 55.8, 67.0, 79.0, 115.0,
123.2, 126.0, 126.1, 127.5, 127.8, 128.4, 128.5, 128.9, 137.1, 143.4,
143.6, 160.6, 163.4.
Yield: 1.06 g (69%); yellow solid.
IR (diamond-ATR, neat): 501, 622, 635, 664, 702, 729, 752, 769, 1066,
1204, 1349, 1385, 1448, 1536, 1593, 3057, 3209, 3308 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.57–2.62 (m, 1 H), 2.86–2.99 (m, 2
H), 3.11–3.19 (m, 1 H), 6.20 (d, J = 8.0 Hz, 1 H), 6.57 (s, 1 H), 7.28–7.61
(m, 10 H), 7.95–7.99 (m, 1 H), 8.29 (d, J = 8.0 Hz, 1 H), 8.46 (d, J = 8.0
Hz, 1 H), 8.67 (s, 1 H), 9.97 (s, 1 H).
HRMS (ESI): m/z [M – Br]+ calcd for C25H24N3O2: 398.1863; found:
398.1857.
13C NMR (100 MHz, DMSO-d6):  = 21.2, 30.0, 67.3, 79.0, 117.0, 125.2,
126.0, 126.2, 127.5, 127.8, 128.1, 128.4, 128.9, 131.8, 135.9, 139.2,
143.4, 143.5, 148.2, 163.8.
(S)-5-(Hydroxydiphenylmethyl)-2-mesityl-6,7-dihydro-5H-pyrro-
lo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (6l)
NHC 6l4b was prepared according to TP2. (1) Compound 4a′(3.2 g, 9.3
HRMS (ESI): m/z [M – Br]+ calcd for C24H21N4O3: 413.1608; found:
413.1590.
–
mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g, 10.2
mmol, 1.1 equiv). (2) Mesitylhydrazine (1.53 g, 10.2 mmol, 1.1 equiv).
(3) Anhydrous DCM (80 mL) and (EtO)3CH (12.3 mL, 74 mmol, 8
equiv). (4) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL, 74 mmol,
8 equiv). (5) Anhydrous CH3OH (300 mL) and TMSBr (3.0 mL, 23
mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The obtained crude
product was purified by flash column chromatography (silica gel,
DCM/acetone, 2:1) and recrystallized from (benzene/Et2O, 1:9) to give
the pure NHC compound 6l.
(S)-2-(2,6-Dimethylphenyl)-5-(hydroxydiphenylmethyl)-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Bromide (6j)
NHC 6j was prepared according to TP2. (1) Compound 4a′ (3.2 g, 9.3
mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g, 10.2
–
mmol, 1.1 equiv). (2) 2,6-Dimethylphenylhydrazine (1.8 g, 10.2 mmol,
1.1 equiv). (3) Anhydrous DCM (80 mL) and (EtO)3CH (12.3 mL, 74
mmol, 8 equiv). (4) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL,
74 mmol, 8 equiv). (5) Anhydrous CH3OH (300 mL) and TMSBr (3.0
mL, 23 mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude prod-
uct was purified by flash column chromatography (silica gel, DCM/ac-
etone, 2:1) and recrystallized from (hexane/Et2O, 9:1) to give the pure
NHC compound 6j.
Yield: 3.90 g (84%); white solid.
IR (diamond-ATR, neat): 445, 507, 551, 587, 632, 658, 699, 764, 852,
971, 1015, 1189, 1385, 1448, 1493, 1585, 2955, 3057, 3229 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 1.96 (s, 6 H), 2.32 (s, 3 H), 2.67–
2.73 (m, 1 H), 2.88–2.98 (m, 1 H), 3.09–3.19 (m, 2 H), 6.13–6.15 (m, 1
H), 6.75 (s, 1 H), 7.11 (s, 2 H), 7.29–7.34 (m, 2 H), 7.39 (t, J = 8.0 Hz, 4
H), 7.50 (d, J = 8.0 Hz, 4 H), 9.26 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 16.8, 20.6, 21.5, 29.9, 67.5, 79.0,
126.0, 126.4, 127.7, 127.9, 128.5, 128.8, 129.1, 131.9, 134.8, 141.1,
141.2, 143.2, 143.4, 163.8.
Yield: 3.55 g (80%); white solid.
IR (diamond-ATR, neat): 577, 614, 631, 658, 699, 754, 767, 968, 1181,
1385, 1448, 1585, 2961, 3057, 3153, 3223 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.00 (s, 6 H), 2.68–2.73 (m, 1 H),
2.91–3.01 (m, 1 H), 3.10–3.20 (m, 2 H), 6.18 (d, J = 4.0 Hz, 1 H), 6.76 (s,
1 H), 7.29–7.34 (m, 4 H), 7.38–7.41 (m, 4 H), 7.46 (t, J = 8.0 Hz, 1 H),
7.50 (d, J = 8.0 Hz, 4 H), 9.33 (s, 1 H).
HRMS (ESI): m/z [M – BF4]+ calcd for C27H28N3O: 410.2227; found:
410.2223.
13C NMR (100 MHz, DMSO-d6):  = 16.9, 21.5, 29.9, 67.5, 79.0, 125.9,
126.3, 127.7, 127.8, 128.5, 128.6, 128.8, 131.3, 134.3, 135.2, 141.0,
143.2, 143.4, 163.9.
(S)-5-(Hydroxydiphenylmethyl)-2-mesityl-6,7-dihydro-5H-pyrro-
lo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (6l); Alternative
Protocol without DCM Treatment
HRMS (ESI): m/z [M – Br]+ calcd for C26H26N3O: 396.2070; found:
NHC 6l was prepared according to TP2 but without treatment with
DCM and (EtO)3CH (8 equiv) (see Scheme 4). (1) Compound 4a′ (3.2 g,
396.2061.
–
9.3 mmol, 1 equiv), anhydrous DCM (60 mL) and Me3O+BF4 (1.5 g,
10.2 mmol, 1.1 equiv). (2) Mesitylhydrazine (1.53 g, 10.2 mmol, 1.1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

L
V. Dhayalan et al.
Paper
Synthesis
equiv). (3) Anhydrous PhCl (80 mL) and (EtO)3CH (12.3 mL, 74 mmol,
8 equiv). (4) Anhydrous CH3OH (300 mL) and TMSBr (3.0 mL, 23
mmol, 2.5 equiv) dissolved in CH3OH (30 mL). The crude product was
purified by flash column chromatography (silica gel, DCM/acetone,
2:1) and recrystallized from (benzene/Et2O, 1:9) to give the pure NHC
compound 6l.
13C NMR (100 MHz, DMSO-d6):  = 21.3, 29.7, 67.5, 78.9, 117.2 (d, J =
18.0 Hz), 123.4 (d, J = 11.0 Hz), 125.8 (d, J = 4.0 Hz), 126.0, 126.5,
127.6, 127.9, 128.4, 128.9, 133.2 (d, J = 8.0 Hz), 140.7 (d, J = 5.0 Hz),
143.1, 143.4, 153.1, 155.6, 163.6.
19F NMR (376 MHz, DMSO-d6):  = –148.30 (s, 4 F), –123.22 (s, 1 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C24H21FN3O: 386.1663; found:
Yield: 3.30 g (71%); white solid.
386.1659.
(S)-5-[Hydroxy(diphenyl)methyl]-2-phenyl-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (7a)
(S)-5-(Hydroxydiphenylmethyl)-2-pentafluorophenyl-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (7c)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 6a (110 mg, 0.25
mmol, 1 equiv) in anhydrous DCM (4 mL). HBF4·OEt2 (51 L, 0.36
mmol, 1.5 equiv) was added and the reaction mixture was stirred at
20 °C for 3 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 5mL of CH3OH and the solvent
was removed in vacuo (the water bath should not exceed 50 °C) to re-
move residual acids, this process was repeated twice. The residue was
dried under high vacuum for 12 h at 60 °C to give the pure NHC com-
pound 7a.2b
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 6e (150 mg, 0.28
mmol, 1 equiv) in anhydrous DCM (4 mL). HBF4·OEt2 (57 L, 0.42
mmol, 1.5 equiv) was added and the reaction mixture was stirred at
20 °C for 3 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C) to remove
residual acids, this process was repeated twice. The residue was dried
under high vacuum for 12 h at 60 °C to give the pure NHC compound
7c.2b To test whether the obtained compound required further purifi-
cation it was recrystallized from ether. While the yield was decreased
by only 10%, the proton and fluorine NMR remained identical, there-
fore, the compound is reported without the recrystallization step.
Yield: 113 mg (99%); white solid.
IR (diamond-ATR, neat): 521, 629, 699, 761, 828, 972, 1036, 1051,
Yield: 150 mg (98%); white solid.
1198, 1286, 1390, 1449, 1493, 1519, 1587, 3032, 3064, 3151 cm–1
.
IR (diamond-ATR, neat): 520, 635, 699, 738, 762, 872, 972, 1001,
1032, 1068, 1169, 1376, 1449, 1510, 1526, 1596, 2964, 3031, 3061,
1H NMR (400 MHz, DMSO-d6):  = 2.55–2.62 (m, 1 H), 2.88–3.09 (m, 2
H), 3.09–3.17 (m, 1 H), 6.13 (d, J = 8.0 Hz, 1 H), 6.56 (s, 1 H), 7.29 (t, J =
8.0 Hz, 1 H), 7.35–7.39 (m, 3 H), 7.45 (t, J = 8.0 Hz, 2 H), 7.52 (d, J = 8.0
Hz, 2 H), 7.58 (d, J = 4.0 Hz, 2 H), 7.62–7.68 (m, 3 H), 7.78 (d, J = 4.0 Hz,
2 H), 9.59 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.2, 29.9, 67.1, 79.0, 121.4, 126.0,
126.1, 127.5, 127.9, 128.4, 128.9, 130.1, 130.7, 135.3, 137.7, 143.3,
143.5, 163.7.
3153 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.65–2.71 (m, 1 H), 2.86–2.95 (m, 1
H), 2.99–3.09 (m, 1 H), 3.15–3.23 (m, 1 H), 6.16 (dd, J = 8.0, 4.0 Hz, 1
H), 6.79 (s, 1 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.34–7.40 (m, 3 H), 7.42–7.48
(m, 4 H), 7.56 (d, J = 4.0 Hz, 2 H), 9.62 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.4, 29.7, 68.1, 78.8, 111.1 (m),
126.1, 127.7, 128.1, 128.5, 128.9, 136.2 (m), 138.7 (m), 141.5 (m),
142.9, 143.2, 143.5, 144.1 (m), 164.8.
19F NMR (376 MHz, DMSO-d6):  = –148.29 (s, 4 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C24H22N3O: 368.1757; found:
368.1752.
19F NMR (376 MHz, DMSO-d6):  = –160.08 (t, J = 22.6 Hz, 2 F), –148.32
(s, 4 F), –147.71 (t, J = 22.3 Hz, 1 F), –145.44 (d, J = 15.0 Hz, 2 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C24H17F5N3O: 458.1286; found:
458.1281.
(S)-2-(2-Fluorophenyl)-5-(hydroxydiphenylmethyl)-6,7-dihydro-
5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (7b)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 6b (100 mg, 0.21
mmol, 1 equiv) in anhydrous DCM (4 mL). HBF4·OEt2 (43 L, 0.32
mmol, 1.5 equiv) was added and the reaction mixture was stirred at
20 °C for 3 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 5 mL of CH3OH and the solvent
was removed in vacuo (the water bath should not exceed 50 °C) to re-
move residual acids, this process was repeated twice. The residue was
dried under high vacuum for 12 h at 60 °C to give the pure NHC com-
pound 7b.
(S)-5-(Hydroxydiphenylmethyl)-2-(4-methoxyphenyl)-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (7d)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 6k (110 mg, 0.22
mmol, 1 equiv) in anhydrous DCM (4 mL). HBF4·OEt2 (47 L, 0.34
mmol, 1.5 equiv) was added and the reaction mixture was stirred at
20 °C for 3 h. The reaction mixture was diluted in CH3OH (10 mL) and
then transferred into a single-neck flask. The solvent was removed in
vacuo (the water bath should not exceed 50 °C). The obtained crude
product was dissolved in 5 mL of CH3OH and the solvent was removed
in vacuo (the water bath should not exceed 50 °C) to remove residual
acids, this process was repeated twice. The residue was dried under
high vacuum for 12 h at 60 °C to give the pure NHC compound 7d.4f
Yield: 97 mg (98%); white solid.
IR (diamond-ATR, neat): 521, 629, 648, 696, 762, 825, 969, 1033,
1049, 1200, 1232, 1289, 1369, 1448, 1495, 1523, 1592, 3027, 3058,
Yield: 105 mg (98%); white solid.
IR (diamond-ATR, neat): 518, 561, 634, 701, 762, 832, 972, 1016,
1041, 1175, 1256, 1306, 1393, 1449, 1523, 1585, 2841, 3065, 3143
3111, 3177 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 2.61–2.68 (m, 1 H), 2.91–3.05 (m, 2
H), 3.12–3.21 (m, 1 H), 6.16 (d, J = 8.0 Hz, 1 H), 6.65 (s, 1 H), 7.30 (t, J =
8.0 Hz, 1 H), 7.36–7.46 (m, 5 H), 7.51 (t, J = 8.0 Hz, 3 H), 7.57–7.64 (m,
3 H), 7.69–7.77 (m, 2 H), 9.33 (s, 1 H).
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

M
V. Dhayalan et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6):  = 2.56–2.62 (m, 1 H), 2.89–3.00 (m, 2
H), 3.07–3.14 (m, 1 H), 3.84 (s, 3 H), 6.11 (d, J = 8.0 Hz, 1 H), 6.55 (s, 1
H), 7.19 (d, J = 12.0 Hz, 2 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.34–7.39 (m, 3
H), 7.44 (t, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 4.0 Hz, 2
H), 7.69 (d, J = 8.0 Hz, 2 H), 9.46 (s, 1 H).
Na2SO4 and concentrated in vacuo. The crude residue was purified by
flash column chromatography (silica gel was pre-neutralized with tri-
ethylamine, n-hexane/EtOAc, 1:1) to furnish compound 9b as a color-
less oil (6.016 g, 99%).
13C NMR (100 MHz, DMSO-d6):  = 21.3, 29.8, 55.8, 67.1, 79.0, 115.0,
123.2, 126.0, 126.1, 127.5, 127.8, 128.4, 128.5, 128.9, 137.1, 143.3,
143.6, 160.6, 163.4.
19F NMR (376 MHz, DMSO-d6):  = –148.31 (s, 4 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C25H24N3O2: 398.1863; found:
(S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}pyrrolidin-2-one (9c)
Precursor 9c was prepared according to a previous report.7c A dry, ar-
gon-flushed, two-neck Schlenk flask equipped with a magnetic stir
bar and a septum was charged with alcohol 8 (2.0 g, 17.4 mmol, 1
equiv) in anhydrous DMF (120 mL), imidazole (3.0 g, 43.6 mmol, 2.5
equiv) was added at 20 °C and the resulting mixture stirred for 5 min
followed by the addition of tert-butyldiphenylsilyl chloride (TBDPSCl)
(5.73 g, 20.88 mmol, 1.2 equiv). The mixture was stirred at 20 °C for
24 h, then quenched with sat. aqueous NH4Cl (60 mL) and extracted
with Et2O (5 × 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude residue was purified by
flash column chromatography (silica gel was pre-neutralized with tri-
ethylamine, n-hexane/EtOAc, 1:1) to furnish compound 9c as a color-
less oil (6.0 g, 98%).
398.1853].
(S)-5-(Hydroxymethyl)pyrrolidin-2-one (8)
Precursor 8 was prepared according to a modified literature proce-
dure.6 A dry, argon-flushed, two-neck Schlenk flask equipped with a
magnetic stir bar and a septum was charged with acid 1 (20.0 g, 155
mmol, 1 equiv) in anhydrous CH3OH (400 mL). SOCl2 (17.0 mL, 233
mmol, 1.5 equiv) was added dropwise at 0 °C and the mixture slowly
warmed to 20 °C over 4 h. After full consumption of the starting ma-
terial (TLC monitoring), the CH3OH was removed under reduced pres-
sure and the residue dried under high vacuum for 4 h. The product
was used in the next step without further purification. EtOH (300 mL)
was added to the reaction flask followed by the portionwise addition
of NaBH4 (11.8 g, 310 mmol, 2.0 equiv) at 0 °C, after which the mix-
ture was slowly warmed to 20 °C over 24 h. The mixture was
quenched with a 5% aqueous solution of citric acid (800 mL) until the
solution became clear with a solid grey precipitate. The solution was
then decanted from the precipitate and the precipitate was washed
with EtOH and decanted once more. The solvent from the combined
supernatant was removed under reduced pressure. A solution of 35%
CH3OH in EtOAc (500 mL) was added to the obtained crude oil and the
resulting mixture stirred for 0.5 h and then filtered. The solvents were
removed under reduced pressure and the obtained solid was dis-
solved in DCM (800 mL) and filtered. The DCM was removed under
reduced pressure to furnish 8 as a pure, colorless solid (15 g, 84%).
(S)-5-{[(Trimethylsilyl)oxy]methyl}pyrrolidin-2-one (9d)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with alcohol 8 (1.0 g, 8.7
mmol, 1 equiv) in anhydrous DMF (60 mL), imidazole (1.5 g, 22 mmol,
2.5 equiv) was added at 20 °C and the resulting mixture stirred for 5
min followed by the addition of trimethylsilyl chloride (TMSCl) (1.13
g, 10.44 mmol, 1.2 equiv). The mixture was stirred at 20 °C for 24 h,
then quenched with sat. aqueous NH4Cl (60 mL) and extracted with
Et2O (5 × 30 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude residue was analyzed by
TLC and NMR revealing the recovery of 95% of the starting material.
TIPS/TBS-Protected Reduced Pre-Catalysts 10 (Scheme 6); Typical
Procedure 3 (TP3)
(1) A dry, argon-flushed Schlenk flask equipped with a magnetic stir
bar and a septum was charged with 9a–c (3.9 mmol, 1 equiv) in anhy-
drous DCM (20 mL). Me3O+BF4– (4.3 mmol, 1.1 equiv) was added and
the reaction mixture was stirred at 20 °C for 24 h.
(S)-5-{[(Triisopropylsilyl)oxy]methyl}pyrrolidin-2-one (9a)
Precursor 9a was prepared according to a previous report.7b A dry, ar-
gon-flushed, two-neck Schlenk flask equipped with a magnetic stir
bar and a septum was charged with alcohol 8 (2.0 g, 17.4 mmol, 1
equiv) in anhydrous DMF (120 mL), imidazole (3.0 g, 43.6 mmol, 2.5
equiv) was added at 20 °C and the resulting mixture stirred for 5 min
followed by the addition of triisopropylsilyl chloride (TIPSCl) (4.0 g,
20.9 mmol, 1.2 equiv). The mixture was stirred at 20 °C for 24 h, then
quenched with sat. aqueous NH4Cl (60 mL) and extracted with Et2O
(5 × 30 mL). The combined organic phases were dried over Na2SO4
and concentrated in vacuo. The crude residue was purified by flash
column chromatography (silica gel was pre-neutralized with triethyl-
amine, n-hexane/EtOAc, 1:1) to furnish compound 9a as a colorless oil
(4.6 g, 97%).
(2) Arylhydrazine (4.3 mmol, 1.1 equiv) was added to the solution and
the reaction mixture was stirred at 20 °C for 24 h. The solvent was re-
moved in vacuo and the residue dried under high vacuum for 12 h.
This product was used in the next step without further purification.
(3) The reaction mixture was dissolved in anhydrous PhCl (30 mL),
(EtO)3CH (31.2 mmol, 8 equiv) was added and the reaction mixture
was stirred at 130 °C for 24 h under an argon atmosphere. The solvent
was removed in vacuo and the residue was dried under high vacuum
for 12 h at 30–40 °C and then purified by flash column chromatogra-
phy (silica gel, acetone/DCM) or recrystallized from Et2O to give com-
pounds 10a–j.
(S)-2-Phenyl-5-{[(triisopropylsilyl)oxy]methyl}-6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (10a)
(S)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}pyrrolidin-2-one (9b)
Precursor 9b was prepared according to a previous report.7b A dry, ar-
gon-flushed, two-neck Schlenk flask equipped with a magnetic stir
bar and a septum was charged with alcohol 8 (3.0 g, 26.06 mmol, 1
equiv) in anhydrous DMF (180 mL), imidazole (4.4 g, 65.2 mmol, 2.5
equiv) was added at 20 °C and the resulting mixture stirred for 5 min
followed by the addition of tert-butyldimethylsilyl chloride (TBSCl)
(4.71 g, 31.26 mmol, 1.2 equiv). The mixture was stirred at 20 °C for
24 h, then quenched with sat. aqueous NH4Cl (60 mL) and extracted
with Et2O (5 × 30 mL). The combined organic phases were dried over
NHC 10a was prepared according to TP3. (1) Compound 9a (3.0 g, 11
mmol, 1 equiv), anhydrous DCM (70 mL) and Me3O+BF4– (1.79 g, 12.2
mmol, 1.1 equiv). (2) Phenylhydrazine (1.2 mL, 12.2 mmol, 1.1 equiv).
(3) Anhydrous PhCl (30 mL) and (EtO)3CH (14.6 mL, 88 mmol, 8
equiv). The crude product was purified by flash column chromatogra-
phy (silica gel, DCM/acetone, 200:40) and washed with Et2O to give
the pure NHC compound 10a.7b
Yield: 3.50 g (69%); white solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

N
V. Dhayalan et al.
Paper
Synthesis
IR (diamond-ATR, neat): 520, 640, 687, 767, 881, 974, 1034, 1045,
1115, 1382, 1463, 1589, 2867, 2943, 3137 cm–1
1H NMR (400 MHz, CD3CN):  = 0.96–0.99 (m, 18 H), 1.04–1.13 (m, 3
H), 2.58–2.66 (m, 1 H), 2.89–2.99 (m, 1 H), 3.25 (t, J = 8.0 Hz, 2 H),
4.04–4.15 (m, 2 H), 4.95–5.00 (m, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.72 (t,
J = 8.0 Hz, 2 H), 7.86 (d, J = 8.0 Hz, 2 H), 10.78 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 11.2, 17.7, 21.4, 29.5, 61.5, 64.0,
120.8, 130.9, 130.7, 135.5, 137.9, 163.1.
HRMS (ESI): m/z [M – BF4]+ calcd for C21H34N3OSi: 372.2466; found:
372.2460.
(S)-2-(4-Fluorophenyl)-5-{[(triisopropylsilyl)oxy]methyl}-6,7-di-
hydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate
(10c)
.
NHC 10c was prepared according to TP3. (1) Compound 9a (1.0 g, 3.68
mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4– (599 mg, 4.1
mmol, 1.1 equiv). (2) 4-Fluorophenylhydrazine (510 mg, 4.1 mmol,
1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (4.9 mL, 29.4
mmol, 8 equiv). The crude product was purified by flash column chro-
matography (silica gel, DCM/acetone, 200:40) and washed with Et2O
to give the pure NHC compound 10c.
Yield: 1.48 g (84%); white solid.
IR (diamond-ATR, neat): 518, 640, 680, 691, 764, 844, 882, 1009,
1034, 1058, 1109, 1238, 1384, 1454, 1523, 1592, 2867, 2891, 2944,
(S)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-phenyl-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate
(10a′)
2958 cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.03–1.06 (m, 18 H), 1.11–1.20 (m, 3
H), 2.55–2.64 (m, 1 H), 2.90–2.99 (m, 1 H), 3.16–3.30 (m, 2 H), 3.97
(dd, J = 12.0, 4.0 Hz, 1 H), 4.16 (dd, J = 8.0, 4.0 Hz, 1 H), 4.88–4.95 (m, 1
H), 7.38–7.43 (m, 2 H), 7.78 (dd, J = 8.0, 4.0 Hz, 2 H), 9.56 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 12.6, 18.2, 22.6, 30.1, 63.8, 65.3, 118.2
(d, J = 23.0 Hz), 125.2 (d, J = 8.0 Hz), 133.0 (d, J = 3.0 Hz), 137.9, 164.4,
164.6 (d, J = 248.0 Hz).
NHC 10a′ was prepared according to TP3. (1) Compound 9b (1.0 g,
4.36 mmol, 1 equiv), anhydrous DCM (70 mL) and Me3O+BF4– (709 mg,
4.8 mmol, 1.1 equiv). (2) Phenylhydrazine (518 mg, 4.8 mmol, 1.1
equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.8 mL, 34.87
mmol, 8 equiv). The crude product was purified by flash column chro-
matography (silica gel, DCM/acetone, 200:50) and washed with Et2O
to give the pure NHC compound 10a′.7b
19F NMR (376 MHz, CD3CN):  = –151.78 (s, 4 F), –110.67 (s, 1 F).
Yield: 1.278 g (70%); white solid.
HRMS (ESI): m/z [M – BF4]+ calcd for C21H33FN3OSi: 390.2371; found:
390.2365.
IR (diamond-ATR, neat): 520, 684, 778, 837, 1035, 1054, 1112, 1136,
1278, 1381, 1472, 1526, 1599, 2858, 2874, 2931, 2954 cm–1
.
1H NMR (400 MHz, CD3CN):  = 0.08 (s, 3 H), 0.11 (s, 3 H), 0.88 (s, 9 H),
2.51–2.60 (m, 1 H), 2.88–2.98 (m, 1 H), 3.15–3.29 (m, 2 H), 3.86 (dd,
J = 12.0, 4.0 Hz, 1 H), 4.08 (dd, J = 8.0, 4.0 Hz, 1 H), 4.86–4.92 (m, 1 H),
7.65–7.70 (m, 3 H), 7.76–7.78 (m, 2 H), 9.59 (s, 1 H).
(S)-2-(Perfluorophenyl)-5-{[(triisopropylsilyl)oxy]methyl}-6,7-di-
hydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate
(10d)
13C NMR (100 MHz, CD3CN):  = –5.4, –5.3, 18.8, 22.6, 26.1, 30.1, 63.6,
63.6, 64.9, 122.4, 131.3, 131.9, 136.7, 137.7, 164.3.
HRMS (ESI): m/z [M – BF4]+ calcd for C18H28N3OSi: 330.1996; found:
330.1994.
NHC 10d was prepared according to TP3. (1) Compound 9a (1.06 g,
3.9 mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4– (635 mg,
4.13 mmol, 1.1 equiv). (2) Perfluorophenylhydrazine (849 mg, 4.3
mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.2 mL,
31.2 mmol, 8 equiv). The crude product was purified by flash column
chromatography (silica gel, DCM/acetone, 200:30) and washed with
Et2O to give the pure NHC compound 10d.
(S)-2-(3-Fluorophenyl)-5-{[(triisopropylsilyl)oxy]methyl}-6,7-di-
hydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate
(10b)
Yield: 1.20 g (56%); white solid.
IR (diamond-ATR, neat): 520, 680, 788, 881, 979, 1004, 1038, 1051,
NHC 10b was prepared according to TP3. (1) Compound 9a (1.06 g,
3.9 mmol, 1 equiv), anhydrous DCM (20 mL) and Me3O+BF4– (635 mg,
4.3 mmol, 1.1 equiv). (2) 3-Fluorophenylhydrazine (542 mg, 4.3
mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.2 mL,
31.2 mmol, 8 equiv). The crude product was purified by flash column
chromatography (silica gel, DCM/acetone, 9:1) and washed with Et2O
to give the pure NHC compound 10b.
1111, 1264, 1356, 1463, 1531, 1598, 2866, 2888, 2943, 2953 cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.04–1.06 (m, 18 H), 1.11–1.20 (m, 3
H), 2.54–2.62 (m, 1 H), 2.91–3.00 (m, 1 H), 3.19–3.33 (m, 2 H), 3.98
(dd, J = 12.0, 8.0 Hz, 1 H), 4.18 (dd, J = 12.0, 4.0 Hz, 1 H), 4.93–5.00 (m,
1 H), 9.58 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 12.5, 18.2, 22.9, 30.1, 64.8, 65.0, 112.4
(m), 13.80 (m), 140.5 (m), 142.3 (m), 145.4 (m), 146.2 (m), 143.2,
165.6.
19F NMR (376 MHz, CD3CN):  = –161.15 (t, J = 18.8 Hz, 2 F), –151.89
(s, 4 F), –148.98 (t, J = 22.6 Hz, 1 F), –146.87 (d, J = 18.8 Hz, 2 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C21H29F5N3OSi: 462.1995; found:
Yield: 1.43 g (77%); white solid.
IR (diamond-ATR, neat): 504, 645, 679, 691, 768, 881, 1038, 1062,
1112, 1205, 1378, 1462, 1593, 2840, 2867, 2927 cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.03–1.06 (m, 18 H), 1.11–1.20 (m, 3
H), 2.56–2.65 (m, 1 H), 2.90–3.00 (m, 1 H), 3.17–3.31 (m, 2 H), 3.98
(dd, J = 12.0, 4.0 Hz, 1 H), 4.16 (dd, J = 12.0, 4.0 Hz, 1 H), 4.90–4.96 (m,
1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.57–7.63 (m, 2 H), 7.67–7.70 (m, 1 H),
9.64 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 12.6, 18.2, 22.6, 30.2, 63.8, 65.3, 110.2
(d, J = 27.0 Hz), 118.9 (d, J = 21.0 Hz), 133.3 (d, J = 9.0 Hz), 137.7 (d, J =
10.0 Hz), 138.1, 162.6, 164.6, 165.0.
462.1992.
(S)-5-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-(perfluorophe-
nyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluo-
roborate (10d′)
NHC 10d′ was prepared according to TP3. (1) Compound 9b (1.0 g,
4.36 mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4– (709 mg,
4.8 mmol, 1.1 equiv). (2) Perfluorophenylhydrazine (949 mg, 4.8
mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.8 mL,
19F NMR (376 MHz, CD3CN):  = –151.74 (s, 4 F), –110.81 (s, 1 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C21H33FN3OSi: 390.2371; found:
390.2366.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

O
V. Dhayalan et al.
Paper
Synthesis
34.87 mmol, 8 equiv). The crude product was purified by flash col-
umn chromatography (silica gel, DCM/acetone, 200:50) and washed
with Et2O to give the pure NHC compound 10d′.
(S)-2-[4-(Trifluoromethyl)phenyl]-5-{[(triisopropylsi-
lyl)oxy]methyl}-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-
ium Tetrafluoroborate (10e)
NHC 10e was prepared according to TP3. (1) Compound 9a (1.0 g, 3.68
Yield: 900 mg (40%); white solid.
mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4 (599 mg,
–
IR (diamond-ATR, neat): 520, 744, 781, 835, 864, 978, 1001, 1029,
4.1mmol, 1.1 equiv). (2) 4-(Trifluoromethyl)phenylhydrazine (713
mg, 4.1 mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH
(4.9 mL, 29.44 mmol, 8 equiv). The crude product was purified by
flash column chromatography (silica gel, DCM/acetone, 200:40) and
washed with Et2O to give the pure NHC compound 10e.
1064, 1092, 1259, 1526, 1603, 2860, 2887, 2931, 2953 cm–1
.
1H NMR (400 MHz, CD3CN):  = 0.09 (s, 3 H), 0.11 (s, 3 H), 0.88 (s, 9 H),
2.51–2.60 (m, 1 H), 2.90–3.00 (m, 1 H), 3.18–3.32 (m, 2 H), 3.88 (dd,
J = 12.0, 8.0 Hz, 1 H), 4.10 (dd, J = 12.0, 4.0 Hz, 1 H), 4.94–5.00 (m, 1 H),
9.62 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = –5.5, –5.4, 18.8, 22.9, 26.1, 30.0, 64.6,
112.4 (m), 137.9 (m), 140.6 (m), 143.2, 143.3 (m), 145.5, (m), 146.1
(m), 165.5.
19F NMR (376 MHz, CD3CN):  = –161.37 (t, J = 22.6 Hz, 2 F), –152.04
(s, 4 F), –149.32 (t, J = 22.6 Hz, 1 F), –146.90 (d, J = 18.8 Hz, 2 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C18H23F5N3OSi: 420.1525; found:
Yield: 1.30 g (67%); white solid.
IR (diamond-ATR, neat): 521, 602, 660, 681, 767, 839, 851, 977, 1034,
1047, 1068, 1112, 1138, 1168, 1324, 1381, 1463, 1531, 1605, 2866,
2890, 2938 cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.03–1.06 (m, 18 H), 1.11–1.20 (m, 3
H), 2.58–2.66 (m, 1 H), 2.92–3.02 (m, 1 H), 3.19–3.33 (m, 2 H), 4.00
(dd, J = 12.0, 4.0 Hz, 1 H), 4.18 (dd, J = 12.0, 4.0 Hz, 1 H), 4.92–4.98 (m,
1 H), 7.95–8.01 (m, 4 H), 9.73 (s, 1 H).
420.1520.
13C NMR (100 MHz, CD3CN):  = 12.6, 18.2, 22.6, 30.2, 64.0, 65.3,
123.1, 124.6 (q, J = 270.0 Hz), 128.6 (q, J = 4.0 Hz), 132.9 (q, J = 33.0
Hz), 138.4, 139.3, 164.8.
19F NMR (376 MHz, CD3CN):  = –151.73 (s, 4 F), –63.39 (s, 3 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C22H33F3N3OSi: 440.2340; found:
(S)-5-{[(tert-Butyldiphenylsilyl)oxy]methyl}-2-(perfluorophenyl)-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluorobo-
rate (10d′′)
NHC 10d′′ was prepared according to TP3. (1) Compound 9c (2.14 g,
6.0 mmol, 1 equiv), anhydrous DCM (40 mL) and Me3O+BF4– (900 mg,
4.8 mmol, 1.0 equiv). (2) Perfluorophenylhydrazine (1.2 g, 6.0 mmol,
1.0 equiv). (3) Anhydrous PhCl (60 mL) and (EtO)3CH (8.0 mL, 48
mmol, 8 equiv). The crude product was recrystallized from i-PrOH to
give the pure NHC compound 10d′′.7c
440.2322.
(S)-2-[3,5-Bis(trifluoromethyl)phenyl]-5-{[(tert-butyldimethylsi-
lyl)oxy]methyl}-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-
ium Tetrafluoroborate (10f)
Yield: 1.80 g (48%); white solid.
NHC 10f was prepared according to TP3. (1) Compound 9b (1.0 g, 4.36
mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4– (709 mg, 4.8
mmol, 1.1 equiv). (2) [3,5-Bis(trifluoromethyl)phenyl]hydrazine (1.17
g, 4.8 mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.8
mL, 34.87 mmol, 8 equiv). The crude product was purified by flash
column chromatography (silica gel, DCM/acetone, 200:50) and
washed with Et2O to give the pure NHC compound 10f.
IR (diamond-ATR, neat): 508, 612, 704, 741, 857, 1068, 1115, 1263,
1429, 1489, 1530, 1605, 2861, 2934, 2959, 3068 cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.03 (s, 9 H), 2.54–2.62 (m, 1 H), 2.90–
3.00 (m, 1 H), 3.20–3.35 (m, 2 H), 3.98 (dd, J = 12.0, 4.0 Hz, 1 H), 4.10
(dd, J = 12.0, 4.0 Hz, 1 H), 5.04–5.11 (m, 1 H), 7.43–7.53 (m, 6 H), 7.64
(t, J = 8.0 Hz, 4 H), 9.68 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 19.7, 22.8, 27.1, 30.2, 64.4, 65.3, 112.4
(m), 129.0, 129.1, 131.3, 131.3, 133.1, 133.3, 136.4, 136.4, 138.0 (m),
140.6 (m), 143.2, 143.4 (m), 145.5 (m), 146.1 (m), 165.6.
19F NMR (376 MHz, CD3CN):  = –161.20 (t, J = 15.0 Hz, 2 F), –151.90
(s, 4 F), –149.10 (t, J = 26.0 Hz, 1 F), –146.84 (d, J = 22.6 Hz, 2 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C28H27F5N3OSi: 544.1838; found:
Yield: 1.60 g (66%); white solid.
IR (diamond-ATR, neat): 521, 682, 698, 779, 836, 1029, 1066, 1136,
1183, 1278, 1364, 1381, 1528, 1603, 2863, 2887, 2933, 2957 cm–1
.
1H NMR (400 MHz, CD3CN):  = 0.11 (s, 3 H), 0.13 (s, 3 H), 0.90 (s, 9 H),
2.52–2.60 (m, 1 H), 2.90–3.00 (m, 1 H), 3.19–3.32 (m, 2 H), 3.87 (dd,
J = 12.0, 8.0 Hz, 1 H), 4.09 (dd, J = 8.0, 4.0 Hz, 1 H), 4.90–4.96 (m, 1 H),
8.28–8.29 (m, 1 H), 8.37 (s, 2 H), 9.76 (s, 1 H).
544.1838.
13C NMR (100 MHz, CD3CN):  = –5.4, –5.3, 18.9, 22.6, 26.2, 30.1, 64.2,
64.9, 123.6 (q, J = 3.0 Hz), 123.7 (q, J = 271.0 Hz), 125.7 (q, J = 3.0 Hz),
134.0 (q, J = 34.0 Hz), 137.8, 139.2, 164.8.
19F NMR (376 MHz, CD3CN):  = –151.83 (s, 4 F), –63.58 (s, 6 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C20H26F6N3OSi: 466.1744; found:
(S)-2-(Perfluorophenyl)-5-{[(triisopropylsilyl)oxy]methyl}-6,7-di-
hydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate
(10d); Alternative Protocol with DCM Treatment
NHC 10d was prepared according to TP3 modified with an additional
step involving treatment with DCM and (EtO)3CH (8 equiv).
466.1738.
(1) Compound 9a (1.06 g, 3.9 mmol, 1 equiv), anhydrous DCM (20 mL)
–
and Me3O+BF4 (635 mg, 4.13 mmol, 1.1 equiv). (2) Perfluorophenyl-
(S)-2-[4-(Trifluoromethoxy)phenyl]-5-{[(triisopropylsi-
lyl)oxy]methyl}-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-
ium Tetrafluoroborate (10g)
hydrazine (849 mg, 4.3 mmol, 1.1 equiv). (3) Anhydrous DCM (30 mL)
and (EtO)3CH (5.2 mL, 31.2 mmol, 8 equiv), 40 °C, 1 h. (4) Anhydrous
PhCl (30 mL) and (EtO)3CH (5.2 mL, 31.2 mmol, 8 equiv). The crude
product was purified by flash column chromatography (silica gel,
DCM/acetone, 200:30) and washed with Et2O to give the pure NHC
compound 10d.
NHC 10g was prepared according to TP3. (1) Compound 9a (1.06 g, 3.9
mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4– (635 mg, 4.3
mmol, 1.1 equiv). (2) 4-(Trifluoromethoxy)phenylhydrazine (826 mg,
4.3 mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.2
Yield: 1.08 g (50%); white solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

P
V. Dhayalan et al.
Paper
Synthesis
mL, 31.2 mmol, 8 equiv). The crude product was purified by flash col-
umn chromatography (silica gel, DCM/acetone, 9:1) and washed with
Et2O to give the pure NHC compound 10g.
(S)-2-(2,6-Dimethylphenyl)-5-{[(triisopropylsilyl)oxy]methyl}-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluorobo-
rate (10i)
NHC 10i was prepared according to TP3. (1) Compound 9a (1.06 g, 3.9
mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4– (635 mg, 4.3
mmol, 1.1 equiv). (2) 2,6-Dimethylphenylhydrazine (585 mg, 4.3
mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.2 mL,
31.2 mmol, 8 equiv). The crude product was purified by flash column
chromatography (silica gel, DCM/acetone, 85:15) and washed with
Et2O to give the pure NHC compound 10i.
Yield: 1.29 g (61%); white solid.
IR (diamond-ATR, neat): 500, 633, 772, 859, 919, 1035, 1046, 1108,
1169, 1256, 1520, 1598, 3024, 3091, 3194 cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.03–1.06 (m, 18 H), 1.11–1.20 (m, 3
H), 2.58–2.66 (m, 1 H), 2.91–3.01 (m, 1 H), 3.17–3.31 (m, 2 H), 4.00
(dd, J = 12.0, 4.0 Hz, 1 H), 4.18 (dd, J = 12.0, 4.0 Hz, 1 H), 4.93–4.97 (m,
1 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.87 (d, J = 8.0 Hz, 2 H), 9.67 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 12.6, 18.2, 22.6, 30.2, 63.9, 65.3, 121.1
(q, J = 265.0 Hz), 123.7, 124.7, 135.2, 138.1, 151.2, 164.6.
Yield: 1.39 g (73%); white solid.
IR (diamond-ATR, neat): 521, 662, 681, 781, 855, 882, 974, 1025,
1055, 1099, 1196, 1288, 1386, 1462, 1588, 1689, 2865, 2890, 2942
19F NMR (376 MHz, CD3CN):  = –151.65 (s, 4 F), –58.73 (s, 3 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C22H33F3N3O2Si: 456.2289;
cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.04–1.07 (m, 18 H), 1.11–1.20 (m, 3
H), 2.11 (s, 6 H), 2.58–2.66 (m, 1 H), 2.93–3.03 (m, 1 H), 3.17–3.32 (m,
2 H), 4.00 (dd, J = 12.0, 8.0 Hz, 1 H), 4.19 (dd, J = 12.0, 4.0 Hz, 1 H),
4.93–4.99 (m, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.48 (t, J = 8.0 Hz, 1 H),
9.37 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 12.5, 17.5, 18.3, 22.8, 30.0, 63.9, 65.1,
129.9, 132.7, 135.4, 136.5, 140.9, 164.8.
found: 456.2283.
(S)-2-[4-(Trifluoromethoxy)phenyl]-5-{[(triisopropylsi-
lyl)oxy]methyl}-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-
ium Tetrafluoroborate (10g); Alternative Protocol with DCM
Treatment
NHC 10g was prepared according to TP3 modified with an additional
step involving treatment with DCM and (EtO)3CH (8 equiv).
HRMS (ESI): m/z [M – BF4]+ calcd for C23H38N3OSi: 400.2779; found:
400.2766.
(1) Compound 9a (1.06 g, 3.9 mmol, 1 equiv), anhydrous DCM (30 mL)
–
and Me3O+BF4 (635 mg, 4.3 mmol, 1.1 equiv). (2) 4-(Trifluorome-
(S)-2-Mesityl-5-{[(triisopropylsilyl)oxy]methyl}-6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (10j)
thoxy)phenylhydrazine (826 mg, 4.3 mmol, 1.1 equiv). (3) Anhydrous
DCM (30 mL) and (EtO)3CH (5.2 mL, 31.2 mmol, 8 equiv), 40 °C, 1 h.
(4) Anhydrous PhCl (30 mL) and (EtO)3CH (5.2 mL, 31.2 mmol, 8
equiv). The crude product was purified by flash column chromatogra-
phy (silica gel, DCM/acetone, 9:1) and washed with Et2O to give the
pure NHC compound 10g.
NHC 10j was prepared according to TP3. (1) Compound 9a (1.06 g, 3.9
mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4– (635 mg, 4.3
mmol, 1.1 equiv). (2) Mesitylhydrazine (646 mg, 4.3 mmol, 1.1 equiv).
(3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.2 mL, 31.2 mmol, 8
equiv). The crude product was purified by flash column chromatogra-
phy (silica gel, DCM/acetone, 85:15) and washed with Et2O to give the
pure NHC compound 10j.
Yield: 860 mg (40%); white solid.
(S)-2-(4-Isopropylphenyl)-5-{[(triisopropylsilyl)oxy]methyl}-6,7-
dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate
(10h)
Yield: 1.70 g (87%); white solid.
IR (diamond-ATR, neat): 521, 662, 681, 707, 765, 854, 882, 945, 975,
1025, 1055, 1201, 1289, 1386, 1461, 1588, 2866, 2943 cm–1
.
NHC 10h was prepared according to TP3. (1) Compound 9a (1.06 g,
3.9 mmol, 1 equiv), anhydrous DCM (30 mL) and Me3O+BF4– (635 mg,
4.3 mmol, 1.1 equiv). (2) 4-Isopropylphenylhydrazine (646 mg, 4.3
mmol, 1.1 equiv). (3) Anhydrous PhCl (30 mL) and (EtO)3CH (5.2 mL,
31.2 mmol, 8 equiv). The crude product was purified by flash column
chromatography (silica gel, DCM/acetone, 9:1) and washed with Et2O
to give the pure NHC compound 10h.
1H NMR (400 MHz, CD3CN):  = 1.04–1.06 (m, 18 H), 1.10–1.19 (m, 3
H), 2.06 (s, 6 H), 2.37 (s, 3 H), 2.56–2.65 (m, 1 H), 2.92–3.01 (m, 1 H),
3.15–3.30 (m, 2 H), 3.40 (dd, J = 12.0, 4.0 Hz, 1 H), 4.18 (dd, J = 12.0,
4.0 Hz, 1 H), 4.91–4.97 (m, 1 H), 7.13 (s, 2 H), 9.39 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 12.5, 17.4, 18.3, 21.2, 22.8, 29.9, 63.8,
65.1, 130.4, 133.0, 136.1, 140.9, 143.2, 164.7.
HRMS (ESI): m/z [M – BF4]+ calcd for C24H40N3OSi: 414.2935; found:
Yield: 1.43 g (73%); white solid.
414.2932.
IR (diamond-ATR, neat): 483, 521, 642, 691, 837, 851, 882, 977, 1012,
1028, 1046, 1068, 1091, 1115, 1216, 1394, 1461, 1525, 1586, 2866,
2943, 2951 cm–1
.
(S)-5-(Hydroxymethyl)-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-
c][1,2,4]triazol-2-ium Tetrafluoroborate (11a)
1H NMR (400 MHz, CD3CN):  = 1.03–1.06 (m, 18 H), 1.11–1.20 (m, 3
H), 1.28 (s, 3 H), 1.29 (s, 3 H), 2.56–2.64 (m, 1 H), 2.90–3.09 (m, 2 H),
3.15–3.30 (m, 2 H), 3.97 (dd, J = 12.0, 8.0 Hz, 1 H), 4.16 (dd, J = 8.0, 4.0
Hz, 1 H), 4.87–4.93 (m, 1 H), 7.52–7.55 (m, 2 H), 7.66 (d, J = 8.0 Hz, 2
H), 9.56 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 12.6, 18.2, 22.6, 24.0, 30.2, 34.6, 63.6,
65.3, 122.3, 129.2, 134.5, 137.4, 153.4, 164.3.
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10a (300 mg, 0.66
mmol, 1 equiv) in anhydrous PhCl (30 mL). HBF4·OEt2 (100 L, 0.726
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
20 °C for 10 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo at less than 50 °C. The obtained crude product was
dissolved in 10 mL of CH3OH and the solvent was removed in vacuo
(the water bath should not exceed 50 °C) to remove residual acids and
solvents, this process was repeated three times. The residue was dried
under high vacuum for 12 h at 40 °C. The crude product was washed
with Et2O to give the pure compound 11a.
HRMS (ESI): m/z [M – BF4]+ calcd for C24H40N3OSi: 414.2935; found:
414.2917.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

Q
V. Dhayalan et al.
Paper
Synthesis
Yield: 190 mg (95%); white solid.
(S)-2-(4-Fluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrro-
lo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11c)
IR (diamond-ATR, neat): 465, 508, 521, 689, 774, 972, 1028, 1054,
1224, 1380, 1466, 1515, 1585, 2956, 3075, 3120, 3499 cm–1
.
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10c (200 mg, 0.42
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (64 L, 0.46
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
50 °C for 1 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single neck-flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) and then washed with Et2O to give the pure compound 11c.
1H NMR (400 MHz, DMSO-d6):  = 2.51–2.56 (m, 1 H), 2.80–2.89 (m, 1
H), 3.17–3.34 (m, 2 H), 3.65–3.71 (m, 1 H), 3.88–3.93 (m, 1 H), 4.81–
4.87 (m, 1 H), 5.44 (t, J = 8.0 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.69 (t, J =
8.0 Hz, 2 H), 7.94 (d, J = 8.0 Hz, 2 H), 10.81 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.2, 28.9, 61.6, 62.3, 120.6, 130.2,
130.4, 135.6, 138.2, 162.6.
HRMS (ESI): m/z [M – BF4]+ calcd for C12H14N3O: 216.1131; found:
216.1129.
(S)-5-(Hydroxymethyl)-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-
c][1,2,4]triazol-2-ium Tetrafluoroborate (11a); Prepared from
10a′
Yield: 120 mg (89%); white solid.
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10a′ (300 mg, 0.72
mmol, 1 equiv) in anhydrous PhCl (30 mL). HBF4·OEt2 (110 L, 0.79
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
20 °C for 1 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with Et2O to give the pure compound 11a.
IR (diamond-ATR, neat): 521, 697, 849, 972, 1004, 1028, 1059, 1165,
1231, 1376, 1449, 1521, 1585, 2947, 3074, 3107, 3515 cm–1
.
1H NMR (400 MHz, CD3CN):  = 2.46–2.55 (m, 1 H), 2.84–2.94 (m, 1
H), 3.14–3.29 (m, 2 H), 3.60 (dd, J = 8.0, 4.0 Hz, 1 H), 3.66–3.72 (m, 1
H), 3.97–4.02 (m, 1 H), 4.80–4.86 (m, 1 H), 7.37–7.41 (m, 2 H), 7.83
(dd, J = 8.0, 4.0 Hz, 2 H), 9.72 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 22.4, 29.7, 63.2, 63.8, 124.9 (d, J = 9.0
Hz), 129.3, 133.1 (d, J = 2.0 Hz), 138.3, 164. 4 (d, J = 247.0 Hz), 165.6.
19F NMR (376 MHz, CD3CN):  = –152.83 (s, 4 F), –111.07 (s, 1 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C12H13FN3O: 234.1037; found:
234.1027.
Yield: 200 mg (92%); white solid.
(S)-5-(Hydroxymethyl)-2-(perfluorophenyl)-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11d)
(S)-2-(3-Fluorophenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-pyrro-
lo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11b)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10d (300 mg, 0.55
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (98 L, 0.72
mmol, 1.3 equiv) was added and the reaction mixture was stirred at
80 °C for 2 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) and then washed with Et2O to give the pure compound 11d.
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10b (200 mg, 0.42
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (64 L, 0.46
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
50 °C for 0.5 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) to give the pure compound 11b.
Yield: 160 mg (74%); white solid.
Yield: 125 mg (93%); white semi-solid.
IR (diamond-ATR, neat): 523, 630, 744, 862, 976, 995, 1022, 1058,
1379, 1495, 1510, 1525, 1600, 1659, 3077, 3123, 3391 cm–1
.
IR (diamond-ATR, neat): 454, 518, 677, 787, 867, 881, 981, 1032,
1049, 1221, 1286, 1386, 1461, 1522, 1592, 1609, 2961, 3105, 3135,
1H NMR (400 MHz, CD3CN):  = 2.47–2.56 (m, 1 H), 2.86–2.95 (m, 1
H), 3.18–3.32 (m, 2 H), 3.63–3.74 (m, 2 H), 3.98–4.03 (m, 1 H), 4.87–
4.93 (m, 1 H), 9.73 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.5, 28.9, 61.4, 63.3, 111.3 (m),
136.4 (m), 138.9 (m), 141.2 (m), 141.7 (m), 143.8, 143.9 (m), 164.0.
19F NMR (376 MHz, CD3CN):  = –161.37 (t, J = 19.0 Hz, 2 F), –152.47
(s, 4 F), –149.39 (t, J = 23.0 Hz, 1 F), –146.70 (d, J = 19.0 Hz, 2 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C12H9F5N3O: 306.0660; found:
3541 cm–1
.
1H NMR (400 MHz, CD3CN):  = 2.47–2.55 (m, 1 H), 2.86–2.94 (m, 1
H), 3.20–3.26 (m, 2 H), 3.58–3.71 (m, 2 H), 4.00 (dd, J = 8.0, 4.0 Hz, 1
H), 4.81–4.87 (m, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.63–7.71 (m, 3 H), 9.78
(s, 1 H).
13C NMR (100 MHz, CD3CN):  = 22.5, 29.8, 63.2, 63.9, 110.0 (d, J =
28.0 Hz), 118.1 (d, J = 3.0 Hz), 118.8, 133.1 (d, J = 10.0 Hz), 137.7 (d, J =
10.0 Hz), 138.6, 163.8 (d, J = 246.0 Hz), 164.1.
306.0657.
19F NMR (376 MHz, CD3CN):  = –151.29 (s, 4 F), –110.96 (s, 1 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C12H13FN3O: 234.1037; found:
234.1033.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

R
V. Dhayalan et al.
Paper
Synthesis
(S)-5-(Hydroxymethyl)-2-(perfluorophenyl)-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11d); Prepared
from 10d′
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) and then recrystallized from acetone/CHCl3/hexane (1:3:7) to
give the pure compound 11f.
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10d′ (300 mg, 0.59
mmol, 1 equiv) in anhydrous PhCl (30 mL). HBF4·OEt2 (89 L, 0.65
mmol, 1.3 equiv) was added and the reaction mixture was stirred at
20 °C for 1 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) and then washed with Et2O to give the pure compound 11d.
Yield: 130 mg (82%); white solid.
IR (diamond-ATR, neat): 415, 524, 682, 702, 717, 845, 899, 976, 1008,
1054, 1135, 1189, 1285, 1364, 1518, 1598, 3081, 3105, 3132, 3498
cm–1
.
1H NMR (400 MHz, CD3CN):  = 2.47–2.56 (m, 1 H), 2.87–2.97 (m, 1
H), 3.24–3.29 (m, 2 H), 3.63–3.73 (m, 2 H), 4.02 (dt, J = 12.0, 4.0 Hz, 1
H), 4.85–4.92 (m, 1 H), 8.27 (s, 1 H), 8.41 (s, 2 H), 9.96 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 22.5, 29.7, 63.1, 64.3, 123.2, 123.3,
123.7 (q, J = 271.0 Hz), 125.5 (m), 133.9 (q, J = 35.0 Hz), 137.9, 139.6,
164.5.
19F NMR (376 MHz, CD3CN):  = –151.92 (s, 4 F), –63.55 (s, 6 F).
Yield: 192 mg (83%); white solid.
HRMS (ESI): m/z [M – BF4]+ calcd for C14H12F6N3O: 352.0879; found:
352.0864.
(S)-5-(Hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11e)
(S)-5-(Hydroxymethyl)-2-[4-(trifluoromethoxy)phenyl]-6,7-dihy-
dro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11g)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10e (300 mg, 0.56
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (86 L, 0.62
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
50 °C for 1 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was recrystallized from benzene to give the pure com-
pound 11e.
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10g (300 mg, 0.55
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (83 L, 0.61
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
50 °C for 1 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) and then washed with Et2O to give the pure compound 11g.
Yield: 180 mg (87%); white solid.
IR (diamond-ATR, neat): 428, 480, 504, 523, 601, 661, 697, 754, 848,
974, 1029, 1054, 1065, 1115, 1165, 1322, 1381, 1421, 1446, 1529,
Yield: 120 mg (56%); white solid.
IR (diamond-ATR, neat): 458, 520, 568, 794, 854, 1015, 1162, 1179,
1595, 1755, 2867, 2948, 3087, 3118, 3535 cm–1
.
1189, 1238, 1269, 1526, 1599, 3097, 3130, 3537 cm–1
.
1H NMR (400 MHz, CD3CN):  = 2.46–2.57 (m, 1 H), 2.82–2.96 (m, 1
H), 3.15–3.32 (m, 2 H), 3.56–3.73 (m, 2 H), 3.92–4.04 (m, 1 H), 4.83–
4.89 (m, 1 H), 7.93–8.03 (m, 4 H), 9.87 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 22.5, 29.8, 63.2, 64.0, 122.9, 124.6 (q,
J = 270.0 Hz), 128.5 (q, J = 4.0 Hz), 132.7 (q, J = 33.0 Hz), 138.9, 139.4,
164.3.
1H NMR (400 MHz, CD3CN):  = 2.47–2.55 (m, 1 H), 2.85–2.92 (m, 1
H), 3.16–3.30 (m, 2 H), 3.58–3.72 (m, 2 H), 4.01 (dt, J = 12.0, 4.0 Hz, 1
H), 4.81–4.88 (m, 1 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.91 (d, J = 8.0 Hz, 2 H),
9.77 (s, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 21.2, 28.9, 61.7, 62.5, 119.9 (q, J =
257.0 Hz), 122.8, 123.0, 134.4, 138.8, 149.0, 162.7.
19F NMR (376 MHz, CD3CN):  = –152.12 (s, 4 F), –63.37 (s, 3 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C13H13F3N3O: 284.1005; found:
19F NMR (376 MHz, CD3CN):  = –151.78 (s, 4 F), –58.74 (s, 3 F).
HRMS (ESI): m/z [M – BF4]+ calcd for C13H13F3N3O2: 300.0954; found:
284.1005.
300.0950.
(S)-2-[3,5-Bis(trifluoromethyl)phenyl]-5-(hydroxymethyl)-6,7-di-
hydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate
(11f)
(S)-5-(Hydroxymethyl)-2-(4-isopropylphenyl)-6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11h)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10h (300 mg, 0.6
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (90 L, 0.66
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
20 °C for 0.5 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10f (200 mg, 0.36
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (50 L, 0.40
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
20 °C for 0.5 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

S
V. Dhayalan et al.
Paper
Synthesis
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) to give the pure compound 11h.
Yield: 650 mg (94%); white solid.
IR (diamond-ATR, neat): 521, 674, 842, 871, 974, 1002, 1018, 1032,
1068, 1203, 1288, 1380, 1449, 1515, 1590, 2965, 3030, 3141 cm–1
.
Yield: 194 mg (94%); white semi-solid.
1H NMR (400 MHz, CD3CN):  = 2.07 (s, 6 H), 2.36 (s, 3 H), 2.47–2.56
(m, 1 H), 2.86–2.95 (m, 1 H), 3.19–3.24 (m, 2 H), 3.60 (t, J = 8.0 Hz, 1
H), 3.68–3.74 (m, 1 H), 3.97–4.02 (m, 1 H), 4.84–4.90 (m, 1 H), 7.13 (s,
2 H), 9.43 (s, 1 H).
IR (diamond-ATR, neat): 521, 550, 647, 838, 975, 1012, 1032, 1049,
1286, 1389, 1421, 1452, 1525, 1586, 2873, 2933, 2963, 3137, 3539
cm–1
.
1H NMR (400 MHz, CD3CN):  = 1.28 (d, J = 8.0 Hz, 6 H), 2.47–2.58 (m,
1 H), 2.85–2.94 (m, 1 H), 3.00–3.07 (m, 1 H), 3.14–3.28 (m, 2 H), 3.57–
3.59 (m, 1 H), 3.67–3.73 (m, 1 H), 3.98–4.03 (m, 1 H), 4.80–4.86 (m, 1
H), 7.51 (dd, J = 8.0, 4.0 Hz, 2 H), 7.72 (d, J = 8.0 Hz, 2 H), 9.72 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 16.9, 20.7, 21.4, 28.8, 61.5, 62.4,
129.1, 132.0, 134.8, 141.2, 141.5, 162.9.
HRMS (ESI): m/z [M – BF4]+ calcd for C15H20N3O: 258.1601; found:
258.1599.
13C NMR (100 MHz, CD3CN):  = 22.4, 24.0, 29.8, 34.6, 63.2, 63.7,
122.2, 129.1, 134.7, 137.8, 153.1, 163.8.
HRMS (ESI): m/z [M – BF4]+ calcd for C15H20N3O: 258.1601; found:
258.1594.
Funding Information
This work was supported by the Israel Science Foundation (Grant No.
14-50-00126). V.D. gratefully acknowledges the Israeli Council for
Higher Education's Planning and Budgeting Committee (PBC) for a
postdoctoral fellowship. K.M. gratefully acknowledges the Kreitman
(S)-2-(2,6-Dimethylphenyl)-5-(hydroxymethyl)-6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (11i)
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10i (300 mg, 0.62
mmol, 1 equiv) in anhydrous PhCl (20 mL). HBF4·OEt2 (93 L, 0.67
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
20 °C for 1 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) to give the pure compound 11i.
Graduate School for a postdoctoral fellowship.
I
sra
e
lS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(1
1
9
3/17)
Acknowledgment
Mass spectrometry was performed with the help of Dr. Meital Shema-
Mizrachi and Dr. Mark M. Karpasas.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611786.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
Yield: 140 mg (68%); white semi-solid.
IR (diamond-ATR, neat): 521, 664, 784, 972, 1028, 1195, 1228, 1385,
References
1452, 1515, 1589, 1742, 2930, 2967, 3088, 3128, 3552 cm–1
.
(1) (a) Paul, M.; Breugst, M.; Neudorfl, J.-M.; Sunoj, R. B.; Berkessel,
A. J. Am. Chem. Soc. 2016, 138, 5044. (b) Langdon, S. M.; Legault,
C. Y.; Gravel, M. J. Org. Chem. 2015, 80, 3597. (c) Neel, A. J.;
Hilton, M. J.; Sigman, M. S.; Toste, F. D. Nature 2017, 543, 637.
(d) Davis, H. J.; Phipps, R. J. Chem. Sci. 2017, 8, 864. (e) Toste, F.
D.; Sigman, M. S.; Miller, S. J. Acc. Chem. Res. 2017, 50, 609.
(f) Ward, T. R.; Collot, J.; Gradinaru, J.; Loosli, A.; Skander, M.;
Letondor, C.; Joseph, E.; Klein, G. Chimia 2003, 57, 586.
(g) Dougherty, D. A. Science 1996, 271, 163.
1H NMR (400 MHz, CD3CN):  = 2.06 (s, 3 H), 2.13 (s, 3 H), 2.19 (s, 1 H),
2.57–2.68 (m, 1 H), 2.96–3.06 (m, 1 H), 3.19–3.32 (m, 2 H), 4.20–4.25
(m, 1 H), 4.63 (dd, J = 12.0, 4.0 Hz, 1 H), 5.04–5.10 (m, 1 H), 7.32 (d, J =
8.0 Hz, 2 H), 7.48 (t, J = 8.0 Hz, 1 H), 9.47 (s, 1 H).
13C NMR (100 MHz, CD3CN):  = 17.5, 20.8, 22.5, 30.0, 60.9, 64.5,
129.9, 132.7, 135.3, 136.6, 141.5, 164.5, 171.3.
HRMS (ESI): m/z [M – BF4]+ calcd for C14H18N3O: 244.1444; found:
244.1441.
(2) (a) O’Toole, S. E.; Connon, S. J. Org. Biomol. Chem. 2009, 7, 3584.
(b) Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org.
Chem. 2009, 74, 9214.
(S)-5-(Hydroxymethyl)-2-mesityl-6,7-dihydro-5H-pyrrolo[2,1-
c][1,2,4]triazol-2-ium Tetrafluoroborate (11j)
(3) (a) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis,
T. Chem. Rev. 2015, 115, 9307. (b) Massey, R. S.; Collett, C. J.;
Lindsay, A. G.; Smith, A. D.; O’Donoghue, A. C. J. Am. Chem. Soc.
2012, 134, 20421. (c) Li, Z.; Li, X.; Cheng, J. P. J. Org. Chem. 2017,
82, 9675. (d) Niu, Y.; Wang, N.; Munoz, A.; Xu, J.; Zeng, H.; Rovis,
T.; Lee, J. K. J. Am. Chem. Soc. 2017, 139, 14917. (e) Marion, N.;
Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46,
2988. (f) Fu, Z.; Xu, J.; Zhu, T.; Leong, W. W.; Chi, Y. R. Nat. Chem.
2013, 5, 835. (g) Enders, D.; Niemeier, O.; Henseler, A. Chem.
Rev. 2007, 107, 5606. (h) Rovis, T. Chem. Lett. 2008, 37, 2.
(4) (a) Zheng, C.; Yao, W.; Zhang, Y.; Ma, C. Org. Lett. 2014, 16, 5028.
(b) Ye, S.; He, L.; Zhang, Y.-R.; Huang, X.-L. Synthesis 2008, 2825.
(c) White, N. A.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 14674.
(d) Sun, L. H.; Liang, Z. Q.; Jia, W. Q.; Ye, S. Angew. Chem. Int. Ed.
A dry, argon-flushed, two-neck Schlenk flask equipped with a mag-
netic stir bar and a septum was charged with NHC 10j (1.0 g, 2.0
mmol, 1 equiv) in anhydrous PhCl (80 mL). HBF4·OEt2 (301 L, 2.2
mmol, 1.1 equiv) was added and the reaction mixture was stirred at
20 °C for 8 h. The reaction mixture was diluted with CH3OH (10 mL)
and then transferred into a single-neck flask. The solvent was re-
moved in vacuo (the water bath should not exceed 50 °C). The ob-
tained crude product was dissolved in 10 mL of CH3OH and the sol-
vent was removed in vacuo (the water bath should not exceed 50 °C)
to remove residual acids and solvents, this process was repeated three
times. The residue was dried under high vacuum for 12 h at 40 °C. The
crude product was washed with hexane (3 × 10 mL) and Et2O (3 × 10
mL) and then recrystallized from Et2O to give the pure compound
11j.7a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T

T
V. Dhayalan et al.
Paper
Synthesis
2013, 52, 5803. (e) Soeta, T.; Tabatake, Y.; Ukaji, Y. Tetrahedron
2012, 68, 10188. (f) Nakano, Y.; Lupton, D. W. Angew. Chem. Int.
Ed. 2016, 55, 3135. (g) Kerr, M. S.; Read de Alaniz, J.; Rovis, T.
J. Org. Chem. 2005, 70, 5725. (h) He, M.; Uc, G. J.; Bode, J. W.
J. Am. Chem. Soc. 2006, 128, 15088. (i) Fang, X.; Chen, X.; Lv, H.;
Chi, Y. R. Angew. Chem. Int. Ed. 2011, 50, 11782. (j) He, M.;
Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418.
(k) Wurz, N. E.; Daniliuc, C. G.; Glorius, F. Chem. Eur. J. 2012, 18,
16297. (l) Piel, I.; Steinmetz, M.; Hirano, K.; Frohlich, R.;
Grimme, S.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 4983.
(m) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F.
Nature 2014, 510, 485. (n) Hirano, K.; Biju, A. T.; Piel, I.; Glorius,
F. J. Am. Chem. Soc. 2009, 131, 14190. (o) Zhang, Y.-R.; He, L.;
Wu, X.; Shao, P.-L.; Ye, S. Org. Lett. 2008, 10, 277. (p) Ling, K. B.;
Smith, A. D. Chem. Commun. 2011, 47, 373.
(5) (a) Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367.
(b) Campbell, C. D.; Concellón, C.; Smith, A. D. Tetrahedron:
Asymmetry 2011, 22, 797.
(6) Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron 2001, 57,
6353.
(7) (a) Zheng, P.; Gondo, C. A.; Bode, J. W. Chem. Asian J. 2011, 6,
614. (b) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem.
Int. Ed. 2006, 45, 1463. (c) Enders, D.; Grossmann, A.; Fronert, J.;
Raabe, G. Chem. Commun. 2010, 46, 6282. (d) Knight, R. L.;
Leeper, F. J. J. Chem. Soc., Perkin Trans 1 1998, 1891.
(8) An, L.; Xiao, Y. L.; Zhang, S.; Zhang, X. Angew. Chem. Int. Ed.
2018, 57, 6921.
(9) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.
(10) Dhayalan, V.; Knochel, P. Synthesis 2015, 47, 3246.
(11) Kumar, Y.; Jaiswal, Y.; Kumar, A. Org. Lett. 2018, 20, 4964.
(12) Suzuki, N.; Fujita, T.; Ichikawa, J. Org. Lett. 2015, 17, 4984.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–T