LETTER
Chiral Bifunctional (Thio)Urea N-Heterocyclic Carbenes
883
7.84–7.78 (m, 2 H, ArH), 7.67 (m, 3 H, ArH), 4.91–4.82 (m, 1 H,
NCH), 4.04 (dd, J = 13.2, 3.8 Hz, 1 H, CH2N3), 3.73 (dd, J = 13.2,
8.6 Hz, 1 H, CH2N3), 3.33–3.13 (m, 2 H, CH2), 3.03–2.90 (m, 1 H,
CH2), 2.54 (m, 1 H, CH2). 13C NMR (100 MHz, CD3CN): d = 163.8,
138.1, 136.6, 131.9, 131.2, 122.2, 61.0, 53.3, 31.0, 22.2. IR: 3123
(w), 2115 (s), 1586 (m), 1519 (w), 1468 (w), 1446 (w), 1392 (w),
1292 (m), 1227 (m), 1034 (s), 974 (m), 916 (w), 875 (w), 771 (s),
739 (w), 711 (m), 689 (m), 671 (w) cm–1. ESI-HRMS: m/z calcd for
C12H13N6+ [M – BF4]: 241.1202; found: 241.1214.
ring. The synthesis included a late-stage introduction of
diversity which allowed an easy access to diverse ana-
logues. Four different triazolium (thio)ureas were synthe-
sized in good overall yield (14–30%) over seven steps
from (S)-pyroglutamic acid (6). Alternatively the precata-
lysts can be obtained from commercially available (S)-5-
(hydroxymethyl)pyrrolidin-2-one (8) in five steps (overall
yield: 28–61%).
(S)-2-Phenyl-5-[(3-phenylureido)methyl]-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium Tetrafluoroborate (3a)
Table 1 Evaluation of Triazolium-(thio)urea 3a–d in the Benzoin
Reactiona
Azide 7 (1.48 g, 4.50 mmol) was dissolved in MeOH (75 mL) under
N2. Pd/C (148 mg) was then added. The flask was purged with H2.
After 1 h under H2 (3 bar), the reaction was filtered on a minimal
quantity of Celite and washed with MeOH (50 mL). Solvents were
removed under vacuum to give the amine (1.34 g) as a yellow gum
catalyst 3n (5 mol%)
O
O
K2CO3 (5 mol%)
Ph
THF
Ph
R
Ph
H
OH
10
1
9
which was used without further purification. H NMR (400 MHz,
CD3CN): d = 9.88 (s, 1 H, H-triazolium), 7.85–7.76 (m, 2 H, ArH),
7.71–7.60 (m, 3 H, ArH), 4.72 (m, 1 H, NCH), 3.34–3.14 (m, 4 H,
CH2 and NCH2), 3.01–2.87 (m, 2 H, CH2), 2.62–2.36 (m, 3 H, CH2,
NH2, and H2O).
Entry
Precatalyst
Yield (%)
ee (%)
64
1
2
3
4
3a
3b
3c
3d
47
81
85
17
60
Phenylisocyanate (240 mL, 2.20 mmol, 1 equiv) was added to a stir-
ring solution of the amine (667 mg, 2.20 mmol, 1 equiv) in MeCN
(7.5 mL). The reaction was stirred at r.t. overnight. Solvents were
removed under vacuum. The crude mixture was purified by flash
column chromatography (CH2Cl2–MeOH = 90:10) to give 3a (706
mg, 1.68 mmol, 75% over two steps) as a slightly yellow solid. 1H
NMR (400 MHz, CD3CN): d = 9.81 (s, 1 H, CH-triazolium), 7.79–
7.74 (m, 2 H, ArH), 7.66–7.61 (m, 3 H, ArH), 7.45 (s, 1 H, NH),
7.36 (dd, J = 9.0, 1.5 Hz, 2 H, ArH), 7.23 (m, 2 H, ArH), 6.97 (m, 1
H, ArH), 5.77 (br t, J = 6.0 Hz, 1 H, NH), 4.93 (m, 1 H, NCH), 3.88–
3.80 (m, 1 H, NCH2), 3.52–3.41 (m, 1 H, NCH2), 3.32–3.12 (m, 2
H, CH2), 3.00–2.89 (m, 1 H, CH2), 2.66–2.53 (m, 1 H, CH2). 13C
NMR (100 MHz, CD3CN): d = 163.0, 155.7, 139.7, 137.5, 135.7,
130.9, 130.3, 128.8, 122.3, 121.3, 118.6, 61.5, 42.1, 30.1, 21.3. IR:
3403 (w), 3133 (w), 1685 (m), 1597 (s), 1547 (s), 1500 (m), 1442
(m), 1394 (m), 1315 (w), 1229 (m), 1061 (s), 763 (s), 694 (m) cm–1.
ESI-HRMS: m/z calcd for C19H20N5O+ (M – BF4]: 334.1668; found:
334.1661.
42
90
a Reaction conditions: benzaldehyde (1 mmol), catalyst (5 mol%),
K2CO3 (5 mol%) in THF (1 mL), 23 °C, 15 h.
The observed activity of the catalysts in the benzoin reac-
tion demonstrated that the catalysts were stable toward in-
tramolecular acid–base self-quenching. Thio(ureas) are
known to activate electrophiles such as imines and ni-
troolefins stronger than simple carbonyl groups. Conse-
quently, the synthesized catalysts would be expected to
favor intermolecular reactions of aldehydes with such
electrophiles over the homobenzoin reaction. Investiga-
tions are currently undergoing toward this goal in our lab-
oratory.
Supporting Information for this article is available online at
(S)-5-(Azidomethyl)-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-
c][1,2,4]triazol-2-ium Tetrafluoroborate (7)
Acknowledgment
(S)-5-(Azidomethyl)pyrrolidin-2-one (5, 1.00 g, 7.10 mmol, 1
equiv) dissolved in CH2Cl2 (5 mL) was added dropwise to a suspen-
sion of Me3OBF4 (1.08 g, 7.10 mmol, 1 equiv) in CH2Cl2 (35 mL).
After 4.5 h, phenyl hydrazine (775 mL, 7.85 mmol, 1.1 equiv) was
added to the colorless solution. After 3 h, the solution was reduced
under vacuum. HC(OMe)3 (14 mL) and MeOH (2 mL) were added
under air. The reaction was stirred in a sealed tube at 80 °C for 20
h. Once cooled, MeOH was added until precipitation, and the result-
ing precipitate was collected by filtration. The mother liquors were
concentrated under vacuum to half of the initial volume. The result-
ing precipitate was filtered. Both solids were combined and dried
under vacuum to give a slightly brown solid (1.20 g). The mother
liquors were concentrated under vacuum. The resulting oil was dis-
solved in MeCN (10 mL) and slowly added to Et2O (150 mL). Fil-
tration gave a slightly brown solid (986 mg). All solids were
combined, dried under high vacuum to yield 7 (2.13 g, 6.48 mmol,
91%) as a slightly brown solid. Rf = 0.4 (CH2Cl2–MeOH = 9:1, UV).
1H NMR (400 MHz, CD3CN): d = 9.81 (s, 1 H, CH-triazolium),
EPFL is acknowledged for financial support.
References
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Synlett 2010, No. 6, 881–884 © Thieme Stuttgart · New York