The Journal of Organic Chemistry
Article
13C NMR (125. MHz, d6-DMSO, 25 °C): δ 153.7, [153.5(broad), 152.9
(broad)], 151.0, 148.0, [144.5 (broad), 143.9 (broad)], [143.6 (broad),
142.9 (broad)], 130.5, 128.8, [125.2 (broad), 124.9 (broad)], [125.0
(broad), 124.5(broad)], 120.6, 117.2, [50.7 (broad), 50.4 (broad)]. 1H
NMR and 13C NMR spectra can be found in the Supporting Information
importance for metallo-enzymatic acyl- and phosphoryl-transfer
processes involving the replacement of poor leaving groups of
normally difficult-to-solvolyze species.
(Figures 10S and 11S). UV−vis: ε262 nm = 14800
40 M−1 cm−1.
EXPERIMENTAL SECTION
■
HRMS: ESI-Orbitrap Velos Pro C19H17N4O4, m/z calcd 365.12443(+),
m/z found 365.12419 (+), PPM-0.6571. Mp = 108−110 °C dec.
(iii) Synthesis of O-Methyl-2,2′-bis(2-picolyl)carbamate (4d).
Dipicolylamine (DPA) (1.36 mL (7.55 mmol)) was dissolved in 30
mL of dry CH2Cl2 followed by the addition of 1.58 mL of triethylamine.
Immediately, 613 μL of methylchloroformate was added to the solution
by syringe under argon, and the reaction mixture was heated to reflux for
5 h after which it was allowed to cool to room temperature and stirred
overnight. It was washed with 2 × 50 mL portions of deionized water
followed by 2 × 50 mL of saturated KCl and finally a 50 mL portion of
deionized water. The separated organic layer was dried over anhydrous
Na2SO4 and filtered and the solvent evaporated under vacuum. The
resulting crude dark brown oil was purified by MPLC (Biotage). On the
basis of TLC results (90% ethyl acetate/10% methanol; Rf = 0.37), the
following gradient system of ethyl acetate and methanol was chosen: 2
column volumes (CV) of 2% MeOH/98% ethyl acetate; 10 CV 2%
methanol progressing to 20% methanol; and 4 CV of 20% methanol.
Elution of the product was monitored at 280 and 310 nm with a flow rate
of 20 mL/min. The acquired fractions (9 mL) were scanned for product
peaks and then evaporated under vacuum to retrieve the purified
(a) Materials. Copper(II) trifluoromethanesulfonate (98%),
ytterbium(III) trifluoromethanesulfonate (99.9%), trifluoromethylsul-
fonic acid (≥99%), methyl chloroformate (99%), isopropyl chlor-
oformate (98%), triphosgene (98%), and 2,2′-bis(2-picolyl)amine
(97%) were commercially available and used as obtained.
(b) General Methods. NMR spectra were recorded at 400 MHz.
+
+
[CH3OH2 ] and [C2H5OH2 ] concentrations were determined
potentiometrically using a combination glass electrode (Accumet
model no. 13-620-292) calibrated with certified standard aqueous
buffers (pH 4.00 and 10.00) as described previously.18 The sspH values in
methanol were determined by subtracting a correction constant of
−2.243 from the electrode readings and the autoprotolysis constant for
s
methanol was set at 10−16.77 M2. The pH values for the kinetic
s
experiments were measured postreaction to avoid the possibility of
inhibitory effects of KCl leaching from the electrode.
(i) Synthesis of O-p-Nitrophenyl-2,2′-bis(2-picolyl)carbamate, 4a.
O-p-Nitrophenyl-2,2′-bis(2-picolyl)carbamate was synthesized by mix-
ing 300 μL (1.67 mmol) of 2,2′-bis(2-picolyl)amine and 370 mg (1.1
equiv) of 4-nitrophenyl chloroformate in 20 mL of CH2Cl2 at room
temperature with stirring. Approximately 1 g of solid sodium
bicarbonate was added to the mixture as a base. The reaction progress
was followed by TLC (30% hexane−70% ethyl acetate) and was
completed after 60 min after which time it was washed with water,
aqueous ammonia, and dilute HCl. The product HCl salt19 was obtained
after solvent removal as a yellowish crystalline material (154 mg, 0.35
mmol, 21%). 1H NMR (400 MHz, D2O, 25 °C): δ 8.73−8.60 (bm, 2H),
8.60−8.45 (bm, 2H), 8.14−7.85(bm, 6H), 7.24−7.14 (bm, 2H), 5.27
(bs, 2H), 5.11(bs, 2H). 13C NMR (100.6 MHz, D2O, 25 °C): δ
[154.6(broad), 154.5 (broad)], 150.6, 150.1, [147.8 (broad), 147.7
(broad)], 145.1, [141.5 (broad), 141.4], 126.6, [126.0 (broad),
1
product as yellowish oil (224 mg, 0.87 mmol, 12%). H NMR (400
MHz, CD3CN, 25 °C): δ 8.48 (d, 2H, J = 4.42 Hz), 7.69 (td, 2H, J = 7.70
Hz, J = 1.64) 7.33−7.18 (m, 4H), 4.60 (bs, 4H), 3.65 (s,3H). 13C NMR
(100.58 MHz, CD3CN, 25 °C): δ 158.7, 158.1, 150.2, 137.6, 123.2,
[122.6 broad), 122.2 (broad)], 53.3, [53.6 (broad), 53.2 (broad)]. The
1H NMR and 13C NMR spectra can be found in the Supporting
Information (Figures 3S and 4S). The FTIR-IR spectrum of 4d showed
a CO absorbance at 1699 cm−1. UV−vis: ε260 nm = 6760 M−1 cm−1.
HRMS: EI-Orbitrap Velos Pro C14H15N3O2, m/z calcd 257.1155(+),
m/z found 257.1164(+), PPM +3.50.
1
125.7(broad)], 125.2, 122.5, [49.9 (broad), 49.8 (broad)]. H NMR
(iv) Synthesis of O-Isopropyl-2,2′-bis(2-picolyl)carbamate (4e). To
an oven-dried 100 mL round-bottom flask containing 20 mL of CH2Cl2
was added bis(2-picolyl)amine (0.678 mL, 3.76 mmol). The flask was
fitted with a condenser and placed in an oil bath. Triethylamine (0.733
mL, 5.264 mmol) was added, and the solution was allowed to stir under
argon for 15 min. Isopropyl chloroformate (4.55 mL, 4.55 mmol) was
added dropwise to the flask, and the oil bath was heated to 40 °C for 4.5
h, after which the solution was allowed to stir while returning to room
temperature overnight. The solvent was removed by rotary evaporation,
and the crude product was dried under vacuum via an oil pump to give a
brown oil. Approximately half of the material was redissolved in the
minimum amount of dichloromethane (∼5 mL), and the solution was
used to prepare a sample for Biotage MPLC purification with the
parameters required for separation being determined from TLC trials.
Ultimately, an Rf value of 0.31 in a solvent mixture of 50:50 hexanes/
ethyl acetate was used to select the solvent gradient program (hexane/
ethyl acetate gradient elution starting 88:12 for 45 mL; ramp to 0:100%
over 350 mL; maintain 0:100% for 200 mL; fractions: 9 mL; flow rate: 25
mL/min. The UV−vis absorbance of the eluting fractions was followed
at 270 and 310 nm. Fractions corresponding to the peaks on elution
and 13C NMR spectra can be found in the Supporting Information
(Figures 1S and 2S). UV−vis: ε262 nm = 24263 88 M−1 cm−1. HRMS:
ESI-Orbitrap Velos Pro C19H17N4O4, m/z calcd 365.12443(+), m/z
found 365.12412 (+), PPM −0.845. Mp = 43 °C dec.
(ii) Synthesis of O-m-Nitrophenyl-2,2′-bis(2-picolyl)carbamate,
4b. Triphosgene (675 mg (2.27 mmol)) was dissolved in 30 mL of dry
toluene followed by cooling to 0 °C, after which 994 μL (6.25 mmol) of
diethylaniline was added with stirring over 15 min. Subsequently, 791
mg (5.69 mmol) of 3-nitrophenol was slowly added over 5 min. The
resulting reaction mixture was allowed to warm to room temperature for
2 h. after which it was washed with 2 × 50 mL of ice-cold water and dried
over magnesium sulfate for 20 min. Following filtration, the solvent was
removed to give 900 mg of a yellow oil (82% yield based on 3-
nitrophenol) which was used without further purification in the next
step.
3-Nitrophenyl chloroformate (272 mg, 1.35 mmol) was dissolved in
30 mL of dry CH2Cl2, followed by the addition of 243 μL (1.35 mmol)
of bis(2-picolyl)amine with stirring at room temperature. Solid sodium
bicarbonate (500 mg) was added to the reaction mixture, which was
allowed to stir for 150 min. Approximately half of the reaction mixture
was filtered from its solid precipitate and was used for product
purification with an MPLC Biotage SP1 instrument. The solvent
gradient system comprised ethyl acetate and hexane; 2 CV of hexane; 10
CV 0% ethyl acetate progressing to 100% ethyl acetate; and then 4 CV of
100% ethyl acetate. Elution of the product was monitored at 280 and
310 nm with a flow rate of 20 mL/min. The acquired fractions (9 mL)
containing the product were combined, and the dissolved material was
converted into an HCl salt by the gradual addition of concentrated HCl.
This yielded a white precipitate; the organic layer was decanted and the
residual white solid dried under vacuum to give 35 mg of product, 0.08
mmol, 6%.19 1H NMR (400 MHz, d6-DMSO, 25 °C): δ 8.85 (bs, 2H),
8.45 (bm,1H) 8.38 (bm,1H) 8.12−8.07 (bm, 2H), 8.05−7.95 (m, 2H),
7.88 (t,1H) 7.82 (t,1H), 7.72−7.62 (m,2H) 5.26 (bs, 2H), 5.11(bs, 2H).
1
profiles were analyzed by H NMR, and those containing the desired
product were combined and solvent removed using rotary evaporation
to yield a colorless oil (187 mg, 0.66 mmol, 17%). 1H NMR (400 MHz,
CD3CN, 25 °C): δ 8.47 (d, 2H, J = 4.42 Hz), 7.70 (td, 2H, J = 7.70 Hz, J′
= 1.65 Hz) 7.33−7.17 (m, 4H), 4.86 (septet, 1H, J = 6.22 Hz), 4.63 (bs,
2H) 4.57 (bs, 2H), 1.13 (d, 6H J = 6.31 Hz). 13C NMR (100.58 MHz,
CD3CN, 25 °C): δ [158.9(broad),158.8(broad)], 157.1, 150.0, 137.6,
123.1, [122.5(broad),122.2 (broad)], 69.7, [53.5(broad), 53.1 (broad)],
1
22.2. H NMR and 13C NMR spectra can be found in the Supporting
Information (Figures 5S and 6S). The FTIR-IR spectrum of 4d showed
a CO absorbance at 1693 cm−1. UV−vis: ε260 nm = 7799 M−1 cm−1.
HRMS:EI-Orbitrap Velos Pro C16H19N3O2, m/z calcd 285.1477(+), m/
z found 285.1468(+), PPM −3.3.
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J. Org. Chem. 2015, 80, 1357−1364