Journal of the American Chemical Society
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added dropwise at room temperature. After vigorous stirring
overnight, volatiles were removed in vacuo, and CHCl3 (50 mL)
and water (50 mL) were added. The organic layer was separated, the
aqueous layer was extracted with CHCl3 (2 × 30 mL), and the
combined organic extracts were washed with brine (20 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (25% EtOAc in hexanes) to give cis-
5 (600 mg, 50% yield for two steps) as a white solid: mp 76−77 °C;
1H NMR (500 MHz, CDCl3) δ 7.32−7.20 (m, 5H), 6.23 (s, 1H), 5.83
(s, 1H), 3.02 (dd, J = 8.8, 10.0 Hz, 1H), 2.41 (dd, J = 6.6, 8.8 Hz, 1H),
1.71 (dd, J = 6.6, 10.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 168.1,
134.4, 128.9, 128.3, 127.4, 37.0, 34.3, 21.3; HRMS (ESI+) m/z calcd
for C10H1179BrNO [M + H] 240.0024, found 240.0009; calcd for
C10H1181BrNO [M + H] 242.0004, found 241.9989.
(white solid, 218 mg, 38%, mp 51.6 −53.2 °C). These compounds
were consistent with 1H NMR data in the literature,55 but we provide a
more detailed tabulation below.
Data for cis-3b: 1H NMR (500 MHz, CDCl3) δ 7.40−7.26 (m, 5H),
2.53 (ddd, J = 7.5, 8.5, 8.5 Hz, 1H), 1.83 (ddd, J = 6.0, 8.5, 9.0 Hz,
1H), 1.59−1.55 (m, 2H); 13C NMR (126 MHz, CDCl3): δ 135.2,
128.6, 128.0, 127.7, 119.4, 23.2, 12.9, 6.4; HRMS (ESI) m/z calcd for
C10H10N [M + H] 144.0735, found 144.0808.
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Data for trans-3b: H NMR (500 MHz, CDCl3) δ 7.35−7.11 (m,
5H), 2.63 (ddd, J = 5.0, 7.0, 9.5 Hz, 1H), 1.62 (ddd, J = 5.5, 5.5, 9.5
Hz, 1H), 1.55 (ddd, J = 5.0, 5.5, 9.0 Hz, 1H), 1.45 (ddd, J = 5.5, 7.0,
9.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 137.6, 128.8, 127.4,
126.4, 121.1, 24.9, 15.3, 6.7; HRMS (ESI) m/z calcd for C10H10N [M
+ H] 144.0735, found 144.0808.
General Procedure for Mg/Br Exchange/DOCH3 Trapping
Experiments. Four flame-dried 10 mL long-neck round-bottom flasks
(custom built, necks 7.5 cm long) were each charged with bromonitrile
2b (trans or cis,12.5 mg, 0.0563 mmol) and a magnetic stirbar, capped
with rubber septa, and purged with nitrogen. Freshly distilled solvent
(1.0 mL) was then added, and the flasks were all placed in the same
constant-temperature bath set at the required temperature using the
appropriate cooling method (described above). After these reaction
flasks were allowed to cool to the correct temperature for 15 min, i-
PrMgCl (2.2 equiv, 0.124 mL of 1.0 M commercial solution, precooled
for 15 min in a separate flask in the same dewar) was added. At this
point [Mg]total = 0.110 M and [2b]0 = 0.05 M. Following the desired
delay time t, the reactions were quenched by a quick addition of
CH3OD (99.98% D, 0.1 mL) from a flask that had been precooled to
the reaction temperature for 15 min using a syringe that had also been
precooled by flushing several times with cold CH3OD. After removal
of each flask from the cooling bath, solvent was removed in vacuo. The
residue was dissolved in CDCl3, filtered to remove Mg salts, and
cis-1-Bromo-2-phenylcyclopropanecarbonitrile (cis-2b).
Amide cis-5 (989 mg, 4.1 mmol) and p-TsCl (2.5 g, 13.0 mmol)
were combined in pyridine (40 mL) and stirred at 80 °C for 1 day. A
100 mL volume of aqueous HCl (6 M) solution was added, and the
resulting aqueous solution was extracted with ethyl acetate (3 × 30
mL). The combined organic solution was washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (4% EtOAc in hexanes) to give cis-
1
2b (805 mg, 88%) as a colorless oil: H NMR (500 MHz, CDCl3) δ
7.43−7.26 (m, 5H), 2.99 (dd, J = 8.1, 9.9 Hz, 1H), 2.17 (dd, J = 7.3,
8.1 Hz, 1H), 1.95 (dd, J = 7.3, 9.9 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 133.2, 129.0, 128.6, 128.0, 117.3, 35.3, 24.0, 11.6. Anal.
Calcd for C10H8BrN: C, 54.08; H, 3.63; N, 6.31. Found: C, 54.35; H,
3.71; N, 6.26.
trans-1-Bromo-2-phenylcyclopropanecarboxamide (trans-
5). To a solution of trans-429 (3.2 g) in THF (105 mL) was added
a solution of LiOH·H2O (7.6 g) in water (105 mL) at 0 °C. The
resulting solution was stirred at room temperature overnight. The
THF was removed in vacuo, and the remaining aqueous solution was
acidified with 3 M HCl with stirring until a large amount of white
precipitate appeared. The white solid was filtered and washed with
hexanes to give the corresponding carboxylic acid. This material (1.2 g,
5 mmol) was dissolved in thionyl chloride (7.3 mL, 100 mmol), and
DMF (0.5 mL) was added. After the solution was stirred overnight at
room temperature, the volatiles were removed in vacuo and the
residue was dissolved in 30 mL of CHCl3. Concentrated NH4OH (37
mL) was added dropwise at room temperature, after which the
reaction mixture was stirred vigorously overnight. Volatiles were
removed in vacuo, and CHCl3 (50 mL) and water (50 mL) were
added into the reaction mixture. The organic layer was separated, and
the aqueous layer was extracted with CHCl3 (2 × 30 mL). The
combined organic fractions were washed with brine (20 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified by
silicon gel column chromatography (25% EtOAc in hexanes) to give
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analyzed by H NMR spectroscopy. In each case >99% conversion of
starting material and >95% deuterium incorporation in 3b were
observed, allowing easy measurement of the dr value of d1-3b.
cis-1-Deuterio-2-phenylcyclopropanecarbonitrile (cis-d1-
3b). This compound was prepared from cis-2b (50 mg, 0.23 mmol)
using the procedure above, −78 °C, using a 1 min delay time and a
CH3OD quench. The product was obtained in quantitative yield as an
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oil (32 mg), and the observed dr was <2:98: H NMR (500 MHz,
CDCl3) δ 7.40−7.33 (m, 2H), 7.32−7.26 (m, 4H), 2.53 (t, J = 7.9 Hz,
1H), 1.60−1.47 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 135.2,
1
128.6, 128.0, 127.6, 119.4, 23.1, 12.8, 6.2 (1:1:1 triplet, JC−D = 26.7
Hz); HRMS (ESI) m/z calcd for C10H9DN [M + H] 145.0798, found
145.0859.
trans-1-Deuterio-2-phenylcyclopropanecarbonitrile (trans-
d1-3b). This compound was prepared from trans-2b (50 mg, 0.23
mmol) using the procedure above, −78 °C, using a 1 min delay time
and a CH3OD quench. The product was obtained in quantitative yield
as a white solid (31 mg, 98% yield, mp 51.1−52.8 °C), and the
observed dr was >98:2: 1H NMR (500 MHz, CDCl3) δ 7.35−7.23 (m,
3H), 7.13−7.07 (m, 2H), 2.62 (dd, J = 9.2, 6.8 Hz, 1H), 1.71−1.52
(m, 1H), 1.44 (t, J = 6.7, 5.5, 1.2 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 137.6, 128.8, 127.4, 126.3, 121.0, 24.8, 15.1, 6.4 (1:1:1
triplet, 1JC−D = 26.8 Hz); HRMS (ESI) m/z calcd for C10H9DN [M +
H] 145.0798, found 145.0866.
Mg/Br Exchange/DOCH3 Trapping Experiments at Varying
[Mg]total in Et2O. Reactions at [Mg]total of 0.025 and 0.125 M were
performed in Et2O similarly to the general procedure above. Reactions
at [Mg]total = 0.006 and 0.0125 M were performed in 50 and 25 mL
round-bottom flasks, respectively. In both of these cases, 0.1 mL or
100 equiv of CH3OD was added to ensure rapid and complete quench
of the organomagnesium species in these solutions of significantly
larger volume.
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trans-5 (980 mg, 82%) as a white solid: mp 117−118 °C; H NMR
(400 MHz, CDCl3) δ 7.38−7.21 (m, 5H), 6.81 (s, 1H), 6.35 (s, 1H),
3.07−2.95 (m, 1H), 2.23 (dd, J = 6.0, 10.2 Hz, 1H), 1.75 (dd, J = 6.0,
8.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 171.7, 136.2, 129.3,
128.2, 127.5, 38.6, 32.5, 23.1; HRMS (ESI+) m/z calcd for
C10H1179BrNO [M + H] 240.0024, found 240.0000; calcd for
C10H1181BrNO [M + H] 242.0004, found 241.9980.
trans-1-Bromo-2-phenylcyclopropanecarbonitrile (trans-
2b). trans-5 (900 mg, 3.8 mmol) was dehydrated with the same
procedure given for cis-2b to afford trans-2b (724 mg, 87%) as a white
1
solid: mp 53−54 °C; H NMR (500 MHz, CDCl3) δ 7.41−7.35 (m,
3H), 7.25−7.21 (m, 2H), 2.95 (dd, J = 8.7, 10.2 Hz, 1H), 2.21 (dd, J =
7.1, 10.2 Hz, 1H), 1.86 (dd, J = 7.1, 8.7 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 133.3, 129.4, 128.6, 128.5, 119.9, 31.9, 22.4, 14.4.
Anal. Calcd for C10H8BrN: C, 54.08; H, 3.63; N, 6.31. Found: C,
54.26; H, 3.67; N, 6.30.
Mg/Br Exchange/DOCH3 Trapping Experiments at Varying
[Et2O]. Four flame-dried 10 mL long-neck round-bottom flasks
(custom built necks 7.5 cm long) were each charged with bromonitrile
trans-2b (12.6 mg, 0.0567 mmol) and a magnetic stirbar, capped with
rubber septa, and purged with nitrogen. Freshly distilled Et2O (1.5
mL) and toluene (8 mL) were added (total volume 9.5 mL) to achieve
cis- and trans-2-Phenylcyclopropanecarbonitrile (cis-3b and
trans-3b). These compounds were prepared according to the method
of Kaiser et al.54 from trimethylsulfoxonium iodide (1.1 g, 5 mmol)
and cinnamonitrile (516.6 mg, 4 mmol). After aqueous workup the
residue was purified by silica gel column chromatography (2−5%,
EtOAc in hexanes) to give cis-3b (oil, 97 mg, 17%) and trans-3b
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dx.doi.org/10.1021/ja407348s | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX