The Journal of Organic Chemistry
Note
(1.23 g, 84% yield); thermal decomposition of the compound
prohibits melting point measurement. [α]D −21 (c 0.01, DMSO).
1H NMR (400 MHz, DMSO-d6): δ 0.8 (d, J = 6.7 Hz, 3H), 1.9−2.1
Notes
The authors declare no competing financial interest.
(m, 2H), 2.1−2.3 (m, 2H), 2.5−2.6 (d, J = 14.9 Hz, 1H), 2.7−2.8 (m,
1H), 2.8−3.0 (s+m, 14H), 3.0−3.5 (m, 6H), 3.9 (d, J = 16.5 Hz, 1H),
4.1 (d, J = 16.5 Hz, 1H), 4.9−5.1 (m, 1H), 6.1 (d, J = 8.0 Hz, 1H), 6.5
(d, J = 8.3 Hz, 1H), 6.9−7.0 (d, J = 9.2 Hz, 1H), 7.0−7.1 (d, J = 9.0
Hz, 1H), 7.1 (s, 1H), 7.3 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
18.5, 24.6, 29.7, 34.5, 34.7, 35.9, 44.4, 45.4, 46.3, 49.9, 54.8, 119.0,
123.9, 124.1, 127.9, 129.3, 131.3, 131.8, 133.9, 135.1, 139.1, 142.2,
142.5, 145.6, 165.5, 168.0, 169.7, 172.0. HRMS (ESI-Orbitrap) calcd
for C32H39N9O3: [M + H] m/z 598.3254, found 598.3246.
ACKNOWLEDGMENTS
We thank Amgen’s molecular structure group for determing the
structure of 12.
■
REFERENCES
■
(1) March, J. Advanced Organic Chemistry, 2nd ed.; McGraw-Hill:
New York, 1977; p 816.
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(7) For an example of a bisulfite adduct used directly in a catalytic
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Sodium 2-((S)-2-Cyanopyrrolidin-1-yl)-1-hydroxy-2-oxoethane-
sulfonate (2a). White crystalline solid (26.96 g, 91% yield); thermal
decomposition of the compound prohibits melting point measure-
1
ment. H NMR (400 MHz, D2O): diastereomeric mixture (∼1:1) δ
2.05−2.16 (m, 4H), 2.27−2.33 (m, 4H), 3.65−3.71 (m, 1H), 3.80−
3.83 (m, 1H), 4.74−4.77 (m, 1H), 4.80−4.82 (m, 1H), 5.27 (s, 1H),
5.29 (s, 1H). 13C NMR (100 MHz, D2O): 24.6, 24.8, 29.3, 29.5, 47.3,
47.6, 47.7, 47.8, 81.2, 81.2, 118.7, 118.9, 167.1, 166.9. HRMS (ESI-
Orbitrap) calcd for C7H9N2NaO5S: [M + Na] m/z 279.0028, found
279.0017.
Sodium 1-Hydroxy-2-morpholino-2-oxoethanesulfonate (2e).
White crystalline solid (2.2 g, 75% yield); thermal decomposition of
1
the compound prohibits melting point measurement. H NMR (400
(8) For an example of a bisulfite adduct used directly in a
diastereoselective Strecker reaction, see: Seki, M.; Hatsudab, M.;
Yoshida, S. Tetrahedron Lett. 2004, 45, 6579−6581.
(9) Oil that must be stored in solution, shown to have poor stability
above −20 °C.
MHz, D2O): δ 3.55−3.81 (m, 4H), 5.50 (s, 1H). 13C NMR (100
MHz, D2O): δ 43.2, 46.8, 66.1, 79.4, 166.3. HRMS (ESI-Orbitrap)
calcd for C6H10NNaO6S: [M + Na] m/z 270.0024, found 270.0013.
(S)-1-(2-(Phenylamino)acetyl)pyrrolidine-2-carbonitrile (3d). Pu-
rification by silica gel chromotography (70% EtOAc/Heptane) gave
the product as a tan crystalline solid (108 mg, 51% yield); mp 105−
107 °C. [α]D −25.74 (c 0.035, DMSO). 1H NMR (400 MHz, CDCl3):
δ 2.16−2.31 (m, 4H), 3.43−3.45 (m, 1H), 3.59−3.62 (m, 1H), 3.84 (s,
2H), 4.76−4.79 (dd, J = 7.24, 3.72 Hz, 1H), 6.61−6.63 (m, 2H),
6.72−6.76 (m, 1H), 7.17−7.21 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 24.9, 29.8, 45.3, 46.2, 46.5, 113.0, 117.9, 118.0, 129.2, 146.9,
168.4. HRMS (ESI-Orbitrap) calcd for C13H15N3O: [M + H] m/z
230.1293, found 230.1282.
(10) For the synthesis and reported instability of the morpholino
phenyl glyoxal substrate, see: Liu, Q.; Perreault, S.; Rovis, T. J. Am.
Chem. Soc. 2008, 130, 14066−14067.
(11) Bisulfite adducts 2a−2e have been observed to be bench stable
for at least 12 months.
(12) Yield based upon quantitative 1H NMR of the substrate against
an external standard.
(13) See Supporting Information for details regarding base screen.
(14) The cyclization side product arises as a result of an
intramolecular reaction of the free amine and proline nitrile.
2-(Hexylamino)-1-morpholinoethanone (3g). Purification by silica
gel chromotography (70% EtOAc/Heptane) gave the product as a
clear colorless oil (170 mg, 55% yield). 1H NMR (400 MHz, CDCl3):
δ 0.88 (t, J = 6.50 Hz, 3H), 1.21−1.41 (m, 6H), 1.52 (quin, J = 7.40
Hz, 2H), 1.86 (s, 1H), 2.59 (t, J = 7.24 Hz, 2H), 3.41 (s, 4H), 3.58−
3.73 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 14.1, 22.6, 27.0, 30.2,
31.8, 42.1, 45.0, 50.3, 50.6, 66.6, 66.9, 169.9. HRMS (ESI-Orbitrap)
calcd for C12H24N2O2: [M + H] m/z 229.1916, found 229.1903.
2-(Cyclohexylamino)-1-morpholinoethanone (3h). Purification by
silica gel chromotography (10% MeOH/DCM) gave the product as a
1
clear colorless oil (223 mg, 54% yield). H NMR (400 MHz, DMSO-
(15) It should be noted that conducting the reaction in MeOH
results in precipitation of the product from the reaction mixture, which
is believed to be primarily responsible for reduced levels of the side
d6): δ 0.93−1.07 (m, 2H), 1.08−1.28 (m,3 H), 1.46−1.58 (m, 1H),
1.60−1.71 (m, 2H), 1.73−1.86 (m, 2H), 2.29 (tt J=9.78, 3.52 Hz, 1H),
3.30 (br s, 1H), 3.36 (s, 2H), 3.38−3.47 (m, 4H), 3.51−3.62 (m, 4H).
13C NMR (100 MHz, CDCl3): δ 24.8, 26.0, 33.4, 42.1, 44.9, 47.7, 56.9,
66.5, 66.8, 170.0. HRMS (ESI-Orbitrap) calcd for C12H22N2O2: [M +
H] m/z 227.1760, found 227.1748.
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ASSOCIATED CONTENT
* Supporting Information
Spectral data for all new compounds is available free of charge
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S
AUTHOR INFORMATION
Corresponding Author
■
Present Addresses
5995−5996.
†Alcon, 6201 South Freeway, R7-28, Fort Worth, TX, 76134.
‡Department of Chemistry, Columbia University, 3000 Broad-
way, New York, NY, 10027.
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dx.doi.org/10.1021/jo3023878 | J. Org. Chem. 2013, 78, 1655−1659