Organic Process Research & Development
TECHNICAL NOTE
temperature increased from 15 to 39 °C. (1-ethoxycyclopro-
pyl)oxy]trimethylsilane (645.6 g, 3.7 mol, 1.2 equiv) was
charged, followed by sodium cyanoborohydride (290.9 g, 4.63
mol, 1.5 equiv) and methanol (1.48 kg, 46.3 mol, 15 equiv). The
jacket temperature was set at 65 °C. The course of the reaction
was monitored by 1H NMR. Upon completion (∼4 h after the
internal temperature reached 55 °C), the jacket temperature was
cooled to 5 °C. The reaction was carefully quenched with aq
NaOH (4 N, 2.8 L, 11.1 mol, 3.6 equiv) over 15 min while the
internal temperature was maintained below 30 °C. The jacket
temperature was set to 20 °C. The layers were separated, and the
bottom aqueous layer was extracted with TBME (5 vol, 1.5 L).
The combined organic solution was washed with saturated brine
(1 L), then water (1 L).26 To the TBME solution was added
HCl/IPA (5 N, 1.24 L, 6.2 mol, 2 equiv) in one portion. After
stirring vigorously for 10 min, the crude product was subjected to
distillation (200 Torr with the jacket temperature at 70 °C). After
removing 3.5 L of distillate, IPA (30 vol, 9 L) was added for
constant-volume distillation (azeotropic removal of water). The
moisture content of the distillate (started at ∼12 wt %) was
constantly monitored. When the distillate KF dropped below 3.0
wt %, the jacket temperature was decreased to 50 °C. TBME
(6 L) was charged while maintaining the internal temperature
between 35 to 47 °C. A white solid crashed out after the first
500 mL of TBME addition. After addition, the jacket was cooled
down from 50 to 20 °C over 3 h. The resulting white slurry was
gently stirred at 20 °C for another hour. The solid was filtered,
washed with TBME (3 L), and dried in a vacuum oven (45 °C, 15
Torr, nitrogen) to a constant mass. Amine 11 was obtained as a
white solid (420 g, potency 92%, corrected yield 72%). Data for
Compound 11: Melting Point = 135ꢀ137 °C; 1H NMR: (500
MHz, CD3OD, 23 °C) δ = 0.93ꢀ1.25 (m, 8 H), 3.01ꢀ3.05 (m, 2
H), 4.01 (d, J = 7.6 Hz, 2 H), 5.58 (ddd, J = 10.1, 1.0, 0.6 Hz, 1 H),
5.67 (ddd, J = 17.0, 1.3, 1.3 Hz, 1 H), 6.16ꢀ6.24 (m, 1 H); 13C
NMR: (125 MHz, CD3OD, 23 °C) δ = 127.9, 126.3, 61.1, 39.7,
rinsing with extra methanol (200 mL) afforded a colorless
solution. Methanol was replaced with toluene (0.75 L) via
solvent swap, maintaining internal temperature below 35 °C
(50ꢀ70 Torr). The resulting white slurry was filtered, rinsed
with extra toluene (1 L), and dried in a vacuum oven (20 °C, 15
Torr, nitrogen) to a constant mass. Compound 2 was obtained as
a white solid (103 g, 99% potency, corrected yield 72%). Data for
1
Compound 2: Melting Point = 130ꢀ131 °C; H NMR (500
MHz, CD3OD, 23 °C) δ = 0.90ꢀ1.06 (m, 8 H), 2.86ꢀ2.91 (m, 2
H); 13C NMR (125 MHz, CD3OD, 23 °C) δ = 31.9, 4.0; IR
(film) νmax: 2923, 2700, 2464, 2375, 2086, 1597, 1472, 1410,
1209, 1031, 840 cmꢀ1; HRMS [M þ H] calcd for C6H12N =
98.0970; found = 98.0957.
’ AUTHOR INFORMATION
Corresponding Author
*martin.eastgate@bms.com; ke.chen4@bms.com
’ ACKNOWLEDGMENT
We thank Dr. David Kronenthal, Dr. Rajendra Deshpande,
and Dr. Wendel Doubleday for supporting this work. We also
thank Dr. Catherine Gatzemeyer for analytical support, Dr.
Omid Soltani and Lawrenzo Heit for technical contributions,
Dr. Monica Fitzgerald for discussions, Elizabeth Khattak for
obtaining IR-spectra, Dr. Jonathan Marshall for HRMS data, Dr.
Qi Gao for X-ray crystallography and Dr. Lydia Breckenridge for
ICP-MS analysis.
’ REFERENCES
(1) CAS 73121-95-6 (DCPA as freebase 1); CAS 246257-69-2 (HCl
salt 2).
(2) For reviews, see: Friedrich, E. C. In The Chemistry of the
Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: New York, 1987; Part
1, pp 633ꢀ700. Aksenov, V. S.; Terent’eva, G. A.; Savinykh, Yu. V. Russ.
Chem. Rev. 1980, 49, 549.
(3) Standard cross-coupling conditions often led to the formation of
the corresponding N-allylated product, derived from ring-opening of the
cyclopropyl moiety. See: Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.;
Kawasaki, M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653–1655.
(4) For selected reviews, see: Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046–2067. Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131–209. Kienle, M.; Dubbaka, S. R.; Brade, K; Knochel, P.
Eur. J. Org. Chem. 2007, 4166–4176.
4.9, 4.3; IR (film): νmax 3047, 2415, 1481, 1410, 1049, 947 cmꢀ1
;
HRMS [M þ H] calcd for C9H16N = 138.1283; found =
138.1274.
Compound 2.
(5) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219–224.
(6) De Maijere, A.; Chaplinski, V.; Gerson, F.; Pascal, M.; Haselbach,
E. J. Org. Chem. 1999, 64, 6951–6959.
(7) In our experience hydrogenation of either N-benzyl- or N-
benzhydryl-dicyclopropylamine over Pd/C or Pd(OH)2 gave significant
quantities of the ring-opened N-propyl-cyclopropylamine 3. Removal of
N-benzyl was slower and produced more N-propyl-cyclopropylamine 3
than cleavage of N-benzyhydryl; carrying out the hydrogenolysis under
acidic conditions also reduced this impurity—though never below 5%.
These results are in slight contrast to literature precedent (ref 6),
although they may be related to differences in reaction time and/or
more sensitive analytical methods.
(8) For a similar phenomenon, see: Li, D.; Wang, Y.; Yang, C.; Han,
K. Dalton Trans. 2009, 291–297.
(9) Dewar, M. J. S.; Kirschner, S. J. Am. Chem. Soc. 1971,
93, 4290–4291.
To a 2-L Chemglass reactor flushed with nitrogen was charged
with allyl-bis(cyclopropylamine) 11 (185 g, 1.1 mol, 1.0 equiv.),
N,N-dimethylbarbituric acid (166.3 g, 1.1 mol, 1 equiv), tetrakis-
(triphenylphosphine)palladium (24.6 g, 21.3 mmol, 2 mol %)
and DCM (1.5 L). The crude mixture was stirred at 20 °C under
nitrogen while the course of the reaction was monitored by 1H
NMR. Upon completion (∼1 h), the crude mixture was stirred
overnight open to air (to oxidize Pd). DCM (8 vol) was replaced
with a mixture of DMF/TBME (0.75 L, 1:4 v/v) via solvent swap
with the internal temperature maintained below 30 °C. The
resulting light-yellow slurry was filtered and washed with DMF/
TBME (0.3 L, 1:9 v/v) then TBME (1 L). The resulting yellow
solid (117.4 g, mixture of PdCl2(PPh3)2 and amine 2) was
treated with methanol (370 mL) to form a yellow slurry.
Filtration through a Whatman Zapcap filter (0.45 μm) and
(10) For the instability of cyclopropanone, see: Rothgery, E. F.;
Holt, R. J.; McGee, H. A., Jr. J. Am. Chem. Soc. 1974, 97, 4971–4973.
(11) Gillaspy, M. L., Lefker, B. A., Hada, W. A. Hoover, D. J.
Tetrahedron Lett., 1995, 36, 41, 7399-7402.
891
dx.doi.org/10.1021/op2000755 |Org. Process Res. Dev. 2011, 15, 886–892