Concise synthesis of 3,7-dioxa-9-aza-bicyclo[3,3,1]-nonane

Article abstract of DOI:10.1021/jo051982z

The basicity of an amine has a great impact on physicochemical properties and pharmacokinetics. To attenuate the basicity of morpholine, a bicyclic amine was designed and synthesized with the introduction of an additional β-oxygen. A transannular cyclizat

Full text of DOI:10.1021/jo051982z

SCHEME 1. Retrosynthetic Analysis
Concise Synthesis of
3,7-Dioxa-9-aza-bicyclo[3,3,1]-nonane
Cheol-Min Park
Cancer Research, Global Pharmaceutical R&D,
Abbott Laboratories, 100 Abbott Park Rd.,
Abbott Park, Illinois 60064
cheol-min.park@abbott.com
ReceiVed September 21, 2005
pholine derivative 2, followed by ether bond formation between
C2 and O3. However, all attempts to make the C2-O3 bond
failed as a result of either the participation of the amino group
or incompatibility of the amino protecting groups. Thus, we
turned our attention to alternative routes (Scheme 1, paths b
and c), which involved formation of an eight-membered ring
followed by bicycle formation via transannular cyclization.5
Although we expected that the proximity of the secondary amine
to an electrophilic C1 site in 3 or 4 would allow formation of
the desired [3,3,1] bicyclic system, we reasoned that it would
be difficult to achieve the anti relationship necessary to make
the C1-N9 bond by an SN2-type displacement (path b). We
therefore focused on path c, which involved formation of a
bridgehead hemi-aminal followed by reduction.
The synthesis commenced with differential protection of the
amino group of amino diol 6 with 2,4-dimethoxybenzyl and
benzyl groups (Scheme 2). The selection of the protecting groups
was crucial to avoid neighboring group participation in the
subsequent ether bond forming step. After investigation of
suitable electrophiles for the eight-membered ring formation,
the bis-allylic chloride was found to give the best yield of the
bis-ether 8. Oxidative cleavage6 of the olefin 87 revealed the
latent keto group, and subsequent selective deprotection of the
dimethoxybenzyl group in 9 under acidic conditions led to the
spontaneous formation of the hemi-aminal 10.
The basicity of an amine has a great impact on physico-
chemical properties and pharmacokinetics. To attenuate the
basicity of morpholine, a bicyclic amine was designed and
synthesized with the introduction of an additional â-oxygen.
A transannular cyclization and reduction of a bridgehead
R-chloro amine functionality produces the topographically
unusual amine (pKa ) 6.7) in good yield.
As part of a small molecule drug discovery program, we
became interested in evaluating the incorporation of structurally
diverse amines as a way to modulate pharmaceutical properties.
The basicity of amines1 has a great impact on physicochemical
properties such as aqueous solubility and pharmacokinetics.2
Among the amines considered, a symmetrical bicyclic amine3
such as 3,7-dioxa-9-aza-bicyclo[3,3,1]-nonane 1 drew our
attention in terms of both attenuated basicity due to the â-oxygen
atoms4 and the steric shielding around nitrogen. However, an
extensive literature search revealed that the synthesis of this
molecule had not been reported to date. Herein, we report the
first synthesis of 3,7-dioxa-9-aza-bicyclo[3,3,1]-nonane 1.
Several attempts were made to reduce the alcohol in 10 to
the alkane; however, reaction conditions involving carbocation
intermediates such as triethylsilane-TFA8 were very sluggish,
presumably because of the inability to form the bridgehead
(4) (a) Perrin, C. L.; Ohta, B. K.; Kuperman, J. J. Am. Chem. Soc. 2003,
125, 15008. (b) Baeten, A.; De Profit, F.; Geerlings, P. Chem. Phys. Lett.
1995, 235, 17. (c) Ponec, R.; Girones, X.; Carbo′-Dorca, R. J. Chem. Inf.
Comput. Sci. 2002, 42, 564. (d) Graton, J.; Berthelot, M.; Laurence, C. J.
Chem. Soc., Perkin Trans. 2 2001, 2130.
(5) (a) White, J. D.; Hrnciar, P. J. Org. Chem. 2000, 65, 9129. (b)
Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2713. (c) Ader, T.
A.; Champey, C. A.; Kuznetsova, L. V.; Li, T.; Lim, Y.-H.; Rucando, D.;
Sieburth, S. M. Org. Lett. 2001, 3, 2165.
Retrosynthetically, we considered three approaches (Scheme
1). Path a involved formation of the 1,5-cis substituted mor-
(1) (a) Perrin, D. D.; Dempsey, B.; Serjeant, E. P. pKa Prediction for
Organic Acids and Bases, 1st ed.; Chapman and Hall: New York, 1981.
(b) Chiang, Y.; Kresge, A. J.; Walsh, P. A. J. Org. Chem. 1990, 55, 1309.
(c) Caskey, D. C.; Damrauer, R.; McGoff, D. J. Org. Chem. 2002, 67, 5098.
(d) Staley, R. H.; Beauchamp, J. L. J. Am. Chem. Soc. 1974, 96, 1604. (e)
Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; Hoover, D. J. Tetrahedron
Lett. 1995, 36, 7399.
(6) O’Connor, P. D.; Mander, L. N.; McLachlan, M. M. W. Org. Lett.
2004, 6, 703.
(7) One-pot cleavage procedure using OsO4-NaIO4 destroyed the
dimethoxybenzyl group with further complication on the substrate.
(8) (a) Olkhovik, V.; Masalov, N.; Jansen, B. J. M.; Groot, A.
Tetrahedron Lett. 2001, 42, 4903. (b) Atarashi, S.; Choi, J.-K.; Ha, D.-C.;
Hart, D. J.; Kuzmich, D.; Lee, C.-S.; Ramesh, S.; Wu, S. C. J. Am. Chem.
Soc. 1997, 119, 6226.
(2) Avdeef, A. Curr. Top. Med. Chem. 2001, 1, 277.
(3) Alder, R. W. Tetrahedron 1990, 46, 683.
10.1021/jo051982z CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/19/2005
J. Org. Chem. 2006, 71, 413-415
413

SCHEME 2a
radical-mediated reduction of a bridgehead R-chloro amine as
key steps has been described.
Experimental Section
2-[Benzyl-(2,4-dimethoxy-benzyl)-amino]-propane-1,3-diol (7).
To a solution of 6 (3.0 g, 32.967 mmol) in MeOH (165 mL) was
added 2,4-dimethoxybenzaldehyde (5.473 g, 32.967 mmol) at room
temperature, and the mixture was stirred for 1 h. Na(OAc)3BH
(9.785 g, 46.154 mmol) was added in one portion. The solution
was stirred at room temperature for 5 h and treated with silica gel
(27 g). The slurry was concentrated to powder and purified by flash
chromatography (5%-15% MeOH (7 N NH3)/DCM) to give 6.990
g (89%) of the amino diol: 1H NMR (300 MHz, CDCl3) δ 7.11
(d, J ) 8.2 Hz, 1H), 6.45 (d, J ) 2.4 Hz, 1H), 6.42 (dd, J ) 2.4,
8.2 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.74 (s, 2H), 3.67 (dd, J )
4.8, 11.2 Hz, 2H), 3.53 (dd, J ) 5.1, 11.2 Hz, 2H), 3.06 (br, 3H),
2.72 (quint, J ) 2.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 160.3,
158.6, 130.5, 120.0, 103.9, 98.7, 61.8, 58.7, 55.3, 55.3, 46.0; HRMS
(ESI) calcd for C12H20NO4 (M + H) 242.1387, found 242.1387.
To a solution of the amino diol (6.99 g, 29.247 mmol) in DCM
was added benzaldehyde (3.41 g, 32.172 mmol) and acetic acid
(1.7 mL, 29.247 mmol) at room temperature, and the mixture was
stirred for 1 h. Na(OAc)3BH (8.681 g, 40.946 mmol) was added in
one portion, and the solution was stirred at room temperature for
1 day. Additional portions of benzaldehyde (1.55 g, 14.624 mmol)
and Na(OAc)BH (4.34 g, 20.473 mmol) were added, and the
resulting mixture was stirred for another day. Solvent was removed
in vacuo, and the residue was partitioned between ethyl acetate
and 1 N NaOH. After the organic layer was separated, the aqueous
layer was extracted with ethyl acetate three times. The combined
organic layers were dried over MgSO4. After concentration, the
residue was purified by flash chromatography (0-60% acetonitrile
(containing 1% 7 N NH3 in MeOH)/DCM) to give 7.262 g (76%)
of 7: 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 5H), 7.08 (d, J )
8.0 Hz, 1H), 6.43 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.77 (s, 2H),
3.75 (s, 2H), 3.73 (dd, J ) 8.3, 11.1 Hz, 2H), 3.57 (dd, J ) 5.5,
11.1 Hz, 2H), 2.99 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 160.4,
158.8, 139.7, 132.0, 128.8, 128.2, 126.9, 119.2, 104.2, 98.8, 60.5,
59.8, 55.3, 55.3, 53.8, 48.8; HRMS (ESI) calcd for C19H26NO4 (M
+ H) 332.1856, found 332.1858.
a DMB ) 2,4-dimethoxybenzyl.
SCHEME 3
Benzyl-(2,4-dimethoxy-benzyl)-(7-methylene-[1,5]dioxocan-3-
yl)-amine (8). To a solution of tetrabutylammonium iodide (279
mg, 0.757 mmol) and NaH (333 mg, 8.327 mmol) in DMF (65
mL) at 50 °C was slowly added a solution of 7 (1.253 g, 3.785
mmol) and 3-chloro-2-chloromethyl-1-propene (473 mg, 3.785
mmol) in THF (15 mL) by a syringe pump over 1 h. The solution
was stirred for 1 hour and quenched with aqueous NaHCO3. The
mixture was partitioned between ethyl acetate and aqeous NaHCO3.
After the organic layer was separated, the aqueous layer was
extracted with ethyl acetate three times. The combined organic
layers were dried over MgSO4. After concentration, the residue was
purified by flash chromatography (0-40% ethyl acetate/hexane)
to give 664 mg (46%) of 8: 1H NMR (400 MHz, CDCl3) δ 7.31
(m, 2H), 7.25 (m, 3H), 7.17 (m, 1H), 6.43 (dd, J ) 8.3, 2.5 Hz,
1H), 6.39 (d, J ) 2.2 Hz, 1H), 5.12 (s, 2H), 4.13 (d, J ) 12.9 Hz,
2H), 4.06 (d, J ) 12.9 Hz, 2H), 3.88 (dd, J ) 12.0, 6.8 Hz, 2H),
3.77 (s, 3H), 3.76 (dd, J ) 12.0, 6.8 Hz, 2H), 3.75 (s, 3H), 3.72 (s,
2H), 3.62 (s, 2H), 2.99 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
159.6, 158.6, 146.2, 140.7, 130.4, 128.3, 128.0, 126.5, 120.4, 118.5,
104.1, 98.2, 75.1, 68.5, 58.0, 55.3, 55.2, 54.8, 48.2; HRMS (ESI)
calcd for C23H30NO4 (M + H) 384.2169, found 384.2171.
iminium ion intermediate. Thus, reduction under radical condi-
tions was investigated. The hydroxyl group was converted to
chloride 11 using thionyl chloride at reflux,9 and tributylstan-
nane-mediated reduction10 of chloride 11 smoothly provided the
benzyl-protected amine 12. The final deprotection was carried
out under Pd black-HCO2H conditions11 to give 1 as a formic
acid salt. The structure was confirmed by both NMR analysis
and X-ray crystallography (Supporting Information).
The pKa of 1 was determined to be 6.7 by standard titration.
This attenuation in basicity of 1.7 pKa units with respect to
morpholine (pKa ) 8.4)12 is consistent with an additive inductive
effect of the second â-oxygen to the morpholine backbone in 1
(Scheme 3).
In summary, a synthesis of 3,7-dioxa-9-aza-bicyclo[3,3,1]-
nonane involving transannular hemi-aminal formation and
(9) (a) Mukaiyama, T.; Yanagisawa, M.; Iida, D.; Hachiya, I. Chem. Lett.
2000, 6, 606. (b) Kitching, M. S.; Clegg, W.; Elsegood, M. R. J.; Griffin,
R. J.; Golding, B. T. Synlett 1999, 997.
(10) Bachi, M. D.; Frolow, F.; Hoornaert, C. J. Org. Chem. 1983, 48,
1841.
(11) Fleet, G. W. J.; Ramsden, N. G.; Molyneux, R. J.; Jacob, G. S.
Tetrahedron Lett. 1988, 29, 3603.
(12) Hall, H. K. J. Am. Chem. Soc. 1957, 79, 5441.
7-[Benzyl-(2,4-dimethoxy-benzyl)-amino]-[1,5]dioxocan-3-
one (9). To a solution of 8 (1.868 g, 4.877 mmol) in THF-H2O
(20 mL/5 mL) was added OsO4 (2.5%, 1.2 mL, 0.0975 mmol) and
NMO (628 mg, 5.365 mmol) at room temperature, and the mixture
was stirred for 10 h. The solution was concentrated and filtered
through a small pad of silica gel to give 1.52 g (75%) of the diol.
414 J. Org. Chem., Vol. 71, No. 1, 2006

To a solution of the diol (580 mg, 1.391 mmol) in benzene (7 mL)
was added lead tetraacetate (739 mg, 1.669 mmol) at room
temperature, and the mixture was stirred for 2 h (the reaction should
be carefully monitored to avoid overoxidation). The mixture was
filtered through a small pad of Celite, and the filtrate was
concentrated and purified by flash chromatography (0-50% ethyl
acetate/hexane) to give 460 mg of 9 (86%): 1H NMR (500 MHz,
CDCl3) δ 7.30 (m, 4H), 7.21 (m, 2H), 6.45 (dd, J ) 8.1, 2.5 Hz,
1H), 6.42 (d, J ) 2.2 Hz, 1H), 4.16 (d, J ) 16.2 Hz, 2H), 4.03 (d,
J ) 16.2 Hz, 2H), 3.96 (d, J ) 6.6 Hz, 4H), 3.79 (s, 3H), 3.77 (s,
3H), 3.71 (s, 2H), 3.64 (s, 2H), 3.27 (dt, J ) 12.9, 6.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 211.4, 159.9, 158.7, 140.1, 130.4,
128.3, 128.2, 126.8, 119.8, 104.2, 98.3, 78.2, 72.9, 57.9, 55.3, 55.2,
54.4, 48.0; HRMS (ESI) calcd for C22H28NO5 (M + H) 386.1962,
found 386.1963.
9-Benzyl-3,7-dioxa-9-aza-bicyclo[3,3,1]nonan-1-ol Trifluoro-
acetic Acid Salt (10). A solution of 9 (242 mg, 0.629 mmol) in
trifluoroacetic acid (4.5 mL) was heated at 60 °C for 8 h and
concentrated. The residue was purified by flash chromatography
(0-50% acetonitrile/DCM) to give 117 mg of 10 (53%): 1H NMR
(300 MHz, CDCl3) δ 7.40-7.20 (m, 5H), 4.10 (s, 2H), 4.02 (dd, J
) 10.8, 2.4 Hz, 2H), 3.86 (d, J ) 10.3 Hz, 2H), 3.75 (d, J ) 11.4
Hz, 2H), 3.69 (d, J ) 9.9 Hz, 2H), 2.71 (br, 1H); 13C NMR (75
MHz, CDCl3) δ 139.2, 128.5, 128.1, 127.0, 78.1, 71.4, 66.1, 53.8,
47.2; HRMS (ESI) calcd for C13H18NO3 236.1281, found 236.1282.
9-Benzyl-1-chloro-3,7-dioxa-9-aza-bicyclo[3,3,1]nonane Hy-
drochloric Acid Salt (11). To a solution of 10 (400 mg, 1.150
mmol) in benzene (6 mL)-DCM (2 mL) was added thionyl chloride
(1.2 mL, 17.02 mmol), and the solution was refluxed for 6 h. After
evaporation of the solvent, the residue was purified by flash
chromatography (0-80% ethyl acetate/hexane) to give 250 mg of
11 (76%): 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J ) 6.9 Hz,
2H), 7.33 (dd, J ) 7.5, 7.5 Hz, 2H), 7.26 (t, J ) 7.2 Hz, 1H), 4.25
(s, 2H), 4.12 (dd, J ) 10.61, 5.31 Hz, 2H), 4.11 (d, J ) 10.29 Hz,
2H), 4.03 (d, J ) 10.29 Hz, 2H), 3.79 (d, J ) 11.23 Hz, 2H), 2.71
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 138.0, 128.5, 128.5, 127.3,
81.8, 72.4, 66.1, 54.6, 49.4; HRMS (ESI) calcd for C13H17NO2Cl
(M + H) 254.0942, found 254.0944.
9-Benzyl-3,7-dioxa-9-aza-bicyclo[3,3,1]nonane (12). To a solu-
tion of 11 (150 mg, 0.523 mmol) in benzene (3 mL) was added
tributyltin hydride (239 µL, 0.889 mmol) and AIBN (19 mg, 0.119
mmol), and the solution was refluxed for 24 h. After concentration,
the residue was purified by HPLC (C-8 reverse phase column).
The TFA salt of 12 was free-based by filtration through a small
pad of silica gel using 50% ethyl acetate (containing 1% 7 N NH3
in MeOH)/hexane to give 87 mg of 12 (76%): 1H NMR (400 MHz,
CDCl3) δ 7.39 (d, J ) 7.4 Hz, 2H), 7.32 (dd, J ) 7.7, 7.1 Hz, 2H),
7.25 (dd, J ) 7.4, 7.4 Hz, 1H), 4.17 (d, J ) 12.6 Hz, 4H), 4.05 (s,
2H), 3.86 (d, J ) 11.1 Hz, 4 H), 2.45 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 138.2, 128.5, 128.4, 127.2, 67.2, 55.5, 52.5; HRMS (ESI)
calcd for C13H18NO2 (M + H) 220.1332, found 220.1333.
3,7-Dioxa-9-aza-bicyclo[3,3,1]nonane Formic Acid Salt (1-
HCO2H). To a solution of 12 (87 mg, 0.397 mmol) in 5% HCO2H-
MeOH (4 mL) was added Pd black (9 mg), and the mixture was
stirred for 2 h. After filtration, the solution was concentrated to
give 64 mg of 1 as a formic acid salt (99%): 1H NMR (400 MHz,
CDCl3) δ 8.36 (s, 1H), 4.12 (dd, J ) 12.0, 2.2 Hz, 4H), 4.07 (dd,
J ) 12.0, 2.2 Hz, 4H), 3.25 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 168.0, 69.0, 49.2; HRMS (ESI) calcd for C6H12NO2 (M + H)
130.0863, found 130.0859
Acknowledgment. The author thanks R4N6 chemistry group
for support, the staff of Structural Chemistry for NMR, MS,
and X-ray studies, and Deliang Zhou for pKa determination.
Supporting Information Available: Copies of 1H NMR spectra
for new compounds and crystallographic data for 1-HCO2H in CIF
format. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO051982Z
J. Org. Chem, Vol. 71, No. 1, 2006 415