The synthesis of azabicyclic heterocycles

Article abstract of DOI:10.1016/j.tetlet.2010.03.123

An efficient approach to a oxa-azabicyclo[3.2.1] derivatives has been achieved via a double-Mannich reaction of N,N-bis(methoxymethyl)-1-phenylethanamine with symmetrical and unsymmetrical ketones.

Full text of DOI:10.1016/j.tetlet.2010.03.123

Tetrahedron Letters 51 (2010) 2998–3001
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis of azabicyclic heterocycles
*
Etzer Darout , Arindrajit Basak
Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach to a oxa-azabicyclo[3.2.1] derivatives has been achieved via a double-Mannich
reaction of N,N-bis(methoxymethyl)-1-phenylethanamine with symmetrical and unsymmetrical
ketones.
Received 25 February 2010
Revised 29 March 2010
Accepted 30 March 2010
Available online 3 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
hol resulting in the formation of a single diastereomer.6 However,
attempts to form the oxo-methylene bridge by tosylation of the C-
Bridged azabicycles have recently found increasing use as key
components of biologically active substrates including receptor li-
gands for the management of cough and anxiety,1 as GPR119 mod-
ulators,2 and pest control agents.3 During recent prosecution of a
project targeting diabetes, we sought to obtain the previously un-
known azabicyclo heterocycle, 1, which was viewed as a novel
component of desired therapeutic agents.
5 hydroxy of 2a, followed by an intramolecular SN2 displacement
did not provide the desired bicyclic product.7 When 2a was sub-
jected to the Appel conditions,8 the desired oxobridge derivative
1 was isolated in 57% yield.
Although the approach to the bridged alcohol 1 was successful,
a more expedient and general approach to this intermediate and
other azabicycles was sought. Bis-(aminol) ethers, such as 7, have
been shown to be efficient bis-aminoalkylating agents for the syn-
thesis of tertiary amines including bridged heterocycles.9,10 A dou-
ble-Mannich reaction involving such a bis-(aminol) ether and 3-
oxotetrahydrofuran (6), could provide the azabicyclic ketone 5 in
a single step as shown in Scheme 3.
To validate this strategy, we focused our attention on the dou-
ble-Mannich reaction unsymmetrical ketones. While we were
encouraged by the evidence of recent applications of this strat-
egy,10 there were limitations of the previously published work.11
First, the R group in 7 would have to allow for an efficient dou-
ble-Mannich reaction as well as be readily cleavable under rela-
tively mild conditions. Second, reaction conditions that could
successfully annulate more challenging unsymmetrical and/or
five-membered ring ketones had to be investigated.
2. Results and discussion
Our initial approach to this oxa-azabicyclo[3.2.1] system is
shown in Scheme 1. The hypothesis was that 1-azasugar derivative
2 could undergo an intramolecular etherification upon selective
activation of the C-5 hydroxyl group to provide 1. The 1-azasugars
2 can in turn be derived from the chiral pool4 or from prochiral5
precursors such as 3 which is accessible from commercially avail-
able 2-methylidene-1,3-propanediol (4).
In a modification to a route described by Espeel, the 1-azasugar
2a was isolated via hydroboration/oxidation, followed by hydrog-
enolysis of the benzyl ether to provide the desired triol (Scheme
2). Hydroboration occurs from the face opposite of the allylic alco-
OH
HO
HO
OH
OH
OBn
N
N
N
O
R
OH OH
O
O
O
R
O
O
O
4
1a R= i-Pr
1b R= t-Bu
2a R= i-Pr
3
2b R= t-Bu
Scheme 1. Activation of 1-azasugar to produce bicyclooctane 2.
* Corresponding author.
E-mail address: Etzer.Darout@Pfizer.com (E. Darout).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.123

E. Darout, A. Basak / Tetrahedron Letters 51 (2010) 2998–3001
2999
OH
HO
OH
O
1. BH3, THF
HO
OBn
OH
0 °C to 23 °C
CBr4, PPh3
N
O
N
N
2. H2O2, NaOH
3. H2, 50 psi
Pd(OH)2, 1 N HCl,
MeOH
CH3CN, 0 °C to 23 °C
57%
O
O
O
1a
O
O
22% unoptimized
4
2a
Scheme 2. Sequence to bycyclooctane derivative 2a.
OH
O
O
MeO
N
R
OMe
N
O
O
+
N
R
O
O
6
O
5
7a R= Bn
7b R= CH(CH3)Ph
1
Scheme 3. The double-Mannich approach to 3-azabicyclo[3.2.1]octane derivatives.
Table 1
Bis-aminolalkynation of selected cyclic ketones
product. Instead what was observed by GC–MS analysis were prod-
ucts derived from an intermolecular double-Mannich reaction to
give products corresponding to 17 (Fig. 1a). Because the reactivities
of the protons distal to the oxygen and proximal to the oxygen are
different, there will be an intrinsic difference in the rates of the first
Mannich reaction. Depending on this rate, one could expect inter-
Entry Substrate
Conditions
Product
Yield
(%)
O
O
Ph
(a) MeSiCl3, MeCN
(b) MeSiCl3,
80
59
N
molecular reaction at one of these a-carbons to be faster than the
1
CH2Cl2
intramolecular cyclization. The challenge here was to find condi-
tions that would allow for the second Mannich to occur only after
the starting ketone 6 had undergone the first Mannich reaction.
Ultimately, it was found that adding methanol prior to the addition
of the furan allowed the reaction to proceed as envisioned to afford
the desired product (Fig. 1b).
The addition of methanol improved the reactions with other ke-
tone substrates as well. The double-Mannich reaction of cyclo-
pentanone 11 to form its 3-azabicyclo[3.2.1]octanone derivative
12 has proven to be a difficult transformation.12 However, as entry
3 shows, the desired azabicycle is formed in high yield under these
reaction conditions. The Mannich reaction of 2-indanone 13, entry
5, gave high yields of the desired product 14 with and without the
addition of methanol. Previously published work had shown this
substrate to be a poor double-Mannich substrate with N,N-bis(eth-
oxymethyl)-1-propylamine, yielding only 11% of the desired sub-
strate.11 The dramatic improvement observed in this sequence is
probably attributed to a Thorpe-Ingold effect13 imparted by the
O
O
8
9
O
O
(a) MeSiCl3, MeCN
(b) MeSiCl3,
MeCN
Ph
Ph
Ph
Trace
60a
N
N
2
O
6
MeOH (2 equiv)
O
O
10
12
O
MeSiCl3, MeCN
MeOH (2 equiv)
3
78b
11
O
O
(a) MeSiCl3, MeCN
(b) MeSiCl3,
MeCN
76
78
N
4
MeOH (2 equiv)
14
13
O
OMe
O
Ph
a-methylbenzyl substituent of the bis(methoxyethyl)amine. An-
OMe
N
MeSiCl3, MeCN
MeOH (2 equiv)
5
45c
other test case for the efficiency of the Mannich reaction was 2-
methoxycyclohexanone 15. Although subjecting this ketone to
the standard protocol afforded the desired azabicycle 16 in a mod-
est 45% yield, it is a significant improvement over previously pub-
lished work.11
16
15
a
b
c
Compound was carried on and characterized after further transformations.
Product was isolated as ketone-48% and as its dimethylketal derivative-31%.
Product was isolated as ketone-25% and as its dimethylketal derivative-20%.
The addition of methanol is believed to serve two important
roles: it leads to the in situ generation of HCl and this helps pro-
mote the first Mannich reaction as well as the protonation of the
intermediate which inhibits the second Mannich reaction. The
use of HCl instead of trichloromethylsilane in the double-Mannich
reaction of bis(aminol) ethers has been shown to stop after a single
Mannich addition.10 Methanol may also attenuate the reactivity of
the Lewis acid for a slower generation of the second iminium spe-
cies. Reduction of ketone 10 gave a single diastereomer 1b, with
the hydroxyl anti to the oxobridge (Scheme 4). Hydrogenolysis of
1b proved difficult but was efficiently executed using flow hydro-
genation.14 Carbamate formation gave 1 which was confirmed by
spectral comparison with the product of the Appel reaction.
We found that (R)-N,N-bis(methoxymethyl)-1-phenylethan-
amine (7b) satisfied our requirements. Table 1 illustrates the scope
of this chemistry with a variety of cyclic ketones. As shown in entry
1, treatment of 4-oxotetrahydropyranone with the bisaminol ether
reagent provided the desired azabicyclic ketone in 80% yield with
acetonitrile as the solvent and 59% yield when dichloromethane
was used. We then turned our attention to the more challenging
case exemplified in Scheme 3.
Treatment of 3-oxotetrahydrofuran (6) (entry 2) under the
same reaction conditions did not yield the desired azabicyclic

3000
E. Darout, A. Basak / Tetrahedron Letters 51 (2010) 2998–3001
(a) Reaction without methanol
O
O
RO
OR
N
O
17
(b) Reaction with methanol
O
Ph
N
O
10
Mass= 231
Figure 1. Comparison of double-Mannich reaction of 3-oxotetrahydrofuran with and without methanol.
1H), 5.02 (t, J = 5.37 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d ppm
O
Ph
1. NaBH4, THF/MeOH
170.4, 157.0, 80.2, 70.7, 70.7, 69.8, 69.7, 45.4, 44.6, 43.8, 42.8,
35.2, 28.6, 28.6, 21.1.
1b
N
2. H-cube, 10 bar
O
Compound 2a: 1H NMR (D2O, 500 MHz)
d ppm 1.11 (d,
Boc2O/MeOH, 40 °C
10
45%
J = 6.20 Hz, 6H) 1.50–1.57 (m, 1H) 2.57 (q, J = 13.3 Hz, 2H) 3.19–
3.24 (m, 1H) 3.30–3.33 (m, 1H) 3.44–3.52 (m, 1H) 3.67 (dd,
J = 11.5, 3.3 Hz, 1H) 4.02 (br s, 1H) 4.65–4.73 (m, 1H); 13C NMR
(D2O, 125 MHz) 156.8, 100.0, 73.7, 70.9, 60.3, 47.7, 45.0, 43.7, 21.4.
Compound 9: To a stirred solution of bis-methoxymethyl-(1-
phenyl-ethyl)-amine (750 mg, 3.58 mmol) and tetrahydro-4H-pyr-
an-4-one 8 (150 mg, 1.50 mmol) in MeCN was added MeSiCl3
Scheme 4. Synthesis of 8-hydroxy-6-oxa-3-azabicyclo[3.2.1]octane 1b.
3. Conclusion
In conclusion, two distinct syntheses of 3-azabicyclo[3.2.1]oct-
anol were accomplished. The more concise route relied on an
unprecendented
oxotetrahydrofuran. The use of methanol as an additive was also
found to be critical to the success of this transformation.
(400 lL, 3.41 mmol) at room temperature. The resulting mixture
double-Mannich
reaction
with
3-
was stirred for 50 h, then the reaction was quenched with aqueous
sodium bicarbonate and the reaction mixture was diluted with
EtOAc. The bi-layer was separated and the aqueous portion was ex-
tracted with EtOAc. The combined extracts were washed with
brine, dried (Na2SO4), and filtered and the filtrate was concentrated
under reduced pressure. The residue was purified by flash column
chromatography (ISCO combiflash, EtOAc/heptane 0–100%) to pro-
vide desired compound (317 mg, 88%). The same reaction was also
performed in CH2Cl2 (Yield, 215 mg, 60%) 1H NMR (CDCl3,
4. Experimental
Compound 1a: Characterized as its acetate derivative (Rf 0.4
EtOAc/heptanes 1:2) 1H NMR (CDCl3, 500 MHz) d ppm 1.25 (d,
J = 6.35 Hz, 6H) 2.15 (s, 3H) 2.53–2.65 (m, 1H) 3.06–3.12 (m, 1H)
3.24–3.31 (m, 1H) 3.75–4.05 (m, 4H) 4.14–4.23 (m, 1H) 4.89–
4.97 (m, 1H) 5.03 (t, J = 5.49 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
d ppm 170.3, 156.9, 100.0, 70.7, 70.7, 70.9, 69.8, 69.7, 69.1, 69.0,
45.1, 43.4, 43.2, 35.2, 22.5, 21.1.
Compound 1b: To a solution of 10 (700 mg, 3.03 mmol) in THF/
EtOH (24.8 mL (1:1)) was added NaBH4 (694 mg, 18.2 mmol). The
mixture was stirred for 18 h and concentrated. The residue was
partitioned between 20 mL of TBME and 1 N NaOH (1:1). The mix-
ture was stirred for 30 min and the layers separated. The organic
layer was dried over MgSO4, filtered, and concentrated to give a
clear oil (694 mg). The oil was dissolved in methanol (24 mL) and
Boc2O (734 mg, 3.33 mmol) was added. The solution was passed
through a Pd(OH)2 cartridge using an H-CubeÒ Continuous-flow
Hydrogenation Reactor at 50 bar and 50 °C. The crude material
was concentrated, dissolved in pyridine (10 mL), and acetic anhy-
dride (1 mL) was added. After 16 h, the mixture was concentrated
and purified by flash column chromatography (ISCO combiflash)
(Rf 0.42 EtOAc/heptanes 1:1) 1H NMR (CDCl3, 500 MHz) d ppm
1.47 (s, 9H) 2.15 (s, 3H) 2.54–2.64 (m, 1H) 3.05 (dd, J = 24.9, 13.4,
1H) 3.23 (dd, J = 33.0, 12.9, 1H) 3.75–4.00 (m, 5H) 4.10–4.25 (m,
500 MHz)
d ppm 1.39 (d, J = 6.83 Hz, 3H) 2.52 (tt, J = 6.01,
2.90 Hz, 2H) 2.88–2.99 (m, 2H) 3.05–3.11 (m, 1H) 3.14–3.20 (m,
1H) 3.54 (q, J = 6.83 Hz, 1H) 3.89 (dt, J = 11.16, 3.32 Hz, 2H) 4.20
(t, J = 9.64 Hz, 2H) 7.20–7.39 (m, 6H); 13C NMR (CDCl3, 125 MHz)
d ppm 212.2, 143.5, 128.2, 127.1, 126.9, 73.4, 73.3, 63.0, 55.2,
54.7, 49.6, 49.5, 18.8.
Compound 10: To a stirred solution of bis-methoxymethyl-(1-
phenyl-ethyl)-amine (1.0 g, 11.6 mmol) and methanol (1.00 mL)
in MeCN (19 mL) was added MeSiCl3 (2.34 mL, 19.7 mmol) drop-
wise at room temperature. To this solution was added 3-
oxotetrahydrofuran (6) dropwise and the resulting mixture was
stirred for 16 h. Water (5 mL) was added and the mixture was basi-
fied with 1 N NaOH to pH >9. Diethyl ether (30 mL) was added and
after 10 min the layers were separated. The ether layer was washed
with brine, dried (MgSO4), and filtered, and the filtrate was concen-
trated under reduced pressure. The residue was purified by flash
column chromatography (ISCO combiflash, EtOAc/heptane 1:1) to
provide the desired compound (1.6 g, 60%) as a mixture of diaste-
reomers. 1H NMR (CDCl3, 500 MHz) d ppm 1.32–1.34 (m), 2.15 (t,
J = 4.6 Hz), 2.26 (t, J = 4.5 Hz) 2.45–2.56 (m) 2.61–2.76 (m) 3.04–

E. Darout, A. Basak / Tetrahedron Letters 51 (2010) 2998–3001
3001
3.11 (m) 3.33 (s) 3.34 (s) 3.47 (q, J = 6.6 Hz) 3.57 (q, J = 6.7 Hz)
3.66–3.67 (m) 3.75–3.79 (m) 3.96–4.02 (m) 4.13 (d, J = 6.8 Hz)
4.19 (d, J = 6.8 Hz) 4.45 (dd, J = 7.2, 2.1 Hz) 7.15–7.36 (m); 13C
NMR (CDCl3, 125 MHz) d ppm 213.2, 145.4, 143.1, 128.6, 128.5,
128.2, 127.6, 127.5, 126.9, 101.9, 70.9, 68.3, 64.1, 62.9, 59.3, 53.0,
51.5, 50.1, 48.6, 45.5, 40.8, 40.5, 18.9, 17.8.
1.92–2.02 (series of m) 2.16–2.20 (m), 2.25–2.29 (m), total 4H]
[2.41–2.48 (m) 2.55–2.61 (m), total 3H] [2.97 (td, J = 12.69,
6.10 Hz) 3.12 (dd, J = 10.73, 2.20 Hz) 3.32–3.20 (m), 3.38–3.35
(m), total 3H], [3.40 (s), 3.31 (s), total 3H], 3.40–3.44 (m, 1H)
7.23–7.34 (m, 5H); 13C NMR (CDCl3, 125 MHz) d ppm 214.4,
143.5, 143.3, 128.3, 127.1, 127.0, 80.3, 64.1, 63.9, 61.3, 60.8, 57.6,
56.6, 51.3, 48.7, 48.6, 38.1, 37.8, 33.7, 33.4, 21.4, 19.5; GC–MS
(M+) 273.
Compound 12: Ketone: 1H NMR (CDCl3, 500 MHz) d ppm 1.37 (d,
J = 6.59 Hz, 3H) 1.79–1.89 (m, 2H) 1.98–2.12 (m, 3H) 2.16–2.21 (m,
1H) 2.49 (d, J = 10.49 Hz, 1H) 2.56 (d, J = 10.49 Hz, 1H) 2.91 (ddd,
J = 10.49, 4.39, 2.93 Hz, 1H) 3.08 (ddd, J = 10.37, 4.27, 2.93 Hz,
1H) 3.60 (q, J = 6.67 Hz, 1H) 7.23–7.27 (m, 1H) 7.31–7.38 (m,
4H); 13C NMR (CDCl3, 125 Hz) MHz) d ppm 144.2, 128.2, 127.2,
126.9, 62.1, 59.8, 57.9, 45.5, 22.6, 22.5, 19.3; GC–MS (M+) 229.
Dimethylacetal: 1H NMR (CDCl3, 500 MHz) d ppm 1.31 (d,
J = 6.83 Hz, 3H) 1.62–1.77 (m, 4H) 1.98 (d, J = 1.46 Hz, 1H) 2.13
(d, J = 2.20 Hz, 1H) 2.30–2.34 (m, 1H) 2.37–2.41 (m, 1H) 2.46 (d,
J = 10.00 Hz, 1H) 2.69–2.76 (m, 1H) 3.19 (s, 3H) 3.24 (s, 3H) 3.42
(q, J = 6.51 Hz, 1H) 7.20–7.23 (m, 1H) 7.30 (t, J = 7.56 Hz, 2H)
7.34–7.37 (m, 2H); 13C NMR (CDCl3, 125 MHz) d ppm 146.2,
128.1, 127.2, 126.5, 108.0, 63.6, 53.7, 51.1, 49.2, 47.4, 38.1, 38.0,
25.5, 20.3; GC–MS (M+) 275.
Acknowledgments
I would like to thank Kim McClure, Ben Stevens, Vincent Mas-
citti, and Ralph Robinson for helpful discussions and suggestions
and Ben Thuma for his help with the H-cubeÒ.
References and notes
1. Ho, G. D.; Anthes, J.; Bercovici, A.; Caldwell, J. P.; Cheng, K.-C.; Cui, X.; Fawzi, A.;
Fernandez, X.; Greenlee, W. J.; Hey, J.; Korfmacher, W.; Lu, S. X.; McLeod, R. L.;
Ng, F.; Torhan, A. S.; Tan, Z.; Tulshian, D.; Varty, G. B.; Xu, X.; Zhang, H. Bioorg.
Med. Chem. Lett. 2009, 19, 2519–2523.
2. Xia, Y. B.; Craig, D.; Greenlee, W. J.; Chackalamannil, S.; Jayne, C. L.; Stamford, A.
W.; Dai, X.; Harris, J. M.; Neustadt, B. R.; Neelamkavil, S. F.; Shah, U. G.; Lankin,
C. M.; Liu, H. WO 2009/055331.
3. Endo, Y.; Uenaka, G.; Shirai, Y. WO 2008/026658.
4. Espeel, P. E. R.; Piens, K.; Callewaert, N.; Van der Eycken, J. Synlett 2008, 15,
2321–2325.
5. Compain, P.; Martin, O. R. Iminosugars; Wiley: Chichester, 2007.
6. Dunkelblumk, E.; Klein, J. Tetrahedron 1968, 24, 5701–5710.
7. Herrera, A. J.; Beneitez, M. T.; Amorim, L.; Canada, F. J.; Jimenez-Barbero, J.;
Sinay, P.; Bleriot, Y. Carbohydr. Res. 2007, 342, 1876–1887.
8. Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801–811.
9. Heaney, H.; Papageorgiou, G. Tetrahedron 1996, 52, 3473–3486.
10. Buckley, B. R.; Bulman-Page, P. C.; Heaney, H.; Sampler, E. P.; Carley, S.; Brocke,
C.; Brimble, M. A. Tetrahedron 2005, 61, 5876–5888.
11. Halliday, J. I.; Chebib, M.; Turner, P.; Mcleod, M. D. Org. Lett. 2006, 8, 3399–
3401.
12. Lowe, J. A.; Drozda, S. E.; Mclean, S.; Bryce, D. K.; Crawford, R. T.; Snider, R. M.;
Longo, K. P.; Nagahisa, A.; Tsuchiya, M. J. Med. Chem. 1994, 37, 2831–
2841.
Compound 14: (Rf 0.6 EtOac/heptanes 1:20) 1H NMR (CDCl3,
500 MHz) d ppm 1.24 (d, J = 6.83 Hz, 3H) 2.73 (d, J = 10.73 Hz,
1H) 2.80 (d, J = 10.98 Hz, 1H) 3.13–3.16 (m, 2H) 3.34–3.38 (m,
2H) 3.62 (q, J = 6.83 Hz, 1H) 6.87 (dd, J = 6.59, 2.93 Hz, 2H) 7.17–
7.20 (m, 3H) 7.23–7.28 (m, 2H) 7.34–7.38 (m, 2H); 13C NMR (CDCl3,
125 MHz) d ppm 215.3, 143.9, 139.9, 139.8, 128.4, 127.7, 127.6,
127.2, 127.0, 122.5, 122.4, 57.7, 54.7, 53.6, 53.4; GC–MS (M+) 277.
Compound 16: Ketone (Rf 0.69 EtOAc/heptanes 1:2).
Diastereomers: 1H NMR (CDCl3, 500 MHz) d ppm 1.33 (d,
J = 6.59 Hz), 1.45–1.48 (m) 1.61 (br s) 1.59 (d, J = 6.83 Hz) 1.81–
1.96 (m), 2.12–2.14 (m) 1.98–2.04 (m), 2.35 (dd, J = 10.25,
2.44 Hz) 2.48–2.56 (m) 2.73–2.89 (m) 3.12 (s) 3.22–3.26 (m) 3.32
(s), 3.33(s), 3.35(s) 7.21–7.33 (m) 7.31 (d, J = 2.68 Hz); 13C NMR
(CDCl3, 125 MHz) d ppm 145.7, 128.2, 127.2, 126.6, 100.5, 78.5,
78.3, 65.3, 65.1, 56.9, 55.3, 54.0, 49.14, 49.11, 49.0, 48.9, 37.4,
37.3, 31.5, 27.7, 27.4, 21.4, 21.3, 20.3, 20.4; GC–MS (M+) 319.
Dimethylacetal (Rf 0.63 EtOAc/heptanes 1:2).
13. Beesley, R. M.; Ingold, C. K.; Thorpe, J. C. J. Chem. Soc. 1915, 107,
1080.
14. Hydrogenolysis of the substrate was performed on an H-CubeÒ Continuous-
flow Hydrogenation Reactor manufactured by ThalesNano.
Diastereomers: 1H NMR (CDCl3, 500 MHz) d ppm [1.39 (d,
J = 6.59 Hz) 1.40 (d, J = 6.59 Hz), total 3H] 1.63–1.67 (m, 1H)