A concise synthesis of 6-oxa-3-azabicyclo[31.1]heptane hydrotosylate

Article abstract of DOI:10.1055/s-0030-1260116

Bridged bicyclic morpholines are important building blocks in medicinal chemistry research. The bicyclic morpholine 6-oxa-3-azabicyclo[3.1.1]heptane (2a) is of particular interest as a morpholine isostere because it is achiral and shows properties similar

Full text of DOI:10.1055/s-0030-1260116

PAPER
2619
A Concise Synthesis of 6-Oxa-3-azabicyclo[3.1.1]heptane Hydrotosylate
S
ynthesis of 6-Oxa
o
-3-azabicycl
n
o[3.1.1]hepta
n
ne G. Wishka,a Paul Beagley,b Jessica Lyon,b Kathleen A. Farley,a Daniel P. Walker*a
a
Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, USA
Fax +1(860)6860013; E-mail: daniel.p.walker.pfizer@gmail.com
Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Rd., Chapel-en-le-Frith, High Peak, SK23 0PG, UK
b
Received 4 May 2011
F
Abstract: Bridged bicyclic morpholines are important building
blocks in medicinal chemistry research. The bicyclic morpholine 6-
oxa-3-azabicyclo[3.1.1]heptane (2a) is of particular interest as a
morpholine isostere because it is achiral and shows properties sim-
ilar to that of morpholine based on a derived analogue. The first syn-
thesis of morpholine 2a (tosylate salt) is described. The six-step
sequence begins with inexpensive starting materials and uses
straightforward chemistry.
O
N
F
O
Cl
NH
N
O
N
O
N
O
MeO
N
NH
gifitinib
O
Key words: stereoselective synthesis, bicyclic compounds, hetero-
cycles, alkylation, hydrogenation
linezolid
Morpholines are used extensively in drug discovery re-
search. Numerous drugs approved by the FDA and other
regulatory agencies for the treatment of human diseases
contain a morpholine ring. Some recent examples are
shown in Figure 1, including linezolid (Zyvox®),1 gifi-
tinib (Iressa®),2 and reboxetine (Vestra®).3 Over the years,
several types of bridged bicyclic morpholines have been
developed as morpholine isosteres (Figure 2); many of
these morpholine isosteres have shown desirable biologi-
cal activities for a number of pharmacological targets.4 Of
the parent morpholines in Figure 2, 6-oxa-3-azabicyc-
lo[3.1.1]heptane (2a) shows particular promise of becom-
ing a useful morpholine isostere due to its similarity in
structure and properties to morpholine. For example,
compound 2b, which is an analogue derived from mor-
pholine 2a, was shown to have very similar lipophilicity,
solubility, and in vitro pharmacokinetic properties to that
of the parent morpholine analogue (1).5 In addition, 2a is
achiral, which eliminates the need to separate and test the
individual enantiomers. Of the remaining morpholines in
Figure 2, 3a and 4a are also achiral, and a number of re-
cent reports have shown their utility as effective morpho-
line isosteres.4d,e However, Log P (clogP) calculations on
their derived piperonyl analogues, 3b and 4b, respective-
ly, suggest that both morpholines 3a and 4a increase lipo-
philicity compared to morpholine. The remaining two
morpholines, 5a and 6a, have also been utilized success-
fully as morpholine surrogates;4c,f however, both of these
morpholines are chiral.
O
O
O
N
H
reboxetine
Figure 1 Drugs possessing a directly linked morpholine ring
ly available. A piperonyl analogue possessing 2a was
recently published by Carreira (Scheme 1).10 Surprising-
ly, despite the potential for bridged bicyclic morpholine
2a to become a useful morpholine isostere in medicinal
chemistry research, to date, no accounts describing the
preparation of 2a have appeared in the literature. While it
is conceivable that morpholine 2a could be derived from
2b via hydrogenolysis of the piperonyl group, the pub-
lished synthesis of 2b is low-yielding, and it is nonstereo-
selective. In addition, the use of stoichiometric amounts of
toxic tributyltin methoxide to generate oxetane 7 was con-
sidered a drawback if larger quantities of 2b would be re-
quired. Thus, we became interested in developing an
improved synthetic route to prepare morpholine 2a. We
detail below a practical and stereoselective synthesis of 6-
oxa-3-azabicyclo[3.1.1]heptane hydrotosylate (2a·TsOH),
which constitutes the first synthesis of this potentially use-
ful building block.
Our synthesis of 2a commenced from ( )-epichlorohy-
drin, an inexpensive, readily available starting material
(Scheme 2). Because the chirality of epichlorohydrin will
be removed later in the synthesis via the formation of a
symmetrical intermediate (vide infra), we saw no practical
or strategic advantage in starting from enantiomerically
pure epichlorohydrin. Using a modification of the Phar-
macia & Upjohn procedure,11 reaction of (4-methoxyphe-
nyl)methanimine, generated in situ from 4-methoxy-
benzaldehyde and concentrated aqueous ammonia, with
The synthesis of the parent bridged bicyclic morpholines
3a,6 4a,7 5a,8 and 6a9 (Figure 2) have been previously de-
scribed, and several of these morpholines are commercial-
SYNTHESIS 2011, No. 16, pp 2619–2624
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260116; Art ID: M58811SS
© Georg Thieme Verlag Stuttgart · New York

2620
D. G. Wishka et al.
PAPER
cold (0 °C) solution of morpholinone 10 with potassium
hexamethyldisilazide generated the corresponding lactam
enolate that underwent subsequent intramolecular alkyla-
tion by the primary alkyl chloride. The use of potassium
hexamethyldisilazide to effect the intramolecular cycliza-
tion proved to be crucial as other strong bases, such as
lithium diisopropylamide, led to lower yields or no reac-
tion.14 Reduction of the lactam carbonyl with borane–
dimethyl sulfide complex smoothly gave rise, after acidic
workup, to achiral morpholine 13.
R
R
R
N
N
N
O
O
O
3a R = H
1 R = piperonyl
clogP = 1.8a
2a R = H
3bc R = piperonyl
2b R = piperonyl
clogP = 2.3a
mlogP = 1.6b
clogP = 1.6a
mlogP = 1.8b
R
N
R
N
R
N
O
O
O
4a R = H
5a R = H
6a R = H
4bc R = piperonyl
clogP = 2.2a
5bc R = piperonyl
clogP = 2.1a
6bc R = piperonyl
clogP = 2.2a
OMe
PMB
NH
O
O
O
a
c
piperonyl =
b
OH
Cl
92%
94%
N
Cl
OH
Cl
9
Figure 2 Novel synthetic target 2a and selected bridged bicyclic
morpholine isosteres 3a–6a utilized in medicinal chemistry. Lipo-
a
philicity, Log P (clogP), values were calculated using ACD labs, ver-
sion 9.3 (Advanced Chemistry Development, Toronto, ON, Canada).
b Measured Log P (mlogP), see ref. 5. c Analogues 3b–6b are virtual
compounds created to illustrate how their lipophilicities compare to
the known morpholine analogues 1 and 2b.
8
O
O
PMB
N
PMB
Cl
d
N
+
O
83%
O
O
Cl
CHO
OBn
a
c
b
10 (73%)
11 (7%)
OH
OBn
OMs
OH
OBn
83%
84%
32%
O
PMB
e
OH
O
PMB
N
O
O
N
71%
O
d,e
f
O
O
O
N
12
13
20% over 3 steps
2b
Scheme 2 Reagents and conditions: (a) 4-methoxybenzaldehyde,
28% aq NH3, t-BuOMe, 0 °C to r.t., 48 h; (b) NaBH4, MeOH, 0 °C, 1
h; (c) 1. ClCH2COCl, CH2Cl2–aq NaOH, 0 °C, 1 h; 2. 40% aq NaOH,
r.t., 4 h; (d) KHMDS (2.0 equiv), toluene–THF (1:1), 0 °C 1.5 h; (e)
BH3·SMe2, THF, 0 °C to r.t., 24 h.
OBn
7 (cis/trans ca. 1:1)
OMs
Scheme 1 Carreira’s synthesis of 6-oxa-3-azabicyclo[3.1.1]heptane
2b utilizing Chung’s disubstituted oxetane 7. Reagents and condi-
tions: (a) allylmagnesium bromide, Et2O, 0 °C to reflux; (b) MCPBA,
CH2Cl2, 0 °C, 12 h; (c) Bu3SnOMe, 120 to 220 °C, 3 h; (d) H2, 20%
Pd(OH)2, MeOH, 1.2 bars, 2 h; (e) MsCl, pyridine, 0 °C to r.t., over-
night; (f) piperonylamine, dioxane, reflux, 16 h.
The final transformation of this process involved removal
of the 4-methoxybenzyl (PMB) moiety. Initially, this
transformation proved to be challenging. For instance, ex-
posure of amine 13 to either trifluoroacetic acid15 or ceri-
um(IV) ammonium nitrate16 gave rise to a complex
mixture of products. Conversely, hydrogenolysis of 13
[H2, Pd(OH)2, MeOH, 3.45 bars, 24 h] gave no reaction.
Interestingly, treatment of 13 under transfer hydrogena-
tion conditions [H2, Pd(OH)2, cyclohexene, MeOH, re-
flux, 24 h] initially gave a trace of the desired product
(based on the 500 MHz 1H NMR spectrum), but the prod-
uct appeared to decompose as the reaction progressed.
Suspecting that the amine may be unstable toward the cat-
alyst, the reaction was repeated in the presence of di-tert-
butyl dicarbonate (Scheme 3). Under these conditions,
amine 13 was smoothly transformed into Boc-protected
amine 14. Treatment of carbamate 14 with hydrogen chlo-
ride in diethyl ether gave rise to a new compound; unfor-
tunately, spectral data of the crude product were
inconsistent with a symmetrical molecule. High-resolu-
( )-epichlorohydrin gave rise (92%) to imine 8. Sodium
borohydride reduction of imine 8 in methanol afforded a
94% yield of the known amino alcohol 9.12 In the original
synthesis of amino alcohol 9, ( )-epichlorohydrin was
treated with 4-methoxybenzylamine to give 9 directly;12
however, in our hands, the two-step process provided ma-
terial of higher purity and better overall yield, especially
on larger scale. Subjection of amino alcohol 9 to chloro-
acetyl chloride under Schotten–Baumann conditions ini-
tially provided an a-chloroamide, which upon exposure to
concentrated aqueous sodium hydroxide effected ring clo-
sure, furnishing a 73% yield of morpholinone 10. It is in-
teresting to note that under these conditions less than 10%
of epoxide 11 was formed. Similar results have been ob-
served by others on a related system.13 Bridged bicyclic
morpholinone 12 was realized in 83% yield via an in-
tramolecular cyclization reaction. Thus, treatment of a
Synthesis 2011, No. 16, 2619–2624 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Oxa-3-azabicyclo[3.1.1]heptane
2621
tion mass spectrometry and 1D NMR experiments con- 1H and 13C NMR spectra were collected on either a Varian Inova
500 with a 5 mm 4NG probe at 25 °C or a Varian Inova 400 with a
5 mm DBG probe at 25 °C relative to TMS (d = 0.0). HRMS were
firmed the new compound as chlorohydroxypiperidine 15.
Additional 2D NMR experiments were consistent with the
acquired on an Agilent 1200 LCMS TOF with UV detection. IR
hydroxy group and chlorine atom possessing a trans-rela-
spectra and combustion analyses were performed by QTI Intertek,
tionship (data not shown). The trans-orientation possibly
Whitehouse, NJ. Melting points were recorded on a Thomas Hoover
arises via a stereospecific acid-catalyzed oxetane ring
melting point apparatus and are uncorrected. Reactions were moni-
tored by TLC using Analtech silica gel GF 250 micron plates. The
plates were visualized either by UV inspection or by staining with
an (NH4)2MoO4/Ce(SO4)2 mixture. Flash chromatography was per-
formed on a Biotage unit or glass column using EMD silica gel
(230–400 mesh). All reagents were purchased from the Aldrich
Chemical Co. and used without further purification. All solvents
were HPLC grade unless otherwise stated. Anhydrous solvents
were purchased from EMD Chemical Co. and used as supplied.
opening by chloride ion.17
HO
Boc
H
a
b
N
NH⋅HCl
13
H
87%
41%
O
Cl
15
14
Scheme 3 Reagents and conditions: (a) cyclohexene, Boc2O,
Pd(OH)2, MeOH, reflux, 1.5 h; (b) HCl, Et2O–dioxane, r.t., 48 h.
( )-(E)-1-Chloro-3-(4-methoxybenzylideneamino)propan-2-ol
(8)
To a mechanically stirred mixture of 4-methoxybenzaldehyde (60.6
mL, 0.500 mol) in t-BuOMe (500 mL) and 28% aq NH3 (50.7 mL,
0.75 mol) in a 2-L, 3-neck round bottom flask equipped with a drop-
Fortunately, the challenges associated with removing the
4-methoxybenzyl group were resolved in a straightfor-
ward manner. Toward this end, hydrogenolysis of amine ping funnel was added dropwise racemic epichlorohydrin (39.2 mL,
0.500 mol). The mixture was stirred at r.t. (22 °C) for 18 h. Addi-
tional 28% aq NH3 (20 mL, 0.30 mol) and racemic epichlorohydrin
(20 mL, 0.255 mol) were added, and stirring at r.t. was continued for
an additional 4 h. The layers were separated, and the organic layer
was concentrated in vacuo to a thick oil. Heptane (500 mL) was
slowly added to a vigorously stirred soln of the above oil in t-
BuOMe (450 mL), which caused a white precipitate to form. The
13 in the presence of one equivalent of 4-toluenesulfonic
acid gave rise (84%) to bicyclic morpholine 2a·TsOH
(Scheme 4). Spectral data of 2a·TsOH were in complete
agreement with the desired product. As further proof of
structure, reductive amination of piperonal in the presence
of 2a·TsOH afforded tertiary amine 2b. The spectral prop-
erties of our 2b were consistent with 2b reported by mixture was stirred for 18 h at r.t., followed by cooling to 0 °C. The
Carreira.10
precipitate was filtered and washed with heptane. The precipitate
was dried in vacuo to afford 8 as an off-white solid; yield: 105.2 g
(92%); mp 68–70 °C; Rf = 0.19 (EtOAc–hexanes, 30:70).
⋅TsOH
a
b
IR (film): 3151, 2937, 2842, 1640, 1608, 1257, 1174, 1027, 842,
816 cm–1.
NH
2b
13
84%
81%
O
1H NMR (500 MHz, DMSO-d6): d = 8.25 (s, 1 H), 7.69 (d, J = 8.66
Hz, 2 H), 6.99 (d, J = 8.79 Hz, 2 H), 5.25 (d, J = 5.40 Hz, 1 H),
3.95–3.88 (m, 1 H), 3.80 (s, 3 H), 3.71 (dd, J = 10.98, 4.63 Hz, 1 H),
3.66 (ddd, J = 11.96, 5.49, 1.22 Hz, 1 H), 3.59 (dd, J = 10.98, 5.61
Hz, 1 H), 3.55 (ddd, J = 11.96, 5.98, 0.86 Hz, 1 H).
2a⋅TsOH
Scheme 4 Reagents and conditions: (a) H2, Pd(OH)2, TsOH·H2O,
MeOH, 3.45 bars, 36 h; (b) piperonal, NaBH(OAc)3, i-Pr2NEt,
CH2Cl2, r.t., 48 h.
13C NMR (125 MHz, DMSO-d6): d = 161.6, 161.2, 129.5, 128.9,
114.0, 70.13, 63.63, 55.26, 48.12.
HRMS (ESI): m/z [M + H]+ calcd for C11H15ClNO2: 228.0786;
found: 228.0788.
Because the oxetane ring in 14 was found to be unstable
towards dry hydrogen chloride (Scheme 3), we were
somewhat concerned about the chemical stability of the
oxetane ring in the gut for per oral dosed analogues pos-
sessing morpholine 2a. However, we were pleased to find
that analogue 2b was stable in simulated gastric fluid (t1/2
>370 min).18 Furthermore, compound 13 was stable to 1.0
M aqueous hydrochloric acid at 60 °C for 30 minutes.19
Thus, based on two examples, the oxetane ring appears to
possess reasonable stability towards dilute aqueous hy-
drochloric acid.
Anal. Calcd for C11H14ClNO2 (227.7): C, 58.02; H, 6.20; N, 6.15.
Found: C, 57.84; H, 6.09; N, 6.03.
( )-1-Chloro-3-(4-methoxybenzylamino)propan-2-ol (9)
To a stirred soln of imine 8 (50.0 g, 0.22 mol) in MeOH (500 mL)
at 0 °C was added NaBH4 (10.0 g, 0.26 mol) in small portions. After
complete addition, the reaction was stirred at 0 °C for 1 h. The re-
action was quenched at 0 °C with 1.0 M aq HCl (250 mL); the pH
of the mixture was ca. 8. (Note: It is important to maintain the pH
>5. In one run, a significant amount of decomposition occurred
when the pH was adjusted to <4.) The mixture was concentrated to
a volume of ca. 250 mL of liquid. The mixture was basified with 6.0
M aq NaOH soln until pH 13. The aqueous layer was extracted with
EtOAc (2 × 250 mL). The organic layer was washed with brine,
dried (anhyd MgSO4), filtered, and concentrated in vacuo to afford
9 as a white solid; yield: 47.6 g (94%); mp 71–73 °C; Rf = 0.14
(EtOAc).
In summary, we have developed a concise, gram-scale
synthesis of 6-oxa-3-azabicyclo[3.1.1]heptane hydrotosy-
late (2a·TsOH). The six-step synthesis features straight-
forward chemistry starting from inexpensive ( )-
epichlorohydrin. Given the structural similarities between
2a and morpholine, and the physicochemical and in vitro
pharmacokinetic similarities of analogue 2b to that of
morpholine analogue 1, it is anticipated that bicyclic mor-
pholine 2a will become a useful building block and mor-
pholine isostere in medicinal chemistry research.
IR (film): 3260, 2906, 2757, 1611, 1252, 1031, 832, 809 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.24 (d, J = 8.24 Hz, 2 H), 6.88 (d,
J = 8.55 Hz, 2 H), 3.90–3.85 (m, 1 H), 3.81 (s, 3 H), 3.76 (ABq,
JAB = 13.05 Hz, DnAB = 12.83 Hz, 2 H), 3.55 (d, J = 5.37 Hz, 2 H),
Synthesis 2011, No. 16, 2619–2624 © Thieme Stuttgart · New York

2622
D. G. Wishka et al.
PAPER
3-(4-Methoxybenzyl)-6-oxa-3-azabicyclo[3.1.1]heptan-2-one
2.83 (dd, J = 12.33, 3.91 Hz, 1 H), 2.70 (dd, J = 12.33, 7.93 Hz, 1
H), 2.75–2.60 (br s, 2 H).
(12)
To a stirred soln of chloride 10 (2.55 g, 9.45 mmol) in anhyd THF–
toluene (90 mL, 1:1) at 0 °C under argon was added dropwise 1.0 M
KHMDS in THF (18.9 mL). [Note: The color of the KHMDS soln
(Aldrich brand) was light yellow. In one run, where the KHMDS
was dark yellow, the yield dropped to 64%.] The mixture was
stirred at 0 °C for 1.5 h. The reaction was quenched with sat. aq
NH4Cl soln (50 mL), followed by stirring for 1 h at 0 °C. The insol-
uble material was removed by filtration, and the filter cake was
washed with EtOAc (25 mL). The filtrate layers were separated, and
the aqueous layer was extracted with EtOAc (25 mL). The organic
layer was dried (anhyd Na2SO4), filtered, and concentrated in vac-
uo. The crude product was purified by flash chromatography (silica
gel, Biotage, 100 g SNAP cartridge, EtOAc–heptane, 12:88 →
100:0) to afford 12 as a white solid; yield: 1.83 g (83%); mp 87–89
°C; Rf = 0.19 (hexanes–EtOAc, 30:70).
13C NMR (125 MHz, CDCl3): d = 158.8, 131.7, 129.3, 113.9, 69.40,
55.25, 53.09, 51.33, 47.38.
HRMS (ESI): m/z [M + H]+ calcd for C11H17ClNO2: 230.0942;
found: 230.0937.
Anal. Calcd for C11H16ClNO2 (229.7): C, 57.51; H, 7.02; N, 6.10.
Found: C, 57.30; H, 7.07; N, 5.97.
6-(Chloromethyl)-4-(4-methoxybenzyl)morpholin-3-one (10)
and 2-Chloro-N-(4-methoxybenzyl)-N-(oxiran-2-ylmethyl)acet-
amide (11)
To a rapidly stirred mixture of amine 9 (24.6 g, 0.107 mol) in
CH2Cl2 (250 mL) and 1.0 M aq NaOH (118 mL, 0.118 mol) at 0 °C
was added dropwise a soln of chloroacetyl chloride (8.95 mL, 0.112
mol) in CH2Cl2 (50 mL). After complete addition, the mixture was
stirred at 0 °C for 1 h, followed by warming to r.t.. Concd 10.0 M
aq NaOH (80 mL, 0.800 mol) was added, and the mixture was rap-
idly stirred for 4 h. The mixture was diluted with H2O (120 mL) and
the layers were separated. The aqueous layer was extracted with
CH2Cl2 (150 mL). The combined organic layers were washed with
H2O, dried (anhyd MgSO4), filtered, and concentrated in vacuo to a
light-yellow oil. The crude product was purified by chromatography
(silica gel, Biotage, 325 g SNAP cartridge, heptane–EtOAc, gradi-
ent 7:93 → 60:40) to afford epoxide 11; further elution afforded
morpholinone 10.
IR (film): 3260, 2906, 2837, 1651, 1252, 1177, 1091 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.22 (d, J = 8.79 Hz, 2 H, HAr),
6.86 (d, J = 8.66 Hz, 2 H, HAr), 4.85–4.81 (m, 1 H, H5), 4.74 and
4.43 (ABq, J = 14.65 Hz, 1 H, ArCH2N), 4.52 (dd, J = 6.46, 3.91
Hz, 1 H, H1), 3.80 (s, 3 H, Ar-OCH3), 3.63 (dd, J = 11.96, 2.93 Hz,
1 H, H4eq), 3.36 (dt, J = 9.03, 6.59 Hz, 1 H, H7exo), 3.25 (d,
J = 11.84 Hz, 1 H, H4ax), 2.09 (d, J = 9.03 Hz, 1 H, H7endo).
13C NMR (125MHz, CDCl3): d = 170.8, 159.1, 129.5, 128.3, 114.1,
80.37, 79.07, 55.24, 48.81, 47.30, 33.67.
HRMS (ESI): m/z [M + H]+ calcd for C13H16NO3: 234.1125; found:
234.1122.
Morpholinone 10
Colorless oil; yield: 21.0 g (73%); Rf = 0.28 (hexanes–EtOAc, 1:1).
IR (film): 2915, 2837, 1648, 1243, 1029, 819 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.21 (d, J = 8.66 Hz, 2 H), 6.87 (d,
J = 8.66 Hz, 2 H), 4.56 (ABq, JAB = 14.40 Hz, DnAB = 78.38 Hz, 2
H), 4.31 (ABq, JAB = 16.60 Hz, DnAB = 63.14 Hz, 2 H), 3.97–3.93
(m, 1 H), 3.81 (s, 3 H), 3.58 (dd, J = 11.60, 5.37 Hz, 1 H), 3.49 (dd,
J = 11.59, 5.98 Hz, 1 H), 3.31–3.22 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 166.0, 159.3, 129.7, 127.8, 114.2,
72.83, 67.72, 55.26, 49.03, 47.86, 43.35.
Anal. Calcd for C13H15NO3 (233.3): C, 66.93; H, 6.48; N, 6.00.
Found: C, 66.93; H, 6.32; N, 5.94.
3-(4-Methoxybenzyl)-6-oxa-3-azabicyclo[3.1.1]heptane (13)
To a stirred soln of 12 (4.20 g, 18.0 mmol) in THF (100 mL) at 0 °C
under argon atmosphere was added dropwise 2.0 M BH3·SMe2
complex in THF (22.5 mL). After complete addition, the mixture
was allowed to slowly warm to r.t. and stir overnight. The mixture
was cooled to 0 °C, and MeOH (20 mL) was added dropwise. After
complete addition, the mixture was allowed to warm to r.t. and stir
for 30 min. The solvent was removed in vacuo to afford a viscous
oil. 1.0 M aq HCl (50 mL) was added, and the mixture was heated
to 60 °C for 30 min (Note: heating to >65 °C resulted in the forma-
tion of an unidentified impurity that complicated the subsequent hy-
drogenolysis reaction). The mixture was cooled to r.t., and the pH
was adjusted to 13 with concd aq NaOH. The aqueous layer was ex-
tracted with EtOAc (5 × 50 mL). The combined organic layers were
washed with brine, dried (anhyd MgSO4), filtered, and concentrated
in vacuo to an oil. The crude product was purified by flash chroma-
tography (silica gel, acetone–hexanes, 20:80) to afford 13 as a col-
orless oil; yield: 2.80 g (71%); Rf = 0.31 (hexanes–EtOAc, 30:70).
Note: this oil was stored under argon at 0 °C as it turns yellow when
exposed to the air for prolonged periods (>24 h).
HRMS (ESI): m/z [M + H]+ calcd for C13H17ClNO3: 270.0891;
found: 270.0889.
Anal. Calcd for C13H16ClNO3 (269.7): C, 57.89; H, 5.98; N, 5.19.
Found: C, 57.86; H, 6.00; N, 5.12.
Epoxide 11
Colorless oil; yield: 2.0 g (7.0%); Rf = 0.36 (hexanes–EtOAc).
1H NMR (500 MHz, DMSO-d6): 2 rotomers present (2:1): d = 7.19
(d, J = 8.54 Hz, 0.67 H), 7.18 (d, J = 8.55 Hz, 1.34 H), 6.93 (d,
J = 8.54 Hz, 0.67 H), 6.89 (d, J = 8.55 Hz, 1.34 H), 4.64 (d,
J = 14.76 Hz, 0.33 H), 4.58 (ABq, JAB = 16.60 Hz, DnAB = 29.27
Hz, 0.67 H), 4.48 (ABq, JAB = 13.55 Hz, DnAB = 9.80, 1.34 H),
4.45–4.41 (m, 1.67 H), 3.74 (s, 1 H), 3.73 (s, 2 H), 3.66 (dd,
J = 15.99, 2.69 Hz, 0.67 H), 3.53 (dd, J = 14.28 Hz, 0.33 H), 3.30–
3.20 (m, 1 H), 3.14 (m, 0.67 H), 3.01 (m, 0.33 H), 2.74 (t, J = 4.40
Hz, 0.67 H), 2.65 (t, J = 4.52 Hz, 0.33 H), 2.57 (dd, J = 4.63, 2.68
Hz, 0.67 H), 2.44 (dd, J = 4.89, 2.57 Hz, 0.33 H).
13C NMR (125 MHz, DMSO-d6): 2 rotomers present (2:1):
d = 166.4, 165.4, 158.7, 158.5, 129.3, 129.1, 129.0, 128.4, 114.1,
113.8, 72.20, 66.88, 55.05, 55.01, 50.92, 50.04, 49.36, 48.39, 47.32,
44.70, 44.63, 42.14.
IR (film): 2957, 2805, 1611, 1240 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.25 (d, J = 8.42 Hz, 2 H), 6.89
(d, J = 8.67 Hz, 2 H), 4.40 (d, J = 6.10 Hz, 2 H), 3.74 (s, 3 H), 3.64
(s, 2 H), 3.94 (d, J = 11.47 Hz, 2 H), 3.83 (dd, J = 7.42, 6.46 Hz, 1
H), 2.62 (d, J = 11.27 Hz, 2 H), 2.25 (d, J = 7.69, Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 158.2, 130.1, 129.8, 113.5,
78.73, 59.64, 54.95 (2 C), 29.98.
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO2: 220.1332; found:
220.1325.
HRMS (ESI): m/z [M + H]+ calcd for C13H17ClNO3: 270.0891;
found: 270.0894.
%Water (KF): 0.43.
Anal. Calcd for C13H17NO2·0.43 H2O: C, 70.89; H, 7.83; N, 6.36.
Found: C, 70.74; H, 7.79; N, 6.30.
Synthesis 2011, No. 16, 2619–2624 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Oxa-3-azabicyclo[3.1.1]heptane
2623
6-Oxa-3-azabicyclo[3.1.1]heptane Hydrotosylate (2a·TsOH)
Amine 13 (1.1 g, 5.0 mmol), TsOH·H2O (950 mg, 5.0 mmol), and
20% Pd(OH)2 on activated carbon (220 mg) in MeOH (50 mL) was
placed in a Parr bottle and hydrogenated at 3.45 bars for 36 h. The
mixture was filtered through Celite, and the filter cake was washed
with MeOH (40 mL). The filtrate was concentrated in vacuo to a
semisolid. Trituration of the semisolid in EtOAc (20 mL) afforded
a white precipitate. The precipitate was filtered, washed with
EtOAc (20 mL), and dried in vacuo to afford 2a·TsOH as a white
solid; yield: 1.14 g (84%); mp 268–270 °C.
13C NMR (125 MHz, CDCl3): d = 156.1, 79.73, 78.04, 77.87, 48.58,
47.81, 31.76, 28.45.
HRMS (ESI): m/z [M + Na]+ calcd for C10H17NO3Na: 222.1107;
found: 222.1101.
trans-5-Chloropiperidin-3-ol Hydrochloride (15)
To a stirred soln of 14 (240 mg, 1.2 mmol) in Et2O (5.0 mL) was
added dry 4.0 M HCl in dioxane (1.0 mL). The soln was stirred at
r.t. for 48 h. The precipitate was filtered, washed with Et2O and
dried in vacuo to afford 15 as a white solid; yield: 85 mg (41%).
1H NMR (500 MHz, DMSO-d6): d = 9.7–9.1 (br s, 2 H), 5.60 (br s,
1 H), 4.55–4.45 (m, 1 H), 4.10–4.05 (m, 1 H), 3.37 (dd, J = 12.49,
3.91 Hz, 1 H), 3.12–3.03 (m, 2 H), 2.93 (dd, J = 12.68, 4.88 Hz, 1
H), 2.19–2.10 (m, 1 H), 2.01–1.94 (m, 1 H).
IR (film): 3008, 2816, 1611, 1186 cm–1.
+
1H NMR (500 MHz, DMSO-d6): d = 9.6–9.1 (br s, 2 H, NH2 ), 7.50
(d, J = 7.93 Hz, 2 H, HAr), 7.12 (d, J = 7.93 Hz, 2 H, HAr), 4.57 (d,
J = 6.71 Hz, 2 H, H1, H5), 3.43 (d, J = 13.06 Hz, 2 H, H2eq, H4eq),
3.36 (d, J = 12.87 Hz, 2 H, H2ax, H4ax), 3.20 (dd, J = 9.64, 7.20 Hz,
1 H, H7exo), 2.29 (s, 3 H, Ar-CH3), 2.06 (d, J = 9.88 Hz, 1 H, H7endo).
HRMS (ESI): m/z [M + H]+ calcd for C5H11ClNO: 136.0524; found:
136.0520.
13C NMR (125 MHz, DMSO-d6): d = 145.4, 137.8, 128.1, 125.5,
76.98, 45.64, 28.84, 20.77.
HRMS (ESI): m/z [M + H]+ calcd for C5H10NO: 100.0762; found:
100.0757.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Anal. Calcd for C12H17NO4S (271.3): C, 53.12; H, 6.32; N, 5.16.
Found: C, 52.96; H, 6.35; N, 4.98.
Acknowledgment
We thank David R. Anderson and Antonia F. Stepan of Pfizer for
helpful discussions during the preparation of this manuscript. We
thank Jonathan N. Bauman of Pfizer for analytical support.
3-(1,3-Benzodioxol-5-ylmethyl)-6-oxa-3-azabicyclo[3.1.1]hep-
tane (2b)
To a stirred soln of 2a·TsOH (271 mg, 1.0 mmol), piperonal (167
mg, 1.1 mmol), and i-Pr2NEt (0.191 mL, 1.1 mmol) in CH2Cl2 (10
mL) at r.t. was added NaBH(OAc)3 (780 mg, 3.5 mmol). The turbid
mixture was stirred for 48 h. Sat. aq Na2CO3 (10 mL) was added,
and the mixture was vigorously stirred for 2 h. The layers were sep-
arated, and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were dried (anhyd K2CO3), filtered, and
concentrated in vacuo to an oil. The oil, dissolved in MeOH (10
mL), was treated with TsOH (225 mg, 1.15 mmol). The mixture was
concentrated in vacuo to a solid. The solid was partitioned between
Et2O (10 mL) and H2O (10 mL) (to remove excess piperonal). The
aqueous layer was extracted with Et2O (10 mL). The aqueous layer
was poured into sat. Na2CO3 soln (10 mL) and extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried (an-
hyd K2CO3), filtered, and concentrated in vacuo to afford 2b as a
colorless oil; yield: 192 mg (81%).
1H NMR (500 MHz, CDCl3): d = 6.89 (d, J = 1.46 Hz, 1 H), 6.79
(dd, J = 7.81, 1.58 Hz, 1 H), 6.75 (d, J = 7.82 Hz, 1 H), 5.94 (s, 2
H), 4.49 (d, J = 6.11 Hz, 2 H), 3.67 (s, 2 H), 3.04 (d, J = 11.23 Hz,
2 H), 3.00 (q, J = 7.69 Hz, 1 H), 2.78 (d, J = 11.59 Hz, 2 H), 2.41
(d, J = 7.81 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 147.6, 146.5, 132.6, 121.7, 109.1,
107.8, 100.8, 80.11, 60.70, 55.31, 30.51.
References and notes
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tert-Butyl 6-Oxa-3-azabicyclo[3.1.1]heptane-3-carboxylate (14)
Compound 13 (233 mg, 1.1 mmol), Boc2O (464 mg, 2.2 mmol),
20% Pd(OH)2 on activated carbon (233 mg), and cyclohexene (6.7
mL) in MeOH (25 mL) were placed in a 100-mL flask and heated
to reflux for 1.5 h. The mixture was filtered through Celite, and the
filter cake was washed with MeOH. The filtrate was concentrated in
vacuo to afford an oil. The crude product was purified by column
chromatography (silica gel, Biotage, 25 g SNAP cartridge, EtOAc–
heptane, 12:88 → 100:0) to afford 14 as a colorless oil; yield: 184
mg (87%); Rf = 0.25 (hexanes–EtOAc, 1:1).
IR (film): 2977, 2873, 1680, 1170 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.62 (m, 1 H), 4.55 (m, 1 H), 3.65–
3.60 (m, 3 H), 3.56 (dd, J = 12.81, 1.22 Hz, 1 H), 3.17 (q, J = 6.59
Hz, 1 H), 1.86 (d, J = 8.90 Hz, 1 H), 1.49 (s, 9 H).
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Synthesis 2011, No. 16, 2619–2624 © Thieme Stuttgart · New York

2624
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Synthesis 2011, No. 16, 2619–2624 © Thieme Stuttgart · New York