Synthesis and Properties of 2-Oxa-6-azaspiro[3.3]heptane Sulfonate Salts

Article abstract of DOI:10.1055/s-0036-1588733

An improved synthesis of the bicyclic spiro compound 2-oxa-6-azaspiro[3.3]heptane is presented. While this compound is often isolated as an oxalate salt, its isolation as a sulfonic acid salt yields a more stable and more soluble product. With these improved properties access to a wider range of reaction conditions with the spirobicyclic 2-oxa-6-azaspiro[3.3]heptane has been enabled.

Full text of DOI:10.1055/s-0036-1588733

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
A
psp
Synthesis
R. N. van der Haas et al.
PSP
Synthesis and Properties of 2-Oxa-6-azaspiro[3.3]heptane Sulfon-
ate Salts
Richard N. S. van der Haas*a
Jeroen A. Dekkera
Jorma Hassfeldb
Anastasia Hagerb
Peter Feyb
Philipp Rubenbauerb
Eric Damena
Br
Br
OH
Br
O
NH2
RSO –
3 steps
3
50% yield
stable
soluble
scalable
a
Mercachem Process Research B.V., Kerkenbos 1013,
6
546BB Nijmegen, The Netherlands
b
Bayer Pharma AG, Chemical Development Wuppertal,
Friedrich-Ebert-Strasse 217–333, 42117 Wuppertal,
Germany
Richard.vanderHaas@mercachem.com
Received: 13.12.2016
Accepted after revision: 31.01.2017
Published online: 02.03.2017
alate salt 4a. The first literature example utilizing this ap-
proach describes an experiment on a five gram scale, which
yielded the hemioxalate salt 4a in 81% yield.
DOI: 10.1055/s-0036-1588733; Art ID: ss-2016-t0855-psp
Abstract An improved synthesis of the bicyclic spiro compound 2-oxa-
HO
Br
Br
Br
KOH
6-azaspiro[3.3]heptane is presented. While this compound is often iso-
O
N
Tos
EtOH
SO NH
2
2
lated as an oxalate salt, its isolation as a sulfonic acid salt yields a more
stable and more soluble product. With these improved properties ac-
cess to a wider range of reaction conditions with the spirobicyclic 2-
oxa-6-azaspiro[3.3]heptane has been enabled.
1b
2
3
Mg
C2H2O4
COOH
COOH
O
NH
O
NH ·
MeOH
sonication
Et2O/EtOH
Key words azetidines, oxetanes, spiro compounds, hydrogenolysis,
salt formation
4
4a
Scheme 1 Preparation of 2-oxa-6-azaspiro[3.3]heptane oxalate salt
(
4a) via the method developed by Carreira et al.
Introduction
Recently, the increasing need for three dimensionally
shaped heterocyclic ring systems resulted in a rapidly
growing interest in the application of the 6-oxa-2-
azaspiro[3.3]heptane fragment as a building block for new
However, the scalability of this process to a scale bigger
3
than one kilogram of the oxalate 4a is challenging. Specifi-
cally the removal of magnesium salts by filtration was
found to be sluggish and a lot of the product was lost at this
stage. Already on a 100 g scale, the oxalate salt 4a was iso-
lated in yields of only 47% or less. Moreover, as the literature
also points out, the oxalate product may contain partially
hydrated oxalic acid, which hampers an easy determination
of the actual content of 2-oxa-6-azaspiro[3.3]heptane oxa-
late.4b At the same time, complex equipment is required for
the sonication conditions used in the deprotection step.
1,2
drug candidates. For instance, this moiety was reported to
be a structural surrogate for morpholine in a number of
3
drug-like molecules.
Until recently, 2-oxa-6-aza-
spiro[3.3]heptane (4) was usually prepared from tribromo-
pentaerythritol (1b) (also known as FR-513, a commercially
available flame retardant) via the method first described by
4
Carreira et al. (Scheme 1). This route involves a cyclization
5
reaction under basic conditions with p-toluenesulfonamide
A patent application describes a variation of a 100 g
(
2) towards the N-tosylated spiro compound 3, followed by
scale experiment in which the use of sonication in the
deprotection step is replaced by refluxing in methanol. The
magnesium is then added in portions, to avoid a too strong
exothermic effect and after completion of the reaction the
magnesium salts are removed in a similar manner as de-
scribed above. Additionally, the application describes inves-
tigations towards alternative acids for the salt formation
step including hydrochloric acid, p-toluenesulfonic acid,
and acetic acid (Scheme 2).
removal of the tosyl group. The deprotection step is per-
formed by sonication of a mixture of intermediate 3 and
magnesium turnings in methanol at room temperature
during a period of one hour. A sluggish filtration to remove
the magnesium salts formed in the deprotection reaction
and treatment of the filtrate with oxalic acid affords the ox-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
Synthesis
R. N. van der Haas et al.
PSP
Mg
Brønsted acid
dure (Scheme 3). Ultimately, this approach was proven on
scale, and a total of 65 kg of the oxalate salt 4a was pre-
pared in two batches. Interestingly, this route involves pre-
cipitation of the crude benzyl protected 2-oxa-6-
azaspiro[3.3]heptane with HCl yielding the bench-stable
O
N
Tos
O
NH
MeOH/MTBE
MeOH
reflux
3
4
C2H2O4 (1 equiv)
AcOH (1 equiv)
HCl (1 equiv)
COOH
O
O
O
O
NH ·
6
COOH
HCl salt 6c. Also in our hands, this approach was proven to
4
a
work well and no significant oxetane ring opening reaction
was observed during the precipitation step.1 The authors
did not comment in detail on the moderate yield in com-
pound 6c, but it is likely that concurrent formation of unde-
sired 3,3-bis(benzylaminomethyl)oxetane (7) as side prod-
uct is the major cause (Scheme 4).
,5
NH ·AcOH
4b
HO
Cl
NH ·HCl
NH
4c
formed instead
PTSA (1 equiv)
Bn
NH ·PTSA
Br BnNH2
N
H
O
O
N
Bn
O
4d
base
Br
NH
5b
6
7
Bn
Scheme 2 Preparation of salts from 2-oxa-6-azaspiro[3.3]heptane (4)
described in the patent literature
Scheme 4 Reaction products from the amination of 3,3-bis(bro-
momethyl)oxetane (5b) with benzylamine
According to this patent application, both HCl and p-tol-
uenesulfonic acid proved to be unsuccessful. In the case of
p-toluenesulfonic acid, a viscous undefined material was
obtained while HCl resulted in ring opening of the oxetane
In a recent project, driven by a demand for large quanti-
ties of 2-oxa-6-azaspiro[3.3]heptane (4), we initially pre-
pared the compound on a multi-kilogram scale utilizing the
reductive removal of the tosyl protective group in com-
pound 3. In line with the reported observations, we also
struggled with a tedious workup procedure. Thus, to im-
prove the protocol, we decided to explore alternative pro-
tecting groups involved in the preparation of compound 4
anticipating a high impact. In addition, the follow-up chem-
istry revealed challenges related to thermal decomposition
and a poor solubility of the oxalate 4a. Moreover, it was dif-
ficult to follow the reaction progress and the reaction could
only be performed in a limited concentration range. For
these reasons, the evaluation of different non-oxalate salts
became a topic of interest.
moiety.
However,
using
acetic
acid,
2-oxa-6-
azaspiro[3.3]heptane acetate (4b) was isolated in 86% yield
on a 100 g scale, by simply evaporating a solution of the
amine in methanol and acetic acid. Compared with the oxa-
late (yield 67%) a slightly better product yield was obtained,
but a major advantage of the acetate salt was that the com-
position of the isolated material could now be determined
1
via H NMR spectroscopy. In addition, it is much easier to
remove an excess of acetic acid by (co-)evaporation.
In a recent paper, the authors describe that in an at-
tempt to scale up the original procedure for the preparation
of oxalate 4a, the reductive removal of the tosyl protecting
group from intermediate 3 at 100 L scale turned out to be
In this article, we describe a new scalable and reliable
synthetic procedure for the preparation of spiro compound
4 utilizing sulfonate salts. Also the stability of the isolated
sulfonate salts in methanol and their application has been
investigated in a model reaction.
3
even more problematic. Though conversion was good,
much material was lost during the workup, and low yields
(<35%) of poor quality material were observed. For this rea-
son, the authors switched to a benzyl-protecting group,
leading to a more operable deprotection and workup proce-
Bn-NH2
Bu4N HSO4
aq NaOH
Bu4N HSO4–
+
+
–
HO
Br
Br
Br
Br
Br
HCl
aq NaOH
O
O
N
Bn
O
N
·HCl
Bn
toluene
3 °C, 23 h
toluene
83 °C, 20 h
1,4-dioxane
2
1
5b
6
6c
55% (3 steps)
H2 (4 bar)
Pd/C
C2H2O4
aq NaOH
toluene
COOH
O
N
Bn
O
NH
O
NH ·
iPrOH/H2O
5 °C
EtOH
COOH
45 °C, 16 h
6
4
4a
99%
94%
89%
Scheme 3 Recently published synthetic approach for the preparation of 2-oxa-6-azaspiro[3.3]heptane hemioxalate (4a) via benzylamino intermediate 6
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
Synthesis
R. N. van der Haas et al.
PSP
Results and Discussion
amines that were participating in the envisioned cycliza-
tion when stirred with DBU in DMF at 80 °C. The analogues
with o-nosyl- (XVI), p-nosyl- (XV), benzyl (I), and 4-meth-
oxybenzyl (III) as N-protecting group were successfully
prepared on gram scale by cyclization with 3,3-bis(halo-
genmethyl)oxetane 5a or 5b in DMF at 80 °C using DBU as
base. For most of the other amines the preparation of N-
protected 2-oxa-6-azaspiro[3.3]heptanes either failed or
was not investigated because of safety issues or incompati-
ble deprotection conditions.
As depicted in the general route (Scheme 5), it is possi-
ble to prepare the N-protected 2-oxa-6-azaspiro[3.3]hep-
tane 8 in either one or two steps, and both approaches were
investigated. Initially, we investigated 16 different protect-
ing groups using corresponding amines in cyclization reac-
tions towards N-protected 2-oxa-6-azaspiro[3.3]heptanes
(Figure 1). After a series of test experiments, five amines,
including tosyl-, o-nosyl-, p-nosyl-, benzyl-, and 4-meth-
oxybenzylamine, were found suitable for this application
(Table 1).
Table 1 Preparation of N-Protected 2-Oxa-6-azaspiro[3.3]heptane
Derivatives
a,b
H2N PG
KOH
Amine
Oxetane
Yield test scale
Scale-up
Isolated yield
EtOH
reflux
(% area in GCMS) (amount 5a or 5b) (%)
I
5a
5b
5a
5b
5a
5b
5a
5b
5a
5a
5b
64c
68c
70
20 gc
129 gd
–
57
70
–
HO
X
X
X
NaOEt
X
H N PG
2
O
O
N
PG
I
EtOH
reflux
base
X
II
1
1
a : X = Cl
b : X = Br
5a : X = Cl
5b : X = Br
8
0e
II
26
1.0 g
1.0 g
45 g
–
III
III
IV
IV
XV
XVI
81
45
56
–
acid (HX)
56
O
NH
O
NH2 X
deprotection
salt formation
72
4
4a-s
37
–
–
Scheme 5 Two possible approaches towards 2-oxa-6-aza-
–
1.0 g
1.0 g
–
82
73
–
spiro[3.3]heptane and its acid salts
75 (17)f
57 (70)f
O
XVI
H2N
a
H2N
Selected results obtained on 0.35 mmol (test) scale and on larger scale.
Conditions: Reaction vials (8 mL, magnetically stirred, screw capped) were
H2N
b
I
II
III
each charged with 85% pure 3,3-bis(bromomethyl)oxetane (5b; 100 mg,
.348 mmol) or 96% pure 3,3-bis(chloromethyl)oxetane (5a; 64 mg, 0.394
0
O2N
H2N
N
S
mmol) in DMF (1 mL) containing the amine (1.1 equiv) and DBU (2.5 equiv).
The reaction vials were closed and stirred for 18 h at 80 °C. Samples were
taken after 18 h. Sample preparation: 20 μL of each reaction mixture was di-
luted with MeCN (1400 μL). The resulting solution was analyzed by GC/MS.
O
S
H2N
2
H N
S
O
IV
V
VI
c
Reaction performed at 100 °C.
Reaction performed at 60 °C.
Isolation of the allyl protected product failed due to its poor stability.
Yield after 1 h in parentheses.
d
O
H
N
O
OH
e
2
H N
H2N
H2N
f
O
O
VII
VIII
X
It was found that both 3,3-bis(chloromethyl)oxetane
5a) and its bromo analogue 5b are suitable for these syn-
O
O
NH3
H2N
(
H2N
O
H2N
O
XIII
theses, but overall, reactions were much faster with 3,3-
bis(bromomethyl)oxetane (5b). The crude oxetane 5b is
generally obtained in good purity (>90%) but when neces-
sary it may also be purified by distillation (56 °C/0.10
mbar).
IX
XI
XII
NO2
O2N
O
O
O
S
H2N
CF3
S
H2N
H2N
O
O
In the next step, we focused on the preparation of the
benzyl derivative 6, as we expected its deprotection to be
more promising than utilizing sulfonamides using a simple
palladium-catalyzed hydrogenolysis with formation of tol-
uene as a volatile by-product. First, the synthesis of N-ben-
zyl-2-oxa-6-azaspiro[3.3]heptane (6) was screened in order
to investigate the effect of solvents (1,4-dioxane, MeCN, and
DMF), substrate concentration (100 or 50 mg/mL), and base
(DIPEA, K CO , Cs CO , DBU, and K PO ) on the conversion
XIV
XV
XVI
Figure 1 List of amines initially investigated for the cyclization reaction
towards 2-oxa-6-azaspiro[3.3]heptane derivatives
The tosyl-protected analogue could be directly prepared
from erythritol tribromide according to the literature pro-
cedure. Table 1 summarizes the results obtained from the
4b
2
3
2
3
3
4
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Synthesis
R. N. van der Haas et al.
PSP
and selectivity of the reaction. During this screening both
,3-bis(chloromethyl)oxetane (5a) as well as 3,3-bis(bro-
momethyl)oxetane (5b) were investigated as substrates for
the cyclization reaction. Among the bases, DBU showed the
best performance with respect to conversion and selectivity
for the target compound. The experiments performed in
tably, both salts from PTSA and methanesulfonic acid were
severely contaminated. The TFA salt could also be prepared
but similar to the acetic acid salt it was very hygroscopic.
Surprisingly, also the HCl salt 4c could be obtained as a
white solid. Upon filtration, however, the appearance rapid-
ly changed from a white solid to a sticky material.
3
1
,4-dioxane and in DMF (at 100 °C) gave better results com-
pared to the reactions performed in MeCN (at 80 °C). Nota-
bly, when the reaction was performed in DMF, potassium
phosphate as base also showed an efficient formation of the
desired cyclization product 6. Moreover, we could also
show that the experiments at higher concentration experi-
ments (100 mg/mL) gave slightly better conversions than
the experiments at 50 mg/mL with only a little loss in selec-
tivity. Ultimately, when performing the reaction with 3,3-
bis(bromomethyl)oxetane (5b) at 60 °C still complete con-
version was achieved after stirring overnight.
Table 2 Formation of Salts from 4b at Room Temperature on a 100
mg Scalea
Salt
Acid
oxalic acid
Yield (%)
Appearance
4
4
4
a
c
54
23c
65c
67
56c
–
white powder
sticky solid
HClb
d
PTSA
white powderd
white powder
sticky solid
PTSA (n-BuOH)
TFA
4e
Next, investigations on the debenzylation of N-benzyl-
4
4
f
citric acid
viscous oil
2
-oxa-6-azaspiro[3.3]heptane (6) using Pd on activated car-
g
h
MeSO
3
H
–
viscous oild
bon (10% Pd) under hydrogen atmosphere showed that this
step is best performed under 5 bar hydrogen atmosphere in
methanol with a catalytic amount of acetic acid. After 16
hours of stirring, complete conversion was observed and
the catalyst was filtered off to yield a filtrate containing 2-
oxa-6-azaspiro[3.3]heptane as its free base. Notably, the
hydrogenolysis also worked well on an 8.0 gram scale with
4
camphor sulfonic acid
55
white powder
a
Conditions: To a stirred solution of 2-oxa-6-azaspiro[3.3]heptane acetate
4b; 100 mg) in MeOH (1.0 mL) at r.t. was added 1.1 equivalent of the acid.
(
The resulting mixture was stirred at r.t. for 1.5 h after which precipitates
were filtered off. When no precipitate was formed, the solvent was re-
moved and the residue was triturated with Et
A solution of 3 N HCl in MeOH was used.
2
O (2.0 mL).
b
c
These salts were obtained after concentration and trituration with Et
Contains impurities.
2
O.
d
1.0 equivalent of acetic acid. Concentration and subsequent
trituration in MTBE yielded the product as its acetic acid
salt 6b, which was found to be bench stable upon storage in
a closed vessel under nitrogen atmosphere.
Preparation of the PTSA salt was also tested in n-butanol
as a less polar solvent and indeed, a precipitate was formed
almost immediately after adding the acid and after 1.5
hours, the expected salt was collected by filtration in 67%
yield with good purity. The salt formation with PTSA was
further investigated using a slightly modified procedure.
Additionally the salt formation was also investigated with
nine other acids (Scheme 6, Table 3).
Among the mono acids only the two sulfonate salts 4d
and 4k could directly be filtered off from the reaction mix-
ture and both gave an easy to handle solid in good yield.
The benzoate salt 4j did not precipitate and after trituration
a very hygroscopic material was obtained. No solid could be
isolated from the experiment with mandelic acid. Notably,
at 25 °C the PTSA salt 4d remained in solution, but upon
cooling down also this experiment gave the expected salt in
good yield. This time no ring opening product was ob-
served, probably due to the use of equimolar amounts of
acid.
Except for malic acid all bivalent acids resulted in pre-
cipitation of the expected salts from the reaction mixture.
The benchmark experiment with 0.50 equivalent of oxalic
acid gave the hemioxalate salt 4s in 85% yield while with
1,5-naphthalenedisulfonic acid (Armstrong’s acid) the salt
4r was isolated as a fine crystalline powder in an excellent
94% yield. All other hemi salts were obtained in poor yields
and the isolated salts from sulfuric (4m), fumaric (4n), and
Salt Formation
A
study towards salt formation with 2-oxa-6-
azaspiro[3.3]heptane was started using the isolated acetate
salt. In this study, we aimed for the isolation of a thermally
stable nonhygroscopic crystalline salt with good solubility
(Scheme 6).
HX
O
NH ·AcOH
O
NH2 X
MeOH/MTBE
4b
4a–s
Scheme 6 Preparation of salts from 2-oxa-6-azaspiro[3.3]heptane
In a first experiment, seven different acids (1.1 equiv)
were added to a methanolic solution of acetate salt 4b at
room temperature (Scheme 6, Table 2). With oxalic acid (4a,
benchmark) and with camphor sulfonic acid (4h) a precipi-
tate was formed at room temperature in methanol and the
formed solids could simply be filtered off. In all other cases,
methanol was evaporated and the residue was triturated
with MTBE after which the expected salt could be isolated
as solid. Exceptions are the citrate and the methanesulfonyl
salt, which remained as viscous oils (entries 4f and 4g). No-
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
Synthesis
R. N. van der Haas et al.
PSP
Table 3 Formation of Salts from 4b at 0 °C on a 200 mg Scalea
HO
Br
Br
Br
NaOEt
Br H N PG
2
O
O
N PG
EtOH
reflux
Br DBU
Salt
Acid (equiv)
Precipitation at 0 °C Yield (%)
1b
5b
6: PG = Bn
9: PG = PMB
4
4
4
4
4
4
4
4
4
4
d
PTSA (1.0)
yes
noc
no
97
85
0
d
PTSA (1.0)b
Pd/C, H2
AcOH
RSO3H
MeOH
i
R-mandelic acid (1.0)
benzoic acid (1.0)
2-naphthalenesulfonic acid (1.0)
O
NH
O
NH2
MeOH
jd
k
noe
yes
yes
yes
noc
yes
64
76
56f
51f
61f
7f
RSO3–
4
4d,k,r
md
nd
p
2 4
H SO (0.5)
Scheme 7 Synthesis of 2-oxa-6-azaspiro[3.3]heptane sulfonate salts
fumaric acid (0.5)
malic acid (0.5)
In a similar procedure, the PMB-protected 2-oxa-6-
azaspiro[3.3]heptane (9, see Scheme 7) was also prepared
in 56% yield (after distillation). The hydrogenolysis of the
PMB group was found to be successful using one equivalent
of acetic acid. Eventually, the 2-oxa-6-azaspiro[3.3]heptane
compound was isolated as its hemi-naphthalenesulfonate
salt 4r in an overall yield of 41% starting from tribromopen-
taerythritol and 4-methoxybenzylamine.
qd
r
D-tartaric acid (0.5)
1,5-naphthalenedisulfonic acid (0.5) yes
oxalic acid (0.5) yes
94f
86f
4
s
a
Conditions: To a stirred solution of 2-oxa-6-azaspiro[3.3]heptane acetate
4b; 200 mg) in MeOH (2 mL) at 0 °C was added 1 equiv of monoacid or 0.5
(
equiv of diacid as a solution in EtOH (2 mL). The resulting mixture was stirred
at 0 °C for 1 h after which the precipitate was collected by filtration.
b
Salt formation tested at r.t.
c
A solid precipitated after stirring for 30 min at 0 °C.
d
Isolated as hygroscopic salts.
When no precipitate was formed, the mixture was concentrated and the
e
Stability Studies
residue was triturated with MTBE (3 mL).
f
Assumed to be the hemi salt.
It was mentioned in literature that differential scanning
calorimetry (DSC) analysis of the oxalate salt as well as the
free base indicated that both compounds exhibit a relatively
low thermostability with significant heat release (>1000
tartaric acid (4q) were slightly hygroscopic. After removal
of the solvent, the malic acid salt 4p could be isolated as a
dry powder via trituration in MTBE.
In conclusion, the 2-oxa-6-azaspiro [3.3]heptane could
easily be isolated as a salt with a number of acids and on
small scale, especially the hemi-1,5-naphthalenedisulfonic
acid salt 4r, the PTSA salt (4d, 97% yield), and hemioxalate
salt (4s, 86% yield) were obtained in excellent yields.
3
J/g). This means that safe working conditions on large scale
should be ensured and for this reason we also investigated
the stability of the isolated sulfonate salts 4d and 4r.
As described above, it was shown that the sulfonate
salts can be isolated as bench stable compounds. However,
since it was also observed that ring opening of the oxetane
ring occurs with an excess of sulfonic acid the amount of
acid should be carefully dosed when preparing these salts.
The question arose if the salt 4d itself is stable and this was
tested on 100 mg scale by stirring it overnight in a methan-
olic solution at reflux temperature. But still the pure and
crystalline PTSA salt 4d could be recovered in 83% yield af-
ter trituration with MTBE.
The thermal stability of the isolated sulfonate salts 4d
and 4r was further investigated by DSC analysis and com-
pared with both the oxalate and the hemioxalate salts 4a
and 4s, respectively. As shown in Figure 2, both sulfonate
salts were stable at temperatures up to 176 °C (4d) and 200
°C (4r). Contrary, the oxalate salts appear to decompose at
much lower temperatures of 145 °C (4a) and 143 °C (hemi
salt 4s) with broad decomposition temperature ranges.
Even the free base was found to be rather unstable (peak at
156 °C, onset around 110 °C). Similar observations were
made using the melting apparatus. While the tosylate salt
initially showed a clear melting point around 182 °C other
compounds were found to decompose around the peak
temperatures observed in the DSC analyses. These stability
Scale-Up
Next, the preparation of 2-oxa-6-azaspiro[3.3]heptane
hemi-naphthalene-1,5-disulfonate salt 4r was scaled up
starting from 200 g of tribromopentaerythritol (Scheme 7).
After distillation of the 3,3-bis(bromomethyl)oxetane, the
subsequent ring closure with benzylamine followed by dis-
tillation yielded N-benzyl-2-oxa-6-azaspiro[3.3]heptane (6)
in good yield (60% in 2 steps) and purity. The hydrogenoly-
sis of N-benzyl-2-oxa-6-azaspiro[3.3]heptane (6) was suc-
cessful on that scale under the conditions described above.
After filtration and partial concentration, treatment with
0.50 equivalent of naphthalene-1,5-disulfonic acid yielded
the desired 2-oxa-6-azaspiro[3.3]heptane as its hemisul-
7
fonate salt in 84% yield with a purity assay of 96%. Overall
the 2-oxa-6-azaspiro[3.3]heptane salt 4r could be prepared
in three steps from tribromopentaerythritol with an un-
precedented overall yield of 50%.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
Synthesis
R. N. van der Haas et al.
PSP
Figure 2 DSC analyses of 2-oxa-6-azaspiro[3.3]heptane (4) and its salts: oxalate 4a, hemioxalate 4s, p-toluenesulfonate 4d, and hemi-naphthalenedi-
sulfonate 4r
observations led to the conclusion that the better solubility
of the sulfonate salts combined with their better stability
should open new perspectives for synthetic applications of
N
N
N
N
DIPEA
O
NH2 X
Cl
O
N
solvent
40 °C
4
d,r,s
10
11
2
-oxa-6-azaspiro[3.3]heptane.
(see Table 4)
Scheme 8 Reaction of 2-oxa-6-azaspiro[3.3]heptane salts with 2-chlo-
ropyrimidine
Application in Synthesis
Table 4 Results from 100 mg Scale Reactions of 4d, 4r, and 4s with 2-
While the oxalate salts are barely soluble in most sol-
vents, it is to be expected that the sulfonate salts have a
wider solvent window for chemical conversions. In the lit-
erature, most reactions performed with both oxalate salts
are usually performed in either highly polar solvents such
Chloropyrimidine in the Presence of DIPEA at 40 °Ca
Salt
Counter ion
Solvent
Conversion (%)b
0 min 66 h
3
2
as DMSO or DMF or in a refluxing less polar solvent. The
88c
4
4
4
4
d
r
PTSA
MeCN
MeCN
MeCN
THF
77
28
0
latter solvents often give rise to poor isolated product
yields. We tested the aromatic nucleophilic substitution re-
action of 2-oxa-6-azaspiro[3.3]heptane sulfonate salts 4d
and 4r and hemioxalate salt 4s (1.0 equiv) with 2-chloropy-
rimidine (10) in acetonitrile using diisopropylethylamine (2
equiv) as base (Scheme 8). Within 30 minutes at 40 °C the
two sulfonate salts indeed showed partial conversion in
acetonitrile while the hemioxalate salt showed no reaction
at all (Table 4). Notably, under these conditions the reaction
mixture with tosylate salt 4d gave a clear solution. After
stirring for 66 hours at room temperature, sulfonate salt 4r
showed full conversion in a clean reaction. The tosylate salt
hemi-naphthalenedisulfonate
98
10
84
62
1
s
hemioxalate
d
PTSA
21
<0.5
0
4r
4s
hemi-naphthalenedisulfonate
THF
hemioxalate
PTSA
THF
4
d
MTBE
17
74
a
Conditions: A mixture of 2-oxa-6-azaspiro[3.3]heptane salt 4d, 4r, or 4s
(100 mg), i-Pr NEt (1.0 equiv), and 2-chloropyrimidine (10; 1.0 equiv) in
2
MeCN (1.0 mL) or THF (1.0 mL) was stirred at 40 °C. Samples (15 μL) were
diluted in MeOH (1.2 mL) and analyzed.
b
Measured as area% by HPLC analysis.
Isolated in 71% yield after aqueous workup.
c
4
d stalled at 88% conversion. Aqueous workup of the reac-
tion with PTSA salt 4r yielded 71% of the expected adduct
1. In contrast, the oxalate 4s still showed only 10% conver-
gave partial conversion, the oxalate gave no reaction at all.
Notably, even in MTBE good conversion was observed with
PTSA salt 4r. These results confirm that most likely the bet-
ter reactivity of the sulfonate salts should be ascribed to
their better solubility in most solvents.
1
sion after 66 hours at 40 °C. Similar results were obtained
when testing the reactions in THF. However, due to a lower
solubility of the three salts in this solvent the reaction
slowed down significantly and while the sulfonate salts
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
Synthesis
R. N. van der Haas et al.
PSP
1
Conclusion
H NMR (CDCl , 400 MHz): δ = 7.33–7.22 (m, 5 H), 4.74 (s, 4 H), 3.54
3
(
s, 2 H), 3.36 (s, 4 H).
1
3
In summary, a robust and scalable preparation of the bi-
cyclic spiro compound 2-oxa-6-azaspiro[3.3]heptane sul-
fonate salts has been presented. In a model reaction, these
sulfonate salts were shown to allow for a wider range of re-
action conditions compared to the commercially available
oxalate salt 4s and among the tested salts PTSA salt 4d
shows the highest reaction rate.
C NMR (DMSO-d , 100 MHz): δ = 138.3 (C), 128.2 (CH), 128.1 (CH),
6
1
26.8 (CH), 80.0 (CH ), 62.9 (CH ), 62.5 (CH ), 38.5 (C).
2 2 2
+
·
+·
MS (EI, 70 eV): m/z (%) = 91.1 (100, [Bn] ), 188 (10, [M – 1] ), 189 (7,
+
·
[
M] ).
6
-(p-Methoxybenzyl)-2-oxa-6-azaspiro[3.3]heptane (9)
A 2 L reaction flask was charged with bis(bromomethyl)oxetane (5b;
5.51 g, 177 mmol), p-methoxybenzylamine (29.4 g, 214 mmol), and
4
DMF (820 mL). DBU (59.5, 391 mmol) was added dropwise at r.t. After
the addition of DBU was completed, the reaction mixture was heated
to 60 °C and stirred for an additional 21 h. The mixture was then
All solvents and reagents were obtained from commercial sources
and were used without purification. Products and intermediates were
purified by distillation or by crystallization. Reactions were conduct-
cooled to r.t. and partitioned in a mixture of brine (250 mL), H O (250
2
mL), EtOAc (250 mL), and MTBE (250 mL). The aqueous phase was ex-
tracted with a 1:1 mixture of MTBE and EtOAc (2 × 200 mL). The com-
bined organic phases were dried (Na SO ). Removal of residual sol-
1
ed under a N2 atmosphere, unless stated otherwise. H NMR spectra
were recorded in CDCl , DMSO-d , or D O using a Bruker Biospin NMR
3
6
2
2
4
apparatus at 400 MHz; chemical shifts (δ) are reported versus TMS as
an internal standard. GC/MS chromatograms were measured using an
Agilent 6890N GCMS apparatus equipped with a 5973 MS detector.
LCMS chromatograms were measured using an Agilent system (1100
Binary Pump, G1312A, degasser; autosampler, ColCom, DAD detector:
Agilent G1315B, 220–320 nm, MSD: Agilent LC/MSD G6130B ESI,
pos/neg 100–800). Melting points were determined with a Büchi
melting point apparatus.
vent by in vacuo distillation afforded 21.4 g (51%) of product 9 as a
yellow oil.
1
H NMR (DMSO-d , 400 MHz): δ = 7.13 (d, J = 8.6 Hz, 2 H), 6.84 (d,
6
J = 8.6 Hz, 2 H), 4.58 (s, 4 H), 3.71 (s, 3 H), 3.38 (s, 2 H), 3.21 (s, 4 H).
13C NMR (DMSO-d
113.6 (CH), 80.0 (CH
, 100 MHz): δ = 158.2 (C), 130.1 (C), 129.5 (CH),
6
), 62.7 (CH
), 61.9 (CH
), 55.0 (OCH ), 38.4 (C).
2
2
2
3
+·
+·
MS (EI, 70 eV): m/z (%) = 121.2 (100, [PMB] ), 218.2 (5, [M – 1] ),
+
·
219.2 (11, [M] ).
3
,3-Bis(bromomethyl)oxetane (5b)8
An oven-dried reaction flask was charged with pentaerythritol
tribromide (200 g, 616 mmol) and absolute EtOH (1 L). At tempera-
ture <20 °C, a freshly prepared NaOEt (253 mL, 677 mmol, 21% in
EtOH) was added over 10 min. The reaction mixture was heated to re-
flux (76 °C) and a suspension was formed. After 3 h, GC analysis
showed full conversion of the pentaerythritol. The reaction mixture
was cooled to r.t. and the solid material was removed by filtration.
2-Oxa-6-azaspiro[3.3]heptane (4)
steel autoclave was charged with 6-benzyl-2-oxa-6-
azaspiro[3.3]heptane (6; 68.0 g, 359 mmol) and MeOH (2 L). The au-
A
4 L
toclave was flushed with N2 and Pd/C (10% w/w, nonreduced, Acros,
38.2 g, 35.2 mmol) was added, followed by AcOH (2.15 g, 35.9 mmol).
The autoclave was closed and flushed three times with H (4 bar). The
2
stirrer was started and 5 bar of H pressure was applied. The reaction
2
The filtrate was partitioned between MTBE (400 mL) and H O (550
2
mixture was stirred at 30 °C for 24 h. During the first 6 h, the auto-
clave was refilled to 5 bar three times (pressure dropped to 3–4 bar).
In the final 18 h, the pressure dropped to 3.2 bar. GC analysis showed
full conversion to 2-oxa-6-azaspiro[3.3]heptane (4). The autoclave
mL). The aqueous phase was extracted with MTBE (250 mL). The
combined organic phases were washed successively with H O (250
2
mL) and brine (150 mL), dried (Na SO ), filtered, and concentrated in
2
4
vacuo. The residue was distilled with a short path distillation setup
56 °C/0.1 mbar) and 130 g (85%) of 5b was collected as an almost col-
was flushed thoroughly with N and the reaction mixture was filtered
2
(
through Celite. The filtrate was concentrated in vacuo to a volume of
orless oil.
~1400 mL, which yielded a concentrated solution of free base in
1
H NMR (CDCl , 400 MHz): δ = 4.44 (s, 4 H), 3.86 (s, 4 H).
methanol (~256 mmol/L).
3
3
,3-Bis(chloromethyl)oxetane (5a)9
2-Oxa-6-azaspiro[3.3]heptane Hemi-Naphthalene-1,5-disulfonate
(4r)
9
Prepared according to the literature procedure. Product was isolated
as a colorless oil after bulb-to-bulb distillation (62 °C/0.10 mbar).
The above concentrated solution of 2-oxa-6-azaspiro[3.3]heptane (4)
1
in MeOH (1400 mL) was cooled to 2–3 °C. A solution of naphthalene-
H NMR (CDCl , 400 MHz): δ = 4.46 (s, 4 H), 3.95 (s, 4 H).
3
1,5-disulfonic acid tetrahydrate (65.0 g, 180 mmol, 0.5 equiv) in EtOH
(
800 mL) was added dropwise over 20 min. Halfway during the addi-
6
-Benzyl-2-oxa-6-azaspiro[3.3]heptane (6)
tion the reaction mixture turned into a white suspension. After stir-
ring for 30 min at 2 °C, MTBE (500 mL) was added. The white suspen-
sion was allowed to stir at 2–5 °C for another 2 h before the white sol-
id product was collected by filtration. The salt 4r was obtained as a
crystalline white solid; yield: 76.0 g (86%); mp not observed; decom-
position at 225 °C.
In a 2 L reaction flask, bis(bromomethyl)oxetane (5b; 129 g, 518
mmol) was dissolved in anhyd DMF (1300 mL). At r.t., benzylamine
(61.1 g, 570 mmol) and DBU (166 g, 1088 mmol) were added. The re-
action mixture was stirred for 18 h at 60 °C at which point, GC analy-
sis showed clean conversion into 6. The reaction mixture was poured
into a stirring mixture of MTBE/EtOAc (1 L:1 L) and brine/H O (1 L:0.5
L). The aqueous phase was extracted twice with MTBE/EtOAc (1:1,
2
1
H NMR (D O, 400 MHz): δ = 8.73 (d, J = 8.7 Hz, 2 H), 8.10 (d, J = 7.2
2
Hz, 2 H), 7.64–7.60 (dd, J = 8.7, 7.2 Hz, 2 H), 4.70 (s, 8 H), 4.16 (s, 8 H).
1
800 mL and 400 mL) and with EtOAc (2 × 250 mL). The combined or-
3
C NMR (DMSO-d , 100 MHz): δ = 143.6 (C), 129.5 (C), 129.1 (CH),
ganic phases were washed with brine, dried (Na SO ), filtered, and
concentrated in vacuo. The residue was purified by a short-path dis-
6
2
4
1
24.1 (CH), 124.0 (CH), 78.8 (CH ), 54.3 (CH ), 40.2 (C).
2
2
tillation (96 °C/0.02 mbar) providing 69 g (70%) of 6 as a colorless oil.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
Synthesis
R. N. van der Haas et al.
PSP
Using the same protocol, the same salt 4r was also prepared starting
from 6-(4-methoxybenzyl)-2-oxa-6-azaspiro[3.3]heptane (9) on a
6-(Pyrimidin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (11)
A mixture of 2-chloropyrimidine (10; 100 mg, 0.873 mmol), 2-oxa-6-
azaspiro[3.3]heptane p-toluenesulfonate (4d; 237 mg, 0.873 mmol),
5.00 g scale giving 4.10 g of the desired product (74%).
and i-Pr NEt (0.304 mL, 1.75 mmol) in MeCN (1.00 mL) was stirred at
40 °C for 66 h at r.t. The resulting mixture was concentrated under re-
duced pressure. The residue was partitioned between EtOAc (4 mL)
2
2
-Oxa-6-azaspiro[3.3]heptane Acetate (4b)5
A 500 mL glass autoclave was charged with 6-benzyl-2-oxa-6-
azaspiro[3.3]heptane (6; 8.00 g, 42.3 mmol) and MeOH (160 mL). The
autoclave was flushed with N2 and Pd/C (10% w/w, nonreduced,
Acros, 4.50 g, 4.23 mmol) was added, followed by AcOH (2.56 g, 42.7
and sat. aq Na CO (4 mL). The organic phase was separated, dried
2
3
(
(
1
Na SO ), and concentrated under reduced pressure to yield 110 mg
71%) of a white powder; mp 109–110 °C.
2 4
mmol). The autoclave was closed and flushed three times with H (3
H NMR (DMSO-d , 400 MHz): δ = 8.32 (d, J = 4.8 Hz, 2 H), 6.57 (t, J =
2
6
bar) before the final pressure of 5 bar was applied. The reaction was
allowed to stir for 18 h at 30 °C. The autoclave was flushed with N2
and the solid material was removed by filtration through Celite. The
filtrate was concentrated in vacuo and a colorless oil was collected.
MTBE (50 mL) was added and a white solid precipitated. The solid
4.8 Hz, 1 H), 4.87 (s, 4 H), 4.30 (s, 4 H).
13
C NMR (DMSO-d , 100 MHz): δ = 162.5 (C), 157.8 (CH), 110.6 (CH),
6
7
9.9 (CH ), 59.2 (CH ), 38.1 (C).
2
2
was collected by filtration, washed on the filter with Et O, and dried
to yield 4b as a very hygroscopic white solid (4.68 g, 70%). Concentra-
2
References
tion of the mother liquor, followed by stirring the residue in Et O,
yielded an extra 0.65 g (10%) of 4b as a white very hygroscopic solid.
2
(
(
1) Carreira, E. M.; Fessard, T. M. Chem. Rev. 2014, 114, 8257.
2) (a) Casaubon, R. L.; Narayan, R.; Oalmann, C.; Vu, C. B. Patent
PCT Int. Appl. WO2013059587, 2013. (b) Burns, C. J. Patent PCT
Int. Appl. WO2014000032, 2014. (c) Bentley, J. M.; Brookings, D.
C.; Brown, J. A.; Cain, T. P.; Gleave, L. J.; Heifetz, A.; Jackson, V. E.;
Johnstone, C.; Leigh, D.; Madden, J.; Porter, J. R.; Selby, M. D.;
Zhu, Z. Patent PCT Int. Appl. WO2014009296, 2014.
1
H NMR (DMSO-d , 400 MHz): δ = 8.0–7.0 (s, 2 H + H O from solvent),
6
2
4
.61 (s, 4 H), 3.85 (s, 4 H), 1.78 (s, 3 H).
2-Oxa-6-azaspiro[3.3]heptane p-Toluenesulfonate (4d)
A 100 mL glass autoclave was charged with 6-benzyl-2-oxa-6-
azaspiro[3.3]heptane (6; 2.00 g, 10.6 mmol) and MeOH (40 mL). The
(
3) Golden, M.; Legg, D.; Milne, D.; Bharadwaj, A. M.; Deepthi, K.;
Gopal, M.; Dokka, N.; Nambiar, S.; Ramachandra, P.; Santhosh,
U.; Sharma, P.; Sridharan, R.; Sulur, M.; Linderberg, M.; Nilsson,
A.; Sohlberg, R.; Kremers, J.; Oliver, S.; Patra, D. Org. Process Res.
Dev. 2016, 20, 675.
autoclave was flushed with N and Pd/C (10% w/w, nonreduced, Acros,
2
1.12 g, 1.06 mmol) was added, followed by AcOH (698 mg, 11.6
mmol). The autoclave was closed and flushed three times with H O (4
2
bar) before the final pressure of 5 bar was applied. The reaction was
allowed to stir for 18 h at 30 °C. The autoclave was flushed with N2
and the solid material was removed by filtration through Celite. The
filtrate was concentrated in vacuo and a colorless oil was collected.
(4) (a) Burkhard, J.; Carreira, E. M. Org. Lett. 2008, 10, 3525.
(b) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.;
Märki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler,
F.; Schneider, J.; Alker, A.; Schweizer, W. B.; Müller, K.; Carreira,
E. M. Angew. Chem. Int. Ed. 2008, 47, 4512.
The oil was dissolved in n-BuOH (15 mL). A solution of PTSA·H O (2.21
2
g, 11.6 mmol) in n-BuOH (5 mL) was added dropwise at r.t. A white
solid precipitated, which was collected by filtration, and washed on
the filter with n-BuOH and MTBE successively. After drying, 2.03 g
(5) Wu, H.; Peng, X. J.; Li, P.; Dong, C. C.; Chen, S. H.; Chen, S. J.; Ma,
R. J. Chinese Patent CN102746312, 2011.
(6) (a) Miller, D.; Clark, P.; Melton, T. British Patent GB1169027,
(71%) of 4d was collected as a white solid; mp 182–183 °C.
1966. (b) So far, only the preparation of the p-toluenesulfonate
1
H NMR (DMSO-d , 400 MHz): δ = 8.6–8.2 (s, 2 H) 7.47 (d, J = 8.0 Hz, 2
6
salt 6d from freshly distilled free base 6 has been described,
H), 7.12 (d, J = 8.0 Hz, 2 H), 4.65 (s, 4 H), 4.12 (s, 4 H), 2.29 (s, 3 H).
however, the yield was only 26%.
13
1
C NMR (DMSO-d , 100 MHz): δ = 145.2 (C), 138.0 (C), 128.2 (CH),
(7) The purity assay was determined by quantitative H NMR spec-
troscopy with pentaerythritol as internal standard.
6
1
25.5 (CH), 78.8 (CH ), 54.3 (CH ), 40.2 (C).
2
2
(
8) Overberger, C. G.; Okamoto, Y.; Bulacovschi, V. Macromolecules
975, 8, 31.
9) US Patent 2005282826, 2005, p. 29.
1
(
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H