Synthesis and differential functionalisation of pyrrolidine and piperidine based spirodiamine scaffolds

Article abstract of DOI:10.1016/j.tet.2013.03.064

The synthesis and differential substitution/protection of a series of spirodiamine scaffolds are described. Methods for selective access to the two mono-N-methyl isomers based on 2,7-diazaspiro[4.5]decane are also described. Key precursors associated with this chemistry are prone to rearrangement and methods for circumventing this issue are reported. While direct mono-carbamoylation (Boc) was not efficient, selective deprotection of doubly Boc-protected derivatives derived from symmetrical diamines provided mono-Boc variants. N-Arylation, exemplified by a series of monosubstituted spirodiamines incorporating the 2-chloro-5-pyridyl moiety, which is a privileged nicotinic agonist substructure, has also been carried out to provide monoarylated secondary and tertiary spirodiamines variants.

Full text of DOI:10.1016/j.tet.2013.03.064

Accepted Manuscript
Synthesis and Differential Functionalisation of Pyrrolidine and Piperidine based
Spirodiamine Scaffolds
Kamil Weinberg, Axel Stoit, Chris G. Kruse, Mairi F. Haddow, Timothy Gallagher
PII:
S0040-4020(13)00453-5
10.1016/j.tet.2013.03.064
TET 24155
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 January 2013
Revised Date: 27 February 2013
Accepted Date: 18 March 2013
Please cite this article as: Weinberg K, Stoit A, Kruse CG, Haddow MF, Gallagher T, Synthesis and
Differential Functionalisation of Pyrrolidine and Piperidine based Spirodiamine Scaffolds, Tetrahedron
(2013), doi: 10.1016/j.tet.2013.03.064.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Changes in text indicated by highlight
The changes requested in the edited pages sent to me –
remove strucutre numbers in the abstract and change ml to
mL in experimental – have been made.
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Synthesis and differential functionalisation of
Leave this area blank for abstract info.
pyrrolidine and piperidine based spirodiamine scaffolds
Kamil Weinberg,a,b Axel Stoit,c Chris G. Kruse,c Mairi F. Haddow,a and Timothy Gallaghera
aSchool of Chemistry, University of Bristol, Bristol TS, United Kingdom; bDepartment of Pharmacy and Applied
Pharmacy, Medical University of Łódź, Łódź, Poland cSolvay Pharmaceuticals, 1381 CP Weesp, The Netherlands

ACCEPTED MANUSCRIPT
Synthesis and Differential Functionalisation of Pyrrolidine and Piperidine based
Spirodiamine Scaffolds
Kamil Weinberg,a,b Axel Stoit,c† Chris G. Kruse,c† Mairi F. Haddow,a and Timothy Gallaghera*
aSchool of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
bDepartment of Pharmacy and Applied Pharmacy, Medical University of Łódź, ul.
Muszyńskiego 1, 90-151 Łódź, Poland
cSolvay Pharmaceuticals, 1381 CP Weesp, The Netherlands.
Abstract
The synthesis and differential substitution/protection of a series of spirodiamine scaffolds is
described. Methods for selective access to the two mono-N-methyl isomers based on 2,7-
diazaspiro[4.5]decane are also described. Key precursors associated with this chemistry are
prone to rearrangement and methods for circumventing this issue are reported. While direct
mono-carbamoylation (Boc) was not efficient, selective deprotection of doubly Boc-protected
derivatives derived from symmetrical diamines provided mono-Boc variants. N-Arylation,
exemplified by a series of monosubstituted spirodiamines incorporating the 2-chloro-5-
pyridyl moiety, which is a privileged nicotinic agonist substructure, has also been carried out
to provide monoarylated secondary and tertiary spirodiamines variants.
† Current address: Pharma Plexus Holland BV, 3584 CH Utrecht, The Netherlands
2

ACCEPTED MANUSCRIPT
Introduction
Nitrogen-based heterocycles based on spirodiamine scaffolds are of significant interest in
medicinal chemistry, catalysis and materials chemistry by providing a well defined and
comparatively rigid three dimensional quality to a multisite interaction, be it involving a
receptor/enzyme as the target or as the basis of a ligand for a metal-based catalyst. In terms of
biologically active molecules,1a spiroamines have found application as potential antibacterial1b
and antitumour drugs,2 agonists of various protein receptors3 including neural receptors,4 and
as peptidomimetics.5 Spiroamine-based scaffolds are also found in Nature, as exemplified by
the antimalarial alkaloid manzamine (and related molecules) which are isolated from marine
sponges,6 and have also been identified in a structurally diverse range of natural products
derived from plants7 and fungi.8 More recently, there has been a significant increase in the
awareness of the importance of three dimensionality as a design element within drug
candidates.9 This may involve chirality, but even without explicit consideration of chirality, an
increase in the proportion of sp3 centres, at the expense of more often used sp2-based
structures, can have a profound effect on biological profile that is not just limited to intrinsic
activity but will also link to key physicochemical parameters. Consequently, the desirability
of sp3 centres is now recognized as an important critical factor in terms of enhancing a
candidate’s likelihood of successful translation from laboratory to clinic to market, and new
opportunities for chemical methodologies in this area are of value. In this sense,
spirodiamines not only offer “three dimensionality” but, and depending on the specific
scaffold, also chirality.
In terms of background, a number of spirodiamine scaffolds A-F (Figure 1; based on 4-, 5- or
6-membered rings) are known, and the various methods for the synthesis of each of these
scaffolds (as opposed to specific individual examples) is reviewed briefly here. It is important
to appreciate that these spirodiamines are not necessarily reported/available in their “parent”
(i.e. unsubstituted on the rings or via N) forms, and we have omitted benzofused variants, as
well as comparatively reactive β−lactam derivatives. Aminal (aminoacetal) isomers/variants
have been ignored simply because of the susceptibility of such latter systems to
isomerisation/ring opening and hence scrambling of the spiro stereocentre.
3

ACCEPTED MANUSCRIPT
N
N
N
N
N
N
N
N
N
N
N
N
A1
A2
B1
B2
B3
C1
N
N
N
N
N
N
N
N
N
N
C2
C3
C4
C5
D1
N
N
N
N
N
N
N
N
N
N
N
N
D2
E1
E2
E3
E4
E5
N
N
N
N
N
N
N
N
N
N
F1
F2
F3
F4
F5
Figure 1. Azetidine/pyrrolidine/piperidine spirodiamine scaffolds. No absolute stereochemistry should be
inferred and scaffolds (i.e. molecular frameworks) are shown without substituents or associated functionality.
References to specific examples of structures incorporating each scaffold are included in the text below, but
generally β−lactam and benzo-fused variants have been excluded. Aziridine variants are not shown, given the
comparatively high reactivity of these systems, and configurationally labile aminal isomers are also excluded.
Several synthetic strategies, including stereoselective approaches, have been applied
depending on the structure of the target scaffold, and given the utility of these systems as the
basis of more complex structures, it is appropriate to provide a brief overview of the more
commonly exploited methods available. A number of these and related spiroamine scaffolds
have only been reported or otherwise exploited in the patent literature, but this underscores
the potential and perceived importance of these units in drug discovery.
4

ACCEPTED MANUSCRIPT
The most common stereoselective approach to pyrrolidine variants has involved the alkylation
of L-proline or its derivatives, followed by the cyclization step to achieve the spirocycle. This
provides an entry to pyrrolidine-based scaffolds encompassing 2,5-diazaspiro[3.4]octane B1,5
1,7-diazaspiro[4.4]nonane D1,10 1,7-diazaspiro[4.5]decane E111 and the seven-membered
(azepane-based) 1,7-diazaspiro[4.6]undecane (not shown)12 which have been obtained in most
cases in enantiopure form.
Other, more varied ways of stereocontrolled construction of diazaspiro systems, often applied
in alkaloid synthesis, have included ring-contracting pinacol rearrangements to access 2,7-
diazaspiro[4.4]nonane D2,13 synthesis of this same scaffold by electrocyclisation,14 and
synthesis of the core structure of manzamine that contains the 2,7-diazaspiro[4.5]decane E4
structure via intramolecular stereocontrolled Michael addition to a 2-pyrrolidone derivative.15
Spirodiamine skeletons have been obtained via the reaction of geminally disubstituted (i.e. the
nascent spiro-centre is already established) azetidine, pyrrolidine or piperidine derivatives
with an amine in order to close the second ring, usually involving formation of an amine or an
imide. Using this method, 2,6-diazaspiro[3.3]heptane A2,10d,f 1,6-diazaspiro[3.4]octane B2,10d
2,6-diazaspiro[3.4]octane B3,10g 2,5-diazaspiro[3.5]nonane C1,4 2,5-diazaspiro[3.6]nonane
C2,10g 2,7-diazaspiro[3.5]nonane C3,10e,f diazaspiro[4.5]decanes E416 and E5,17 and
diazaspiro[5.5]undecanes F3,18 F419 and F520 systems have been prepared. One of the
geminal substituents can itself already be e.g. an amine or amide so that the cyclization step
does not necessarily require an external amine, such as in the syntheses of diamine scaffolds
C4,4b C5,21a-d D1,21e E1,21e E2,21f E321e and E421g and F1.21e Both rings of a nascent spiro
system can be also closed in the same step, as in the syntheses of the 2,7-
diazaspiro[4.4]nonane scaffold D222 and the 2,8-diazaspiro[5.5]undecane structure F3.1,23 In
several cases, the second ring of a diazaspiro scaffold was established via ring closing
metathesis, and this process has been applied successfully to generate the 2,6-
diazaspiro[4.5]decane E3,24 1,8-diazaspiro[5.5]undecane F1,25 1,9-diazaspiro[5.5]undecane
F2,24,25c,25d and analogous systems based on a pyrrolidine and piperidine spirofused to an
azepane moiety (not shown in Figure 1, but included here for completeness), such as 2,7-
diazaspiro[4.6]undecane,24 3,7-diazaspiro[5.6]dodecane24 and 3,8-diazaspiro[5.6]dodecane24
ring systems. One synthesis of the 2,7-diazaspiro[4.4]nonane scaffold D2 and an example of
the 1,6-diazaspiro[3.4]octane B2 skeleton have been described in which the second
heterocyclic ring was constructed via dipolar cycloaddition.10d,26
5

ACCEPTED MANUSCRIPT
Importantly, a major application of spirodiamines is as spacer units within, for example,
medicinal chemistry. Carreira27a-c has recently provided elegant entries to 1,5-
diazaspiro[3.3]heptanes A1 and 1,6-diazaspiro[3.3]heptanes A2 and exemplified how the
spatial disposition of functionality based on these scaffolds is exploitable. Meyers et al. have
made extensive use of spirocycles, including A1, C3, D2, E5, and F5, within candidates for
inhibition of fatty acid amide hydrolase (FAAH), and Lachance,10f Tang21e and Meyers27d have
reported the exploitation of mono-Boc variants of various spirodiamines, and this work is
relevant to aspects of the studies reported here (see below).
Results and Discussion
Our objective was to define new entries or improve existing methods for the synthesis of a
series of spirodiamines based on pyrrolidines and piperidines to provide access to a range of
molecular scaffolds that were also amenable to further (and selective)
manipulation/substitution. Our aim was to develop a synthetic platform to provide
scaffolds/substitution variants that would present the pharmacophore associated nicotinic
ligands (a basic amine and a pyridyl-based π-system) and this is discussed in more detail
below. Our targets primarily encompassed scaffolds that incorporated a 1,3-diaminopropane
relationship between the two amine moieties (e.g. D2, E4, and F3) with a key issue being an
ability to differentiate between the two amine centres, in both symmetrical systems (i.e. where
the two ring sizes are the same as in D2 or F3) and in cases where the rings sizes are different
(e.g. E4).
Specific targets showing target substitution patterns are shown in Figure 2 with 1 and 2
corresponding to scaffold D2, 3 and 4 to the bispiperidine-based diazaspirocycle F3, and 5-7
to scaffold E4; in this latter case, the issue of differentiation (5 vs. 6) is more complex
because of two differently sized rings are involved. Distinguishing between the two amine
sites has been explored either during the construction of the spirocycle (as in 1 and 3 or as in 5
vs. 6) or once the diazaspirocycle has been established via differential amine protection of e.g.
diamines 2 and 4, both of which were prepared (as racemates) as previously described.1b
6

ACCEPTED MANUSCRIPT
Figure 2. Target spirodiamines 1-7 based on scaffolds D2, E4 and F3.
Mono N-methylspirodiamines.
2-Methyl-2,7-diazaspiro[4.4]nonane 1, in which the two pyrrolidine nitrogen centres are
differentiated, was prepared as previously reported1b and the sequence used (as shown in
Scheme 1) has broad applicability. The key steps involved a double alkylation of ethyl
cyanoacetate, nitrile reduction and lactamization (to establish the first heterocyclic ring)
followed by imide formation; MeNH2 was used but this approach does offer an opportunity to
incorporate a series of other N-substituents by judicious choice of the amine reagent. Global
reduction then furnished the target mono N-methyl spirodiamine 1.
Scheme 1.1 Reagents and conditions: a) ethyl bromoacetate, Et3N, EtOH/H2O; b) H2 (4 atm), PtO2, EtOH/AcOH;
c) MeNH2, H2O; d) LiAlH4, THF.
An analogous approach provided access to 2-methyl-2,8-diazaspiro[5.5]undecane 3 (Scheme
2). A double Michael reaction involving ethyl cyanoacetate and methyl acrylate yielded
cyanotriester 8.18 Catalytic hydrogenation and in situ cyclization of the intermediate
7

ACCEPTED MANUSCRIPT
aminoester resulted in the formation of the six-membered lactam 9.28 Reaction of 9 with N-
methylamine did not provide the target imide directly, rather diamide 10 which was cyclized
under acidic conditions to give imide 11.29 Global reduction of 11 with LiAlH4 led to the
racemic monomethylated spirodiamine 3.
Scheme 2. Reagents and conditions: a) methyl acrylate, Et3N, EtOH/H2O; b) H2 (4 atm), PtO2, EtOH/AcOH; c)
MeNH2, H2O; d) p-TsOH . H2O, p-xylene; e) LiAlH4, THF.
Both diamines 1 and 3 are symmetrical in the sense that both rings are the same (pyrrolidine
and piperidine respectively) in each case. Targets 5 and 6 (2-methyl-2,7-diazaspiro[4.5]decane
and 7-methyl-2,7-diazaspiro[4.5]decane respectively, Figure 230) are not only differentiated in
terms of secondary vs. tertiary amines (also the case for 1 and 3) but here the two constituent
rings are of a different size, which raises an important regiocontrol issue.
Our approach to 5 and 6 was based on modification and application of the chemistry outlined
in Schemes 1 and 2. This involved reaction of ethyl cyanoacetate with two different
alkylating agents to achieve the requisite rings sizes and the differential ester
substitution/reactivity patterns necessary in order to provide each target selectively.
Cyanotriester 13 provided an entry to 5 and was prepared as shown in Scheme 4, together
with a more highly differentiated variant 15 required for spirodiamine isomer 6. Alkylation of
ethyl cyanoacetate with ethyl chloroacetate provided, as the main product, the
monosubstituted adduct 12;31 complete transesterfication was also observed under these
conditions. Michael addition of 12 to methyl acrylate (in ethanol and water) gave triesters 13
and 14, which were separated by flash chromatography. Partial transesterification also took
place in this case (see below), but interestingly only at the most hindered ester residue. This
1
outcome was determined by long range H/13C NMR correlations and is presumed to reflect
8

ACCEPTED MANUSCRIPT
the higher electrophilicity associated with ester moiety adjacent to the cyano residue. Given
the added complication associated with transesterification in going from 12 to 13/14, it is
pertinent to note that (and in our hands) the Michael addition reaction (12 → 13/14) was
unsuccessful when methanol was used as solvent.32
Scheme 3. Reagents and conditions: a) ethyl chloroacetate, Na, MeOH; b) methyl acrylate, Et3N, EtOH/H2O; c)
ethyl chloroacetate, t-BuOK, t-BuOH.
A similar, but more controlled sequence was carried out to provide the fully differentiated
triester 15 required for the synthesis of 6, also shown in Scheme 3. This involved
monoalkyation of ethyl cyanoacetate with tert-butyl chloroacetate and use of potassium tert-
butoxide and tert-butanol served to avoid transesterification. Subsequent Michael addition
involving methyl acrylate then provided triester 15.
Triesters 13, 14 and 15 were individually subjected to nitrile hydrogenation and it was our
expectation that five-membered lactams (in preference to six-membered ring isomers) would
be favoured in the case of 13 and 14 (Scheme 4). However, in all three cases, six-membered
lactams 16 (from 13) and 17 (from 14), and 18 (in this case the expected product from 15)
were observed exclusively. In the case of 16 and 17, this outcome was deduced by IR
spectroscopy: a carbonyl band below 1666 and 1663 cm-1 respectively indicating a six-
membered lactam, but also see below. Further evidence came from transesterification of 18
(HCl/MeOH) which provided 16, identical to the lactam obtained from 13, as judged by IR,
1H and 13C NMR.
Both 16 and 17 were exposed individually (and also as a mixture) to aqueous methylamine
and subsequent cyclization occurred to give imide 19 as the only product observed, the
structure of which was unambiguously established by X-ray crystallography (Figure 3).33
9

ACCEPTED MANUSCRIPT
Global hydride reduction of 19 then provided the monomethylated target 2-methyl-2,7-
diazaspiro[4.5]decane 5.
Figure 3. Crystal structure of imide 19. Thermal ellipsoids are shown at the 50% probability level.
Scheme 4. Reagents and conditions: a) H2 (4 atm), PtO2, EtOH/AcOH; b) H2 (7.5 atm), PtO2, EtOH (yields
shown relate to this procedure); c) HCl, MeOH; d) MeNH2, H2O; e) LiAlH4, THF.
Based on these observations, in order to direct five rather than six-membered ring
lactamization (as in 13 → 16) to generate the isomeric mono N-methyl diazaspirodiamine 6
we required a cyanotriester variant with a blocking group on the longer alkyl chain (Scheme
5). Michael addition of diester 12 to tert-butyl acrylate gave triesters 20 and 21. Again,
ethanol was necessary here because the corresponding addition process in methanol failed and
these ester products were separated by flash chromatography.
10

ACCEPTED MANUSCRIPT
Scheme 5. Reagents and conditions: a) tert-butyl acrylate, Et3N, EtOH/H2O; b) H2 (8 atm), PtO2, EtOH; c) HCl,
MeOH; d) MeNH2, H2O, r.t. to 180oC; e) MeNH2, H2O, r.t.; f) p-TsOH.H2O, xylene; g) LiAlH4, THF.
Hydrogenation of 20 and 21 did provide the desired five-membered lactams 22 and 26
respectively, which were transesterified with acidic methanol to give the methyl esters 23 and
27 needed to secure the second (six-membered) ring. The IR spectra of 22/23 and 26/27
showed a band at approx. 1727-1721 cm-1, indicating the presence of a five-membered
lactam. In the reactions of lactams 23 and 27 with methylamine, formation of diamide
intermediate 24 was anticipated (cf Scheme 2). Surprisingly, while dimethyl ester 27 reacted
at elevated temperature (step d; Scheme 5) with methylamine to give 24, in the case of the
mixed methyl/ethyl diester 23, rearrangement was observed and the only product obtained
was the five-membered ring imide 19. This is the same product as that derived by amine
condensation of 16 or 17 (Scheme 4) and this outcome was confirmed by direct and careful
comparison of the product obtained by the earlier procedure. The rearrangement associated
with 23 → 19 must involve lactam cleavage and subsequent reclosure with the hindered
(quaternary centre) ethyl ester associated with 23 presumably more susceptible to
11

ACCEPTED MANUSCRIPT
intramolecular rather than intermolecular nucleophilic displacement. This rearrangement was
suppressed fully in the case of 23 by conducting the aminolysis step (step e; Scheme 5) at
room temperature which cleanly then provided 24 from both 23 and 27. Conversion of 24 to
imide 25 occurred with acid catalysis, although small amounts of rearrangement (to give 19,
which was confirmed by careful comparison, and for which the crystallographic data are
available, see Figure 3) were observed here; this reaction has been studied under a series of
different conditions (solvents, temperatures and reaction times), and details of this are shown
in Table 2 (see Experimental Section). Hydride reduction of 25 then provided access to the N-
methylated piperidine 6, the regioisomer of the N-methyl pyrrolidine 5.
It is appropriate to point out that care must be exercised in assigning product structures in this
area. While reasonable assumptions regarding ester reactivity may hold generally, these are
not universal and the lability and propensity of the heterocyclic ring systems described here to
undergo ring opening and reclosure under transamidation conditions, for which a number of
mechanistic variants may operate, must be borne in mind.
Mono N-Boc spirodiamines.
While mono N-methylated variants such as 1, 3, 5 and 6 do differentiate the two nitrogen
centres as secondary vs. tertiary amines, the ability to release a secondary amine function
from, for example, a mono-Boc protected spirodiamine represented an attractive option.
Lachance,10f Meyers27d and Tang21e have all reported mono-Boc spirodiamines, and Meyers27d
has described carbamate 29 (see below), although no experimental details are reported. 2,7-
Diazaspiro[4.4]nonane 2 and 2,8-diazaspiro[5.5]undecane 4 were prepared and although
methods have been reported to be effective in achieving monoacylation of diamines,34 in our
hands and despite extensive experimentation, bisacylation of these two substrates was always
the major reaction pathway observed. The problem of accessing mono Boc-spirodiamines was
best overcome by bisacylation (generating 28 and 30) followed by careful treatment with
trifluoroacetic acid which provided the desired mono-Boc protected derivatives 29 and 31
(Scheme 6). The yields of the deprotection procedures have not been optimised since a
significant advantage here is the marked difference in polarity between e.g. 2, 28 and 29
which facilitates isolation and purification of 29.
12

ACCEPTED MANUSCRIPT
Scheme 6. Reagents and conditions: a) Boc2O, EtOH; b) TFA, DCM.
2,7-Diazaspiro[4.5]decanes
2,7-Diazaspiro[4.5]decane 7, previously only reported in the patent literature, was prepared as
shown in Scheme 7. Malononitrile was alkylated sequentially with ethyl bromoacetate and
ethyl acrylate to give diester 32, hydrolysed under acidic conditions to provide bisimide 33
which was reduced with LiAlH4 to give spirodiamine 7.35
Scheme 7. Reagents and conditions: a) ethyl bromoacetate, Triton B, THF; b) ethyl acrylate, Triton B, dioxan c)
H2SO4, AcOH; d) LiAlH4, THF; e) Boc2O, EtOH; f) TFA, DCM.
As anticipated in this case, monoprotection of 7 gave the bisBoc adduct as the major product.
However, there was no obvious selectivity for one mono-Boc isomer over the other and
although subsequent cleavage of one Boc residue (cf Scheme 6) was achieved, again no
selectivity was observed (Scheme 7)36 This lack of selectivity combined with the issue of
separating the isomeric mono-Boc adducts derived from 7 effectively marks a limit to the
usefulness of this methodology and further reactions of 7 were not pursued.
Mono N-Arylation of Spirodiamine Scaffolds
13

ACCEPTED MANUSCRIPT
Our interest in spirodiamines as scaffolds for medicinal chemistry was prompted in part by
the opportunity afforded by the diamine moiety to provide both a secondary amine
(anticipated to be protonated at physiological pH) and a means for the ready (and flexible)
attachment of a second potential binding moiety, such as a heteroaryl unit. Such a system
would provide a means of rapidly exploring ligand space associated with, for example, the
binding mode of neuronal nicotinic ligands, such as epibatidine 3437 and the anatoxin-
a/epibatidine hybrid UB165 35,38 where both an ammonium (via a π-cation interaction) and
H-bond accepting π-system (here the 2-chloro-5-pyridyl unit is common) are prerequisites for
nicotinic recognition.39 Using an array of spirodiamines, N-arylation of one amine site would
allow ready synthesis of a library of spatially diverse ligands (Figure 4).
Figure 4. Nicotinic ligands epibatidine 34 and UB165 35 and variants based on arylation of spirodiamine
scaffolds.
With this in mind we have explored the feasibility of N-arylation of N-methyl and N-Boc
spirodiamine variants using Pd-catalysed Buchwald-Hartwig arylation of pyridyl halides. A
variety of reagents/ligands were examined and either Xantphos or P(i-BuNCH2CH2)3N (as
described for this purpose by Verkade40) in the presence of Pd2(dba)3 proved reliable and
efficient combinations to prepare a variety of 2-, 3- and 4-substituted pyridines.41 These
reactions were carried out in the N-methyl and N-Boc series and representative examples
were based on use of 2-chloro-5-iodopyridine as the arylating agent (cf Figure 4) are
illustrated in Table 1. In the case of the N-Boc variants, cleavage of the N-Boc residue
following N-arylation was carried out using trifluoroacetic acid to provide the corresponding
secondary amine. It should be also noted that we were unsuccessful in achieving a selective
monoarylation of either diamine 2 or 4, and given the lack of regioselectivity seen in Scheme
7, we did not apply this chemistry to diamine 7.
Spirodiamine
N-Arylated Product (%)
dBoc cleavage
14

ACCEPTED MANUSCRIPT
Ar
N
N/A
NMe
1
36 (a31%)
29
37 (b61%);
38 (100%)
N/A
39 (b78%; c76%)
3
NH
Ar
N
NBoc
NBoc
31
40 (b80%)
41 (100%)
N/A
42 (b84%)
5
N/A
6
43 (b34%)
a
Table 1. In all cases shown, 2-chloro-5-iodopyridine was used and Ar= 5-(2-chloropyridyl); In this case the
b
result using rac-BINAP is shown, which is typical of the lower yields observed with this ligand; Yield using
Xantphos; cYield using P(i-BuNCH2CH2)3N; dBoc cleavage was carried out using CF3CO2H in CH2Cl2 and in the
cases shown was essentially quantitative.
Clearly, the ready accessibility of a secondary amine site allows a range of other, well-
established methodologies of library synthesis to be exploited and once again, access to the N-
15

ACCEPTED MANUSCRIPT
Boc derivatives allows for efficient “mono” functionalization of the scaffold core and
subsequent liberation of a second potential site for further substitution.
Conclusions
In summary, we described the synthesis (and in some cases an alternative synthesis) of a
series of spirodiamine scaffolds containing 5- and 6-membered rings, where differentiation of
the amine sites can be achieved via either N-methylation or N-Boc protection. In terms of the
construction of the diamine scaffold, the care must be taken in terms of predicting/assuming
the stereo/regiochemical outcome of cyclization reactions that are inevitably done under
equilibrating conditions. This is because rearrangement is not only possible but the feasibility
of an alternative pathway has been demonstrated. Accordingly, control of reaction conditions
in certain cases is essential, as is careful analysis of product structure. The product diamines
are readily amenable to both protection (which allows for differentiation) and N-arylation, and
further details of other aspects of this chemistry, in terms of the use of these scaffolds in
library generation, will be reported in due course.
Experimental
General
All reactions that involved air/moisture sensitive compounds were performed under an
atmosphere of dry nitrogen with either flame dried or oven dried glassware. 1H and 13C NMR
spectra were recorded at the specified field strength and in the solvent indicated using
standard pulse techniques on Jeol Lambda 300 (300 MHz), Jeol JNM-GX270 (270 MHz), and
Jeol JNM-ECP400 (400 MHz) spectrometers at ambient temperatures. Chemical shifts (δH)
are reported in parts per million (ppm) and are referenced to TMS or the residual solvent
peak. Coupling constants (J) are quoted to the nearest 0.1 Hz. Assignments of signals were
made where possible, using COSY, DEPT, HMQC and HMBC experiments as necessary.
Mass spectra were recorded using a VG Autospec (EI/CI mode) and a VG Quattro (ESI mode)
and infrared spectra were recorded on a Perkin Elmer Spectrum One FTIR spectrometer as a
thin film between NaCl plates. Absorptions maxima (υmax) are reported in wavenumbers (cm-
1).
2-Methyl-2,7-diazaspiro[4.4]nonane (1)
16

ACCEPTED MANUSCRIPT
LiAlH4 in pellets (2.07 g; 54.5 mmol) was stirred vigorously in dry THF (40 mL) under N2
atmosphere until a suspension of powder was formed (4 h). This suspension was transferred
dropwise via a cannula to the stirred suspension of 2-methyl-2,7-diazaspiro[4.4]nonane-1,3,8-
trione1b (2.27 g; 12.5 mmol) in dry THF (40 mL) under N2 atmosphere (both suspensions
were cooled to 0-5oC during transfer). The mixture was then heated in reflux overnight under
N2 atmosphere, cooled to 0-5oC, diluted with THF (50 mL) and the following were slowly
added dropwise in 0-5oC: water (2.5 mL), 15% aq. NaOH (2.5 mL) and water (7.5 mL). The
resulting slurry was filtered through Celite, the solids were washed with THF (500 mL) and
the combined filtrates were concentrated in vacuo to give a yellow oil which was distilled
under vacuum (bp 32-36oC at 1.5 mmHg) to give diamine 1 (0.90 g; 52%) as a colourless oil.
δH (270 MHz, CD3OD) 2.94-2.85 (2H, m, CH2CH2NMe), 2.80, 2.71 (2H, 2d, J 10.9,
CH2NMe), 2.68-2.57 (2H, m, CH2CH2NH), 2.57, 2.48 (2H, 2d, J 9.6, CH2NH), 2.34 (3H, s,
CH3), 1.93-1.70 (4H, m, CH2CH2NH, CH2CH2NMe); δC (75.5 MHz, CD3OD) 68.1
(CH2NMe), 59.8 (CH2NH), 57.1 (CH2CH2NMe), 50.8 (C4o), 46.4 (CH2CH2NH), 42.7 (CH3),
40.9 (CH2CH2NH), 38.4 (CH2CH2NMe); m/z (CI) 141 (M+H+); HRMS: Found: M+H+,
141.1384. C8H17N2 requires 141.1386. The characterisation of 1 as its HCl salt is given
elsewhere.1b
Methyl 4-(ethoxycarbonyl)-7-oxo-4-piperidinepropionate (9)
3-Ethyl-1,5-dimethyl 3-cyano-1,3,5-pentanetricarboxylate (15.3 g; 53.0 mmol) was dissolved
in ethanol (50 mL) and glacial acetic acid (100 mL) and platinum oxide (1.0 g) was added.
The mixture was hydrogenated in a Parr-shaker flask (4 atm, room temp.) for 2.5 days. TLC
showed a mixture of product and starting material. More PtO2 (0.5 g) was added and the
mixture was further hydrogenated overnight in the same conditions. The mixture was filtered
through Celite and the solids were washed with methanol. The combined filtrates were
concentrated in vacuo and worked up using AcOEt/sat. NaHCO3. The organic layer was dried
with MgSO4 and concentrated to give lactam 9 (10.54 g; 76%) as a pale yellow oil, which
solidified when cooled, but was used in the next step without further purification. IR (neat): ν
3242, 2955, 1725, 1663; δH (400 MHz, CDCl3) 6.03 (1H, br s, NH), 4.21, 4.20 (2H, 2q, J 7.1,
OCH2CH3), 3.73 (1H, ddd, J 12.2, 3.8, 2.7, CH2NH), 3.68 (3H, s, OCH3), 3.17 (1H, d, J 12.2,
CH2NH), 2.46-2.38 (2H, m, CH2CH2CONH), 2.34-2.22 (3H, m, CH2CH2COOMe (2H),
CH2CH2CONH (1H)), 2.06-1.92 (2H, m, CH2CH2COOMe), 1.82-1.68 (1H, ddd, J 13.7, 9.3,
7.3, CH2CH2CONH), 1.28 (3H, t, J 7.1, OCH2CH3); δC (100.5 MHz, CDCl3) 173.3, 173.2
(COOR), 170.7 (CONH), 61.5 (OCH2CH3), 51.9 (OCH3), 48.4 (CH2NH), 44.4 (C 4o), 31.5
17

ACCEPTED MANUSCRIPT
(CH2CH2COOMe), 29.1 (CH2CH2CONH), 28.5 (CH2CH2COOMe), 28.3 (CH2CH2CONH),
14.2 (OCH2CH3); m/z (EI+) 257 (M+); HRMS: Found: M+, 257.1257. C12H19NO5 requires
257.1258.
N-Methyl 4-(methylaminocarbonyl)-7-oxo-4-piperidinepropionamide (10)
A solution of 9 (4.08 g; 15.9 mmol) in 40% aqueous methylamine (8 mL) was stirred
overnight at room temp. The mixture was gradually heated in oil bath to 180oC over 1.5 h
while the volatiles were distilled off. The yellow solid residue obtained was recrystallised
from ethanol to give the bisamide 10 (3.05 g; 80%) as colourless crystals mp 255-256oC
(EtOH). IR (neat): ν 3333, 3284, 3095, 1676, 1651, 1634, 1558; δH (400 MHz, D2O) 3.62,
3.19 (2H, 2d, J 13.0, CH2NH), 2.74 (3H, s, CH3), 2.67 (3H, s, CH3), 2.45-2.22 (2H, m,
CH2CH2CONH), 2.20-2.06 (3H, m, CH2CH2COOMe (2H), CH2CH2CONH (1H)), 1.98-1.77
(3H, m, CH2CH2CONHMe (2H), CH2CH2CONH (1H)); δC (100.5 MHz, D2O) 176.9, 175.8,
174.8 (CONH), 47.2 (CH3), 44.0 (CH3), 32.6 (C 4o), 30.8 (CH2NH), 28.0 (CH2CH2CONH),
27.4 (CH2CH2CONH), 26.3 (CH2CH2CONHMe), 26.0 (CH2CH2CONHMe); m/z
(electrospray, positive) 242 (M+H+); HRMS: Found: M+H+, 242.1497. C11H20N3O3 requires
242.1499. Anal. calcd. for C11H19N2O3: C, 54.74; H, 7.94; N, 17.42. Found: C, 54.54; H, 7.94;
N, 17.67.
2-Methyl-2,8-diazaspiro[5.5]undecane-1,3,9-trione (11)
A suspension of 10 (9.78 g; 40.6 mmol) and p-TsOH.H2O (8.53 g; 44.6 mmol) in p-xylene (80
mL) was heated in reflux overnight. The mixture was evaporated to dryness and worked up
using water/AcOEt. The aqueous layer was evaporated to dryness and the residue was
purified by chromatography (silica gel; DCM:MeOH 9:1) to give spirocycle 11 (7.97 g; 94%)
as a colourless solid. mp 169oC (EtOH). IR (neat): ν 3187, 1716, 1671, 1652; δH (400 MHz,
D2O) 3.65, 3.27 (2H, 2d, J 13.0, CH2NH), 3.06 (3H, s, CH3), 2.91-2.71 (2H, m,
CH2CH2CONH), 2.50-2.34 (2H, m, CH2CH2CONMe), 2.26 (1H, ddd, J 13.0, 7.0, 5.5
CH2CH2CONH), 2.18-1.87 (3H, m, CH2CH2CONH (1H), CH2CH2CONMe (2H)); δC (100.5
MHz, D2O) 177.6 (CONH), 175.4, 174.7 (CONMe), 47.7 (CH2NH), 39.9 (C 4o), 28.3
(CH2CH2CONMe), 27.0 (CH2CH2CONH), 27.0 (CH2CH2CONMe), 27.0 (CH3), 24.7
(CH2CH2CONH); m/z (EI+) 210 (M+); HRMS: Found: M+, 210.0996. C10H14N2O3 requires
210.0999. Anal. calcd. for C10H14N2O3: C, 57.12; H, 6.72; N, 13.33. Found: C, 56.98; H, 6.61;
N, 13.46.
18

ACCEPTED MANUSCRIPT
2-Methyl-2,8-diazaspiro[5.5]undecane (3)
LiAlH4 in pellets (4.6 g; 121.5 mmol) was stirred vigorously in dry THF (100 mL) under N2
atmosphere until a suspension of powder was formed (4 h). This suspension was transferred
dropwise via a cannula to the stirred suspension of 11 (5.68 g; 27 mmol) in dry THF (110 mL)
under N2 atmosphere (both suspensions were cooled to 0-5oC during transfer). The mixture
was then heated in reflux overnight under a N2 atmosphere, then cooled to 0-5oC, diluted with
THF (50 mL) and the following were slowly added dropwise in 0-5oC: water (5 mL), 15% aq.
NaOH (5 mL) and water (15 mL). The resulting slurry was filtered through Celite, the solids
were washed with thoroughly with THF (500 mL) and the combined filtrates were
concentrated in vacuo to give a brown oil which was distilled under vacuum (bp 55-60oC/1.5
mmHg) to give spirodiamine 3 (2.92 g; 64%) as a colourless oil. δH (300 MHz, CD3OD) 2.70-
2.40 (4H, m, CH2NMe, CH2CH2CH2NMe), 2.35-1.85 (4H, m, CH2NH, CH2CH2CH2NH),
2.10 (3H, s, CH3), 1.60-1.10 (8H, m, CH2CH2CH2NMe, CH2CH2CH2NMe, CH2CH2CH2NH,
CH2CH2CH2NH); δC (75.5 MHz, CD3OD) 65.2 (CH2NMe), 57.9 (CH2CH2CH2NMe), 55.2
(CH2NH), 47.6 (CH2CH2CH2NH), 47.2 (CH3), 35.5 (C 4o), 33.7 (CH2CH2CH2NMe), 30.9
(CH2CH2CH2NH), 22.8 (CH2CH2CH2NH), 22.3 (CH2CH2CH2NMe); m/z (CI) 169 (M+H+);
HRMS: Found: M+H+, 169.1697. C10H21N2 requires 169.1699.
2-Ethyl-1,4-dimethyl 2-cyano-1,2,4-butanetricarboxylate (13) and trimethyl 2-cyano-
1,2,4-butanetricarboxylate (14)
Cyanodiester 1231 (1.63 g; 9.53 mmol) was dissolved in ethanol-water 1:1 (10 mL) and Et3N
(1.65 mL) was added. The mixture was cooled to 0-5oC and methyl acrylate (0.9 mL; 9.6
mmol) was added dropwise. The mixture was warmed to room temp. and stirred for 3 h. It
was then concentrated, acidified with 2M HCl to pH 4 and extracted (3xAcOEt). The
combined organic extracts were dried with MgSO4, concentrated in vacuo and
chromatographed on silica gel in hexane:AcOEt 7:3 13 (742 mg; 29%; Rf 0.24) and 14 (616
mg; 25%; Rf 0.2) as colourless oils. Note that mixed fractions were also obtained which were
processed successfully in the following stages. Data for 13: δH (270 MHz, CDCl3) 4.21, 4.20
(2H, 2q, J 7.2, OCH2CH3), 3.72 (3H, s, OCH3), 3.68 (3H, s, OCH3), 3.07, 2.81 (2H, 2d, J
17.0, CH2COOMe), 2.62 (1H, ddd, J 16.5, 9.2, 6.6, CH2CH2COOMe), 2.46 (1H, ddd, J 16.5,
9.8, 6.3, CH2CH2COOMe), 2.35-2.08 (2H, m, CH2CH2COOMe), 1.35 (3H, t, J 7.2,
OCH2CH3); δC (100.5 MHz, CDCl3) 171.7, 169.0, 167.4 (COOR), 117.9 (CN), 63.4
(OCH2CH3), 52.4 (OCH3), 52.1 (OCH3), 45.1 (C 4o), 40.7 (CH2COOMe), 32.0
(CH2CH2COOMe), 29.7 (CH2CH2COOMe), 14.0 (OCH2CH3); m/z (electrospray, positive)
19

ACCEPTED MANUSCRIPT
+
+
289 (M+NH4 ); HRMS: Found: M+NH4 , 289.1396. C12H21N2O6 requires 289.1394. Data for
14: δH (270 MHz, CDCl3) 3.84 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.68 (3H, s, OCH3), 3.08,
2.83 (2H, 2d, J 17.1, CH2COOMe), 2.61 (1H, ddd, J 16.3, 9.2, 6.7, CH2CH2COOMe), 2.46
(1H, ddd, J 16.3 9.7 6.3, CH2CH2COOMe), 2.32-2.10 (2H, m, CH2CH2COOMe); δC (100.5
MHz, CDCl3) 171.6, 168.9, 168.3 (COOMe), 117.8 (CN), 53.9 (OCH3), 52.5 (OCH3), 52.1
(OCH3), 45.1 (C 4o), 40.7 (CH2COOMe), 32.0 (CH2CH2COOMe), 29.7 (CH2CH2COOMe);
+
+
m/z (electrospray, positive) 275 (M+NH4 ); HRMS: Found: M+NH4 , 275.1238. C11H19N2O6
requires 275.1238.
1-t-Butyl-2-ethyl-4-methyl 2-cyano-1,2,4-butanetricarboxylate (15)
(i) 1-t-Butyl-2-ethyl 2-cyano-1,2-ethanedicarboxylate
Ethyl cyanoacetate (2.4 mL; 22.5 mmol) was dissolved in dry t-butanol (20 mL) at room
temp. and ButOK (2.52 g; 22.5 mmol) was added. The resulting suspension was stirred for 15
min. and a solution of t-butyl chloroacetate (1.1 mL, 7.5 mmol) in dry t-butanol (4 mL) was
added. The mixture was stirred at room temperature overnight, then poured into ice (50 g)
with concentrated HCl (2 mL), and water (20 mL) was added. The resulting mixture was
extracted (3x DCM), the combined extracts were dried with MgSO4 and concentrated in
vacuo. The residue was distilled under vacuum (bp 118-125oC at 1.0 mmHg) to give the
monoalkylated title compound (0.65 g; 37%) as a colourless oil. δH (400 MHz, CDCl3) 4.28
(2H, q, J 7.0, OCH2CH3), 3.84 (1H, t, J 6.5, CH), 2.92 (1H, dd, J 16.0, 6.5 CH2COOBut), 2.84
(1H, dd, J 16.0, 6.5, CH2COOBut), 1.46 (9H, s, C(CH)3)3), 1.32 (3H, t, J 7.0, OCH2CH3); δC
(100.5 MHz, CDCl3) 168.0, 165.2 (COOR), 116.0 (CN), 82.8 (C(CH3)3), 63.3 (OCH2CH3),
34.8 (CH2COOBut), 33.2 (CH), 28.0 (C(CH3)3), 14.0 (OCH2CH3); m/z (CI) 228 (M+H+);
HRMS: Found: M+H+, 228.1232. C11H18NO4 requires 228.1236.
(ii) 1-t-Butyl-2-ethyl-4-methyl 2-cyano-1,2,4-butanetricarboxylate (15)
The cyanodiester (from part (i)) (0.30 g; 1.32 mmol) was dissolved in ethanol-water 1:1 (2
mL), cooled to 0-5oC and Et3N (0.23 mL) was added. After 15 min. of stirring, methyl
acrylate (0.13 mL; 1.39 mmol) was added dropwise. The mixture was stirred at 0-5oC for 2 h,
allowed to warm to room temperature and stirred for further 4 h. The mixture was then
concentrated, diluted with water, acidified with 2M HCl to pH 4 and extracted (3x AcOEt).
The combined extracts were dried with MgSO4, concentrated in vacuo and chromatographed
on silica gel in hexane:AcOEt 4:1 to give the bisalkylated ester 15 (242 mg; 64%) as a
colourless oil. δH (300 MHz, CDCl3) 4.37-4.21 (2H, m, OCH2CH3), 3.70 (3H, s, OCH3), 3.00,
20

ACCEPTED MANUSCRIPT
2.74 (2H, 2d, J 16.9, CH2COOBut), 2.64 (1H, ddd, J 16.4, 9.6, 6.5, CH2CH2COOMe), 2.48
(1H, ddd, J 16.4, 10.0, 6.2, CH2CH2COOMe), 2.30-2.10 (2H, m, CH2CH2COOMe), 1.46 (9H,
s, C(CH3)3), 1.35 (3H, t, J 7.0, OCH2CH3); δC (75.5 MHz, CDCl3) 171.8, 171.8, 167.4
(COOR), 118.1 (CN), 82.8 (C(CH3)3), 63.2 (OCH2CH3), 52.0 (OCH3), 45.4 (C 4o), 42.0
(CH2COOBut), 32.0 (CH2CH2COOMe), 29.6 (CH2CH2COOMe), 27.9 (C(CH3)3), 14.0
+
+
(OCH2CH3); m/z (electrospray, positive) 331 (M+NH4 ); HRMS: Found: M+NH4 , 331.1865.
C15H27N2O6 requires 331.1865.
Methyl 3-(ethoxycarbonyl)-6-oxo-3-piperidineacetate (16) from triester 13
Cyanotriester 13 (742 mg; 2.74 mmol) was dissolved in ethanol (7 mL) and glacial acetic acid
(7 mL), PtO2 (80 mg) was added and the mixture was hydrogenated in a Parr-shaker flask (4
atm, room temp.) for 4 days. TLC showed the disappearance of starting material. The solution
was decanted with a pipette and the catalyst was washed twice with methanol. The combined
supernatants were concentrated in vacuo and worked up in AcOEt/sat. NaHCO3aq. The
organic layer was dried with MgSO4, concentrated in vacuo and chromatographed on silica
gel (DCM:MeOH 19:1) to give lactam 16 (556 mg; 84%) as a pale yellow oil. IR (neat): ν
3231, 2956, 1727, 1666, 1197; δH (270 MHz, CDCl3) 6.31 (1H, s, NH), 4.20 (2H, q, J 6.9,
OCH2CH3) 3.77 (1H, d, J 12.9, CH2NH), 3.65 (3H, s, OCH3), 3.31 (1H, d, J 12.9, CH2NH),
2.75, 2.65 (2H, 2d, J 15.8, CH2COOMe), 2.50-2.30 (2H, m, CH2CONH), 2.30-2.14 (1H, m,
CH2CH2CONH), 1.95-1.80 (1H, m, CH2CH2CNH), 1.24 (3H, t, J 6.9, OCH2CH3); δC (100.5
MHz, CDCl3) 173.2 (CONH), 171.0, 170.6 (COOR), 61.6 (OCH2CH3), 51.8 (OCH3), 47.8
(CH2NH), 43.0 (C 4o), 39.8 (CH2COOMe), 29.1 (CH2CH2CONH), 28.1 (CH2CH2CONH),
14.1 (OCH2CH3); m/z (CI) 244 (M+H+); HRMS: Found: M+H+, 244.1182. C11H18NO5
requires 244.1185.
Cyanotriester 13 (0.92 g; 3.39 mmol) was dissolved in ethanol (20 mL), PtO2 (0.1 g) was
added and the mixture was hydrogenated in an autoclave (7.5 atm) for 2 days. TLC still
showed the presence of starting material. PtO2 (0.05 g) was added and hydrogenation was
continued overnight. The solution was decanted with a pipette and the catalyst was washed
twice with methanol. The combined supernatants were concentrated in vacuo and
chromatographed on silica gel (DCM:MeOH 19:1) to give lactam 16 (0.69 g; 84%) as a
colourless oil, identical with that obtained above.
Methyl 3-(methoxycarbonyl)-6-oxo-3-piperidineacetate (17)
21

ACCEPTED MANUSCRIPT
Cyanotriester 14 (616 mg; 2.4 mmol) was dissolved in ethanol (6 mL) and glacial acetic acid
(6 mL), PtO2 (70 mg) was added and the mixture was hydrogenated in a Parr-shaker flask (4
atm, room temp.) for 4 days. TLC showed the consumption of starting material. The solution
was decanted with a pipette and the catalyst was washed twice with methanol. The combined
supernatants were concentrated in vacuo and worked up in AcOEt/sat. NaHCO3aq. The
organic layer was dried with MgSO4, concentrated in vacuo and chromatographed on silica
gel (DCM:MeOH 19:1) to give lactam 17 (190 mg; 35%) as a low melting solid which proved
difficult to recrystallise. IR (neat): ν 3217, 2954, 1728, 1663; δH (400 MHz, CDCl3) 5.82 (1H,
s, NH), 3.80 (1H, dd, J 12.7, 1.8, CH2NH), 3.75 (3H, s, OCH3), 3.67 (3H, s, OCH3), 3.33 (1H,
dd, J 12.7, 1.8, CH2NH), 2.77, 2.67 (2H, 2d, J 15.6, CH2COOMe), 2.50-2.34 (2H, m,
CH2CONH), 2.29-2.18 (1H, m, CH2CH2CONH), 1.95-1.85 (1H, m, CH2CH2CNH); δC (100.5
MHz, CDCl3) 173.7 (CONH), 171.2, 170.6 (COOMe), 52.6 (OCH3), 51.9 (OCH3), 47.7
(CH2NH), 43.0 (C 4o), 39.9 (CH2COOMe), 29.1 (CH2CH2CONH), 28.1 (CH2CH2CONH);
m/z (EI+) 229 (M+); HRMS: Found: M+, 229.0941. C10H15NO5 requires 229.0945.
Cyanotriester 14 (1.76 g; 6.85 mmol) was dissolved in ethanol (80 mL), PtO2 (0.2 g) was
added and the mixture was hydrogenated in an autoclave (7.5 atm) for 3 days. TLC still
showed the presence of starting material. PtO2 (0.1 g) was added and hydrogenation was
continued overnight. The solution was decanted with a pipette and the catalyst was washed
twice with methanol. The combined supernatants were concentrated in vacuo and
chromatographed on silica gel (DCM:MeOH 19:1) to give lactam 17 (1.36 g; 87%) as a
colourless oil, which was identical to that obtained above.
t-Butyl 3-(ethoxycarbonyl)-6-oxo-3-piperidineacetate (18)
Cyanotriester 15 (0.25 g; 0.8 mmol) was dissolved in ethanol (10 mL), PtO2 (50 mg) was
added and the mixture was hydrogenated in an autoclave (7.5 atm) for 2 days. TLC still
showed the presence of starting material. Further PtO2 (30 mg) was added and hydrogenation
was continued overnight. The solution was decanted and the catalyst was washed twice with
methanol. The combined supernatants were concentrated in vacuo and chromatographed on
silica gel (DCM:MeOH 19:1) to give lactam 18 (217 mg; 95%) as a colourless oil. δH (400
MHz, CDCl3) 6.61 (1H, s, NH), 4.20 (2H, q, J 7.0, OCH2CH3) 3.77 (1H, dd, J 12.8, 1.6,
CH2NH), 3.36 (1H, dd, J 12.8, 1.6 CH2NH), 2.67, 2.58 (2H, 2d, J 15.8, CH2COOBut), 2.45-
2.30 (2H, m, CH2CONH), 2.21 (1H, ddd, J 13.5, 6.0, 6.0, CH2CH2CONH), 1.88 (1H, ddd, J
13.5, 7.5, 7.5, CH2CH2CNH), 1.43 (9H, s, C(CH3)3), 1.27 (3H, t, J 7.0, OCH2CH3); δC (100.5
22

ACCEPTED MANUSCRIPT
MHz, CDCl3) 173.2 (CONH), 171.3, 169.3 (COOR), 81.5 (C(CH3)3), 61.4 (OCH2CH3), 47.8
(CH2NH), 42.9 (C 4o), 41.4 (CH2COOBut), 29.1 (CH2CH2CONH), 28.2 (CH2CH2CONH),
28.0 (C(CH3)3), 14.1 (OCH2CH3); m/z (electrospray, positive) 286 (M+H+); HRMS: Found:
M+H+, 286.1644. C14H24NO5 requires 286.1649.
Methyl 3-(ethoxycarbonyl)-6-oxo-3-piperidineacetate (16) from 18
Tert-Butyl ester 18 (436 mg; 1.53 mmol) was dissolved in MeOH (10 mL) and concentrated
HCl (0.5 mL) was added dropwise while stirring. The mixture was heated in reflux for 5 h. It
was concentrated in vacuo and worked up in DCM/sat. NaHCO3aq. The combined organic
extracts were dried with MgSO4, concentrated in vacuo and chromatographed on silica gel
(DCM:MeOH 9:1) to give lactam 16 (183 mg; 49%) as a pale yellow oil, identical with that
obtained above.
2-Methyl-2,7-diazaspiro[4.5]decane-1,3,8-trione (19) from 16
A solution of 16 (547 mg; 2.25 mmol) in 40% aqueous methylamine (3 mL) was stirred
overnight at room temp. The mixture was gradually heated in oil bath to 170oC over 1.5 h
while the volatiles were distilled off. Work up as above gave lactam 19 (289 mg; 66%) as
colourless crystals. For characterization, see below.
2-Methyl-2,7-diazaspiro[4.5]decane-1,3,8-trione (19) from 17
A solution of dimethyl ester 17 (177 mg; 0.77 mmol) in 40% aqueous methylamine (2 mL)
was stirred overnight at room temp. The mixture was gradually heated in oil bath to 170oC
over 1.5 h while the volatiles were distilled off. The pale pink solid residue obtained was
recrystallised from ethanol to give imide 19 (110 mg; 73%) as white crystals mp 185-190oC.
IR (neat): ν 3166, 3033, 1772, 1703, 1650, 1410; δH (300 MHz, D2O) 3.48, 3.22 (2H, 2d, J
12.8, CH2NH), 2.83 (3H, s, CH3), 2.70 (2H, s, CH2CONMe), 2.52-2.22 (2H, m,
CH2CH2CONH), 2.09 (1H, ddd, J 13.5, 9.5, 7.5, CH2CH2CONH), 1.85 (1H, ddd, J 13.5, 6.5,
4.0, CH2CH2CONH); δC (75.5 MHz, D2O) 183.1, 179.6 (CONMe), 175.1 (CONH), 48.4
(CH2NH), 42.8 (C 4o), 38.9 (CH2CONMe), 28.2 (CH2CH2CONH), 27.7 (CH2CH2CONH),
25.6 (CH3); m/z (EI+) 196 (M+); HRMS: Found: M+, 196.0845. C9H12N2O3 requires
196.0842.
2-Methyl-2,7-diazaspiro[4.5]decane (5)
23

ACCEPTED MANUSCRIPT
Imide 19 (1.43 g; 7.3 mmol) was suspended in dry THF (30 mL) in 0-5oC under N2 and 1M
solution of LiAlH4 in THF (29 mL; 29 mmol) was added dropwise. The ice bath was removed
and the mixture was heated in reflux overnight under N2. It was cooled to 0-5oC and the
following were slowly added dropwise in 0-5oC: water (1.5 mL), 15% NaOHaq (1.5 mL) and
water (4.5 mL). The resulting slurry was filtered through Celite, the solids were washed with
THF (250 mL) and the combined filtrates were concentrated in vacuo to give a yellow oil
which was distilled under vacuum (bp 66oC at 2.5 mmHg) to give spirodiamine 4 (755 mg;
67%) as a colourless oil. δH (400 MHz, CDCl3) 2.77-2.68 (2H, m, CH2CH2NMe), 2.66, 2.59
(2H, 2d, J 11.7, CH2NMe), 2.59-2.51 (1H, m, CH2CH2CH2NH), 2.50-2.40 (2H, m, CH2NH,
CH2CH2CH2NH), 2.29 (3H, s, CH3), 2.23 (1H, d, J 9.3, CH2NH), 1.73 (1H, br s, NH), 1.68-
1.39 (6H, m, CH2CH2NMe, CH2CH2CH2NH, CH2CH2CH2NH); δC (100.5 MHz, CD3OD)
67.2 (CH2NMe), 57.5 (CH2NH), 56.0 (CH2CH2NMe), 46.6 (CH2CH2CH2NH), 42.6 (CH3),
42.1 (C 4o), 37.2 (CH2CH2CH2NH), 36.9 (CH2CH2NMe), 24.5 (CH2CH2CH2NH); m/z
(electrospray, positive) 155 (M+H+); HRMS: Found: M+H+, 155.1541. C9H19N2 requires
155.1548.
1-t-Butyl-3-ethyl-4-methyl 3-cyano-1,3,4-butanetricarboxylate (20) and 1-t-butyl-3,4-
dimethyl 3-cyano-1,3,4-butanetricarboxylate (21)
Cyanodiester 12 (1.16 g; 6.78 mmol) was dissolved in ethanol-water 1:1 (12 mL), cooled to 0-
5oC and Et3N (1.2 mL) was added dropwise. After 15 min. t-butyl acrylate (1.05 mL; 0.92 g;
7.14 mmol) was added dropwise. The mixture was stirred at 0-5oC for 1.5 h, allowed to warm
to room temp. and stirred for further 2 h. It was then concentrated, diluted with water,
acidified with 2N HCl to pH 4 and extracted 3x with AcOEt. The combined organic extracts
were dried with MgSO4, concentrated in vacuo and chromatographed on silica gel in
hexane:AcOEt 4:1) to give 20 (0.61 g; 29%; Rf 0.27) and 21 (0.77 g; 38%; Rf 0.23) as
colourless oils. Data for 20: δH (270 MHz, CDCl3) 4.30, 4.29 (2H, 2q, J 6.9, OCH2CH3), 3.72
(3H, s, OCH3), 3.07, 2.80 (2H, 2d, J 17.1, CH2COOMe), 2.53 (1H, ddd, J 16.2, 9.5, 6.0,
CH2CH2COOBut), 2.36 (1H, ddd, J 16.2, 9.6, 6.6, CH2CH2COOBut), 2.26-2.00 (2H, m,
CH2CH2COOBut), 1.43 (9H, s, C(CH3)3), 1.34 (3H, t, J 6.9, OCH2CH3); δC (100.5 MHz,
CDCl3) 170.5, 169.0, 167.8 (COOR), 118.0 (CN), 81.4 (C(CH3)3), 63.3 (OCH2CH3), 52.4
(OCH3), 45.2 (C 4o), 40.7 (CH2COOMe), 32.1 (CH2CH2COOBut), 31.0 (CH2CH2COOBut),
28.1 (C(CH3)3), 14.0 (OCH2CH3); m/z (CI) 314 (M+H+); HRMS: Found: M+H+, 314.1598.
C15H24NO6 requires 314.1604. Data for 21: δH (270 MHz, CDCl3) 3.84 (3H, s, OCH3), 3.72
(3H, s, OCH3), 3.08, 2.81 (2H, 2d, J 17.1, CH2COOMe), 2.53 (1H, ddd, J 16.0, 9.5, 6.0,
24

ACCEPTED MANUSCRIPT
CH2CH2COOBut), 2.36 (1H, ddd, J 16.0, 10.0, 6.0, CH2CH2COOBut), 2.25-2.05 (2H, m,
CH2CH2COOBut), 1.43 (9H, s, C(CH3)3); δC (100.5 MHz, CDCl3) 170.4, 169.0, 168.4
(COOR), 118.0 (CN), 81.4 (C(CH3)3), 53.9 (OCH3), 52.4 (OCH3), 45.1 (C 4o), 40.8
(CH2COOMe), 32.1 (CH2CH2COOBut), 31.0 (CH2CH2COOBut), 28.1 (C(CH3)3); m/z (CI)
300 (M+H+); HRMS: Found: M+H+, 300.1445. C14H22NO6 requires 300.1447.
t-Butyl 4-(ethoxycarbonyl)-6-oxo-4-pyrrolidinepropionate (22)
Cyanotriester 20 (0.56 g; 1.79 mmol) was dissolved in ethanol (12 mL), PtO2 (60 mg) was
added and the mixture was hydrogenated in an autoclave (8 atm) for 2 days. TLC showed the
absence of starting material. The solution was decanted with a pipette and the catalyst was
washed twice with methanol. The combined supernatants were concentrated in vacuo and
chromatographed on silica gel (DCM:MeOH 19:1) to give lactam 22 (0.32 g; 63%) as a
colourless oil which solidified when chilled. An analytical sample was recrystallised from
AcOEt/hexane to give pure 22 as white crystals mp 95-97oC. IR (neat): ν 3196, 3102, 2935,
1722, 1712, 1685, 1366; δH (400 MHz, CDCl3) 6.11 (1H, s, NH), 4.19 (2H, q, J 7.1,
OCH2CH3), 3.77, 3.25 (2H, 2d, J 10.0, CH2NH), 2.85, 2.26 (2H, 2d, J 17.1, CH2CONH),
2.23-1.98 (4H, m, CH2CH2COOBut), 1.44 (9H, s, C(CH3)3), 1.27 (3H, t, J 7.1, OCH2CH3); δC
(100.5 MHz, CDCl3) 175.6 (CONH), 173.9, 171.6 (COOR), 80.9 (C(CH3)3), 61.7
(OCH2CH3), 49.8 (CH2NH), 49.2 (C 4o), 39.0 (CH2CONH), 32.7 (CH2CH2COOBut), 31.2
+
(CH2CH2COOBut), 28.1 (C(CH3)3), 14.2 (OCH2CH3); m/z (CI) 303 (M+NH4 ); HRMS:
+
Found: M+NH4 , 303.1913. C14H27N2O5 requires 303.1914. Anal. calcd. for C14H23NO5: C,
58.91; H, 8.13; N, 4.91. Found: C, 58.90; H, 8.30; N, 5.00.
t-Butyl 4-(methoxycarbonyl)-6-oxo-4-pyrrolidinepropionate (26)
Cyanotriester 21 (0.72 g; 2.41 mmol) was dissolved in ethanol (15 mL), PtO2 (80 mg) was
added and the mixture was hydrogenated in an autoclave (8 atm) for 3 days. TLC still showed
the presence of starting material. PtO2 (50 mg) was added and hydrogenation was continued
overnight. The solution was decanted with a pipette and the catalyst was washed twice with
methanol. The combined supernatants were concentrated in vacuo and chromatographed on
silica gel (DCM:MeOH 19:1) to give lactam 26 (0.43 g; 66%) as a colourless oil which
solidified. An analytical sample was recrystallised from AcOEt/hexane to give pure 26 as
white crystals mp 117-118oC. IR (neat): ν 3199, 3107, 2886, 1733, 1721, 1682, 1224; δH (270
MHz, CDCl3) 6.62 (1H, s, NH), 3.75 (1H, d, J 10.2, CH2NH), 3.72 (3H, s, OCH3), 3.24 (1H,
d, J 10.2, CH2NH), 2.83, 2.25 (2H, 2d, J 17.1, CH2CONH), 2.22-1.92 (4H, m,
25

ACCEPTED MANUSCRIPT
CH2CH2COOBut), 1.41 (9H, s, C(CH3)3); δC (100.5 MHz, CDCl3) 175.9 (CONH), 174.4,
171.6 (COOR), 80.9 (C(CH3)3), 52.7 (OCH3), 50.0 (CH2NH), 49.2 (C 4o), 39.1 (CH2CONH),
32.7 (CH2CH2COOBut), 31.2 (CH2CH2COOBut), 28.1 (C(CH3)3); m/z (CI) 289 (M+NH4 );
+
+
HRMS: Found: M+NH4 , 289.1758. C13H25N2O5 requires 289.1758.
Methyl 4-(ethoxycarbonyl)-6-oxo-4-pyrrolidinepropionate (23)
Tert-butyl ester 22 (0.26 g; 0.91 mmol) was dissolved in MeOH (7 mL) and concentrated HCl
(0.2 mL) was added dropwise while stirring. The mixture was heated in reflux for 2 h,
allowed to cool down to room temp. and neutralised with sat. NaHCO3aq (2 mL). Methanol
was evaporated in vacuo and the residue was worked up in DCM/water. The combined
organic extracts were dried with MgSO4, concentrated in vacuo and chromatographed on
silica gel (DCM:MeOH 9:1) to give methyl ester 23 (208 mg; 94%) as a colourless oil. IR
(neat): ν 3245, 2955, 1724, 1692; δH (400 MHz, CDCl3) 6.08 (1H, s, NH), 4.19 (2H, q, J 7.1,
OCH2CH3), 3.77 (1H, d, J 9.8, CH2NH), 3.68 (3H, s, OCH3), 3.26 (1H, d, J 9.8, CH2NH),
2.87 (1H, d, J 17.1, CH2CONH), 2.38-2.04 (5H, m, CH2CONH (1H), CH2CH2COOBut
(4H)), 1.28 (3H, t, J 7.1, OCH2CH3); δC (100.5 MHz, CDCl3) 175.5 (CONH), 173.7, 172.7
(COOR), 61.8 (OCH2CH3), 49.8 (CH2NH), 49.2 (C4o), 39.0 (CH2CONH), 32.6
(CH2CH2COOMe), 29.8 (CH2CH2COOMe), 14.2 (OCH2CH3); m/z (CI) 244 (M+H+); HRMS:
Found: M+H+, 244.1186. C11H18NO5 requires 244.1185.
Methyl 4-(methoxycarbonyl)-6-oxo-4-pyrrolidinepropionate (27)
Tert-butyl ester 26 (0.29 g; 1.07 mmol) was dissolved in MeOH (8 mL) and concentrated HCl
(0.25 mL) was added dropwise while stirring. The mixture was heated in reflux for 2 h,
allowed to cool down to room temp. and neutralised with sat. NaHCO3aq (3 mL). Methanol
was evaporated in vacuo and the residue was worked up in DCM/water. The combined
organic extracts were dried with MgSO4, concentrated in vacuo and chromatographed on
silica gel (DCM:MeOH 9:1) to give lactam 27 (172 mg; 70%) as a colourless oil. IR (neat): ν
3232, 2955, 1727, 1692; δH (400 MHz, CDCl3) 6.05 (1H, s, NH), 3.80 (1H, d, J 10.0,
CH2NH), 3.74 (3H, s, OCH3), 3.68 (3H, s, OCH3), 3.27 (1H, d, J 10.0, CH2NH), 2.87 (1H, d,
J 17.1, CH2CONH), 2.37-2.23 (3H, m, CH2CONH (1H), CH2CH2COOMe (2H)), 2.21-2.06
(2H, m, CH2CH2COOMe); δC (100.5 MHz, CDCl3) 175.5 (CONH), 174.2, 172.7 (COOR),
52.7 (OCH3), 51.9 (OCH3), 49.8 (CH2NH), 49.2 (C 4o), 39.0 (CH2CONH), 32.6
(CH2CH2COOMe), 29.8 (CH2CH2COOMe); m/z (CI) 230 (M+H+); HRMS: Found: M+H+,
230.1028. C10H16NO5 requires 230.1028.
26

ACCEPTED MANUSCRIPT
2-Methyl-2,7-diazaspiro[4.5]decane-1,3,8-trione (19) from 23
A solution of ethyl ester 23 (205 mg; 0.84 mmol) in 40% aqueous methylamine (2.5 mL) was
stirred overnight at room temp. The mixture was gradually heated in oil bath to 180oC over
1.5 h while the volatiles were distilled off. The solid residue obtained was recrystallised from
ethanol to give spirocycle 19 (57 mg; 34%) which was identical in all respects to that obtained
above.
N-Methyl 4-(methylaminocarbonyl)-6-oxo-4-pyrrolidinepropionamide (24) from 27
A solution of dimethyl ester 27 (170 mg; 0.74 mmol) in 40% aqueous methylamine (2 mL)
was stirred overnight at room temp. The mixture was gradually heated in oil bath to 180oC
over 1.5 h while the volatiles were distilled off. A semi-solid residue was obtained, which was
recrystallised from ethanol to give bisamide 24 (155 mg; 92%) as white crystals mp 178-
180oC. IR (neat): ν 3296, 3087, 2946, 1676, 1632, 1552; δH (270 MHz, D2O) 3.73, 3.37 (2H,
m, CH2NH), 2.85 (1H, d, J 11.5, CH2CONH), 2.74 (3H, s, CH3), 2.69 (3H, s, CH3), 2.39 (1H,
d, J 11.5, CH2CONH), 2.23-2.12 (2H, m, CH2CH2CONHMe), 2.12-1.97 (2H, m,
CH2CH2CONHMe); δC (100.5 MHz, D2O) 178.5, 176.5, 175.6 (CONH), 50.1 (CH3), 49.6
(CH3), 39.0 (C 4o), 33.6 (CH2NH), 31.3 (CH2CONH), 26.3 (CH2CH2CONHMe), 26.1
(CH2CH2CONHMe); m/z (CI) 228 (M+H+); HRMS: Found: M+H+, 228.1348. C10H18N3O3
requires 228.1348. Anal. calcd. for C10H17N3O3: C, 52.83; H, 7.54; N, 18.50. Found: C, 52.81;
H, 7.47; N, 18.60.
Bismethyl ester 27 (1.28 g; 5.59 mmol) was dissolved in methanol (15 mL), 40% aqueous
methylamine (10 mL; 116 mmol) was added and the mixture was stirred overnight at room
temp. TLC showed complete disappearance of starting material. The mixture was
concentrated in vacuo and worked up in DCM/water. The aqueous layer was concentrated in
vacuo and chromatographed on silica gel (CHCl3:EtOH:NH3aq 25:25:1) to give biamide 24
(1.10 g; 87%) as a white solid which was identical to that obtained above.
N-Methyl 4-(methylaminocarbonyl)-6-oxo-4-pyrrolidinepropionamide (24) from 23
Methyl ethyl diester 23 (240 mg; 1.0 mmol) was dissolved in methanol (3 mL), 40% aqueous
methylamine (0.1 mL; 1.16 mmol) was added and the mixture was stirred overnight at room
temp. TLC showed mainly starting material. MeNH2 solution (0.8 mL) was gradually added
over 2 days until complete disappearance of starting material on TLC. The mixture was
27

ACCEPTED MANUSCRIPT
concentrated in vacuo and worked up in DCM/water. The aqueous layer was concentrated in
vacuo and chromatographed on silica gel (CHCl3:EtOH:NH3aq 25:25:1) to give bisamide 24
(166 mg; 74%) as a white solid which was identical to that obtained above.
Note that in general, bisamide 24 did not require purification and was generally used directly
in the next step.
7-Methyl-2,7-diazaspiro[4.5]decane-3,6,8-trione (25)
A suspension of crude 24 (1.7 g; 7.49 mmol) and p-TsOH.H2O (1.57 g; 8.21 mmol; 1.1 eq) in
p-xylene (20 mL) was heated at reflux overnight. The mixture was then evaporated to dryness
and worked up in water/AcOEt. The organic phase was concentrated to dryness and the
residue was chromatographed on silica gel (CHCl3:EtOH:NH3aq 25:25:1) to give a white
1
solid (1.30 g; conv. 89%) containing 25 and 19 in 3:1 ratio by H NMR. Purification was
achieved by recrystallisation from EtOH to give 25 as colourless crystals, mp 186-196oC. IR
(neat): ν 3238, 2683, 1669, 1356, 1273, 1112, 1021, 1011; δH (400 MHz, D2O; no trace of 19
detectable) 3.81, 3.49 (2H, 2d, J 10.8, CH2NH), 3.10 (3H, s, CH3), 2.84 (1H, d, J 17.4,
CH2CONH), 2.83, 2.79 (2H, 2d, J 6.6, CH2CH2CONMe), 2.57 (1H, d, J 17.4, CH2CONH),
2.16, 2.15 (2H, 2d, J 6.6, CH2CH2CONMe); δC (100.5 MHz, D2O) 178.4, 177.7, 175.4
(CONH), 51.0 (CH2NH), 45.4 (C 4o), 40.2 (CH2CONH) 29.2 (CH2CH2CONMe), 27.4
(CH2CH2CONMe), 25.3 (CH3); m/z (CI) 197 (M+H+); HRMS: Found: M+H+, 197.0925.
C9H13N2O3 requires 197.0926. Anal. calcd. for C9H12N2O3: C, 55.08; H, 6.17; N, 14.28.
Found: C, 55.29; H, 5.99; N, 14.22.
Isomers 19 and 25 were purified by crystallisation as these isomers were inseparable by
conventional chromatography and HPLC. The extent of isomerisation that occurred depended
on the conditions used. This reaction was examined under a series of conditions with
conversions and product ratios shown in Table 2 below. It should also be noted that although
trace amounts of 19 were observed in samples of 25, following reduction and N-arylation, the
corresponding N-arylated derivatives (e.g. 42 and 43 below) are readily separated by
chromatography.
28

ACCEPTED MANUSCRIPT
Table 2.
Solvent
Amount
Time
Conversion
25 : 19
(1H NMR)
3 : 1
(all at reflux)
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene*
p-xylene**
MeOH
p-TsOH (eq)
(h)
(%)
89
1.1
0.3
0.3
1.0
1.1
1.1
1.1
1.1
overnight
overnight
<30
<30
66
-
4
-
4
1.5
9 : 1
93
7 : 1
2
74
8 : 1
overnight
overnight
73
1 : 1
EtOH
51
5.5 : 1
*Enhancement of 25 to >19:1 ratio (starting from 7:1 mixture) was achieved by
recrystallisation from EtOH. **Reaction was carried out under gentle N2 flow with a valve
open to release MeNH2.
7-Methyl-2,7-diazaspiro[4.5]decane (6)
To a suspension of 25 (0.79 g; 4.03 mmol) in dry THF (25 mL) in 0-5oC under N2 was added
dropwise LiAlH4 (18 mL; 18 mmol, 1M solution in THF). The ice bath was removed and the
mixture was heated in reflux overnight under N2 after which time it was cooled to 0-5oC and
the following were slowly added dropwise in 0-5oC: water (0.8 mL), 15% NaOHaq (0.8 mL)
and water (2.5 mL). The resulting slurry was filtered through Celite, the solids were washed
with THF (150 mL) and the combined filtrates were concentrated in vacuo to give a yellow
oil which was distilled under vacuum (bp 82-85oC at 2.5 mmHg) to give spirodiamine 6 (254
mg; 41%) as a colourless oil. δH (400 MHz, CD3OD) 2.90, 2.88 (2H, 2d, J 7.0, CH2NMe),
2.81-2.48 (4H, m, CH2CH2CH2NMe, CH2NH), 2.45-2.15 (2H, m, CH2CH2NH), 2.22 (3H, s,
CH3), 1.75-1.35 (6H, m, CH2CH2CH2NMe, CH2CH2CH2NMe, CH2CH2NH); δC (100.5 MHz,
CDCl3) 66.0 (CH2NH), 62.4 (CH2NMe), 56.2 (CH2CH2CH2NMe), 47.0 (CH3), 46.3
(CH2CH2NH), 43.2 (C 4o), 34.8 (CH2CH2NH), 34.3 (CH2CH2CH2NMe), 23.7
(CH2CH2CH2NMe); m/z (CI) 155 (M+H+); HRMS: Found: M+H+, 155.1541. C9H19N2
requires 155.1548.
2,7-Di-t-butylcarboxy-2,7-diazaspiro[4.4]nonane (28)
29