N-alkylation-intramolecular michael addition: New reaction manifold for high throughput annulation of amines

Article abstract of DOI:10.1055/s-0029-1217962

Parallel synthesis of -substituted pyrrolidines, piper-idines, morpholines, piperazines and diazaspirocycles was achieved in a single reaction step via the annulation of primary amines with halo-2-alkenyl esters, amides, nitriles and phenylsulfones.

Full text of DOI:10.1055/s-0029-1217962

LETTER
2857
N-Alkylation–Intramolecular Michael Addition: New Reaction Manifold for
High Throughput Annulation of Amines
N
-Alkylation–Int
a
ramolecula
l
r
Micha
u
el
A
dditionm Macleod, Paul A. Tuthill, Roland E. Dolle*
Department of Medicinal Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA
Fax +1(484)5951513; E-mail: rdolle@adolor.com
Received 5 June 2009
Bunce and co-workers reported the one-pot synthesis of
Abstract: Parallel synthesis of a-substituted pyrrolidines, piper-
idines, morpholines, piperazines and diazaspirocycles was achieved
in a single reaction step via the annulation of primary amines with
halo-2-alkenyl esters, amides, nitriles and phenylsulfones.
N-benzyl heterocycles bearing an a-acetate residue by re-
action of 6- or 7-halo-2-alkenoates with benzylamine.4
The reaction proceeds by a tandem N-alkylation–intramo-
lecular Michael addition. Products yielding five- and six-
membered rings formed easily while higher order rings
were not obtained. We believed that the relatively mild re-
action conditions (EtOH, 80 °C, 36 h) and modest yields
(ca. 50%) were compatible with primary amines possess-
ing a diverse range of functionality. To investigate this,
iodides 7 and 8 were prepared and reacted with the prima-
ry amines a1–a4 (Figure 1).
Key words: heterocycle, amine, annulation, intramolecular, paral-
lel synthesis
Chemical libraries of amides, sulfonamides, ureas and
higher order amines derived from high throughput amine
derivatization chemistries are useful in discovering bio-
logically active compounds.1 Our laboratory has devel-
oped a new family of solid- and solution-phase annulation
reagents, termed SPAn reagents, for the single-step con-
version of primary amines to heterocycles.2 SPAn re-
agents, adaptable to semi-automated library production,
complement existing methodology for generating acyclic
amine derivatives. Two reaction manifolds for amine an-
nulation were previously described. These include the tan-
dem SN2 displacement–intramolecular acylation of resin-
bound haloalkyl esters affording lactams2 and the in-
tramolecular N-dialkylation of resin-bound bismesylates
affording piperidines, piperazines, and diazaspirocycles.3
In this Letter, we describe the application of a third reac-
tion manifold to amine annulation, tandem N-alkylation–
intramolecular Michael addition (SN2-Michael reaction),
affording a-substituted pyrrolidines 1, piperidines 2, mor-
pholines 3, piperazines 4 and novel diazaspirocycles 5 and
6 (Scheme 1).
SPAn reagents
I
CO2Et
I
CONRBn
n
n
9: n = 1; R = H
7: n = 1
8: n = 2
10: n = 2; R = H
11: n = 1; R = Me
12: n = 2; R = Me
I
I
CN
O
SO2Ph
13
14
Cl
I
I
n
O
CO2Me
CO2Me
O
15: n = 1
16: n = 2
17
I
n
N
CO2Me
NBoc
SO2Me
18
19: n = 1
20: n = 2
Me
Amine inputs
NH2
NH2
NH2
Ph
N
RNH2
SPAn
a2
a1
a4
a3
reagent
NH2
Ph
O
NH2
Me
NH2
N
Ph
a6
H
a5
Y
n
O
X
n
N
N
Me
N
O
N
R
N
O
R
OH
Ph
R
1: n = 1
2: n = 2
NH2
3: Y = O
5: n = 1
6: n = 2
BocN
Me
X = CO2R, CONR2, 4: Y = NSO2Me
SO2Ph, CN
a8
O
HO
NH2
a7
Scheme 1 High throughput amine derivatization
Figure 1 SPAn reagents and amine inputs used in this study
Treatment of one equivalent of amine with one equivalent
of iodide in EtOH (0.3 mM) at 80 °C for 72 hours was de-
termined to be the optimized general procedure for annu-
SYNLETT 2009, No. 17, pp 2857–2861
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217962; Art ID: S05609ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

2858
C. Macleod et al.
LETTER
lation under thermal reaction conditions (entries 1–8, lated amine. It was therefore advantageous to routinely
Table 1). In many instances the purity of crude products purify the products. This was conveniently carried out us-
1a–d/2a–d was <75%, which did not meet our purity cri- ing a multichannel CombiFlash system. The yields of the
teria for biological screening. The major by-product purified products 1a–d/2a–d ranged from 40–75%.
present in varying amounts was the corresponding dialky-
Table 1 Amine Annulation Products
SPAn reagents
n
7–16
X
RNH2
N
R
EtOH, 80 °C, 72 h
or MW, DIPEA, DMSO,
150 °C, 15 min
1,2
Entry
1
Amine
a1
a2
a3
a4
a1
a2
a3
a4
a1
a2
a1
a2
a5
a3
a1
a2
a2
a3
a5
a1
a2
a6
a1
a2
a4
a2
a2
a3
a5
SPAn reagent Product
R
n
1
1
1
1
2
2
2
2
1
1
2
2
1
2
1
1
2
1
2
2
2
2
2
2
2
1
2
1
2
X
Yield (%)a
(55) 61
(60) 73
(60) 58
(45) 52
(60) 81
(55) 65
(48) 43
(52) 55
45
7
7
1a
1b
1c
1d
2a
2b
2c
2d
1e
1f
(4-phenyl)phenethyl
3-pyridinylmethyl
cyclohexyl
CO2Et
2
CO2Et
3
7
CO2Et
4
7
2-methoxyethyl
(4-phenyl)phenethyl
3-pyridinylmethyl
cyclohexyl
CO2Et
5
8
CO2Et
6
8
CO2Et
7
8
CO2Et
8
8
2-methoxyethyl
(4-phenyl)phenethyl
3-pyridinylmethyl
(4-phenyl)phenethyl
3-pyridinylmethyl
3-indolylethyl
CO2Et
9
9
CONHBn
CONHBn
CONHBn
CONHBn
CONHBn
CONHBn
CON(Me)Bn
CON(Me)Bn
CON(Me)Bn
CON(Me)Bn
CON(Me)Bn
CN
10
11
12
13
14
15
17
18
19
20
21
22
23
24
25
26
27
28
29
30
9
38
10
10
9
2e
2f
70
72
1g
2g
1h
1i
35
10
11
11
12
11
12
13
13
13
14
14
14
15
16
15
16
cyclohexyl
60
(4-phenyl)phenethyl
3-pyridinylmethyl
3-pyridinylmethyl
cyclohexyl
62
60
2h
1j
53
46
2i
3-indolylethyl
51
2j
(4-phenyl)phenethyl
3-pyridinylmethyl
2,2-diphenylethyl
(4-phenyl)phenethyl
3-pyridinylmethyl
2-methoxyethyl
3-pyridinylmethyl
3-pyridinylmethyl
cyclohexyl
78
2k
2l
CN
86
CN
87
2m
2n
2o
1k
2p
1l
SO2Ph
85
SO2Ph
85
SO2Ph
85
CO2H
92
CO2H
90
CO2H
92
2q
3-indolylethyl
CO2H
98
a Isolated yields in brackets are from the thermal reaction conditions while all other yields are from the microwave-assisted reaction conditions.
Synlett 2009, No. 17, 2857–2861 © Thieme Stuttgart · New York

LETTER
N-Alkylation–Intramolecular Michael Addition
2859
Given the success of this initial study, a set of annulation
reagents was conceived to diversify the a,b-unsaturated
ester.5 The new SPAn reagents included the a,b-unsatur-
ated amides 9–12, a,b-unsaturated nitrile 13 and a,b-un-
saturated phenyl sulfone 14. The optimized reaction
conditions used to prepare 1a–d/2a–d from 7 and 8 were
only modestly successful in the annulation of amine a1
with 9–12. The yields were generally poor (<30%). In
fact, the desired products derived from the tandem SN2-
Michael reaction with reagents 13 and 14 were not ob-
served under these reaction conditions. Conducting the re-
actions in a variety of solvents, temperatures and reaction
times did not lead to a significant improvement in yield.
The application of microwaves was then investigated to
potentially circumvent this problem. After some experi-
mentation, optimized reaction conditions were identified:
one equivalent each amine and SPAn reagent with five
equivalents of either diisopropylethylamine (DIEA) or
macroporous carbonate resin (MP-carbonate) in DMSO at
150 °C for 15 minutes. Under microwave-assisted condi-
tions, SPAn reagents 9–14 reacted smoothly with a range
of amines to give a-substituted pyrrolidines and pipe-
ridines (entries 9–30, Table 1). The resin-bound SPAn re-
agents 15/16 (1.5 equiv) were found sufficiently reactive
as their alkyl chlorides and performed well with a range of
amines furnishing carboxylic acids (entries 27–30,
Table 1) after standard TFA-mediated resin cleavage in
high yield without resorting to chromatography. The mi-
crowave reaction conditions were also successfully ap-
plied to 7/8 → 1a–d/2a–d, significantly reducing reaction
time from three days to less than one hour. DMSO was the
critical solvent choice for the microwave-assisted annula-
tion as poor results were achieved with EtOH and other
solvents. Further structure diversity in the annulation
products was possible by introducing a heteroatom into
the iodoalkenyl chain as per a,b-unsaturated iodoalkyl
ether 17 and sulfonamide 18 (Scheme 2). The correspond-
ing morpholines 3a,b and N-methylsulfonyl piperazines
4a,b were obtained in ca. 60–90% yield from representa-
tive amines a2 and a6 under the optimized microwave-as-
sisted reaction conditions.
1) 19, 20, MW,
O
n
DMSO, 150 °C
RNH2
Me
2) HCl–dioxane
then Et3N–EtOH
N
R
O
NBoc
Me
21
n
Me
N
O
N
R
5a: R = 3-pyridinylmethyl; n = 1 (31%)
5b: R = 2,2-diphenylethyl; n = 1 (42%)
6a: R = 3-pyridinylmethyl; n = 2 (55%)
6b: R = 3-indolylethyl; n = 2 (40%)
Scheme 3 Spirocyclic annulation products
ica gel chromatography to remove unwanted dimer, and
then treated with 4 N HCl–dioxane in EtOH (80 °C 1 h)
followed by triethylamine in EtOH (80 °C, 2 h). Lactams
5a,b and 6a,b were isolated in up to 55% yield establish-
ing the feasibility of spirocyclic ring formation. Further
refinement of this two-pot three-step process is ongoing
using the microwave protocol and exploring alternatives
to nitrogen protection.
As a demonstration of the utility of the new SPAn re-
agents to generate structure–activity relationship (SAR)
information, 6b-naltrexamine a7 was derivatized with re-
agents 7/8 and 15/16 (Table 2). The novel heterocyclic de-
rivatives 1m,n and 2r,s (obtained as mixture of their
respective diastereomers) were screened for binding (Ki)
against the human opioid receptors m, k, and d.6 The re-
sulting nascent SAR indicates that agents 1m and 2r are
potent dual k/d ligands with ca. 6- to 13-fold selectivity
over m. Interestingly, the m receptor appears relatively in-
sensitive to the change in the pendent ester versus carbox-
ylic acid group (esters 1m/2r versus acids 1n/2s). This is
in contrast to the k and d receptor affinity which is clearly
sensitive to the negatively charged carboxylate group (up
to a 15-fold loss in affinity). In a final study, mono-N-
Boc-protected diamine a8 was annulated with reagents 7
and 8 followed by Boc-deprotection and acylation with 4-
trifluoromethylphenylacetic acid furnishing 22a and 22b
(obtained as a mixture of their respective diastereomers).
This is the first demonstration of bidirectional functional-
ization of a diamine using first a SPAn reagent and then
traditional N-acylation. Compounds 22a and 22b dis-
played opioid receptor binding with 22a being a four-fold
more potent k ligand (Ki = 200 nM).
Y
17, 18, MW,
DMSO, 150 °C
O
RNH2
Me
(Yield)
N
R
O
3a: R = 3-pyridinylmethyl; Y = O (61%)
3b: R = 2,2-diphenylethyl; Y = O (91%)
4a: R = 3-pyridinylmethyl; Y = NSO2Me (73%)
4b: R = 2,2-diphenylethyl; Y = NSO2Me (65%)
In summary, a-substituted pyrrolidines, piperidines, mor-
pholines, piperazines and diazaspirocycles were obtained
in a single reaction step from primary amines and SPAn
reagents 7–20.7 Microwave irradiation resulted in a sub-
stantial reduction in overall reaction time versus conven-
tional heating, improvement in product yields and was
essential for the formation of derivatives with a-methyl-
cyano (13 → 2j–l) and a-methyl(phenylsulfonyl) (14 →
2m–o) ring substituents. The new annulation chemistry
represents a valuable complement to existing acyclic
amine derivatization methodologies. Further examples of
Scheme 2 Morpholine and piperazine annulation products
The iodoacrylates 19 and 20 were also examined as SPAn
reagents (Scheme 3). It was thought that the Boc-N-meth-
ylaminomethyl group at the C-3 position in combination
with the ester function might act as a latent N-methylca-
prolactam. Amines a2, a5 and a6 were reacted with 19/20
under the optimized thermal reaction conditions. The in-
termediate SN2-Michael adducts (21) were purified by sil-
Synlett 2009, No. 17, 2857–2861 © Thieme Stuttgart · New York

2860
C. Macleod et al.
LETTER
corresponding chloroalkenoic acids to Wang resin under
Table 2 Biologically Active Annulation Products
standard reaction conditions.
N
(6) DeHaven, R. N.; Cassel, J. A.; Windh, R. T.; DeHaven-
Hudkins, D. L. In Current Protocols in Pharmacology;
Enna, S. J.; Williams, M.; Barrett, J. F.; Ferkany, J. W.;
Kenakin, T.; Porsolt, R. D., Eds.; John Wiley and Sons: New
York, 2005, 1.4.1–1.4.44.
(7) General Procedure for High-Throughput Annulation:
DMSO (750 mL) and diisopropylethylamine (DIPEA, 150
mL) were added to Milestone CombiCHEM Microwave
reaction vials containing the individual SPAn reagents (0.30
mmol). The amines (0.30 mmol) were then added and the
reaction vials transferred to a 48-well Milestone
OH
7, 8, 15, 16,
MW, DMSO, 150 °C
amine
a7
O
O
HO
N
OR
1m,n: n = 1
2r,s: n = 2
n
1) 7, 8,
MW, DMSO,
150 °C
F3C
O
CombiCHEM plate. The unit was securely fitted to the
Milestone CombiCHEM rotor and inserted into the
Milestone Microwave (equipped with thermocouple). A
microwave program (with rotation of the CombiCHEM
block) was applied: full power (500 W) ramping from 25 °C
→ 150 °C over a period of 25 min and holding at 150 °C for
15 min. Upon cooling, the CombiCHEM block was removed
and transferred to a Genevac. The vials were concentrated in
vacuo and the resulting residues were purified by silica gel
chromatography to give the annulation products.
2-{1-[2-(1H-Indol-3-yl)methyl]pyrrolidin-2-yl}-N-
benzylacetamide (1g): 1H NMR (400 MHz, CDC13): d =
8.55 (s, 1 H), 8.20 (s, 1 H), 6.95–7.55 (m, 9 H), 5.65 (m, 1
H), 4.00, 4.34 (m, 2 × 1 H), 2.45–3.45 (m, 6 H), 0.90–2.05
(m, 7 H). 13C NMR (75 MHz, CDC13): d = 172.7, 137.7,
136.8, 128.5, 127.4, 127.1, 123.0, 121.5, 119.8, 118.5,
113.0, 110.8, 65.5, 56.1, 55.1, 44.0, 32.5, 30.8, 23.4, 21.5.
MS (ESI): m/z = 362 [M + H]+. HRMS (TOF): m/z [M + H]+
calcd for C23H28N3O: 362.2232; found: 362.2245.
2-{1-[2-(1H-Indol-3-yl)ethyl]piperidin-2-yl}-N-benzyl-
N-methylacetamide (2i): 1H NMR (400 MHz, CDC13) d =
8.68, 8.78 (m, 1 H), 6.95–7.55 (m, 9 H), 4.52 (m, 2 H), 4.00
(m, 1 H), 2.95–3.70 (m, 6 H), 2.80, 2.95 (2 × s, 3 H, NMe
rotomers), 0.90–2.20 (m, 9 H). MS (ESI): m/z = 390 [M +
H]+. HRMS (TOF): m/z [M + H]+ calcd for C25H32N3O:
390.2545; found: 390.2561.
amine
a8
n
N
2) TFA–CH2Cl2 (1:1)
3) 4-F3CC6H4CH2CO2H,
DIC, CH2Cl2
N
O
22a: n = 1
22b: n = 2
O
Entry
Prod
1m
2r
R
Et
Et
H
H
–
Ki(m) nM Ki(k) nM Ki(d) nM
1
2
3
4
5
6
32
91
5.4
6.8
6.0
6.7
1n
55
40
91
2s
44
54
200
840
81
22a
22b
1840
1500
1100
>5000
–
SPAn reagents affording medicinally relevant heterocy-
cles will be reported subsequently.
References and Notes
(1) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales,
G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem. 2008, 10,
753.
(2) (a) Dolle, R. E.; Macleod, C.; Martinez-Teipel, B. I.; Barker,
W. M.; Seida, P.; Herbetz, T. Angew. Chem. Int. Ed. 2005,
44, 5830. (b) The acronym SPAn is derived from solid/
solution-phase annulation.
2-[1-(2,2-Diphenylethyl)piperidin-2-yl]acetonitrile (2l):
1H NMR (400 MHz, CDC13): d = 7.10–7.35 (m, 10 H), 4.15
(m, 1 H), 3.12 (m, 1 H), 2.95 (m, 1 H), 2.75 (m, 1 H), 2.65
(m, 1 H), 2.30 (m, 3 H), 1.30–1.75 (m, 6 H). 13C NMR (75
MHz, CDC13): d = 144.0, 129.3, 128.5, 126.0, 117.9, 59.8,
59.5, 57.9, 49.3, 31.1, 26.2, 22.8, 22.3. MS (ESI): m/z = 305
[M + H]+. HRMS (TOF): m/z [M + H]+ calcd for C21H25N2:
305.2018; found: 305.2050.
(3) Macleod, C.; Martinez-Teipel, B. I.; Barker, W. M.; Dolle,
R. E. J. Comb. Chem. 2006, 8, 132.
(4) Bunce, R. A.; Peeples, C. J.; Jones, P. B. J. Org. Chem. 1992,
3-{[2-(Phenylsulfonylmethyl)piperidin-1-
yl]methyl}pyridine (2n): 1H NMR (400 MHz, CDC13): d =
8.45 (m, 1 H), 7.98 (m, 1 H), 7.50–7.75 (m, 6 H), 7.20 (m, 1
H), 3.25–3.60 (m, 5 H), 2.30 (m, 2 H), 1.40–1.90 (m, 6 H).
13C NMR (75 MHz, CDC13): d = 150.8, 146.9, 145.5, 139.5,
137.0, 133.1, 129.5, 128.0, 122.5, 64.8, 65.9, 59.4, 55.6,
55.5, 29.9, 26.8, 22.5. MS (ESI): m/z = 331 [M + H]+. HRMS
(TOF): m/z [M + H]+ calcd for C18H23N2O2S: 331.1480;
found: 331.1492.
57, 1727.
(5) SPAn reagents 7–12 and 15–18 were prepared from the
requisite chloroalkyl aldehydes and the Horner–Emmons–
Wadsworth reaction: (a) Kametani, T.; Higashiyama, K.;
Otomasu, H.; Honda, T. Israel. J. Chem. 1986, 27, 57.
(b) Lipshutz, B. H.; Chrisman, W.; Noson, K.; Papa, P.;
Sclafani, J. A.; Vivian, R. W.; Keith, J. M. Tetrahedron
2000, 56, 2779. (c) SPAn reagents 13 and 14 were obtained
and used as a mixture of E- and Z-isomers by the cross-
metathesis reaction of 6-chlorohex-1-ene with acrylonitrile
and phenyl vinyl sulfone. SPAn reagents 19 and 20 were
derived from the modification of experimental procedures
described by: Dieter, R. K.; Lu, K. J. Org. Chem. 2002, 67,
847. (d) Because the iodo-based solution-phase reagents
gave annulation products in consistently higher yield and
purity than the corresponding chloro congeners, the
Finkelstein Cl → I exchange reaction was used (5 equiv NaI,
acetone, reflux, 3 h) to prepare the final reagent set. SPAn
reagents 15 and 16 were obtained via DIC coupling of the
2-{1-[2-(1H-Indol-3-yl)ethyl]piperidin-2-yl}acetic Acid
(2q): 1H NMR (400 MHz, CDC13): d = 10.95 (s, 1 H), 7.38,
7.60 (2 × d, J = 7.4 Hz, 2 × 1 H), 6.85–7.20 (m, 3 H), 1.50–
3.50 (m, 15 H). 13C NMR (75 MHz, CDC13): d = 180.0,
136.2, 127.0, 123.1, 121.1, 120.2, 119.5, 113.9, 110.5, 67.0,
58.1, 57.9, 55.0, 32.3, 26.1, 23.8, 23.5. MS (ESI): m/z = 287
[M + H]+. HRMS (TOF): m/z [M + H]+ calcd for
C17H23N2O2: 287.1793; found: 287.1810.
Methyl 2-[4-(2,2-Diphenylethyl)morpholin-3-yl]acetate
(3b): 1H NMR (400 MHz, CDC13): d = 7.10–7.35 (m, 10 H),
4.10 (m, 1 H), 3.65 (s, 3 H), 3.40–3.60 (m, 4 H), 2.90–3.10
Synlett 2009, No. 17, 2857–2861 © Thieme Stuttgart · New York

LETTER
(m, 3 H), 2.65 (m, 1 H), 2.50 (m, 2 H), 2.30 (m, 1 H). 13
N-Alkylation–Intramolecular Michael Addition
2861
C
CDC13): d = 7.10–7.35 (m, 10 H), 4.05 (t, J = 7.5, 1 H), 3.40
(s, 3 H), 3.17 (d, J = 10.2 Hz, 1 H), 2.65–3.00 (m, 5 H), 2.50,
2.12 (2 × d, J = 17.2 Hz, 2 × 1 H), 1.75 (m, 4 H). MS (ESI):
m/z = 335 [M + H]+. HRMS (TOF): m/z [M + H]+ calcd for
C22H27N2O: 335.2123; found: 335.2148.
NMR (75 MHz, CDC13): d = 174.1, 144.8, 129.9, 129.1,
126.6, 72.3, 69.0, 64.1, 660.9, 52.3, 51.8, 38.1. MS (ESI): m/
z = 340 [M + H]+. HRMS (TOF): m/z [M + H]+ calcd for
C21H26NO3: 340.1913; found: 340.1944.
Methyl 2-[4-(Methylsulfonyl)-1-(pyridin-3-
Ethyl {6b-[17-(Cyclopropylmethyl)-3,14-dihydroxy-4,5-
epoxymorphinan-6b-yl]pyrrolidin-2-yl}acetate (1m):
mixture of diastereomers. 1H NMR (400 MHz, CDC13): d =
6.71, 6.74 (2 × d, J = 8.1 Hz, 2 × 0.5 H), 6.52, 6.54 (2 × d,
J = 8.1 Hz, 2 × 0.5 H), 4.75 (d, J = 7.4, 0.5 H), 4.53 (d, J =
8.2 Hz, 0.5 H), 4.21 (m, 1 H), 4.07 (dd, J = 7.0, 14.0 Hz, 1
H), 3.60 (br s, 1 H), 1.38–3.20 (m, 24 H), 1.30, 1.21 (2 × t,
J = 7.1 Hz, 2 × 1.5 H), 0.85 (m, 1 H), 0.54 (s, 2 H), 0.15 (s,
2 H). MS (ESI): m/z = 483 [M + H]+. HRMS (TOF): m/z [M
+ H]+ calcd for C28H39N2O5: 483.2859; found: 483.2885.
ylmethyl)piperazin-2-yl]acetate (4a): 1H NMR (400 MHz,
CDC13): d = 8.50 (m, 2 H), 7.35, 7.75 (m, 2 × 1 H), 3.70 (s,
3 H), 3.62 (m, 2 H), 3.50 (m, 1 H), 2.92 (s, 3 H), 2.20–2.75
(m, 8 H). 13C NMR (75 MHz, CDC13): d = 173.8, 152.0,
147.8, 156.1, 137.0, 123.2, 60.8, 60.1, 54.7, 51.8, 51.1, 48.5,
40.2, 38.3. MS (ESI): m/z = 328 [M + H]+. HRMS (TOF):
m/z [M + H]+ calcd for C14H22N3O4S: 328.1331; found:
328.1362.
1-(2,2-Diphenylethyl)-7-methyl-1,7-
diazaspiro[4.4]nonan-8-one (5b): 1H NMR (400 MHz,
Synlett 2009, No. 17, 2857–2861 © Thieme Stuttgart · New York

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