Synthesis of highly substituted 2-spiropiperidines

Article abstract of DOI:10.1039/C8OB01272E

2-Spiropiperidines are a highly desirable, yet under represented structure in drug discovery. 2-Spiropiperidines were synthesised in either a two-pot or one-pot reaction. In the two-pot reaction, the addition of a Weiler dianion to N-Boc imines, followed by deprotection and in situ condensation with a cyclic ketone generated functionalised 2-spiropiperidines in good to excellent yields. In the one-pot reaction, the addition of Chan's diene to N-Boc imines under Maitland-Japp conditions, followed by the addition of sodium bicarbonate and a cyclic ketone formed functionalised 2-spiropiperidines in moderate to good yields.

Full text of DOI:10.1039/C8OB01272E

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Synthesis of highly substituted 2-spiropiperidines
Samuel D. Griggs,a Nathan Thompson,a Daniel T. Tape,b Marie Fabrea and Paul. A. Clarke*a
Received 00th January 20xx,
Accepted 00th January 20xx
2-Spiropiperidines are a highly desirable, yet under represented structure in drug discovery. 2-Spiropiperidines were
synthesised in either a two-pot or one-pot reaction. In the two-pot reaction, the addition of a Weiler dianion to N-Boc
imines, followed by deprotection and in situ condensation with a cyclic ketone generated functionalised 2-spiropiperidines
in good to excellent yields. In the one-pot reaction, the addition of Chan’s diene to N-Boc imines under Maitland-Japp
conditions, followed by the addition of sodium bicarbonate and a cyclic ketone formed functionalised 2-spiropiperidines in
moderate to good yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
synthesis of spiropiperidines, we decided to investigate the
modification of these processes to enable the synthesis of 2-
spiropiperidines.14
Introduction
Spiropiperidines are an increasingly important structural unit,
appearing in both natural products and drug discovery
programs.1 In the natural product arena they are present in
several
alkaloid
classes,
including
histrionicotoxin,2
nankakurine,3 pinnaic acid,4 etc. Within the context of drug
discovery they are desired due to their well-defined
conformations, and novel intellectual property value.5 For
these reasons over the last few years an increasing number of
6
routes for their synthesis have been described.1, However,
the majority of these routes are directed at providing access to
3- or 4-spiropiperidines, with limited methods available for the
synthesis of 2-spiropiperidines.6 Those methods available for
the formation of 2-spiropiperidines rely either on the use of
toxic organotin-reagents,7 alkylation and reductive cyclisation
of aminonitriles,8 or ring-closing metathesis,9 and often require
the prior synthesis of advanced precursors.
Scheme 1 Maitland-Japp syntheses of highly functionalised piperidines
We previously reported the synthesis of highly substituted
Results and discussion
piperidines via
a
modification of the Maitland-Japp
tetrahydropyran synthesis; the replacement of an aldehyde Initial investigations with N-tosyl imines
with either an N-aryl10, 11 or N-tosyl imine.12 N-Aryl imines were
Due to the lack of availability of diketene, our initial study
forced us to use the dianion of methyl acetoacetate,15 which
was added to the N-tosyl imine of benzaldehyde . It was
hoped that the resultant -amino- -ketoester , which was
formed in 44% yield could be cyclised onto a ketone (acetone)
under Maitland-Japp conditions.12, 16 Treatment of
-amino-
ketoester with acetone, TiCl4 and pyridine in THF led only to
the isolation of the Knoevenagel product in 26% yield and re-
isolated . Submission of -amino- -ketoester to TiCl4 in
CH2Cl2 and stirring for an extended period of time led to
formed in situ from anilines and aryl ketones in the same pot
as N-aryl enamines, formed by the condensation of anilines
1
with β-ketoesters. The N-aryl-β-enaminoester underwent
Stork enamine-like condensation13 with the N-aryl imines and
δ
β
2
cyclisation to form highly substituted piperidines (Scheme
).10, 11 N-Tosyl imines were reacted with diketene to form
1A δ-
δ
β-
2
amino-
aldehyde to generate highly substituted non-symmetrical
piperidines (Scheme 1
).12 Given our previous contributions to
β-ketoesters which were treated in situ with an
3
2
δ
β
3
B
the synthesis of piperidines and the increasing interest in the
elimination of tosyl amide, and the formation of
cyclisation to the piperidine was observed (Scheme 2).
4; no
The identity of
4
was confirmed via its synthesis from
-ketoester 617 was treated
δ-
hydroxy-β-ketoester
with Ac2O, Et3N, DMAP in CH2Cl2 at room temperature, which
6
.
δ
-Hydroxy-
β
resulted in acylation of the hydroxyl and concomitant
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elimination of acetic acid. Enone
5
was then subjected to which were stable enough to be isolated. It was found that
-N-Boc-amino- -ketoesters could be isolated and
in 13% yield (Scheme 2), the stored for several weeks without detriment. Cyclisation of -N-
spectroscopic data of which was identical to that formed Boc-amino- -ketoesters was achieved by removal of the N-
through the elimination of tosyl amide from Boc group with HCl in dioxane to form the HCl salt. The HCl salt
was “cracked” with NaHCO3 in the presence of a ketone
Maitland-Japp conditions (TiCl4, acetone, pyridine in THF) these
which led to the formation of
δ
β
8
4
δ
β
8
3.
9,
which promoted cyclisation and yielded the desired 2-
spiropiperidine 10 (Scheme 3, Table 1 and Table 2).
Scheme 2 Attempted cyclisation with N-tosyl amine 2 and acetone
Scheme 3 Two-step synthesis of 2-spiropiperidines 10
Table 1 Synthesis of δ-N-Boc-amino-β-ketoesters 9
It was disheartening that cyclisation conditions which yielded
piperidines with N-tosyl amines and aldehydes did not
generate piperidines when ketones were used. We believe
that this is due to a destabilising interaction in the transition
state, not present in the cyclisation with aldehydes (Fig. 1). If
cyclisation were to occur via TS1 then there is a 1,3-diaxial
interaction between the Ph-group and the axial Me-group. The
alternative chair conformation TS2 suffers from an A1,2-like
destabilising interaction between the N-tosyl group and the
equatorial Me-group.
N-Boc sulfone 7
R
Me
Yield 9 (%)
a
b
c
d
e
f
76
65
50
73
77
53
56
58
57
68
Pr
iPr
Ph
4-FC6H4
4-MeOC6H4
3-pyridyl
methyl thiazole
N-methyl pyrazole
4-CNC6H4
g
h
i
j
Fig 1 Destabilising interactions which disfavour cyclisation of 3. Proton on N
omitted for clarity
Attempts to deprotect 3
with Mg/MeOH,18 and hence form the
free amine for cyclisation, resulted in decomposition of the
substrate and so the further use of N-tosyl imines was
abandoned. Our attention turned to the use of N-Boc imines,
which we reasoned could be synthesised efficiently and easily
deprotected.
Two-pot synthesis of 2-spiropiperidines
Known aryl N-Boc imines were prepared from the appropriate
aryl aldehyde according to literature procedures,19-21 and were
isolated. These aryl N-Boc imines were treated with the Weiler
dianion of methyl acetoacetate15 to generate
-ketoesters. Other N-Boc imines proved to be too unstable to
be isolated and were generated in situ from their N-Boc
sulfone precursor . In these cases 3 eq. of NaH was used to
form the N-Boc imine in situ before the addition of the Weiler
dianion, which led to the formation of the the -N-Boc-amino-
-ketoesters . This procedure was so facile that it became our
δ-N-Boc-amino-
β
7
δ
β
9
standard protocol for all N-Boc imines used, including those
2 | J. Name., 2012, 00, 1-3
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Table 2 Synthesis of 2-spiropiperidines 10
Entry
9 R
Ketone 10
Yield 11
(%)
85
dra 11
a
b
c
a Me
a Me
acetone
cyclohexanone
cyclopentanone
cyclobutanone
4-pyranone
2.5:1
7:1
85
a Me
43
5:1
Fig 2 1H NMR data supporting the formation of 11e
β
-CO2Me diastereomer
d
e
f
a Me
57
2.5:1
4.5:1
7:1
a Me
59
d Ph
cyclohexanone
acetone
78
g
h
i
e 4-FC6H4
e 4-FC6H4
e 4-FC6H4
e 4-FC6H4
f 4-MeOC6H4
g 3-pyridyl
g 3-pyridyl
g 3-pyridyl
g 3-pyridyl
h methyl thiazole
i N-methyl pyrazole
j 4-CNC6H4
j 4-CNC6H4
97
1.8:1
5:1
cyclohexanone
4-pyranone
75
56
2:1
j
4-thiopyranone
4-pyranone
63
1:1
k
l
33
2:1
acetone
86
1.5:1
1.5:1
2:1
m
n
o
p
q
r
4-pyranone
76
N-Cbz-4-piperidone
4-thiopyranone
4-pyranone
67
75
0.95:1
1:1
75
4-pyranone
50
2.5:1
1:1
cyclobutanone
2-oxetanone
63
s
43
1.6:1
a) The ratio of diastereomers was determined by 1H NMR analysis of the crude
reaction mixture. In most cases the β-CO2Me diastereomer dominated and is
report first in the dr ratio.
Fig 3 X-ray crystal structure of 11i showing the axial methyl esterǂ
One-pot synthesis of 2-spiropiperidines
A range of were prepared
(Table 1) from N-Boc sulfone precursors derived from
aliphatic 7a-c and aromatic aldehydes (7d-j), including spiropiperidines realised, attention turned to the re-
δ-N-Boc-amino-
β
-ketoesters
9
With
a two-pot procedure for the synthesis of 2-
7
(
)
several from the GSK aldehyde library.22 Aldehydes were
selected after discussions with GSK, which highlighted
compounds that would be of interest to medicinal chemists.
Selected aldehyde derivatives included thiazole, pyrazole,
pyridyl functionality and substituted aromatics (7e-j). All were
isolated in good yields. Acetone and a selection of cyclic
ketones (four to six membered rings), including N-, O- and S-
heteroatom-containing cyclic ketones, all underwent smooth
development of a one-pot procedure. Previous studies had led
to the development of a one-pot Maitland-Japp synthesis of
piperidines12 (Scheme 1
B), however; the lack of availability of
diketene necessitated the use of an alternative nucleophile. As
one variant of the one-pot Maitland-Japp synthesis of
tetrahydropyrans (THPs) had utilised the bis-silyl enolether of
methyl acetoacetate17 (Chan’s diene 13) it was decided to
investigate this as the nucleophile. It was also decided to
investigate the addition and cyclisation steps independently at
first in order to ensure both reactions were viable. As TiCl4 had
promoted the addition of Chan’s diene to aldehydes, that was
examined first. It was found that TiCl4 promoted the addition
cyclisation with
δ-N-Boc-amino-β-ketoesters 9 to form 2-
spiropiperidines 11a-s in good to excellent yields. The
piperidines were formed as a mixture of diasteromeric methyl
esters, and there was no evidence that the diastereomeric
esters interconverted during isolation and purification. In most
examples the major diastereomer was determined to have the
of Chan’s diene to N-Boc imine 11e to form δ-N-Boc-amino-β-
ketoester 9e in 61% yield. However, submission of 9e to TiCl4
in the presence of cyclohexanone did not result in cyclisation
at either -78 °C or RT, and only the re-isolation of 9e (Scheme
4).
axial
3.39 ppm) displayed a ‘W-coupling’ of 1.0 Hz to H-5
ppm) indicating both their equatorial positions. A coupling
constant of 3.5 Hz was seen between H-5 and H-6 indicating
a syn-relationship, while there was an 11.5 Hz coupling
between H-6 and H-5 3.06 ppm) indicating an anti-
β
-ester group. In the representative case of 11e H-3 (
δ
α (δ
2.64
α
α
α
β (δ
relationship (Fig 2). This stereochemical arrangement was
confirmed by an X-ray crystal structure of 11iǂ (Fig. 3).
Presumably the ester group is axial to avoid a destabilising
steric interaction with the protons on the adjacent spiro-ring.
Scheme 4: Attempted one-pot synthesis of 2-spiropiperidine 10h
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It was rationalised that the N-Boc group was inhibiting the
cyclisation both electronically and sterically, and we were
somewhat surprised that it remained intact in the presence of
TiCl4 at RT. To solve this problem and develop a one-pot
method, conditions had to be devised to affect removal of the
N-Boc group under conditions compatible with both the
Mannich-like addition and cyclisation reactions. It was
rationalised that the addition of MeOH to the reaction after
the formation of 9e would generate HCl by methanolysis of the
TiCl4. The HCl generated in situ would remove the N-Boc
group, revealing the amine as the HCl salt. At this stage,
Table 3 One-pot synthesis of 2-spiropiperidines 10
addition of a base and a ketone should free the amine and
14
Entry
Ar 12
Ketone 10
Yield
11 (%)
h 61
i 69
dra 11
initiate cyclisation to 11h
.
Indeed, when 12e was treated
with Chan’s diene and TiCl4 at -78 °C, Mannich-like addition
occurred to generate 9e (by TLC). At this point MeOH was
introduced to the reaction and the temperature was raised to
RT. After a short while both cyclohexanone and NaHCO3 were
added to the reaction and stirred at RT. This procedure yielded
11h after work up and purification in 61% yield (Scheme 5). It
is worth noting that the two-step procedure yielded 11h in
57% yield over the two steps.
1
2
e p-FC6H4
e p-FC6H4
cyclohexanone
4-pyranone
5:1
2:1
3
f p-MeOC6H4
h methyl thiazole
j 4-CNC6H4
4-pyranone
k 62
p 49
r 37
1.5:1
2.5:1
3.5:1
3:1
2.5:1b
4:1b
4
4-pyranone
5
cyclobutanone
4-thiopyranone
N-Cbz-4-piperidone
N-Cbz-4-piperidone
cyclohexanone
acetone
6
h methyl thiazole
h methyl thiazole
j 4-CNC6H4
t 55
7
u 45
v 24
w 28
x 24
8
9
k 4-CF3C6H4
1.5:1
1:1.5c
10
h methyl thiazole
a) The ratio of diastereomers was determined by 1H NMR analysis of the crude
reaction mixture. In most cases the β-CO2Me diastereomer dominated and is
report first in the dr ratio. b) The ratio of diastereomers was determined by 1H
NMR analysis after silica plug chromatography. c) α-CO2Me was the major
diastereomer.
Interestingly the major product in the formation of 11x (entry
10) was the α-CO2Me diastereomer. The diastereomeric ratio
did not change upon resubmission to the reaction conditions.
Scheme 5 Successful one-pot synthesis of 2-spiropiperidine 10h
The configuration of this diastereomer was determined by
comparison of the chemical shifts of H3 and H5β, along with
their coupling constants. The proton H3 ( 3.60 ppm) appeared
With a one-pot procedure developed its scope was explored
δ
as a singlet and at a chemical shift reminiscent of the minor
using several different δ-N-Boc-imines 12 and ketones 10
(Table 3). For the majority of cases (entry 1-4, 6 and 7) the
diastereomers formed in other examples. The proton assigned
one-pot reaction generated 2-spiropiperidines in moderate to
as H5β had a chemical shift of
constant of 11.0 Hz to H6
δ
2.40 ppm and a coupling
good yields, and in examples 11h
higher yields than for the two-pot procedure. 2-
Spiropiperidines 11t 11u 11v 11w and 11x (entries 6-10) had
, 11i, 11k and 11p these were
α, indicating their trans-diaxial
relationship (Fig 4).
,
,
,
not been synthesised previously by the two-pot method. In the
cases of entries 7 and 8, the diastereomeric ratio of 11u and
11v had to be determined after silica plug filtration due to the
overlapping peaks of some impurities.
Fig 4 1H NMR data supporting the formation of 11x
α-CO2Me diastereomer
Conclusions
Simple and robust two-pot and one-pot procedures for the
synthesis of 2-spiropiperidines have been developed. These
methods are applicable to
a large range of differently
functionalised 2-spiropiperidines, and allow for the synthesis
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of piperidines spirofused to 4-, 5-, and 6-membered carbo- and 7.86 (m, 2H), 7.62-7.56 (m, 1H), 7.54-7.47 (m, 2H), 5.07 (d, J =
heterocyclic rings and substituted at the C3 and C6 positions of 11.0 Hz, 1H), 4.84 (td, J = 11.0, 3.5 Hz, 1H), 2.24-2.13 (m, 1H),
the piperidine ring. The ease of these procedures will allow the 1.79-1.65 (m, 1H), 1.62-1.48 (m, 1H), 1.46-1.35 (m, 1H), 1.24 (s,
evaluation of 2-spiropiperidnes in drug discovery programs 9H), 0.95 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3): δ
and they will be of use in the synthesis of spirocyclic alkaloid 153.9, 137.1, 133.9, 129.4, 129.1, 80.8, 70.7, 28.3, 28.1, 18.8,
natural products.
13.6 ppm; IR (ATR): νmax 3286, 2960, 2874, 1690, 1526, 1310,
1246, 1144, 1083 cm-1; HRMS (ESI) 336.1243 (M + Na+.
C15H23NNaO4S requires 336.1240).
Experimental
(1-Benzenesulfonyl-2-methyl-propyl)-carbamic acid tert-butyl
ester (7c)
General
Isobutyraldehyde (4.67 mL, 51.3 mmol) yielded 4.93 g (47%) as
Unless otherwise noted all compounds were bought from
commercial suppliers and used without further purification.
Where a solvent is described as “dry” it was purified by
PureSolv alumina columns from Innovative Technologies.
a
white solid. Spectroscopic data was identical to that
previously reported.24 mp 116-117.5 oC; 1H NMR (400 MHz,
CDCl3): δ 7.91-7.86 (m, 2H), 7.64-7.58 (m, 1H), 7.55-7.49 (m,
2H), 5.14 (d, J = 11.0 Hz, 1H), 4.84 (dd, J = 11.0, 3.5 Hz, 1H),
2.82-2.73 (m, 1H), 1.22 (s, 9H), 1.14 (d, J = 7.0 Hz, 3H), 1.07 (d,
J = 7.0 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3): δ 154.2, 138.2,
133.8 , 129.2, 129.1, 80.9, 74.4, 28.1, 26.8, 20.8, 17.0 ppm; IR
(ATR): νmax 3356, 3232, 3142, 2965, 1704, 1364, 1307, 1141,
1082 cm-1; HRMS (ESI) 226.1404 (M + Na+. C10H21NNaO3
requires 226.1414 for the methanol adduct (-SO2Ph, +OMe)).
Melting points were determined using
a Stuart SMP3
apparatus. Infra-red spectra were acquired on
a
ThermoNicolet Avatar 370 FT-IR spectrometer. Nuclear
magnetic resonance spectra were recorded on a Jeol ECS-400,
a Jeol 500 Avance III HD 500 or a Jeol AV500 at ambient
temperature. Coupling constants (J) are quoted in Hertz. Mass
spectrometry was performed by the University of York mass
spectrometry service using electron spray ionisation (ESI)
technique. Thin layer chromatography was performed on
glass-backed plates coated with Merck Silica gel 60 F254. The
plates were developed using ultraviolet light, acidic aqueous
ceric ammonium molybdate or basic aqueous potassium
permanganate. Liquid chromatography was performed using
forced flow (flash column) with the solvent systems indicated.
The stationary phase was silica gel 60 (220–240 mesh) supplied
by Fluorochem or silica gel Merck TLC grade 11695 supplied by
Sigma-Aldrich.
(Benzenesulfonyl-phenyl-methyl)-carbamic acid tert-butyl ester
(7d)
Benzaldehyde (1.52 mL, 15 mmol) yielded 3.26 g (94%) as a
white solid. Spectroscopic data was identical to that previously
o
1
reported.19 mp 158-161 C; H NMR (400 MHz, CDCl3): δ 7.92
(d, J = 7.5 Hz, 2H), 7.64 (dd, J = 7.5, 7.5 Hz, 1H), 7.53 (dd, J =
7.5, 7.5 Hz, 2H), 7.48-7.39 (m, 5H), 5.94 (d, J = 10.5 Hz, 1H),
5.87 (d, J = 10.5 Hz, 1H), 1.25 (s, 9H) ppm; 13C NMR (101 MHz,
CDCl3): δ 153.6, 137.0, 134.1, 130.0, 129.6, 129.2, 129.1, 128.9,
125.1, 81.4, 74.0, 28.1 ppm; IR (ATR): νmax 3355, 3274, 2978,
1693, 1508, 1306, 1141 cm-1; HRMS (ESI) 260.1257 (M + Na+.
C13H19NNaO3 requires 260.1257 for the methanol adduct (-
SO2Ph, +OMe)).
General procedure for the synthesis of benzenesulfonyl carbamic
esters 721
To a solution of aldehyde (53.6 mmol) in water, methanol and
formic acid (2:1:0.7, 142 mL) was added tert-butyl carbamate
(35.7 mmol) and benzenesulfinic acid sodium salt (71.4 mmol).
The mixture was stirred at room temperature for 3 days. The
precipitate was filtered and washed with water (150 mL) and
hexane (300 mL).
[Benzenesulfonyl-(4-fluoro-phenyl)-methyl]-carbamic acid tert-
butyl ester (7e)
4-Fluorobenzaldehyde (9.61 mL, 90.0 mmol) yielded 19.9 g
(91%) as a white solid. Spectroscopic data was identical to that
previously reported.19 mp 167-170 oC; 1H NMR (400 MHz,
CDCl3): δ 7.95-7.86 (m, 2H), 7.69-7.61 (m, 1H), 7.58-7.51 (m,
2H), 7.48-7.39 (m, 2H), 7.13-7.05 (m, 2H), 5.94 (d, J = 10.5 Hz,
1H), 5.85 (d, J = 10.5 Hz, 1H), 1.24 (s, 9H) ppm; 13C NMR
(101 MHz, CDCl3): δ 163.7 (d, J = 251 Hz), 153.6, 136.8, 134.2,
131.0 (d, J = 8.5 Hz), 129.6, 129.2, 125.9 (d, J = 3.5 Hz), 116.0
(d, J = 21.5 Hz), 81.5, 73.3, 28.1 ppm; 19F NMR (376 MHz,
CDCl3): δ -110.7 ppm; IR (ATR): νmax 3367, 2972, 1703, 1506,
1309, 1140 cm-1; HRMS (ESI) 278.1150 (M + Na+. C13H18FNNaO3
requires 278.1163 for the methanol adduct (-SO2Ph, +OMe)).
(1-Benzenesulfonyl-ethyl)-carbamic acid tert-butyl ester (7a)
Acetaldehyde (3 mL, 53.6 mmol) yielded 8.27 g (81%) as a
white solid. Spectroscopic data was identical to that previously
o
1
reported.23 mp 129-131 C; H NMR (400 MHz, CDCl3): δ 7.94-
7.85 (m, 2H), 7.66-7.58 (m, 1H), 7.57-7.48 (m, 2H), 5.08 (d, J =
10.5 Hz, 1H), 4.99 (dq, J = 10.5, 7.0 Hz, 1H), 1.62 (d, J = 7.0 Hz,
3H), 1.20 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3): δ 153.5,
136.7, 134.0, 129.5, 129.2, 80.9, 66.9, 28.1, 13.0 ppm; IR (ATR):
νmax 3337, 2973, 1691, 1518, 1313, 1145 cm-1; HRMS (ESI)
308.0918 (M + Na+. C13H19NNaO4S requires 308.0927).
[Benzenesulfonyl-(4-methoxy-phenyl)-methyl]-carbamic acid tert-
butyl ester (7f)
(1-Benzenesulfonyl-butyl)-carbamic acid tert-butyl ester (7b)
4-Anisaldehyde (3.85 mL, 31.7 mmol) yielded 5.63 g (71%) as a
white solid. Spectroscopic data was identical to that previously
Butyraldehyde (1.15 mL, 12.8 mmol) yielded 1.33 g (50%) as a
white solid; mp 117-118 oC; 1H NMR (400 MHz, CDCl3): δ 7.91-
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o
1
reported.19 mp 156-158 C; H NMR (400 MHz, CDCl3): δ 8.05- CDCl3): δ 7.92 (d, J = 7.5 Hz, 2H), 7.73-7.64 (m, 3H), 7.62-7.53
7.97 (m, 2H), 7.67-7.59 (m, 1H), 7.57-7.49 (m, 2H), 7.37 (d, J = (m, 4H), 6.00 (d, J = 10.5 Hz, 1H), 5.93 (d, J = 10.5 Hz, 1H), 1.24
8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 5.88 (d, J = 10.5 Hz, 1H), (s, 9H) ppm; 13C NMR (101 MHz, CDCl3): δ 153.5, 136.4, 135.1,
5.76 (d, J = 10.5 Hz, 1H), 3.82 (s, 3H), 1.24 (s, 9H) ppm; 13C 134.6, 132.5, 129.8, 129.6, 129.4, 118.2, 113.8, 81.9, 77.4, 28.1
NMR (101 MHz, CDCl3): δ 160.4, 153.2, 137.1, 134.0, 130.3, ppm; IR (ATR): νmax 3369, 2962, 2235, 1701, 1506, 1308, 1143
129.6, 129.2, 121.8, 114.4, 81.3, 73.6, 55.5, 28.1 ppm; IR (ATR): cm-1; HRMS (ESI) 285.1213 (M + Na+. C14H18N2NaO3 requires
νmax 3361, 2967, 1695, 1503, 1310, 1162, 1149 cm-1; HRMS 285.1210 for the methanol adduct (-SO2Ph, +OMe)).
(ESI) 290.1350 (M + Na+. C14H21NNaO4 requires 290.1363 for
the methanol adduct (-SO2Ph, +OMe)).
General procedure for the synthesis of N-Boc-δ-amino-β-
ketoesters 9
(Benzenesulfonyl-pyridin-3-yl-methyl)-carbamic acid tert-butyl
ester (7g)
To a solution of diisopropylamine (21.0 mmol) in THF (30 mL)
at -78 °C was added n-BuLi (2.5M in hexanes, 21.0 mmol). The
solution was stirred for 10 mins at -78 °C then a further 5 mins
at room temperature. A solution of methyl acetoacetate (10.5
mmol) in THF (6 mL) was added over 10 mins at -78 °C, then
stirred for a further 40 mins. The imine was prepared by the
portionwise addition of sulfone (3.50 mmol) to a suspension of
NaH (7.00 mmol) in THF (12 mL) at room temperature. The
subsequent mixture was stirred for 20 mins, then immediately
transferred to the dianion mixture at -50 °C. The reaction was
stirred for 30 mins, then quenched with 10 M acetic acid in
THF (2.5 mL). The mixture was warmed to room temperature
and concentrated in vacuo. The residue was partitioned
between EtOAc (30 mL) and water (25 mL). The aqueous layer
was extracted with EtOAc (2 x 25 mL). Organics were
combined, washed with water (50 mL) and brine (50 mL), dried
(MgSO4), filtered and concentrated in vacuo. The residue was
purified by column chromatography (ethyl acetate/hexane) to
afford the protected δ-amino-β-ketoester.
Nicotinaldehyde (7.8 mL, 83.0 mmol) yielded 9.09 g (47%) as a
white solid. Spectroscopic data was identical to that previously
reported.25 mp 168.5-171 oC; 1H NMR (400 MHz, CDCl3): δ 8.68
(dd, J = 5.0, 1.5 Hz, 1H), 8.66 (br d, J = 1.5 Hz, 1H) 7.96-7.90 (m,
2H), 7.85 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 7.68 (dd, J = 7.5, 7.5 Hz,
1H), 7.57 (dd, J = 7.5, 7.5 Hz, 2H), 7.38 (dd, J = 8.0, 5.0 Hz, 1H),
6.03 (d, J = 10.5 Hz, 1H), 5.98 (d, J = 10.5 Hz, 1H), 1.25 (s, 9H)
ppm; 13C NMR (101 MHz, CDCl3): δ 153.6, 151.0, 150.1, 136.5,
136.4, 134.5, 129.6, 129.4, 126.4, 123.7, 81.8, 72.0, 28.1 ppm;
IR (ATR): νmax 3200, 3064, 2979, 1716, 1531, 1303, 1140 cm-1;
HRMS (ESI) 239.1392 (M + H+. C12H19N2O3 requires 239.1390
for the methanol adduct (-SO2Ph, +OMe)).
[Benzenesulfonyl-(4-methyl-thiazol-5-yl)-methyl]-carbamic acid
tert-butyl ester (7h)
4-Methylthiazole-5-carbaldehyde (6.68 g, 52.5 mmol) yielded
6.70 g (52%) as an off-white solid; mp 167-169 oC; 1H NMR
(400 MHz, CDCl3): δ 8.80 (s, 1H), 7.93-7.87 (m, 2H), 7.67 (dd, J
= 7.5, 7.5 Hz, 1H), 7.57 (dd, J = 7.5, 7.5 Hz, 2H), 6.26 (d, J = 10.5
Hz, 1H), 5.59 (d, J = 10.5 Hz, 1H), 3.42 (s, 3H), 1.27 (s, 9H) ppm;
13C NMR (101 MHz, CDCl3): δ 154.5, 153.5, 153.3, 136.2, 134.5,
129.6, 129.4, 121.1, 81.9, 68.4, 28.1, 15.7 ppm; IR (ATR): νmax
3153, 3071, 2976, 1707, 1535, 1302, 1140 cm-1; HRMS (ESI)
259.1114 (M + H+. C11H19N2O3 requires 259.1111 for the
methanol adduct (-SO2Ph, +OMe)).
5-tert-Butoxycarbonylamino-3-oxo-hexanoic acid methyl ester
(9a)
Sulfone 7a (1.00 g, 3.50 mmol) yielded 681 mg (76%) as a
white
solid
after
column
chromatography
(20%
EtOAc/hexane); mp 55-56 °C; 1H NMR (400 MHz, CDCl3): δ 4.80
(br s, 1H), 4.08-3.94 (m, 1H), 3.72 (s, 3H), 3.49 (d, J = 15.5 Hz,
1H), 3.43 (d, J = 15.5 Hz, 1H), 2.79 (dd, J = 17.0, 5.5 Hz, 1H),
2.69 (dd, J = 17.0, 5.5 Hz, 1H), 1.41 (s, 9H), 1.20 (d, J = 7.0 Hz,
3H) ppm; 13C-NMR (101 MHz, CDCl3): δ 201.6, 167.6, 155.2,
79.5, 52.5, 49.4, 49.1, 43.3, 28.5, 20.6 ppm; IR (ATR): νmax
3366, 3312, 3000, 2976, 1737, 1702, 1679, 1535 cm-1; HRMS
(ESI) 282.1321 (M + Na+. C12H21NNaO5 requires 282.1312).
[Benzenesulfonyl-(1-methyl-1H-pyrazol-4-yl)-methyl]-carbamic
acid tert-butyl ester (7i)
1-Methyl-1H-pyrazole-4-carbaldehyde (1.5 g, 13.6 mmol)
1
yielded 1.42 g (71%) as a white solid; mp 153.7-156.5 oC; H
NMR (400 MHz, CDCl3): δ 7.95-7.89 (m, 2H), 7.66 (s, 1H), 7.66-
7.59 (m, 2H), 7.54 (dd, J = 7.5, 7.5 Hz, 2H), 5.95 (d, J = 10.5 Hz,
1H), 5.73 (d, J = 10.5 Hz, 1H), 3.92 (s, 3H), 1.21 (s, 9H) ppm; 13
5-tert-Butoxycarbonylamino-3-oxo-octanoic acid methyl ester (9b)
C
Sulfone 7b (400 mg, 1.28 mmol) yielded 238 mg (65%) as a
NMR (101 MHz, CDCl3): δ 153.5, 138.9, 136.6, 134.2, 130.7,
129.7, 129.2, 125.0, 81.3, 67.4, 39.4, 28.1 ppm; IR (ATR): νmax
3359, 2971, 1709, 1521, 1303, 1148, 1136 cm-1; HRMS (ESI)
264.1305 (M + Na+. C11H19N3NaO3 requires 264.1319 for the
methanol adduct (-SO2Ph, +OMe)).
white
solid
after
column
chromatography
(20%
EtOAc/hexane); mp 53-55 °C; 1H NMR (400 MHz, CDCl3): δ 4.78
(d, J = 7.5 Hz, 1H), 3.95-3.79 (m, 1H), 3.72 (s, 3H), 3.50 (d, J =
15.5 Hz, 1H), 3.43 (d, J = 15.5 Hz, 1H), 2.73 (d, J = 5.5 Hz, 2H),
1.52-1.22 (m, 4H), 1.40 (s, 9H), 0.89 (t, J = 7.0 Hz, 3H) ppm; 13C-
NMR (101 MHz, CDCl3): δ 201.9, 167.6, 155.6, 79.4, 52.5, 49.4,
47.7, 47.3, 36.8, 28.5, 19.5, 13.9 ppm; IR (ATR): νmax 3288,
2964, 2933, 1742, 1704, 1679, 1539, 1262, 1173 cm-1; HRMS
(ESI) 310.1636 (M + Na+. C14H25NNaO5 requires 310.1625).
[Benzenesulfonyl-(4-cyano-phenyl)-methyl]-carbamic acid tert-
butyl ester (7j)
4-Cyanobenzaldehyde (8.40 g, 64.1 mmol) yielded 14.9 g (94%)
as a white solid. Spectroscopic data was identical to that
previously reported.20 mp 151-154 oC; 1H NMR (400 MHz,
6 | J. Name., 2012, 00, 1-3
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1243, 1163, 1037 cm-1; HRMS (ESI) 352.1743 (M + H+.
C18H26NO6 requires 352.1755).
5-tert-Butoxycarbonylamino-6-methyl-3-oxo-heptanoic acid
methyl ester (9c)
Sulfone 7c (2.00 g, 6.39 mmol) yielded 917 mg (50%) as a white
5-tert-Butoxycarbonylamino-3-oxo-5-pyridin-3-yl-pentanoic acid
methyl ester (9g)
solid after column chromatography (20% EtOAc/hexane); mp
1
60-62 °C; H NMR (400 MHz, CDCl3): δ 4.75 (br d, J = 9.0 Hz,
1H), 3.81-3.71 (m, 1H), 3.73 (s, 3H), 3.56 (d, J = 16.0 Hz, 1H), Sulfone 7g (5.00 g, 14.4 mmol) yielded 2.58 g (56%) as an off-
3.47 (d, J = 16.0 Hz, 1H), 2.77 (dd, J = 16.0, 4.5 Hz, 1H), 2.69 white solid after column chromatography (100% ethyl
1
(dd, J = 16.0, 7.0 Hz, 1H), 1.91-1.79 (m, 1H), 1.42 (s, 9H), 0.90 acetate); mp 96.5-99.5 °C; H NMR (400 MHz, CDCl3): δ 8.58-
(d, J = 7.0 Hz, 6H) ppm; 13C-NMR (101 MHz, CDCl3): δ 202.0, 8.54 (m, 1H), 8.50 (dd, J = 4.5, 1.5 Hz, 1H), 7.64 (ddd, J = 8.0,
167.7, 155.7, 79.4, 52.7, 52.4, 49.0, 45.6, 31.8, 28.4, 19.5, 18.6 1.5, 1.5 Hz, 1H), 7.26 (dd, J = 8.0, 4.5 Hz, 1H), 5.51 (br s, 1H),
ppm; IR (ATR): νmax 3356, 2974, 2958, 1748, 1713, 1686, 1525, 5.13 (br s, 1H), 3.69 (s, 3H), 3.45 (d, J = 15.5 Hz, 1H), 3.40 (d, J =
1307, 1128 cm-1; HRMS (ESI) 310.1618 (M + Na+. C14H25NNaO5 15.5 Hz, 1H), 3.24 (dd, J = 17.0, 4.0 Hz, 1H), 3.08 (dd, J = 17.0,
requires 320.1625).
4.0 Hz, 1H), 1.41 (s, 9H) ppm; 13C-NMR (101 MHz, CDCl3): δ
200.6, 167.3, 155.1, 148.9, 148.2, 136.9, 134.2, 123.5, 80.3,
52.6, 49.3, 48.8, 48.1, 28.4 ppm; IR (ATR): νmax 3208, 2982,
1756, 1709, 1542, 1365, 1282, 1178, 1082, 1005 cm-1; HRMS
(ESI) 323.1594 (M + H+. C16H23N2O5 requires 323.1601).
5-tert-Butoxycarbonylamino-3-oxo-5-phenyl-pentanoic acid
methyl ester (9d)
Sulfone 7d (1.00 g, 2.89 mmol) yielded 672 mg (73%) as a
white
solid
after
column
chromatography
(20%
EtOAc/hexane); mp 83.7-85.5 °C; 1H NMR (500 MHz, CDCl3): δ
7.34-7.22 (m, 5H), 5.34 (br s, 1H), 5.10 (br s, 1H), 3.68 (s, 3H),
5-tert-Butoxycarbonylamino-5-(4-methyl-thiazol-5-yl)-3-oxo-
pentanoic acid methyl ester (9h)
3.42 (d, J = 15.5 Hz, 1H), 3.38 (d, J = 15.5 Hz, 1H), 3.17 (dd, J = Sulfone 7h (5.00 g, 13.6 mmol) yielded 2.69 g (58%) as a pale
16.5, 6.0 Hz, 1H), 3.04 (dd, J = 16.5, 6.0 Hz, 1H) 1.41 (s, 9H) red solid after column chromatography (50-100% ethyl
1
ppm; 13C-NMR (101 MHz, CDCl3): δ 200.9, 167.4, 155.2, 141.2, acetate/hexane); mp 91.5-94 °C; H NMR (400 MHz, CDCl3): δ
128.8, 127.7, 126.3, 79.9, 52.5, 51.0, 49.5, 48.8, 28.4 ppm; IR 8.60 (s, 1H), 5.41 (dd, J = 14.0, 6.0 Hz, 1H), 5.27 (br s, 1H), 3.71
(ATR): νmax 3393, 2978, 1752, 1718, 1681, 1170, 1152 cm-1; (s, 3H), 3.46 (d, J = 15.5 Hz, 1H), 3.42 (d, J = 15.5 Hz, 1H), 3.21
HRMS (ESI) 344.1463 (M
344.1468).
+
Na+. C17H23NNaO5 requires (dd, J = 17.5, 6.0 Hz, 1H), 3.06 (dd, J = 17.5, 6.0 Hz, 1H), 2.49 (s,
3H), 1.41 (s, 9H) ppm; 13C-NMR (101 MHz, CDCl3): δ 200.2,
167.2, 154.8, 150.5, 149.9, 132.7, 80.4, 52.7, 51.5, 49.4, 44.5,
5-tert-Butoxycarbonylamino-5-(4-fluoro-phenyl)-3-oxo-pentanoic
acid methyl ester (9e)
28.4, 15.5 ppm; IR (ATR): νmax 3214, 2976, 1752, 1719, 1701,
1532, 1277, 1172, 1127, 1003 cm-1; HRMS (ESI) 343.1314 (M +
Na+. C15H23N2O5S requires 343.1322).
Sulfone 7e (5.00 g, 13.7 mmol) yielded 3.59 g (77%) as a white
solid after column chromatography (15-20% EtOAc/hexane);
1
mp 87-88.5 °C; H NMR (400 MHz, CDCl3): δ 7.30-7.23 (m, 2H),
5-tert-Butoxycarbonylamino-5-(1-methyl-1H-pyrazol-4-yl)-3-oxo-
pentanoic acid methyl ester (9i)
7.05-6.97 (m, Hz, 2H), 5.33 (br s, 1H), 5.13-5.01 (m, 1H), 3.69
(s, 3H), 3.42 (d, J = 15.5 Hz, 1H), 3.38 (d, J = 15.5 Hz, 1H), 3.16 Sulfone 7i (1.3 g, 3.51 mmol) yielded 652 mg (57%) as a
(dd, J = 17.0, 6.0 Hz, 1H), 3.02 (dd, J = 17.0 Hz, 6.0 Hz, 1H), 1.41 colourless oil after column chromatography (50-100% ethyl
(s, 9H) ppm; 13C-NMR (101 MHz, CDCl3): δ 200.7, 167.4, 162.1 acetate/hexane); 1H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H),
(d, J = 247.0 Hz), 155.2, 137.2, 128.1 (d, J = 8.0 Hz), 115.6 (d, J = 7.30 (s, 1H), 5.22 (br s, 1H), 5.12-5.03 (m, 1H), 3.85 (s, 3H),
21.5 Hz), 80.1, 52.6, 50.4, 49.5, 48.7, 28.4 ppm; 19F NMR (376 3.73 (s, 3H), 3.48 (d, J = 15.5 Hz, 1H), 3.44 (d, J = 15.5 Hz, 1H),
MHz, CDCl3): δ -116.7 ppm; IR (ATR): νmax 3306, 2982, 1741, 3.12 (dd, J = 17.0, 6.0 Hz, 1H), 3.05 (dd, J = 17.0, 6.0 Hz, 1H),
1713, 1673, 1535, 1511, 1365, 1328, 1286, 1221, 1161, 999 1.44 (s, 9H) ppm; 13C-NMR (101 MHz, CDCl3): δ 201.1, 167.4,
cm-1; HRMS (ESI) 340.1556 (M + H+. C17H23FNO5 requires 155.2, 137.2, 128.4, 122.5, 79.9, 52.5, 49.4, 48.4, 43.0, 39.1,
340.1555).
28.4 ppm; IR (ATR): νmax 3355, 2976, 1744, 1705, 1512, 1365,
1245, 1162, 1015cm-1; HRMS (ESI) 326.1697 (M
C15H24N3O5 requires 326.1711).
+
H+.
5-tert-Butoxycarbonylamino-5-(4-methoxy-phenyl)-3-oxo-
pentanoic acid methyl ester (9f)
5-tert-Butoxycarbonylamino-5-(4-cyano-phenyl)-3-oxo-pentanoic
acid methyl ester (9j)
Sulfone 7f (3.00 g, 7.95 mmol) yielded 1.49 g (53%) as a yellow
oil after column chromatography (15-20% EtOAc/hexane); 1H
NMR (400 MHz, CDCl3): δ 7.24-7.19 (m, 2H), 6.89-6.84 (m, 2H), Sulfone 7j (2.00 g, 5.38 mmol) yielded 1.26 g (68%) as a white
5.20 (br s, 1H), 5.11-5.01 (m, 1H), 3.80 (s, 3H), 3.70 (s, 3H), solid after column chromatography (15-25% EtOAc/hexane);
1
3.43 (d, J = 16.0 Hz, 1H), 3.41 (d, J = 16.0 Hz, 1H), 3.15 (dd, J = mp 93-95.5 °C; H NMR (400 MHz, CDCl3): δ 7.64-7.60 (m, 2H),
16.5, 6.5 Hz, 1H), 3.05 (dd, J = 16.5, 6.5 Hz, 1H), 1.42 (s, 9H) 7.45-7.40 (m, 2H), 5.53 (br s, 1H), 5.13 (br s, 1H), 3.70 (s, 3H),
ppm; 13C-NMR (101 MHz, CDCl3): δ 200.7, 167.3, 159.0, 155.0, 3.43 (d, J = 15.5 Hz, 1H), 3.38 (d, J = 15.5 Hz, 1H), 3.22 (dd, J =
133.3, 127.4, 114.1, 79.8, 55.3, 52.4, 50.5, 49.4, 48.8, 28.3 17.5, 4.5 Hz, 1H), 3.05 (dd, J = 17.5, 4.5 Hz, 1H), 1.41 (s, 9H)
ppm; IR (ATR): νmax 3356, 2974, 2839, 1748, 1708, 1679, 1512, ppm; 13C-NMR (101 MHz, CDCl3): δ 200.3, 167.3, 155.1, 147.0,
132.6, 127.2, 118.8, 111.4, 80.4, 52.7, 50.5, 49.3, 47.9, 28.4
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DOI: 10.1039/C8OB01272E
ARTICLE
Journal Name
6-Methyl8-oxo-5-aza-spiro[3.5]nonane-9-carboxylic acid methyl
ester (11d)
ppm; IR (ATR): νmax 3343, 2995, 2955, 2228, 1751, 1707, 1676,
1525, 1271, 1249, 1166, 1152 cm-1; HRMS (ESI) 369.1421 (M +
Na+. C18H22N2NaO5 requires 369.1421).
Hydrochloride salt of 9a (72.4 mg, 0.371 mmol) yielded 52.6
mg (67%, 2.5:1 dr) as
a yellow oil after column
General procedure for the synthesis of 2-spiropiperidines 11
chromatography (trimethylamine deadened silica, 5%
methanol/dichloromethane); 1H NMR (400 MHz, CDCl3): δ 3.70
(s, 3H), 3.55 (d, J = 1.0 Hz, 1H), 2.98 (dqd, J = 10.5, 6.5, 4.0 Hz,
1H), 2.34 (dd, J = 13.5, 10.5 Hz, 1H), 2.27 (ddd, J = 13.5, 4.0, 1.0
Hz, 1H), 2.01-1.75 (m, 6H), 1.23 (d, J = 6.5 Hz, 3H) ppm; 13C
NMR (101 MHz, CDCl3): δ 204.4, 169.1, 65.4, 63.0, 52.3, 48.4,
48.1, 32.4, 31.6, 22.5, 14.4 ppm; IR (ATR): νmax 2956, 1705,
1434, 1329, 1193, 1166 cm-1; HRMS (ESI) 212.1275 (M + H+.
C11H18NO3 requires 212.1281).
Protected δ-amino-β-ketoester (3.00 mmol) was stirred in 4M
HCl in dioxane (45.0 mmol) for 3h at room temperature. The
mixture was concentrated in vacuo to afford the hydrochloride
salt which was used without further purification.
To a suspension of hydrochloride salt (0.308 mmol) and ketone
(1.54 mmol) in CH2Cl2 (1 mL), was added NaHCO3 (129 mg,
1.54 mmol). The reaction was stirred for 16h at room
temperature, then filtered and concentrated in vacuo. The
residue was purified by column chromatography to afford 2-
spiropiperidin-4-ones.
2-Methyl-4-oxo-9-oxa-1-aza-spiro[5.5]undecane-5-carboxylic acid
methyl ester (11e)
Hydrochloride salt of 9a (280 mg, 1.44 mmol) yielded 233 mg
2,2,6-Trimethyl-4-oxo-piperidine-3-carboxylic acid methyl ester
(11a)
(67%, 4.5:1 dr) as
a
colourless oil after column
chromatography (8% ethyl acetate/dichloromethane then 50%
1
ethyl acetate/dichloromethane); H NMR (400 MHz, CDCl3): δ
Hydrochloride salt of 9a (60 mg, 0.308 mmol) yielded 52 mg
1
(85%, 2.5:1 dr) as a yellow oil without further purification; H
3.88 (ddd, J = 11.5, 10.0, 3.0 Hz, 1H), 3.72 (ddd, J = 11.5, 10.0,
3.0 Hz, 1H), 3.67 (s, 3H), 3.63 (ddd, J = 11.5, 11.5, 4.0 Hz, 1H),
3.56 (ddd, J = 11.5, 11.5, 4.0 Hz, 1H), 3.26 (d, J = 1.0 Hz, 1H),
3.06 (dqd, J = 10.5, 6.0 Hz, 3.5 Hz, 1H), 2.48 (dd, J = 13.5, 10.5
Hz, 1H), 2.30 (ddd, J = 13.5, 3.5, 1.0 Hz, 1H), 1.67-1.54 (m, 2H),
1.48-1.36 (m, 2H), 1.25 (d, J = 6.0 Hz, 3H) ppm; 13C NMR
(101 MHz, CDCl3): δ 205.0, 168.9, 66.8, 63.3, 62.8, 58.2, 52.3,
47.5, 46.9, 36.5, 33.6, 22.8 ppm; IR (ATR): νmax 2956, 2867,
1703, 1435, 1333, 1162 cm-1; HRMS (ESI) 242.1386 (M + H+.
C12H20NO4 requires 242.1387).
NMR (500 MHz, CDCl3): δ 3.69 (s, 3H), 3.22 (d, J = 1.0 Hz, 1H),
3.18 (dqd, J = 10.5, 6.5, 3.5 Hz, 1H), 2.47 (dd, J = 13.5, 10.5 Hz,
1H), 2.32 (ddd, J = 13.5, 3.5, 1.0 Hz, 1H), 1.26 (d, J = 6.5 Hz, 3H),
1.18 (s, 3H), 1.09 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3): δ
205.7, 169.7, 66.8, 57.9, 52.3, 48.4, 46.9, 28.2, 26.1, 22.8 ppm;
IR (ATR): νmax 2967, 1705, 1610, 1534, 1434, 1136 cm-1; HRMS
(ESI) 200.1289 (M + H+. C10H18NO3 requires 200.1281).
2-Methyl-4-oxo-1-aza-spiro[5.5]undecane-5-carboxylic acid methyl
ester (11b)
Hydrochloride salt of 9a (60 mg, 0.308 mmol) yielded 63 mg
4-Oxo-2-phenyl-1-aza-spiro[5.5]undecane-5-carboxylic acid methyl
ester (11f)
(85%, 7:1 dr) as a yellow oil. Aqueous work-up was performed,
1
partitioning between ethyl acetate and 2N aq. NaOH; H NMR
Hydrochloride salt of 9b (116 mg, 0.451 mmol) yielded 105 mg
(78%, 7:1 dr) as a yellow oil after successively washing an ethyl
acetate layer with water (15 times); 1H NMR (400 MHz, CDCl3):
δ 7.48-7.27 (m, 5H), 4.11 (dd, J = 11.0, 4.0 Hz, 1H), 3.72 (s, 3H),
3.41 (br s, 1H), 3.08 (dd, J = 13.5, 11.0, 1H), 2.53 (ddd, J = 13.5,
4.0, 1.0 Hz, 1H), 1.76-1.29 (m, 10H) ppm; 13C NMR (101 MHz,
CDCl3): δ 205.4, 169.5, 142.5, 128.9, 127.8, 126.7, 66.6, 60.4,
55.5, 52.2, 46.3, 36.6, 33.3, 25.7, 21.5, 21.0 ppm; IR (ATR): νmax
2930, 2855, 1702, 1434, 1327, 1192, 1162 cm-1; HRMS (ESI)
302.1754 (M + H+. C18H24NO3 requires 302.1751).
(500 MHz, CDCl3): δ 3.67 (s, 3H), 3.34 (br s, 1H), 3.15 (dqd, J =
10.5, 6.5, 3.5 Hz, 1H), 2.51 (dd, J = 13.5, 10.5 Hz, 1H), 2.30
(ddd, J = 13.5, 3.5, 1.0 Hz, 1H), 1.60-1.30 (m, 10H), 1.25 (d, J =
6.5 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3): δ 206.1, 169.5,
65.8, 60.3, 52.1, 47.5, 47.2, 36.6, 33.7, 25.8, 22.9, 21.6, 21.1
ppm; IR (ATR): νmax 2930, 2856, 1703, 1434, 1327, 1161 cm-1;
HRMS (ESI) 240.1592 (M + H+. C13H22NO3 requires 240.1594).
7-Methyl-9-oxo-6-aza-spiro[4.5]decane-10-carboxylic acid methyl
ester (11c)
Hydrochloride salt of 9a (65.8 mg, 0.337 mmol) yielded 32.4
6-(4-Fluoro-phenyl)-2,2-dimethyl-4-oxo-piperidine-3-carboxylic
acid methyl ester (11g)
mg (43%, 5:1 dr) as a pink oil after column chromatography
(trimethylamine
deadened
silica,
5%
methanol/dichloromethane); 1H NMR (400 MHz, CDCl3): δ 3.69
(s, 3H), 3.24 (d, J = 1.0 Hz, 1H), 3.06 (dqd, J = 10.5, 6.5, 3.5 Hz,
1H), 2.43 (dd, J = 13.5, 10.5 Hz, 1H), 2.31 (ddd, J = 13.5, 3.5, 1.0
Hz, 1H), 1.82-1.50 (m, 7H), 1.36 (m, 1H), 1.24 (d, J = 6.5 Hz, 3H)
ppm; 13C NMR (101 MHz, CDCl3): δ 205.3, 169.9, 69.2, 66.1,
52.3, 49.6, 47.6, 39.2, 36.1, 24.3, 23.7, 22.3 ppm; IR (ATR): νmax
2957, 1704, 1435, 1329, 1268, 1192, 1158 cm-1; HRMS (ESI)
226.1440 (M + H+. C12H20NO3 requires 226.1438).
Hydrochloride salt of 9e (110 mg, 0.399 mmol) yielded 108 mg
1
(97%, 1.8:1 dr) as a yellow oil without further purification; H
NMR (500 MHz, CDCl3): δ 7.44 (m, 2H), 7.09-7.03 (m, 2H), 4.16
(dd, J = 11.5, 3.5 Hz, 1H), 3.75 (s, 3H), 3.33 (d, J = 1.0 Hz, 1H),
3.00 (dd, J = 13.5, 11.5 Hz, 1H), 2.50 (ddd, J = 13.5, 3.5, 1.0 Hz,
1H), 1.24 (s, 3H), 1.21 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3):
δ 204.7, 169.7, 162.4 (d, J = 247.0 Hz), 137.9 (d, J = 3.5 Hz),
128.3 (d, J = 8.5 Hz), 115.8 (d, J = 21.5 Hz), 67.1, 58.0, 56.2,
52.4, 46.0, 28.4, 26.0 ppm; 19F NMR (376 MHz, CDCl3): δ -
114.42 ppm; IR (ATR): νmax 2969, 1748, 1705, 1603, 1509, 1222,
8 | J. Name., 2012, 00, 1-3
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1195, 1152, 1125 cm-1; HRMS (ESI) 280.1342 (M + Na+. 1226, 1196, 1161 cm-1; HRMS (ESI) 338.1205 (M + H+.
C15H19FNO3 requires 280.1343).
C17H21FNO3S requires 338.1221).
2-(4-Fluoro-phenyl)-4-oxo-1-aza-spiro[5.5]undecane-5-carboxylic
acid methyl ester (11h)
2-(4-Methoxy-phenyl)-4-oxo-9-oxa-1-aza-spiro[5.5]undecane-5-
carboxylic acid methyl ester (11k)
Hydrochloride salt of 9e (69.5 mg, 0.248 mmol) yielded 59 mg Hydrochloride salt of 9f (757 mg, 2.63 mmol) yielded 290 mg
(75%, 5:1 dr) as a yellow oil after successively washing an ethyl (33%, 2:1 dr) as a pale red solid after column chromatography
1
acetate layer with water (5 times); 1H NMR (400 MHz, CDCl3): δ (0-80% ethyl acetate/cyclohexane); mp 118-121 oC; H NMR
7.46-7.39 (m, 2H), 7.10-7.03 (m, 2H), 4.10 (dd, J = 11.5, 4.0 Hz, (400 MHz, CDCl3): δ 7.43-7.36 (m, 2H), 6.98-6.92 (m, 2H), 4.08
1H), 3.73 (s, 3H), 3.41 (br s, 1H), 3.04 (dd, J = 13.5, 11.5 Hz, (dd, J = 11.0, 3.5 Hz, 1H), 4.03-3.64 (m, 4H), 3.84 (s, 3H), 3.76
1H), 2.52 (ddd, J = 13.5, 4.0, 1.0 Hz, 1H), 1.80-1.29 (m, 10H) (s, 3H), 3.42 (d, J = 1.0 Hz, 1H), 3.10 (dd, J = 13.5, 11.0 Hz, 1H),
ppm; 13C NMR (101 MHz, CDCl3): δ 205.1, 169.6, 162.3 (d, J = 2.57 (ddd, J = 13.5, 3.5, 1.0 Hz, 1H-5), 2.15 (br s, 1H), 1.85-1.70
247.0 Hz), 138.4 (d, J = 3.0 Hz), 128.4 (d, J = 8.0 Hz), 115.8 (d, J (m, 2H), 1.65-1.44 (m, 2H) ppm; 13C-NMR (101 MHz, CDCl3): δ
= 21.0 Hz), 66.5, 60.3, 54.8, 52.3, 46.3, 36.6, 33.4, 25.7, 21.6, 204.4, 168.9, 159.2, 134.1, 127.7, 114.2, 67.0, 63.3, 62.7, 58.2,
21.1 ppm; 19F NMR (376 MHz, CDCl3): δ -114.7 ppm; IR (ATR): 55.3, 54.9, 52.3, 46.2, 36.6, 33.3 ppm; IR (ATR): νmax 3318,
νmax 2933, 2856, 1705, 1600, 1510, 1439, 1329, 1224, 1159 cm- 2965, 2947, 2865, 1732, 1701, 1515, 1297, 1243,1159, 1024
1
;
HRMS (ESI) 320.1645 (M
+
H+. C18H23FNO3 requires cm-1. HRMS (ESI) 334.1637 (M + H+. C18H24NO5 requires
334.1649).
320.1656).
2-(4-fluoro-phenyl)-4-oxo-9-oxa-1-aza-spiro[5.5]undecane-5-
carboxylic acid methyl ester (11i)
6-(3-pyridyl)-2,2-dimethyl-4-oxo-piperidine-3-carboxylic acid
methyl ester (11l)
Hydrochloride salt of 9e (129 mg, 0.468 mmol) yielded 84.5 mg Hydrochloride salt of 9g (80 mg, 0.310 mmol) yielded 70 mg
1
(56%, 2:1 dr) as a white solid after column chromatography (86%, 1.5:1 dr) as a yellow oil without further purification; H
(trimethylamine
deadened
silica,
20%
ethyl NMR (500 MHz, CDCl3): δ 8.65 (d, J = 2.0 Hz, 1H), 8.55 (dd, J =
acetate/dichloromethane); mp 110.5-113 oC; 1H NMR (500 4.5, 2.0 Hz, 1H), 7.80 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 7.31 (dd, J =
MHz, CDCl3): δ 7.45-7.40 (m, 2H), 7.11-7.06 (m, 2H), 4.09 (dd, J 8.0, 4.5 Hz, 1H), 4.21 (dd, J = 11.5, 4.0 Hz, 1H), 3.73 (s, 3H),
= 11.5, 3.5 Hz, 1H), 3.90 (ddd, J = 11.5, 10.5, 3.0 Hz, 1H), 3.81 3.13 (d, J = 1.0 Hz, 1H), 3.01 (dd, J = 13.5, 11.5 Hz, 1H), 2.52
(ddd, J = 11.5, 10.5, 3.0 Hz, 1H), 3.74 (s, 3H), 3.72-3.64 (m, 2H), (ddd, J = 13.5, 4.0, 1.0 Hz, 1H), 1.24 (s, 3H), 1.22 (s, 3H) ppm;
3.40 (d, J = 1.0 Hz, 1H), 3.06 (dd, J = 13.5, 11.5 Hz, 1H), 2.57 13C NMR (101 MHz, CDCl3): δ 204.3, 169.7, 149.5, 148.8, 137.4,
(ddd, 13.5, 3.5, 1.0 Hz, 1H), 2.14 (br s, 1H), 1.81-1.75 (m, 1H), 134.1, 123.9, 66.9, 58.0, 54.2, 52.2, 45.4, 28.3, 25.8 ppm; IR
1.73 (ddd, J = 14.0, 10.5, 4.0 Hz, 1H), 1.59 (ddd, J = 14.0, 10.5, (ATR): νmax 2969, 1707, 1429, 1197, 1153 cm-1; HRMS (ESI)
4.0 Hz, 1H), 1.52-1.46 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3): 263.1393 (M + Na+. C14H19N2O3 requires 263.1390).
δ 204.2, 169.0, 162.1 (d, J = 245.0 Hz), 138.8 (d, J = 3.0 Hz),
4-Oxo-2-pyridin-3-yl-9-oxa-1-aza-spiro[5.5]undecane-5-carboxylic
128.3 (d, J = 14.0 Hz), 115.8 (d, J = 21.5 Hz), 67.0, 63.4, 62.8,
58.3, 54.9, 52.5, 46.1, 36.7, 33.4 ppm; 19F NMR (376 MHz,
CDCl3): δ -114.0 ppm; IR (ATR): νmax 2963, 2868, 1706, 1603,
1511, 1223, 1160 cm-1; HRMS (ESI) 322.1445 (M + H+.
acid methyl ester (11m)
Hydrochloride salt of 9g (1.50 g, 5.81 mmol) yielded 1.40 g
(79%, 1.5:1 dr) as a yellow oil after column chromatography
(50% ethyl acetate/dichloromethane then 100% ethyl acetate);
1H NMR (400 MHz, CDCl3): δ 8.69 (d, J = 2.0 Hz, 1H), 8.58 (dd, J
= 5.0, 2.0 Hz, 1H), 7.82 (ddd, J = 8.0, 2.0, 2.0 Hz, 1H), 7.34 (dd, J
= 8.0, 5.0 Hz, 1H), 4.17 (dd, J = 11.5, 3.5 Hz, 1H), 3.90 (ddd, J =
11.5, 11.5, 2.5 Hz, 1H), 3.81 (ddd, J = 11.5, 11.5, 2.5 Hz, 1H),
C17H21FNO4 requires 322.1449), 344.1269 (M
C17H21FNO4 requires 344.1269).
+
Na+.
2-(4-Fluoro-phenyl)-4-oxo-9-thia-1-aza-spiro[5.5]undecane-5-
carboxylic acid methyl ester (11j)
Hydrochloride salt of 9e (189 mg, 0.686 mmol) yielded 171 mg 3.74 (s, 3H), 3.74-3.64 (m, 2H), 3.41 (d, J = 0.5 Hz, 1H), 3.09
(63%, 1:1 dr) as a colourless oil after column chromatography (dd, J = 13.5, 11.5 Hz, 1H), 2.61 (ddd, J = 13.5, 3.5, 0.5 Hz, 1H),
(trimethylamine
deadened
silica,
10-20%
ethyl 2.20 (br s, 1H), 1.83-1.69 (m, 2H), 1.65-1.56 (m, 1H), 1.53-1.45
acetate/hexane); 1H NMR (400 MHz, CDCl3): δ 7.45-7.39 (m, (m, 1H) ppm; 13C NMR (101 MHz, CDCl3): δ 203.5, 168.9, 149.4,
2H), 7.11-7.04 (m, 2H), 4.04 (dd, J = 11.0, 4.0 Hz, 1H), 3.73 (s, 148.7, 137.2, 134.0, 123.8, 67.0, 63.3, 62.7, 58.3, 53.1, 52.5,
3H), 3.33 (br s, 1H), 3.22-3.12 (m, 1H), 3.04 (dd, J = 13.5, 11.0 45.3, 36.5, 33.2 ppm; IR (ATR): νmax 2952, 2872, 1706, 1428,
Hz, 1H), 3.06-2.93 (m, 1H), 2.56 (ddd, J = 13.5, 4.0, 0.5 Hz, 1H), 1337, 1195, 1166 cm-1; HRMS (ESI) 305.1486 (M + H+.
2.41-2.32 (m, 2H), 2.12-1.93 (m, 2H), 1.84-1.77 (m, 2H), 1.70 C16H21N2O4 requires 305.1496).
(ddd, J = 14.5, 11.5, 14.5 Hz, 1H) ppm; 13C NMR (101 MHz,
4-Oxo-2-pyridin-3-yl-1,9-diaza-spiro[5.5]undecane-5,9-dicarboxylic
acid 9-benzyl ester 5-methyl ester (11n)
CDCl3): δ 204.3, 169.0, 162.4 (d, J = 247.5 Hz), 137.8 (d, J = 3.5
Hz), 128.3 (d, J = 8.0 Hz), 115.8 (d, J = 21.5 Hz), 67.4, 59.3, 54.4,
52.5, 45.7, 37.3, 34.3, 23.4, 22.8 ppm; 19F NMR (376 MHz,
CDCl3): δ -114.3 ppm; IR (ATR): νmax 2962, 2922, 1705, 1510,
Hydrochloride salt of 9g (145 mg, 0.562 mmol) yielded 145 mg
(67%, 2:1 dr) as a yellow oil after column chromatography
(50% ethyl acetate/dichloromethane then 100% ethyl acetate);
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1H NMR (400 MHz, CDCl3): δ 8.66 (br s, 1H), 8.56 (dd, J = 5.0,
1.5 Hz, 1H), 7.78 (ddd, J = 8.0, 1.5, 1.5 Hz, 1H), 7.37-7.26 (m,
6H), 5.10 (s, 2H), 4.20-4.06 (m, 1H), 3.92-3.75 (m, 2H), 3.71 (s,
3H), 3.45-3.16 (m, 2H), 3.30 (d, J = 0.5 Hz, 1H), 3.07 (dd, J =
13.5, 11.5 Hz, 1H), 2.60 (ddd, J = 13.5, 3.0, 0.5 Hz, 1H), 1.91-
1.34 (m, 4H) ppm; 13C NMR (101 MHz, CDCl3): δ 203.1, 168.8,
155.2, 149.5, 148.6, 137.0, 136.7, 133.9, 128.6, 128.1, 127.9,
123.8, 67.2, 66.8, 58.8, 53.2, 52.5, 45.0, 39.5, 39.0, 35.5, 32.3
ppm; IR (ATR): νmax 2951, 1694, 1427, 1246, 1164 cm-1; HRMS
(ESI) 438.2032 (M + H+. C24H28N3O5 requires 438.2023).
6-(4-Cyano-phenyl)-8-oxo-5-aza-spiro[3.5]nonane-9-carboxylic
acid methyl ester (11r)
Hydrochloride salt of 9j (102 mg, 0.362 mmol) yielded 67.5 mg
(63%, 1:1 dr) as a yellow oil after column chromatography
(33% ethyl acetate/hexane); 1H NMR (400 MHz, CDCl3): δ 7.69-
7.64 (m, 2H), 7.57-7.50 (m, 2H), 4.04 (dd, J = 11.5, 3.5 Hz, 1H),
3.76 (s, 3H), 3.65 (d, J = 1.0 Hz, 1H), 2.86 (dd, J = 13.5, 11.5 Hz,
1H), 2.52 (ddd, J = 13.5, 3.5, 1.0 Hz, 1H), 2.29-2.20 (m, 1H),
2.15-2.05 (m, 1H), 2.04-1.86 (m, 4H) ppm; 13C-NMR (101 MHz,
CDCl3): δ 202.9, 169.0, 147.1, 132.8, 127.5, 118.7, 111.8, 65.1,
63.0, 56.0, 52.5, 46.8, 32.6, 31.7, 14.2; IR (ATR): νmax 3313,
2952, 2227, 1707, 1607, 1435, 1290, 1197, 1165 cm-1; HRMS
4-Oxo-2-pyridin-3-yl-9-thia-1-aza-spiro[5.5]undecane-5-carboxylic
acid methyl ester (11o)
Hydrochloride salt of 9g (103.6 mg, 0.402 mmol) yielded 77.5 (ESI) 299.1383 (M + H+. C17H19N2O3 requires 299.1390).
mg (75%, 0.95:1 dr) as a yellow oil after column
6-(4-Cyano-phenyl)-8-oxo-2-oxa-5-aza-spiro[3.5]nonane-9-
carboxylic acid methyl ester (11s)
chromatography (50% ethyl acetate/hexane then 100% ethyl
1
acetate). H NMR (400 MHz, CDCl3): δ 8.68-8.64 (m, 1H), 8.58-
8.54 (m, 1H), 7.79 (ddd, 8.0, 2.0, 2.0 Hz, 1H), 7.35-7.28 (m, 1H),
4.10 (br s, 1H), 3.71 (s, 3H), 3.33 (d, J = 1.0 Hz, 1H), 3.20-3.09
(m, 1H), 3.05 (dd, 13.5, 11.5 Hz, 1H), 3.06-2.90 (m, 1H), 2.58
(ddd, 13.5, 4.0, 1.0 Hz, 1H), 2.40-2.28 (m, 2H), 2.12-2.05 (m,
1H), 1.82-1.77 (m, 2H), 1.70 (ddd, J = 14.5, 11.5, 3.0, 1H) ppm;
13C NMR (101 MHz, CDCl3): δ 203.6, 168.9, 149.5, 148.7, 137.1,
134.0, 123.8, 67.4, 59.3, 52.7, 52.5, 44.9, 37.2, 34.2, 23.3, 22.7
ppm; IR (ATR): νmax 3310, 2952, 2920, 1703, 1424, 1268, 1195,
1162 cm-1; HRMS (ESI) 321.1260 (M + H+. C16H21N2O3S requires
321.1267).
Hydrochloride salt of 9j (93 mg, 0.330 mmol) yielded 42.8 mg
(43%, 1.6:1 dr) as a yellow oil after column chromatography
(60% ethyl acetate/hexane); 1H NMR (400 MHz, CDCl3): δ 7.70-
7.66 (m, 2H), 7.57-7.51 (m, 2H), 4.92 (d, J = 7.5 Hz, 1H), 4.61 (d,
J = 7.5 Hz, 1H), 4.56 (d, J = 6.5 Hz, 1H), 4.50 (d, J = 6.5 Hz, 1H),
4.02 (dd, J = 11.5, 3.5 Hz, 1H), 3.93 (d, J = 1.5 Hz, 1H), 3.79 (s,
3H), 2.72 (dd, J = 13.5, 11.5 Hz, 1H), 2.56 (ddd, J = 13.5, 3.5, 1.5
Hz, 1H) ppm; 13C-NMR (101 MHz, CDCl3): δ 200.9, 167.9, 146.3,
132.9, 127.5, 118.6, 112.3, 80.9, 80.1, 62.9, 62.4, 56.1, 53.0,
47.5 ppm; IR (ATR): νmax 3302, 2874, 2228, 1717, 1608, 1441,
1345, 1297 1225 cm-1; HRMS (ESI) 301.1179 (M + H+.
C16H17N2O4 requires 301.1183).
2-(4-Methyl-thiazol-5-yl)-4-oxo-9-oxa-1-aza-spiro[5.5]undecane-5-
carboxylic acid methyl ester (11p)
Hydrochloride 9i (99 mg, 0.356 mmol) yielded 86 mg (75%, 1:1 General procedure for the synthesis of N-Boc imines 12
dr) as an off-white solid after column chromatography (50%
A suspension of benzenesulfonyl carbamic ester (8.15 mmol),
ethyl acetate/dichloromethane then 100% ethyl acetate); mp
K2CO3 (48.9 mmol) and Na2SO4 (57.1 mmol) in THF (82 mL) was
98-101 oC; 1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 4.41 (dd, J
stirred at reflux for 3h. The mixture was cooled to rt, filtered
= 11.0, 3.5 Hz, 1H), 3.90-3.76 (m, 2H), 3.73 (s, 3H), 3.71-3.64
through a sintered funnel and concentrated in vacuo. The
(m, 2H), 3.38 (br s, 1H), 3.05 (dd, J = 13.5, 11.0 Hz, 1H), 2.63
imine was used without further purification.
(ddd, J = 13.5, 3.5, 1.0 Hz, 1H), 2.47 (s, 3H), 1.80-1.54 (m, 3H),
1.51-1.41 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3): δ 202.5,
(4-Fluoro-benzylidene)-carbamic acid tert-butyl ester (12e)
168.7, 150.2, 149.9, 133.0, 66.8, 63.3, 62.7, 58.1, 52.6, 48.8,
Sulfone 7e (1.12 g, 3.07 mmol), K2CO3 (2.54 g, 18.4 mmol) and
47.1, 36.5, 33.4, 16.6 ppm; IR (ATR): νmax 2953, 2865, 1706,
Na2SO4 (3.05 g, 21.5 mmol) gave the title compound (635 mg,
1435, 1338, 1255, 1196, 1165 cm-1; HRMS (ESI) 325.1201 (M +
2.86 mmol, 93% yield) as a white solid. Spectroscopic data was
H+. C15H21N2O4S requires 325.1217).
identical to that previously reported.19 1H NMR (400 MHz,
CDCl3): δ 8.85 (s, 1H), 7.96-7.90 (m, 2H), 7.18-7.11 (m, 2H),
2-(1-Methyl-1H-pyrazol-4-yl)-4-oxo-9-oxa-1-aza-
1.58 (s, 9H) ppm.
spiro[5.5]undecane-5-carboxylic acid methyl ester (11q)
Hydrochloride salt of 9h (203 mg, 0.776 mmol) yielded 119 mg
(4-Methoxy-benzylidene)-carbamic acid tert-butyl ester (12f)
(50%, 2.5:1 dr) as a yellow oil after column chromatography (0-
Sulfone 7f (1.07 g, 2.84 mmol), K2CO3 (2.35 g, 17.0 mmol) and
1
50% ethanol/ethyl acetate); H NMR (400 MHz, CDCl3): δ 7.52
Na2SO4 (2.83 g, 19.9 mmol) gave the title compound (601 mg,
(s, 1H), 7.40 (s, 1H), 4.13 (dd, J = 11.0, 3.5 Hz, 1H), 4.00-3.63
2.56 mmol, 90% yield) as a white solid. Spectroscopic data was
identical to that previously reported.19 1H NMR (400 MHz,
(m, 4H), 3.91 (s, 3H), 3.72 (s, 3H), 3.38 (d, J = 1.0 Hz, 1H), 2.97
(dd, J = 13.5, 11.0 Hz, 1H), 2.63 (ddd, J = 13.5, 3.5, 1.0 Hz, 1H),
1.80-1.67 (m, 2H), 1.61-1.44 (m, 2H) ppm; 13C-NMR (101 MHz,
CDCl3): δ 8.87 (s, 1H), 7.91-7.85 (m, 2H), 6.98-6.91 (m, 2H),
3.86 (s, 3H), 1.57 (s, 9H) ppm.
CDCl3): δ 203.7, 168.7, 137.1, 127.6, 123.8, 67.1, 63.2, 62.7,
58.0, 52.3, 47.4, 46.1, 39.0, 36.5, 33.3 ppm; IR (ATR): νmax 3282,
3248, 1704, 1562, 1435, 1296, 1218, 1159 cm-1; HRMS (ESI)
308.1594 (M + H+. C15H22N3O4 requires 308.1605).
(4-Methyl-thiazol-5-ylmethylene)-carbamic acid tert-butyl ester
(12h)
10 | J. Name., 2012, 00, 1-3
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Sulfone 7h (3.00 g, 8.15 mmol), K2CO3 (6.75 g, 48.9 mmol) and 3.05-2.94 (m, 1H), 2.62 (ddd, J = 13.7, 3.5, 1.0 Hz, 1H), 2.48 (s,
Na2SO4 (8.11 g, 57.1 mmol) gave the title compound (1.81 g, 3H), 2.42-2.33 (m, 2H), 2.12-1.75 (m, 4H), 1.71 (ddd, J = 14.5,
8.07 mmol, 99% yield) as an orange oil. 1H NMR (400 MHz, 11.7, 3.2 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3): δ 202.6,
CDCl3): δ 9.17 (d, J = 0.5 Hz, 1H), 8.88 (s, 1H), 2.68 (s, 3H), 1.55 168.7, 150.3, 149.8, 133.1, 67.2, 59.1, 52.6, 48.4, 46.9, 37.2,
(s, 9H) ppm; 13C NMR (101 MHz, CDCl3): δ 162.3, 161.8, 161.7, 34.3, 23.3, 22.7, 15.7 ppm; IR (ATR): νmax 3314, 2952, 2922,
158.2, 129.7, 82.7, 27.8, 16.3 ppm; IR (ATR): νmax 2982, 2931, 1705, 1434, 1415, 1315, 1266, 1196, 1163 cm-1; HRMS (ESI)
1705, 1600, 1512, 1366, 1243, 1150 cm-1; HRMS (ESI) 281.0917 341.0990 (M + H+. C15H21N2O3S2 requires 341.0988).
(M + Na+. C11H18N2NaO3S requires 281.0930 for the methanol
2-(4-Methyl-thiazol-5-yl)-4-oxo-1,9-diaza-spiro[5.5]undecane-5,9-
adduct).
dicarboxylic acid 9-benzyl ester 5-methyl ester (11u)
(4-Cyano-benzylidene)-carbamic acid tert-butyl ester (12j)
Imine 12h (119 mg, 0.527 mmol), TiCl4 (231 μL, 2.11 mmol),
Chan’s diene (260 mg, 1.05 mmol), MeOH (341 μL, 8.43 mmol),
1-Z-4-piperidone (615 mg, 2.64 mmol) and NaHCO3 (1.77 g,
21.1 mmol). Purification by column chromatography (40%
EtOAc/hexane then 80% EtOAc/hexane) gave the title
compound (107 mg, 0.473 mmol, 45% yield) as an orange oil;
1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.39-7.27 (m, 5H),
5.11 (s, 2H), 4.46-4.33 (m, 1H), 3.95-3.76 (m, 2H), 3.73 (s, 3H),
3.43-3.24 (m, 2H), 3.29 (br. s, 1H), 3.05 (dd, J = 13.5, 11.2 Hz,
1H), 2.70-2.60 (m, 1H), 2.46 (s, 3H), 2.04 (br. s, 1H), 1.93-1.37
(m, 4H) ppm; 13C NMR (101 MHz, CDCl3): δ 202.3, 168.7, 155.2,
150.3, 149.9, 136.7, 132.9, 128.6, 128.2, 128.1, 67.3, 66.7,
58.5, 52.7, 48.9, 47.0, 39.5, 39.1, 35.6, 32.4, 15.7 ppm; IR
(ATR): νmax 2951, 1698, 1432, 1247, 1165 cm-1; HRMS (ESI)
458.1747 (M + H+. C23H28N3O5S requires 458.1744).
Sulfone 7j (1.15 g, 3.13 mmol), K2CO3 (2.59 g, 18.8 mmol) and
Na2SO4 (3.11 g, 21.9 mmol) gave the title compound (723 mg,
3.13 mmol, 100% yield) as
a white amorphous solid.
Spectroscopic data was identical to that previously reported.20
1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 8.03-7.97 (m, 2H),
7.79-7.74 (m, 2H), 1.58 (s, 9H) ppm.
(4-Trifluoromethyl-benzylidene)-carbamic acid tert-butyl ester
(12k)
Sulfone 7k (1.09 g, 2.63 mmol), K2CO3 (2.18 g, 15.8 mmol) and
Na2SO4 (2.61 g, 18.4 mmol) gave the title compound (710 mg,
2.60 mmol, 99% yield) as a white amorphous white solid.
Spectroscopic data was identical to that previously reported.19
1H NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.02 (d, J = 8.2 Hz,
2H), 7.73 (d, J = 8.2 Hz, 2H), 1.59 (s, 9H) ppm.
2-(4-Cyano-phenyl)-4-oxo-1,9-diaza-spiro[5.5]undecane-5,9-
dicarboxylic acid 9-benzyl ester 5-methyl ester (11v)
General procedure for the one-pot synthesis of 2-spiropiperidines
11
Imine 12j (131 mg, 0.570 mmol), TiCl4 (250 μL, 2.28 mmol),
Chan’s diene (296 mg, 1.14 mmol), MeOH (368 μL, 9.12 mmol),
1-Z-4-piperidone (664 mg, 2.85 mmol) and NaHCO3 (1.92 g,
22.8 mmol). Purification by column chromatography (30%
EtOAc/hexane) gave the title compound (62 mg, 0.137 mmol,
Neat TiCl4 (4.56 mmol) was added dropwise to a solution of
o
imine (1.14 mmol) in CH2Cl2 (11.4 mL) at -78 C. Chan’s diene
(2.28 mmol) was added dropwise and the mixture was stirred
o
for 30 mins at -78 C. MeOH (18.2 mmol) was added and the
1
24% yield) as a yellow oil; H NMR (400 MHz, CDCl3): δ 7.71-
mixture was stirred at rt for 4h. Ketone (5.70 mmol) and
NaHCO3 (45.6 mmol) were sequentially added, and the
reaction was stirred overnight at rt. The reaction was
quenched with 1.59M citric acid in MeOH (11.4 mmol), and the
mixture was cooled to 0 oC. Water (8 mL) was carefully added,
followed by dilution with CH2Cl2 (10 mL) and the mixture was
stirred vigorously for 30 mins at rt. The layers were separated
and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL).
Organics were combined, washed with sat. aq. NaHCO3 (20
mL) and brine (20 mL), dried (MgSO4), filtered and
concentrated in vacuo. The crude residue was purified by
column chromatography.
7.64 (m, 2H), 7.59-7.52 (m, 2H), 7.39-7.28 (m, 5H), 5.10 (s, 2H),
4.19-4.08 (m, 1H), 3.92-3.75 (m, 2H), 3.73 (s, 3H), 3.46-3.34 (m,
1H), 3.32 (d, J = 1.0 Hz, 1H), 3.32-3.18 (m, 1H), 3.03 (dd, J =
13.7, 11.5 Hz, 1H), 2.61 (dd, J = 13.7, 3.5 Hz, 1H), 1.89-1.37 (m,
4H) ppm; 13C NMR (101 MHz, CDCl3): δ 203.0, 169.0, 155.2,
146.8, 136.7, 132.8, 128.6, 128.2, 128.0, 127.5, 118.6, 112.0,
67.3, 66.7, 58.9, 55.0, 52.6, 45.2, 39.5, 39.0, 35.6, 32.3 ppm; IR
(ATR): νmax 2952, 2227, 1694, 1431, 1231, 1164, 1120 cm-1;
HRMS (ESI) 462.2025 (M + H+. C26H28N3O5 requires 462.2023),
484.1841 (M + Na+. C26H27N3NaO5 requires 484.1843).
4-Oxo-2-(4-trifluoromethyl-phenyl)-1-aza-spiro[5.5]undecane-5-
carboxylic acid methyl ester (11w)
2-(4-Methyl-thiazol-5-yl)-4-oxo-9-thia-1-aza-spiro[5.5]undecane-5-
carboxylic acid methyl ester (11t)
Imine 12k (314 mg, 1.15 mmol), TiCl4 (504 μL, 4.60 mmol),
Chan’s diene (598 mg, 2.30 mmol), MeOH (743 μL, 18.4 mmol),
cyclohexanone (595 μL, 5.75 mmol) and NaHCO3 (3.86 g, 46.0
mmol). Purification by column chromatography (10%
EtOAc/hexane) gave an inseparable mixture of product and
cyclohexanone. The mixture was dissolved in EtOAc (20 mL)
and washed with water (10 x 10 mL), dried (MgSO4), filtered
and concentrated to give the title compound (117 mg, 0.322
Imine 12h (149 mg, 0.659 mmol), TiCl4 (289 μL, 2.64 mmol),
Chan’s diene (343 mg, 1.32 mmol), MeOH (424 μL, 10.5 mmol),
tetrahydro-4H-thiopyran-4-one (383 mg, 3.30 mmol) and
NaHCO3 (2.22 g, 26.4 mmol). Purification by column
chromatography (40% EtOAc/hexane) gave the title compound
(123 mg, 0.362 mmol, 55% yield) as a red oil; 1H NMR (400
MHz, CDCl3): δ 8.67 (s, 1H), 4.43-4.32 (m, 1H), 3.72 (s, 3H), 3.31
(br. s, 1H), 3.16-3.06 (m, 1H), 3.02 (dd, J = 13.7, 11.5 Hz, 1H),
1
mmol, 28% yield) as a yellow oil; H NMR (400 MHz, CDCl3): δ
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J. Name., 2013, 00, 1-3 | 11
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DOI: 10.1039/C8OB01272E
ARTICLE
Journal Name
6
Y. Troin and M. E. Sinibaldi, Targets in Heterocyclic Systems:
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2009, 13, 120-146.
W.-Y. Siau and J. W. Bode, J. Am. Chem. Soc. 2014, 136,
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R. J. Bahde and S. D. Rychnovsky, Org. Lett., 2008, 10, 4017-
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7.67-7.55 (m, 4H), 4.18 (dd, J = 11.2, 3.8 Hz, 1H), 3.73 (s, 3H),
3.42 (br. s, 1H), 3.06 (dd, J = 13.5, 11.2 Hz, 1H), 2.57 (ddd, J =
13.5, 3.8, 1.0 Hz, 1H), 1.78-1.29 (m, 10H) ppm; 13C NMR
(101 MHz, CDCl3): δ 204.6, 169.5, 146.4, 130.0 (q, J = 32.4 Hz),
127.1, 125.9 (q, J = 3.5 Hz), 124.1 (q, J = 273 Hz), 66.6, 60.3,
54.9, 52.3, 45.8, 36.6, 33.3, 25.6, 21.5, 21.0 ppm; 19F NMR (376
MHz, CDCl3): δ -62.4 ppm; IR (ATR): νmax 2933, 2857, 1706,
1324, 1164, 1123, 1068 cm-1; HRMS (ESI) 370.1606 (M + H+.
C19H23F3NO3 requires 370.1625).
7
8
9
10 P. A. Clarke, A. V. Zaytzev and A. C. Whitwood, Tetrahedron
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8895.
2,2-Dimethyl-6-(4-methyl-thiazol-5-yl)-4-oxo-piperidine-3-
carboxylic acid methyl ester (11x)
Imine 12h (321 mg, 1.42 mmol), TiCl4 (623 μL, 5.68 mmol),
Chan’s diene (738 mg, 2.84 mmol), MeOH (917 μL, 22.7 mmol),
acetone (630 μL, 8.52 mmol) and NaHCO3 (4.77 g, 56.8 mmol).
Purification by column chromatography (75% EtOAc/hexane)
gave the title compound (96 mg, 0.341 mmol, 24% yield) as a
1
red solid; mp 101.5-106 °C; H NMR (400 MHz, CDCl3): δ 8.64
(s, 1H), 4.62 (dd, J = 11.0, 3.5 Hz, 1H), 3.74 (s, 3H), 3.61 (s, 1H),
2.59 (dd, J = 13.5, 3.5 Hz, 1H), 2.43-2.40 (m, 1H), 2.41 (s, 3H),
1.44 (s, 3H), 1.32 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3): δ
202.3, 168.4, 151.2, 148.7, 134.1, 66.9, 56.8, 52.0, 49.5, 48.9,
30.0, 22.7, 15.5 ppm; IR (ATR): νmax 2953, 1747, 1713, 1435,
1341, 1276, 1192, 1121 cm-1; HRMS (ESI) 283.1112 (M + H+.
C13H19N2O3S requires 283.1111).
20 A. S. Tsai, M. E. Tauchert, R. G. Bergman and J. A. Ellman, J.
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Conflicts of interest
There are no conflicts to declare.
22 For GSK compounds for lead oriented synthesis, contact
free.buildingblocks@gsk.com
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,
Acknowledgements
24 R. C. F. Jones, C. C. M. Law and M. R. J. Elsegood, ARKIVOC,
2013, , 81-97.
We thank the Department of Chemistry, University of York,
GlaxoSmithKline (SDG) and the ERASMUS+ program (MF) for
financial support and Dr. A. C. Whitwood for X-ray
crystallographic analysis.
3
25 C. Rampalakos and W. D. Wulff, Adv. Synth. Catal. 2008, 350
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Notes and references
‡ X-ray crystal structure of 11i with thermal ellipsoids shown at
50%. CCDC 1549997 contains the supplementary crystallographic
data for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
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12 | J. Name., 2012, 00, 1-3
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