Exploitation of the Ugi-Joullié Reaction in the Synthesis of Libraries of Drug-Like Bicyclic Hydantoins

Article abstract of DOI:10.1055/s-0034-1378704

A general and efficient method for the synthesis of drug-like fused bicyclic hydantoins is reported. An Ugi-Joullié reaction/cyclisation sequence was exploited as the key complexity-generating process in which trifluoroacetic acid was employed as synthetic equivalent for chloroformic acid. Exemplar diversification of the bicyclic scaffolds was performed to enable subsequent translation to the synthesis of large small molecule libraries, leading to the production of >1000 compounds for addition to the screening collection of the European Lead Factory.

Full text of DOI:10.1055/s-0034-1378704

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2391–2406
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special topic
J. D. Firth et al.
Special Topic
Synthesis
Exploitation of the Ugi–Joullié Reaction in the Synthesis of Libraries
of Drug-Like Bicyclic Hydantoins
James D. Firtha
Rong Zhanga
Rémy Morgentinb
Rachel Guilleuxb
Tuomo Kalliokoskic
Stuart Warrinera,d
Richard Fostera,d
Stephen P. Marsdena
Adam Nelson*a,d
a School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
b Edelris, 115 Avenue Lacassagne, 69003 Lyon, France
c Lead Discovery Center GmbH, Otto-Hahn-Straße 15, 44227
Dortmund, Germany
d Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK
a.s.nelson@leeds.ac.uk
Received: 30.03.2015
Accepted: 16.04.2015
Published online: 19.06.2015
DOI: 10.1055/s-0034-1378704; Art ID: ss-2015-c0208-st
The synthesis of four substrates for Ugi–Joullié reactions
was achieved using our previously reported method.12
Thus, the required N-Boc-appended propargylic sulfon-
amides 3 were prepared by treatment of propargylic sul-
fonamides 2 with sodium hydride, and reaction with cyclic
sulfamidates 113 (Scheme 1). Treatment of terminal alkyne
products 3 (R3 = H) with either 5 mol% Au(PPh3)Cl and 5
mol% AgSbF6, or 1 mol% of the N-heterocyclic carbene com-
plex Au(IPr)Cl14 and 1 mol% AgSbF6, in 1,4-dioxane at 100 °C
yielded the tetrahydropyrazines 4a–c in 35–76% yield over
the two steps. In contrast, with an intermediate 1,2-disub-
stituted alkyne 3d (in which R3 = Et), hydration occurred
distal to the N-nitrophenylsulfonyl group to give, without
subsequent cyclisation, the ketone 5 in 48% overall yield.12
In order to assess the effect of a basic amine on the Ugi–
Joullié reaction, the benzyl-protected amino ketone 8
(Scheme 2) was also prepared. Reductive amination of
benzaldehyde with the amine 6, to give 7, was followed by
aza-Michael reaction with methyl vinyl ketone to give the
β-amino ketone 8 in 66% overall yield.
Abstract A general and efficient method for the synthesis of drug-like
fused bicyclic hydantoins is reported. An Ugi–Joullié reaction/cyclisa-
tion sequence was exploited as the key complexity-generating process
in which trifluoroacetic acid was employed as synthetic equivalent for
chloroformic acid. Exemplar diversification of the bicyclic scaffolds was
performed to enable subsequent translation to the synthesis of large
small molecule libraries, leading to the production of >1000 compounds
for addition to the screening collection of the European Lead Factory.
Key words multicomponent reactions, scaffolds, libraries, Ugi reac-
tion, hydantoin
Controlling molecular properties is crucial in drug dis-
covery, and guidelines have been developed to direct me-
dicinal chemists towards drug-like chemical space.1 Key
properties, such as molecular weight,2 lipophilicity2,3 and
the fraction of sp3-hybridised carbons4 correlate strongly
with the successful translation of clinical candidates. Multi-
component reactions (MCRs),5 especially the Ugi reaction,
have been widely exploited in the synthesis of small mole-
cule libraries.6 However, many products of four-component
(4-CR) Ugi reactions are linear and peptidic, and can suffer
from poor drug-likeness.7 In contrast, the use of cyclic
imines in the three-component (3-CR) Ugi–Joullié reaction8
leads to the formation of more drug-like nitrogen heterocy-
cles.9,10d Here, we describe the exploitation of trifluoroace-
tic acid as a synthetic equivalent for chloroformic acid,11
which can facilitate subsequent cyclisation to yield hydan-
toins that are fused to either a six- or seven-membered het-
erocycle. Furthermore, we demonstrate the value of two bi-
cyclic scaffolds in the synthesis of diverse drug-like screen-
ing compounds.
An initial investigation into the deprotection/3-CR8,12
was performed by treating 5 with TFA in dichloromethane
to generate, presumably, the cyclic iminium ion 9; subse-
quent treatment with 1-isocyano-2-methoxyethane in eth-
anol gave the 3-CR product 10a in 71% yield (Scheme 3). It
was envisaged that decoration of 10a might enable the syn-
thesis of a library of diverse 1,4-diazepanes. However, treat-
ment of 10a with K2CO3 in MeOH–H2O15 did not result in
the removal of the trifluoroacetamide; instead, the bicyclic
hydantoin 11a was obtained in 86% yield. Presumably, base-
catalysed attack of the secondary amide onto the trifluoro-
acetamide was followed by expulsion of the trifluoromethyl
anion to yield the observed hydantoin.10 In this sequence,
TFA serves as a reagent for the deprotection of the Boc
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Boc
N
A
R1
R2
O2
S
Boc
N
N
O
Ns
Boc
NH
R1
R2
R1
R2
4 (from 3 with R3 = H)
NaH
DMF
method A or B
1
Boc
N
Ns
NH
O
N
Ns
R3
H
R3
N
Et
3
2
Ns
5 (from 3 with R3 = Et)
B
Boc
N
Boc
Boc
N
Boc
N
Ph
NH
O
N
N
N
N
Et
2-Ns
2-Ns
4-Ns
2-Ns
4a, 49% then 72%a
(via 3a)
4b, 94% then 74%a
(via 3b)
4c, 81% then 90%b
(via 3c)
5, 56% then 86%b
(via 3d)
Scheme 1 Synthesis of substrates for the Ugi–Joullié reactions. Panel A: Synthetic scheme. Panel B: Specific substrates prepared. a Method A:
Au(PPh3)Cl (5 mol%), AgSbF6 (5 mol%), 1,4-dioxane, 100 °C. b Method B: Au(IPr)Cl (1 mol%), AgSbF6 (1 mol%), 1,4-dioxane, 100 °C. 2-Ns: 2-nitrophenyl-
sulfonyl; 4-Ns: 4-nitrophenylsulfonyl.
Boc
H
group; is the acidic component in the 3-CR; and provides
the necessary leaving group for hydantoin formation. Im-
portantly, hydantoins have a privileged place within medic-
inal chemistry,16 hence skeletally novel variants of these
molecules would be valuable for populating lead-genera-
tion libraries.
TFA
OMe
N
NH
TFA
CN
O
CH2Cl2, 16 h
EtOH, 16 h
N
Et
N
2-Ns
2-Ns
9
5
OMe
Boc
NH
Boc
NH
Boc
NH
O
F3C
1. PhCHO, 4Å MS
CH2Cl2, 16 h
O
N
O
MVK
O
OMe
N
N
O
N
H
K2CO3
2. NaBH4
MeOH, 2 h
EtOH, 2 h
NH2
NH
N
MeOH–H2O
16 h
Bn
Bn
N
N
6
7, 76%
8, 87%
2-Ns
2-Ns
10a, 71%
11a, 86%
Scheme 2 Synthesis of β-amino ketone 8
Scheme 3 Synthesis of bicyclic hydantoin 11a
The method was exploited in the efficient synthesis of a
wide range of bicyclic scaffolds in which a hydantoin is
fused to a six- or seven-membered heterocycle. The results
are summarised in Table 1. With the ketone 5, the deprotec-
tion/3-CR proceeded smoothly, and gave the trifluoroacet-
amide 10b in 80% yield; subsequent base-mediated cyclisa-
tion gave the required bicyclic hydantoin 11b in 36% yield
(Table 1, entry 1). It was anticipated that the bicyclic hydan-
toins might be obtained without purification of the inter-
mediate trifluoroacetamides. To this end, the benzyl-pro-
tected β-amino ketone 8 was treated with TFA in dichloro-
methane, followed by treatment with an isonitrile in EtOH,
before finally being subjected to K2CO3 in EtOH at 70 °C; the
hydantoins 11c–e were isolated in 75–95% overall yield
over three steps (entries 2–4). Both 2-nitrophenylsulfonyl-
and benzyl-protected substrates (5 and 8, respectively) may
thus be exploited in the synthesis of bicyclic hydantoins.
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Table 1 Scope of the Synthesis of Bicyclic Hydantoins
Entry
Substrate
Methoda,b
Trifluoroacetamide
Hydantoin
Ugi yield (%),c cyclisation yield (%)c
Bn
F3C
O
O
N
O
N
N
Bn
O
N
H
1
5
A1, B1
80, 36
N
N
2-Ns
10b
2-Ns
11b
O
N
O
N
N
N
N
N
2
8
A1, B2
–
75d
O
N
Bn
11c
n-Bu
O
N
O
3
4
5
8
A1, B2
A1, B2
A1, B2
–
95d
N
Bn
11d
CO2Et
O
N
O
8
–
81d
N
Bn
11e
Bn
F3C
O
O
N
O
N
N
Bn
O
N
4a
H
77, 41
N
2-Ns
2-Ns
12a
13a
O
N
O
N
6
4c
A2, B2
–
91d
Ph
N
O
N
4-Ns
13b
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J. D. Firth et al.
Special Topic
Ugi yield (%),c cyclisation yield (%)c
72d
Synthesis
Table 1 (continued)
Entry
Substrate
Methoda,b
Trifluoroacetamide
Hydantoin
Bn
O
N
Ph
N
O
7
4c
A2, B2
–
N
4-Ns
13c
n-Bn
O
N
N
Ph
O
8
4c
A2, B2
–
52d
N
4-Ns
13d
F3C
O
O
O
N
N
N
9
5
A1, B3
66, 73
H
N
O
N
2-Ns
10f
HN
14
F3C
O
Bn
O
N
O
N
N
Bn
N
O
10
4b
A1, B3
86, 87
H
N
N
H
2-Ns
15
12e
a Method A1: TFA then isonitrile (2.0 equiv), EtOH, r.t.; Method A2: TFA then isonitrile (2.0 equiv), CH2Cl2, r.t., 1 h, then Et3N (5.0 equiv), 2 h.
b Method B1: K2CO3 (10 equiv), MeOH–H2O, r.t., 16 h; Method B2: K2CO3 (5.0 equiv), EtOH, 70 °C; Method B3: PhSH (1.2 equiv) K2CO3 (3.0 equiv), DMF, r.t.
c Product isolated by flash column chromatography.
d Yield over 2 steps.
Pleasingly, treatment of the enantiomerically enriched
tetrahydropyrazine 4a with TFA, and then benzyl isocya-
nide, gave the trifluoroacetamide 12a as a single diastereo-
mer, in 77% yield (entry 5). Subsequent base-mediated cy-
clisation gave the hydantoin 13a in 41% yield. The relative
configuration of 13a was determined by analysis of the
NMR spectra: an axial–axial coupling of 10.2 Hz between Ha
and Hb and a strong NOESY cross peak between Hb and the
methyl group on the ring junction were both observed (Fig-
ure 1).
Modified conditions for the 3-CR were required with
the phenyl-substituted tetrahydropyrazine 4c as sub-
strate.17 Use of non-nucleophilic dichloromethane as a sol-
vent, followed by addition of Et3N to neutralize excess TFA
and expedite Mumm rearrangement, led to formation of
the intermediate trifluoroacetamides (which were not iso-
lated); hydantoin formation then occurred readily to yield,
as single diastereoisomers, the substituted hydantoins
13b–d in 52 to 91% yields (entries 6–8). The relative config-
uration of 13b was determined by observation of a strong
NOESY cross peak indicating the close proximity of the
methyl and phenyl substituents on the piperazine ring (Fig-
ure 1).
Finally, treatment of the intermediate 2-nitrophenylsul-
fonyl-protected trifluoroacetamides 10f and 12e (prepared
from 5 and 4b respectively) with PhSH and an excess of
K2CO3 resulted in both hydantoin formation and N-depro-
tection to give 14 and 15 in 73% and 87% yield, respectively
(entries 9 and 10).
10.2 Hz
N
Ha
H
O
O
Bn
R
H
N
N
N
Me
2-Ns
N
N
O
O
Hb
Me
NOE
Ph
4-Ns
Me
NOE
13a
13b
Figure 1 Determination of the relative configuration of 13a and 13b
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J. D. Firth et al.
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Synthesis
F3C
Bn
Bn
O
F3C
O
O
N
N
O
Bn
N
N
N
O
O
N
H
PhSH, K2CO3
MeCN, 16 h
K2CO3
EtOH
70 °C, 4 h
N
H2N
16, 70%
HN
17, 41%
Ns-2
10b
Scheme 4 Formation and reaction of the stable zwitterion 16
An investigation into the selective removal of the 2-ni-
trophenylsulfonyl protecting group of 10b without con-
comitant hydantoin formation was undertaken. Treatment
of 10b with 1.5 equivalents of PhSH and K2CO3 led to the
unexpected isolation of stable zwitterion 16 in 70% yield
(Scheme 4). The structure of 16 was determined unambigu-
ously by X-ray crystallography and shows a hydrogen bond
between the oxy and ammonium ions (Figure 2). Subse-
quent treatment of 16 with excess K2CO3 led to formation of
the fused bicyclic hydantoin 17 in 41% yield, proving the in-
termediacy of 16 in base-mediated hydantoin formation.
→ 24 and 23 → 27), reductive amination (e.g., 19 → 25 and
22 → 28), urea formation (e.g., 18 → 26 and 23 → 29) and
amidation (e.g., 21 → 30). These exemplar compounds were
purified by mass-directed HPLC, an approach which would
facilitate the subsequent production of large numbers of
screening compounds.
Use of ethyl isocyanoacetate in the key deprotec-
tion/Ugi/cyclisation sequence to form 11e led to the intro-
duction of an ester group that could be exploited as a site
for further scaffold decoration. After functionalisation of
secondary amine 20 to give the sulfonamide 31, saponifica-
tion of the ethyl ester group was performed prior to TBTU-
mediated amidation. For example, amide 32 was synthe-
sised and purified by mass-directed HPLC (Scheme 6).
The use of a three-component Ugi–Joullié reaction/cy-
clisation as a key complexity-generating procedure allowed
rapid construction of the bicyclic core of the hydantoin
scaffolds 11 and 13 and defined the scope and limitations of
the methods for use in library synthesis. In both cases, a li-
brary was subsequently nominated for production and sub-
sequent incorporation into the European Lead Factory com-
pound collection.19 The nominated libraries were selected
to target drug-like space in accordance with the overall ob-
jectives of the European Lead Factory consortium (see Fig-
ure 4 for the molecular properties of exemplar compounds
and the nominated libraries). Notably, a large proportion of
the nominated library compounds fall within drug-like
space.1 Additionally, the nominated compounds had a high
proportion of sp3-hybridised carbons, which can be an at-
tractive feature in clinical candidates.4
Figure 2 X-ray crystal structure of the stable zwitterion 1618
Due to their molecular properties, the substituted bicy-
clic hydantoins 11c–e and 13b–d were considered to be
ideal scaffolds for the synthesis of drug-like compounds.
Removal of the benzyl group from 11c–e proceeded
smoothly under transfer hydrogenation conditions using
Pearlman’s catalyst; the secondary amines 18–20 were ob-
tained in 86–97% yield (Scheme 5). Deprotection of the 4-
nitrophenylsulfonyl protected scaffolds 13b–d was accom-
plished using PhSH and K2CO3, giving secondary amines
21–23 in 57–78% yield. The deprotected scaffolds fulfilled
drug-like criteria, having low molecular weight and logP
values.
In this paper, the development of methods for the syn-
thesis of bicyclic fused hydantoins via an Ugi–Joullié reac-
tion has been described. This led to the successful synthesis
of >1000 novel compounds that will be added to the Euro-
pean Lead Factory screening collection (the Joint European
Compound Library, JECL).
All nonaqueous reactions were performed under an atmosphere of N2
unless otherwise stated. THF, CH2Cl2, toluene and MeCN were dried
and purified by means of a Pure Solv MD solvent purification system
(Innovative Technology Inc.). Anhydrous DMF and 1,4-dioxane were
obtained in SureSeal bottles from Sigma-Aldrich. All other solvents
used were of chromatography or analytical grade. PE refers to petro-
leum spirit (bp 40–60 °C). Commercially available starting materials
Rapid construction of the scaffolds was followed by dec-
oration (see Figure 3 for examples). The secondary amines
18–23 were shown to be amenable to sulfonylation (e.g., 19
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J. D. Firth et al.
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Synthesis
O
N
R
n-Bu
O
CO2Et
O
O
N
O
O
N
N
N
N
Pd(OH)2/C (cat.)
NH4+HCOO–
N
N
N
O
O
O
EtOH, 70 °C, 2 h
N
HN
HN
HN
Bn
11c–e
18, 86%
19, 87%
20, 97%
O
N
R
Bn
n-Bu
O
N
O
O
O
N
N
N
N
PhSH
K2CO3
Ph
O
Ph
N
Ph
N
Ph
N
O
O
O
DMF or
MeCN
N
N
H
N
H
N
H
4-Ns
13b–d
21, 78%
22, 57%
23, 73%
Scheme 5 Deprotection of the molecular scaffolds
n-Bu
O
O
N
O
n-Bu
O
Bn
N
Ph
N
N
O
N
O
N
N
N
O
n-Bu
O
Ph
N
O
N
Ph
O
N
O
n-Bu
O
N
Ph
N
N
O
N
N
O
N
HN
O
N
O
N
N
N
O
SO2
N
N
O2S
N
O
S
HN
Bn
O
F
OMe
29, 53%c
24, 68%a
26, 70%c
27, 35%a
25, 74%b
28, 74%b
30, 71%d
Figure 3 Exemplar decorated scaffolds. a Method: Sulfonyl chloride, i-Pr2NEt, DMA, r.t., 16 h. b Method: Aldehyde/ketone, NaBH(OAc)3, AcOH, DMA,
60 °C, 16 h. c Method: Isocyanate, i-Pr2NEt, DMA, r.t., 16 h. d Method: Carboxylic acid, TBTU, i-Pr2NEt, DMA, r.t., 16 h. DMA: Dimethylacetamide; TBTU:
O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.
HN
were obtained from Sigma-Aldrich, Fluka, Acros or Alfa-Aesar and
O
SO2Cl
O
CO2Et
were used without purification unless stated. TLC was carried out on
aluminum backed silica gel (Merck silica gel 60 F254) plates supplied
by Merck. Flash chromatography was carried out using silica gel 60
(60–63 μm particles) supplied by Merck. Mass-directed HPLC purifi-
cation was carried out using an Agilent 1260 Infinity HPLC system
comprising an Agilent 6120 Quadrupole LC/MS and Agilent G1968D
active splitter.
O
O
N
N
N
O
N
O
1. LiOH, THF
MeOH, H2O
OMe
N
20
N
O2S
2.
Et3N
CH2Cl2
O
H2N
O2S
Optical rotation measurements were carried out at the sodium D-line
(589 nm) on a Schmidt + Haensch Polatronic H532 polarimeter in-
strument. IR spectra were recorded on a PerkinElmer One FT-IR spec-
trometer. High-resolution mass spectra (HRMS) were recorded on a
Bruker MaXis Impact spectrometer with electrospray ionisation (ESI)
TBTU, DIPEA
DMA
OMe
OMe
31, 99%
Scheme 6 Diversification of 20
32, 63%
1
source. H, 13C and 19F NMR spectral data were collected on a Bruker
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2391–2406

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J. D. Firth et al.
Special Topic
Synthesis
tert-Butyl N-{(2R)-2-[N-(Prop-2-yn-1-yl)-2-nitrobenzenesulfon-
amido]propyl}carbamate (3a)
2-Nitro-N-(prop-2-yn-1-yl)benzene-1-sulfonamide (2.63 g, 11.0
mmol) and tert-butyl (5R)-5-methyl-2,2-dioxo-1,2λ⁶,3-oxathiazoli-
dine-3-carboxylate (2.36 g, 9.95 mmol) gave a crude product, which
was purified by flash column chromatography (SiO2, CH2Cl2) to give
sulfonamide 3a (1.92 g, 49%) as an amorphous yellow solid; Rf = 0.14
(CH2Cl2); [α]D28 –39 (c = 0.28, MeOH).
IR (ATR): 3428, 3291, 2979, 1706, 1544, 1367, 1159, 584 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.15 (dd, J = 7.4, 1.6 Hz, 1 H, Ns 3-H),
7.73–7.66 (m, 2 H, Ns 4-H and 5-H), 7.64 (dd, J = 7.2, 2.0 Hz, 1 H, Ns 6-
H), 4.90 (t, J = 6.7 Hz, 1 H, NH), 4.19 (dd, J = 18.9, 2.4 Hz, 1 H, 1′-HA),
4.16–4.07 (m, 2 H, 1′-HB and 2-H), 3.28 (app t, J = 6.7 Hz, 2 H, 1-CH2),
2.21 (t, J = 4.2 Hz, 1 H, 3′-H), 1.40 (s, 9 H, t-C4H9), 1.20 (d, J = 6.8 Hz, 3
H, CH3).
13C NMR (126 MHz, CDCl3): δ = 155.9, 147.9, 133.7, 133.6, 131.9,
131.7, 124.2, 72.8, 54.3, 43.2, 32.0, 28.4, 16.1, 14.1. Boc quaternary
carbons were not observed.
HRMS (ESI): m/z [M + H]+ calcd for C17H23N3O6S: 398.1386; found:
398.1380, –1.5 ppm error.
tert-Butyl N-{2-[N-(Prop-2-yn-1-yl)-2-nitrobenzenesulfonami-
do]ethyl}carbamate (3b)
2-Nitro-N-(prop-2-yn-1-yl)benzene-1-sulfonamide (5.98 g, 24.9
mmol) and tert-butyl 2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylate
(5.05 g, 22.6 mmol) gave a crude product, which was purified by flash
column chromatography (SiO2, CH2Cl2) to give the sulfonamide 3b12
(8.15 g, 94%) as an amorphous yellow solid; Rf = 0.4 (CH2Cl2).
IR (ATR): 3289, 2978, 1697, 1591, 1543, 1365, 1163, 589 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.07 (dd, J = 7.4, 1.7 Hz, 1 H, Ns 3-H),
7.76–7.68 (m, 2 H, Ns 4-H and 5-H), 7.66 (dd, J = 7.4, 1.7 Hz, 1 H, Ns 6-
H), 4.88 (br s, 1 H, NH), 4.27 (d, J = 2.2 Hz, 2 H, 1′-CH2), 3.55 (t, J = 5.9
Hz, 2 H, 2-CH2), 3.38 (br s, 2 H, 1-CH2), 2.22 (t, J = 2.2 Hz, 1 H, 3′-H),
1.44 (s, 9 H, t-C4H9).
13C NMR (126 MHz, CDCl3): δ = 156.0, 148.3, 133.8, 132.6, 131.7,
131.0, 124.2, 79.6, 77.3, 74.2, 46.7, 38.0, 37.0, 28.3.
Figure 4 Molecular properties of exemplar screening compounds syn-
thesised during validation work (blue, enlarged for clarity) and com-
pounds nominated for library production (green). Panel A: Library
based on hydantoins with a fused seven-membered heterocycle. Panel
B: Library based on hydantoins with a fused six-membered heterocycle.
tert-Butyl N-{1-Phenyl-2-[N-(prop-2-yn-1-yl)-4-nitrobenzenesul-
fonamido]ethyl}carbamate (3c)
4-Nitro-N-(prop-2-yn-1-yl)benzene-1-sulfonamide (4.62 g, 19.2
mmol) and tert-butyl 4-phenyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide (5.23 g, 17.5 mmol) gave a crude product, which was pu-
rified by flash column chromatography (SiO2, 80:20 to 75:25 hexane–
EtOAc) to give the sulfonamide 3c12 (6.53 g, 81%) as an amorphous
white solid; Rf = 0.3 (80:20 hexane–EtOAc).
1H NMR (500 MHz, CDCl3): δ = 8.33–8.31 (m, 2 H, Ns 3-H and 5-H),
8.02–7.99 (m, 2 H, Ns 2-H and 4-H), 7.38–7.35 (m, 2 H, C6H5), 7.32–
7.29 (m, 3 H, C6H5), 5.31 (br s, 1 H, NH), 4.94 (br s, 1 H, 1-H), 4.28 (d,
J = 18.2 Hz, 1 H, 1′-HA), 4.14–4.11 (m, 1 H, 1′-HB), 3.56 (dd, J = 14.1,
10.0 Hz, 1 H, 2-HA), 3.34 (dd, J = 14.1, 4.4 Hz, 1 H, 2-HB), 2.06–2.05 (m,
1 H, 3′-H), 1.45 (s, 9 H, t-C4H9).
Advance500 or DPX300 spectrometer. Chemical shifts (δ) are quoted
in parts per million (ppm) and referenced to the residual solvent
peak.
Opening of Cyclic Sulfamidates 1 with Propargylic Sulfonamides 2;
General Procedure
NaH (60% suspension in mineral oil, 1.1 equiv) was added in one por-
tion to nitrobenzenesulfonamide 2 (1.1 equiv) in DMF (0.2 M) at r.t.
under N2. The resulting suspension was stirred for 10 min, then cyclic
sulfamidate 1 (1.0 equiv) was added in one portion. The resulting sus-
pension was stirred at r.t. for 16 h. The reaction mixture was acidified
with aq 5 M HCl (6 equiv), stirred for 1 h and basified with aq K2CO3,
then extracted with EtOAc (3 × 100 mL). The combined organic layers
were washed with brine (100 mL), dried (MgSO4) and evaporated un-
der reduced pressure to give the crude product, which was purified by
column chromatography.
13C NMR (125 MHz, CDCl3): δ = 155.5, 150.2, 144.6, 139.2, 129.0,
128.9, 128.1, 126.3, 124.2, 80.1, 75.6, 75.0, 52.0, 51.3, 36.9, 28.3.
HRMS (ESI): m/z [M + H]+ calcd for C22H25N3O6S: 460.1537; found:
460.1543, 1.3 ppm error.
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Synthesis
tert-Butyl N-{2-[N-(Pent-2-yn-1-yl)-2-nitrobenzenesulfonami-
13C NMR (126 MHz, CDCl3): δ = 152.5, 148.3, 134.0, 131.7, 131.3,
do]ethyl}carbamate (3d)
130.7, 124.2, 120.2, 108.0, 81.7, 44.6, 41.6, 28.3, 20.1.
2-Nitro-N-(pent-2-yn-1-yl)benzene-1-sulfonamide (4.84 g, 18.0
mmol) and tert-butyl 2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylate
(3.66 g, 16.4 mmol) gave a crude product, which was purified by flash
column chromatography (SiO2, 25:25:50 PE–Et2O–CHCl3) to give the
sulfonamide 3d12 (3.78 g, 56%) as an amorphous yellow solid; Rf =
0.65 (50:50 PE–EtOAc).
tert-Butyl 6-Methyl-4-(4-nitrobenzenesulfonyl)-2-phenyl-1,2,3,4-
tetrahydropyrazine-1-carboxylate (4c)
By Method B, 3c (4.59 g, 10.0 mmol) gave a crude product, which was
purified by flash column chromatography (SiO2, 80:20 PE–EtOAc) to
give the tetrahydropyrazine 4c12 (4.11 g, 90%) as an amorphous or-
ange solid; Rf = 0.29 (80:20 PE–EtOAc).
IR (ATR): 3419, 2978, 2937, 1708, 1545, 1366, 1167 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.12 (d, J = 8.8 Hz, 2 H, Ns 3-H and 5-
H), 7.67 (d, J = 8.8 Hz, 2 H, Ns 2-H and 4-H), 7.12–7.08 (m, 3 H, C6H5),
7.32–7.29 (d, J = 6.9 Hz, 2 H, C6H5 2-H and 6-H), 6.00 (s, 1 H, 5-H), 5.59
(br s, 1 H, 2-H), 4.33 (d, J = 12.6 Hz, 1 H, 3-HA), 3.44 (dd, J = 12.6, 3.6
Hz, 1 H, 3-HB), 2.17 (s, 3 H, CH3), 1.43 (s, 9 H, t-C4H9).
1H NMR (500 MHz, CDCl3): δ = 8.06 (dd, J = 7.4, 1.8 Hz, 1 H, Ns 3-H),
7.72–7.65 (m, 2 H, Ns 4-H and 5-H), 7.63 (dd, J = 7.4, 1.8 Hz, 1 H, Ns 6-
H), 4.82 (s, 1 H, NH), 4.20 (s, 2 H, 1′-CH2), 3.51 (t, J = 5.8 Hz, 2 H, 2-
CH2), 3.36 (q, J = 5.8 Hz, 2 H, 1-CH2), 2.04 (q, J = 7.5 Hz, 2 H, 4′-CH2),
1.44 (s, 9 H, t-C4H9), 0.98 (t, J = 7.5 Hz, 3 H, 5′-CH3).
13C NMR (126 MHz, CDCl3): δ = 152.5, 149.9, 143.7, 137.4, 128.5,
127.7, 127.3, 125.7, 124.2, 118.8, 107.9, 82.2, 53.3, 47.7, 28.2.
HRMS (ESI): m/z [M + Na]+ calcd for C22H25N3O6SNa: 482.1356; found:
13C NMR (126 MHz, CDCl3): δ = 148.5, 133.7, 133.0, 131.6, 131.2,
124.2, 88.2, 79.7, 72.3, 46.7, 38.3, 37.6, 28.5, 13.7, 12.3. Boc C=O was
not observed.
482.1356, 0.0 ppm error.
Gold-Catalysed Hydration of Propargylic Sulfonamides 3; General
Procedure
tert-Butyl N-{2-[N-(3-Oxopentyl)2-nitrobenzenesulfonamido]eth-
Method A: Au(PPh3)Cl (5 mol%), AgSbF6 (5 mol%) and cyclisation sub-
strate 3 (1.0 equiv) were combined in 1,4-dioxane (0.2 M) and stirred
at 100 °C for 16 h under N2. The reaction mixture was cooled to r.t.
and concentrated in vacuo to give the crude product.
yl}carbamate (5)
By Method B, 3d (3.78 g, 9.19 mmol) gave a crude product, which was
purified by flash column chromatography (SiO2, 50:50 PE–EtOAc) to
give the ketone 512 (3.39 g, 86%) as an amorphous orange solid; Rf =
0.26 (50:50 PE–EtOAc).
Method B: Au(IPr)Cl (1 mol%), AgSbF6 (1 mol%) and cyclisation sub-
strate 3 (1.0 equiv) were combined in 1,4-dioxane (0.2 M) and stirred
at 100 °C under N2 until completion was observed by TLC. The reac-
tion mixture was cooled to r.t. and concentrated in vacuo to give the
crude product.
IR (ATR): 3403, 2978, 1709, 1544, 1367, 1164 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.01 (d, J = 7.3 Hz, 1 H, Ns 3-H), 7.76–
7.67 (m, 2 H, Ns 4-H and 5-H), 7.63 (d, J = 7.3 Hz, 1 H, Ns 6-H), 4.85 (t,
J = 6.3 Hz, 1 H, NH), 3.56 (t, J = 6.3 Hz, 2 H, 2-CH2), 3.40 (t, J = 6.5 Hz, 2
H, 2′-CH2), 3.31 (q, J = 6.3 Hz, 2 H, 1′-CH2), 2.81 (t, J = 6.5 Hz, 2 H, 1′-
CH2), 2.43 (q, J = 7.3 Hz, 2 H, 4′-CH2), 1.43 (s, 9 H, t-C4H9), 1.03 (t, J =
7.3 Hz, 3 H, 5′-CH3).
tert-Butyl (3R)-3,6-Dimethyl-4-(2-nitrobenzenesulfonyl)-1,2,3,4-
tetrahydropyrazine-1-carboxylate (4a)
By Method A, 3a (2.42 g, 6.09 mmol) gave a crude product, which was
purified by flash column chromatography (SiO2, 30:20:50 PE–Et2O–
CHCl3) to give the tetrahydropyrazine 4a (1.75 g, 72%) as an orange
oil; Rf = 0.81 (30:70 PE–EtOAc); [α]D28 +182 (c = 0.06, MeOH).
13C NMR (126 MHz, CDCl3): δ = 209.3, 133.9, 132.7, 131.9, 131.2,
124.4, 48.5, 43.5, 41.7, 39.3, 36.4, 28.5, 7.7, Boc quaternary carbons
were not observed.
IR (ATR): 3099, 2977, 2933, 1701, 1545, 1366, 1246, 1176 cm–1
.
tert-Butyl N-{2-[Benzyl(3-oxobutyl)amino]ethyl}carbamate (8)
1H NMR (500 MHz, CDCl3): δ = 8.07–7.93 (m, 1 H, Ns 3-H), 7.80–7.69
(m, 2 H, Ns 4-H and 5-H), 7.68–7.60 (m, 1 H, Ns 6-H), 5.95 (app t, J =
1.1 Hz, 1 H, 5-H), 4.36–4.27 (m, 1 H, 3-H), 4.19 (dd, J = 13.1, 1.9 Hz, 1
H, 2-HA), 2.58 (dd, J = 13.1, 2.3 Hz, 1 H, 2-HB), 2.11 (d, J = 1.1 Hz, 3 H, 6-
CH3), 1.50 (s, 9 H, t-C4H9), 1.17 (d, J = 6.6 Hz, 3 H, 3-CH3).
13C NMR (125 MHz, CDCl3): δ = 153.2, 148.3, 133.9, 131.7, 131.6,
130.8, 124.2, 119.5, 106.5, 81.5, 49.8, 46.1, 28.2, 20.0, 17.1.
Benzaldehyde (2.30 mL, 22.6 mmol) was added dropwise to a stirred
suspension of N-Boc-ethylenediamine (3.29 g, 20.5 mmol) and 4Å MS
(3.0 g) in CH2Cl2 (30 mL) at r.t. under N2. The resulting solution was
stirred at r.t. for 16 h, filtered through Celite, washed with CH2Cl2 (50
mL), and concentrated under reduced pressure. The residue was taken
up in MeOH (30 mL) and cooled to 0 °C. NaBH4 (1.55 g, 41.1 mmol)
was added portionwise over 10 min and the resulting solution was
allowed to warm to r.t. and stirred at r.t. for 2 h, then concentrated
under reduced pressure. H2O (20 mL), aq 1 M HCl (20 mL) and EtOAc
(30 mL) were added and the layers were separated. The aqueous layer
was extracted with EtOAc (2 × 20 mL), then basified with aq 2 M
NaOH (20 mL) and extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried (MgSO4) and evaporated under reduced
pressure to give the crude secondary amine 7 (3.91 g, 76%) as a pale
yellow oil that was used without further purification.
HRMS (ESI): m/z [M + H]+ calcd for C17H23N3O6S: 398.1386; found:
398.1387, 0.3 ppm error.
tert-Butyl 6-Methyl-4-(2-nitrobenzenesulfonyl)-1,2,3,4-tetrahy-
dropyrazine-1-carboxylate (4b)
By Method A, 3b (6.22 g, 16.2 mmol) gave a crude product, which was
purified by flash column chromatography (SiO2, 70:30 PE–EtOAc) to
give the tetrahydropyrazine 4b12 (4.61 g, 74%) as an amorphous yel-
low solid; Rf = 0.61 (50:50 PE–EtOAc).
The crude secondary amine 7 was dissolved in EtOH (30 mL) and
methyl vinyl ketone (2.51 mL, 31.0 mmol) was added dropwise under
N2. The resulting solution was stirred at r.t. for 2 h and concentrated
under reduced pressure to give the crude product, which was purified
by column chromatography (SiO2, 60:40 to 40:60 hexane–EtOAc) to
give the amino ketone 8 (4.33 g, 87%, 66% over 2 steps) as a pale yel-
low oil; Rf = 0.25 (50:50 PE–EtOAc).
IR (ATR): 2977, 2933, 1702, 1455, 1369, 1171, 776 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.99 (dd, J = 7.4, 1.7 Hz, 1 H, Ns 3-H),
7.78–7.70 (m, 2 H, Ns 4-H and 5-H), 7.66 (dd, J = 7.4, 1.7 Hz, 1 H, Ns 6-
H), 6.01 (s, 1 H, 5-H), 3.68–3.64 (m, 2 H, 3-CH2), 3.64–3.60 (m, 2 H, 2-
CH2), 2.09 (s, 3 H, CH3), 1.50 (s, 9 H, t-C4H9).
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Synthesis
IR (ATR): 3367, 2975, 2931, 2813, 1702, 1495, 1452, 1390, 1363, 1246,
1165, 1049, 964, 734, 698 cm–1
N-Benzyl-5-ethyl-1-(2-nitrobenzenesulfonyl)-4-(trifluoroacetyl)-
1,4-diazepane-5-carboxamide (10b)
.
1H NMR (500 MHz, CDCl3): δ = 7.35–7.30 (m, 2 H, C6H5), 7.30–7.24 (m,
3 H, C6H5), 4.95 (br s, 1 H, NH), 3.58 (s, 2 H, CH2Ph), 3.20 (app d, J = 5.5
Hz, 2 H, 1′-CH2), 2.80 (t, J = 6.9 Hz, 2 H, 1-CH2), 2.60 (t, J = 6.9 Hz, 2 H,
2-CH2), 2.55 (t, J = 5.5 Hz, 2 H, 2′-CH2), 2.10 (s, 3 H, 4-CH3), 1.46 (s, 9 H,
t-C4H9).
By Method A1, 5 (700 mg, 1.63 mmol) and benzyl isocyanide (400 μL,
3.26 mmol) gave a crude product, which was purified by flash col-
umn chromatography (SiO2, 40:60 PE–EtOAc) to give the trifluoroac-
etamide 10b12 (710 mg, 80%) as an amorphous white solid; Rf = 0.44
(50:50 PE–EtOAc).
IR (ATR): 3422, 2977, 1695, 1666, 1543, 1371, 1152 cm–1
.
13C NMR (126 MHz, CDCl3): δ = 208.1, 156.0, 138.9, 128.8, 128.3,
1H NMR (500 MHz, CDCl3): δ = 7.97 (dd, J = 10.1, 4.9 Hz, 1 H, Ns 3-H),
7.78–7.70 (m, 2 H, Ns 4-H and 5-H), 7.68 (dd, J = 7.4, 1.6 Hz, 1 H, Ns 6-
H), 7.41–7.26 (m, 5 H, C6H5), 5.92 (t, J = 5.2 Hz, 1 H, NH), 4.54–4.39 (m,
2 H, 1′-CH2), 4.25 (dd, J = 16.8, 5.7 Hz, 1 H, 3-HA), 4.11 (dd, J = 14.4, 5.7
Hz, 1 H, 2-HA), 3.90 (dd, J = 14.8, 7.0 Hz, 1 H, 7-HA), 3.64 (dd, J = 14.8,
10.7 Hz, 1 H, 7-HB), 3.52 (dd, J = 16.8, 9.0 Hz, 1 H, 3-HB), 3.39 (dd, J =
14.4, 9.0 Hz, 1 H, 2-HB), 2.76–2.56 (m, 2 H, CH3CH2), 1.94 (dd, J = 16.8,
7.0 Hz, 1 H, 6-HA), 1.69–1.58 (m, 1 H, 6-HB), 0.96 (t, J = 7.2 Hz, 3 H,
CH3CH2).
13C NMR (126 MHz, CDCl3): δ = 170.7, 157.0 (d, J = 35.5 Hz), 148.1,
137.8, 133.9, 132.5, 131.9, 130.5, 128.9, 127.7, 124.5, 116.3 (q, J =
287.9 Hz), 69.2, 49.8, 48.5, 44.0, 43.9, 37.4, 26.9, 7.9, benzyl C-2 and
benzyl C-6 were not observed;
127.1, 78.9, 58.6, 53.3, 48.5, 41.5, 38.1, 30.0, 28.4.
HRMS (ESI): m/z [M + H]+ calcd for C18H29N2O3: 321.2178; found:
321.2187, 2.8 ppm error.
3-CR Ugi–Joullié Reaction; General Procedure A
Method A1: TFA (4.0 equiv) was added to a stirred solution of sub-
strate 4 or 5 (1.0 equiv) in CH2Cl2 (0.1 M) at r.t. under N2 and stirred
until completion was observed by TLC. Then, the mixture was con-
centrated under reduced pressure to give a crude product that was
dissolved in EtOH (0.05 M) and cooled to 0 °C. Isonitrile (2.0 equiv)
was added and the mixture stirred at r.t. until completion was ob-
served by TLC, then concentrated under reduced pressure.
Method A2: TFA (4.0 equiv) was added to a stirred solution of sub-
strate 4c (1.0 equiv) in CH2Cl2 (0.1 M) at r.t. under N2 and stirred until
completion was observed by TLC. Then, the mixture was concentrated
under reduced pressure to give a crude product that was dissolved in
CH2Cl2 (0.05 M) and cooled to 0 °C. Isonitrile (2.0 equiv) was added
and the mixture stirred at r.t. until completion was observed by TLC.
Then, Et3N (5.0 equiv) was added and the resulting solution stirred at
r.t. for 2 h. H2O (10–25 mL/mmol) was added, the two layers were
separated and the aqueous layer was extracted with CH2Cl2 (3 × 10–
25 mL/mmol). The combined organic layers were dried (MgSO4) and
evaporated under reduced pressure to give the crude product
19F NMR (282 MHz, CDCl3): δ = –68.3.
(2R,5R)-N-Benzyl-2,5-dimethyl-4-(2-nitrobenzenesulfonyl)-1-(tri-
fluoroacetyl)piperazine-2-carboxamide (12a)
By Method A1, 4a (350 mg, 0.880 mmol) and benzyl isocyanide (210
μL, 1.76 mmol) gave a crude product, which was purified by flash col-
umn chromatography (SiO2, 30:70 PE–EtOAc) to give the trifluoroac-
etamide 12a (356 mg, 77%) as an amorphous white solid; Rf = 0.40
(30:70 PE–EtOAc); [α]D28 +49 (c = 0.05, MeOH).
IR (ATR): 3367, 2935, 1699, 1543, 1362, 1216, 1154 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.15–8.10 (m, 1 H, Ns 3-H), 7.81–7.73
(m, 2 H, Ns 4-H and 5-H), 7.73–7.68 (m, 1 H, Ns 6-H), 7.39–7.33 (m, 2
H, C6H5 3-H and 5-H), 7.32–7.25 (m, 3 H, C6H5 2-H, 4-H and 6-H), 6.18
(t, J = 5.3 Hz, 1 H, NH), 4.52 (dd, J = 14.9, 5.3 Hz, 1 H, 1′-HA), 4.37–4.31
(m, 1 H, 5-H), 4.28 (dd, J = 14.9, 5.3 Hz, 1 H, 1′-HB), 3.99 (d, J = 14.2 Hz,
1 H, 3-HA), 3.90 (dd, J = 14.7, 4.7 Hz, 1 H, 6-HA), 3.57–3.47 (m, 2 H, 3-
HB and 6-HB), 1.31–1.27 (m, 6 H, 2-CH3 and 5-CH3).
13C NMR (126 MHz, CDCl3): δ = 169.2, 157.3 (d, J = 36.3 Hz), 137.5,
134.1, 133.3, 132.1, 131.4, 128.7, 127.7, 127.6, 124.6, 115.9 (app d, J =
288.5 Hz), 64.9, 51.0, 49.9, 46.8, 44.2, 19.0, 18.0;
N-(2-Methoxyethyl)-5-ethyl-1-(2-nitrobenzenesulfonyl)-4-(triflu-
oroacetyl)-1,4-diazepane-5-carboxamide (10a)
By Method A1, 5 (450 mg, 1.05 mmol) and 1-isocyano-2-meth-
oxyethane (179 mg, 2.10 mmol) gave a crude product, which was pu-
rified by flash column chromatography (SiO2, 30:70 PE–EtOAc) to give
the trifluoroacetamide 10a (380 mg, 71%) as a yellow oil; Rf = 0.26
(20:80 PE–EtOAc).
IR (ATR): 3280, 2937, 1742, 1698, 1682, 1545, 1372, 1162 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.01–7.92 (m, 1 H, Ns 3-H), 7.77–7.63
(m, 3 H, Ns 4-H, 5-H and 6-H), 5.99 (t, J = 4.7 Hz, 1 H, NH), 4.20 (dd, J =
16.5, 5.9 Hz, 1 H, 3-HA), 4.15–4.03 (m, 1 H, 2-HA), 3.86 (dd, J = 14.1, 6.7
Hz, 1 H, 7-HA), 3.63–3.54 (m, 1 H, 7-HB), 3.53–3.43 (m, 4 H, 2-HB, 3-HB
and 1′-CH2), 3.42–3.30 (m, 5 H, 2′-CH2 and 4′-CH3), 2.72–2.51 (m, 2 H,
CH3CH2), 1.93 (dd, J = 18.7, 6.7 Hz, 1 H, 6-HA), 1.65 (dt, J = 18.7, 7.3 Hz,
1 H, 6-HB), 0.93 (t, J = 7.2 Hz, 3 H, CH3CH2).
19F NMR (282 MHz, CDCl3): δ = –69.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H23F3N4O6S: 529.1368; found:
529.1376, 1.5 ppm error.
N-Cyclopropyl-5-ethyl-1-(2-nitrobenzenesulfonyl)-4-(trifluoro-
acetyl)-1,4-diazepane-5-carboxamide (10f)
13C NMR (126 MHz, CDCl3): δ = 170.9, 148.1, 133.8, 132.6, 131.9,
130.6, 124.4, 70.8, 69.2, 58.8, 49.9, 48.4, 44.0, 39.6, 37.3, 26.9, 7.9, tri-
fluoroacetamide carbons were not observed.
19F NMR (282 MHz, CDCl3): δ = –68.4.
HRMS (ESI): m/z [M + H]+ calcd for C19H25F3N4O7S: 511.1474; found:
By Method A1, 5 (910 mg, 2.12 mmol) and cyclopropyl isocyanide
(420 μL, 5.28 mmol) gave a crude product, which was purified by
flash column chromatography (SiO2, 50:50 PE–EtOAc) to give the tri-
fluoroacetamide 10f (690 mg, 66%) as an amorphous white solid; Rf =
0.36 (30:70 PE–EtOAc).
511.1485, 2.2 ppm error.
IR (ATR): 3401, 2975, 1693, 1664, 1543, 1451, 1370, 1143, 729 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.87 (dd, J = 7.3, 1.9 Hz, 1 H, Ns 3-H),
7.68–7.61 (m, 2 H, Ns 4-H and 5-H), 7.59 (dd, J = 7.5, 1.7 Hz, 1 H, Ns 6-
H), 5.75 (s, 1 H, NH), 4.13 (dd, J = 16.7, 5.7 Hz, 1 H, 3-HA), 4.01 (dd, J =
14.3, 5.7 Hz, 1 H, 2-HA), 3.78 (dd, J = 14.7, 6.8 Hz, 1 H, 7-HA), 3.53 (dd,
J = 14.7, 10.7 Hz, 1 H, 7-HB), 3.39 (dd, J = 16.7, 8.9 Hz, 1 H, 3-HB), 3.29
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(dd, J = 14.3, 8.9 Hz, 1 H, 2-HB), 2.61–2.54 (m, 1 H, 1′-H), 2.53–2.44 (m,
2 H, CH3CH2), 1.78 (dd, J = 16.4, 6.8 Hz, 1 H, 6-HA), 1.54–1.42 (m, 1 H,
6-HB), 0.85 (t, J = 7.4 Hz, 3 H, CH3CH2), 0.73–0.63 (m, 2 H, 2′-HA and 3′-
HA), 0.51–0.44 (m, 1 H, 2′-HB), 0.40–0.31 (m, 1 H, 3′-HB).
13C NMR (126 MHz, CDCl3): δ = 172.3, 157.0 (d, J = 35.6 Hz), 148.1,
133.9, 132.5, 132.0, 130.5, 124.4, 116.3 (q, J = 288.4 Hz), 68.9, 49.8,
48.4, 43.9, 37.1, 26.8, 22.9, 7.8, 6.8, 6.4.
IR (ATR): 2936, 1769, 1708, 1544, 1451, 1368, 1165 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.01 (dd, J = 7.6, 1.6 Hz, 1 H, Ns 3-H),
7.77–7.69 (m, 2 H, Ns 4-H and 5-H), 7.67 (dd, J = 7.2, 1.8 Hz, 1 H, Ns 6-
H), 4.25–4.16 (m, 1 H, 5-HA), 3.91–3.82 (m, 2 H, 6-HA and 8-HA), 3.81–
3.70 (m, 2 H, 1′-CH2), 3.62–3.55 (m, 2 H, 6-HB and 8-HB), 3.32 (s, 3 H,
4′-CH3), 3.19–3.09 (m, 2 H, 2′-CH2), 2.69–2.57 (m, 2 H, 5-HB and 9-HA),
2.11–2.02 (m, 1 H, 9-HB), 1.92 (dq, J = 14.6, 7.3 Hz, 1 H, CH3CH2 1-HA),
1.74 (dq, J = 14.6, 7.3 Hz, 1 H, CH3CH2 1-HB), 0.80 (t, J = 7.3 Hz, 3 H,
CH3CH2).
13C NMR (126 MHz, CDCl3): δ = 175.3, 156.4, 147.9, 133.9, 132.6,
131.8, 130.9, 124.4, 68.5, 68.1, 58.5, 48.0, 44.8, 41.7, 39.4, 38.3, 29.0,
7.3.
HRMS (ESI): m/z [M + H]+ calcd for C18H24N4O7S: 441.1444; found:
441.1446, –0.5 ppm error.
19F NMR (282 MHz, CDCl3): δ = –68.4.
HRMS (ESI): m/z [M + H]+ calcd for C19H23F3N4O6S: 493.1368; found:
493.1363, –1.0 ppm error.
N-Benzyl-2-methyl-4-(2-nitrobenzenesulfonyl)-1-(trifluoroace-
tyl)piperazine-2-carboxamide (12e)
By Method A1, 4b (650 mg, 1.70 mmol) and benzyl isocyanide (410
μL, 3.40 mmol) gave a crude product which was purified by flash col-
umn chromatography (SiO2, 80:20 CH2Cl2–Et2O) to give the trifluoro-
acetamide 12e12 (750 mg, 86%) as an amorphous white solid; Rf = 0.53
(30:70 PE–EtOAc).
2-Benzyl-9a-ethyl-7-(2-nitrobenzenesulfonyl)octahydro-1H-imid-
azolidino[1,5-d][1,4]diazepine-1,3-dione (11b)
By Method B1, 10b (630 mg, 0.740 mmol) gave a crude product,
which was purified by flash column chromatography (SiO2, 40:60 PE–
EtOAc) to give the hydantoin 11b (200 mg, 36%) as an amorphous
white solid; Rf = 0.43 (20:80 PE–EtOAc).
IR (ATR): 3368, 2937, 1699, 1673, 1542, 1370, 1216, 1145, 732 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.03 (dd, J = 7.6, 1.2 Hz, 1 H, Ns 3-H),
7.81–7.72 (m, 2 H, Ns 4-H and 5-H), 7.70 (dd, J = 7.6, 1.3 Hz, 1 H, Ns 6-
H), 7.43–7.35 (m, 2 H, C6H5 2-H and 6-H), 7.34–7.25 (m, 3 H, C6H5 3-H,
4-H and 5-H), 6.20 (t, J = 5.0 Hz, 1 H, NH), 4.52–4.36 (m, 2 H, 1′-CH2),
4.03–3.92 (m, 1 H, 5-HA), 3.88–3.75 (m, 3 H, 3-HA, 5-HB and 6-HA),
3.70 (d, J = 13.8 Hz, 1 H, 3-HBb), 3.59–3.46 (m, 1 H, 6-HB), 1.72 (s, 3 H,
CH3).
13C NMR (126 MHz, CDCl3): δ = 169.2, 156.9 (d, J = 36.6 Hz), 148.1,
137.4, 134.3, 132.0, 131.4, 131.2, 128.8, 127.8, 127.7, 124.5, 115.9 (q,
J = 288.5 Hz), 64.3, 51.8, 44.3, 44.2, 41.4, 18.2.
IR (ATR): 2927, 1767, 1709, 1544, 1449, 1366, 1165 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.01 (dd, J = 7.6, 1.3 Hz, 1 H, Ns 3-H),
7.86–7.60 (m, 3 H, Ns 4-H, 5-H and 6-H), 7.50–7.18 (m, 5 H, C6H5),
4.74–4.63 (m, 2 H, 1′-CH2), 4.28–4.15 (m, 1 H, 5-HA), 3.97–3.77 (m, 2
H, 6-HA and 8-HA), 3.23–3.04 (m, 2 H, 6-HB and 5-HB), 2.68–2.48 (m, 2
H, 8-HB and 9-HA), 2.13–2.00 (m, 1 H, 9-HB), 1.89 (dq, J = 14.7, 7.4 Hz,
1 H, CH3CH2 1-HA), 1.73 (dq, J = 14.7, 7.4 Hz, 1 H, CH3CH2 1-HB), 0.64 (t,
J = 7.4 Hz, 3 H, CH3CH2).
13C NMR (126 MHz, CDCl3): δ = 175.0, 156.2, 147.9, 136.0, 133.9,
132.5, 131.8, 130.9, 128.7, 128.5, 128.0, 124.4, 67.9, 48.1, 44.9, 42.7,
41.8, 39.2, 29.1, 7.3.
19F NMR (282 MHz, CDCl3): δ = –69.6.
Hydantoin Formation; General Procedure B
HRMS (ESI): m/z [M + H]+ calcd for C22H24N4O6S: 473.1495; found:
473.1490, –1.1 ppm error.
Method B1: K2CO3 (10 equiv) was added to a stirred solution of sub-
strate 10 or 12 (1.0 equiv) in 2:1 MeOH–H2O (0.05 M), stirred at r.t.
overnight and concentrated under reduced pressure. The residue was
diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic phases were washed with brine (30 mL), dried
(MgSO4) and concentrated under reduced pressure to give the crude
product.
7-Benzyl-9a-methyl-2-[2-(morpholin-4-yl)ethyl]octahydro-1H-
imidazolidino[1,5-d][1,4]diazepine-1,3-dione (11c)
By Methods A1 and B2, 8 (1.11 g, 3.46 mmol) and 2-morpholinoethyl
isocyanide (955 μL, 6.93 mmol) gave a crude product, which was pu-
rified by flash column chromatography (SiO2, 95:5 CH2Cl2–MeOH) to
give the hydantoin 11c (998 mg, 75%) as a pale yellow oil; Rf = 0.21
(95:5 CH2Cl2–MeOH).
Method B2: The trifluoroacetamide from method A was dissolved in
EtOH (0.05 M), K2CO3 (5.0 equiv) was added and the resulting mixture
stirred at 70 °C for 16 h. The mixture was cooled to r.t. and concen-
trated under reduced pressure. The residue was partitioned between
H2O (10–25 mL/mmol) and CH2Cl2 (10–25 mL/mmol); the two layers
were separated and the aqueous layer was extracted with CH2Cl2 (3 ×
10–25 mL/mmol). The combined organic layers were dried (MgSO4)
and evaporated under reduced pressure to give the crude product.
IR (ATR): 2950, 2853, 2810, 1767, 1704, 1455, 1420, 1354, 1116 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H, C6H5), 4.01–3.92
(ddd, J = 13.3, 3.0, 2.3 Hz, 1 H, 5-HA), 3.76–3.60 (m, 7 H, 1′-CH2, mor-
pholine 2-CH2 and 6-CH2 and CHAHBPh), 3.57 (d, J = 13.3 Hz, 1 H,
CHAHBPh), 3.10 (ddd, J = 13.3, 11.2, 1.6 Hz, 1 H, 5-HB), 2.82 (br d, J =
12.9 Hz, 1 H, 6-HA), 2.74 (dd, J = 13.3, 7.4 Hz, 1 H, 8-HA), 2.67–2.45 (m,
7 H, 6-HB, 2′-CH2 and morpholine 3-CH2 and 5-CH2), 2.42 (dd, J = 15.1,
7.3 Hz, 1 H, 9-HA), 2.05 (dd, J = 13.3, 10.3 Hz, 1 H, 8-HB), 1.96 (dd, J =
15.1, 10.2 Hz, 1 H, 9-HB), 1.40 (s, 3 H, CH3).
Method B3: PhSH (1.2 equiv) was added to a stirred solution of sub-
strate 10 or 12 (1.0 equiv) and K2CO3 (3.0 equiv) in DMF or MeCN (0.1
M) and the mixture was stirred at r.t. overnight. The reaction mixture
was concentrated under reduced pressure to give the crude product.
13C NMR (126 MHz, CDCl3): δ = 176.9, 156.2, 138.5, 128.7, 128.3,
127.2, 67.1, 64.4, 63.0, 55.2, 54.9, 53.3, 50.8, 40.8, 38.4, 35.5, 23.6.
9a-Ethyl-2-(2-methoxyethyl)-7-(2-nitrobenzenesulfonyl)octahy-
dro-1H-imidazolidino[1,5-d][1,4]diazepine-1,3-dione (11a)
HRMS (ESI): m/z [M + H]+ calcd for C21H31N4O3: 387.2391; found:
By Method B1, 10a (380 mg, 0.740 mmol) gave a crude product,
which was purified by flash column chromatography (SiO2, 30:70 PE–
EtOAc) to give the hydantoin 11a (280 mg, 86%) as a yellow oil; Rf =
0.26 (20:80 PE–EtOAc).
387.2396, 1.3 ppm error.
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Synthesis
7-Benzyl-2-butyl-9a-methyloctahydro-1H-imidazolidino[1,5-
d][1,4]diazepine-1,3-dione (11d)
13C NMR (126 MHz, CDCl3): δ = 174.2, 156.5, 147.6, 135.7, 134.2,
134.0, 132.1, 131.1, 128.7, 128.4, 127.9, 124.4, 61.6, 52.3, 49.0, 42.6,
42.6, 19.3, 16.3.
HRMS (ESI): m/z [M + H]+ calcd for C21H22N4O6S: 459.1338; found:
459.1340, 0.4 ppm error.
By Methods A1 and B2, 8 (1.00 g, 3.12 mmol) and butyl isocyanide
(652 μL, 6.24 mmol) gave a crude product, which was purified by
flash column chromatography (SiO2, 50:50 hexane–EtOAc) to give the
hydantoin 11d (980 mg, 95%) as a pale yellow oil; Rf = 0.28 (50:50
hexane–EtOAc).
(5R*,8aS*)-8a-Methyl-2-[2-(morpholin-4-yl)ethyl]-7-(4-nitroben-
zenesulfonyl)-5-phenyloctahydroimidazolidino[1,5-a]piperazine-
1,3-dione (13b)
IR (ATR): 2935, 2872, 2813, 1765, 1698, 1450, 1416, 1376, 1352, 1088,
761, 729, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.33–7.22 (m, 5 H, C6H5), 3.95 (ddd, J =
14.9, 3.4, 2.2 Hz, 1 H, 5-HA), 3.59 (d, J = 13.3 Hz, 1 H, CHAHBPh), 3.54 (d,
J = 13.3 Hz, 1 H, CHAHBPh), 3.51 (t, J = 7.3 Hz, 2 H, 1′-CH2), 3.06 (ddd,
J = 14.9, 11.2, 2.0 Hz, 1 H, 5-HB), 2.80–2.76 (m, 1 H, 6-HA), 2.76–2.70
(m, 1 H, 8-HA), 2.48 (ddd, J = 13.1, 11.2, 2.2 Hz, 1 H, 6-HB), 2.38 (dd, J =
14.5, 7.3 Hz, 1 H, 9-HA), 1.97–1.85 (m, 2 H, 8-HB and 9-HB), 1.64–1.57
(m, 2 H, 2′-CH2), 1.36 (s, 3 H, CH3), 1.37–1.28 (m, 2 H, 3′-CH2), 0.93 (t,
J = 7.4 Hz, 3 H, 4′-CH3).
13C NMR (126 MHz, CDCl3): δ = 176.8, 156.2, 138.5, 128.7, 128.3,
127.2, 64.3, 62.9, 54.7, 51.1, 40.7, 38.6, 38.2, 30.2, 23.6, 19.9, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H27N3O2: 330.2176; found:
330.2184, 2.4 ppm error.
By methods A2 and B2, 4c (1.00 g, 2.18 mmol) and 2-morpholinoethyl
isocyanide (600 μL, 4.35 mmol) gave a crude product, which was pu-
rified by flash column chromatography (SiO2, 70:30 to 50:50 CH2Cl2–
EtOAc) to give the hydantoin 13b (1.09 g, 91%) as a white solid, mp
149–151 °C; Rf = 0.3 (50:50 CH2Cl2–EtOAc).
IR (ATR): 2853, 1771, 1702, 1525, 1450, 1420, 1272, 1115, 658 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.44 (d, J = 8.8 Hz, 2 H, Ns 3-H and 5-
H), 8.01 (d, J = 8.8 Hz, 2 H, Ns 2-H and 4-H), 7.59 (d, J = 7.6 Hz, 2 H,
C6H5 2-H and 6-H), 7.42 (t, J = 7.6 Hz, 2 H, C6H5 3-H and 5-H), 7.34 (t,
J = 7.6 Hz, 1 H, C6H5 4-H), 5.49 (d, J = 4.4 Hz, 1 H, 5-H), 4.70 (d, J = 12.5
Hz, 1 H, 6-HA), 3.86 (dd, J = 11.3, 1.2 Hz, 1 H, 8-HA), 3.71–3.59 (m, 2 H,
1′-CH2), 3.49 (br s, 4 H, morpholine 2-CH2 and 6-CH2), 2.67–2.52 (m, 3
H, 2′-CH2 and 6-HB), 2.50–2.35 (m, 4 H, morpholine 3-CH2 and 5-CH2),
2.31 (d, J = 11.3 Hz, 1 H, 8-HB), 1.14 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 173.8, 155.0, 150.7, 141.0, 137.7,
128.9, 128.8, 128.1, 127.1, 124.7, 67.0, 59.7, 54.7, 51.7, 48.6, 46.7,
35.9, 20.7.
HRMS (ESI): m/z [M + H]+ calcd for C25H30N5O7S: 544.1860; found:
544.1873, 2.4 ppm error.
Ethyl 2-{7-Benzyl-9a-methyl-1,3-dioxooctahydro-1H-imidazolidi-
no[1,5-d][1,4]diazepin-2-yl}acetate (11e)
By methods A1 and B2, 8 (2.00 g, 6.24 mmol) and ethyl cyanoacetate
(1.36 mL, 12.5 mmol) gave a crude product, which was purified by
flash column chromatography (SiO2, 30:70 hexane–EtOAc) to give the
hydantoin 11e (1.82 g, 81%) as a white solid; mp 72–73 °C; Rf = 0.43
(30:70 hexane–EtOAc).
IR (ATR): 2977, 1767, 1746, 1707, 1449, 1209, 760, 746 cm–1
.
(5R*,8aS*)-2-Benzyl-8a-methyl-7-(4-nitrobenzenesulfonyl)-5-
phenyloctahydroimidazolidino[1,5-a]piperazine-1,3-dione (13c)
1H NMR (500 MHz, CDCl3): δ = 7.34–7.28 (m, 4 H, C6H5), 7.28–7.23 (m,
1 H, C6H5), 4.28 (d, J 17.4 Hz, 1 H, 3′-HA), 4.23 (d, J = 17.4 Hz, 1 H, 3′-
HB), 4.22 (app dq, J = 7.1, 1.6 Hz, 2 H, CH2Me), 4.01–3.95 (m, 1 H, 5-
HA), 3.61 (d, J = 13.3 Hz, 1 H, CHAHBPh), 3.57 (d, J = 13.3 Hz, 1 H,
CHAHBPh), 3.10 (ddd, J = 14.7, 11.2, 1.7 Hz, 1 H, 5-HB), 2.83–2.78 (m, 1
H, 6-HA), 2.75 (dd, J = 13.5, 7.2 Hz, 1 H, 8-HA), 2.55–2.48 (m, 1 H, 6-HB),
2.45 (dd, J = 15.3, 7.2 Hz, 1 H, 9-HA), 2.13 (dd, J = 13.7, 10.1 Hz, 1 H, 8-
HB), 1.98 (dd, J = 14.9, 9.8 Hz, 1 H, 9-HB), 1.43 (s, 3 H, CH3), 1.29 (t, J =
7.1 Hz, 3 H, 4′-CH3).
13C NMR (126 MHz, CDCl3): δ = 176.4, 167.1, 155.2, 138.7, 128.7,
128.3, 127.2, 65.0, 62.9, 61.8, 54.7, 50.8, 40.9, 39.7, 38.3, 23.6, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H26N3O4: 360.1918; found:
360.1926, 2.2 ppm error.
By methods A2 and B2, 4c (500 mg, 1.09 mmol) and benzyl isocya-
nide (265 μL, 2.18 mmol) gave a crude product, which was purified by
flash column chromatography (SiO2, 70:30 to 50:50 hexane–EtOAc) to
give the hydantoin 13c (412 mg, 72%) as a white solid; mp 180–
181 °C; Rf = 0.3 (70:30 hexane–EtOAc).
IR (ATR): 3103, 1771, 1705, 1527, 1461, 1435, 1350, 1200, 696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.42 (d, J = 8.9 Hz, 2 H, Ns 3-H and 5-
H), 7.99 (d, J = 8.9 Hz, 2 H, Ns 2-H and 4-H), 7.59 (d, J = 7.6 Hz, 2 H,
C6H5 2-H and 6-H), 7.42–7.29 (m, 8 H, C6H5), 5.49 (d, J = 4.5 Hz, 1 H, 5-
H), 4.67 (d, J = 12.5 Hz, 1 H, 6-HA), 4.65 (s, 2 H, 1′-CH2), 3.86 (dd, J =
11.3, 1.3 Hz, 1 H, 8-HA), 2.65 (dd, J = 12.5, 4.8 Hz, 1 H, 6-HB), 2.24 (d, J =
11.3 Hz, 1 H, 8-HB), 1.14 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 173.3, 154.7, 150.7, 141.1, 137.7,
135.6, 128.9, 128.8, 128.8, 128.7, 128.1, 127.1, 124.7, 59.7, 51.3, 48.7,
46.7, 42.9, 20.8, one C atom of C6H5 was not observed.
(6R,8aR)-2-Benzyl-6,8a-dimethyl-7-(2-nitrobenzenesulfonyl)octa-
hydroimidazolidino[1,5-a]piperazine-1,3-dione (13a)
HRMS (ESI): m/z [M + H]+ calcd for C26H25N4O6S: 521.1489; found:
521.1499, 1.9 ppm error.
By method B2, 12a (93 mg, 0.180 mmol) gave a crude product, which
was purified by flash column chromatography (SiO2, 30:70 PE–EtOAc)
to give the hydantoin 13a (34 mg, 41%) as a white solid; mp 170–
172 °C; Rf = 0.47 (30:70 PE–EtOAc); [α]D27 +41 (c = 0.20, MeOH).
(5R*,8aS*)-2-Butyl-8a-methyl-7-(4-nitrobenzenesulfonyl)-5-
phenyloctahydroimidazolidino[1,5-a]piperazine-1,3-dione (13d)
IR (ATR): 2934, 1775, 1711, 1542, 1415, 1350, 1157, 734, 583 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.03–7.98 (m, 1 H, Ns 3-H), 7.68–7.61
(m, 2 H, Ns 4-H and 5-H), 7.60–7.56 (m, 1 H, Ns 6-H), 7.29–7.20 (m, 5
H, C6H5), 4.50–4.40 (m, 2 H, 1′-CH2), 4.05 (dd, J = 14.3, 6.1 Hz, 1 H, 5-
HA), 3.92–3.82 (m, 1 H, 6-H), 3.61 (d, J = 14.7 Hz, 1 H, 8-HA), 3.49 (d, J =
14.7 Hz, 1 H, 8-HB), 2.68 (dd, J = 14.3, 10.2 Hz, 1 H, 5-HB), 1.36 (s, 3 H,
8a-CH3), 1.04 (d, J = 6.6 Hz, 3 H, 6-CH3).
By methods A2 and B2, 4c (500 mg, 1.09 mmol) and butyl isocyanide
(265 μL, 2.18 mmol) gave a crude product, which was purified by
flash column chromatography (SiO2, 99:1 CH2Cl2–Et2O) to give the hy-
dantoin 13c (274 mg, 52%) as a white solid, mp 216–217 °C; Rf = 0.3
(99:1 CH2Cl2–Et2O).
IR (ATR): 2958, 2865, 1768, 1702, 1526, 1441, 1418, 1368, 1199, 1115,
659 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2391–2406

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Special Topic
Synthesis
1H NMR (500 MHz, CDCl3): δ = 8.44 (d, J = 8.9 Hz, 2 H, Ns 3-H and 5-
H), 8.01 (d, J = 8.9 Hz, 2 H, Ns 2-H and 4-H), 7.60 (d, J = 7.6 Hz, 2 H,
C6H5 2-H and 6-H), 7.41 (t, J = 7.6 Hz, 2 H, C6H5 3-H and 5-H), 7.34 (t,
J = 7.6 Hz, 1 H, C6H5 4-H), 5.49 (d, J = 4.5 Hz, 1 H, 5-H), 4.69 (d, J = 12.5
Hz, 1 H, 6-HA), 3.87 (dd, J = 11.3, 1.4 Hz, 1 H, 8-HA), 3.58–3.43 (m, 2 H,
1′-CH2), 2.66 (dd, J = 12.5, 4.8 Hz, 1 H, 6-HB), 2.25 (d, J = 11.3 Hz, 1 H,
8-HB), 1.64–1.54 (m, 2 H, 2′-CH2), 1.32–1.27 (m, 2 H, 3′-CH2), 1.14 (s, 3
H, CH3), 0.93 (t, J = 7.4 Hz, 3 H, 4′-CH3).
13C NMR (126 MHz, CDCl3): δ = 173.6, 155.0, 150.6, 141.1, 137.8,
128.9, 128.8, 128.1, 127.1, 124.6, 59.7, 51.7, 48.6, 46.7, 39.0, 30.5,
20.7, 19.9, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C23H27N4O6S: 487.1651; found:
487.1647, –0.8 ppm error.
tography (SiO2, 90:10 CH2Cl2–MeOH) to give the zwitterion 16 (330
mg, 70%) as a white solid; mp 140–142 °C; Rf = 0.32 (90:10 CH2Cl2–
MeOH).
IR (ATR): 3305, 2963, 2936, 2880, 1707, 1453, 1294, 1164 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 7.3 Hz, 2 H, C6H5 3-H and 5-
H), 7.35–7.30 (m, 2 H, C6H5 2-H and 6-H), 7.28–7.22 (m, 1 H, C6H5 4-
H), 4.67 (q, J = 15.3 Hz, 2 H, 1′-CH2), 3.73–3.62 (m, 1 H, 5-HA), 3.16
(ddd, J = 15.9, 7.3, 3.4 Hz, 1 H, 6-HA), 2.95–2.85 (m, 3 H, 6-HB and 8-
CH2), 2.85–2.78 (m, 1 H, 5-HB), 2.09–1.94 (m, 3 H, 9-CH2 and NH), 1.78
(dq, J = 14.8, 7.4 Hz, 1 H, CH3CH2 1-HA), 1.61 (dq, J = 14.8, 7.4 Hz, 1 H,
CH3CH2 1-HB), 0.91 (t, J = 7.4 Hz, 3 H, CH3CH2).
13C NMR (126 MHz, CDCl3): δ = 174.8, 137.5, 128.5, 128.1, 127.1,
122.6 (app d, J = 289.7 Hz), 96.9 (app d, J = 33.0 Hz), 67.2, 43.8, 41.9,
40.8, 40.1, 34.5, 30.5, 8.1.
2-Cyclopropyl-9a-ethyloctahydro-1H-imidazolidino[1,5-d][1,4]di-
azepine-1,3-dione (14)
19F NMR (282 MHz, CDCl3): δ = –79.78.
HRMS (ESI): m/z [M + H]+ calcd for C17H22F3N3O2: 358.1742; found:
By method B3, 10f (370 mg, 0.750 mmol) gave a crude product, which
was purified by flash column chromatography (SiO2, 90:10 CH2Cl2–
MeOH) to give the hydantoin 14 (130 mg, 73%) as an amorphous or-
ange solid; Rf = 0.19 (90:10 CH2Cl2–MeOH).
358.1732, –2.8 ppm error.
2-Benzyl-9a-ethyloctahydro-1H-imidazolidino[1,5-d][1,4]diaze-
pine-1,3-dione (17)
IR (ATR): 3461, 2967, 2936, 1766, 1701, 1428, 1352 cm–1
.
K2CO3 (522 mg, 3.78 mmol) was added to a solution of zwitterion 16
(270 mg, 0.760 mmol) in EtOH (4 mL) and stirred at 70 °C for 4 h. The
reaction mixture was cooled, concentrated under reduced pressure,
diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The
combined organic phases were washed with brine (5 mL), dried
(MgSO4) and concentrated under reduced pressure to give a crude
product, which was purified by flash chromatography (SiO2, 90:10
CH2Cl2–MeOH) to yield the hydantoin 17 (89 mg, 41%) as a yellow oil;
Rf = 0.24 (90:10 CH2Cl2–MeOH).
1H NMR (500 MHz, CDCl3): δ = 4.09–3.95 (m, 1 H, 5-HA), 3.01–2.92 (m,
2 H, 6-Ha and 8-HA), 2.91–2.81 (m, 2 H, 5-HB and 6-HB), 2.67–2.59 (m,
1 H, 8-HB), 2.50 (dd, J = 14.7, 5.9 Hz, 1 H, 9-HA), 2.22 (dd, J = 14.7, 10.8
Hz, 1 H, 9-HB), 2.09 (br s, 1 H, NH), 1.82 (dq, J = 14.2, 7.4 Hz, 1 H,
CH3CH2 1-HA), 1.74 (ddd, J = 15.3, 10.8, 1.2 Hz, 1 H, 1′-HA), 1.62 (dq, J =
14.2, 7.4 Hz, 1 H, CH3CH2 1-HB), 1.02–0.83 (m, 4 H, 2′-CH2 and 3′-CH2),
0.69 (t, J = 7.4 Hz, 3 H, CH3CH2).
13C NMR (126 MHz, CDCl3): δ = 176.5, 157.0, 67.6, 48.0, 44.9, 42.8,
41.2, 29.7, 21.8, 7.3, 5.3, 5.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H19N3O2: 238.1555; found:
238.1555, 0.0 ppm error.
IR (ATR): 3341, 2967, 2937, 1764, 1703, 1448, 1350 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.42–7.36 (m, 2 H, C6H5 3-H and 5-H),
7.34–7.23 (m, 3 H, C6H5 2-H, 4-H and 6-H), 4.71–4.63 (m, 2 H, 1′-CH2),
4.10–4.00 (m, 1 H, 5-HA), 3.00–2.83 (m, 4 H, 5-HB, 6-CH2 and 8-HA),
2.51 (dd, J = 15.2, 6.4 Hz, 1 H, 8-HB), 2.18 (dd, J = 14.7, 10.7 Hz, 1 H, 9-
HA), 1.84 (dq, J = 14.6, 7.4 Hz, 1 H, CH3CH2 1-HA), 1.74 (ddd, J = 14.7,
10.8, 1.3 Hz, 1 H, 9-HB), 1.69–1.58 (m, 2 H, CH3CH2 1-HB and NH), 0.62
(t, J = 7.4 Hz, 3 H, CH3CH2).
13C NMR (126 MHz, CDCl3): δ = 175.8, 156.6, 136.4, 128.6, 128.5,
127.8, 68.5, 48.2, 44.9, 43.2, 42.5, 41.5, 29.8, 7.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H21N3O2: 288.1712; found:
2-Benzyl-8a-methyloctahydroimidazolidino[1,5-a]piperazine-1,3-
dione (15)
By method B3, 12e (1.51 g, 2.94 mmol) gave a crude product, which
was purified SCX cartridge (eluting with sat. NH3 in MeOH) to give the
hydantoin 15 (665 mg, 87%) as a yellow solid; mp 109–111 °C; Rf =
0.62 (90:10 CH2Cl2–MeOH).
IR (ATR): 3337, 2949, 1764, 1702, 1438, 1418, 1141, 700 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.42–7.27 (m, 5 H, C6H5), 4.78–4.63 (m,
2 H, 1′-CH2), 4.01 (dd, J = 13.2, 3.6 Hz, 1 H, 5-HA), 3.09 (d, J = 12.2 Hz, 1
H, 8-HA), 3.07–2.95 (m, 2 H, 6-CH2), 2.68–2.55 (m, 2 H, 5-HB and 8-
HB), 1.79 (br s, 1 H, NH), 1.55 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 175.5, 154.4, 136.3, 128.7, 128.3,
127.8, 59.7, 52.1, 45.7, 42.3, 38.2, 17.7.
288.1716, 1.4 ppm error.
Debenzylation of Benzylamines 11c–e; General Procedure
Ammonium formate (5.0 equiv) was added to a stirred suspension of
diazepine 11 (1.0 equiv) and 20% Pd(OH)2/C (10 wt%) in EtOH (0.1 M).
The resulting mixture was heated to 70 °C and stirred at 70 °C for 2 h,
cooled to r.t., filtered through Celite, washed with EtOH (100 mL) and
concentrated under reduced pressure. The residue was partitioned
between sat. aq NaHCO3 (30 mL) and CH2Cl2 (30 mL), the two layers
were separated and the aqueous layer was extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried (MgSO4) and evapo-
rated under reduced pressure to give the crude secondary amine.
HRMS (ESI): m/z [M + H]+ calcd for C14H17N3O2: 260.1399; found:
260.1401, 0.8 ppm error.
(3R*,9aR*)-2-Benzyl-9a-ethyl-1-oxo-3-(trifluoromethyl)octahy-
dro-1H-imidazolidino[1,5-d][1,4]diazepin-7-ium-3-olate (16)
K2CO3 (271 mg, 1.96 mmol) was added to a stirred solution of the sul-
fonamide 10b (710 mg, 1.31 mmol) and PhSH (0.20 mL, 1.96 mmol)
in MeCN (13 mL), and the mixture was stirred at r.t. overnight. Excess
K2CO3 was removed by filtration and the mixture was concentrated
under reduced pressure. The residue was purified by flash chroma-
9a-Methyl-2-[2-(morpholin-4-yl)ethyl]octahydro-1H-imidazolidi-
no[1,5-d][1,4]diazepine-1,3-dione (18)
Diazepine 11c (990 mg, 2.56 mmol) gave the crude secondary amine
18 (660 mg, 87%) as a pale yellow oil, which was used without further
purification.
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IR (ATR): 3336, 2938, 2856, 2809, 1759, 1697, 1459, 1421, 1348, 1072,
749 cm–1
1H NMR (500 MHz, CDCl3): δ = 4.03–3.96 (m, 1 H, 5-HA), 3.72–3.54 (m,
6 H, 1′-CH2 and morpholine 2-CH2 and 6-CH2), 2.98–2.79 (m, 4 H, 5-
which was purified by column chromatography (SiO2, 98:2 to 95:5
CH2Cl2–MeOH) to give the secondary amine 21 (564 mg, 78%) as a
white solid; mp 92–93 °C; Rf = 0.3 (95:5 CH2Cl2–MeOH).
.
IR (ATR): 3340, 2806, 1761, 1693, 1452, 1423, 1111, 702 cm–1
.
H
B, 6-CH2 and 8-HA), 2.62–2.37 (m, 7 H, 9-HA, 2′-CH2 and morpholine
1H NMR (500 MHz, CDCl3): δ = 5.30 (d, J = 4.7 Hz, 1 H, 5-H), 3.83 (d, J =
13.4 Hz, 1 H, 6-HA), 3.71 (td, J = 6.3, 1.6 Hz, 2 H, 1′-CH2), 3.66 (br t, J =
4.6 Hz, 4 H, morpholine 2-CH2 and 6-CH2), 3.08 (d, J = 12.2 Hz, 1 H, 8-
HA), 3.01 (dd, J = 13.4, 4.9 Hz, 1 H, 6-HB), 2.80 (d, J = 12.2 Hz, 1 H, 8-
HB), 2.70–2.59 (m, 2 H, 2′-CH2), 2.59–2.46 (m, 4 H, morpholine 3-CH2
and 5-CH2), 1.75 (br s, 1 H, NH), 1.09 (s, 3 H, CH3).
3-CH2 and 5-CH2), 2.31 (dd, J = 14.1, 10.6 Hz, 1 H, 8-HB), 1.84–1.68 (m,
2 H, 9-HB and NH), 1.36 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 176.1, 157.1, 67.1, 64.3, 55.2, 53.3,
48.2, 44.8, 43.2, 41.9, 35.5, 23.8:
HRMS (ESI): m/z [M + H]+ calcd for C14H24N4O3: 297.1921; found:
297.1928, 2.4 ppm error.
13C NMR (126 MHz, CDCl3): δ = 175.9, 155.9, 139.4, 128.5, 127.4,
127.3, 67.2, 59.7, 55.1, 53.4, 52.4, 49.3, 46.5, 35.7, 20.7.
HRMS (ESI): m/z [M + H]+ calcd for C19H27N4O3: 359.2078; found:
2-Butyl-9a-methyloctahydro-1H-imidazolidino[1,5-d][1,4]diaze-
pine-1,3-dione (19)
359.2083, 1.4 ppm error.
Diazepine 11d (906 mg, 2.75 mmol) gave the crude secondary amine
19 (564 mg, 86%) as a pale yellow oil, which was used without further
purification.
Denosylation of Nitrosulfonamides 13c,d; General Procedure
PhSH (2.0 equiv) was added to a stirred solution of piperazine 13c,d
(1.0 equiv) and K2CO3 (3.0 equiv) in DMF (0.1 M) at r.t. The resulting
suspension was stirred at r.t. for 1 h, aq 2 M NaOH (20 mL) and EtOAc
(20 mL) were added and the layers separated. The aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine, dried (MgSO4) and evaporated under reduced
pressure to give the crude product.
IR (ATR): 3336, 2934, 2872, 1762, 1693, 1452, 1418, 1378, 1346, 1088,
763 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.07–3.98 (m, 1 H, 5-HA), 3.51 (t, J = 7.3
Hz, 2 H, 1′-CH2), 2.99–2.82 (m, 4 H, 5-HB, 6-CH2 and 8-HA), 2.52 (dd,
J = 15.1, 6.5 Hz, 1 H, 9-HA), 2.20 (dd, J = 14.2, 10.5 Hz, 1 H, 8-HB), 1.77
(ddd, J = 15.1, 10.5, 1.4 Hz, 1 H, 9-HB), 1.69 (br s, 1 H, NH), 1.64–1.55
(m, 2 H, 2′-CH2), 1.37 (s, 3 H, CH3), 1.31 (dt, J = 14.7, 7.4 Hz, 2 H, 3′-
CH2), 0.92 (t, J = 7.4 Hz, 3 H, 4′-CH3).
(5R*,8aS*)-2-Benzyl-8a-methyl-5-phenyloctahydroimidazolidi-
no[1,5-a]piperazine-1,3-dione (22)
13C NMR (126 MHz, CDCl3): δ = 176.7, 156.1, 64.2, 48.2, 45.0, 43.1,
Nitrosulfonamide 13c (396 mg, 0.76 mmol) gave a crude product,
which was purified by flash column chromatography (SiO2, 99:1 to
98:2 CH2Cl2–MeOH) to give the secondary amine 22 (145 mg, 57%) as
a colourless oil; Rf = 0.2 (98:2 CH2Cl2–MeOH).
41.6, 38.6, 30.2, 23.3, 19.9, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C12H22N3O2: 240.1707; found:
240.1713, –2.4 ppm error.
IR (ATR): 3337, 2937, 2865, 2809, 1760, 1697, 1436, 1418, 1348, 1113,
Ethyl 2-[9a-Methyl-1,3-dioxooctahydro-1H-imidazolidino[1,5-
d][1,4]diazepin-2-yl]acetate (20)
750, 696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 8.0 Hz, 2 H, C6H5), 7.42 (d,
J = 7.6 Hz, 2 H, C6H5) 7.36 (t, J = 7.6 Hz, 4 H, C6H5), 7.32–7.28 (m, 2 H,
C6H5), 5.30 (d, J = 4.7 Hz, 1 H, 5-H), 4.74 (s, 2 H, 1′-CH2), 3.80 (d, J =
13.4 Hz, 1 H, 6-HA), 3.08 (d, J = 12.2 Hz, 1 H, 8-HA), 3.00 (dd, J = 13.4,
4.9 Hz, 1 H, 6-HB), 2.73 (d, J = 12.2 Hz, 1 H, 8-HB), 1.73 (br s, 1 H, NH),
1.10 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 175.4, 155.6, 139.3, 136.2, 128.7,
128.5, 128.3, 127.8, 127.4, 127.4, 59.9, 52.3, 49.4, 46.5, 42.5, 20.7.
HRMS (ESI): m/z [M + H]+ calcd for C20H22N3O2: 336.1707; found:
336.1708, 0.3 ppm error.
Diazepine 11e (1.0 g, 2.78 mmol) gave the crude secondary amine 20
(726 mg, 97%) as a pale yellow oil, which was used without further
purification.
IR (ATR): 2977, 2936, 1771, 1744, 1707, 1452, 1381, 1348, 1208, 1155,
765 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.27 (d, J = 17.4 Hz, 1 H, 3′-HA), 4.22 (d,
J = 17.4 Hz , 1 H, 3′-HB), 4.20 (q, J = 7.1 Hz, 2 H, 3′-CH2), 4.04 (br d, J =
14.4 Hz, 1 H, 5-HA), 3.01–2.85 (m, 4 H, 5-HB, 6-CH2 and 8-HA), 2.58
(dd, J = 15.2, 6.4 Hz, 1 H, 9-HA), 2.43 (dd, J = 14.1, 10.8 Hz, 1 H, 8-HB),
1.80 (dd, J = 15.2, 10.7 Hz, 1 H, 9-HB), 1.73 (br s, 1 H, NH), 1.42 (s, 3 H,
CH3), 1.27 (t, J = 7.2 Hz, 3 H, 4′-CH3).
(5R*,8aS*)-2-Butyl-8a-methyl-5-phenyloctahydroimidazolidi-
no[1,5-a]piperazine-1,3-dione (23)
13C NMR (126 MHz, CDCl3): δ = 176.4, 167.1, 155.2, 64.9, 61.9, 48.2,
44.8, 43.3, 41.7, 39.7, 23.3, 14.1.
Nitrosulfonamide 13d (262 mg, 0.54 mmol) gave a crude product,
which was purified by flash column chromatography (SiO2, 98:2
CH2Cl2–MeOH) to give the secondary amine 23 (120 mg, 73%) as a co-
lourless oil; Rf = 0.2 (98:2 CH2Cl2–MeOH).
HRMS (ESI): m/z [M + H]+ calcd for C12H20N3O4: 270.1448; found:
270.1452, 1.5 ppm error.
(5R*,8aS*)-8a-Methyl-2-[2-(morpholin-4-yl)ethyl]-5-phenylocta-
hydroimidazolidino[1,5-a]piperazine-1,3-dione (21)
IR (ATR): 3344, 2957, 2932, 1760, 1694, 1443, 1417, 1304, 1071, 698
cm–1
.
PhSH (410 μL, 4.00 mmol) was added to a stirred solution of 4-nitro-
sulfonamide 13b (1.09 g, 2.00 mmol) and K2CO3 (829 mg, 6.00 mmol)
in MeCN (50 mL) at r.t. The resulting suspension was stirred at r.t. for
16 h and the volatiles removed under reduced pressure. The residue
was partitioned between H2O (50 mL) and CH2Cl2 (50 mL), the two
layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were dried (MgSO4)
and evaporated under reduced pressure to give the crude product,
1H NMR (500 MHz, CDCl3): δ = 7.50 (d, J = 7.6 Hz, 2 H, C6H5 2-H and 6-
H), 7.36 (t, J = 7.6 Hz, 2 H, C6H5 3-H and 5-H), 7.29 (t, J = 7.6 Hz, 1 H,
C6H5 4-H), 5.30 (d, J = 4.5 Hz, 1 H, 5-H), 3.81 (d, J = 13.4 Hz, 1 H, 6-HA),
3.65–3.51 (m, 2 H, 1′-CH2), 3.08 (d, J = 12.2 Hz, 1 H, 8-HA), 3.01 (dd, J =
13.4, 4.9 Hz, 1 H, 6-HB), 2.74 (d, J = 12.2 Hz, 1 H, 8-HB), 1.73 (br s, 1 H,
NH), 1.71–1.61 (m, 2 H, 2′-CH2), 1.43–1.32 (m, 2 H, 3′-CH2), 1.09 (s, 3
H, CH3), 0.97 (t, J = 7.4 Hz, 3 H, 4′-CH3).
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Synthesis
13C NMR (126 MHz, CDCl3): δ = 175.6, 155.9, 139.4, 128.5, 127.4,
127.4, 59.7, 52.4, 49.3, 46.5, 38.7, 30.2, 20.7, 20.0, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C17H24N3O3: 302.1863; found:
302.1866, 0.9 ppm error.
purified by mass-directed auto-prep (5–95% MeOH–H2O with 0.1%
ammonia buffer) to give the urea 26 (45 mg, 70%) as a white solid; mp
128–130 °C.
IR (ATR): 3369, 1766, 1700, 1585, 1455, 1241, 1056, 933, 755 cm–1
.
1H NMR (500 MHz, CD3OD): δ = 7.23–7.16 (m, 4 H, C6H5), 7.15–7.08
(m, 1 H, C6H5), 4.28 (d, J = 15.4 Hz, 1 H, CHAHBPh), 4.24 (d, J = 15.4 Hz,
1 H, CHAHBPh), 3.99 (ddd, J = 14.6, 4.1, 3.2 Hz, 1 H, 5-HA), 3.81 (dt, J =
14.6, 3.4 Hz, 1 H, 6-HA), 3.63 (ddd, J = 15.3, 8.1, 1.6 Hz, 1 H, 8-HA), 3.55
(t, J = 6.2 Hz, 2 H, 1′-CH2), 3.51–3.48 (m, 4 H, morpholine 2-CH2 and 6-
H), 3.19–3.15 (m, 1 H, 5-HB), 3.11–3.00 (m, 2 H, 6-HB and 8-HB), 2.47
(t, J = 6.2 Hz, 2 H, 2′-CH2), 2.37 (br s, 4 H, morpholine 3-CH2 and 5-
CH2), 2.16 (ddd, J = 15.2, 8.1, 2.5 Hz, 1 H, 9-HA), 1.86 (ddd, J = 15.2, 8.2,
2.3 Hz, 1 H, 9-HB), 1.31 (s, 3 H, 9a-CH3).
13C NMR (126 MHz, CD3OD): δ = 178.2, 159.4, 157.2, 141.5, 129.3,
128.1, 127.8, 68.0, 65.1, 56.2, 54.4, 46.3, 45.3, 43.4, 41.6, 38.6, 36.6,
21.5.
HRMS (ESI): m/z [M + Na]+ calcd for C22H31N5O4Na: 452.2274; found:
452.2260, –3.1 ppm error.
2-Butyl-9a-methyl-7-(2-methylpropanesulfonyl)octahydro-1H-
imidazolidino[1,5-d][1,4]diazepine-1,3-dione (24)
Isobutanesulfonyl chloride (39 μL, 0.30 mmol) was added to a solu-
tion of secondary amine 19 (36 mg, 0.15 mmol) and i-Pr2NEt (65 μL,
0.38 mmol) in DMA (1.2 mL) at r.t. The resulting solution was stirred
at r.t. for 16 h. The reaction was quenched with H2O (0.1 mL) and the
product was purified by mass-directed auto-prep (5–95% MeOH–H2O
with 0.1% ammonia buffer) to give the sulfonamide 24 (37 mg, 68%)
as a colourless oil.
IR (ATR): 2959, 2933, 1766, 1700, 1450, 1319, 1141, 865, 765 cm–1
.
1H NMR (500 MHz, CD3OD): δ = 4.00 (ddd, J = 14.5, 3.4, 2.4 Hz, 1 H, 5-
HA), 3.67–3.59 (m, 2 H, 6-HA and 8-HA), 3.41 (t, J = 7.1 Hz, 2 H, 1′-CH2),
3.14 (ddd, J = 14.5, 10.6, 2.3 Hz, 1 H, 5-HB), 3.09–3.01 (m, 1 H, 6-HB),
2.80 (d, J = 6.5 Hz, 2 H, CH2SO2), 2.63 (ddd, J = 14.7, 9.2, 2.0 Hz, 1 H, 8-
HB), 2.31 (ddd, J = 15.5, 7.4, 2.0 Hz, 1 H, 9-HA), 2.06 (hept, J = 6.7 Hz, 1
H, CH), 1.93 (ddd, J = 15.5, 9.2, 2.2 Hz, 1 H, 9-HB), 1.54–1.44 (m, 2 H,
2′-CH2), 1.32 (s, 3 H, 9a-CH3), 1.28–1.18 (m, 2 H, 3′-CH2), 0.98 (d, J =
6.7 Hz, 6 H, 2 × CH3), 0.85 (t, J = 7.4 Hz, 3 H, 4′-CH3).
13C NMR (126 MHz, CD3OD): δ = 177.9, 157.3, 65.2, 58.8, 48.3, 45.3,
42.7, 41.6, 39.6, 31.3, 25.8, 22.7, 22.5, 20.8, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H30N3O4S: 360.1952; found:
360.1951, –0.2 ppm error.
(5R*,8aS*)-2-Butyl-7-(3-fluorobenzenesulfonyl)-8a-methyl-5-
phenyloctahydroimidazolidino[1,5-a]piperazine-1,3-dione (27)
3-Fluorobenzenesulfonyl chloride (40 μL, 0.30 mmol) was added to a
solution of secondary amine 23 (45 mg, 0.15 mmol) and i-Pr2NEt (65
μL, 0.38 mmol) in DMA (1.2 mL) at r.t. The resulting solution was
stirred at r.t. for 16 h. The reaction was quenched with H2O (0.1 mL)
and the product was purified by mass-directed auto-prep (5–95%
MeOH–H2O with 0.1% ammonia buffer) to give the sulfonamide 27
(24 mg, 35%) as a white solid; mp 132–135 °C.
IR (ATR): 2937, 1766, 1699, 1445, 1419, 1348, 1187, 763, 577 cm–1
.
2-Butyl-9a-methyl-7-(thiophen-3-ylmethyl)octahydro-1H-imid-
azolidino[1,5-d][1,4]diazepine-1,3-dione (25)
1H NMR (500 MHz, CD3OD): δ = 7.72 (dd, J = 5.6, 4.0 Hz, 2 H, ArH),
7.69–7.66 (m, 1 H, ArH), 7.66–7.62 (m, 2 H, ArH), 7.55–7.49 (m, 1 H,
ArH), 7.43 (t, J = 7.6 Hz, 2 H, ArH), 7.36 (t, J = 7.2 Hz, 1 H, ArH), 5.47 (d,
J = 4.7 Hz, 1 H, 5-H), 4.69 (d, J = 13.0 Hz, 1 H, 8-HA), 3.77 (dd, J = 11.4,
1.5 Hz, 1 H, 6-HA), 3.60–3.48 (m, 2 H, 1′-CH2), 2.78 (dd, J = 13.0, 4.7 Hz,
1 H, 8-HB), 2.51 (d, J = 11.4 Hz, 1 H, 6-HB), 1.69–1.55 (m, 2 H, 2′-CH2),
1.42–1.29 (m, 2 H, 3′-CH2), 1.11 (s, 3 H, CH3), 0.97 (t, J = 7.4 Hz, 3 H, 4′-
CH3).
13C NMR (126 MHz, CDCl3): δ = 173.9, 162.7 (d, J = 253.2 Hz), 155.1,
138.0, 137.3 (d, J = 6.6 Hz), 131.4 (d, J = 7.8 Hz), 128.8, 128.0, 127.3,
123.4, 120.9 (d, J = 21.2 Hz), 115.0 (d, J = 24.2 Hz), 59.8, 51.7, 48.6,
46.7, 39.0, 30.1, 20.8, 19.9, 13.6.
3-Thiophenecarboxaldehyde (33 μL, 0.38 mmol) was added to a solu-
tion of secondary amine 19 (36 mg, 0.15 mmol) and AcOH (17 μL,
0.30 mmol) in DMA (1.2 mL) and the resulting mixture was stirred at
r.t. for 10 min. Sodium triacetoxyborohydride (95 mg, 0.45 mmol)
was added and the mixture heated to 60 °C for 16 h. The reaction was
quenched with H2O (0.1 mL) and the product was purified by mass-
directed auto-prep (5–95% MeOH–H2O with 0.1% ammonia buffer) to
give the piperidine 25 (37 mg, 74%) as a colourless oil.
IR (ATR): 2935, 2874, 1765, 1700, 1425, 1417, 1378, 1343, 791 cm–1
.
1H NMR (500 MHz, CD3OD): δ = 7.25 (dd, J = 4.9, 3.0 Hz, 1 H, Ar 5-H),
7.13–7.09 (m, 1 H, Ar 2-H), 6.96 (dd, J = 4.9, 1.2 Hz, 1 H, Ar 4-H), 3.79
(ddd, J = 15.1, 3.5, 2.3 Hz, 1 H, 5-HA), 3.58 (d, J 13.5 Hz, 1 H, CHAHBAr),
3.53 (d, J = 13.5 Hz, 1 H, CHAHBAr), 3.39 (t, J = 7.1 Hz, 2 H, 1′-CH2), 3.08
(ddd, J = 15.1, 11.1, 2.0 Hz, 1 H, 5-HB), 2.78–2.66 (m, 2 H, 6-HA and 8-
HA), 2.35 (ddd, J = 13.3, 11.2, 2.3 Hz, 1 H, 6-HB), 2.29–2.19 (m, 1 H, 9-
HA), 1.89 (ddd, J = 15.5, 10.4, 1.4 Hz, 1 H, 9-HB), 1.79–1.69 (m, 1 H, 8-
HB), 1.50–1.41 (m, 2 H, 2′-CH2), 1.25 (s, 3 H, CH3), 1.24–1.14 (m, 2 H,
3′-CH2), 0.84 (t, J = 7.4 Hz, 3 H, 4′-CH3).
13C NMR (126 MHz, CD3OD): δ = 178.4, 157.9, 139.9, 139.4, 126.6,
124.3, 65.7, 58.0, 55.3, 51.7, 41.1, 39.4, 38.5, 31.2, 23.6, 20.8, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H26N3O2S: 336.1740; found:
336.1749, 2.7 ppm error.
HRMS (ESI): m/z [M + Na]+ calcd for C23H26FN3O4SNa: 482.1526;
found: 482.1508, 3.7 ppm error.
(5R*,8aS*)-2-Benzyl-8a-methyl-7-(1-methylpiperidin-4-yl)-5-
phenyloctahydroimidazolidino[1,5-a]piperazine-1,3-dione (28)
N-Methyl-4-piperidone (46 μL, 0.38 mmol) was added to a solution of
secondary amine 22 (50 mg, 0.15 mmol) and AcOH (46 μL, 0.30
mmol) in DMA (1.2 mL) and the resulting mixture was stirred at r.t.
for 10 min. Sodium triacetoxyborohydride (95 mg, 0.45 mmol) was
added and the mixture heated to 60 °C for 16 h. The reaction was
quenched with H2O (0.1 mL) and the product was purified by mass-
directed auto-prep (5–95% MeOH–H2O with 0.1% ammonia buffer) to
give the piperidine 28 (48 mg, 74%) as a white solid; mp 72–74 °C.
N-Benzyl-9a-methyl-2-[2-(morpholin-4-yl)ethyl]-1,3-dioxoocta-
hydro-1H-imidazolidino[1,5-d][1,4]diazepine-7-carboxamide (26)
IR (ATR): 2934, 2779, 1765, 1701, 1496, 1434, 1278, 1073, 696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.49 (d, J = 8.2 Hz, 2 H, C6H5), 7.37–7.22
(m, 8 H, C6H5), 5.28 (d, J = 4.3 Hz, 1 H, 5-H), 4.71 (d, J = 14.9 Hz, 1 H ,
1′-HA), 4.67 (d, J = 14.9 Hz, 1 H, 1′-HB), 3.68 (d, J = 12.5 Hz, 1 H, 6-HA),
2.95–2.93 (m, 3 H, 8-HA and piperidine 3-CH2), 2.62 (dd, J = 12.5, 4.7
Benzyl isocyanate (37 μL, 0.30 mmol) was added to a solution of sec-
ondary amine 18 (45 mg, 0.15 mmol) and i-Pr2NEt (65 μL, 0.38 mmol)
in DMA (1.2 mL) at r.t. The resulting solution was stirred at r.t. for 16
h. The reaction was quenched with H2O (0.1 mL) and the product was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2391–2406

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J. D. Firth et al.
Special Topic
Synthesis
Hz, 1 H, 6-HB), 2.57 (tt, J = 11.5, 3.7 Hz, 1 H, piperidine 4-H), 2.30–2.28
(m, 4 H, 8-HA and NCH3), 2.16–2.04 (m, 2 H, piperidine 3-CH2), 1.92–
1.77 (m, 2 H, piperidine 2-CH2), 1.75–1.57 (m, 2 H, piperidine 2-CH2),
1.10 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 177.1, 157.1, 141.6, 137.8, 129.4,
129.2, 128.9, 128.9, 128.6, 128.3, 62.5, 56.2, 56.1, 56.1, 51.7, 51.6,
46.1, 42.5, 28.8, 28.5, 21.6.
Ethyl 2-[7-(4-Methoxybenzenesulfonyl)-9a-methyl-1,3-dioxoocta-
hydro-1H-imidazolidino[1,5-d][1,4]diazepin-2-yl]acetate (31)
4-Methoxybenzenesulfonyl chloride (414 mg, 2.01 mmol) was added
to a stirred solution of secondary amine 20 (360 mg, 1.34 mmol) and
Et3N (372 μL, 2.67 mmol) in CH2Cl2 (5 mL) at 0 °C at r.t. and the result-
ing solution was warmed to r.t. and stirred for 16 h. H2O (10 mL) was
added, the two layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 10 mL). The combined organic layers were
dried (MgSO4) and evaporated under reduced pressure to give the
crude product, which was purified by column chromatography (elut-
ing with 50:50 to 0:100 hexane–EtOAc) to give the sulfonamide 31
(585 mg, 99%) as a white solid; mp 134–136 °C; Rf = 0.16 (50:50 hex-
ane–EtOAc).
HRMS (ESI): m/z [M + H]+ calcd for C26H33N4O2: 433.2604; found:
433.2602, –0.5 ppm error.
(5R*,8aS*)-2-Butyl-N-(4-methoxyphenyl)-8a-methyl-1,3-dioxo-5-
phenyloctahydroimidazolidino[1,5-a]piperazine-7-carboxamide
(29)
IR (ATR): 2980, 2944, 1769, 1739, 1704, 1594, 1576, 1452, 1327, 1259,
4-Methoxyphenyl isocyanate (39 μL, 0.30 mmol) was added to a solu-
tion of secondary amine 23 (45 mg, 0.15 mmol) and i-Pr2NEt (65 μL,
0.38 mmol) in DMA (1.2 mL) at r.t. The resulting solution was stirred
at r.t. for 16 h. The reaction was quenched with H2O (0.1 mL) and the
product was purified by mass-directed auto-prep (5–95% MeOH–H2O
with 0.1% ammonia buffer) to give the urea 29 (36 mg, 53%) as a
white solid; mp 89–91 °C.
1158, 1022, 769 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 8.9 Hz, 2 H, Ar 2-H and 6-H),
6.96 (d, J = 8.9 Hz, 2 H Ar 3-H and 5-H), 4.22 (d, J = 17.5 Hz, 1 H, 1′-HA),
4.18 (d, J = 17.5 Hz, 1 H, 1′-HB), 4.18–4.11 (m, 3 H, 3′-CH2 and 5-HA),
3.86 (s, 3 H, OCH3), 3.85–3.81 (m, 2 H, 6-HA and 8-HA), 3.20 (ddd, J =
13.6, 11.2, 1.9 Hz, 1 H, 5-HB), 2.78 (ddd, J = 13.1, 11.5, 1.6 Hz, 1 H, 6-
HB), 2.59 (dd, J = 15.5, 6.5 Hz, 1 H, 9-HA), 2.44 (dd, J = 14.6, 10.0 Hz, 1
H, 8-HB), 2.10 (ddd, J = 15.5, 10.0, 1.4 Hz, 1 H, 9-HB), 1.45 (s, 3 H, CH3),
1.22 (t, J = 7.2 Hz, 3 H, 4-CH3).
13C NMR (126 MHz, CDCl3): δ = 175.8, 167.0, 163.1, 154.9, 130.2,
129.1, 114.5, 64.6, 62.0, 55.6, 48.0, 44.7, 41.7, 39.8, 39.4, 23.3, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H26N3O7S: 440.1486; found:
440.1492, 1.5 ppm error.
IR (ATR): 3331, 2955, 2932, 1766, 1697, 1509, 1416, 1230 cm–1
.
1H NMR (500 MHz, CD3OD): δ = 7.56 (d, J = 8.0 Hz, 2 H, ArH), 7.40 (t,
J = 7.6 Hz, 2 H, ArH), 7.36–7.25 (m, 3 H, ArH), 6.92–6.89 (m, 2 H, ArH),
5.45 (br s, 1 H, 5-H), 4.90 (d, J = 14.3 Hz, 1 H, 8-HA), 4.20 (d, J = 13.0 Hz,
1 H, 6-HA), 3.81 (s, 3 H, OCH3), 3.66–3.57 (m, 2 H, 1′-CH2), 3.44 (dd, J =
14.3, 5.1 Hz, 1 H, 8-HB), 3.08 (d, J = 13.0 Hz, 1 H, 6-HB), 1.74–1.63 (m, 2
H, 2′-CH2), 1.47–1.37 (m, 2 H, 3′-CH2), 1.16 (s, 3 H, CH3), 1.01 (t, J = 7.4
Hz, 3 H, 4′-CH3).
N-(Furan-2-ylmethyl)-2-[7-(4-methoxybenzenesulfonyl)-9a-
methyl-1,3-dioxooctahydro-1H-imidazolidino[1,5-d][1,4]diaze-
pin-2-yl]acetamide (32)
13C NMR (126 MHz, CD3OD): δ = 176.3, 158.2, 158.0, 157.5, 140.3,
133.1, 129.6, 128.1, 125.2, 115.2, 115.0, 61.5, 55.6, 51.9, 50.5, 45.2,
39.8, 30.9, 21.4, 20.7, 13.7.
LiOH (92 mg, 3.86 mmol) was added to a stirred solution of ester 31
(565 mg, 1.29 mmol) in 4:1:1 THF–MeOH–H2O (18 mL) at r.t. and the
resulting solution was stirred at r.t. for 1 h, then concentrated under
reduced pressure. H2O (10 mL), aq 1 M HCl (10 mL) and EtOAc (20 mL)
were added and the layers were separated. The aqueous layer was ex-
tracted with EtOAc (2 × 10 mL). The combined organic layers were
dried (MgSO4) and evaporated under reduced pressure to give the
crude carboxylic acid (530 mg, quant) as a white solid, which was
used without further purification.
1H NMR (500 MHz, CDCl3): δ = 7.21 (br s, 1 H, CO2H), 7.65 (d, J = 8.9
Hz, 2 H, Ar 2-H and 6-H), 6.96 (d, J = 8.9 Hz, 2 H Ar 3-H and 5-H), 4.26
(d, J = 17.9 Hz, 1 H, 1′-HA), 4.22 (d, J = 17.9 Hz, 1 H, 1′-HB), 4.16–4.10
(m, 1 H, 5-HA), 3.86 (s, 3 H, OCH3), 3.85–3.79 (m, 2 H, 6-HA and 8-HA),
3.20 (dd, J = 13.3, 11.1 Hz, 1 H, 5-HB), 2.76 (app t, J = 11.6 Hz, 1 H, 6-
HB), 2.55 (dd, J = 15.5, 6.4 Hz, 1 H, 9-HA), 2.40 (dd, J = 14.2, 9.6 Hz, 1 H,
8-HB), 2.13–2.05 (m, 1 H, 9-HB), 1.44 (s, 3 H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C25H31N4O4: 451.2340; found:
451.2342, 0.4 ppm error.
(5R*,8aS*)-7-Cyclohexanecarbonyl-8a-methyl-2-[2-(morpholin-4-
yl)ethyl]-5-phenyloctahydroimidazolidino[1,5-a]piperazine-1,3-
dione (30)
TBTU (77 mg, 0.24 mmol) was added to a solution of cyclohexane car-
boxylic acid (29 mg, 0.23 mmol), secondary amine 21 (50 mg, 0.15
mmol) and i-Pr2NEt (65 μL, 0.38 mmol) in DMA (1.2 mL) and the re-
sulting mixture was stirred at r.t. for 16 h. The reaction was quenched
with H2O (0.1 mL) and the product was purified by mass-directed
auto-prep (5–95% MeOH–H2O with 0.1% ammonia buffer) to give the
amide 30 (50 mg, 71%) as a white solid; mp 67–69 °C.
IR (ATR): 2928, 2852, 1766, 1701, 1446, 1144, 702 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.48 (d, J = 7.4 Hz, 2 H, C6H5 2-H and 6-
H), 7.35 (t, J = 7.4 Hz, 2 H, C6H5 3-H and 5-H), 7.32–7.27 (m, 1 H, C6H5
4-H), 5.52 (d, J = 3.5 Hz, 1 H, 5-H), 5.45 (d, J = 14.3 Hz, 1 H, 6-HA), 4.02
(d, J = 13.0 Hz, 1 H, 8-HA), 3.79–3.73 (m, 2 H, 1′-CH2), 3.68 (t, J = 4.4 Hz,
4 H, morpholine 2-CH2 and 6-CH2), 3.16 (d, J = 13.0 Hz, 1 H, 8-HB),
2.96 (dd, J = 14.3, 4.0 Hz, 1 H, 6-HB), 2.74–2.63 (m, 2 H, 2′-CH2), 2.61–
2.41 (m, 5 H, morpholine 3-CH2 and 5-CH2 and Cy 1-H), 1.88–1.20 (m,
10 H, Cy), 1.05 (s, 3 H, CH3).
TBTU (77 mg, 0.24 mmol) was added to a solution of crude carboxylic
acid (66 mg, 0.15 mmol), furfurylamine (20 μL, 0.23 mmol) and i-
Pr2NEt (65 μL, 0.38 mmol) in DMA (1.2 mL) and the resulting mixture
was stirred at r.t. for 16 h. The reaction was quenched with H2O (0.1
mL) and the product was purified by mass-directed auto-prep (5–95%
MeOH–H2O with 0.1% ammonia buffer) to give the amide 32 (46 mg,
63%) as a white solid; mp 76–78 °C.
13C NMR (126 MHz, CD3OD): δ = 178.0, 176.0, 157.0, 140.0, 129.5,
128.8, 128.0, 68.0, 61.2, 56.2, 54.5, 52.0, 51.6, 43.1, 41.3, 36.8, 30.5,
30.3, 26.8, 26.5, 26.3, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C26H37N4O4: 469.2809; found:
469.2806, –0.7 ppm error.
IR (ATR): 3323, 2943, 1770, 1706, 1451, 1256, 1150, 699, 587 cm–1
.
1H NMR (500 MHz, CD3OD): δ = 7.66–7.59 (m, 2 H, Ar 2-H and 6-H),
7.31 (dd, J = 1.9, 0.8 Hz, 1 H, furan 5-H), 7.01–6.94 (m, 2 H, Ar 3-H and
5-H), 6.23 (dd, J = 3.2, 1.9 Hz, 1 H, furan 4-H), 6.15–6.11 (m, 1 H, furan
3-H), 4.23 (s, 2 H, 4′-CH2), 4.05 (d, J = 16.5 Hz, 1′-HA), 4.00 (d, J = 16.5
Hz, 1′-HA), 3.98 (ddd, J = 15.0, 3.2, 2.5 Hz, 1 H, 5-HA), 3.77 (s, 3 H,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2391–2406

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J. D. Firth et al.
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OCH3), 3.73–3.65 (m, 2 H, 6-HA and 8-HA), 3.20–3.13 (m, 1 H, 5-HB)
2.75 (ddd, J = 13.4, 11.0, 2.3 Hz, 1 H, 6-HB), 2.57 (ddd, J = 14.6, 9.5, 1.6
Hz, 1 H, 8-HB), 2.39 (ddd, J = 15.6, 7.2, 1.6 Hz, 1 H, 9-HA), 1.95 (ddd, J =
15.6, 9.5, 2.0 Hz, 1 H, 9-HB), 1.34 (s, 3 H, 9a-CH3).
13C NMR (126 MHz, CD3OD): δ = 177.9, 168.1, 164.7, 156.9, 152.5,
143.3, 131.4, 130.3, 115.2, 111.3, 108.2, 65.8, 56.2, 45.6, 45.3, 42.3,
41.6, 39.8, 37.2, 22.6.
(9) (a) Koopmanschap, G.; Ruijter, E.; Orru, R. V. A. Beilstein J. Org.
Chem. 2014, 10, 544. (b) Rossen, K.; Sager, J.; DiMichele, L. M.
Tetrahedron Lett. 1997, 38, 3183. (c) Chapman, T. M.; Davies, I.
G.; Gu, B.; Block, T. M.; Scopes, D. I. C.; Hay, P. A.; Courtney, S.
M.; McNeill, L. A.; Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc.
2004, 127, 506. (d) Nenajdenko, V. G.; Gulevich, A. V.;
Balenkova, E. S. Tetrahedron 2006, 62, 5922. (e) Banfi, L.; Basso,
A.; Cerulli, V.; Rocca, V.; Riva, R. Beilstein J. Org. Chem. 2011, 7,
976. (f) Xia, L.; Li, S.; Chen, R.; Liu, K.; Chen, X. J. Org. Chem.
2013, 78, 3120.
HRMS (ESI): m/z [M + H]+ calcd for C22H27N4O7S: 491.1595; found:
491.1594, –0.1 ppm error.
(10) (a) Hulme, C.; Ma, L.; Romano, J. J.; Morton, G.; Tang, S.-Y.;
Cherrier, M.-P.; Choi, S.; Salvino, J.; Labaudiniere, R. Tetrahedron
Lett. 2000, 41, 1889. (b) Ignacio, J. M.; Macho, S.; Marcaccini, S.;
Pepino, R.; Torroba, T. Synlett 2005, 3051. (c) Sañudo, M.;
García-Valverde, M.; Marcaccini, S.; Torroba, T. Tetrahedron
2012, 68, 2621. (d) Brockmeyer, F.; Kröger, D.; Stalling, T.;
Ullrich, P.; Martens, J. Helv. Chim. Acta 2012, 95, 1857.
(11) Compton, R. G.; Bamford, C. H.; Tipper, C. F. H. Decomposition
and Isomerization of Organic Compounds; Elsevier: Amsterdam,
1971, 400.
Acknowledgment
We acknowledge support from the Innovative Medicines Initiative
Joint Undertaking under grant agreement no 115489, resources of
which are composed of financial contribution from the European
Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA
companies’ in-kind contribution. We also thank EPSRC for a Ph.D. stu-
dentship.
(12) James, T.; Simpson, I.; Grant, J. A.; Sridharan, V.; Nelson, A. Org.
Lett. 2013, 15, 6094.
(13) Bower, J. F.; Rujirawanich, J.; Gallagher, T. Org. Biomol. Chem.
2010, 8, 1505.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378704.
(14) (a) Marion, N.; Ramón, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2008,
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
131, 448. (b) Au(IPr)Cl
= Chloro[1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene]gold(I).
(15) Newman, H. J. Org. Chem. 1965, 30, 1287.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2391–2406