Multidimensional screening and methodology development for condensations involving complex 1,2-diketones

Article abstract of DOI:10.1055/s-0029-1218813

Multidimensional reaction screening with complex cycloheptane-1,2-diones is described. The studies resulted in the discovery of regioselective Lewis acid mediated condensation reactions with substituted ureas, and a diastereoselective hydrogenation process that proceeds through an interesting isomerization of allylpalladium hydride. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218813

2254
PAPER
Multidimensional Screening and Methodology Development for
Condensations Involving Complex 1,2-Diketones
M
ultidime
o
nsional Reac
h
tion Screeni
n
ng for 1,2-Diketone
R
s
. Goodell, Bo Leng, Tracy K. Snyder, Aaron B. Beeler,* John A. Porco Jr.*
Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
590 Commonwealth Avenue, Boston, MA 02215, USA
Fax +1(617)3582847; E-mail: porco@bu.edu
Received 22 April 2010
Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday
heteropolycyclic compounds, with the generation of high-
ly complex chemotypes. In the current study, we evaluat-
ed a wide range of condensation partners5–14 with complex
cycloheptane-1,2-diones. Herein, we report on the results
Abstract: Multidimensional reaction screening with complex cy-
cloheptane-1,2-diones is described. The studies resulted in the dis-
covery of regioselective Lewis acid mediated condensation
reactions with substituted ureas, and a diastereoselective hydroge-
nation process that proceeds through an interesting isomerization of of our initial screening studies and on the subsequent de-
allylpalladium hydride.
velopment of regioselective condensation reactions to af-
ford novel heterocyclic frameworks.
Key words: reaction discovery, regioselectivity, condensation,
diastereoselectivity, hydrogenations
As shown in Scheme 1, the synthesis of the target scaf-
folds for screening began with the [5 + 2] cycloaddition of
the quinone monoketal 1 with (1E)-prop-1-en-1-ylben-
zene to give the bicyclo[3.2.1]octanoid 2. Retro-Dieck-
mann-type ring-opening of 2 afforded the corresponding
cycloheptenones 3.4,15 Subsequent acid-mediated O-dem-
ethylation of the a-methoxyenone 4 afforded the 1,2-dike-
tone 5. Interestingly, O-demethylation of the secondary
amides 6 afforded the a-hydroxy ketones 7.
Multidimensional reaction screening1,2 is an efficient
high-throughput approach for the discovery of new
synthetic methodologies and complex chemotypes.3,4 Pre-
vious reaction-screening efforts utilizing bicyclo
[3.2.1]octanoids led to the discovery of a retro-Dieckmann-
type fragmentation that afforded highly functionalized cy-
cloheptenones.4 We were interested in using the cyclohep-
tenone scaffolds as substrates for additional reaction–
discovery projects, with a focus on condensation reac-
tions. Condensation reactions of 1,2-dicarbonyl com-
pounds provide a facile access to heterocyclic or
Preliminary efforts to probe the reactivity of scaffolds 5
and 7 were carried out by using known imidazole-forming
conditions. Whereas the reaction with scaffold 5 afforded
the desired imidazole 8, the reaction with scaffold 7 unex-
O
MeO
O
(1E)-prop-1-en-1-ylbenzene
MeO
OMe
OMe
(2 equiv)
O
amine (2 equiv)
R2
N
H
CSA (1 equiv)
DBU (1.2 equiv)
MeO
R1
Ph
Me
H2O (0.75 equiv)
MeCN, r.t., 2 h, 52%
MeCN, r.t., 1 h
40–65%
Ph
)-3
O
O
Me
HN
(
)-2
H
1
(
Ph
MeO
O
N
O
O
1.2 M aq HCl
DMSO
NH4OAc, PhCHO
N
N
N
O
100 °C, 4 h
78%
EtOH, 80 °C, 1 h
36%
Ph
Ph
Ph
O
O
Me
Me
(
Me
(
(
)-4
)-8
)-5
H
R
R
MeO
HO
Me
O
*
O
O
N
R
1.2 M aq HCl
DMSO
N
N
NH4OAc, PhCHO
EtOH, 80 °C, 3 h
O
O
H
100 °C, 4 h
N
Ph
Ph
O
Ph
Me
Me
(
(
)-6a, R = H
)-6b, R = OMe
(
(
)-7a, R = H, 99%
)-7b, R = OMe, 97%
(
(
)-9a, R = H, 72%, dr >15:1
)-9b, R = OMe, 61%, dr >15:1
Scheme 1 Scaffold synthesis and preliminary results
SYNTHESIS 2010, No. 13, pp 2254–2270
x
x.
x
x
.
2
0
1
0
Advanced online publication: 11.06.2010
DOI: 10.1055/s-0029-1218813; Art ID: C02110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2255
pectedly gave the oxazoline 9 with a high diastereoselec- densation with benzene-1,2-diamine or (1S,2S)-(+)-
tivity (Scheme 1). The structure of the major diastereomer cyclohexane-1,2-diamine afforded pyrazines 10 and 11,
of oxazoline 9 was confirmed by X-ray crystallographic respectively.6 Reactions with 2-aminobenzenethiol7 or 2-
analysis.16,17
amino-5-methylphenol8 also resulted in the formation of
adducts, but the products were complex mixtures that
were unstable to isolation. The reaction of methyl hydra-
zonothiocarbamate hydroiodide under acid conditions re-
sulted in the formation of 2:1 mixture of the regioisomeric
triazines 12a and 12b.9 Although the two regioisomers
were isolated, the structures could not be assigned on the
basis of standard NMR analyses. The condensation reac-
tion of 2-aminobenzaldehyde gave a mixture of four quin-
oline products (13a–d). Interestingly, these quinoline
products were obtained under acid conditions, in contrast
to typical conditions for the Friedländer condensation (po-
tassium hydroxide, ethanol, reflux).10 Additionally, acid-
catalyzed condensations using urea,11 guanidine hydro-
chloride,12 or benzenecarboximidamide hydrochloride13
afforded the cycloheptadiene products 14, 15, and 16a, re-
spectively. In the case of the reaction with urea, the
alkenyl imidazolone 16a readily oxidized to the corre-
sponding cycloheptatriene 16b upon exposure to air.
Having established preliminary reactivity, we carried out
a comprehensive multidimensional reaction screen utiliz-
ing scaffolds 5 and 7b (Figure 1). For this screen, 18 con-
densation partners were selected using ethanol or
acetonitrile as solvent (80 °C, 24 h) in the presence of ei-
ther pyridinium tosylate (PPTS) or diisopropylethylamine
(DIPEA), or without any additive.
Each reaction was performed by using 3 mmol of substrate
(approximately a 1 mg scale) with 1.0 equiv of both the re-
action partner and the additive (a total reaction volume of
60 mL, 0.05 M). When the reaction partners were used as
their hydrochloride salts, 2.0 equivalents of the base were
used. Each reaction was prepared in a 1 mL, oven-dried,
glass vial, with minimal exposure to air, from stock solu-
tions of the reagents prepared in either ethanol or acetoni-
trile. The vials were capped with silicone rubber septa and
placed in a heated reaction block (80 °C) that was fastened
to an orbital shaker and agitated for 24 hours. The mix-
tures were diluted to 1 mL and analyzed by ultra-perfor-
mance liquid chromatography/mass spectrometry (UPLC/
MS) with an evaporative light-scattering detector
(ELSD).18 Reactions that afforded >20% conversion into
major products were subsequently scaled up, and the reac-
tion products were isolated for characterization.
Although screening studies with the a-hydroxy ketone 7b
as a substrate indicated successful conversions into new
products, we found that these products were generally un-
stable to purification. This suggests that, although an imi-
ne is formed initially, subsequent cyclization does not
occur due to the unexpected stability of the N-acylhemi-
aminal. However, we did observe some reactions of 7b
with isocyanates14 (DIPEA, MeCN, 80 °C, 24 h) to give
As anticipated, 1,2-diketone scaffold 5 underwent a num-
ber of reactions to afford new products (Figure 2). Con-
Reaction conditions
catalyst
DIEA
PPTS
blank
temp, time
solvent
EtOH
80 °C
24 h
MeCN
Reaction partners
NH2
Me
HN
O
O
NH2
Me
H2N
NH2
NH2
SH
N
NH2
HO
NH2
NH2
⋅HCl
S
H2N
O
Ph
HI
O
Me
NH2
(
)-5
H2N
N
H2N
NH2
NH2
CHO
MeO
O
NH2
⋅HCl
NH2
O
O
NH
Ph
NH2
H2N
H2N
CN
MeO
NH2
O
HO
H
N
Me
N
NH2
NH2
O
S
HN
NH2
(
)-7b
O
O
O
N
Me
NC
NH2
⋅HCl NH2
N
H
MeO
N
H
O
H2N
Me
Me
S
C
Me
O
N
N
N
C
C
O
Figure 1 Multidimensional screening parameters
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2256
J. R. Goodell et al.
PAPER
MeS
N
SMe
N
N
N
N
N
N
N
N
N
+
N
N
N
N
O
Ph
O
Ph
Me
O
Ph
Ph
Me
O
Me
Me
10
11
12a
12b
NH2
N
O
N
N
O
HN
HN
N
N
O
N
N
Ph
Me
N
Ph
O
Me
Ph
O
Me
Ph
O
Me
13a
13b
14
15
O
O
N
N
N
O
HN
HN
NH
NH
Ph
N
O
N
+
N
Ph
N
Ph
O
Me
Me
Ph
O
Me
O
16a
Me
13c
13d
16b
O
O
MeO
MeO
Me
O
O
N
Bn
N
N
N
O
O
Ph
Ph
Me
Me
17
18
Figure 2 Representative condensation products
the unusual alkenyl oxazolidinones 17 and 18 (Figure 2). creasing the regioselectivity of the reaction. Unexpected-
Surprisingly, 17 and 18 were remarkably stable under ly, the addition of scandium(III) triflate resulted in an
both acidic and basic conditions.
inversion of the regioselectivity (Table 1, entry 3). Addi-
tion of 4 Å molecular sieves resulted in a slight enhance-
ment of the inversion, and additional enhancement was
achieved by conducting the reaction at 0 °C for 16 h, and
by using extensively dried methyl hydrazonothiocarbam-
ate hydroiodide (Table 1, entry 7). The conversion was ul-
timately improved by using two equivalents of the
hydrazonothiocarbamate (Table 1, entry 11). To the best
our knowledge, this study represents the first use of a
Lewis acid to invert the regioselectivity of a 1,2-dicarbo-
nyl condensation reaction.
We next selected the condensation of 1,2-diketone 5 with
methyl hydrazonothiocarbamate hydroiodide for initial
follow-up, with the goal of developing a regioselective
condensation reaction. Although there are numerous re-
ports of reactions with 1,2-dicarbonyl compounds, few
studies address the problem of regioselectivity when non-
symmetric substrates were used.19 In general, regioselec-
tivity is a direct result of the inherent reactivity of the
carbonyl compounds.19c,e Although some modest advanc-
es have been made, achieving regioselectivity with com-
plex scaffolds remains
a
significant challenge. Although two regioisomers were isolated, we were unable
Accordingly, we conducted a series of triazene-forming to assign the structures of products 12a and 12b by stan-
reactions using various catalysts and conditions (Table 1). dard NMR analysis due to overlapping of key proton res-
onances. Attempts to grow suitable crystals for X-ray
Generally, the replacement of ethanol by 2,2,2-trifluoroet-
analysis were also unsuccessful. We therefore sought to
hanol or acetonitrile enhanced the regioselectivity 3-fold.
synthesize an alternative substrate with fewer, more de-
Conversely, the use of tetrahydrofuran–water (9:1) re-
fined, proton resonances. Previous work had shown that
duced the regioselectivity (Table 1, entry 2). These results
the bicyclo[3.2.1]octanoid 2 undergoes a retro-Dieck-
suggest that nucleophilic solvents such as ethanol and wa-
mann-type ring opening with pyrrolidine in the presence
ter react with the slightly more electrophilic ketone to
of 1,5,7-triazabicyclo[4.4.0]dec-5-ene.4 Unfortunately,
form a hemiketal or a hydrate, respectively, thereby de-
this methodology is limited in terms of the scope of the
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2257
Table 1 Optimization of Triazine Regioselectivity
MeS
N
SMe
N
N
O
O
N
N
N
SMe
+
optimization
N
N
N
H2N
HI
N
+
NH2
Ph
Ph
Ph
O
O
O
Me
Me
)-5
Me
)-12b
(
(
)-12a
(
Entry
Solvent
EtOH
Temp
r.t.
Time (h)
Catalysta
–
Additive
–
Ratio 12a/12b
Conv. (%)b
1
2
4
4
2:1
100
100
100
79
THF–H2O (9:1)
THF–H2O (9:1)
TFEc
r.t.
–
–
1:1
3
r.t.
2
Sc(OTf)3
–
–
1:2
4
r.t.
2
–
6:1
5
TFE
r.t.
2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
La(OTf)3
Zn(OTf)2
Sc(OTf)3
Sc(OTf)3
–
5:1
51
6
TFE
r.t.
2
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
1:3
30
7
TFE
0 °C
0 °C
0 °C
0 °C
0 °C
16
16
16
16
16
1:14
1:10
1:1
68
8
TFE
85
9
TFE
50
10
11
MeCN
MeCN
1:17
1:24d
57
70
a Lewis acid (1 equiv).
b Calculated from UPLC/ELSD percent conversions.
c 2,2,2-Trifluoroethanol.
d Methyl hydrazonothiocarbamate hydroiodide (2 equiv).
secondary amine reagent. Thus, a revised route to the cy- steps. Subsequent O-demethylation followed by conden-
cloheptenone scaffold was developed that would allow for sation with methyl hydrazonothiocarbamate hydroiodide,
greater variability of the tertiary amide. We found that afforded triazines 22a and 22b.
performing the fragmentation reaction with water in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
With triazines 22a and 22b in hand, we were able to de-
termine their regiochemistries by means of 15N-heteronu-
gave the corresponding carboxylic acid 19 as a viable
functional handle (Scheme 2). Coupling of 19 with dimeth-
ylamine using O-(7-azabenzotriazol-1-yl)-N,N,N¢,N¢-tet-
ramethyluronium hexafluorophosphate (HATU) afforded
the desired cycloheptenone 20 in 65% yield over two
clear multiple-bond coherence (15N-HMBC) NMR
analysis20 (Scheme 2).17 Based on these experiments, we
postulated that the inherently more reactive ketone is in
the position beta to the phenyl group (C1), and that the
O
MeO
MeO
O
O
O
H
H2O–MeCN
Me
N
HATU
MeO
Ph
Me
HO
Me2NH
CH2Cl2
DBU (1 equiv)
Me
r.t., 4 h
98%
H
Ph
Ph
O
O
Me
66%
Me
(
)-2
(
)-19
( )-20
1.2 M aq HCl
DMSO
100 °C, 1.5 h
76%
MeS
N
SMe
N
15N-HMBC
N
N
N
O
O
C-2
N
H
H
H
H
SMe
C-1
Me
Me
Me
N
H
H
EtOH
H
+
+
N
N
H2N
HI
N
Me
H
Me
r.t., 6 h
Me
NH2
Ph
Ph
O
(
Ph
( )-21
O
(
Me
)-22a, 30%
Me
O
Me
(3 equiv)
)-22b, 19%
Scheme 2 Synthesis of alternative triazines
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2258
J. R. Goodell et al.
PAPER
Lewis acid may preferentially activate the ketone in the catalyst. Thus, the use of a Lewis acid instead of a Brøn-
position beta to the amide group (C2).
sted acid ultimately rendered the C2 ketone more reactive.
To further understand the mechanism leading to regiose-
lectivity, we turned our attention to condensation with
urea, which was also identified in the initial screen. Our
first objective, however, was to control the oxidative pro-
cess that occurred during the reaction. We found that de-
gassing the reaction with argon was effective in
preventing the oxidative process (Table 2, entry 2),
whereas purging with oxygen increased the degree of ox-
idation (Table 2, entry 3).
Table 3 Lewis Acid Screening Results
Me
O
N
NH
Ph
O
N
H2N
N
Me
O
O
Me
(
O
H
)-23a
(1.2 equiv)
+
MeCN, 4 Å MS
O
N
Me
80 °C, 12 h
HN
Ph
L.A. (0.2 equiv)
O
N
Table 2 Oxidation During Urea Condensation
Me
(
)-5
O
O
O
N
O
HN
HN
O
NH
NH
Ph
H2N
NH2
Ph
O
Me
(
(1.2 equiv)
+
)-23b
N
CSA, MeCN
80 °C, 20 h
N
N
Entry
Catalyst
CSAb
Ratio 23a/23b
Ph
Ph
O
Me
(
O
O
Me
Me
( )-16b
)-5
(
)-16a
1
2
3
4
5
6
7
8
9
2:1
1:2
1:2
1:2
1:2
1:4
1:4
1:8
1:9
Entry
Atmosphere
Ratio 16a/16ba
Sc(OTf)3
Yb(OTf)3
Y(OTf)3
La(OTf)3
Mg(OTf)2
Fe(OTf)2
Mn(OTf)2
Zn(OTf)2
1
2
3
air
1:1
32:1
1:3
argon
O2
a Calculated from UPLC/ELSD percentage conversions.
Having developed a viable method for controlling oxida-
tion, our next step was to attempt the condensation reac-
tion of nonsymmetrical N-ethylurea. As anticipated, the
condensation reaction with 1,2-diketone 5 gave a mixture
of the regioisomers 23a and 23b (Scheme 3). Regiochem-
ical assignments were confirmed by one-dimensional nu-
clear Overhauser effect (1D NOE) analysis.17 As the
unsubstituted urea nitrogen is expected to be the more re-
active, we predicted that the initial condensation should
occur with the slightly more electrophilic C1 ketone
group, as observed for condensation with methyl hydra-
zonothiocarbamate hydroiodide (see Scheme 2).
a Calculated from UPLC/ELSD percent conversions.
b CSA (1 equiv).
To gain an insight into the role of the Lewis acid, mecha-
nistic studies were initiated by means of 1H and 13C NMR
analyses of substrate 5 in the presence of zinc triflate
(Figures 3 and 4). We observed a downfield shift of all the
cycloheptane-1,2-dione ring protons except the a-phenyl-
methine proton (D) which shifted slightly upfield
(Figure 3). The addition of zinc triflate did not significant-
ly alter the coupling constants, indicating that the confor-
mation of the cycloheptane-1,2-dione ring was not
changed significantly. 13C NMR spectra revealed a selec-
tive broadening of the two ketone resonances at 196 ppm
and 197 ppm; because zinc(II) is diamagnetic, we did not
expect the observed resonance broadening. We propose
that iron(II), which is a common impurity (1–20 ppm) in
Next, we conducted a Lewis acid screen to determine if re-
giochemical control would be possible with substituted
ureas. Generally, substituted ureas were found to be sub-
stantially less reactive than methyl hydrazonothiocarbam-
ate hydroiodide, which required alternative conditions to
achieve regioselectivity. As shown in Table 3, all the
Lewis acids that we examined resulted in inversion of re-
gioselectivity, with zinc triflate being the most effective
O
Me
H
O
O
Me
9%
H2N
N
Me
6%
N
O
HN
N
H
O
N
NH
(1.2 equiv)
H
H
+
CSA (1 equiv)
MeCN, 4 Å MS
N
N
Ph
Ph
Ph
O
80 °C, 12 h
O
Me
(
O
(
Me
Me
)-23b, 38%
)-5
( )-23a, 22%
Scheme 3 The condensation reaction of ethylurea
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2259
Figure 3 1H NMR evidence for mechanism (in CD3CN)
Figure 4 13C NMR evidence for chelation (in CD3CN)
zinc triflate, is probably responsible for the resonance
broadening, suggesting that iron(II) or zinc(II) may be
chelated by the 1,2-diketone and not by the more Lewis
basic amide functionality. Since iron(II) triflate also in-
duces a significant inversion in regioselectivity, it is likely
that these Lewis acids share a common metal-coordina-
tion site.
Primarily on the basis of 1H and 13C NMR studies, we pro-
pose a mechanism for the regioselective condensation
(Figure 5). By using conformational analysis followed by
energy minization,21 we determined that, in the absence of
zinc(II) triflate, the oxygen lone pair on the amide carbo-
nyl is positioned in close proximity to the a-phenyl-
methine group, altering its electronic environment. We
believe that chelation of zinc(II) triflate to the 1,2-dike-
Figure 5 Proposed stereoelectronic effects leading to regioselecti-
vity in the condensation reaction
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2260
J. R. Goodell et al.
PAPER
tone lowers the LUMO for both carbonyl groups, trigger- Diastereoselective hydrogenation of the alkenyl imida-
ing the rotation of the amide carbonyl to form a stabilizing zolone 23a with 10% palladium-on-carbon (H-Cube, 50
n–p* interaction with the C1 ketone group. The C2 ketone bar, 50 °C) afforded cycloheptene 40 as a single diastereo-
group cannot undergo a similar n–p* interaction due to mer (Scheme 5). The stereochemical assignment was con-
significant steric clash upon further rotation of the amide. firmed by 1D NOE analysis.17 Diastereoselectivity is
It is also noteworthy that replacement of the pyrrolidine probably achieved through steric interaction imparted by
with N-methylcyclohexylamine resulted in complete loss the pseudo-axial methyl group, which effectively blocks
of regioselectivity, probably as a result of greater steric in- the re-face (Scheme 5). Unfortunately, reduction of the
teractions inhibiting the rotation of the amide.
styrenyl olefin did not result in an appreciable decrease in
oxidative decomposition.
Next, we probed additional substituted ureas (Table 4).
We found that the zinc(II) triflate mediated reaction re-
tained a reasonable degree of regioselectivity over a wide
range of functionalities. However, a slight reduction in se-
lectivity was observed on increasing the steric bulk of the
substituent on the urea (Table 4, entries 1–4). Additional-
ly, we observed that a greater electron deficiency was ac-
companied by a slight decrease in yield (Table 4, entries
8–10). In the case of N-acetylurea, no reaction was ob-
served. Condensations with 1,3-disubstituted ureas, such
as 1-methyl-3-phenylurea or 1-ethyl-3-phenylurea, indi-
cated that the phenyl-substituted nitrogen is the more nu-
cleophilic (Table 4, entries 12 and 13). Reactions with a
Brønsted acid catalyst (10-camphorsulfonic acid; CSA)
were also carried out in select cases. Whereas both allyl-
urea and (4-chlorophenyl)urea showed a similar regiose-
lectivity to ethylurea, 1-ethyl-3-phenylurea gave similar
results to the zinc(II) triflate mediated reaction. The zinc
triflate mediated regioselective condensation was also ap-
plied to a substituted thiourea, with good results. In this
instance, however, a stoichiometric amount of zinc triflate
was required to achieve a comparable regioselectivity
(Table 4, entry 14).
Scheme 5 Diastereoselective reduction of alkenyl imidazolone
23a21
Interestingly, N-acylation of cycloheptene 40 resulted in
only a slight increase in stability, which suggests that the
electronic structure of the imidazolone ring plays a signif-
icant role in the oxidative decomposition. It should be not-
ed that imidazolone rings with a greater electron density,
such as the disubstituted urea condensates 33–35, under-
went decomposition more readily. Initial attempts to fully
reduce alkenyl imidazolone 23a with 10% palladium-on-
carbon under extremely harsh conditions (H-Cube, 90 bar,
80 °C) still afforded the cycloheptene 40 as the major
product together with a product derived from the reduc-
tion of the phenyl ring. However, full reduction of 23a
was achieved by using Raney Ni (H-Cube, 90 bar, 80 °C)
to afford imidazolidinone 41 as a 1:1 mixture of diastereo-
Due to the oxidative instability of alkenyl imidazolones,
we sought to determine the oxidation/reduction potential
of these interesting ring systems with the intention of in-
creasing their stability. We first oxidized the alkenyl imi-
dazolone 23a by using 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ; 1.2 equiv) to afford the desired cy-
cloheptatriene 37, along with the pseudo-aromatic cyclo-
heptimidazolone (2-hydroxy-1,3-diazaazulene)22 38
(Scheme 4). Acylation of the urea prevented over-oxida-
tion and afforded the cycloheptatriene 39 exclusively in
moderate yield over the two steps.
O
O
O
HN
N
HN
N
N
N
DDQ
(1.2 equiv)
Me
Me
Me
+
CH2Cl2
r.t., 2 h
N
N
N
Ph
Ph
Ph
O
O
O
Me
Me
Me
)-23a
(
(
)-37, 32%
( )-38, 48%
O
O
O
HN
Me
N
N
N
N
1) Ac2O, MeCN,
Et3N, 80 °C, 2 h
Me
Me
N
2) DDQ (1.2 equiv)
CH2Cl2, r.t., 2 h
Ph
Ph
O
O
(
Me
)-23a
Me
)-39, 50%
(
Scheme 4 Further transformations of cycloheptadiene 23a
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2261
Table 4 Scope and Regioselectivity of the Urea Condensation Reaction
X
X
R1
R2
O
N
N
R1
O
R2
N
N
substitued urea
+
N
N
acid catalyst
MeCN, 100 °C, 2 h
sealed-tube
N
Ph
Ph
O
Ph
O
Me
O
Me
major (a)
Me
minor (b)
degassed
Entry
Urea
X
O
R1
R2
Et
Yield (%)a,b
92 (99)b
Products
Regioisomeric ratio (a/b)
O
1
H
H
H
H
H
Et
H
23a/23b
77:23 (47:53)b
H2N
H2N
H2N
H2N
H2N
N
H
Me
O
O
O
O
O
2
3
4
5
6
7
8
O
O
O
O
O
O
O
Me
99
24a/24b
25a/25b
26a/26b
27a/27b
28a/28b
29a/29b
30a/30b
66:34
Me
N
H
Me
Me
i-Pr
99
71:29
N
H
Me
Me
t-Bu
allyl
88
65:35
N
H
Me
98 (96)b
91
82:18 (46:54)b
81:19
N
H
propargyl
Bn
H2N
H2N
N
H
O
O
98
82:18
N
H
Ph
H
H
Ph
99
77:23
H2N
H2N
N
H
Cl
O
O
9
O
4-ClC6H4
85 (96)b
31a/31b
85:15 (46:54)b
N
H
Br
10
11
12
13
14
O
O
O
O
S
H
4-BrC6H4
80
32a/32b
33
76:24
H2N
Me
N
H
O
Et
Ph
Ph
H
Et
93
–
N
N
Me
H
H
O
O
Me
Et
98
34a/34b
35a/35b
36a/36b
76:24
Me
N
N
H
H
99 (99)b
99
78:22 (64:36)b
80:20c
N
H
N
H
Me
S
Et
H2N
N
H
Me
a Combined isolated yield when using Zn(OTf)2 (0.2 equiv) and 4 Å MS.
b Combined isolated yield when using CSA (1.0 equiv).
c Required 1.0 equiv of Zn(OTf)2 and 4 Å MS.
mers (Scheme 6). Hydrogenation of the imidazolone ole- Unfortunately, hydrogenation with Raney Ni under harsh
fin effectively eliminated the occurrence of oxidative H-Cube conditions was highly inconsistent because of
decomposition.
variability between batches of the catalyst cartridges. As
a result, an alternative more reliable approach for reduc-
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2262
J. R. Goodell et al.
PAPER
O
O
O
HN
Me
HN
Me
HN
N
N
N
H-Cube, Raney Ni
90 bar, 80 °C
Me
Me
Me
MeOH, 0.5 mL/min
quantitative
(dr 1:1)
+
N
N
N
Ph
)-41b
Ph
O
Ph
O
O
O
O
Me
(
)-41a
(
(
)-23a
O
O
O
O
Me
N
Me
N
N
N
H-Cube, 10% Pd/C
30 bar, 90 °C
Me
Me
EtOAc, 0.5 mL/min
quantitative
single diastereomer
N
N
Ph
Ph
Me
O
Me
N
(
)-43
(
)-42
O
N
O
N
O
O
Me
N
Me
H-Cube, 10% Pd/C
50 bar, 50 oC
Me
Me
EtOAc, 0.5 mL/min
quantitative
single diastereomer
N
N
Ph
Ph
Me
(
O
Me
(
)-45
)-44
Scheme 6 Hydrogenations of alkenyl imidazolone 23a
ing the imidazolone olefin was required. Remarkably, we able to isolate intermediate 48 under milder conditions
discovered that full reduction of the acetylated alkenyl (H-Cube, 10 bar, 40 °C). Stereochemical assignments for
imidazolone 42 with 10% palladium-on-carbon occurred 48 were confirmed by 1D NOE analysis.17 Diastereoselec-
under considerably milder conditions (H-Cube, 30 bar, tive hydrogenation of the resulting enamine afforded the
90 °C) to afford imidazolidinone 43 as a single diastereo- fully reduced product 43. Diastereoselectivity in the final
mer (Scheme 6). We also observed full reduction of the reduction is the result of blocking of the re-face by the
acetylated alkenyl imidazolone 44 to afford imidazolidi- flanking phenyl and N-acylurea groups. Further evidence
none 45 as a single diastereomer, albeit under slightly for the allylpalladium hydride isomerization mechanism
harsher conditions.
was provided by a failed attempt to reduce the acetylated
imidazolone 49 (H-Cube, 10 bar 40 °C) (Scheme 8).
As previously described, we propose that the styrenyl ole-
fin initially undergoes diastereoselective hydrogenation We were also able to isolate enamine 48 by treatment of
by the well-established Horiuti–Polanyi half-hydrogena- 49 with acetic acid (Scheme 8). The selectivity of the
tion mechanism23 to give the allylpalladium hydride inter- acid-mediated isomerization suggests that the observed
mediate 46 (Scheme 7). Subsequent isomerization occurs syn-diastereomer is thermodynamically favored. Accord-
with retention of stereochemistry to afford intermediate ingly, we performed computational studies21 for imida-
47, which may, in part, be favored due to stabilization by zolone 49 and both the syn- and anti-diastereomers from
coordination of the amide acetyl oxygen.24 Subsequent re- isomerization. As shown in Scheme 9, the ground-state
ductive elimination of palladium provides the net 1,4-ad- energy of the syn-diastereomer 48 is 1 kcal lower than that
dition product 48 as a single diastereomer. We were also of the parent imidazolone 49 and 4.8 kcal lower than that
allylpalladium
hydride
Me
Horiuti–Polanyi
half-hydrogenation
mechanism
Me
O
Me
O
O
O
O
O
O
N
N
O
N
N
N
N
Me
Pd
Me
Pd
Me
Pd/C
H2
H
H
O
N
N
N
H
H
Ph
Ph
Ph
Me
Me
(
Me
47
)-42
46
O
O
H
O
O
Me
N
Me
10 %
N
N
N
Me
6 % Me
H2
H
8 %
N
N
H
Ph
Ph
O
O
Me
(
Me
48
)-43
Scheme 7 Proposed mechanism for diastereoselective hydrogenation
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2263
O
O
O
O
O
O
Me
N
Me
Me
N
N
N
H-Cube, 10% Pd/C
10 bar, 40 °C
N
N
Me
Me
Me
AcOH, MeCN
N
N
N
80 °C, 2 h
90%
EtOAc, 0.5 mL/min
Ph
Ph
Ph
O
O
O
Me
Me
)-43
Me
(
)-48
(
(
)-49
Scheme 8 Reduction/isomerization of an N-acetylimidazolone
O
O
O
O
O
O
Me
Me
Me
N
N
N
N
N
N
Me
Me
Me
N
N
N
O
O
O
Me
48
Me
49
Me
50
– 1.0 kcal
(chair)
0.0 kcal
(chair)
+ 3.8 kcal
(boat)
O
O
O
HN
HN
HN
N
N
N
Me
Me
Me
N
N
N
O
O
O
Me
Me
Me
51
+ 5.6 kcal
(chair)
40
0.0 kcal
(chair)
52
+ 8.4 kcal
(boat)
Scheme 9 Ground-state energetics of imidazolone isomerizations21
of the anti-diastereomer 50. These results confirmed that chemical library is currently underway, and will be report-
the syn-diastereomer 48 is thermodynamically favored.
ed in due course.
Interestingly, similar calculations performed on imida-
zolone 40, which lacks the N-acetyl group, showed that
isomerization to either the syn- or the anti-diastereomer is
not favored, with ground-state energies of +5.6 and +8.4
kcal, respectively (Scheme 9). These findings, in part,
help to explain the results obtained for the Raney nickel
hydrogenation, in which diastereoselective reduction of
imidazolone 40 was not observed. Without isomerization
1H NMR spectra were recorded at 400 MHz at r.t. unless otherwise
stated. 13C NMR spectra were recorded at 100.0 MHz at r.t. unless
otherwise stated. Chemical shifts are reported in ppm relative to
CDCl3 (1H, d = 7.27; 13C, d = 77.0) or CD3OD (1H, d = 3.31; 13C,
d = 49.0). Data for 1H NMR are reported as follows: chemical shift,
multiplicity (ovrlp = overlapping, s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), coupling constants (reported as values
in Hz), and integration. IR spectra were recorded on a Nicolet
to afford bulky functional groups flanking the olefin, hy- Nexus 670 FT-IR spectrophotometer. High-resolution mass spectra
were recorded at the Boston University Chemical Instrumentation
Center by using a Waters Q-TOF mass spectrometer. Analytical LC
was performed on a Waters Acquity UPLC with PDA, ELS, and SQ
drogenation occurs equally from both the si- and re-faces.
To summarize, multidimensional screening of condensa-
tions reactions enabled the discovery of regioselective
Lewis acid mediated condensation reactions of a densely
functionalized 1,2-diketone scaffold. We determined that
regioselective condensations may be conducted by using
Lewis acid chelation, with the 1,2-diketone leading to a
proposed n–p* interaction with a pendant amide carbonyl.
This unique approach to achieving regioselectivity ap-
pears to rely on a presence of a proximal amide group that
detectors. An Acquity UPLC BEH 2.1 × 50 mm, 1.7 mM C18 column
was used for analytical LC. Analytical TLC was performed on 0.25
mm silica gel 60-F plates. Flash chromatography was performed us-
ing 200–400 mesh silica gel. Yields refer to chromatographically
and spectroscopically pure materials unless otherwise stated.
MeCN, THF, and CH2Cl2 were purified by passage through two
packed columns of neutral alumina. All reactions were carried out
in oven-dried glassware under an argon atmosphere unless other-
wise noted. The ArthurTM Suite Reaction Planner was used in plan-
can undergo a stabilizing n–p* interaction with the nearest ning the experimental procedures.
neighboring carbonyl group. Regioselective condensa-
(4S*,5R*,6S*)-5-Methyl-4-phenyl-6-(pyrrolidin-1-ylcarbon-
yl)cycloheptane-1,2-dione (5); Typical Procedure
tions with substituted ureas led to the discovery of a novel
diastereoselective hydrogenation reaction that proceeds
through an interesting allylpalladium hydride isomeriza-
tion. Taken together, these discoveries provide a regiose-
lective and diastereoselective route to a number of densely
functionalized cycloheptane urea scaffolds. The applica-
tion of the developed methodology to the synthesis of a
A 20 mL vial was charged with cycloheptenone 4 (170 mg, 0.52
mmol) followed by DMSO (10 mL). When cycloheptenone 4 had
fully dissolved, 1.2 M aq HCl (10 mL) was added, and the mixture
was heated to 100 °C with stirring for 4 h. The mixture was cooled,
diluted with H2O (25 mL), and extracted with CH2Cl2 (20 mL × 3).
The organic layer was washed with brine (25 mL), dried (Na2SO4),
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2264
J. R. Goodell et al.
PAPER
filtered, and concentrated in vacuo to give a crude product that was
purified by flash chromatography [SiO2, CH2Cl2–EtOAc (9:1)];
yield: 124 mg (0.40 mmol; 76%).
(dd, J = 16.0, 2.0 Hz, 1 H), 3.29 (dd, J = 13.3, 12.0 Hz, 1 H), 3.67–
3.75 (m, 1 H), 7.21–7.29 (m, 3 H), 7.32–7.38 (m, 2 H).
13C NMR (100 MHz, CD3CN): d = 19.7, 36.2, 39.4, 44.5, 45.1, 46.1,
48.2, 50.5, 128.0, 128.4, 130.1, 147.4, 174.1, 195.8, 197.0.
IR (thin film): 2973, 1710, 1701, 1653, 1635, 1616, 1559, 1465,
1457, 703 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C17H21NNaO3: 310.1419;
1H NMR (400 MHz, CD3CN): d = 0.73 (d, J = 7.0 Hz, 3 H), 1.79–
1.87 (m, 2 H), 1.88–1.94 (m, 2 H), 2.40–2.49 (m, 1 H), 2.55 (dd,
J = 13.3, 1.6 Hz, 1 H), 2.88 (dd, J = 16.0, 7.0 Hz, 1 H), 3.00–3.07
(m, 1 H), 3.11 (dd, J = 16.0, 2.0 Hz, 1 H), 3.29 (d, J = 13.3, 12.0 Hz,
1 H), 3.32–3.38 (m, 2 H), 3.43–3.51 (m, 2 H), 3.54–3.62 (m, 1 H),
7.22–7.28 (m, 3 H), 7.32–7.38 (m, 2 H).
13C NMR (100 MHz, CD3CN): d = 19.9, 25.4, 27.2, 44.4, 45.1, 47.0,
48.3, 48.9, 48.9, 50.6, 128.0, 128.4, 130.2, 147.5, 172.4, 195.6,
197.0.
found: 310.1407.
(5S*,6R*,7S*)-6-Methyl-2,5-diphenyl-7-(pyrrolidin-1-ylcarbo-
nyl)-1,4,5,6,7,8-hexahydrocyclohepta[d]imidazole (8); Typical
Procedure
An oven-dried vial was charged sequentially with diketone 5 (40
mg, 0.13 mmol), NH4OAc (40 mg, 0.52 mmol), anhyd EtOH (1
mL), and PhCHO (15 mL, 0.14 mmol). The vial was sealed with a
Teflon-lined cap and heated to 80 °C for 3 h with continuous stir-
ring. The mixture was cooled, concentrated in vacuo, and purified
by flash chromatography [SiO2, CH2Cl2–MeOH (gradient 30:1 to
10:1)]; yield: 18 mg (0.046 mmol; 36%).
HRMS (ESI): m/z [M + 1]+ calcd for C19H24NO3: 314.1756; found:
314.1751.
IR (thin film): 3057, 2971, 2877, 1635, 1493, 1437, 1380, 1265,
773, 734, 702 cm–1.
(1S*,2R*,3S*,6S*)-7-Benzyl-6-hydroxy-2-methyl-3-phenyl-7-
azabicyclo[4.2.1]nonane-5,8-dione (7a)
Yield: 38 mg (0.11 mmol; 99%).
1H NMR (400 MHz, CD3OD): d = 1.12 (d, J = 7.0 Hz, 3 H), 1.73–
1.82 (m, 4 H), 2.40 (t, J = 6.8 Hz, 1 H), 2.76 (d, J = 14.5 Hz, 1 H),
2.88–2.98 (m, 1 H), 2.98–3.07 (ovrlp m, 1 H), 3.02–3.10 (ovrlp m,
1 H), 3.05–3.12 (ovrlp m, 1 H), 3.13–3.20 (ovrlp m, 1 H), 3.13–3.23
(ovrlp m, 1 H), 3.17–3.25 (ovrlp m, 1 H), 3.25–3.32 (m, 1 H), 3.32–
3.40 (m, 1 H), 7.15–7.22 (m, 1 H), 7.22–7.31 (m, 4 H), 7.35–7.42
(m, 1 H), 7.42–7.49 (m, 2 H), 7.84 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CD3OD): d = 14.7, 24.0, 25.0, 26.9, 29.3, 41.4,
43.2, 47.1, 47.2, 126.3, 127.6, 129.2, 129.5, 129.9, 130.1, 130.2,
132.0, 133.2, 144.9, 147.0, 175.2.
IR (thin film): 3415, 2935, 1690, 1454, 1401, 1380, 1348, 1138,
1117, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (d, J = 7.0 Hz, 3 H), 2.08–
2.17 (m, 1 H), 2.20 (d, J = 13.6 Hz, 1 H), 2.33 (d, J = 18.2 Hz, 1 H),
2.39 (t, J = 11.7 Hz, 1 H), 2.51 (dd, J = 13.6, 8.7 Hz, 1 H), 2.75 (dd,
J = 18.2, 11.7 Hz, 1 H), 2.89 (d, J = 8.7 Hz, 1 H), 4.15 (d, J = 14.7
Hz, 1 H), 4.72 (d, J = 14.7 Hz, 1 H), 4.88 (s, 1 H), 6.88 (d, J = 7.8
Hz, 2 H), 7.17–7.22 (m, 1 H), 7.22–7.29 (m, 3 H), 7.32 (t, J = 7.2
Hz, 2 H), 7.36–7.40 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 19.7, 39.0, 42.0, 43.7, 44.6, 47.0,
47.6, 89.1, 126.6, 126.8, 128.0, 128.5, 128.9, 129.8, 136.4, 144.2,
173.5, 205.9.
HRMS (ESI): m/z [M + 1]+ calcd for C26H30N3O: 400.2389; found:
400.2389.
(2R*,3aS*,6S*,7R*,8S*)-4-Benzyl-7-methyl-2,8-diphenyl-
6,7,8,9-tetrahydro-2H-3a,6-methano[1,3]oxazolo[5,4-b]azocin-
5-one (9a)
HRMS (ESI): m/z [M + 1]+ calcd for C22H24NO3: 350.1756; found:
350.1764.
Purified by flash chromatography [SiO2, PE–CH2Cl2–EtOAc
(6:3:1)]; yield: 26 mg (0.058 mmol; 72%).
(1S*,2R*,3S*,6S*)-6-Hydroxy-7-(4-methoxybenzyl)-2-methyl-
3-phenyl-7-azabicyclo[4.2.1]nonane-5,8-dione (7b)
Yield: 37 mg (0.098 mmol; 97%).
IR (thin film): 3030, 2965, 2936, 1698, 1494, 1454, 1395, 1153,
1044, 1017, 736, 699, 668 cm–1.
IR (thin film): 3425, 2935, 1690, 1513, 1247, 1177, 1138, 1112,
1032, 703, 668 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (d, J = 6.6 Hz, 3 H), 2.09–
2.16 (ddq, J = 10.9, 6.6, 1.8 Hz, 1 H), 2.21 (d, J = 12.9 Hz, 1 H),
2.40 (ddd, J = 12.9, 10.9, 2.3 Hz, 1 H), 2.67 (dd, J = 19.0, 2.3 Hz, 1
H), 2.69 (dd, J = 12.9, 8.6 Hz, 1 H), 2.80 (ddd, J = 19.0, 12.9, 3.1
Hz, 1 H), 2.82 (dd, J = 8.6, 1.8 Hz, 1 H), 4.40 (d, J = 14.9 Hz, 1 H),
4.60 (d, J = 14.9 Hz, 1 H), 6.82 (d, J = 3.1 Hz, 1 H), 6.92 (d, J = 7.4
Hz, 2 H), 7.14–7.22 (m, 1 H), 7.23–7.29 (m, 3 H), 7.34–7.40 (m, 7
H), 7.49 (d, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 20.6, 37.4, 39.5, 43.2, 44.2, 44.4,
47.7, 103.1, 105.5, 126.1, 126.7, 126.8, 127.9, 128.5, 128.6, 128.8,
128.9, 129.0, 136.9, 138.4, 144.7, 170.9, 173.1.
HRMS (ESI): m/z [M + 1]+ calcd for C29H29N2O2: 437.2229; found:
437.2236.
1H NMR (400 MHz, CDCl3): d = 0.90 (d, J = 7.0 Hz, 3 H), 2.08–
2.16 (m, 1 H), 2.18 (d, J = 13.7 Hz, 1 H), 2.33 (dd, J = 18.2, 2.0 Hz,
1 H), 2.37 (td, J = 12.0, 2.0 Hz, 1 H), 2.49 (dd, J = 13.7, 8.6 Hz, 1
H), 2.74 (dd, J = 18.2, 12.0 Hz, 1 H), 2.87 (dd, J = 8.6, 2.0 Hz, 1 H),
3.77 (s, 3 H), 4.06 (d, J = 14.7 Hz, 1 H), 4.70 (d, J = 14.7 Hz, 1 H),
4.90 (s, 1 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.89 (d, J = 7.0 Hz, 2 H),
7.15–7.21 (m, 1 H), 7.22–7.28 (m, 2 H), 7.30 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 19.7, 39.0, 41.2, 43.6, 44.4, 46.9,
47.6, 55.2, 89.1, 113.6, 126.6, 126.8, 128.8, 128.5, 131.2, 144.2,
159.2, 173.4, 206.1.
HRMS (ESI): m/z [M + 1]+ calcd for C23H26NO4: 380.1862; found:
380.1867.
(2R*,3aS*,6S*,7R*,8S*)-4-(4-Methoxybenzyl)-7-methyl-2,8-
diphenyl-6,7,8,9-tetrahydro-2H-3a,6-methano[1,3]oxazolo[5,4-
b]azocin-5-one (9b)
Purified by flash chromatography [SiO2, PE–CH2Cl2–EtOAc
(6:3:1)]; yield: 22 mg (0.048 mmol; 61%).
(1S*,2R*,3S*)-N,N,2-Trimethyl-5,6-dioxo-3-phenylcyclohep-
tanecarboxamide (21)
Yield: 60 mg (0.21 mmol; 73%).
IR (thin film): 2960, 1709, 1684, 1653, 1635, 1617, 1559, 1506,
1457, 1419, 704 cm–1.
1H NMR (400 MHz, CD3CN): d = 0.71 (d, J = 6.6 Hz, 3 H), 2.41–
2.50 (m, 1 H), 2.55 (dd, J = 13.3, 1.6 Hz, 1 H), 2.83 (dd, J = 16.0,
7.4 Hz, 1 H), 2.89 (s, 3 H), 2.95–3.02 (m, 1 H), 3.09 (s, 3 H), 3.10
IR (thin film): 3029, 2936, 2836, 1696, 1513, 1395, 1278, 1248,
1178, 1036, 736, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (d, J = 6.6 Hz, 3 H), 2.06–
2.15 (ddq, J = 10.9, 6.6, 1.8 Hz, 1 H), 2.18 (d, J = 12.5 Hz, 1 H),
2.35 (ddd, J = 12.5, 10.9, 2.3 Hz, 1 H), 2.64 (dd, J = 19.0, 2.3 Hz, 1
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2265
H), 2.66 (dd, J = 12.5, 8.1 Hz, 1 H), 2.78 (ddd, J = 19.0, 12.5, 3.3
Hz, 1 H), 2.79 (dd, J = 8.1, 1.8 Hz, 1 H), 3.79 (s, 3 H), 4.27 (d, J =
14.8 Hz, 1 H), 4.61 (d, J = 14.8 Hz, 1 H), 6.82–6.93 (m, 5 H), 7.13–
7.21 (m, 1 H), 7.22–7.28 (m, 2 H), 7.34–7.44 (m, 7 H).
13C NMR (100 MHz, CDCl3): d = 20.5, 37.4, 39.5, 42.6, 44.1, 44.4,
47.7, 55.3, 103.1, 105.5, 113.8, 126.1, 126.6, 126.7, 128.6, 128.7,
128.9, 129.1, 130.5, 138.4, 144.8, 159.2, 171.1, 173.0.
(m, 2 H), 3.33–3.39 (m, 1 H), 3.39–3.43 (m, 1 H), 7.10–7.17 (m, 3
H), 7.21–7.26 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.9, 18.4, 35.7, 37.3, 37.9, 40.7,
41.3, 43.6, 45.1, 126.5, 128.7, 145.7, 156.5, 160.5, 170.7, 171.9.
HRMS (ESI): m/z [M + 1]+ calcd for C19H25N4OS: 357.1749; found:
357.1757.
HRMS (ESI): m/z [M + 1]+ calcd for C30H31N2O3: 467.2335; found:
467.2323.
(6S*,7R*,8S*)-N,N,7-Trimethyl-3-(methylsulfanyl)-6-phenyl-
6,7,8,9-tetrahydro-5H-cyclohepta[e][1,2,4]triazine-8-carbox-
amide (22b)
(6S*,7R*,8S*)-7-Methyl-3-(methylsulfanyl)-8-phenyl-6-(pyrro-
lidin-1-ylcarbonyl)-6,7,8,9-tetrahydro-5H-cyclohep-
ta[e][1,2,4]triazine (12a) and (6S*,7R*,8S*)-7-Methyl-3-
(methylsulfanyl)-6-phenyl-8-(pyrrolidin-1-ylcarbonyl)-6,7,8,9-
tetrahydro-5H-cyclohepta[e][1,2,4]triazine (12b); Typical Pro-
cedure
An oven-dried vial was charged with diketone 5 (40 mg, 0.13
mmol) followed by anhyd EtOH (1 mL). Next,
H2NC(SMe)=NNH2·HI (91 mg, 0.39 mmol) was added and the
mixture was stirred for 6 h at r.t. The mixture was then concentrated
in vacuo and the residue was purified by flash chromatography
[SiO2, CH2Cl2–EtOAc (gradient 9:1 to 3:1)] to give the regiosomers
12a and 12b.
Yield: 9 mg (0.025 mmol; 19%); Rf = 0.29 (CH2Cl2–MeOH, 20:1).
IR (thin film): 2929, 1635, 1517, 1492, 1375, 1296, 1261, 1155,
1133, 729, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.67 (d, J = 6.9 Hz, 3 H), 2.16–
2.25 (m, 1 H), 2.54 (s, 3 H), 2.77 (s, 3 H), 3.02 (dd, J = 14.2, 2.0 Hz,
1 H), 3.07 (s, 3 H), 3.22 (dd, J = 14.2, 11.0 Hz, 1 H), 3.36–3.44 (m,
3 H), 3.44–3.50 (m, 1 H), 7.09–7.18 (m, 3 H), 7.21–7.27 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.8, 19.0, 35.7, 37.9, 41.8, 44.1,
44.6, 126.6, 128.7, 145.6, 155.1, 161.6, 171.4, 172.2.
HRMS (ESI): m/z [M + 1]+ calcd for C19H25N4OS: 357.1749; found:
357.1745.
(1S*,2R*,3S*)-6-Methoxy-2-methyl-5-oxo-3-phenylcyclohept-
2-enecarboxylic Acid (19)
12a
Yield: 19 mg (0.050 mmol; 38%); Rf = 0.55 (CH2Cl2–MeOH, 20:1).
A vial was charged with bicyclo[3.2.1]octanoid 2 (40 mg, 0.16
mmol) followed by MeCN (1 mL) and H2O (100 mL). Next, DBU
(24 mL, 0.16 mmol) was added, and the mixture was stirred at r.t. for
4 h. The mixture was diluted with H2O (1 mL), acidified (pH ~3) by
addition of 1 M HCl, and extracted with CH2Cl2 (3 × 10 mL). The
organic layer was washed with brine (25 mL), dried (Na2SO4), fil-
tered, and evaporated in vacuo. The crude material was purified by
flash chromatography [SiO2, CH2Cl2–MeOH (20:1)]; yield: 43 mg
(0.16 mmol; 98%); Rf = 0.30 (CH2Cl2–MeOH, 20:1).
IR (thin film): 2953, 2927, 2873, 1628, 1445, 1376, 1343, 1265,
1165, 734, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.69 (d, J = 7.0 Hz, 3 H), 1.72–
1.83 (m, 2 H), 1.85–1.94 (m, 2 H), 2.11–2.25 (m, 1 H), 2.58 (s, 3 H),
3.08 (dd, J = 15.2, 7.8 Hz, 1 H), 3.18–3.27 (m, 3 H), 3.28–3.44 (m,
6 H), 7.10–7.18 (m, 3 H), 7.21–7.28 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.9, 18.7, 24.3, 26.3, 37.5, 41.0,
43.5, 44.1, 45.0, 45.6, 47.0, 126.4, 128.7, 145.9, 156.6, 160.6,
170.2, 170.6.
IR (thin film): 3063, 2964, 2933, 1734, 1684, 1653, 1456, 1203,
1175, 1145, 735, 703 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.87 (d, J = 6.3 Hz, 3 H), 2.53–
2.60 (m, 2 H), 2.80 (d, J = 17.4 Hz, 1 H), 3.05 (dd, J = 17.4, 11.9
Hz, 1 H), 3.71 (s, 3 H), 3.95 (t, J = 5.2 Hz, 1 H), 5.97 (d, J = 6.1 Hz,
1 H), 7.15–7.20 (m, 2 H), 7.20–7.26 (m, 1 H), 7.27–7.34 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.4, 41.4, 44.2, 45.8, 48.3, 55.5,
106.1, 127.0, 127.7, 128.8, 143.5, 153.1, 178.0, 197.0.
HRMS (ESI): m/z [M + 1]+ calcd for C16H19O4: 275.1283; found:
275.1291.
HRMS (ESI): m/z [M + 1]+ calcd for C21H27N4OS: 383.1906; found:
383.1893.
12b
Yield: 9 mg (0.025 mmol; 19%); Rf = 0.33 (CH2Cl2–MeOH, 20:1).
IR (thin film): 2972, 2873, 1630, 1443, 1376, 1295, 1262, 734, 702
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.74 (d, J = 6.6 Hz, 3 H), 1.76–
1.89 (m, 2 H), 1.91–2.02 (m, 2 H), 2.23 (m, 1 H), 2.60 (s, 3 H), 3.07
(dd, J = 14.1, 2.0 Hz, 1 H), 3.19–3.29 (m, 2 H), 3.33 (m, 2 H), 3.40
(dd, J = 14.9, 2.7 Hz, 1 H), 3.45–3.52 (m, 2 H), 3.53–3.62 (m, 2 H),
7.15–7.23 (m, 3 H), 7.27–7.33 (m, 2 H).
(1R*,6S*,7R*)-3-Methoxy-N,N,7-trimethyl-4-oxo-6-phenyl-
cyclohept-2-ene-1-carboxamide (20)
A vial was charged with cycloheptenone 19 (40 mg, 0.15 mmol) fol-
lowed by CH2Cl2 (1 mL). Next, a 2.0 M soln of Me2NH in THF
(0.38 mL, 0.75 mmol), DIPEA (31 mL, 0.18 mmol), and HATU (63
mg, 0.17 mmol) were added, and the mixture was stirred at r.t. for 6
h. The mixture was concentrated in vacuo, and resulting residue was
purified by flash chromatography [SiO2, CH2Cl2–MeOH (20:1)];
yield: 30 mg (0.10 mmol; 66%).
13C NMR (100 MHz, CDCl3): d = 13.8, 19.4, 24.3, 26.3, 35.2, 44.0,
44.2, 44.4, 44.5, 45.5, 46.9, 126.5, 128.7, 145.8, 155.2, 161.4,
170.4, 171.3.
HRMS (ESI): m/z [M + 1]+ calcd for C21H27N4OS: 383.1906; found:
383.1915.
(6S*,7R*,8S*)-N,N,7-Trimethyl-3-(methylsulfanyl)-8-phenyl-
6,7,8,9-tetrahydro-5H-cyclohepta[e][1,2,4]triazine-6-carbox-
amide (22a)
IR (thin film): 2962, 2932, 1683, 1646, 1495, 1456, 1399, 1209,
1142, 731, 703 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.76 (d, J = 6.6 Hz, 3 H), 2.21–
2.34 (m, 1 H), 2.53 (dd, J = 12.2, 9.2 Hz, 1 H), 2.59 (d, J = 17.6 Hz,
1 H), 2.98 (s, 3 H), 3.21 (s, 3 H), 3.42 (dd, J = 17.6, 12.2 Hz, 1 H),
3.66 (s, 3 H), 4.39 (t, J = 5.5 Hz, 1 H), 6.24 (d, J = 5.5 Hz, 1 H),
7.19–7.27 (m, 3 H), 7.29–7.35 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.4, 36.2, 37.4, 40.5, 40.8, 46.0,
48.0, 55.5, 109.4, 126.9, 127.6, 128.8, 144.1, 152.5, 171.4, 197.3.
Yield: 14 mg (0.039 mmol; 30%); Rf = 0.52 (CH2Cl2–MeOH, 20:1).
IR (thin film): 2928, 1634, 1493, 1376, 1341, 1261, 1132, 734, 703
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.68 (d, J = 6.9 Hz, 3 H), 2.14–
2.24 (m, 1 H), 2.57 (s, 3 H), 2.79 (s, 3 H), 3.01 (s, 3 H), 3.06 (dd,
J = 15.0, 7.6 Hz, 1 H), 3.20 (dd, J = 15.0, 2.8 Hz, 1 H), 3.26–3.33
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2266
J. R. Goodell et al.
PAPER
HRMS (ESI): m/z [M + Na]+ calcd for C18H23NNaO3: 324.1576;
found: 324.1594.
1H NMR (400 MHz, CD3OD): d = 1.17 (d, J = 7.2 Hz, 3 H), 1.20 (t,
J = 7.0 Hz, 3 H), 1.80–1.90 (m, 4 H), 2.64 (dd, J = 17.9, 3.5 Hz, 1
H), 2.99 (dd, J = 12.9, 3.5 Hz, 1 H), 3.12 (dd, J = 17.9, 12.9 Hz, 1
H), 3.18–3.25 (m, 2 H), 3.34–3.49 (m, 3 H), 3.71–3.84 (m, 2 H),
6.36 (s, 1 H), 7.26 (t, J = 7.3 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.46
(d, J = 8.0 Hz, 2 H).
(5S*,6S*)-6-Methyl-7-phenyl-5-(pyrrolidin-1-ylcarbonyl)-
3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one (16a) and
(6R*)-6-Methyl-5-phenyl-7-(pyrrolidin-1-ylcarbonyl)-3,6-dihy-
drocyclohepta[d]imidazol-2(1H)-one (16b)
A vial was charged with diketone 5 (40 mg, 0.13 mmol), urea (10
mg, 0.17 mmol), and CSA (30 mg, 0.13 mmol), followed by anhyd
EtOH (1 mL). The mixture was heated to 80 °C and stirred for 20 h.
The mixture was then concentrated in vacuo and purified by flash
chromatography [SiO2, CH2Cl2–acetone (1:1)] to afford diene 16a
and triene 16b.
NOESY (400 MHz, CD3OD): irrad. d = 6.36 (beta-phenyl, CH) 9%
enhancement at 3.77 (alpha-urea, CH2).
13C NMR (100 MHz, CD3OD): d = 12.5, 15.2, 24.6, 25.1, 26.9, 35.9,
40.5, 41.0, 47.2, 47.9, 113.3, 118.4, 121.0, 126.7, 128.4, 129.8,
144.3, 145.5, 154.5, 175.0.
HRMS (ESI): m/z [M + 1]+ calcd for C22H28N3O2: 366.2182; found:
366.2189.
16a
Yield: 21 mg (0.062 mmol; 48%); Rf = 0.1 (CH2Cl2–acetone, 1:1).
23b
Yield: 10 mg (0.027 mmol; 21%); Rf = 0.29 (CH2Cl2–MeOH, 20:1).
IR (thin film): 2971, 2874, 1700, 1684, 1653, 1635, 1437, 1373,
1040, 734, 698 cm–1.
IR (thin film): 2973, 2874, 1700, 1696, 1684, 1653, 1635, 1617,
1437, 1374, 765, 732, 698 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.16 (d, J = 7.0 Hz, 3 H), 1.78–
1.90 (m, 4 H), 2.62 (dd, J = 17.5, 2.4 Hz, 1 H), 2.97 (dd, J = 12.7,
2.4 Hz, 1 H), 3.09 (dd, J = 17.5, 12.7 Hz, 1 H), 3.15–3.25 (m, 2 H),
3.33–3.48 (m, 3 H), 6.31 (s, 1 H), 7.23 (t, J = 7.4 Hz, 1 H), 7.32 (t,
J = 7.6 Hz, 2 H), 7.43 (d, J = 7.4 Hz, 2 H).
13C NMR (100 MHz, CD3OD): d = 12.8, 24.4, 25.2, 26.9, 40.3, 41.3,
47.2, 47.9, 115.0, 118.5, 121.1, 126.5, 128.3, 129.7, 143.8, 145.0,
155.8, 175.2.
1H NMR [400 MHz, CD2Cl2–CD3OD (1:5.2)]: d = 1.17 (d, J = 7.0
Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.80–1.92 (m, 4 H), 2.69 (dd, J
= 17.5, 3.2 Hz, 1 H), 2.97 (dd, J = 12.7, 3.2 Hz, 1 H), 3.12 (dd, J =
17.5, 12.7 Hz, 1 H), 3.17–3.26 (m, 2 H), 3.36–3.51 (m, 3 H), 3.61–
3.83 (m, 2 H), 6.31 (s, 1 H), 7.24 (t, J = 7.43 Hz, 1 H), 7.33 (t, J =
7.24 Hz, 2 H), 7.43 (d, J = 8.02 Hz, 2 H).
NOESY (400 MHz, CD3OD): irrad. d = 2.69 (beta-amide, CH2) 6%
enhancement at 3.72 (alpha-urea, CH2).
HRMS (ESI): m/z [M + 1]+ calcd for C20H24N3O2: 338.1869; found:
13C NMR [100 MHz, CD2Cl2–CD3OD (1:5.2)]: d = 12.7, 15.1, 23.7,
24.9, 26.7, 36.5, 39.8, 41.2, 46.9, 47.7, 114.7, 117.2, 121.1, 126.2,
128.0, 129.4, 143.3, 144.6, 154.0, 174.7.
HRMS (ESI): m/z [M + 1]+ calcd for C22H28N3O2: 366.2182; found:
366.2189.
338.1870.
16b
Yield: 14 mg (0.042 mmol; 32%); Rf = 0.15 (CH2Cl2–acetone, 1:1).
IR (thin film): 2970, 1699, 1684, 1653, 1576, 1559, 1436, 1419,
723, 697 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.06 (d, J = 7.4 Hz, 3 H), 1.65–
1.95 (m, 4 H), 3.17–3.26 (m, 1 H), 3.37–3.48 (m, 3 H), 4.02 (q, J =
7.4 Hz, 1 H), 6.61 (s, 1 H), 6.65 (s, 1 H), 7.25–7.32 (m, 1 H), 7.32–
7.39 (m, 2 H), 7.54 (d, J = 7.8 Hz, 2 H).
(5S*,6S*)-3-tert-Butyl-6-methyl-7-phenyl-5-(pyrrolidin-1-yl-
carbonyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one
(26a)
Yield: 29 mg (0.074 mmol; 57%); Rf = 0.15 (CH2Cl2–MeOH, 20:1).
13C NMR (100 MHz, CD3OD): d = 14.2, 24.7, 27.1, 39.4, 47.2, 51.3,
114.3, 118.0, 122.1, 126.3, 126.9, 128.3, 128.9, 129.7, 136.6, 143.5,
155.9, 172.7.
HRMS (ESI): m/z [M + 1]+ calcd for C20H22N3O2: 336.1712; found:
366.1706.
IR (thin film): 2970, 1675, 1635, 1591, 1430, 1128, 1032, 766, 698
cm–1.
1H NMR (400 MHz, CD2Cl2–CD3OD, 1:9.4): d = 1.20 (d, J = 7.0
Hz, 3 H), 1.67 (s, 9 H), 1.76–1.89 (m, 4 H), 2.59 (dd, J = 18.1, 4.0
Hz, 1 H), 2.92 (dd, J = 13.1, 4.0 Hz, 1 H), 3.10 (dd, J = 18.1, 13.1
Hz, 1 H), 3.13–3.20 (m, 2 H), 3.33–3.48 (m, 3 H), 6.70 (s, 1 H),
7.21–7.30 (m, 1 H), 7.32–7.42 (m, 4 H).
13C NMR [100 MHz, CD2Cl2–CD3OD (1:9.4)]: d = 11.9, 24.6, 25.0,
26.7, 31.4, 40.0, 40.6, 47.0, 47.7, 58.1, 117.3, 119.3, 122.0, 126.5,
128.0, 129.6, 142.5, 144.9, 154.8, 174.5.
(5S*,6S*)-3-Ethyl-6-methyl-7-phenyl-5-(pyrrolidin-1-ylcarbo-
nyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one (23a)
and (5S*,6S*)-1-Ethyl-6-methyl-7-phenyl-5-(pyrrolidin-1-yl-
carbonyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one
(23b); Typical Procedure
An oven-dried vial was charged with activated 4 Å MS (approx. 25
mg), diketone 5 (40 mg, 0.13 mmol), EtNHCONH2 (12 mg, 0.14
mmol), and Zn(OTf)2 (10 mg, 0.026 mmol), followed by anhyd
MeCN (1 mL). The mixture was then degassed by bubbling argon
through the soln for 15 min. Finally, the vial was sealed with a
Teflon-lined cap, heated to 100 °C, and stirred for 5 h. The mixture
was then cooled and filtered through Celite to remove the MS. The
resulting filtrate was concentrated in vacuo and purified by flash
chromatography [SiO2, CH2Cl2–MeOH (gradient 50:1 to 20:1)] to
afford imidazolinones 23a and 23b.
HRMS (ESI): m/z [M + 1]+ calcd for C24H32N3O2: 394.2495; found:
394.2505.
(5S*,6S*)-1-tert-Butyl-6-methyl-7-phenyl-5-(pyrrolidin-1-yl-
carbonyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one
(26b)
Yield: 16 mg (0.040 mmol; 31%); Rf = 0.26 (CH2Cl2–MeOH, 20:1).
(5S*,6S*)-6-Methyl-7-phenyl-3-prop-2-yn-1-yl-5-(pyrrolidin-1-
ylcarbonyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-
one (28a)
Yield: 36 mg (0.096 mmol; 74%); Rf = 0.17 (CH2Cl2–MeOH, 20:1).
23a
IR (thin film): 2971, 2874, 1685, 1635, 1593, 1431, 1387, 734, 700,
633 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.17 (d, J = 7.0 Hz, 3 H), 1.78–
1.96 (m, 4 H), 2.63 (dd, J = 18.1, 3.0 Hz, 1 H), 2.70 (t, J = 2.5 Hz,
Yield: 33 mg (0.090 mmol; 71%); Rf = 0.20 (CH2Cl2–MeOH, 20:1).
IR (thin film): 3164, 2973, 2873, 1700, 1697, 1684, 1653, 1635,
1617, 1437, 759, 733, 699 cm–1.
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2267
1 H), 2.98 (dd, J = 12.9, 3.0 Hz, 1 H), 3.12 (dd, J = 18.1, 12.9 Hz, 1
H), 3.18–3.28 (m, 2 H), 3.38–3.50 (m, 3 H), 4.45 (dd, J = 18.4, 2.5
Hz, 1 H), 4.61 (dd, J = 18.4, 2.5 Hz, 1 H), 6.53 (s, 1 H), 7.27 (t, J =
7.3 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.47 (d, J = 7.4 Hz, 2 H).
(5S*,6S*)-3-Ethyl-6-methyl-7-phenyl-5-(pyrrolidin-1-ylcarbo-
nyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazole-2(1H)-thione
(36a)
Yield: 39 mg (0.10 mmol; 79%), Rf = 0.31 (CH2Cl2–MeOH, 20:1).
13C NMR (100 MHz, CD3OD): d = 12.6, 24.4, 25.0, 26.8, 30.4, 40.2,
40.8, 47.1, 47.8, 73.5, 79.2, 113.4, 118.4, 121.1, 126.6, 128.3,
129.6, 143.9, 145.2, 154.0, 174.8.
HRMS (ESI): m/z [M + 1]+ calcd for C23H26N3O2: 376.2025; found:
376.2018.
IR (thin film): 3174, 3055, 2971, 2933, 2873, 1636, 1608, 1476,
1448, 1414, 1378, 1276, 1210, 1137, 758, 733, 698 cm–1.
1H NMR (400 MHz, CD2Cl2–CD3OD, 1:4.1): d = 1.16 (d, J = 7.0
Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.86 (m, 4 H), 2.74 (dd, J = 17.9,
3.4 Hz, 1 H), 2.97 (dd, J = 13.1, 3.4 Hz, 1 H), 3.19 (ovrlp dd, J =
17.9, 13.1 Hz, 1 H), 3.19–3.27 (m, 2 H), 3.34–3.49 (m, 3 H), 4.08–
4.29 (m, 2 H), 6.40 (s, 1 H), 7.27–7.33 (m, 1 H), 7.38 (t, J = 7.6 Hz,
2 H), 7.46 (d, J = 7.4 Hz, 2 H).
13C NMR (100 MHz, CD2Cl2–CD3OD, 1:4.1): d = 11.9, 13.4, 22.9,
23.9, 25.7, 38.7, 39.3, 45.9, 46.7, 111.9, 123.4, 125.5, 125.6, 127.5,
128.5, 142.7, 146.0, 158.7, 173.2.
(5S*,6S*)-6-Methyl-7-phenyl-1-prop-2-yn-1-yl-5-(pyrrolidin-1-
ylcarbonyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-
one (28b)
Yield: 8 mg (0.022 mmol; 17%); Rf = 0.22 (CH2Cl2–MeOH, 20:1).
(5S*,6S*)-6-Methyl-3,7-diphenyl-5-(pyrrolidin-1-ylcarbonyl)-
3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one (30a)
Yield: 41 mg (0.099 mmol; 76%), Rf = 0.17 (CH2Cl2–MeOH, 20:1).
HRMS (ESI): m/z [M + 1]+ calcd for C22H28N3OS: 382.1953; found:
382.1947.
IR (thin film): 2972, 2875, 1700, 1696, 1684, 1635, 1595, 1499,
1437, 1379, 757, 732, 700, 668 cm–1.
(5S*,6S*)-1-Ethyl-6-methyl-7-phenyl-5-(pyrrolidin-1-ylcarbo-
nyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazole-2(1H)-thione
(36b)
1H NMR (400 MHz, CD2Cl2–CD3OD, 1:6.8): d = 1.23 (d, J = 7.03
Hz, 3 H), 1.75–1.94 (m, 4 H), 2.71 (dd, J = 18.4, 3.1 Hz, 1 H), 3.00
(dd, J = 12.9, 3.1 Hz, 1 H), 3.19–3.24 (m, 2 H), 3.21 (ovrlp dd, J =
18.4, 12.9 Hz, 1 H), 3.36–3.50 (m, 3 H), 5.98 (s, 1 H), 7.14–7.22 (m,
1 H), 7.23–7.27 (m, 4 H), 7.31 (d, J = 7.42 Hz, 2 H), 7.38–7.43 (m,
1 H), 7.47–7.52 (m, 2 H).
13C NMR (100 MHz, CD2Cl2–CD3OD, 1:6.8): d = 12.7, 24.4, 25.0,
26.8, 40.1, 40.8, 47.0, 47.8, 113.9, 119.4, 121.2, 126.3, 128.1,
129.2, 129.3, 129.4, 130.3, 135.3, 143.7, 144.7, 154.2, 174.7.
Yield: 10 mg (0.026 mmol; 20%), Rf = 0.40 (CH2Cl2–MeOH, 20:1).
6R*)-1-Ethyl-6-methyl-7-phenyl-5-(pyrrolidin-1-ylcarbonyl)-
3,6-dihydrocyclohepta[d]imidazol-2(1H)-one (37) and 1-Ethyl-
6-methyl-7-phenyl-5-(pyrrolidin-1-ylcarbonyl)cyclohep-
ta[d]imidazol-2(1H)-one (38); Typical Procedure
An oven-dried vial was charged with the ethylimidazolone 20a (40
mg, 0.13 mmol), followed by anhyd CH2Cl2 (1 mL). DDQ (36 mg,
0.16 mmol) was added, and the mixture was stirred at r.t. for 2 h.
The mixture was diluted with CH2Cl2 (10 mL) then washed with sat.
aq NaHCO3 (2 × 10 mL) and brine (10 mL). The organic portion
was dried (Na2SO4), filtered, and concentrated in vacuo. The result-
ing residue was purified by flash chromatography [SiO2, CH2Cl2–
MeOH (gradient 50:1 to 20:1)] to give 37 and 38.
HRMS (ESI): m/z [M + 1]+ calcd for C26H28N3O2: 414.2182; found:
414.2183.
(5S*,6S*)-6-Methyl-1,7-diphenyl-5-(pyrrolidin-1-ylcarbonyl)-
3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one (30b)
Yield: 12 mg (0.030 mmol; 23%), Rf = 0.24 (CH2Cl2–MeOH, 20:1).
37
(5S*,6S*)-1-Ethyl-6-methyl-3,7-diphenyl-5-(pyrrolidin-1-yl-
carbonyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one
(35a)
Yield: 33 mg (0.090 mmol; 71%).
IR (thin film): 3172, 2974, 2874, 1700, 1596, 1443, 1405, 1378,
750, 732, 698 cm–1.
Yield: 44 mg (0.10 mmol; 77%), Rf = 0.36 (CH2Cl2–MeOH, 20:1).
1H NMR [400 MHz, CD2Cl2–CD3OD (1:6)]: d = 1.04 (d, J = 7.2 Hz,
3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.61–1.94 (m, 4 H), 3.15–3.24 (m, 1
H), 3.33–3.47 (m, 3 H), 3.73–3.95 (m, 2 H), 3.99–4.09 (m, 1 H),
6.64 (s, 1 H), 6.65 (s, 1 H), 7.26–7.33 (m, 1 H), 7.34–7.40 (m, 2 H),
7.56 (d, J = 7.8 Hz, 2 H).
13C NMR [100 MHz, CD2Cl2–CD3OD (1:6)]: d = 12.7, 13.7, 24.0,
25.8, 35.4, 38.0, 45.9, 49.5, 111.7, 116.5, 120.1, 125.0, 127.1,
127.3, 127.6, 128.3, 135.2, 142.2, 153.0, 171.1.
IR (thin film): 2972, 2873, 1695, 1636, 1419, 1387, 764, 721, 696
cm–1.
1H NMR (400 MHz, CD3OD): d = 1.22 (d, J = 7.0 Hz, 3 H), 1.27 (t,
J = 7.2 Hz, 3 H), 1.75–1.90 (m, 4 H), 2.36 (d, J = 15.2 Hz, 1 H),
2.91–3.07 (m, 2 H), 3.16–3.28 (m, 2 H), 3.32–3.44 (m, 3 H), 3.83–
3.95 (m, 2 H), 6.48 (s, 1 H), 7.23–7.32 (m, 1 H), 7.34–7.41 (m, 4 H),
7.47 (d, J = 7.4 Hz, 1 H), 7.49–7.58 (m, 4 H).
NOESY (400 MHz, CD3OD): irrad. d = 6.48 (beta-phenyl, CH) 9%
enhancement at 3.90 (alpha-urea, CH2).
13C NMR (100 MHz, CD3OD): d = 12.6, 15.2, 25.1, 26.9, 36.6, 40.4,
41.1, 47.1, 47.8, 112.8, 118.4, 122.0, 126.8, 128.6, 129.2, 129.8,
129.8, 130.6, 135.7, 144.1, 146.7, 153.4, 174.9.
HRMS (ESI): m/z [M + 1]+ calcd for C28H32N3O2: 442.2495; found:
442.2494.
HRMS (ESI): m/z [M + 1]+ calcd for C22H26N3O: 364.2025; found:
364.2024.
38
Yield: 10 mg (0.027 mmol; 21%).
IR (thin film): 2958, 2924, 2852, 1701, 1635, 1616, 1653, 1447,
1418, 1078, 731, 703 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.28 (t, J = 7.2 Hz, 3 H), 1.96–
2.08 (m, 4 H), 2.24 (s, 3 H), 3.15–3.24 (m, 1 H), 3.32–3.41 (m, 1 H),
3.56–3.66 (m, 1 H), 3.66–3.74 (m, 1 H), 4.10 (q, J = 7.2 Hz, 2 H),
7.40 (d, J = 7.4 Hz, 2 H), 7.47–7.52 (m, 1 H), 7.52–7.59 (m, 2 H),
7.64 (s, 1 H), 7.86 (s, 1 H).
(5S*,6S*)-3-Ethyl-6-methyl-1,7-diphenyl-5-(pyrrolidin-1-yl-
carbonyl)-3,4,5,6-tetrahydrocyclohepta[d]imidazol-2(1H)-one
(35b)
Yield: 13 mg (0.029 mmol; 22%), Rf = 0.29 (CH2Cl2–MeOH, 20:1).
13C NMR (100 MHz, CD3OD): d = 13.8, 23.8, 25.3, 26.9, 37.1, 47.0,
49.7, 120.5, 125.8, 129.1, 129.6, 130.1, 139.1, 145.2, 146.5, 151.4,
155.0, 163.7, 167.2, 170.4.
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2268
J. R. Goodell et al.
PAPER
HRMS (ESI): m/z [M + 1]+ calcd for C22H24N3O2: 362.1869; found:
362.1873.
6.5 Hz, 2 H), 1.95–2.05 (m, 3 H), 2.07–2.17 (m, 2 H), 2.38 (ddd,
J = 15.8, 11.3, 1.8 Hz, 1 H), 2.76 (dq, J = 14.0, 7.0 Hz, 1 H), 3.06
(dd, J = 11.1, 3.3 Hz, 1 H), 3.12 (dd, J = 10.2, 2.7 Hz, 1 H), 3.25–
3.35 (m, 1 H), 3.35–3.46 (m, 2 H), 3.55 (dt, J = 10.2, 6.8 Hz, 1 H),
3.68 (dt, J = 10.2, 6.6 Hz, 1 H), 4.12 (ddd, J = 10.9, 3.9, 2.3 Hz, 1
H), 4.20 (ddd, J = 10.9, 4.7, 1.6 Hz, 1 H), 7.16–7.22 (m, 3 H), 7.26–
7.32 (m, 2 H).
13C NMR (100 MHz, CD3OD): d = 7.6, 12.6, 25.2, 27.2, 27.2, 28.3,
36.5, 39.8, 43.6, 45.0, 47.2, 48.0, 53.0, 58.1, 127.3, 129.1, 129.3,
147.2, 163.9, 176.1.
(6R*)-1-Acetyl-3-ethyl-6-methyl-5-phenyl-7-(pyrrolidin-1-yl-
carbonyl)-3,6-dihydrocyclohepta[d]imidazol-2(1H)-one (39)
Yield: 22 mg (0.055 mmol; 50%).
IR (thin film): 2973, 2875, 1724, 1621, 1603, 1409, 1372, 1358,
1317, 1276, 749, 731, 700 cm–1.
1H NMR (400 MHz, CD3OD): d = 1.00 (d, J = 7.0 Hz, 3 H), 1.27 (t,
J = 7.2 Hz, 3 H), 1.80–1.98 (m, 4 H), 2.68 (s, 3 H), 3.37–3.57 (m, 3
H), 3.57–3.67 (m, 1 H), 3.77–3.98 (m, 2 H), 4.03–4.10 (m, 1 H),
6.65 (s, 1 H), 7.30–7.36 (m, 1 H), 7.36–7.41 (m, 3 H), 7.68 (d, J =
7.0 Hz, 2 H).
HRMS (ESI): m/z [M + 1]+ calcd for C22H32N3O2: 370.2495; found:
370.2500.
41b
13C NMR (100 MHz, CD3OD): d = 13.1, 14.2, 25.3, 26.0, 27.2, 37.1,
39.4, 47.3, 51.3, 111.6, 120.0, 120.5, 127.4, 128.2, 128.7, 129.2,
129.6, 143.2, 152.4, 172.1, 173.8.
Yield: 20 mg (0.054 mmol; 49%).
IR (thin film): 2971, 2873, 1689, 1631, 1436, 1375, 1272, 732, 702
cm–1.
HRMS (ESI): m/z [M + 1]+ calcd for C24H28N3O3: 406.2131; found:
406.2128.
1H NMR (400 MHz, CD3OD): d = 0.73 (d, J = 7.0 Hz, 3 H), 1.06 (t,
J = 7.2 Hz, 3 H), 1.81 (dd, J = 14.8, 3.9 Hz, 1 H), 1.84–1.90 (m, 2
H), 1.94–2.08 (m, 4 H), 2.11–2.26 (m, 2 H), 2.95 (dd, J = 10.2, 3.1
Hz, 1 H), 2.99–3.09 (m, 2 H), 3.26–3.34 (m, 1 H), 3.37–3.46 (m, 2
H), 3.53 (dt, J = 10.2, 7.0 Hz, 1 H), 3.72 (dt, J = 10.5, 6.6 Hz, 1 H),
3.95 (ddd, J = 11.3, 9.8, 3.91 Hz, 1 H), 4.02 (ddd, J = 11.3, 9.8, 4.3
Hz, 1 H), 7.15–7.25 (m, 3 H), 7.27–7.35 (m, 2 H).
(5S*,6R*,7R*)-1-Ethyl-6-methyl-7-phenyl-5-(pyrrolidin-1-yl-
carbonyl)-3,4,5,6,7,8-hexahydrocyclohepta[d]imidazol-2(1H)-
one (40)
A soln of imidazolone 23a (40 mg, 0.11 mmol) in MeOH (10 mL)
was passed at 0.5 mL/min through a 10% Pd/C cartridge at 50 bar
and 50 °C in an H-Cube hydrogenator. The collected mixture was
concentrated in vacuo and the resulting residue was purified by
flash chromatography [SiO2, CH2Cl2–MeOH (gradient 50:1 to
20:1)]; yield: 40 mg (0.11 mmol; 99%).
NOESY (400 MHz, CD3OD): irrad. d =3.95 (a-NH, CH) 4% en-
hancement at 2.95 (a-amide, CH), and 1% at 1.81 (b-amide, CH2);
irrad. d = 4.02 (a-NEt, CH) 6% enhancement at 3.01 (a-phenyl,
CH), 2% at 1.06 (CH3).
IR (thin film): 3049, 2973, 1699, 1684, 1653, 1635, 1457, 1437,
1419, 736, 701 cm–1.
13C NMR (100 MHz, CD3OD): d = 8.0, 13.2, 25.1, 27.2, 28.2, 28.8,
36.2, 40.1, 47.2, 47.6, 47.9, 48.0, 55.2, 59.9, 127.2, 128.9, 129.3,
147.6, 162.9, 175.6.
HRMS (ESI): m/z [M + 1]+ calcd for C22H32N3O2: 370.2495; found:
370.2494.
1H NMR (400 MHz, CD3OD): d = 0.93 (d, J = 7.0 Hz, 3 H), 1.15 (t,
J = 7.2 Hz, 3 H), 1.81–1.93 (m, 2 H), 1.96–2.07 (m, 2 H), 2.11–2.21
(m, 1 H), 2.40 (dd, J = 16.4, 3.5 Hz, 1 H), 2.62 (dd, J = 15.0, 2.1 Hz,
1 H), 2.93–3.05 (m, 1 H), 3.06–3.25 (m, 3 H), 3.32–3.37 (m, 1 H),
3.45 (dt, J = 11.8, 7.2 Hz, 1 H), 3.55 (dt, J = 10.2, 7.0 Hz, 1 H), 3.62–
3.70 (m, 2 H), 3.76 (dt, J = 10.4, 6.5 Hz, 1 H), 7.18–7.28 (m, 1 H),
7.32–7.36 (m, 4 H).
(3aS*,5R*,6R*,7S*,8aR*)-1-Acetyl-3-ethyl-6-methyl-5-phenyl-
7-(pyrrolidin-1-ylcarbonyl)octahydrocyclohepta[d]imidazol-
2(1H)-one (43)
NOESY (400 MHz, CD3OD): irrad. d = 0.93 (CH3) 3% enhance-
ment at 3.00 (b-NH, CH), 4% at 3.14 (b-NEt, CH).
13C NMR (100 MHz, CD3OD): d = 6.6, 15.4, 23.7, 25.1, 25.2, 27.1,
36.2, 42.2, 47.2, 48.0, 48.7, 50.0, 117.3, 118.9, 127.7, 128.4, 129.6,
147.0, 154.4, 175.0.
HRMS (ESI): m/z [M + 1]+ calcd for C22H30N3O2: 368.2338; found:
368.2346.
A soln of imidazolone 42 (40 mg, 0.098 mmol) in EtOAc (10 mL)
was passed at 0.5 mL/min through a 10% Pd/C cartridge at 30 bar
and 90 °C in an H-Cube hydrogenator. The collected mixture was
concentrated in vacuo and the resulting residue was purified by
flash chromatography [SiO2, CH2Cl2–MeOH (gradient 50:1 to
20:1)]; yield: 40 mg (0.098 mmol; 99%); Rf = 0.39 (CH2Cl2–MeOH,
20:1).
IR (thin film): 2972, 2875, 1726, 1679, 1634, 1426, 1377, 1351,
1270, 726, 703, 617 cm–1.
(3aS*,5S*,6R*,7R*,8aR*)-1-Ethyl-6-methyl-7-phenyl-5-(pyrro-
lidin-1-ylcarbonyl)octahydrocyclohepta[d]imidazol-2(1H)-one
(41a) and (3aR*,5S*,6R*,7R*,8aS*)-1-Ethyl-6-methyl-7-phe-
nyl-5-(pyrrolidin-1-ylcarbonyl)octahydrocyclohepta[d]imida-
zol-2(1H)-one (41b)
A soln of imidazolone 23a (40 mg, 0.11 mmol) in MeOH (10 mL)
was passed at 0.5 mL/min through a Raney Ni cartridge at 90 bar
and 80 °C in an H-Cube hydrogenator. The collected mixture was
concentrated in vacuo and the resulting residue was purified by pre-
parative HPLC to give 41a and 41b.
1H NMR (400 MHz, CD3OD): d = 0.74 (d, J = 6.8 Hz, 3 H), 1.10 (t,
J = 7.2 Hz, 3 H), 1.79–1.92 (m, 2 H), 1.93–2.06 (m, 4 H), 2.12–2.25
(m, 3 H), 2.45 (s, 3 H), 3.00–3.12 (m, 2 H), 3.22 (dq, J = 14.5, 7.5
Hz, 1 H), 3.28–3.35 (m, 1 H), 3.40–3.57 (m, 3 H), 3.78 (dt, J = 10.2,
6.4 Hz, 1 H), 4.03 (td, J = 9.9, 6.3 Hz, 1 H), 4.42–4.54 (m, 1 H),
7.13–7.26 (m, 3 H), 7.27–7.35 (m, 2 H).
NOESY (400 MHz, CD3OD): irrad. d = 4.03 (a-NEt, CH) 3% en-
hancement at 3.01 (a-phenyl/a-amide, CH), 5% at 4.48 (a-NAc,
CH); irrad. d = 4.48 (a-NAc, CH) 6% enhancement at 3.01 (a-
amide/a-phenyl, CH), 5% at 4.03 (a-NEt, CH).
13C NMR (100 MHz, CD3OD): d = 8.0, 12.6, 24.2, 25.1, 25.4, 27.2,
28.3, 36.8, 39.7, 46.0, 47.2, 47.9, 56.0, 57.4, 127.3, 128.9, 129.3,
147.6, 155.8, 172.2, 175.2.
41a
Yield: 20 mg (0.054 mmol; 50%).
IR (thin film): 2971, 2928, 2874, 1700, 1684, 1676, 1653, 1635,
1617, 1457, 1437, 1379, 1276, 731, 703 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.76 (d, J = 6.6 Hz, 3 H), 0.96 (t,
J = 7.2 Hz, 3 H), 1.78 (dd, J = 16.0, 4.3 Hz, 1 H), 1.86 (dq, J = 7.0,
HRMS (ESI): m/z [M + 1]+ calcd for C24H34N3O3: 412.2600; found:
412.2582.
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

PAPER
Multidimensional Reaction Screening for 1,2-Diketones
2269
(3aR*,5S*,6R*,7R*,8aS*)-1-Acetyl-3-ethyl-6-methyl-7-phenyl-
5-(pyrrolidin-1-ylcarbonyl)octahydrocyclohepta[d]imidazol-
2(1H)-one (45)
A soln of imidazolone 44 (40 mg, 0.098 mmol) in EtOAc (10 mL)
was passed at 0.5 mL/min through a 10% Pd/C cartridge at 50 bar
and 50 °C in an H-Cube hydrogenator. The collected mixture was
concentrated in vacuo and the resulting residue was purified by
flash chromatography [SiO2, CH2Cl2–MeOH (gradient 50:1 to
20:1)]; yield: 40 mg (0.098 mmol; 99%); Rf = 0.41 (CH2Cl2–MeOH,
20:1).
Acknowledgment
This work was generously supported by the NIGMS CMLD Initia-
tive (P50 GM067041) and Merck Research Laboratories (Boston).
We thank Dr Emil Lobkovsky (Cornell University) for X-ray crys-
tal structure analysis and Dr Paul Ralifo (Boston University) and
James Loo (UCSC) for assistance with NMR. We also thank Pro-
fessors John Snyder and Scott Schaus (Boston University) and Dr
Scott Berk (Merck Boston) for helpful discussions. NMR (CHE-
0619339) and MS (CHE0443618) facilities at Boston University
are supported by the NSF. Computational analysis was supported
by the Boston University Scientific Computing Facility. We also
thank Waters Corporation and Thales (H-Cube) Corporation for as-
sistance with instrumentation.
IR (thin film): 2971, 2874, 1727, 1678, 1634, 1426, 1377, 1352,
1323, 1270, 733, 715, 701, 615 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.66 (d, J = 6.8 Hz, 3 H), 1.14 (t,
J = 7.1 Hz, 3 H), 1.79–1.92 (m, 3 H), 1.95–2.09 (m, 3 H), 2.16–2.31
(m, 3 H), 2.43 (s, 3 H), 2.94 (dd, J = 9.3, 2.0 Hz, 1 H), 3.15 (dd, J =
11.1, 3.7 Hz, 1 H), 3.21 (dq, J = 14.5, 7.0 Hz, 1 H), 3.34 (s, 1 H),
3.41–3.62 (m, 3 H), 3.73 (dt, J = 10.2, 6.5 Hz, 1 H), 4.01 (ddd, J =
11.6, 8.80, 6.0 Hz, 1 H), 4.45–4.56 (m, 1 H), 7.13–7.20 (m, 3 H),
7.23–7.31 (m, 2 H).
References
(1) For discussions of reaction screening approaches, see:
(a) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366.
(b) Kana, W. M.; Rosenman, M. M.; Sakurai, K.; Snyder, T.
M.; Liu, D. R. Nature (London, U.K.) 2004, 431, 545.
(c) Miller, S. J. Nat. Biotechnol. 2004, 22, 1378.
(2) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A. Jr. J. Am.
Chem. Soc. 2007, 129, 1413.
NOESY (400 MHz, CD3OD): irrad. d = 4.01 (a-NEt, CH) 2% en-
hancement at 1.14 (NEt, CH3), 3% at 2.22 (CH), 3% at 2.94 (a-
amide, CH), 5% at 4.51 (a-NAc, CH); irrad. d = 4.51 (a-NAc, CH)
7% enhancement at 3.15 (a-phenyl, CH), 5% at 4.01 (a-NEt, CH).
(3) For recent examples of reaction screening/discovery, see:
(a) Han, C.; Rangarajan, S.; Voukides, A. C.; Beeler, A. B.;
Johnson, R.; Porco, J. A. Jr. Org. Lett. 2009, 11, 413.
(b) Liang, B.; Kalidindi, S.; Porco, J. A. Jr.; Stephenson, C.
R. J. Org. Lett. 2010, 12, 572. (c) Treece, J. L.; Goodell, J.
R.; Velde, D. V.; Porco, J. A. Jr.; Aubé, J. J. Org. Chem.
2010, 75, 2028. (d) Kinoshita, H.; Ong, W. W.; Ingham, O.
J.; Beeler, A. B.; Porco, J. A. Jr. J. Am. Chem. Soc. 2010, in
press.
(4) Goodell, J. R.; McMullen, J. P.; Zaborenko, N.; Maloney, J.
R.; Ho, C.-H.; Jensen, K. F.; Porco, J. A. Jr.; Beeler, A. B.
J. Org. Chem. 2009, 74, 6169.
(5) Nicolaou, K. C.; Montagnon, T.; Ulven, T.; Baran, P. S.;
Zhong, Y.-L.; Sarabia, F. J. Am. Chem. Soc. 2002, 124,
5718.
(6) For examples of condensations with 1,2-diamines, see:
(a) Zhao, Z.; Robinson, R. G.; Barnett, S. F.; Defeo-Jones,
D.; Jones, R. E.; Hartman, G. D.; Huber, H. E.; Duggan, M.
E.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2008, 18, 49.
(b) Rong, F.; Chow, S.; Yan, S.; Larson, G.; Hong, Z.; Wu,
J. Bioorg. Med. Chem. Lett. 2007, 17, 1663.
13C NMR (100 MHz, CD3OD): d = 8.3, 12.6, 24.2, 25.2, 25.4, 27.2,
27.7, 36.8, 39.9, 45.2, 47.3, 48.0, 49.9, 55.6, 58.2, 127.2, 128.7,
129.2, 146.5, 155.9, 172.0, 175.5.
HRMS (ESI): m/z [M + 1]+ calcd for C24H34N3O3: 412.2600; found:
412.2582.
(3aR*,5S*,6R*,7S*)-3-Acetyl-1-ethyl-6-methyl-7-phenyl-5-
(pyrrolidin-1-ylcarbonyl)-3,3a,4,5,6,7-hexahydrocyclohep-
ta[d]imidazol-2(1H)-one (48)
A soln of imidazolone 42 (30 mg, 0.074 mmol) in EtOAc (7.5 mL)
was passed at 0.5 mL/min through a 10% Pd/C cartridge at 10 bar
and 40 °C in an H-Cube hydrogenator. The collected mixture was
concentrated in vacuo, and the resulting residue was purified by
flash chromatograph [SiO2, CH2Cl2–MeOH (gradient 50:1 to
20:1)]; yield: 24 mg (0.058 mmol; 79%).
IR (thin film): 2971, 2932, 2875, 1740, 1734, 1695, 1684, 1635,
1419, 1374, 1232, 703, 626, 603 cm–1.
1H NMR (500 MHz, CD3OD, 45 °C): d = 0.86 (d, J = 6.8 Hz, 3 H),
1.20 (t, J = 7.2 Hz, 3 H), 1.72–1.80 (m, 1 H), 1.81–1.93 (m, 2 H),
1.95–2.04 (m, 2 H), 2.06–2.11 (m, 1 H), 2.14 (d, J = 13.4 Hz, 1 H),
2.49 (s, 3 H), 3.27–3.31 (m, 1 H), 3.33–3.37 (m, 1 H), 3.41–3.47 (m,
1 H), 3.47–3.54 (m, 1 H), 3.54–3.61 (m, 1 H), 3.61–3.69 (m, 1 H),
3.75–3.84 (m, 1 H), 3.95 (d, J = 5.1 Hz, 1 H), 4.97 (d, J = 11.2 Hz,
1 H), 5.10 (d, J = 5.6 Hz, 1 H), 7.21–7.25 (m, 1 H), 7.32–7.41 (m, 4
H).
(7) For an example of a condensation with 2-
aminobenzenethiol, see: Santes, V.; Rojas-Lima, S.;
Santillan, R. L.; Farfán, N. Monatsh. Chem. 1999, 130, 1481.
(8) For an example of a condensation with 2-aminophenol, see:
Mackenzie, N. E.; Surendrakumar, S.; Thomson, R. H.
J. Chem. Soc., Perkin Trans. 1 1986, 2233.
NOESY (400 MHz, CD3OD): irrad. d = 3.95 (a-phenyl, CH) 8% en-
hancement at 3.35 (a-amide, CH), 6% at 4.97 (a-NAc, CH); irrad.
d = 4.97 (a-NAc, CH) 7% enhancement at 3.35 (a-amide, CH), 7%
at 3.95 (a-phenyl).
13C NMR (125 MHz, CD3OD, 45 °C): d = 8.7, 12.0, 24.3, 25.0, 26.1,
27.1, 36.2, 39.9, 47.1, 47.8, 50.6, 57.5, 98.8, 127.6, 128.7, 129.6,
138.7, 145.9, 154.6, 171.7, 174.4.
(9) For an example of a triazine formation, see: Benson, S. C.;
Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257.
(10) For representative examples of the Friedlander reaction,
see: (a) Thummel, R. P.; Lefoulon, F. J. Org. Chem. 1985,
50, 666. (b) Riesgo, E. C.; Hu, Y.-Z.; Bouvier, F.; Thummel,
R. P.; Scaltrito, D. V.; Meyer, G. J. Inorg. Chem. 2001, 40,
3413.
(11) For representative condensations of 1,2-ketones with ureas,
see: (a) Muccioli, G. G.; Wouters, J.; Scriba, G. K. E.;
Poppitz, W.; Poupaert, J. H.; Lambert, D. M. J. Med. Chem.
2005, 48, 7486. (b) Muccioli, G. G.; Fazio, N.; Scriba, G. K.
E.; Poppitz, W.; Cannata, F.; Poupaert, J. H.; Wouters, J.;
Lambert, D. M. J. Med. Chem. 2006, 49, 417.
HRMS (ESI): m/z [M + 1]+ calcd for C24H32N3O3: 410.2444; found:
410.2438.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York

2270
J. R. Goodell et al.
PAPER
(19) For examples of nonsymmetric condensations, see:
(12) For examples of condensations of 1,2-ketones with
guanidine, see: Nishimura, T.; Kitajima, K. J. Org. Chem.
1979, 44, 818.
(13) For an example of a condensation of a 1,2-ketone with a
benzamidine, see: Baldwin, J. J.; Christy, M. E.; Denny, G.
H.; Habecker, C. H.; Freedman, M. B.; Lyle, P. A.;
Ponticello, G. S.; Varga, S. L.; Gross, D. M.; Sweet, C. S.
J. Med. Chem. 1986, 29, 1065.
(14) For reactions of a-hydroxy ketones with isocyanates, see:
(a) Martínez, R.; Jiménez-Vázquez, H. A.; Tamariz, J.
Tetrahedron 2000, 56, 3857. (b) Santoyo, B. M.; González-
Romero, C.; Merino, O.; Martínez-Palou, R.; Fuentes-
Benites, A.; Jiménez-Vázquez, H. A.; Delgado, F.; Tamariz,
J. Eur. J. Org. Chem. 2009, 2505.
(15) Büchi, G.; Mak, C.-P. J. Am. Chem. Soc. 1977, 99, 8073.
(16) Crystallographic data for compound 9a have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC 771959. Copies can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or
e-mail: deposit@ccdc.cam.ac.uk].
(a) Taylor, E. C.; Perlman, K. L.; Kim, Y.-H.; Sword, I. P.;
Jacobi, P. A. J. Am. Chem. Soc. 1973, 95, 6413. (b) Eid, M.
M.; Badawy, M. A.; Ibrahim, Y. A. J. Heterocycl. Chem.
1983, 20, 1255. (c) Palanki, M. S. S.; Dneprovskaia, E.;
Doukas, J.; Fine, R. M.; Hood, J.; Kang, X.; Lohse, D.;
Martin, M.; Noronha, G.; Soll, R. M.; Wrasidlo, W.; Yee, S.;
Zhu, H. J. Med. Chem. 2007, 50, 4279. (d) Rong, F.; Chow,
S.; Yan, S.; Larson, G.; Hong, Z.; Wu, J. Bioorg. Med.
Chem. Lett. 2007, 17, 1663. (e) Mukaiyama, H.; Nishimura,
T.; Kobayashi, S.; Ozawa, T.; Kamada, N.; Komatsu, Y.;
Kikuchi, S.; Oonota, H.; Kusama, H. Bioorg. Med. Chem.
2007, 15, 868. (f) Kuboki, A.; Yamamoto, T.; Taira, M.;
Arishige, T.; Konishi, R.; Hamabata, M.; Shirahama, M.;
Hiramatsu, T.; Kuyama, K.; Ohira, S. Tetrahedron Lett.
2008, 49, 2558.
(20) (a) Kolehmainen, E.; Šaman, D.; Piskala, A.; Masojidková,
M. Magn. Reson. Chem. 1995, 33, 690. (b) Boyd, M.; Hay,
M. P.; Boyd, P. D. W. Magn. Reson. Chem. 2006, 44, 948.
(21) Conformational analysis (Macromodel 9.6) using OPLS
2005 force field, optimization (JAGUAR 7.5, 1998 ed.) and
B3LYP, 6-31g**, Schrodinger, Inc.: Portland, OR, 2008.
(22) Ebine, S.; Takahashi, K.; Nozoe, T. Bull. Chem. Soc. Jpn.
1988, 61, 2690.
(23) Smith, G. V.; Notheisz, F. Heterogeneous Catalysis in
Organic Chemistry; Academic Press: New York, 1999.
(24) For examples of coordination of a carbonyl oxygen to
palladium(II), see: (a) Domhöver, B.; Kläui, W.
(17) See the supporting information for representative
characterization data for compounds 22a, 22b, 23a, 41a,
41b, and 48, and X-ray crystal structure data for compound
9a. This information is available through the Internet at
www.thieme-connect.com/ejournals/toc/synthesis.
(18) Mazzeo, J. R.; Neue, U. D.; Kele, M.; Plumb, R. S. Anal.
Chem. 2005, 77, 460A.
J. Organomet. Chem. 1996, 522, 207. (b) Al-Jeboori, M. J.;
Al-Dujaili, A. H. Transition Met. Chem. (N.Y.) 2009, 34,
109.
Synthesis 2010, No. 13, 2254–2270 © Thieme Stuttgart · New York