Cationic dirhodium carboxylate-catalyzed synthesis of dihydropyrimidones from propargyl ureas

Article abstract of DOI:10.1016/j.tet.2013.04.071

Cationic Rh(II) complexes are able to catalyze the regioselective hydroamination of propargyl ureas in a 6-endo fashion. This transformation permits access to interesting substitution patterns of dihydropyrimidines, which have found use as nucleotide exch

Full text of DOI:10.1016/j.tet.2013.04.071

Tetrahedron 69 (2013) 5744e5750
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cationic dirhodium carboxylate-catalyzed synthesis of
dihydropyrimidones from propargyl ureas
,
c
,
,c,e,f
Miao Yang a, Shannon J. Odelberg b d, Zongzhong Tong d, Dean Y. Li b
,
,
Ryan E. Looper a
*
a Department of Chemistry, University of Utah, Salt Lake City, UT 84112, United States
b Department of Medicine, Cardiology Division, University of Utah, Salt Lake City, UT 84132, United States
c Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, United States
d Navigen Inc., Salt Lake City, UT 84108, United States
e Department of Oncology, University of Utah, Salt Lake City, UT 84112, United States
f The Key Laboratory for Human Disease Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan
Provincial People’s Hospital, Chengdu, Sichuan 610072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Cationic Rh(II) complexes are able to catalyze the regioselective hydroamination of propargyl ureas in
a 6-endo fashion. This transformation permits access to interesting substitution patterns of dihy-
dropyrimidines, which have found use as nucleotide exchange factor inhibitors.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 11 March 2013
Received in revised form 9 April 2013
Accepted 11 April 2013
Available online 19 April 2013
Keywords:
Dihydropyrimidone
Heterocycle
Hydroamination
Rhodium catalysis
ARF 6
1. Introduction
cyclization operable but they can occur through either the urea
nitrogen or oxygen (Fig. 1).
Accessible through multicomponent reactions, the dihydropyr-
imidone scaffold has been prevalent in both pharmaceutical and
academic screening campaigns for decades.1 Given the cornucopia
of biological activities reported for this heterocyclic core,2 meth-
odologies have developed advancing the vetted Biginelli conden-
sation3 to include enantioselective variants and orthogonal
substitution patterns.4,5 Recently Rovis and co-workers reported an
The cyclization of propargyl ureas and related prop-
argylcarbamates has been extensively studied, most frequently using
salts of gold,8 silver,9 palladium,10 and copper.11 Kinetically favored,
cyclization to form the five-membered ring is most commonly ob-
served, both with N- and O-connectivity. Recently Toste and co-
workers described the isolation of the dihydrooxazinoneimine in
significant quantities from the cationic Au(I)-catalyzed cyclization of
N-Ts-propargyl ureas,8o but without fail the six-membered rings are
the minor component of the cyclization event. To the best of our
knowledge the cyclization of propargyl ureas, selectively in a 6-endo
fashion through the urea nitrogen, has not been observed. Achieving
this selectivity would greatly add to our ability to create new sub-
stitutionpatternsofabiomedicallysignificantsmallmoleculescaffold.
enantioselective Rh(I) catalyzed [4þ2] cycloaddition of
a,b-un-
saturated imines and isocyanates to generate dihydropyrimidones,
highlighting the continuing need for methodologies to access this
core.6
Our group has recently been interested in the cyclization of
propargylguanidines, particularly from the vantage of controlling
the cyclization in either a 5-exo or 6-endo fashion.7 The application
of this strategy to propargyl ureas introduces an added level of
selectivity, that is, not only are 5-exo and 6-endo modes of
2. Results and discussion
2.1. Cationic Rh(II) cyclizations of propargyl ureas
Having noted the ability of dirhodium(II)-carboxylates to se-
lectively catalyze the 6-endo cyclization of propargylguanidines, in
* Corresponding author. Tel.: þ1 801 585 0408; e-mail address: r.looper@utah.
edu (R.E. Looper).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.071

M. Yang et al. / Tetrahedron 69 (2013) 5744e5750
5745
Fig. 1. Dihydropyrimidone strategy.
direct contrast to other
p
-Lewis acids, we were encouraged to ex-
nucleophilic than the related guanidines. Therefore it is likely that
the nucleophilicity of the urea nitrogen and the electrophilicity of
the metalealkyne complex, might be critically coupled to the suc-
cess of this reaction. Defining the limits of reactivity at these posi-
tions became the emphasis of our study on substrate scope (Table
2). With the phenyl substituted alkyne (R1¼Ph), cyclization is pro-
ductive with urea substituents that span the electronic spectrum
from p-MeOPh to p-NO2Ph (e.g., 2aee). The p-NO2ePh substituted
urea 2e proved to be a highly crystalline solid, from which we were
able to unambiguously prove the connectivity of these dihy-
dropyrimidones via X-ray crystallography. Electron rich alkynes
(e.g., p-MeOPh substituted) also reacted well with electron rich and
poor ureas, 2feh. If the alkyne is electron poor (e.g., p-CF3Ph
substituted) it reacts well with most ureas (2iek) but fails to react
with an electron poor p-NO2Ph substituted urea (e.g., 2n). Other
electron poor alkynes can also react as long as the urea is not ex-
tremely electron poor (2lem). The reaction is also successful if the
substrate is N1,N3-dialkyl substituted (2o,p) or N1,N3-alkyl/aryl
substituted (2q). Alkyl substituted alkynes, while reactive gave
complex mixtures that were intractable on a preparative scale.
However, ene-ynes and yne-ynes react cleanly to give (2ret), which
are logical precursors to alkyl substitution patterns. Substrates
bearing an N3-Tosyl or N3-Boc group are also not reactive, further
defining that highly electron-withdrawing groups shut down the
reaction. It is noteworthy that all of the successful cyclizations
resulted in exclusive formation of the dihydropyrimidone.
plore the use of these catalysts in the cyclization of propargyl
ureas.7b From our previous research AgOAc and Rh2(Oct)4 were
preferred to selectively promote the 5-exo and 6-endo modes of
cyclization, respectively.
We initially examined the ability of p-Lewis acids to catalyze the
cyclization of propargylurea 1a (Table 1). Surprisingly AgOAc failed
to catalyze the cyclization at room temperature or 70 ꢀC (entries 2
and 3) although Van der Eycken has recently reported that this
transformation is possible with 20 mol % AgOTf at 110 ꢀC, con-
firming that the propargyl ureas are much less nucleophilic than
their di-Boc guanidine counterparts.9e More discouraging was the
fact that Rh2(Oct)4 also failed to promote the cyclization (entries 4
and 5). The more Lewis-acidic Rh2(TFA)4 was then examined. While
unreactive at room temperature (entry 6), formation of a single
cyclization product (2a) occurred when the temperature was in-
creased to 70 ꢀC, albeit in 50% isolated yield (entry 7). Encourag-
ingly, the product did appear to have cyclized in a 6-endo fashion as
evidenced by the coupling constant of the vinylic proton at C5
(3J¼4.0 Hz). Further the 13C chemical shifts of C5 and C6 were much
more consistent with enamine connectivity versus that of an enol-
ether. We anticipated that a suitable cationic Rh(II) complex, with
more labile ligands, might lend the greater Lewis acidity and im-
prove the reactivity. To test this assumption, we turned our atten-
tion to the cationic catalyst [Rh2(OAc)2(MeCN)6][BF4]2.12 To our
Table 1
When contemplating this unique reactivity, it is quite remark-
able that Rh(II) catalyzes this bond forming event with two-fold
thermodynamic selectivity: first to generate the 6-endo product
and secondly to generate the CeN bond. One potential explanation
for this is the Markovnikov-selective hydration of the alkyne fol-
lowed by condensation of the urea on the resultant ketone. How-
ever, the addition of water (up to 1 equiv) or desiccants did not
affect the efficiency of the reaction. Further, Rh(II) does not appear
to be a competent Lewis acid for the condensation of a preformed
ureaeketone.13 Examples of alkyne activation by dirhodium(II)
complex are quite rare.14 Thus further investigations are warranted
to understand this unique selectivity, and the potential reversibility
of the initial amino- or oxo-rhodation.
Catalysts and solvents screen
Entry Catalyst (5 mol %)
Solvent
CH2Cl2
HOAc/CH2Cl2 rt
HOAc/CH2Cl2 70
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Temp (ꢀC) Isolated
yield (%) 2a
NR
1
2
3
4
5
6
7
8
N/A
AgOAc
AgOAc
Rh2(Oct)4
Rh2(Oct)4
Rh2(TFA)4
Rh2(TFA)4
80
NR
NR
NR
NR
NR
50
2.2. Application of the resultant dihydropyrimidones
rt
70
rt
70
80
A testament to the value of these scaffolds, we identified com-
pound 2k capable of inhibiting proliferation of the LN-229 glio-
blastoma cell line (IC50¼25
mM) (Fig. 2). The EGF-dependent
[Rh2(OAc)2(MeCN)]2[BF4]2 CH2Cl2
94
proliferation of glioblastoma cells has been directly linked to the
activation of Adenosine diphosphate-ribosylation factor 6 (ARF6).15
Known inhibitors of this enzyme, e.g., secin-44, are comprised of
a 1,2-disubstituted triazole, which shares the diaryl-orientation as
delivered by the methodology described above.16 One drawback
with the triazole inhibitors is their poor solubility. We reasoned
*
All reactions were run at 0.1 M in a Schlenk tube under a N2 atmosphere for 24 h.
delight, this provided 2a in 94% isolated yield with no trace of the
other three possible cyclization products observable by 1H NMR.
As mentioned, the competency of the more Lewis-acidic Rh(II)
catalysts suggests that the propargyl ureas are inherently less

5746
M. Yang et al. / Tetrahedron 69 (2013) 5744e5750
Table 2
Reaction scope
that replacement of the triazole backbone with a dihydropyr-
imidine should reduce the amount of unsaturation, increase po-
larity and thus increase solubility. To test this we prepared the
analog 4 bearing the secin sidechains, via reduction of the nitro
group in 2h with Ni2B followed EDCI mediated coupling to 5-
bromofuroic acid. Indeed compound 4 inhibits marked activation
of ARF6. As shown in Fig. 2B, activation of ARF6 occurs only in the
presence of ARNO (ARF nucleotide-binding site opener) (lanes 1
and 2).17 Addition of 4 inhibits this activation by nearly 50% at
50 M (lane 3), suggesting that this small molecule might be useful
m
for inhibiting cellular behaviors that are controlled by activated
ARF6. We further investigated whether compound 4 can inhibit cell
proliferation, and it does so in a dose dependent manner with an
IC50 of 17
similar to secin-44, which has an IC50 of 15
an inactive variant secin-44neg (in which an acetyl group replaces
m
M (Fig. 2C, all measurements after 48 h).18 This activity is
mM and contrasts with

M. Yang et al. / Tetrahedron 69 (2013) 5744e5750
5747
Fig. 2. Manipulation of the secin scaffold for increased solubility.
the bromofuranoic acid appendage). Moreover, 4 had improved
solubility (soluble up to 100 M) compared to secin-44, which will
enable us to better evaluate the inhibition of ARF6 activation as
a therapeutic target in vivo.
chromatography was performed on Merck silica gel Kieselgel 60
(230e400 mesh) from EM science with the indicated HPLC grade
solvents.
m
H NMR spectra were recorded on Varian Unity-300 MHz, Inova-
400 MHz, or VXR-500 MHz as indicated. The chemical shifts (d) of
proton resonances are reported relative to CHCl3 using the fol-
lowing format: chemical shift in parts per million (ppm) [multi-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
app¼apparent), coupling constant(s) (J in Hz), integral]. 13C NMR
spectra were recorded at 75, 100, or 125 MHz. The chemical shifts of
carbon resonances are reported relative to the deuterated solvent
peak.20,21 Infrared spectra were obtained using a Thermo Nicolet
380-FT IR spectrometer fitted with a SmartOrbit sample system. All
absorptions are reported in cmꢁ1 relative to polystyrene. Mass
spectra were determined by ESI/APCI-TOF for HRMS in the Uni-
versity of Utah mass spectrometry facility.
3. Conclusions
In conclusion, we have demonstrated that cationic dirhodiu-
m(II) is capable of catalyzing the chemo- and regioselective
hydroamination of propargyl ureas. The ability of Rh(II) to selec-
tively catalyze the 6-endo selective cyclization through the urea
nitrogen further illustrates its unique ability to activate alkynes for
nucleophilic addition. This methodology delivers dihydropyr-
imidones with as of yet unexplored substitution patterns, in high
yield and as single regioisomers. These new structures have found
use in cascade reactions and as nucleotide exchange factor
inhibitors.
4.2. Substrate preparation: synthesis of propargyl ureas
4. Experimental section
4.1. General
Given the focus of this manuscript, details for the preparation
and spectral characterization of the substrate propargyl ureas cor-
responding to 1aet are given in Supplementary data section.
All reactions requiring anhydrous condition were conducted in
flame-dried glassware under a positive pressure of nitrogen.
Commercially available reagents were used as received; otherwise,
materials were purified according to Purification of Laboratory
Chemicals.19 Dichloromethane (CH2Cl2) and tetrahydrofuran
(THF) were degassed with nitrogen and passed through a solvent
purification system (Innovative Technologies Pure Soly). Triethyl-
amine (Et3N) was distilled from CaH2 immediately prior to use.
Reactions were monitored by TLC and visualized by a dual short
wave/long wave UV lamp and stained with KMnO4. Flash
4.3. Cationic Rh(II)-catalyzed hydroamination of propargyl
ureas
4.3.1. Representative procedure for the synthesis of 2aet: 3-methyl-1,6-
diphenyl-3,4-dihydropyrimidin-2(1H)-one (2a). [Rh2(OAc)2(CH3CN)6]
[BF4]2 (16.6 mg, 0.022 mmol, 5 mol %), 1-methyl-3-phenyl-1-(3-
phenylprop-2-ynyl)urea (1a, 116 mg, 0.44 mmol, 1.0 equiv), and
CH2Cl2 (4.5 mL) were mixed in a flame-dried Schlenk tube under N2.
The reaction mixture was stirred at 80 ꢀC overnight. The resulting

5748
M. Yang et al. / Tetrahedron 69 (2013) 5744e5750
solution was purified through the flash column chromatography
(silica gel, hexane/EtOAc¼6:1 to 1:1) to give the product 2a
6.9 Hz, 2H), 6.66 (dd, J¼2.1, 6.6 Hz, 2H), 5.27 (t, J¼4.0 Hz, 1H), 4.08
(d, J¼4.0 Hz, 2H), 3.71 (s, 3H), 3.02 (s, 3H); 13C NMR (CDCl3,
(109 mg, 94%). 1H NMR (CDCl3, 500 MHz)
d
7.14e7.00 (m, 10H), 5.13
125 MHz) d 159.3, 154.0, 145.7, 144.7, 140.6, 128.75, 128.73, 127.6,
(t, J¼4.0 Hz, 1H), 4.09 (d, J¼4.0 Hz, 2H), 3.00 (s, 3H); 13C NMR
123.2, 102.8, 55.1, 47.6, 35.5; IR (neat) 2926, 2838, 1680, 1606, 1593,
1511, 1488, 1434, 1403, 1338, 1292, 1246, 1176, 1111, 1070, 1030, 877,
843, 757, 696, 589 cmꢁ1; HRMS (ESI) calculated for C18H18N3O4 m/z
(MþH) 340.1297, obsd 340.1298.
(CDCl3, 100 MHz) d 154.6, 141.7, 139.4, 136.0, 128.9, 127.8, 127.8, 127.7,
127.6, 125.9,100.9, 48.0, 35.3; IR (neat) 3853, 3744, 3648, 3060, 2923,
2360, 2338, 1700, 1676, 1489, 1280, 908, 727, 693, 623 cmꢁ1; HRMS
(ESI) calculated for C17H16N2ONa m/z (MþNa) 287.1160, obsd
287.1159.
4.3.9. 1-(4-Methoxyphenyl)-3-methyl-6-(4-(trifluoromethyl)phe-
nyl)-3,4-dihydropyrimidin-2(1H)-one
500 MHz)
(2i). 1H
NMR
(CDCl3,
4.3.2. 1-(4-Methoxyphenyl)-3-methyl-6-phenyl-3,4-dihydropyrimidin-
d
7.39 (d, J¼8.0 Hz, 2H), 7.24 (d, J¼7.5 Hz, 2H), 7.05 (dd,
2(1H)-one (2b). 1H NMR (CDCl3, 500 MHz)
d
7.10e7.02 (m, 7H), 6.65
(dd, J¼2.0, 6.0 Hz, 2H), 5.06 (t, J¼4.0 Hz, 1H), 4.08 (d, J¼4.0 Hz, 2H),
3.67 (s, 3H), 2.99 (s, 3H); 13C NMR (CDCl3, 100 MHz)
157.4, 154.9,
J¼1.5, 7.0 Hz, 2H), 6.69 (dd, J¼6.5, 7.0 Hz, 2H), 5.15 (t, J¼4.0 Hz, 1H),
4.12 (J¼4.0 Hz, 2H), 3.70 (s, 3H), 3.01 (s, 3H); 13C NMR (CDCl3,
d
125 MHz) d 157.6, 154.7, 140.8, 139.7, 132.0, 129.8, 128.1, 124.8,
141.9, 136.2, 132.4, 130.1, 128.0, 127.7, 127.6, 113.2, 100.3, 55.2, 48.1,
35.4; IR (neat) 2932, 2835, 2359, 2241, 1675, 1654, 1607, 1509, 1493,
1239, 724 cmꢁ1; HRMS (ESI) calculated for C18H19N2O2 m/z (MþH)
295.1447, obsd 295.1447.
124.77, 124.74, 124.71, 113.4, 101.8, 55.2, 48.0, 35.4; IR (neat) 2936,
2839, 1712, 1671, 1608, 1510, 1441, 1410, 1322, 1246, 1165, 1110, 1066,
1018, 830, 737, 556 cmꢁ1
;
HRMS (ESI) calculated for
C19H17N2O2F3Na m/z (MþNa) 385.1140, obsd 385.1152.
4.3.3. 1-(4-Chlorophenyl)-3-methyl-6-phenyl-3,4-dihydropyrimidin-
4.3.10. 3-Methyl-1-phenyl-6-(4-(trifluoromethyl)phenyl)-3,4-
2(1H)-one (2c). 1H NMR (CDCl3, 500 MHz)
d
7.14e7.06 (m, 9H), 5.15
dihydropyrimidin-2(1H)-one (2j). 1H NMR (CDCl3, 500 MHz)
d 7.36
(t, J¼4.0 Hz,1H), 4.09 (d, J¼4.0 Hz,1H), 3.00 (s, 3H); 13C NMR (CDCl3,
(d, J¼8.0 Hz, 2H), 7.22 (d, J¼8.5 Hz, 2H), 7.21e7.12 (m, 4H),
100 MHz) d 154.4, 141.4, 138.1, 135.7, 131.4, 130.1, 128.0, 127.9, 127.8,
7.05e7.03 (m, 1H), 5.20 (t, J¼4.0 Hz, 1H), 4.11 (d, J¼4.5 Hz, 2H), 3.00
101.6,18.0, 35.4; IR (neat) 3853, 3743, 3688, 3058, 2926, 2360, 2340,
1680, 1576, 1489, 1282, 1091, 746 cmꢁ1; HRMS (ESI) calculated for
C17H16N2OCl m/z (MþH) 299.0951, obsd 299.0958.
(s, 3H); 13C NMR (CDCl3, 125 MHz)
d 154.4, 140.7, 139.6, 139.1, 128.8,
128.6, 128.3, 128.1, 128.0, 126.2, 124.83, 124.80,124.78, 124.74, 102.6,
48.0, 35.4; IR (neat) 2929, 2348, 2246, 1676, 1488, 1404, 1365, 1320,
1281,1248,1163,1107,1066,1017, 908, 845, 763, 695, 601, 552 cmꢁ1
;
4.3.4. 1-(4-Bromophenyl)-6-phenyl-3-methyl-3,4-dihydropyrimidin-
HRMS (ESI) calculated for C18H16N2OF3 m/z (MþH) 333.1215, obsd
2(1H)-one (2d). 1H NMR (CDCl3, 500 MHz)
d
7.25e7.00 (m, 9H), 5.16
333.1223.
(t, J¼4.0 Hz,1H), 4.08 (d, J¼4.0 Hz,1H), 3.00 (s, 3H); 13C NMR (CDCl3,
100 MHz)
d
154.3, 141.3, 138.6, 135.7, 130.9, 130.4, 128.0, 127.9, 127.8,
4.3.11. 1-(4-Bromophenyl)-3-methyl-6-(4-(trifluoromethyl)phenyl)-
3,4-dihydropyrimidin-2(1H)-one (2k). 1H NMR (CDCl3, 500 MHz)
119.4, 101.7, 47.9, 35.4; IR (neat) 2923, 2361, 2338, 1677, 1664, 1484,
1249, 915, 868, 822, 744 cmꢁ1
;
HRMS (ESI) calculated for
d
7.40 (d, J¼7.5 Hz, 2H), 7.30e7.21 (m, 4H), 7.02 (dd, J¼1.5, 8.0 Hz,
C17H15N2ONaBr m/z (MþNa) 365.0265, obsd 365.0265.
2H), 5.23 (t, J¼4.0 Hz, 1H), 4.10 (d, J¼4.0 Hz, 2H), 3.00 (s, 3H); 13C
NMR (CDCl3, 125 MHz) d 154.1, 139.3, 138.3, 131.3, 130.2, 127.9, 125.1,
4.3.5. 3-Methyl-1-(4-nitrophenyl)-6-phenyl-3,4-dihydropyrimidin-
124.8, 119.6.103.5, 47.9, 35.4; IR (neat) 2931, 2360, 2339, 1679,1485,
1403, 1364, 1322, 1248, 1164, 1122, 1067, 1013, 846, 823, 785, 603,
551 cmꢁ1; HRMS (ESI) calculated for C18H14N2OF3NaBr m/z (MþNa)
433.0139, obsd 433.0146.
2(1H)-one (2e). 1H NMR (CDCl3, 500 MHz)
d 7.99e7.97 (m, 2H),
7.35e7.33 (m, 2H); 7.14e7.07 (m, 5H), 5.31 (t, J¼4.0 Hz, 1H), 4.10 (d,
J¼4.0 Hz, 1H), 3.3 (s, 3H); 13C NMR (CDCl3, 125 MHz)
d 153.4, 145.6,
144.7, 140.8, 135.2, 128.6, 128.3, 128.2, 127.4, 123.1, 103.9, 47.7, 35.5;
IR (neat) 2927, 2245, 1946, 1682, 1592, 1516, 1493, 1403, 1342, 1247,
1112, 854, 754, 590 cmꢁ1; HRMS (ESI) calculated for C17H16N3O3 m/z
(MþNa) 310.1192, obsd 310.1193.
4.3.12. 6-(4-Chlorophenyl)-3-methyl-1-phenyl-3,4-dihydropyrimidin-
2(1H)-one (2l). 1H NMR (CDCl3, 500 MHz)
d 7.17e7.02 (m, 9H), 5.13
(t, J¼4.0 Hz,1H), 4.09 (d, J¼4.0 Hz, 2H), 3.00 (s, 3H); 13C NMR (CDCl3,
125 MHz) d 154.5, 140.8, 139.2, 134.6, 133.4, 129.1, 128.9, 128.0, 126.2,
4.3.6. 1,6-Bis(4-methoxyphenyl)-3-methyl-3,4-dihydropyrimidin-
101.5, 48.0, 35.4; IR (neat) 3234, 3050, 2922, 2049, 1677, 1660, 1591,
1488, 1432, 1398, 1278, 1244, 1105, 1088, 1013, 909, 828, 773, 754,
744, 697, 564 cmꢁ1; HRMS (ESI) calculated for C17H16N2OCl m/z
(MþH) 299.0951, obsd 299.0949.
2(1H)-one (2f). 1H NMR (CDCl3, 500 MHz)
d
7.02e7.00 (m, 4H),
6.66e6.61 (m, 4H), 5.00 (t, J¼4.0 Hz,1H), 4.04 (d, J¼4.0 Hz, 2H), 3.68
(s, 3H), 3.67 (s, 3H), 2.97 (s, 3H); 13C NMR (CDCl3, 125 MHz)
158.7,
d
157.3, 155.0, 141.7, 132.4, 130.0, 129.2, 128.6, 113.1, 113.0, 99.4, 55.1,
54.9, 48.0, 35.3; IR (neat) 2933, 2836, 2361, 2338, 2241, 1675, 1652,
1608, 1509, 1437, 1360, 1290, 1241, 1174, 1109, 1031, 907, 827, 723,
592 cmꢁ1; HRMS (ESI) calculated for C19H21N2O3 m/z (MþH)
325.1552 obsd 325.1558.
4.3.13. 3-Methyl-6-(4-nitrophenyl)-1-phenyl-3,4-dihydropyrimidin-
2(1H)-one (2m). 1H NMR (CDCl3, 500 MHz)
d
7.97 (d, J¼9.5 Hz, 2H),
7.29 (d, J¼6.5 Hz, 1H), 7.17e7.23 (m, 4H), 7.07e7.06 (m, 1H), 5.28 (t,
J¼4.0 Hz, 1H), 4.14 (d, J¼4.0 Hz, 2H), 3.02 (s, 3H); 13C NMR (CDCl3,
125 MHz)
d 154.2, 146.9, 142.5, 140.2, 139.0, 128.6, 128.4, 128.3,
4.3.7. 6-(4-Methoxyphenyl)-3-methyl-1-phenyl-3,4-dihydropyrimidin-
126.5, 123.2, 103.8, 48.0, 35.5; IR (neat) 3076, 2924, 2853, 2244,
1674,1597,1515,1489, 1434,1402,1342,1314,1281,1249,1108, 1013,
910, 852, 767, 729, 699, 561 cmꢁ1; HRMS (ESI) calculated for
C17H15N3O3 m/z (MþH) 332.1011, obsd 332.1015.
2(1H)-one (2g). 1H NMR (CDCl3, 500 MHz)
d 7.14e6.61 (m, 9H), 5.07
(t, J¼4.0 Hz, 1H), 4.06 (d, J¼4.0 Hz, 2H), 3.68 (s, 3H), 2.99 (s, 3H); 13C
NMR (CDCl3, 125 MHz)
d 158.8, 154.7, 131.4, 139.5, 129.1, 129.0, 128.5,
127.8, 125.8, 113.1, 100.2, 55.0, 48.0, 35.4; IR (neat) 2932, 2836, 2360,
2242, 1658, 1608, 1511, 1487, 1431, 1401, 1356, 1289, 1243, 1174, 1028,
908, 865, 761, 724, 696, 592 cmꢁ1; HRMS (ESI) calculated for
C18H19N2O2 m/z (MþH) 295.1447, obsd 295.1448.
4.3.14. 1-(4-Methoxybenzyl)-3-methyl-6-phenyl-3,4-dihydropyri-
midin-2(1H)-one (2o). 1H NMR (CDCl3, 300 MHz)
d 7.29e7.27 (m,
2H); 7.15e7.12 (m, 2H), 6.87e6.84 (m, 2H), 6.71e6.68 (m, 2H), 4.82
(t, J¼3.9 Hz,1H), 4.56 (s, 2H), 4.92 (d, J¼3.9 Hz,1H), 3.73 (s, 3H), 2.95
4.3.8. 6-(4-Methoxyphenyl)-3-methyl-1-(4-nitrophenyl)-3,4-
(s, 3H); 13C NMR (CDCl3, 75 MHz)
d 158.3, 155.8, 141.8, 135.7, 131.4,
dihydropyrimidin-2(1H)-one (2h). 1H NMR (CDCl3, 300 MHz)
d
8.00
128.4, 128.2, 128.1, 113.5, 100.2, 55.1, 47.8, 46.7, 35.4; IR (neat) 2932,
2834, 2360, 2339, 1652, 1611, 1510, 1494, 1442, 1242, 1174, 1031, 815,
(dd, J¼2.4, 4.2 Hz, 2H), 7.34 (dd, J¼2.4, 7.2 Hz, 2H), 7.00 (dd, J¼2.4,

M. Yang et al. / Tetrahedron 69 (2013) 5744e5750
5749
727, 700, 645, 568 cmꢁ1; HRMS (ESI) calculated for C19H20N2O2Na
m/z (MþNa) 331.1422, obsd 331.1431.
the aniline, which was used for the coupling reaction without fur-
ther purification.
Under N2, DCM (2.0 mL) was added to a mixture of 5-
bromofuran-2-carboxylic acid (21.0 mg, 0.11 mmol), EDCI (96 mg,
0.5 mmol), DMAP (15.3 mg, 0.125 mmol), and 1-(4-aminophenyl)-
6-(4-methoxyphenyl)-3-methyl-3,4-dihydropyrimidin-2(1H)-one
(16.0 mg, 0.05 mmol). The mixture was stirred at room temperature
overnight until the aniline had been consumed as judged by TLC
analysis. The mixture was diluted with EtOAc (5 mL), washed with
NaHCO3 (aq), HCl (1 M), NaHCO3 (aq), brine, and dried over MgSO4.
After filtration, the solution was concentrated and the residue was
purified through preparative TLC (silica gel, EtOAc/hexane¼3:1) to
give the coupling product (4, 13.0 mg, 50%). 1H NMR (CDCl3,
4.3.15. 1-Butyl-3-methyl-6-phenyl-3,4-dihydropyrimidin-2(1H)-one
(2p). 1H NMR (CDCl3, 500 MHz)
d 7.35e7.24 (m, 5H), 4.82 (t,
J¼4.0 Hz, 1H), 4.10 (d, J¼4.0 Hz, 1H), 3.45e3.42 (m, 2H), 2.94 (s,
3H), 1.31e1.29 (m, 2H), 1.10e1.06 (m, 2H), 0.71 (t, J¼7.5 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) d 155.9, 141.9, 135.9, 128.1, 128.0, 99.9, 99.8,
47.7, 43.7, 35.2, 31.5, 19.5, 13.6; IR (neat) 2955, 2928, 2870, 2360,
2338, 1652, 1493, 1431, 1400, 1275, 1083, 765, 700 cmꢁ1; HRMS
(ESI) calculated for C15H21N2O m/z (MþH) 245.1654, obsd
245.1652.
4.3.16. 3-(4-Methoxybenzyl)-1,6-diphenyl-3,4-dihydropyrimidin-
500 MHz) d 7.91 (s, 1H), 7.44e7.42 (m, 2H), 7.12e7.10 (m, 2H),
2(1H)-one (2q). 1H NMR (CDCl3, 500 MHz)
d
7.50 (dd, J¼2.5, 7.0 Hz,
7.02e7.00 (m, 2H), 6.64e6.62 (m, 2H), 6.46 (d, J¼4.0 Hz,1H), 5.06 (t,
2H), 7.43e7.19 (m, 10H), 7.04 (dd, J¼2.5, 7.0 Hz, 2H), 5.26 (t,
J¼4.0 Hz, 1H), 4.06 (d, J¼4.0 Hz, 2H), 3.69 (s, 3H), 2.99 (s, 3H); 13C
J¼4.0 Hz, 1H), 4.74 (s, 2H), 4.14 (d, J¼4.0 Hz, 2H), 3.98 (s, 3H); 13C
NMR (CDCl3, 125 MHz)
d 159.0, 154.8, 154.6, 149.3, 141.4, 136.0,
NMR (CDCl3, 125 MHz)
d
159.0, 154.5, 141.4, 139.5, 135.9, 129.7,
134.9, 129.6, 129.2, 128.4, 124.7, 119.2, 117.4, 114.6, 113.2, 100.2, 55.0,
48.0, 35.4; IR (neat) 3303, 2930, 2359, 2341, 1654; 1602, 1511, 1463,
1405, 1357, 1295, 1248, 1174, 1144, 1108, 1012, 952, 925, 854, 833,
798, 735, 668 cmꢁ1; HRMS (ESI) calculated for C23H20N3O4NaBr m/z
(MþNa) 504.0535, obsd 504.0553.
129.3, 128.9, 128.7, 128.6, 128.5, 127.8, 127.6, 127.5, 126.6, 125.9,
113.9, 113.8, 101.3, 55.1, 50.8, 45.0; IR (neat) 2928, 2834, 2173, 2065,
1709, 1660, 1512, 1445, 1283, 1246, 1174, 1110, 1032, 816, 757, 696,
614, 566 cmꢁ1; HRMS (ESI) calculated for C24H23N2O2 m/z (MþH)
371.1760, obsd 371.1763.
4.5. Arf6 pull-down experiments
4.3.17. 6-Cyclohexenyl-3-methyl-1-phenyl-3,4-dihydropyrimidin-
2(1H)-one (2r). 1H NMR (CDCl3, 500 MHz)
d 7.27e7.14 (m, 5H), 5.73
4.5.1. Plasmid DNA construction. The ARF6 and ARNO coding se-
quences were amplified by PCR and then ligate into pcDNA3.1/myc-
His A (Invitrogen) in fusion with Myc and a C-terminal His Tag.
(d, J¼4.0 Hz, 2H), 4.89 (t, J¼4.0 Hz, 1H), 3.94 (d, J¼4.0 Hz, 1H), 2.93
(s, 3H), 2.03e1.86 (m, 2H), 1.59e1.57 (m, 2H), 1.32e1.25 (m, 2H),
1.21e1.16 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d 154.6, 144.5, 139.4,
134.4, 129.4, 129.1, 128.9, 127.5, 126.0, 97.7, 47.9, 35.3, 27.4, 25.1, 22.1,
21.6; IR (neat) 3330, 3058, 2929, 2857, 1708, 1649, 1596, 1489, 1435,
1396, 1339, 1265, 1104, 1072, 920, 833, 802, 755, 731, 695, 641,
576 cmꢁ1; HRMS (ESI) calculated for C17H21N2O m/z (MþH)
269.1654, obsd 269.1654.
4.5.2. Active ARF6 pull-down. The plasmid DNA was transfected
into HEK293T cell using Lipofectamine 2000 (Invitrogen)
when cell density is around 90%. The medium was changed
to DMEMþ1% FBS at 24 h post transfection and incubated over-
night. The compound was diluted with DMEMþ1% FBS according
to 1:200 to get final concentration of 50 mM or 100 mM in 0.5%
4.3.18. 6-Cyclohexenyl-1-(4-methoxybenzyl)-3-methyl-3,4-
DMSO. Transfected cell was treated with compound or DMSO only
for 4 h before pull-down. The pull-down was performed using
active Arf6 pull-down and detection kit from Thermo Scientific
(cat#: 26186).
dihydropyrimidin-2(1H)-one (2s). 1H NMR (CDCl3, 500 MHz)
d 7.13
(d, J¼9.0 Hz, 2H), 6.80 (dd, J¼2.0, 7.0 Hz, 2H), 5.65e5.64 (m, 1H),
4.68 (t, J¼4.0 Hz,1H), 4.57 (s, 2H), 3.78 (d, J¼4.0 Hz, 2H), 3.76 (s, 3H),
2.87 (s, 3H), 2.04e2.02 (m, 2H), 1.92e1.91 (m, 2H), 1.56e1.55 (m,
4H); 13C NMR (CDCl3, 100 MHz)
d 158.3, 155.9, 144.0, 133.6, 132.0,
128.8, 128.3, 113.5, 97.1, 55.1, 47.5, 46.6, 35.1, 28.4, 25.0, 22.3, 21.7; IR
(neat) 2931, 2835, 2243, 1646, 1511, 1440, 1403, 1379, 1289, 1244,
1174, 1035, 905, 818, 724, 645, 570 cmꢁ1; HRMS (ESI) calculated for
C19H25N2O2 m/z (MþH) 313.1916, obsd 313.1911.
4.6. Solubility determinations
Solubility determinations were made by adding a 10 mM solu-
tion of secin-44 or compound 4 in DMSO to pull-down medium
(DMEMþ1% FBS) to final concentrations of 1, 10, 50, 100 and
4.3.19. 6-(Hex-1-ynyl)-3-methyl-1-phenyl-3,4-dihydropyrimidin-
200 mM. After standing overnight the solutions were observed
2(1H)-one (2t). 1H NMR (CDCl3, 400 MHz)
d
7.35e7.32 (m, 2H),
under a microscope and the concentration at which the compound
began crystallizing was noted as its maximum solubility.
7.28e7.24 (m, 1H), 7.25e7.22 (m, 2H), 5.19 (t, J¼4.0 Hz, 1H), 4.02 (d,
J¼4.0 Hz, 2H), 2.93 (s, 3H), 2.00 (t, J¼6.8 Hz, 1H), 1.14e1.09 (m, 2H),
1.05e0.99 (m, 2H), 0.74 (t, J¼7.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
Acknowledgements
d
153.6, 139.4, 129.6, 128.1, 127.2, 125.1, 103.3, 94.4, 74.4, 48.6, 35.1,
29.8, 21.4, 18.5, 13.4; IR (neat) 2955, 2928, 2870, 2360, 2229, 1668,
1597, 1488, 1433, 1325, 1284, 1250, 1101, 1070, 1023, 913, 760, 695,
567 cmꢁ1; HRMS (ESI) calculated for C17H21N2O m/z (MþH)
269.1654, obsd 269.1652.
We are thankful to Dr. Jim Muller for help with mass spectral
analysis. R.E.L. is grateful to the National Institutes of Health,
General Medical Sciences (R01-GM090082 and P41-GM08915) for
financial support of this research. D.Y.L. is supported by grants from
the National Institutes of Health, NCI (R01HL066277) and the De-
partment of Defense (W81XWH0910260).
4.4. Synthesis of the secin-44 analogue (4)
N2H4$H2O (101.0 mg) was added to a reflux mixture of
nickel boride7 (12.8 mg), 6-(4-methoxyphenyl)-3-methyl-1-(4-
nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one (2h) (16.1 mg,
0.05 mmol) in absolute EtOH (4.0 mL) and stirred at reflux for
30 min. Then, the solution was cooled to room temperature, filtered
through a short pad of Celite. The filtrate was concentrated to give
Supplementary data
Analytical data for all new compounds including 1H and 13C
NMR spectra. Supplementary data associated with this article can
be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2013.04.071.

5750
M. Yang et al. / Tetrahedron 69 (2013) 5744e5750
10. Palladium: (a) Majumdar, K. C.; De, Mirupam; Roy, B. Synthesis 2010, 4207; (b)
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