Gold catalyzed cyclization of alkyne-tethered dihydropyrimidones

Article abstract of DOI:10.1021/ol2015658

Dihydropyrimidones are an important class of biologically active heterocycles accessible from the multicomponent Biginelli condensation. Further manipulation of the dihydropyrimidone skeleton gives access to unique heterocycles. Presented herein is a Au-c

Full text of DOI:10.1021/ol2015658

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4228–4231
Gold Catalyzed Cyclization of
Alkyne-Tethered Dihydropyrimidones
Lauren E. Brown, Peng Dai, John A. Porco Jr., and Scott E. Schaus*
Department of Chemistry and Center for Chemical Methodology and Library
Development, Life Sciences and Engineering Building, Boston University,
24 Cummington Street, Boston, Massachusetts 02215, United States
seschaus@bu.edu
Received June 10, 2011
ABSTRACT
Dihydropyrimidones are an important class of biologically active heterocycles accessible from the multicomponent Biginelli condensation.
Further manipulation of the dihydropyrimidone skeleton gives access to unique heterocycles. Presented herein is a Au-catalyzed cyclization of
alkyne-tethered dihydropyrimidones to yield pyridopyrimidones.
Dhydropyrimidones (DHPMs), the products of the
classic Biginelli three-component reaction,1 possess a wide
range of intriguing pharmacological properties and thusly
have attracted great synthetic interest.2 Following our
development of an organocatalytic route to access either
enantiomer of the DHPM core and enantioenriched
DHPM library collections,3 we have been pursuing meth-
ods to further manipulate the scaffold. In addition to our
discoveryofaDHPM-derivedguanidine chemotypewhich
exhibits intriguing activity against select geographic iso-
lates of P. falciparum,4 we also recently reported the
synthesis and identification of a DHPM-derived pyrido-
pyrimidone that exhibits broad-spectrum activity against
orthopoxviruses.5 Herein we describe the discovery of a
Au-catalyzed cyclization of propargyl-tethered DHPMs
that gives rise to the tetrahydropyridopyrimidone motif.
Initial efforts focused on probing the intramolecular
reactivity of DHPM derivatives 1 and 2 possessing alkynes
attached to the N1 enamide nitrogen (Figure 1). Our initial
screen6 included a selection of alkynophilic metal catalysts,
two different solvents (polar and nonpolar), and three
different reaction conditions. All reactions were analyzed
by TLC as well as UPLC/MS/ELSD. While substrate 2
was unreactive under all conditions screened, we were
pleased to observe that a common product was formed
(1) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416.
(2) (a) Kappe, C. O. Tetrahedron 1993, 49, 6937–6963. (b) Kappe,
C. O. Acc. Chem. Res. 2000, 33, 879–888. (c) Kappe, C. O. Eur. J. Med.
Chem. 2000, 35, 1043–1058. (d) Borowsky, B.; Durkin, M. M.; Ogoza-
lek, K.; Marzabadi, M. R.; Deleon, J.; Lagu, B.; Heurich, R.; Lichtblau,
H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.; Branchek, T. A.;
Gerald, C.; Vaysse, P. H. J.; Forray, C. Nat. Med. 2002, 8, 825–830.
(3) (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem.
Soc. 2005, 127, 11256–11257. (b) Lou, S.; Dai, P.; Schaus, S. E. J. Org.
Chem. 2007, 72, 9998–10008.
(4) Brown, L. E.; Cheng, K. C.-C.; Wei, W.-G.; Yuan, P.; Dai, P.;
Trilles, R.; Ni, F.; Yuan, J.; MacArthur, R.; Guha, R.; Johnson, R. L.;
Su, X.-z.; Dominguez, M. M.; Snyder, J. K.; Beeler, A. B.; Schaus, S. E.;
Inglese, J.; Porco, J. A., Jr. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6775–
6780.
(5) Dower, K.; Filone, C. M.; Hodges, E. N.; Bjornson, Z. B.;
Rubins, K. H.; Brown, L. E.; Schaus, S. E.; Hensley, L.; Connor, J. H.
2011, submitted for review.
(6) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2007, 129, 1413–1419.
Figure 1. Screened catalysts and conditions.
r
10.1021/ol2015658
Published on Web 07/13/2011
2011 American Chemical Society

when 1 was heated in the presence of gold or platinum, as
well as in trace amounts with GaCl3. The product of the
reaction was determined to be compound 3 by UPLC-MS
and 2D NMR, bearing a unique bicyclic tetrahydropyr-
idopyrimidone structural framework.7
Additional substrates were synthesized by subjecting
compound 1 to hydrolysis/amide formation (18), N3-
alkylation (19), and reduction (20) (Scheme 1).
Dihydropyrimidones analogous to 1 possessing N1
propargyl groups were synthesized to be evaluated in
the cyclization reaction. However, our ability to prepare
substrates with our previous methodology was limited by
the necessity of employing propargyl isocyanates: prepara-
tion of low molecular weight isocyanates is inconvenient
due to both volatility and the use of phosgene. Since the
commercial availability of propargylic isocyanates and
ureas is limited, substrate synthesis necessitated a more
general route to N1-propargylated DHPMs.
Scheme 1. Synthesis of Additional Substrates for Reaction
Screen
Table 1. Synthesis of N1-Propargylated DHPMs
We then set out to determine the generality of the
cyclization reaction. During the initial optimization using
substrate 1, we determined that 10 mol % AuCl provided
the optimal yield. However, across AuCl sources we
encountered a wide variance in reactivity on repetition of
the parent reaction. Reproducibility issues led us to under-
go a second screen of gold catalysts and conditions. We
determined that, for consistently productive yields, certain
substrates required an increased catalyst loading up to 30
mol %. We also identified HAuCl4 asa similarly activeand
more dependable catalyst for a number of substrates.13
Interestingly, while AuClPPh3 alone gave trace product,
cationic gold catalyst systems such as AuClPPh3/AgOTf
and AuClPPh3/AgBF4 were wholly unreactive for sub-
strates 1 and 14.
DHPM
R1
R2
R3
n
product yield (%)
5
5
5
5
5
5
6
6
6
7
8
CO2CH3 CH3
CO2CH3 CH3
CO2CH3 CH3
CO2CH3 CH3
CO2CH3 CH3
CO2CH3 CH3
CH3
CH3
TMS
H
1
2
1
1
1
1
1
1
1
1
1
1
69
56
67
85
46
84
68
76
73
72
83
2
9
10
11
12
13
14
15
16
17
Ph
C5H11
CH3
TMS
H
COCH3
COCH3
COCH3
CN
CH3
CH3
CH3
CH3
CH3
CO2CH3 CH2CH3 CH3
Table 2 depicts the scope and limitations of the reaction.
Aliphatic, aromatic, and silyl alkynes all cyclized in good
to excellent yields (entries 1À2, 4À7). Notably, silyl al-
kynes 9 and 14 demonstrated the most efficient cyclization;
while compound 1 required prolonged heating to induce
cyclization, silyl alkyne 14showed91%conversionafter 14
h at rt (20 mol % HAuCl4, percent converson determined
by crude 1H NMR).
Kappe and co-workers developed N1-selective alkyla-
tion of DHPMs using a Mitsunobu reaction employing
TMAD and TBP.8 While the reaction worked quite well
for some substrates, in our hands the reaction proved
problematic for the range of alkynols we utilized giving
mixtures of N1 and N3 alkylation products. We there-
fore developed a modified protocol employing N3-acylated
DHPMs 5À8,9 thus avoiding the inherent selectivity
issue and making use of readily available propargylic
alcohols.10 Furthermore, by decreasing the pKa of the N1
proton, we are able to use common Mitsunobu reagents,
instead of TMAD and pyrophoric TBP.11 As depicted in
Table 1, the protocol was employed to synthesize alkyne
cyclization precursors from both known and novel DHPMs.12
The functionality at C5 proved to be critical to the
outcome of the reaction. In addition to ester and ketone
(11) Koppel, I.; Koppel, J.; Degerbeck, F.; Grehn, L.; Ragnarsson,
U. J. Org. Chem. 1991, 56, 7172–7174.
(12) (a) Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1. (b) Kappe,
C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26, 55–64. (c) Hu, E. H.;
Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 10, 3454–3457. (d)
Perez, R.; Beryozkina, T.; Zbruyev, O.; Haas, W.; Kappe, C. O. J. Comb.
Chem. 2002, 4, 501–510.
(13) For examples of HAuCl4-mediated reactions of alkynes, see: (a)
Arcadi, A.; Alfonsi, M.; Chiarini, M.; Marinelli, F. J. Organomet. Chem.
2009, 694, 576–582. (b) Shu, X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-G.;
Guo, L.-N.; Liang, Y.-M. Adv. Synth. Catal. 2008, 350, 243–248. (c) Ji,
K.-G.; Shen, Y.-W.; Shu, X.-Z.; Xiao, H.-Q.; Bian, Y.-J.; Liang, Y.-M.
Adv. Synth. Catal. 2008, 350, 1275–1280. (d) Wegner, H. A.; Ahles, S.;
Neuburger, M. Chem.;Eur. J. 2008, 14, 11310–11313. (e) Georgy, M.;
Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc. 2005, 127, 14180–
14181. (f) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489–4492. (g)
Kato, K.; Teraguchi, R.; Kusakabe, T.; Motodate, S.; Yamamura, S.;
Mochida, T.; Akita, H. Synlett 2007, 63–66.
(7) For the synthesis of DHPM-derived hexahydropyridopyrimi-
dines, see: Singh, K.; Singh, S. Tetrahedron 2008, 64, 11718–11723.
(8) Dallinger, D.; Kappe, C. O. Synlett 2002, 11, 1901–1903.
(9) (a) Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Mol. Div. 2003,
7, 229–245. (b) Kosolov, M. A.; Orlov, V. D. Zh. Org. Farm. Khim. 2005,
3, 17–22. (c) Mobinikhaledi, A.; Forughifar, N.; Habibi, M.; Kalate, Z.
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(10) A method for selective N1 DHPM alkylation employing alkyl
bromides has also been disclosed: Singh, K.; Arora, D.; Poremsky, E.;
Lowery, J.; Moreland, R. S. Eur. J. Med. Chem. 2009, 44, 1997–2001.
Org. Lett., Vol. 13, No. 16, 2011
4229

Davies17 is a notable example. For our system, we propose
a vinylogous Conia-ene reaction18 with dual activation,
both oxophilic and alkynophilic, by the gold catalyst,19 as
depicted in Figure 2. A 6-endo-dig cyclization followed by
protodemetalation and double bond isomerization gives
rise to the observed product.
Table 2. Substrate Scope of Gold-Mediated Cyclization
entry
substrate
catalysta,b
product (yield)
1
1
C
3 (63%)
2
9
B
23 (93%)
3
10
11
12
13
14
15
16
17
18
19
20
A, B, C, D, E
No reaction
24 (57%)
4
B
5
A
25 (58%)
6
C
26 (65%)
7
D
27 (94%)
8
A, B, C, D, E
No reaction
No reaction
No reaction
28 (27%)
9
B, D
B, D
E
10
11
12
13
14
E
29 (20%)
B, D
C
Decomposed
30 (50%)
21 (R1 = COCH3,
R2 = H,
R3 = CH3, R4 = Ac)
22 (R1 = COCH3,
R2 = H,
15
B
31 (20%)
Figure 2. Proposed mechanism for pyridopyrimidone formation.
R3 = TMS, R4 = Ac)
a Catalyst loadings: (A) 10 mol % AuCl; (B) 20 mol % AuCl; (C) 10
mol % HAuCl4À3H2O; (D) 20 mol % HAuCl4À3H2O; (E) 30 mol %
AuCl. b Loadings reported are for optimized yields.
To investigate the proposed mechanism, we performed
deuterium labeling experiments (Scheme 2). We first pre-
pared deuterated substrate 19-d3, which cyclized in 14%
yield with deuterium distribution as depicted. In addition,
we performed the cyclization of compound 1 in the pre-
sence of D2O. From these experiments, we can conclude
that (1) significant enolization occurs prior to cyclization,
as evidenced by the percent deuterium incorporation at the
nonacidic γ-positions of 29-d6 and 3-d6; (2) deuterium
depletion at the acidic γ-protons of recovered starting mate-
rials 19-d3 and 1-d3 is suggestive of equilibration with the ε-
protons of their respective cyclization products; and (3) the
enolization of both 1 and 3 are gold-promoted, as there is no
substrates, amide 18 (entry 11) cyclized in low yield, while
substrates lacking a carbonyl (entries 9, 13) failed to cyclize.
We also investigated the effect of substituents at the N3
position of the DHPM. Acylated and alkylated substrates
cyclized but with consistently lower conversions (entries 12,
14À15) and often requiring an increased catalyst loading.
While substitution of the alkyne was widely tolerated,
terminal alkynes 10 and 15 showed erratic reactivity, with
conversions generally below 5%. However, the target
pyridopyrimidone products of these cyclizations could be
reliably accessed via AgF-mediated desilylation14 of cy-
clized vinylsilanes 23 and 27.5 Lastly, we observed that
substitution of an ethyl group at the C6-DHPM position
also shuts down the reaction (entry 10).
Our attention next turned to elucidating the mechanism
of this transformation. A search for similar cyclizations of
alkynyl enamides togive six-membered rings gaveonly one
example: an undesired side reaction in the Au-catalyzed
cycloisomerization of propargylated enamides to give
pyrroles.15 In addition, a number of examples of nucleo-
philic CÀC bond formation at activated alkynes have been
recently disclosed, employing β-dicarbonyls, silyl and alkyl
enol ethers, and enamines as carbon nucleophiles.16 There
exist far fewer instances of such reactions employing
unactivated enolizable carbonyls; the recent disclosure by
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Org. Lett., Vol. 13, No. 16, 2011

Scheme 2. Deuterium Labeling Studies
Figure 3. Plot of the steady-state initial rate of product forma-
tion vs auric acid concentration cubed for the conversion of 14
to 27 (ClCH2CH2Cl, 25 °C).
Figure 4. Proposed bimetallic Au(III) carbonyl activation.
deuterium incorporation seen at any CÀH position in two
control experiments performed in the absence of catalyst.
Intrigued by the notion that the gold catalystmay serve a
dual function in promoting the reaction, we then under-
took a kinetic study to gain further insight. The third-order
rate plot of the room-temperature cyclization of substrate
14 in the presence of auric acid is depicted in Figure 3.
Kinetic data clearly indicate a multiple-order dependence
on the catalyst, supporting our proposed dual catalyst
activation. The apparent third-order dependence on the
catalyst is intriguing and may arise from binuclear Au(III)
Lewis acid activation of the carbonyl (Figure 4).20
We hypothesize that the challenges of reproducibility
result from the relatively low catalytic activity of unstabilized
gold(I) and (III) species under harsh reaction conditions,
which is well-documented.21 While gold is not generally
known to cycle between oxidation states, AuCl will dispro-
portionate to AuCl3 and colloidal Au0 upon heating.22 The
π-acidity of Au(I) and Au(III) are both well-established;
calculations demonstrate Au(III) to be a superior oxophilic
Lewis acid. Phosphine-ligated Au(I) salts, more broadly
utilized due to their increased stability, may not be sufficiently
oxophilic to promote the requisite enolization.23
In summary, we have discovered an interesting gold
catalyzed cyclization of alkyne-tethered dihydropyrimidones.
An effective protocol employing the Mitsunobu reaction was
also developed to prepare a wide panel of reaction precursors.
Mechanistic experiments suggest a dual role for the gold cat-
alyst in this reaction, activating both the alkyne and nucleo-
phile toward the desired reaction. Further studies, including
applicability of this reaction to library synthesis and further
biological evaluation of the pyridopyrimidones are currently
under investigation and will be reported in due course.
Acknowledgment. Financial support from the NIH
(P50 GM067041, P41 GM076263, and P41 GM086180)
is gratefully acknowledged. We thank Professor Aaron
Beeler (Boston University) for helpful discussions.
(20) DeHaan, F. P.; Brown, H. C. J. Am. Chem. Soc. 1969, 91, 4844–
4850.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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