Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters

Article abstract of DOI:10.1016/j.tet.2005.12.061

Multifunctionalized dihydropyrimidine-5-carboxylic amides and esters are generated in a multistep sequence integrating a variety of enabling and high throughput technologies such as automated or parallel microwave synthesis, the use of polymer-supported reagents, fluorous synthesis and purification strategies, and a continuous flow hydrogenation system. The key dihydropyrimidine-5-carboxylic acid intermediates are obtained in two steps by Biginelli multicomponent condensation of benzyl or allyl β-ketoesters with aldehydes and urea/thioureas, followed by suitable benzyl or allyl deprotection strategies. Further functionalization of the acid cores with amines using polymer-supported coupling reagents or with alcohols utilizing Mitsunobu chemistry provides the desired amides or esters, respectively.

Full text of DOI:10.1016/j.tet.2005.12.061

Tetrahedron 62 (2006) 4651–4664
Microwave-assisted solution phase synthesis of
dihydropyrimidine C5 amides and esters
*
Bimbisar Desai, Doris Dallinger and C. Oliver Kappe
Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 2 November 2005; revised 11 December 2005; accepted 11 December 2005
Available online 24 March 2006
Abstract—Multifunctionalized dihydropyrimidine-5-carboxylic amides and esters are generated in a multistep sequence integrating a variety
of enabling and high throughput technologies such as automated or parallel microwave synthesis, the use of polymer-supported reagents,
fluorous synthesis and purification strategies, and a continuous flow hydrogenation system. The key dihydropyrimidine-5-carboxylic acid
intermediates are obtained in two steps by Biginelli multicomponent condensation of benzyl or allyl b-ketoesters with aldehydes and
urea/thioureas, followed by suitable benzyl or allyl deprotection strategies. Further functionalization of the acid cores with amines using
polymer-supported coupling reagents or with alcohols utilizing Mitsunobu chemistry provides the desired amides or esters, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
F
1. Introduction
F
Modern drug discovery steadily relies on high speed organic
synthesis and combinatorial chemistry techniques for the
O
R2
N
N
N
rapid generation of compound libraries. Microwave-assisted
organic synthesis1,2 and combinatorial chemistry together
with high throughput screening (HTS) methods are being
instrumental for the rapid synthesis, screening, and identi-
fication of compounds with new and improved biological
activities.3
X
Y
H
N
R1
O
R5
R4
R3
Chart 1.
Over the years, research interest in multifunctionalized
3,4-dihydropyrimidin-2(1H )-ones (DHPMs), viz. the Bigi-
nelli scaffold, has surged rapidly, owing to the pharmacolog-
ical properties associated with many derivatives of this
privileged heterocyclic core.4–7 Reports describe several
DHPMs that have been identified, for example, calcium
channel modulators,5 or small molecules targeting the mi-
totic machinery.6 Notably, 4-aryldihydropyrimidinone het-
erocycles attached to an aminopropyl-4-piperidine moiety
via a C5 amide linkage (see Chart 1) have proven to be
excellent templates for selective a1a receptor subtype antag-
onists to warrant further consideration for the treatment of
Benign Prostatic Hyperplasia (BPH).7 In the synthesis of
these DHPM-5-carboxamides, amide bond formation be-
tween the requisite amines and the corresponding DHPM
acids was performed using standard solution phase amide
coupling chemistry involving carbodiimide coupling re-
agents.7,8
This approach of introducing structural diversity appealed to
our ongoing interest in the microwave-induced high speed
synthesis9 and decoration10 of the Biginelli scaffold. In the
present work we describe a rapid microwave-induced poly-
mer-assisted solution phase synthesis (PASP) and high
throughput purification of diverse DHPM C5 amides starting
from a corresponding set of structurally diverse DHPM C5
acid cores and selected amines (see Scheme 1). With
a high diversity of commercially available amines but lim-
ited availability of b-ketoamides, the synthesis of amides
via the acid precursors has been chosen. In addition, the
acid cores generated would also serve as excellent precur-
sors for other interesting chemistries.
To introduce more diversity at the C5 position, we also syn-
thesized a set of DHPM C5 esters 7 starting from the acids
using Mitsunobu chemistry (Scheme 1). Via this protocol
more diverse and novel ester-functionalities could be estab-
lished by using the corresponding alcohols. Besides the
standard Mitsunobu conditions, a fluorous Mitsunobu pro-
tocol was employed to facilitate the product isolation and
purification.
Keywords: Microwave synthesis; Continuous flow techniques; Pyrimidines;
Amide couplings; Fluorous synthesis; Mitsunobu reaction.
* Corresponding author. Tel.: +43 316 380 5352; fax: +43 316 380 9840;
e-mail: oliver.kappe@uni-graz.at
URL: http://www.maos.net
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.061

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B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
(DHPMs) of type 4 and has been extensively reported in
R2
the literature.11,12 By far, library generation through auto-
mated sequential microwave-assisted Biginelli multicompo-
nent condensation is most attractive in combining speed,
diversity, and efficiency.9 Improvements in the classical
Biginelli multicomponent protocol have favored the more
tolerant Lewis acids over a mineral acid viz. conc. HCl as
the catalyst for yield improvements.13 The use of solvents
such as ethanol, acetic acid, THF, dioxane, acetonitrile, en-
vironmentally benign ionic liquids or solvent-free protocols
has also been reported.12
O
R5
N
NH
R6
R4
N
R1
6
X
amide
synthesis
R2
r
C5 este
O
n
ctio
ote
epr
O-d
HO
NH
R2
Mitsunobu
R4
N
R1
5
X
O
R7
O
NH
As a starting point in our study, we have generated a small set
(11 examples) of 4-aryl-DHPM C5 benzyl (Bn) and allyl
(All) esters 4 using six different aldehydes 1A–F, three
urea/thiourea 2a–c, and three CH-acidic carbonyl 3a–g
building blocks (Figs. 1 and 2). This set of esters were syn-
thesized in order to conveniently prepare DHPM acids 5. In
the synthesis of DHPM benzyl/allyl esters 4, Yb(OTf)3 as
the Lewis acid catalyst and acetonitrile as the reaction sol-
vent were chosen based on previous optimization studies
on a larger and more diverse set of microwave-induced Bigi-
nelli multicomponent cyclocondensations.9,10 Synthesis of
both the DHPM C5 benzyl and allyl esters was performed
to allow for a subsequent C5 O-deprotection using classical
debenzylation and deallylation strategies (see below). The
microwave-assisted sequential synthesis of DHPM esters 4
(4 mmol scale) utilized an excess (6 mmol) of the CH-acidic
carbonyl building blocks 3, which has led to improved yields
in other Biginelli condensations.12 In our case, the cyclocon-
densation has also been translated to 40 mmol scale using
microwave-assisted parallel synthesis under nearly identical
reaction conditions. For this scale-up synthesis (40 mmol) in
a multimode cavity, the reaction mixtures were irradiated in
parallel at preset conditions to afford the structurally diverse
set of DHPM benzyl/allyl esters 4.14 The small scale
(4 mmol) synthesis of the 4-aryl-DHPM C5 benzyl/allyl es-
ters 4 involved sequential heating (120 ꢀC for 20 min) of the
corresponding reaction mixtures in a single-mode micro-
wave reactor. The isolated yields obtained from each of
the microwave (MW) heating runs are described in Table 1.
R4
N
X
R1
7
R2
1
R2
O
O
Biginelli
condensation
R3
O
H
R3
O
O
NH
+
NH2
R4
O
R4
N
X
HN
R1
X
R3 = benzyl or allyl
R1
3
2
4
Scheme 1. Retrosynthetic strategy toward DHPM amide and ester libraries.
A microwave-induced combinatorial set and a parallel scale-
up synthesis of structurally diverse DHPM C5 benzyl and
allyl ester form the starting point in the synthesis of the
DHPM C5 acid cores (Scheme 1).
2. Results and discussion
2.1. Microwave-assisted synthesis of DHPM esters 4
The Lewis acid-catalyzed multicomponent cyclocon-
densation of an aldehyde 1, urea 2, and a b-ketoester 3 (Bi-
ginelli condensation) constitutes the most elegant synthesis
of multifunctionalized 3,4-dihydropyrimidin-2(1H)-ones
Aldehydes 1A-F
Me
Cl
Br
NO2
Cl
H
O
H
O
H
O
H
O
H
O
H
O
E
D
F
C
A
B
Urea 2a-c
O
O
S
NH2
NH2
NH
NH2
NH2
NH2
c
b
a
Me
CH-acidic carbonyl compounds 3α−γ
O
O
O
O
O
O
O
Me
Ph
O
Ph
Ph
O
Me
Figure 1. Aldehyde, urea, and b-ketoester building blocks.

B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
4653
Me
O
O
O
O
Bn
Bn
Bn
Bn
O
NH
O
NH
O
NH
O
NH
Me
N
H
4Aa
O
Ph
N
H
4Aa
O
Me
N
Me
4Ab
O
Me
N
H
4Ba
O
Br
Cl
NO2
O
O
O
O
All
All
All
All
O
NH
O
NH
O
NH
O
NH
Me
N
O
Me
N
H
4Ac
S
Me
N
H
4Ea
O
Me
N
H
4Da
O
Me
4Cb
Me
NO2
O
O
O
Cl
NH
All
All
All
O
NH
O
NH
O
Me
N
H
4Bc
S
Me
N
S
Me
N
S
H
H
4Fc
4Cc
Figure 2. Dihydropyrimidine esters generated by Biginelli multicomponent condensations.
Reaction mixtures with 3a and 3g as the CH-acidic carbonyl
component (R3¼benzyl) provided easy access to the desired
DHPMs 4Aaa, 4Aag, 4Aba, and 4Baa in 24–62% isolated
yields. In each of these cases, the reaction mixture becomes
completely homogeneous over 20 min of microwave heating
at the optimized temperature of 120 ꢀC. A low solubility of
the resulting cyclocondensed DHPMs upon overnight stand-
ing under refrigeration (4 ꢀC) afforded complete precipita-
tion of the desired corresponding DHPM benzyl esters in
>95% HPLC purity. We also undertook a scale-up synthesis
(4 mmol–40 mmol) of DHPM benzyl esters 4Aaa, 4Aag,
4Aba, and 4Bba, switching from a single-mode microwave
to a multimode microwave reactor capable of parallel syn-
thesis.14 Maintaining identical reaction conditions (catalyst,
solvent and ratio of building blocks) in each of the cases pro-
vided the target compounds in multigram quantities and in
similar yields (see Section 4 for details).
The above generated DHPM benzyl esters exemplify a rela-
tive simplicity in terms of overall core diversity. The C6 phe-
nyl substituent in 4Aag and N1-methyl substituent in 4Aba
posed as robust diversity factors on the heterocyclic core.
The synthesis of other DHPM C5 benzyl esters is similarly
feasible by introducing diversity also in C2 (X¼O or S)
and the phenyl ring on C4 positions of the DHPM core. How-
ever, under identical deprotecting conditions this does not
ensure to selectively carry out O-debenzylations without in-
advertently affecting some of the other diversity points (the
functional group substituents like NO2, Cl, Br on the phenyl
ring C4 position). The synthesis of DHPM allyl esters 4Cbb,
4Acb, 4Dab, 4Eab, 4Ccb, 4Bcb, and 4Fcb became imper-
ative for some of the structurally diverse building blocks,
in particular with the aldehydes 1C–F and/or thiourea 2c,
to retain the diversity in the resulting DHPM cores whilst
selectively affording O-deprotections (deallylation) on the
DHPM esters 4 under non-reducing conditions. The micro-
wave-assisted synthesis (4 mmol and 40 mmol scale) was
afforded under identical conditions as in the case of the
4-aryl-DHPM C5 benzyl esters, described in Table 1. In
some cases, the relatively low yields of the DHPM allyl
esters (e.g., for 4Fcb) may be attributed to the higher solu-
bility of the DHPMs rendered by the allyl functionality.
Table 1. Microwave-assisted synthesis of dihydropyrimidine benzyl/allyl
esters 4a
R2
R2
1
O
O
Yb(OTf)3, MeCN
R3
R3
O
H
O
NH
O
MW, 120 °C, 20 min
+
NH2
R4
N
R1
X
R4
O
HN
R1
X
3
2
4
Entry
DHPM
R1
R2
R3
R4
X
Yield (%)b
1
2
3
4
5
6
7
8
4Aaa
4Aag
4Aba
4Baa
4Cbb
4Acb
4Dab
4Eab
4Ccb
4Bcb
4Fcb
H
H
Me
H
Me
H
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
Me
Ph
O
O
O
O
O
S
O
O
S
62
17
28
43
35
46
74
48
61
67
37
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-Me
3-NO2
H
4-Cl
4-Br
3-NO2
4-Me
2-Cl
2.2. Synthesis of DHPM acids 5a–d by catalytic
transfer hydrogenation of DHPM benzyl esters 4
9
10
11
S
S
H
The next stage in our study was to gain access to compounds
5a–d by devising a facile catalytic transfer hydrogenation
of DHPM benzyl esters 4Aaa, 4Aag, 4Aba and 4Baa,
a
Single-mode microwave on a 4 mmol scale.
Isolated yield of pure compounds (>95% purity by HPLC at 215 nm).
b

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B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
Table 2. Deprotection of DHPM benzyl esters 4a
injector (with up to 10 mL/min flow rate), allowing a contin-
uous monitoring of reaction progress by sampling and also
large scale hydrogenations in flow under optimized condi-
tions.18
R2
R2
O
O
Pd/C
H2 or HCO2NH4
Bn
H
O
NH
O
NH
The O-benzyl deprotection of DHPM benzyl esters 4Aaa,
4Aag, 4Aba, and 4Baa was afforded in a flow manner in
the H-CubeÔ using a 5% Pd/C catalyst (CatCartÔ) column
by preparing 0.025 M stock solutions using 30% AcOH in
EtOH as solvent (25 mL). A continuous flow (1 mL/min
flow rate) of 30% AcOH in EtOH is set through the H-
CubeÔ while maintaining a low (atmospheric) hydrogen
pressure at 40–45 ꢀC system temperature. After equilibrat-
ing the H-CubeÔ with the above conditions of H2 pressure
and system temperature, the stock solution of substrate
4Aaa was injected at 1 mL/min flow rate. A continuous
sampling (reaction monitoring) enabled to identify quantita-
tive conversion (by HPLC) to the desired corresponding
DHPM acid 5a. An entire cycle of 25 mL reaction mixture
(4Aaa) extended for 25–30 min to provide a complete and
clean conversion with 95% isolated yield of the desired
product 5a (Table 2). Similar conditions were applied to
carry out transfer hydrogenations on DHPM benzyl esters
4Aag, 4Aba, and 4Baa to afford quantitative conversions
(by HPLC) to the corresponding DHPM C5 acids 5b, 5c,
and 5d (80%, 85%, and 85% isolated yields, respectively).
The activity of 5% Pd/C catalyst column was retained for
several cycles of similar and/or different chemistries (for
a new example/substrate, the catalyst bed is rinsed with
the reaction solvent prior to initiating a hydrogenation).
R4
N
R1
4
O
R4
N
O
R1
5a-d
DHPM
R1
H
R2
R4
Conditionsa
Yield (%)b
Product
4Aaa
H
H
H
Me
rt
MW
CF
66
62
95
5a
4Aag
4Aba
H
Ph
rt
MW
CF
65
60
80
5b
5c
5d
Me
H
Me
Me
rt
MW
CF
57
55
85
4Baa
4-Me
rt
MW
CF
56
53
85
a
Conditions: rt: room temperature catalytic transfer hydrogenation
(HCOONH4, 25 ꢀC, 8–10 h; 5 mmol); MW: microwave-assisted catalytic
transfer hydrogenation (HCOONH4, 120 ꢀC, 20 min; 0.5 mmol); CF:
continuous flow hydrogenation. For details see text.
b
Yields are isolated yields of pure product.
respectively, in the presence of a suitable catalyst. So far, the
synthesis of DHPM C5 carboxylic acids has been reported
both in solution15 and on solid phase.16 The solution phase
studies have involved Pd-catalyzed hydrogenation of benzyl
esters using hydrogen or allyl deprotection. In our approach
the DHPM benzyl esters were easily transfer hydrogenated
in the presence of catalytic 5% Pd/C using ammonium
formate as the in situ hydrogen source and methanol as the
solvent. Within 20 min of microwave heating at 120 ꢀC,
the catalytic transfer hydrogenations afforded quantitative
conversions and good to moderate isolated yields of the
corresponding DHPM acids (Table 2). Similar results were
obtained by carrying out the same reaction at room temper-
ature in a sealed vessel for 8–10 h.
It was evident that transfer hydrogenation of DHPM benzyl
esters 4Aag, 4Aba, and 4Baa in the H-CubeÔ flow system
has a clear advantage to afford excellent yields of the desired
acids 5a–d by simple evaporation of the collected mixture
after exposure of the reaction mixture to hydrogenation con-
ditions. This makes the flow reactor an ideal candidate for
automated generation of compound libraries from a library
of its corresponding precursors.18
2.4. Microwave-assisted synthesis of DHPM acids
5e–k by Pd(0) catalyzed O-deallylation
2.3. Hydrogenation of DHPM benzyl esters 4 in a
flow manner
The mild and selective method of Pd(0) catalyzed removal of
allyl protecting groups19 using 5 mol % of Pd(PPh3)4 as
a catalyst and diethyl amine as a base formed the basis of
transforming DHPM allyl esters 4Cbb, 4Acb, 4Dab,
4Eab, 4Ccb, 4Bcb, and 4Fcb (ca. 0.5 mmol scale) to the
corresponding DHPM acids 5e–k under non-reducing condi-
tions (Table 3).
The hydrogenation for O-benzyl deprotection on DHPM
benzyl esters 4Aaa, 4Aag, 4Aba, and 4Baa has addition-
ally been carried out in a continuous flow manner using
a continuous flow hydrogenation apparatus.17
This hydrogenation technology consists of a compact device
capable to generate hydrogen gas in situ (up to 100 bars of
H2 pressure and 100 ꢀC system temperature) and enabling
catalytic hydrogenations in a flow mode. The electrolytic de-
composition of water within the flow reactor (H-CubeÔ)
generates hydrogen in the required quantity. The hydrogena-
tion takes places within a heterogeneous catalyst (CatCartÔ)
column. The exchangeable heterogeneous catalyst car-
tridges are advantageous for the final purification and isola-
tion of the desired product over the conventional batch
catalytic heterogeneous hydrogenations. Only homogeneous
reaction mixtures are entered into the H-Cube via an HPLC
Within 20 min of microwave heating at 100 ꢀC in THF,
a smooth and selective O-allyl deprotection was possible
in the presence of the Pd(0) catalyst and the nucleophilic
amine. Under these conditions, the nucleophile selectively
scavenges the allyl group to afford the desired DHPM acids
5e–k. The O-allyl deprotections have also been performed at
room temperature under otherwise similar conditions (Table
3), and on a ca. 5 mmol scale in parallel (rt) providing sim-
ilar yields.
In summary, a set of 11 DHPM C5 carboxylic acids has been
prepared on a multigram scale by either a Pd-catalyzed

B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
4655
Table 3. Microwave-assisted O-deallylation of DHPM allyl esters 4
R2
Table 4. Microwave-assisted DHPM C5 amide synthesisa
R2
R2
R2
PS-Carbodiimide
O
O
O
O
Pd(PPh3)4
diethylamine
HOBt, R5NH2, DMA
H
All
H
H
O
NH
O
NH
N
NH
O
NH
MW, 100-120 °C, 15 min
R5
R4
N
R1
X
R4
N
R1
X
R4
N
R1
X
R4
N
R1
X
4
5e-k
6a-j
5e-k
DHPM amides
R1
R2
R4
R5
X
Yields (%)b
DHPM R1
R2
R4
X
O
Conditionsa Yield (%)b Product
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
Me
H
H
H
H
H
H
Me
H
H
H
Me
2-Cl
4-Me
4-Br
3-NO2
H
Me
Ph
Bn
Bn
Pr
Bn
Bn
Bn
Pr
Pr
Pr
Bn
O
O
O
O
S
S
O
S
84
88
89
87
60
51
37
57
52
54
4Cbb
4Acb
4Dab
4Eab
4Ccb
4Bcb
Me 3-NO2 Me
rt
MW
82
49
5e
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
Me
Me
Me
S
rt
MW
64
59
5f
4-Cl
4-Br
O
O
S
rt
MW
73
60
5g
5h
5i
rt
MW
73
58
S
O
6j
3-NO2
3-NO2 Me
rt
MW
57
56
a
For conditions, see Section 4.
Yields are isolated yields of pure product.
b
4-Me
2-Cl
Me
Me
S
rt
MW
56
61
5j
the amine component from the reaction mixture, affording
a clean conversion to the corresponding DHPM amides
(6a–j) (by HPLC monitoring). It was also evident that short
term microwave heating (5 min) of the reaction mixture re-
sulted mostly in the formation of the corresponding DHPM
hydroxybenzotriazole active ester, retaining the unreacted
starting amine (monitored by HPLC). The integration of
a polymer-supported carbodiimide as an acid activating re-
agent (readilyremovedbysimplepost-reaction filtration)and
a subsequent purification of the filtrate by filtering through
a pre-packed Si-carbonate SPE cartridge,20 aided a high
throughput delivery of the corresponding DHPM amides
6a–j (see Table 4) in high purity after solvent evaporation.21
4Fcb
S
rt
MW
63
59
5k
a
Conditions: rt: room temperature deallylation with 5 mol % Pd(PPh3)4 in
THF (ca. 5 mmol, 25 ꢀC, 4–5 h); MW: microwave-assisted deallylation
with 5 mol % Pd(PPh3)4 in THF (0.6–0.7 mmol, 100 ꢀC, 20 min). See
Section 4 for details.
b
Yields are isolated yields of pure product.
debenzylation or a deallylation strategy. The acid cores 5a–k
were used as starting materials in a subsequent microwave-
assisted decoration procedure to synthesize libraries of
DHPM C5 amides.
2.5. Microwave-induced polymer-assisted solution
phase synthesis of DHPM C5 amides from diverse
DHPM acids 5 and selected amines
2.6. Microwave-assisted Mitsunobu esterifications of
DHPM C5 acids using fluorous synthesis and
purification strategies
The multifunctionalized DHPM C5 carboxylic acids 5a–j
prepared by conventional and microwave-induced debenzyl-
ation and deallylation strategies were subsequently utilized
as platforms to introduce structural diversity on the C5
position of the DHPM heterocycle. We subjected the
DHPM acids 5a–j to an existing rapid analoging amidation
protocol20 involving a polymer-assisted solution phase
microwave-assisted synthesis and purification by solid-phase
extraction (SPE). A simple representative set of amides was
prepared in moderate to high yields, using benzylamine and
propylamine as the starting amines. The polymer-
assisted solution phase (PASP) microwave synthesis of the
corresponding DHPM C5 amides was best afforded using
DMA (N,N-dimethylacetamide) as the solvent. The highly
polar DMA as the solvent ensured complete homogeneity
of the reaction mixture (excluding the polymer-supported
carbodiimide resin) and effective microwave heating of the
reaction mixture. On the other hand, the use of solvents
such as acetonitrile gave compromising yields, and at
instances showed uncharacterizable by-products and/or in-
complete conversions (by HPLC). In case of DMA as the
solvent, 15 min of microwave heating was found sufficient
to completely consume the starting DHPM acids (5a–j) and
For the synthesis of DHPMs with more diverse and novel C5
ester moieties we wanted to perform esterification reactions
employing a Mitsunobu protocol. The Mitsunobu reaction is
a versatile method for the condensation of alcohols with var-
ious acidic nucleophiles promoted by triphenylphosphine
(TPP) and diethyl- or diisopropyl azodicarboxylate
(DEAD or DIAD) as the classical set of Mitsunobu re-
agents.22 Since there are considerably more alcohols com-
mercially available compared to b-ketoesters, diversity can
potentially very rapidly be introduced at this position start-
ing from DHPM C5 acids 5. Nevertheless, the drawback of
Mitsunobu protocol is the purification step, which usually
requires a careful chromatography to separate the product
from many by-products of this transformation (triphenyl-
phosphine oxide, hydrazide, and excess alcohol) and there-
fore limits this reaction in the context of combinatorial/
high throughput synthesis. Therefore, several strategies
have been investigated to facilitate the purification step, em-
ploying, for example, polymer-bound or fluorous Mitsunobu
reagents.23–26
For the esterification of DHPM C5 acids 5 we decided ini-
tially upon a protocol using a combination of the fluorous

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B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
Table 5. Synthesis of C5-esters using a fluorous Mitsunobu protocol
Mitsunobu (F-Mitsunobu) reagents diphenyl-[4-(1H,1H,
2H,2H-perfluorodecyl)phenyl]phosphine 8 (F-TPP) and
bis(1H,1H,2H,2H,3H,3H-perfluorononyl) azodicarboxylate
9 (F-DIAD, Chart 2). Compared to polymer-bound reagents,
which cannot be employed concurrently in this process and
create heterogeneous reaction mixtures (therefore leading to
slower reactions), fluorous reagents enable classical solution
phase reaction conditions. They are soluble in most organic
solvents like THF, DCM or MeOH, creating homogeneous
reaction conditions, and due to the fluorous tag, product iso-
lation can be easily performed by a fluorous solid-phase
extraction (F-SPE) through fluorous silica gel.27
1. F-TPP, F-DIAD (1.8 equiv each)
O
Ph
O
Ph
THF
R7
MW, 110 °C, 30 min
H
O
NH
O
NH
2. F-NCO (scavenging)
MW, 110 °C, 30 min
3. F-SPE (purification)
Me
N
R1
O
Me
N
R1
O
5a,c
7a-e
Entry
DHPM esters
R1
R7
Yield (%)a
1
2
3
4
5
7a
7b
7c
7d
7e
H
n-Bu
30b,c
69b
44c
46c
43
Me
Me
Me
Me
3-F-PhCH2
n-Pr
i-Pr
Cyclohexyl
O
O
a
C8F17(CH2)2
PPh2
Yields are isolated yields.
Mitsunobu reaction at 110 ꢀC for 10 min.
No scavenging step.
C6F13
O
N
N
O
C6F13
b
c
8
9
Chart 2.
tion to the N1-substituted DHPM C5 acid 5c (R1¼Me). The
same reaction conditions have been employed for the reac-
tion with 3-fluorobenzyl alcohol (Table 5). The only issue
that had to be considered for this non-volatile alcohol was
the removal of excess alcohol after the reaction, since
1.8 equiv of the alcohol were used. Therefore, we wanted
to introduce a scavenging step by again using a fluorous
reagent. We selected fluorous isocyanate 10 (F-NCO, 2-
(perfluorooctyl)ethyl isocyanate, Chart 3) as electrophilic
scavenger, which has been previously employed as scaven-
ger for amines.30 After some scavenging optimizations, we
found that 3.2 equiv of the F-NCO reagent and 4 equiv of
Et3N (in relation to the DHPM C5 acid) were necessary to
remove all the remaining acid. The scavenging step was
best performed under microwave irradiation at 110 ꢀC for
30 min. Note that the scavenging step for this particular
reaction with 3-fluorobenzyl alcohol could be performed
within 15 min, furnishing full conversion. In other cases (en-
try 5, Table 5) the time for scavenging of excess alcohol was
prolonged to 30 min. Subsequent F-SPE and acid removal by
filtration through a cartridge filled with Amberlite IRA-900
resin provided product 7b in 69% isolated yield and 96% pu-
rity.
For our initial optimization experiments we utilized the
DHPM acid 5a (R1¼H) and n-butanol as primary alcohol
and made investigations on appropriate solvents, tempera-
ture, time, and molar ratios of the reaction partners. The
best conditions turned out to be THF as solvent, 1.8 equiv
each of the alcohol, F-TPP, and F-DIAD, and microwave
irradiation at 110 ꢀC for 10 min. With this set of conditions
a conversion of 80% (HPLC) could be achieved. Reducing
or increasing the temperature did not improve the conver-
sion. By adding more equivalents of the reagents a slight
increase in product concentration could be established by
HPLC analysis, but due to the rather high cost of the fluorous
reagents we decided to limit the amount of reagents to
1.8 equiv. Although it is known for Mitsunobu chemistry
that the sequence of adding individual reagents can be cru-
cial for the success of the reaction,22,25 in our case a different
order of reagent addition did not improve the conversion (for
more details on the reaction conditions, see Section 4). After
the completion of the reaction the F-reagents and F-by-prod-
ucts were removed by F-SPE. By eluting the reaction mix-
ture with 80% MeOH in H2O the F-reagents are retained
on the F-silica and the ‘organic’ compounds can be easily
separated. Since in our case only an 80% conversion was
reached, some unreacted acid 5a remained in the reaction
mixture. For the removal of unreacted acid the mixture
was subsequently passed through a cartridge filled with basic
ion exchange Amberlite IRA-900 resin in carbonate form.28
After evaporation of the solvent, the DHPM C5 ester 7a was
obtained in 95% purity. Unfortunately isolated product
yields remained in the 30% region and could not be im-
proved (Table 5). For secondary or other primary alcohols
(like 3-fluorobenzyl alcohol), unsatisfactory conversion
and very low isolated product yields were obtained. We as-
sumed that perhaps the free N1–H moiety could somehow
interfere with the reactivity of the acid, although no N1-
alkylation was observed. In a previous publication we have
shown that for the N1-alkylation of the DHPMs the more
reactive Mitsunobu reagents tributylphosphine (TBP) in
combination with N,N,N0,N0-tetramethyl azodicarboxamide
(TMAD) have to be used since the pKa of the nucleophilic
NH was too high.29
NCO
C8F17
10
Chart 3.
For DHPM acid precursor 5c, reasonable yields and pu-
ritiesꢁ94% could also be achieved for secondary alcohols
such as i-propanol (46%) and cyclohexanol (43%) (Table
5), requiring an increased reaction time of 30 min at
110 ꢀC as compared to 10 min for primary alcohols. How-
ever, the above mentioned fluorous protocol failed for
more complex alcohols such as 1-butynol or longer chained
alcohols like hexanol.
2.7. Reactivity studies of the fluorous Mitsunobu
reagents F-TPP and F-DIAD
In summary, rather unsatisfactory results were obtained by
applying the F-Mitsunobu protocol. Since full conversion
could only be reached in a single case (entry 2, Table 5)
and the subsequent purification steps turned out to be more
Since the results for the esterification of the N1–H DHPM C5
acid 5a have been rather disappointing, we turned our atten-

B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
Table 7. Synthesis of C5-esters via a classical Mitsunobu protocol
R2
4657
Table 6. Reactivities of F-TPP and F-DIAD
Ph
Ph
R2
Mitsunobu reagents
i-propanol, THF
HO2C
i-PrO2C
NH
NH
O
O
TPP, DIAD (1.5 eq each)
THF
MW, 110 °C, 30 min
R7
Me
N
O
Me
N
O
O
NH
O
HO
Me
NH
R7 OH
Me
Me
rt, 0.5-10 min
Me
N
R1
N
R1
O
5c
7d
Yield (%)a
7b-r
17 examples
Entry
Mitsunobu reagents
5a,c,e
1
2
3
4
TPP/DIAD
75
71
49
36b
F-TPP/DIAD
TPP/F-DIAD
TPP/F-DIAD
Entry DHPM acid
Alcohol
OH
OH
t (min) Yield (%)a Product
1
2
3
4
5a
5c
5a
5c
5
0.5
10
10
80
7f
96
7c
7g
7d
a
Yields are isolated yields.
rt, overnight.
26b
75b
b
5
6
5a
5c
5
0.5
82
86
7h
7i
OH
OH
troublesome than expected, we performed reactivity studies
on the F-Mitsunobu reagents. For these investigations, we
examined Mitsunobu esterification of the N1-methyl-
DHPM acid 5c with i-propanol under several different con-
ditions (Table 6). Initial experiments were performed with
the classical Mitsunobu tandem TPP/DIAD using the opti-
mized conditions of the F-Mitsunobu protocol for secondary
alcohols (MW, 110 ꢀC, 30 min). After column chromatogra-
phy, product 7d could be isolated in 75% yield with 99% pu-
rity, which was an improvement of 30% in yield compared to
the F-Mitsunobu procedure. In a direct comparison experi-
ment the combinations F-TPP/DIAD and TPP/F-DIAD
were subsequently compared. By using the F-TPP/DIAD
tandem nearly the same isolated yield (71%) was obtained
after column chromatography compared to the ‘all non-fluo-
rous’ TPP/DIAD combination (75% yield). Applying the
TPP/F-DIAD combination, an isolated yield of only 49% af-
ter column chromatography could be achieved. We therefore
conclude that F-DIAD has considerably lower reactivity in
these esterifications as compared to standard DIAD. Longer
reaction times did not lead to higher conversions. Similarly,
performing the reaction at room temperature over night also
did not increase the yield (entry 4, Table 6). As these studies
indicate, it is the lower reactivity of the F-DIAD reagent,
which limits the reaction progress.
F
5
0.5
92
98
7j
7b
7
8
5a
5c
9
10
5a
5c
5
0.5
79
89
7k
7l
OH
O
11
12
5a
5c
5
0.5
70
99
7m
7n
OH
13
14
5a
5c
5
0.5
63
83
7o
7p
OH
H
O
15
16
5c
5c
5e
10
43b
56b
86
7e
7q
7r
OH
OH
O
10
10
17
OH
a
Yields are isolated yields.
Alcohol, TPP, and DIAD, each of 1.8 equiv.
b
sion in the case of N1-methyl (5c) and 50% for the N1-
unsubstituted acid (5a). Longer reaction times or more
equivalents of reagents did not improve the conversion.
2.8. Mitsunobu esterifications of DHPM C5 acids
using classical reaction conditions
With these optimized protocols for primary and secondary
alcohols we now prepared a set of 17 examples of DHPM
C5 esters (Table 7). After purification by standard column
chromatography, the products 7b–7r could be obtained in
moderate to excellent yields (26–99%) and in puritiesꢁ97%.
The yields for the N1–H DHPM esters are in general some-
what lower than those for the N1-methyl products, especially
if a secondary alcohol such as i-propanol is used (26% yield
compared to 75%, see Table 7). If more hindered secondary
alcohols, like cyclohexanol (entry 15) or the racemic 1-
2(furyl)-1-propanol (entry 16) are employed in the reaction
with N1-methyl DHPM acid, yields are moderate and in the
case of cyclohexanol identical to that of the F-Mitsunobu
protocol (43%, see also Table 5).
Since we could not achieve satisfactory results for the ester-
ification of the DHPM acids 5 via the F-Mitsunobu reaction,
we therefore decided to use the classical Mitsunobu condi-
tions (TPP/DIAD), which have shown to be superior in yield
(see Table 6).
Further optimizations with respect to temperature, time, and
molar equivalents of reagents with both N1–H (5a) and N1-
methyl (5c) DHPM acids were performed with n-propanol
and i-propanol using the TPP/DIAD reagent couple. Ulti-
mately, we discovered that only 1.5 equiv each of propanol,
TPP, and DIAD were sufficient at room temperature to ob-
tain full conversion according to HPLC analysis. The reac-
tion times for both 5a and 5c were surprisingly very short:
5 min for the N1–H analog 5a and only 30 s for the N1-
methyl DHPM acid 5c. For the reaction with i-propanol
1.8 equiv each of alcohol, TPP, and DIAD were necessary
for 10 min at room temperature for achieving 78% conver-
3. Conclusion
In conclusion, the efficiency of high speed sequential batch
and parallel microwave synthesis has been applied to

4658
B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
generate a set of multifunctionalized dihydropyrimidinone
esters. An easy access to the valuable carboxylic acid plat-
form on the multifunctionalized DHPM heterocycle was
found by microwave-assisted ester deprotections. The scope
of flow methodology for high purity and throughput delivery
of DHPM acid precursors have also been demonstrated. A
rapid microwave-induced polymer-assisted solution phase
(PASP) analoging protocol has been instrumental to intro-
duce structural diversity, in the form of DHPM C5 amides.
By applying a standard Mitsunobu protocol we were able
to synthesize DHPM C5 esters with novel functionalities
at the C5 position in excellent yields and in very short reac-
tion times.
2.450 GHz (Biotage AB, Uppsala).9 Reaction times refer
to hold times at the temperatures indicated, not to total irra-
diation times. The temperature was measured with an IR
sensor on the outside of the reaction vessel.
All microwave scale-up synthesis has been performed in
a Synthos 3000 multimode batch reactor (Anton Paar
GmbH).14 The instrument is equipped with two magnetrons,
operating at a frequency of 2.45 GHz with continuous micro-
wave output power from 0 to 1400 W. The reactor cavity en-
compasses a 16-vessel rotor and its protection lid. The rotor
carries 16 reaction vessels, which are 100 mL PTFE–TFM
(maximum filling volume 60 mL) made, equipped with
a pressure releasevalve on its seal and individually resting in-
side ceramic jackets, to enable reactions under high pressure
(maximum pressure 40 bars). The temperature is monitored
using an internal gas balloon thermometer placed in one ref-
erence vessel and additionally by exterior IR thermography.
4. Experimental
4.1. General
Fluorous reagents were obtained from Fluorous Technolo-
gies Inc. (F-TPP: F017039, F-DIAD: F026100, F-NCO:
F017032, F-Silica: 801-0100B). Amberlite IRA-900 Cl ion
exchange resin was obtained from Acros (202315000).
THF used for Mitsunobu reaction was obtained from Aldrich
(puriss; over molecular sieve, 87371). Solvents for column
chromatography have been distilled prior to use. TLC analy-
sis was performed on Merck precoated 60 F254 plates. Melt-
ing points were obtained on a Gallenkamp melting point
apparatus, Model MFB-595 in open capillary tubes. 1H
NMR and 13C NMR spectra were recorded on Bruker
AMX360 and 500 instruments in CDCl3 or DMSO-d6. IR
spectra were taken on a Perkin–Elmer 298 spectrophotome-
ter in KBr pellets. Mass spectra were taken on a Hewlett-
Packard LC/MSD 1100 series instrument in the atmospheric
pressure chemical ionization (negative or positive APCI)
mode. HPLC analysis was carried out on two different Shi-
madzu systems. The Shimadzu LC-10 includes LC10-AT
(VP) pumps, an autosampler (S-10AXL), and a dual wave-
length UV detector. The separations were carried out using
a C18 reversed phase analytical column, LiChrospher 100
(E. Merck, 100ꢂ3 mm, particlesize 5 mm)at 25 ꢀC and a mo-
bile phase from (A) 0.1% TFA in 90:10 water/MeCN and (B)
0.1% TFA acid in MeCN (all solvents were HPLC grade,
Acros; TFA was analytical reagent grade, Aldrich). The fol-
lowing gradient was applied: linear increase from solution
30% B to 100% B in 7 min, hold at 100% solution B for
2 min. The Shimadzu LC-20 system includes an LC-20AD
pump, an SIL-20A autosampler, a diode array detector
(SPD-M20A), a column oven (CTO-20A), and a degasser
(DGU-20A5). The separations were carried out using a Path-
finderÒAS100 reversed phase analytical column (150ꢂ
4.6 mm, particle size 5 mm) at 25 ꢀC and a mobile phase
from (A) 0.1% TFA in 90:10 water/MeCN and (B) 0.1%
TFA acid in MeCN (all solvents were HPLC grade, Acros;
TFA was analytical reagent grade, Aldrich). The following
gradient was applied: linear increase from solution 20% B
to 100% B in 7 min, hold at 100% solution B for 1 min.
4.3. Continuous flow hydrogenations
All hydrogenations (O-benzyl deprotections) were con-
ducted in a flow manner using the H-CubeÔ (Thales Nano-
technology Inc.)18 operating at 0–100 bars of in situ H2
pressure and up to 100 ꢀC of maximum temperature with
an HPLC-like platform and a maximum flow rate of 9 mL/
min. The benzyl deprotections were catalyzed by 10% Pd/
C (average particle size: 32–40 microns) catalyst beds (Cat-
CartÔ), used as available from Thales and were deactivated
after usage by introduction into sodium bisulfite solution.
4.4. General procedure for microwave-assisted
synthesis of DHPM benzyl/allyl esters 4 (4 mmol)
A microwave process vial (2–5 mL) equipped with a mag-
netic stirrer bead was charged with the aldehyde 1A–F
(4 mmol), b-ketoester 3a–g (6 mmol), urea/thiourea 2a–c
(4 mmol), and Yb(OTf)3 (248 mg, 10 mol %) as the catalyst
in acetonitrile (3 mL). The process vial was sealed using an
aluminum crimp equipped with a Teflon septum. The sealed
vial was introduced in the microwave cavity using a robotic
gripper and microwave irradiated at a set temperature of
120 ꢀC for 20 min. After completion of irradiation time,
the reaction mixture was cooled to room temperature
through rapid gas-jet cooling and the desired DHPM was
isolated (Fig. 2). In most instances the DHPM products pre-
cipitated from the reaction mixture upon cooling to room
temperature. In the synthesis of compounds 4Aba, 4Cbb,
4Acb, 4Dab, 4Eab, 4Ccb, and 4Fcb the reaction mixture
was poured over crushed ice after the irradiation to induce
complete precipitation of product. The precipitates were fil-
tered and washed with crushed ice–ethanol mixture to yield
HPLC pure products. For isolated yields see Table 1.
4.5. General procedure for microwave-assisted
synthesis of DHPM benzyl/allyl esters 4 (40 mmol)
Scale-up synthesis has been performed in a Synthos 3000
multimode batch reactor. The PTFE–TFM reaction vessels
are charged with Teflon coated stirrer bars. Reaction mix-
tures were prepared in individual vessels with a set of corre-
sponding aldehydes 1A–F (40 mmol), urea/thiourea 2a–c
(40 mmol), and b-diketoester 3a–g (60 mmol) components
4.2. Microwave irradiation experiments
Small scale microwave-assisted synthesis was carried out in
an EmrysÔ Synthesizer or Initiator 8 single-mode micro-
wave instrument producing controlled irradiation at

B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
4659
in 20 mL of acetonitrile (see Fig. 1 for building blocks). The
PTFE vessels were introduced in ceramic jackets, appropri-
ately sealed, and fitted into the rotor positions. The rotor
fitted with the sealed reaction vessels is equipped with its
protection lid and introduced in the reactor cavity. The reac-
tion mixtures are then irradiated at a preset temperature of
120 ꢀC for 20 min (with 3 min programmed ramp). After
completion of the reaction, the mixture is allowed to cool
to 40 ꢀC by a built-in fan-assisted cooling. The reaction mix-
tures are worked up individually and the product yields eval-
uated upon isolation.
4.5.8. Allyl 6-methyl-4-(4-bromophenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4Eab). Mp 195–
196 ꢀC. 1H NMR (DMSO-d6) d 2.26 (s, 3H), 4.48 (m, 2H),
5.07–5.12 (m, 2H), 5.13–5.14 (d, J¼3 Hz, 1H), 5.77–5.88
(m, 1H), 7.17–7.53 (m, 4H), 7.79 (br s, 1H), 9.30 (br s, 1H).
MS (ES+) m/z 351 (M+1).
4.5.9. Allyl 6-methyl-4-(3-nitrophenyl)-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4Ccb). Mp 182–
183 ꢀC. 1H NMR (DMSO-d6) d 2.33 (s, 3H), 4.51 (m, 2H),
5.07–5.12 (m, 2H), 5.34 (d, J¼3.6 Hz, 1H), 5.77–5.88
(m, 1H), 7.67–8.18 (m, 4H), 9.97 (br s, 1H), 10.55 (br s, 1H).
MS (ES+) m/z 333.9 (M+1).
Isolated yields: 4Aaa (48%), 4Aag (25%), 4Aba (36%),
4Baa (39%), 4Cbb (59%), 4Acb (60%), 4Dab (59%),
4Eab (66%), 4Ccb (47%), 4Bcb (76%), and 4Fcb (17%).
4.5.10. Allyl 6-methyl-4-tolyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (4Bcb). Mp 161–162 ꢀC.
1H NMR (DMSO-d6) d 2.26 (s, 3H), 2.29 (s, 3H), 2.49
(s, 3H), 4.49 (m, 2H), 5.08–5.13 (m, 2H), 5.14–5.15
(d, J¼3.9 Hz, 1H), 5.78–5.88 (m, 1H), 7.08–7.15 (m, 4H),
9.64 (br s, 1H), 10.34 (br s, 1H). MS (ES+) m/z 303 (M+1).
4.5.1. Benzyl 6-methyl-4-phenyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (4Aaa). Mp 166 ꢀC (lit.15d
168 ꢀC). 1H NMR (DMSO-d6) d 2.26 (s, 3H), 5.01–5.03 (m,
2H), 5.15 (d, J¼2.8 Hz, 1H), 7.13–7.29 (m, 10H), 7.75 (br
s, 1H), 9.26 (br s, 1H). MS (ES+) m/z 323.1 (M+1).
4.5.11. Allyl 6-methyl-4-(2-chlorophenyl)-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (4Fcb). Mp
4.5.2. Benzyl 4,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (4Aag). Mp 210 ꢀC (lit.15d 209 ꢀC).
1H NMR (DMSO-d6) d 4.79 (m, 2H), 5.26 (d, J¼3.6 Hz),
6.79–7.38 (m, 15H), 7.88 (br s, 1H), 9.33 (s, 1H). MS
(ES+) m/z 385.2 (M+1).
1
107–108 ꢀC. H NMR (DMSO-d6) d 2.340 (s, 3H), 4.43
(m, 2H), 4.93–5.05 (m, 2H), 5.65 (d, J¼3.2 Hz, 1H), 5.68–
5.79 (m, 1H), 7.27–7.42 (m, 4H), 9.61 (br s, 1H), 10.41
(br s, 1H). MS (ES+) m/z 323.1 (M+1).
4.5.3. Benzyl 1,6-dimethyl-4-phenyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (4Aba). Mp 119–120 ꢀC
4.6. General procedure for the microwave-assisted
synthesis of DHPM acids 5a–d by catalytic transfer
hydrogenation
1
(lit.15d 118 ꢀC). H NMR (DMSO-d6) d 2.51 (s, 3H), 3.10
(s, 3H), 5.03–5.11 (m, 2H), 5.17 (d, J¼3.6 Hz, 1H), 7.16–
7.29 (m, 10H), 7.96 (d, J¼3.8 Hz, 1H). MS (ES+) m/z
337.2 (M+1).
A microwave process vial (2–5 mL) equipped with a mag-
netic stirrer bead was charged with 0.60 mmol of the appro-
priate DHPM C5 benzyl ester 4Aaa, 4Aag, 4Aba or 4Baa,
5% Pd/C (10% w/w), and ammonium formate (0.37 mg,
10 equiv) in methanol (3 mL). The process vial was sealed
with an aluminum crimp equipped with a Teflon septum. The
sealed vial was introduced in the microwave cavity using
a robotic gripper and microwave irradiated at a set tempera-
ture of 120 ꢀC for 20 min. After completion of the irradia-
tion, the reaction mixture was cooled to room temperature,
the contents transferred to a round bottom flask, and evapo-
rated to dryness. The residue was treated with 0.5 M KOH
solution (5–8 mL), stirred vigorously, and filtered under
gravity. The filtrate was acidified with 2 M HCl to pH 4–5
and the resulting precipitates of the corresponding 4-aryl-
DHPM C5 acids 5a–d were collected by suction filtration
and recrystallized from ethanol. For yields refer to Table 2.
4.5.4. Benzyl 6-methyl-4-tolyl-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4Baa). Mp 170–171 ꢀC. 1H
NMR (DMSO-d6) d 2.25 (s, 3H), 2.26 (s, 3H), 3.32 (s, 3H),
4.97–5.06 (m, 2H), 5.12 (d, J¼3.2 Hz, 1H), 7.06–7.28
(m, 9H), 7.69 (br s, 1H), 9.22 (br s, 1H). MS (ES+) m/z
337.2 (M+1).
4.5.5. Allyl 1,6-dimethyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4Cbb). Mp 125–
1
126 ꢀC (lit.9a 122–123). H NMR (DMSO-d6) d 2.49 (s,
3H), 3.11 (s, 3H), 4.53 (m, 2H), 5.08–5.13 (m, 2H), 5.31
(d, J¼3.9 Hz, 1H), 5.81–5.88 (m, 1H), 7.64–7.67 (m, 2H),
8.06 (br s, 1H), 8.12–8.18 (m, 2H). MS (ES+) m/z 332.1
(M+1).
4.5.6. Allyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (4Acb). Mp 154–155 ꢀC.
1H NMR (DMSO-d6) d 2.30 (s, 3H), 4.50 (br, 2H), 5.05–
5.10 (m, 2H), 5.19 (br, 1H), 5.78–5.86 (m, 1H), 7.20–7.34
(m, 5H), 9.67 (s, 1H), 10.37 (s, 1H). MS (ES+) m/z 288.9
(M+).
4.7. General procedure for the continuous flow
hydrogenation of DHPM C5 benzyl esters 4
A hydrogenation flow apparatus (H-CubeÔ) capable of gen-
erating hydrogen gas in situ (100 bars and 100 ꢀC system
temperature) has been utilized for the synthesis of the
DHPM C5 carboxylic acids 5a–d by a continuous flow
O-benzyl deprotection of DHPM C5 benzyl esters 4 (Table
2). Stock solutions (0.60 mmol, 0.025 M) of the DHPM ben-
zyl esters (4Aaa, 4Aag, 4Aba, 4Baa, Fig. 2) were prepared
in 30% AcOH in EtOH (25 mL). The H-CubeÔ was equip-
ped with a fresh 5% Pd/C catalyst (CatCartÔ) column and
then purged with the solvent mixture (30% AcOH in
4.5.7. Allyl 6-methyl-4-(4-chlorophenyl)-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4Dab). Mp 174–
176 ꢀC. 1H NMR (DMSO-d6) d 2.26 (s, 3H), 4.48 (m, 2H),
5.06–5.11 (m, 2H), 5.15–5.16 (d, J¼3.2 Hz, 1H), 5.77–
5.88 (m, 1H), 7.23–7.40 (m, 4H), 7.79 (br s, 1H), 9.30
(br s, 1H). MS (ES+) m/z 306.9 (M+1).

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B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
EtOH). Initially, the solvent flow is regulated to 1 mL/min
while maintaining a low hydrogen pressure (ca. atmospheric
pressure) and the system temperature set to 40–45 ꢀC. The
solvent flow is allowed to equilibrate with the set conditions.
Thereafter, the reaction mixture stock solution is injected at
1 mL/min flow rate and exposed to the preset hydrogenation
conditions. The injected mixture is analyzed by continuous
sampling and the progress of the reaction is monitored by
HPLC. The entire cycle of 25 mL stock solution is com-
pleted in 25–30 min. The corresponding DHPM carboxylic
acids 5a–d were isolated in ca.100 mg quantities and yields
determined after evaporating the solvent from the collected
mixture after exposure to the hydrogenation conditions in
the H-CubeÔ (Table 2).
taining 6.0 mmol of the corresponding DHPM allyl esters
4Cbb, 4Acb, 4Dab, 4Eab, 4Ccb, 4Bcb, and 4Fcb,
5 mol % of Pd(PPh3)4 (0.346 mg), and diethyl amine
(4.38 g, 10 equiv) are prepared in 15 mL THF. The reaction
mixture is stoppered and allowed to stir at room tempera-
ture for 4–5 h to enable complete conversion. Thereafter,
the reaction mixture is evaporated to dryness under reduced
pressure and the solid residue is treated with 0.5 M KOH
solution (10–15 mL), vigorously stirred, and filtered under
gravity. The filtrate is acidified by 2 M HCl till pH 4–5 and
the resulting precipitates of the corresponding 4-aryl-
DHPM C5 carboxylic acids 5e–k are collected by suction
filtration and recrystallized from ethanol. For yields, see
Table 3.
4.8. General procedure for the room temperature
synthesis of DHPM acids 5a–d by catalytic transfer
hydrogenation
4.10.1. 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-phenylpyri-
midine-5-carboxylic acid (5a). Mp 210 ꢀC (lit.15d 210–
1
213 ꢀC). H NMR (DMSO-d6) d 2.22 (s, 3H), 5.09 (br s,
1H), 7.22–7.66 (m, 5H), 7.66 (br s, 1H), 9.07 (br s, 1H),
In 50 mL single neck round bottom flasks equipped with
magnetic stirrer beads, individual reaction mixtures of
6.0 mmol of the corresponding DHPM benzyl esters
4Aaa, 4Aag, 4Aba, and 4Baa, 5% Pd/C (10% w/w) and
ammonium formate (3.78 g, 10 equiv) are suspended in
15 mL of methanol. The reaction flask is sealed with a rubber
septum and a balloon maintained on it. After allowing the re-
action mixture to stir at room temperature for 8–10 h to en-
able complete reaction, the solvent is completely evaporated
under reduced pressure. The solid residue is treated with
0.5 M KOH solution (10–15 mL), vigorously stirred, and fil-
tered under gravity. The filtrate is acidified by 2 M HCl till
pH 4–5 and the resulting precipitates of the corresponding
DHPM carboxylic acids 5a–d are collected by suction filtra-
tion and recrystallized from ethanol. For yields, see Table 2.
11.88 (br s, 1H). MS (ES+) m/z 233.2 (M+1).
4.10.2. 1,2,3,4-Tetrahydro-2-oxo-4,6-diphenylpyrimi-
dine-5-carboxylic acid (5b). Mp 160 ꢀC (lit.15d 163 ꢀC).
1H NMR (DMSO-d6) d 5.22 (d, J¼3.6 Hz, 1H), 7.30–7.39
(m, 10H), 7.89 (br s, 1H), 9.13 (s, 1H). MS (ES+) m/z 295
(M+1).
4.10.3. 1,2,3,4-Tetrahydro-1,6-dimethyl-2-oxo-4-phenyl-
pyrimidine-5-carboxylic acid (5c). Mp 235 ꢀC (lit.15d
237 ꢀC). 1H NMR (DMSO-d6) d 2.48 (s, 3H), 3.07 (s, 3H),
5.12 (d, J¼3.9 Hz, 1H), 7.20–7.30 (m, 5H), 7.89 (d,
J¼3.2 Hz, 1H). MS (ES+) m/z 247 (M+1).
4.10.4. 1,2,3,4-Tetrahydro-6-methyl-2-oxo-4-p-tolylpyri-
1
midine-5-carboxylic acid (5d). Mp 220–223 ꢀC. H NMR
4.9. General procedure for the microwave-assisted
synthesis of DHPM acids 5e–k by palladium-catalyzed
O-deallylation
(DMSO-d6) d 2.21 (s, 3H), 2.25 (s, 3H), 5.14 (d,
J¼3.6 Hz, 1H), 7.11–7.12 (m, 4H), 7.62 (br s, 1H), 9.04
(br s, 1H), 11.84 (s, 1H). MS (ES+) m/z 247 (M+1).
A microwave process vial (2–5 mL) equipped with a mag-
netic stirrer bead was charged with 0.60 mmol of the corre-
sponding DHPM allyl esters 4Cbb, 4Acb, 4Dab, 4Eab,
4Ccb, 4Bcb, and 4Fcb, 5 mol % of Pd(PPh3)4 (0.034 g),
and diethyl amine (0.438 mg, 10 equiv) in THF (3 mL) as
the solvent. The process vial was sealed using an aluminum
crimp equipped with a Teflon septum. The sealed vial was
introduced in the microwave cavity using a robotic gripper
and microwave irradiated at a set temperature of 100 ꢀC
for 20 min. After completion of irradiation time, the reaction
mixture is cooled to room temperature through rapid gas-jet
cooling and the reaction mixture is transferred into a round
bottom flask and evaporated to dryness. To this residue
0.5 M KOH (5–8 mL) is added, vigorously stirred, and fil-
tered under gravity. The filtrate is acidified with 2 M HCl
to pH 4–5 and the resulting DHPM C5 carboxylic acid pre-
cipitates are filtered under suction and recrystallized from
ethanol. For yields, see Table 3.
4.10.5. 1,2,3,4-Tetrahydro-1,6-dimethyl-4-(3-nitro-
phenyl)-2-oxopyrimidine-5-carboxylic acid (5e). Mp
200–201 ꢀC. 1H NMR (DMSO-d6) d 2.49 (s, 3H), 3.08
(s, 3H), 5.26 (d, J¼3.9 Hz, 1H), 7.62–8.10 (m, 4H), 8.13
(br s, 1H), 12.34 (br s, 1H). MS (ES+) m/z 292.2 (M+1).
4.10.6. 1,2,3,4-Tetrahydro-6-methyl-4-phenyl-2-thioxo-
pyrimidine-5-carboxylic acid (5f). Mp 209–210 ꢀC. 1H
NMR (DMSO-d6) d 2.27 (s, 3H), 5.14 (d, J¼3.6 Hz, 1H),
7.20–7.34 (m, 5H), 9.72 (br s, 1H), 10.24 (br s, 1H). MS
(ES+) m/z 249.1 (M+1).
4.10.7. 4-(4-Chlorophenyl)-1,2,3,4-tetrahydro-6-methyl-
2-oxopyrimidine-5-carboxylic acid (5g). Mp 199–
200 ꢀC. 1H NMR (DMSO-d6) d 2.23 (s, 3H), 5.13 (d,
J¼3.4 Hz, 1H), 7.23–7.39 (m, 4H), 7.71 (br s, 1H), 9.16
(br s, 1H), 11.92 (br s, 1H). MS (ES+) m/z 267 (M+1).
4.10. General procedure for the room temperature
synthesis of DHPM acids 5e–k by palladium-catalyzed
O-deallylation
4.10.8. 4-(4-Bromophenyl)-1,2,3,4-tetrahydro-6-methyl-
2-oxopyrimidine-5-carboxylic acid (5h). Mp 174–
175 ꢀC. 1H NMR (DMSO-d6) d 2.22 (s, 3H), 5.08 (d,
J¼3.2 Hz, 1H), 7.17–7.53 (m, 4H), 7.70 (br s, 1H), 9.13
(br s, 1H), 11.92 (br s, 1H). MS (ES+) m/z 311.1 (M+1).
In 50 mL single neck round bottom flasks equipped with
a magnetic stirrer bead, individual reaction mixtures con-

B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
4661
4.10.9. 1,2,3,4-Tetrahydro-6-methyl-4-(3-nitrophenyl)-
2-thioxopyrimidine-5-carboxylic acid (5i). Mp 204–
205 ꢀC. 1H NMR (DMSO-d6) d 2.30 (s, 3H), 5.30 (d,
J¼3.6 Hz, 1H), 7.16–8.16 (m, 4H), 9.72 (br s, 1H), 10.42
(br s, 1H), 12.39 (br s, 1H). MS (ES+) m/z 294.1 (M+1).
4.11.3. N-Propyl-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-
4-phenyl-pyrimidine-5-carboxamide (6c). Mp 239–
241 ꢀC (MeCN). Anal. Calcd (C16H21N3O2) C, 66.88; H,
1
7.37; N, 14.62. Found: C, 66.85; H, 7.44; N, 14.62. H
NMR (DMSO-d6) d 0.74 (br, 3H), 1.33 (m, 2H), 2.09
(s, 3H), 3.02 (br, 5H), 5.15 (s, 1H), 7.18–7.30 (m, 5H),
7.60 (s, 1H), 7.81 (br, 1H); 13C NMR d 11.8, 16.8, 22.7,
29.7, 41.0, 54.3, 110.0, 126.5, 127.7, 128.8, 138.0, 144.2,
154.6, 167.3. MS (pos. APCI) m/z 288.2 (M+1).
4.10.10. 1,2,3,4-Tetrahydro-6-methyl-2-thioxo-4-p-tolyl-
pyrimidine-5-carboxylic acid (5j). Mp 208–209 ꢀC. 1H
NMR (DMSO-d6) d 2.25 (s, 3H), 2.26 (s, 3H), 2.49 (s,
3H), 5.09 (d, J¼3.6 Hz, 1H), 7.08–7.15 (m, 4H), 9.54 (br
s, 1H), 10.20 (br s, 1H), 12.14 (br s, 1H). MS (ES+) m/z
262.9 (M+1).
4.11.4. N-Benzyl-1,2,3,4-tetrahydro-6-methyl-2-oxo-4-
p-tolylpyrimidine-5-carboxamide (6d). Mp 223–226 ꢀC
(MeCN). Anal. Calcd (C20H21N3O2): C, 71.62; H, 6.31; N,
12.53. Found: C, 71.04; H, 6.22; N, 12.22. 1H NMR
(DMSO-d6) d 2.00 (s, 3H), 2.28 (s, 3H), 4.21 (br, 2H),
5.25 (br, 1H), 6.97–7.17 (m, 9H), 7.43 (s, 1H), 8.06
(br, 1H), 8.53 (s, 1H); 13C NMR d 17.4, 21.1, 42.2, 55.2,
105.4, 126.9, 127.4, 128.4, 129.3, 136.8, 137.8, 140.2,
141.8, 153.0, 166.8. MS (pos. APCI) m/z 336.4 (M+1).
4.10.11. 4-(2-Chlorophenyl)-1,2,3,4-tetrahydro-6-
methyl-2-thioxopyrimidine-5-carboxylic acid (5k). Mp
1
206–208 ꢀC. H NMR (DMSO-d6) d 2.31 (s, 3H), 5.58 (d,
J¼3.4 Hz, 1H), 7.25–7.43 (m, 5H), 9.49 (br s, 1H), 10.29
(br s, 1H), 12.12 (br s, 1H). MS (ES+) m/z 283 (M+1).
4.11. General procedure for the amidation of acids
to DHPM amides
4.11.5. N-Benzyl-1,2,3,4-tetrahydro-6-methyl-2-thioxo-
4-(2-chlorophenyl)-pyrimidine-5-carboxamide (6e). Mp
235–237 ꢀC. 1H NMR (DMSO-d6) d 1.98 (s, 3H), 4.13 (br,
1H), 4.26 (br, 1H), 5.68 (1H), 6.92–7.40 (m, 9H), 8.29 (s,
1H), 9.17(br, 1H), 9.86 (br, 1H); 13C NMR d 16.6, 42.5,
53.6, 106.6, 126.9, 127.2, 128.0, 128.5, 130.0, 132.2,
134.2, 139.7, 140.2, 166.2, 174.3. MS (pos. APCI) m/z
372.6 (M+1).
In a small microwave process vial (0.5–2.5 mL), a mixture
of the corresponding DHPM acids 2a–d (0.050 mmol), poly-
mer-supported carbodiimide (PS-carbodiimide, 1.29 mequiv/g
loading, Argonaut part no. 800370) (150 mg, 0.1 mmol,
2.0 equiv), 1-hydroxybenzotriazole (7 mg, 0.051 mmol),
and benzylamine or n-propylamine (0.050 mmol) was sus-
pended in N,N-dimethylacetamide (DMA) (2 mL). The pro-
cess vial was sealed appropriately, introduced into the
single-mode microwave cavity, and microwave irradiated
at 100 ꢀC for 15 min. After completion of the irradiation
time, the reaction vial was rapidly cooled to room tempera-
ture by compressed air (gas-jet cooling) and the mixture was
diluted with MeOH (2 mL). The reaction mixture was fil-
tered through a pre-packed column of Si-carbonate (1 g,
0.8 mmol/g loading, Silicycle Inc.) and washed with several
aliquots of MeOH (3ꢂ3 mL) under gravity. The filtrate col-
lected was evaporated under reduced pressure to yield the
corresponding DHPM amides as colorless solids in 37–
89% yield. The purity of those compounds was >95% by
4.11.6. N-Benzyl-1,2,3,4-tetrahydro-6-methyl-2-thioxo-
4-p-tolyl-pyrimidine-5-carboxamide (6f). Mp 216–
1
217 ꢀC. H NMR (DMSO-d6) d 2.03 (s, 3H), 2.28 (s, 3H),
4.17–4.28 (m, 2H), 5.27 (s, 1H), 6.98–7.19 (m, 9H), 8.26
(m, 1H), 9.30 (br, 1H), 9.81 (s, 1H); 13C NMR d 16.8,
21.1, 42.5, 55.2, 107.2, 126.9, 127.0, 127.4, 128.4, 129.4,
135.0, 137.3, 139.9, 140.5, 166.4, 174.2. MS (pos. APCI)
m/z 352.5 (M+1).
4.11.7. N-Propyl-1,2,3,4-tetrahydro-6-methyl-2-oxo-
4-(4-bromophenyl)-pyrimidine-5-carboxamide (6g). Mp
234–236 ꢀC. Anal. Calcd (C15H18BrN3O2): C, 51.15; H,
1
5.15; N, 11.93. Found: C, 50.67; H, 4.95; N, 11.45. H
1
HPLC (215 nm) and H NMR analysis.
NMR (DMSO-d6) d 0.70 (t, J¼7.2 Hz, 3H), 1.32 (m, 2H),
1.97 (s, 3H), 2.90 (m, 2H), 5.21 (s, H), 7.15–7.18 (d, 2H),
7.49–7.52 (br, 2H), 7.55 (br, 1H), 7.57 (t, J¼5 Hz, 1H),
8.55 (s, 1H); 13C NMR d 11.7, 17.2, 22.7, 54.9, 105.3,
120.7, 129.0, 131.6, 134.4, 144.1, 153.0, 166.5. MS (pos.
APCI) m/z 352.5 (M+1).
4.11.1. N-Benzyl-1,2,3,4-tetrahydro-6-methyl-2-oxo-
4-phenyl-pyrimidine-5-carboxamide (6a). Mp 210–212 ꢀC
(MeCN). H NMR (DMSO-d6) d 2.02 (s, 3H), 4.22 (br,
1
2H), 5.30 (br, 1H), 6.96–7.31 (m, 10H), 7.49 (s, 1H), 8.10
(br, 1H), 8.56 (s, 1H); 13C NMR d 17.4, 42.5, 55.5, 105.2,
126.9, 127.0, 127.4, 127.7, 128.5, 128.8, 138.0, 140.2,
144.7, 153.0, 166.8. MS (pos. APCI) m/z 322.3 (M+1).
Anal. Calcd (C19H19N3O2): C, 71.01; H, 5.96; N, 13.08.
Found: C, 70.83; H, 5.96; N, 12.97.
4.11.8. N-Propyl-1,2,3,4-tetrahydro-6-methyl-2-thioxo-
4-(3-nitrophenyl)-pyrimidine-5-carboxamide (6h). Mp
240–241 ꢀC. 1H NMR (DMSO-d6) d 0.68 (t, J¼7.5 Hz,
3H), 1.30 (m, 2H), 2.03 (s, 3H), 2.96 (m, 2H), 5.40
(s, 1H), 7.65–7.70 (m, 2H), 7.81 (t, J¼5.2 Hz, 1H), 8.07
(s, 1H), 8.14 (d, J¼7.2 Hz, 1H), 9.45 (br, 1H), 10.0
(s, 1H); 13C NMR d 11.7, 16.8, 22.6, 54.7, 106.6, 121.6,
123.0, 130.7, 133.5, 135.6, 145.5, 148.2, 165.9, 174.7. MS
(pos. APCI) m/z 335.4 (M+1).
4.11.2. N-Benzyl-1,2,3,4-tetrahydro-2-oxo-4,6-diphenyl-
pyrimidine-5-carboxamide (6b). Mp 175–177 ꢀC (MeCN).
1H NMR (DMSO-d6) 3.83–3.89 (dd, J¼5.07, 5.42 Hz, 1H),
3.98–4.04 (dd, J¼6.21, 6.00 Hz, 1H), 5.26 (br, 1H), 6.67
(br, 2H), 7.10 (br, 3H), 7.34–7.36 (m, 10H), 7.49 (br, 1H),
7.55 (s, 1H), 8.68 (s, 1H); 13C NMR d 42.6, 56.5, 107.4,
126.8, 127.3, 127.3, 127.9, 128.4, 128.5, 128.8, 128.9,
129.4, 134.5, 144.1, 153.2, 166.9. MS (pos. APCI) m/z
384.6 (M+1).
4.11.9. N-Propyl-1,2,3,4-tetrahydro-6-methyl-2-thioxo-
4-phenyl-pyrimidine-5-carboxamide (6i). Mp 174–176 ꢀC.
1H NMR (DMSO-d6) d 0.71 (t, J¼7.2 Hz, 3H), 1.31
(m, 2H), 1.99 (s, 3H), 2.49–2.99 (m, 2H), 5.25 (s, 1H),

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B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
7.18–7.35 (m, 5H), 7.75 (t, J¼5.2 Hz, 1H), 9.30 (br, 1H),
9.81 (s, 1H); 13C NMR d 11.7, 16.7, 22.6, 55.9, 107.6,
108.4, 126.8, 128.0, 128.9, 139.4, 166.3. MS (pos. APCI)
m/z 290.4 (M+1).
for N1-unsubstituted products. For the products 7k and 7l
a mixture of hexane/THF and for 7p hexanes/EtOAc were
used. For yields and purities see text and Table 7.
4.13.1. 3-Fluorobenzyl 1-methyl-6-methyl-4-phenyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (7b).
1H NMR (CDCl3) d 2.57 (s, 3H), 3.26 (s, 3H), 5.01–5.05
and 5.09–5.13 (2m, 2H), 5.40 (d, J¼2.9 Hz, 1H), 5.58 (br
s, 1H), 6.79 (d, J¼9.5 Hz, 1H), 6.91–7.01 (m, 2H), 7.19–
7.31 (m, 6H). MS (ES+) m/z 355.5 (M+1).
4.11.10. N-Benzyl-1,2,3,4-tetrahydro-1,6-dimethyl-2-
oxo-4-(3-nitrophenyl)-pyrimidine-5-carboxamide (6j).
Mp 241–242 ꢀC. 1H NMR (DMSO-d6) d 2.16 (s, 3H), 3.05
(s, 3H), 4.17–4.23 (dd, J¼5.7, 5.7 Hz, 1H), 4.25–4.31 (dd,
J¼6.12, 6.12 Hz, 1H), 5.35 (s, 1H), 6.99–7.01 (m, 1H),
7.16–7.18 (m, 3H), 7.59–7.67 (m, 2H), 7.82 (d, J¼2.5 Hz,
1H), 8.06 (br, 1H), 8.13–8.15 (m, 1H), 8.38–8.42 (m, 1H);
13C NMR d 17.0, 29.8, 53.9, 108.0, 121.5, 122.8, 127.0,
127.4, 128.5, 130.5, 133.6, 139.8, 140.0, 146.2, 148.2,
153.5, 167.0. MS (pos. APCI) m/z 381.6 (M+1).
4.13.2. Propyl 1-methyl-6-methyl-4-phenyl-2-oxo-1,2,
3,4-tetrahydropyrimidine-5-carboxylate (7c). 1H NMR
(CDCl3) d 0.85 (t, J¼7.4 Hz, 3H), 1.54–1.64 (m, 2H),
2.54 (s, 3H), 3.25 (s, 3H), 4.02 (t, J¼6.6 Hz, 2H), 5.39
(d, J¼2.9 Hz, 1H), 5.58 (br s, 1H), 7.25–7.33 (m, 5H). MS
(ES+) m/z 289.5 (M+1).
4.12. General procedure for the synthesis of DHPM
C5 esters using a fluorous Mitsunobu protocol
4.13.3. i-Propyl 1-methyl-6-methyl-4-phenyl-2-oxo-1,2,
3,4-tetrahydropyrimidine-5-carboxylate (7d). 1H NMR
(CDCl3) d 1.06 (d, J¼6.2 Hz, 3H), 1.24 (d, J¼6.2 Hz, 3H),
2.52 (s, 3H), 3.25 (s, 3H), 4.94–5.04 (m, 1H), 5.38
(d, J¼2.7 Hz, 1H), 5.55 (br s, 1H), 7.25–7.33 (m, 5H). MS
(ES+) m/z 289.5 (M+1).
A small microwave vial (0.5–2 mL) was charged with
0.07 mmol of the corresponding DHPM acid 5a or c, F-TPP
(89 mg, 1.8 equiv), and anhydrous THF (0.5 mL). After stir-
ring for a few seconds, the corresponding alcohol (1.8 equiv)
and F-DIAD (106 mg, 1.8 equiv) were added, the vial was
capped, flushed with argon, and heated at 110 ꢀC for the
times given in Table 5. After cooling to 50 ꢀC, F-NCO re-
agent (110 mg, 3.2 equiv, 0.22 mmol) and Et3N (39 mL,
4 equiv, 0.28 mmol) were added and the vial was again
heated in the microwave reactor at 110 ꢀC for 30 min (entries
2 and 5, Table 5). Subsequently, the solvent was evaporated,
the mixture dissolved in ca. 300–400 mL MeOH, and passed
through a cartridge filled with 2.5 g of F-silica, which was
pre-conditioned with 5 mL THF and 15 mL H2O, with
8 mL of 80% MeOH in H2O. The solvent was evaporated
then the residue was dissolved in 0.5 mL of THF and passed
through a cartridge filled with 700 mg Amberlite IRA-900
resin in carbonate form (1.5 g for entries 3–5), which was
pre-conditioned with 8 mL MeOH and 10–20 mL THF,
with 10 mLTHF. The solvent was evaporated and the residue
was washed two times with toluene, which was also removed
by evaporation. For yields and purities see text and Table 5.
4.13.4. Cyclohexyl 1-methyl-6-methyl-4-phenyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (7e). 1H
NMR (CDCl3) d 1.22–1.54 (m, 9H), 1.82–1.85 (m, 1H),
2.54 (s, 3H), 3.24 (s, 3H), 4.74–4.79 (m, 1H), 5.40 (d,
J¼2.8 Hz, 1H), 5.57 (br s, 1H), 7.25–7.33 (m, 5H). MS
(ES+) m/z 329.4 (M+1).
4.13.5. Propyl 6-methyl-4-phenyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (7f). H NMR (DMSO-
1
d6) d 0.74 (t, J¼7.4 Hz, 3H), 1.47 (sex, J1¼6.9 Hz,
J2¼7.1 Hz, 2H), 2.26 (s, 3H), 3.83–3.94 (m, 2H), 5.14 (d,
J¼3.0 Hz, 1H), 7.22–7.34 (m, 5H), 7.73 (br s, 1H), 9.19
(br s, 1H). MS (ES+) m/z 275.7 (M+1).
4.13.6. i-Propyl 6-methyl-4-phenyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (7g). H NMR (DMSO-
1
d6) d 0.98 (d, J¼6.2 Hz, 3H), 1.15 (d, J¼6.2 Hz, 3H), 2.24
(s, 3H), 4.75–4.86 (m, 1H), 5.12 (d, J¼2.8 Hz, 1H), 7.22–
7.34 (m, 5H), 7.72 (br s, 1H), 9.16 (br s, 1H). MS (ES+)
m/z 275.3 (M+1).
4.12.1. Butyl 6-methyl-4-phenyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (7a). H NMR (DMSO-
d6) d 0.78 (t, J¼7.3 Hz, 3H), 1.09–1.19 (m, 2H), 1.39–1.47
(m, 2H), 2.25 (s, 3H), 3.86–3.99 (m, 2H), 5.13 (d,
J¼3.0 Hz, 1H), 7.21–7.35 (m, 5H), 7.73 (br s, 1H), 9.20
(br s, 1H). MS (ES+) m/z 289.1 (M+1).
1
4.13.7. 3-Butynyl 6-methyl-4-phenyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (7h). H NMR (DMSO-
1
d6) d 2.25 (s, 3H), 2.42–2.45 (m, 2H), 2.85 (br s, 1H),
3.95–4.07 (m, 2H), 5.14 (d, J¼2.8 Hz, 1H), 7.21–7.33
(m, 5H), 7.77 (br s, 1H), 9.24 (br s, 1H). MS (ES+) m/z
285.3 (M+1).
4.13. General procedure for the synthesis of DHPM C5
esters under classical Mitsunobu conditions
A small microwave vial (0.5–2 mL) was charged with
0.1 mmol of the corresponding DHPM acid 5a, 5c or 5e, tri-
phenylphosphine (TPP, 39 mg, 1.5 equiv), and anhydrous
THF (0.7 mL). After stirring for a few seconds, the corre-
sponding alcohol (1.5 equiv) and diisopropyl azodicarboxy-
late (DIAD, 29.5 mL, 1.5 equiv) were added and the mixture
was stirred for the time given in Table 7. For secondary alco-
hols, 1.8 equiv each of alcohol, TPP, and DIAD was used.
Subsequently, the solvent was evaporated and the reaction
mixture was purified by column chromatography using
DCM/EtOAc for N1-methyl substituted and CHCl3/acetone
4.13.8. 3-Butynyl 1-methyl-6-methyl-4-phenyl-2-oxo-1,2,
3,4-tetrahydropyrimidine-5-carboxylate (7i). 1H NMR
(CDCl3) d 1.97 (t, J¼2.5 Hz, 1H), 2.43–2.47 (m, 2H), 2.54
(s, 3H), 3.26 (s, 3H), 4.17 (t, J¼6.6 Hz, 2H), 5.40
(d, J¼3.0 Hz, 1H), 5.59 (br s, 1H), 7.26–7.33 (m, 5H). MS
(ES+) m/z 299.4 (M+1).
4.13.9. 3-Fluorobenzyl 6-methyl-4-phenyl-2-oxo-1,2,
3,4-tetrahydropyrimidine-5-carboxylate (7j). 1H NMR
(DMSO-d6) d 2.28 (s, 3H), 4.97–5.00 and 5.07–5.11 (2m,

B. Desai et al. / Tetrahedron 62 (2006) 4651–4664
4663
2H), 5.19 (d, J¼3.0 Hz, 1H), 6.88 (d, J¼10.0 Hz, 1H), 6.96
(d, J¼7.6 Hz, 1H), 7.06–7.11 (m, 1H), 7.20–7.34 (m, 6H),
7.77 (br s, 1H), 9.30 (br s, 1H). MS (ES+) m/z 341.4 (M+1).
(m, 1H), 5.28 (d, J¼3.5 Hz, 1H), 7.63–7.69 (m, 2H), 8.06
(br s, 1H), 8.12–8.14 (m, 2H). MS (ES+) m/z 334.5 (M+1).
4.13.10. cis-3,7-Dimethyl-2,6-octadien-1-yl 6-methyl-4-
phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxyl-
ate (7k). 1H NMR (DMSO-d6) d 1.52 (s, 3H), 1.60 (s, 3H),
1.67 (s, 3H), 1.99 (br s, 4H), 2.23 (s, 3H), 4.44 (d,
J¼7.0 Hz, 2H), 5.03 (br s, 1H), 5.12 (d, J¼2.6 Hz, 1H),
5.21 (t, J¼7.0 Hz, 1H), 7.20–7.31 (m, 5H), 7.73 (br s, 1H),
9.19 (br s, 1H). MS (ES+) m/z 369.3 (M+1).
Acknowledgments
The authors thank the Austrian Science Fund (FWF,
P15582) for financial support. The provision of microwave
reactors from Biotage AB (Uppsala) and Anton Paar
GmbH (Graz) is gratefully acknowledged. We also want to
thank Thales Nanotechnology Inc. for providing the hydro-
genation device and Fluorous Technologies Inc. for the sup-
ply of fluorous reagents.
4.13.11. cis-3,7-Dimethyl-2,6-octadien-1-yl 1-methyl-6-
methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (7l). 1H NMR (DMSO-d6) d 1.52 (s, 3H), 1.60
(s, 3H), 1.68 (s, 3H), 2.00 (br s, 4H), 2.46 (s, 3H), 3.08
(s, 3H), 4.43–4.53 (m, 2H), 5.04–5.05 (m, 1H), 5.13 (d,
J¼3.5 Hz, 1H), 5.23 (t, J¼6.8 Hz, 1H), 7.17–7.31 (m, 5H),
7.96 (br d, J¼3.6 Hz, 1H). MS (ES+) m/z 383.4 (M+1).
References and notes
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4.13.12. Furfuryl 6-methyl-4-phenyl-2-oxo-1,2,3,4-tetra-
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d6) d 2.22 (s, 3H), 5.00 (s, 2H), 5.11 (d, J¼3.1 Hz, 1H),
6.39–6.43 (m, 2H), 7.15–7.29 (m, 5H), 7.65 (d, J¼0.8 Hz,
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(M+1).
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1
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4664
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