A mild, efficient synthesis of gem -difluorodihydrouracils

Article abstract of DOI:10.1055/s-0029-1218587

Carbodiimides react effectively with -aryl/alkyl - hydroxy-,- difluorocarboxylic acids to afford a vast array of fully substituted gem-difluorodihydrouracils through a two step reaction sequence. In the first step, condensation between the two reactants leads in most cases to the formation of a mixture of the desired dihydrouracils and N-acylurea co-products. However, the latter could be easily recovered and efficiently converted into the target compounds. The sequence works well in very mild conditions (CHl 20C) and the reaction resulted to be completely regioselective when asymmetric carbodiimides were used. When the N-acylurea derivatives are not sufficiently stable for isolation, the process could be done in a one-pot fashion leading to the direct formation of the desired dihydrouracils, although in lower yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218587

PAPER
651
A Mild, Efficient Synthesis of gem-Difluorodihydrouracils
S
ynthesis of
g
r
em-Diflu
a
orodihydr
o
n
uracils cesca Olimpieri,a Santos Fustero,b Alessandro Volonterio,*,a Matteo Zanda*,c,d
a
Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘G. Natta’ del Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy
Fax +39(02)23993080; E-mail: alessandro.volonterio@polimi.it
b
c
d
Departamento de Quimica Organica, Universidad de Valencia, 46100 Burjassot, Spain
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK
C.N.R. – I.C.R.M., via Mancinelli 7, 20131 Milano, Italy
Received 19 October 2009
of biologically important compounds such as b-ureido-
alcohols and acids4 or a-substituted b-amino acids.5 To
date, the most utilized strategy to prepare substituted
DHUs is the strongly acidic or basic cyclization of b-ure-
Abstract: Carbodiimides react effectively with b-aryl/alkyl-b-hy-
droxy-a,a-difluorocarboxylic acids to afford a vast array of fully
substituted gem-difluorodihydrouracils through a two step reaction
sequence. In the first step, condensation between the two reactants
leads in most cases to the formation of a mixture of the desired di- idopropionic acids, obtained either from reactions of a,b-
unsaturated acids and urea derivatives6 or from b-amino
hydrouracils and N-acylurea co-products. However, the latter could
acids and isocyanates,7 which requires extended reaction
be easily recovered and efficiently converted into the target com-
pounds. The sequence works well in very mild conditions (CH2Cl2,
time, high temperature, and generally produces low
20 °C) and the reaction resulted to be completely regioselective
yields, or by hydrogenation of uracil derivatives.8 An al-
when asymmetric carbodiimides were used. When the N-acylurea
ternative synthesis of DHUs consists in the reductive de-
sulfurization of 2-thiobarbiturates9 though sodium
amalgam, Zn/HCO2H, Raney nickel or, more recently,
nickel boride.10 However, the latter methodologies suffer
from 1) low to moderate yield and 2) the starting 2-
thiobarbiturates have to be prepared by condensation be-
tween malonic acid derivatives and thiourea, which often
features modest yields due to the presence of side reac-
tions like hydrolysis of the malonate, decarbethoxylation,
transesterification, and urea degradation.11 For all these
reasons a better synthesis of DHUs is required.
derivatives are not sufficiently stable for isolation, the process could
be done in a one-pot fashion leading to the direct formation of the
desired dihydrouracils, although in lower yields.
Key words: N-heterocycles, fluorine, dihydrouracils, carbodi-
imide, domino reaction, N-acylureas
Many small synthetic organic molecules with high medic-
inal potential contain heterocyclic rings. The range of eas-
ily accessible and suitably functionalized heterocyclic
building blocks is, however, surprisingly limited and the
construction of even a small array of relevant heterocyclic
compounds is far from trivial. Heterocyclic chemistry
therefore continues to attract the attention of medicinal
and synthetic chemists, and the development of novel
methodologies allowing for efficient access to heterocy-
cles is still highly beneficial.1 One of the challenges of
medicinal chemistry is the promotion of the structural di-
versity of a ligand, which can be achieved by the attach-
ment of pharmacophoric groups to the rigidified
molecule. Small, substituted heterocyclic compounds of-
fer a unique possibility of different kinds and degrees of
substitution. In particular, 5,6-dihydrouracils (DHUs)
have been widely used in biological screenings resulting
in numerous pharmaceutical applications.2 C-Glucosylat-
ed DHUs have also proven to be C-linked analogues of N-
linked natural products.3 The observed activities usually
do not arise from the heterocycle itself, but from the dif-
ferent ligands that have been attached to it. For this reason
there is a lot of interest in developing new strategies for a
straightforward synthesis of substituted DHUs both in so-
lution and in solid phase. Furthermore, reductive or hy-
drolytic DHU ring opening has been used for the synthesis
Fluorine containing heterocyclic compounds have attract-
ed much interest because of their unique chemical, physi-
cal, and biological activities.12 Much attention has been
paid to pharmaceuticals and agricultural chemicals con-
taining a gem-difluoromethylene unit13 because many se-
lectively fluorinated analogues of biologically important
compounds exhibit a dramatic enhancement in terms of
biological activity and because the CF2 group is consid-
ered to be isopolar and isosteric with an ether oxygen.14 In
particular, significant efforts have been made toward the
synthesis of compounds containing a difluoromethylene
group adjacent to a carbonyl group1,3 because a,a-difluoro
ketones have been successfully used as inhibitors of hy-
drolytic enzymes, and greatly enhanced biological activi-
ty has been reported compared with their nonfluorinated
analogues.12 There are in general two complementary ap-
proaches to such an important unit. One is the substitution
of a carbonyl or an active methylene group by various
fluorinating agents derived from fluorine gas, and the oth-
er is the use of gem-difluoromethylene-containing build-
ing blocks. The former approach can be hardly applied to
complex molecules because of the low selectivity of
fluorinating reagents such as SF4 and diethylminosulfur
trifluoride (DAST). Instead, the latter approach is pre-
dominantly employed despite the limited availability of
gem-difluoromethylene-containing building blocks. Ex-
SYNTHESIS 2010, No. 4, pp 0651–0660
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Advanced online publication: 07.12.2009
DOI: 10.1055/s-0029-1218587; Art ID: Z21709SS
© Georg Thieme Verlag Stuttgart · New York

652
F. Olimpieri et al.
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Br
(EWG)H
EWG
O
OH
or
Ar
OH
R1
O
+
N
C
N
R2
R1
R1
Br
(EWG)H
O
N
N
H
O
or
Ar
O
EWG
O
N
R2
H
N
O
R2
O
O
O
O
H(EWG)
EWG
O
N acyl migration
N acyl migration
R1
Ar
R1
N
N
R2
N
N
R2
H
H
Br
R2
R2
R1
R1
N
N
N
N
or
(EWG)H
EWG
O
O
Ar
O
O
O
N acyl migration
R1
R1
in situ
2 N NaOH
O
O
N
N
NaH, DMF
(EWG)H
EWG
or
N
N
R2
R2
Ar
O
O
Scheme 1 One-pot, domino processes leading to 1,3,5-trisubstituted hydantoins
ploiting the building block methodology, a range of gem- ureas (NAUs) that could be cyclized to the target com-
difluoro heterocycles has been recently synthesized in- pounds.
cluding unsaturated lactams,15 dihydropyranones,16 g- and
The strategies above led to the formation of the target het-
erocycles in very mild conditions (room temperature,
b-lactams,17 and furanones18 among others.
As a part of a research program focused on the develop- avoiding the use of strong acids/bases) and in high yields
ment of novel, mild, and efficient procedures for the syn- making this methodology suitable for the preparation of
thesis of small heterocycles through the use of libraries of such compounds. We therefore decided to in-
carbodiimides,19 we wish to report the straightforward vestigate the use of this methodology for the preparation
synthesis of gem-difluoro-DHUs by means a new domino of N,N¢-disubstituted difluoro-DHUs 5 starting from dif-
process between easily accessible b-hydroxy-a,a-difluo- ferently substituted carbodiimides 4 and easily accessible
rocarboxylic acids and carbodiimides. In this paper, we b-hydroxy-a,a-difluorocarboxylic acids 3 (Scheme 2).
provide a full account on scope and limits of this new
methodology, which has been studied in detail.
O
OH
F
R1
R3
R2
F
Recently, we demonstrated that carbodiimides, when
treated with suitable carboxylic acids in the absence of a
nucleophile, are useful reagents for the synthesis of small
heterocycles, such as hydantoins19a–c and barbiturates.19d,e
The former could be synthesized by means of a regiospe-
cific domino process consisting in a condensation step be-
tween the two reactants, namely activated a,b-unsaturated
acids or a-haloarylacetic acids with carbodiimides, lead-
ing to the formation of O-acylisourea intermediates,
which undergo nucleophilic aza-Michael reaction or halo-
gen displacement, respectively, followed by final O → N
acyl migration step (Scheme 1). In some cases, the O →
N acyl migration process resulted to be competitive with
the nucleophilic step leading to the corresponding N-acyl-
COOH
N
N
R3
Br
COOEt
3
F
F
O
1
+
+
F
F
R1
N
C
N
R2
R3CHO
5
2
4
Scheme 2 Retrosynthetic analysis for the preparation of N,N¢-di-
substituted difluoro-DHUs
The key step of this sequence is the nucleophilic displace-
ment of the hydroxy group, or related leaving groups, by
the O-acylisourea intermediate or, more likely, by the N-
acylurea derivatives, which should be formed after the
condensation between 3 and 4 and subsequent O → N acyl
migration. In any case, this step is favored by the presence
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York

PAPER
Synthesis of gem-Difluorodihydrouracils
653
of the vicinal difluoromethylene moiety that, due to the
strong electronegativity of the fluorine atoms, renders this
carbon highly electrophilic. To render such carbon even
more electrophilic we prepared different b-hydroxy-a,a-
difluorocarboxylic acids 3 having an aryl substituent in
the b position. To this end, we used a known Reformatsky
reaction between bromodifluoroacetic acid ester 1 and
three different aryl aldheydes 2a–c having an electron-
rich, -neutral, and -poor aromatic ring, respectively, fol-
lowed by basic hydrolysis of the resulting ethyl esters
(Scheme 3).
Table 1 Reaction between b-Aryl-b-hydroxy-a,a-difluorocarbox-
ylic Acids and Asymmetric N,N¢-Dialkylcarbodiimides
O
R2
R2
O
N
N
OH
F
COOH
F
F
R1
5
+
F
TMP
R1
3
+
CH2Cl2
OH
O
O
R2
N
R2
N
H
R2
N
C
N
R2
F
F
4
R1
F
6
F
OH
Entry R1 (acid) R2 (carbodiimide)
DHU, Yield NAU,Yield
Br
COOEt
COOH
1) Zn, THF
reflux
1
(%)a
(%)a
F
F
+
2) LiOH
THF–H2O
R
3
1
2
3
4
5
6
OMe (3a) c-C6H11 (4a)
OMe (3a) i-Pr (4b)
5a, 24
traceb
traceb
5d, 24
5e, 35
–
6a, 61
6b, 78
6c, 83
6d, 55
6e, 49
6f, 98
CHO
3a R = OMe (73%)
3b R = H (65%)
3c R = CN (60%)
R
H (3b)
c-C6H11 (4a)
i-Pr (4b)
2
H (3b)
Scheme 3 Synthesis of b-aryl-b-hydroxydifluoro acids
CN (3c)
c-C6H11 (4a)
i-Pr (4b)
Thus, compounds 3a–c were reacted with commercially
available symmetric N,N¢-dialkylcarbodiimides such as
CN (3c)
DCC (4a), and DIC (4b) (Table 1). After fine tuning of a Isolated yields.
b Detected by the 1H NMR spectrum of the crude.
the key parameters, such as solvent, presence of a base,
and temperature, the optimized conditions were to run the
reaction in apolar solvents (CH2Cl2) at room temperature
and in the presence of a base, 2,4,6-trimethylpyridine
(TMP).
the reaction sequence involves a proton transfer from the
carboxylic acid 3 to the basic nitrogen of the carbodiimide
4, followed by addition of the carboxylate to form the O-
acylisourea 7 which, in the absence of a nucleophile or a
base, can be stable for many hours (Scheme 4).20
To our surprise, the reaction between b-(4-methoxyphe-
nyl)-b-hydroxy-a,a-difluorocarboxylic acid 3a and DCC
(4a) gave an almost 3:1 mixture of the expected NAU de-
rivative 6a and the DHU 5a in excellent overall yields
(Table 1, entry 1). The formation of the latter compound
was unexpected at this stage because the hydroxyl group
is known to be a scarce leaving group if not protonated.
The reaction between the same acid 3a and DIC (4b) pro-
vided the nearly exclusive formation of the NAU 6b in
good yield, with the corresponding DHU detected in trace
amounts by NMR spectrum of the crude. The acid 3b
bearing an electron-neutral aromatic ring in b position re-
acted with 4a producing the expected NAU derivative 6c
in very good yield essentially as the only product, while
with DIC (4b) a nearly 2:1 mixture of NAU 6d and the tar-
get DHU 5d was still obtained (Table 1, entries 3, 4). Fi-
nally, by reacting in the same conditions b-(4-
Intermediate 7 undergoes a rearrangement, the so-called
O → N acyl migration, to give the NAU 6, which is a fre-
quently found by-product in the condensation reaction be-
tween carboxylic acids and alcohols or amines promoted
by carbodiimides, and the major product in our synthesis.
However, O-acylisourea 7 could exist in equilibrium with
the zwitterion 8, which irreversibly undergoes loss of H2O
affording the benzylic carbocation 9 and triggering the
formation of DHU 5 by intramolecular nucleophilic attack
of a nitrogen and subsequent O → N acyl migration.21
Such equilibrium is probably shifted towards the O-acyli-
sourea 7 because: 1) the nitrogen atom is more basic than
the oxygen and 2) the carbocation is destabilized by the
presence of the vicinal gem-difluoro moiety.22 In fact, the
DHU compounds 5, when formed, are always found as
minor products.
cyanophenyl)-b-hydroxy-a,a-difluorocarboxylic
acid
(3c) and carbodiimides 4a,b we achieved the formation of
a ca. 1.5:1 mixture of NAU 6e and DHU 5e and the exclu-
sive formation of NAU 6f, respectively, in excellent
yields (Table 1, entries 5, 6). The direct formation of the
unexpected DHU compounds 5 during the reaction be-
tween acids 3a–c and carbodiimides 4a,b is probably due
to the formation of a transient benzylic carbocation due to
a partial protonation of the hydroxy group. Presumably,
In order to validate our synthetic methodology, we had to
find the way to convert the NAU derivatives 6 into the tar-
get DHUs 5 in mild condition and high yields. This could
be achieved by treating compounds 6 with Deoxofluor in
dichloromethane overnight at room temperature
(Scheme 5).
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York

654
F. Olimpieri et al.
PAPER
OH
reactive. In fact, by treating carbodiimide 4c with acids
3a,b in the same conditions described above, we were
able to detect the presence of the expected NAU com-
COOH
+
R2
N
C
N
R2
F
F
1
R1
3
pounds only by H NMR of the crude reaction mixture,
4
whereas after flash chromatography we recovered only
the amide 10. However, by treating the reaction mixture in
situ with an excess of Deoxofluor after the NAU deriva-
tives were formed, we were able to recover the target
N,N¢-diaryl-DHUs 5g,h, which proved to be more stable
than the corresponding NAUs, although in lower yields.
OH
F
H
COO
R2
N C N
R2
F
R1
OH
R2
COOH
OH
F
O
N
N
C
N
+
H
F
F
R1
4c
O
N
R2
3a,b
F
TMP, CH2Cl2
O O
R1
7
OH
N
O acyl
migration
N
N
H
F
F
R2
R1
OH
F
O
O
OH2
F
O
N
6g,h
R2
N
R2
N
O
N
R2
H
F
F
R1
R1
8
Deoxofluor
CH2Cl2
6
FC
(45–52%)
– H2O
OH
O
R2
O
O
N
NH
N
N
F
F
O
N
R2
R1
O
F
F
R1
9
F
F
10g,h
R1
5g,h
Scheme 6 Synthesis of N,N¢-diaryl-DHUs
O
R2
N
R2
O
To our surprise, the behavior of asymmetric carbodi-
imides, namely carbodiimides having different substitu-
ents at the nitrogen atoms in terms of steric hindrance
(‘weakly asymmetric’) or nucleophilic character (‘strong-
ly asymmetric’)19c resulted to be different as compared
with the symmetric ones. ‘Weakly asymmetric’ carbodi-
imides, such as N-allyl or -c-C6H11, N¢-tert-butylcarbodi-
imides 4d,e, respectively, reacted smoothly with b-aryl-b-
hydroxy-a,a-difluorocarboxylic acids 3a–c to afford
NAU and DHU derivatives in ratios depending on the ‘de-
gree’ of the asymmetry and on the electronic feature of the
b-aryl substituent on the acids, although in all cases with
total regiocontrol (Table 2). N-Allyl-N¢-tert-butylcarbodi-
imide 4d, bearing a primary and a tertiary alkyl group at
the nitrogen atoms, reacted with acids 3a,b giving rise to
the formation of modest yields of NAU derivatives 6i,j,
respectively, having the bulky tert-butyl group attached to
the imide nitrogen, while an almost 3:1 mixture NAU/
DHU derivatives 5k and 6k, respectively, were obtained
with acid 3c bearing an electron-withdrawing group at the
para position of the aromatic ring (Table 2, entries 1–3).
N
F
F
R1
5
Scheme 4 The proposed mechanism for the formation of 5
O
OH
F
O
O
R2
R2
O
N
N
F
R2
N
R2
N
Deoxofluor
H
F
CH2Cl2
R1
F
6a–f
(75–93%)
R1
5a–f
Scheme 5 Synthesis of the target DHUs
Next, we turned our attention on the reactivity of less ba-
sic/nucleophilic N,N¢-diarylcarbodiimides, and in particu-
lar commercially available bis(p-tolyl)carbodiimide (4c)
with acids 3a,b (Scheme 6). In these cases, the resulting
NAU derivatives resulted to be very instable probably due
to the electron-withdrawing nature of the aryl substituent
that renders the system highly electron-deficient and thus
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Synthesis of gem-Difluorodihydrouracils
655
Table 2 MReaction between b-Aryl-b-hydroxy-a,a-difluorocar-
this time we could isolate the desired DHUs 5p,q in rea-
sonable yields and as the only regioisomers, by perform-
ing the cyclization step (step B) in a one-pot fashion
(Table 3, entries 4 and 5).
boxylic Acids and Asymmetric Carbodiimides
O
R2
R3
O
N
N
OH
Table 3 Reaction between b-Alkyl-b-hydroxy-a,a-difluorocarbox-
ylic Acids and Carbodiimides
COOH
F
F
R1
F
F
O
TMP
5
R1
R2
R1
R3
O
3
CH2Cl2
+
N
N
OH
+
OH
O
O
COOH
O
R2
N
C
N
R3
R1
R2
R2
R2
R1
R3
O
F
F
3
F
F
TMP
4
N
R3
6
N
H
Deoxofluor
N
N
5
+
F
F
+
CH2Cl2
B
R1
N
C
N
R3
A
OH
F
O
O
F
F
4
R2
5
R1
N
R3
6
N
Entry R1 (acid) R2
R3 (carbo- DHU, Yield NAU, Yield
H
diimide) (%)a
(%)a
6i, 33
6j, 45
6k, 42
–
F
1
2
3
4
5
6
OMe (3a) allyl
t-Bu (4d)
t-Bu (4d)
–
–
Entry R1 (acid) R2
R3 (carbo-
diimide)
DHU,YieldNAU,Yield
H (3b)
allyl
allyl
(%)a
(%)a
6m, 41
6n, 45
6o, 58
–
CN (3c)
CN (3c)
t-Bu (4d) 5k, 15
1b
2b
3b
4c
5c
Bn (3d)
Bn (3d)
c-C6H11 c-C6H11 (4a) 5m, 26
c-C6H11 t-Bu (4e) 5l, 51
i-Pr
i-Pr (4b)
i-Pr (4b)
Ph (4f)
5n, 20
5o, 35
5p, 51
5q, 53
b
b
OMe (3a) Bn
Ph (4f)
Ph (4f)
–
–
–
n-Bu (3e) i-Pr
Bn (3d) Bn
n-Bu (3e) Bn
b
b
CN (3c) Bn
–
a Isolated yields.
Ph (4f)
–
bA complex mixture of unidentified products were formed.
a Isolated yields.
b One-step A.
These results confirm that O-acylurea derivatives like 7
(Scheme 4), bearing different substituents at the two ni-
trogen atoms, have more propensity to undergo O → N
acyl transfer than the corresponding derivatives having
two identical N-substituents, as already observed in previ-
ous works.19c,f Conversely, N-cyclohexyl-N¢-tert-butyl-
carbodiimide 4e, bearing two substituents more similar
both in terms of sterical hindrance and electronic features,
reacted with acid 3c leading to the formation of DHU 5l
in a complete chemo- and regioselective fashion (Table 2,
entry 4). Unexpectedly, when ‘highly asymmetric’ N-ben-
zyl-N¢-phenylcarbodiimide (4f) was reacted with acids
3a,c we could isolate neither the corresponding NAU nor
the DHU derivatives, regardless the use of a multi-step or
a one-pot procedure (Table 2, entries 5 and 6).
c One-pot, two steps A + B.
In conclusion, we have developed a new, straightforward
two-step procedure for the synthesis of novel compounds
such as gem-difluoro-DHUs. The process, which takes
place in very mild conditions, is based on the condensa-
tion between easily accessible b-substituted b-hydroxy-
a,a-difluorocarboxylic acids and carbodiimides. This
leads to the formation of the corresponding NAU deriva-
tives or, in most cases, to a mixture of the desired DHU
and NAU derivatives, which could be cyclized to the tar-
get compounds very efficiently. When the NAU deriva-
tives are not stable because of the electron-poor character
of the N-substituents which renders these substrates very
reactive, the process could be done in a one-pot fashion
leading to the direct formation of the desired DHU, al-
though in lower yields. A large array of fully substituted
gem-difluoro-DHUs can be synthesized through this
method, which looks particularly suitable for solid-phase/
combinatorial chemistry. Resolution of this issue, as well
as the development of a stereoselective version of the pro-
cess,24 is currently in progress in our laboratories.
Finally, we explored the reactivity of b-alkyl-b-hydroxy-
a,a-difluorocarboxylic acids 3d,e, which were synthe-
sized in analogy with the b-aryl analogues (see experi-
mental section). In these cases the carbocations like 9 (see
the proposed mechanism in Scheme 4) should be less sta-
ble, thus, in theory, more difficult to form than the corre-
sponding benzylic ones. However, the reactions of acids
3d,e with symmetric N,N¢-dialkylcarbodiimides 4a,b led
to the formation of mixtures of NAU/DHU derivatives
5m–o and 6m–o (Table 3, entries 1–3).23 Interestingly,
when b-alkyl,b-hydroxy-a,a-difluorocarboxylic acids
3d,e were reacted with ‘strongly asymmetric’ carbodi-
imide 4f, again we were not able to isolate the NAU inter-
mediates after the condensation step (Table 3, step A), but
1H NMR spectra were run on spectrometers 250, 400, or 500 MHz.
Chemical shifts are expressed in ppm (d), using TMS as internal
standard for 1H and 13C nuclei (dH and dC = 0.00), while C6F6 was
used as external standard (dF = 162.90) for 19F. Commercially avail-
able reagent grade solvents were employed without purification.
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York

656
F. Olimpieri et al.
PAPER
Commercially unavailable carbodiimides were prepared according
to the literature procedure.19 b-Alkyl-b-hydroxy-a,a-difluorocar-
boxylic acids 3d,e were prepared as shown in Scheme 3 and de-
scribed in the literarure.25
19F NMR (235 MHz, CDCl3): d = –117.7 (dd, J = 282.8, 3.2 Hz, 1
F), –124.2 (dd, J = 282.8, 18.6 Hz, 1 F).
ESI: m/z (%) = 413.1 [M+ + Na, 100%].
5,5-Difluoro-1,3-diisopropyl-6-phenyldihydropyrimidine-
2,4(1H,3H)-dione (5d)
Rf = 0.67 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.45 (s, 5 H), 5.29 (dd, J = 18.7,
2.7 Hz, 1 H), 5.00 (dt, J = 13.8, 6.9 Hz, 1 H), 3.96 (dt, J = 12.3, 6.2
Hz, 1 H), 1.48 (d, J = 12.0 Hz, 3 H), 1.46 (d, J = 12.1 Hz, 3 H), 1.14
(d, J = 6.3 Hz, 3 H), 1.10 (d, J = 6.3 Hz, 3 H).
Reaction of b-Aryl/alkyl-b-hydroxy-a,a-difluorocarboxylic
Acids 3 with Carbodiimides 4; General Procedure
To a 0.1 M solution of 3 in CH2Cl2 were added TMP (1 equiv) fol-
lowed by carbodiimide 4 (1.5 equiv) at r.t. After stirring overnight,
aq 1 N HCl was added to acidic pH and the mixture extracted with
CH2Cl2 (2 × 2 mL). The combined organic layers were dried
(Na2SO4), concentrated under vacuum, and the crude purified by
flash chromatography over silica gel affording NAUs 6, and even-
tually DHUs 5 (Tables 1– 3).
13C NMR (63 MHz, CDCl3): d = 139.4, 130.0, 129.6, 128.6, 127.9,
127.5, 126.9, 75.7, 49.0, 46.4, 24.0, 23.6, 19.2, 18.8.
19F NMR (235 MHz, CDCl3): d = –118.1 (dd, J = 283.4, 3.1 Hz, 1
F), –124.3 (dd, J = 283.4, 18.7 Hz, 1 F).
ESI: m/z (%) = 343.1 [M+ + Na, 100%].
Cyclization of N-Acylureas 6 to 5,6-Dihydrouracils; General
Procedure
To a 0.1 M solution of 6 in CH2Cl2, was added Deoxofluor (1.6
equiv) dropwise at r.t. After stirring overnight, sat. aq NaHCO3 was
added to basic pH and the mixture extracted with CH2Cl2 (2 × 2
mL). The combined organic layers were dried (Na2SO4), concen-
trated under vacuum, and the crude purified by flash chromatogra-
phy over silica gel affording DHUs 5.
4-(1,3-Dicyclohexyl-5,5-difluoro-2,6-dioxohexahydropyrimi-
din-4-yl)benzonitrile (5e)
Rf = 0.50 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.76 (d, J = 8.2 Hz, 2 H), 7.56 (d,
J = 8.1 Hz, 2 H), 5.35 (d, J = 19.3 Hz, 1 H), 4.57 (tt, J = 12.1, 3.6
Hz, 1 H), 3.66 (m, 1 H), 2.40 (dqd, J = 27.9, 12.3, 3.2 Hz, 2 H), 1.84
(d, J = 13.1 Hz, 2 H), 1.70 (m, 8 H), 1.36 (m, 8 H).
13C NMR (101 MHz, C6D12): d = 159.1 (t, J = 29.3 Hz), 138.3,
134.7, 132.4, 128.8, 128.4, 128.2, 118.0, 114.1, 106.7 (t, J = 252.1
Hz), 75.6 (dd, J = 29.6, 24.0 Hz), 57.4, 53.9, 33.9, 33.6, 28.6, 28.2,
26.3, 26.2, 25.8, 25.3, 24.2, 24.1.
19F NMR (235 MHz, CDCl3): d = –118.2 (dd, J = 283.9, 1.8 Hz, 1
F), –123.7 (dd, J = 283.9, 19.5 Hz, 1 F).
ESI: m/z (%) = 438.1 [M+ + Na, 100%].
1,3-Dicyclohexyl-5,5-difluoro-6-(4-methoxyphenyl)dihydropy-
rimidine-2,4(1H,3H)-dione (5a)
Rf = 0.72 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.35 (d, J = 8.6 Hz, 2 H), 6.96 (d,
J = 8.8 Hz, 2 H), 5.23 (dd, J = 18.4, 3.2 Hz, 1 H), 4.58 (t, J = 12.1
Hz, 1 H), 3.84 (s, 3 H), 3.65 (m, 1 H), 2.43 (m, 2 H), 1.83 (d,
J = 12.9 Hz, 2 H), 1.68 (m, 8 H), 1.34 (m, 8 H).
13C NMR (101 MHz, C6D12): d = 160.9, 139.3, 129.0, 114.6 (dd,
J = 1744.5, 283.8 Hz), 114.2, 76.3 (dd, J = 29.6, 25.1 Hz), 57.1,
55.3, 53.7, 34.0, 33.6, 28.6, 28.2, 26.3, 25.9, 25.3, 24.2.
19F NMR (235 MHz, CDCl3): d = –117.7 (dd, J = 282.3, 3.2 Hz, 1
F), –124.5 (dd, J = 282.3, 18.5 Hz, 1 F).
ESI: m/z (%) = 443.1 [M+ + Na, 100%].
4-(5,5-Difluoro-1,3-diisopropyl-2,6-dioxohexahydropyrimidin-
4-yl)benzonitrile (5f)
Rf = 0.71 (hexanes–EtOAc, 70:30).
1H NMR (400 MHz, CDCl3): d = 7.76 (d, J = 8.3 Hz, 2 H), 7.58 (d,
J = 8.2 Hz, 2 H), 5.36 (dd, J = 19.8, 1.8 Hz, 1 H), 4.98 (hept, J = 7.0
Hz, 1 H), 3.95 (hept, J = 6.3 Hz, 1 H), 1.48 (d, J = 12.5 Hz, 3 H),
1.46 (d, J = 12.4 Hz, 3 H), 1.16 (d, J = 6.3 Hz, 3 H), 1.10 (d, J = 6.3
Hz, 3 H).
13C NMR (63 MHz, CDCl3): d = 159.0 (t, J = 29.3 Hz), 138.6,
134.5, 132.4, 128.2, 118.0, 114.0, 106.5 (dd, J = 253.7, 250.1 Hz),
75.6 (dd, J = 29.7, 23.9 Hz), 49.3, 46.6, 24.1, 23.6, 19.2, 18.7.
19F NMR (235 MHz, CDCl3): d = –118.8 (dd, J = 284.4, 2.8 Hz, 1
F), –123.9 (dd, J = 284.4, 19.8 Hz, 1 F).
ESI: m/z (%) = 368.1 [M+ + Na, 100%].
5,5-Difluoro-1,3-diisopropyl-6-(4-methoxyphenyl)dihydropyri-
midine-2,4(1H,3H)-dione (5b)
Rf = 0.52 (hexanes–EtOAc, 90:10).
1H NMR (400 MHz, CDCl3): d = 7.36 (d, J = 8.6 Hz, 2 H), 6.96 (d,
J = 8.8 Hz, 2 H), 5.23 (dd, J = 18.9, 3.1 Hz, 1 H), 4.99 (dt, J = 13.8,
6.9 Hz, 1 H), 3.93 (dt, J = 12.6, 6.3 Hz, 1 H), 3.84 (s, 3 H), 1.48 (d,
J = 11.6 Hz, 3 H), 1.46 (d, J = 11.6 Hz, 3 H), 1.12 (d, J = 6.3 Hz, 3
H), 1.09 (d, J = 6.3 Hz, 3 H).
13C NMR (101 MHz, CDCl3): d = 160.9, 159.8 (dd, J = 30.2, 29.2
Hz), 139.6, 129.0, 121.5, 114.2, 114.2, 114.1, 109.6, 107.1, 107.1,
104.6, 76.4 (dd, J = 30.1, 23.9 Hz), 55.3, 48.9, 46.4, 24.1, 23.7,
19.2, 18.8.
5,5-Difluoro-6-(4-methoxyphenyl)-1,3-di-p-tolyldihydropyrim-
idine-2,4(1H,3H)-dione (5g)
Rf = 0.27 (hexanes–EtOAc, 80:20).
1H NMR (300 MHz, CDCl3): d = 7.33 (d, J = 8.6 Hz, 1 H), 7.25 (d,
J = 8.6 Hz, 1 H), 7.12 (d, J = 8.3 Hz, 1 H), 6.94 (d, J = 11.2 Hz, 1
H), 6.92 (d, J = 11.2 Hz, 2 H), 6.78 (d, J = 8.3 Hz, 1 H), 5.49 (dd,
J = 16.9, 4.1 Hz, 1 H), 3.78 (s, 2 H), 2.35 (s, 2 H), 2.19 (s, 1 H).
19F NMR (282 MHz, CDCl3): d = –116.5 (dd, J = 285.1, 4.0 Hz, 1
F), –122.3 (dd, J = 285.1, 16.9 Hz, 1 F).
19F NMR (235 MHz, CDCl3): d = –118.3 (dt, J = 240.2, 30.6 Hz, 1
F), –124.8 (dt, J = 151.0, 38.3 Hz, 1 F).
ESI: m/z (%) = 363.0 [M+ + Na, 100%].
1,3-Dicyclohexyl-5,5-difluoro-6-phenyldihydropyrimidine-
2,4(1H,3H)-dione (5c)
Rf = 0.83 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.44 (m, 5 H), 5.29 (dd, J = 18.5,
3.3 Hz, 1 H), 4.58 (m, 1 H), 3.67 (td, J = 8.7, 4.4 Hz, 1 H), 2.42 (m,
2 H), 1.83 (d, J = 12.8 Hz, 2 H), 1.69 (m, 8 H), 1.35 (m, 8 H).
ESI: m/z (%) = 459.1 [M+ + Na, 100%].
13C NMR (63 MHz, CDCl3): d = 159.7 (t, J = 29.5 Hz), 155.7,
139.2, 130.0, 128.7, 127.5, 57.2, 53.7, 33.9, 33.5, 28.5, 28.2, 26.2,
25.9, 25.3, 24.2.
5,5-Difluoro-6-phenyl-1,3-di-p-tolyldihydropyrimidine-
2,4(1H,3H)-dione (5h)
Rf = 0.46 (hexanes–EtOAc, 80:20).
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York

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Synthesis of gem-Difluorodihydrouracils
657
1H NMR (300 MHz, CDCl3): d = 7.31 (m, 7 H), 7.14 (d,, J = 8.4 Hz,
2 H), 6.97 (d, J = 7.7, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 5.56 (dd,
J = 17.3, 1.9 Hz, 1 H), 2.35 (s, 3 H), 2.20 (s, 3 H).
13C NMR (63 MHz, CDCl3): d = 159.5 (t, J = 29.4 Hz), 139.4,
135.0, 129.4, 128.7, 127.3, 107.6 (dd, J = 251.9, 249.6 Hz), 48.7,
46.3, 33.0, 32.9, 23.8, 23.6, 19.1, 18.8.
19F NMR (282 MHz, CDCl3): d = –116.7 (dd, J = 285.5, 3.6 Hz, 1
F), –122.00 (dd, J = 285.5, 17.2 Hz, 1 F).
19F NMR (235 MHz, CDCl3): d = –119.6 (dd, J = 282.7, 3.1 Hz, 1
F), –125.6 (dd, J = 282.7, 17.9 Hz, 1 F).
ESI: m/z (%) = 429.1 [M+ + Na, 100%].
ESI: m/z (%) = 325.2 [M+ + H, 15], 347.2 [M+ + Na, 100].
4-(3-Allyl-1-tert-butyl-5,5-difluoro-2,6-dioxohexahydropyrimi-
din-4-yl)benzonitrile (5k)
Rf = 0.48 (hexanes–EtOAc, 80:20).
6-Butyl-5,5-difluoro-1,3-diisopropyldihydropyrimidine-
2,4(1H,3H)-dione (5o)
Rf = 0.84 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.70 (d, J = 8.4 Hz, 2 H), 7.52 (d,
J = 8.2 Hz, 2 H), 5.80 (ddt, J = 16.4, 10.2, 6.2 Hz, 1 H), 5.26 (m, 2
H), 5.16 (dd, J = 10.2, 1.1 Hz, 1 H), 4.43 (d, J = 6.0 Hz, 2 H), 1.20
(s, 9 H).
1H NMR (400 MHz, CDCl3): d = 4.95 (dt, J = 13.8, 6.9 Hz, 1 H),
4.20 (m, 1 H), 3.89 (dt, J = 12.6, 6.3 Hz, 1 H), 1.79 (m, 2 H), 1.47
(m, 4 H), 1.43 (d, J = 6.9 Hz, 3 H), 1.42 (d, J = 6.9 Hz, 3 H), 1.10
(d, J = 6.3 Hz, 6 H), 0.95 (t, J = 7.2 Hz, 3 H).
13C NMR (63 MHz, CDCl3): d = 157.8 (t, J = 36.6 Hz), 139.9,
135.2, 135.1, 132.6, 132.4, 132.2, 132.2, 132.1, 130.1, 129.9, 128.9,
128.5, 116.2 (dd, J = 320.4, 99.7 Hz), 116.1, 114.3, 113.0, 43.3,
29.7, 29.4, 28.7, 27.7.
13C NMR (63 MHz, CDCl3): d = 154.3 (t, J = 51.6 Hz), 144.8, 119.3
(dd, J = 285.9, 276.5 Hz), 71.8 (dd, J = 52.0, 27.5 Hz), 48.7, 44.2,
43.4, 42.0, 31.4, 30.2, 29.7, 27.5, 27.2, 27.0, 22.9, 22.3, 20.8, 13.8,
13.7.
19F NMR (235 MHz, CDCl3): d = –119.5 (d, J = 286.1 Hz, 1 F),
–122.8 (dd, J = 286.1, 19.7 Hz, 1 F).
19F NMR (235 MHz, CDCl3): d = –119.2 (dd, J = 282.8, 3.8 Hz, 1
F), –126.0 (dd, J = 282.7, 17.0 Hz, 1 F).
ESI: m/z (%) = 370.1 [M+ + Na, 100%].
ESI: m/z (%) = 313.1 [M+ + Na, 100%].
4-(1-tert-Butyl-3-cyclohexyl-5,5-difluoro-2,6-dioxohexahydro-
pyrimidin-4-yl)benzonitrile (5l)
Rf = 0.60 (hexanes–EtOAc = 80:20).
1,6-Dibenzyl-5,5-difluoro-3-phenyldihydropyrimidine-2,4-di-
one (5p)
Rf = 0.64 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.60 (dd, J = 70.0, 8.3 Hz, 4 H),
5.25 (dd, J = 19.4, 2.2 Hz, 1 H), 4.45 (tt, J = 12.0, 3.6 Hz, 1 H), 2.30
(dqd, J = 28.7, 12.4, 3.6 Hz, 2 H), 1.76 (d, J = 13.2 Hz, 2 H), 1.58
(d, J = 12.0 Hz, 3 H), 1.28 (m, 1 H), 1.21 (s, 9 H), 1.11 (m, 2 H).
13C NMR (101 MHz, CDCl3): d = 159.3 (t, J = 29.4 Hz), 155.1,
132.5, 128.4, 121.8 (dd, J = 2792.5, 228.7 Hz), 117.9, 114.2, 76.0
(dd, J = 29.6, 23.8 Hz), 57.6, 53.6, 30.3, 28.6, 28.3, 26.3, 25.3.
19F NMR (235 MHz, CDCl3): d = –118.1 (d, J = 284.0 Hz, 1 F),
–123.8 (dd, J = 284.1, 19.5 Hz, 1 F).
ESI: m/z (%) = 390.1 [M+ + H, 100], 412.2 [M+ + Na, 25].
1H NMR (400 MHz, CDCl3): d = 7.50 (dd, J = 7.7, 1.4 Hz, 2 H),
7.33 (ddd, J = 10.0, 6.2, 2.7 Hz, 4 H), 7.22 (m, 3 H), 7.10 (dd,
J = 13.1, 7.3 Hz, 2 H), 6.99 (dd, J = 8.7, 4.3 Hz, 2 H), 6.78 (m, 2 H),
5.20 (d, J = 4.4 Hz, 2 H), 4.49 (ddt, J = 17.8, 10.0, 3.0 Hz, 1 H), 3.04
(ddd, J = 24.8, 14.7, 6.4 Hz, 2 H).
13C NMR (63 MHz, CDCl3): d = 159.3, 155.3, 143.8, 141.0, 139.0,
136.3, 135.9, 134.1, 129.5, 129.3, 128.7, 128.6, 128.2, 128.0, 127.9,
127.3, 126.3, 124.1, 122.9, 122.8, 46.4, 34.9, 32.7, 32.6.
19F NMR (235 MHz, CDCl3): d = –120.2 (dd, J = 284.7, 3.3 Hz, 1
F), –124.7 (dd, J = 284.7, 17.7 Hz, 1 F).
ESI: m/z (%) = 347.1 [M+ + Na, 100%].
6-Benzyl-1,3-dicyclohexyl-5,5-difluorodihydropyrimidine-
2,4(1H,3H)-dione (5m)
Rf = 0.83 (hexanes–EtOAc, 80:20).
1-Benzyl-6-butyl-5,5-difluoro-3-phenyldihydropyrimidine-
2,4(1H,3H)-dione (5q)
Rf = 0.74 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.27 (m, 3 H), 7.21 (d, J = 5.8 Hz,
2 H), 4.44 (dt, J = 12.2, 3.7 Hz, 1 H), 4.26 (m, 1 H), 3.22 (dt, J = 9.1,
4.7 Hz, 1 H), 3.04 (dd, J = 14.4, 2.5 Hz, 1 H), 2.98 (d, J = 10.3 Hz,
1 H), 2.28 (m, 2 H), 1.71 (d, J = 13.9 Hz, 3 H), 1.54 (m, 5 H), 1.22
(m, 8 H), 1.07 (m, 2 H).
13C NMR (63 MHz, CDCl3): d = 159.7 (t, J = 29.3 Hz), 139.3,
135.0, 133.8, 129.5, 128.9, 128.7, 128.4, 127.7, 127.3, 127.1, 107.6
(dd, J = 252.1, 249.1 Hz), 56.8, 56.7, 55.8, 53.9, 34.9, 33.7, 33.6,
32.8, 32.7, 28.8, 28.4, 28.2, 26.2, 26.0, 25.8, 25.5, 25.3, 24.7, 24.5.
1H NMR (400 MHz, CDCl3): d = 7.33 (m, 7 H), 6.98 (m, 3 H), 5.23
(s, 2 H), 4.31 (m, 1 H), 1.74 (ddd, J = 22.9, 11.5, 5.2 Hz, 2 H), 1.31
(m, 4 H), 0.82 (t, J = 7.1 Hz, 3 H).
19F NMR (235 MHz, CDCl3): d = –118.6 (dd, J = 285.3, 4.7 Hz, 1
F), –125.1 (dd, J = 285.3, 15.6 Hz, 1 F).
ESI: m/z (%) = 395.1 [M+ + Na, 100%].
N-Cyclohexyl-N-(cyclohexylcarbamoyl)-2,2-difluoro-3-hy-
droxy-3-(4-methoxyphenyl)propanamide (6a)
Rf = 0.16 (hexanes–EtOAc, 80:20).
19F NMR (235 MHz, CDCl3): d = –119.6 (d, J = 282.3 Hz, 1 F),
–125.3 (dd, J = 282.3, 18.4 Hz, 1 F).
ESI: m/z (%) = 405.1 [M+ + H, 20], 427.1 [M+ + Na, 100%].
1H NMR (400 MHz, CDCl3): d = 7.36 (d, J = 8.6 Hz, 2 H), 6.90 (d,
J = 8.7 Hz, 2 H), 5.73 (br s, 1 H), 5.20 (dd, J = 18.9, 6.1 Hz, 1 H),
4.17 (t, J = 11.9 Hz, 1 H), 3.81 (s, 3 H), 3.62 (m, 1 H), 1.95 (t,
J = 10.9 Hz, 2 H), 1.81 (d, J = 11.9 Hz, 4 H), 1.72 (m, 2 H), 1.62 (m,
4 H), 1.34 (m, 4 H), 1.16 (m, 4 H).
6-Benzyl-5,5-difluoro-1,3-diisopropyldihydropyrimidine-
2,4(1H,3H)-dione (5n)
Rf = 0.80 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.35 (dd, J = 11.2, 4.5 Hz, 2 H),
7.28 (m, 3 H), 4.92 (dt, J = 13.8, 6.9 Hz, 1 H), 4.37 (ddt, J = 17.9,
10.1, 3.0 Hz, 1 H), 3.64 (dt, J = 12.6, 6.3 Hz, 1 H), 3.11 (m, 2 H),
1.41 (t, J = 6.8 Hz, 6 H), 1.06 (d, J = 6.3 Hz, 3 H), 0.85 (d, J = 6.3
Hz, 3 H).
13C NMR (63 MHz, CDCl3): d = 160.1 (t, J = 11.8 Hz), 160.1,
151.5, 130.0, 129.2, 127.0, 114.0, 113.7, 73.7 (dd, J = 30.0, 23.8
Hz), 56.2, 55.3, 50.5, 32.4, 32.2, 30.8, 30.1, 25.8, 25.4, 25.2, 24.6.
19F NMR (235 MHz, CDCl3): d = –105.5 (dd, J = 265.7, 5.9 Hz, 1
F), –118.2 (dd, J = 265.7, 18.8 Hz, 1 F).
ESI: m/z (%) = 381.1 [M+ + Na, 100%].
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York

658
F. Olimpieri et al.
PAPER
2,2-Difluoro-3-hydroxy-N-isopropyl-N-(isopropylcarbamoyl)-
3-(4-methoxyphenyl)propanamide (6b)
ESI: m/z (%) = 434.0 [M+ + H, 9], 456.1 [M+ + Na, 100], 471.2 [M+
+ K, 58].
Rf = 0.23 (hexanes–EtOAc, 70:30).
3-(4-Cyanophenyl)-2,2-difluoro-3-hydroxy-N-isopropyl-N-(iso-
propylcarbamoyl)propanamide (6f)
Rf = 0.21 (hexanes–EtOAc, 70:30).
1H NMR (400 MHz, CDCl3): d = 7.33 (d, J = 8.2 Hz, 2 H), 6.88 (d,
J = 8.7 Hz, 2 H), 6.11 (d, J = 6.7 Hz, 1 H), 5.18 (dt, J = 19.7, 5.1 Hz,
1 H), 4.53 (dt, J = 13.6, 6.8 Hz, 1 H), 4.34 (d, J = 4.2 Hz, 1 H), 3.89
(dq, J = 13.4, 6.7 Hz, 1 H), 3.79 (s, 3 H), 1.28 (d, J = 12.4 Hz, 3 H),
1.26 (d, J = 12.5 Hz, 3 H), 1.18 (d, J = 9.6 Hz, 3 H), 1.16 (d, J = 9.6
Hz, 3 H).
13C NMR (63 MHz, CDCl3): d = 162.9 (t, J = 28.8 Hz) 160.0, 151.6,
129.2, 127.0, 115.8 (dd, J = 266.4, 253.5 Hz), 113.7, 73.3 (dd,
J = 30.9, 23.5 Hz), 55.2, 48.7, 43.6, 22.1, 21.7, 20.7, 19.6.
1H NMR (400 MHz, CDCl3): d = 7.68 (d, J = 8.5 Hz, 2 H), 7.58 (d,
J = 8.1 Hz, 2 H), 5.69 (br s, 1 H), 5.31 (dt, J = 8.4, 5.0 Hz, 1 H), 4.58
(dt, J = 13.6, 6.9 Hz, 1 H), 4.37 (d, J = 4.6 Hz, 2 H), 3.97 (dq,
J = 13.2, 6.6 Hz, 1 H), 1.35 (d, J = 9.0 Hz, 3 H), 1.33 (d, J = 9.1 Hz,
3 H), 1.20 (t, J = 6.1 Hz, 6 H).
13C NMR (63 MHz, CDCl3): d = 162.7 (t, J = 28.7 Hz), 151.8,
140.2, 131.9, 128.7, 118.5, 115.4, 115.3 (dd, J = 267.0, 258.1 Hz),
112.8, 111.2, 73.5 (dd, J = 29.7, 23.9 Hz), 49.0, 44.0, 22.1, 20.6,
20.1.
19F NMR (235 MHz, CDCl3): d = –105.2 (dd, J = 263.3, 5.8 Hz, 1
F), –119.0 (dd, J = 263.3, 19.7 Hz, 1 F).
ESI: m/z (%) = 381.0 [M+ + Na, 100%].
19F NMR (235 MHz, CDCl3): d = –104.1 (dd, J = 272.9, 5.4 Hz, 1
F), –117.1 (dd, J = 273.0, 19.3 Hz, 1 F).
ESI: m/z (%) = 376.1 [M+ + Na, 100%].
N-Cyclohexyl-N-(cyclohexylcarbamoyl)-2,2-difluoro-3-hy-
droxy-3-phenylpropanamide (6c)
Rf = 0.32 (hexanes–EtOAc, 80:20).
N-(Allylcarbamoyl)-N-tert-butyl-2,2-difluoro-3-hydroxy-3-(4-
methoxyphenyl)propanamide (6i)
Rf = 0.28 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 4.2 Hz, 2 H), 7.37 (m,
3 H), 5.63 (d, J = 6.2 Hz, 1 H), 5.24 (m, 1 H), 4.17 (t, J = 12.1 Hz,
1 H), 4.04 (d, J = 4.2 Hz, 1 H), 3.62 (m, 1 H), 1.94 (m, 2 H), 1.83 (t,
J = 13.8 Hz, 4 H), 1.71 (m, 2 H), 1.60 (m, 4 H), 1.32 (m, 4 H), 1.15
(m, 4 H).
13C NMR (63 MHz, CDCl3): d = 162.7, 151.5, 135.0, 128.9, 128.6,
128.5, 128.3, 128.2, 127.9, 127.7, 115.6 (dd, J = 266.0, 257.0 Hz),
74.1 (dd, J = 29.5, 24.1 Hz), 56.2, 50.6, 32.4, 32.2, 30.7, 30.2, 25.8,
25.4, 25.2, 24.6.
1H NMR (250 MHz, CDCl3): d = 8.11 (br s, 1 H), 7.41 (d, J = 8.4
Hz, 2 H), 6.94 (d, J = 8.6 Hz, 2 H), 5.86 (qd, J = 10.6, 5.3 Hz, 1 H),
5.30 (d, J = 3.8 Hz, 1 H), 5.21 (d, J = 5.0 Hz, 2 H), 4.45 (d, J = 4.9
Hz, 2 H), 3.83 (s, 3 H), 1.40 (s, 9 H).
13C NMR (63 MHz, CDCl3): d = 160.2, 151.5, 133.2, 129.9, 129.4,
126.5, 117.3, 113.7, 73.3 (dd, J = 29.4, 23.0 Hz), 55.3, 51.9, 46.5,
28.5.
19F NMR (235 MHz, CDCl3): d = –103.9 (d, J = 285.3 Hz, 1 F),
–118.7 (dd, J = 285.3, 20.5 Hz, 1 F).
ESI: m/z (%) = 393.1 [M+ + Na, 100%], 409.0 [M+ + K, 77%].
19F NMR (235 MHz, CDCl3): d = –105.7 (dd, J = 267.1, 6.2 Hz, 1
F), –117.4 (dd, J = 267.0, 18.5 Hz, 1 F).
ESI: m/z (%) = 431.1 [M+ + Na, 100].
2,2-Difluoro-3-hydroxy-N-isopropyl-N-(isopropylcarbamoyl)-
3-phenylpropanamide (6d)
Rf = 0.31 (hexanes–EtOAc, 70:30).
N-(Allylcarbamoyl)-N-tert-butyl-2,2-difluoro-3-hydroxy-3-phe-
nylpropanamide (6j)
Rf = 0.55 (hexanes–EtOAc, 70:30).
1H NMR (400 MHz, CDCl3): d = 7.44 (m, 5 H), 5.82 (br s, 1 H), 5.26
(dd, J = 18.9, 6.0 Hz, 1 H), 4.55 (dt, J = 13.4, 6.7 Hz, 1 H), 4.09 (br
s, 1 H), 3.91 (td, J = 13.4, 6.6 Hz, 1 H), 1.32 (t, J = 6.9 Hz, 6 H),
1.17 (t, J = 6.9 Hz, 6 H).
13C NMR (63 MHz, CDCl3): d = 163.0, 151.6, 151.1, 135.0, 128.9,
128.5, 128.2, 127.9, 127.8, 127.5, 127.3, 74.0 (m), 48.8, 43.7, 22.1,
22.0, 20.6, 19.8.
19F NMR (235 MHz, CDCl3): d = –105.6 (dd, J = 266.6, 6.2 Hz, 1
F), –117.8 (dd, J = 266.6, 19.0 Hz, 1 F).
ESI: m/z (%) = 351.1 [M+ + Na, 100%].
1H NMR (400 MHz, CDCl3): d = 7.99 (br s, 1 H), 7.42 (m, 5 H), 5.84
(ddd, J = 21.8, 10.5, 5.3 Hz, 1 H), 5.30 (dd, J = 20.5, 3.5 Hz, 1 H),
5.17 (m, 2 H), 4.43 (d, J = 4.6 Hz, 2 H), 3.66 (br s, 1 H), 1.39 (s, 9
H).
13C NMR (63 MHz, CDCl3): d = 166.3 (t, J = 30.0 Hz), 151.6,
134.5, 133.1, 129.0, 128.2, 127.8, 115.6 (dd, J = 268.7, 258.1 Hz),
117.4, 73.6 (dd, J = 30.1, 23.1 Hz), 51.9, 46.6, 29.5, 28.5.
19F NMR (235 MHz, CDCl3): d = –103.9 (d, J = 285.8 Hz, 1 F),
–118.1 (dd, J = 285.6, 20.6 Hz, 1 F).
ESI: m/z (%) = 363.0 [M+ + Na, 100%].
3-(4-Cyanophenyl)-N-cyclohexyl-N-(cyclohexylcarbamoyl)-2,2-
difluoro-3-hydroxypropanamide (6e)
Rf = 0.10 (hexanes–EtOAc, 80:20).
N-(Allylcarbamoyl)-N-tert-butyl-3-(4-cyanophenyl)-2,2-difluo-
ro-3-hydroxypropanamide (6k)
Rf = 0.15 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.66 (d, J = 8.3 Hz, 2 H), 7.57 (d,
J = 8.1 Hz, 2 H), 5.74 (d, J = 7.1 Hz, 2 H), 5.29 (dd, J = 19.4, 5.4
Hz, 1H), 4.60 (br s, 1 H), 4.18 (t, J = 11.9 Hz, 1 H), 3.64 (m, 1 H),
1.94 (t, J = 8.5 Hz, 2 H), 1.83 (d, J = 13.2 Hz, 4 H), 1.65 (m, 6 H),
1.35 (m, 4 H), 1.19 (m, 4 H).
1H NMR (400 MHz, CDCl3): d = 7.60 (d, J = 8.3 Hz, 2 H), 7.52 (d,
J = 8.3 Hz, 2 H), 5.77 (m, 1 H), 5.27 (dd, J = 20.3, 3.9 Hz, 1 H), 5.10
(ddd, J = 6.8, 3.6, 2.1 Hz, 2 H), 4.34 (d, J = 5.5 Hz, 2 H), 1.24 (s, 9
H).
13C NMR (63 MHz, CDCl3): d = 162.2 (t, J = 28.5 Hz), 151.7,
140.4, 132.4, 131.9, 128.7, 128.2, 118.5, 115.5 (dd, J = 267.4, 258.0
Hz), 112.6, 73.4 (dd, J = 29.9, 23.9 Hz), 56.4, 50.7, 32.4, 32.3, 30.8,
30.2, 25.8, 25.3, 25.1, 24.6.
19F NMR (235 MHz, CDCl3): d = –104.0 (dd, J = 269.2, 4.6 Hz, 1
F), –117.4 (dd, J = 269.2, 19.5 Hz, 1 F).
13C NMR (63 MHz, CDCl3): d = 171.1, 165.6, 157.4, 151.6, 132.9,
132.1, 131.9, 128.9, 117.7, 115.7, 115.6 (dd, J = 185.9, 175.1 Hz),
73.0 (dd, J = 29.6, 23.4 Hz), 63.6, 43.0, 28.4.
19F NMR (235 MHz, CDCl3): d = –103.1 (d, J = 285.0 Hz, 1 F),
–117.8 (dd, J = 285.0, 19.4 Hz, 1 F).
ESI: m/z (%) = 358.1 [M+ + Na, 100%].
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York

PAPER
Synthesis of gem-Difluorodihydrouracils
659
N-Cyclohexyl-N-(cyclohexylcarbamoyl)-2,2-difluoro-3-hy-
droxy-4-phenylbutanamide (6m)
Rf = 0.37 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 7.24 (d, J = 6.6 Hz, 2 H), 7.18 (m,
3 H), 5.94 (br d, J = 6.8 Hz, 1 H), 4.29 (m, 1 H), 4.12 (tt, J = 12.3,
3.5 Hz, 1 H), 3.60 (m, 1 H), 2.99 (d, J = 14.0 Hz, 1 H), 2.73 (m, 1
H), 1.91 (m, 2 H), 1.82 (d, J = 12.3 Hz, 1 H), 1.74 (d, J = 11.8 Hz,
3 H), 1.65 (m, 3 H), 1.57 (m, 4 H), 1.29 (m, 4 H), 1.15 (m, 4 H).
Nawrot, B.; Malkiewicz, A.; Agris, P. F. Nucleosides
Nucleotides 1996, 15, 1009; and references cited therein.
(f) Temperilli, A.; Ruggieri, D.; Salvati, P. Eur. J. Med.
Chem. 1988, 23, 77. (g) Skaric, V.; Matulic-Adamic, J.
Helv. Chim. Acta 1983, 66, 687.
(3) (a) Dondoni, A.; Massi, A.; Sabbatini, S. Tetrahedron Lett.
2001, 42, 4495. (b) Sano, H.; Mio, S.; Kitagawa, J.; Sugai,
S. Tetrahedron: Asymmetry 1994, 5, 2233.
(4) (a) Kondo, Y.; Witkop, B. J. Am. Chem. Soc. 1968, 90, 764.
(b) Kunieda, T.; Witkop, B. J. Am. Chem. Soc. 1971, 93,
3478. (c) Cerutti, P.; Kondo, Y.; Landis, W. R.; Witkop, B.
J. Am. Chem. Soc. 1968, 90, 771. (d) Kautz, J.; Schnackerz,
K. D. Eur. J. Biochem. 1989, 181, 431. (e) Jahnke, K.;
Podschun, B.; Schnackerz, K. D.; Kautz, J.; Cook, P. F.
Biochemistry 1993, 32, 5160. (f) Sander, E. G. J. Am. Chem.
Soc. 1969, 91, 3629.
13C NMR (63 MHz, CDCl3): d = 151.5, 136.8, 129.5, 128.6, 127.7
(dd, J = 724.6, 698.4 Hz), 126.9, 73.3 (dd, J = 30.3, 24.3 Hz), 56.1,
50.5, 35.5, 32.5, 32.2, 30.7, 30.1, 25.9, 25.4, 25.2, 24.6.
19F NMR (235 MHz, CDCl3): d = –107.1 (dd, J = 266.8, 5.9 Hz, 1
F), –118.7 (dd, J = 266.7, 18.0 Hz, 1 F).
ESI: m/z (%) = 423.1 [M+ + H, 5], 445.1 [M+ + Na, 100].
(5) (a) Dietrich, R. F.; Sakurai, T.; Kenyon, G. L. J. Org. Chem.
1979, 44, 1894. (b) Rachina, V.; Blagoeva, I. Synthesis
1982, 967.
(6) Zee-Cheng, K.-Y.; Robins, R. K.; Cheng, C. C. J. Org.
Chem. 1961, 26, 1877.
2,2-Difluoro-3-hydroxy-N-isopropyl-N-(isopropylcarbamoyl)-
4-phenylbutanamide (6n)
Rf = 0.20 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, C6D12): d = 7.34 (m, 2 H), 7.26 (m, 3 H), 6.16
(br s, 1 H), 4.57 (dt, J = 13.4, 6.7 Hz, 1 H), 4.38 (m, 1 H), 3.99 (td,
J = 13.4, 6.7 Hz, 1 H), 3.09 (d, J = 5.5 Hz, 1 H), 2.82 (dd, J = 13.9,
10.6 Hz, 1 H), 1.35 (d, J = 6.7 Hz, 3 H), 1.31 (d, J = 6.8 Hz, 3 H),
1.23 (d, J = 8.3 Hz, 3 H), 1.22 (d, J = 8.3 Hz, 3 H).
13C NMR (63 MHz, CDCl3): d = 162.5 (t, J = 25.8 Hz), 151.6,
136.7, 129.5, 128.6, 128.4, 126.9, 116.5 (t, J = 260.7 Hz), 73.2 (dd,
J = 31.1, 24.4 Hz), 48.6, 43.7, 42.0, 35.5, 22.3, 21.9, 20.6, 19.8.
19F NMR (235 MHz, CDCl3): d = –107.0 (dd, J = 267.9, 6.0 Hz, 1
F), –118.9 (dd, J = 267.9, 18.2 Hz, 1 F).
ESI: m/z (%) = 343.2 [M+ + H, 10], 365.2 [M+ + Na, 100].
(7) Schlögl, K. Monatsh. Chem. 1958, 89, 61.
(8) Kondo, Y.; Witkop, B. J. Am. Chem. Soc. 1969, 91, 5264.
(9) Boon, W. R.; Carrington, H. C.; Greenhalgh, N.; Vasey, C.
H. J. Chem. Soc. 1954, 3263; and references cited therein.
(10) Khurana, J.; Kukreja, G.; Bansal, G. J. Chem. Soc., Perkin
Trans. 1 2002, 2520.
(11) (a) Hilgetag, G.; Martini, A. Weygand/Hilgetag Preparative
Organic Chemistry; Wiley: New York, 1972, 493. (b) For a
recent improvement of this reaction by microwave
irradiation, see: Devi, I.; Bhuyan, P. J. Tetrahedron Lett.
2005, 46, 5727.
(12) (a) Hiyama, T. Organofluorine Compounds; Springer-
Verlag: Berlin, 2000. (b) Fluorine in Bioorganic
Chemistry; Welch, J. T.; Eswarakrishnan, S., Eds.; Wiley:
New York, 1991. (c) Ojima, I. Fluorine in Medicinal
Chemistry and Chemical Biology; Wiley: New York, 2009.
(13) For a review on the synthesis of gem-difluoromethylene
compounds, see: Tozer, M. J.; Herpin, T. F. Tetrahedron
1996, 52, 8619.
(14) (a) Chambers, R. D.; Jaouhari, R.; O’Hagan, D. Tetrahedron
1989, 45, 5101. (b) Takahashi, L. H.; Radhakrisshnan, R.;
Rosenfield, R. E. Jr.; Meyer, E. F. Jr.; Trainor, D. A. J. Am.
Chem. Soc. 1989, 111, 3368. (c) Witkowski S., Rao Y. K.,
Premchandran R. H., Halushka P. V., Fried J.; J. Am. Chem.
Soc.; 1992, 114: 8464.
2,2-Difluoro-3-hydroxy-N-isopropyl-N-(isopropylcarbam-
oyl)heptanamide (6o)
Rf = 0.23 (hexanes–EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): d = 6.05 (br s, 1 H), 4.56 (dt, J = 13.6,
6.8 Hz, 1 H), 4.11 (ddt, J = 16.0, 12.4, 6.3 Hz, 1 H), 3.97 (dq,
J = 13.3, 6.7 Hz, 1 H), 3.21 (d, J = 6.4 Hz, 1 H), 1.55 (m, 2 H), 1.39
(m, 4 H), 1.34 (d, J = 10.1 Hz, 3 H), 1.33 (d, J = 10.1 Hz, 3 H), 1.21
(d, J = 6.5 Hz, 6 H), 0.92 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): d = 163.6 (t, J = 29.2 Hz), 152.2,
117.2 (dd, J = 264.6, 256.8 Hz), 72.6 (dt, J = 39.7, 19.8 Hz), 49.0,
44.1, 42.3, 29.1, 27.8, 22.8, 22.6, 22.5, 22.4, 20.9, 20.4, 14.2.
19F NMR (235 MHz, CDCl3): d = –107.2 (dd, J = 270.1, 6.6 Hz, 1
F), –118.7 (dd, J = 270.1, 18.2 Hz, 1 F).
ESI: m/z (%) = 331.2 [M+ + Na, 100%].
(15) Fustero, S.; Sanchez-Rossello, M.; Jimenez, D.; Sanz-
Cervera, J. F.; del Pozo, C.; Aceña, J. L. J. Org. Chem. 2006,
71, 2706.
(16) Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.; Gouverneur,
V. Angew. Chem. Int. Ed. 2008, 47, 7927.
(17) (a) Fustero, S.; Fernandez, B.; Bello, P.; del Pozo, C.;
Arimitsu, S.; Hammond, G. B. Org. Lett. 2007, 9, 4251.
(b) Boyer, N.; Gloanec, P.; De Nanteuil, G.; Jubault, P.;
Quirion, J. C. Tetrahedron 2007, 63, 12352.
Acknowledgment
We thank Politecnico di Milano, ‘Progetto Giovani Ricercatori
2007–2008’ for economic support.
(18) Schuler, M.; Monney, A.; Governeur, V. Synlett 2009, 1733.
(19) (a) Volonterio, A.; Zanda, M. Tetrahedron Lett. 2003, 44,
8549. (b) Volonterio, A.; Zanda, M. Lett. Org. Chem. 2005,
2, 44. (c) Volonterio, A.; Ramirez de Arellano, C.; Zanda,
M. J. Org. Chem. 2005, 70, 2161. (d) Volonterio, A.;
Zanda, M. Org. Lett. 2007, 9, 841. (e) Volonterio, A.;
Zanda, M. J. Org. Chem. 2008, 73, 7486. (f) Olimpieri, F.;
Volonterio, A.; Zanda, M. Synlett 2008, 3016.
(20) For a study on the mechanism and kinetics of reaction
between carbodiimides and carboxylic acids, see:
(a) Klausner, Y. S.; Bodansky, M. Synthesis 1972, 453.
(b) Rebek, J.; Fitler, D. J. Am. Chem. Soc. 1973, 95, 4052.
References
(1) For a recent issue of Chem. Rev. completely devoted to
heterocycles see: Chem. Rev. 2004, 104, 2125–2812.
(2) (a) Holley, R. W.; Apgar, J.; Everett, G. A.; Madison, J. T.;
Marquisee, M.; Merril, S. H.; Penswick, J. R.; Zamir, A.
Science 1965, 147, 1462. (b) Wu, S.; Janusz, J. M.; Sheffer,
J. B. Tetrahedron Lett. 2000, 41, 1159; and references cited
therein. (c) Wu, S.; Janusz, J. M. Tetrahedron Lett. 2000, 41,
1165. (d) Steinberg, S.; Misch, A.; Sprinzl, M. Nucl. Acids
Res. 1993, 21, 3011. (e) Stuart, J. W.; Basti, M. M.; Smith,
W. S.; Forrest, B.; Guenther, R.; Sierzputowska-Gracz, H.;
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York

660
F. Olimpieri et al.
PAPER
(24) Recently an organocatalytic asymmetric alkylation with
carbocation intermediates formed by dehydration of
protonated alcohols has been developed: Cozzi, P. G.;
Benfatti, F.; Zoli, L. Angew. Chem. Int. Ed. 2009, 48, 1313.
(25) Otaka, A.; Watanabe, H.; Mitsuyama, E.; Yukimasa, A.;
Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001, 42, 285.
(21) It is worth nothing that NAU derivatives are stable under the
reaction condition for days and did not interconvert into the
corresponding DHUs.
(22) Richard, J. P.; Amyes, T. I.; Bei, L.; Stubblefield, V. J. Am.
Chem. Soc. 1990, 112, 9513.
(23) The hypothesis that DHU derivatives are directly formed via
a carbocation intermediate, rather than via intramolecular
nucleophilic substitution, is supported by the following
experiment. Conversion of the hydroxy group of compound
11 into a good leaving group, such as a mesylate, followed
by ester hydrolysis, and reacting the resulting acid 12 with
carbodiimide 4b afforded the NAU derivative 13 as the only
product (Scheme 7) (no traces of the DHU derivative were
detected by 1H NMR spectroscopy).
OH
OMs
1) MsCl, Et3N, CH2Cl2
COOEt
COOH
2) LiOH, H2O–THF
(88%)
F
F
F
F
12
11
OMs
F
O
O
DIC, TMP
N
N
H
CH2Cl2 (61%)
F
13
Scheme 7
Synthesis 2010, No. 4, 651–660 © Thieme Stuttgart · New York