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Synthesis 2010(4): 651-660  
DOI: 10.1055/s-0029-1218587
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Mild, Efficient Synthesis of gem-Difluorodihydrouracils

Francesca Olimpieria, Santos Fusterob, 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 Departamento de Quimica Organica, Universidad de Valencia, 46100 Burjassot, Spain
c Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK
d C.N.R. - I.C.R.M., via Mancinelli 7, 20131 Milano, Italy

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Publication History

Received 19 October 2009
Publication Date:
07 December 2009 (online)

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Abstract

Carbodiimides react effectively with β-aryl/alkyl-β-hydroxy-α,α-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 (CH2Cl2, 20 ˚C) 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.

Key words

N-heterocycles - fluorine - dihydrouracils - carbodi­imide - domino reaction - N-acylureas

Many small synthetic organic molecules with high medicinal potential contain heterocyclic rings. The range of easily 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 heterocycles is still highly beneficial. [¹] One of the challenges of medicinal chemistry is the promotion of the structural diversity of a ligand, which can be achieved by the attachment of pharmacophoric groups to the rigidified molecule. Small, substituted heterocyclic compounds offer 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-Glucosylated 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 different 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 solution and in solid phase. Furthermore, reductive or hydrolytic DHU ring opening has been used for the synthesis of biologically important compounds such as β-ureido­alcohols and acids [4] or α-substituted β-amino acids. [5] To date, the most utilized strategy to prepare substituted DHUs is the strongly acidic or basic cyclization of β-ureidopropionic acids, obtained either from reactions of α,β-unsaturated acids and urea derivatives [6] or from β-amino acids and isocyanates, [7] which requires extended reaction time, high temperature, and generally produces low yields, or by hydrogenation of uracil derivatives. [8] An alternative synthesis of DHUs consists in the reductive de­sulfurization of 2-thiobarbiturates [9] 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 between malonic acid derivatives and thiourea, which often features modest yields due to the presence of side reactions like hydrolysis of the malonate, decarbethoxylation, transesterification, and urea degradation. [¹¹] For all these reasons a better synthesis of DHUs is required.

Fluorine containing heterocyclic compounds have attracted much interest because of their unique chemical, physical, and biological activities. [¹²] Much attention has been paid to pharmaceuticals and agricultural chemicals containing a gem-difluoromethylene unit [¹³] because many selectively fluorinated analogues of biologically important compounds exhibit a dramatic enhancement in terms of biological activity and because the CF2 group is considered 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 group [¹] [³] because α,α-difluoro ketones have been successfully used as inhibitors of hydrolytic enzymes, and greatly enhanced biological activity has been reported compared with their nonfluorinated analogues. [¹²] There are in general two complementary approaches 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 other is the use of gem-difluoromethylene-containing building 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 predominantly employed despite the limited availability of gem-difluoromethylene-containing building blocks. Exploiting the building block methodology, a range of gem-difluoro heterocycles has been recently synthesized including unsaturated lactams, [¹5] dihydropyranones, [¹6] γ- and β-lactams, [¹7] and furanones [¹8] among others.

As a part of a research program focused on the development of novel, mild, and efficient procedures for the synthesis of small heterocycles through the use of carbodiimides, [¹9] we wish to report the straightforward synthesis of gem-difluoro-DHUs by means a new domino process between easily accessible β-hydroxy-α,α-difluorocarboxylic acids and carbodiimides. In this paper, we provide a full account on scope and limits of this new methodology, which has been studied in detail.

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 hydantoins [¹9a-c] and barbiturates. [¹9d] [e] The former could be synthesized by means of a regiospecific domino process consisting in a condensation step between the two reactants, namely activated α,β-unsaturated acids or α-haloarylacetic acids with carbodiimides, leading to the formation of O-acylisourea intermediates, which undergo nucleophilic aza-Michael reaction or halogen 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-acyl­ureas (NAUs) that could be cyclized to the target compounds.

Scheme 1 One-pot, domino processes leading to 1,3,5-trisubstituted hydantoins

The strategies above led to the formation of the target heterocycles in very mild conditions (room temperature, avoiding the use of strong acids/bases) and in high yields making this methodology suitable for the preparation of libraries of such compounds. We therefore decided to investigate the use of this methodology for the preparation of N,N′-disubstituted difluoro-DHUs 5 starting from differently substituted carbodiimides 4 and easily accessible β-hydroxy-α,α-difluorocarboxylic acids 3 (Scheme  [²] ).

Scheme 2 Retrosynthetic analysis for the preparation of N,N′-disubstituted difluoro-DHUs

The key step of this sequence is the nucleophilic displacement 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 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 β-hydroxy-α,α-difluorocarboxylic acids 3 having an aryl substituent in the β 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, followed by basic hydrolysis of the resulting ethyl esters (Scheme  [³] ).

Scheme 3 Synthesis of β-aryl-β-hydroxydifluoro acids

Thus, compounds 3a-c were reacted with commercially available symmetric N,N′-dialkylcarbodiimides such as DCC (4a), and DIC (4b) (Table  [¹] ). After fine tuning of 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).

Table 1 Reaction between β-Aryl-β-hydroxy-α,α-difluorocarbox­ylic Acids and Asymmetric N,N′-Dialkylcarbodiimides

Entry R¹ (acid) R² (carbodiimide) DHU, Yield (%)a NAU, Yield (%)a
1 OMe (3a) c-C6H11 (4a) 5a, 24 6a, 61
2 OMe (3a) i-Pr (4b) traceb 6b, 78
3 H (3b) c-C6H11 (4a) traceb 6c, 83
4 H (3b) i-Pr (4b) 5d, 24 6d, 55
5 CN (3c) c-C6H11 (4a) 5e, 35 6e, 49
6 CN (3c) i-Pr (4b) - 6f, 98
a Isolated yields.
b Detected by the ¹H NMR spectrum of the crude.

To our surprise, the reaction between β-(4-methoxyphenyl)-β-hydroxy-α,α-difluorocarboxylic acid 3a and DCC (4a) gave an almost 3:1 mixture of the expected NAU derivative 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) provided 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 β position reacted 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 target DHU 5d was still obtained (Table  [¹] , entries 3, 4). Finally, by reacting in the same conditions β-(4-cyanophenyl)-β-hydroxy-α,α-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 exclusive 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 between 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, 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]

Scheme 4 The proposed mechanism for the formation of 5

Intermediate 7 undergoes a rearrangement, the so-called O → N acyl migration, to give the NAU 6, which is a frequently found by-product in the condensation reaction between 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-acylisourea 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.

In order to validate our synthetic methodology, we had to find the way to convert the NAU derivatives 6 into the target 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] ).

Scheme 5 Synthesis of the target DHUs

Next, we turned our attention on the reactivity of less basic/nucleophilic N,N′-diarylcarbodiimides, and in particular 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 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 compounds only by ¹H NMR of the crude reaction mixture, 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 derivatives 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.

Scheme 6 Synthesis of N,N′-diaryl-DHUs

To our surprise, the behavior of asymmetric carbodi­imides, namely carbodiimides having different substituents at the nitrogen atoms in terms of steric hindrance (‘weakly asymmetric’) or nucleophilic character (‘strongly asymmetric’) [¹9c] resulted to be different as compared with the symmetric ones. ‘Weakly asymmetric’ carbodiimides, such as N-allyl or -c-C6H11, N′-tert-butylcarbodiimides 4d,e, respectively, reacted smoothly with β-aryl-β-hydroxy-α,α-difluorocarboxylic acids 3a-c to afford NAU and DHU derivatives in ratios depending on the ‘degree’ of the asymmetry and on the electronic feature of the β-aryl substituent on the acids, although in all cases with total regiocontrol (Table  [²] ). N-Allyl-N′-tert-butylcarbodiimide 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).

Table 2 MReaction between β-Aryl-β-hydroxy-α,α-difluorocarboxylic Acids and Asymmetric Carbodiimides

Entry R¹ (acid) R² R³ (carbo­diimide) DHU, Yield (%)a NAU, Yield (%)a
1 OMe (3a) allyl t-Bu (4d) - 6i, 33
2 H (3b) allyl t-Bu (4d) - 6j, 45
3 CN (3c) allyl t-Bu (4d) 5k, 15 6k, 42
4 CN (3c) c-C6H11 t-Bu (4e) 5l, 51 -
5 OMe (3a) Bn Ph (4f) -b -b
6 CN (3c) Bn Ph (4f) -b -b
a Isolated yields.
bA complex mixture of unidentified products were formed.

These results confirm that O-acylurea derivatives like 7 (Scheme  [4] ), bearing different substituents at the two nitrogen atoms, have more propensity to undergo O → N acyl transfer than the corresponding derivatives having two identical N-substituents, as already observed in previous works. [¹9c] [f] Conversely, N-cyclohexyl-N′-tert-butylcarbodiimide 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-benzyl-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).

Finally, we explored the reactivity of β-alkyl-β-hydroxy-α,α-difluorocarboxylic acids 3d,e, which were synthesized in analogy with the β-aryl analogues (see experimental section). In these cases the carbocations like 9 (see the proposed mechanism in Scheme  [4] ) should be less stable, thus, in theory, more difficult to form than the corresponding 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 β-alkyl,β-hydroxy-α,α-difluorocarboxylic acids 3d,e were reacted with ‘strongly asymmetric’ carbodi­imide 4f, again we were not able to isolate the NAU intermediates after the condensation step (Table  [³] , step A), but this time we could isolate the desired DHUs 5p,q in reasonable yields and as the only regioisomers, by performing the cyclization step (step B) in a one-pot fashion (Table  [³] , entries 4 and 5).

Table 3 Reaction between β-Alkyl-β-hydroxy-α,α-difluorocarboxylic Acids and Carbodiimides

Entry R¹ (acid) R² R³ (carbo­diimide) DHU, Yield (%)a NAU, Yield (%)a
1b Bn (3d) c-C6H11 c-C6H11 (4a) 5m, 26 6m, 41
2b Bn (3d) i-Pr i-Pr (4b) 5n, 20 6n, 45
3b n-Bu (3e) i-Pr i-Pr (4b) 5o, 35 6o, 58
4c Bn (3d) Bn Ph (4f) 5p, 51 -
5c n-Bu (3e) Bn Ph (4f) 5q, 53 -
a Isolated yields.
b One-step A.
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 condensation between easily accessible β-substituted β-hydroxy-α,α-difluorocarboxylic acids and carbodiimides. This leads to the formation of the corresponding NAU derivatives or, in most cases, to a mixture of the desired DHU and NAU derivatives, which could be cyclized to the target compounds very efficiently. When the NAU derivatives 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, although 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 process, [²4] is currently in progress in our laboratories.

¹H NMR spectra were run on spectrometers 250, 400, or 500 MHz. Chemical shifts are expressed in ppm (δ), using TMS as internal standard for ¹H and ¹³C nuclei (δH and δC = 0.00), while C6F6 was used as external standard (δF = 162.90) for ¹9F. Commercially available reagent grade solvents were employed without purification. Commercially unavailable carbodiimides were prepared according to the literature procedure. [¹9] β-Alkyl-β-hydroxy-α,α-difluorocarboxylic acids 3d,e were prepared as shown in Scheme  [³] and described in the literarure. [²5]

Reaction of β-Aryl/alkyl-β-hydroxy-α,α-difluorocarboxylic Acids­ 3 with Carbodiimides 4; General Procedure

To a 0.1 M solution of 3 in CH2Cl2 were added TMP (1 equiv) followed 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 eventually DHUs 5 (Tables  [¹] -  [³] ).

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), concentrated under vacuum, and the crude purified by flash chromatography over silica gel affording DHUs 5.

1,3-Dicyclohexyl-5,5-difluoro-6-(4-methoxyphenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (5a)

R f  = 0.72 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

5,5-Difluoro-1,3-diisopropyl-6-(4-methoxyphenyl)dihydropyrimidine-2,4(1 H ,3 H )-dione (5b)

R f  = 0.52 (hexanes-EtOAc, 90:10).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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.

¹9F NMR (235 MHz, CDCl3): δ = -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(1 H ,3 H )-dione (5c)

R f  = 0.83 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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).

¹³C NMR (63 MHz, CDCl3): δ = 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.

¹9F NMR (235 MHz, CDCl3): δ = -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(1 H ,3 H )-dione (5d)

R f  = 0.67 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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).

¹³C NMR (63 MHz, CDCl3): δ = 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): δ = -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%].

4-(1,3-Dicyclohexyl-5,5-difluoro-2,6-dioxohexahydropyrimidin-4-yl)benzonitrile (5e)

R f  = 0.50 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

4-(5,5-Difluoro-1,3-diisopropyl-2,6-dioxohexahydropyrimidin-4-yl)benzonitrile (5f)

R f  = 0.71 (hexanes-EtOAc, 70:30).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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-6-(4-methoxyphenyl)-1,3-di- p -tolyldihydropyrimidine-2,4(1 H ,3 H )-dione (5g)

R f  = 0.27 (hexanes-EtOAc, 80:20).

¹H NMR (300 MHz, CDCl3): δ = 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): δ = -116.5 (dd, J = 285.1, 4.0 Hz, 1 F), -122.3 (dd, J = 285.1, 16.9 Hz, 1 F).

ESI: m/z (%) = 459.1 [M+ + Na, 100%].

5,5-Difluoro-6-phenyl-1,3-di- p -tolyldihydropyrimidine-2,4(1 H ,3 H )-dione (5h)

R f  = 0.46 (hexanes-EtOAc, 80:20).

¹H NMR (300 MHz, CDCl3): δ = 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).

¹9F NMR (282 MHz, CDCl3): δ = -116.7 (dd, J = 285.5, 3.6 Hz, 1 F), -122.00 (dd, J = 285.5, 17.2 Hz, 1 F).

ESI: m/z (%) = 429.1 [M+ + Na, 100%].

4-(3-Allyl-1- tert -butyl-5,5-difluoro-2,6-dioxohexahydropyrimidin-4-yl)benzonitrile (5k)

R f  = 0.48 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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).

¹³C NMR (63 MHz, CDCl3): δ = 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.

¹9F NMR (235 MHz, CDCl3): δ = -119.5 (d, J = 286.1 Hz, 1 F), -122.8 (dd, J = 286.1, 19.7 Hz, 1 F).

ESI: m/z (%) = 370.1 [M+ + Na, 100%].

4-(1- tert -Butyl-3-cyclohexyl-5,5-difluoro-2,6-dioxohexahydropyrimidin-4-yl)benzonitrile (5l)

R f  = 0.60 (hexanes-EtOAc = 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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].

6-Benzyl-1,3-dicyclohexyl-5,5-difluorodihydropyrimidine-2,4(1 H ,3 H )-dione (5m)

R f  = 0.83 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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.

¹9F NMR (235 MHz, CDCl3): δ = -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%].

6-Benzyl-5,5-difluoro-1,3-diisopropyldihydropyrimidine-2,4(1 H ,3 H )-dione (5n)

R f  = 0.80 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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 (235 MHz, CDCl3): δ = -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 (%) = 325.2 [M+ + H, 15], 347.2 [M+ + Na, 100].

6-Butyl-5,5-difluoro-1,3-diisopropyldihydropyrimidine-2,4(1 H ,3 H )-dione (5o)

R f  = 0.84 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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 (%) = 313.1 [M+ + Na, 100%].

1,6-Dibenzyl-5,5-difluoro-3-phenyldihydropyrimidine-2,4-dione (5p)

R f  = 0.64 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

1-Benzyl-6-butyl-5,5-difluoro-3-phenyldihydropyrimidine-2,4(1 H ,3 H )-dione (5q)

R f  = 0.74 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = -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-hydroxy-3-(4-methoxyphenyl)propanamide (6a)

R f  = 0.16 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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).

¹³C NMR (63 MHz, CDCl3): δ = 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): δ = -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%].

2,2-Difluoro-3-hydroxy- N -isopropyl- N -(isopropylcarbamoyl)-3-(4-methoxyphenyl)propanamide (6b)

R f  = 0.23 (hexanes-EtOAc, 70:30).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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.

¹9F NMR (235 MHz, CDCl3): δ = -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%].

N -Cyclohexyl- N -(cyclohexylcarbamoyl)-2,2-difluoro-3-hydroxy-3-phenylpropanamide (6c)

R f  = 0.32 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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.

¹9F NMR (235 MHz, CDCl3): δ = -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)

R f  = 0.31 (hexanes-EtOAc, 70:30).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

3-(4-Cyanophenyl)- N -cyclohexyl- N -(cyclohexylcarbamoyl)-2,2-difluoro-3-hydroxypropanamide (6e)

R f  = 0.10 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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).

¹³C NMR (63 MHz, CDCl3): δ = 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): δ = -104.0 (dd, J = 269.2, 4.6 Hz, 1 F), -117.4 (dd, J = 269.2, 19.5 Hz, 1 F).

ESI: m/z (%) = 434.0 [M+ + H, 9], 456.1 [M+ + Na, 100], 471.2 [M+ + K, 58].

3-(4-Cyanophenyl)-2,2-difluoro-3-hydroxy- N -isopropyl- N -(isopropylcarbamoyl)propanamide (6f)

R f  = 0.21 (hexanes-EtOAc, 70:30).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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 -(Allylcarbamoyl)- N - tert -butyl-2,2-difluoro-3-hydroxy-3-(4-methoxyphenyl)propanamide (6i)

R f  = 0.28 (hexanes-EtOAc, 80:20).

¹H NMR (250 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

N -(Allylcarbamoyl)- N - tert -butyl-2,2-difluoro-3-hydroxy-3-phenylpropanamide (6j)

R f  = 0.55 (hexanes-EtOAc, 70:30).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

N -(Allylcarbamoyl)- N - tert -butyl-3-(4-cyanophenyl)-2,2-difluoro-3-hydroxypropanamide (6k)

R f  = 0.15 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

N -Cyclohexyl- N -(cyclohexylcarbamoyl)-2,2-difluoro-3-hydroxy-4-phenylbutanamide (6m)

R f  = 0.37 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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).

¹³C NMR (63 MHz, CDCl3): δ = 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): δ = -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].

2,2-Difluoro-3-hydroxy- N -isopropyl- N -(isopropylcarbamoyl)-4-phenylbutanamide (6n)

R f  = 0.20 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, C6D12): δ = 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): δ = 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): δ = -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].

2,2-Difluoro-3-hydroxy- N -isopropyl- N -(isopropylcarbamoyl)heptanamide (6o)

R f  = 0.23 (hexanes-EtOAc, 80:20).

¹H NMR (400 MHz, CDCl3): δ = 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): δ = 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): δ = -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%].

Acknowledgment

We thank Politecnico di Milano, ‘Progetto Giovani Ricercatori 2007-2008’ for economic support.

21

It is worth nothing that NAU derivatives are stable under the reaction condition for days and did not interconvert into the corresponding DHUs.

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).

Scheme 7

21

It is worth nothing that NAU derivatives are stable under the reaction condition for days and did not interconvert into the corresponding DHUs.

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).

Scheme 7

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Scheme 1 One-pot, domino processes leading to 1,3,5-trisubstituted hydantoins

Scheme 2 Retrosynthetic analysis for the preparation of N,N′-disubstituted difluoro-DHUs

Scheme 3 Synthesis of β-aryl-β-hydroxydifluoro acids

Scheme 4 The proposed mechanism for the formation of 5

Scheme 5 Synthesis of the target DHUs

Scheme 6 Synthesis of N,N′-diaryl-DHUs

Scheme 7