Synthesis of pyrimidinyl arylglycines through subsequent Mitsunobu and Petasis reactions

Article abstract of DOI:10.1016/j.tet.2008.03.035

The synthesis of highly functionalized pyrimidinyl arylglycines is presented. The highlight in our synthetic sequence includes selective O-alkylation of 2-(benzylsulfanyl)-4(3H)-pyrimidinones with N-Boc β-aminoalcohols under Mitsunobu conditions, Petasis

Full text of DOI:10.1016/j.tet.2008.03.035

Tetrahedron 64 (2008) 5226–5235
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pyrimidinyl arylglycines through subsequent
Mitsunobu and Petasis reactions
,
b,
*
David Font a, Montserrat Heras a , Jose M. Villalgordo
*
´
a Department of Chemistry, Faculty of Sciences, University of Girona, Campus de Montilivi, E-17071 Girona, Spain
b Villapharma Research, Pol´ıgono Industrial Oeste, c/Paraguay, Parcela 7/5-A, Mo´dulo A, E-30169 Murcia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of highly functionalized pyrimidinyl arylglycines is presented. The highlight in our
synthetic sequence includes selective O-alkylation of 2-(benzylsulfanyl)-4(3H)-pyrimidinones with
N-Boc b-aminoalcohols under Mitsunobu conditions, Petasis reaction with glyoxylic acid and phenyl-
boronic acid and nucleophilic ipso-substitution of the activated sulfur with morpholine. The unexpected
spontaneous Smiles rearrangement of several pyrimidinyl amines is also discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 12 February 2008
Received in revised form 10 March 2008
Accepted 12 March 2008
Available online 14 March 2008
Keywords:
Arylglycines
Pyrimidines
Mitsunobu reaction
Petasis reaction
Smiles rearrangement
Nucleophilic ipso-substitution
1. Introduction
an increasing variety of boronic acids and amines are commercially
available and (iii) it proceeds at room temperature in a wide range
In drug discovery, interest in non-proteinogenic a-amino acids1
is continuously increasing as a result of their potential pharmaco-
logical properties and their utility as building blocks in the synthesis
of peptidic and non-peptidic compounds.2 Arylglycines constitute
a particularly important class of non-proteinogenic a-amino acids.
In fact, arylglycine residues are found in the structure of glycopep-
tide antibiotics, such as vancomycin and teicoplanin.3 Nocardicins
a type of monocyclic b-lactam antibiotics, also contain the arylgly-
cine moiety.4 In addition, it was recently discovered that some
arylglycines could selectively modulate the activity of metabotronic
glutamate receptors (mGluRs), and are used to develop new drugs
for the treatment of various neurodegenerative diseases.5 Owing to
this range of potent biological activities, intense research has been
undertaken to obtain new arylglycines derivatives.6
The Petasis reaction, or boronic Mannich reaction, involves the
three-component coupling of an amine, an aldehyde and an orga-
noboron compound. One of the most important uses of the Petasis
reaction is the synthesis of arylglycines employing glyoxylic acid as
the aldehyde component and an arylboronic acid as the organo-
boron derivative.7 This reaction is ideally suited for combinatorial
chemistry8 because: (i) it is a multi-component condensation; (ii)
of solvents. In general, this reaction is more efficient with second-
ary amines and sterically hindered primary amines.9
Our ongoing research is based on the development of efficient
methodologies for the preparation of libraries of relevant core
structures with a high degree of molecular diversity through com-
binatorial chemistry.10 In this way, we have recently described the
solution and solid-phase synthesis of 2,6-disubstituted 4-alkoxy-
pyrimidines.10b Our synthetic approach is based on the selective
O-alkylation of 2-(alkylsulfanyl)-4(3H)pyrimidinones 1 with alkyl
halides under basic conditions or with alcohols under Mitsunobu
conditions, followed by a nucleophilic ipso-substitution of the cor-
responding activated sulfur with a variety of nucleophiles (phen-
oxides, Grignard reagents, and primary and secondary amines). This
last step is useful not only for introducing molecular diversity but
also as cleavage reaction on solid-phase synthesis (Scheme 1).
R2
R2
O
O
N
O
N
i) R2-OH
PPh3 /DIAD
or
HN
N
N
1) m-CPBA
2) NuH
R
R
S
N
1
R1
S
R1
Nu
R1
ii) R2-X / Base
R= Benzyl, Merrifield resin
1 = H, Me, Ph
R
* Corresponding authors. Tel.: þ34 972418274; fax: þ34 972418150.
E-mail address: montserrat.heras@udg.edu (M. Heras).
Scheme 1. Synthesis of 2,6-disubstituted 4-alkoxypyrimidines.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.035

D. Font et al. / Tetrahedron 64 (2008) 5226–5235
5227
Within this context, we report here the extension of this
methodology towards the synthesis of highly functionalized py-
rimidines substituted at position 4 with an arylglycine residue. The
results of this investigation are disclosed herein.
whereas the primary amines 4a and 4b (Table 1, entries 1 and 2) are
stable and did not undergo Smiles rearrangement. On the other
hand, when the pyrimidine ring is substituted at position 6 with
a phenyl group, the pyrimidines 4 kept stable even those bearing
the most nucleophilic amines (Table 1, entries 5, 7 and 10).
Probably, the steric effect of the phenyl group prevents the
spontaneous Smiles rearrangement. In agreement with the addi-
tion–elimination mechanism proposed for this reaction, the rear-
rangement of compounds 4 involves the formation of a spiro
Meisenheimer complex intermediate by nucleophilic attack of the
amine group and the subsequent elimination of alcohol group
(Scheme 3).
2. Results and discussion
Consistent with this goal, we reasoned that the incorporation of
an arylglycine residue at position 4 of a pyrimidine ring could be
achieved via selective O-alkylation of 2-(alkylsulfanyl)-4(3H)-pyr-
imidinones 1 with N-Boc b-aminoalcohols under Mitsunobu con-
ditions, followed by subsequent acidic removal of the N-Boc
protecting group and Petasis reaction with glyoxylic acid and an
arylboronic acid. Thus, when the easily available 2-(benzyl-
sulfanyl)-4(3H)-pyrimidinones10b 1 were treated with different
primary and secondary N-Boc aminoalcohols 2, PPh3 and DIAD in
anhydrous THF at room temperature for 1–5 h, 4-alkoxypyr-
imidines 3 were obtained in good yields (Scheme 2, Table 1). Re-
moval of the N-Boc group was carried out by treatment of
compounds 3 with TFA/CH2Cl2 (1:1) at room temperature giving
the corresponding amines 4 in good yields (Scheme 2, Table 1).
R2
R2
H
N
R3
N
OH
H
O
N
R3
N
N
R3 N
N
O
R2
R1
N
Bn
Bn
Bn
S
R1
S
S
N
R1
4
5
R1 = H, Me
Meisenheimer
complex
Scheme 3. Proposed mechanism for alcohols 5.
Boc
H
N
N
O
R3
O
R3
O
Recently, several examples of the Smiles rearrangement re-
R2
R1
R2
R1
action were reported as a synthetic tool in the preparation of pyr-
imidinic scaffolds.12 This rearrangement normally requires basic or
acid conditions and/or high temperature. However, to the best our
knowledge the spontaneous N–O-type Smiles rearrangement of
compounds 4 constitutes the first example involving a pyrimidine
ring that occurs at room or low temperature.
The Petasis reaction was then studied with the stable amines 4
(Table 1, entries 1, 2, 5, 7, 9 and 10), which did not undergo the
Smiles rearrangement. Thus, treatment of the amines 4a, 4b, 4e, 4g,
4i and 4j with glyoxylic acid and phenylboronic acid in CH2Cl2 at
room temperature afforded arylglycines 6 (Scheme 4, Table 2).
Since the isolation of compounds 6 proved to be problematic,
we decided to treat the crude product with CsCO3 and CH3I in order
to obtain the corresponding methyl esters 7 (Scheme 4, Table 2).
The Petasis reaction proceeded well with the secondary amines and
i)
ii)
N
N
HN
Bn
Bn
Bn
S
N
1
R1
R3
S
N
3
S
N
4
Smiles
rearrangement
R3
R2
R2
HO
HO
=
HO
N
NH
2a
NH
OH
2
Boc
N
Boc
2b
Boc
Boc
N
N
HO
HO
Bn
S
N
N
5
R1
2c
Boc
2d
Scheme 2. Reagents and conditions: (i) 2, DIAD, PPh3, THF, rt, 1–5 h; (ii) TFA/CH2Cl2
(1:1), 0 ꢀC to rt, 30 min to 1 h.
In several cases (Table 1, entries 3, 4, 6 and 8), the isolated
amines 4 were not stable and slowly underwent a spontaneous
Smiles rearrangement11 to produce the alcohol derivatives 5 at
room temperature or even when stocked inside the refrigerator. It
should be noted that the amines 4 were the sole products observed
by TLC during the acidic removal of the N-Boc group and that the
formation of compounds 5 were detected after the neutralization
step performed during the work-up. As evidenced in Table 1, this
rearrangement is favoured by the nucleophilicity of the amine
group. Secondary and sterically hindered primary amines (Table 1,
entries 3, 4, 6 and 8) easy underwent Smiles rearrangement
Ph
CO2CH3
R3
Ph
CO2H
H
N
N
N
O
R3
i)
O
O
R3
ii)
R2
R1
R2
R1
R2
R1
N
N
N
Bn
Bn
Bn
S
N
4
S
N
7
S
N
6
Scheme 4. Reagents and conditions: (i) OHC–CO2H, PhB(OH)2, (ii) MeI, Cs2CO3, DMF,
rt, 1 h.
Table 1
Yields for the sequence depicted in Scheme 2
Entry
R1
2
R2
R3
3 (yield)a
4 (yield)a
5 (yield)a
1
2
3
4
5
6
7
8
9
10
H
Ph
H
Me
Ph
Me
Ph
H
2a
2a
2b
2b
2b
2c
2c
2d
2d
2d
H
H
H
H
H
H
H
Me
Me
3a (75)
3b (82)
3c (84)
3d (96)
3e (84)
3f (84)
3g (74)
3h (88)
3i (93)
3j (89)
4a (92)
4b (89)
4c (74)b
4d (60)b
4e (97)
4f (67)b
4g (90)
4h (60)b
4i (83)
CH(CH3)2
CH(CH3)2
CH(CH3)2
H
5c (21)
5d (15)
5f (30)
5h (28)
H
–(CH2)3–
–(CH2)3–
–(CH2)3–
Me
Ph
4j (89)
a
Isolated % yield after purification by flash chromatography.
Yield calculated after flash chromatography. Amine 4 was slowly turning up into alcohol 5 at room and low temperature.
b

5228
D. Font et al. / Tetrahedron 64 (2008) 5226–5235
Table 2
Table 3
Yields for the sequence depicted in Scheme 4
Yields for the sequence depicted in Scheme 5
Entry
R1
R2
R3
6 (yield)a
7 (yield)a
drc (%)
40
Entry
Compound
R1
R2
R3
Yielda (%)
1
2
3
4
5
6
H
H
H
H
H
H
Me
d
d
1
2
3
4
8e
8g
8i
Ph
Ph
Me
Ph
CH(CH3)2
H
H
Me
62
75
65
73
Ph
Ph
Ph
Me
Ph
CH(CH3)2
H
7e (55)b
7g (50)
7i (68)
7j (94)
–(CH2)3–
–(CH2)3–
8j
–(CH2)3–
–(CH2)3–
70
73
a
Isolated % yield after purification by flash chromatography.
6j (86)
a
Isolated % yield after purification by flash chromatography.
Compound 7e was obtained as an inseparable diastereomeric mixture.
Diastereomeric ratio was calculated by HPLC of the Petasis reaction crude
b
c
To circumvent this problem, the amino group was protected as
its hydrochloric salt and the amount of m-CPBA was reduced to
1.2 equiv. The subsequent nucleophilic ipso-substitution displace-
ment with morpholine afforded the pyrimidinyl arylglycines 8 in
good yields (Scheme 5, Table 3).
product.
sterically hindered primary amines (Table 2, entries 3, 4, 5 and 6).
These results are in agreement with precedent literature.9
When the Petasis reaction was carried out with the chiral
amines 4e, 4i and 4j, the arylglycine 6j and arylglycinates 7e, 7i and
7j were obtained as a diastereomeric mixture (Table 2). In agree-
ment with previous reports,9b the chiral secondary amines 4i and 4j
(Table 2, entries 5 and 6) underwent the Petasis reaction in much
greater stereoselectivity than the chiral primary amine 4e (Table 2,
entry 3). The two diastereomers could easily be separated by flash
chromatography except in the case of 7e (Table 2, entry 3). In the
case of 6j the unambiguous assignment of the major diastereomer
6ja was achieved by X-ray analysis (Fig. 1).
In order to increase the molecular diversity of arylglycinates 7 at
position 2 of the pyrimidine ring, we focused our attention on the
nucleophilic displacement of the benzylsulfanyl group through the
methodology described previously.10 Thus, arylglycinates 7 were
treated with 2.5 equiv of m-CPBA at 0 ꢀC to afford the corre-
sponding sulfones. Unfortunately, this reaction also produced the
oxidation of tertiary and secondary amines to N-oxides and nitro-
nes, respectively.
3. Conclusion
In summary, an efficient synthetic strategy to prepare highly
functionalized pyrimidinyl arylglycines via a subsequent Mitsu-
nobu and Petasis reaction has been described. Best results were
obtained with secondary and sterically hindered primary amines.
The nucleophilic ipso-substitution of the activated sulfur with nu-
cleophiles allows the introduction of additional molecular diversity
over the pyrimidine ring. Several pyrimidinyl amines 4 underwent
an unexpected spontaneous Smiles rearrangement even at low
temperature. Future efforts will focus on the application of this
method to the preparation of new pyrimidinyl arylglycines through
combinatorial chemistry.
4. Experimental
4.1. General
All commercially available chemicals were used as purchased
without further purification. DMF was dried over activated mo-
lecular sieves (4 Å). THF was dried over Na/benzophenone prior to
use. Melting points (capillary tube) were measured with an Elec-
trothermal digital melting point apparatus IA 91000 and are un-
corrected. IR spectra were recorded on a Mattson-Galaxy Satellite
FT-IR using a single reflection ATR system as a sampling accessory.
Bands are characterized as broad (br), strong (s), medium (m) and
weak (w). NMR spectra were recorded on a Brucker DPX200 Ad-
vance spectrometer. 1H NMR spectra were recorded at 200 MHz. 13
C
NMR spectra and DEPT experiments were determined at 50 MHz.
Spectra recorded in CDCl3 were referenced to residual CHCl3 at
7.26 ppm for 1H and 77.0 ppm for 13C. Spectra recorded in DMSO-d6
were referenced to residual DMSO at 2.49 ppm for 1H and 39.5 ppm
for 13C. Coupling constants (J) are given in hertz (Hz). The following
abbreviations were used for spin multiplicity: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, sept¼septet, m¼multiplet,
dd¼double doublet, br¼broad. EI mass spectra were recorded on
a Thermo Quest 2000 series apparatus for the EI (70 eV). ESI mass
spectra were recorded using a Navigator quadrupole instrument.
FAD mass spectra were recorded on a VG Quattro instrument, using
3-NBA or 1-thioglycerol as the matrix. High resolution mass spectra
(HRMS) were determined under conditions of ESI on a Bucker
Figure 1. ORTEP diagram of pyrimidinyl arylglycine 6ja.
Ph
CO2CH3
Ph
CO2CH3
R3
N
N
O
R3
O
R2
R1
R2
R1
1) HCl / CH2Cl2
2) m-CPBA (1.2 equiv) / 0 °C-rt / 1 h
3) morpholine (2.5 equiv) / dioxane / 60 °C
N
N
Bn
S
N
7
N
N
8
O
Scheme 5. Synthesis of arylglycinates 8.

D. Font et al. / Tetrahedron 64 (2008) 5226–5235
5229
MicroTof-Q instrument using a lock-spray source. Optical rotations
were measured on a Perkin–Elmer polarimeter 241, using the so-
dium D line. High performance liquid chromatography (HPLC)
analyses were carried out using a Dionex P680 instrument. Sepa-
rations were achieved on an analytical C18 Kromasil reversed phase
column (4.6 mmꢁ40 mm; 3.5 mm particle size). Analytical thin
layer chromatography (TLC) was performed on precoated TLC
plates, silica gel 60 F254 (Merck). The spots on the TLC plates were
visualized with UV/visible light (254 nm) and/or stained with
a solution of potassium permanganate (1.5 g/100 mL H2O). Flash
chromatography (FC) purifications were performed on silica gel 60
(230–400 mesh, Merck).
(100), 138 (39), 137 (71), 136 (89). Anal. Calcd for C24H27N3O3S: C,
65.88; H, 6.22; N, 9.60; S, 7.33. Found: C, 65.98; H, 6.41; N, 9.72;
S, 7.70.
4.2.3. tert-Butyl (S)-1-(2-(benzylsulfanyl)pyrimidin-4-yloxy)-
3-methylbutan-2-ylcarbamate (3c)
Synthesized according to general procedure (4 h) from pyr-
imidinone 1a (546 mg, 2.50 mmol), PPh3 (787 mg, 3.00 mmol),
N-Boc-L-valinol 2b (610 mg, 3.00 mmol) and DIAD (0.58 mL,
3.00 mmol), 847 mg (84%) of compound 3c was obtained as a col-
ourless solid. Mp: 113–114 ꢀC. TLC: Rf 0.32 (n-hexane/ethyl acetate
4:1). IR (ATR): 3369 (m), 2987 (w), 2934 (w), 1690 (s), 1569 (s), 1546
(s), 1521 (s), 1461 (w), 1436 (s), 1399 (m), 1364 (m), 1321 (s), 1285
(s), 1228 (s), 1173 (s), 1157 (s), 1075 (m), 1042 (m), 996 (s), 979 (w),
937 (m) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 8.26 (d, J¼5.6 Hz,
1H), 7.49–7.24 (m, 5H), 6.43 (s, J¼5.6 Hz, 1H), 4.67 (br, 1H), 4.43 (s,
2H), 4.38–4.30 (m, 2H), 3.88–3.69 (m, 1H), 1.91 (sept, J¼6.8 Hz, 1H),
1.47 (s, 9H), 0.99 (d, J¼6.8 Hz, 6H). 13C NMR (CDCl3, 50 MHz):
d (ppm) 171.3 (s), 168.6 (s), 157.4 (d), 155.7 (s),137.5 (s),128.8 (d, 2C),
128.5 (d, 2C), 127.1 (d), 103.9 (d), 79.3 (s), 66.9 (t), 54.8 (d), 35.2 (t),
29.6 (d), 28.3 (q, 3C), 19.5 (q), 18.4 (q). MS (ESI) m/z: 462
[MþCH3CNþNH4]þ, 426 [MþNa]þ, 404 [MþH]þ. Anal. Calcd for
4.2. General procedure for the Mitsunobu reaction. Synthesis
of pyrimidines 3
The appropriate 2-(benzylsulfanyl)pyrimidin-4(3H)-one
1
(1.0 equiv) was dissolved in dry THF (3 mL/mmol pyrimidinone)
under a nitrogen atmosphere, and the solution was cooled in an ice
bath. Triphenylphosphine (1.0–1.3 equiv) and the corresponding N-
Boc protected aminoalcohols 2 (1.0–1.3 equiv) were added. DIAD
(1.0–1.3 equiv) was added dropwise as a THF solution (1 mL/mmol
DIAD). The resulting mixture was warmed to room temperature
and stirred under nitrogen. Upon completion of the reaction (TLC
monitoring), the solvent was removed under reduced pressure and
the resulting residue was purified by flash chromatography
(n-hexane/ethyl acetate 9:1) to afford pyrimidines 3.
C21H29N3O3S: C, 62.50; H, 7.24; N, 10.41; S, 7.95. Found: C, 62.38; H,
7.51; N, 10.69; S, 8.25.
4.2.4. tert-Butyl (S)-1-(2-(benzylsulfanyl)-6-methylpyrimidin-
4-yloxy)-3-methylbutan-2-ylcarbamate (3d)
Synthesized according to general procedure (2 h) from
2-(benzylsulfanyl)-6-methylpyrimidin-4(3H)-one (1b) (696 mg,
3.00 mmol), PPh3 (944 mg, 3.6 mmol), N-Boc-L-valinol 2b (732 mg,
4.2.1. tert-Butyl 2-(2-(benzylsulfanyl)pyrimidin-4-yloxy)-
ethylcarbamate (3a)
Synthesized according to general procedure (3 h) from 2-(benz-
ylsulfanyl)pyrimidin-4(3H)-one (1a) (1.0 g, 4.58 mmol), PPh3
(1.32 g, 5.04 mmol), N-Boc-ethanolamine 2a (812 mg, 5.04 mmol)
and DIAD (0.98 mL, 5.04 mmol), 1.24 g (75%) of compound 3a was
obtained as a colourless solid. Mp: 101–102 ꢀC. TLC: Rf 0.55 (n-
hexane/ethyl acetate 1:1). IR (KBr): 3373 (s), 3291 (w), 3260 (w),
3023 (w), 2978 (m), 2932 (m), 1687 (s), 1561 (s), 1532 (s), 1439 (s),
3.60 mmol) and DIAD (0.70 mL, 3.60 mmol), 1.20 g (96%) of com-
pound 3d was obtained as a colourless solid. Mp: 131–133 ꢀC. TLC:
Rf 0.35 (n-hexane/ethyl acetate 4:1). IR (ATR): 3372 (m), 3032 (w),
2978 (w), 2961 (w), 2869 (w), 1681 (s), 1577 (s), 1547 (s), 1522 (s),
1497 (w), 1459 (m), 1439 (m), 1410 (w), 1367 (m), 1350 (s), 1281 (s),
1244 (s), 1167 (s), 1048 (m), 1034 (m), 1007 (w), 943 (w), 921 (w),
897 (m) cmꢂ1 1H NMR (CDCl3, 200 MHz): d (ppm) 7.48–7.25 (m,
.
1321 (s), 1259 (s), 1236 (s), 1167 (s) cmꢂ1
.
1H NMR (CDCl3,
5H), 6.27 (s, 1H), 4.63 (br, 1H), 4.42 (s, 2H), 4.34–4.28 (m, 2H), 3.82–
3.69 (m, 1H), 2.40 (s, 3H), 1.88 (sept, J¼6.8 Hz, 1H), 1.46 (s, 9H), 0.97
(d, J¼6.8 Hz, 6H). 13C NMR (CDCl3, 50 MHz): d (ppm) 170.4 (s), 169.1
(s), 167.8 (s), 155.7 (s), 137.9 (s), 128.8 (d, 2C), 128.4 (d, 2C), 127.0 (d),
102.3 (d), 79.2 (s), 66.7 (t), 54.8 (d), 35.2 (t), 29.6 (d), 28.3 (q, 3C),
23.7 (q), 19.5 (q), 18.4 (q). MS (ESI) m/z: 418 [MþH]þ. Anal. Calcd for
200 MHz): d (ppm) 8.26 (d, J¼5.6 Hz,1H), 7.45–7.25 (m, 5H), 6.41 (d,
J¼5.6 Hz, 1H), 4.98 (br, 1H), 4.41 (s, 2H), 4.39 (t, J¼5.4 Hz, 2H), 3.50
(q, J¼5.4 Hz, 3H), 1.47 (s, 9H). 13C NMR (CDCl3, 50 MHz): d (ppm)
171.2 (s), 168.3 (s), 157.4 (d), 155.7 (s), 137.4 (s), 128.7 (d, 2C), 128.4
(d, 2C), 127.0 (d), 103.8 (d), 79.5 (s), 65.7 (t), 39.6 (t), 35.2 (t), 28.3 (q,
3C). MS (FAB) m/z (%): 363 ([Mþ2]þ,12), 362 ([Mþ1]þ, 57), 306 (12),
220 (19), 219 (100), 218 (24), 154 (23), 137 (14), 136 (21). Anal. Calcd
for C18H23N3O3S: C, 59.81; H, 6.41; N, 11.63; S, 8.87. Found: C, 59.63;
H, 6.59; N, 11.41; S, 8.49.
C22H31N3O3S: C, 63.28; H, 7.48; N, 10.06; S, 7.68. Found: C, 63.11; H,
7.70; N, 10.25; S, 7.97.
4.2.5. tert-Butyl (S)-1-(2-(benzylsulfanyl)-6-phenylpyrimidin-
4-yloxy)-3-methylbutan-2-ylcarbamate (3e)
4.2.2. tert-Butyl 2-(2-(benzylsulfanyl)-6-phenylpyrimidin-4-yloxy)-
ethylcarbamate (3b)
Synthesized according to general procedure (3 h) from
pyrimidinone 1c (1.47 g, 5.00 mmol), PPh3 (1.44 g, 5.50 mmol),
Synthesized according to general procedure (3 h) from 2-
N-Boc-L-valinol 2b (1.12 g, 5.50 mmol) and DIAD (1.10 mL,
(benzylsulfanyl)-6-phenylpyrimidin-4(3H)-one
(1c)
(900 mg,
5.50 mmol), 2.01 g (84%) of compound 3e was obtained as a col-
ourless solid. Mp: 130–131 ꢀC. TLC: Rf 0.80 (n-hexane/ethyl acetate
1:1). IR (ATR): 3368 (w), 2967 (w), 1680 (s), 1565 (s), 1524 (s),
3.06 mmol), PPh3 (963 mg, 3.67 mmol), N-Boc-ethanolamine 2a
(592 mg, 3.67 mmol) and DIAD (0.71 mL, 3.67 mmol), 1.10 g (82%)
of compound 3b was obtained as a colourless solid. Mp: 105–
106 ꢀC. TLC: Rf 0.59 (n-hexane/ethyl acetate 1:1). IR (KBr): 3391
(s), 2976 (m), 2924 (m), 2869 (w), 1692 (s), 1574 (s), 1529 (s),
1421 (m), 1380 (m), 1262 (s), 1221 (m), 1168 (s), 1046 (m), 901
1406 (w), 1357 (m), 1270 (m), 1242 (m), 1174 (s), 1004 (m) cmꢂ1
.
1H NMR (CDCl3, 200 MHz): d (ppm) 8.09–8.02 (m, 2H), 7.52–7.48
(m, 5H), 7.39–7.24 (m, 3H), 6.84 (s, 1H), 4.74 (d, J¼9.2 Hz, 1H), 4.55
(s, 2H), 4.40 (dd, J¼12.0 Hz, J0¼5.2 Hz, 1H), 4.38 (dd, J¼12.0 Hz,
J0¼4.2 Hz, 1H), 3.82–3.74 (m, 1H), 1.94 (sept, J¼6.8 Hz, 1H), 1.48 (s,
9H), 1.02 (d, J¼6.8 Hz, 6H). 13C NMR (CDCl3, 50 MHz): d (ppm)
170.9 (s), 169.8 (s), 164.8 (s), 155.7 (s), 137.9 (s), 136.5 (s), 130.6 (d),
128.79 (d, 2C), 128.70 (d, 2C), 128.5 (d, 2C), 128.4 (d), 127.0 (d, 2C),
99.0 (d), 79.3 (s), 67.0 (t), 54.9 (d), 35.4 (t), 29.6 (d), 28.3 (q, 3C),
19.5 (q), 18.4 (q). MS (ESI) m/z: 480 [MþH]þ. Anal. Calcd for
(m) cmꢂ1 1H NMR (CDCl3, 200 MHz): d (ppm) 8.10–8.00 (m, 2H),
.
7.50–7.48 (m, 5H), 7.40–7.27 (m, 3H), 6.84 (s, 1H), 4.91 (br, 1H),
4.53 (s, 2H), 4.47 (t, J¼5.4 Hz, 2H), 3.55 (q, J¼5.4 Hz, 3H), 1.49 (s,
9H). 13C NMR (CDCl3, 50 MHz): d (ppm) 171.0 (s), 169.6 (s), 164.9
(s), 155.7 (s), 137.8 (s), 136.5 (s), 130.7 (d), 128.78 (d, 2C), 128.72
(d, 2C), 128.5 (d), 127.07 (d, 2C), 127.04 (d, 2C), 99.0 (d), 79.5 (s),
65.8 (t), 39.8 (t), 35.4 (t), 28.3 (q, 3C). MS (FAB) m/z (%): 439
([Mþ2]þ, 12), 438 ([Mþ1]þ, 40), 295 (27), 176 (21), 155 (33), 154
C
27H33N3O3S: C, 67.61; H, 6.93; N, 8.76; S, 6.69. Found: C, 67.44; H,
7.08; N, 8.94; S, 6.91.

5230
D. Font et al. / Tetrahedron 64 (2008) 5226–5235
4.2.6. tert-Butyl 2-(2-(benzylsulfanyl)-6-methylpyrimidin-4-
yloxy)ethylmethylcarbamate (3f)
200 MHz): d (ppm) 7.48–7.25 (m, 5H), 6.27 (s, 1H), 4.43 (s, 2H),
4.32–4.08 (m, 3H), 3.47–3.32 (m, 2H), 2.40 (s, 3H), 1.95–1.83 (m,
4H), 1.49 (s, 9H). 13C NMR (CDCl3, 50 MHz): d (ppm) 170.3 (s), 169.1
(s), 167.7 (s), 154.4 (s), 137.8 (s), 128.8 (d, 2C), 128.3 (d, 2C), 126.9 (d),
102.2 (d), 79.5 (s), 66.5 (t), 55.7 (d), 46.6 (t), 35.1 (t), 28.4 (q, 3C),
26.7 (t), 23.6 (q), 22.9 (t). MS (ESI) m/z: 474 [MþCH3CNþNH4]þ, 438
[MþNa]þ, 416 [MþH]þ. Anal. Calcd for C22H29N3O3S: C, 63.59; H,
7.03; N, 10.11; S, 7.72. Found: C, 63.72; H, 7.20; N, 10.03; S, 7.48.
Synthesized according to general procedure (5 h) from pyr-
imidinone 1b (697 mg, 3.00 mmol), PPh3 (1.02 g, 3.90 mmol), N-
Boc-2-(methylamino)ethanol 2c (683 mg, 3.90 mmol) and DIAD
(0.76 mL, 3.90 mmol), 981 mg (84%) of compound 3f was obtained
as a colourless oil. TLC: Rf 0.71 (n-hexane/ethyl acetate 1:1). IR
(ATR): 2975 (m), 2929 (w), 1695 (s), 1581 (s), 1548 (w), 1454 (m),
1393 (m), 1341 (m), 1283 (s), 1158 (s) cmꢂ1 1H NMR (CDCl3,
.
200 MHz): d (ppm) 7.45–7.20 (m, 5H), 6.24 (s, 1H), 4.43–4.40 (m,
4.2.10. (S)-tert-Butyl 2-((2-(benzylsulfanyl)-6-phenylpyrimidin-4-
yloxy)methyl)pyrrolidine-1-carboxylate (3j)
Synthesized according to general procedure (3 h) from pyr-
imidinone 1b (1.77 g, 6.00 mmol), PPh3 (1.89 g, 7.20 mmol), N-Boc-
4H), 3.55 (t, J¼5.4 Hz, 2H), 2.92 (s, 3H), 2.38 (s, 3H), 1.44 (s, 9H). 13
C
NMR (CDCl3, 50 MHz): d (ppm) 170.2 (s), 168.8 (s), 164.6 (s), 155.4
(s), 137.7 (s), 128.6 (d, 2C), 128.2 (d, 2C), 126.8 (d), 102.2 (d), 79.4 (s),
64.0 (t), 47.6 (t), 35.0 (t), 28.2 (q, 4C), 23.53 (q). MS (EI) m/z (%): 289
([Mꢂ100(Boc)]ꢃþ, 48), 258 (12), 256 (16), 234 (15), 233 (100), 199
(13), 167 (31), 136 (35). Anal. Calcd for C20H27N3O3S: C, 61.67; H,
6.99; N, 10.79; S, 8.23. Found: C, 61.43; H, 7.21; N, 10.62; S, 8.54.
L-prolinol 2d (1.45 g, 7.20 mmol) and DIAD (1.40 mL, 7.20 mmol),
2.49 g (87%) of compound 3j was obtained as a colourless oil. TLC: Rf
0.67 (n-hexane/ethyl acetate 1:1). IR (ATR): 2972 (m), 1689 (s), 1569
(s), 1535 (s), 1390 (s), 1263 (m), 1207 (m), 1167 (m), 1107 (m), 768
(m) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 8.09–8.042 (m, 2H),
7.52–7.49 (m, 5H), 7.39–7.27 (m, 3H), 6.84 (s, 1H), 4.40 (s, 2H), 4.35–
4.2.7. tert-Butyl 2-(2-(benzylsulfanyl)-6-phenylpyrimidin-4-
yloxy)ethylmethylcarbamate (3g)
4.20 (m, 3H), 3.48–3.30 (m, 2H), 2.00–1.90 (m, 4H), 1.51 (s, 9H). 13
C
Synthesized according to general procedure (3 h) from pyr-
imidinone 1c (1.82 g, 6.25 mmol), PPh3 (1.84 g, 7.00 mmol), N-Boc-
2-(methylamino)ethanol 2c (1.22 g, 7.00 mmol) and DIAD (1.35 mL,
7.00 mmol), 2.25 g (80%) of compound 3g was obtained as a col-
ourless oil. TLC: Rf 0.64 (n-hexane/ethyl acetate 1:1). IR (ATR): 3062
(w), 3029 (w), 2974 (w), 2930 (w), 1690 (s), 1568 (s), 1535 (s), 1494
(m), 1480 (m), 1451 (m), 1411 (m), 1390 (m), 1366 (m), 1344 (m),
1307 (m), 1289 (m), 1267 (s), 1206 (s), 1150 (s), 1070 (w), 1038 (w),
1021 (m), 989 (w) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 8.09–
8.03 (m, 2H), 7.52–7.49 (m, 5H), 7.40–7.28 (m, 3H), 6.82 (s, 1H),
4.55–4.51 (m, 4H), 3.63 (t, J¼5.4 Hz, 2H), 2.98 (s, 3H), 1.51 (s, 9H).
13C NMR (CDCl3, 50 MHz): d (ppm) 170.9 (s), 169.6 (s), 164.8 (s),
155.6 (s), 137.8 (s), 136.5 (s), 130.6 (d), 128.8 (d, 2C), 128.7 (d, 2C),
128.5 (d, 2C), 128.4 (d), 127.0 (d, 2C), 99.3 (d), 79.6 (s), 64.5 (t), 47.7
(t), 35.3 (t), 28.2 (q, 5C). MS (ESI) m/z: 452 [MþH]þ. Anal. Calcd for
NMR (CDCl3, 50 MHz): d (ppm) 170.9 (s), 169.8 (s), 164.8 (s), 154.5
(s),137.9 (s),136.6 (s),130.6 (d),128.8 (d),128.6 (d, 2C),128.4 (d, 2C),
127.0 (d, 3C), 99.0 (d), 79.5 (s), 66.8 (t), 55.8 (d), 46.6 (t), 35.4 (t),
28.4 (q, 3C), 22.2 (q), 21.9 (t). MS (FAB) m/z (%): 478 ([Mþ1]þ, 38),
296 (25), 295 (100), 281 (19), 221 (17), 207 (36), 154 (23), 147 (60),
129 (63). Anal. Calcd for C27H31N3O3S: C, 67.90; H, 6.54; N, 8.80; S,
6.71. Found: C, 67.74; H, 6.67; N, 8.69; S, 6.98.
4.3. General procedure for the N-Boc removal. Synthesis of
amines 4 and alcohols 5
The appropriate pyrimidine 3 (1.0 equiv) was dissolved in
CH2Cl2 (1.5 mL/mmol pyrimidine) and the solution was cooled in an
ice bath. TFA (1.5 mL/mmol pyrimidine) was added dropwise and
the resulting mixture was stirred at 0 ꢀC. Upon completion of the
reaction (TLC monitoring), the solvent was removed under reduced
pressure and the residue was dissolved in AcOEt (30 mL), washed
with a saturated NaHCO3 solution (2ꢁ10 mL) and brine (1ꢁ10 mL).
The organic layer was dried (MgSO4), filtered and concentrated. The
resulting crude material was purified by flash chromatography (n-
hexane/ethyl acetate 1:4 to 0:1) to provide pure pyrimidines 4 or in
some case together with the corresponding Smiles rearrangement
compound 5.
C
25H29N3O3S: C, 66.49; H, 6.47; N, 9.31; S, 7.10. Found: C, 66.33; H,
6.67; N, 9.25; S, 7.25.
4.2.8. (S)-tert-Butyl 2-((2-(benzylsulfanyl)pyrimidin-4-yloxy)-
methyl)pyrrolidine-1-carboxylate (3h)
Synthesized according to general procedure (1 h) from pyr-
imidinone 1a (1.09 g, 5.00 mmol), PPh3 (1.51 g, 5.75 mmol), N-Boc-
L-prolinol 2d (1.16 g, 5.75 mmol) and DIAD (1.16 mL, 5.75 mmol),
1.76 g (88%) of compound 3h was obtained as a colourless oil. TLC:
Rf 0.74 (n-hexane/ethyl acetate 1:2). IR (ATR): 2974 (m), 2934 (w),
2880 (w), 1690 (s), 1556 (s), 1435 (m), 1390 (s), 1316 (s), 1167
(s) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 8.25 (d, J¼5.6 Hz, 1H),
7.47–7.21 (m, 5H), 6.42 (d, J¼5.6 Hz, 1H), 4.43 (s, 2H), 4.35–4.15 (m,
3H), 3.48–3.31 (m, 2H), 1.95–1.85 (m, 4H), 1.48 (s, 9H). 13C NMR
(CDCl3, 50 MHz): d (ppm) 171.2 (s), 168.5 (s), 155.2 (d), 154.4 (s),
137.5 (s), 128.8 (d, 2C), 128.4 (d, 2C), 127.0 (d), 103.8 (d), 79.4 (s),
66.7 (t), 55.6 (d), 46.5 (t), 35.2 (t), 28.4 (q, 3C), 23.6 (t), 22.9 (t). MS
(FAB) m/z (%): 402 ([Mþ1]þ, 18), 328 (12), 220 (14), 219 (100), 218
(11), 154 (12), 147 (17). Anal. Calcd for C21H27N3O3S: C, 62.82; H,
6.78; N, 10.47; S, 7.99. Found: C, 62.96; H, 6.95; N, 10.63; S, 8.28.
4.3.1. 2-(2-(Benzylsulfanyl)pyrimidin-4-yloxy)ethanamine (4a)
Synthesized according to general procedure (35 min) from py-
rimidine 3a (1.0 g, 2.77 mmol), 665 mg (92%) of compound 4a was
obtained as a colourless oil. TLC: Rf 0.47 (CH2Cl2/MeOH/NH3
12:2:0.2). IR (film): 3370 (w), 3060 (w), 3030 (br), 2937 (m), 1684
(m), 1573 (s), 1539 (s), 1498 (m), 1412 (m), 1344 (w), 1272 (m), 1209
(s),1016 (m), 841 (m) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 8.24
(d, J¼5.6 Hz, 1H), 7.45–7.23 (m, 5H), 6.42 (d, J¼5.6 Hz, 1H), 4.41 (s,
2H), 4.35 (t, J¼5.4 Hz, 2H), 3.03 (t, J¼5.4 Hz, 2H), 1.45 (br, 2H). 13
C
NMR (CDCl3, 50 MHz): d (ppm) 171.0 (s), 168.5 (s), 157.2 (d), 137.4
(s), 128.7 (d, 2C), 128.3 (d, 2C), 126.9 (d), 103.7 (d), 68.6 (t), 40.7 (t),
35.1 (t). MS (EI) m/z (%): 261 ([M]ꢃþ, 10), 228 (82), 184 (27), 152 (15),
139 (97). Anal. Calcd for C13H15N3OS: C, 59.74; H, 5.79; N, 16.08; S,
12.27. Found: C, 59.57; H, 5.95; N, 16.17; S, 12.51.
4.2.9. (S)-tert-Butyl 2-((2-(benzylsulfanyl)-6-methylpyrimidin-4-
yloxy)methyl)pyrrolidine-1-carboxylate (3i)
Synthesized according to general procedure (4 h) from pyr-
imidinone 1b (697 mg, 3.00 mmol), PPh3 (1.02 g, 3.90 mmol), N-
Boc-L-prolinol 2d (784 mg, 3.90 mmol) and DIAD (0.75 mL,
4.3.2. tert-Butyl 2-(2-(benzylsulfanyl)-6-phenylpyrimidin-4-
yloxy)ethylcarbamate (4b)
3.90 mmol), 1.16 g (93%) of compound 3i was obtained as a colour-
less oil. TLC: Rf 0.36 (n-hexane/ethyl acetate 4:1). IR (ATR): 2973
(w), 2930 (w), 2879 (w), 1689 (s), 1578 (s), 1545 (s), 1494 (w), 1443
(m), 1389 (s), 1361 (s), 1339 (m), 1281 (s), 1250 (m), 1161 (s), 1133
Synthesized according to general procedure (45 min) from py-
rimidine 3b (950 mg, 2.17 mmol), 651 mg (89%) of compound 4b
was obtained as a colourless oil. TLC: Rf 0.20 (n-hexane/ethyl ace-
tate 1:4). IR (film): 3057 (w), 3025 (w), 2962 (br), 2893 (m), 1578
(s), 1547 (s), 1498 (m), 1452 (m), 1405 (m), 1347 (m), 1299 (m), 1272
(w), 1107 (m), 1043 (m), 1002 (w), 910 (w) cmꢂ1 1H NMR (CDCl3,
.

D. Font et al. / Tetrahedron 64 (2008) 5226–5235
5231
(m), 1217 (m), 1019 (m), 846 (w), 768 (m), 696 (m) cmꢂ1. 1H NMR
(CDCl3, 200 MHz): d (ppm) 8.01–8.04 (m, 2H), 7.53–7.47 (m, 5H),
7.35–7.27 (m, 3H), 6.86 (s, 1H), 4.54 (s, 2H), 4.43 (t, J¼5.4 Hz, 2H),
3.10 (t, J¼5.4 Hz, 2H), 1.56 (br, 2H). 13C NMR (DMSO-d6, 50 MHz):
d (ppm) 171.0 (s), 169.2 (s), 164.1 (s), 137.9 (s), 135.6 (s), 131.1 (d),
128.9 (d, 2C), 128.7 (d, 2C), 128.4 (d, 2C), 127.03 (d), 126.9 (d, 2C),
99.1 (d), 63.3 (t), 37.8 (t), 34.4 (t). MS (FAB) m/z (%): 338 ([Mþ1]þ,
42), 207 (29), 155 (57), 154 (100), 149 (21), 139 (25), 138 (64), 137
(90). Anal. Calcd for C19H19N3OS: C, 67.63; H, 5.68; N, 12.45; S, 9.50.
Found: C, 67.51; H, 5.91; N, 12.57; S, 9.78.
109 ꢀC. TLC: Rf 0.63 (CH2Cl2/MeOH/NH3 12:2:0.2). IR (ATR): 3273
(br), 3146 (br), 3062 (w), 3031 (w), 2957 (m), 2927 (m), 2871 (w),
1592, 1493, 1452 (m), 1426 (m), 1390 (m), 1364 (m), 1344 (w), 1284
(s), 1218 (m), 1187 (s), 1069 (m), 1030 (m), 968 (m), 912 (w), 832
(m) cmꢂ1 1H NMR (CDCl3, 200 MHz): d (ppm) 7.49–7.25 (m, 5H),
.
5.95 (s, 1H), 4.81 (br, 1H), 4.39 (s, 2H), 3.81–3.65 (m, 3H), 2.30 (s,
3H), 1.93 (sept, J¼6.8 Hz, 1H), 0.99 (d, J¼6.8 Hz, 3H), 0.95 (d,
J¼6.8 Hz, 3H). 13C NMR (CDCl3, 50 MHz): d (ppm) 170.0 (s), 165.2 (s),
162.8 (s), 138.3 (s), 128.9 (d, 2C), 128.3 (d, 2C), 126.8 (d), 100.0 (d),
63.7 (t), 58.0 (d), 35.0 (t), 29.6 (d), 23.7 (q),19.5 (q),18.8 (q). MS (ESI)
m/z: 635 [2MþH]þ, 318 [MþH]þ. Anal. Calcd for C17H23N3OS: C,
64.32; H, 7.30; N,13.24; S, 10.10. Found: C, 64.51; H, 7.52; N,13.39; S,
10.45.
4.3.3. N-Boc protecting group removal from pyrimidine 3c
According to the general procedure (45 min) and starting from
3c (710 mg, 1.76 mmol), 395 mg (74%)13 of amine 4c and 83 mg
(21%) of alcohol 5c were obtained.
4.3.5. (S)-1-(2-(Benzylsulfanyl)-6-phenylpyrimidin-4-yloxy)-
3-methylbutan-2-amine (4e)
4.3.3.1. (S)-1-(2-(Benzylsulfanyl)pyrimidin-4-yloxy)-3-methylbutan-
2-amine (4c). Isolated as a colourless oil. TLC: Rf 0.59 (CH2Cl2/
MeOH/NH3 12:2:0.2). 1H NMR (CDCl3, 200 MHz): d (ppm) (10:1,
amine 4c/alcohol 5c)14 8.26 (d, J¼5.6 Hz, 1H), 7.49–7.23 (m, 5H),
6.46 (d, J¼5.6 Hz, 1H), 4.44 (s, 2H), 4.41 (dd, J¼10.6 Hz, J0¼3.8 Hz,
1H), 4.16 (dd, J¼10.6 Hz, J0¼8.0 Hz, 1H), 3.00–2.91 (m, 1H), 1.78
(sept, J¼6.8 Hz, 1H), 1.49 (s, 2H), 1.02 (d, J¼6.8 Hz, 6H). 13C NMR
(CDCl3, 50 MHz): d (ppm) 171.2 (s), 168.8 (s), 157.3 (d), 137.6 (s),
128.8 (d, 2C), 128.5 (d, 2C), 127.2 (d), 104.0 (d), 70.1 (t), 55.5 (d), 35.2
(t), 30.9 (d), 19.3 (q), 17.9 (q). MS (ESI) m/z: 607 [2MþH]þ, 304
[MþH]þ. Anal. Calcd for C16H21N3OS: C, 63.33; H, 6.98; N, 13.85; S,
10.57. Found: C, 63.19; H, 7.14; N, 13.99; S, 10.32.
Synthesized according to general procedure (30 min) from
pyrimidinone 3e (1.92 g, 4.00 mmol), 1.36 g (90%) of compound 4e
was obtained as a colourless solid. Mp: 176–178 ꢀC. TLC: Rf 0.55
(CH2Cl2/MeOH/NH3 12:2:0.2). IR (ATR): 2969 (w), 2928 (w), 2895
(w), 1689 (m), 1569 (s), 1536 (s), 1493 (m), 1455 (w), 1415 (w), 1364
(m), 1315 (m), 1270 (m), 1201 (s), 1177 (s), 1136 (s), 1022 (m), 915
(w) cmꢂ1 1H NMR (CDCl3, 200 MHz): d (ppm) 8.10–8.05 (m, 2H),
.
7.54–7.48 (m, 5H), 7.39–7.28 (m, 3H), 6.88 (s, 1H), 4.54 (s, 2H), 4.44
(dd, J¼10.8 Hz, J0¼4.0 Hz, 1H), 4.22 (dd, J¼10.8 Hz, J0¼8.0 Hz, 1H),
3.04–2.95 (m, 1H), 1.80 (sept, J¼6.6 Hz, 1H), 1.41 (br, 2H), 1.03 (d,
J¼6.6 Hz, 6H). 13C NMR (CDCl3, 50 MHz): d (ppm) 170.8 (s), 169.9 (s),
164.7 (s), 137.9 (s), 136.6 (s), 130.6 (d), 128.77 (d, 2C), 128.67 (d, 2C),
128.4 (d, 2C), 127.0 (d, 3C), 99.1 (d), 70.2 (t), 55.5 (d), 35.3 (t), 30.9
(d), 19.3 (q), 17.9 (q). MS (ESI) m/z: 380 [MþH]þ. Anal. Calcd for
4.3.3.2. (S)-2-(2-(Benzylsulfanyl)pyrimidin-4-ylamino)-3-methyl-
butan-1-ol (5c). Isolated as a colourless solid. Mp: 89–91 ꢀC. TLC: Rf
0.51 (CH2Cl2/MeOH/NH3 12:2:0.2). IR (ATR): 3273 (w), 3149 (w),
3084 (w), 3053 (w), 2957 (w), 2869 (w), 1600 (s), 1580 (s), 1484 (s),
1451 (m), 1344 (s), 1325 (m), 1264 (w), 1187 (s), 1071 (m), 1025 (m),
C22H25N3OS: C, 69.62; H, 6.64; N, 11.07; S, 8.45. Found: C, 69.83; H,
6.48; N, 11.19; S, 8.81.
4.3.6. N-Boc protecting group removal from pyrimidine 3f
Synthesized according to the general procedure (45 min) and
starting from 3f (800 mg, 2.05 mmol), 397 mg (67%)13 of amine 4f
and 178 mg (30%) of alcohol 5f were obtained.
996 (m) cmꢂ1 1H NMR (DMSO-d6, 200 MHz): d (ppm) 7.94 (d,
.
J¼5.8 Hz, 1H), 7.51–7.31 (m, 5H), 6.36 (d, J¼5.8 Hz, 1H), 4.73–4.67
(m, 1H), 4.40 (s, 2H), 4.06 (br, 1H), 3.58–3.55 (m, 2H), 1.99 (sept,
J¼6.8 Hz,1H), 0.97 (d, J¼6.8 Hz, 3H), 0.95 (d, J¼6.8 Hz, 3H). 13C NMR
(DMSO-d6, 200 MHz): d (ppm) 168.9 (s), 161.9 (s), 153.6 (d), 138.7
(s), 128.7 (d, 2C), 128.3 (d, 2C), 126.7 (d), 102.4 (d), 60.8 (t), 56.1 (d),
33.7 (t), 28.3 (d), 19.4 (q), 18.2 (q). MS (ESI) m/z: 607 [2MþH]þ, 304
[MþH]þ. Anal. Calcd for C16H21N3OS: C, 63.33; H, 6.98; N, 13.85; S,
10.57. Found: C, 63.28; H, 7.11; N, 13.71; S, 10.74.
4.3.6.1. 2-(2-(Benzylsulfanyl)-6-methylpyrimidin-4-yloxy)-N-meth-
ylethanamine (4f). Isolated as a colourless oil. TLC: Rf 0.21 (CH2Cl2/
MeOH 10:1). 1H NMR (CDCl3, 200 MHz): d (ppm) (10:7, amine 4f/
alcohol 5f)14 7.46–7.22 (m, 5H), 6.26 (s, 1H), 4.47–4.42 (m, 2H), 4.40
(s, 2H), 2.97 (t, J¼5.2 Hz, 2H), 2.50 (s, 3H), 2.37 (s, 3H).
4.3.4. N-Boc protecting group removal from pyrimidine 3d
Synthesized according to the general procedure (1 h) and
starting from 3d (1.15 g, 2.75 mmol), 523 mg (60%)13 of amine 4d
and 131 mg (15%) of alcohol 5d were obtained.
4.3.6.2. 2-(N-(2-(Benzylsulfanyl)-6-methylpyrimidin-4-yl)-N-meth-
ylamino)ethanol (5f). Isolated as a colourless solid. Mp: 95–96 ꢀC.
TLC: Rf 0.55 (CH2Cl2/MeOH 10:1). IR (ATR): 3196 (br), 2944 (w),
2910 (w), 2868 (w), 1581 (s), 1502 (s), 1406 (s), 1310 (m), 1195 (s),
1036 (m), 811 (w), 709 (m) cmꢂ1 1H NMR (CDCl3, 200 MHz):
.
4.3.4.1. (S)-1-(2-(Benzylsulfanyl)-6-methylpyrimidin-4-yloxy)-3-
methylbutan-2-amine (4d). Isolated as a colourless oil. TLC: Rf 0.77
(CH2Cl2/MeOH/NH3 12:2:0.2). IR (ATR): 3061 (w), 2957 (w), 2926
(w), 2871 (w), 1578 (s), 1543 (s), 1492 (m), 1440 (m), 1417 (m), 1350
(m), 1338 (m), 1280 (s), 1112 (w), 1041 (m), 971 (w) cmꢂ1. 1H NMR
(CDCl3, 200 MHz): d (ppm) 7.49–7.25 (m, 5H), 6.29 (s, 1H), 4.43 (s,
2H), 4.39 (dd, J¼10.6 Hz, J0¼4.0 Hz, 1H), 4.13 (dd, J¼10.6 Hz,
J0¼7.8 Hz, 1H), 2.97–2.88 (m, 1H), 2.28 (s, 3H), 1.75 (sept, J¼6.8 Hz,
1H), 1.29 (s, 2H), 0.95 (d, J¼6.8 Hz, 6H). 13C NMR (CDCl3, 50 MHz):
d (ppm) 170.4 (s), 169.3 (s), 167.7 (s), 137.9 (s), 128.8 (d, 2C), 128.4 (d,
2C), 127.0 (d), 102.4 (d), 70.0 (t), 55.5 (d), 35.2 (t), 30.9 (d), 23.7 (q),
19.5 (q), 18.8 (q). MS (ESI) m/z: 635 [2MþH]þ, 318 [MþH]þ. Anal.
Calcd for C17H23N3OS: C, 64.32; H, 7.30; N, 13.24; S, 10.10. Found: C,
64.49; H, 7.48; N, 13.11; S, 10.42.
d (ppm) 7.45–7.20 (m, 5H), 6.00 (s, 1H), 4.37 (s, 2H), 3.79–3.67 (m,
4H), 3.26 (br, 1H), 3.06 (s, 3H), 2.28 (s, 3H). 13C NMR (CDCl3,
50 MHz): d (ppm) 169.3 (s), 165.1 (s), 162.1 (s), 138.1 (s), 128.6 (d,
2C), 128.2 (d, 2C), 126.7 (d), 97.2 (d), 60.6 (t), 51.8 (d), 36.51 (q), 34.9
(t), 23.8 (q). MS (EI) m/z: 290 ([Mþ1]þ, 34), 289 ([M]þ, 100), 258
(52), 256 (68), 212 (37), 167 (81), 165 (33), 136 (86). Anal. Calcd for
C15H19N3OS: C, 62.25; H, 6.62; N, 14.52; S, 11.08. Found: C, 62.39; H,
6.85; N, 14.41; S, 11.39.
4.3.7. 2-(2-(Benzylsulfanyl)-6-phenylpyrimidin-4-yloxy)-
N-methylethanamine (4g)
Synthesized according to general procedure (1 h) from pyr-
imidinone 3g (1.58 g, 3.5 mmol), 1.10 g (90%) of 4g was obtained as
a colourless oil. TLC: Rf 0.30 (CH2Cl2/MeOH 10:1). IR (ATR): 3212
(br), 3060 (w), 3028 (w), 2944 (w), 2846 (w), 2725 (w), 1569 (s),
1535 (s),1495 (m),1450 (m),1412 (m),1372 (m),1340 (m),1309 (m),
1267 (s), 1289 (m), 1228 (m), 1208 (s), 1147 (w), 1119 (w), 1019 (m),
4.3.4.2. (S)-2-(2-(Benzylsulfanyl)-6-methylpyrimidin-4-ylamino)-3-
methylbutan-1-ol (5d). Isolated as a colourless solid. Mp: 106–

5232
D. Font et al. / Tetrahedron 64 (2008) 5226–5235
920 (w), 980 (w) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 8.09–
8.03 (m, 2H), 7.52–7.48 (m, 5H), 7.40–7.28 (m, 3H), 6.86 (s, 1H),
4.54–4.50 (m, 4H), 3.00 (t, J¼5.6 Hz, 2H), 2.54 (s, 3H). 13C NMR
(CDCl3, 50 MHz): d (ppm) 169.9 (s), 168.8 (s), 163.8 (s), 136.9 (s),
135.6 (s), 129.6 (d), 127.8 (d, 2C), 127.7 (d, 2C), 127.4 (d, 2C), 126.0 (d,
3C), 98.2 (d), 64.8 (t), 49.4 (t), 35.3 (q), 34.4 (t). MS (ESI) m/z: 352
[MþH]þ. Anal. Calcd for C20H21N3OS: C, 68.35; H, 6.02; N, 11.96; S,
9.12. Found: C, 68.49; H, 6.27; N, 12.11; S, 9.39.
128.71 (d, 2C), 128.58 (d, 2C), 128.45 (d), 127.1 (d, 2C), 99.1 (d), 67.8
(t), 57.4 (d), 46.0 (t), 35.4 (t), 27.5 (t), 24.7 (t). MS (FAB) m/z (%): 379
([Mþ2]þ, 28), 378 ([Mþ1]þ, 100), 377 (10), 295 (16), 154 (19), 136
(21). Anal. Calcd for C22H23N3OS: C, 70.00; H, 6.14; N, 11.13; S, 8.49.
Found: C, 69.83; H, 6.31; N, 11.28; S, 8.67.
4.4. General procedure for the Petasis reaction. Synthesis
of arylglycines 6
4.3.8. N-Boc protecting group removal from pyrimidine 3h
Synthesized according to the general procedure (30 min) and
starting from 3h (1.5 g, 3.74 mmol), 680 mg (60%)13 of amine 4h
and 310 mg (28%) of alcohol 5h were obtained.
To a suspension of glyoxylic acid monohydrate (1.05 equiv) in
dichloromethane (6 mL/mmol pyrimidine) phenylboronic acid
(1.05 equiv) and the appropriate pyrimidine 4 (1.0 equiv) were
added. The resulting mixture was stirred at room temperature
under nitrogen atmosphere. Upon completion of the reaction (TLC
monitoring) solvent was removed under reduced pressure and the
resulting crude product was purified by flash chromatography
(ethyl acetate/methanol 10:1) or used in the next step without
more purification.
4.3.8.1. 2-(Benzylsulfanyl)-4-[((S)-pyrrolidin-2-yl)methoxy]pyr-
imidine (4h). Isolated as a colourless oil. TLC: Rf 0.36 (CH2Cl2/MeOH
10:1). 1H NMR (CDCl3, 200 MHz): d (ppm) (10:9, amine 4h/alcohol
5h)14 8.24 (d, J¼5.6 Hz, 1H), 7.49–7.26 (m, 5H), 6.44 (d, J¼5.6 Hz,
1H), 4.43 (s, 2H), 4.40–4.24 (m, 3H), 3.07–2.98 (m, 2H), 1.90–1.81
(m, 4H).
4.4.1. Petasis reaction of the pyrimidine 4j
Synthesized according to the general procedure (20 h) and
starting from 4j (943 mg, 2.5 mmol), 1.09 g (86%) of arylglycine 6j
was obtained as a separable diastereomeric mixture (dr¼73%) of
6ja (1.06 g, 83%) and 6jb (0.03 g, 3%).
4.3.8.2. [(S)-1-(2-(Benzylsulfanyl)pyrimidin-4-yl)pyrrolidin-2-yl]me-
thanol (5h). Isolated as a colourless oil. TLC: Rf 0.50 (CH2Cl2/MeOH
10:1). IR (ATR): 3257 (br), 3025 (w), 2968 (w), 2928 (w), 2871 (w),
1572 (s), 1536 (m), 1473 (s), 1362 (m), 1339 (m), 1275 (w), 1225 (w),
1174 (w), 1147 (m), 1044 (w), 1023 (w), 798 (w), 751 (s) cmꢂ1
.
1H
4.4.1.1. (R)-2-[(S)-2-((2-(Benzylsulfanyl)-6-phenylpyrimidin-4-yloxy)-
methyl)pyrrolidin-1-yl]-2-phenylacetic acid (6ja). Isolated as a col-
ourless solid. Mp: 148–149 ꢀC. TLC: Rf 0.31 (CHCl3/MeOH/NH3
12:2:0.2). [a]2D5 ꢂ95.0 (c 0.4, DMF). IR (ATR): 3061 (w), 2953 (w),
1570 (s), 1536 (s), 1493 (m), 1307 (m), 1071 (m), 1028 (m), 919 (m),
NMR (CDCl3, 200 MHz): d (ppm) 7.98 (d, J¼6.0 Hz, 1H), 7.47–7.24
(m, 5H), 6.05 (d, J¼6.0 Hz, 1H), 4.46–4.17 (m, 3H), 3.71 (dd,
J¼11.0 Hz, J0¼4.6 Hz, 1H), 3.65 (dd, J¼11.0 Hz, J0¼6.8 Hz, 1H), 3.52–
3.37 (m, 2H), 2.14–1.86 (m, 4H). 13C NMR (CDCl3, 50 MHz): d (ppm)
170.0 (s), 160.0 (s), 154.9 (d), 137.6 (s), 129.4 (d, 2C), 128.9 (d, 2C),
127.6 (d), 100.8 (d), 65.8 (t), 60.2 (d), 47.6 (t), 35.0 (t), 28.5 (t), 23.6
(t). MS (FAB) m/z (%): 303 ([Mþ2]þ, 21), 302 ([Mþ1]þ, 100), 301 (9),
270 (10). Anal. Calcd for C16H19N3OS: C, 63.76; H, 6.35; N, 13.94; S,
10.64. Found: C, 63.58; H, 6.60; N, 13.72; S, 10.31.
839 (m), 755 (m), 731 (m) cmꢂ1 1H NMR (DMSO-d6, 200 MHz):
.
d (ppm) 8.27–8.24 (m, 2H), 7.60–7.40 (m, 13H), 7.24 (s, 1H), 4.70 (s,
1H), 4.60 (s, 2H), 4.26–4.14 (m, 2H), 3.53 (br, 1H), 3.0 (br, 1H), 2.60
(br, 1H), 2.00–1.80 (m, 4H). 13C NMR (DMSO-d6, 50 MHz): d (ppm)
172.5 (s), 170.0 (s), 169.6 (s), 164.0 (s), 138.1 (s), 136.8 (s), 135.7 (s),
131.0 (d), 128.9 (d, 2C), 128.80 (d, 2C), 128.76 (d, 3C), 128.39 (d, 2C),
128.24 (d), 126.99 (d, 2C), 126.96 (d, 2c), 98.9 (d), 69.5 (d), 68.7 (t),
59.1 (d), 51.4 (t), 34.4 (t), 27.9 (t), 22.9 (t). HRMS (ESI) m/z: calcd for
4.3.9. 2-(Benzylsulfanyl)-6-methyl-4-[((S)-pyrrolidin-2-yl)-
methoxy]pyrimidine (4i)
Synthesized according to general procedure (45 min) from py-
rimidine 3i (710 mg, 1.71 mmol), 447 mg (83%) of compound 4i was
obtained as a colourless solid. Mp: 101–104 ꢀC. TLC: Rf 0.29 (CH2Cl2/
MeOH 10:1). IR (ATR): 2962 (w), 2944 (w), 1666 (s), 1576 (s), 1547
(m), 1441 (m), 1349 (m), 1287 (m), 1202 (s), 1167 (s), 1129 (s), 1046
(s), 969 (w) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 7.46–7.22 (m,
5H), 6.29 (s, 1H), 4.64 (dd, J¼14.0 Hz, J0¼4.0 Hz, 1H), 4.43 (dd,
J¼14.0 Hz, J0¼8.0 Hz, 1H), 4.40 (s, 2H), 3.99–2.87 (m, 1H), 3.35–3.29
(m, 2H), 2.19–1.79 (m, 4H). 13C NMR (CDCl3, 50 MHz): d (ppm) 170.3
(s), 168.6 (s), 168.2 (s), 137.7 (s), 128.8 (d, 2C), 128.4 (d, 2C), 127.1 (d),
102.3 (d), 64.3 (t), 58.4 (d), 45.1 (t), 35.2 (t), 26.6 (t), 23.7 (t), 23.6 (q).
MS (ESI) m/z: 631 [2MþH]þ, 316 [MþH]þ. Anal. Calcd for
C
30H30N3O3S1 [MþH]þ 512.2002; found 512.2022.
4.4.1.2. (S)-2-[(S)-2-((2-(Benzylsulfanyl)-6-phenylpyrimidin-4-yloxy)-
methyl)pyrrolidin-1-yl]-2-phenylacetic acid (6jb). Isolated as a col-
ourless solid. Mp: 131–132 ꢀC. TLC: Rf 0.24 (CHCl3/MeOH/NH3
12:2:0.2). IR (ATR): 2958 (w), 2930 (m), 2858 (m), 1570 (s), 1538 (s),
1365 (m), 1270 (m), 1206 (m), 1018 (m), 696 (s) cmꢂ1 1H NMR
.
(DMSO-d6, 200 MHz): d (ppm) 8.27–8.23 (m, 2H), 7.60–7.35 (m,
13H), 7.23 (s, 1H), 4.73 (s, 1H), 4.57 (s, 2H), 4.26–4.13 (m, 2H), 3.46
(br, 1H), 3.00 (br, 1H), 2.80 (br, 1H), 2.05–1.75 (m, 4H). 13C NMR
(DMSO-d6, 50 MHz): d (ppm) 173.0 (s), 170.0 (s), 169.7 (s), 164.0 (s),
138.3 (s), 138.8 (s), 135.7 (s), 131.0 (d), 128.8 (d, 2C), 128.70 (d, 2C),
128.6 (d, 2C), 128.4 (d, 2C), 128.1 (d, 2C), 127.5 (d), 127.0 (d, 2C),
126.7 (d, 2C), 98.9 (d), 68.8 (d), 68.3 (t), 59.3 (d), 49.5 (t), 34.3 (t),
28.3 (t), 23.1 (t). MS (FAB) m/z (%): 512 ([Mþ1]þ, 21), 466 (10), 281
(21), 221 (18), 218 (100), 207 (27), 174 (22), 172 (27).
C
17H21N3OS: C, 64.73; H, 6.71; N, 13.32; S, 10.17. Found: C, 64.57; H,
6.90; N, 13.18; S, 10.39.
4.3.10. 2-(Benzylsulfanyl)-6-phenyl-4-[((S)-pyrrolidin-2-yl)-
methoxy]pyrimidine (4j)
Synthesized according to general procedure (45 min) from py-
rimidine 3j (2.20 g, 4.61 mmol), 1.54 g (89%) of compound 4j was
obtained as a colourless oil. TLC: Rf 0.45 (CH2Cl2/MeOH/NH3
12:2:0.2). IR (ATR): 2972 (w), 1538 (s), 1538 (m), 1513 (w), 1494 (m),
1452 (w), 1410 (w), 1266 (m), 1227 (w), 1200 (s), 1176 (m), 1130 (m),
1021 (w), 919 (w), 758 (m), 716 (m), 693 (s) cmꢂ1. 1H NMR (CDCl3,
200 MHz): d (ppm) 8.0–8.10 (m, 2H), 7.50–7.25 (m, 8H), 6.86 (s, 1H),
4.81 (br, 1H), 4.52 (s, 2H), 4.50 (dd, J¼11.2 Hz, J0¼4.4 Hz, 1H), 4.36
(dd, J¼11.2 Hz, J0¼7.4 Hz, 1H), 3.70–3.65 (m, 1H), 3.20–3.10 (m, 2H),
2.05–1.50 (m, 4H). 13C NMR (CDCl3, 50 MHz): d (ppm) 170.8 (s),
169.5 (s), 164.9 (s), 137.8 (s), 136.4 (s), 130.7 (d), 128.79 (d, 2C),
4.5. General procedure for the esterification reaction.
Synthesis of arylglycinates 7
To a suspension of Cs2CO3 (1.15 equiv) in dry DMF (5 mL/mmol
amino acid) the appropriate arylglycine 6 (1.0 equiv) was added.
The resulting mixture was stirred for 15 min at room temperature
and then methyl iodide (1.2 equiv) was added. Upon completion of
the reaction (TLC monitoring) solvent was removed under reduced
pressure and the residue was partitioned between AcOEt (20 mL/
mmol) and H2O (20 mL/mmol). The organic layer was separated
and the aqueous layer was extracted with AcOEt (3ꢁ20 mL/mmol).

D. Font et al. / Tetrahedron 64 (2008) 5226–5235
5233
Then the organic layers were combined, washed with brine, dried
over MgSO4 and concentrated. The resulting crude material was
purified by flash chromatography (n-hexane/ethyl acetate 14:1 to
9:1) to provide pure arylglycinates 7.
(s), 170.41 (s), 169.1 (s), 167.6 (s), 138.0 (s), 136.2 (s), 129.1 (d, 2C),
128.98 (d, 2C), 128.45 (d, 2C), 128.4 (d, 2C), 128.2 (d), 127.0 (d), 102.3
(d), 69.5 (d), 68.8 (t), 59.1 (d), 51.83 (q), 51.82 (t), 35.2 (t), 28.4 (t),
23.7 (q), 23.2 (t). HRMS (ESI) m/z: calcd for C26H30N3O3S1 [MþH]þ
464.2002; found 464.2011.
4.5.1. Methyl 2-[(S)-1-(2-(benzylsulfanyl)-6-phenylpyrimidin-4-
yloxy)-3-methylbutan-2-ylamino]-2-phenylacetate (7e)
4.5.3.2. (S)-Methyl 2-((S)-2-((2-(benzylsulfanyl)-6-methylpyrimidin-
4-yloxy)methyl)pyrrolidin-1-yl)-2-phenylacetate (7ib). Isolated as
a colourless oil. TLC: Rf 0.31 (n-hexane/ethyl acetate 4:1). [a]D25
ꢂ11.11 (c 0.05, CH3OH). IR (ATR): 3026 (w), 2949 (w), 2923 (w),
2853 (w), 1736 (m), 1544 (s), 1494 (w), 1451 (m), 1448 (m),1412 (w),
1350 (m), 1281 (s), 1240 (w), 1202 (w), 1164 (s), 1042 (w), 700
(m) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 7.48–7.26 (m, 10H),
6.23 (s, 1H), 4.78 (s, 1H), 4.41 (s, 2H), 4.18–4.15 (m, 2H), 3.74 (s, 3H),
3.38–3.35 (m, 1H), 2.99–2.92 (m, 1H), 2.83–2.81 (m, 1H), 2.39 (s,
3H), 2.09–1.79 (m, 4H). 13C NMR (CDCl3, 200 MHz): d (ppm) 172.6
(s), 170.4 (s), 169.2 (s), 167.7 (s), 138.0 (s), 137.4 (s), 128.9 (d, 2C),
128.7 (d, 2C), 128.46 (d, 2C), 128.42 (d, 2C), 128.0 (d), 127.0 (d), 102.3
(d), 69.2 (d), 68.5 (t), 59.6 (d), 51.6 (q), 49.8 (t), 35.2 (t), 28.8 (t), 23.7
(q), 23.5 (t). HRMS (ESI) m/z: calcd for C26H30N3O3S1 [MþH]þ
464.2002; found 464.2011.
Synthesized according to the general procedures and starting
from 4e (1.326 g, 3.5 mmol), 1.01 g (55%) of arylglycinate 7e was
obtained as an inseparable diastereomeric mixture (dr¼40%).
TLC: Rf 0.78 (n-hexane/ethyl acetate 1:1). IR (ATR): 3061 (w),
3028 (w), 2956 (w), 1735 (s), 1567 (s), 1534 (s), 1493 (m), 1450
(m), 1412 (m), 1265 (s), 1204 (m), 1170 (w), 1011 (m), 694
(m) cmꢂ1. 1H NMR (CDCl3, 200 MHz) major diastereomer: d (ppm)
8.10–8.03 (m, 2H), 7.52–7.29 (m, 13H), 6.78 (s, 1H), 4.67 (s, 1H),
4.51 (s, 2H), 4.38–4.25 (m, 2H), 3.73 (s, 3H), 2.84–2.76 (m, 1H),
2.08–1.87 (m, 1H), 1.06 (d, J¼6.8 Hz, 3H), 1.04 (d, J¼6.8 Hz, 3H);
minor diastereomer: d (ppm) 8.10–8.03 (m, 2H), 7.52–7.29 (m,
13H), 6.86 (s, 1H), 4.67 (s, 1H), 4.55 (s, 2H), 4.45–4.34 (m, 2H),
3.66 (s, 3H), 2.69–2.61 (m, 1H), 2.36–1.97 (m, 1H), 1.01 (d,
J¼6.8 Hz, 3H), 0.94 (d, J¼6.8 Hz, 3H). 13C NMR (CDCl3, 50 MHz)
major diastereomer: d (ppm) 173.7 (s), 170.5 (s), 169.7 (s), 164.6
(s), 138.7 (s), 137.9 (s), 136.6 (s), 130.6 (d), 128.8 (d, 2C), 128.7 (d,
2C), 128.57 (d, 2C), 128.51 (d), 127.9 (d, 2C), 127, 7 (d), 127.4 (d,
2C), 127.0 (d, 2C), 99.27 (d), 67.3 (t), 63.6 (d), 59.6 (d), 52.1 (q),
35.3 (t), 29.7 (d), 18.6 (q), 18.5 (q); minor diastereomer: d (ppm)
173.7 (s), 170.5 (s), 169.7 (s), 164.6 (s), 138.7 (s), 137.9 (s), 136.6 (s),
130.6 (d), 128.8 (d, 2C), 128.7 (d, 2C), 128.57 (d, 2C), 128.45 (d),
127.9 (d, 2C), 127.7 (d), 127.4 (d, 2C), 127.0 (d, 2C), 99.22 (d), 67.3
(t), 63.4 (d), 58.6 (d), 52.1 (q), 35.3 (t), 29.6 (d), 18.9 (q), 18.8 (q).
HRMS (ESI) m/z: calcd for C31H34N3O3S1 [MþH]þ 528.2315; found
528.2293.
4.5.4. (R)-Methyl 2-((S)-2-((2-(benzylsulfanyl)-6-phenylpyrimidin-
4-yloxy)methyl)pyrrolidin-1-yl)-2-phenylacetate (7ja)
Synthesized according to general procedure from amino acid 6ja
(767 mg, 1.50 mmol), 740 mg (94%) of compound 7ja was obtained
as a colourless solid. Mp: 148–149 ꢀC. TLC: Rf 0.92 (n-hexane/ethyl
acetate 1:1). [a]2D5 ꢂ99.65 (c 0.273, CH3OH). IR (ATR): 3029 (w),
2950 (w), 1740 (m), 1570 (s), 1567 (s), 1534 (s), 1494 (m), 1450 (m),
1412 (m), 1356 (w), 1307 (m), 1288 (m), 1266 (s), 1230 (m), 1204 (s),
1164 (m), 1140 (m), 1015 (m) cmꢂ1 1H NMR (CDCl3, 200 MHz):
.
d (ppm) 8.08–8.03 (m, 2H), 7.53–7.27 (m, 13H), 6.78 (s, 1H), 4.24 (s,
1H), 4.52 (s, 2H), 4.24 (dd, J¼10.8 Hz, J0¼5.2 Hz, 1H), 4.12 (s, 2H),
4.24 (dd, J¼10.8 Hz, J0¼6.8 Hz, 1H), 3.71 (s, 3H), 3.48–3.41 (m, 1H),
3.10–3.07 (m, 1H), 2.60–2.48 (m, 1H), 2.08–1.80 (m, 4H). 13C NMR
(CDCl3, 50 MHz): d (ppm) 173.4 (s), 171.6 (s), 170.4 (s), 165.3 (s),
138.6 (s), 137.3 (s), 136.9 (s), 131.2 (d), 129.8 (d, 2C), 129.6 (d, 2C),
129.4 (d, 2C), 129.1 (d, 4C), 128.9 (d), 127.7 (d, 3C), 99.8 (d), 70.2 (d),
69.7 (t), 59.8 (d), 52.6 (q), 52.5 (t), 36.1 (t), 29.1 (t), 23.9 (t). HRMS
4.5.2. Methyl 2-(N-(2-(2-(benzylsulfanyl)-6-phenylpyrimidin-4-
yloxy)ethyl)-N-methylamino)-2-phenylacetate (7g)
Synthesized according to general procedure from pyrimidine 4g
(1.053 g, 3.00 mmol), 1.49 g (50%) of compound 7g was obtained as
a colourless oil. TLC: Rf 0.42 (n-hexane/ethyl acetate 4:1). IR (ATR):
3060 (w), 3029 (w), 2950 (w), 1735 (m), 1568 (s), 1535 (s), 1494 (m),
1451 (m), 1413 (m), 1375 (m), 1345 (s), 1309 (m), 1289 (m), 1266 (s),
1242 (m),1207 (s), 1158 (m),1021 (s), 998 (m) cmꢂ1. 1H NMR (CDCl3,
200 MHz): d (ppm) 8.07–8.02 (m, 2H), 7.52–7.29 (m, 12H), 6.78 (s,
1H), 4.5 (s, 2H), 4.47 (s, 1H), 4.44–4.42 (m, 2H), 3.75 (s, 3H), 3.06–
3.82 (m, 2H), 2.47 (s, 3H). 13C NMR (CDCl3, 50 MHz): d (ppm) 171.3
(s), 169.8 (s), 168.6 (s), 163.6 (s), 136.9 (s), 135.6 (s), 135.2 (s), 129.6
(d), 127.9 (d, 2C), 127.8 (d, 2C), 127.77 (d, 2C), 127.71 (d, 2C), 127.4 (d,
2C), 127.2 (d, 2C), 126.9 (d), 126.0 (d), 98.3 (d), 71.5 (d), 63.4 (t), 51.2
(t), 50.8 (q), 39.2 (q), 34.4 (t). HRMS (ESI) m/z: calcd for
(ESI) m/z: calcd for
526.2151.
C
31H32N3O3S1 [MþH]þ 526.2159; found
4.6. General procedure for the synthesis of 2-morpholino-
pyrimidines 8
The appropriate arylglycinates 7 (1.0 equiv) was dissolved in
diethyl ether (3 mL/mmol) and the solution was cooled in an ice
bath. This solution was bubbled for 15 min with gaseous HCl,
generated in situ by a reaction of NaCl with concentrated sulfuric
acid. The resulting white solid precipitate was collected by filtration
and washed sequentially with small portion of diethyl ether and n-
pentane. Then, the hydrochloride compound was dissolved in
CH2Cl2 (5 mL/mmol) and m-CPBA (1.2 equiv) was added in small
portions. The resulting mixture was warmed to room temperature
and stirred for 1 h. After this time, the solvent was removed under
reduced pressure and the residue was dissolved in AcOEt (20 mL),
washed with saturated NaHCO3 solution (2ꢁ10 mL) and brine
(1ꢁ10 mL). The organic layer was dried (MgSO4), filtered and con-
centrated. Next, the crude material was dissolved in dry 1,4-di-
oxane and morpholine (2.5 equiv) was added. The reaction mixture
was the stirred under a nitrogen atmosphere at 60 ꢀC. Upon com-
pletion of the reaction (TLC monitoring), the solvent was removed
under reduced pressure, and the resulting residue was purified by
flash chromatography (n-hexane/ethyl acetate 14:1 to 9:1) to afford
compounds 8.
C
29H30N3O3S1 [MþH]þ 500.2002; found 500.2015.
4.5.3. Petasis reaction and esterification of pyrimidine 4i
According to the general procedure and starting from 4i
(475 mg, 1.5 mmol), 314 mg (68%) of arylglycinate 7i was obtained
as a separable diastereomeric mixture (dr¼70%) of 7ia (250 mg,
54%) and 7ib (64 mg, 14%).
4.5.3.1. (R)-Methyl 2-((S)-2-((2-(benzylsulfanyl)-6-methylpyrimidin-
4-yloxy)methyl)pyrrolidin-1-yl)-2-phenylacetate (7ia). Isolated as
a colourless oil. TLC: Rf 0.23 (n-hexane/ethyl acetate 4:1). [a]D27
ꢂ133.24 (c 0.352, CH3OH). IR (ATR): 3026 (w), 2949 (w), 2924 (w),
2871 (w), 1739 (m), 1578 (s), 1542 (s), 1493 (w), 1448 (m), 1410 (m),
1350 (m), 1279 (s), 1239 (m), 1197 (m), 1162 (s), 1039 (m), 1001 (w),
911 (m) cmꢂ1 1H NMR (CDCl3, 200 MHz): d (ppm) 7.45–7.22 (m,
.
10H), 6.18 (s,1H), 4.63 (s,1H), 4.37 (s, 2H), 4.13–3.96 (m, 2H), 3.65 (s,
3H), 3.34–3.31 (m, 1H), 3.03–3.00 (m, 1H), 2.49–2.34 (m, 1H), 2.33
(s, 3H),1.92–1.64 (m, 4H). 13C NMR (CDCl3, 200 MHz): d (ppm) 172.7

5234
D. Font et al. / Tetrahedron 64 (2008) 5226–5235
4.6.1. Methyl 2-((S)-1-(2-morpholino-6-phenylpyrimidin-4-yloxy)-
3-methylbutan-2-ylamino)-2-phenylacetate (8e)
1:1). [a]2D5 ꢂ100.29 (c 0.168, CH3OH). IR (ATR): 2955 (w), 2895 (w),
2850 (w), 1738 (m), 1558 (s), 1493 (m), 1445 (m), 1393 (m), 1352
(m), 1299 (w), 1264 (m), 1204 (m), 1142 (m), 1112 (m), 1075 (w),
1022 (m), 990 (m) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm) 8.06–
8.01 (m, 2H), 7.48–7.34 (m, 8H), 6.46 (s, 1H), 4.7 (s, 1H), 4.19–4.11
(m, 2H), 3.93–3.79 (m, 8H), 3.71 (s, 3H), 3.49–3.42 (m, 1H), 3.12–
3.06 (m, 1H), 2.60–2.48 (m, 1H), 1.94–1.77 (m, 4H). 13C NMR (CDCl3,
50 MHz): d (ppm) 172.8 (s), 170.7 (s), 165.2 (s), 161.7 (s), 137.9 (s),
136.4 (s), 130.0 (d), 129.1 (d, 2C), 128.5 (d, 4C), 128.2 (d), 126.9 (d,
2C), 92.5 (d), 69.7 (d), 68.3 (t), 66.9 (t, 2C), 59.6 (d), 51.9 (q), 51.8 (t),
44.4 (t, 2C), 28.5 (t), 23.1 (t). HRMS (ESI) m/z: calcd for C28H33N4O4
[MþH]þ 489.2496; found 489.2497.
Synthesized according to general procedure from arylglycinate
7e (0.90 g, 1.7 mmol), 516 mg (62%) of an inseparable di-
astereomeric mixture of compound 8e was obtained as a colourless
oil. TLC: Rf 0.39 (n-hexane/ethyl acetate 4:1). IR (ATR): 2956 (w),
2924 (w), 2852 (w), 1737 (m), 1558 (s), 1493 (m), 1448 (m), 1396
(m), 1340 (m), 1301 (w), 1266 (s), 1249 (w), 1206 (s), 1170 (w), 1115
(m), 1023 (m), 988 (w), 770 (m), 695 (m) cmꢂ1 1H NMR (CDCl3,
.
200 MHz) major diastereomer: d (ppm) 8.08–8.02 (m, 2H), 7.50–
7.31 (m, 13H), 6.45 (s, 1H), 4.65 (s, 1H), 4.35–4.15 (m, 2H), 3.85–3.77
(m, 8H), 3.72 (s, 3H), 2.86–2.77 (m, 1H), 2.09–1.85 (m, 1H), 1.08 (d,
J¼6.8 Hz, 3H), 1.04 (d, J¼6.8 Hz, 3H); minor diastereomer: d (ppm)
8.08–8.02 (m, 2H), 7.50–7.31 (m, 13H), 6.51 (s, 1H), 4.65 (s, 1H),
4.55–4.38 (m, 2H), 3.95–3.85 (m, 8H), 3.67 (s, 3H), 2.77–2.51 (m,
1H), 2.09–1.85 (m, 1H), 1.02 (d, J¼6.8 Hz, 3H), 0.93 (d, J¼6.8 Hz, 3H).
13C NMR (CDCl3, 50 MHz) major diastereomer: d (ppm) 174.4 (s),
171.5 (s), 165.94 (s), 162.4 (s), 139.36 (s), 138.6 (s), 130.7 (d), 129.3 (d,
2C), 129.2 (d, 2C), 128.64 (d), 128.12 (d, 2C), 127.6 (d, 2C), 93.5 (d),
67.6 (t, 2C), 66.96 (t), 64.30 (d), 60.14 (d), 52.91 (q), 45.12 (t, 2C),
30.2 (d), 19.27 (q), 19.15 (q); minor diastereomer: d (ppm) 174.4 (s),
171.4 (s), 165.90 (s), 162.3 (s), 139.45 (s), 138.6 (s), 130.7 (d), 129.3 (d,
2C), 129.2 (d, 2C), 128.64 (d), 128.12 (d, 2C), 127.6 (d, 2C), 93.5 (d),
67.6 (t, 2C), 67.03 (t), 64.36 (d), 59.97 (d), 52.86 (q), 45.08 (t, 2C),
30.4 (d), 19.56 (q), 19.27 (q). HRMS (ESI) m/z: calcd for
4.7. X-ray crystallographic details of compound 6ja
C30H29N3O3S$DMF Mr¼511.62, orthorhombic, space group
P22121, a¼5.4908(6) Å, b¼14.5712(17) Å, c¼38.386(5) Å, V¼
3071.2(6) Å3, Z¼4, Dx¼1.265 g cmꢂ3
,
T¼100(2) K, crystal di-
mensions: 0.2ꢁ0.1ꢁ0.08 mm. The measurements were carried out
on a BRUCKER SMART APEX CCD diffractometer using graphite-
monochromated Mo Ka radiation (l¼0.71073 Å) from an X-ray
Tube. The measurements were made in the range 2.12–27.00ꢀ for q.
Full-sphere data collection was carried out with u and 4 scans. A
total of 42,657 reflections were collected of which 6675
[R(int)¼0.1082] were unique. The programs that were used follow:
data collection Smart version 5.631 (Bruker AXS 1997–02); data
reduction Saintþversion 6.36A (Bruker AXS 2001); absorption
correction SADABS version 2.10 (Bruker AXS 2001). Crystal struc-
ture solution was achieved using SHELXTL Version 6.14 (Bruker AXS
2000–2003). A considerable amount of electron density attributable
to partially disordered DMF solvent molecule was removed with the
SQUEEZE option of PLATON.15 The DMF molecule is, however, in-
cluded in the reported chemical formula and derived values (e.g.,
formula weight, F_000, etc.). Non-hydrogen atoms were refined
anisotropically. The hydrogen atoms were placed in geometrically
optimized positions and refined without constrains. The chosen
enantiomer was based on the assumption that the chiral centre in
the pyrrolidine ring has the S-configuration as a result of the known
configuration of the reagents used in the reaction.
C
28H34N4NaO4 [MþNaþH]þ 513.2472; found 513.2463.
4.6.2. Methyl 2-(N-(2-(2-morpholino-6-phenylpyrimidin-
4-yloxy)ethyl)-N-methylamino)-2-phenylacetate (8g)
Synthesized according to general procedure from arylglycinate
7g (1.248 g, 2.5 mmol), 866 mg (75%) of compound 8g was obtained
as a colourless oil. TLC: Rf 0.62 (n-hexane/ethyl acetate 1:1). IR
(ATR): 3062 (w), 2953 (w), 1736 (m), 1558 (s), 1493 (m), 1448 (m),
1397 (m), 1363 (m), 1341 (m), 1301 (m), 1266 (s), 1207 (s), 1156 (m),
1115 (s), 1069 (w), 1023 (s), 995 (m) cmꢂ1 1H NMR (CDCl3,
.
200 MHz): d (ppm) 8.05–8.00 (m, 2H), 7.49–7.3 (m, 8H), 6.46 (s,1H),
4.48–4.42 (m, 3H), 3.87–3.80 (m, 8H), 3.75 (s, 3H), 3.07–3.85 (m,
2H), 2.49 (s, 3H). 13C NMR (CDCl3, 50 MHz): d (ppm) 172.2 (s), 170.5
(s), 165.2 (s), 161.6 (s), 137.9 (s), 136.3 (s), 130.0 (d), 128.7 (d, 2C),
128.5 (d, 4C), 128.2 (d), 126.85 (d, 2C), 92.7 (d), 72.6 (d), 66.9 (t, 2C),
63.6 (t), 52.4 (t), 51.8 (q), 44.3 (t, 2C), 40.3 (q). HRMS (ESI) m/z: calcd
for C26H31N4O4 [MþH]þ 463.2340; found 463.2307.
Acknowledgements
Financial support from MCYT of Spain (Project No. PB-94-0509).
Dr. D.F. thanks the University of Girona for a predoctoral fellowship.
4.6.3. (R)-Methyl 2-((S)-2-((6-methyl-2-morpholinopyrimidin-
4-yloxy)methyl)pyrrolidin-1-yl)-2-phenylacetate (8ia)
`
Thanks are also due to Mr. Xavier Fontrodona (Serveis Tenics de
Synthesized according to general procedure from arylglycinate
7ia (510 mg, 1.10 mmol), 304 mg (65%) of compound 8ia was
obtained as a colourless oil. TLC: Rf 0.46 (n-hexane/ethyl acetate
1:1). [a]2D7 ꢂ110.07 (c 0.21, CH3OH). IR (ATR): 2955 (w), 2920 (w),
2851 (w), 1739 (m),1568 (s),1494 (m),1444 (m),1397 (m),1301 (w),
1273 (m), 1244 (m), 1199 (m), 1161 (s), 1114 (m), 1041 (m), 1014 (m),
999 (m), 911 (w), 700 (m) cmꢂ1. 1H NMR (CDCl3, 200 MHz): d (ppm)
7.46–7.3 (m, 5H), 5.87 (s, 1H), 4.68 (s, 1H), 4.08–4.03 (m, 2H), 3.78–
3.74 (m, 8H), 3.69 (s, 3H), 3.40–3.32 (m, 1H), 3.10–3.03 (m, 1H),
2.52–2.37 (m, 1H), 2.28 (s, 3H), 1.93–1.75 (m, 4H). 13C NMR (CDCl3,
200 MHz): d (ppm) 172.7 (s), 169.9 (s), 167.9 (s), 161.5 (s), 136.2 (s),
129.0 (d, 2C), 128.4 (d, 2C), 128.1 (d), 95.5 (d), 69.6 (d), 67.9 (t), 66.8
(t, 2C), 59.5 (d), 51.83 (q), 51.82 (t), 44.3 (t, 2C), 28.4 (t), 24.0 (q), 23.0
(t). HRMS (ESI) m/z: calcd for C23H31N4O4 [MþH]þ 427.2340; found
427.2316.
Recerca, Universitat de Girona) for recording the X-ray crystallo-
graphic data for 6ja.
Supplementary data
CCDC-664273 contains the supplementary crystallographic data
for compounds 6ja. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.03.035.
References and notes
1. (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539; (b) Asymmetric synthesis of novel
sterically constrained amino acids; Symposium-in-print. Hruby, V. J., Solo-
shonok, V. A., Eds. Tetrahedron 2001, 57, 6329; (c) Barfoot, C. W.; Harvey, J. E.;
Kenworthy, M. N.; Kilburn, J. P.; Ahmed, M.; Taylor, R. J. K. Tetrahedron 2005, 61,
3403.
4.6.4. (R)-Methyl 2-((S)-2-((2-morpholino-6-phenylpyrimidin-
4-yloxy)methyl)pyrrolidin-1-yl)-2-phenylacetate (8ja)
Synthesized according to general procedure from arylglycinate
7ja (652 mg, 1.25 mmol), 445 mg (73%) of compound 8ja was
obtained as a colourless oil. TLC: Rf 0.66 (n-hexane/ethyl acetate
2. (a) Hannesian, S.; McNughton-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetra-
hedron 1997, 53, 12789; (b) Beck, G. Synlett 2002, 837.

D. Font et al. / Tetrahedron 64 (2008) 5226–5235
5235
3. (a) Nicolau, K. C.; Boddy, C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed.
1999, 38, 2096; (b) Kahne, D.; Leimkuhler, C.; Lu, W.; Walsh, C. Chem. Rev. 2005,
105, 425.
4. (a) Townsend, C. A.; Brown, A. M. J. Am. Chem. Soc. 1983, 105, 913; (b) Kelly, W.
L.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124, 8186.
5. (a) Moloney, M. G. Nat. Prod. Rep. 1999, 16, 485; (b) Conway, S. J.; Miller, J. C.;
Howson, P. A.; Clark, B. P.; Jane, D. E. Bioorg. Med. Chem. Lett. 2001, 11, 777; (c)
Ma, D.; Zhu, W. J. Org. Chem. 2001, 66, 348; (d) Ma, D.; Ding, K.; Tian, H.;
Wang, B.; Cheng, D. Tetrahedron: Asymmetry 2002, 13, 961 and references
cited therein.
6. (a) Willians, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889; (b) Calı´, P.; Begtrup,
M. Synthesis 2002, 63; (c) Hang, J.; Li, H.; Deng, L. Org. Lett. 2002, 4, 3321 and
references cited therein; (d) Boto, A.; Herna´ndez, R.; Montoya, A.; Sua´rez, E.
Tetrahedron Lett. 2002, 43, 8269 and references cited therein; (e) Tohma, S.;
Rikimaru, K.; Endo, A.; Shimamoto, K.; Kan, T.; Fukuyama, T. Synthesis 2004,
8. (a) Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023; (b)
Klopfenstein, S. R.; Chen, J. J.; Golebiowski, A.; Li, M.; Peng, S. X.; Shao, X. Tet-
rahedron Lett. 2000, 41, 4835; (c) Naskar, D.; Roy, A.; Seibel, W. L.; West, L.;
Portlo, D. E. Tetrahedron Lett. 2003, 44, 6297; (d) Portlock, D. E.; Naskar, D.;
West, L.; Ostaszewski, R.; Chen, J. J. Tetrahedron Lett. 2003, 44, 5121; (e) Danieli,
E.; Trabocchi, A.; Menchi, G.; Guarna, A. Eur. J. Org. Chem. 2007, 1659.
9. (a) Petasis, N. A.; Boral, S. Tetrahedron Lett. 2001, 42, 539; (b) Southwood, T. J.;
Curry, M. C.; Hutton, C. A. Tetrahedron 2006, 62, 236.
10. (a) Font, D.; Heras, M.; Villalgordo, J. M. Synthesis 2002, 1833; (b) Font, D.;
Heras, M.; Villalgordo, J. M. J. Comb. Chem. 2003, 5, 311; (c) Font, D.; Linden, A.;
Heras, M.; Villalgordo, J. M. Tetrahedron 2006, 62, 1433.
11. For recent examples of Smiles rearrangements, see: (a) Selvakumar, N.; Srinivas,
D.; Azhagan, A. M. Synthesis 2002, 2421; (b) Buchstaller, H.-P.; Anlauf, U. Syn-
thesis 2005, 693; (c) El Kaı¨m, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005,
44, 7961 and references cited therein.
´
909; (f) Pulley, S. R.; Czako, B.; Brown, D. Tetrahedron Lett. 2005, 46, 9039 and
12. (a) Wang, H.-Y.; Liao, Y.-X.; Guo, Y.-L.; Tang, Q.-H.; Lu, L. Synlett 2005, 1239; (b)
El Kaı¨m, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019; (c) Xiang,
J.; Zheng, L.; Chen, F.; Dang, Q.; Bai, X. Org. Lett. 2007, 9, 765.
references cited therein; (g) Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed.
2006, 45, 6360.
7. (a) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463; (b)
Koolmeister, T.; So¨dergen, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5965; (c)
Grigg, R.; Sridharan, V.; Thayaparan, A. Tetrahedron Lett. 2003, 44, 9017; (d)
McLean, N. J.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2004, 45, 993; (e) Nanda,
K. K.; Trotter, W. Tetrahedron Lett. 2005, 46, 2025; (f) Follman, M.; Graul, F.;
Scha¨fer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1099.
13. Yield calculated after flash chromatography. Amine 4 was slowly turning into
alcohol 5 even when stocked inside the refrigerator.
14. It was impossible to obtain pure 1H NMR spectra of amine 4. During the dry-
ness process amine 4 turned partially into alcohol 5.
15. Spek, A. L. PLANTON: A Multipurpose Crystallographic Tool; University of Utrecht:
Utrecht, The Netherlands, 2005.