Xanthate based radical cascade toward multicomponent formation of pyrrolopyrimidines

Article abstract of DOI:10.3390/molecules16119261

A short sequential synthesis of pyrrolidino- pyridines and pyrimidines illustrates the potential of combining Ugi-Smiles couplings with radical tin-free processes.

Full text of DOI:10.3390/molecules16119261

Molecules 2011, 16, 9261-9273; doi:10.3390/molecules16119261
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Xanthate Based Radical Cascade Toward Multicomponent
Formation of Pyrrolopyrimidines
Laurent El Kaïm *, Laurence Grimaud * and Patil Pravin
Laboratoire DCSO ENSTA-Polytechnique-CNRS, UMR 7652, Ecole Nationale Supérieure de
Techniques Avancées, 32 Bd Victor, 75739 Paris Cedex 15, France
* Authors to whom correspondence should be addressed; E-Mails: laurent.elkaim@ensta.fr (L.E.K.);
grimaud@dcso.polytechnique.fr (L.G.); Tel.: +33145525537; Fax: +33145528322.
Received: 28 September 2011; in revised form: 23 October 2011 / Accepted: 28 October 2011 /
Published: 4 November 2011
Abstract: A short sequential synthesis of pyrrolidino- pyridines and pyrimidines illustrates
the potential of combining Ugi-Smiles couplings with radical tin-free processes.
Keywords: Ugi-Smiles coupling; xanthates; multicomponent reactions; radical processes;
isocyanides
1. Introduction
Among multi-component reactions (MCRs), the Ugi reaction has a privileged position due to its
broad synthetic significance [1,2]. Its four points of diversity combined with possible further
transformations of the resulting adducts have became very popular in heterocyclic synthesis. Indeed,
the Ugi reaction has been associated with a wide range of post-condensation reactions in order to form
even more complex scaffolds, including cycloadditions [3-9], metal-catalyzed processes [10-15] and
cyclocondensations [16-21]. Among this very impressive bibliography, the combination of Ugi or
Passerini reactions with radical chemistry has been scarcely documented [22-27]. Among the various
radical systems explored in our group, we have mostly studied the potential of xanthate radical transfer
resulting in various cyclizations of Ugi xanthate adducts bearing suitable alkene [22], alkyne [25] or
aryl [26] moieties. In all these examples, α-chloroacetic acid was used as the acidic partner to
introduce the xanthate moiety via a nucleophilic substitution. However, these intramolecular
post-condensations did not exploit the full potential of the xanthate radical transfer. Indeed, compared

Molecules 2011, 16
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to tin hydride chemistry, the reversible nature of the addition of radicals onto the thiocarbonyl group is
associated with high yielding intermolecular couplings between xanthates and alkenes [28,29]. Herein,
we propose to explore this feature and to further increase the molecular diversity of the Ugi step
through a xanthate triggered addition/cyclization cascade to form new heterocyclic systems (Scheme 1).
Scheme 1. Synthetic strategy towards pyrrolidino fused systems.
2. Results and Discussion
Developing the radical chemistry of xanthates, the Zard group has reported various synthetic
approaches towards fused cyclic systems such as indanes, indolines or azaindolines [30-35]. These
syntheses feature an intermolecular addition of a xanthate on an alkene followed by an intramolecular
trapping with a suitably positioned aryl group. As part of our ongoing interest in Ugi-type reactions,
we naturally imagined to synthesize the radical acceptor through a Ugi-Smiles coupling. Indeed, we
recently developed the use of electron-deficient phenols as acid surrogates in Ugi reactions to form
N-arylamino carboxamides [36,37]. The use of a partner substituted with an alkene, such as allylamine,
in this reaction would afford in one step an interesting substrate to test the tandem radical process
(Scheme 1). Concerning the phenol, most reported Ugi-Smiles couplings involve a nitro group to
perform the Smiles rearrangement. As nitroaryl derivatives are often associated with inhibition of
radical chain processes, we prefer the use of hydroxy heterocycles (pyridines, pyrimidines) which also
led to efficient multicomponent couplings [38]. N-allylaminopyridines and N-allylaminopyrimidines
are known to react with xanthate under radical conditions, however the scope of these reactions seems
to be limited by the nucleophilic behavior of the cyclic nitrogen atom. Indeed all reported radical
tandem were performed on 2- or 5-halosubstituted heterocycles (chloro and fluoro) in order to lower
the reactivity at the nitrogen center (Scheme 2) [31-35].

Molecules 2011, 16
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Scheme 2. Selected examples from Zard’s group [31,33].
O
EtOSCS
SCSOEt
DLP
Me
Me
50%
O
O
Cl
N
N
Me
Cl
Cl
N
N
DCE
reflux
O
Cl
Cl
N
N
DLP (10%)
DCE reflux
Ac
Ac
Ac
84%
Cl
Cl
Cl
O
SCSOEt
O
N
SCSOEt
N
DLP
N
MeO
OMe
72%
OMe
Cl
N
N
N
N
DCE
reflux
N
N
DLP (10%)
DCE reflux
Ac
Ac
Ac
2.1. Four-Component Coupling Towards Radical Substrates
Various Ugi-Smiles adducts were thus prepared starting with allylamine as the amine partner. The
latter was coupled with different hydroxy- pyridines and pyrimidines. The MCR coupling was
performed under classical conditions using methanol as solvent. The starting radical substrates were
obtained in modest to good yields.
Table 1. Preparation of the radical substrates.
Product
Entry
R1
R2
R3
R4
Y
Z
(%)
1
2
3
4
5
6
7
Et
i-Bu
i-Bu
Et
H
Et
Cy
Cy
t-Bu
Cy
p-MeBn
Cy
Me
H
H
Ph
Ph
H
Me
H
H
Me
Me
H
N
N
N
N
N
N
CH
CH
N
N
N
1a (38%)
1b (69%)
1c (43%)
1d (61%)
1e (60%)
1f (41%)
1g (68%)
CNO2
N
i-pr
p-ClBn
Me
Me
N
2.2. Radical Cascade
In previous studies on xanthate additions on N-allylamino- pyridines and pyrimidines, a first
1,2-addition product on the alkene could be obtained and isolated under heating with substoichiometric
amounts of a radical initiator such as dilauroyl peroxide (DLP) in refluxing 1,2-dichloroethane (DCE)
or ethyl acetate. Then the intermediate adducts could cyclize under treatment with further DLP or
di-tert-butyl peroxide (more than 1 equivalent) at higher temperature allowing cleaner reactions (Scheme 3).

Molecules 2011, 16
9264
Even if the yields are expected to be lower, we preferred to perform the cascade under a single set of
experimental conditions in order to keep the multicomponent sequence as short as possible. When
adduct 1a was refluxed in DCE (0.2 M) with DLP added in 15 mol% portions every twenty minutes,
we could isolate the desired cyclized pyrrolidine 2a as a 9:1 mixture of diastereomers [39] in 48%
isolated yield, after overall addition of 1.5 equivalent of DLP (Scheme 3).
Scheme 3. Radical reaction conditions.
This sequence is initiated by decomposition of the xanthate into the electrophilic radical I, which is
then trapped by the alkene moiety to give intermediate II. The latter is an electron-rich radical that can
react with the starting xanthate to form intermediate IV. The latter being slightly less reactive than the
starting xanthate towards radicals issued from DLP, accumulates in the medium and reacts when
further amount of DLP is added without much 1 left to enter in the chain process. After addition of the
radical onto the aryl ring, the intermediate species III further aromatize through interaction with the
DLP (Scheme 4).
Scheme 4. Plausible mechanism.
To evaluate the scope of this cyclization, the reaction was performed with the Ugi-Smiles adducts
formerly prepared and the results are displayed in Table 2.

Molecules 2011, 16
9265
Table 2. Radical additions-Cyclizations.
Entry
Ugi-Smiles adduct
Xanthate
Cyclized product
Yield (%)
1
24
27
1b
1c
2b (dr 4:1)
2
2c (dr 2:1)
2d (dr 2.3:1)
2e (dr 1.5:1)
3
4
55
44
1d
1d
5
6
7
8
27
48
34
43
1e
2f
1f
2g (dr 3:1)
1a
2h (dr 4:1)
1g
2i (dr 2.3:1)

Molecules 2011, 16
9266
Pyridines and pyrimidines without any halogen substitutent at the 2 or 5 position can act as radical
trapping agents in this sequence. In the study disclosed by Zard, initial attempts with 2-aminopyridine
or 2-amino-5-methylpyridine as starting materials led to successful 1,2-addition product with the
xanthate, but no indolizine could be formed in the following cyclization step [31]. Chloro or fluoro
substituents are expected to lower the electron density in the aromatic ring leading to easier addition of
the nucleophilic intermediate radical species, and this may explain the moderate yields observed. In
our case, the reaction turns out to be poorly efficient with 4-aminopyridines, with yields not exceeding
30% (Table 2, Entries 1–2), a nitro group at the 5-position of the 2-aminopyridine ring activates the
cyclization as a higher 48% isolated yield could be obtained (Table 2, Entry 6). Pyrimidines, in
agreement with their higher electrophilicity, are better partners, giving yields over 50% with simple
alkyl or aryl susbtituents on the heterocyclic core (Table 2, Entry 3).
3. Experimental
3.1. General
1H-NMR spectra were recorded on a 400 MHz spectrometer (Bruker Avance 400), using CDCl3
13
solvent as reference and/or internal deuterium lock. C-NMR spectra were recorded on a 100.6 MHz
spectrometer (Bruker Avance 400). Two-dimensional NMR spectroscopy [1H -1H COSY spectra,
13
1
1H - C COSY spectra (HSQC) and long-range H -13C COSY spectra (HMBC)], were carried out to
determine the correlation between 1H and C. The chemical shifts for all NMR spectra are expressed
13
in parts per million to high frequency of TMS reference. Coupling constants (J) are quoted in Hz and
are recorded to the nearest 0.1 Hz. The IR spectra were obtained using ATR accessories on a Bruker
Tensor 27 instrument. High-resolution (HR) mass spectra were recorded on a Hewlett-Packard HP
5989B spectrometer. TLC was carried out using precoated plates of silica gel 60F254 (SDS-Carlo-Erba).
3.2. Ugi-Smiles Coupling Procedure
To a 1 M solution of hydroxyheteroaromatic compound in methanol were added successively
1.0 equivalent of amine, 1.0 equivalent of aldehyde and 1.0 equivalent of isocyanide. The resulting
mixture was stirred at 65 °C for 18–36 h. The solvent was removed afterwards under reduced pressure
to afford the Ugi-Smiles product after purification by flash chromatography on silica gel.
3.3. DLP-Cyclisation Reaction Procedure
A solution of Ugi-Smiles adduct (1.0 mmol) and xanthate (1.2 mmol) in 1,2-dichloroethane (1.0 M)
was refluxed for 5 min under argon before DLP was added (60 g, 0.15 mmol) from the top of the
condenser. Portions of DLP (60 mg, 0.15 mmol) were added every 20 min until complete
disappearance of Ugi-Smile adduct and the starting xanthate, then the remaining DLP was added every
20 min until complete disappearance of the intermediate (TLC monitoring). Concentration under
reduced pressure afforded an oily pale brown residue, which was purified by flash chromatography
eluting with petroleum ether/diethyl ether to give the pure product as a mixture of two diastereomers.
In all the cases, the spectral data are given for the major diastereomer.

Molecules 2011, 16
9267
2-(N-Allyl-N-(2,6-dimethylpyrimidin-4-yl)amino)-N-cyclohexylbutanamide (1a). Yellow solid, (1.0 gm,
38%), mp 124–125 °C; 1H-NMR: δ (ppm) 6.69 (br s, 1H), 6.11 (s, 1H), 5.86–5.69 (m, 1H), 5.27–5.01
(m, 3H), 4.08 (dd, 1H, J = 4.8, 17.0 Hz), 3.84 (d, 1H, J = 17.0 Hz), 3.75–3.63 (m, 1H), 2.51 (s, 3H),
3.32 (s, 3H), 2.13–2.00 (m, 1H), 1.92–1.81 (m, 1H), 1.78–1.59 (m, 3H), 1.58–1.46 (m, 2H), 1.40–1.22
13
(m, 2H), 1.20–1.06 (m, 2H), 1.02–0.93 (m, 1H), 0.90 (t, 3H, J = 7.3 Hz); C-NMR: δ (ppm) 170.1,
166.1, 165.3, 162.6, 133.5, 116.9, 100.3, 58.8, 47.6, 47.3, 32.9, 32.7, 26.1, 25.5, 24.5, 24.4, 24.3, 21.9,
10.9; IR (thin film): 2929, 2855, 2356, 1657, 1583, 1539, 1479, 1448, 1403, 1343, 1273, 1177, 1089 cm−1;
HRMS: Calcd. for C19H30N4O: 330.2420, Found: 330.2425.
2-(N-Allyl-N-(pyridin-4-yl)amino)-N-cyclohexyl-4-methylpentanamide (1b). Pale yellow solid,
1
(475 mg, 69%), mp 110–111 °C, H-NMR: δ (ppm) 8.23 (dd, 2H, J = 1.6, 5.2 Hz), 6.59 (dd, 2H,
J = 1.6, 5.2 Hz), 5.95–5.80 (m, 2H), 5.29–5.21 (m, 2H), 4.25 (t, 1H, J = 6.9 Hz), 4.00 (dd, 1H, J = 5.2,
17.2 Hz), 3.90 (dd, 1H, J = 5.2, 17.2 Hz), 3.80–3.69 (m, 1H), 2.08–2.00 (m, 1H), 1.86–1.76 (m, 2H),
1.70–1.53 (m, 5H), 1.39–1.25 (m, 2H), 1.15–1.00 (m, 3H), 0.92 (d, 3H, J = 6.7, Hz), 0.90 (d, 3H,
J = 6.7 Hz); 13C-NMR: δ (ppm) 169.9, 153.0, 150.2, 133.2, 118.1, 108.3, 61.0, 49.7 , 48.4, 37.7, 32.9,
25.4, 25.2, 24.7, 22.9, 22.1; IR (thin film): 2930, 2853, 1652, 1596, 1544, 1513, 1450, 1235, 1169 cm−1;
HRMS: Calcd. for C20H31N3O: 329.2467, Found: 329.2467.
2-(N-Allyl-N-(pyridin-4-yl)amino)-N-tert-butyl-4-methylpentanamide (1c). Pale yellow solid, (360 mg,
43%), mp 111–112 °C, 1H-NMR: δ (ppm) 8.25 (dd, 2H, J = 1.6, 5.0 Hz), 6.59 (dd, 2H, J = 1.6, 5.0 Hz),
5.90–5.80 (m, 2H), 5.28–5.19 (m, 2H), 4.19 (dd, 1H, J = 5.9, 8.0 Hz), 4.00 (ddt, 1H, J = 1.5, 5.0,
17.2 Hz), 3.89 (ddt, 1H, J = 1.5, 5.0, 17.2 Hz), 2.04–1.95 (m, 1H), 1.65–1.53 (m, 2H), 1.27 (s, 9H),
13
0.91 (d, 3H, J = 6.6 Hz), 0.89 (d, 3H, J = 6.6 Hz); C-NMR: δ (ppm) 170.0, 153.0, 149.8, 133.1,
117.9, 108.3, 61.4, 51.4, 49.6, 37.5, 28.5, 25.0, 22.8, 22.2; IR (thin film): 2964, 2930, 2871, 1676,
1596, 1544, 1513, 1454, 1367, 1266, 1231, 1172 cm−1; HRMS: Calcd. for C18H29N3O: 303.2311,
Found: 303.2309.
2-(N-Allyl-N-(6-methyl-2-phenylpyrimidin-4-yl)amino)-N-cyclohexylbutanamide (1d). white solid,
(600 mg, 61%), mp 114–115 °C, 1H-NMR: δ (ppm) 8.50–8.27 (m, 2H), 7.60–7.38 (m, 3H), 6.60 (br s,
1H), 6.24 (s, 1H), 5.94–5.76 (m, 1H), 5.42–5.03 (m, 3H), 4.11 (d, 1H, J = 17.0 Hz), 3.96 (d, 1H,
J = 17.0 Hz), 3.77–3.61 (m, 1H), 2.45 (s, 3H), 2.24–2.08 (m, 1H), 1.89–1.74 (m, 2H), 1.68–1.36 (m,
4H), 1.33–1.13 (m, 2H), 1.04–0.80 (m, 6H); 13C-NMR: δ (ppm) 170.2, 166.0, 162.8, 162.6, 138.2,
133.5, 130.2, 128.4, 127.9, 117.1, 101.3, 59.7, 47.7, 32.8, 32.6, 25.3, 24.6, 24.4, 24.3, 21.6, 11.1; IR
(thin film): 2929, 2850, 1658, 1591, 1570, 1526, 1474, 1443, 1377, 1260, 1208, 1181, 1024 cm−1;
HRMS: Calcd. for C24H32N4O: 392.2576, Found: 392.2575.
2-(N-Allyl-N-(6-methyl-2-phenylpyrimidin-4-yl)amino)-N-p-tolylmethan-acetamide (1e). white solid,
1
(498 mg, 60%), mp 124–125 °C, H-NMR: δ (ppm) 8.43–8.24 (m, 2H), 7.52–7.35 (m, 3H), 7.02 (d,
2H, J = 8.0 Hz), 6.94 (d, 2H, J = 8.0 Hz), 6.79 (br s, 1H), 6.25 (s, 1H), 5.91–5.80 (m, 1H), 5.31–5.14
(m, 2H), 4.39 (s, 2H), 4.29 (s, 2H), 4.16 (s, 2H), 2.44 (s, 3H), 2.25 (s, 3H); 13C-NMR: δ (ppm) 169.5,
166.4, 163.3, 162.1, 137.9, 136.9, 134.7, 131.3, 130.2, 129.2, 128.2, 128.0, 127.3, 117.8, 99.9, 52.2,
51.4, 42.9, 24.5, 21.0; IR (thin film): 2920, 2356, 1653, 1591, 1570, 1531, 1496, 1439, 1408, 1374,
1260, 1230, 1194, 1068, 1024 cm−1; HRMS: Calcd. for C24H26N4O: 386.2107, Found: 386.2104.

Molecules 2011, 16
9268
2-(N-Allyl-N-(5-nitropyridin-2-yl)amino)-N-cyclohexylbutanamide (1f). Yellow solid, (508 mg, 41%),
1
mp 111–112 °C, H-NMR: δ (ppm) 9.04 (d, 1H, J = 2.2 Hz), 8.21 (dd, 1H, J = 2.2, 9.4 Hz), 6.52 (d,
1H, J = 9.4 Hz), 6.18 (br s, 1H), 5.87–5.72 (m, 1H), 5.38-5.11 (m, 3H), 4.23 (dd, 1H, J = 4.8, 17.0 Hz),
4.03 (d, 1H, J = 17.0 Hz), 3.78–3.66 (m, 1H), 2.19–2.03 (m, 1H), 1.96–1.83 (m, 1H), 1.80–1.49 (m,
5H), 1.43–1.22 (m, 2H), 1.21–1.06 (m, 2H), 1.05–0.88 (m, 4H); 13C-NMR: δ (ppm) 169.2, 160.7,
145.6, 132.9, 132.7, 126.7, 117.6, 106.7, 60.0, 48.0, 47.9, 32.9, 32.8, 25.4, 24.5, 21.9, 10.8; IR (thin
film): 2924, 2850, 1657, 1588, 1570, 1496, 1413, 1325, 1286, 1251, 1111 cm−1; HRMS: Calcd. for
C18H26N4O3: 346.2005, Found: 346.2016.
N-(4-Chlorobenzyl)-2-(N-allyl-N-(2,6-dimethylpyrimidin-4-yl)amino)-3-methylbutanamide (1g). White
1
solid, (2.1 gm, 68%), mp 97–98 °C, H-NMR: δ (ppm) 7.23 (d, 2H, J = 8.2 Hz), 7.07 (d, 2H,
J = 8.2 Hz), 6.13 (s, 1H), 5.70–5.55 (m, 1H), 5.13 (d, 2H, J = 13.3 Hz), 4.91 (br s, 1H), 4.40–4.25 (m,
2H), 4.10–3.90 (m, 2H), 2.56–2.42 (m, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 1.02 (d, 3H, J = 6.4 Hz),
13
0.81 (d, 3H, J = 6.4 Hz); C-NMR: δ (ppm) 170.9, 166.1, 165.4, 162.6, 136.7, 133.1, 133.0, 128.9,
128.7, 117.4, 100.6, 42.6, 26.5, 26.1, 24.1, 19.9, 19.1; IR (thin film): 2968, 1671, 1583, 1535, 1474,
1403, 1339, 1268, 1203, 1085 cm−1; HRMS: Calcd. for C21H27ClN4O: 386.1873, Found: 386.1868.
Ethyl 3-(7-(1-(cyclohexylcarbamoyl)propyl)-6,7-dihydro-2,4-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-5-
1
yl)propanoate (2a). Yellow liquid, (200 mg, 48%), H-NMR: δ (ppm) 6.43 (d, 1H, J = 7.5 Hz), 4.40
(t, 1H, J = 7.7 Hz), 4.06 (q, 2H, J = 6.8 Hz), 3.80–3.63 (m, 2H), 3.40–3.25 (m, 2H), 2.45 (s, 3H),
2.34–2.20 (m, 5H), 2.10–1.95 (m, 2H), 1.90–1.70 (m, 4H), 1.69–1.46 (m, 3H), 1.40–1.05 (m, 8H),
0.88 (t, 3H, J = 7.3 Hz); 13C-NMR: δ (ppm) 172.8), 169.1, 166.3, 166.2, 157.2, 116.4, 60.6, 57.9, 50.5,
47.8, 35.0, 32.9, 32.8, 30.4, 28.9, 25.8, 25.4, 24.5, 24.4, 20.8, 20.5, 14.2, 10.7; IR (thin film): 2929,
2855, 2356, 1731, 1657, 1609, 1570, 1517, 1448, 1400, 1312, 1277, 1260, 1168, 1168, 1089, 1028 cm−1;
HRMS: Calcd. for C23H36N4O3: 416.2787, Found: 416.2767.
Ethyl
3-(1-(1-(cyclohexylcarbamoyl)-3-methylbutyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-
1
propanoate (2b). Pale yellow liquid, ( 100 mg, 24%), H-NMR: δ (ppm) 8.21 (s, 1H), 8.12 (d, 1H,
J = 5.8 Hz), 6.55 (d, 1H, J = 5.8 Hz), 6.04 (br s, 1H), 4.10 (q, 2H, J = 7.1 Hz), 3.93 (t, 1H, J = 6.5 Hz),
3.80–3.60 (m, 3H), 3.00–2.88 (m, 1H), 2.29 (t, 2H, J = 7.0 Hz), 2.02 (dd, 1H, J = 7.0, 13.4 Hz),
13
1.95–1.78 (m, 4H), 1.74–1.50 (m, 6H), 1.35–1.15 (m, 11H), 0.95–0.82 (m, 2H); C-NMR: δ (ppm)
173.0, 171.1, 148.1, 147.6, 146.1, 127.0, 107.0, 60.4, 60.2, 49.3, 48.2, 39.6, 33.7, 33.0, 32.8, 30.3,
30.0, 29.0, 25.3, 24.8, 24.7, 24.5, 22.2, 14.1; IR (thin film): 2924, 2840, 2361, 1727, 1644, 1660, 1517,
1448, 1374, 1277, 1260, 1163, 1098, 1064, 1028 cm−1; HRMS: Calcd. for C24H37N3O3: 415.2835,
Found: 415.2837.
Ethyl
3-(1-(1-(tert-butylcarbamoyl)-3-methylbutyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-
1
propanoate (2c). Pale brown liquid, (85 mg, 27%), H-NMR: δ (ppm) 8.23 (s, 1H), 8.14 (d, 1H,
J = 5.8 Hz), 6.55 (d, 1H, J = 5.8 Hz), 5.85 (br s, 1H), 4.10 (q, 2H, J = 7.1 Hz), 3.82 (t, 1H, J = 6.5 Hz),
3.74–3.62 (m, 2H), 3.00–2.87 (m, 1H), 2.30 (t, 2H, J = 7.0 Hz), 2.26–2.17 (m, 1H), 2.06–196 (m, 1H),
13
1.94–1.83 (m, 1H), 1.65–1.55 (m, 2H), 1.32 (s, 9H), 1.31–1.18 (m, 9H); C-NMR: δ (ppm) 173.0,
171.1, 156.2, 148.0, 146.7, 127.4, 107.0, 60.9, 60.4, 51.2, 49.4, 39.6, 33.8, 33.3, 30.3, 28.5, 24.6, 22.2,

Molecules 2011, 16
9269
14.2;. IR (thin film): 2960, 2933, 2361, 1727, 1666, 1596, 1543, 1505, 1448, 1365, 1277, 1255, 1220,
1163 cm−1; HRMS: Calcd. for C22H35N3O3: 389.2678, Found: 389.2679.
Ethyl
3-(7-(1-(cyclohexylcarbamoyl)propyl)-6,7-dihydro-4-methyl-2-phenyl-5H-pyrrolo[2,3-d]-
pyrimidin-5-yl)propanoate (2d). Pale yellow liquid, (265 mg, 55%), 1H-NMR: δ (ppm) 8.40–8.30 (m,
2H), 7.54–7.38 (m, 3H), 6.52 (br s, 1H), 4.63–4.45 (m, 1H), 4.09 (q, 2H, J = 7.0 Hz), 3.80–3.60 (m,
2H), 3.50–3.25 (m, 2H), 2.40 (s, 3H), 2.37–2.24 (m, 2H), 2.18–1.96 (m, 2H), 1.94–1.70 (m, 4H),
13
1.63–1.38 (m, 3H), 1.34–1.14 (m, 6H), 1.05–0.80 (m, 5H); C-NMR: δ (ppm) 172.8, 169.3, 166.6,
163.0, 157.9, 138.2, 130.0, 128.2, 127.7, 117.5, 60.6, 58.2, 50.7, 47.9, 35.2, 32.8, 32.7, 30.4, 28.8,
25.3, 24.4, 24.2, 21.0, 20.9, 14.2, 10.8; IR (thin film): 2972, 2929, 2850, 1731, 1662, 1605, 1562,
1531, 1452, 1377, 1312, 1246, 1163 cm−1, HRMS: Calcd. for C28H38N4O3: 478.2944, Found:
478.2950.
N-Cyclohexyl-2-(5,6-dihydro-4-methyl-5-(3-oxobutyl)-2-phenylpyrrolo[2,3-d]pyrimidin-7-yl)butan-amide
(2e). Yellow liquid, (75 mg, 44%), 1H-NMR: δ (ppm) 8.40–8.25 (m, 2H), 7.55–7.35 (m, 3H), 6.50 (d,
1H, J = 8.0Hz), 4.50 (t, 1H, J = 6.6 Hz), 3.78–3.58 (m, 2H), 3.45–3.25 (m, 2H), 2.47 (t, 2H, J = 7.5 Hz),
2.40 (s, 3H), 2.16–2.00 (m, 5H), 1.90–1.66 (m, 4H), 1.60–1.34 (m, 4H), 1.30–1.14 (m, 2H), 1.10–0.85
(m, 5H); 13C-NMR: δ (ppm) 207.9, 169.3, 166.5, 162.9, 157.8, 138.1, 130.0, 128.2, 127.7, 117.7, 58.2,
51.2, 47.8, 39.4, 35.1, 32.7, 30.0, 27.4, 25.3, 24.4, 24.3, 21.1, 21.0, 10.8; IR (thin film): 2929, 2853,
1710, 1656, 1603, 1564, 1508, 1454, 1377, 1317, 1247, 1159, 1064 cm−1, HRMS: Calcd. for
C27H36N4O2: 448.2838, Found: 448.2836.
Ethyl
3-(7-(N-p-tolylmethan-carbamoylmethyl)-6,7-dihydro-4-methyl-2-phenyl-5H-pyrrolo[2,3-d]-
1
pyrimidin-5-yl)propanoate (2f). Pale yellow liquid, (125 mg, 27%), H-NMR: δ (ppm) 8.28 (d, 2H,
J = 7.6 Hz), 7.45–7.34 (m, 3H), 7.10 (d, 2H, J = 7.6 Hz), 7.00 (d, 2H, J = 7.6 Hz), 6.95 (br s, 1H),
4.50–4.25 (m, 3H), 4.08–3.95 (m, 3H), 3.75–3.65 (m, 1H), 3.45–3.35 (m, 2H), 2.40 (s, 3H), 2.33–2.20
13
(m, 5H), 2.10–2.00 (m, 1H), 1.96–1.85 (m, 1H), 1.20 (t, 3H, J = 7.0 Hz); C-NMR: δ (ppm) 173.0,
169.0, 167.0, 163.6, 158.5, 138.0, 137.1, 135.0, 130.1, 129.4, 128.3, 128.0, 127.6, 117.4, 60.8, 55.8,
49.5, 43.2, 35.8, 30.8, 28.7, 21.1, 21.0, 14.2; IR (thin film): 2924, 2356, 1731, 1662, 1605, 1583, 1570,
1518, 1448, 1377, 1325, 1260, 1172, 1024 cm−1, HRMS: Calcd. for C28H32N4O3: 472.2474, Found :
472.2473.
Ethyl
3-(1-(1-(cyclohexylcarbamoyl)propyl)-2,3-dihydro-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-
1
propanoate (2g). Pale brown liquid, (297 mg, 48%), H-NMR: δ (ppm) 8.86 (s, 1H), 7.92 (s, 1H),
6.04 (br s, 1H), 4.05 (t, 1H, J = 7.5 Hz), 4.15 (q, 2H, J = 7.2 Hz), 4.00–3.83 (m, 1H), 3.79–3.62 (m,
1H), 3.55–3.30 (m, 2H), 2.44–2.30 (m, 2H), 2.20–1.98 (m, 2H), 1.94–1.76 (m, 3H), 1.74–1.64 (m,
3H), 1.62–1.50 (m, 2H), 1.34–1.25 (m, 6H), 1.20–1.10 (m, 1H), 0.95 (t, 3H, J = 7.2 Hz); 13C-NMR: δ
(ppm) 172.5, 168.1, 164.6, 146.7, 136.6, 126.7, 125.7, 60.8, 58.5, 51.9, 48.2, 36.2, 33.0, 31.0, 30.9,
29.5, 25.4, 24.6, 24.5, 21.4, 14.3, 10.7; I.R. (thin film): 2933, 2850, 2356, 1731, 1657, 1609, 1574,
1517, 1496, 1443, 1377, 1291, 1186, 1090, 1024 cm−1, HRMS: Calcd. for C22H32N4O5: 432.2373,
Found: 432.2386.

Molecules 2011, 16
9270
N-Cyclohexyl-2-(5,6-dihydro-2,4-dimethyl-5-(3-oxo-3-phenylpropyl)pyrrolo[2,3-d]pyrimidin-7-yl)-
1
butanamide (2h). Pale brown liquid, (150 mg, 34%), H-NMR: δ (ppm) 7.90 (d, 2H, J = 7.8 Hz),
7.58–7.54 (m, 1H), 7.48–7.41 (m, 2H), 6.48 (d, 1H, J = 7.8 Hz), 4.41 (t, 1H, J = 7.7 Hz), 3.80–3.65 (m,
2H), 3.46–3.30 (m, 2H), 3.08–2.83 (m, 2H), 2.45 (s, 3H), 2.30 (s, 3H), 2.26–2.14 (m, 1H), 2.08–1.96
13
(m, 1H), 1.94–1.40 (m, 7H), 1.30–0.98 (m, 5H), 0.90 (t, 3H, J = 7.3 Hz); C-NMR: δ (ppm) 199.3,
169.2, 166.3, 166.1, 157.2, 136.6, 133.2, 128.6, 127.9, 116.8, 58.0, 50.7, 47.9, 35.2, 34.1, 33.0, 32.8,
28.2, 25.8, 25.4, 24.4, 21.1, 20.6, 10.8; IR (thin film): 2929, 2853, 1671, 1611, 1568, 1515, 1446, 1404,
1358, 1317, 1270, 1259, 1202, 1083 cm−1, HRMS: Calcd. for C27H36N4O2: 448.2838, Found: 448.2843.
Ethyl 3-(7-(1-(4-chlorobenzylcarbamoyl)-2-methylpropyl)-6,7-dihydro-2,4-dimethyl-5H-pyrrolo[2,3-
1
d]pyrimidin-5-yl)propanoate (2i). Pale yellow liquid, (203 mg, 43%), H-NMR: δ (ppm) 7.22 (d, 2H,
J = 8.0 Hz), 7.07 (d, 2H, J = 8.0 Hz), 6.97 (d, 1H, J = 6.0 Hz), 4.39 (dd, 2H, J = 6.0, 14.7 Hz), 4.12 (q,
2H, J = 7.0 Hz), 4.04–3.97 (m, 1H), 3.73 (t, 1H, J = 7.0 Hz), 3.40–3.20 (m, 2H), 2.51–2.38 (m, 1H),
2.35 (s, 3H), 2.28 (s, 3H), 2.23 (t, 2H, J = 7.5 Hz), 2.10–1.90 (m, 1H), 1.80–1.65 (m, 1H), 1.25 (t, 3H,
J = 7.0 Hz), 1.00 (d, 3H, J = 7.0 Hz), 0.87 (d, 3H, J = 7.0 Hz); 13C-NMR: δ (ppm) 172.8, 169.6, 166.1,
165.9, 157.3, 136.7, 133.2, 128.9, 128.7, 116.6, 64.0, 60.6, 51.5, 42.6, 35.2, 30.6, 28.9, 26.4, 25.7,
20.6, 19.5, 19.1, 14.2; IR (thin film): 2964, 2924, 1731, 1671, 1609, 1570, 1531, 1469, 1403, 1273,
1177, 1094, 1011 cm−1, HRMS: Calcd. for C25H33ClN4O3: 472.2241, Found : 472.2244.
4. Conclusions
The reported two-step cascade constitutes a concise entry into pyrrolidino- pyridines and
pyrimidines. Compared with previous results obtained on xanthate cascades performed on
N-allylamino- pyridine and pyrimidines, these new couplings significantly widen the scope of these
reactions. The modest efficiency of the whole process is counter-balanced by the simple experimental
procedure and the straightforward access to important biologically relevant scaffolds [40-43]. This
work is a new example of the potential of radical chemistry in Ugi post-condensations.
Acknowledgements
P. P. thanks the ANR-CP2D Program (ANR MUSE) for a fellowship.
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