Access to saturated fused pyrimidine derivatives via a flexible N -vinyl tertiary enamide synthesis

Article abstract of DOI:10.1055/s-0030-1261228

An array of tetrasubstituted saturated fused pyrimidines has been synthesized through two-sequential, simple, and efficient one-pot operations. The strategic utilization of the N-PMB group proved critical in the ability to construct a broad range of N-vinyl tertiary enamide starting materials. This stands as a flexible approach to functionalized pyrimidines with the capability of manipulating either ketone, acid chloride, or nitrile reaction partners. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261228

LETTER
2387
Access to Saturated Fused Pyrimidine Derivatives via a Flexible N-Vinyl
Tertiary Enamide Synthesis
Pyrimidines from
R
n
eadilyAcce
t
ssible
h
N
-
Vinyl Enam
o
ides ny A. Estrada,* Joseph P. Lyssikatos, Frédéric St-Jean, Philippe Bergeron
Genentech, Small Molecule Drug Discovery 1 DNA Way, South San Francisco, CA 94080, USA
Fax +1(650)7424943; E-mail: estrada.anthony@gene.com
Received 8 June 2011
can be difficult to handle and synthesize. Furthermore,
although recent advances have been made in transition-
metal-catalyzed C–N bond formation,4 this area still has a
limited scope and can have issues with irreproducibility.
Abstract: An array of tetrasubstituted saturated fused pyrimidines
has been synthesized through two-sequential, simple, and efficient
one-pot operations. The strategic utilization of the N-PMB group
proved critical in the ability to construct a broad range of N-vinyl
tertiary enamide starting materials. This stands as a flexible ap-
proach to functionalized pyrimidines with the capability of manip-
ulating either ketone, acid chloride, or nitrile reaction partners.
Rc
Rc
Rd
Rc
Rd
O
Rd
X
Key words: bicyclic compounds, enamides, imines, medicinal
chemistry, pyrimidines
N-acylation
O
+
+
Cl
Ra
cross-
coupling
N
Ra
NH2
O
H
aryl/heteroaryl
aniline
H2N
Ra
The pyrimidine heterocycle is an extremely prevalent mo-
tif in nature (e.g., nitrogen bases uracil, thymine, and cy-
tosine) and pharmaceuticals (e.g., protein kinase
inhibitors imatinib mesylate, gefitinib, erlotinib, dasa-
tinib, lapatinib, and pazopanib).1 Several classical ap-
proaches to the synthesis of pyrimidines rely on the
condensation of amidine or guanidine functionalities with
a 1,3-dicarbonyl derivative.1 While these have proven to
be reliable and robust entries into pyrimidine scaffolds,
recent strategies have focused on improving issues such as
regioselectivity, substrate flexibility, availability of start-
ing materials, and functional-group tolerability of reaction
conditions. A recent review by Movassaghi et al. high-
lights some of these recent advancements,1f which in-
cludes a novel, one-step pyrimidine synthesis developed
in his laboratory.2 Herein we report a complementary ap-
proach, which provides convenient access to N-vinyl ter-
tiary enamides and their subsequent conversion into
tetrasubstituted, saturated fused pyrimidines.
X = Br, I
Scheme 1 Retrosynthesis of secondary enamide with existing me-
thodology
After some experimentation, we were pleased to find that
the strategic protection of the enamide nitrogen (3,
Scheme 2) with a p-methoxybenzyl moiety served a cru-
cial role. This protecting group enabled us to rapidly con-
struct a diverse array of N-vinyl tertiary enamides 3 from
abundantly available ketone and acid chloride reaction
partners. Thus, initial condensation of a cyclohexanone
derivative 1 with p-methoxybenzylamine in the presence
of Ti(OEt)4 or 4 Å molecular sieves generates imine/
enamine intermediate 2.5 The enamine is then captured in
situ with an appropriate acid chloride to furnish N-vinyl
tertiary enamides 3 followed by pyrimidine formation to
yield 4.6–8 Other nitrogen protecting groups that we tested
either resulted in no reaction (benzyl) or unsatisfactory
yields (3,4-dimethoxybenzyl, and tert-butyl) for the con-
version of 3 into 4. The 4-methoxybenzyl protecting
After a thorough investigation of the conditions devel-
oped by Movassaghi and co-workers,2 we decided that an
alternative synthetic route for the generation of N-vinyl
tertiary enamides was a necessary development going for-
ward (Scheme 1). The existing method focused on the for-
mation of secondary N-aryl enamides, prepared by
acylation of the corresponding anilines (Scheme 1),3
which are efficiently transformed into quinazoline,
thieno-, and pyrrolopyrimidine products. While this
stands as a highly useful contribution for the synthesis of
the aforementioned heterocycles, this was not the focus of
our efforts. Alternatively, the current construction of N-
vinyl tertiary enamides requires the synthesis or accessi-
bility of vinyl bromide or iodide coupling partners, which
Ti(OEt)4 or
4 Å MS
CH2Cl2
Rx
H2N
40 °C, 12 h
Rx
+
OMe
N
O
PMB
1
2
O
then Et3N
0 to 25 °C
0.5–6 h
Tf2O, 2-ClPyr
CH2Cl2
–78 to 25 °C
15 min to 1 h
Rb
Cl
Ra
N
O
Rx
Rx
Rb
N
Ra
N
Ra
N
PMB
SYNLETT 2011, No. 16, pp 2387–2391
x
x
.x
x
.2
0
1
1
4
3
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1261228; Art ID: S05211ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 General route for the construction of N-vinyl tertiary en-
amides 3 and saturated fused pyrimidines 4

2388
A. A. Estrada et al.
LETTER
group provides the desirable balance of chemical stability, Empirically, the majority of the reactions, monitored by
allowing for starting-material generation, and enabling for TLC and LC-MS, are complete after only 15 minutes at
the necessary departure, presumably through formation of ambient temperatures.13 This was anticipated as it is
a stabilized benzylic carbocation.9
known that N-vinyl enamides are more reactive than the
N-aryl enamide counterparts.2,14,15 As a result, this method
avoids the need for refluxing or microwave irradiation and
stands as a flexible and direct approach to nonaryl fused
pyrimidines.
With respect to the key conversion of 3 into 4, we have yet
to generate any experimental evidence that would suggest
an alternative mechanism to that put forth by Movas-
saghi.2,10 We came to this conclusion after carrying out
1
several H NMR and 19F NMR mechanistic studies with With our newly established protocol in place, we set out
difluorinated N-vinyl tertiary enamides.11 The difficulty to explore the generality and scope of the current method
in identifying stable intermediates can be attributed to our (results summarized in Table 1). Entries 1–9 demonstrate
highly reactive system where product formation can be that both electron-withdrawing and electron-donating 3-
detected between –40 and –20 °C. We do suspect, howev- and 4-phenyl substitution at C-2 (Ra) are tolerated. Both
er, that a nitrilium species (IV, Scheme 3) may be a key cyano and methoxy derivatives, respectively, allow for
intermediate in our reaction pathway. This hypothesis is derivatization post-pyrimidine formation. Slightly lower
supported by the propensity of N-alkyl enamides, in con- yields (60%) and longer reaction times (12–18 h) were ob-
trast to N-aryl enamides, to proceed through nitrilium in- served with 2-phenyl substitution (not shown), most like-
termediates prior to trapping with nucleophilic reaction ly as a result of steric effects. Entries 10–15 show the
partners under similar conditions.12
successful formation of pyrimidine derivatives with vary-
ing regioisomeric heteroaromatic substitution at C-2 with
yields ranging from 83–91%. This is especially attractive
to medicinal chemists as 2–3 heterocycles (depending on
substitution at Rb) can be efficiently installed in a one-step
procedure. Additionally, entries 14 and 15 exhibit that
aryl halides react cleanly using this protocol, thereby al-
lowing for pre-installation of synthetic handles for further
chemical manipulation. Finally, flexibility with respect to
the saturated fused ring system is depicted in entries 16–
18. N-Cbz piperidine (20a) and cyclohexyl acetal (21a)
fused pyrimidine derivatives (entries 17 and 18) further
demonstrate the compatibility of inherent functional
groups with the survival of the acid-sensitive ketone
equivalent (entry 18) standing as a testament to the mild
nature of the process.
Tf2O
OTf
2-ClPyr
CH2Cl2
O
OTf
Ra
N
Cl
N
Ra
N
N
Ra
PMB
PMB
OTf
OTf
OTf
PMB
III
I
II
Rb
N
Rb
N
Rb
OTf
N
N
Ra
N
Ra
N
Ra
IV
VI
V
Scheme 3 Mechanistic proposal for the formation of saturated fused
pyrimidines IV from N-vinyl tertiary enamides I
Table 1 Synthesis of Highly Functionalized Saturated Fused Pyrimidines via N-Vinyl Tertiary Enamidesa
Entry
Amide
Nitrile
Product
Yield (%)b
Rb
N
Rb
O
N
N
Ra
N
Ra
PMB
1
2
3
4
5
6
7
8
9
3-MeOC6H4 9
3-MeOC6H4 9
CH2c-Pr
c-Hex
9a
9b
77
75
79
77
83
83
90
85
66
4-MeOC6H4 10
4-MeOC6H4 10
3-CNC6H4 11
3-CNC6H4 11
4-CNC6H4 12
4-CNC6H4 12
4-CNC6H4 12
CH2c-Pr
c-Hex
10a
10b
11a
11b
12a
12b
12c
CH2c-Pr
c-Hex
CH2c-Pr
c-Hex
4-OTHP
Synlett 2011, No. 16, 2387–2391 © Thieme Stuttgart · New York

LETTER
Pyrimidines from Readily Accessible N-Vinyl Enamides
2389
Table 1 Synthesis of Highly Functionalized Saturated Fused Pyrimidines via N-Vinyl Tertiary Enamidesa (continued)
Entry
Amide
Nitrile
Product
Yield (%)b
Rb
Rb
O
N
N
N
Ra
N
N
Ra
PMB
O
Rb
86
91
83
89
84
10
11
12
13
c-Hex
N
O
N
O
PMB
13
24
25
16
13a
14a
15a
16a
Rb
N
O
N
N
N
O
CH2c-Pr
N
O
PMB
Rb
N
O
c-Hex
N
S
S
PMB
Rb
N
O
S
c-Hex
N
S
PMB
Rb
N
O
N
N
S
14
c-Hex
S
PMB
Cl
Cl
17
18
17a
18a
Rb
N
90
O
N
15
16
17
c-Hex
c-Hex
c-Hex
N
PMB
N
Cl
N
Cl
Rb
82
78
F
F
F
F
O
N
S
S
N
N
PMB
19
19a
Rb
N
CbzN
O
CbzN
N
N
PMB
CN
CN
20
20a
Synlett 2011, No. 16, 2387–2391 © Thieme Stuttgart · New York

2390
A. A. Estrada et al.
LETTER
Table 1 Synthesis of Highly Functionalized Saturated Fused Pyrimidines via N-Vinyl Tertiary Enamidesa (continued)
Entry
Amide
Nitrile
Product
Yield (%)b
Rb
N
Rb
O
N
N
Ra
N
Ra
Rb
PMB
O
O
O
O
O
N
18
c-Hex
85
N
N
PMB
CN
CN
21
21a
a Reaction conditions: enamide (0.5–0.7 mmol), Tf2O (1.1 equiv), 2-ClPyr (1.2 equiv), nitrile (1.1–2.0 equiv), CH2Cl2 (0.12 M), –78 °C (5 min)
to 0 °C (5 min) to 25 °C (5–60 min).
b Isolated yield.
tered, and concentrated. The resulting residue was purified by flash
column chromatography (0 → 60% EtOAc–heptanes) to afford 18
as a light yellow oil (5.2 g 76%). FTIR (neat): 2931, 2835, 2365,
As with most synthetic methodologies, there are limita-
tions with this process. A potential drawback with respect
to the N-vinyl tertiary enamide synthesis is that the use of
nonsymmetrical ketones with accessible a-protons will
give rise to a thermodynamic mixture of regioisomeric
enamides. This can, however, be advantageous in a me-
dicinal-chemistry setting in exploring structure–activity
relationships. A second limitation is that reaction partners
possessing basic nitrogen moieties predominantly give
unsatisfactory yields. This can potentially be overcome
(entry 17, Table 1) by protecting the nitrogen as a carba-
mate (N-Cbz, N-Alloc, and N-Troc provide the best re-
sults).
1
1632, 1582, 1511, 1396, 1281, 1175, 1103, 1032 cm–1. H NMR
(400 MHz, CDCl3): d = 8.53 (s, 1 H), 7.81 (dd, J = 8.2, 2.4 Hz, 1 H),
7.37–7.20 (m, 3 H), 6.85 (d, J = 8.7 Hz, 2 H), 5.27 (s, 1 H), 4.74 (s,
2 H), 3.80 (s, 3 H), 1.97–1.79 (m, 4 H), 1.51 (dd, J = 8.8, 2.9 Hz, 2
H), 1.39 (dt, J = 5.6, 4.7 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
d = 166.7, 159.12, 152.3, 148.7, 138.3 (2 C), 131.9, 130.2 (2 C),
130.0, 129.5, 123.7, 113.9 (2 C), 55.3, 50.0, 29.0, 24.8, 22.6, 21.3.
HRMS (ES): m/z calcd for C20H21ClN2O2H+ [M + H+]: 357.1370;
found: 357.1370.
N-Cyclohexenyl-N-(4-methoxybenzyl)furan-3-carboxamide
(13, Table 1)
To a mixture of cyclohexanone (0.361 mL, 3.48 mmol, 1.0 equiv)
and 4-methoxybenzylamine (0.455 mL, 3.48 mmol, 1.0 equiv) in
CH2Cl2 (14 mL, 0.25 M) was added Ti(OEt)4 (3.61 mL, 17.4 mmol,
5.0 equiv), and the reaction mixture was stirred at 42 °C for 12 h
with a reflux condenser. After cooling the mixture to 0 °C, Et3N
(0.898 mL, 6.44 mmol, 1.85 equiv), and furan-3-carbonyl chloride
(0.500 g, 3.83 mmol, 1.10 equiv) were added. After stirring for 10
min at 0 °C the reaction mixture was warmed to r.t. and stirred until
complete by LC-MS. Upon completion, H2O (5 mL) was added and
the resulting slurry was filtered through Celite®. The filter cake was
washed with CH2Cl2 (2 × 5 mL). The combined organic extract was
washed with sat. aq NH4Cl solution (5 mL), dried (Na2SO4), fil-
tered, and concentrated. The resulting residue was purified by flash
In conclusion, we have expanded upon a synthetic method
recently developed by Movassaghi and co-workers that
provides expedient access to functionalized cycloalkyl
fused pyrimidines in good to excellent yields. Advantages
to this complementary approach include the following:
the ability to readily synthesize a wide range of starting
materials in a simple and efficient one-pot procedure,
mild reaction conditions that tolerate most functional
groups, short reaction times, and generation of saturated
fused pyrimidines, which are synthetically challenging
targets. Utilization of this methodology for the construc-
tion of novel and medicinally active therapeutics has been column chromatography (0 → 25% EtOAc–heptanes) to afford 13
described and will be further reported in the near future.16
as a light yellow solid (684 mg 63%); mp: 67 °C. FTIR (neat): 2920,
2837, 2363, 1607, 1584, 1504, 1404, 1245, 1230, 1174, 1162, 1035
cm–1. 1H NMR (500 MHz, CDCl3): d = 7.83 (s, 1 H), 7.33 (m, 1 H),
7.26 (d, J = 10.0 Hz, 2 H), 6.83 (d, J = 10.0 Hz, 2 H), 6.70 (m, 1 H),
5.50 (br s, 1 H), 4.70 (s, 2 H), 3.79 (s, 3 H), 2.07–2.04 (m, 2 H),
2.00–1.90 (m, 2 H), 1.65–1.59 (m, 2 H), 1.56–1.50 (m, 2 H). 13C
NMR (125 MHz, CDCl3): d = 162.8, 159.0, 145.4, 142.4, 139.0,
130.4 (2 C), 130.3, 128.7, 122.5, 113.8 (2 C), 111.3, 55.4, 50.8,
28.7, 25.0, 22.9, 21.5. HRMS (ES): m/z calcd for C19H21NO3H+ [M
+ H+] 312.1600; found: 312.1636.
6-Chloro-N-cyclohexenyl-N-(4-methoxybenzyl)nicotinamide
(18, Table 1)
To a mixture of cyclohexanone (2.0 mL, 19 mmol, 1.0 equiv) and
4-methoxybenzylamine (2.5 mL, 19 mmol, 1.0 equiv) in CH2Cl2
(76 mL, 0.25 M) was added crushed, flame-dried 4 Å MS (5 weight
equiv), and the reaction mixture was stirred at 42 °C for 12 h in a
sealed tube. After cooling the mixture to 0 °C, Et3N (4.98 mL, 35.7
mmol, 1.85 equiv) and 6-chloronicotinoyl chloride (3.74 g, 21.2
mmol, 1.10 equiv) were added. After stirring for 10 min at 0 °C the
reaction mixture was warmed to r.t. and stirred until complete by
LC-MS. Upon completion, H2O (20 mL) was added, and the result-
ing slurry was filtered through Celite®. The filter cake was washed
with CH2Cl2 (2 × 10 mL). The combined organic extract was
washed with sat. aq NH4Cl solution (20 mL), dried (Na2SO4), fil-
4-(Cyclopropylmethyl)-2-(furan-2-yl)-5,6,7,8-tetrahydro-
quinazoline (14a, Table 1)
Trifluoromethanesulfonic anhydride (0.119 mL, 0.706 mmol, 1.10
equiv) was added dropwise over 1 min to a stirred mixture of N-cy-
clohexenyl-N-(4-methoxybenzyl)furan-2-carboxamide (14, 0.200
g, 0.642 mmol, 1.00 equiv), 2-cyclopropylacetonitrile (0.119 mL,
Synlett 2011, No. 16, 2387–2391 © Thieme Stuttgart · New York

LETTER
Pyrimidines from Readily Accessible N-Vinyl Enamides
2391
1.28 mmol, 2.00 equiv), and 2-chloropyridine (0.073 mL, 0.771
mmol, 1.20 equiv) dissolved in CH2Cl2 (5.35 mL, 0.12 M) at –78 °C.
After 5 min, the reaction mixture was warmed to 0 °C for 5 min and
then to r.t. until completion by LC-MS (5 min). The mixture was
then quenched with 1 N NaOH (5 mL), separated, and the aqueous
phase extracted with CH2Cl2 (2×). The combined organic extract
was dried (Na2SO4), filtered, and concentrated. The resulting resi-
due was purified by flash column chromatography (0 → 15%
EtOAc–heptanes) to afford 14a as a light yellow solid (148 mg,
91%); mp 107 °C. FTIR (neat): 2935, 1585, 1548, 1489, 1422,
(5) For the use of Ti(OEt)4 as a Lewis acid and water scavenger,
see: (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.;
Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (b) Cogan,
D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(c) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.;
Fanelli, D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
(6) Imase, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett.
2008, 10, 3563.
(7) For the synthesis of tri- and tetrasubstituted pyrimidines
from the nucleophilic addition of two equivalents of nitriles
to activated ketones, see: Martínez, A. G.; Fernández, A. H.;
Fraile, A. G.; Subramanian, L. R.; Hanack, M. J. Org. Chem.
1992, 57, 1627.
(8) For the synthesis of bicyclic 4-aminopyrimidines from the
reaction of dinitriles with mononitriles, see: Chercheja, S.;
Simpson, J. K.; Lam, H. W. Tetrahedron 2011, 67, 3839.
(9) Spectroscopic studies and experiments with carbocation
scavengers (thioanisole, triethylsilane, etc.) were
unsuccessful in identifying the PMB-containing side
product.
(10) For detailed studies involving the activation of amides with
trifluoromethanesulfonic anhydride and pyridine, see:
(a) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79,
1694. (b) Charette, A. B.; Mathieu, S.; Martel, J. Org. Lett.
2005, 7, 5401.
1
1385, 1019 cm–1. H NMR (400 MHz, CDCl3): d = 7.57 (s, 1 H),
7.23 (d, J = 3.3 Hz, 1 H), 6.51 (dd, J = 3.4, 1.7 Hz, 1 H), 2.91 (t,
J = 5.7 Hz, 2 H), 2.71 (t, J = 5.7 Hz, 2 H), 2.66 (d, J = 6.7 Hz, 2 H),
1.89–1.82 (m, 4 H), 1.20–1.13 (m, 1 H), 0.53–0.49 (m, 2 H), 0.28–
0.24 (m, 2 H). 13C NMR (100 MHz, CDCl3): d = 168.4, 165.5,
154.8, 153.0, 144.4, 125.5, 112.1, 112.0, 38.9, 32.9, 25.0, 22.8,
22.4, 9.6, 4.8 (2 C). HRMS (ES): m/z calcd for C16H18N2OH+ [M +
H+]: 255.1499; found: 255.1468.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(11) Temperature-controlled experiments were performed with a
Bruker 500 MHz, Avance III spectrometer with a 5 mm
Bruker PABBO cryoprobe with data collection at –70 °C,
–40 °C, –20 °C, 0 °C, and 30 °C.
(12) Medley, J. W.; Movassaghi, M. J. Org. Chem. 2009, 74,
1341.
We thank Alan Deese, Steve Huhn, Baiwei Lin, Chris Hamman,
and Mengling Wong for analytical support. We also thank Zach
Sweeney and Travis Remarchuk for helpful suggestions regarding
the preparation of this manuscript.
(13) Successful formation of saturated fused pyrimidine products
can also be achieved in the absence of 2-chloropyridine,
although longer reaction times are required (4–72 h) and
lower yields (10–15% loss) are typically obtained.
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see: Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455.
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Synlett 2011, No. 16, 2387–2391 © Thieme Stuttgart · New York

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