Dehydrosulfurative C-N Cross-Coupling and Concomitant Oxidative Dehydrogenation for One-Step Synthesis of 2-Aryl(alkyl)aminopyrimidines from 3,4-Dihydropyrimidin-1H-2-thiones

Article abstract of DOI:10.1021/acs.orglett.6b02617

A method for the synthesis of 2-aryl(alkyl)aminopyrimidines from readily available 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative C-N cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system is described. This reaction protocol provides unprecedented diversity of fully substituted 2-aryl(alkyl)aminopyrimidines in a single step from a wide range of DHPMs and amine coupling partners.

Full text of DOI:10.1021/acs.orglett.6b02617

Letter
pubs.acs.org/OrgLett
Dehydrosulfurative C−N Cross-Coupling and Concomitant Oxidative
Dehydrogenation for One-Step Synthesis of
2‑Aryl(alkyl)aminopyrimidines from 3,4-Dihydropyrimidin‑1H‑2-
thiones
Nguyen Huu Trong Phan,† Hyeji Kim,† Hyunik Shin,‡ Hee-Seung Lee,§ and Jeong-Hun Sohn*,†
†Department of Chemistry, College of Natural Sciences, Chungnam National University, Dajeon 305-706, Korea
‡Yonsung Fine Chemicals R&D Center, Suwon 443-380 Korea
§Department of Chemistry, KAIST, Daejeon 305-701 Korea
S
* Supporting Information
ABSTRACT: A method for the synthesis of 2-aryl(alkyl)-
aminopyrimidines from readily available 3,4-dihydropyrimidin-
1H-2-thiones (DHPMs) via dehydrosulfurative C−N cross-
coupling and concomitant oxidative dehydrogenation under a
Pd/Cu catalytic system is described. This reaction protocol
provides unprecedented diversity of fully substituted 2-aryl-
(alkyl)aminopyrimidines in a single step from a wide range of
DHPMs and amine coupling partners.
he 2-aryl(alkyl)aminopyrimidine motifs are embedded as a
privileged substructure and a key binding fragment toward
targets in many important drugs, such as the hypocholester-
olemic agent rosuvastatin (Crestor)1 and the potent anticancer
drug imatinib (Gleevec)2 (Figure 1). They have also been proven
Organosulfur compounds have become increasingly impor-
tant as promising electrophilic coupling partners in transition-
metal-catalyzed C−C coupling reactions. In particular, Pd-
catalyzed/Cu-mediated Liebeskind−Srogl dehydrosulfurative
C−C cross-coupling of thioamide, thiourea, or thiourethane
fragments containing latent free thiol functionalities with
nucleophilic organometallic reagents or terminal alkynes has
attracted much attention in synthetic organic chemistry.7−9 The
success of these reaction protocols led us to envision
dehydrosulfurative C−N cross-coupling of DHPMs with aryl
or alkylamines. To the best of our knowledge, no reports have
been published describing the employment of a thiono (latent
free thiol) group as a leaving group of the electrophilic coupling
partner in C−N cross-coupling reactions.10 Recently, we
developed a Cu-catalyzed oxidative dehydrogenation reaction
of 2-alkylthiodihydropyrimidines to produce 2-alkylthiopyrimi-
dines,11 which was applied to the cascade reaction for the
conversion of DHPMs to 2-arylthiopyrimidines via C−S cross-
coupling and oxidative dehydrogenation.12 We envisaged a
possible one-pot reaction method combining the dehydrosulfur-
ative C−N cross-coupling of DHPM with amine and oxidative
dehydrogenation using a Pd/Cu catalytic system. Since the
oxidative dehydrogenation of 2-alkylthiopyrimidines worked
best under air, we thought that the reaction of the
dehydrosulfurative C−N cross-coupling of DHPM 1 with
amine under argon, followed by oxidative dehydrogenation
under air, could provide a one-pot synthesis of the target 2
(Scheme 1). Due to the simple preparation of DHPM substrates
T
Figure 1. Structures of rosuvastatin and imatinib.
to trigger the inhibition of protein kinases or receptors in many
development candidates.3 Despite their biological importance,
the synthetic strategy toward these compounds is limited in
scope and generality, especially for the rapid generation of a
diverse range of such compounds. Usually, the fully substituted 2-
aryl(akyl)aminopyrimidines are obtained by nucleophilic
aromatic substitution or metal-catalyzed C−N cross-coupling
of pyrimidines containing halides or other leaving groups at the
C2 position with amines, most of which require synthesis of
pyrimidine partners in multiple steps from 3,4-dihydropyrimi-
din-1H-2-thiones (DHPMs) or related starting materials.4−6
Herein, we report a one-step synthesis of fully substituted 2-
aryl(alkyl)aminopyrimidines from DHPMs via dehydrosulfur-
ative C−N cross-coupling and concomitant oxidative dehydro-
genation under a Pd/Cu catalytic system.
Received: August 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02617
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Organic Letters
Letter
Scheme 1. Plan for the One-Pot Synthesis of Fully Substituted
2-Aryl(alkyl)aminopyrimidines from DHPMs
Table 1. Optimization of Reaction Conditions
b
entry
[Pd]
[Cu]
CuI
base
solvent
yield (%)
1
2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
22
20
trace
33
66
68
70
78
55
72
78
53
93
0
CuBr
DMF
3
Cu(OAc)2
CuI/CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
DMF
possessing diverse substituents at C4−C6 using the Biginelli
three-component reaction with versatile β-ketoesters, aldehydes,
and thiourea,13 the reaction method could provide a shortcut to
diverse fully substituted 2-aryl(alkyl)aminopyrimidines.
The initial studies were carried out with DHPM 1a (0.18
mmol) and aniline (2.0 equiv) in the presence of Pd(PPh3)4 (20
mol %), Cu(I)-thiophene-2-carboxylate (CuTC, 3.0 equiv), and
K2CO3 (4.0 equiv) in DMF (2.0 mL) at 100 °C for 18 h under Ar
to detect intermediate I. Interestingly, the reaction afforded only
pyrimidine 2a4b in 70% yield, without any observation of the
expected product I under Ar (Scheme 2). The reaction
4
DMF
5
DMF
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMF
7
dioxane
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
8
9
10
11
12
13
14
15
16
17
18
19
20
Cs2CO3
tBuONa
Et3N
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
c
Scheme 2. Initial Result of the Reaction
CuTC
CuTC
CuTC
CuTC
CuTC
58
d
85
e
35
f
82
g
90
a
Reaction conditions: 1a (0.18 mmol), PhNH2 (0.36 mmol), [Pd] (20
mol %), [Cu] (0.54 mmol), t-BuONa, LiHMDS (1.5 equiv) or other
base (4.0 equiv), and solvent (2.0 mL) at 100 °C for 18 h under Ar.
b
c
d
Isolated yield. With 5 mol % of Pd(OAc)2. With 10 mol % of
e
f
g
conditions under air produced messy results and provided 2a
in less than 10% yield. This led us to perform further
optimization studies under argon without any consideration of
the aerobic conditions for the oxidative dehydrogenation (Table
1).
Pd(OAc)2. With 1.5 equiv of CuTC. At 80 °C Reflux conditions.
results. Halide groups F, Cl, and I gave the desired products 2d,
2e,4h and 2f,4h respectively, in 78−95% yields, and other
electron-withdrawing groups such as nitro and cyano groups
yielded 2g4h (77%) and 2h4h (94%), respectively. Heterobicyclic
8-aminoquinoline was also suitable as a reaction partner to
produce 2i in 58% yield. We observed that the steric hindrance of
the functional group in an arylamine significantly affected the
reaction under the optimal reaction conditions. For example, the
reaction with sterically hindered o-methylaniline gave 2j4h in only
16% yield. After examining literature precedents on desulfurative
cross-couplings, we found that reaction conditions including
TBSCl and Pd(PPh3)4 instead of Pd(OAc)2 improved the
reaction yield in the production of 2j (65%).14 When the reaction
conditions were applied to bicyclic aminonaphthalenes and
heterocyclic aminopyridine, the desired products 2k−m6a were
produced in 51−58% yields. Aliphatic amines were also
investigated as the coupling partners and gave the desired
products in 70−75% (2n,o4e) and 49% (2p4e) yields for 1° and
2° amines, respectively, when PdCl2 and ligand P(o-toyl)3 were
used.
With respect to the Cu source, CuTC was found to be superior
to other Cu(I) or Cu(II) salts, such as CuI, CuBr, Cu(OAc)2, or a
mixture of CuI/CuTC (1:1) (entries 1−4). When Pd(OAc)2 and
PdCl2 were used, yields similar to those with Pd(PPh3)4 were
obtained (entries 5 and 6). Although Pd(PPh3)4 afforded a
slightly higher yield, Pd(OAc)2 was chosen for further
optimization due to its higher stability, lower price, and easier
isolation of the desired product. Regarding solvents, PhCH3 was
found to be more effective than other solvents such as DMF or
dioxane (entries 6−8). With respect to the base, the desired
product was also observed in the absence of a base (entry 9), but
a base was shown to be an important factor for increasing the
yield of the reaction. LiHMDS gave the product in 93% yield and
was shown to be better than other bases such as K2CO3, Cs2CO3,
Et3N, and t-BuONa (entries 8 and 10−13). No desired product
was obtained in the absence of either a Pd source or a Cu source
(entries 14 and 15), and less Pd(OAc)2 or CuTC reduced the
yield of the reaction (entries 16−18). Varying the reaction
temperature did not improve the reaction yield (entries 19 and
20).
For the reaction scope with respect to the DHPM substrates,
we performed the reaction with various substituents at C4−C6 in
the DHPMs 1 (Figure 3). We observed that Et, i-Pr, and t-Bu for
R1 afforded the corresponding products in good yields (3a−e15).
However, t-Bu exhibited the lowest yield, which might have been
Under optimal conditions, the reaction scope was sub-
sequently explored with diverse DHPMs and amines. With
respect to the arylamines, the reaction method was compatible
with a wide range of functional groups (Figure 2). Electron-
donating methyl and methoxy groups afforded the desired
products 2b4h and 2c,4b respectively, in high yields. In the case of
electron-withdrawing groups, the reaction also exhibited good
t
attributable to the decomposition of the CO2 Bu group under the
reaction conditions. Regarding the substituents at C6 (R2), both
aliphatic and aromatic groups were compatible and resulted in
good reaction yields regardless of their steric bulk. The effects of
B
DOI: 10.1021/acs.orglett.6b02617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Scope of the reaction with respect to amine. Reaction
conditions: 1a (0.18 mmol), amine (0.36 mmol), Pd(OAc)2 (20 mol
%), CuTC (0.54 mmol), LiHMDS (0.27 mmol), and solvent (2.0 mL)
Figure 3. Scope of the reaction with respect to DHPM and amine.
Reaction conditions: 1 (0.18 mmol), amine (0.36 mmol), Pd(OAc)2 (20
mol %), CuTC (0.54 mmol), LiHMDS (0.27 mmol), and PhCH3 (2.0
mL) at 100 °C under Ar. Yields are isolated yields. aPdCl2 and P(o-toyl)3
were used.
a
at 100 °C under Ar. Yields are isolated yields. Pd(PPh3)4 and TBSCl
(1.0 equiv) were used. bPdCl2 and P(o-toyl)3 were used.
the substituents at C4 (Ar) were also investigated. Studies of the
electronic effect by varying the para-substituent on the Ar moiety
showed no distinct preference toward either electron-donating
or -withdrawing groups. Electron-donating methyl or methoxy
group delivered the corresponding product, 3f or 3k,
respectively, in excellent yield. Halide groups F, Cl, Br, and I
yielded the desired products (3g−j4h,6a and 3l) in 62−90%
yields, and we did not observe any evidence of the competing
Buchwald−Hartwig amination reaction in these studies. The
electron-withdrawing NO2 group also delivered the desired
product in high yield (3m). Substrates possessing bicycles and
heterocycles at C4, such as 2-naphthyl, 3-pyridinyl, or 2-
thiophenyl groups, were also suitable for the reaction method
(3n,o and 3q). Reactions of some of the above DHMP
compounds with various amine compounds, such as aryl,
heteroaryl, bicyclic amines, and aliphatic morpholine, were
performed to expand the scope of the reaction method. As a
result, all of the reactions produced the desired products in
moderate to good yields (3p and 3r−v).
Dehydrosulfurative C−N cross-coupling and Biginelli reaction
offer diverse 2-amino groups and C4/C6 substituents,
respectively, but diversification of the substituents at C5 is
limited in light of the general synthesis of fully substituted 2-
aminopyrimidine derivatives. For the diversification of C5
substituents, we attempted a decarboxylative arylation reaction16
of the obtained pyrimidinyl ester compound. Hydrolysis of
compound 2a produced the corresponding acid, which was
reacted with PhBr in the presence of PdCl2, CuO, and PPh3 in
NMP at 130 °C for 12 h. As a result, we obtained the desired
product 4 in 61% yield over two steps (Scheme 3).17 Overall, we
Scheme 3. Decarboxylative Arylation at C5 of 2a
showed that the reaction sequence of the Biginelli three-
component reaction followed by dehydrosulfurative C−N cross-
coupling/oxidative dehydrogenation and then decarboxylative
arylation is a highly efficient route for the general synthesis of
fully substituted 2-aminopyrimidines.
In summary, we have developed a reaction method for the one-
step synthesis of the fully substituted 2-aryl(alkyl)-
aminopyrimidines from DHPMs via dehydrosulfurative C−N
cross-coupling and oxidative dehydrogenation using a Pd/Cu
catalytic system.18 The reaction method proceeded efficiently
with a wide range of DHPM and amine coupling partners. The
reaction sequence of the Biginelli three-component reaction
followed by dehydrosulfurative C−N cross-coupling/oxidative
dehydrogenation and then decarboxylative arylation could offer
C
DOI: 10.1021/acs.orglett.6b02617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Wang, X.-C. Tetrahedron 2015, 71, 2113−2118. (b) Gong, H. − P.;
Zhang, Y.; Da, Y. − X.; Zhang, Z.; Quan, Z. − J.; Wang, X. − C. Chin.
Chem. Lett. 2015, 26, 667−671.
simple preparation and diversification of 2-aryl(alkyl)-
aminopyrimidines, which have been used as prominent
substructures of drug molecules.
(7) For Pd-catalyzed/Cu-mediated Liebeskind and Srogl C−C cross-
coupling of thioether-type species with nucleophilic organometallic
reagents, see: (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260−11261. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
2000, 2, 3229. (c) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001,
3, 91−93. (d) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979−981.
(e) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554−3557.
(f) Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2007,
129, 15734−15735. (g) Musaev, D. G.; Liebeskind, L. S. Organometallics
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02617.
■
S
Detailed experimental procedures and characterization
1
data of compounds 2a−p, 3a−v and 4 and their H and
13C NMR spectra (PDF)
́
2009, 28, 4639−4642. For reviews, see: (h) Prokopcova, H.; Kappe, C.
O. Angew. Chem., Int. Ed. 2009, 48, 2276−2286. (i) Wang, L.; He, W.;
Yu, Z. Chem. Soc. Rev. 2013, 42, 599−621.
AUTHOR INFORMATION
Corresponding Author
(8) For the dehydrosulfurative C−C cross-couplings of five- or six-
membered heterocycles possessing thioamide, thiourea, or thiourethane
fragments with boronic acids, stannanes, siloxanes, or terminal alkynes,
see: (a) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771−774.
(b) Prokopcova, H.; Kappe, C. O. J. Org. Chem. 2007, 72, 4440−4448.
■
*E-mail: sohnjh@cnu.ac.kr.
Notes
(c) Silva, S.; Sylla, B.; Suzenet, F.; Tatibouet, A.; Rauter, A. P.; Rollin, P.
̈
The authors declare no competing financial interest.
Org. Lett. 2008, 10, 853−856. (d) Silva, S.; Tardy, S.; Routier, S.;
Suzenet, F.; Tatibouet, A.; Rauter, A. P.; Rollin, P. Tetrahedron Lett.
̈
ACKNOWLEDGMENTS
■
2008, 49, 5583−5586. (e) Arshad, N.; Hashim, J.; Kappe, C. O. J. Org.
Chem. 2009, 74, 5118−5121. (f) Guinchard, X.; Roulland, E. Org. Lett.
2009, 11, 4700−4703. (g) Sun, Q.; Suzenet, F.; Guillaumet, G. J. Org.
Chem. 2010, 75, 3473−3476. (h) Sun, Q.; Suzenet, F.; Guillaumet, G.
Tetrahedron Lett. 2012, 53, 2694−2698.
T h i s w o r k w a s s u p p o r t e d b y N R F g r a n t s
(2014R1A1A4A01007933, 2016R1A2A1A05005509) and the
research fund of Chungnam National University.
(9) For the dehydrosulfurative C−C cross-couplings of mercaptopyr-
REFERENCES
■
imidines with terminal alkynes, see: Maltsev, O. V.; Pothig, A.;
̈
(1) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K.
Bioorg. Med. Chem. 1997, 5, 437−444.
(2) Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nat.
Rev. Drug. Discovery 2002, 1, 493−502.
(3) For selected references, see: (a) Noble, E. M. M.; Endicott, J. A.;
Johnson, L. N. Science 2004, 303, 1800−1805. (b) Cohen, P. Nat. Rev.
Drug Discovery 2002, 1, 309−315. (c) Saklatvala, J. Curr. Opin.
Pharmacol. 2004, 4, 372−377. (d) Traxler, P.; Bold, G.; Buchdunger,
E.; Caravatti, G.; Furet, P.; Manley, P.; O’Reilly, T.; Wood, J.;
Zimmermann, J. Med. Res. Rev. 2001, 21, 499−519. (e) Lagoja, I. M.
Chem. Biodiversity 2005, 2, 1−50. (f) Han, Y. T.; Choi, G. − I.; Son, D.;
Kim, N. − J.; Yun, H.; Lee, S.; Chang, D. J.; Hong, H. − S.; Kim, H.; Ha,
H. − J.; Kim, Y. − H.; Park, H. − J.; Lee, J.; Suh, Y. − G. J. Med. Chem.
2012, 55, 9120−9135.
Hintermann, L. Org. Lett. 2014, 16, 1282−1285.
(10) There have been two reports where Ar−SMe was used as an
electrophilic coupling partner in Pd-catalyzed C−N cross-coupling with
aryl and alkylamines. (a) Sugahara, T.; Murakami, K.; Yorimitsu, H.;
Osuka, A. Angew. Chem., Int. Ed. 2014, 53, 9329−9333. (b) Gao, K.;
Yorimitsu, H.; Osuka, A. Eur. J. Org. Chem. 2015, 2015, 2678−2682.
(11) Phan, N. H. T.; Sohn, J.-H. Tetrahedron 2014, 70, 7929−7935.
(12) (a) Lee, O. S.; Lee, H.; Kim, H.; Shin, H.; Sohn, J. − H.
Tetrahedron 2015, 71, 2936−2944. (b) Lee, O. K.; Kim, H.; Lee, H. − S.;
Shin, H.; Sohn, J. − H. B. Kor. Chem. Soc. 2016, 37, 242−245.
(13) For selected reviews, see: (a) Singh, K.; Singh, K. Adv. Heterocycl.
Chem. 2012, 105, 223−308. (b) Suresh; Sandhu, J. S. ARKIVOC 2012,
66−133. (c) Wan, J.-P.; Liu, Y. Synthesis 2010, 2010, 3943−3953.
(d) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879−888.
(4) For selected examples, see ref 3f. (a) Kang, F. − A.; Kodah, J.;
Guan, Q.; Li, X.; Murray, W. V. J. Org. Chem. 2005, 70, 1957−1960.
(b) Matloobi, M.; Kappe, C. O. J. Comb. Chem. 2007, 9, 275−284.
(c) Wang, X. − C.; Yang, G. − J.; Quan, Z. − J.; Ji, P. − Y.; Liang, J. − L.;
Ren, R. − G. Synlett 2010, 2010, 1657−1660. (d) Wang, X. − C.; Yang,
G. − J.; Jia, X. − D.; Zhang, Z.; Da, Y. − X.; Quan, Z. − J. Tetrahedron
2011, 67, 3267−3272. (e) Singh, K.; Singh, K.; Wan, B.; Franzblau, S.;
Chibale, K.; Balzarini, J. Eur. J. Med. Chem. 2011, 46, 2290−2294.
(f) Singh, K.; Kaur, H.; Chibale, K.; Balzarini, J.; Little, S.; Bharatam, P.
V. Eur. J. Med. Chem. 2012, 52, 82−97. (g) Quan, Z. − J.; Lv, Y.; Wang,
Z. − J.; Zhang, Z.; Da, Y. − X.; Wang, X. − C. Tetrahedron Lett. 2013, 54,
1884−1887. (h) Quan, Z.; Jing, F.; Zhang, Z.; Da, Y.; Wang, X. Chin. J.
Chem. 2013, 31, 1495−1502. (i) Xing, T.; Wei, K. − J.; Quan, Z. − J.;
Wang, X. − C. Synthesis 2015, 47, 3925−3935. (j) Yang, Q.; Quan, Z.;
Wu, S.; Du, B.; Wang, M.; Li, P.; Zhang, Y.; Wang, X. Tetrahedron 2015,
71, 6124−6134. (k) Wei, K. − J.; Quan, Z.; Zhang, Z.; Da, Y.; Wang, X.
Org. Biomol. Chem. 2016, 14, 2395−2398.
(14) (a) Graham, T. H.; Liu, W.; Shen, D. M. Org. Lett. 2011, 13,
6232−6235. (b) Matsumura, T.; Niwa, T.; Nakada, M. Tetrahedron Lett.
2012, 53, 4313−4316.
(15) Jean, J. V. E.; Nadeg
̀
e, L.; Yves, V. H.; Lutz, T. ARKIVOC 2003,
22−28.
(16) For selected reviews, see: (a) Satoh, T.; Miura, M. Synthesis 2010,
2010, 3395−3409. (b) Rodriguez, N.; Goossen, L. Chem. Soc. Rev. 2011,
40, 5030−5048. (c) Weaver, V.; Recio, A., III; Grenning, A. J.; Tunge, J.
A. Chem. Rev. 2011, 111, 1846−1913. (d) Cornella, J.; Larrosa, I.
Synthesis 2012, 44, 653−676.
(17) Optimization of the reaction conditions is currently underway,
and the results will be reported in due course.
(18) For a possible mechanism of the reaction, see the Supporting
Information.
(5) Other strategies to the targets using three-component reaction with
aldehydes, β-ketonitriles, and substituted guanidines lack the efficient
supply of the desired substituted guanidines. Val, C.; Crespo, A.; Yaziji,
V.; Coelho, A.; Azuaje, J.; El Maatougui, A.; Carbajales, C.; Sotelo, E.
ACS Comb. Sci. 2013, 15, 370−378.
(6) The route involving 2-NH2-pyrimidine intermediates for the C−N
cross-coupling to form the targets requires the three-step reaction
sequence for the synthesis of the intermediates from DHPMs.
(a) Zhang, Y.; Quan, Z. − J.; Gong, H. − P.; Da, Y. − X.; Zhang, Z.;
D
DOI: 10.1021/acs.orglett.6b02617
Org. Lett. XXXX, XXX, XXX−XXX