Cycloadditions of 1,2,3-Triazines Bearing C5-Electron Donating Substituents: Robust Pyrimidine Synthesis

Article abstract of DOI:10.1021/acs.orglett.5b01870

The examination of the cycloaddition reactions of 1,2,3-triazines 17-19, bearing electron-donating substituents at C5, are described. Despite the noncomplementary 1,2,3-triazine C5 substituents, amidines were found to undergo a powerful cycloaddition to p

Full text of DOI:10.1021/acs.orglett.5b01870

Letter
pubs.acs.org/OrgLett
Cycloadditions of 1,2,3-Triazines Bearing C5-Electron Donating
Substituents: Robust Pyrimidine Synthesis
Christopher M. Glinkerman and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: The examination of the cycloaddition reactions of
1,2,3-triazines 17−19, bearing electron-donating substituents at C5,
are described. Despite the noncomplementary 1,2,3-triazine C5
substituents, amidines were found to undergo a powerful cyclo-
addition to provide 2,5-disubstituted pyrimidines in excellent yields
(42−99%; EDG = SMe > OMe > NHAc). Even select ynamines and
enamines were capable of cycloadditions with 17, but not 18 or 19, to provide trisubstituted pyridines in modest yields (37−40%
and 33% respectively).
defining the scope of the 1,2,3-triazine cycloaddition reactions,
he inverse electron demand Diels−Alder reaction of
Telectron-deficient heterocyclic azadienes is a highly these studies have also found application in the total syntheses
of (−)-pyrimidoblamic acid and P-3A13 as well as the late-stage
effective method for the synthesis of challenging heterocyclic
ring systems.1 In efforts that have expanded the range of
heterocycles accessible by this powerful cycloaddition strategy,
divergent total syntheses of dihydrolysergic acid, dihydroly-
sergol, and a series of heterocyclic derivatives.14
Perhaps the most remarkable of the cycloaddition reactions
of 1,2,3-triazines and the most effective of those examined to
date is their reactions with amidines to provide pyrimidines.
The efficiency and robust nature of these reactions led to our
further study of 1,2,3-triazines that contain electron-donating
groups at C5. It was expected that this modification would
decrease the overall reactivity of the 1,2,3-triazines, perhaps
even to the point of preventing the anticipated cycloaddition
chemistry. Herein, we show that while such substituents do
slow the rate of reaction of the 1,2,3-triazines, their reaction
with amidines remained remarkably effective, providing the
product pyrimidines in excellent yields. In selected cases, even
less effective dienophiles, such as ynamines and enamines, were
found to be capable of cycloaddition, albeit in more modest
yields.
Three previously unreported 1,2,3-triazines were chosen to
probe the effects of electron-donating substituents on the
reactivity and regioselectivity of the cycloaddition reactions
with amidines, ynamines, and enamines. These 1,2,3-triazines,
5-(methylthio)-1,2,3-triazine (17), 5-methoxy-1,2,3-triazine
(18), and 5-(N-acetylamino)-1,2,3-triazine (19), were selected
to provide a range of electronic effects on which to base an
analysis (Scheme 1).
we have systematically explored the reactions of 1,2,4,5-
tetrazines,2 1,2,4-triazines,3 1,3,5-triazines,4 1,3,4-oxadiazoles,5
and 1,2-diazines.6 Frequently, these methodological studies
were inspired by their use as the key steps in the total synthesis
of complex natural products, providing nonobvious or effective
solutions to the preparation of their core structures.7−10
Additional applications include their reactions with strained
olefins and alkynes as bioorthogonal bioconjugation reagents
because of their extraordinarily efficient and rapid rates of
cycloaddition.11 Recently, our efforts extended to 1,2,3-
triazines, examining the synthesis and cycloaddition reaction
scope of the parent 1,2,3-triazine and a series of 1,2,3-triazines
that contain electron-withdrawing groups at sites where their
electronic impact was both consonant and dissonant to that
innate to the 1,2,3-triazine core (Figure 1).12 In addition to
5-(Methylthio)-1,2,3-triazine (17, ALD00502) was accessed
by the simultaneous deprotonation and lithium−halogen
exchange of commercially available 4-bromopyrazole (8) with
subsequent trapping of the C-lithiate by dimethyl disulfide to
provide pyrazole 11 (91%).15 Subsequent N-amination of 11
Received: June 29, 2015
Figure 1. Previous studies with 1,2,3-triazines.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of 1,2,3-Triazines 17−19
Figure 2. Optimization of the reaction of 17 with amidines.
with monochloramine16 provided a mixture of N-amino
pyrazole 14 and starting 11 (74%, 98% brsm, ∼3.4:1) that
was inseparable by chromatography. Nevertheless, when the
mixture of N-amino pyrazole 14 and pyrazole 11 was treated
with NaIO4 under biphasic oxidative ring expansion con-
ditions,17 5-(methylthio)-1,2,3-triazine (17) (56−74%) was
obtained in good yield and was readily separable from products
derived from pyrazole 11.
Preparation of 5-methoxy-1,2,3-triazine (18, ALD00500) was
achieved starting with 4-methoxypyrazole (12), which was
prepared from 9 in a known three-step sequence (56%
overall).18 This pyrazole 12 was subjected to N-amination
with monochloramine16 (56%) and the subsequent NaIO4
oxidative ring expansion17 to provide 18 in good yield (70−
88%).
served to increase neither the reaction rate nor yield. In fact,
their inclusion was observed to decrease the isolated yield of
cycloaddition products in some cases (Figure 2, entries 4, 5). As
a result, molecular sieves were omitted from the optimized
reaction conditions.
With effective conditions in hand and with use of an
extended reaction time of 24 h, the reaction of 1,2,3-triazine 17
with a wide variety of aliphatic and aryl amidines was explored
(Figure 3). The cycloadditions proceeded smoothly at 40 °C to
The synthesis of 5-(N-acetylamino)-1,2,3-triazine (19) began
with the reduction of commercially available 4-nitropyrazole
(10) (quant.) followed by bisacylation (83%) of 4-amino-
pyrazole and subsequent monodeacylation (94%) to provide
13.19 While it is reported that 4-aminopyrazole can be
monoacylated selectively (vs N1),20 doing so was found to be
challenging, frequently providing mixtures of des-, mono-, and
bisacylation products in our hands. N-Amination of pyrazole 13
with monochloramine16 provided the penultimate substrate 16
in good yield (62%). Oxidative ring expansion under biphasic
conditions17 generates 1,2,3-triazine 19, but the solubility of the
compound did not allow its extraction from the aqueous phase.
As such, a new monophasic protocol, utilizing NaIO4 in
acetonitrile under sonication, was developed and optimized to
provide a modest yield (34%) of 5-(N-acetylamino)-1,2,3-
triazine (19).
Based on previous studies,12 it was expected that the
reactions of 1,2,3-triazines 17−19 with free-based amidines
would proceed with a C4/N1 regioselectivity to furnish
symmetrical pyrimidine products. The electron-donating
substituents raise the LUMOdiene relative to 1,2,3-triazine and
suggest they should slow or even preclude the cycloaddition
reaction (reactivity: MeS > MeO > AcNH). Initial studies with
17 revealed that reactions at 25 °C typically required 24−90 h
to achieve full consumption of the limiting reagent, but that
product pyrimidine was produced even under such mild
reaction conditions (Figure 2, entries 1, 2). Although increases
in reaction time provided further yield improvements (Figure 2,
entry 3), simply warming the reactions in which the amidine
was the limiting reagent at 40 °C provided acceptable reaction
times and superb isolated yields (Figure 2, entry 4). Since the
most valuable component of the reactions is likely to be the
amidine, further studies focused on a reaction stoichiometry of
1.0 equiv of amidine and 1.5 equiv of 1,2,3-triazine.
Figure 3. Reaction of 1,2,3-triazine 17 with amidines.
afford the 2-substituted-5-(methylthio)pyrimidines in excellent
yields (generally >90%). Qualitatively, the relative reaction
rates tracked with the amidine electronic character, with the
electron-rich amidines (e.g., 20j) reacting most rapidly (ca. 2 h)
and the electron-poor amidines (e.g., 20b and 20e) requiring
the full 24 h to achieve comparable conversions. Even the
sterically encumbered amidine 20k provided a superb
conversion to pyrimidine 21k.
With 5-methoxy-1,2,3-triazine (18), the reaction rate
decreased and a reoptimization of the reaction temperature
was conducted. It was determined that a reaction temperature
of 90 °C was effective in promoting the cycloaddition in high
yields (42−97%) over a convenient time frame (24 h) (Figure
4). Consistent with observations made with 1,2,3-triazine 17,
the rate of cycloaddition of 18 tracked closely with the
electronic character of the amidine and those bearing aromatic
Finally, although not extensively examined and unlike
previously disclosed examples, the inclusion of molecular sieves
B
DOI: 10.1021/acs.orglett.5b01870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 6. Reaction of 1,2,3-triazines with 15N-labeled amidines.
Figure 4. Reaction of 1,2,3-triazine 18 with amidines.
We also examined the reactivity of 17−19 toward other
candidate dienophiles including ynamines and enamines. Since
both classes are less reactive in their cycloaddition reactions
with 1,2,3-triazines than amidines, it was anticipated that their
cycloadditions might be difficult to promote. An extensive
survey of the reaction conditions for both ynamines and
enamines was undertaken and included the exploration of the
solvent, reaction time, temperature, additives, concentration,
and stoichiometry. In the case of ynamines, the optimal
reaction conditions identified were modestly effective in
promoting the cycloaddition reaction of 1,2,3-triazine 17
(37−40%), providing the product of cycloaddition across
C4/N1, whereas the 1,2,3-triazines 18 and 19 failed to react to
an appreciable extent (Figure 7). Similarly, the cycloaddition
reaction of selected enamines were only moderately effective in
the case of 1,2,3-triazine 17 (33%) (Figure 7).
substituents generally provided higher yields of the 2-
substituted-5-methoxypyrimidines than those bearing aliphatic
substituents.
The introduction of a C5 N-acetylamino substituent resulted
in a further decrease in reaction rate with 19, which required
reexamination of the reaction parameters. Unlike 1,2,3-triazine
18, further increasing the reaction temperature was ineffective.
Instead, extended reaction times (72 h) at 90 °C were found to
afford moderate to good isolated yields (43−79%) of the
pyrimidine products (Figure 5).
Figure 5. Reaction of 1,2,3-triazine 19 with amidines.
Figure 7. Reaction of 17 with ynamines and enamines.
It is possible, even likely, that the reactions of amidines with
1,2,3-triazines represent stepwise addition−cyclization reactions
proceeding through polar intermediates, although we have not
yet detected such intermediates or isolated intercepted
products diagnostic of their intermediacy. As a result, we
conducted the reaction of 1,2,3-triazines 17 and 4 (ALD00106)
with amidine 15N-20g doubly labeled with 15N. Each reaction
produced the pyrimidine product in superb yields (97−98%),
and each was generated with incorporation of a single 15N label
(Figure 6). This is consistent with a single-step cycloaddition,
and while not ruling out stepwise addition−cyclization
mechanisms, the latter would have been expected to provide
at least mixtures of singly and doubly 15N labeled pyrimidine
products perhaps even favoring the doubly labeled product.
A detailed study of the cycloaddition reactions of 1,2,3-
triazines bearing C5 electron-donating groups was conducted.
Despite the unfavorable electronic effects of the substituents,
1,2,3-triazines 17−19 were found to participate in a powerful
cycloaddition with a wide variety of amidines (reactivity: 17 >
18 > 19), providing the corresponding pyrimidines in excellent
yields (42−99%). Remarkably, 1,2,3-triazine 17, but not 18 and
19, was even capable of reaction with a select set of ynamines
and enamines, highlighting the highly reactive nature of the
1,2,3-triazine core. In addition to the intrinsic use of such 1,2,3-
triazine cycloaddition reactions with amidines for the synthesis
of individual substituted pyrimidines, the ability to use virtually
any and all readily accessible substituted 1,2,3-triazines in the
C
DOI: 10.1021/acs.orglett.5b01870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Soc. 1991, 113, 4230. (g) Boger, D. L.; Menezes, R. F.; Honda, T.
Angew. Chem., Int. Ed. Engl. 1993, 32, 273. (h) Boger, D. L.; Honda,
T.; Menezes, R. F.; Colletti, S. L.; Dang, Q.; Yang, W. J. Am. Chem. Soc.
1994, 116, 82. (i) Boger, D. L.; Honda, T. J. Am. Chem. Soc. 1994, 116,
5647. (j) Boger, D. L.; Colletti, S. L.; Honda, T.; Menezes, R. F. J. Am.
Chem. Soc. 1994, 116, 5607. (k) Boger, D. L.; Honda, T.; Dang, Q. J.
Am. Chem. Soc. 1994, 116, 5619. (l) Boger, D. L.; Hong, J.; Hikota, M.;
Ishida, M. J. Am. Chem. Soc. 1999, 121, 2471. (m) Boger, D. L.;
Wolkenberg, S. E. J. Org. Chem. 2000, 65, 9120.
(8) (a) Boger, D. L.; Patel, M. J. Org. Chem. 1988, 53, 1405.
(b) Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418.
(c) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J.
Am. Chem. Soc. 1999, 121, 54. (d) Boger, D. L.; Soenen, D. R.; Boyce,
C. W.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479. (e) Boger,
D. L.; Hong, J. J. Am. Chem. Soc. 2001, 123, 8515. (f) Hamasaki, A.;
Zimpleman, J. M.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2005, 127,
10767. (g) Oakdale, J. S.; Boger, D. L. Org. Lett. 2010, 12, 1132.
(9) (a) Wolkenberg, S. E.; Boger, D. L. J. Org. Chem. 2002, 67, 7361.
(b) Yuan, Q.; Ishikawa, H.; Boger, D. L. Org. Lett. 2005, 7, 741.
(c) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am.
Chem. Soc. 2006, 128, 10596. (d) Ishikawa, H.; Colby, D. A.; Seto, S.;
Va, P.; Tam, A.; Kakei, H.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am.
Chem. Soc. 2009, 131, 4904. (e) Ishikawa, H.; Colby, D. A.; Boger, D.
L. J. Am. Chem. Soc. 2008, 130, 420. (f) Campbell, E. L.; Zuhl, A. M.;
Liu, C. M.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 3009. (g) Sasaki,
Y.; Kato, D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 13533.
(h) Lajiness, J. P.; Jiang, W.; Boger, D. L. Org. Lett. 2012, 14, 2078.
(i) Xie, J.; Wolfe, A. L.; Boger, D. L. Org. Lett. 2013, 15, 868. (j) Lee,
K.; Boger, D. L. J. Am. Chem. Soc. 2014, 136, 3312. (k) Lee, K.; Boger,
D. L. Tetrahedron 2015, 71, 3741.
amidine cycloaddition reaction permits the late-stage divergent
synthesis of a series of substituted pyrimidines from a common
amidine intermediate.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01870.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: boger@scripps.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support of the National
Institutes of Health (D.L.B., CA042056) and the award of an
NSF fellowship (C.M.G.).
REFERENCES
■
(1) (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D. L.
Chem. Rev. 1986, 86, 781. (c) Boger, D. L.; Weinreb, S. M. Hetero
Diels−Alder Methodology in Organic Synthesis; Academic: San Diego,
1987.
(10) (a) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc.
(2) (a) Carboni, R. A.; Lindsey, R. V. J. Am. Chem. Soc. 1959, 81,
4342. (b) Sauer, J.; Wiest, H. Angew. Chem., Int. Ed. Engl. 1962, 1, 269.
(c) Boger, D. L.; Panek, J. S. Tetrahedron Lett. 1983, 24, 4511.
(d) Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D. J. Org.
Chem. 1984, 49, 4405. (e) Boger, D. L.; Panek, J. S.; Coleman, R. S.;
Sauer, J.; Huber, F. X. J. Org. Chem. 1985, 50, 5377. (f) Boger, D. L.;
Sakya, S. M. J. Org. Chem. 1988, 53, 1415. (g) Sakya, S. M.; Groskopf,
K. K.; Boger, D. L. Tetrahedron Lett. 1997, 38, 3805. (h) Boger, D. L.;
Schaum, R. P.; Garbaccio, R. M. J. Org. Chem. 1998, 63, 6329.
(i) Soenen, D. R.; Zimpleman, J. M.; Boger, D. L. J. Org. Chem. 2003,
68, 3593. (j) Hamasaki, A.; Ducray, R.; Boger, D. L. J. Org. Chem.
2006, 71, 185.
(3) (a) Steigel, A.; Sauer, J. Tetrahedron Lett. 1970, 11, 3357.
(b) Neunhoeffer, H.; Fruhauf, H.−W. Leibigs Ann. Chem. 1972, 758,
120. (c) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179.
(d) Boger, D. L.; Panek, J. S.; Meier, M. M. J. Org. Chem. 1982, 47,
3763. (f) Boger, D. L.; Panek, J. S. Tetrahedron Lett. 1984, 25, 3175.
(4) (a) Neunhoeffer, H.; Bachmann, M. Chem. Ber. 1975, 108, 3877.
(b) Boger, D. L.; Schumacher, J.; Panek, J. S.; Mullican, M. D.; Patel,
M. J. Org. Chem. 1982, 47, 2673. (c) Boger, D. L.; Dang, Q.
Tetrahedron 1988, 44, 3379. (d) Boger, D. L.; Dang, Q. J. Org. Chem.
1992, 57, 1631. (e) Boger, D. L.; Kochanny, M. J. J. Org. Chem. 1994,
59, 4950.
(5) (a) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc.
2002, 124, 11292. (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B. S. J.;
Ishikawa, H.; Yuan, Z.−Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128,
10589.
(6) (a) Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 1973,
437. (b) Boger, D. L.; Coleman, R. S. J. Org. Chem. 1984, 49, 2240.
(c) Kessler, S. N.; Wegner, H. A. Org. Lett. 2010, 12, 4062.
(d) Sumaria, C. S.; Tuerkmen, Y. E.; Rawal, V. H. Org. Lett. 2014, 16,
3236.
1993, 115, 10733. (b) Boger, D. L.; Huter, O.; Mbiya, K.; Zhang, M. J.
̈
Am. Chem. Soc. 1995, 117, 11839. (c) Boger, D. L.; Hong, J. J. Am.
Chem. Soc. 1998, 120, 1218. (d) Boger, D. L.; Ichikawa, S.; Jiang, H. J.
Am. Chem. Soc. 2000, 122, 12169. (e) Blagg, B. S. J.; Boger, D. L.
Tetrahedron 2002, 58, 6343. (f) Schnermann, M. J.; Boger, D. L. J. Am.
Chem. Soc. 2005, 127, 15704.
(11) (a) Blackman, M. L.; Royzen, M.; Fox, J. M. J. Am. Chem. Soc.
2008, 130, 13518. (b) Devaraj, N. K.; Weissleder, R.; Hilderbrand, S.
A. Bioconjugate Chem. 2008, 19, 2297.
(12) (a) Anderson, E. D.; Boger, D. L. Org. Lett. 2011, 13, 2492.
(b) Anderson, E. D.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 12285.
(c) Anderson, E. D.; Duerfeldt, A. S.; Zhu, K.; Glinkerman, C. M.;
Boger, D. L. Org. Lett. 2014, 16, 5084.
(13) Duerfeldt, A. S.; Boger, D. L. J. Am. Chem. Soc. 2014, 136, 2119.
(14) Lee, K.; Poudel, Y.; Glinkerman, C. M.; Boger, D. L.
Tetrahedron 2015, http://dx.doi.org/10.1016/j.tet.2015.05.093.
(15) Ahn, K.; Boehm, M.; Cabral, S.; Carpino, P. A.; Futatsugi, K.;
Hepworth, D.; Dung, D. W.; Orr, S.; Wang, J. Diacylglycerol
Acyltransferase 2 Inhibitors. WO 2013/150416 A1, October 10, 2013.
(16) Hynes, J.; Doubleday, W. W.; Dyckman, A. J.; Godfrey, J. D.;
Grosso, J. A.; Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69, 1368.
(17) (a) Itoh, T.; Ohsawa, A.; Okada, M.; Kaihoh, T.; Igeta, H. Chem.
Pharm. Bull. 1985, 33, 3050. (b) Itoh, T.; Okada, M.; Nagata, K.;
Yamaguchi, K.; Ohsawa, A. Chem. Pharm. Bull. 1990, 38, 2108.
(18) Oslob, J.; McDowell, R.; Johnson, R.; Yang, H.; Evanchik, M.;
Haria, C.; Cai, H.; Hu, L. Heterocyclic Modulators of Lipid Synthesis.
WO 2014/008197 A1, January 9, 2014.
(19) (a) Harrison, R.; Ramsden, N.; Major, J.; Morel, A.; Convery,
L.; Sunose, M.; Lynch, R.; Adrego, R.; Jones, A. Heterocyclyl
Pyrimidine Analogues as TYK2 Inhibitors. WO 2013/174895 A1,
November 28, 2013. (b) Giles, D.; Parnell, E.; Renwick, J. J. Chem. Soc.
C 1966, 1179. (c) Lu, Y.; Kraatz, H. Inorg. Chim. Acta 2004, 357, 159.
(20) Linnanen, T.; Wohlfahrt, G.; Nanduri, S.; Ujjin-Amatada, R.;
Rajagopalan, S.; Mukherjee, S. Protein Kinase Inhibitors. WO 2013/
053983 A1, April 18, 2013.
(7) (a) Boger, D. L.; Panek, J. S. J. Am. Chem. Soc. 1985, 107, 5745.
(b) Boger, D. L.; Panek, J. S.; Duff, S. R.; Yasuda, M. J. Org. Chem.
1985, 50, 5790. (c) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J.
Org. Chem. 1985, 50, 5782. (d) Boger, D. L.; Coleman, R. S. J. Am.
Chem. Soc. 1987, 109, 2717. (e) Boger, D. L.; Coleman, R. S. J. Am.
Chem. Soc. 1988, 110, 4796. (f) Boger, D. L.; Zhang, M. J. Am. Chem.
D
DOI: 10.1021/acs.orglett.5b01870
Org. Lett. XXXX, XXX, XXX−XXX