Synthesis of 7-aza-5-deazapurine analogues via copper(I)-catalyzed hydroamination of alkynes and 1-iodoalkynes

Article abstract of DOI:10.1021/jo1016376

A new method for the synthesis of dihydroimidazo[1,2-a][1,3,5]triazin-4(6H) -ones via copper(I)-catalyzed hydroamination was developed. In addition, for the first time, iodoalkynes were shown to participate in the copper(I)-catalyzed intramolecular hydroamination reaction with exclusive formation of E-isomers.

Full text of DOI:10.1021/jo1016376

pubs.acs.org/joc
The construction of imidazo[1,2-a]-s-triazine (1) core can
Synthesis of 7-Aza-5-deazapurine Analogues via
Copper(I)-Catalyzed Hydroamination of Alkynes
and 1-Iodoalkynes
commence from 2-aminoimidazole (2),1c,3a,b 5-azacytosine
(3, X=NH2),3c,d or 1,3,5-triazine heterocycles (3, X=Cl)
(Scheme 1).2a,b,3e,f However, these methodologies have not
proven to be practical due to the low conversions and limited
substrate scope. We envisioned assembling the imidazo-
[1,2-a]-s-triazine ring system via transition-metal-catalyzed
hydroamination of alkynyl triazinones 4,4 which are easily
accessible from cyanuric chloride (5).
Larissa B. Krasnova, Jason E. Hein, and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute,
La Jolla, California 92037, United States
fokin@scripps.edu
SCHEME 1. Synthetic Routes to 7-Aza-5-deazapurines
Received August 18, 2010
First, we examined the effect of different transition metal cata-
lysts on the intramolecular cyclization of triazine 6 as a model
substrate. The results of a focused screen employing group 11
transition metals are presented in Table 1.5 Although gold(I) and
silver(I) salts promoted the reaction at ambient temperature, the
yields were moderate, and long reaction times were required
(entries 1 and 2). In contrast, copper(I) salts were more active
catalysts for the desired intramolecular cyclization (entries
3-11).6 The addition of water increased the yield of the reaction
(cf. entries 3 and 4). The optimal results were obtained when
copper(I) acetylide was generated in situ (entries 9-11).7
The addition of tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine
(TBTA) ligand further improved the efficiency of the reaction
(entry 11).8
A new method for the synthesis of dihydroimidazo[1,2-a]-
[1,3,5]triazin-4(6H)-ones via copper(I)-catalyzed hydro-
amination was developed. In addition, for the first time,
iodoalkynes were shown to participate in the copper(I)-
catalyzed intramolecular hydroamination reaction with
exclusive formation of E-isomers.
A general method for the preparation of 1,3,5-triazine-
2-ones (4) was then investigated. Temperature-controlled se-
quential displacement of chlorines in 5 provides facile access to
substituted 1,3,5-triazines (Scheme 1).9 However, conversion
of less electrophilic intermediates, such as 8, to the corresponding
The unique role that purine and pyrimidine heterocycles
play in biology makes them timeless subjects of research in
disciplines encompassing the fields of organic synthesis,
medicinal chemistry, biotechnology, and materials science.1
Small molecules containing the imidazo[1,2-a]-s-triazine
fragment, which is an analogue of 5-aza-7-deazapurine, have
shown promising activity in the treatment of type 1 diabetes,
rhinovirus infections and against the Flaviviridae family of
viruses.2 Whether the goal is the discovery of compounds
with new biological function or expansion of the genetic
alphabet, a methodology that allows simple and reliable
access to novel purine analogues would be a valuable addi-
tion to these fields. Herein, we report a new approach toward
dihydroimidazo[1,2-a][1,3,5]triazinone derivatives via a cop-
per-catalyzed hydroamination, delivering a practical, scal-
able, and versatile route to these rarely studied heterocycles.
(3) (a) Prisbe, E. J.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1978,
43, 4774–4784. (b) Prisbe, E. J.; Verheyden, J. P. H.; Moffatt, J. G. J. Org.
Chem. 1978, 43, 4784–4794. (c) Nair, V.; Lyons, A. G.; Purdy, D. Tetra-
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Urata, H.; Itoh, M.; Hayashizaki, Y. Tetrahedron Lett. 2007, 48, 3801–3803.
(e) Balasubramanian, K. K.; Bindumadhavan, G. V.; Udupa, M. R.; Krebs,
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Balasubramanian, K. K. Tetrahedron 1985, 41, 111–120.
(4) For recent reviews on transition-metal-catalyzed hydramination of
€
alkynes, see: (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada,
M. Chem. Rev. 2008, 108, 3795–3892. (b) Severin, R.; Doye, S. Chem. Soc.
Rev. 2006, 36, 1407–1420. (c) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem.
2007, 4555–4563.
(5) An expanded screen of catalysts can be found in the Supporting
Information.
(6) For a recent example of a one-pot cascade Mannich-Cu(I)-promoted
hydroamination of alkynes, see: Wang, H.-F.; Yang, T.; Xu, P.-F.; Dixon,
D. J. Chem. Commun. 2009, 3916–3918.
(7) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599.
(8) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853–2855.
(9) For recent reviews on the chemistry of 1,3,5-triazines, see: (a) Blotny,
G. Tetrahedron 2006, 62, 9507–9522. (b) Gamez, P.; Reedijk, J. Eur. J. Inorg.
Chem. 2006, 29–42. (c) Giacomelli, G.; Porcheddu, A.; de Luca, L. Curr. Org.
Chem. 2004, 8, 1497–1519.
(1) (a) Seela, F.; Melenewski, A. Eur. J. Org. Chem. 1999, 485–496. (b)
Seela, F.; Melenewski, A.; Wei, C. Bioorg. Med. Chem. Lett. 1997, 7, 2173–
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8662 J. Org. Chem. 2010, 75, 8662–8665
Published on Web 11/24/2010
DOI: 10.1021/jo1016376
r
2010 American Chemical Society

Krasnova et al.
JOCNote
TABLE 1. Optimization of the Reaction Conditionsa
entry
catalyst
Au(PPh3)Clc
AgNO3
additive
yield,b %
1
2
3
4
5
6
7
8
9
AgBF4 (5 mol %)
44
60
52
64
42
46
60
68
70
82
99
d
e
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
1
CuOTf ꢀ /2 PhMe
CuOAc
CuI
CuTC
CuSO4
CuSO4
CuSO4
NaAsc (20 mol %)
NaAsc (1 equiv)
NaAsc (20 mol %),
TBTA (10 mol %)
10
11
aConditions: 6 (0.5 mmol), 10 mol % of catalyst, CH3CN/H2O (2/1,
0.1M), 50 °C, 6 h unless noted otherwise. bIsolated yield of 7. c5 mol %,
DCE, rt, 48 h. d20 mol %, CH3CN, rt, 48 h. eCH3CN without water.
SCHEME 2. Cleavage of N-O Bond with Cu(II)/NaAsc/O2
1,3,5-triazin-2-ol (10) via direct addition of hydroxide is proble-
matic (Scheme 2).5
FIGURE 1. Substrate scope for the Cu(I)-catalyzed hydroamination.
SCHEME 3. Deuterium-Labeling Experiment
N,N-Dialkylhydroxylamine-substituted triazines (9) have been
converted to the corresponding hydroxyl derivatives under acidic
conditions or with prolonged heating.10 While these conditions
failed to produce the desired product, treatment of 9 with CuSO4
and sodium ascorbate gave the desired 1,3,5-triazin-2-ol (10).
In order to achieve good conversions, a stoichiometric amount
of sodium ascorbate has to be employed.11
With the developed procedure in hand, the scope of the
direct intramolecular hydroamination was examined (Figure 1).
Both N-dimethyl- and N-diethylhydroxylamine derivatives were
utilized and gave similar results (12a).12 The regiochemistry of
12a was confirmed by single-crystal X-ray analysis, allowing the
showed exchange of only acetylenic protons, excluding the
intermediacy of allene species.
In principle, the acetylide intermediate can be trapped with
other electrophiles in situ, for example, with electrophilic iodine
reagents. Our group recently reported a copper-catalyzed iodin-
ation of terminal alkynes with N-iodomorpholine.13 In addition,
a CuI/TTTA catalytic system was shown to activate 1-iodoal-
kynes toward the cycloaddition with organic azides.13 We
envisioned that the same catalytic system could be employed
in hydroamination of 1-iodoalkynes. Thus, several substrates
were treated with N-iodomorpholine in the presence of CuI and
TTTA (Figure 2) forming vinyl iodide 15 via 5-exo-dig cycli-
zation of the transient 1-iodoalkyne. Strikingly, this process
generated 15b as a single regioisomer, as confirmed by the
X-ray analysis.
geometry of other cyclized products to be inferred via 1Hand13
C
NMR. While most substrates were easily converted to the corre-
sponding dihydroimidazo[1,2-a][1,3,5]triazinones using the op-
timized conditions within 12-18 h, cyclization to give 12g and
12h was markedly slow requiring the use of a ligand (TBTA or
its analogue, tris((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine,
TTTA).
1,3,5-Triazines containing the NH-propargyl group (10a)
or internal alkynes (10b) failed to undergo cyclization
(Scheme 2). The latter result points to the activation of
the alkyne via σ-copper acetylide intermediate, which was
supported by the results of a deuterium-labeling experiment
(Scheme 3). The reaction performed in deuterated solvent
The LC-MS analysis of the reaction mixture at different
time points indicated that the annulation proceeds through a
(10) Sanders, M. E.; Ames, M. M. Tetrahedron Lett. 1985, 26, 5247–5250.
(11) We are currently investigating the mechanism of this transformation;
a comprehensive report will be published in due course.
(13) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin,
V. V. Angew. Chem., Int. Ed. 2009, 48, 8018–8021.
(12) tert-Butyl peroxide derivatives can be used with equal success (cf. 12j).
J. Org. Chem. Vol. 75, No. 24, 2010 8663

Krasnova et al.
JOCNote
SCHEME 5. Comparative Study of the Reaction Promoted by
CuI/N-Iodomorpholine vs Iodine
regioselectivity.14 To further support this proposal, we pre-
pared starting material 16 and subjected it to the optimized
reaction conditions and, separately, to the treatment with
iodine (Scheme 5). After 18 h at room temperature, the
copper-catalyzed reaction produced exclusively 17 in 85%
isolated yield, whereas reaction with iodine resulted in a
complex mixture of at least four compounds.15
In summary, the new hydroamination protocol allowed
generation of dihydroimidazo[1,2-a][1,3,5]triazinones. Further,
1-iodoalkynes were shown, for the first time, to participate in the
copper(I)-catalyzed intramolecular hydroamination reaction
with the exclusive formation of the E-vinyl iodides. The proce-
dures are simple to perform, utilize inexpensive reagents, and
easily provide access to densely decorated purine analogues con-
taining functional groups amenable for further derivatization.
FIGURE 2. Substrate scope for Cu(I)-catalyzed cyclization.
SCHEME 4. Proposed Sequence of Steps for One-Pot Genera-
tion of 1-Iodoalkynes and Following Cyclization
Experimental Section
Procedure for Intramolecular Hydroamination. Synthesis of
6-Methylene-8-(methylsulfonyl)-2-(1,4-dioxa-8-azaspiro[4.5]decan-
8-yl)-7,8-dihydroimidazo-[1,2-a][1,3,5]triazin-4(6H)-one (12j). A
reaction flask was charged with N-(4-(dimethylaminooxy)-6-(1,
4-dioxa-8-azaspiro[4.5]decan-8-yl)-1,3,5-triazin-2-yl)-N-(prop-2-
ynyl)methanesulfonamide (11j) (1.50 g, 3.64 mmol), CuSO4 (365 μL,
1M, 10 mol %), and acetonitrile/water mixture (2:1, 35 mL).
After addition of sodium ascorbate (0.72 g, 3.64 mmol), the
reaction flask was capped and heated at 50 °C for 5 h.16 Upon
completion, the reaction mixture was cooled and quenched with
NH4OH/brine solution (10 mL, 1:1). The yellow crystalline
precipitate was collected by filtration, washed with NH4OH/brine
and water, and dried in vacuo. Compound 12j was obtained as a
series of steps outlined in Scheme 4. We observed formation
of intermediates A-C during the course of the reaction.
Under the optimized reaction conditions, intermediates A
and B predominate and led to the formation of 15b. The
presence of a proton source and suboptimal Cu(I)/N-iodo-
morpholine/substrate ratios led to the accumulation of
intermediate C and, as a result, generation of byproduct
12j. Since formation of the desired product may be affected
by multiple equilibria, the optimal ratio of the starting
material to N-iodomorpholine is substrate dependent and
was optimized on a case by case basis. Regardless of the
substrate, Cu(I) and TTTA are essential for the formation of
vinyl iodide 15b. Treatment of 11j with N-iodomorpholine
for 24 h at ambient temperature in the absence of a copper
catalyst gave a mixture consisting mostly of starting material
and a small amount of iodoallkyne A.
1
yellow solid (1.10 g, 82% yield): mp 206 °C dec; H NMR (600
MHz, CDCl3) δ 6.19 (s, 1H), 4.82 (s, 1H), 4.59 (s, 2H), 3.96 (s, 6H),
3.91 (s, 2H), 3.38 (s, 3H), 1.71 (s, 4H); 13C NMR (151 MHz, CDCl3)
δ 161.1, 156.1, 152.5, 132.5, 106.9, 97.8, 64.7, 48.3, 42.9, 42.8, 41.3,
35.4, 34.9; HRMS (ESI) 370.1180 (MHþ) (exact 370.1180 for
C14H20N5O5S).
Procedure for One-Pot Generation of Iodoalkyne and Intra-
molecular Cyclization. Synthesis of(E)-6-(Iodomethylene)-8-(methyl-
sulfonyl)-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-7,8-dihydroimidazo-
[1,2-a][1,3,5]triazin-4-(6H)-one (15b). Compound 11j (300 mg,
Thus, preliminary results suggest that the Cu(I)/N-iodo-
morpholine system acts as a mild oxidant, and its reactivity
toward alkynes is fundamentally divergent from the iodoamina-
tion reaction, which is characterized by lower chemo- and
(15) Retention times and molecular ion obtained by LCMS analysis were
used in structure assignment. Another major intermediate of molecular ion
576 corresponds to the addition of two iodine atoms to intermediate of
general structure C (Scheme 4).
(14) Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.; Nakamura, O.
Tetrahedron 1996, 52, 6581–6590.
(16) White precipitate of oxy-triazine intermediate is formed within first
30 min and gradually disappears as a reaction progresses toward 12j.
8664 J. Org. Chem. Vol. 75, No. 24, 2010

Krasnova et al.
JOCNote
0.73 mmol), copper iodide (14 mg, 0.073 mmol, 10 mol %), TTTA
(31 mg, 0.073 mmol, 10 mol %), and N-iodomorpholine (186 mg,
0.55 mmol) were mixed together in dry THF (7.5 mL, 0.1 M). The
reaction tube was flushed with N2, sealed, and stirred at room
temperature for 18 h. Upon completion, the reaction mixture was
quenchedwithsatdNH4Cl (10 mL), and the product was allowed to
crystallize upon slow removal of organic solvent. Beige-yellow
precipitate was collected by filtration, washed with satd NH4Cl
(10 mL), washed extensively with water, and dried in vacuo to give
15b (259 mg, 96% yield): mp 200.5 °C dec; 1H NMR (600 MHz,
DMSO) δ7.11 (t, J = 2.8 Hz, 1H), 4.50 (d, J = 2.7 Hz, 2H), 3.92 (s,
4H), 3.87-3.82(m,2H),3.82-3.79 (m, 2H), 3.47 (s, 3H), 1.70-1.62
(m, 4H); 13C NMR (151 MHz, D2O) δ 161.1, 156.1, 151.1, 134.8,
106.2, 63.9, 61.5, 53.4, 42.2, 42.0, 39.8, 34.6, 34.2; HRMS (ESI)
496.0140 (MHþ) (exact 496.0146 for C14H19IN5O5S). Crystal
suitable for the X-ray crystallographic analysis was obtained upon
slow crystallization from water/DMSO mixture.
Acknowledgment. We gratefully acknowledge financial
support from the National Institute of General Medical
Sciences, National Institutes of Health (GM087620). We
thank Prof. K. Barry Sharpless (TSRI) for helpful discus-
sions. X-ray crystallography was performed by Dr. Arnold
Rheingold and Dr. James A. Golen (UCSD).
Supporting Information Available: Experimental proce-
dures, compound characterization data, crystallographic infor-
mation files (CIFs), and copies of 1H, 13C NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8665