Four-component synthesis of fully substituted 1,2,4-triazoles

Article abstract of DOI:10.1002/anie.200905897

Chemical Equation Presented All 4 one: Palladium-catalyzed carbonylation initiates a highly regioselective triazole synthesis. In this four-partner protocol, the aryl halide, amidine, and hydrazine partners are easily varied, allowing the synthesis of fully substituted 1,2,4-triazoles in a modular fashion. This methodology is demonstrated with the synthesis of druglike and/or pharmaceutically relevant molecules such as deferasirox.

Full text of DOI:10.1002/anie.200905897

Angewandte
Chemie
DOI: 10.1002/anie.200905897
Multicomponent Reactions
Four-Component Synthesis of Fully Substituted 1,2,4-Triazoles**
Steven T. Staben* and Nicole Blaquiere
The generation of a-aza-biaryl linkages continues to chal-
lenge synthetic chemists and is the focus of much research
À
effort. Classic transition-metal-catalyzed C C cross-coupling
remains the most prevalent route for biaryl synthesis;
however, issues with the unavailability and instability of
organometallic reactants for a-heteroatom biaryl coupling
still limit the success of this approach. Importantly, recent
improvements have been made in the mild generation,[1]
increased benchtop stability,[2] controlled release,[3] and mild
coupling[4] of these previously unreliable reaction partners.
À
Direct C H arylation avoids the preparation of stoichiomet-
ric organometallic reagents altogether and has proven to be a
powerful method for the synthesis of biaryls.[5] However,
limitations still exist and reaction optimization for specific
Figure 2. Multicomponent route to 5-aryl-1,2,4-triazoles.
coupling partners is commonplace. As many azole and azine
heterocycles can be generated by the cyclodehydration of
appropriate carbonyl precursors, an alternative approach to
a-aza-biaryl coupling stems from the transition-metal-cata-
lyzed carbonylative coupling of acyclic reagents that can
undergo in situ cyclodehydration (Figure 1). Importantly, a
careful handling of the above-mentioned sensitive metallo-
azole intermediates.[8] Review of the literature revealed few
[9]
À
examples of intermolecular C H arylation of 1,2,4-triazoles.
We thus sought an approach to synthesize triazoles A through
B, a key intermediate in the Einhorn–Brunner stepwise
synthesis of triazoles (Figure 2).[10] We believed a palladium-
catalyzed C-C-N coupling protocol could provide intermedi-
ates B by carbonylative addition of either amidrazones
(path 1) or amidines (path 2) to aryl halides. Herein we
describe the multicomponent synthesis of functionally diverse
5-aryl- and –heteroaryl-1,2,4-triazoles by carbonylative het-
erocyclization.
Figure 1. a-Heteroatom biaryl generation of a-heteroatom biaryls.
Perhaps the most direct way to the Einhorn–Brunner
intermediate B is through carbonylative addition of an
amidrazone (path 1). Armed with the recent successes from
the Buchwald lab in the carbonylative amination of various
aryl halides under atmospheric CO pressures,[11] we believed
similar conditions would be appropriate for this carbonylative
process. To our delight, use of Pd(OAc)2/Xantphos (Xant-
phos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)
with triethylamine in DMF under atmospheric CO led to the
direct conversion of p-iodoanisole to triazole 1a (56% yield,
Scheme 1). Similarly 3-iodopyridine was coupled to carbon
monoxide and a difluorophenyl-substituted amidrazone in
this three-component process to give 1,3,5-substituted 1,2,4-
triazole 1c in 50% yield.[12]
multicomponent carbonylative heterocyclization can provide
access to difficult a-heteroatom biaryl linkages without
requiring the synthesis of any organometallic intermediates.[6]
In the course of a drug-discovery program, we required
access to several 5-aryl-1,2,4-triazoles A from a common aryl
iodide (Figure 2). This class of compounds has been prepared
previously utilizing zinc and stannyl triazoles in Negishi and
Stille C C coupling reactions,[7] but this approach requires the
À
multistep syntheses of differentially substituted triazoles and
[*] Dr. S. T. Staben, N. Blaquiere
Discovery Chemistry Group, Genentech, Inc.
1 DNA Way, South San Francisco, CA 94080 (USA)
E-mail: stevents@gene.com
Albeit direct, the above three-component strategy for the
synthesis of trisubstituted triazoles required the use of
preformed amidrazones. Few amidrazones are commercially
available and, in our hands, their preparation was cumber-
Homepage: http://www.gene.com
[**] We thank Steve Huhn, Bawei Lin, and Chris Hamman for analytical
support. We also thank Tim Heffron, Joe Lyssikatos, Dan Sutherlin,
and Zach Sweeney for helpful suggestions regarding the prepara-
tion of this manuscript.
some. We therefore sought to access intermediate
B
(Figure 1) by the carbonylative coupling of readily available
amidines to aryl halides followed by in situ reaction with
monosubstituted hydrazines (path 2, via acyl amidine C). This
modular four-component approach would promote rapid
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905897.
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
325

Communications
This linchpin protocol was also successful for the coupling
of both aryl and heteroaryl reagents including pyrazolyl,
quinolyl, pyridyl, pyrazyl, and benzothiazyl iodides (products
9, 11 and 13, 10, and 12 respectively). Especially notable
among these is the smooth coupling/cyclization of 2-iodopyr-
azine and 2-iodopyridine (products 10 and 13). These
couplings generate biaryl linkages with three a-heteroatoms
in 65% and 70% yield, respectively. Importantly, triazole
formation was completely regioselective in all cases.[16] The
hydrazino component is easily varied as alkyl, aryl, and
heteroaryl hydrazines cyclize efficiently under the reaction
conditions (products 13 and 15–18).[17] Aqueous hydrazine
can also be used to access 5-aryl-1H triazoles as in 19.
Aryl bromides are also effective reactants in this one-pot,
four-component process. For example, compound 2 is gen-
erated in 74% and 56% yield from the corresponding aryl
iodide and aryl bromide, respectively. When p-iodobromo-
benzene is used and the number of amidine equivalents is
controlled, selective monocarbonylative addition is observed
(product 14, 56% yield), and an important synthetic handle
remains intact for further functionalization .
Scheme 1. Carbonylative addition of amidrazones to aryl iodides for
direct access to fully substituted 1,2,4-triazoles.
access to diverse valuable trisubstituted triazoles, without
required presynthesis.[13]
Application of a one-pot protocol was indeed successful.
Thus, carbonylative coupling with acetamidine[14] followed by
addition of isopropylhydrazine and acetic acid to the crude
reaction mixture gave 2 in 74% overall yield (Scheme 2).
Further investigation revealed that this method has wide
substrate scope. A variety of commercially available alkyl,
aryl, and heteroaryl amidines were successful in this four-
component process (e.g. products 3–5).[15] For aryl substrates,
electron-withdrawing or -donating substitutents are well-
tolerated (e.g. compare products 2, 7, and 15).
Substituted triazoles are present in many important
pharmaceutically active molecules. Although many of the
compounds in Scheme 2 already display druglike attributes,
Scheme 2. Modular synthesis of substituted triazoles. [a] The aryl iodide was used unless otherwise noted. [b] Amidines were typically added as
HCl or HOAc salts. [c] See the Supporting Information for reaction details of each example. [d] Hydrazines were typically added as HCl salts.
[e] Aryl bromide was used. Yields are of analytically pure isolated material from reactions run on a 0.6–2.0 mmol scale.
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Angewandte
Chemie
DMF (8 mL) and triethylamine (1 mL) were added under nitrogen
we wanted to demonstrate the utility of this method through
the synthesis of a pharmaceutically relevant molecule in a
one-pot fashion. Deferasirox (20) is an active pharmaceutical
ingredient in Exjade, an important metal-chelating treatment
for patients with chronic iron overload.[18] A testament to the
robust functional group tolerability of this methodology,
carbonylative coupling of 2-hydroxybenzamidine with 2-
iodophenol preceded addition/cyclization with 4-hydrazino-
benzoic acid to provide 20 in 41% yield after purification by
reverse-phase HPLC (Scheme 3).
purge. Pd(OAc)2 (12 mg, 5 mol%) and Xantphos (31 mg, 5 mol%)
were added. The flask was purged with carbon monoxide for 2 min.
The reaction mixture was heated under a CO atmosphere (balloon)
for 2 h at 808C. The balloon was removed and the reaction mixture
was cooled to room temperature. Isopropylhydrazine hydrochloride
(354 mg, 3.20 mmol) and acetic acid (4 mL) were added. The reaction
mixture was heated at 808C for 1 h. After cooling to room temper-
ature, the mixture was diluted with 75 mL of ethyl acetate and washed
with 5% NaOH (2 ꢀ , 10 mL) and brine (10 mL). The organic layer
was dried over Na2SO4 and concentrated. The crude residue was
purified by flash column chromatography (10–50% EtOAc in
hexanes) to give 3 as a colorless solid (194 mg, 70% yield).
1H NMR (500 MHz, [D6]DMSO): d = 7.53 (m, 2H), 7.09 (m, 2H),
4.56 (hept, J = 6.6 Hz, 1H), 3.83 (s,3H), 2.96 (hept, J = 6.9 Hz, 1H),
1.39 (d, J = 6.6 Hz, 6H), 1.26 ppm (d, J = 6.9 Hz, 6H). 13C NMR
(126 MHz, [D6]DMSO): d = 166.94, 160.16, 152.94, 130.06, 120.70,
114.17, 55.24, 49.62, 27.61, 22.42, 21.62 ppm. HRMS calcd for
C15H22N3O [M+H+] 260.1764, found 260.1614.
Received: October 21, 2009
Published online: December 8, 2009
Scheme 3. One-pot synthesis of deferasirox.
À
Keywords: carbonylation · C C coupling ·
homogeneous catalysis · multicomponent reactions ·
nitrogen heterocycles
.
In conclusion, we have developed a palladium-catalyzed
multicomponent synthesis of trisubstituted triazoles. This
approach features a wide scope, mild reaction temperatures,
and low carbon monoxide pressures. Total yields range from
41% to 79%, or 80–94% per bond for the four bonds created.
The utility of this process is underscored by the synthesis of
druglike and/or pharmaceutically relevant molecules from
commercially available materials.[19] As such, this method
[1] For example, mild zincation of several heterocycles: a) S. H.
Wunderlich, M. Kienle, P. Knochel, Angew. Chem. 2009, 121,
7392; Angew. Chem. Int. Ed. 2009, 48, 7256; b) C. J. Rohbogner,
S. H. Wunderlich, G. C. Clososki, P. Knochel, Eur. J. Org. Chem.
2009, 1781.
[2] Trifluoroborate salts: a) G. A. Molander, N. Ellis, Acc. Chem.
Res. 2007, 40, 275; b) G. A. Molander, B. Canturk, L. E.
Kennedy, J. Org. Chem. 2009, 74, 973; Silanoates: c) S. E.
Denmark, J. D. Baird, Org. Lett. 2006, 8, 793; d) S. E. Denmark,
C. S. Regens, Acc. Chem. Res. 2008, 41, 1486.
À
compares favorably with direct C H arylation technology.
Further application of this strategy is underway and will be
disclosed in due course.
[3] MIDA boronates: D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am.
Chem. Soc. 2009, 131, 6961.
Experimental Section
CAUTION: Carbon monoxide should be handled with extreme care.
These experiments were run in a well-ventilated hood.
[4] For recent examples see: a) N. Kudo, M. Perseghini, G. C. Fu,
Angew. Chem. 2006, 118, 1304; Angew. Chem. Int. Ed. 2006, 45,
1282; b) D. X. Yang, S. L. Colletti, K. Wu, M. Song, G. Y. Li,
H. C. Shen, Org. Lett. 2009, 11, 381; c) K. L. Billingsley, S. L.
Buchwald, Angew. Chem. 2008, 120, 4773; Angew. Chem. Int.
Ed. 2008, 47, 4695.
[5] For recent summary articles see: a) D. Alberico, M. E. Scott, M.
Lautens, Chem. Rev. 2007, 107, 174; b) B. Liꢁgault, D. Lapointe,
L. Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826;
c) L.-C. Campeau, D. R. Stuart, J.-P. Leclerc, M. Bertrand-
Laperle, E. Villemure, H.-Y. Sun, S. Lasserre, N. Guimond, M.
Lecavallier, K. Fagnou, J. Am. Chem. Soc. 2009, 131, 3291; d) O.
Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 2009, 42,
1074. The authors note that the generality of reaction conditions
remains a prominent issue; e) D. A. Colby, R. G. Bergman, J. A.
Ellman, Chem. Rev. 2009, DOI: 10.1021/cr900005n.
[6] For a review on the transition-metal-catalyzed multicomponent
synthesis of heterocycles see: a) D. M. DꢂSouza, T. J. J. Mꢃller,
Chem. Soc. Rev. 2007, 36, 1095; See also b) A. S. Karpov, E.
Merkul, F. Rominger, T. J. J. Mꢃller, Angew. Chem. 2005, 117,
7112; Angew. Chem. Int. Ed. 2005, 44, 6951; c) J. R. Young, R. J.
DeVita, Tetrahedron Lett. 1998, 39, 3931; H.-C. Ryu, Y.-T. Hong,
S.-K. Kang, Heterocycles 2000, 54, 985. For metal-assisted carbon
monoxide mediated heterocycle ring formation see: d) M. D.
Mihovilovic, P. Stanetty, Angew. Chem. 2007, 119, 3684; Angew.
Chem. Int. Ed. 2007, 46, 3612; e) R. D. Dghaym, R. Dhawan,
Representative procedure for the synthesis of 1a (Scheme 1): A
25 mL round-bottom flask with an attached septum was flushed with
nitrogen and charged with 3-iodoanisole (165 mg, 0.71 mmol) and
N’-phenylacetimidohydrazide hydrochloride (197 mg, 1.06 mmol).
Anhydrous DMF (5 mL) and triethylamine (0.40 mL) were added
under nitrogen purge. Pd(OAc)2 (8 mg, 5 mol%) and Xantphos
(20 mg, 5 mol%) were added. The flask was purged with carbon
monoxide for 2 min. The reaction mixture was heated under a CO
atmosphere (balloon) for 1.5 h at 808C. The balloon was removed and
the reaction mixture was cooled to room temperature. The mixture
was diluted with ethyl acetate (50 mL)and washed with 5% NaOH
(10 mL) and brine (10 mL). The organic layer was dried over Na2SO4
and concentrated. The crude residue was purified by flash column
chromatography (5–45% EtOAc in hexanes) to give 1a as a colorless
solid (105 mg, 56% yield). 1H NMR (500 MHz, [D6]DMSO): d =
7.51–7.44 (m, 3H), 7.35 (m, 4H), 6.96–6.90 (m, 2H), 3.76 (s, 3H),
2.35 ppm (s, 3H). 13C NMR (126 MHz, [D6]DMSO): d = 160.25,
159.44, 153.40, 138.06, 129.85, 129.35, 128.72, 125.49, 119.90, 113.93,
55.17, 13.45 ppm. HRMS calcd for C16H16N3O [M+H+] 266.1295,
found 266.131.
Representative procedure for the synthesis of 3 (Scheme 2): A
25 mL round-bottom flask with an attached septum was flushed with
nitrogen and charged with 4-iodoanisole (250 mg, 1.07 mmol) and
isopropylcarbamidine hydrochloride (196 mg, 1.6 mmol). Anhydrous
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B. A. Arndtsen, Angew. Chem. 2001, 113, 3328; Angew. Chem.
[15] Unsuccessful partners included formamidine and trifluroroace-
tamidines, resulting in transformation to 4-methoxybenzamide
presumably through the facile hydrolysis of the unhindered and
highly elecrophilic intermediates. No appreciable products were
formed in an attempted reaction of 2-iodo-1-methylimidazole
and 2-bromopyrimidine with acetamidine. Inorganic bases such
as Na2CO3 and K3PO4 were also competent in the creation of 3,
although the cleanest conversion was observed using NEt3.
Compound 3 was also synthesized in a stepwise fashion. The
acylamidine intermediate shown was isolated in 66% yield by
reverse-phase HPLC to support its intermediacy in the triazole
synthesis (see the Supporting Information for details).
Int. Ed. 2001, 40, 3228; f) R. Dhawan, B. A. Arndtsen, J. Am.
Chem. Soc. 2004, 126, 468; g) B. A. Arndtsen, Chem. Eur. J. 2009,
15, 302.
[7] For a review on the cross-coupling of azoles see: a) M. Schnꢃrch,
R. Flasik, A. F. Khan, M. Spina, M. D. Mihovilovic, P. Stanetty,
Eur. J. Org. Chem. 2006, 3283 – 3307. Stille coupling of 1-methyl-
5-(tributylstannyl)-1H-1,2,4-triazole: b) K. C. Nicolaou, B. A.
Pratt, S. Arseniyadis, M. Wartmann, A. O’Brate, P. Giannaka-
kou, ChemMedChem 2006, 1, 41; c) P. Jones, M. Chambers,
Tetrahedron 2002, 58, 9973. Negishi coupling of (1-methyl-1H-
1,2,4-triazol-5-yl)zinc(II) chloride: d) H. J. Barbosa, et al. , WO
102194, 2006; e) D. S. Middleton, et al. , WO 51972, 2000.
[8] For notes on the instability of metalated azoles with two or more
nitrogen atoms see: M. R. Grimmett, B. Iddon, Heterocycles
1995, 41, 1525.
[9] a) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 12404;
b) H.-Q. Do, R. M. K. Khan, O. Daugulis, J. Am. Chem. Soc.
2008, 130, 15185; For examples of an intramolecular cyclization
see c) B. Laleu, M. Lautens, J. Org. Chem. 2008, 73, 9164.
[10] An intermediate in the Einhorn–Brunner synthesis of triazoles
from imides: a) K. Brunner, Ber. Dtsch. Chem. Ges. 1914, 47,
2671; b) A. Einhorn, E. Bischkopff, B. Szelinski, G. Schupp, E.
Sprꢄngerts, C. Ladisch, T. Mauermayer, Justus Liebigs Ann.
Chem. 1905, 343, 207.
[11] a) J. R. Martinelli, D. A. Watson, D. M. M. Freckmann, T. E.
Barder, S. L. Buchwald, J. Org. Chem. 2008, 73, 7102. For an
excellent review of recent advances in the carbonylation of aryl
halides see: b) A. Brennfꢃhrer, H. Neumann, M. Beller, Angew.
Chem. 2009, 121, 4176; Angew. Chem. Int. Ed. 2009, 48, 4114.
[12] Please see the Supporting Information section for experimental
details. All triazole products have consistent 1H NMR,
13C NMR, and HRMS data.
[13] A typical synthesis of a 5-aryl-1,2,4-triazole from an aryl halide
involves conversion of the aryl halide to a primary benzamide
followed by formation of an acylamidine by heating with a
dimethylamide dialkyl acetal (i.e. dimethylacetamide dimethyl
acetal) and addition/cyclization of a monosubstituted hydrazine.
[14] To the best of our knowledge, this is the first report of a
carbonylative coupling of an amidine to an aryl halide.
[16] No regioisomers were observed by LCMS analysis of the crude
reaction mixtures. Regiochemistry was determined by 2D
NOESY for compounds 4, 10, 11, and 13 as well as by HMBC
correlation for 10 and 13. The remaining compounds were
assigned by analogy.
[17] The cyclization stage is typically run at ꢀ 808C to ensure
complete conversion of the acylamidine intermediate, although
the reaction is often complete at room temperature.
[18] http://www.exjade.com/index.jsp (aka ICL670); a) H. Nick, P.
Acklin, R. Lattmann, P. Buehlmayer, S. Hauffe, J. Schupp, D.
Alberti, Curr. Med. Chem. 2003, 10, 1065; b) U. Heinz, K.
Hegetschweiler, P. Acklin, B. Faller, R. Lattmann, H. P. Schnebli,
Angew. Chem. 1999, 111, 2733; Angew. Chem. Int. Ed. 1999, 38,
2568.
[19] Notably, all aryl halides, amidines, and hydrazines used are
commercially available.
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