Continuous-flow synthesis of 1-substituted benzotriazoles from chloronitrobenzenes and amines in a C-N bond formation/hydrogenation/ diazotization/cyclization sequence

Article abstract of DOI:10.1002/anie.201300615

Two approaches have been developed for the regiospecific continuous-flow synthesis of 1-substituted benzotriazoles. They begin with either an S _NAr reaction at high temperature or Pd catalysis and involve consecutive multiphase processes, allow

Full text of DOI:10.1002/anie.201300615

Angewandte
Chemie
DOI: 10.1002/anie.201300615
Synthetic Methods
Continuous-Flow Synthesis of 1-Substituted Benzotriazoles from
À
Chloronitrobenzenes and Amines in a C N Bond Formation/
Hydrogenation/Diazotization/Cyclization Sequence**
Mao Chen and Stephen L. Buchwald*
Substituted benzotriazoles represent key structural motifs in
compounds that possess antibacterial, antimalarial, and anti-
fungal activities.[1] They are also found in potassium channel
activators,[2] inhibitors of various kinases,[3] and in selective
agonists of human orphan G-protein-coupled receptor
GPR109b.[4] In addition, benzotriazoles are versatile inter-
mediates in the synthesis of important heterocycles, such as
carbazoles, pyridoacridines, carbolines, and tetraazapenta-
lenes.[5] They have also been extensively utilized as synthetic
auxiliaries in benzannulation and alkylation reactions.[6]
Traditionally, 1-substituted benzotriazoles have been
prepared by N-alkylation/arylation of benzotriazoles or
[3+2] cycloaddition of azides and benzynes. The alkylation/
arylation approach often suffers from poor regioselectivities
because of the tautomeric nature of unsymmetrical benzo-
triazoles.[7] Moreover, the arylation reagents are usually
limited to activated heteroaryl halides or aryl halides that
possess strong electron-withdrawing groups. The regioselec-
tivity of 1,3-dipolar cycloadditions of azides is largely
dependent on the steric and electronic properties of benzynes,
and mixtures of regioisomers are often formed.[8] Separation
of 1-, 2-, and 3-substituted benzotriazoles is also oftentimes
not trivial because of their similar physical properties.[9] In
addition, the generation of unstable benzyne intermediates
and the handling of azides on large scale present safety
problems. Thus, the development of a safe and efficient
method to prepare 1-substituted benzotriazoles in a regiospe-
cific fashion is desirable.[10]
Scheme 1. Multistep strategy for the synthesis of 1-substituted benzo-
triazoles under continuous-flow conditions.
tization/cyclization (Scheme 1). These multistep operations in
batch mode are time-consuming and labor-intensive. Addi-
tionally, carrying out high-temperature processes and ther-
mally sensitive diazotization reactions under batch conditions
can be problematic.[11] Continuous-flow processes are useful
alternatives to traditional batch procedures as has been
demonstrated by both industrial and academic chemists.[12]
We felt that a continuous-flow approach would be ideal in our
multistep synthesis of benzotriazoles and would greatly
enhance the practicality of this method.
In this regard, we have designed a multistep synthesis
À
consisting of a C N bond formation/hydrogenation/diazoti-
zation/cyclization sequence starting from 2-chloronitroben-
zenes and amines. Depending on the electronic properties of
À
the chloronitrobenzene, the C N bond-forming step can be
achieved either by nucleophilic aromatic substitution (SNAr;
À
approach A) or by a Pd-catalyzed C N cross-coupling
reaction (approach B) followed by hydrogenation and diazo-
Despite recent advances in multistep synthesis under
continuous-flow conditions pioneered by Ley,[12,13] examples
of such cases, including consecutive multiphase processes in
a continuous line, are still rare.[14] For a sequence of multi-
phase reactions in flow, problems of mass- and heat-transfer
between different phases, varying solubilities of intermediates
over the course of the reaction, compatibility of solvents, as
well as residence-time control for segmented flow all need to
be considered. Herein, we report the development of a multi-
step continuous-flow synthesis of 1-substituted benzotriazoles
under consecutive multiphase reaction conditions.
[*] Dr. M. Chen, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] We thank Novartis International AG for funding. We thank Dr.
Nathan Jui and Dr. Christine Nguyen for assistance with the
preparation of this manuscript. MIT has patents on some of the
ligands and precatalysts used in this work from which S.L.B.
receives royalty payments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300615.
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À
Figure 1. Continuous-flow setup for the C N bond formation/hydrogenation/diazotization sequence of approach A and B. a) In-line check valve;
b) on-off valve; c) pressure gauge; d) 2-stage regulator; e) 2-way valve; BPR: back-pressure regulator; MFC: mass flow controller. For more details,
see the Supporting Information.
À
We began our studies on the C N bond formation/
hydrogenation/diazotization/cyclization
sequence
using
approach A with the setup depicted in Figure 1 with 4-
chloro-3-nitrobenzotrifluoride and p-toluidine as model sub-
strates. In considering the solubility and reactivity constraints
of downstream processes, a mixture of N,N-dimethylaceta-
mide (DMA) and n-hexanol was chosen as the solvent for this
SNAr step.[15] In the flow setup, a solution of 4-chloro-3-
nitrobenzotrifluoride and iPr2NEt in DMA was mixed with p-
toluidine in n-hexanol and introduced into reactor IA at
À
1808C. After C N bond formation was complete, the result-
ing mixture was diluted with CH2Cl2, and was mixed with H2
gas.[16,17] The resulting gas/liquid segmented flow was passed
through a vertically placed[18] packed-bed reactor II (packed
with stainless steel spheres and 5% Pd/C particles) at 458C.
After hydrogenation had finished, the resulting mixture was
directly combined with aqueous HCl and aqueous NaNO2,
and the resulting stream was then introduced into reactor III
to perform diazotization/cyclization.[19] Finally, the resulting
mixture was collected and subsequently purified by column
chromatography to afford 5a in 93% yield of isolated product
(Scheme 2).
With the optimized flow conditions in hand, the substrate
scope with various electrophiles and both aromatic and
aliphatic amines using approach A was investigated
(Scheme 2). Para-, meta-, ortho-, and multi-substituted ani-
lines could be successfully employed. Both electron-rich and
electron-deficient anilines appeared to be effective nucleo-
philes. Substrates with electron-withdrawing groups (R1),
such as a trifluoromethyl, an ester, and a nitrile group, were
converted to products in good yield. Of note, chloro-
(nitro)heteroaryl substrates could also be used to efficiently
access the corresponding triazolopyridines (5e, 5 f, and 5h) or
triazoloquinolines (5i). Although these SNAr reactions were
carried out at high temperatures, only 1.3 equivalents of
amines, including those with low boiling points (e.g., isopro-
pyl and cyclopropyl amine), were required, further demon-
strating the advantage of this flow process. To overcome
clogging problems that initially occurred in preparing 5d and
5e, which have limited solubilities under our conditions,
reactor III was placed in a sonication bath at 458C.[20] With
Scheme 2. Continuous-flow synthesis of 1-substituted benzotriazoles
À
by an SNAr C N bond formation/hydrogenation/diazotization/cycliza-
tion sequence. Yields of isolated products (average of two runs) based
on 1 mmol scale are shown. See the Supporting Information for
details. [a] Sonication at 458C was used in the third step.
this setup, 1-substituted benzotriazoles could be prepared
regiospecifically on a 1 mmol scale in approximately one
hour.[21]
While approach A is successful for chloro(nitro)aromatic
substrates with additional electron-withdrawing groups, it is
not efficient for other substrates. To overcome this limitation,
we developed a Pd-catalyzed version (approach B). After
À
briefly optimizing the C N coupling reaction in EtOH/H2O
with K3PO4 as the base at 808C, palladium precatalyst 6[22]
afforded the desired product 3a in 97% yield (determined by
GC analysis; Scheme 3).
Having identified appropriate reaction conditions for Pd-
À
catalyzed C N bond formation, we next assembled a micro-
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In summary, we have developed an efficient and regio-
specific synthesis of 1-substituted benzotriazoles from chloro-
À
nitrobenzenes and amines by a C N bond formation/hydro-
genation/diazotization/cyclization sequence under continu-
ous-flow conditions. Two approaches beginning either with an
SNAr reaction or Pd catalysis were developed to prepare
unsymmetrically substituted benzotriazoles with a range of
substituents. Of particular note is that benzotriazoles that
bear various N-substituted groups, including alkyl, aryl, and
heteroaryl, can all be efficiently and regiospecifically accessed
with the described method. This protocol represents a suc-
cessful example of a continuous-flow method with consec-
utive multiphase processes.
À
Scheme 3. Pd-catalyzed C N coupling of 2-chloronitrobenzenes and
amines.
fluidic system as shown in Figure 1, approach B.[23] In this flow
setup, the combined biphasic solutions of substrates, base, and
catalyst were first introduced into a packed-bed reactor IB
(packed with stainless steel spheres) at 808C with sonication.
Received: January 24, 2013
Published online: March 1, 2013
Keywords: cross-coupling · flow chemistry · microreactors ·
.
palladium · synthetic methods
À
After Pd-catalyzed C N cross coupling was complete, the
stream containing the intermediate was mixed with streams of
water and CH2Cl2, and the resulting mixture was flowed into
the hydrogenation reactor II and then the diazotization
reactor III with the same setup as for approach A (see
above). To achieve complete hydrogenation of the nitroani-
line intermediate, a longer packed-bed hydrogenation reac-
tor II[24] was used in approach B, and the reaction temper-
atures were increased to 60–808C.
[1] a) P. P. Dixit, P. S. Nair, V. J. Patil, S. Jain, S. K. Arora, N. Sinha,
Bioorg. Med. Chem. Lett. 2005, 15, 3002; b) N. Mishra, P. Arora,
B. Kumar, L. C. Mishra, A. Bhattacharya, S. K. Awasthi, V. K.
Bhasin, Eur. J. Med. Chem. 2008, 43, 1530; c) Z. Rezaei, S.
Khabnadideh, K. Pakshir, Z. Hossaini, F. Amiri, E. Assadpour,
´
Eur. J. Med. Chem. 2009, 44, 3064; d) K. Kopanska, A. Najda, J.
˙
Zebrowska, L. Chomicz, J. Piekarczyk, P. Myjakd, M. Bretner,
Bioorg. Med. Chem. Lett. 2004, 12, 2617.
1-Arylbenzotriazoles that bear electron-donating groups
(methyl, methoxy) could be prepared with approach B
(Scheme 4). Fluorine-substituted benzotriazoles, which were
[2] A. Coi, F. L. Fiamingo, O. Livi, V. Calderone, A. Martelli, I.
Massarelli, A. M. Bianucci, Bioorg. Med. Chem. 2009, 17, 319.
[3] a) C.-Y. Wu, K.-J. King, C.-J. Kuo, J.-M. Fang, J.-T. Wu, M.-Y. Ho,
C.-L. Liao, J.-J. Shie, P.-H. Liang, C.-H. Wong, Chem. Biol. 2006,
13, 261; b) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529.
[4] G. Semple, P. J. Skinner, M. C. Cherrier, P. J. Webb, C. R. Sage,
S. Y. Tamura, R. Chen, J. G. Richman, D. T. Connolly, J. Med.
Chem. 2006, 49, 1227.
[5] a) N. Campbell, B. Barclay, Chem. Rev. 1947, 40, 359; b) D. J.
Hagan, E. Gimenez-Arnau, C. H. Schwalbe, M. F. G. Stevens, J.
Chem. Soc. Perkin Trans. 1 1997, 2739; c) P. Vera-Luque, R.
Alajarin, J. Alvarez-Builla, J. J. Vaquero, Org. Lett. 2006, 8, 415;
d) J. C. Kauer, R. A. Carboni, J. Am. Chem. Soc. 1967, 89, 2633.
[6] a) A. R. Katritzky, S. Rachwal, Chem. Rev. 2010, 110, 1564;
b) A. R. Katritzky, K. Manju, S. K. Singh, N. K. Meher, Tetrahe-
dron 2005, 61, 2555.
[7] a) I. P. Beletskaya, D. V. Davydov, M. Moreno-MaÇas, Tetrahe-
dron Lett. 1998, 39, 5617; b) A. R. Katritzky, J. Wu, Synthesis
1994, 597; c) H.-G. Lee, J.-E. Won, M.-J. Kim, S.-E. Park, K.-J.
Jung, B. R. Kim, S.-G. Lee, Y.-J. Yoon, J. Org. Chem. 2009, 74,
5675; d) S. Ueda, M. Su, S. L. Buchwald, Angew. Chem. 2011,
123, 9106; Angew. Chem. Int. Ed. 2011, 50, 8944.
[8] a) P. H.-Y. Cheong, R. S. Paton, S. M. Bronner, G. Y. J. Im, N. K.
Garg, K. N. Houk, J. Am. Chem. Soc. 2010, 132, 1267; b) F. Shi,
J. P. Waldo, Y. Chen, R. C. Larock, Org. Lett. 2008, 10, 2409.
[9] As a result, mixtures of regioisomers have been used for
biological assays, see Ref. [1a].
[10] For recent examples of the synthesis of 1-substituted benzotria-
zoles using others methods, see: a) R. K. Kumar, M. A. Ali, T.
Punniyamurthy, Org. Lett. 2011, 13, 2102; b) V. Zimmermann, S.
Brꢀse, J. Comb. Chem. 2007, 9, 1114; c) C. Mukhopadhyay, P. K.
Tapaswi, R. J. Butcher, Org. Biomol. Chem. 2010, 8, 4720.
[11] M. A. Nielsen, M. K. Nielsen, T. Pittelkow, Org. Process. Res.
Dev. 2004, 8, 1059.
Scheme 4. Continuous-flow synthesis of 1-substituted benzotriazoles
À
by a Pd-catalyzed C N bond formation/hydrogenation/diazotization/
cyclization sequence. Yields of isolated products (average of two runs)
based on 1 mmol scale are shown. See the Supporting Information for
details. [a] Sonication at 458C was used in the third step.
difficult to obtain using the high-temperature SNAr approach,
could also be generated in good yields. Heterocyclic amines,
such as 5-aminopyrazole and 3-aminopyridine, could be used
as nucleophilic compounds to give the corresponding benzo-
triazoles 5n and 5o in good yields.
[12] For selected reviews of multistep synthesis in flow, see: a) S. V.
Ley, Chem. Rec. 2012, 12, 378; b) D. Webb, T. F. Jamison, Chem.
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Sci. 2010, 1, 675; c) J. Wegner, S. Ceylan, A. Kirschning, Adv.
Synth. Catal. 2012, 354, 17.
[16] For selected examples of hydrogenation in flow, see: a) M.
OꢂBrien, N. Taylor, A. Polyzos, I. R. Baxendale, S. V. Ley, Chem.
Sci. 2011, 2, 1250; b) R. V. Jones, L. Godorhazy, N. Varga, D.
Szalay, L. Urge, F, Darvas, J. Comb. Chem. 2006, 8, 110; c) J.
Kobayashi, Y. Mori, S. Kobayashi, Adv. Synth. Catal. 2005, 347,
1889; d) N. Yoswathananont, K. Nitta, Y. Nishiuchi, M. Sato,
Chem. Commun. 2005, 40; e) J. G. Stevens, R. A. Bourne, M. V.
Twigg, M. Poliakoff, Angew. Chem. 2010, 122, 9040; Angew.
Chem. Int. Ed. 2010, 49, 8856.
[17] It was observed that better segmented flow could be achieved
with a Y-mixer rather than a T-mixer for gas/liquid mixing during
our studies.
[18] During our investigation, we found that a vertically placed
reactor could afford better conversion in the hydrogenation
compared to a horizontally placed reactor.
[19] For selected examples of diazotization in flow, see: a) N.
Chernyak, S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 12466;
b) D. X. Hu, M. OꢂBrien, S. V. Ley, Org. Lett. 2012, 14, 4246.
[20] For selected examples of using sonication to circumvent clogging
problems in flow, see: a) T. Noꢄl, J. R. Naber, R. L. Hartman,
J. P. McMullen, K. F. Jensen, S. L. Buchwald, Chem. Sci. 2011, 2,
287; b) J. Sedelmeier, S. V. Ley, I. R. Baxendale, M. Baumann,
Org. Lett. 2010, 12, 3618; c) T. Horie, M. Sumino, T. Tanaka, Y.
Matsushita, T. Ichimura, J.-i. Yoshida, Org. Process Res. Dev.
2010, 14, 405.
[13] For selected examples of multistep continuous-flow processes,
see: a) C. J. Smith, I. R. Baxendale, H. Lange, S. V. Ley, Org.
Biomol. Chem. 2011, 9, 1938; b) M. D. Hopkin, I. R. Baxendale,
S. V. Ley, Chem. Commun. 2010, 46, 2450; c) I. R. Baxendale,
S. V. Ley, A. C. Mansfield, C. D. Smith, Angew. Chem. 2009, 121,
4077; Angew. Chem. Int. Ed. 2009, 48, 4017; d) F. Lꢁvesque, P. H.
Seeberger, Angew. Chem. 2012, 124, 1738; Angew. Chem. Int.
Ed. 2012, 51, 1706; e) A. Sniady, M. W. Bedore, T. F. Jamison,
Angew. Chem. 2011, 123, 2203; Angew. Chem. Int. Ed. 2011, 50,
2155; f) A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi, J.-i.
Yoshida, Angew. Chem. 2010, 122, 7705; Angew. Chem. Int. Ed.
2010, 49, 7543; g) A. R. Bogdan, S. L. Poe, D. C. Kubis, S. J.
Broadwater, D. T. McQuade, Angew. Chem. 2009, 121, 8699;
Angew. Chem. Int. Ed. 2009, 48, 8547; h) T. P. Petersen, A.
Ritzen, T. Ulven, Org. Lett. 2009, 11, 5134; i) D. Grant, R. Dahl,
N. D. P. Cosford, J. Org. Chem. 2008, 73, 7219; j) H. R. Sahoo,
J. G. Kralj, K. F. Jensen, Angew. Chem. 2007, 119, 5806; Angew.
Chem. Int. Ed. 2007, 46, 5704; k) F. Ullah, Q. Zang, S. Javed, P.
Porubsky, B. Neuenswander, G. H. Lushington, P. R. Hanson,
M. G. Organ, Synthesis 2012, 2547.
[14] For reviews of multiphase reactions in flow, see: a) J. Kobayashi,
Y. Mori, S. Kobayashi, Chem. Asian J. 2006, 1, 22; b) A.
Kirschning, W. Solodenko, K. Mennecke, Chem. Eur. J. 2006, 12,
5972; c) M. Irfan, T. N. Glasnov, C. O. Kappe, ChemSusChem
2011, 4, 300.
[21] For the exact time required for each example, see the Supporting
Information.
[15] For selected examples of SNAr reactions in flow, see: a) A. G.
OꢂBrien, Z. Horvꢃth, F. Lꢁvesque, J. W. Lee, A. Seidel-Morgen-
stern, P. H. Seeberger, Angew. Chem. 2012, 124, 7134; Angew.
Chem. Int. Ed. 2012, 51, 7028; b) J.-K. Lee, M. J. Fuchter, R. M.
Williamson, G. A. Leeke, E. J. Bush, I. F. McConvey, S. Saubem,
J. H. Ryan, A. B. Holmes, Chem. Commun. 2008, 4780; c) B. C.
Hamper, E. Tesfu, Synlett 2007, 2257; d) M. G. Organ, P. R.
Hanson, A. Rolfe, T. B. Samarakoon, U. Farman, J. Flow Chem.
2011, 1, 32.
[22] N. C. Bruno, M. T. Tudge, S. L. Buchwald, Chem. Sci. 2013, 4,
916.
À
[23] For an example of Pd-catalyzed C N bond formation in flow,
see: J. R. Naber, S. L. Buchwald, Angew. Chem. 2010, 122, 9659;
Angew. Chem. Int. Ed. 2010, 49, 9469.
[24] A 7 cm-long reactor II was used for approach A, and a 10 cm-
long reactor II was used for approach B. For more details, see the
Supporting Information.
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