Solution to the C3-Arylation of Indazoles: Development of a Scalable Method

Article abstract of DOI:10.1021/acs.orglett.6b01456

3-(Hetero)arylindazoles are important motifs in several biologically active compounds. Mild and flexible palladium-mediated Negishi reaction conditions are reported for the introduction of (hetero)aryl moieties at the 3-position of N(2)-SEM-protected inda

Full text of DOI:10.1021/acs.orglett.6b01456

Letter
pubs.acs.org/OrgLett
Solution to the C3−Arylation of Indazoles: Development of a Scalable
Method
Kallol Basu,*,‡ Marc Poirier,*,‡ and Rebecca T. Ruck
Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: 3-(Hetero)arylindazoles are important motifs in
several biologically active compounds. Mild and flexible
palladium-mediated Negishi reaction conditions are reported
for the introduction of (hetero)aryl moieties at the 3-position
of N(2)-SEM-protected indazoles in high yields. The requisite
Zn-species are readily obtained via regioselective deprotona-
tion and subsequent transmetalation. The methodology
tolerates a variety of functional groups on both coupling
partners and has been extended to bis-haloarene and
heteroarene coupling partners where the most reactive halogen reacts first, leaving the second halogen for subsequent
functionalization.
ndazoles represent a class of heterocycles that have gained
Itremendous popularity among medicinal chemists in recent
yearsduetotheirgrowingapplications indrugdiscovery.1,2 These
compounds perform as efficient isosteres for privileged structures
such as indoles and benzimidazoles. While indazoles with
different substitution patterns are well-known, indazoles with
(hetero)aryl groups in the 3-position are of increasing interest
(compound 1, Figure 1). Unfortunately, access to this class of
heterocycles is limited because of few general synthetic methods
for their preparation.3
method. It was envisioned that Negishi cross-coupling could
provide an attractive solution to this synthetic challenge. Knochel
described such a strategy, coupling 3-indazolyl zinc species,
generated by regioselective zincation using TMP2Zn·2MgCl2·
2LiCl, with a series of aryl iodides to furnish 3-arylindazoles.8
While attractive, wide application of this methodology is
restricted by the limited availability of aryl iodide coupling
partners; aryl bromides and chlorides were unreactive under the
reported conditions. Given the increasing number of applications
of 3-arylindazoles in the pharmaceutical industry, a general
method for the preparation of this synthetically challenging class
of molecules is needed. In this letter, we report the development
of a simple, mild, robust, and scalable method for the preparation
of 3-arylindazoles that addresses each of these key criteria.
The regioselective 3-lithiation of N(2)-SEM-protected in-
dazole employing n-butyllithium is known (Scheme 1).9 We
hypothesized that such a lithiated species (2B) could be
transmetalated with ZnCl2 to form an intermediate zinc-species
(2C) in situ, which would participate in a palladium-catalyzed
cross-coupling reaction with aryl halides. The strategy was
Figure 1. General strategy for C(3)-arylation of indazoles.
The most common methods for the direct introduction of
(hetero)aryl moieties at C(3) of indazoles rely on Stille4 or
Suzuki−Miyaura5 couplings. Key liabilities of these methods are
the use of toxic tin reagents for the Stille coupling and competing
proto-dehalogenation under standard Suzuki conditions. Re-
cently, iridium,6 copper,7a and palladium-mediated7a,b methods
involving direct C−H activation reactions at the 3-position of
indazoles have been described for the introduction of an aryl
moiety. Unfortunately, these methods require high temperatures
(100−165 °C) and may be incompatible with sensitive
functionalities. As part of a drug discovery program, efficient
access to 3-(hetero)aryl indazoles was required to enable the
preparation of a range of substituted indazoles. Initial attempts
employing both the Stille and Suzuki protocols met with limited
success, thus necessitating the development of an alternative
Scheme 1. Design Plan
Received: May 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01456
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Letter
conceived with a desire to make use of cheap and readily available
(hetero)aryl bromides and chlorides. In order to achieve this goal,
we explored Pd-precatalysts that form reactive mono- or
bisphosphine Pd species in situ due to their ability to oxidatively
add to aryl bromides and chlorides, a feature we hoped we could
exploit in developing this cross-coupling reaction.10
We began our investigation by probing the Negishi coupling
between the Zn-species generated from indazole 2a and 3-
bromobenzonitrile (Table 1) mediated by a variety of palladium
handlingandsuperiorcatalyticactivity, weselectedtheG2-XPhos
precatalyst for further optimization. Higher temperature (40 °C)
significantly improved the reaction kinetics, leading to the
complete consumption of 3-bromobenzonitrile within 1 h.
Employment of 5 mol % catalyst loading proved ideal for our
application, whereas the use of lower catalyst loadings required
extended reaction times to achieve full conversion.
Both electron-poor and electron-rich aromatic bromides were
compatible coupling partners in this chemistry (Scheme 2). The
a
a
Table 1. Catalyst Selection and Reaction Optimization
Scheme 2. Substrate Scope for C(3)-Arylation
a
Conversion based on HPLC area percent, uncorrected. Reaction
conditions: n-BuLi (1.3 equiv, 2.5 M solution in hexane), THF, −70
°C, 45 min, ZnCl2 (1.3 equiv, 1.0 M solution in THF), warm to 0 °C,
30 min, 3-bromobenzonitrile (1.0 equiv), Pd-catalyst (5 mol %), THF,
rt, 15 h.
a
Reaction conditions: n-BuLi (1.3 equiv, 2.5 M solution in hexane),
THF, −70 °C, 45 min, ZnCl2 (1.3 equiv, 1.0 M solution in THF),
precatalysts. After carrying out the reactions at room temperature
for 15 h, it was found that 5 mol % of G2-XPhos, RuPhos, and
XantPhos precatalysts provided high conversions to product
(85% by HPLC), while other G2-precatalysts (e.g., SPhos,
warm to 0 °C, 30 min, (Het)ArBr (1.0 equiv), G2-XPhos (5 mol %),
b
THF, 40 °C, 1 h. 2-Chloropyrazine was used as coupling partner.
cYields in the parentheses are for reactions conducted at room
temperature.
t
tBuXantPhos, P(o-Tol)3, Bu3P) resulted in low conversions
(∼10%). Interestingly, reactions catalyzed by Pd(PPh3)4
proceeded in 60% conversion after 15 h.11 Other palladium
sourcessuchasPd(PPh3)2Cl2 andPd(dppf)Cl2 provedineffective
at catalyzing the cross-coupling reaction at room temperature
(<10% conversion byHPLC). Additionally, the couplingreaction
performed poorly in the presence of Pd(OAc)2 (5 mol %) and
XPhos (10 mol %) (entry 12). These observations suggested a
poor reducing ability of the intermediate Zn-species to convert
Pd(II) to Pd(0) under the reaction conditions. Given its ease of
cross-coupling reaction was successfully extended to nucleophile-
and base-sensitive aryl bromides, such as 4-bromobenzaldehyde
and 3-bromoacetophenone, to produce 3c and 3d in high yields.
Reactions with 4-bromochlorobenzene occurred exclusively at
the bromo substituent, enabling the synthesis of compound 3f,
which is suitable for additional functionalization at the chloride.
Thepresenceofanorthosubstituentonthearylbromidesubstrate
B
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Letter
a
had nodetrimental effect on the reaction, asillustrated bythe high
isolated yield of compound 3g (92%).
Scheme 4. Scale-up of a Key Intermediate
We next turned our attention to the coupling reaction with
substituted indazole derivatives. Reactions with sterically
hindered 4-methylindazole provided compounds 3j and 3k in
84% and 87% isolated yields, a testament to the robustness of this
newly developed method. 5-Chloroindazole derivatives (3l, 3m,
and 3n) were produced in moderate to high yields (59−68%)
when coupled at 40 °C. Products derived from electron-rich
indazoles, (3o and 3p) were also prepared, albeit in modest yields
at40°C. Gratifyingly, theyieldswereimprovedsignificantly(81%
and 74%, respectively) by carrying out the reactions at room
temperature, demonstrating the sensitive nature of zinc species
generated from electron-rich indazoles at higher temperatures.
In order to achieve a broader substrate scope for this
transformation, we next explored the coupling reaction with
aromatic chlorides (Scheme 3). To this end, we tested the
a
Reaction conditions: n-BuLi (1.3 equiv, 2.5 M solution in hexane),
THF, −70 °C, 45 min, ZnCl2 (1.3 equiv, 1.0 M solution in THF),
warm to 0 °C, 30 min, 4a (1.0 equiv), Pd(PPh3)4 (5 mol %), rt,
overnight.
5awasisolatedin70%yield(Scheme4). Employingthisprotocol,
we were able to prepare 150 g of 5a in 70% yield, demonstrating
the robustness and scalability of this strategy.
Extension of this observation to other activated dihalo-aryl
derivatives is further illustrated in Table 2. The examples follow
Scheme 3. Substrate Scope for C(3)-Arylation with Aryl
Chlorides
a
a
Table 2. C(3)-Arylation of Indazoles with Dihalides
a
Reaction conditions: n-BuLi (1.3 equiv, 2.5 M solution in hexane),
THF, −70 °C, 45 min, ZnCl2 (1.3 equiv, 1.0 M solution in THF),
warm to 0 °C, 30 min, Ar−Cl (1.0 equiv), G2-XPhos (5 mol %), THF,
40 °C, 5 h.
reaction between chlorobenzene with the zinc species derived
fromindazole 2ainthepresence ofG2-XPhos precatalyst atroom
temperature. This combination resulted in low conversion (<5%)
after 24 h; however, the reaction proceeded to completion when
carried out at elevated temperature (40 °C) for 5 h, furnishing the
desired adduct 3q in 88% isolated yield. These optimized
conditions were then tested on other electron-deficient, base-
sensitive, electron-rich and sterically demanding aryl chlorides to
furnish the desired adducts in high isolated yields (Scheme 3).
As part of a medicinal chemistry program, we needed to
synthesize multigram quantities of compound 5a, where the
chloride would be utilized as a handle for late-stage derivatization
for rapid SAR development (Scheme 4). While Suzuki coupling
reactions gave the product in low yield (20%), our newly
optimized Negishi conditions described here resulted in an
unselective reaction resulting in the formation of a number of
undesired byproducts. The effects of temperature and concen-
tration were briefly probed without much success, leading us to
conclude that the high reactivity of the G2-XPhos precatalyst is
detrimental to cross-coupling reactions with activated bis-halo
aryl derivatives such as compound 4a.
a
Reaction conditions: n-BuLi (1.3 equiv, 2.5 M solution in hexane),
THF, −70 °C, 45 min, ZnCl2 (1.3 equiv, 1.0 M solution in THF),
warm to 0 °C, 30 min, 4 (1.0 equiv), Pd(PPh3)4 (5 mol %), rt,
overnight.
the expected reactivity trend whereby the coupling occurs
preferentially at the more reactive halogen, and the less reactive
carbon−halogen bond remains intact. Reactions with aryl iodides
4b and 4c afforded 5b and 5c in 78% and 93% yields when using
Pd(PPh3)4.12 Giventhecollective resultspresented here, itisclear
that this new protocol has broad applications for accessing
chemical entities that are difficult to access by previous methods.
Wehypothesized thatalessactivePd-catalystcouldprovidethe
desired selectivity, and we turned our attention to Pd(PPh3)4,
which had exhibited only modest reactivity in our original catalyst
screening. Indeed, when the cross-coupling reaction was carried
out with 1.1 equiv of 4,6-dichloropyrimidine (4a) in the presence
of 5 mol % Pd(PPh3)4 at room temperature, the desired product
C
DOI: 10.1021/acs.orglett.6b01456
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Letter
Author Contributions
The SEM group in the resulting 3-arylindazoles can be easily
removed in high yields by treatment with HCl in methanol at 50
°C for 30 min (Scheme 5) to reveal the unprotected indazole
‡These authors contributed equally to this work.
Notes
a
The authors declare no competing financial interest.
Scheme 5. Removal of SEM Group
ACKNOWLEDGMENTS
■
The authors thank Patrick Fier, Jingjun Yin, L.-C. Campeau,
Kevin Maloney, and Jeffrey Kuethe (all at Merck) for helpful
adviceandguidanceduringthepreparation ofthemanuscript. We
also thank Peter Dormer (Merck) for help with NMR studies for
structure confirmation.
REFERENCES
■
(1) (a) Stadlbauer, W. Sci. Synth 2002, 12, 227. (b) Malamas, M. S.;
Millen, J.J. Med.Chem. 1991,34,1492. (c)Peruncheralathan, S.;Khan,T.
A.;Ila, H.;Junjappa, H. Tetrahedron2004, 60, 3457. (d)Pabba, C.;Wang,
H.-J.; Mulligan, S. R.; Chen, Z.-J.; Stark, T. M.; Gregg, B. T. Tetrahedron
Lett. 2005, 46, 7553. (e) Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S.
Tetrahedron 1999, 55, 6917. (f) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.;
Rodgers, J. D.; Nugiel, D. A. J. Org. Chem. 1997, 62, 5627. (g) Batt, D. G.;
Petraitis, J. J.; Houghton, G. C.; Modi, D. P.; Cain, G. A.; Corjay, M. H.;
Mousa, S. A.; Bouchard, P. J.; Forsythe, M. S.; Harlow, P. P.; Barbera, F.
A.; Spitz, S. M.; Wexler, R. R.; Jadhav, P. K. J. Med. Chem. 2000, 43, 41.
(2)(a)LoGrasso, P.;Kamenecka, T. Mini-Rev. Med. Chem. 2008, 8, 755.
(b)Ali, S.;BashirAhmad, D.;Vidya, P.;Mazahar, F. Mini-Rev. Med.Chem.
2013, 13, 1792. (c) Clutterbuck, L. A.; Garcia Posada, C.; Visintin, C.;
Riddall, D. R.; Lancaster, B.; Gane, P. J.; Garthwaite, J.; Selwood, D. L. J.
Med. Chem. 2009, 52, 2694. (d) Magano, J.; Waldo, M.; Greene, D.;
Nord, E. Org. Process Res. Dev. 2008, 12, 877. (e) Ananda, T.; Maninder,
M.; Sharad, W.; Shyam, A.; Balasubramanian, N. Med. Chem. Res. 2012,
21, 1509.
(3) (a) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem.
2008, 2008, 4073. (b) Gaikwad, D. D.; Chapolikar, A. D.; Devkate, C. G.;
Warad, K. D.; Tayade, A. P.; Pawar, R. P.; Domb, A. J. Eur. J. Med. Chem.
2015, 90, 707. (c) Chen, C.; Tang, G.; He, F.; Wang, Z.; Jing, H.; Faesler,
R. Org. Lett. 2016, 18, 1690. (d) Cheng, Y.;Li, G.; Liu, Y.;Shi, Y.; Gao, G.;
Wu, D.; Lan, J.; You, J. J. Am. Chem. Soc. 2016, 138, 4730.
(4) Fraile, A.; Martín, M. R.; Ruano, J. L. G.; Díaz, J. A.; Arranz, E.
Tetrahedron 2011, 67, 100.
a
Reaction conditions: HCl (4.0 M solution in 1,4-dioxane, 1 equiv),
MeOH, 50 °C, 30 min.
pharmacophores. Combined with its facile regioselective
installation and the exquisitely selective C(3)-deprotonation it
enables, this simple deprotection renders this strategy general for
preparing this useful class of compounds.
In summary, a challenging problem associated with the direct
introduction of (hetero)aryl moieties at the C(3) position of
indazoles has been solved through the development of a mild,
practical, robust, and scalable Negishi coupling protocol. This
method exhibits high functional group tolerance and is opera-
tionally simple. While the use of the highly active G2-XPhos
precatalyst provides convenient access to 3-arylindazoles within 1
h, the judicious choice of the less active Pd(PPh3)4 at room
temperature provides access to halogenated indazole adducts in
which the remaining halogen can be subjected to late-stage
derivatization. Additionally, the successful coupling of aryl
chlorides under these conditions provides a unique choice of
coupling partners not previously demonstrated. The robustness
and scalability of this methodology was demonstrated by the
synthesis of150gof indazole 5ainasinglereaction. Weanticipate
rapid adoption of this methodology toward the preparation of 3-
arylindazoles possessing a range of functionality and substitution
patterns.
(5) Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron 1999,
55, 6917.
(6) Sadler, S. A.; Hones, A. C.; Roberts, B.; Blakemore, D.; Marder, T.
B.; Steel, P. G. J. Org. Chem. 2015, 80, 5308.
(7) (a) Hattori, K.; Yamaguchi, K.; Yamaguchi, J.; Itami, K. Tetrahedron
2012, 68, 7605. (b) Ye, M.; Edmunds, A. J. F.; Morris, J. A.; Sale, D.;
Zhang, Y.; Yu, J. − Q. Chem. Sci. 2013, 4, 2374.
(8) Unsinn, A.; Knochel, P. Chem. Commun. 2012, 48, 2680.
(9) Luo, G.; Chen, L.; Dubowchik, G. J. Org. Chem. 2006, 71, 5392.
(10) For a review on palladium precatalysts, see: Bruneau, A.; Roche,
M.; Alami, M.; Messaoudi. ACS Catal. 2015, 5, 1386.
(11) This is in stark contrast to Knochels’s finding where Pd(PPh3)4
failed to participate in the coupling reaction.
(12) Structure of 5d was confirmed by 2D-NMR studies.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b01456.
Experimental data and characterization of all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kallol.basu@merck.com.
*E-mail: marc.poirier@merck.com.
D
DOI: 10.1021/acs.orglett.6b01456
Org. Lett. XXXX, XXX, XXX−XXX