Efficient Pd-catalyzed coupling of tautomerizable heterocycles with terminal alkynes via C-OH bond activation using PyBrOP

Article abstract of DOI:10.1021/ol100657n

The direct alkynylation of tautomerizable heterocylcles is described via a two-step process involving in situ C-OH activation with bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) followed by Sonogashira coupling with a wide range of alkyl or a

Full text of DOI:10.1021/ol100657n

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2286-2289
Efficient Pd-Catalyzed Coupling of
Tautomerizable Heterocycles with
Terminal Alkynes via C-OH Bond
Activation Using PyBrOP
Ce Shi and Courtney C. Aldrich*
Center for Drug Design, Academic Health Center, UniVersity of Minnesota,
Minneapolis, Minnesota 55455
aldri015@umn.edu
Received March 19, 2010
ABSTRACT
The direct alkynylation of tautomerizable heterocylcles is described via a two-step process involving in situ C-OH activation with
bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) followed by Sonogashira coupling with a wide range of alkyl or aryl terminal
alkynes using a copper-free system employing PdCl2(CH3CN)2 and 2-(dicyclohexylphosphino)biphenyl.
The Sonogashira coupling reaction1 of (hetero)aryl and vinyl
halides with terminal alkynes is the most straightforward and
efficient method to construct (hetero)arylalkynes and enynes,2
which are important substructures in organic materials,3
natural products, and medicinal agents.4 With regard to
heteroaryl halides, the corresponding iodides, bromides, and
even chlorides have been successfully employed. However,
the less reactive heteroaryl bromides and chlorides typically
require elevated temperatures with bulky phosphine ligands.5
Heteroaryl halides are conventionally derived from het-
eroarenes or heteroarenols, which are more readily available.
The conversion of these precursors to the required heteroaryl
halides can be costly and often requires toxic reagents or
multiple-step syntheses.6 Therefore, direct C-H or C-OH
activation of heteroarene compounds for cross-coupling
processes is greatly desired.7,8
(5) For recent examples, see: (a) Hundertmark, T.; Littke, A. F.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729–1731. (b) Eckhardt,
M; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642–13643. (c) Gelman, D.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993–5996. (d) Karpov,
A. S.; Muller, T. J. J. Synthesis 2003, 2815–2826. (e) Elangovan, A.; Wang,
Y.-H.; Ho, T.-I. Org. Lett. 2003, 5, 1841–1844. (f) Liang, Y.; Xie, Y.-X.;
Li, J.-H. J. Org. Chem. 2006, 71, 379–381. (g) Yi, C.; Hua, R. J. Org.
Chem. 2006, 71, 2535–2537. (h) Nakatsuji, H.; Ueno, K.; Misaki, T.;
Tanabe, Y. Org. Lett. 2008, 10, 2131–2134.
(1) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467–4470.
(2) For recent reviews, see: (a) Sonogashira, K. In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; pp 203-229. (b) Sonogashira, K. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; pp 493-529. (c) Negishi, E.; Anastasia, L.
Chem. ReV. 2003, 103, 1979–2017. (d) Chinchilla, R.; Na´jera, C. Chem.
ReV. 2007, 107, 874–922.
(6) For examples, see: (a) Nair, V.; Young, D. A. J. Org. Chem. 1985,
50, 406–408. (b) Liu, J.; Janeba, Z.; Robins, M. J. Org. Lett. 2004, 6, 2917–
2919.
(7) For recent examples and reviews, see: (a) Godula, K.; Sames, D.
Science 2006, 312, 67–72. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174–238. (c) Seregin, I. V.; Gevorgyan, V. Chem. Soc.
ReV. 2007, 36, 1173–1193. (d) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett
2008, 949–957. (e) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc.
2008, 130, 11300–11302. (f) Kang, F.-A.; Sui, Z.; Murray, W. V. Eur. J.
Org. Chem. 2009, 461–479. (g) Kang, F. A.; Lanter, J. C.; Cai, C.; Sui, Z.;
Murray, W. V. Chem. Commun. 2010, 46, 1347–1349.
(3) (a) Bunz, U. H. F. Chem. ReV. 2000, 100, 1605–1644. (b) Lee, S. H.;
Nakamura, T.; Tsutsui, T. Org. Lett. 2001, 3, 2005–2007.
(4) (a) Cooke, J. W. B.; Bright, R.; Coleman, M. J.; Jenkins, K. P. Org.
Process Res. DeV. 2001, 5, 383–386. (b) Dai, W. M.; Lai, K. W.; Wu, A.;
Hamaguchi, W.; Lee, M. Y. H.; Zhou, L.; Ishii, A.; Nishimoto, S. J. Med.
Chem. 2002, 45, 758–761.
(8) Brathe, A.; Gundersen, L.; Nissen-Meyer, J.; Rise, F.; Spilsberg, B.
Bioorg. Med. Chem. Lett. 2003, 13, 877–880.
10.1021/ol100657n  2010 American Chemical Society
Published on Web 04/22/2010

Recently, Kang and co-workers reported the Pd-catalyzed
cross-coupling reactions of tautomerizable heterocycles with
aryl boronic acids via C-OH bond activation using pho-
phonium salts as activating reagents.7e This new protocol
demonstrated excellent reactivity and chemoselectivity,
which makes it an attractive route for direct arylation of
tautomerizable heterocycles. With our longstanding interest
in synthesis and diversification of heterocycles, especially
in the field of nucleoside chemistry,10 we became very
interested in applying the C-OH activation strategy into
other types of cross-coupling reactions. Herein, we report
our studies of the Sonogashira-type reactions of tautomer-
izable heterocycles activated by bromotripyrrolidinophos-
phonium hexafluorophosphate (PyBrOP) with terminal alkynes
(Scheme 1).
Table 1. Optimization of Cross-Coupling of 2-Quinoxalinone
with 1-Octynea
convb yieldc
“Pd” conditions
(%)
(%)
condition A:d PdCl2(PPh3)2, CuI, rt
condition B:d, e PdCl2(CH3CN)2 t-Bu3P, CuI, rt
condition C:d, e PdCl2(CH3CN)2 t-Bu3P, CuI,
65 °C
100
<10
91
<10
100
<10
condition D:e, f PdCl2(CH3CN)2/P*, Cs2CO3,
85 °C
87
condition E:e, f PdCl2(CH3CN)2/P*, CuI,
Cs2CO3, 85 °C
Scheme 1
.
Pd-Catalyzed Sonogashira Reaction of
Tautomerizable Heterocycles
a General conditions: 2-quinoxalinone (0.5 mmol), PyBrOP (1.2 equiv),
and Et3N (3 equiv) in 1,4-dioxane (4 mL) at rt for 2 h; then, Pd catalyst (5
mol %), 1-octyne (1.5 equiv), with or without CuI (5 mol %), with or without
Cs2CO3 (2.5 equiv) at indicated temperature for 4 h. b Monitored by LC-MS
and 1H NMR. c Isolated yields. d 6 equiv of Et3N were used. e Pd:P ) 1:3.
f P* ) 2-(dicyclohexylphosphino)biphenyl.
Next, we investigated the substrate scope using the optimal
conditions A and D. An array of tautomerizable heterocycles
were reacted with various terminal alkynes under both
conditions, and the results are reported in Tables 2 and 3.
Under condition A, quinoxalinone 1 and benzothiazolinone
2 successfully cross-coupled with a wide variety of aryl- and
alkylacetylenes to afford 1a-f and 2d in yields ranging from
63 to 93% (Table 2). Condition A also showed excellent
functional group tolerance (-OH, -NO2, -NH2, -TMS),
and undesirable etherification or amination were not observed
in 1c and 1e (Table 2). However, the classic Sonogashira
conditions failed for substrates 3-6 (Table 3) providing no
observed cross-coupled products. Additionally, condition A
failed for coupling of 1 with 2-ethynylpyridine. For these
cases, the Buchwald catalyst system in condition D was
investigated.
Considering the diversity of tautomerizable heterocycles
and terminal alkynes, we initially explored a range of
conditions for direct alkynylation of the model substrate
2-quinoxalinone with 1-octyne. 2-Quinoxalinone was first
activated in situ with PyBrOP (1.2 equiv) and triethylamine
(3 equiv) in 1,4-dioxane at room temperature for 2 h. Several
cross-coupling conditions developed for Sonogashira cou-
pling reactions were explored. The cross-coupling was
conveniently monitored by electrospray mass spectrometry
with the dissaperance of the active alkoxyphosphonium salt
at m/z 386.2 and concomitant formation of the cross-coupling
product at m/z 239.3 [M + H]+. The classic Sonogashira
coupling conditions employing catalytic PdCl2(PPh3)2 and
CuI (condition A) furnished the desired cross-coupling
product in 91% yield in 4 h at room temperature (Table 1).
The PdCl2(CH3CN)2/t-Bu3P/CuI catalytic system in condi-
tions B and C developed by Buchwald for Sonogashira
coupling of aryl bromides led to only homocoupling of the
alkynes.5a Under condition D, a copper-free system employ-
ing PdCl2(CH3CN)2 and 2-(dicyclohexylphosphino)biphenyl
at 85 °C utilized for less reactive aryl chlorides,5c the cross-
coupling proceeded smoothly with an 87% isolated yield.
Addition of CuI to condition D provided condition E.5c
Unfortunately, only homocoupling of the alkyne was ob-
served with condition E.
The highly functionalized pyrazolo[3,4-b]pyridine 3
smoothly coupled under condition D with phenylacetylene
and triethylsilylacetylene to provide 3d and 3h in 87% and
77% yields, respectively (Table 3). Importantly, other
methods to activate the carboxamide function of 3 including
chlorination and triflation were unsuccessful due to the
presence of the basic pyridine moieties serving to highlight
the utility of the PyBrOP mediated activation. Coupling of
thieno[3,2-d]pyrimidin-4-one 4 and pyrimidin-2(1H)-one 5
employing condition D with phenylacetylene, tert-buty-
lacetylene, and 1-cyclohexenylacetylene provided 4d, 4i, 5d,
and 5j in yields ranging from 76 to 91% demonstrating the
generality of condition D.
(9) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.;
Hughes, D. L. Org. Lett. 2003, 5, 4191–4194.
(10) (a) Neres, J.; Labello, N. P.; Somu, R. V.; Boshoff, H. I.; Wilson,
D. J.; Vannada, J.; Chen, L.; Barry, C. E.; Bennett, E. M.; Aldrich, C. C.
J. Med. Chem. 2008, 51, 5349–5370. (b) Gupte, A.; Boshoff, H. I.; Wilson,
D. J.; Neres, J.; Labello, N. P.; Somu, R. V.; Xing, C.; Barry, C. E., III;
Aldrich, C. C. J. Med. Chem. 2008, 51, 7495–7507. (c) Grimes, K. D.;
Gupte, A.; Aldrich, C. C. Synthesis 2010, 1441-1448.
6-Alkynylpurine ribonucleosides have attracted attention
due to their potent cytostatic activity.11 Conventionally, these
have been prepared from protected inosines, which must be
Org. Lett., Vol. 12, No. 10, 2010
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Table 2. Substrate Screening under Conditions Aa
Table 3. Substrate Screening under Conditions Da
a General conditions: substrates (0.5 mmol), PyBrOP (1.2 equiv),
and Et3N (6 equiv) in 1,4-dioxane (4 mL) at rt for 2 h, followed by
conditions A: PdCl2(PPh3)2 (5 mol %), CuI (5 mol %), alkyne (1.5 equiv),
at rt until mass spectra shows no activated substrates. b Determined by
LC-MS and H NMR. c Isolated yields. d A solution of alkyne in 1.5 mL
1
of 1,4-dioxane was injected into the reaction vessel over 1.5 h via syringe
pump.
first converted to 6-iodopurine derivatives to obtain sufficient
reactivity to participate in cross-coupling with alkynes.6b
However, using PyBrOP activation and condition D, cross-
coupling of protected inosine derivative 6 with phenylacety-
lene and triethylsilylacetylene provided 6d and 6h in 78%
and 61% yields, respectively (Table 3).
As reported by Buchwald,5c we confirmed the trimeth-
ylsilyl (TMS) group was not compatible under condition
D, as significant desilylation of the products were ob-
served. Instead, triethylsilylacetylene was used to afford
the more stable TES-protected products (3h and 6h, Table
3). Condition D suffered from lower functional group
tolerance as 6-nitrobenzothiazolinone 2 failed to couple
due to reduction of the nitro group, and condition D also
required protection of the ribofuranosyl hydroxyl groups
in 6 to prevent Pd-catalyzed etherification. For both
conditions A and D, we observed that slow addition of
the alkyne was required to ensure complete conversion
of substrates, when using electron-rich arylacetylene (1f,
Table 2) or electron-deficient heterocycles (3 and 6, Table
3). Overall, condition A is recommended due to its greater
functional group tolerance and practicality since this is
performed at room temperature; however, condition D,
a General conditions: substrates (0.5 mmol), PyBrOP (1.2 equiv), and
Et3N (3 equiv) in 1,4-dioxane (4 mL) at rt for 2 h, followed by conditiond
D: PdCl2(CH3CN)2 (5 mol %), 2-(dicyclohexylphosphino)biphenyl (15 mol
%), and Cs2CO3 (2.5 equiv) were preincubated with the activated substrates
at rt for 25 min at 85 °C, followed by addition of alkynes. b Determined by
LC-MS and 1H NMR. c Isolated yields. d A solution of alkyne in 1,4-
dioxane (1.5 mL) was injected into the reaction vessel over 1.5 h via syringe
pump.
which require elevated temperatures, is more versatile
and allow coupling of a wider range of heterocyclic
substrates.
We propose the following mechanism for the copper-
free direct alkynylation of tautomerizable heterocycles,
based on the studies by Soheili9 (Scheme 2). The
tautomerizable heterocycle is first activated by PyBrOP
in the presence of triethylamine to afford the phosphonium
salt I. Once the active Pd(0) species is formed, the
catalytic cycle begins with the oxidative addition of the
(11) (a) Brathe, A.; Gundersen, L.-L; Nissen-Meyer, J.; Rise, F.;
Spilsberg, B. Bioorg. Med. Chem. Lett. 2003, 13, 887–880. (b) Hocek, M.;
Stepnicka, P.; Ludvik, J.; Cisarova, I.; Votruba, I.; Reha, D.; Hobza, P.
Chem.sEur. J. 2004, 10, 2058–2066.
2288
Org. Lett., Vol. 12, No. 10, 2010

Cs2CO3 and ligand exchange provides Pd(II) acetylide
complex IV, which undergos reductive elimination to
afford the cross-coupling product and regenerate the Pd(0)
species.
Scheme 2
. Proposed Mechanism of Copper-Free Sonogashira
Coupling of Tautomerizable Heterocycles
In conclusion, we have developed an efficient Pd-catalyzed
system for direct alkynylation of tautomerizable heterocycles
via C-OH bond activation using PyBrOP. The protocols
showed great versatility and efficiency, enabling cross-
couplings between a variety of tautomerizable heterocycles
and terminal alkynes with diverse electronic and steric
features. The mechanism of the direct Cu-free cross-coupling
is proposed to proceed through a stepwise process of C-OH
activation using PyBrOP followed by Cu-free Sonogashira-
type catalytic cycle.
Acknowledgment. We thank the NIH (AI070219) for
support.
Note Added after ASAP Publication. A citation reporting
the direct Sonogashira reaction of tautomerizable hetero-
cycles with alkynes using the classic Sonogashira conditions
was inadvertently omitted from ref 7 in the version published
ASAP April 22, 2010; the corrected version was published
on the Web May 14, 2010.
Supporting Information Available: Experimental pro-
cedures and characterization as well as NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
phosphonium salt I to generate Pd(II) complex II. Next,
ligand dissociation followed by alkyne complexation leads
to Pd(II) complex III. Deprotonation of the alkyne by
OL100657N
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