Palladium-Catalyzed Alkynylation and Concomitant ortho Alkylation of Aryl Iodides

Article abstract of DOI:10.1021/acscatal.6b00169

We report an efficient alkynylation reaction of aryl iodides with simultaneous ortho-alkylaton of aryl rings. The reaction between three simple reagents - aryl halides, alkynes, and alkyl halides - formed aryl-alkynyl bonds carrying hindered aryl rings in

Full text of DOI:10.1021/acscatal.6b00169

Letter
pubs.acs.org/acscatalysis
Palladium-Catalyzed Alkynylation and Concomitant ortho Alkylation
of Aryl Iodides
Chuanhu Lei, Xiaojia Jin, and Jianrong (Steve) Zhou*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
S
* Supporting Information
ABSTRACT: We report an efficient alkynylation reaction of
aryl iodides with simultaneous ortho-alkylaton of aryl rings. The
reaction between three simple reagentsaryl halides, alkynes,
and alkyl halidesformed aryl−alkynyl bonds carrying
hindered aryl rings in one step. The reaction proceeded via a
Catellani-type pathway in the presence of norbornene. From a
synthetic perspective, this reaction allows quick access toward
many 1,2,3-substituted arenes and multiply substituted
benzofurans, after manipulation of alkyne groups. These
compounds are difficult to synthesize otherwise.
KEYWORDS: alkynylation, CH activation, Catellani reaction, benzofuran, palladium catalysis
onogashira coupling of aryl halides allows efficient
formation of aryl−alkynyl bonds from terminal alkynes
Herein, we report a general alkynylation/ortho monoalkyla-
tion reaction of aryl iodides with several types of terminal
alkynes (eq 2). Different from Catallani reaction, the reaction
produces 1,2,3-substituted arenes and heteroarenes, resulting in
two different alkyl groups at ortho positions of (hetero)aryl
rings. More importantly, this reaction allows quick access to
many other 1,2,3-substituted arenes and substituted benzofur-
ans by derivatization of alkyne groups in the products.
The reaction follows a typical pathway proposed by Catellani
(eq 2).5 The key steps include norbornene insertion into
oxidative adducts, base-assisted ortho CH cleavage to form a
palladacycle, oxidative addition of alkyl halides,6 and subse-
quent selective aryl−alkyl coupling. At the end of the catalytic
cycle, ortho-alkylarylpalldium species have been trapped with a
series of carbon nucleophiles and olefins, due to efforts by
Catellani,7 Lautens,8 and others.9 However, in trapping with
terminal alkynes, the reaction was not generally useful as
premature alkynyl coupling proceeded too fast with several
upstream organopalladium species which posed a main
challenge.
S
directly.1 It has become one of the most practiced coupling
reactions and has found many applications in the synthesis of
pharmaceuticals and advanced materials.2 In 2004, Catellani et
al. described a variant of alkynylation, which introduced two
identical alkyl chains at ortho positions of aryl iodides (eq 1).3
Initially, we used a model reaction of 2-iodotoluene, t-
butylacetylene, and 1-bromohexane (eq 3) to search for suitable
catalysts and conditions (Table 1). After many experiments, we
identified that the desired coupling proceeded in good yield
(88%) when palladium acetate and tri(2-furyl)phosphine were
used as the catalyst combination (entry 1). Without added
phosphine, the reaction still afforded 59% yield (entry 2). The
ancillary ligand can also be triphenylphosphine, which gave 83%
yield (entry 3). When the loading of Pd(OAc)2 and tri(2-
The reaction was limited to only phenyl iodide and para-
substituted aryl iodides with only one alkyne, phenylacetylene.
Other terminal alkynes were reported to afford low yields,
including aliphatic alkynes, silyl acetylenes, and even electroni-
cally perturbed aryl acetylenes. Furthermore, slow addition of
reagents over a few days was necessary to minimize side
reaction such as premature alkynylation of aryl iodides.
Notably, Gu et al. recently realized alkynylation of aryl iodides
with ortho alkylation, by using 1,1-dimethyl-2-alkynols as alkyne
surrogates.4 However, these compounds were mostly synthe-
sized from the parent terminal alkynes.
Received: January 18, 2016
Revised: February 1, 2016
© XXXX American Chemical Society
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Letter
Table 1. Optimization of Palladium Catalysts and
Conditions (Calibrated GC Yields and GC Conversion of
ArX)
entry
conditions
no change
conv (%)
P (%)
A (%)
B (%)
1
2
3
4
5
6
7
8
9
10
100
75
88
59
83
60
54
68
40
85
81
79
10
11
6
1
5
no P(2-furyl)3
PPh3
100
100
100
100
100
100
100
100
3
Pd(OAc)2 (5%)
K2CO3
10
5
30
12
21
2
K3PO4
6
DMF solvent
nornornene (0.5×)
no NaI
1
14
16
5
1
Figure 1. Scope of alkyl halides in alkynylation and ortho alkylation.
3
1-iodohexane
15
furyl)phosphine was halved, the yield dropped to 64% and a
significant amount of byproduct B was detected (entry 4). B
was derived from premature alkynyl coupling of a 2-
arylnorbornylpalladium complex.
The choice of the base and solvent was also very important
(Table 1). For example, weaker bases such as potassium
carbonate and potassium phosphate led to a significant amount
of byproduct B (entries 5−6), due to inefficient ortho CH
activation to form the key palladacycle. Furthermore, MeCN
was the solvent of choice. In other solvents such as DMF, a very
complex mixture resulted (entry 7). Thus, our understanding is
that the judicious choice of the base and solvent ensured that
the acetylide anion was produced in low concentrations from
alkynes during catalysis, which helped to prevent premature
alkynyl couplings. The challenge is that the same base should
also be strong enough for ortho CH activation to form the
palladacycle (eq 2). The typical procedure used 2 equiv of
norbornene and 2 equiv of NaI to ensure good yields of
coupling products during isolation of products. When the
amount of norbornene was reduced to 0.5 equiv, the yield from
the model reaction still remained good (entry 8). Moreover,
without the additive NaI, the yield dropped slightly (entry 9).
We also found that 1-iodohexane can be used to replace alkyl
bromide and NaI (entry 10).
The new procedure was successfully applied to couplings of
many primary alkyl bromide and base-sensitive esters and
nitriles groups were tolerated (Figure 1). In reactions using
alkyl iodides, NaI was unnecessary. Two examples of secondary
alkyl iodides also reacted to give moderate yields. In the
coupling of isopropyl iodide, t-butylacetylene did give the
desired product, but it was too volatile for isolation. In the
reaction of n-hexyl chloride, n-Bu4NI was added to in situ
convert it to the alkyl iodide which eventually afforded good
yield. However, t-butyl iodide did not afford the desired
product and only provided byproducts A and B.
Figure 2. Scope of aryl iodides carrying (a) ortho-substituents and (b)
para-substituents in alkynylation and ortho alkylation.
pyridine, too. In reactions of PhI and para-substituted aryl
halides, only 2,6-dialkylation products were isolated in
reasonably good yields (Figure 2b). The dialkylation was also
observed with 3-iodothiophene. We noticed that meta-
substituted aryl iodides led to major products with structures
similar to B (see Table 1).
Next, we examined the scope of alkynes using 2-tolyl and 2-
anisyl iodides. Fortunately, our method was applicable to
terminal alkyl alkynes and silyl alkynes after fine-tuning of
ancillary phosphines. A sampling of the ligand effect is shown in
Figure 3. For couplings of 1-octyne, tri(2-furyl)phosphine gave
very poor yields while electron-neutral ligands including PPh3
With respect to the scope of aryl iodides, aryl iodides bearing
ortho CF3 and OMe groups reacted smoothly (Figure 2a).
Notably the reaction of 1-iodonaphthalene resulted in selective
C2 alkylation. The procedure was applicable to a substituted
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Scheme 1. Functional Group Manipulation of Alkynes: (a)
Hydrogenation and Semihydrogenation; (b) Acidic
Hydration and trans Dihalogenation; (c) Electrophilic
Cyclization To Form Benzofurans
When the alkyne was treated with ICl, we obtained a product
derived from trans dihalogenation, and no cyclization was
detected (Scheme 1b).12 The position of the iodine in the
product was confirmed by HMBC-NMR spectroscopy. A
similar trans dihalogenation reaction took place in the presence
of I2. Furthermore, acid-catalyzed hydration of the alkyne
afforded selectively a highly hindered aryl ketone.13
Substituted benzofurans are commonly present in bioactive
natural products,14 drug candidates,15 and advanced materials.16
In recent years, many metal-catalyzed reactions were invented
to build the heterocyclic rings.17 When the alkyne was treated
with I2 and a disulfide (PhS)2 in the presence of PdCl2 catalyst,
electrophilic annulation took place to form a benzofuran ring.18
We suspected that prior O-demethylation of the anisole by
thiophenol was critical to initiating the electrophilic cyclization.
We next conducted BBr3-promoted O-demethylation, and
subsequent iodonium-induced cyclization proceeded smoothly
to form substituted 2-iodobenzofurans (Scheme 1c).19 Without
demethylation, we could not realize the cyclization under many
conditions. The multiply substituted benzofurans bearing C7
alkyl groups are difficult to synthesize otherwise.
We added TEMPO (1 equiv) to the model reaction (eq 3) to
trap possible radical species. No TEMPO-trapped species was
detected while the yields of the product and byproducts were
virtually unchanged.
To gain support for the Catellani-type pathway (shown in eq
2), we synthesized and tested competence of a palladacycle D
under conditions similar to catalytic reactions (Figure 4a). The
stoichiometric reaction gave a complex mixture containing the
desired product P in modest yield (∼30%). The main
byproduct C was derived from direct C−C reductive
elimination from palladacycle D.20 Adding tri-2-furylphosphine
to the stoichiometric reaction did not improve the yield of P
but reduced the amount of byproduct C.
Figure 3. Scope of (a,b) aliphatic alkynes, (c) silyl alkynes, and (d)
aryl alkynes in alkynylation and ortho alkylation.
provided moderate yields (Figure 3a). The main byproducts
were identified to be of type A and B. For couplings of
isopropyl acetylene and silyl acetylenes, we found that slightly
electron-rich tri(4-tolyl)phosphine was the ligand of choice
(Figure 3b,c). In comparison, both tri(2-furyl)phosphine and
PPh3 afforded much lower yields. For aromatic alkynes, to our
surprise, phosphines inhibited the productive pathway. The
desired products were obtained in reasonable yields under
phosphine-free conditions, after we adjusted the base and
solvent (Figure 3d). Thus, terminal alkynes bearing both
electron−rich and poor aryl groups reacted to give satisfactory
yields. Notably, slow addition of reagents was not used. In
comparison, Catellani conditions (as in eq 1) only led to poor
yields for reactions of these alkynes.
Our method for aryl alkynylation and ortho alkylation allows
quick access to many 1,2,3-substituted benzene derivatives
(Scheme 1a). For examples, the alkyne was fully hydrogenated
by palladium over charcoal to give three different alkyl groups
at neighboring positions on the arene. There are no other
simple reactions to prepare them, especially if three alkyl
groups are different.10 In addition, palladium-catalyzed transfer
hydrogenation via Hua’s procedure11 gave a cis olefin with
complete geometric selectivity.
We also studied H/D exchange between t-butylacetylene and
CD3CN solvent in the presence of cesium carbonate. Rather
slow deprotonation was observed at 60 °C over hours as judged
by both proton and deteuron NMR spectroscopies (Figure 4b).
Comparatively, phenylacetylene bearing a more acidic CH
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(2) Examples: (a) King, A.; Yasuda, N. Top. Organometal. Chem.
2004, 6, 205−245. (b) Frigoli, S.; Fuganti, C.; Malpezzi, L.; Serra, S.
Org. Process Res. Dev. 2005, 9, 646−650.
(3) Motti, E.; Rossetti, M.; Bocelli, G.; Catellani, M. J. Organomet.
Chem. 2004, 689, 3741−3749.
(4) (a) Sun, F.; Li, M.; Gu, Z. Org. Chem. Frontiers 2016, DOI:
10.1039/c1035qo00391a. Realated alkynylation reactions with ortho
amination using acetylenic carboxylic aicds as alkyne surrogates:.
(b) Sun, F.; Gu, Z. Org. Lett. 2015, 17, 2222−2225. (c) Pan, S.; Ma,
X.; Zhong, D.; Chen, W.; Liu, M.; Wu, H. Adv. Synth. Catal. 2015, 357,
3052−3056.
(5) Reviews: (a) Catellani, M.; Motti, E.; Della Ca’, N. Acc. Chem.
Res. 2008, 41, 1512−1522. (b) Chiusoli, G. P.; Catellani, M.; Costa,
M.; Motti, E.; Della Ca’, N.; Maestri, G. Coord. Chem. Rev. 2010, 254,
456−469. (c) Martins, A.; Mariampillai, B.; Lautens, M. Top. Curr.
Chem. 2009, 292, 1−33. (d) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J.
S. Chem. Rev. 2010, 110, 824−889. (e) Ferraccioli, R. Synthesis 2013,
45, 581−591. (f) Ye, J.; Lautens, M. Nat. Chem. 2015, 7, 863−870.
(6) (a) Tremont, S. J.; Hayat Ur Rahman. J. Am. Chem. Soc. 1984,
106, 5759−5760. (b) Bocelli, G.; Catellani, M.; Ghelli, S. J. Organomet.
Chem. 1993, 458, C12−C15.
Figure 4. (a) Stoichiometric reaction of complex D. H/D exchange of
(b) t-butyl acetylene and (c) phenyl acetylene in the presence of a
base.
(7) Examples: (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew.
Chem., Int. Ed. Engl. 1997, 36, 119−122. (b) Catellani, M.; Motti, E.;
Minari, M. Chem. Commun. 2000, 36, 157−158. (c) Della Ca’, N.;
Maestri, G.; Catellani, M. Chem. - Eur. J. 2009, 15, 7850−7853.
(8) Examples: (a) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem.
Soc. 2005, 127, 13148−13149. (b) Martins, A.; Alberico, D.; Lautens,
M. Org. Lett. 2006, 8, 4827−4829. (c) Rudolph, A.; Rackelmann, N.;
Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485−1488.
(d) Blaszykowski, C.; Aktoudianakis, E.; Alberico, D.; Bressy, C.;
Hulcoop, D. G.; Jafarpour, F.; Joushaghani, A.; Laleu, B.; Lautens, M. J.
Org. Chem. 2008, 73, 1888−1897. (e) Blanchot, M.; Candito, D. A.;
Larnaud, F.; Lautens, M. Org. Lett. 2011, 13, 1486−1489.
(f) Weinstabl, H.; Suhartono, M.; Qureshi, Z.; Lautens, M. Angew.
Chem., Int. Ed. 2013, 52, 5305−5308.
(9) Examples: (a) Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu, Z. J. Am. Chem.
Soc. 2013, 135, 9318−9321. (b) Zhang, H.; Chen, P.; Liu, G. Angew.
Chem., Int. Ed. 2014, 53, 10174−10178. (c) Lei, C.; Jin, X.; Zhou, J.
Angew. Chem., Int. Ed. 2015, 54, 13397−13400.
(10) Li, C.; Chen, T.; Li, B.; Xiao, G.; Tang, W. Angew. Chem., Int. Ed.
2015, 54, 3792−3796.
(11) Li, J.; Hua, R.; Liu, T. J. Org. Chem. 2010, 75, 2966−2970.
(12) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.
Synlett 1999, 1999, 1432−1434. (b) Yue, D.; Yao, T.; Larock, R. C. J.
Org. Chem. 2005, 70, 10292−10296.
(13) (a) Olivi, N.; Thomas, E.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Synlett 2004, 15, 2175−2179. (b) Hintermann, L.; Labonne, A.
Synthesis 2007, 2007, 1121−1150. (c) Jacubert, M.; Hamze, A.; Provot,
O.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2009, 50,
3588−3592.
(14) Examples: (a) La Clair, J. J.; Rheingold, A. L.; Burkart, M. D. J.
Nat. Prod. 2011, 74, 2045−2051. (b) Bharate, S. B.; Sawant, S. D.;
Singh, P. P.; Vishwakarma, R. A. Chem. Rev. 2013, 113, 6761−6815.
(c) Simonetti, S. O.; Larghi, E. L.; Bracca, A. B. J.; Kaufman, T. S. Nat.
Prod. Rep. 2013, 30, 941−969.
(15) Examples: (a) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem.
2002, 45, 2670−2673. (b) Aslam, S. N.; Stevenson, P. C.; Phythian, S.
J.; Veitch, N. C.; Hall, D. R. Tetrahedron 2006, 62, 4214−4226.
(c) Zareba, K. M. Drugs Today 2006, 42, 75−86. (d) Bakunov, S. A.;
Bakunova, S. M.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.;
Tidwell, R. R. J. Med. Chem. 2008, 51, 6927−6944. (e) Zhang, P.;
Yang, Y.; Zheng, X.; Huang, W.; Ma, Z.; Shen, Z. Chem. Pharm. Bull.
2012, 60, 270−274. (f) Yempala, T.; Sridevi, J. P.; Yogeeswari, P.;
Sriram, D.; Kantevari, S. Bioorg. Med. Chem. Lett. 2013, 23, 5393−
5396.
bond underwent faster H/D exchange (Figure 4c). Thus, we
concluded that the catalytic conditions produced the acetylide
anion in low concentrations, and the deprotonation process
may not need the assistance of palladium catalysts.
In summary, we report a general method for alkynylation of
the aryl halides with ortho alkylation. More importantly, the
reaction allows convenient access to many 1,2,3-substituted
arenes and substituted benzofurans by simple transformations
of alkyne groups. These benzene and benzofuran derivatives
with unique patterns of substitution are difficult to synthesize
via other reactions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b00169.
■
S
Procedures for alkyne couplings, characterization of
products PDF)
Clean NMR spectra of products as proof of purity for
isolated compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: jrzhou@ntu.edu.sg.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Singapore Ministry of Education Academic Research
Fund (MOE2013-T2-2-057 and MOE2014-T1-001-021) for
financial support.
REFERENCES
■
(1) Reviews: (a) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu,
G. C. Org. Lett. 2000, 2, 1729−1731. (b) Sonogashira, K. J. Organomet.
Chem. 2002, 653, 46−49. (c) Gelman, D.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2003, 42, 5993−5996. (d) Negishi, E.-i.; Anastasia, L.
́
Chem. Rev. 2003, 103, 1979−2018. (e) Chinchilla, R.; Najera, C.
Chem. Rev. 2007, 107, 874−922. (f) Doucet, H.; Hierso, J.-C. Angew.
Chem., Int. Ed. 2007, 46, 834−871. (g) Singh, B. K.; Kaval, N.; Tomar,
S.; Van der Eycken, E.; Parmar, V. S. Org. Process Res. Dev. 2008, 12,
(16) Examples: (a) Tsuji, H.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura,
E. J. Am. Chem. Soc. 2007, 129, 11902−11903. (b) Walker, B.;
Tamayo, A. B.; Dang, X.-D.; Zalar, P.; Seo, J. H.; Garcia, A.;
468−474. (h) Chinchilla, R.; Naj
́
era, C. Chem. Soc. Rev. 2011, 40,
5084−5121.
1638
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Letter
Tantiwiwat, M.; Nguyen, T.-Q. Adv. Funct. Mater. 2009, 19, 3063−
3069.
(17) Reviews: (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem.
Rev. 2003, 103, 893−930. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004,
104, 2285−2310. (c) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
4644−4680. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108,
3395−3442. (e) Abu-Hashem, A. A.; Hussein, H. A. R.; Aly, A. S.;
Gouda, M. A. Synth. Commun. 2014, 44, 2285−2312. (f) Heravi, M.
M.; Zadsirjan, V. Adv. Heterocycl. Chem. 2015, 117, 261−376.
(18) Du, H.-A.; Zhang, X.-G.; Tang, R.-Y.; Li, J.-H. J. Org. Chem.
2009, 74, 7844−7848.
(19) Li, Y.-L.; Li, J.; Yu, S.-N.; Wang, J.-B.; Yu, Y.-M.; Deng, J.
Tetrahedron 2015, 71, 8271−8277.
(20) (a) Catellani, M.; Chiusoli, G. P.; Ricotti, S. J. Organomet. Chem.
1985, 296, C11−C15. (b) Chai, D. I.; Thansandote, P.; Lautens, M.
Chem. - Eur. J. 2011, 17, 8175−8188. (c) Wu, X.; Zhou, J. Chem.
Commun. 2013, 49, 11035−11037.
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