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C. J. Maddocks et al.
Letter
Synlett
52, 8611. (k) Natte, K.; Dumrath, A.; Neumann, H.; Beller, M.
Angew. Chem. Int. Ed. 2014, 53, 10090. (l) Qi, X.; Li, C.-L.; Jiang,
L.-B.; Zhang, W.-Q.; Wu, X.-F. Catal. Sci. Technol. 2016, 6, 3099.
(m) Jiang, L.-B.; Qi, X.; Wu, X.-F. Tetrahedron Lett. 2016, 57,
3368. (n) Wu, F.-P.; Peng, J.-B.; Meng, L.-S.; Qi, X.; Wu, X.-F.
ChemCatChem 2017, 9, 3121. (o) Peng, J.-B.; Qi, X.; Wu, X.-F.
Synlett 2017, 28, 175.
Li
O
NH
O
(1.1 equiv)
(2.4 equiv)
3a
2.0 mmol
THF (4 mL)
120 °C
4 h
0 °C to r.t.
MeO
11, 67%
1 h
Scheme 5 One-pot two-step ketone synthesis from 3a
(7) Fujihara, T.; Hosoki, T.; Katafuchi, Y.; Iwai, T.; Terao, J.; Tsuji, Y.
Chem. Commun. 2012, 48, 8012.
(8) Ueda, T.; Konishi, H.; Manabe, K. Org. Lett. 2012, 14, 3100.
(9) Godfrey, A. G.; Masquelin, T.; Hemmerle, H. Drug Discovery
Today 2013, 18, 795.
reactor. Importantly, we verified that this reagent will not
begin to generate CO pressure in the reactions until they are
heated. We also demonstrated the ease with which a repre-
sentative 8-acyloxyquinoline product from these carbon-
ylations could be converted into a range of amide and ester
derivatives or even a ketone. We expect that this method
will be useful in medicinal-chemistry laboratories, as well
as in other settings where it is desirable to avoid the use of
high-pressure CO sources.
(10) Ueda, T.; Konishi, H.; Manabe, K. Org. Lett. 2012, 14, 5370.
(11) N-Hydroxysuccinimidyl formate has also been reported to act
as a solid CO surrogate that yields active esters, but it liberates
CO at room temperature when treated with Et3N; see Support-
ing Information of: Barré, A.; Tînţaş, M.-L.; Alix, F.; Gembus, V.;
Papamicaël, C.; Levacher, V. J. Org. Chem. 2015, 80, 6537.
(12) Suggs, J. W.; Pearson, G. D. N. Tetrahedron Lett. 1980, 21, 3853.
(13) Ho, T.-L. Synth. Commun. 1977, 7, 393.
(14) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder, T.
E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102.
Funding Information
(15) (a) For a report on the second-generation palladacycle family,
see: Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073. (b) For a report on the use of the fourth-generation
Xantphos palladacycle in carbonylations, see: Friis, S. D.;
Skrydstrup, T.; Buchwald, S. L. Org. Lett. 2014, 16, 4296.
(16) Barnard, C. F. J. Org. Process Res. Dev. 2008, 12, 566.
(17) It is crucial that reactions are always conducted at or above the
minimum working volume for the tube size chosen to avoid
overheating and possible vessel failure due to incorrect tem-
perature measurements in the microwave.
This research was funded by Eli Lilly and Company.
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Acknowledgment
The authors would like to thank Dana Laird, Brian Schaefer, George
Vandeveer, and Jesse Jacobsen for useful conversations, as well as for
their assistance with the preparation of substrates and reagents.
(18) When using high loadings of Xantphos-Pd-G2, small amounts
of 8-quinolyl benzoate derived from phenyl transfer from the
ligand were sometime seen. For an earlier report of phenyl
transfer from Xantphos in carbonylations, see reference 11.
(19) Quinolin-8-yl 4-Methoxybenzoate (3a); Typical Procedure
4-Bromoanisole (378 mg, 2.02 mmol), quinolin-8-yl formate (2,
383 mg, 2.21 mmol, 1.1 equiv), and Xantphos-Pd-G2 (36 mg,
0.040 mmol, 2.0 mol%) were added to a 2–5 mL Biotage micro-
wave tube (Part no. 351521) under N2. Toluene (4.0 mL) and
Et3N (0.56 mL, 4.0 mmol, 2.0 equiv) were added sequentially,
and the tube was capped and heated in a Biotage Initiator
microwave at 120 °C for 60 min. When heating was complete
and the microwave cavity had been opened, significant solid
formation was observed in the tube. The contents of the tube
were transferred to a separatory funnel with CH2Cl2 (30 mL),
and the resulting mixture was washed with H2O (20 mL). The
organic layer was separated and injected directly onto a silica
column (80 g). The product was eluted with a 0–10% gradient of
MeCN in CH2Cl2 then dried at 35 °C under a vacuum to give an
off-white solid; yield: 496 mg (88%).
Supporting Information
Supporting information for this article is available online at
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References and Notes
(1) New addresses: J. Richardson, Sai Life Sciences Limited, Base-
ment A, Block 33, Alderley Park, Macclesfield, SK10 4TG, UK.
C. Maddocks, Department of Chemistry, University of York,
Heslington, York, YO10 5DD, UK.
(2) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318
.
(3) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(4) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed.
2009, 48, 4114.
(5) Peng, J.-B.; Geng, H.-Q.; Wu, X.-F. Chem 2019, 5, 526.
(6) (a) Carpentier, J.-F.; Castanet, Y.; Brocard, J.; Mortreux, A.; Petit,
F. Tetrahedron Lett. 1991, 32, 4705. (b) Simonato, J.-P.; Walter,
T.; Métivier, P. J. Mol. Catal. A: Chem. 2001, 171, 91. (c) Kaiser,
N.-F. K.; Hallberg, A.; Larhed, M. J. Comb. Chem. 2002, 4, 109.
(d) Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem.
Soc. 2002, 124, 3806. (e) Morimoto, T.; Fujioka, M.; Fuji, K.;
Tsutsumi, K.; Kakiuchi, K. Chem. Lett. 2003, 32, 154.
(f) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.
(g) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrystrup, T. J. Am.
Chem. Soc. 2011, 133, 18114. (h) Nakaya, R.; Yorimitsu, H.;
Oshima, K. Chem. Lett. 2011, 40, 904. (i) Brancour, C.; Fukuyama,
T.; Mukai, Y.; Skrydstrup, T.; Ryu, I. Org. Lett. 2013, 15, 2794.
(j) Ueda, T.; Konishi, H.; Manabe, K. Angew. Chem. Int. Ed. 2013,
1H NMR (400 MHz, CDCl3): = 8.88 (dd, J = 4.3, 1.6 Hz, 1 H), 8.29
(d, J = 9.0 Hz, 2 H), 8.18 (dd, J = 8.4, 1.6 Hz, 1 H), 7.74 (dd, J = 7.4,
2.2 Hz, 1 H), 7.52–7.59 (m, 2 H), 7.41 (dd, J = 8.4, 4.3 Hz, 1 H),
7.00 (d, J = 9.0 Hz, 2 H), 3.89 (s, 3 H). 13C NMR (101 MHz, CDCl3):
= 165.4, 164.1, 150.8, 148.0, 141.8, 136.2, 132.9, 129.8, 126.5,
126.1, 122.1, 121.9, 121.9, 114.1, 55.7.
(20) A conversion of 8-acyloxyquinolines into ketones by using orga-
noaluminum reagents has been reported; see: Tolstikov, G. A.;
Valitov, F. Kh.; Kuchin, A. V. Zh. Obshch. Khim. 1982, 52, 1328.
(21) For an early example of the conversion of a morpholinoamide
into a ketone, see: Pettit, G. R.; Baumann, M. F.; Rangammal, K.
N. J. Med. Chem. 1962, 5, 800.
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