Transition-metal-free C-arylation at room temperature by arynes

Article abstract of DOI:10.1021/ol301768r

A facile, fluoride-induced transition-metal-free chemoselective α-arylation of β-dicarbonyl compounds (malonamide esters) at room temperature using aryne intermediates has been demonstrated. Selective mono- or diarylation and generation of a quaternary benzylic stereocenter have also been achieved. The methodology will be highly useful for the synthesis of a library of CNS depressant barbiturate drugs like Phenobarbital.

Full text of DOI:10.1021/ol301768r

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Transition-Metal-Free C-Arylation
at Room Temperature by Arynes
Ranjeet A. Dhokale, Pramod R. Thakare, and Santosh B. Mhaske*
National Chemical Laboratory (CSIR-NCL), Division of Organic Chemistry,
Pune 411008, India
sb.mhaske@ncl.res.in
Received June 27, 2012
ABSTRACT
A facile, fluoride-induced transition-metal-free chemoselective r-arylation of β-dicarbonyl compounds (malonamide esters) at room temperature
using aryne intermediates has been demonstrated. Selective mono- or diarylation and generation of a quaternary benzylic stereocenter have also
been achieved. The methodology will be highly useful for the synthesis of a library of CNS depressant barbiturate drugs like Phenobarbital.
The R-arylation of β-dicarbonyl compounds has become
a widely used method,1,2 which provides an easy access
to important classes of biologically active natural/synthetic
products.3 This transformation is usually carried out by transi-
tion-metal-catalyzed1 (Scheme 1) or rarely by organomediated2
reactions. Introduction of the “Benzyne” species4 in 1953 by
Roberts et al. opened up a new avenue for chemists to explore.
Particularly, fluoride-induced milder reaction condi-
tions5 for in situ generation of arynes have captured the
attention of synthetic organic chemists. Since then the
high reactivity of arynes due to its distinct electrophili-
city has been utilized efficiently and has resulted in a
diverse range of useful compounds including complex
bioactivenatural products.6 The most commonly observed
and well studied reactions are the insertion of arynes into
Scheme 1. Previous and Prospective C-Arylation
(3) R-Aryl acids/malonates (modulators in mammalian membranes):
(a) Beyer, J.; Jensen, B. S.; Strøbæk, D.; Christophersen, P.; Teuber, L.
WO Patent 00/37422, 2000. Chloropeptin I and II: (b) Hegde, V. R.; Dai, P.;
Patel, M.; Gullo, V. P. Tetrahedron Lett. 1998, 39, 5683. Lucuminic acid:
(c) Takeda, T.; Gonda, R.; Hatano, K. Chem. Pharm. Bull. 1997, 45, 697.
Polymastiamide A: (d) Kong, F.; Andersen, R. J. J. Org. Chem. 1993, 58,
6924. Vulculic acid: (e) Kimura, Y.; Nishibe, M.; Nakajima, H.;
Hamasaki, T. Agric. Biol. Chem. 1991, 55, 1137. (f) Nonsteroidal anti-
inflammatory drugs: Rieu, J.-P.; Boucherle, A.; Cousse, H.; Mouzin, G.
Tetrahedron 1986, 42, 4095. Vancomycin: (g) Sheldrick, G. M.; Jones,
P. G.; Kennard, O.; Williams, D. H.; Smith, G. A. Nature 1978, 271, 223.
(4) Roberts, J. D.; Simmons, H. E., Jr.; Carlsmith, L. A.; Vaughan,
C. W. J. Am. Chem. Soc. 1953, 75, 3290.
(5) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211.
(6) For recent reviews on arynes, see: (a) Tadross, P. M.; Stoltz, B. M.
Chem. Rev. 2012, 112, 3550. (b) Gampe, C. M.; Carreira, E. M. Angew.
Chem., Int. Ed. 2012, 51, 3766. (c) Bhojgude, S. S.; Biju, A. T. Angew.
Chem., Int. Ed. 2012, 51, 1520. (d) Bhunia, A.; Yetra, S. R.; Biju, A. T.
(1) (a) Huang, Z.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
1028. (b) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett.
2007, 9, 3469. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234. (d) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(e) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541. (f) Fox,
J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 1360.
ꢀ
(2) (a) Aleman, J.; Richter, B.; Jørgensen, K. A. Angew. Chem., Int.
~
ꢀ
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Ed. 2007, 46, 5449. (b) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 3670. (c) Huang, X.; Maulide, N. J. Am.
Chem. Soc. 2011, 133, 8510.
Chem. Soc. Rev. 2012, 41, 3140. (e) Pena, D.; Perez, D.; Guitian, E.
Angew. Chem., Int. Ed. 2006, 45, 3579. (f) Wenk, H. H.; Winkler, M.;
Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502.
r
10.1021/ol301768r
XXXX American Chemical Society

the elementꢀelement σ-bond and π-bond;6,7 however ex-
amples of aryne insertion into the CꢀH σ-bond to directly
provide C-arylated products are rare and to date are known
for only a few substrates such as anilines,8 aldehydes,9 and
β-enamino esters/ketones.10 A literature survey revealed
that in the case of R-unsubstituted β-dicarbonyl com-
pounds Stoltz et al.11 and Yoshida et al.12 have observed
the insertion of benzyne into the CꢀC σ-bond as the only
product. Stoltz et al. also noticed the C-arylation as a side
product only on R-methyl β-keto ester.11 Wang et al. have
reported13 CuBr-trichloroaceticacidcatalyzed C-arylation
on 1,3-diones using anthranilic acid and isoamylnitrite at
60 °C, and Leake et al. reported phenylation of dialkyl
malonates using bromobenzene and sodium amide in poor
yields.14
Scheme 3. Aryne Reactivity and Present Work
While working on a methodology development pro-
ject, we carried out a reaction of malonamide ester15
1
In view of the literature precedent (Scheme 3) the
chemoselective C-arylation at milder reaction conditions
on substrate 1 was intriguing and prompted us to take up
further investigations. Reported herein are studies on the
C-arylation of malonamide esters15 and its application.
Complete consumption of the substrate 1 and monoary-
lated product 4 was considered as the reference point
during the optimization of the protocol. Several attempts
(Table 1, entries 1ꢀ7) using varying ratios of substrate, CsF,
silyl triflate 2, and organic/inorganic bases always pro-
vided a mixture of 4, 5, and 1. We conducted one reaction
(Table 1, entry 8) without any base and by using an excess
amount of CsF. Gratifyingly, 1 and 4 were completely
consumed within 4 h to provide a 70% yield of product 5.
Further optimizations provided the best reaction condi-
tions (Table 1, entry 10), which provided exclusively 5 in
high yields (86%). Use of 18-crown-6 ether (Table 1, entry 11)
gave only a 63% yield.
(1.00 equiv) with benzyne precursor 216 (2.00 equiv) in the
presence of CsF (6.00 equiv) and NaHCO3 (2 equiv) using
Scheme 2. Initial Studies on Aryne Methodology
acetonitrile as a solvent at rt (Scheme 2). We were expect-
ing the quinolinedione compound 3; however, to our sur-
prise we observed only C-arylated products 4 and 5. A
general reactivity pattern of arynes with active methylene
compounds11,12,17 and amides18 as observed in the litera-
ture is depicted in Scheme 3.
The optimized arylation protocol (Table 1, entry 10) was
used for screening malonamide esters15 (Tables 2 and 3) in
the search for a more reactive and selective substrate. First,
malonamide esters containing primary aromatic amines
(Table 2, entries 2ꢀ6) were tested. With a simple phenyl-
malonamide ester (Table 2, entry 2) the corresponding
diarylated product was obtained in 72% yield. Malon-
amide ester (p-methoxyphenylmalonamide ester) contain-
ing an electron-donating group provided the expected
diarylated product in 75% yield (Table 2, entry 3). A
further increase in electron-donating groups on the aro-
matic amine (Table 2, entry 4) did not show an improve-
ment in the yield. Interestingly with p-toludine as the
aromatic amine (Table 2, entry 5) only a 55% yield of
the diarylated product was observed, and with p-nitroani-
line as the aromatic amine (Table 2, entry 6), though the
reaction was fast, the yield reduced to 46%. Malonamide
esters containing aliphatic primary amines (Table 2, entries
7ꢀ9) were also studied. The malonamide ester containing
(7) Selected references on recent developments in aryne chemistry:
(a) Hamura, T.; Chuda, Y.; Nakatsuji, Y.; Suzuki, K. Angew. Chem., Int.
Ed. 2012, 51, 3368. (b) Lu, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org.
Chem. 2012, 77, 2279. (c) Rogness, D. C.; Markina, N. A.; Waldo, J. P.;
Larock, R. C. J. Org. Chem. 2012, 77, 2743. (d) Rodrıguez-Lojo, D.;
~
ꢀ
ꢀ
Cobas, A.; Pena, D.; Perez, D.; Guitian, E. Org. Lett. 2012, 14, 1363.
(e) Yoshioka, E.; Kohtani, S.; Miyabe, H. Angew. Chem., Int. Ed. 2011,
50, 6638. (f) Yoshida, H.; Asatsu, Y.; Mimura, Y.; Ito, Y.; Ohshita, J.;
Takaki, K. Angew. Chem., Int. Ed. 2011, 50, 9676.
(8) Pirali, T.; Zhang, F.; Miller, A. H.; Head, J. L.; McAusland, D.;
Greaney, M. F. Angew. Chem., Int. Ed. 2012, 51, 1006.
(9) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761.
(10) Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029.
(11) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
(12) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3292.
(13) Yang, Y.-Y.; Shou, W.-G.; Wang, Y.-G. Tetrahedron Lett. 2007,
48, 8163.
(14) Leake, W. W.; Levine, R. J. Am. Chem. Soc. 1959, 81, 1627.
(15) Please see Supporting Information.
(18) Selected references on the reaction of amides with arynes:
(a) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168. (b) Gilmore,
C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558.
(c) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112.
(d) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem.,
Int. Ed. 2002, 41, 3247.
~
ꢀ
ꢀ
(16) Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis 2002, 1454.
(17) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Tetrahedron
Lett. 2005, 46, 6729.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Arylation Protocol
Table 2. Screening of Malonamide Esters
CsF, additives
1 (1:00 equiv) þ 2
4=5
f
CH3CN, rt
2
CsF
additives
time 4/5, yield
entry (equiv) (equiv)
(equiv)
(h)
(%)
1
2.00
2.00
2.00
2.00
4.00
4.00
4.00
2.50
3.30
4.00
4.00
6.00
8.00
NaHCO3 (1.0)
NaHCO3 (1.0)
NaHCO3 (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
ꢀ
6
20
24
12
13
12
48
4
5/25
7/26
10/20
5/55
30/5
35/5
35/5
0/70
0/75
0/86
5/63
2
3
4.00
4
12.00
5.00
5
6
6.00
7
6.00
8
15.00
16.50
8.00
8.00
9
ꢀ
4
10
11
ꢀ
5
18-crown-6 (2.0)
6
benzylamine (Table 2, entry 7) was quite reactive but
provided the expected diarylated product in only a 40%
yield. The other two malonamide esters containing pri-
mary aliphatic moieties (Table 2, entries 8 and 9) could not
furnish any useful product. Then the effect on malon-
amide ester containing secondary aliphatic/aromatic amines
(Table 2, entries 10 and 11) was studied. Diphenylmalon-
amide ester (Table 2, entry 10) was less reactive and
provided only a 50% yield of the diaryl product. In the
case of the dialkyl amine containing substrate (Table 2,
entry 11), we could not see any useful product. Monoalkyl
or dialkyl malonamides (Table 2, entries 8, 9, 11) fail to
give any product plausibly because methylene protons are
less acidic than aryl malonamides.
Malonamide ester 6 (Table 3, entry 1), which is a combi-
nation of an aromaticꢀaliphatic amine, interestingly pro-
vided only the monoarylated product in 90% yield. This
observation was confirmed by the treatment of 6 with
various aryne precursors 7/8 (Table 3, entries 2 and 3),
and in those cases also, the only corresponding monoaryl
products were obtained in 55% and 62% yields respectively.
The acidity of methylene protons in the malonamide
ester 6 is finely balanced between mono/dialkyl malo-
namides and aryl malonomides, which probably results
in selective monoarylation. The screening study
(Tables 2 and 3) provided two important substrates, 1
(for diarylation) and 6 (for selective monoarylation).
Though substrate 1 emerged as the best for diarylation
among the other substrates under study, we believe that
further screening of malonamide esters containing aro-
matic amines with other halide substituents might pro-
vide a more reactive substrate than ester 1.
applications and in many natural products.19 The con-
struction of such quaternary stereocenters is a much more
demanding and challenging task.20 R-Substituted malon-
amide esters15,21 containing p-chloroaniline were used. The
R-methyl substituted malonamide ester (Table 4, entry 1)
provided the corresponding arylated compound in 85%
yield; however the R-ethyl substituted substrate (Table 4,
entry 2) provided the expected compound in very high yields
(92%). The R-butyl substituted substrate (Table 4, entry 3)
provided the expected compound in quantitative yields
(97%). Similarly the R-benzyl substituted malonamide ester
provided the expected arylated product (Table 4, entry 4) in
excellent yields (90%). Arylation of the R-phenyl substituted
We envisaged that the arylation protocol could be applied
for the generation of racemic quaternary stereocenters,
which are found in several important molecules in medicinal
(20) (a) Hong, S.; Lee, J.; Kim, M.; Park, Y.; Park, C.; Kim,
M.-H.; Jew, S.-S.; Park, H.-G. J. Am. Chem. Soc. 2011, 133, 4924.
(b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591.
(21) R-Substituted malonamide ester preparation: (a) Peng, B.;
Zhang, S.; Yu, X.; Feng, X.; Bao, M. Org. Lett. 2011, 13, 5402.
(b) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett.
(19) (a) Christoffers, J., Baro, A., Eds. Quaternary Stereocenters -
Challenges and Solutions for Organic Synthesis; Wiley-VCH: Weinheim,
2005. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388.
ꢀ
2007, 9, 3469. (c) Keglevich, G.; Novak, T.; Vida, L.; Greiner, I. Green
Chem. 2006, 8, 1073 and references cited therein.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Substrate for Selective Monoarylation
Table 4. Generation of Quaternary Stereocenters
substrate with 3,4-difluorinated aryne precursor 7 furnished
the expected product in 60% yield (Table 4, entry 5).
Interestingly all the compounds synthesized by this metho-
dology (Tables 2ꢀ4) are new,22 and analogues of these
compounds are very well-known sedative-tranquillizers.23
The products obtained in Tables 2 and 3 can also serve
as important precursors to CNS depressant barbiturates
drugs. Phenobarbital is one of the most widely used anti-
convulsant barbiturate drugs,24 and using simple organic
transformations,25 its synthesis should be possible starting
from the product 9 (Table 4, entry 2) obtained by our
methodology. Similarly a library of such compounds can
be prepared for SAR studies.
malonamide esters. The preferential chemoselective
C-arylation over the N-arylation/aryne insertion into the
CꢀN σ-bond, the formation of selective mono- or diary-
lated products, and an easy access to compounds contain-
ing racemic benzylic quaternary stereocenters are note-
worthy. The generalization work and application of the
present methodology to the total synthesis of drugs and
bioactive natural products is in progress.
Acknowledgment. R.A.D. thanks UGC, New Delhi for
the Research fellowship. S.B.M. thanks DST, New Delhi
for the Ramanujan Fellowship and FAST-Track grant.
Inconclusion, we have disclosedthe application of aryne
chemistry for the R-arylation of R-substituted/unsubstituted
(22) The product of entry 1 (Table 3) is known, but its synthesis is not
reported: Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249.
(23) Loev, B.; Macko, E.; Fried, I. M. J. Med. Chem. 1969, 12, 854.
(24) (a) “WHO Model List of Essential Medicines”. World Health
Organization. March 2005. http://whqlibdoc.who.int/hq/2005/a87017_
eng.pdf. (b) Kwan, P.; Brodie, M. J. Epilepsia 2004, 45, 1141.
(25) (a) Glatzhofer, D. T.; Roy, R. R.; Cossey, K. N. Org. Lett. 2002,
4, 2349. (b) Yoon, J. H.; Park, Y. J.; Lee, J. H.; Yoo, J.; Jun, C.-H. Org.
Lett. 2005, 7, 2889. (c) Arai, K.; Tamura, S.; Kawai, K.-i.; Nakajima, S.
Chem. Pharm. Bull. 1989, 37, 3117.
Supporting Information Available. Experimental de-
tails, analytical and spectra data as well as copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX