Copper-bisphosphine-initiated pentafluorophenylation of aldehydes and ketones

Article abstract of DOI:10.1055/s-0029-1219159

In the presence of substoichiometric quantities of a copper-bisphosphine complex, a variety of aldehydes and reactive ketones undergo pentafluorophenylation using pentafluorophenyl-trimethylsilane. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219159

LETTER
615
Copper–Bisphosphine-Initiated Pentafluorophenylation of Aldehydes and
Ketones
P
entafluoroph
a
m
A
ldehyde
s
and
K
e
a
tones ntha Brogan,a Neil B. Carter,b Hon Wai Lam*a
a
School of Chemistry, University of Edinburgh, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK
Fax +44(131)6506453; E-mail: h.lam@ed.ac.uk
b
Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, UK
Received 30 October 2009
Dedicated to our friend and mentor Professor Gerald Pattenden on the occasion of his 70th birthday.
ploying the toxic combination of 18-crown-6/KCN as
initiator15b), and only one example of a successful reaction
with a ketone has been described.15d A more detailed eval-
uation of the scope of pentafluorophenylation of alde-
hydes and ketones using 1 under user-friendly reaction
conditions is therefore warranted, and in this communica-
tion, we describe the results of such a study.
Abstract: In the presence of substoichiometric quantities of a
copper–bisphosphine complex, a variety of aldehydes and reactive
ketones undergo pentafluorophenylation using pentafluorophenyl-
trimethylsilane.
Key words: aldehydes, copper, ketones, nucleophilic addition,
pentafluorophenylation
In considering potential reagents to promote carbonyl
pentafluorophenylation using 1, we were prompted to ex-
amine copper–dppe complexes, in view of their successful
use in combination with the Ruppert–Prakash reagent
(TMSCF3) for the trifluoromethylation of aldehydes16 and
the direct silylation of bisactivated cyclopropenes con-
ducted within our group.17 A brief study of reaction pa-
rameters led to the selection of Cu(OAc)2 (10 mol%),
dppe (10 mol%), and TMSC6F5 (1.1 equiv) in THF as ef-
fective conditions for carbonyl pentafluorophenylation.18
After the reaction had stopped progressing as observed by
TLC analysis, a solution of HCl was added to deprotect
the TMS ether that is the initial product of pentafluo-
rophenylation.
Incorporation of fluorine into a molecule often has a pro-
found effect on its physical, chemical, and biological
properties. As a result, organofluorine compounds have
numerous applications in pharmaceuticals,1 agrochemi-
cals,2 and functional materials.3 Of the common fluorine-
containing functional groups, pentafluorophenyl substitu-
ents are an important subset. Pentafluorophenyl com-
pounds are of utility in medicinal chemistry,4 electron-
transport devices,5 light-emitting diodes,6 printing,7 liquid
crystal displays,8 and fluorous biphasic ligands.9 In prin-
ciple, a simple approach for the introduction of pentafluo-
rophenyl groups is the addition of a nucleophilic
pentafluorophenyl synthon to an aldehyde or ketone, and
this strategy has been accomplished by the use of
pentafluorophenyllithium10 or the Grignard reagent.10b,11
However, the drawback of such reagents is their limited
compatibility with sensitive functional groups. Accord-
ingly, the development of milder conditions for the pen-
tafluorophenylation of aldehydes and ketones is desirable.
OH
F
dppe (10 mol%)
F
F
O
Cu(OAc)2 (10 mol%)
R
TMSC6F5 (1)
(1.1 equiv)
+
THF, r.t., then HCl
R
H
F
F
2a–i
In this context, the increasing interest in the chemistry of
fluoroalkyl silanes12 led us to consider the use of penta-
fluorophenyltrimethylsilane (1) as an alternative reagent
for the pentafluorophenylation of carbonyl compounds.
The commercial availability and stability of 1, coupled
with reaction conditions for pentafluorophenyl transfer
that were anticipated to be relatively mild, rendered this
compound attractive for pentafluorophenylation.
OH
OH
OH
Me
C6F5
C6F5
C6F5
C6F5
C6F5
2c 97%
2f 69%
2a 77%
2b 77%
NO2 OH
Cl
OH
OH
MeO
C6F5
C6F5
While reagent 1 has mainly been employed in the pen-
tafluorophenylation of C=N bonds using a variety of
methods,13,14 the corresponding reactions with carbonyl
compounds are less common.15 Existing studies of pen-
tafluorophenylation of aldehydes using 115a–c contain only
limited descriptions of substrate scope (in one case em-
Cl
2e 84%
2d 88%
OH
OH
OH
C6F5
Ph
C6F5
N
S
2g 62%
2h 38%
2i 42%
Scheme 1 Pentafluorophenylation of unsaturated aldehydes. Cited
yields are of isolated material.
SYNLETT 2010, No. 4, pp 0615–0617
Advanced online publication: 22.12.2009
0
1.
0
3.
2
0
1
0
DOI: 10.1055/s-0029-1219159; Art ID: D30809ST
© Georg Thieme Verlag Stuttgart · New York

616
S. Brogan et al.
LETTER
dppe (10 mol%)
Cu(OAc)2 (10 mol%)
TMSC6F5 (1) (1.1 equiv)
Scheme 1 presents the results of pentafluorophenylation
of a range of unsaturated aldehydes under these condi-
tions. The yields obtained for aromatic aldehydes were
generally good (69–97%), with substrates of varying ster-
ic and electronic properties all being tolerated. Heteroaro-
matic aldehydes were more problematic, generally giving
lower conversions or complex mixtures of products.19
However, 4-pyridinecarboxaldehyde did provide the de-
sired product 2g in 62% yield, while 2-thiophenecarbox-
aldehyde gave 2h in 38% yield. a,b-Unsaturated
aldehydes such as cinnamaldehyde again resulted in lower
conversions than their aromatic counterparts 2i.
O
HO Ph
C6F5
Ph
THF, r.t., then HCl
O2N
O2N
2n 48%
Equation 2
this stage. However, our current hypothesis is that the
Cu(OAc)2–dppe complex merely serves to initiate an
autocatalytic process in direct analogy to mechanisms
proposed for carbonyl trifluoromethylation using the
Ruppert–Prakash reagent (TMSCF3).20
Aliphatic aldehydes were found to be highly reactive un-
der these conditions, and complete consumption of start-
ing material was generally observed within 15 minutes at
room temperature. However, these reactions also provid-
ed a number of unidentified side products. Decreasing the
reaction temperature to –78 °C offered some improve-
ment in minimizing side-product formation, but isolated
yields of the products 2j–l remain modest due to varying
levels of decomposition observed during the workup and
purification process (Scheme 2).
In conclusion, the pentafluorophenylation of aldehydes
and ketones using pentafluorophenyltrimethylsilane in the
presence of substoichiometric Cu(OAc)2 and dppe has
been described. Aromatic aldehydes are the best sub-
strates, whereas heteroaryl and aliphatic aldehydes lead to
somewhat inferior results. Finally, only highly electro-
philic ketones successfully undergo pentafluorophenyl-
ation under these conditions. The development of
improved protocols for the incorporation of pentafluo-
rophenyl and other fluorine-containing substituents is in
progress.
OH
F
dppe (10 mol%)
F
F
O
Cu(OAc)2 (10 mol%)
R
TMSC6F5 (1)
(1.1 equiv)
+
THF, –78 °C, then HCl
Representative Experimental Procedure for Pentafluorophenyl-
ation of Aldehydes and Ketones
R
H
F
2j–l
F
A solution of Cu(OAc)2 (18.2 mg, 0.10 mmol) and dppe (39.8 mg,
0.10 mmol) in THF (3 mL) was stirred at r.t. for 30 min. The appro-
priate aldehyde or ketone (1.00 mmol) was then added, followed by
TMSC6F5 (210 mL, 1.10 mmol) over 0.5 min, and the reaction was
stirred at r.t. until complete consumption of the carbonyl compound
as observed by TLC analysis, or until no further reaction progress
could be seen (in the case of aliphatic aldehydes, the mixture was
cooled to –78 °C before the addition of TMSC6F5 and the reaction
was thereafter maintained at –78 °C). The reaction was quenched
with 1 mL of HCl solution (ca. 1 M in MeOH–H2O, made up by di-
luting 8.2 mL of 37% HCl up to 100 mL with MeOH), and the mix-
ture was stirred at r.t. for 1 h. The mixture was filtered through a
short plug of SiO2 using EtOAc (ca. 50 mL) as eluent, and the fil-
trate was concentrated in vacuo. Purification of the residue by col-
umn chromatography afforded the desired alcohol.
OH
OH
OH
Me
Me
Me
C6F5
C6F5
Ph
C6F5
Me
Me
2j 44%
2k 45%
2l 56%
Scheme 2 Pentafluorophenylation of aliphatic aldehydes. Cited
yields are of isolated material.
Extension of this protocol to more challenging ketone
substrates was then explored. With enolizable ketones
such as acetophenone, only conversion into the corre-
sponding trimethylsilyl enol ether was obtained, which is
consistent with previous reports.15b,d With benzophenone,
a nonenolizable substrate, no reaction was obtained. How-
ever, more electrophilic ketones such as ethyl pyruvate
and 4-nitrobenzophenone did lead to the desired products
2m and 2n, respectively, though in modest yields
(Equation 1 and Equation 2).
Data for 2f
Colorless oil (210 mg, 69%); Rf = 0.18 (10% EtOAc–hexane). IR
(film): 3486 (OH), 2360, 1652, 1606, 1588, 1503, 1274, 1228,
1
1038, 988 cm–1. H NMR (360 MHz, CDCl3): d = 7.27 (1 H, t,
J = 7.9 Hz, ArH), 6.98 (1 H, br s, ArH), 6.92 (1 H, d, J = 7.9 Hz,
ArH), 6.84 (1 H, dd, J = 8.1, 2.5 Hz, ArH), 6.18 (1 H, s, CHOH),
3.81 (3 H, s, OCH3), 3.40 (1 H, br s, OH). 13C NMR (90.6 MHz,
CDCl3): d = 159.8 (C), 144.6 (2 × C, dm, J = 250 Hz), 142.2 (C),
140.8 (C, dm, J = 250 Hz), 137.6 (2 × C, dm, J = 250 Hz), 129.7
(CH), 117.5 (CH), 116.8 (C, t, J = 14.8 Hz), 113.2 (CH), 111.2
(CH), 67.2 (CH), 55.1 (CH3). 19F NMR (235 MHz, CDCl3): d =
–143.0 (2 F, dd, J = 21.9, 7.7 Hz), –154.7 (1 F, t, J = 21.3 Hz),
–161.5 (2 F, ddd, J = 21.9, 21.3, 7.7 Hz). HRMS (EI): m/z calcd for
C14H9F5O2 [M]+: 304.0517; found: 304.0516.
dppe (10 mol%)
Cu(OAc)2 (10 mol%)
TMSC6F5 (1) (1.1 equiv)
O
HO Me
EtO2C C6F5
2m 31%
EtO2C
Me
THF, r.t., then HCl
Equation 1
The exact role of Cu(OAc)2 and dppe in promoting carbo-
nyl pentafluorophenylation is not clearly understood at
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 4, 615–617 © Thieme Stuttgart · New York

LETTER
Pentafluorophenylation of Aldehydes and Ketones
617
Ed. 2006, 55, 517. (d) Dilman, A. D.; Gorokhov, V. V.;
Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Acknowledgment
This work was supported by the EPSRC and Syngenta. The EPSRC
National Mass Spectrometry Service Centre at the University of
Wales, Swansea, is thanked for providing high-resolution mass
spectra.
Tetrahedron Lett. 2006, 47, 6217. (e) Levin, V. V.; Dilman,
A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky,
V. A. Tetrahedron Lett. 2006, 47, 8959. (f) Dilman, A. D.;
Levin, V. V.; Karni, M.; Apeloig, Y. J. Org. Chem. 2006, 71,
7214. (g) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.;
Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A.
Mendeleev Commun. 2007, 17, 105. (h) Dilman, A. D.;
Gorokhov, V. V.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Russ. Chem. Bull., Int. Ed. 2007, 56,
1522. (i) Dilman, A. D.; Arkhipov, D. E.; Levin, V. V.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.;
Tartakovsky, V. A. J. Org. Chem. 2007, 72, 8604.
(j) Levin, V. V.; Kozlov, M. A.; Song, Y.-H.; Dilman, A. D.;
Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Tetrahedron Lett. 2008, 49, 3108. (k) Dilman, A. D.;
Arkhipov, D. E.; Levin, V. V.; Belyakov, P. A.; Korlyukov,
A. A.; Struchkova, M. I.; Tartakovsky, V. A. J. Org. Chem.
2008, 73, 5643.
References and Notes
(1) See, for example: (a) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (b) Kirk,
K. L. Org. Process Res. Dev. 2008, 12, 305. (c) Müller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(d) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127,
303.
(2) Theodoridis, G. In Advances in Fluorine Science, Vol. 2;
Tressaud, A., Ed.; Elsevier: Dordrecht, 2006, 121.
(3) Pagliaro, M.; Ciriminna, R. J. Mater. Chem. 2005, 15, 4981.
(4) Zahn, A.; Brotschi, C.; Leumann, C. J. Chem. Eur. J. 2005,
11, 2125.
(14) For one isolated example of 1,4-pentafluorophenylation of
arylidenemalononitriles, see: Dilman, A. D.; Levin, V. V.;
Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Tetrahedron Lett. 2008, 49, 4352.
(5) Sakamoto, Y.; Suzuki, T.; Miura, A.; Fujikawa, H.; Tokito,
S.; Taga, Y. J. Am. Chem. Soc. 2000, 122, 1832.
(6) Montes, V. A.; Li, G.; Pohl, R.; Shinar, J.; Anzenbacher, P.
Adv. Mater. 2004, 16, 2001.
(15) (a) Webb, A. F.; Sethi, D. S.; Gilman, H. J. Organomet.
Chem. 1970, 21, P61. (b) Gostevskii, B. A.; Kruglaya,
O. A.; Albanov, A. I.; Vyazankin, N. S. J. Organomet.
Chem. 1980, 187, 157. (c) Fujita, M.; Obayashi, M.;
Hiyama, T. Tetrahedron 1988, 44, 4135. (d) Vyazankina,
O. A.; Gostevskii, B. A.; Vyazankin, N. S. J. Organomet.
Chem. 1985, 292, 145.
(7) (a) Malhotra, S. L. US 5,744,273, 1998. (b) Malhotra, S. L.
US 5,897,940, 1999.
(8) Matsui, M.; Shirai, K.; Tanaka, N.; Funabiki, K.;
Muramatsu, H.; Shibata, K.; Abe, Y.; Ohgomori, Y.
J. Mater. Chem. 1999, 9, 2755.
(9) Clarke, M. L. J. Organomet. Chem. 2003, 665, 65.
(10) (a) Coe, P. L.; Stephens, R.; Tatlow, J. C. J. Chem. Soc.
1962, 3227. (b) Jung, M. E.; Jung, Y. H.; Miyazawa, Y.
Tetrahedron Lett. 1990, 31, 6983. (c) Gupta, H. K.;
Stradiotto, M.; Hughes, D. W.; McGlinchey, M. J. J. Org.
Chem. 2000, 65, 3652.
(16) Mizuta, S.; Shibata, N.; Ogawa, S.; Fujimoto, H.; Nakamura,
S.; Toru, T. Chem. Commun. 2006, 2575.
(17) Fordyce, E. A. F.; Wang, Y.; Luebbers, T.; Lam, H. W.
Chem. Commun. 2008, 1124.
(18) Initial investigations employed benzaldehyde as a test
substrate. The use of toluene instead of THF16 provided only
minimal conversions (<5%). Decreasing the loadings of
Cu(OAc)2 and dppe to 5 mol%, or replacement of Cu(OAc)2
with Cu(acac)217 resulted in lower conversions.
(11) (a) Garner, C. M.; Terech, P.; Allegraud, J.-J.; Mistrot, B.;
Nguyen, P.; de Geyer, A.; Rivera, D. J. Chem. Soc., Faraday
Trans. 1998, 94, 2173. (b) Elshani, S.; Du, H.; Laintz, K. E.;
Natale, N. R.; Wai, C. M.; Elkarim, N. S. A.; Bartsch, R. A.
Tetrahedron 2000, 56, 4651.
(19) For example, 2-furancarboxaldehyde and 1-methylindole-2-
carboxaldehyde showed only low conversions (ca. 20% and
<5%, respectively), while 2-pyridinecarboxaldehyde
resulted in a complex mixture of products.
(20) For example, see: (a) Prakash, G. K. S.; Yudin, A. K. Chem.
Rev. 1997, 97, 757. (b) Gawronski, J.; Wascinska, N.;
Gajewy, J. Chem. Rev. 2008, 108, 5227.
(12) Uneyama, K. J. Fluorine Chem. 2008, 129, 550.
(13) (a) Nishida, M.; Fukaya, H.; Hayakawa, Y.; Ono, T.; Fujii,
K.; Uekusa, H. Helv. Chim. Acta 2006, 89, 2671.
(b) Dilman, A. D.; Levin, V. V.; Belyakov, P. A.;
Struchkova, M. I.; Tartakovsky, V. A. Synthesis 2006, 447.
(c) Dilman, A. D.; Arkhipov, D. E.; Belyakov, P. A.;
Struchkova, M. I.; Tartakovsky, V. A. Russ. Chem. Bull., Int.
Synlett 2010, No. 4, 615–617 © Thieme Stuttgart · New York