Palladium-catalyzed tandem fluorination and cyclization of enynes

Article abstract of DOI:10.1021/ol103039x

A novel palladium-catalyzed tandem fluorination and cyclization of enynes has been developed. A favorable cis-fluoropalladation is proposed as a key step to construct a vinyl-F bond, and the final C_sp3-Pd bond is reduced by alcohol. This transf

Full text of DOI:10.1021/ol103039x

ORGANIC
LETTERS
2011
Vol. 13, No. 4
772–775
Palladium-Catalyzed Tandem Fluorination
and Cyclization of Enynes
Haihui Peng and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences,354 Fenglin Road, Shanghai, China, 200032
gliu@mail.sioc.ac.cn
Received December 15, 2010
ABSTRACT
A novel palladium-catalyzed tandem fluorination and cyclization of enynes has been developed. A favorable cis-fluoropalladation is proposed as a
key step to construct a vinyl-F bond, and the final Csp3-Pd bond is reduced by alcohol. This transformation represents an efficient road to
synthesize fluorinated lactams.
Molecules bearing a fluorine moiety significantly improve
many of their properties, including solubility, bioavailability,
and metabolic stability and are of great importance in phar-
maceuticals.1 Novel methods for the synthesis of fluorinated
molecules based on C-F bond formation are therefore in
great demand. However, very few effective approaches are
available for directly constructing a C-F bond.2,3We are
particularly intrigued by the prospect of developing transition-
metal-catalyzed fluorination of unsaturated C-C bonds to
achieve C-F bond formation under mild conditions.4,5
Palladium-catalyzed cyclization of enynes is an efficient
strategy for the synthesis of cyclic compounds, particularly
heterocycles. Such a process is inherently atom economical
and results in a significant increase in structural com-
plexity.6 For instance, oxidative cyclization of enynes, in-
itiated by nucleopalladation of alkynes, has been extensively
studied (eq 1).7 Recently, Tse and Sanford have indepen-
dently reported palladium-catalyzed enyne cyclization for
the construction of bicyclic products, which was proposed to
be initiated by acetoxypalladation of the alkyne moiety and
facilitated by using PhI(OAc)2 as an oxidant (eq 1a).8
(1) (a) Welch, J. T.; Eswarakrishman, S., Eds. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991. (b) Banks, R. E., Smart, B. E., Tatlow,
J. C., Eds. Organofluorine Chemistry: Principles and Commercial Appli-
cations; Plenum Press: New York, 1994.
(2) For reviews on fluorination of organic compounds, see: (a)
Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong,
C.-H. Angew. Chem., Int. Ed. 2005, 44, 192–212. (b) Shimizu, M.;
Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214–231. (c) Pihko, P. M.
Angew. Chem., Int. Ed. 2006, 45, 544–547.
(3) (a) Smoekh, L.; Shanzer, A. J. Am. Chem. Soc. 1982, 104, 5836–
5837. (b) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165–1168. (c) Li, Y.; Ni, C.; Liu, J.; Zhang, L.;
Zheng, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693–1696. (d) Anbarasan,
P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 2219–2222.
(4) For recent reviews on transition-metal-catalyzed C-F bond
formation, see: (a) Brown, J. M.; Gouverneur, V. Angew. Chem., Int.
Ed. 2009, 48, 8610–8614. (b) Grushin, V. V. Acc. Chem. Res. 2010, 43,
160–171. (c) Furuya, T.; Klein, J. E. M. N.; Ritter, T. Synthesis 2010,
1804–1821. For recent examples, see:(d) Hull, K. L.; Anani, W. Q.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134–7135. (e) Wang, X.;
Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520–7521. (f)
Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47,
5993–5996. (g) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.;
(5) (a) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354–
16355. (b) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc.
2010, 132, 2856–2857.
^
(6) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed.
2008, 47, 4268–4315.
(7) For reviews on the halopalladation of alkynes, see: (a) Lu, X.; Ma,
S. In Transition Metal Catalyzed Reaction; Murahashi, E.-I., Davis, S. G.,
Eds.; IUPAC: 1999; pp 133-157. (b) Lu, X.; Zhu, G.; Wang, Z. Synlett
1998, 115–121. (c) Lu, X. In Handbook of Organopalladium Chemistry
for Organic Synthesis, Vol. 2; Nigishi, E.-I., Ed.; Wiley-VCH: Weiheim,
2002; pp 227-2287.
Garcıa-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661–
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r
10.1021/ol103039x
Published on Web 01/20/2011
2011 American Chemical Society

Related cyclization initiated via halopalladation of triple
bonds has been demonstrated by Lu and others (eq 1b).9
However, the cyclization reaction of enynes involving fluor-
ination is unknown. This is because the challenging fluorina-
tion of triple bonds is extremely rare. So far, only gold-
catalyzed fluorination of alkynes was reported by Sadighi,
Gouverneur, and Nevado, respectively.10
Table 1. Screening Results: Pd-Catalyzed Fluorination and
Cyclizaiton of Enyne 1aa
Very recently, our group has reported a Pd(OAc)2/BC
(bathocuproine)-catalyzed intermolecular aminofluorina-
tion of vinylarenes, where a fluoropalladation of styrene
was proposed as the key step for the formation of the C-F
bond.5b We postulate that, if fluoropalladation of triple
bond occurs, the cyclization of enynes might be expected
to afford the corresponding fluorinated cyclic products
(eq 1c).11 Importantly, the fluorination of a triple bond is
also a good model to study the stereochemistry of fluoro-
palladation, which is a suspended question in the aminofluo-
rination of styrenes.5b Herein, we report a novel palladium-
catalyzed tandem fluorination and cyclization of enynes,
which is possibly initiated by a favorable cis-fluoropallada-
tion of a triple bond to construct a vinyl C-F bond.
Interestingly, we also observed that the newly formed
Csp3-Pd bond in the catalytic cycle was reduced by
an alcohol, as clearly demonstrated by the deuterated
experiments.
a The reaction conditions: 1a (0.2 mmol), NFSI (0.5 mmol), Pd-
(TFA)2 (5 mol %), BC (7.5 mol %), and additive in N,N-dimethyl-
acetamide (DMA, 0.5 mL) at 50 °C. b 19F NMR yield with trifluoro-
methylbenezene as internal standard, and the ratio was detected by F
NMR for the crude products. c Pd(OAc)2 (5 mol %). d 3 (3 equiv) instead of
NFSI. e 4(3 equiv) instead of NFSI. f 4-NO2C6H4OH (20 mol %) was added.
excess of Et3SiH was used as a reducing agent instead of
iPrOH, the reaction gave a single isomer E-2a, but in low
yield (entry 7). No reaction occurred in the absence of the
palladium catalyst or ligand BC. The very low conversions
occurred in the presence of other fluorinating reagents, such
as 3 and 4 (entries 8-9). Finally, the addition of 2,4-tert-
butyl-phenol has no significant effect on this reaction, and
the slightly better result was obtained in the presence of
4-nitrophenol (entry 10).12
With the optimized reaction conditions, the scope of this
cyclic fluorination reaction was investigated with a variety of
enynes. As summarized in Table 2, substrates 1a and 1b
bearing electron-withdrawing groups on the nitrogen atom
gave the lactams 2a and 2b in 70% and 66% yields with
moderate Z/E ratios, respectively (entries 1-2). Substrate 1c
bearing a benzyl group afforded the product 2c in 49% yield
with an opposite Z/E ratio (entry 3). Substrate 1d bearing an
ester group produced the fluorinated lactone 2d in a slightly
lower yield (entry 4). Furthermore, the enynes 1e-1m syn-
thesized from aryl substituted propiolic acid were evaluated
under the standard reaction conditions (entries 5-13). The
substrates bearing an electron-donating group on the aro-
matic ring afforded a cyclic product with good yield (entries
5-8). In contrast, the yields were slightly lower for the reac-
tion of substrates with electron-withdrawing groups (entries
9-11). A trace amount of the desired product was detected
for the reaction of 1l with a strong electron-withdrawing
nitro group (entry 12). For substrate 1n, the reaction also
proceeded to give cyclic fluorinated product 2n in mode-
rate yield (entry 14). Unfortunately, substrates 1o with
Our initial studies focused on the Pd-catalyzed cyclization
of enyne 1a with N-fluorobenzenesulfonimide (NSFI). We
were delighted to find that a small amount of cyclic product
2a was observed when the reaction was treated with Pd-
(TFA)2/BC in DMA (N,N-dimethylacetamide, Table 1,
entry 1). The addition of water was beneficial for the yield,
but the best yield (39%) was obtained in the presence of 3
equiv of water (entry 2). A series of protic additives were
investigated, and the isopropyl alcohol was proven to be the
best additive to give 2a in 67% yield (entries 3-6). When an
(8) (a) Tong, X.; Beller, M.; Tse, M. K. J. Am. Chem. Soc. 2007, 129,
4906–4907. (b) Welbes, L. L.; Lyons, T. W.; Cychosz, K. A.; Sanford,
M. S. J. Am. Chem. Soc. 2007, 129, 5836–5837.
(9) (a) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245–1250. (b) Zhu, G.;
Ma, S.; Lu, X. J. Chem. Soc., Chem. Commun. 1995, 271–273. (c) Yin,
G.; Liu, G. Angew. Chem., Int. Ed. 2008, 47, 5442–5445. (d) Li, Y.;
Jardine, K. J.; Tan, R.; Song, D.; Dong, V. M. Angew. Chem., Int. Ed.
2009, 48, 9690–9692.
(10) (a) Akana, J. A.; Bhattacharyya, K. X.; Muller, P.; Sadighi, J. P.
J. Am. Chem. Soc. 2007, 129, 7736–7737. (b) Schuler, M.; Silva, F.;
Bobbio, C.; Tessier, A.; Gouverneur., V. Angew. Chem., Int. Ed. 2008,
47, 7927–7930. (c) Haro, T. d.; Nevado, C. Chem. Commun. 2011, 47,
248–249.
(11) For the recent synthesis of fluorinated cyclic products via
1,6-enynes, see: Takachi, M.; Chatani, N. Org. Lett. 2010, 12, 5132–
5134.
(12) Although the role of 4-nitrophenol is currently not understood,
those observations suggest against a radical mechanism.
Org. Lett., Vol. 13, No. 4, 2011
773

Table 2. Palladium-Catalyzed Tandem Fluorination and Cy-
clizaiton of Enynesa
Figure 1. X-ray of Z-2e (left) and E-2e (right).
Scheme 1. Proposed Mechanism for the Palladium-Catalyzed
Tandem Fluorination and Cyclization of Enyne
a Reactions were conducted at 0.3 mmol scale. b Isolated yield. c The
ratio of E/Z isomers which were determined by 19F NMR. d 78%
conversion of 1q. e E-2n (trans/cis = 4:1), Z-2n (trans/cis = 2:1).
alcohol to give fluorinated cyclic product 2a (Scheme 1).14 In
the case of 1q, the formation of 5 is likely generated from the
reduction of a vinyl-Pd complex by alcohol.
alkyl-terminated alkyne and 1p with disubstituted alkene
afforded trace amount of cyclic products (entries 15-16).
The reaction of 1q bearing an internal double bond was
found to yield cyclization product 2q in 37% yield, along with
the hydrofluorination product 5 in 13% yield (entry 17). The
configurations of both E- and Z-2e were determined by the
X-ray crystallographic analysis (Figure 1).
Mechanistically, fluoropalladation is much less understood
than chloro- or bromopalladation in part due to its scarcity.
Similar to the mechanism of aminofluorination of styrene,5b
we proposed that this cyclization is initiated by fluoropallada-
tion of alkyne,13 followed by alkene insertion into a vinyl-Pd
bond to form a new Csp3-Pd bond, which was reduced by
Importantly, the formation of mixture products 2a with
an E/Z ratio of 5:1 indicated that both cis- and trans-
fluoropalladation of the triple bond occur simultaneously
and the cis-fluoropalladation is favored (path a, Scheme 1),
which maybe due to the strong interaction between fluoride
and palladium.15 The less favored trans-fluoropalladation
proceeds via trans-nucleophilic attack of the triple bond by
a free fluoride anion which is generated from decomposi-
tion of NFSI (path b).16,17 When the free fluoride anion was
(15) For review on the interactions between fluoride and a transition
metal, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41,
26–47.
(13) A single relative fluorogoldation has been reported in ref 10a.
For selected examples of chloropalladation of alkyne, see ref 7 and (a)
Muniz, K. Angew. Chem., Int. Ed. 2009, 48, 9412–9423. (b) Yang, S.-R.;
Jiang, H.; Li, Y.-Q.; Chen, H.-J.; Luo, W.; Xu, Y.-B. Tetrahedron. 2008,
64, 2930–2937. (c) Li, Y.; Liu, X.; Jiang, H.; Feng, Z. Angew. Chem., Int.
Ed. 2010, 49, 3338–3341. (d) Huang, J.; Zhou, L.; Jiang, H. Angew.
Chem., Int. Ed. 2006, 45, 1945–1949.
(14) The alternative mechanism, which initiates by Pd(II)-catalyzed
alcohol oxidation and the following Pd-hydride addition to alkene is
unlikely. For details see Supporting Information.
(16) The time course experiment monitored by 19F NMR noted that
the palladium-catalyzed decomposition of NFSI is prior to the cycliza-
tion of enyne. For more details, see the Supporting Information.
(17) The F- is possibly generated from the reaction of NFSI with a
nucleophilic reagent (such as H2O, ROH, and amine); for the details, see:
(a) Antelo, J. M.; Crugeiras, J.; Leis, J. R.; Rois, A. J. Chem. Soc., Perkin
Trans. 2 2000, 2071–2076. (b) Roy, A.; Schneller, S. W. Org. Lett. 2005,
7, 3889–3891. (c) Giovanelli, E.; Doris, E.; Rousseau, B. Tetrahedron
Lett. 2006, 47, 8457–8458.
774
Org. Lett., Vol. 13, No. 4, 2011

trapped by a large excess of Et3SiH, only cis-fluoropallada-
tion occurs (Table 1, entry 7).
In conclusion, we have developed a novel palladium-
catalyzed tandem fluorination of alkyne and cyclization
of enyne using NFSI as a fluorinating reagent. In this
transformation, a fluoropalladation of alkyne is proposed
to form a vinyl-F bond, and the relevant Csp3-Pd bond is
reduced by alcohol to give a fluorinated cyclic product.
Further mechanistic study on this reaction is in progress.
Lastly, we sought to investigate the origin of the proton
incorporated into the cyclic product by using two deuterium-
labeled isopropanols. It is surprising that no deuterium
incorporating into the product was observed in the pre-
sence ofiPrOD. Meanwhile, deuterium labeled product2a-
i
d1 was obtained when PrOH-d8 was used, even in the
Acknowledgment. We thank the CAS, NSFC (20821002,
20872155, 20972175 and 20923005), 973 Program of China
(2009CB825300), and STCSM (08PJ1411600 and 08dj-
1400100) for financial support. G.L. thanks Prof. Qilong Shen
at SIOC and Prof Hairong Guan at the University of
Cincinnati for helpful discussions.
presence of H2O (eq 2). These observations suggest thatthe
cleavageof a Csp3;Pd bond proceeds through a sequential
alcohol oxidation/reductive elimination pathway,18 in
which the N(SO2Ph)2 anion functions as a base to
promote the formation of a Pd-alkoxide intermediate
(Scheme 1, right side). This unprecedented method
presents a new strategy to quench the Csp3-Pd bond
under mild conditions. These results in eq 2 simulta-
neously suggest that cleavage of the Csp3-Pd bond by
HF is unlikely.19
Supporting Information Available. Detailed experimen-
tal procedures and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Although the palladium-catalyzed alcohol oxidation has been
extensively studied, the C-Pd complex quenched by this way is un-
known. This process only appears in one case to address a side reaction
€
in aryliodide carbonylation. For details, see: Hu, Y.; Liu, J.; Lu, Z.; Luo,
X.; Zhang, H.; Lan, Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 3153–3158.
(19) If the Csp3-Pd bond is cleavaged by HF which generated in situ,
the formation of the mixture of 2a and 2a-d1 should be expected; for
details see the Supporting Information.
Org. Lett., Vol. 13, No. 4, 2011
775