Visible-light-mediated fluoroalkylation of isocyanides with ethyl bromofluoroacetates: Unified synthesis of mono- and difluoromethylated phenanthridine derivatives

Article abstract of DOI:10.1021/ol501081h

A practical and unified strategy has been described for the preparation of mono- and difluoromethylated phenanthridine derivatives using a visible-light-promoted alkylation and decarboxylation sequence from biphenyl isocyanides with ethyl bromofluoroacetate (EBFA) or ethyl bromodifluoroacetate (EBDFA). These reactions could be carried out at room temperature in good to excellent chemical yields. Both stepwise and one-pot procedures have been developed, which makes this strategy more attractive.

Full text of DOI:10.1021/ol501081h

Letter
pubs.acs.org/OrgLett
Visible-Light-Mediated Fluoroalkylation of Isocyanides with Ethyl
Bromofluoroacetates: Unified Synthesis of Mono- and
Difluoromethylated Phenanthridine Derivatives
Xiaoyang Sun and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science and Institute of Chemical Biology and Drug Innovation, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
S
* Supporting Information
ABSTRACT: A practical and unified strategy has been
described for the preparation of mono- and difluoromethylated
phenanthridine derivatives using a visible-light-promoted
alkylation and decarboxylation sequence from biphenyl
isocyanides with ethyl bromofluoroacetate (EBFA) or ethyl
bromodifluoroacetate (EBDFA). These reactions could be
carried out at room temperature in good to excellent chemical
yields. Both stepwise and one-pot procedures have been
developed, which makes this strategy more attractive.
ver the past two decades, fluorine-containing organic
molecules have received increasing attention because of
synthesis of difluoromethyl aromatic and heteroaromatic
compounds.6a,b Both coupling and decarboxylation reactions
were carried out at an elevated temperature. Hu’s group
developed a new monofluoromethylation of aryl iodides with α-
fluorinated arylsulfonyl-substituted active methylene com-
pounds. However, the subsequent desulfonylation is plagued
by strong reductive conditions (Bu3SnH at 110 °C).6c,d Thus, a
catalytic method to form mono- and difluoromethylated
aromatic compounds under mild conditions with simple and
cheap fluorine sources is very valuable and provides an
important tool for synthetic and medicinal chemistry.
Ethyl bromodifluoroacetate (EBDFA, 2a) and ethyl bromo-
fluoroacetate (EBFA, 2b) are two commercially available liquids
and can be purchased in bulk quantities, which are ideal
materials for fluoromethylations.8 However, partial fluorome-
thylation with these two readily available fluorine reagents is
less studied.9 Very recently, we succeeded in incorporating
these two building blocks into heteroarenes using visible-light-
promoted somophilic isocyanide insertion (Figure 1C).10,11 We
contemplate whether the ester moieties can be removed under
mild conditions. If so, mono- and difluoromethylated
phenanthridine derivatives can be accessed rapidly with an
alkylation and decarboxylation sequence.
O
the elevated reactivity, lipophilicity, and bioactivity compared to
their nonfluorinated counterparts.1 Promoted by a wide range
of applications, organofluorine chemistry is booming and offers
fruitful results to chemists across many disciplines.2 In this field,
the great development of new methodologies for highly
efficient and selective incorporation of a trifluoromethyl
group (CF3) into diverse skeletons has been achieved by
numerous synthetic chemists.3 Yet, compared to trifluorome-
thylation chemistry, the analogous mono- or difluoromethyla-
tion (selective introduction of a CF2H or CH2F group into
organic molecules) is much less studied.4 Incorporation of
partially fluoromethyl groups into organic molecules is a
challenging task and remains mainly unexplored.
Recently, significant progress has been achieved on mono-
and difluoromethylation of aromatic compounds based on two
major strategies.5−7 One is the direct transfer of a “CF2H” or
“CH2F” group into arenes (Figure 1A).5 For example, Baran
and co-workers reported elegant direct oxidative fluoromethy-
lations of heterocycles using zinc fluoromethanesulfinates as
fluorine sources.5a,b Hartwig’s group described stoichiometric
copper-mediated difluoromethylation of aryl iodides with
trimethylsilyl difloromethane (TMSCF2H) at 120 °C.5c
Prakash and co-workers also reported an alternative stoichio-
metric copper-mediated difluoromethylation of aryl iodides
with tributyl(difluoromethyl) stannane (n-Bu3SnCF2H) at
more than 100 °C.5d The other is the transfer of a
functionalized fluoromethyl group (such as “CF2R” or
“CFHR”), followed by removal of the functional groups, to
give a CF2H or CH2F group (Figure 1B).6 Based on this
strategy, Amii and co-workers reported a stoichiometric CuI-
mediated three-step approach (C−C coupling of aryl iodides
with TMSCF2CO2Et, hydrolysis, and decarboxylation) for the
In order to examine this design, phenanthridine derivative 3a,
which could be prepared from biphenyl isocyanide 1a with
EBDFA (2a) according to our previous work,10 was treated
with a mixture of 1 M K2CO3 (aq) in methanol. An acidic
workup at room temperature was followed after hydrolysis was
completed as indicated by TLC monitoring. To our delight, the
desired 6-difluoromethylated phenanthridine derivative 5a was
Received: April 14, 2014
Published: May 21, 2014
© 2014 American Chemical Society
2938
dx.doi.org/10.1021/ol501081h | Org. Lett. 2014, 16, 2938−2941

Organic Letters
Letter
a
,b
Scheme 2. Scope of Isocyanides of Difluoromethylation
Figure 1. Major strategies of mono- and difluoromethylation of arenes.
generated directly without further operations in quantitative
yield. Similarly, 6-monofluoromethylated phenanthridine de-
rivative 6a could also be produced quantitatively with the same
procedure (Scheme 1).
Scheme 1. Room Temperature Decarboxylation
a
Reaction conditions: Step 1: 1 (0.2 mmol, 1.0 equiv), 2a (0.4 mmol,
2.0 equiv), Na2HPO4 (0.24 mmol, 1.2 equiv), and Ir(ppy)3 (0.002
mmol, 1.0 mol %) in dry DMF (2.0 mL) were irradiated by 3 W blue
LED; Step 2: 3 (0.1 mmol) in 1 M K2CO3 (1 mL) and CH3OH (1
b
c
mL), then diluted HCl (aq). Isolated yield. 3.0 equiv of 2a were
used.
difluoromethylated phenanthridine derivatives in high yields
(76−100%).
The great success prompted us to investigate the generalities
of this stepwise fluoromethylation. First, a series of 6-
difluoromethylated phenanthridine derivatives were prepared
enabled by the alkylation and decarboxylation sequence from
biphenyl isocyanides and EBDFA (2a) as shown in Scheme 2.
A variety of biphenyl isocyanides were employed to react with
2a under the established alkylation conditions. The correspond-
ing 6-alkylated phenanthridine derivatives were prepared in
good to perfect yields (60−100%). The substituents on both
benzene rings did not affect this transformation significantly.
The subsequent decarboxylation also worked quite well. All the
isolated 6-alkylated phenanthridine derivatives could go
through hydrolysis and decarboxylation smoothly to afford 6-
We then turned our attention to prepare 6-monofluoro-
methylated phenanthridine derivatives as shown in Scheme 3. A
broad range of 2-isocyanobiphenyl compounds reacted
smoothly with EBFA (2b) to give the corresponding 6-
alkylated phenanthridine derivatives in satisfactory yields (59−
88%). After alkylation, the subsequent decarboxylation also
worked smoothly. All the 6-alkylated phenanthridine derivatives
afforded 6-monofluoromethylated phenanthridine derivatives in
good to excellent yields (73−100%) after hydrolysis and acidic
workup.
The miscibility of DMF with MeOH and H2O prompted us
to investigate the possibility of a one-pot procedure for the
synthesis of di- and monofluoromethylated phenanthridine
2939
dx.doi.org/10.1021/ol501081h | Org. Lett. 2014, 16, 2938−2941

Organic Letters
Letter
a
,b
Scheme 3. Scope of Isocyanides of
Monofluoromethylation
Scheme 4. A One-Pot Procedure
a
,b
a
Reaction conditions: Step 1: 1 (0.2 mmol, 1.0 equiv), 2b (0.4 mmol,
2.0 equiv), Na2HPO4 (0.24 mmol, 1.2 equiv), and Ir(ppy)3 (0.002
mmol, 1.0 mol %) in dry DMF (2.0 mL) were irradiated by 3 W blue
LED; Step 2: 4a (0.1 mmol) in 1 M K2CO3 (1 mL) and CH3OH (1
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a or 2b (0.4 mmol,
2.0 equiv), Na2HPO4 (0.24 mmol, 1.2 equiv), and Ir(ppy)3 (0.002
mmol, 1.0 mol %) in dry DMF (2.0 mL) were irradiated by 3 W blue
LED; After the alkylation was complete, to the solution were added 1
M K2CO3 (1 mL) and MeOH (1 mL), and then diluted HCl (aq) was
b
c
mL), then diluted HCl (aq). Isolated yield. 3.0 equiv of 2b were
used.
b
c
added. Isolated yield. 10 mmol scale.
derivatives, which can improve the overall efficiency of this
transformation significantly. After the alkylation step was
complete, the solution was treated with 1 M K2CO3 (aq, 1
mL) and MeOH (1 mL) at room temperature directly. And
then the reaction mixture was acidified to about pH 3 with
diluted HCl (aq). Fortunately, we found the sequential one-pot
protocol worked quite well for a number of substrates without
significantly affecting the yield compared to the stepwise
procedure for both di- and monofluoromethylations (Scheme
4). More importantly, the one-pot procedure could be scaled
up easily with comparable yields. 5a (1.68 g) and 6a (1.20 g)
were prepared when the reaction was run in 10 mmol scale.
This greatly improved the practicability of this synthetic
procedure and provided a convenient route to the preparation
of 6-mono- and difluoromethylated phenanthridine derivatives.
In summary, we have described a practical and unified
strategy for the preparation of 6-mono- and difluoromethylated
phenanthridine derivatives using alkylation and decarboxylation
sequences. Both alkylation and decarboxylation reactions
proceeded at room temperature in good to excellent chemical
yields with a broad substrate scope. Furthermore, the
fluoromethylation reagents (EBDFA, 2a and EBFA, 2b) are
inexpensive and readily available, which serve as ideal fluorine
sources. Both stepwise and one-pot procedures worked quite
well, which makes these protocols ideal choices for the
synthesis of mono- and difluoromethylated heteroarenes.
Further work on the mono- and difluoromethylation of various
substrates using these reagents is underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yushouyun@nju.edu.cn.
2940
dx.doi.org/10.1021/ol501081h | Org. Lett. 2014, 16, 2938−2941

Organic Letters
Letter
(h) Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.;
Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Angew. Chem., Int. Ed.
2011, 50, 7153. (i) Iida, T.; Hashimoto, R.; Aikawa, K.; Ito, S.;
Mikami, K. Angew. Chem., Int. Ed. 2012, 51, 9535. (j) Hu, M.; He, Z.;
Gao, B.; Li, L.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2013, 135, 17302.
(k) Min, Q.; Yin, Z.; Feng, Z.; Guo, W.; Zhang, X. J. Am. Chem. Soc.
2014, 136, 1230. (l) Kosobokov, M. D.; Dilman, A. D.; Struchkova, M.
I.; Belyakov, P. A.; Hu, J. J. Org. Chem. 2012, 77, 2080. (m) Prakash, G.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the 863 program (2013AA092903), the
National Natural Science Foundation of China (21272113),
and the Natural Science Foundation of Jiangsu Province
(BK20131266).
́
K. S.; Paknia, F.; Mathew, T.; Mloston, G.; Joschek, J. P.; Olah, G. A.
Org. Lett. 2011, 13, 4128. (n) Mizuta, S.; Stenhagen, I. S. R.; O’Duill,
M.; Wolstenhulme, J.; Kirjavainen, A. K.; Forsback, S. J.; Tredwell, M.;
Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.; Passchier, J.;
Solin, O.; Gouverneur, V. Org. Lett. 2013, 15, 2648. (o) Zhou, Q.;
Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P.
S. Angew. Chem., Int. Ed. 2013, 52, 3949. (p) Matsuzak, K.; Furukawa,
T.; Tokunaga, E.; Matsumoto, T.; Shiro, M.; Shibata, N. Org. Lett.
2013, 15, 3282.
(8) The price of 2a and 2b from TCI, China: CNY 460/25g (US
$77/25 g) for 2a, CNY 1450/25g (US $242/25 g) for 2b. They can
also be purchased in bulk quantities from a local company with much
lower prices: CNY 1600/kg (US $267/kg) for 2a and CNY 8900/ kg
(US $1483/kg) for 2b.
(9) For selected reactions employing 2a or 2b, see: (a) Kaneda, T.;
Komura, S.; Kitazume, T. J. Fluorine Chem. 2005, 126, 17.
(b) Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Wallace, D. J.;
Davies, A. J.; Kennedy, D. J.; Dolling, U. H. Tetrahedron Lett. 2002, 43,
9271. (c) Cheguillaume, A.; Lacroix, S.; Marchand-Brynaert, J.
Tetrahedron Lett. 2003, 44, 2375. (d) Nguyen, J. D.; Tucker, J. W.;
Konieczynska, M. D.; Stephenson, C. R. J. J. Am. Chem. Soc. 2011, 133,
4160. (e) Wallentin, C.; Nguyen, J. D.; Finkbeiner, P.; Stephenson, C.
R. J. J. Am. Chem. Soc. 2012, 134, 8875.
REFERENCES
■
(1) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford,
2006. (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
̈
(c) Organofluorine Chemistry: Principles and Commercial Applications;
Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New York,
2000. (d) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications;
Elsevier: New York, 1993. (e) Hiyama, T.; Kanie, K.; Kusumoto, T.;
Morizawa, Y.; Shimizu, M. Organofluorine Compounds: Chemistry and
Applications; Springer: Berlin, 2000.
(2) (a) Wen, L.; Shen, Q.; Lu, L. Org. Lett. 2010, 12, 4655. (b) Liu,
C.; So, L.; Lo, J. C. Y.; Chan, M. C. W.; Kaneyoshi, H.; Makio, H.
Organometallics 2012, 31, 5274. (c) Rudnitskaya, A.; Huynh, K.;
Torok, B.; Stieglitz, K. J. Med. Chem. 2009, 52, 878. (d) Watson, W. J.
̈
̈
Org. Process Res. Dev. 2006, 10, 1314. (e) O’Hagan, D. J. Org. Chem.
2012, 77, 3689. (f) Torok, M.; Abid, M.; Mhadgut, S. C.; Torok, B.
̈
̈
̈
̈
Biochemistry 2006, 45, 5377. (g) Amii, H.; Kageyama, K.; Kishikawa,
Y.; Hosokawa, T.; Morioka, R.; Katagiri, T.; Uneyama, K. Organo-
metallics 2012, 31, 1281. (h) Jin, G.; Zhang, X.; Cao, S. Org. Lett. 2013,
15, 3114.
(3) (a) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; Pozo, C.;
́
́
̃
(10) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S.
Angew. Chem., Int. Ed. 2013, 52, 13289.
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.
2014, 114, 2432. (b) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med.
Chem. 2014, 57, 2832. (c) Yamazaki, T.; Tagauchi, T.; Ojima, I. In
Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.;
Wiley-Blackwell: Chichester, 2009; pp 3−46. (d) Hagmann, W. K. J.
Med. Chem. 2008, 51, 4359. (e) Schlosser, M. Angew. Chem. 2006, 118,
5558; Angew. Chem., Int. Ed. 2006, 45, 5432. (f) Shimizu, M.; Hiyama,
T. Angew. Chem. 2005, 117, 218; Angew. Chem., Int. Ed. 2005, 44, 214.
(g) Kirsch, P. In Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications; Wiley-VCH: Weinheim, 2004. (h) Jeschke, P. Chem-
BioChem. 2004, 5, 570.
(11) For other related works on biphenyl isocyanides, see: (a) Liu, J.;
Fan, C.; Yin, H.; Qin, C.; Zhang, G.; Zhang, X.; Yi, H.; Lei, A. Chem.
Commun. 2014, 50, 2145. (b) Zhang, B.; Daniliuc, C. G.; Studer, A.
Org. Lett. 2014, 16, 250. (c) Leifert, D.; Daniliuc, C. G.; Studer, A. Org.
Lett. 2013, 15, 6286. (d) Cheng, Y.; Jiang, H.; Zhang, Y.; Yu, S. Org.
Lett. 2013, 15, 5520. (e) Zhang, B.; Muck-Lichtenfeld, C.; Daniliuc, C.
̈
G.; Studer, A. Angew. Chem., Int. Ed. 2013, 52, 10792. (f) Wang, Q.;
Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846. (g) Tobisu, M.;
Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem., Int. Ed. 2012, 51,
11363.
(4) For recent reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter, T.
Angew. Chem., Int. Ed. 2013, 52, 8214. (b) Hu, J.; Zhang, W.; Wang, F.
Chem. Commun. 2009, 7465. (c) Mace,
Chem. 2012, 2479.
(5) (a) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon,
D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M.
́
Y.; Magnier, E. Eur. J. Org.
́
R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. (b) Fujiwara, Y.;
Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M.
R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494.
(c) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(d) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.; Kulkarni, A.; Masood,
K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, 12090.
(6) (a) Fujikawa, K.; Kobayashi, A.; Amii, H. Synthesis 2012, 44,
3015. (b) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett.
2011, 13, 5560. (c) Zhao, Y.; Ni, C.; Jiang, F.; Gao, B.; Shen, X.; Hu, J.
ACS Catal. 2013, 3, 631. (d) Zhao, Y.; Gao, B.; Ni, C.; Hu, J. Org. Lett.
2012, 14, 6080.
(7) For other related works on mono- and difluoromethylations, see:
(a) Liu, G.; Wang, X.; Lu, X.; Xu, X.; Tokunaga, E.; Shibata, N.
Chemistry Open 2012, 1, 227. (b) Nomura, Y.; Tokunaga, E.; Shibata,
N. Angew. Chem., Int. Ed. 2011, 50, 1885. (c) Liu, J.; Hu, J. Chem.
Eur. J. 2010, 16, 11443. (d) Shen, X.; Zhou, M.; Ni, C.; Zhang, W.;
Hu, J. Chem. Sci. 2013, 5, 117. (e) Zhu, J.; Zhang, W.; Zhang, L.; Liu,
J.; Zheng, J.; Hu, J. J. Org. Chem. 2010, 75, 5505. (f) Wang, X.; Liu, G.;
Xu, X.; Shibata, N.; Tokunaga, E.; Shibata, N. Angew. Chem., Int. Ed.
2014, 53, 1827. (g) Prakash, G. K. S.; Krishnamoorthy, S.; Ganesh, S.
K.; Kulkarni, A.; Haiges, R.; Olah, G. A. Org. Lett. 2014, 16, 54.
2941
dx.doi.org/10.1021/ol501081h | Org. Lett. 2014, 16, 2938−2941