An efficient route to chiral N-heterocycles bearing a C-F stereogenic center via asymmetric hydrogenation of fluorinated isoquinolines

Article abstract of DOI:10.1039/c3cc45341c

An efficient iridium-catalyzed asymmetric hydrogenation of the fluorinated isoquinoline derivatives has been successfully developed for the synthesis of chiral fluorinated tetrahydroisoquinoline derivatives with up to 93% ee. This methodology features the use of a hydrochloride salt as well as a catalytic amount of halogenated hydantoin which were vital for the reactivity, enantioselectivity, and inhibition of the hydrodefluorination pathway. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45341c

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
An efficient route to chiral N-heterocycles bearing a
C–F stereogenic center via asymmetric hydrogenation
of fluorinated isoquinolines†
Cite this: Chem. Commun., 2013,
49, 8537
Received 15th July 2013,
Accepted 22nd July 2013
Ran-Ning Guo, Xian-Feng Cai, Lei Shi, Zhi-Shi Ye, Mu-Wang Chen and
Yong-Gui Zhou*
DOI: 10.1039/c3cc45341c
www.rsc.org/chemcomm
An efficient iridium-catalyzed asymmetric hydrogenation of the
fluorinated isoquinoline derivatives has been successfully developed
for the synthesis of chiral fluorinated tetrahydroisoquinoline deriva-
tives with up to 93% ee. This methodology features the use of a
hydrochloride salt as well as a catalytic amount of halogenated
hydantoin which were vital for the reactivity, enantioselectivity,
and inhibition of the hydrodefluorination pathway.
Scheme 1 Challenges in asymmetric hydrogenation of fluorinated heteroaromatic
compounds.
Fluorine is consistently an integral part of pharmaceuticals,
agrochemicals and materials due to its unique effects on
properties of organic molecules.1 As a fascinating and challenging
topic in organofluorine chemistry, constructing enantioenriched
fluorinated building blocks, especially with a fluorinated stereo-
genic carbon center has become increasingly important.2 Besides
direct asymmetric fluorination,3 asymmetric hydrogenation
of fluorinated prochiral unsaturated compounds provides an
alternative approach for construction of chiral carbon–fluorine
centres. Given the great achievements in catalytic asymmetric
hydrogenation and the utility of chiral fluorinated compounds,
it is a surprise that the asymmetric hydrogenation of fluori-
nated unsaturated compounds was rarely explored. During the
past decades, only a few pioneering works were reported by
Saburi, Nelson, and Andersson4 on asymmetric reduction of
fluorinated olefins. However, these works encountered limited
substrate scope and some degrees of hydrodefluorination beyond
prediction.
fluorinated compounds, the asymmetric hydrogenation of
fluorinated heteroaromatics has been a ‘‘sleeping beauty’’ to date
(Scheme 1). The inherent problems are apparent: the highly
stabilized aromatic structure, unavoidable hydrodefluorination
and the difficulty to control the stereoselectivity.
Considering the easy cleavage of the carbon–fluorine bond
in transition metal catalyzed systems,6 two plausible hydrode-
fluorination pathways in asymmetric hydrogenation are proposed
(Scheme 2). Path A: oxidative addition of C–F to a low-valent
metal, followed by hydrogenolysis, causes hydrodefluorination4d,7
(eqn (1)). Path B: addition of a metal-hydride species to the
CQC–F unit of aromatics, followed by b-fluorine elimination,
causes hydrodefluorination4f,8 (eqn (2)). Based on the analysis
above, we envisioned that the key factor for inhibiting hydro-
defluorination is to regulate the catalytic elementary steps away
from the hydrodefluorination pathways by carefully designing
Asymmetric hydrogenation of heteroaromatic compounds has
been intensively studied and considered as an efficient method
for the synthesis of a variety of new chiral cyclic compounds.5
Fluorination of these products would provide other signifi-
cantly modified structural motifs with desirable properties in
pharmaceuticals or materials. However, as a straightforward
and atom-economic route to the synthesis of the corresponding
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
E-mail: ygzhou@dicp.ac.cn
† Electronic supplementary information (ESI) available: Experimental details.
CCDC 917645. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc45341c
Scheme 2 The plausible hydrodefluorination pathways in transition metal catalyzed
asymmetric hydrogenation of fluorinated aromatic compounds.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 8537--8539 8537

View Article Online
Communication
ChemComm
Table 1 The evaluation of reaction parametersa
the substrate structure. Among the successful examples of
asymmetric hydrogenation of heteroaromatics, a putative mecha-
nism involving enamine–imine isomerization was proposed
(eqn (3)),9 by which the CQC–NH unit was isomerized to
CH–CQN and then reduced. This inspired us to synthesize
4-fluorinated isoquinolines,10 with similar catalytic elementary
steps which would inhibit the hydrodefluorination pathways
proposed above (eqn (1) and (2)). Herein, we described the
first successful example of the asymmetric hydrogenation of
fluorinated heteroaromatics with high chemo-, diastereo- and
enantioselectivity.
Following the hypothesis, asymmetric hydrogenation of
4-fluorinated isoquinolines was carried out with the optimal
system on 3,4-disubstituted isoquinolines: [Ir(cod)Cl]2/(R)-SynPhos/
BCDMH(1-bromo-3-chloro-5,5-dimethylhydantoin)/toluene/70 1C.9b
According to the catalyst activation strategy, the additive here
was supposed to oxidize the low-valent metal to a more active
species,11 which was also coincident with the control experi-
ment: >95% conversion and 74% ee were obtained with 10%
BCDMH in contrast to 14% conversion with no additives.12 In
addition, the HCl generated in situ from reaction of the additive
and [Ir(cod)Cl]2 could accelerate isomerization between iminium
and enamine.9b,d Unfortunately, only moderate enantioselectivity
was obtained albeit with high reactivity.
Considering that the extra Brønsted acid could accelerate
iminium–enamine isomerization preferably as well as activate
substrates to facilitate hydrogenation,9c,13 the asymmetric hydro-
genation of the corresponding isoquinolinium chloride was
examined.14 To our delight, a much better enantioselectivity was
obtained with 26% conversion (86% ee, entry 1, Table 1). Next, the
effect of the reaction medium was tested (entries 2–6). A dramatic
solvent effect was revealed and a mixed solvent of dioxane and
isopropanol with a ratio of 5/1 gave the best result in terms of both
enantioselectivity and conversion (93% ee and >95% conversion,
entry 6). Various halogen sources gave similar ee values between
89–93% (entries 5 and 7–9), and no deterioration of enantio-
selectivity was observed with half-amount of the additive
employed (entry 10). A brief investigation on chiral ligands
was conducted with some commercially available diphosphine
ligands (entries 10–13). Most importantly, stoichiometric acid
as well as 5% additives were vital to establish a final system on
3-butyl-4-fluoro-isoquinolinium chloride to give the best result of
93% ee: [Ir(cod)Cl]2/(R)-SynPhos/DCDMH/H2 (40 bar)/(dioxane–
isopropanol 5 : 1)/30 1C.
Under the optimized conditions, the scope of enantioselective
synthesis of 2 was explored (Table 2). In general, excellent yields
(79–97%) and enantioselectivities (88–93% ee) were obtained
regardless of the properties of the alkyl chain in 3-position of 1
(1a–1h). There is also only little fluctuation in enantioselectivity
and yield no matter the electronic nature and position of sub-
stituents on aromatics (1i–1m). The initial substrate scope explora-
tion demonstrated the potential application of the synthesis to
access various chiral fluorinated tetrahydroisoquinolines, which
Entry
Solvent
Additive
Ligand
eeb (%)
Conv.c (%)
1
2
3
4
5
6
7
8
Toluene
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
I2
BCDMH
DBDMH
DCDMH
DCDMH
DCDMH
DCDMH
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
86
89
79
91
93
87
89
91
91
93
93
87
91
28
88
Dioxane (D)
i-PrOH (P)
D–P (1 : 1)
D–P (5 : 1)
D–P (1 : 5)
D–P (5 : 1)
D–P (5 : 1)
D–P (5 : 1)
D–P (5 : 1)
D–P (5 : 1)
D–P (5 : 1)
D–P (5 : 1)
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
9
10d
11d
12d
13d
a
Reaction conditions: 1aÁHCl (0.20 mmol), (R)-SynPhos (2.2 mol%),
[Ir(COD)Cl]2 (1.0 mol%), H2 (40 bar), solvent (3 mL), additive (10 mol%),
b
20 h, 30 1C. Determined by HPLC analysis of the corresponding
N-4-bromobenzoyl derivative. Determined by 1H NMR, with all reac-
c
d
tion o5% hydrodefluorination by-product and >20 : 1 d.r. DCDMH
(5 mol%).
Table 2 Asymmetric hydrogenation of 4-fluoroisoquinolinium chlorides (1ÁHCl)a
Entry
1ÁHCl (R1/R2/R3)
Yieldb (%)
eec (%)
1
2
3
4
5
6
H/H/n-Bu
H/H/Me
H/H/Et
H/H/n-Pr
H/H/cyclopropyl
H/H/n-pentyl
92 (2a)
92 (2b)d
94 (2c)d
93 (2d)
79 (2e)
97 (2f)
88 (2f) f
95 (2g)
88 (2h)
91 (2i)
93 (2j)
93 (À)
93 (À)
93 (À)
92 (R,R)e
90 (À)
90 (À)
88 (À)
93 (À)
88 (À)
91 (À)
91 (À)
89 (À)
91 (À)
90 (À)
91 (À)
7
8
9
10
H/H/Bn
H/H/phenethyl
F/H/n-Bu
H/F/n-Bu
91 (2j) f
97 (2k)
93 (2l)
11
12
13
Me/H/n-Bu
Cl/H/n-Bu
Me/H/n-Pr
91 (2m)
a
Reaction conditions: 1ÁHCl (0.20 mmol), (R)-SynPhos (2.2 mol%),
[Ir(COD)Cl]2 (1.0 mol%), H2 (40 bar), dioxane–isopropanol (5 : 1,
3 mL), DCDMH (5 mol%), 20 h, 30 1C. Isolated yields. Determined
b
c
represent modified structural motifs in many natural alkaloids by HPLC analysis of the corresponding N-4-bromobenzoyl derivative.
d
and biologically active compounds.15
Determined by the corresponding N-4-bromobenzoyl derivatives due
e
to their highly volatile characteristic. The absolute configuration of 2d
was determined by single-crystal X-ray diffraction analysis of the
the asymmetric hydrogenation of fluorinated isoquinolines 1f corresponding N-4-bromobenzoyl derivative. Gram scale.
To further evaluate the practical utility of the current system,
f
c
8538 Chem. Commun., 2013, 49, 8537--8539
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
(b) H. Amii and K. Uneyama, Chem. Rev., 2009, 109, 2119;
(c) S. A. Macgregor, Chem. Soc. Rev., 2007, 36, 67; (d) E. Clot,
O. Eisenstein, N. Jasim, S. A. Macgregor, J. E. Mcgrady and
R. N. Perutz, Acc. Chem. Res., 2011, 44, 333.
and 1j was carried out on a gram scale (entries 6 and 10,
Table 2), and the desired products 2f and 2j were furnished
with results of 88% ee, 88% yield and 89% ee, 91% yield.
In summary, we have successfully developed an efficient
system to access the chiral fluorinated tetrahydroisoquinolines
via asymmetric hydrogenation of the corresponding fluorinated
isoquinoline derivatives with up to 93% ee. Stoichiometric acid as
well as a catalytic amount of additive were vital for the reactivity,
enantioselectivity and inhibition of the hydrodefluorination path-
way. Further investigation on the application of the developed
strategy and detailed mechanistic studies of the catalytic cycle are
currently ongoing in our laboratory.
7 For selected works on defluorination or hydrodefluorination by
oxidative addition to low-valent transition metals see: (a) H. Yang,
H. R. Gao and R. J. Angelici, Organometallics, 1999, 18, 2285;
(b) N. Y. Adonin and V. F. Starichenko, J. Fluorine Chem., 2000,
101, 65; (c) J. A. Panetier, S. A. Macgregor and M. K. Whittlesey,
Angew. Chem., Int. Ed., 2011, 50, 2783; (d) M. F. Kuehnel, D. Lentz
and T. Braun, Angew. Chem., Int. Ed., 2013, 52, 3328; (e) H. B. Lv,
Y. B. Cai and J. L. Zhang, Angew. Chem., Int. Ed., 2013, 52, 3203.
8 For recent examples of the b-halide elimination process in the
transition metal catalysis system see: (a) L. A. Watson, D. V.
Yandulov and K. G. Caulton, J. Am. Chem. Soc., 2001, 123, 603;
(b) S. A. Strasizar and P. T. Wolczanski, J. Am. Chem. Soc., 2001,
123, 4728; (c) B. M. Kraft and W. D. Jones, J. Am. Chem. Soc., 2002,
124, 8681; (d) T. Braun, D. Noveski, B. Neumann and H.-G.
Stammler, Angew. Chem., Int. Ed., 2002, 41, 2745; (e) R. A. Stockland,
S. R. Foley and R. F. Jordan, J. Am. Chem. Soc., 2003, 125, 796;
( f ) T. R. Cundari and C. D. Taylor, Organometallics, 2003, 22, 4047;
This work was financially supported by the National Natural
Science Foundation of China (21032003 & 21125208) and the
National Basic Research Program of China (2010CB833300).
´
(g) E. Clot, C. Megret, B. M. Kraft, O. Eisenstein and W. D. Jones,
Notes and references
J. Am. Chem. Soc., 2004, 126, 5647.
1 For selected reviews on the unique role of fluorine in organic,
agricultural, medicinal, and material chemistries see: (a) K. Muller,
C. Faeh and F. Diederich, Science, 2007, 317, 1881; (b) W. K. Hagmann,
J. Med. Chem., 2008, 51, 4359; (c) D. O’Hagan, Chem. Soc. Rev., 2008,
37, 308; (d) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur,
Chem. Soc. Rev., 2008, 37, 320; (e) T. Furuya, A. S. Kamlet and T. Ritter,
Nature, 2011, 473, 470.
9 For works on asymmetric hydrogenation of isoquinolines see:
(a) S.-M. Lu, Y.-Q. Wang, X.-W. Han and Y.-G. Zhou, Angew. Chem.,
Int. Ed., 2006, 45, 2260; (b) L. Shi, Z.-S. Ye, L.-L. Cao, R.-N. Guo, Y. Hu
and Y.-G. Zhou, Angew. Chem., Int. Ed., 2012, 51, 8286; (c) A. Iimuro,
K. Yamaji, S. Kandula, T. Nagano, Y. Kita and K. Mashima,
Angew. Chem., Int. Ed., 2013, 52, 2046; (d) Z.-S. Ye, R.-N. Guo, X.-F.
Cai, M.-W. Chen, L. Shi and Y.-G. Zhou, Angew. Chem., Int. Ed., 2013,
52, 3685.
2 For recent reviews on asymmetric synthesis of chiral organofluorine
compounds see: (a) J. A. Ma and D. Cahard, Chem. Rev., 2004, 10 T. Xu and G. Liu, Org. Lett., 2012, 14, 5416.
104, 6119; (b) K. Mikami, Y. Itoh and M. Yamanaka, Chem. Rev., 11 For selected reports on halide effects in transition metal catalysis
¨
2004, 104, 1; (c) C. Bobbio and V. Gouverneur, Org. Biomol. Chem.,
2006, 4, 2065; (d) V. A. Brunet and D. O’Hagan, Angew. Chem.,
Int. Ed., 2008, 47, 1179; (e) J. A. Ma and D. Cahard, Chem. Rev., 2008,
108, Pr1; ( f ) D. Cahard, X. H. Xu, S. Couve-Bonnaire and
X. Pannecoucke, Chem. Soc. Rev., 2010, 39, 558.
3 For selected recent works on direct asymmetric fluorination see:
(a) T. D. Beeson and D. W. C. MacMillan, J. Am. Chem. Soc.,
see: (a) H.-U. Blaser, H.-P. Buser, R. Hausel, H.-P. Jalett and
F. Spindler, J. Organomet. Chem., 2001, 621, 34; (b) C. Y. Legault
and A. B. Charette, J. Am. Chem. Soc., 2005, 127, 8966; (c) T. Yamagata,
H. Tadaoka, M. Nagata, T. Hirao, Y. Kataoka, V. Ratovelomanana-
Vidal, J. P. Genet and K. Mashima, Organometallics, 2006, 25, 2505;
(d) N. Fleury-Bregeot, V. de la Fuente, S. Castillon and C. Claver,
ChemCatChem, 2010, 2, 1346.
2005, 127, 8826; (b) M. Marigo, D. I. Fielenbach, A. Braunton, 12 The additive was supposed to play an important role of catalyst
A. Kjoersgaard and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005,
44, 3703; (c) V. Rauniyar, A. D. Lackner, G. L. Hamilton and
activator by oxidizing a low-valent metal to a more active species,
simultaneously inhibiting hydrodefluorination Path A (eqn (1)).
F. D. Toste, Science, 2011, 334, 1681; (d) F. Li, L. Sun, Y. Teng, 13 For selected works on Brønsted acid effects in asymmetric hydro-
P. Yu, J. C. G. Zhao and J. A. Ma, Chem.–Eur. J., 2012, 18, 14255;
(e) R. J. Phipps, K. Hiramatsu and F. D. Toste, J. Am. Chem. Soc.,
2012, 134, 8376; ( f ) W. T. Meng, Y. Zheng, J. Nie, H. Y. Xiong and
J. A. Ma, J. Org. Chem., 2013, 78, 559; (g) R. J. Phipps and F. D. Toste,
J. Am. Chem. Soc., 2013, 135, 1268.
4 For previous works on asymmetric hydrogenation of vinyl fluorides
see: (a) T. Allmendinger, C. Dandois and B. Walliser, Tetrahedron
Lett., 1991, 32, 2735; (b) M. Saburi, L. M. Shao, T. Sakurai and
Y. Uchida, Tetrahedron Lett., 1992, 33, 7877; (c) S. W. Krska, J. V. Mitten,
M. H. Kress, Y. K. Sun and T. D. Nelson, WO/2006/069287A1, 2006;
(d) M. Engman, J. S. Diesen, A. Paptchikhine and P. G. Andersson,
genation by forming corresponding iminium salts see: (a) G. Hou,
F. Gosselin, W. Li, C. McWilliams, Y. K. Sun, M. Weisel, P. D.
O’Shea, C. Y. Chen, I. W. Davies and X. Zhang, J. Am. Chem. Soc.,
2009, 131, 9882; (b) G. H. Hou, W. Li, M. F. Ma, X. W. Zhang and
X. Zhang, J. Am. Chem. Soc., 2010, 132, 12844; (c) G. H. Hou, R. Tao,
Y. Sun, X. Zhang and F. Gosselin, J. Am. Chem. Soc., 2010, 132, 2124;
(d) D.-S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou and X. Zhang,
J. Am. Chem. Soc., 2010, 132, 8909; (e) D.-S. Wang, J. Tang,
Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan and G.-F. Jiang, Chem.
Sci., 2011, 2, 803; ( f ) D.-S. Wang, Z.-S. Ye, Q.-A. Chen, Y.-G. Zhou,
C.-B. Yu, H.-J. Fan and Y. Duan, J. Am. Chem. Soc., 2011, 133, 8866.
J. Am. Chem. Soc., 2007, 129, 4536; (e) M. Engman, P. Cheruku, 14 Notably, a control experiment on acid amount showed that stoichio-
P. Tolstoy, J. Bergquist, S. F. Volker and P. G. Andersson, Adv. Synth.
Catal., 2009, 351, 375; ( f ) S. W. Krska, J. V. Mitten, P. G. Dormer,
D. Mowrey, F. Machrouhi, Y. K. Sun and T. D. Nelson, Tetrahedron,
2009, 65, 8987.
metric acid is necessary while catalytic amount gave an unsatis-
factory enantioselectivity (89% vs. 41%), probably because of the
difficult dissociation of the hydrogenation product, fluorinated
tetrahydroisoquinolinium chlorides.
5 For reviews on asymmetric hydrogenation of aromatic compounds 15 (a) J. D. Phillipson, M. F. Roberts and M. H. Zenk, The Chemistry and
see: (a) F. Glorius, Org. Biomol. Chem., 2005, 3, 4171; (b) Y.-G. Zhou,
Acc. Chem. Res., 2007, 40, 1357; (c) D.-S. Wang, Q.-A. Chen, S.-M. Lu
and Y.-G. Zhou, Chem. Rev., 2012, 112, 2557.
6 For reviews on transition metal-mediated carbon–fluorine bond
activation including fluorinated aromatics see: (a) J. L. Kiplinger,
T. G. Richmond and C. E. Osterberg, Chem. Rev., 1994, 94, 373;
Biology of Isoquinoline Alkaloids, Springer, Berlin, 1985; (b) R. Paul,
J. A. Coppola and E. Cohen, J. Med. Chem., 1972, 15, 720; (c) N. M.
Gray, B. K. Cheng, S. J. Mick, C. M. Lair and P. C. Contreras,
J. Med. Chem., 1989, 32, 1242; (d) K. W. Bentley, Nat. Prod. Rep.,
2006, 23, 444. For reviews, see: (e) J. D. Scott and R. M. Williams,
Chem. Rev., 2002, 102, 1669.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 8537--8539 8539