Formation of chiral fluoroalkyl products through copper-free enantioselective allylic alkylation catalyzed by an NHC ligand

Article abstract of DOI:10.1039/c2cc36513h

A valuable Cu-free protocol is reported where an NHC ligand has been employed to form quaternary carbon centers bearing fluoroalkyl units. The results obtained, from this allylic substitution, are better in terms of enantioselectivity and regioselectivity compared to the copper catalyzed system.

Full text of DOI:10.1039/c2cc36513h

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Formation of chiral fluoroalkyl products through Copper-free
enantioselective allylic alkylation catalyzed by NHC ligand
David Grassi,a Hailing Li a and Alexandre Alexakis*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
with the copper catalyzed system on our model substrate. To
our delight by using the same ligand, the copper free
50 methodology afforded impressive higher levels of selectivity
and enantioselectivity compared to the copper catalyzed
system (Scheme 1 and Table 1, entry 9). In view of our
previous work with L110 we assume that the absolute
stereochemistry is that shown.
A valuable Cu-free protocol is reported where NHC ligand
has been employed to form quaternary carbon centers
bearing fluoroalkyl unities. The results obtained, from this
allylic substitution, are better in terms of enantioselectivity
γ
10 and regioselectivity compared to the copper catalyzed system.
The fluorine atom is the most electronegative element in the
periodic table. Consequently the carbonꢀfluorine bond is
highly polarized and exhibits interesting and unique
stereoelectronic properties. The replacement of hydrogen by a
15 fluorine atom produces minimal structural changes in terms of
steric hindrance and allows a maximal change of the electron
distribution in the molecule.1 Additionally the presence of a
fluorine atom led to a global change of lipophilicity of the
molecule which can be visualized in the increasing lifetime of
20 fluorinated drugs compared to the non fluorinated analogues.2
3
Various fluorination reactions have been reported
and
55
fluoroalkylations represent powerful and accessible methods t
o build fluorine containing molecules. Enantioselective trifluo
romethylation, difluoromethylation and monofluoromethylatio
25 n are still very challenging compared to diastereoselective
versions.4,5 The great importance of the compounds with a
monofluoromethyl unit in the famous and widespread concept
of isostere based drug design has been clearly demonstrated.6,7
The metal catalyzed allylic monofluoromethylation has been
30 reported using palladium and iridium as transition metal
Scheme 1 Cuꢀfree versus Cuꢀcatalyzed system.
Encouraged by this promising result we began to screen our
library of NHC. The ligand morphology is composed of a
60 bulky blocking part (for instance a mesityl) and a chelating
part bearing a hydroxyl moiety, while the chirality is carried
by the diamino backbone. The chelating part was kept
unchanged and the influence of the blocking part on the
outcome of the reaction was firstly tested. The simpler ligand
65 L2 with a mesityl blocking part (Table 1, Entry 2) afforded
the desired product with a slightly lower ee value but with the
same range of regioselectivity as ligand L1. The ligand L3
with the dissymmetric blocking part methyl/ethyl (Table 1,
entry 3) afforded a lower ee value. The ligand L4 (Table 1,
70 entry 4) with a diethyl part proved to be completely inefficient
in the catalysis. This suggests that the steric bulk on the
blocking part should be modulated in a very appropriate way
and the substitution in para position of the hydroxyl group
must be further investigated. The introduction of a phenyl
75 group on para position of the hydroxyl group in L5 (Table 1,
entry 5) led to an impressive result. The ee could be improved
to 94 % and the regioselectivity obtained was perfect. The
result can be rationalized by a favourable steric environment
of the transition state as the two phenyl group are
80 perpendicular to each other. The increase of bulkiness using
8
catalysts while the construction of tertiary centers could be
achieved with high enantioselectivity. In addition the concept
of using FBSM (fluorobis(phenylsulfonyl)methane) as fluoro
methide equivalent has been previously used in many reaction
35 s such as Mitsonobu reaction, Michael addition and Mannich r
eaction.9 Herein we report the enantioselective construction
of quaternary centers bearing CH2F, CF2H, CF3 groups
through copper free allylic alkylation using bidendate Nꢀ
Heterocyclic Carbene (NHC) ligands. We have developed in
40 our laboratory transition metalꢀfree methods to access systems
that are inaccessible by conventional protocols.10 Instead of
using FBSM as fluoromethide equivalent we decided to
introduce directly the fluoroalkyl moiety on the substrate
and the substrates could be synthesized from commercially
45 available and inexpensive fluoroacetonitrile or ethyl
fluoroacetate (see supporting information for details) in a four
steps procedure. We started by comparing the Cuꢀfree method
[vol], 00–00 |
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1ꢀnaphthyl moiety L6 (Table 1, entry 6) yielded a lower
enantiomeric excess.
satisfactory results in a copper catalyzed system. In some
cases this fact underlined the advantage of the metal free
bidendate NHC ligand catalytic system. Finally the less
reactive and more hindered secondary Grignard reagents were
50 tested. The reaction worked in a similar manner as for the
primary Grignard reagent with the same level of
regioselectivity and enantioselectivity (Table 2, entries 7ꢀ8).
1
2
3
4
L1
: R =OBn, R =R =Et, R =H.
L2: R1=H, R2=R3=R4=Me.
OMe
OMe
Ph
Ph
R2
1
2
3
4
L3
: R =H, R =Me, R =Me, R =H.
N+
5
N
L4: R1=H, R2=R3=Et, R4=H.
O
O
P N
R4
L5: R1=Ph, R2=Me, R3=Et, R4=H.
3
OH
R
1
2
3
4
R1
L6
: R =1-Naphthyl, R =Me, R =Et, R =H.
L7: R1=4-CF3Ph, R2=Me, R3=Et, R4=H.
Cl-
L9 (S,S,S)
1
2
3
4
L8
: R =4-OMePh, R =Me, R =Et, R =H.
Table 2 Scope of Grignard reagents.
1.8 eq RMgBr
CFH2
10 Scheme 2 Chiral ligands used.
3 mol % L5
R
CFH2
Br
Et2O, -15°C, 2-9 h
100% conversion
The last step was to screen the importance of the electronic
density on the phenyl ring on para position of the hydroxyl
group. The introduction of an electron withdrawing group L7
15 (Table 1, entry 7) led to complete loss of selectivity and
enantioselectivity. The introduction of an electron donating
group L8 (Table 1, entry 8) did not improve the efficiency of
the reaction. The use of a phosphoramidite ligand L9 (Table
1, entry 9) in classical literature conditions (with Cu) provided
Entry
RMgBr
Et
Et
Isolated Yield (%) [c]
ee (%) [b]
γ:α [a]
100:0
100:0
100:0
100:0
100:0
1
2[d]
3
4
5
48
68
55
54
54
94
95
93
93
88
n-Pr
n-Bu
2ꢀmethylbutꢀ1ꢀ
11
enyl
Me
i-Pr
20 low conversion combined with a poor ee value of 30 % ee.
6
7
8
50
40
60
100:0
100:0
100:0
85
84
90
Table 1 Ligand screening.
c-Pent
[
55
1.8 eq EtMgBr
3 mol % L*
[a] By 1Hꢀ(NMR). [b] By chiral GC. [c] Yield after purification on silica gel
column chromatography. [d] Reaction done on 2 mmol scale.
CFH2
Et
CFH2
Br
Et2O, -15°C, 2 h
On the other hand, we considered the range of applications of
γ:α [a]
Entry
L
Conversion (%) [a]
ee (% ) [b]
90
60 our catalytic system by studying the scope of the allylic
partner. We synthesized different classes of substrates
including substituted aromatic substrates, branched and linear
aliphatic substrates, and we kept the previously optimized
conditions (3 mol % L5 with 1,8 eq Grignard reagent in
65 diethyl ether at ꢀ15°C). The introduction of a moderate
electron withdrawing group on the phenyl ring is compatible
yielding excellent results in terms of enantioselectivity and
regioselectivity (Table 3, entry 1).
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
100
100
100
100
100
100
100
100
20
94:6
94:6
95:5
ꢀ [c]
100:0
95:5
91:9
75:25
80:20
88
88
ꢀ [c]
94
88
23
87
30 [d]
[a]
[b]
[c]
[d]
By 1Hꢀ(NMR) By chiral GC. Messy reaction.
See ref 12 for
The presence of a moderate electron donating group on the
70 phenyl ring is also well tolerated with 100:0 γ:α ratio and 95%
enantioselectivity (Table 3, entry 2). Nevertheless the
introduction of a strong electron donating group ꢀOMe led to a
decrease of the enantioselectivity while perfect level of
regioselectivity is maintained (Table 3, entry 3). Next we
25 reaction conditions.
With our best ligand in hand we decided to investigate the
scope of Grignard reagents on our model substrate. Different
and representative Grignard reagents were employed to
30 demonstrate the generality of the methodology. The linear 75 tested two bulky and branched aliphatic derivatives with a
primaryalkyls Grignard could be introduced with a perfect
level of regioselectivities combined with excellent enantiosele
ctivities value (up to 95 % ee) and practical isolated yield
(Table 2, entries 1ꢀ5). Of interest was the scaling up of the
cyclohexyl and cyclopentyl moieties. The results obtained
were impressive in terms of both enantioselectivity and
regioselectivity (100:0 γ:α, up to 90 % ee) (Table 3, entries 4ꢀ
5). However the use of a linear aliphatic derivative produced
35 reaction to 2 mmol, mainly to see the impact on the isolated 80 the adduct with a low ee value (18 %) while perfect
yield. To our delight we could improve the isolated yield to 68
% (48 % on 0.4 mmol scale) while maintaining the perfect
level of regioselectivity and no loss of the enantioselectivity (
Table 2, entry 2). This demonstrates the potential of our
regioselectivity was again observed (Table 3, entry 6). All
these results demonstrate that our methodology is widely
applicable in both nucleophile and substrate scopes. The
limitation is the use of non bulky aliphatic derivatives; and
40 methodology for industrial applications. The challenging 85 most of the other substitution patterns could be employed.
MeMgBr reacted well when subjected to our reactions
conditions affording the desired adduct with a good level of
enantioselectivity combined with perfect level of
regioselectivity (Table 2, entry 6). It should be mentionned
45 that the MeMgBr is a nucleophile which is reluctant to give
Table 3 Substrate scope.
a
1.8 eq EtMgBr
CFH2
L5
3 mol %
Et
CFH2
90
R
R
Br
Et2O, -15°C, 2-9 h
100% conversion
2
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γ:α [a]
100:0
100:0
100:0
100:0
100:0
100:0
Entry
R
Isolated Yield (%) [c]
ee (%) [b]
30 centers. The reaction can be directly performed on the
substrate containing the fluoroalkyl moiety. The results
obtained are excellent on a wide range of substrates and
nucleophiles (15 examples, up to 95 % ee, up to 80 % yield,
100:0 γ:α in all cases). Finally the reaction can be scaled up
35 with no erosion of the enantioselectivity or regioselectivity
and importantly with improved yield.
1
2
3
4
5
6
pꢀClC6H4
mꢀMeC6H4
mꢀOMeC6H4
Cy
c-Pent
Ph(CH2)2
42
60
53
60
42
57
94
95
67
87
90
18
[a] By 1Hꢀ(NMR). [b] By chiral GC. [c] Yield after purification on silica gel
column chromatography.
Notes and references
a Department of Organic Chemistry, University of Geneva, Quai Ernest
Ansermet, 30, 1211, Geneva 4, Switzerland; E-mail:
40 alexandre.alexakis@unige.ch; Tel: 0041 (0)22 379 65 22
† Electronic Supplementary Information (ESI) available: Full
experimental details. See DOI: 10.1039/b000000x/
5
Finally we also extended our methodology to the construction
of quaternary centers bearing CF3 and CF2H groups. By
employing the copper free conditions we could obtain the
desirable adduct in high yield (80 %) with a perfect level of
regioselectivity, combined with a good level of enantioselecti
1
(a) J. P. Bégué, D. BonnetꢀDelpon, Bioorganic and Medicinal
Chemistry of Fluorine; Wiley:Hoboken, NJ, 2008; (b) W. K.
Hagmann, J. Med. Chem. 2008, 51, 4359; J. R. McCarthy, Fluorine
in Drug design: A Tutorial Review; 17th Winter Fluorine Conference
(St Petersburg,FL), Jan 9ꢀ14, 2005.
10 vity (79 % ee) when a CF3 group is present. Similarly on a
substrate bearing a CF2H group the copper free system
afforded better results than the copper catalyzed system in
both regioselectivity and enantioselectivity. Again the
phosphoramidite type ligand L9, in combination with copper,
15 afforded miserable results.
2 (a) A. M. Thayer, Chem. Eng. News. 2006, 84, 15; (b) P. Kirsch
Modern, Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, WileyꢀVCH, Weinheim, 2004; (c) Organofluorine
Compounds: Chemistry and Applications (Ed: T. Hiyama), Springer,
New York, 2000; (d) K. Uneyama, Organofluorine Chemistry,
Blackwell, New Dehli, 2006; (e) R. D. Chambers, Fluorine in
Organic Chemistry, Blackwell, Oxford, 2004; (f) Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications
(Eds: R. Filler, Y. Kobayashi, L. M. Yagupolskii), Elsevier, 1993; (g)
Biomedical Fontiers of Fluorine Chemistry ed. I. Ojima, J.R
McCarthy and J. T. Welch, Washington DC, 1996.
Et
CF2H
no reaction
1.8 eq EtMgBr
2.5 mol % CuTC
3 mol % L9, CH2Cl2
-78°C, 2 h
3 (a) B. J. Mann, Chem. Soc. Rev. 1987, 16, 381; (b) G. K. S Prakash, A.
K. Yudin, Chem. Rev. 1997, 97, 757; (c) B. R. Langlois, T. Billard,
Synthesis. 2003, 02, 185; (d) J. A. Ma, D. Cahard, Chem. Rev. 2004,
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(f) V. A. Brunet, D. O'Hagan, Angew. Chem. Int. Ed. 2008, 47, 1179;
(g) D. Cahard, X. Xu, S.CouveꢀBonnaire, X. Pannecoucke, Chem.
Soc. Rev, 2010, 39, 558; Chem. Rev, 2008 , 108, 1.
1.8 eq EtMgBr
2.5 mol % CuTC
L5
1.8 eq EtMgBr
L5
Et
CF2H
Et
CF2H
CF2H
3 mol %
3 mol %
Br
Et2O, -15°C, 2 h
Et2O, -78°C, 15 h
70:30 SN2'/SN
2
60 % yield
100:0 SN2'/SN
95 % ee
90 % ee
2
4 (a) H. Ibrahim, A. Togni, Chem. Commun 2004, 10, 1147; (b) P. M
Pihko, Angew. Chem. Int. Ed. 2006, 45, 544; (c) G. K. S. Prakash, P.
Beier, Angew. Chem. Int. Ed. 2006, 45, 2172; (d) C. Bobbio, V.
Gouverneur, Org. Biomol. Chem. 2006, 4, 2065; (e) T. Fukuzumi, N.
Shibata, M. Sugiura, H. Yasui, S. Nakamura, T. Toru, Angew. Chem.
Int. Ed. 2006, 45, 5095; (f) Y. Li, J. Hu, Angew. Chem. Int. Ed. 2005,
44, 6032; Angew. Chem. Int. Ed. 2005, 44, 5882; (g) Y. Li, C. Ni, J.
Liu, L. Zhang, J. Zheng, L. Zhu, J. Hu, Org. Lett. 2006, 8, 1693; (h)
G. K. S. Prakash, M. Mandal, G. A. Olah, Angew. Chem. Int. Ed.
2001, 40, 609.
1.8 eq Ph(CH2)2MgBr
2.5 mol % CuTC
3 mol % L4
1.8 eq
Ph(CH2)2MgBr
3 mol % L4
CF3
CF3
CF3
Ph
Ph
Messy reaction
Br
Et2O, -15°C, 15 h
Et2O, -15°C, 15 h
80 % yield
1.8 eq Ph(CH2)2MgBr
2.5 mol % CuTC
3 mol % L9,CH2Cl2
-78°C, 15 h
100:0 SN2'/SN
79 % ee
2
CF3
5 (a) T. Takehane, M. Mishina, T. Ishihara, T. Konno, J. Org. Chem.
2006, 71, 3545; (b) M. Kimusa, T. Yamasaki, T. Kituzane, T.
Kubota, Org. Lett. 2004, 25, 4651.
6 (a) G. W. Gribble, J. Chem. Educ. 1973, 50, 460; (b) R. Peters, R. W.
Wakelin, Proc. R. Soc. London Ser. B. 1953; (c) E. Kun, R. J.
Dummel, Methods Enzymol. 1969, 13, 623.
Ph
100 % conv
48:52 SN2'/SN
20 % ee
2
Scheme 3 Extension of the Cuꢀfree methodology in the construction
of CF3 and CF2H quaternary centers.
7 (a) D. O'Hagan, H.S. Rzepa, Chem. Commun. 1997, 7, 645; (b) R. H.
Abeles, A. L. Maycock, Acc. Chem. Res. 1976, 9, 313; (c) R. B.
Silverman, S. M. Nanavati, J. Med. Chem. 1990, 33, 931.
8 (a )T. Fukuzumi, N. Shibata, M. Sugiura, H. Yasui, S. Nakamura, T.
Toru, Angew.Chem. Int. Ed. 2006, 45, 4973; (b) W. B. Liu, S. C.
Zheng, H. He, X. M. Zhao, Chem. Commun 2009, 43, 6604.
To conclude, we have reported herein the first catalytic
20 Asymmetric Allylic Alkylation (AAA) protocol which allows
the construction of quaternary stereocenters bearing
a
monofluoromethyl, difluoromethyl and trifluoromethyl
groups. By using a readily available NHC bidendate ligand (3
steps synthesis) and a readily available organometallic source
25 we managed to obtain highly enantioenriched adducts which
contain two important patterns (presence of a quaternary
center flanked by a CH2F, CF2H or a CF3 group). This method
is complementary to the iridium and palladium catalyzed
AAA which led to the construction of less challenging tertiary
9 (a) G. K. S. Prakash, S. Chacko, S. Alconcel, T. Stewart, T. Mathew, G.
A. Olah, Angew. Chem. Int. Ed. 2007, 46, 5021; Angew. Chem. Int.
Ed. 2007, 46, 4933; (b) S. Mizuta, N. Shibata, Y. Goto, T. Furakawa,
S. Nakamura, T. Toru, J. Am. Chem. Soc. 2007, 129, 6394.
10 (a) O. Jackowski, A.Alexakis, Angew. Chem. Int. Ed. 2010, 49, 3346;
(b) D. Grassi, A. Alexakis, Org. Lett. 2012, 14, 1568; See also (c) Y.
Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128, 15604 ;
11 H. Li, A. Alexakis, Angew. Chem. Int. Ed. 2012, 51, 1055
12 K. TissotꢀCroset, A. Alexakis, Tetrahedron Lett. 2004, 45, 7375.
This journal is © The Royal Society of Chemistry [year]
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