Organocatalytic asymmetric Strecker reaction of di- and trifluoromethyl ketoimines. Remarkable fluorine effect

Article abstract of DOI:10.1021/ol201316z

A highly enantioselective Strecker reaction of difluoromethyl and trifluoromethyl ketoimines was developed. Remarkable fluorine effect on the reactivity and selectivity is observed and discussed.

Full text of DOI:10.1021/ol201316z

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3826–3829
Organocatalytic Asymmetric Strecker
Reaction of Di- and Trifluoromethyl
Ketoimines. Remarkable Fluorine
Effect
Yun-Lin Liu,† Tao-Da Shi,† Feng Zhou,† Xiao-Li Zhao,† Xin Wang,*,‡ and Jian Zhou*,†
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal University, Shanghai 200062, P. R. China, and College of
Chemistry, Sichuan University, Chengdu, Sichuan 610064, P. R. China
wangxin@scu.edu.cn; jzhou@chem.ecnu.edu.cn
Received May 16, 2011
ABSTRACT
A highly enantioselective Strecker reaction of difluoromethyl and trifluoromethyl ketoimines was developed. Remarkable fluorine effect on the
reactivity and selectivity is observed and discussed.
The selective introduction of difluoromethyl (CF2H) or
trifluoromethyl (CF3) groups has become a powerful strategy
to modulate the properties of organic molecules.1 For exam-
ple, the CF2H group can serve as a more lipophilic hydrogen
bond donor than OH and NH groups,2a which is very useful in
drug design. R-Difluoromethylornithine2b is a rationally de-
signed drug for sleeping sickness. As a result, the synthesis of
optically active compounds with a CF2H or CF3 group at the
chiral center has received great attention. While much progress
has been made in the enantioselective trifluoromethylation,3
catalytic asymmetric difluoromethylations4 are less developed.
Because of thechallenges inthe creation of tetrasubstituted
carbon stereogenic centers,5 the catalytic asymmetric
synthesis of R-CF2H bearing tetrasubstituted carbon is
rare,6 and no catalytic asymmetric addition of nucleophilies
to R-CF2H ketoimines was reported. Furthmore, there are
very limited reports based on R-CF3 ketoimines,7 despite
achivements in the catalytic asymmetric reactions based on R-
CF3 ketones.3
† East China Normal University.
‡ Sichuan University.
(1) (a) Hunter, L. Beilstein J. Org. Chem. 2010, DOI: 10.3762/
bjoc.6.38. (b) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal.
2010, 352, 2708. (c) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (d)
Smart, B. E. J. Fluorine Chem. 2001, 109, 3. (e) Schlosser, M. Angew.
Chem., Int. Ed. 1998, 37, 1496.
(2) (a) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60,
1626. (b) Bey, P.; Gerhart, F.; Dorsselaer, V. V.; Danzin, C. J. Med.
Chem. 1983, 26, 1551.
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Eur. J. Org. Chem. 2007, 5969. (b) Shibasaki, M.; Kanai, M. Chem. Rev.
2008, 108, 2853. (c) Riant, O.; Hannedouche, J. Org. Biomol. Chem.
2007, 5, 873. (d) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(6) As far as we know, only two example were reported: (a) Nie, J.;
Zhang, G.-W.; Wang, L.; Fu, A.; Zheng, Y.; Ma, J.-A. Chem. Commun.
2009, 2356. (b) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem.
Commun. 2008, 4360.
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Sukach, V. A.; Golovach, N. M.; Pirozhenko, V. V.; Rusanov, E. B.;
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M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 5530. (d) Enders,
D.; Gottfried, K.; Raabe, G. Adv. Synth. Catal. 2010, 352, 3147. (e)
Huang, G.; Yang, J.; Zhang, X. Chem. Commun. 2011, 47, 5587.
(3) For reviews, see: (a) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A.
Chem. Rev. 2011, 111, 455. (b) Valero, G.; Company, X; Rios, R.
Chem.;Eur. J. 2011, 17, 2018. (c) Tur, F.; Mansilla, J.; Lillo, V. J.;
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Saa, J. M. Synthesis 2010, 1909. (d) Uneyama, K.; Katagiri, T.; Amii, H.
Acc. Chem. Res. 2008, 41, 817. (e) Shibata, N.; Mizuta, S.; Kawai, H.
Tetrahedron: Asymmetry 2008, 19, 2633.
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2009, 7465. For selected examples, see:(b) Liu, J.; Hu, J. Chem.;Eur. J.
2010, 16, 11443. (c) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int.
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r
10.1021/ol201316z
Published on Web 06/30/2011
2011 American Chemical Society

Enantioenriched R-tetrasubstituted R-aminonitriles with
an R-CF2H orCF3 group are versatile for the synthesis of the
fluorinated CR-tetrasubstituted R-amino acids and
diamines,8 interesting subjects of medical investigation.9
However, no catalytic asymmetric synthesis of R-CF2H R-
tetrasubstituted R-aminonitriles was reported, and chiral
auxiliary controlled methods were unsuccessful.9d,e As for
the R-CF3-substituted R-tetrasubstituted R-aminonitriles,
Enders et al. reported the first catalytic method during this
work, which could give a variety of products in excellent ee,
but the reaction time was generally long.7d In our efforts in
the synthesis of tetrasubstituted carbon stereogenic centers,10
we tried to develop a catalytic asymmetric Strecker
reaction11 of R-CF2H- or CF3-substituted ketoimines12
using (thio)urea catalysts.13 Here, we report our results.
During the preparation of racemic samples, we found that
thiourea 413a failed to catalyze the reaction of both 1a and 2a
with TMSCN. In constrast, nonfluorinated ketimine 7 could
afford the desired product 8 in 48% yield (Figure 1, eq 1).
This result was counterintuitive since both CF2H and CF3
groups might enhance the electrophilicity of 1a and 2a toward
cyanide addition. We speculated that the presence of R
fluorine atom interfered with the H-bonding interaction of
imine with both urea hydrogens, as Jacobsen proposed.13d,14
To test this hypothesis, we conducted a theoretical calcula-
Figure 1. Optimized structures of hydrogen-bonded complexes.
The interaction energy on hydrogen bond (ΔE) was calculated at
the B3LYP/6-311G(d,p) level. The basis set superposition error
(BSSE) and zero-point energy corrections were included in it.
(Figure 1), where imine nitrogen interacted with one thiourea
hydrogen and one of the R-fluorine atoms with the other
thiourea hydrogen. In contrast, ketimine 7 preferred a
bridged structure C, with imine 7 hydrogen-bonded to both
thiourea hydrogens. The two kinds of double-hydrogen-
bonding interactions can stabilize complexes A, B and C
with 23.9, 19.9, and 24.1 kJ molꢀ1, respectively. This estab-
lishes a plausible explanation for the much higher reactivity
of imine 7: the bridging interaction shown in complex Ccould
accelerate the reaction via the stabilization of the negatively
charged nitrogen intermediate, as the activation of carbonyl
groups by the oxyanion hole of the enzyme.13a,15 Analogous
calculations also revealed single hydrogen-bonded structures
for the product aminonitrileꢀcatalyst complexes and D, for
example (see the Supporting Information).
tion based on
imine system (see the Supporting Information). The favor-
a
simplified N,N0-dimethylthioureaꢀ
able binding model of imine 1a or 2a with thiourea was Aor B
(8) For reviews, see: (a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev.
2000, 29, 359. (b) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksh, B.
ꢀ
Chem. Soc. Rev. 2008, 37, 1727. (c)Mloston, G.; Obijalska, E.; Heimgartner,
H. J. Fluorine Chem. 2010, 131, 829.
(9) For reviews, see: (a) Qiu, X.-L.; Qing, F.-L. Eur. J. Org. Chem.
2011, 3261. (b) Czekelius, C.; Tzschuche, C. C. Synthesis 2010, 543. (c)
Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31, 335. For auxiliary-
controlled asymmetric synthesis, see: (d) Bravo, P.; Capelli, S.; Meille,
S. V.; Seresini, P.; Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry
1996, 7, 2321. (e) Huguenot, F.; Billac, A.; Brigaud, T.; Portella, C. J.
Org. Chem. 2008, 73, 2564. (f) Ogu, K.; Matsumoto, S.; Akazome, M.;
Ogura, K. Org. Lett. 2005, 7, 589. (g) Wang, H.; Zhao, X.; Li, Y.; Lu, L.
Org. Lett. 2006, 8, 1379.
The above results suggested that thiourea catalyst alone
was inefficient to develop a highly enantioselective Strecker
reaction of imine 1a or 2a with TMSCN, which prompted us
to use a Lewis base to activate the nucleophile TMSCN.16
The reaction of easily available imine 2a and TMSCN was
chosen for optimization, which was run in toluene at room
temperature. Some typical results were shown in Table 1.
As expected, no reaction took place if chiral urea catalysts
9 or 10 were used (entries 1 and 3). Interestingly, the
combination of a chiral thiourea catalyst 9 with an achiral
Lewis base catalyst DMAP afforded the desired product
6a in 66% yield and 25% ee (entry 2), which demonstrated
that dual activation concept indeed worked in this reac-
tion. If using the combined catalyst 10 and DMAP, the
(10) (a) Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.;
Wang, C.; Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176. (b) Cao, J.-J.;
Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010, 49, 4976.
(11) (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. Chem. Rev.
2011, 111, 2626. (b) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875. (c)
€
ꢀ ꢀ
Groger, H. Chem. Rev. 2003, 103, 2795. (d) Merino, P.; Marque-Lopez,
E.; Tejero, T.; Herrera, R. P. Tetraheron 2009, 65, 1219.
(12) For reviews on catalytic asymmetric Strecker reaction of keti-
mines, see: (a) Connon, S. J. Angew. Chem., Int. Ed. 2008, 47, 1176. (b)
Spino, C. Angew. Chem., Int. Ed. 2004, 43, 1764. For selected examples,
see: (c) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 5634. (d) Wang, J.; Hu, X.; Jiang, J.; Gou,
S.; Huang, X.; Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2007, 46, 8468.
(e) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 15118.
(13) For reviews on urea catalysis, see: (a) Zhang, Z.; Schreiner, P. R.
Chem. Soc. Rev. 2009, 38, 1187. (b) Takemoto, Y. Org. Biomol. Chem.
2005, 3, 4299. For urea-catalyzed Strecker reaction, see: (c) Vachal, P.;
Jacobsen, E. N. Org. Lett. 2000, 2, 867. (d) Vachal, P.; Jacobsen, E. N. J.
Am. Chem. Soc. 2002, 124, 10012. (e) Pan, S. C.; Zhou, J.; List, B. Angew.
Chem., Int. Ed. 2007, 46, 612. (f) Zuend, S. J.; Coughlin, M. P.; Lalonde,
M. P.; Jacobsen, E. N. Nature 2009, 461, 968.
(15) Branneby, C.; Carlqvist, P.; Magnusson, A.; Hult, K.; Brinck,
T.; Berglund, P. J. Am. Chem. Soc. 2003, 125, 874 and references therein.
(16) For reviews on Lewis base catalysis, see: (a) Denmark, S. E.;
Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560. For selected
examples of cinchona alkaloid catalyzed addition of TMSCN to elec-
trophiles, see: (b) Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027. (c)
Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900.
(14) For a example of F HꢀN hydrogen bonding, see: (a) Zhao,
3 3 3
X.; Wang, X.-Z.; Jiang, X.-K.; Chen, Y.-Q.; Li, Z.-T.; Chen, G.-J. J. Am.
Chem. Soc. 2003, 125, 15128. For reviews, see: (b) Shimoni, L.; Glusker,
J. P. Struct. Chem. 1994, 5, 383. (c) Dunitz, J. D.; Taylor, R. Chem.;
Eur. J. 1997, 3, 89. For the elucidation of reaction paths by computa-
tional methods on hydrogen bonding, see: (d) Etzenbach-Effers, K.;
Berkessel, A. Top. Curr. Chem. 2010, 291, 1.
Org. Lett., Vol. 13, No. 15, 2011
3827

product 6a was obtained in lower yield and ee (entry 4),
suggesting that the enantioselectivity and reactivity was
greatly influenced by the structure of urea catalysts and
Lewis base catalysts. Based on the above results, we
focused on the use of bifunctional Brønsted acidꢀLewis
base catalysts. Quinidine-derived bifunctional thiourea
catalyst 11 could afford the product 6a in 21% yield with
84% ee (entry 5). To our delight, dihydroqunine derived
thiourea catalyst 1217 improved the ee to 92% (entry 6).
The corresponding urea catalyst catalyst 13 further im-
proved the eeto94% (entry 7). Thepositionof the thiourea
moiety of the catalyst obviously influenced the stereocon-
trol, and Deng’s catalyst 14 afforded 6a in only 7% ee
(entry 8). To confirm the importance of bifurcated hydro-
gen bonding interactions of urea moiety with imine 2a,
other bifunctional catalysts 15ꢀ17 were also tried, and
none of them could afford product 6a in good ee (entries
9ꢀ11). Catalyst 18, without Brønsted acid moiety, failed
to catalyze the reaction (entry 12).
Although excellent ee for product 6a was obtained, the
reactivity is not satisfactory (entry 7). We further tried
the use of alcoholic additives to improve the reactivity of
the Strecker reaction.18 We screened a series of alcohols
and phenols and found that the addition of alcohols or
phenols indeed accelterated the reaction, but most of
them resulted in the diminished ee of product 6a. It
turned out that (CF3)2CHOH (HFIP)18 was promising,
and the use of HFIP (1.0 equiv) as additive could
promote the reaction to finish within 2 days without
loss of ee, which gave product 6a in 97% yield with 94%
ee (entry 13). Increasing the amount of HFIP to 2 equiv
lowered the ee for product 6a, possibly because
of the background reaction (entry 14). We further
examined other solvents using catalyst 13, but toluene
still turned out to be the best. In light of this, the
optimum conditions was determined to run the reaction
in toluene at 25 °C in the presence of 10 mol % of catalyst
13 and 1.0 equiv of HFIP. It also turned out that
nonfluorinated imine 7 was more reactive than imine
1a and 2a, and R-CF2H ketoimine 1a was the least
reactive when using catalyst 13, whether in the presence
of HFIP or not (for details, see the Supporting
Information).
Table 1. Condition Optimization
entrya cat.
additives
time (d) yieldb (%) eec (%)
5
1
2
9
9
DMAP (10 mmol %)
5
5
5
5
5
5
5
5
5
5
5
2
2
66
25
3
10
4
10 DMAP (10 mmol %)
19
21
37
40
36
16
4
11
84
92
94
7
5
11
6
12
7
13
8
14
9
15
20
13
10
10
11
12
13
14
16
17
17
18
13 HFIP (100 mmol %)
13 HFIP (200 mmol %)
97
95
94
90
a On a 0.10 mmol scale. b Isolated yield. c By HPLC analysis.
The remarkable fluorine effects on both the reactivity
and enantioselectivity is very impressive. While a few
reports shown that the coordination of fluorine atom to
metals might alter the stereoselectivity of reactions with
fluorine-containing compounds,20 it is not reported that
the binding model of the (thio)urea catalyst and imines can
be changed if substituting a CH3 group of the substrate for
a CF2H or CF3 group, which dramaticaly influences both
the reactivity and enantioselectivity. This finding might be
useful for the design of new asymmetric catalytic addition
of nucleophiles to R-CF2H or CF3 ketoimines.
Interestingly, fluorinated imine 1a and 2a afforded the
desired product 5a and 6a in 87% and 94% ee under
optimized conditions, respectively. In contrast, the non-
fluorinated imine 7 provided only racemic product 8. The
remarkable fluorine effect on enantiofacial control sup-
ported the proposed models A and B in Figure 1.19
(17) (a) Peschiulli, A.; Quigley, C.; Tallon, S.; Gun’ko, Y. K.; Connon,
S. J. J. Org. Chem. 2008, 73, 6409. (b) Li, B.-J.; Jiang, L.; Liu, M.; Chen,
Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. (c) Vakulya, B.; Varga, S.;
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. For reviews, see: (d)
Connon, S. J. Chem. Commun. 2008, 2499. (e) Marcelli, T.; Hiemstra, H.
Synthesis 2010, 1229.
(18) For the reaction of TMSCN and alcohol, see: (a) Mai, K.; Patil,
G. J. Org. Chem. 1986, 51, 3545. For the use of (CF3)2CHOH (HFIP) as
additives, see: (b) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey,
C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134.
(19) We tried in vain to synthesize the R-CH2F ketoimines, which are
not reported in the literature by a SciFinder search.
At the optimized reaction conditions, we then examined
the substrate scope. First, different substituted R-CF2H
ketoimines 1aꢀp were examined (Table 2). Four different
para-substituted aniline-derived imines 1aꢀd were first tried
(entries 1ꢀ4), and the p-chloroaniline-derived imine 1d
ꢀ
ꢀ
(20) For a review, see: (a) Mikami, K.; Itoh, Y.; Yamanaka, M.
Chem. Rev. 2004, 104, 1. Also see: (b) Hanamoto, T.; Fuchikami, T.
J. Org. Chem. 1990, 55, 4969. (c) Sparr, C.; Gilmour, R. Angew. Chem.,
Int. Ed. 2010, 49, 6520.
3828
Org. Lett., Vol. 13, No. 15, 2011

Table 2. Strecker Reaction of R-CF2H Ketoimines 1
Table 3. Strecker Reaction of R-CF3 Ketoimine 2
entrya
1
R
R1
PMP
5
yieldb (%) eec (%)
1d
2d
1a Ph
1b Ph
1c Ph
1d Ph
5a
73
89
89
85
92
89
70
62
94
81
75
72
90
84
61
42
87
86
86
89
85
86
80
86
92
87
92
87
87
88
86
77
p-EtOC6H4 5b
3d
p-BrC6H4
p-ClC6H4
PMP
5c
5d
5e
5f
4d
5d
1e p-MeC6H4
1f m-MeC6H4
6d
PMP
7d
1g p-MeOC6H4 PMP
1h p-TMSC6H4 PMP
5g
5h
5i
8d
9d
1i
1j
p-ClC6H4
PMP
10d
11e
12e
13e
14e
15e
16f
2-naphthyl
PMP
5j
1k m-MeC6H4
1l
p-ClC6H4
5k
5l
m-MeOC6H4 p-ClC6H4
1m m-ClC6H4
1n p-FC6H4
1o 2-thienyl
1p c-hexyl
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
5m
5n
5o
5p
a On a 0.25 mmol scale. b Isolated yield. c Determined by chiral
HPLC analysis. d At 25 °C, 2ꢀ4 d. e At ꢀ20 °C, 5 d. f At 25 °C, 6 d.
reacted with TMSCN obviously faster than imine 1a and 1b
and afforded the corresponding product 5d in 89% ee (entry
4). Different R-aryl-substituted R-CF2H ketoimines 1eꢀo all
afforded the desired products 5eꢀo in high to excellent ee
(entries 5ꢀ15). R-Cyclohexyl-substituted imine 1p afforded
the corresponding product 5p in 77% ee. It should be noted
that imines 1aꢀp were all used in a mixture of Z and E
isomers because the isolation of pure Z or E isomer failed,21
but imines 27d and 7were obtained and used as a pure isomer.
Trifluoromethyl ketoimine 2 worked efficiently under this
condition (Table 3) and could be scaled up to 5.0 mmol using
5 mol % of catalyst 9 without loss of ee (entry 2). All of the R-
aryl R-CF3 ketoimines 2aꢀk afforded the desired products
6aꢀk in excellent yield and ee (entries 1ꢀ12). R-Alkyl-R-CF3
ketoimines 2lꢀnalso worked well to give the desired products
6lꢀnin high ee (entry 13ꢀ15). Differently substituted aniline-
derived imines 2oꢀr also worked well (entries 16ꢀ19).
The utility of the R-amino nitriles was demonstrated by
the following transformations. Product 6a could be con-
verted to trifluoromethylated imidazolidinone 20 in three
steps without loss of ee. Compound 5a could be transformed
to R-CF2H CR-tetrasubstituted R-amino acid 21 in 66%
yield in two steps.
a On a 0.25 mmol scale. b Isolated yield. c Determined by chiral
HPLC analysis. d On a 5.0 mmol scale, 5 mol % of catalyst, 3 d.
e Reaction time: 6 d. f The absolute configuration of product 6q was
assigned to be R by X-ray analysis (see the Supporting Information).
in air using easily available bifunctional catalyst. A strong
fluorine effect on the reactivity and enantiofacial
control was observed. Based on the theoretical calculations
and experimental data, we proposed a new recognition
model of (thio)urea catalyst and R-CF2H- or CF3-substi-
tuted ketoimines. Experiments are now underway
in our laboratory to develop new asymmetric reactions
for the synthesis of chiral compounds with di- or trifluor-
omethyl at the carbon center on the basis of this new
binding model.
Acknowledgment. We acknowledge financial sup-
port from the National Natural Science Foundation
of China (20801018, 20902025), Shanghai Pujiang
Program (10PJ1403100), and Shanghai Rising-Star
Program (10QA1402000).
Supporting Information Available. Experimental pro-
1
cedures and characterizations, copies of H NMR and
13C NMR of new compounds, and HPLC profiles. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed a general method for
the catalytic asymmetric Strecker reaction of both R-CF2H
and R-CF3 ketoiminesand TMSCN, whichwas carriedout
(21) For the preparation of imine 1, see: Kirij, N. V.; Babadzhanova,
L. A.; Movchun, V. N.; Yagupolskii, Y. L.; Tyrra, W.; Naumann, D.;
Fischer, H. T. M.; Scherer, H. J. Fluorine Chem. 2008, 129, 14.
Org. Lett., Vol. 13, No. 15, 2011
3829