Enantioselective α-and γ-alkylation of α,β- unsaturated aldehydes using dienamine activation

Article abstract of DOI:10.1021/ol102559f

The enantioselective alkylation of α,β-unsaturated aldehydes with stabilized carbocations as electrophiles via the activation as dienamine intermediates is described. This unique application of dienamine catalysis allows for the first enantioselective γ-a

Full text of DOI:10.1021/ol102559f

ORGANIC
LETTERS
2011
Vol. 13, No. 1
70-73
Enantioselective r- and γ-Alkylation of
r,ꢀ-Unsaturated Aldehydes Using
Dienamine Activation
Julian Stiller,† Eugenia Marque´s-Lo´pez,† Raquel P. Herrera,*,§ Roland Fro¨hlich,|
Carsten Strohmann,‡ and Mathias Christmann*,†
Faculty of Chemistry, TU Dortmund UniVersity, Otto-Hahn-Str. 6, 44227 Dortmund,
Germany, Instituto de Ciencia de Materiales de Arago´n, CSIC-UZ, Fundacio´n ARAID,
50009 Zaragoza, Spain, and Institute of Organic Chemistry, UniVersity of Mu¨nster,
Corrensstr. 40, 48149 Mu¨nster, Germany
raquelph@unizar.es; mathias.christmann@tu-dortmund.de
Received October 21, 2010
ABSTRACT
The enantioselective alkylation of r,ꢀ-unsaturated aldehydes with stabilized carbocations as electrophiles via the activation as dienamine
intermediates is described. This unique application of dienamine catalysis allows for the first enantioselective γ-alkylation of linear r,ꢀ-
unsubstituted enals.
The design of novel synthetic methods for the rapid and
stereoselective functionalization of complex molecular scaf-
folds remains a key challenge in organic synthesis.1 Over
the past decade, organocatalysis2 has emerged as a comple-
mentary alternative to metal-catalyzed transformations. In
particular, enamine-,3 iminium-,4 and SOMO-catalysis5 have
vastly added to the synthetic utility and versatility of carbonyl
compounds. Following Yamada’s6 stoichiometric asymmetric
alkylation of proline derived dienamines in the 1970s,
catalytic dienamine activation7 has recently developed as a
powerful extension of enamine catalysis. For a full exploita-
tion of this activation mode, a comprehensive understanding
† Organic Chemistry, TU Dortmund.
§ ICMA, CSIC-University of Zaragoza.
| University of Mu¨nster (X-ray crystallography).
(3) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007,
107, 5471.
‡ Inorganic Chemistry, TU Dortmund (X-ray crystallography).
(1) Asymmetric Synthesis - The Essentials, 2nd ed.; Christmann, M.,
Bra¨se, S., Eds.; Wiley-VCH: Weinheim, 2008.
(4) Erkkila¨, A.; Majander, I.; Pihko, P. M. Chem. ReV. 2007, 107, 5416.
(5) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan,
D. W. C. Science 2007, 316, 582.
(2) For reviews on organocatalysis and its applications in target-oriented
synthesis, see: (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005. (b) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570. (c) de Figueiredo, R. M.;
Christmann, M. Eur. J. Org. Chem. 2007, 2575. (d) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638. (e) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (f)
MacMillan, D. W. C. Nature 2008, 455, 304. (g) Bertelsen, S.; Jørgensen,
K. A. Chem. Soc. ReV. 2009, 38, 2178. (h) Marque´s-Lo´pez, E.; Herrera,
R. P.; Christmann, M. Nat. Prod. Rep. 2010, 27, 1138.
(6) Yamada, S.; Shibasaki, M.; Terashima, S. Tetrahedron Lett. 1973,
14, 381.
(7) For pioneering work, see: (a) Chen, S.-H.; Hong, B.-C.; Su, C.-F.;
Sarshar, S. Tetrahedron Lett. 2005, 46, 8899. (b) Bench, B. J.; Liu, C.;
Evett, C. R.; Watanabe, C. M. H. J. Org. Chem. 2006, 71, 9458. (c)
Bertelsen, S.; Marigo, M.; Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 12973. (d) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.;
Liao, J.-J. Org. Lett. 2006, 8, 2217. (e) Utsumi, N.; Zhang, H.; Tanaka, F.;
Barbas, C. F., III. Angew. Chem., Int. Ed. 2007, 46, 1878.
10.1021/ol102559f  2011 American Chemical Society
Published on Web 12/07/2010

of the associated chemo-, regio-, and stereoselectivity and
their substrate dependence is required. Dienamines are readily
formed by condensation of amines with R,ꢀ-unsaturated
carbonyl compounds via iminium intermediates followed by
deprotonation in the γ-position (Scheme 1). The vinylogy
substrate, we chose (E)-4-phenylpent-2-enal (2a) because the
phenyl group is capable of disfavoring the γ-substitution
pathways sterically and electronically11 (Scheme 2). In the
Scheme 2
.
Rationale for the Observed Products in the
R-Selective Alkylation of 2a
Scheme 1. Formation of Dienamine Intermediates
principle8 dictates bidentate reactivity by transmission of
nucleophilic behavior through the conjugated π-system.
Accordingly, dienamine intermediates can be trapped by
suitable electrophiles E+ in the R- and γ-position. In addition,
dienamines have been employed as an electron-rich diene
component in regular Diels-Alder-type reactions9 as well
as a dienophile in aza-Diels-Alder reactions with an inverse
electron demand.10
In previously reported reactions via dienamine intermedi-
ates, high regioselectivity often required the use of substituted
homologues in order to shut down competing pathways. For
example, γ-disubstituted aldehydes were used by Chen in
selective R-alkylations with nitrostyrenes.11 Recently, Mel-
chiorre employed 3-methylcyclohexenones in γ-substitutions
with nitrostyrenes.12 In our previous work on Rauhut-Currier-
type reactions,13 ꢀ-disubstitution was essential for high
reactivity and selectivity. In order to probe the general
ambident reactivity of dienamine intermediates, we decided
to study their alkylation with stabilized cations derived from
bis[4-(dimethylamino)phenyl]methanol (1).14,15 The enamine
version of this enantioselective SN1-type alkylation16,17
reaction has been pioneered by Cozzi.18,19 As a starting
screening of diarylprolinol-derived catalysts with TFA as a
cocatalyst, only VI, VII, and X were effective in both
reactivity and enantioselectivity affording an E/Z mixture of
3a20 in ratios up to 6:1 (Table 1). Interestingly, less hindered
catalysts II-V (entries 2-5) gave better E/Z ratios at the
cost of lowered enantioselectivity.21 Condensation of 2a with
the amine catalyst affords two interconverting diastereomeric
dienamines, as evidenced by NMR spectroscopy. The E/Z
ratio of the R-alkylation products results directly from the
ratio of the diastereomeric dienamines coupled with their
respective rates of alkylation (Scheme 2).21
As a key factor in dienamine equilibration and carbocation
formation, we screened several organic acids as an additive
as well as different solvents (Table 2). Surprisingly, no
(16) For reviews, see: (a) Melchiorre, P. Angew. Chem., Int. Ed. 2009,
48, 1360. (b) Alba, A.-N.; Viciano, M.; Rios, R. ChemCatChem 2009, 1,
437.
(17) For other approaches, see: (a) Vignola, N.; List, B. J. Am. Chem.
Soc. 2004, 126, 450. (b) Fu, A.; List, B.; Thiel, W. J. Org. Chem. 2006,
71, 320. (c) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc.
2007, 129, 10886. (d) Rios, R.; Sunde´n, H.; Vesely, J.; Zhao, G.-L.;
Eriksson, L.; Co´rdova, A. AdV. Synth. Catal. 2007, 349, 1028. (e) Rios, R.;
Vesely, J.; Sunde´n, H.; Ibrahem, I.; Zhao, G.-L.; Co´rdova, A. Tetrahedron
Lett. 2007, 48, 5835. (f) Ibrahem, I.; Co´rdova, A. Angew. Chem., Int. Ed.
2006, 45, 1952. (g) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton,
K.; MacMillan, D. W. C. Science 2007, 316, 582. (h) Mukherjee, S.; List,
B. J. Am. Chem. Soc. 2007, 129, 11336. (i) Nicewicz, D. A.; MacMillan,
D. W. C. Science 2008, 322, 77. (j) Enders, D.; Wang, C.; Bats, J. W.
Angew. Chem., Int. Ed. 2008, 47, 7539. (k) Shaikh, R. R.; Mazzanti, A.;
Petrini, M.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47,
8707. (l) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am. Chem. Soc.
2010, 132, 9286.
(8) Fuson, R. C. Chem. ReV. 1935, 16, 1.
(9) (a) Hong, B.-C.; Tseng, H.-C.; Chen, S.-H. Tetrahedron 2007, 63,
2840. (b) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Huang, G.-F.; Su, C.-F.;
Liao, J.-H. J. Org. Chem. 2007, 72, 8459. (c) de Figueiredo, R. M.; Fro¨hlich,
R.; Christmann, M. Angew. Chem., Int. Ed. 2008, 47, 1450.
(10) (a) Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.; Chen,
Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5474. For an example of an inverse
electron-demand Diels-Alder reaction, see: (b) Li, J.-L.; Kang, T.-R.; Zhou,
S.-L.; Li, R.; Wu, L.; Chen, Y.-C. Angew. Chem., Int. Ed. 2010, 49, 6418.
(11) Han, B.; Xiao, Y.-C.; He, Z.-Q.; Chen, Y.-C. Org. Lett. 2009, 11,
4660.
(12) Bencivenni, G.; Galzerano, P.; Mazzanti, A.; Bartoli, G.; Melchiorre,
P. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, DOI: 10.1073/pnas.1001150107.
(13) Marque´s-Lo´pez, E.; Herrera, R. P.; Marks, T.; Jacobs, W. C.;
Ko¨nning, D.; de Figueiredo, R. M.; Christmann, M. Org. Lett. 2009, 11,
4116.
(18) (a) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem., Int. Ed. 2009,
48, 1313. (b) Benfatti, F.; Benedetto, E.; Cozzi, P. G. Chem.sAsian J. 2010,
5, 2047.
(14) For a kinetic investigation of reactions involving carbocations, see:
(a) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66. (b)
Kempf, R.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.sEur. J. 2003, 9,
2209. (c) Phan, T. B.; Nolte, C.; Kobayashi, S.; Ofial, A. R.; Mayr, H.
(19) For a more recent example, see: Zhang, L.; Cui, L.; Li, X.; Li, J.;
Luo, S.; Cheng, J.-P. Chem.sEur. J. 2010, 16, 2045.
(20) The absolute configuration of (E)-3a was shown to be R by X-ray
crystallography. See Supporting Information.
J. Am. Chem. Soc. 2009, 131, 11392
.
(21) NMR and computational studies probing the stability of the
dienamine and its connection with the E/Z ratio in the final products will
be reported in due course.
(15) McCLelland, R. A.; Kanagasabapathy, V. M.; Banait, N. S.;
Steenken, S. J. J. Am. Chem. Soc. 1989, 111, 3966
Org. Lett., Vol. 13, No. 1, 2011
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Table 1. R-Alkylation of R,ꢀ-Unsaturated Aldehydes: Catalyst
Screening
Table 2. R-Alkylation of R,ꢀ-Unsaturated Aldehydes: Solvent
and Acid Additive Screening
entry solvent
acid
TFA
t[h] yield[%]a
E:Zb
ee[%]c
1
CHCl3
3
8
78
84
73
78
75
84
85d
91d
82d
86
79
60
92
64
78:22 79 (49)
71:29 73 (77)
67:33 94 (93)
66:34 94 (94)
68:32 78 (80)
69:31 89 (85)
89:11 26 (n.d.)e
83:17 87 (82)
69:31 93 (94)
80:20 88 (86)
80:20 93 (92)
69:31 90 (87)
78:22 92 (>99)
75:25 89 (89)
2
toluene TFA
3
CHCl3
AcOH
28
20
84
20
52
20
20
96
96
37
96
96
4
toluene AcOH
5
Et2O
AcOH
AcOH
6
CH2Cl2
7
CH3CN AcOH
8
C6F6
AcOH
AcOH
TFA
9
xylene
CHCl3
toluene TFA
CHCl3
CHCl3
toluene TFA
10f
11f
12g
13f,g
14f,g
entry
catalyst
t[h]
yield[%]a
E:Zb
ee[%]c
AcOH
TFA
1
2
3
4
5
6
7
8
9
I
II
5
5
8
3
3
3
4
3
3
3
50d
89d
80
85:15
90:10
87:13
90:10
93:7
78:22
75:25
83:17
88:12
86:14
54 (17)
33 (18)
28 (7)
-49 (28)
42 (n.d.)e
79 (49)
88 (72)
59 (47)
61 (39)
81 (51)
III
IV
V
VI
VII
VIII
IX
X
a Yield of isolated product. b Determined by 1H NMR. c Determined
by chiral HPLC for the major isomer (minor isomer in parentheses).
d Conversion by 1H NMR. e Not determined. f Reaction performed at -20
°C. g Catalyst VII was used.
29d
86d
78
96d
64
81
γ-substitution was determined by X-ray crystallographic
analysis of 4f and 4g (Figure 1).22 Finally, when citral (2i)
was used as a ꢀ-substituted R,ꢀ-unsaturated aldehyde (entry
8), the γ-alkylated product 4i was formed exclusively, albeit
as a 7:1 mixture of E/Z isomers. Not surprisingly, R-substi-
tuted aldehydes, notoriously unreactive toward secondary
amine catalysts, did not yield any alkylation product.
In the case of linear aldehydes (Scheme 3), electrophilic
attack of the ambident dienamine I occurs at the less
encumbered γ-position leading to a mixture of (E)- and
(Z)-iminium ions. Hydrolysis of the latter affords the R,ꢀ-
unsaturated aldehydes 4f. In iminium catalysis it was
demonstrated that 2E- and 2Z-enals can interconvert in
the presence of a secondary amines.23 The required
deprotonation/protonation sequence suggests the presence
of the alkylated dienamine II. The E/Z ratio of the final
products is dictated by thermodynamics, thereby explain-
ing the lowered E-selectivity for 4i (smaller energy
difference). In contrast to the R-adduct 3, there is no
significant kinetic discrimination between the γ-substituted
(4) and unreacted aldehyde (2); i.e. products 4 are
substrates for the catalyst that could lead to dienamines
II. This detail has ramifications for the stereochemical
outcome of the γ-substitution. Even if double substitution
can be suppressed, any intermediacy of γ-substituted
10
91
a Yield of isolated product. b Determined by 1H NMR. c Determined
by chiral HPLC for the major and the minor isomer (in parentheses).
Conversion by H NMR. e Not determined.
d
1
obvious correlation between pKa and selectivity was ob-
served. Nevertheless, we were able to identify AcOH and
toluene as useful alternatives to TFA and CHCl3 (entries
1-4). As a general observation, AcOH provides better
enantioselectivities, while TFA gives better E/Z ratios.
Lowering the temperature to -20 °C (entries 10-11) with
TFA as an acid additive resulted in good enantioselectivities
(88-93% ee) with slightly better diastereoselectivities. On
the other hand, no better results were obtained with catalyst
VII (entries 12-14).
The optimized reaction conditions developed for the
R-alkylation of 2a were applied to a variety of differently
substituted R,ꢀ-unsaturated aldehydes (Table 3). When the
phenyl group was replaced by a methyl group (entry 1), the
R-alkylated aldehyde 3b was still a major regioisomer
although in this instance significant amounts of γ-substituted
product 4b could be detected. This observation supports the
idea of electronic destabilization of γ-substitution in 3a, as
it intercepts conjugation with the phenyl ring. Other disub-
stituted aldehydes (entries 2-4) gave similar results and
R-alkylated aldehydes 3c-3e in >92% ee. When linear R,ꢀ-
unsaturated aldehydes were used (entries 5-7), γ-substitution
became the dominating pathway affording aldehydes 4f-h
as the major products. The stereochemical outcome of the
(22) See Supporting Information.
(23) (a) Yang, J. W.; Fonseca, M. T. H.; Vignola, N.; List, B. Angew.
Chem., Int. Ed. 2005, 44, 108. (b) Ouellet, S. G.; Tuttle, J. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
72
Org. Lett., Vol. 13, No. 1, 2011

Table 3. Substrate Scope and Regioselectivity
Scheme 3. Rationale for the Observed Products in the
γ-Selective Alkylation of 2f
In summary, we have developed a simple and highly
enantioselective organocatalytic R- and γ-alkylation of R,ꢀ-
unsaturated aldehydes catalyzed by commercially available
diarylprolinol derivatives with stabilized carbocations as elec-
trophiles.24 To the best of our knowledge, this is the first
enantioselective γ-alkylation of linear R,ꢀ-unsaturated aldehydes
via dienamine activation. In addition, we have provided a basis
for prediction of ambident reactivity for differently substituted
R,ꢀ-unsaturated aldehydes using dienamine activation. The
γ-substitution pathway is disfavored for γ-disubstituted alde-
hydes and shut down completely if one of the substituents is
aromatic. Linear unbranched and ꢀ-substituted R,ꢀ-unsaturated
aldehydes favor γ-substitution, and R-substituted aldehydes are
unreactive using secondary amine catalysts.
a Yield of isolated major product. b Determined by 1H NMR. c ee of
the major product determined by chiral HPLC. d Reaction was carried out
at rt. e CHCl3 was used as solvent. f AcOH (10 mol %) was used as acid
additive. g E:Z ) >99:1. h TFA (1 mol %) was used. i E:Z ) 87:13,
1
determined by H NMR in the crude after reduction with NaBH4 of 4i to
the corresponding alcohol. j Determined in the corresponding alcohol (E)-
5i, see Supporting Information.
Future research will be concerned with improvement of
regiocontrol and the extension of dienamine catalysis toward
other electrophiles.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for a Dozentenstipendium (M.C.), the DFG (Priority
Program 1179 - Organocatalysis), MICINN (CTQ2009-
09028), DGA (PI064/09, Research Group: E-10), the Stiftung
der Deutschen Wirtschaft (sdw) for graduate fellowship
(J.S.), the Humboldt Foundation (postdoctoral (E.M.-L.) and
experienced researcher (R.P.H.) fellowships), and the Arago´n
I+D Foundation for a permanent contract (R.P.H.). Finally,
we thank Jo¨rg Swatschek for the preparation of starting
material.
Supporting Information Available: Experimental pro-
cedures, NMR spectra, X-ray data, and characterization of
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 1. X-ray crystal structure of (4R)-4f.
OL102559F
(24) After submission of our manuscript, two related reports were
published. (a) Bergonzini, G.; Vera, S.; Melchiorre, P. Angew. Chem., Int.
Ed. 2010, 49, DOI: 10.1002/anie.201004761. (b) Han, B.; Xiao, Y.-C.; Yao,
Y.; Chen, Y.-C. Angew. Chem., Int. Ed. 2010, 49, DOI: 10.1002/
anie.201005296.
dienamine II renders its protonation the stereodefining
step, not the attack of dienamine I by the incoming bulky
electrophile.
Org. Lett., Vol. 13, No. 1, 2011
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