Asymmetric Michael addition of nitrobenzyl pyridines to enals via iminium catalysis

Article abstract of DOI:10.1055/s-0030-1259518

The asymmetric Michael addition of nitrobenzyl pyridines to α,β-unsaturated aldehydes is described. This unprecedented transformation highlights the possibility of extending the nucleophile scope of iminium catalysis to include diaryl compounds in which t

Full text of DOI:10.1055/s-0030-1259518

CLUSTER
489
Asymmetric Michael Addition of Nitrobenzyl Pyridines to Enals via Iminium
Catalysis
Asymmetric
M
i
ichael
l
A
dditi
v
on of
N
itrobe
i
nzyl Py
a
ridines to Enals Vera,a Yankai Liu,a Mauro Marigo,b Eduardo C. Escudero-Adán,a Paolo Melchiorre*a,c
a
b
c
ICIQ, Institute of Chemical Research of Catalonia, Av. Països Catalans 16, 43007 Tarragona, Spain
H. Lundbeck A/S, 9 Ottiliavej, 2500 Valby, Copenhagen, Denmark
ICREA, Institució Catalana de Recerca i Estudis Avançats, Pg. Lluís Companys 23, 08010 Barcelona, Spain
Fax +34(977)920 823; E-mail: pmelchiorre@iciq.es
Received 13 December 2010
O
Nu
O
Abstract: The asymmetric Michael addition of nitrobenzyl pyri-
dines to a,b-unsaturated aldehydes is described. This unprecedent-
ed transformation highlights the possibility of extending the
nucleophile scope of iminium catalysis to include diaryl compounds
in which the reactive methylene centre is not activated by classical
electron-withdrawing groups. Indeed, combining the electronic ef-
fects of a p-nitro- or o-nitro-substituted aromatic and of a pyridine
system fulfils the requirements for nucleophile activation. The syn-
thetic utility of the method has been demonstrated via rapid access
to enantioenriched tetrahydro-1-benzazepines.
iminium catalysis
Nu
+
R1
H
R1
H
p-rich nucleophiles
active methylene compound
EtO2C
CO2Et
pKa = 16.4
ref. 4
ref. 6
N
O
X
Ph
pKa = <16.9
ref. 3b
F3C
S
Key words: asymmetric catalysis, secondary amine, Michael addi-
tion, organocatalysis, pyridine
Ph
BF3K
O
pKa = 13.5
ref. 7
ref. 8
ref. 3c
O
Asymmetric aminocatalysis1 is today recognised as an es-
tablished synthetic tool for asymmetrically functionalis-
ing carbonyl compounds. In particular, iminium catalysis
using chiral secondary amine catalysts is a reliable way of
directly introducing a nucleophilic component at the b
position of a,b-unsaturated aldehydes.2 This activation
mode has found successful application in many enantiose-
lective conjugate additions of carbon nucleophiles, a fun-
damental and often employed chemical transformation for
stereoselectively forming a new carbon–carbon bond.
Two principle classes of carbon nucleophile are suitable
substrates for the iminium-catalysed Michael addition to
a,b-unsaturated aldehydes: p-electron-rich nucleophiles,
which undergo Friedel–Crafts-type alkylation,3 and pro-
nucleophilic species bearing an activated methylene
group4–8 (Figure 1).
O2N
pKa = 12.3
CN
Figure 1 Michael addition to enals under iminium catalysis: the nu-
cleophile scope. Activation of the methylene compounds generally
requires at least one, and generally two, electron-withdrawing
functional groups. The pKa values refer to DMSO; see ref 9.
been successfully used in the asymmetric Michael addi-
tion to enals under iminium catalysis.
Here, we show that iminium catalysis of enals can be ex-
tended to include diaryl compounds that do not contain
classical activating electron-withdrawing groups (gener-
ally a carbonyl moiety) directly bound to the nucleophilic
methylene centre. Specifically, we found that the combi-
nation of electron-deficient aryl and heteroaryl groups
strongly increases the acidity of the benzylic protons, ful-
filling the requirements for nucleophile activation. In-
A rationalisation of the acidity-reactivity profiles of the
employed C–H acid substrates points to a functional pKa
barrier for nucleophilic activation that lies between the
pKa values of 16 and 17.4,6,8 Generally, addressing this
criterion requires the presence of two geminal electron-
withdrawing groups, such as 1,3-dicarbonyl compounds.4
For a few specific compounds, the presence of a single
well-tailored electron-withdrawing functional group is
enough to lower the pKa value of the active methylene
moiety to the desired functional level. Nitroalkanes,5 tri-
fluoroethyl thioesters,6 benzofuranone,7 and nitrophenyl-
acetonitrile,8 which can form enolate-like anions,10 have
H
Ar
– H
–O
+
N
O–
Ar
+ H
O
+
N
conjugated enolate-like anion
O–
H
– H
+ H
Ar
Ar
–N
N
conjugated enaminate anion11
SYNLETT 2011, No. 4, pp 0489–0494
x
x.
x
x.
2
0
1
1
Advanced online publication: 27.01.2011
DOI: 10.1055/s-0030-1259518; Art ID: Y02610ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Nucleophile activation by the p-nitrophenyl and pyridyl
groups: stabilisation of the negative charge by conjugation and induc-
tive effects

490
S. Vera et al.
CLUSTER
deed, nitrobenzyl pyridine derivatives 1 proved to be To assess the feasibility of such an aminocatalytic strate-
suitable prochiral nucleophiles that effectively underwent gy, we focused on using some of the most widely em-
a highly stereoselective Michael addition to a range of ployed chiral secondary amines to catalyse the addition of
a,b-unsaturated aldehydes under the iminium activation 1a to cinnamaldehyde (2a) in toluene as the solvent
of chiral secondary amines.
(Table 1). While the use of both proline (A) and the hy-
drochloride salt of the imidazolidinone C resulted in a
sluggish Michael addition process, the catalyst B12 proved
an effective iminium catalyst (entries 1–6).
We reasoned that the delocalising ability of a p-nitro-
substituted aromatic ring and of a pyridine system may be
synergistically combined to produce a strong acidifying
effect on the methylene moiety (Scheme 1).10,11 On these The efficiency of the catalytic system was greatly in-
grounds, we decided to explore the reactivity profile of creased upon addition of a basic co-catalyst. Extensive
4-(4-nitrobenzyl)pyridine (1a) within the context of an optimisations along this line identified DABCO (0.5
iminium-catalysed Michael addition pathway.
equiv) as the more suited additive for designing an effi-
Table 1 Optimisation Studiesa
NO2
NO2
i) secondary amine (20 mol%)
solvent (2 M), 40 °C, 24 h
ii) NaBH4
CH2Cl2–MeOH
+
CHO
Ph
OH
1a
2a
3a
N
Ph
N
dr = 1.2–1.4:1
Me
O
OTMS
N
CO2H
Ph
N
N
H
H
N
H
Ph
A
B
Ph
C
Entry
1
Catalyst
Additive (equiv)b
none
Solvent
Conversion (%)c
ee (%)d
–
A
toluene
neat
12
18
79
47
15
63
75
23
65
83
65
76
78
71
90
2
B
none
–
3
B
Et3N (1)
neat
58:56
80:78
–
4
B
Et3N (1)
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
dioxane
THF
5
C·HCl
B
Et3N (1)
6
DABCO (1)
DABCO (0.5)
DABCO (0.25)
DMAP (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
80:86
78:81
–
7
B
8
B
9
B
63:70
47:47
77:79
79:83
94:94
92:92
92:92
10
11
12
13e
14e,f
15e,f
B
B
B
B
THF
B
THF
B
THF–H2O (9:1)
a The reactions were carried out on a 0.1-mmol scale with 2a (2 equiv) and [1a]0 = 2 M in different solvents. All the reactions afforded a poor
diastereomeric distribution (ranging from 1.4:1 to 1.2:1).
b DABCO: 1,4-diazabicyclo[2.2.2]octane; DMAP: 4-dimethylaminopyridine.
c Determined by 1H NMR analysis of the crude reaction mixture.
d Determined by HPLC analysis, on chiral stationary phases, of the purified alcohol 3a, obtained by in situ NaBH4 reduction of the correspond-
ing aldehyde. The two distinct ee values refer to the enantiomeric excess of both the diastereoisomers.
e Reaction was carried out at r.t.
f The amount of catalyst B used was 10 mol%.
Synlett 2011, No. 4, 489–494 © Thieme Stuttgart · New York

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Asymmetric Michael
Additionof Nitrobenzyl PyridiAsymmetric Michael Addition of Nitrobenzyl Pyridines to EnalsEls
491
cient transformation (entries 6–9). Interestingly, increas- addition of a carbon nucleophile to enals,13 gave also in
ing the amount of DABCO to one equivalent had the present case slightly better yield while keeping high
negligible influence on the conversion (entries 6 and 7), level of enantiocontrol (entry 15).
whereas the use of 0.25 equivalent resulted in a dramatic
reduction of the reaction rate (entries 7 and 8).
We next performed a series of experiments to determine
the scope of the aldehydic component in this asymmetric
A survey of the reaction media (entries 10–12) revealed Michael addition protocol, using 10 mol% of catalyst B.
that both dioxane and THF were suitable solvents for the THF was selected as the reaction medium, since the reac-
Michael addition. THF was selected for further investiga- tion did not always perform with uniform efficiency when
tion since it engenders a higher catalytic activity. Signifi- the THF–water combination was used (entries 3, 5 and 7,
cantly, this allowed the reaction to be carried out at room Table 2).14
temperature, a key parameter for obtaining a much higher
stereoselectivity (94% ee on both the diastereoisomers;
entries 12 and 13). Additionally, it was possible to reduce
As highlighted in Table 2, the method proved successful
for a wide range of enal b-substituents, including differ-
ently substituted aryl groups as well as heteroaryl and al-
the catalyst loading of amine B to 10 mol% without com-
kenyl moieties. The desired products 3 were isolated in
promising the chemical and the enantiomeric purity (entry
high to excellent enantiomeric excess (ee values ranging
14). Aqueous THF, a solvent system selected in the Merck
from 75% to 94%) and good yield.15 The system main-
laboratories for the upscaling of a B-catalysed conjugate
Table 2 Secondary Amine Catalysed Asymmetric Conjugate Addition of 4-(4-Nitrobenzyl)pyridine (1a) to Enalsa
NO2
NO2
i) B (10 mol%)
THF (2 M), 23 °C, 24 h
ii) NaBH4
CH2Cl2–MeOH
CHO
+
OH
R
2
R
N
N
3
1a
dr = 1.2–1.4:1
Entry
1
R
3
Time (h)
24
Yield (%)b
66 (32:34)
57 (27:30)
80 (37:43)
58 (24:34)
60 (21:39)
85 (39:46)
no reaction
75 (34:41)
62 (30:32)
65 (32:33)
66 (33:33)
82 (39:43)
30 (14:16)
ee (%)c
92:92
95:96
92:92
84:88
82:84
92:92
–
Ph
Ph
Ph
3a
3a
3a
3b
3b
3c
3c
3d
3e
3f
2d
3e
48
24
4
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
4-ClC6H4
48
5e
48
6f
24
7e
96
8g
9
24
92:93
96:98
92:94
88:88
88:87
80:80
2-BrC6H4
4-F3CC6H4
4-MeC6H4
2-furyl
24
10
11
12
13
24
3g
3h
3i
24
24
CH2(CH=CH)Me
48
a The reactions were carried out at r.t. on a 0.1-mmol scale, using 2 (2 equiv) and [1a]0 = 2 M in THF, without any precautions for excluding
moisture. All the reactions afforded a poor diastereomeric distribution (ranging from 1.4:1 to 1.2:1).
b The total yield is reported; the values between brackets refer to the yield of the isolated diastereomerically pure compounds 3, which could be
easily separated by chromatography (see supplementary information for details).
c Determined by HPLC analysis on chiral stationary phases. The two distinct ee values refer to the enantiomeric excess of the two diastereo-
isomers.
d Reaction was carried out on a 2.0-mmol scale using 15 mol% of B.
e THF–H2O (9:1) mixture was used as the reaction medium.
f [1a]0 = 1 M in THF.
g Reaction was carried out at 40 °C.
Synlett 2011, No. 4, 489–494 © Thieme Stuttgart · New York

492
S. Vera et al.
CLUSTER
Scheme 2 X-ray structure of the derivative 518
tained its efficiency also when applied on a synthetically Developing new methods for the easy incorporation of
useful scale (2.0 mmol), leading to the formation of the heteroaromatic groups19a in complex molecules is of fun-
adduct 3 with comparable yield and slightly higher enan- damental importance in small-molecule drug discov-
tiopurity (entry 2). Although the conjugate addition pro- ery.19b Therefore, this new organocatalytic methodology
ceeds with poor control over the relative configuration,16 could find application for the generation of potential me-
the synthetic utility of the process is increased by the pos- dicinal agents. To highlight this possibility, an easy and
sibility of easy isolation, by simple chromatography, of stereoselective synthesis of the highly functionalised 1-
the two diastereoisomers for all of the adducts 3.17
benzazepine derivative 8 from the Michael adduct 7d was
accomplished (Scheme 3).20
To determine the stereochemical outcome of the reaction,
the diastereomerically pure aldehyde 4 was readily trans-
formed into 5 by an olefination–reduction sequence fol-
lowed by a ditosylation of the free amino moiety. Crystals
of the derivative 5 were suitable for X-ray analysis, which
unambiguously established the absolute configuration of
the product (Scheme 2).18
Cl
H2, Pd/C (10%)
MeOH, AcOH
NH
NO2
CHO
N
Ph
Ph
7d
single diastereoisomer
after chromatography, 72% ee
N
8
Finally, we studied the possibility of using different diaryl
compounds as the nucleophilic component of the Michael
reaction. The results reported in Table 3 illustrate how
both the p-nitro-substituted aromatic and the pyridine sys-
tem are essential for obtaining nucleophile activation. In-
deed, when the individual acidifying effects are not
combined, the pKa of the benzylic protons is not in a use-
ful range (entries 1–4).
75% yield
72% ee
Scheme 3 Direct synthesis of substituted 2,3,4,5-tetrahydro-1-
benzazepines
In summary, we have demonstrated that diaryl com-
pounds are suitable nucleophilic partners for the iminium-
catalysed Michael addition chemistry.21 In view of the
wide application of heteroaromatics in drug discovery and
the good tolerance for a series of diverse functional
groups demonstrated by the presented organocatalytic
reaction, we believe that this novel approach may be use-
ful to the chemical community.
Significantly, different pyridine isomers were well toler-
ated and the 2-pyridyl analogue reacted well under the es-
tablished reaction conditions (entries 5 and 6). On the
other hand, the less-pronounced acidifying effect of the 2-
nitro aryl moiety was directly reflected in a total loss of re-
activity (entry 8). However, by fine-tuning the electronic
nature of the aryl group, such as including a further elec-
tron-withdrawing chlorine atom, it was possible to regen-
erate the required conditions for nucleophile activation
(entry 9).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 4, 489–494 © Thieme Stuttgart · New York

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Asymmetric Michael
Additionof Nitrobenzyl PyridiAsymmetric Michael Addition of Nitrobenzyl Pyridines to EnalsEls
493
Table 3 Nucleophile Scope: Activation Effects of the Aryl and
Acknowledgment
Pyridyl Moietiesa
This research was supported by the Institute of Chemical Research
of Catalonia (ICIQ) Foundation, and the Ministerio de Educación y
Ciencia (grant Consolider Ingenio 2010, CSD2006-0003). We
thank Dr. Simona Curreli (Chromatography Unit, ICIQ) for her in-
valuable help.
i) B (10 mol%)
THF (2 M), 23 °C, 48 h
HetAr
HetAr
ii) NaBH4
CH2Cl2–MeOH
OH
CHO
+
Aryl
Aryl
Ph
Ph
6
2a
7
dr = 1.2–1.4:1
References and Notes
(1) (a) List, B. Angew. Chem. Int. Ed. 2010, 49, 1730.
(b) MacMillan, D. W. C. Nature (London) 2008, 455, 304.
(c) Barbas, C. F. III. Angew. Chem. Int. Ed. 2008, 47, 42.
(d) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G.
Angew. Chem. Int. Ed. 2008, 47, 6138. (e) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(2) (a) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006,
39, 79. (b) Brazier, J. B.; Tomkinson, N. C. O. Top. Curr.
Chem. 2010, 291, 281.
(3) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370. (b) Austin, J. F.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 1172. (c) Lee, S.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
(4) Malonates, having a pKaof 16, have been used in iminium
catalysis: Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2006, 45, 4305.
(5) For few selected examples, see: (a) Gotoh, H.; Ishikawa, H.;
Hayashi, Y. Org. Lett. 2007, 9, 5307. (b) Palomo, C.;
Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S.
Angew. Chem. Int. Ed. 2007, 46, 8431.
Entry
1
6
7
Yield (%)b ee (%)c
no reaction
–
N
pKa = 26.7
2
3
4
5
<5% conv.
no reaction
<5% conv.
–
NO2
CF3
NO2
–
–
F3C
N
NO2
7a 60 (26:34)
7b 84 (39:45)
84:90
NO2
NO2
(6) Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F. III.
N
Angew. Chem. Int. Ed. 2008, 47, 4588.
(7) Cassani, C.; Tian, X.; Escudero-Adán, E. C.; Melchiorre, P.
Chem. Commun. 2011, 47, 233.
6
85:90
82:83
(8) Cid, M. B.; Duce, S.; Morales, S.; Rodrigo, E.; Ruano, J. L.
Cl
G. Org. Lett. 2010, 12, 3586.
(9) The pKa values are referred to DMSO and are taken from the
Bordwell Tables, see: http://www.chem.wisc.edu/areas/
reich/pkatable/index.htm.
7
8
7c 80 (39:41)
N
NO2
Cl
(10) ‘Enolate-like stabilisation of the anion may be achieved for
any organic compound with an electron-withdrawing
functional group, with at least one p-bond attached to a
saturated carbon atom having at least one hydrogen atom’:
Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic
Chemistry; Oxford University Press: Oxford, 2001, 529.
(11) Anions on an alkyl side chain that are immediately adjacent
to an aromatic ring are subject to varying degrees of
stabilisation; this effect is stronger in the 2- or 4-position of
a pyridine. Such anions are stabilised in much the same way
as an enolate. The word ‘enaminate’ indicates this type of
nitrogen-containing enolate-like anion: Joule, J. A.; Mills,
K. Heterocyclic Chemistry, 5th Ed.; John Wiley & Sons:
Hoboken, 2010, 54–55.
(12) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem. Int. Ed. 2005, 44, 794. (b) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed.
2005, 44, 4212. (c) For a recent review on the efficiency of
TMS-diaryl prolinol catalysts, see: Mielgo, A.; Palomo, C.
Chem. Asian J. 2008, 3, 922.
NO2
no reaction
N
N
NO2
9d
7d 90 (41:49)
n.d./72
Cl
a The reactions were carried out at r.t. on a 0.1-mmol scale, using 2a
(2 equiv) and [6]0 = 2 M in THF. See ref. 9 for information about pKa
values.
b Total yield of the isolated products; the values between brackets re-
fer to the yield of the diastereomerically pure compounds 7, which
could easily be isolated by chromatography (see supplementary infor-
mation for details).
c Determined by HPLC analysis on chiral stationary phases. The two
distinct ee values refer to the enantiomeric excess of the two diastereo-
isomers.
(13) For the industrial scale asymmetric synthesis of
Telcagepant, see: Xu, F.; Zacuto, M.; Yoshikawa, N.;
Desmond, R.; Hoerrner, S.; Itoh, T.; Journet, M.; Humphrey,
G. R.; Cowden, C.; Strotman, N.; Devine, P. J. Org. Chem.
2010, 75, 7829.
d The reaction was carried out at 40 °C with 20 mol% of catalyst B.
n.d.: not determined; it was not possible to measure the ee of one of
the diastereoisomers of 7d.
(14) The lack of consistency in the conversion when using THF–
H2O as the solvent system is probably a consequence of the
Synlett 2011, No. 4, 489–494 © Thieme Stuttgart · New York

494
S. Vera et al.
CLUSTER
poor solubility of some among the unsaturated aldehydes 2
in this reaction media.
approved drugs such as Tolvaptan, Benazepril, Mozavaptan
and Zilpaterol among others.
(15) The presence of an alkyl substituent at the b-position of the
enal is not tolerated under the reaction condition: i.e.,
crotonaldehyde remained unreactive.
(16) The observed modest diastereocontrol is not surprising: the
privileged secondary amine catalysts, such as B, generally
infer high enantioselectivity but with poor diastereocontrol
when promoting the conjugate addition of prochiral carbon
nucleophiles to a,b-unsaturated aldehydes; see, for example,
ref. 6.
(17) Both the diastereomerically pure aldehydes and the
corresponding alcohols are stable, with no epimerisation
events observed after storing in the fridge for several weeks.
The NaBH4 reduction is requested since the alcohols 3 allow
for a far easier HPLC analysis than the aldehyde precursors.
(18) Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre, accession number
CCDC 802673(5), and are available free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
(19) (a) Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F.
Angew. Chem. Int. Ed. 2010, 49, 8082; and references
therein. (b) Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom,
C. R. J. Med. Chem. 2009, 52, 2952.
(21) Experimental Procedure of the 2.0-mmol Scale Reaction
(Table 2, entry 2): In an ordinary vial equipped with a
magnetic stir bar, catalyst B (0.3 mmol, 97.5 mg, 15 mol%)
and cinnamaldehyde (2a; 4 mmol, 503 mL) were dissolved in
THF (1 mL). After 10 min stirring at r.t., 4-(4-nitrobenzyl)-
pyridine (1a; 2.0 mmol, 427 mg) and DABCO (1 mmol,
112.2 mg, 0.5 equiv) were added. The vial was capped and
the resulting mixture was stirred at r.t. After 48 h, the
reaction mixture was cooled to 0 °C, diluted with MeOH (10
mL) and then a suspension of NaBH4 (132.3 mg, 3.5 mmol)
in MeOH (10 mL) was added dropwise. The resulting
mixture was stirred for 30 min at 0 °C and then was
quenched with H2O (30 mL). The product was extracted
with CH2Cl2 (3 × 30 mL) and the organics were dried over
anhyd Na2SO4. The solvent was removed under reduced
pressure and the crude products were purified by flash
chromatography on silica gel (CH2Cl2 → CH2Cl2–MeOH,
95:5). Both of the diastereoisomers of compound 3a were
easily isolated due to the appreciable difference in the Rf.
First diastereoisomer: 187 mg (27% yield); 95% ee; Rf 0.28
(CH2Cl2–MeOH, 95:5); second diastereoisomer: 206 mg
(31% yield); 96% ee; Rf 0.15 (CH2Cl2–MeOH, 95:5). See
Supporting Information for full experimental details and
product characterisation.
(20) Benzazepines are the core structure of numerous
biologically active compounds. More specifically, the
tetrahydro-1-benzazepine scaffold can be found in a series of
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