Copper-catalyzed perkin-acyl-mannich reaction of acetic anhydride with pyridine: Expeditious entry to unconventional piperidines

Article abstract of DOI:10.1021/ol202027k

A regioselective introduction of a methoxycarbonyl methyl group at the C₂ position of unsubstituted pyridine has been accomplished with catalytic amounts of copper(II) triflate in mild reaction conditions. The N-acetyl-1,2-dihydropyridyl acetic

Full text of DOI:10.1021/ol202027k

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5152–5155
Copper-Catalyzed PerkinꢀAcyl-
Mannich Reaction of Acetic
Anhydride with Pyridine:
Expeditious Entry to
Unconventional Piperidines
Stefano Crotti, Francesco Berti, and Mauro Pineschi*
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia,
ꢀ
Universita di Pisa, Via Bonanno 33, 56126 Pisa, Italy
pineschi@farm.unipi.it
Received July 27, 2011
ABSTRACT
A regioselective introduction of a methoxycarbonyl methyl group at the C2 position of unsubstituted pyridine has been accomplished with
catalytic amounts of copper(II) triflate in mild reaction conditions. The N-acetyl-1,2-dihydropyridyl acetic acid methyl ester obtained is a valuable
building block for the synthesis of new polyfunctionalized piperidine derivatives bearing unconventional substitution patterns.
The addition of carbon-based nucleophiles to pyridines
is a powerful strategy to obtain the piperidine subunit,
which is one of the most prominent pharmacophores
found in biologically active compounds.1 It is known that
some hard organometallic reagents can react with pyridine
at the C-2 position selectively.2 Selective functionalizations
at the C-2 position have been effected in a catalytic manner
through C(2)-H activation of pyridines by transition metal
complexes.3 In regard to the addition of metal enolates or
enolate equivalents to pyridines, they have been intro-
duced at the C-2 position only starting from appropriately
substituted pyridinium derivatives.4 When the additions
have been performed on unsubstituted pyridinium species,
a poor regioselectivity, with the predominant formation
of 1,4-dihydropyridines, was invariably observed.5 Apart
from the venerable Perkin reaction,6 the use of aliphatic
carboxylic acid anhydrides such as carbon nucleophile
in aldol or a Mannich-type addition reaction has received
only scant attention.7 On the other hand, acetic anhydride,
most often in combination with pyridine, is a widely
used acylation reagent. The isolation of N-acetyl-1,2-
(1) Reviews: (a) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141–
1156. (b) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729. (c) Laschat,
€
€
S.; Dickner, T. Synthesis 2000, 1781–1813. (d) Kallstrom, S.; Leino, R.
Biorg. Med. Chem. 2008, 16, 601–635.
(2) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Publishing: Oxford, 2000; pp 63ꢀ120.
(5) (a) Albrecht, U.; Preuss, A.; Schmidt, A.; Fischer, C.; Langer, P.
Heterocycles 2010, 80, 289–302. (b) Rudler, H.; Parlier, A.; Sandoval-
Chavez, C.; Herson, P.; Daran, J.-C. Angew. Chem., Int. Ed. 2008, 47,
6843–6846. (c) Rudler, H.; Denise, B.; Xu, Y.; Parlier, A.; Vaissermann,
J. Eur. J. Org. Chem. 2005, 3724–3744. (d) Dhar, T. G. M.; Gluchoswki,
C. Tetrahedron Lett. 1994, 35, 989–992. (e) Akiba, K.; Nishihara, Y.;
Wada, M. Tetrahedron Lett. 1983, 24, 5269–5272.
(3) For selected examples, see: (a) Yotphan, S.; Bergman, R. G.;
Ellman, J. A. Org. Lett. 2010, 12, 2978–2981. (b) Murakami, M.; Hori, S.
J. Am. Chem. Soc. 2003, 125, 4720–4721. (c) Nakao, Y.; Kanyiva, K. S.;
Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448–2449. (d) Tobisu, M.;
Hyodo, N.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 12070–12071.
(4) For examples, see: (a) Comins, D. L.; Sahn, J. Org. Lett. 2005, 7,
5227–5228. (b) Kuethe, J. T.; Comins, D. L. Org. Lett. 2000, 2, 855–857.
(6) Rosen, T. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp
395ꢀ408.
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(c) Bennasar, M.-L.; Zulaica, E.; Alonso, Y.; Vidal, B.; Vazquez, J. T.;
Bosch, J. Tetrahedron: Asymmetry 2002, 13, 95–106. (d) Yamada, S.;
Morita, C. J. Am. Chem. Soc. 2002, 124, 8184–8185. (e) Brice, H.;
Clayden, J.; Hamilton, S. D. Beilstein J. Org. Chem. 2010, 6,
doi:10.3762/bjoc.6.22. (f) Harrison, D. P.; Sabat, M.; Myers, W. H.;
Harman, W. D. J. Am. Chem. Soc. 2010, 132, 17282–17295.
(7) Fleming, I.; Mason, J. B. J. Chem. Soc. C 1969, 2509–2510. (b)
Kurihara, T.; Hata, T. Chem. Lett. 1975, 4, 495–496. (c) Guthrie, R. W.;
Brossi, A.; Mennona, F. A.; Mullin, J. G.; Kierstead, R. W.; Grunberg,
E. J. Med. Chem. 1975, 18, 755–760.
r
10.1021/ol202027k
Published on Web 09/06/2011
2011 American Chemical Society

dihydropyridyl acetic acid (1) in very low yields has been
reported as an artifact during acetylation reactions using
acetic anhydride and pyridine.7a,b We now report the
activation of acetic anhydride by means of metal salts to
give a simple and practical access to N-acetyl-1,2-dihydro-
pyridylaceticacid. Furthermore, wereportsimpleelabora-
tions of this nucleus to give piperidines with unconven-
tional substitution patterns.
Table 1. Screening of Metal Salts As Promoter of the Perkinꢀ
Acyl-Mannich Additiona
We recently noticed that attempted acetylation of cyclo-
hexenyl hydroxylamino alcohol 38 in pyridine afforded N-
acetyl-1,2-dihydropyridine acetic acid 1a as the major
reaction product (Scheme 1). Close examination of the
reaction showed that the presence of tiny amounts of
copper salts present as impurities in starting compound 3
was responsible for the addition of acetic anhydride to
pyridine.
regioisomeric
entry
Lewis acid
TONb
ratio (1a/2a)c
1
Cu(OTf)2
CuCl2
7
85/15
n.d.
2
ꢀ
ꢀ
5
3
CuCl
n.d.
4
FeCl3
70/30
75/25
68/32
80/20
85/15
5
Sc(OTf)3
MgBr2
2
Scheme 1. Unexpected Product from Acetylation Reaction of
Compound 3
6
5
7
8d
Zn(OTf)2
Cu(OTf)2
6
15
a Reaction carried out at rt using 1.0 mmol of metal salt, pyridine (8.1
mL), and Ac2O (9.45 mL). After 24 h the reaction was filtered on a pad of
Celite and evaporated to dryness. b Moles of crude products by weight
per mole of catalyst. c Determined by 1H NMR of the crude mixture.
d Reaction time was 7 d.
coordinates to the carbonyl oxygen of the acetic anhydride
to give a copper enolate species A after deprotonation of
the R-proton by the acetate anion (Scheme 2). The sub-
sequent addition of the in situ generated copper enolate to
N-acetyl pyridinium ion occurs mainly at the C-2 position,
and only this pathway is shown. Additionꢀelimination of
the acetate anion to the in situ formed mixed anhydride B
established an equilibrium in which compound 1a, its
carboxylate anion, and compound B are present. Initial
attempts to work up the reaction by partitioning the crude
mixture with water and AcOEt proved to be difficult and
led to the loss of a large quantity of the products obtained.
On the other hand, a simple filtration on Celite did not lead
to a satisfactory crude reaction product, as it did not
completely remove the metal salt.
Hence, a weighted amount of anhydrous Cu(OTf)2 was
poured into a 1:1 mixture of pyridine and Ac2O and left to
stir overnight. A simple filtration on Celite afforded a
crude mixture containing 1,2-dihydropyridine 1a (85%)
and 1,4-dihydropyridine 2 (15%) (entry 1, Table 1). It
should be noted that despite the presence of soft enoliza-
tion methods for ketones and other carboxylic acid deri-
vatives basedon the use ofLewis acidꢀLewis base systems,
nothing similar has been described for a carboxylic acid
anhydride.9 Lewis acids as promotersfor this reaction were
also briefly surveyed, evaluating the moles of crude pro-
ducts per mole of catalyst (TON), and the regioisomeric
ratios of addition products 1a and 2a.
As shown in Table 1, other Lewis acids gave the corre-
sponding addition products, albeit with a lower TON and
regioisomeric ratio (entries 4ꢀ6). In particular, a good
result was obtained with Zn(OTf)2 (entry 7), while no
reaction was observed with highly coordinated copper
salts such as CuCl and CuCl2 (entries 2 and 3). When the
mixture was allowed to react for seven days in the presence
of Cu(OTf)2, a significant increase in the TON was ob-
tained (entry 8). The lack of reactivity observed in control
experiments in which the metal salt was omitted points to a
“soft enolization” pathway, in which the Cu2þ salt
Moreover, compounds 1a and 2a were not completely
stable during chromatographic purification on silica gel,
making separation of the two regioisomers in a pure state
difficult. Satisfactory removal of the copper salt was
obtained with an aqueous workup in the presence of a
saturated aqueous solution of Na2EDTA. Subsequent
(10) For leading examples, see: (a) Pipecolic acid: Lemire, A.; Charette,
A. B. J. Org. Chem. 2010, 75, 2077–2080. (b) (ꢀ)-Oseltamivir: Satoh, N.;
Akiba, T.; Yokoshima, S.; Fukuyama, T. Tetrahedron 2010, 65, 3229–
3245. (c) Iboga alkaloids: Weinstein, B.; Chang Lin, L.-C.; Fowler, F. W.
J. Org. Chem. 1980, 45, 1657–1661. (d) Sundberg, R. J.; Cherney, R. J.
J. Org. Chem. 1990, 55, 6028–6037. (e) Reserpine: Wender, P. A.;
Schaus, J. M.; White, A. W. J. Am. Chem. Soc. 1980, 102, 6157–6159.
(f) Homoepibatidines: Krow, G. R.; Cheung, O. H.; Hu, Z.; Huang, Q.;
Hutchinson, J.; Liu, N.; Nguyen, K. T.; Ulrich, S.; Yuan, J.; Xiao, Y.;
Wypij, D. M.; Zuo, F.; Carroll, P. J. Tetrahedron 1999, 55, 7747–7756.
Lycopodium alkaloids: Comins, D. L.; Brooks, C. A.; Al-awar, R. S.;
Goehring, R. R. Org. Lett. 1999, 1, 229–231.
(8) Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M. Tetrahedron
Lett. 2010, 51, 2284–2286.
(9) For recent examples, see: (a) Kohler, M. C.; Yost, J. M.; Garnsey,
M. R.; Coltart, D. M. Org. Lett. 2010, 12, 3376–3379. (b) Lim, D.; Zhou,
G.; Coltart, D. M. Org. Lett. 2007, 9, 4139–4142. For a seminal paper,
see:(c) Tirpak, R. E.; Olsen, R. S.; Rathke, M. W. J. Org. Chem. 1985, 50,
4877–4879.
Org. Lett., Vol. 13, No. 19, 2011
5153

Table 2. Regioselectivity of the Nitroso DielsꢀAlder Reaction
of 1,2-Dihydropyridine 1b
Scheme 2. Plausible Reaction Mechanism for the Copper-Cat-
alyzed Soft Enolization PerkinꢀAcyl-Mannich Reaction
ratio
(4/5)a
yield
(%)b
entry
Z
conditions
1
2
Ph
CH2Cl2, rt, 1 h
NaIO4, MeOH/H2O,
0 °C, 3 h
1/99
99/1
5a (70)c
4b (65)
PhCH2CO
PhCH2CO
Boc
3
4
5
6
Et4NIO4/CH2Cl2,
99/1
55/45
56/44
na
4b (42)
ꢀ78 °C, 3 h
NaIO4, MeOH/H2O,
0 °C, 3 h
4c (45)
5c (23)
4c (32)
5c (15)
4c (46)
6 (30)
Boc
Et4NIO4/CH2Cl2,
ꢀ78 °C, 3 h
Boc
CuCl2, H2O2/ THF,
rt, 2 h
treatment with ethereal diazomethane in a 1:1 mixture of
MeOH/Et2O gave the corresponding methyl esters 1b and
2b which were amenable to chromatographic purification
on silica gel.
a Determined by 1H NMR of the crude mixture. b Isolated yield after
chromatographic purification. c A partial retro DielsꢀAlder (ca. 15%)
reaction was found during chromatographic purification.
N-Substituted 1,2-dihydropyridines are very useful for
the synthesis of a variety of interesting compounds by the
use of DielsꢀAlder type reactions.10 The nitroso Dielsꢀ
Alder (NDA) reaction, which has emerged as a powerful
tool for stereoselective organic synthesis,11 has rarely been
applied to 1,2-dihydropyridines as dienophiles.12 Hence,
the influence of the methoxycarbonyl methyl group at the
C2 position of 1,2-dihydropyridine 1b using nitroso dieno-
philes of different kinds on the regioselectivity was exam-
ined. As expected, the reaction occurred at the C3ꢀC6
position of the diene system in a trans fashion with respect
to the substituent at the C2 position, to give cycloadducts
of type 4 or 5 depending on the electronic effects of nitroso
dienophiles.13
In particular, the use of nitrosobenzene gave, with
complete regio- and diastereoselectivity, the 3-oxa-2,5-
diazabicyclo[2.2.2]oct-7-ene 5a (Table 2, entry 1).12,13 In
accordance with previous observations, this direct adduct
showed some decomposition during chromatographic
purification on silica gel.12b The selective obtainment of
the inverse adduct 2-oxa-3,5-diazabicyclo[2.2.2]oct-7-ene
4b was realized by the use of a phenylacetyl nitroso species
generated in situ by oxidation of the corresponding hydro-
xamic acid in both protic and aprotic solvents (entries
2ꢀ3).14 The use of a carbamate-protecting group gave a
mixture of adducts 4c and 5c which were separable by
chromatographic purification on silica gel (entries 4ꢀ5).
The use of H2O2 in combination with catalytic amounts
15
(5 mol %) of CuCl2 or FeCl3 gave adduct 4c with an
increased isolated yield, but also imide 6 deriving from a
ring-opening overoxidation of compound 5c was obtained
(entry 6).
The regioselective introduction of a methoxycarbonyl
methyl group at the C2 position of pyridine opened a new
access to cyclic β-amino acids, such as homopipecolic acid
derivatives, which have a number of interesting features
and have been used to prepare important biologically
active compounds.16 We envisioned that the intrinsic con-
trol of the relative stereochemistry of CꢀN and CꢀO bond
formation during the DielsꢀAlder reaction of 1,2-dihy-
dropyridine 1b with nitroso dienophiles could afford poly-
functionalized piperidines after simple manipulation.
While the reductive cleavage of the NꢀO bond of direct
phenylnitroso cycloadduct 5a was plagued by a competi-
tive retro DielsꢀAlder reaction, the cleavage of the NꢀO
bond of inverse nitroso cycloadducts 4b and 4c showed
some interesting features with acyl or carbamate protect-
ing groups.
(11) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50,
5630–5647.
(12) (a) Knaus, E. E.; Avasthi, K.; Giam, C. S. Can. J. Chem. 1980,
58, 2447–2451. (b) Lemire, A.; Beaudoin, D.; Grenon, M.; Charette,
A. B. J. Org. Chem. 2005, 70, 2368–2371. For a catalytic asymmetric
version, see: (c) Jana, K. C.; Grimme, S.; Studer, A. Chem.;Eur. J.
2009, 15, 9078–9084.
(13) (a) Dubey, S. K.; Knaus, E. E. J. Org. Chem. 1985, 50, 2080–
2086. (b) Defoin, A.; Schmidlin, C.; Streith, J. Tetrahedron Lett. 1984,
25, 4515–4518.
For example, the treatment of N-Boc protected sub-
strate 4b with a stoichiometric amount of Mo(CO)6
afforded polyfunctionalized eneacetamide 7c with 55%
(15) Adamo, M. F. A.; Bruschi, S. J. Org. Chem. 2007, 72, 2666–2669.
(16) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66,
809–823.
(14) This opposite regioselectivity has been explained by considering
the shape of FMO in arylnitroso and acylnitroso species. See: Streith, J.
Synlett 1996, 189–200.
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Org. Lett., Vol. 13, No. 19, 2011

formal [3.3]-sigmatropic rearrangement to give 1,4-dioxa-
zine A, followed by hydrolysis (eq b, Scheme 3). A [3.3]-
sigmatropic rearrangement has been reported to occur for
related amide protected cycloadducts, but not for a carba-
mate protected cycloadduct, with the isolation of a 1,4-
dioxazine.13a The remarkable effect of water on the reac-
tion course could be ascribed to the susceptibility of
nonconcerted Claisen-type rearrangements to hydrogen
bond acceleration.17
Scheme 3. Simple Elaborations of Inverse Adducts
The use of stoichiometric amounts of Cp2Ti(III)Cl at
low temperatures, recently reported by Miller and co-
workers,18 was decisive to cleave the NꢀO bond of inverse
adduct 4b without competitive side reactions. The corre-
sponding gem-diamine 1-N-iminosugar 8, an interesting
class of iminosugars with glycomimetic properties,19 was
obtained in a quantitative yield (eq c, Scheme 3). On the
other hand, N-Boc protected NDA cycloadduct 4c proved
to be scarcely reactive in these reaction conditions.
In conclusion, the carbomethoxy methylation reaction
of acetic anhydride with pyridine has been developed to a
synthetically useful extent. In this way, unconventional
functionalized piperidines can be obtained very easily in a
few steps starting from pyridine. Studies are in progress in
order to assess the biological activity of simple derivatives
of the compounds obtained.
isolated yield, instead of the expected product of NꢀO
cleavage (eq a, Scheme 3).11 Subsequent control experi-
ments performed by 1H NMR in CD3CN or in CD3CN/
D2O mixtures with or without molybdenum(0) showed
that the presence of water was essential to promote the
thermal conversion of cycloadduct 4b and 4c into 7c and
7c, respectively. The same transformation can be also
obtained with wet DMSO at 55 °C for 48 h. The products
7b and 7c could arise through a C4ꢀN3 bond cleavage via a
Acknowledgment. This work was supported by the
ꢀ
Ministero dell’ Istruzione, dell’Universita e della Ricerca
(M.I.U.R. Rome, PRIN 2008, Catalysts, methodologies
and new regio- and stereoselective processes in organic
synthesis) and by the University of Pisa.
(17) Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219–225. The treatment
of compounds 4b and 4c at >85 °C readily gave the corresponding
dihydropyridine 1b, through a retro DielsꢀAlder reaction.
(18) Cesario, C.; Tardibono, L. P., Jr.; Miller, M. J. J. Org. Chem.
2009, 74, 448–451.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For a review, see: Nishimura, Y. J. Antibiot. 2009, 62, 407–423.
Org. Lett., Vol. 13, No. 19, 2011
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