Synthesis and reactivity of β-methoxymethyl enecarbamates

Article abstract of DOI:10.1021/jo901992z

(Chemical Equation Presented) β-Methoxymethyl enecarbamates (e.g., 1) have been prepared in a single step from α-methoxy carbamates. In the presence of a mild Lewis acid, compound 1 underwent substitution with a variety of nucleophiles including indoles,

Full text of DOI:10.1021/jo901992z

pubs.acs.org/joc
During the course of our investigations into iminium ion
Synthesis and Reactivity of β-Methoxymethyl
Enecarbamates
catalyzed Diels-Alder cycloadditions we disclosed a novel
method for the synthesis of 1 and 2.4 β-Substitution of the
enecarbamate with a methoxymethyl group facilitates a
complementary mode of electrophilic reactivity domi-
nated by the formation of a conjugated iminium ion
(Scheme 1).
Patrick D. O’Connor, Michael G. Marino,
ꢀ
Stephanie M. Gueret, and Margaret A. Brimble*
ꢀ
Department of Chemistry, The University of Auckland,
23 Symonds Street, Auckland, New Zealand
SCHEME 1. Conjugated N-Acyliminium Cation Formation
m.brimble@auckland.ac.nz
Received September 16, 2009
Despite the fact that endocyclic analogues of this conju-
gated iminium ion have proven synthetically useful,5,6
the synthesis and reactivity of exocyclic R,β-unsaturated
N-acyliminium ions remains relatively unexplored with the
exception of a single publication by our group relating to
cycloaddition chemistry.4
We herein report a significantly improved method for the
synthesis of β-methoxymethyl enecarbamates 1 and 2 and
explore their subsequent Lewis acid catalyzed reactions with
a range of nucleophiles.
β-Methoxymethyl enecarbamates (e.g., 1) have been pre-
pared in a single step from R-methoxy carbamates. In the
presence of a mild Lewis acid, compound 1 underwent
substitution with a variety of nucleophiles including
indoles, electron-rich aromatics, silyl enol ethers, and 2-
trimethylsilyloxyfuran.
In a previous report4 we detailed an approach to 1 whereby
hemiaminal 3, formed by electrochemical oxidation of 4,7
underwent methylenation using Pihko’s organocatalytic pro-
cedure8 to afford open chain enal 5. Subsequent Lewis acid
mediated cyclization afforded the stable9 adduct 1, in which
the exocyclic disubstituted olefin had migrated to an endo-
cyclic trisubstituted position in conjugation with the carba-
matefunction(Scheme2). Theregioisomeric N,O-acetal 6 was
not observed under the reaction conditions.10
Enecarbamates are a class of stable enamines that are
important building blocks for construction of a range of
nitrogen heterocycles. With a relatively nucleophilic C3-
terminus, enecarbamates are known to engage in “electro-
phile driven” β-substitution reactions.1 Additionally, the
endocyclic π-system displays typical olefin-like reactivity,
hence haloetherification,2a,b cyclopropanation,2c redox,2d-g
and palladium mediated2h reactions are also possible. Owing
to their versatility and ease of synthesis, typically by elimina-
tion of methanol from an R-methoxycarbamate,2a enecarba-
mates possess great potential for the construction of
functionalized heterocycles. The industrial significance of
this class of molecules was recently highlighted by the
manufacture of a proline-like enecarbamate on a scale
exceeding 100 kg.3
Although the aforementioned synthesis of 1 proved ade-
quate for our cycloaddition studies,4 the apparent synthetic
utility of this intermediate (vide infra) prompted us to search
for an alternative, higher yielding preparative method. It was
(4) O’Connor, P. D.; Korber, K.; Brimble, M. A. Synlett 2008, 1036–
1038.
(5) (a) Matsumura, Y.; Minato, D.; Onomura, O. J. Organomet. Chem.
2007, 692, 654–663. (b) Onomura, O.; Kanda, Y.; Nakamura, Y.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 2002, 43, 3229–3231. (c) Onomura, O.;
Kanda, Y.; Imai, E.; Matsumura, Y. Electrochim. Acta 2005, 50, 4926–4935.
(6) (a) Zou, Y.; Che, Q.; Snider, B. B. Org. Lett. 2006, 8, 5605–5608.
(b) Kim, J.; Thomson, R. J. Angew. Chem., Int. Ed. 2007, 46, 3104–3106.
(7) (a) Finkelstein, M.; Ross, S. D. Tetrahedron 1972, 28, 4497–4502.
ꢀ
(b) Cedheim, L.; Eberson, L.; Helgee, B.; Nyberg, K.; Servin, R.; Sternerup, H.
(1) (a) Shono,T.Tetrahedron1984, 40, 811–850. (b) Shono, T.; Matsumura,
Y.;Tsubata, K.;Sugihara, Y.TetrahedronLett. 1982, 23, 1201–1204. (c) Shono,
T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.; Kanazawa, T.;
Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697–6703.
Acta Chem. Scand. B 1975, 29, 617–621. (c) Nyberg, K.; Servin, R. Acta Chem.
Scand. B 1976, 30, 640–642. (d) Shono, T.; Hamaguchi, H.; Matsumura, Y.
J. Am. Chem. Soc. 1975, 97, 4264–4268. (e) Shono, T.; Matsumura, Y.;
Onomura, O.; Ogaki, M.; Kanazawa, T. J. Org. Chem. 1987, 52, 536–541.
(f ) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172–
1176. (g) Shono, T.; Matsumura, Y.; Tsubata, K. Org. Synth. 1985, 63,
206–212.
(8) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538–2541.
(9) The methylenated adducts 1, 2, and 13 were stable for at least a month
when stored below 0 °C. However, prolonged storage resulted in gradual
decomposition.
(10) Gas phase density functional calculations performed at the B3LYP/
6-31þG(d)//B3LYP/6-31þG(d) level support the conclusion that 1 is ther-
modynamically favored over 6 with a Boltzmann distribution of 98:2 based
on unscaled zeropoint corrected electronic energies at 298 K (ΔE = 9.78 kJ/
mol). See the Supporting Information for computational details.
(2) (a) Matsumura, Y.; Terauchi, J.; Yamamoto, T.; Konno, T.; Shono,
T. Tetrahedron 1993, 49, 8503–8512. (b) Shono, T.; Matsumura, Y.; Ono-
mura, O.; Ogaki, M.; Kanazawa, T. J. Org. Chem. 1987, 52, 536–541. (c)
Arenare, L.; Decaprariis, P.; Marinozzi, M.; Natalini, B.; Pellicciari, R.
Tetrahedron Lett. 1994, 35, 1425–1426. (d) Backenstrass, F.; Streith, J.;
Tschamber, T. Tetrahedron Lett. 1990, 31, 2139–2142. (e) Burgess, L. E.;
Gross, E. K. M.; Jurka, J. Tetrahedron Lett. 1996, 37, 3255–3258. (f )
Oppolzer, W.; Bochet, C. G. Tetrahedron Lett. 1995, 36, 2959–2962. (g)
Lei, A. W.; Chen, M.; He, M. S.; Zhang, X. M. Eur. J. Org. Chem. 2006,
4343–4347. (h) Hallberg, A.; Nilsson, K. J. Org. Chem. 1990, 55, 2464–2470.
(3) Yu, J. R.; Truc, V.; Riebel, P.; Hierl, E.; Mudryk, B. Tetrahedron Lett.
2005, 46, 4011–4013.
DOI: 10.1021/jo901992z
r
Published on Web 10/16/2009
J. Org. Chem. 2009, 74, 8893–8896 8893
2009 American Chemical Society

O’Connor et al.
JOCNote
SCHEME 2. Electrochemical Routes to β-Methoxymethyl Enecarbamates
TABLE 1. β-Alkoxymethyl Enecarbamate Synthesis Optimizationa
entry
R
MeOH (equiv)
catalyst (ratio)b
mol % cat.
temp (°C)
time
yield (%)c
1
2
3
4
5
6
7
8
9
10
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
6
6
6
6
6
6
6
4
8
40
pip/pro (1:1)
pip/pro (1:1)
pyrr/pro (1:1)
pip/pro (1:1)
pip/pro (1:1)
pip/pro (3:2)
pip/pro (2:3)
pip/pro (1:1)
pip/pro (1:1)
pip/pro (1:1)
20
20
20
100
3
20
20
20
20
20
25
130
130
130
130
130
130
130
130
130
2 days
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
0
61
55
24
17
47
56
40
54
10
1 h
aIn a typical reaction 200-800 mg of starting material was reacted with 1.5 equiv of 37% (w/w) aqueous formaldehyde and heated with microwave
irradiation in a 10 mL CEM Discovery microwave vessel. Catalysts were prepared as stock solutions of a 1:1 mixture of either piperidine (pip) or
b
pyrrolidine (pyrr) and propionic acid (pro). cIsolated yields after silica gel chromatography.
felt that the direct alkoxymethylation of enecarbamate 12
with an oxonium ion derived from formaldehyde would offer
the best chance of success.
was observed.13 After some degree of experimentation it was
found that microwave irradiation14 of 12 under aqueous
organocatalytic conditions did furnish the desired adduct 1.
Interestingly, the same reaction conditions, when applied to
N,O-acetals 9-11, also resulted in direct conversion of the
starting material to β-methoxymethyl enecarbamates 1, 13,
and 2 after only 1 h at 130 °C. This result initially seemed
surprising considering the similarity of the reaction condi-
tions to those employed in the conversion of 3 to 5.8
To obtain a greater understanding of the conversion of
N,O-acetals to β-methoxymethyl enecarbamates, further
optimization was carried out (Table 1). By systematically
varying the nature of the catalyst and loading (Table 1 entries
2-7), and the methanol-to-formalin ratio (Table 1, entries
8-10), the yield after silica gel chromatography was opti-
mized to approximately 60%.
While R-alkoxycarbamates have been obtained from
N-acyl lactams by hydride reduction,11 in the present work,
a simple electrochemical method was adopted. Toward this
end, the anodic R-oxidation of 4, 7, and 8 with the
Ross-Eberson-Nyberg procedure5 afforded high yields of
N,O-acetals 9-11. The high-yielding conversion of 9 to 12
was next accomplished by NH4Cl mediated elimination.12
Unfortunately, subsequent direct alkylation of 12 with either
paraformaldehyde or dimethoxymethane under acidic anhy-
drous conditions failed to facilitate the desired transforma-
tion to 1, instead heterodimerization of the starting material
(11) (a) Langlois, N.; Rojas, A. Tetrahedron 1993, 49, 77–82. (b) Altman,
K. W. Tetrahedron Lett. 1993, 34, 7721–7724. (c) Dieter, R. K.; Sharma,
R. R. J. Org. Chem. 1996, 61, 4180–4184.
(12) Shono, T.; Matsumura, Y.; Onomura, O.; Yamada, Y. Tetrahedron
Lett. 1987, 28, 4073–4074.
(13) The homo- and heterodimerization of enecarbamates has been
reported; see ref 3 and: Oliveira, D. F.; Miranda, P. C. M. L.; Correia,
C. R. D. J. Org. Chem. 1999, 64, 6646–6652.
Although the exact methanol:formalin:starting material
ratio did not seem critical, biphasic reactant combinations
invariably afforded poor yields and it was therefore deemed
necessary to use sufficient methanol to afford a homoge-
neous reaction mixture.
Having optimized the methoxymethylation step (Table 1),
the versatility of the reaction was next assessed by changing
the alcohol component. In this case N,O-acetals 9-11 were
unsuitable substrates because the additional equivalent of
(14) Conventional heating gave significant amounts of starting material
12 and N,O-acetal 9 byproduct. Microwave-assisted organocatalytic Man-
nich reactions have been described, see: (a) Hosseini, M.; Stiasni, N.; Barbieri,
V.; Kappe, C. O. J. Org. Chem. 2007, 72, 1417–1424. (b) Leadbeater, N. E.;
Torenius, H. M.; Tye, H. Mol. Diversity 2003, 7, 135–144.
8894 J. Org. Chem. Vol. 74, No. 22, 2009

O’Connor et al.
JOCNote
TABLE 2. Enecarbamate Alkoxymethylation
TABLE 3. Nucleophilic Substitution Reactions
entry
R
product
yield (%)a
1
2
3
4
5
Me
Et
CF3CH2
i-Pr
t-Bu
1
52
33
23
19
0
14
15
16
na
aIsolated yield after silica gel chromatography.
methanol contained within the starting material complicated
the outcome of the reaction by forming mixtures of alkoxy-
and methoxymethylenated products. To circumvent this
problem enecarbamate 12 was reacted with various alcohols
under optimized conditions (Table 2).
Less sterically hindered alcohols, e.g., ethanol and 2,2,
2-trifluoroethanol, afforded the corresponding adducts 14
and 15 in better yield compared to using more sterically
demanding alcohols (isopropanol and tert-butanol). The scope
of the alkoxymethylation is currently limited to piperidine
starting materials as acyclic or pyrrolidine derived substrates
failed to cleanly form adducts under the reaction conditions.
A likely mechanism for the transformations illustrated
in Tables 1 and 2 may involve initial hydrolysis of the
N,O-acetal, or enecarbamate, to an open chain aldehyde
that undergoes a Mannich-type reaction with formalde-
hyde.15 The open chain enal (i.e. 5) then cyclizes to form an
R,β-unsaturated N-acyliminium intermediate (cf. Scheme 1)
that reacts with the alcohol present. The product distribution
from the reaction is the likely result of a thermodynamic
equilibrium in which alkoxymethylenated adducts are the
predominant species.
aCH2Cl2, Sc(OTf)3 (5 mol %), 0 °C for 2 h. bCH2Cl2, BF3 Et2O
3
(1 equiv), -78 to 0 °C for 1 h. cIsolated yield after silica gel flash
Having previously demonstrated that β-methoxymethyl
enecarbamates 1 and 2 react as active dienophiles in a limited
range of Diels-Alder cycloadditions,4 it was decided to
examine their reactivity with a range of readily available
nucleophiles such as indoles and silyl enol ethers (Table 3).
Pleasingly, nucleophilic substitution reactions proceeded
in high yields in the presence of a Lewis acid. Reactive enol
ether and indole nucleophiles underwent smooth reaction
in dichloromethane at 0 °C catalyzed by scandium triflate,
chromatography. dIsolated with an inseparable impurity.
O-acetals or unfunctionalized enecarbamates has been de-
monstrated. The acetal or enecarbamate starting materials are
easily prepared and purified by distillation and their conver-
sion proceeds under mild, and near solvent-free conditions
using inexpensive commercially available reagents. The
β-methoxymethyl enecarbamates thus prepared extended
the scope of reactions occurring via generation of the
N-acyliminium ion17 by forming novel adducts with a
variety of electron-rich nucleophiles. Given the potential
for asymmetric hydrogenation,18 β-alkylated enecarba-
mates prepared herein also provide useful heterocyclic
building blocks for the future synthesis of enantiopure
pharmaceuticals and natural products.
while anisole required the use of BF3 Et2O as a catalyst. In
3
general, prolonged reaction times generally resulted in
decomposition. While the putative R,β-unsaturated N-acy-
liminium ion intermediate (Scheme 1) is an ambident elec-
trophile, nucleophilic substitution of 1, 2, and 13 takes place
at the sterically unencumbered exocyclic carbon to give
thermodymanic products.16
In summary a novel method for the construction of
β-alkoxymethyl enecarbamates starting from either cyclic N,
(17) N-Acyliminium cyclizations are used extensively for the construction
of heterocyclic ring systems; see: (a) Marson, C. M.; Pink, J. H.; Smith, C.
Tetrahedron Lett. 1995, 36, 8107–8110. (b) Shono, T.; Matsumura, Y.;
Uchida, K.; Kobayashi, H. J. Org. Chem. 1985, 50, 3243–3245. (c) Shono,
T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103, 1172–1176.
(d) Veenstra, S. J.; Speckamp, W. N. J. Am. Chem. Soc. 1981, 103, 4645–
4646. (e) Flynn, G. A.; Giroux, E. L.; Dage, R. C. J. Am. Chem. Soc. 1987,
109, 7914–7915.
(15) (a) Casas, J.; Sunden, H.; Cordova, A. Tetrahedron Lett. 2004, 45,
6117–6119. (b) Herrera, R. P.; Monge, D.; Martin-Zamora, E.; Fernandez,
R.; Lassaletta, J. M. Org. Lett. 2007, 9, 3303–3306. (c) Mase, N.; Inoue, A.;
Nishio, M.; Takabe, K. Bioorg. Med. Chem. Lett. 2009, 19, 3955–3958.
(16) The C10 alkylated adduct of 1 with anisole (cf. adduct 22) is predicted
be thermodynamically favored over the C2 adduct by 37.7 kJ/mol based on
unscaled zero-point corrected electronic energies at 298 K. See the Experi-
mental Section for computational details.
(18) The asymmetric hydrogenation of β-acyl enecarbamates has been
demonstrated, see: Lei, A.; Chen, M.; He, M.; Zhang, X. Eur. J. Org. Chem.
2006, 19, 4343–4347.
J. Org. Chem. Vol. 74, No. 22, 2009 8895

O’Connor et al.
JOCNote
Experimental Section
General Procedure for the Nucleophilic Substitution of
β-Alkoxymethyl Enecarbamates: Methyl 5-((1H-Indol-3-yl)-
methyl)-3,4-dihydropyridine-1(2H)-carboxylate (17). To a stir-
red solution of 1 (87 mg, 461 μmol) and indole (121 mg,
1.03 μmol) in CH2Cl2 (4 mL) at 0 °C was added Sc(OTf)3
(3.0 mg, 6.1 μmol). After being stirred at 0 °C for 1 h the reaction
was quenched with saturated NaHCO3, extracted with CH2Cl2
(3 ꢀ 20 mL), dried over MgSO4, and evaporated to give the title
compound as a colorless oil that was further purified by silica gel
chromatography eluting with hexane/EtOAc 7:1 to afford the
title compound as a colorless oil (108 mg, 85%): IR (film) 2952,
1682, 1455, 1316 cm-1; 1H NMR (300 MHz, DMSO-d6, 60 °C) δ
(ppm) 10.62 (s-br, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.40 (d, J =
8.1 Hz, 1H), 7.14-7.13 (m, 1H), 7.15-7.17 (m, 2H), 7.04-6.97
(m, 1H), 6.77 (s, 1H), 3.70 (s, 3H), 3.53-3.48 (m, 2H), 3.45 (s,
2H), 2.04-1.98 (m, 2H), 1.81-1.72 (m, 2H); 13C NMR (75 MHz,
DMSO-d6, 60 °C) δ (ppm) 153.7 (C), 137.2 (C), 128.0 (C), 123.6
(CH), 121.3 (CH), 120.8(CH), 119.1 (C), 118.9 (CH), 118.7 (CH),
112.7 (C), 111.9 (CH), 52.9 (CH3), 42.2 (CH2), 31.2 (CH2), 25.2
(CH2), 22.0 (CH2); HRMS (EI) exact mass calcd for C16H18N2O2
270.1368 (Mþ), found 270.1362.
General Procedure for the Conversion of Piperidine Carbamate
N,O-Acetals to β-Methoxymethyl Enecarbamates: Methyl
5-(Methoxymethyl)-3,4-dihydropyridine-1(2H)-carboxylate (1).
A 10 mL CEM pressure vessel equipped with a stirrer bar
was charged with N,O-acetal 9 (2.03 g, 11.0 mmol), 37% (w/w)
formalin (1.40 g, 17.3 mmol), methanol (2.31 g, 72.1 mmol),
and a 1:1 mixture of pyrrolidine and propionic acid (306 mg,
2.11 mmol). The stirred mixture was heated in a CEM Discover
microwave reactor (max power 100 W) to 130 °C for 1 h. After
the reaction was quenched with saturated NaHCO3, the aqu-
eous layer was extracted with EtOAc (3 ꢀ 40 mL) and the
pooled organic fractions were washed with brine and dried
over MgSO4 and the solvent was evaporated in vacuo to give a
yellow oil. The UV active crude product was further purified by
silica gel chromatography, eluting with hexane/EtOAc 10:1 to
give the title compound (1.20 g, 59%) as a colorless oil: IR
(film) 2928, 1714, 1673, 1446, 1354, 1178 cm-1; 1H NMR (400
MHz, CDCl3)19 δ (ppm) 6.95 and 6.82 (s, 1H, H6), 3.86-3.81
(m, 2H, H10), 3.76 (s-br, 3H, H2000), 3.61-3.53 (m, 2H, H2),
3.28 and 3.26 (s-br, 3H, H100), 2.10-2.06 (m, 2H, H3),
1.88-1.81 (m, 2H, H4); 13C NMR (100 MHz, CDCl3)19
δ
Acknowledgment. Financial support for this work from
the New Zealand Foundation for Research Science and
Technology is gratefully acknowledged.
(ppm) 154.1 and 153.6 (C1000), 124.0 and 123.4 (C6), 115.3 and
115.0 (C5), 75.1 (C10), 57.1 and 56.9 (C100), 52.8 (C2000), 42.0 and
41.8 (C2), 23.0 and 22.7 (C4), 21.3 and 21.2 (C3); HRMS (ESI)
exact mass calcd for C9H16NO3 186.1130 (MHþ), found
186.1134.
Supporting Information Available: Spectroscopic data for
all products and Cartesian coordinates for computed structures
with electronic and zero point energy. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Dynamic NMR effects due to hindered rotation about the CO-N
bond.
8896 J. Org. Chem. Vol. 74, No. 22, 2009