Conjugate addition reactions of N-carbamoyl-4-pyridones with organometallic reagents

Article abstract of DOI:10.1021/jo900327q

(Chemical Equation Presented) N-Carbamoyl-4-pyridones undergo conjugate addition reactions with organocuprates and organozincates to afford 2-substituted-2,3-dihydro-4-pyridones providing a direct synthetic approach to substituted piperidines and piperido

Full text of DOI:10.1021/jo900327q

Conjugate Addition Reactions of N-Carbamoyl-4-Pyridones with
Organometallic Reagents
R. Karl Dieter* and Fenghai Guo
Department of Chemistry, Hunter Laboratory, Clemson UniVersity, Clemson, South Carolina 29634-0973
dieterr@clemson.edu
ReceiVed February 13, 2009
N-Carbamoyl-4-pyridones undergo conjugate addition reactions with organocuprates and organozincates
to afford 2-substituted-2,3-dihydro-4-pyridones providing a direct synthetic approach to substituted
piperidines and piperidones. Good to excellent yields of conjugate adducts are achieved with lithium
dialkylcuprates, alkylcyanocuprates, RLi/CuCN (0.3 equiv), and trialkylzincates with copper catalysis.
Copper catalysis in the conjugate addition of Grignard reagents affords modest yields of conjugate adducts.
An enantioenriched phosphoramidite ligand promotes the copper catalyzed conjugate addition of Et2Zn
to a N-carbamoyl-4-pyridone with an er of 91.5:8.5.
Introduction
expansion of pyrrolidine or furan derivatives, and more recently;
(4) ring closing-metathesis on dialkyl substituted nitrogen
derivatives where each alkyl group contains an appropriately
positioned alkene functional group.
The piperidine ring is an important structural feature in many
medicinal compounds and naturally occurring alkaloids.1 This
motif includes both simple and annulated piperidines [e.g.,
indolizidines (1-azabicyclo[4.3.0]nonanes) and quinolizidines (1-
azabicyclo (4.4.0)decanes], and 12 000 piperidine derivatives
were reported in clinical trials2a in a 10 year period. Numerous
asymmetric2b synthetic routes have been developed,3,4 which
generally revolve around four strategic approaches:3a (1) ring
formation via alkylation of a nitrogen center with an acyclic
precursor containing pre-established stereogenic centers; (2)
asymmetric generation of stereocenters and substitution patterns
on an existing six-membered nitrogen heterocycle; (3) ring
Although each of the above strategies relies extensively on
manipulation of the chiral pool for appropriate starting
materials3b or use of chiral auxiliaries,3d,4 these protocols have
been developed into effective methods that can be done on large
scales and provide considerable versatility for the synthesis of
a wide variety of N-heterocycles. In pursuit of a catalytic
asymmetric approach to substituted piperidines or piperidinones,
we were intrigued by the possibility of effecting organocuprate
conjugate addition reactions on 4-pyridones (eq 1). Surprisingly,
we could find no examples of this reaction in the literature.
(1) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645–1680. (b) Watson, P. S.; Jiang, B.; Scott, B. Org.
Lett. 2000, 2, 3679–3681.
(2) (a) Stinson, S. C. C&EN 2001, 79 (20), 45–57. (b) Thayer, A. M. C&EN
2007, 85 (32), 11–19.
(3) For reviews on piperidine and piperidone synthesis see: (a) Cossy, J.
Chem. Rec. 2005, 5, 70–80, and references cited therein. (b) Pearson, M. S. M.;
Mathe´-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159–
2191. (c) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729. (d) Zhou, P.; Chen,
B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003–8030. (e) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989.
(f) Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813. (g) Bailey, P. D.;
Millwood, P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998, 633–640.
(4) For reviews see: (a) Joseph, S.; Comins, D. L. Curr. Opin. Drug DiscoVery
DeV. 2002, 5, 870–880. (b) Comins, D. L. J. Hetero. Chem. 1999, 36, 1491–
1500.
Although organometallic mediated conjugate addition of alkyl
or aryl ligands to 4-pyridones (i.e., 1) could provide a rapid
entry to the highly versatile 2,3-dihydropyridones4 (e.g., 2/3),
the addition of an allyllithium5a reagent to a 4-pyridone and a
dithianyllithium5b reagent to a N-cabamoyl-4-quinolone appear
to be the only reported examples of such a reaction.5 While
(5) (a) Lim, S. H.; Curtis, Michael, D.; Beak, P. Org. Lett. 2001, 3, 711–
714. (b) Alvarez, M.; Ajana, W.; Lopez-Calahorra, F.; Joule, J. A. J. Chem.
Soc., Perkin Trans. 1 1994, 917–919. (c) Albaneze-Walker, J.; Rossen, K.;
Volante, R. P.; Reider, P. J. A conjugate reduction of a N-alkyl-4-pyridone has
also been reported. Tetrahedron Lett. 1999, 40, 4917–4920.
10.1021/jo900327q CCC: $40.75
Published on Web 04/14/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3843–3848 3843

Dieter and Guo
copper4b,6 and rhodium7 mediated conjugate additions to 2,3-
dihydropyridones are well established, the addition of nucleo-
philes to pyridinium salts8a–c is employed as a synthetic
alternative to a 4-pyridone conjugate addition strategy. Similarly,
addition of alkyllithium reagents to quinolinium salts generated
by addition of BF3 ·Et2O or trialkylsilyltriflates to N-cabamoyl-
4-quinolones has also been reported.8d,e We now report that a
variety of organometallic reagents do in fact undergo conjugate
addition reactions with N-carbamoyl-4-pyridones to afford
2-substituted 2,3-dihydro-4-pyridones (eq 1).
TABLE 1. Reactions of N-(Carbamoyl)-4-Pyridones with
Organocuprate Reagents
entry
N-Boc
reagenta
Cpd no.
% yieldb
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1a
1a
1b
1b
1b
1a
1a
1b
1b
1b
1a
1a
1b
1b
1b
1a
1a
1b
1b
1b
1b
1b
1b
Me2CuLi
MeCuCNLi
Me2CuLi
MeCuCNLi
2a
2a
3a
3a
3a
2b
2b
3b
3b
3b
2c
2c
3c
3c
3c
2d
2d
3d
3d
3d
2e
2e
3e
3e
3e
3b
3f
52-58c
36c
69
39
62
83-85
73-75
85-87
77-80
77c
67-70
76
71-75
78
70
59-65
56
66-70
65
62
86
73
80-85
81
75
79
39
52-57
MeLi/CuCN (0.3 equiv)
nBu2CuLi
nBuCuCNLi
nBu2CuLi
9
nBuCuCNLi
nBuLi/CuCN (0.3 equiv)
sBu2CuLi
Results and Discussion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
sBuCuCNLi
Lithium diphenyl- and dialkylcuprates, as well as the corre-
sponding cyanocuprate reagents, readily add to N-carbamoyl-
4-pyridones (Table 1, entries 1-25) when the reaction is
conducted in THF in the presence of trimethylsilylchloride
(TMSCl). No conjugate addition occurs in the absence of
TMSCl. Reaction of lithium dimethylcuprate with the ethyl-
carbamate 1a gave modest yields of the 1,4-adduct accompanied
by formation of a pyridone dimer (entry 1), which was
suppressed by utilization of the tert-butylcarbamate 1b (entry
3). For the more reactive lithium dialkylcuprates (i.e., alkyl )
nBu, sBu, tBu, entries 6 vs 8, 11 vs 13, and 16 vs 18) and lithium
diphenylcuprate entry 21 vs 23) comparable yields were obtained
with both carbamates 1a and 1b.
sBu2CuLi
sBuCuCNLi
sBuLi/CuCN
tBu2CuLi
tBuCuCNLi
tBu2CuLi
tBuCuCNLi
tBuLi/CuCN (0.3 equiv)
Ph2CuLi
PhCuCNLi
Ph2CuLi
PhCuCNLi
PhLi/CuCN (0.3 equiv)
nBuMgCl/CuCN (10 mol%)
EtMgBr/CuBrDMSd,e
EtMgBr/CuBrDMSd,f
Similarly, various methylcuprates (entries 1-4) gave lower
yields than the corresponding butyl (entries 6-9 and 11-19)
and phenylcuprates (entries 21-24), reflecting the facility of
ligand transfer and pyridone reactivity. Consistent with these
reactivity patterns, the cyanocuprate reagents (i.e., RCuCNLi)
generally gave lower yields than the Gilman reagents (i.e.,
R2CuLi), which was significant for the methyl ligand (26-30%,
entries 2 vs 1, 4 vs 3) and very modest (1-13%) to insignificant
for the other ligands (entries 6-9, 11-19, and 21-24). Thus,
for phenyl and alkyl groups larger than methyl, the conjugate
addition reaction is insensitive to cuprate stoichiometry (i.e.,
R2CuLi vs RCuCNLi) and carbamate structure (i.e., 1a vs 1b).
In the interest of developing an asymmetric variation of the
reaction, a series of procedures catalytic in copper were
examined. Although CuCN (10 mol%) effectively catalyzed the
conjugate addition of n-BuMgCl (entry 26) to 1b in THF,
established procedures for copper catalyzed asymmetric con-
jugate addition of Grignard reagents called for changes in solvent
3f
a Reagent prepared by adding R1Li to MX or MX2 (M ) Cu or Zn
and X ) CN and Br, respectively). TMSCl (3.0 equiv) was used unless
noted. b Yields are based upon isolated products purified by column
chromatography. c Pyridone dimer was formed (entry 1, 10%; entry 2,
d
24%; entry 10, 5%). tBuOMe was used as solvent. e 5 Mol% of
CuBr·Me2S was used. f No TMSCl was employed.
and copper(I) salt.9 Reaction of 1b with commercially available
EtMgBr and catalytic quantities (5 mol %) of CuBr ·SMe2 gave
a low yield (39%) of 1,4-adduct in the presence of TMSCl (entry
27) and a better yield in the absence of TMSCl (52-57%) (entry
28). These results are consistent with the observation that the
accelerating effect of TMSCl on 1,4-conjugate additions for both
stoichiometeric cuprates10a,b and procedures catalytic in
copper10c is significantly greater in THF than in diethyl ether
and that in the absence of TMSCl cuprate mediated 1,4-additions
are faster in ether10d than in THF. Utilization of the TMSCl
(2.0 equiv)/HMPA (2.0 equiv) combination10c gave no signifi-
cant increase in chemical yield (42%). These results are
(6) (a) Sebesta, R.; Pizzuti, M.; Boersma, A. J.; Minnaard, A. J.; Feringa,
B. L. Chem. Commun. 2005, 1711–1713. (b) Kranke, B.; Hebrault, D.; Schultz-
Kukula, M.; Kunz, H. Synlett 2004, 671–674. (c) Weymann, M.; Pfrengle, W.;
Schollmeyer, D.; Kunz, H. Synthesis 1997, 1151–1160.
(7) (a) Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Org.
Lett. 2005, 7, 2433–2435. (b) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T.
J. Am. Chem. Soc. 2004, 126, 6240–6241. For rhodium catalyzed addition of
arylzinc reagents to N-carbamoyl-4-quinolones see: (c) Shintani, R.; Yamagami,
T.; Kimura, T.; Hayashi, T. Org. Lett. 2005, 7, 5317–5319.
(8) For a review see: (a) Comins, D. L.; Joseph, S. P. AdV. Nitrogen
Heterocycles 1996, 2, 251–294. (b) Klegraf, E.; Follmann, M.; Schollmeyer,
D.; Kunz, H. Eur. J. Org. Chem. 2004, 3346–3360. (c) Focken, T.; Charette,
A. B. Org. Lett. 2006, 8, 2985–2988. (d) For addition of organometallic reagents
to quinolinium salts see: Beifuss, U.; Ledderhose, S. Synlett 1997, 3, 313–315.
(e) Beifuss, U.; Feder, G.; Bes, T.; uson, I. Synlett 1998, 649–651.
(9) (a) Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2004, 126, 12784–12785. (b) Lopez, F.; Harutyunyan, S. R.;
Meetsma, A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44,
2752–2756. (c) Harutyunyan, S. R.; Lopez, F.; Browne, W. R.; Correa, A.; Pena,
D.; Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem.
Soc. 2006, 128, 9103–9118.
(10) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019–6022.
(b) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett.
1986, 27, 4029–4032. (c) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.;
Kuwajima, I. Tetrahedron 1989, 45, 349–362. (d) House, H. O.; Wilkins, J. M.
J. Org. Chem. 1978, 43, 2443–2454.
3844 J. Org. Chem. Vol. 74, No. 10, 2009

Addition Reactions of N-Carbamoyl-4-Pyridones
SCHEME 1. N-Carbamoyl-4-Pyridone Competition
Experiments
potentially amenable to the development of asymmetric copper
catalyzed conjugate addition of Grignard reagents to N-carbam-
oyl-4-pyridones.
Having achieved success in allylic substitution reactions with
Grignard reagents and 0.3 equivalents11 of CuCN, we examined
this stoichiometry with alkyllithium reagents obtaining conjugate
adducts 3a,b,d (Table 1, entries 5, 10, and 20) in yields
comparable to those obtained with the alkylcyanocuprate
reagents RCuCNLi. When the amount of CuCN was reduced
to 10 mol%, reaction of nBuLi and 1b in the presence of TMSCl
gave 3b (21%), starting material 1b (20%), and a tertiary
alcohol, 1,1-di-n-butyl-1-pentanol (34%), arising from attack
at the carbamate carbonyl (eq 2). In the absence of copper, the
tertiary alcohol was formed in a 34% molar ratio (quantitative
based upon one equivalent of n-BuLi as limiting reagent) after
one hour at -78 °C. These results indicate that CuCN can be
reduced to 0.3 equivalents of the alkyllithium stoichiometry
without deleterious effect perhaps suggesting involvement of a
cuprate species of stoichiometry R3CuLi2 or an aggregate such
that free RLi is not present in solution. Although Ashby12a,b
reported a similar species (i.e., Me3CuLi2) that chemoselectively
afforded 1,4-addition over 1,2-addition to cyclohexenone,
Lipshutz12c showed that when prepared in the absence of LiI
in Et2O or in the presence of LiI in an Et2O:THF solvent mixture
Me3CuLi2 is not a discrete species and these solutions contain
substantial amounts of free MeLi. Further NMR studies involv-
ing scalar coupling measurements also revealed that Me3CuLi2
consisted largely of Me2CuLi and MeLi in halide free THF
solutions.12d Chemical reactions and Gilman tests also revealed
that MeLi was present in Et2O:THF solutions of Me2CuLi free
of LiI, but was not present in solutions of Me2CuLi·LiI.12c
More recent structural studies13a of cuprate reagents [e.g.,
R2CuLi and R2CuLi·LiX (X ) Br, I, CN)] suggest a ho-
modimeric structure 4 in Et2O, and solvent separated ion pairs
(SSIP) in THF that are in equilibrium with minor amounts of
heterodimers 5 (X ) Cl, Br, I, CN). All these studies suggest
that THF solutions of R3CuLi2 stiochiometry should contain
substantial amounts of RLi. As expected, a THF solution of
n-Bu3CuLi2 gave a positive Gilman Test indicative of free
n-BuLi. Reaction of this solution with 1b at -78 C for one
hour gave 1b, dihydropyridone 3a, and tertiary alcohol
(55:35:10 ratio with CuCN and 60:30:10 with CuCN ·2LiCl).
Utilization of 10 mol% of CuCN or CuCN ·2LiCl gave
substantially greater amounts of the tert-alcohol. The cyano
Gilman reagent prepared from either CuCN·2LiCl or CuCN
gave only starting 1b and product 3b after one hour at -78 °C.
In all cases, the addition of LiCl gave lower yields of conjugate
adduct 3b. These results suggest that the n-Bu3CuLi2 composi-
tion is not more reactive toward conjugate addition than the
Gilman reagent, and that free n-BuLi is present in solution for
the former composition. Product distribution then is determined
by the relative rates of reaction between 1b and n-BuLi,
n-Bu2CuLi and 1b, and the rate for regeneration of the Gilman
reagent from n-BuCu and n-BuLi. At 30 mol% CuCN, the
competitive rates favor conjugate addition, while with 10 mol%
CuCN the relative rates favor addition of n-BuLi to the
carbamate carbonyl. Thus, successful utilization of 30 mol%
CuCN will be dependent upon the relative rate of RLi reaction
with a particular substrate as originally observed by Ashby.12b
Computational studies predict aggregate 5 (X ) CN) to be only
slightly more stable than the aggregate arising from exchange
of CN and R perhaps accounting for the anomalous positive
Gilman test displayed by the Lipshutz reagent.13b Nevertheless,
it seems unlikely that a heterodimer 5 (X ) n-Bu, for
n-Bu3CuLi2) is playing any role in these conjugate addition
reactions given the above experimental results.
In order to gauge the reactivity of 1b, a series of competition
experiments were carried out with 2-cyclohexenone, ethyl
crotonate, and N-Boc-2-methyl-2,3-dihydro-4-pyridone (Scheme
1). These individual experiments revealed that 1b is three times
more reactive than ethyl crotonate and one-fourth as reactive
as 2-cyclohexenone toward lithium di-n-butylcuprate and com-
parable in reactivity to dihydropyridone 3a by a factor of 0.8.
J. Org. Chem. Vol. 74, No. 10, 2009 3845

Dieter and Guo
n
TABLE 2.
Reactions of N-(Carbamoyl)-4-Pyridones with
Organozinc Reagents with or without Copper Catalysis
reagent BuZnBr with stoichiometric amounts of CuCN gave
good yields of conjugate adduct (entry 9). In the copper
mediated reactions, the presence of allyl bromide did not
enhance the chemical yield (entries 4-8), and did not effect
allyation of the intermediate enolate. Mixed zincates containing
n-Bu and t-Bu ligands transferred the n-Bu ligand with slightly
greater efficiency (entries 10-12, 38-40% vs 21-31%, re-
spectively).
Reaction of Et2Zn in the presence of stoichiometric amounts
of CuCN gave higher yields (entry 13) than the procedure
catalytic in copper (entry 15). These procedures (entries 13-15)
gave yields slightly lower than those obtained with the zincate
reagents and catalytic amounts of CuCN (entries 4-7). Reaction
of 1b with Et2Zn in the presence of catalytic amounts of
Cu(OTf)2 and methylphosphite afforded the 1,4-adduct 3f in
low yields at -20 °C (entry 16) and in modest yields at room
temperature (entry 17). These reactions required TMSCl to effect
the conjugate addition reaction (entry 18).
The phosphoramidite catalysts have proven to be very
effective for the asymmetric conjugate addition of organozinc
reagents15 to cyclic enones and dihydropyridones.6a Although
no conjugate addition was observed for 1b when literature
protocols6a for 2,3-dihydro-4-pyridone were followed, very good
yields and ers were obtained upon addition of TMSCl.
Thus, employing binapthol catalyst 6a and Cu(OTf)2 a modest
chemical yield and er (eq 3) was achieved for 3f upon addition
of TMSCl. This crucial observation strongly suggests that
TMSCl does not disrupt the Zn-Cu binuclear metal complex15c
that imparts the facial selectivity, while effectively accelerating
the conjugate addition reaction even in toluene. Both chemical
yields and enantioselectivity could be improved by use of
catalyst 6b. A very small improvement in yield and enantiose-
lectivity was achieved utilizing copper 2-thienylcarboxylate
(CuTC) under optimized conditions recently reported.16 These
results clearly illustrate the significantly greater degree of ligand
accelerated catalysis (LAC) promoted by the phosphoramidite
ligands, since in the absence of the ligand the reaction was
limited to 30% conversion of starting material to conjugate
adduct.
entry N-Boc
reagenta
Cpd no. % yieldb
1
2
3
4
5
6
7
8
1a
1b
1b
1a
1a
1a
1b
1a
1b
1b
1b
1b
1b
1a
1b
1b
nBu3ZnLi
nBu3ZnLi
nBu3ZnLic
2b
3b
3b
2b
2b
2b
3b
2b
3b
3b
3b
3b
3f
57
63
78-81
78e
81
82
83
50
nBuMe2ZnLi/CuCNd
nBu3ZnLi/CuCNd
Bu3ZnLi/CuCNc,d
Bu3ZnLi/CuCNc,d
BuZnMe/CuCNc,d
9
nBuZnBr/CuCN (1.0)
nBuZntBu2Li/CuCN (1.0)
nBuZntBu2Li/CuCN (0.1)
nBuZntBu2Li/CuCN (0.1)
Et2Zn (2.0)/CuCN ·2LiCl (1.0)
Et2Zn (2.0)/CuCN ·2LiCl (1.0)
Et2Zn (2.0)/CuCN ·2LiCl (0.1)
Et2Zn/Cu(OTf)2 (5 mol%)/P(OME)3
(-20 °C)g
70
10
11
12
13
14
15
16
40f
38f
40f
77
2f
65
3f
3f
62
31-42
17
18
1b
1b
Et2Zn/Cu(OTf)2, (5 mol%)/P(OME)3
3f
3f
53-58
(25 °C)g
Et2Zn/Cu(OTf)2 (5 mol%)/P(OMe)3
(-20 °C)g,h
0
a Reagent prepared by adding R1Li to ZnBr2 in the absence or
presence of CuCN unless noted. TMSCl (3.0 equiv) was used unless
noted. b Yields are based upon isolated products purified by column
chromatography. c Allyl bromide (1.0 equiv) was present during the
conjugate addition reaction. d Catalytic amount of CuCN (0.1 equiv) was
employed. e By-product 2a was formed in 18% yield. f Product 3d was
also formed (31%, 31%, 21%, entries 10, 11, and 12 respectively).
g Dichloromethane was used as solvent. h No TMSCl was employed.
We next turned our attention to the conjugate addition
reactions of organozincate and organozinc reagents,14 which are
known to occur both with and without copper catalysis (Table
2). Lithium tri-n-butylzincate underwent conjugate addition to
carbamates 1a-b in comparable and modest yields (entries
1-2). In an effort to achieve tandem conjugate addition-R-
allylation, allyl bromide was added to the reaction mixture after
the addition of the zincate reagent. Surprisingly, although
R-allylation was not achieved, the chemical yields of the
conjugate adduct were increased (entries 1-2 vs 3) to 78-81%.
Higher chemical yields were obtained from the zincate reagents
when 10 mol % of CuCN was employed (entries 4-7), although
the mixed n-butyldimethylzincate/CuCN gave significant amounts
of 2a via competitive methyl transfer (entry 4). The mixed
n
dialkylzinc reagent BuZnMe with copper catalysis (entry 8)
gave significantly lower yields, although the monoalkylzinc
The sense of asymmetric induction was determined by
hydrogenation of 3f to the known (R) tetrahydro-2-ethyl-4-
pyridone.6a
(11) Dieter, R. K.; Guo, F. Org. Lett. 2008, 10, 2097–2090.
(12) (a) Ashby, E. C.; Watkins, J. J. J. Am. Chem. Soc. 1977, 99, 5312–
5317. (b) Ashby, E. C.; Lin, J. J.; Watkins, J. J. J. Org. Chem. 1977, 42, 1099–
1102. (c) Lipshutz, B. H.; Kozlowski, J. A.; Breneman, C. M. J. Am. Chem.
Soc. 1985, 107, 3197–3204. (d) Mobley, T. A.; Muller, F.; Berger, S. J. Am.
Chem. Soc. 1998, 120, 1333–1334.
(13) For reviews see: (a) Gschwind, R. M. Chem. ReV. 2008, 108, 3029–
3053. (b) Nakamura, E.; Yoshikai, N. Bull. Chem. Soc. Jpn. 2004, 77, 1–12.
(14) (a) Watson, R. A.; Kjonaas, R. A. Tetrahedron Lett. 1986, 27, 1437–
1440. (b) Erdik, E. Organozinc Reagents in Organic Synthesis; CRC Press: Boca
Raton, 1996; Chapter 4.
(15) (a) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878. For reviews see: (b) Feringa,
B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim, 2002; Chapter 7, pp 224-258. (c)
Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353. (d) Alexakis, A.; Backvall,
J. E.; Krause, N.; Paimies, O.; Dieguez, M. Chem. ReV. 2008, 108, 2796–2823.
(16) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc.
2002, 124, 5262–5263.
3846 J. Org. Chem. Vol. 74, No. 10, 2009

Addition Reactions of N-Carbamoyl-4-Pyridones
solid CuCN (12 mg, 0.1 equiv, 0.13 mmol) in one portion by
opening the septem and adding the solid quickly. The reaction
mixture was stirred for an additional 20 min at -78 °C and a
mixture of N-Boc-4-pyridone 1b (195 mg, 1.0 mmol) and TMSCl
(325 mg, 3.0 mmol) in THF (3.0 mL)] were added dropwise as a
THF solution at -78 °C. The reaction mixture was allowed to warm
up to room temperature during overnight stirring. Then the reaction
mixture was diluted with dichloromethane (5.0 mL), quenched with
saturated aqueous NH4Cl and extracted with dichloromethane (3
× 10.0 mL). The combined organic phase was dried over anhydrous
MgSO4, filtered, concentrated in vacuo, and purified by flash column
chromatography (silica gel, methanol:dichloromethane, 2:98, v/v)
to give 3a (38 mg, 18%) and 2-n-butyl-2,3-dihydro-N-tert-butoxy-
carbonyl-4-pyridone (3b, 197 mg, 78%): IR (neat) 1718, 1672, 1597
cm-1; 1H NMR δ 0.90 (t, J ) 7.20 Hz, 3 H), 1.18-1.36 (m, 4 H),
1.46-1.52 (m, 1 H), 1.55 (s, 9 H), 1.58-1.69 (m, 2 H), 2.44 (dd,
J ) 1.20, 16.50 Hz, 1 H), 2.80 (dd, J ) 6.60, 16.50 Hz, 1 H),
4.46-4.60 (m, 1 H), 5.28 (d, J ) 8.10 Hz, 1 H), 7.74 (d, J ) 7.80
Hz, 1 H); 13C δ 13.9, 22.4, 28.0, 28.1, 30.0, 39.7, 52.9, 83.2, 106.0,
141.1, 151.3, 193.4; mass spectrum m/z (relative intensity) EI 253
(4, M+), 197 (13), 153 (24), 140 (8), 96 (99), 57 (100). Anal. Calcd
for C14H23NO3: C, 66.37; H, 9.15. Found: C, 66.59; H, 9.27.
Competition Experiments: Conjugate Addition Reactions
of Lithium Dialkylcuprates (R2CuLi, 1.0 equiv) with a 1:1
Mixture of N-Carbamoyl-4-pyridone and 2-Cyclohexenone,
Ethyl Crotonate, or N-Boc-6-methyl-5,6-dihydro-4-Pyridone. To
a THF (3.0 mL) solution of CuCN (89 mg, 1.0 mmol, 1.0 equiv)
and LiCl (85 mg, 2.00 equiv) under argon and cooled to -78 °C,
was added commercially available n-BuLi (0.8 mL, 2.0 mmol, 2.5
M). The solution was stirred for an additional 45 min at -78 °C,
followed by addition of a THF (3.0 mL) solution of N-Boc-4-
pyridone (195 mg, 1.0 mmol), the other R,ꢀ-unsaturated carbonyl
compound (1.0 mmol) and TMSCl (543 mg, 5.0 mmol) at -78
°C. The reaction mixture was allowed to warm to room temperature
overnight with stirring. Then the reaction mixture was diluted with
dichloromethane (5.0 mL), quenched with saturated aqueous NH4Cl,
and extracted with dichloromethane (3 × 10.0 mL). The combined
organic phase was dried over anhydrous MgSO4, filtered, concen-
trated in vacuo, and purified by flash column chromatography (silica
gel, 2% methanol: dichloromethane, v/v) to give 3b and the 1,4-
adduct of the corresponding R,ꢀ-unsaturated carbonyl compounds.
Conjugate Addition of Diethylzinc to N-Boc-4-pyridone
Employing a Chiral Phosphoramidite Ligand and Cu(OTf)2.
A modification of Feringa’s procedure6a was employed. A suspen-
sion of Cu(OTf)2 (0.05 mmol) and phosphoramidite 4b (54 mg,
0.10 mmol) in toluene (5.0 mL, freshly distilled) was stirred under
argon at room temperature for 1 h. The starting 4-pyridone 1b (195
mg, 1.00 mmol) and TMSCl (108 mg, 1.0 mmol) was added and
the mixture was stirred at room temperature for 10 min. Then the
reaction mixture was cooled to -40 °C and Et2Zn (1.50 mmol,
1.36 mL, 1.10 M in tolune) was added dropwise over 10 min. The
reaction mixture was stirred for 12 h at -40 °C, and warmed up to
room temperature and stirred for an additional 12 h. The reaction
mixture was quenched with saturated aqueous NH4Cl solution and
extracted with dichloromethane (3 × 10.0 mL). The combined
organic phase was dried over anhydrous MgSO4, filtered, concen-
trated in vacuo, and purified by flash column chromatography (silica
gel, methanol:dichloromethane, gradient, 0-2:100-98, v/v) to give
pure 3f (168 mg, 75%): IR (neat) 1724, 1670, 1598, cm-1; 1H NMR
δ 0.76 (t, J ) 7.30 Hz, 3 H), 1.39 (s, 9 H), 1.42-1.60 (m, 2 H),
2.30 (d, J ) 16.50 Hz, 1 H), 2.65 (dd, J ) 6.85, 16.50 Hz, 1 H),
4.30 (s, 1 H), 5.12 (d, J ) 7.80 Hz, 1 H), 7.59 (d, J ) 7.80 Hz, 1
H); 13C δ 13.9, 22.4, 28.0, 28.1, 30.0, 39.7, 52.9, 83.2, 106.0, 141.1,
151.3, 193.4; mass spectrum m/z (relative intensity) EI 225 (13,
M+), 210 (0.53), 195 (0.05), 169 (44), 140 (15), 125 (20), 110 (7),
96 (95), 82 (5), 57 (100).
The importance of annulated N-heterocycles prompted an
examination of functionalized zinc cuprates (eq 4). Initial efforts
to effect conjugate addition of the 3-(carboethoxy)propylzinc
reagent 7 to 1b proved unsuccessful. Treatment of 1b with the
mono alkylzinc iodide 7, the 3-carboethoxypropyl(methyl)zinc,
or the 3-carboethoxypropyl(dimethyl)zincate in the presence of
CuCN and LiCl gave only recovered 4-pyridone. Treatment of
EtOC(CH2)3ZnI with catalytic quantities of Me2CuLi · LiCN,
following the Lipshutz transmetalation protocol,17 afford the 1,4-
adduct in 49-53% yield along with 3a (<5%).
Summary
In summary, N-carbamoyl-4-pyridones participate in conju-
gate addition reactions with a variety of organocopper and
organozinc reagents. Procedures catalytic in copper can promote
the conjugate addition reactions of Grignard, trialkylzincate, and
dialkylzinc reagents with N-Boc protected 4-pyridones, and the
catalytic process can be extended to functionalized alkylzinc
halides. Utilization of an enantioenriched phosphoramidite
ligand in the presence of TMSCl can promote the enantiose-
lective conjugate addition of Et2Zn to N-Boc-4-pyridone with
very good enantiomeric excesses. This methodology provides
a direct route to the synthetically important 2-substituted-2,3-
dihydropyridones, which can be utilized for the synthesis of
piperidones, piperidines, indolizidenes, and quinolizidenes.
Experimental Section
Conjugate Addition of Organolithium Reagents to N-Boc-4-
Pyridone in the Presence of 30 mol% of CuCN. To CuCN (0.39
mmol, 35 mg, 30 mol%) in THF (3.0 mL) at -78 °C under argon,
was added PhLi (1.30 mmol, 0.72 mL, 1.80 M) and the mixture
was stirred for 30 min. A solution of 4-pyridone 1b (195 mg, 1.0
mmol), and TMSCl (325 mg, 3.0 mmol) in THF (3.0 mL) was
then added in one addition. The reaction mixture was stirred
overnight and allowed to warm up to room temperature. The
reaction mixture was quenched with saturated aqueous NH4Cl,
extracted with Et2O (3 × 10.0 mL), and the combined organic layers
were dried over anhydrous MgSO4, filtered and evaporated to afford
the crude compound. Purification by flash column chromatography
(MeOH/dichloromethane, 98:2, v/v) afforded pure 2-phenyl-2,3-
dihydro-N-tert-butoxycarbonyl-4-pyridone (3e, 205 mg, 75%): IR
1
(neat) 1723, 1663, 1603 cm-1; H NMR δ 1.43 (s, 9 H), 2.76 (d,
J ) 16.50 Hz, 1 H), 3.12 (dd, J ) 7.30, 16.50 Hz, 1 H), 5.33 (d,
J ) 8.20 Hz, 1 H), 5.63 (d, J ) 6.40 Hz, 1 H), 7.14-7.32 (m, 5
H), 7.95 (d, J ) 7.35 Hz, 1 H); 13C δ 28.0, 41.9, 55.8, 83.8, 107.1,
125.8, 127.9, 128.9, 139.0, 143.1, 151.5, 192.1; mass spectrum m/z
(relative intensity) EI 273 (0.3, M+), 173 (51), 145 (6), 104 (100),
91 (11), 78 (20), 51 (8).
Conjugate Addition Reactions of Mixed Trialkylzincates
[R1(R2)2ZnLi/cat. CuCN] with N-Carbamoyl-4-Pyridones. To
a cold (0 °C) THF (4.0 mL) solution of ZnBr2 (294 mg, 1.30 mmol)
under argon was added a commercially available hexane solution
of n-BuLi (1.30 mmol, 0.52 mL, 2.50 M) and MeLi (2.60 mmol,
1.63 mL, 1.60 M in diethyl ether). The mixture was stirred for 30
min at 0 °C and then cooled to -78 °C, followed by addition of
The enantiomeric excess was determined by chiral HPLC analysis
on a CHIRACEL OD column [cellulose tris(3,5-dimethylphenyl-
carbamate) on silica gel] to be 81% ee (hexane/iPrOH, 99:1 (v/v),
(17) Lipshutz, B. H.; Wood, M. R.; Tirado, R. J. Am. Chem. Soc. 1995,
117, 6126–6127.
J. Org. Chem. Vol. 74, No. 10, 2009 3847

Dieter and Guo
flow rate ) 0.352 mL/min, detection at λ ) 286. The (R)-
enantiomer (major) eluted first with a retention time of 28.3 min
followed by the (S)-enantiomer (minor) at 31.7 min.
NMR δ 1.12 (t, J ) 7.35 Hz, 3 H), 1.42 (s, 9 H), 1.44-1.52 (m,
1 H), 1.52-1.63 (m, 2H), 2.13-2.22 (m, 2H), 2.29 (d, J ) 16.50
Hz, 1 H), 2.70 (dd, J ) 6.90, 16.50 Hz, 1 H), 3.99 (q, J ) 7.35
Hz, 2 H), 4.43 (s, 1 H), 5.15 (d, J ) 6.45 Hz, 1 H), 7.61 (s, 1 H);
13C δ 14.3, 21.4, 28.1, 30.1, 33.9, 40.0, 52.7, 60.4, 83.6, 106.2,
142.2, 151.3, 173.0, 193.2; mass spectrum m/z (relative intensity)
EI 311 (0.02, M+), 281 (0.2), 224 (0.05), 210 (30), 182 (0.89), 166
(13), 136 (5), 124 (6), 110 (6), 96 (100), 68 (15), 55 (8). 2-Methyl-
2,3-dihydro-N-Boc-4-pyridone 3a (25 mg, 12%) was isolated as
minor product.
2-(4-Ethoxycarbonylbutyl)-2,3-dihydro-N-tert-butoxycarbo-
nyl-4-pyridone (8). Using a modification of Lipshutz’s procedure,17
4-ethoxycarbonylbutylzinc bromide (1.20 mmol, 2.40 mL, 0.50 M
in THF) was added to a cold (-78 °C) THF solvent (3.0 mL) under
argon, whereupon MeLi (1.20 mmol, 0.75 mL of 1.60 M in diethyl
ether) was added and the mixture was stirred for 45 min. At the
same time dimethyl cuprate was prepared by adding MeLi (0.48
mmol, 0.30 mL of 1.60 M in diethyl ether) to CuCN (43 mg, 0.48
mmol) in THF (2.0 mL) in a separate flask at -78 °C and stirring
for 45 min. The dimethyl cuprate solution was transferred via
syringe into the flask containing the zinc reagent and the reaction
mixture was stirred for 10 min at -78 °C. The cooling bath was
then removed and N-Boc-4-pyridone 1b [(195 mg, 1.0 mmol
premixed with TMSCl (326 mg, 3.0 mmol) in THF (3.0 mL)] was
added immediately in one addition. The reaction mixture was stirred
overnight, diluted with dichloromethane (5.0 mL), quenched with
saturated aqueous NH4Cl, and extracted with dichloromethane (3
× 10.0 mL). The combined organic phase was dried over anhydrous
MgSO4, filtered, concentrated in vacuo, and purified by flash column
chromatography (silica gel, 2% methanol: dichloromethane, v/v)
Acknowledgment. This work was generously supported by
the ACS-Petroleum Research Fund (42853-AC1). The NSF
Chemical Instrumentation Program supported purchase of a
JEOL 500 MHz NMR instrument (CHE-9700278).
Supporting Information Available: General experimental
information, materials, general procuedures, data reduction, and
1H and 13C NMR spectra for 2a-f, 3(a,c,d), and 2-n-butyl-6-
methyl-N-Boc-4-piperidinone. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
to give 8 (165 mg, 53%): IR (neat) 1722, 1670, 1601 cm-1; H
JO900327Q
3848 J. Org. Chem. Vol. 74, No. 10, 2009