Aza Diels-Alder reactions utilizing 4-iodo-2-trimethylsilyloxy-butadiene

Article abstract of DOI:10.1016/j.tet.2005.10.018

The aza Diels-Alder reaction is described for a novel diene. Imines bearing benzyl and aromatic protecting groups both work well. Moderate diastereoselectivities can be obtained using the simple α-methylbenzyl chiral auxiliary.

Full text of DOI:10.1016/j.tet.2005.10.018

Tetrahedron 61 (2005) 11837–11842
Aza Diels–Alder reactions utilizing
4-iodo-2-trimethylsilyloxy-butadiene
*
Cody Timmons, Adiseshu Kattuboina, Lauren McPherson, James Mills and Guigen Li
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
Received 3 August 2005; revised 27 September 2005; accepted 10 October 2005
Available online 2 November 2005
Abstract—The aza Diels–Alder reaction is described for a novel diene. Imines bearing benzyl and aromatic protecting groups both work
well. Moderate diastereoselectivities can be obtained using the simple a-methylbenzyl chiral auxiliary.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
limited number of methods available for the removal of
N-aryl protecting groups. A practically attractive alternative
would be the use of more easily cleaved protecting group,
such as tosyl2f or benzyl.
The aza Diels–Alder reaction is among the most powerful
methodologies for the construction of six-membered
nitrogen heterocycles. Such compounds are of interest in
the field of medicinal chemistry and have emerged as
important building blocks in organic synthesis.1
Recently, we have reported the preparation of a novel iodo
diene from the reaction of 3-butyn-2-one and trimethylsilyl
iodide (Scheme 1).5 The diene has been characterized in situ
by performing the reaction in deuterated solvent. This diene
has been found to react with aldehydes in an aldol type fashion
in either the absence or in the presence of an appropriate
catalyst to produce the resulting halo-aldol type products in
high yield and E/Z stereoselectivity. Such products contain
several sites of functionalization and therefore are quite
versatile synthetic intermediates. In an effort to extend the
scope of this process, we sought to utilize imines as
electrophilicacceptorstoprovidetheanalogoushalo-Mannich
type products. Such a reaction would complement our earlier
methodology in which normal asymmetric halo-Mannich type
products were obtained from the reaction between chiral
cyclopropyl imides and imines in the presence of Et2AlI
and were cyclized to five-membered N-heterocycles.6
Recently, a few reports have surfaced regarding the reaction
of Danishefsky’s diene and imines to produce dihydro-
pyridones.2 Such products are potentially quite versatile
intermediates for the synthesis of N-heterocyclic natural
products, such as indolizidines and related alkaloids.3
Additionally, the enantioselective conjugate addition of
nucleophiles to dihydropyridones has recently emerged as
an important topic of interest in the field of asymmetric
synthesis.4
As a whole, the majority of the Diels–Alder strategies for
the preparation of dihydropyridones have utilized imines
prepared from aniline or other similar aromatic amines.
Such a strategy presents challenges with regard to the
OH
O
O
TMSO
RCHO
R
+
TMSI
I
I
Scheme 1.
Keywords: Aza Diels–Alder; Dihydropyridones; Magnesium iodide.
*
Corresponding author. Tel.: C1 806 742 3015; fax: C1 806 742 1289; e-mail: guigen.li@ttu.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.018

11838
C. Timmons et al. / Tetrahedron 61 (2005) 11837–11842
2. Results and discussion
completion.7 However, with 100% Lewis acid loading the
reaction proceeded to completion in 22 h at 0 8C in CH2Cl2
1
as monitored by H NMR analysis of the crude reaction
Initial attempts at this halo-Mannich reaction utilized the
benzenesulfonyl-protected imine of 4-tolualdehyde. In the
absence of catalyst, the desired product was formed in 20%
yield after 24 h at 0 8C in CH2Cl2. The reaction was clean,
with only starting materials and products observed in the
crude reaction mixture. The structure of the product was
mixtures. Furthermore, a 2 to 1 ratio of diene to imine was
found to be favorable for reasonable reaction rates and high
yields. It should be noted that a 1:1 ratio of diene to imine
did not result in the complete consumption of imine even
after 48 h at 0 8C. With regard to solvents, both THF and
toluene work, albeit with somewhat diminished yields.
Acetonitrile was found to give unsatisfactory results.
confirmed by H, 13C, DEPT and 2-D NMR techniques
(COSY and HMQC). In particular, a doublet at 5.56 ppm
in the H NMR spectrum was easily assigned as an N–H
1
1
proton. In an effort to improve the yield, various conditions
were explored. Extended reaction times did not lead to an
increased conversion percentage. The use of other solvents
(THF, ether, acetonitrile, toluene) failed to facilitate any
improvements. When a number of Lewis acid catalysts
(TiCl4, SnCl4, MgI2, Et2AlI) were screened, only the first
two produced any product at all, while the use of the others
all resulted in no product formation. Unfortunately, even
with high catalyst loading (up to 100%) the highest yield
obtained was w35–40%. The use of 4-tosyl and 2-nosyl
protecting groups were found to provide similar results.
In light of the above results, the optimized reaction
conditions were found to be as follows: 2.0 equiv
iodosilyloxy diene (prepared by stirring 3-butyn-2-one and
TMSI in dry CH2Cl2 at 0 8C for 30 min under an inert
atmosphere) were added to benzyl-protected imine
(1.0 equiv) and MgI2 (1.0 equiv) in CH2Cl2 under an inert
atmosphere. The reaction was stirred at 0 8C for 22 h
before being quenched with 1 N HCl and subjected to
standard extractive workup. The results of this reaction
process utilizing a variety of benzyl-protected imines8 are
summarized in Table 1.
With these initial discouraging results in hand, we then
turned our attention to utilizing other protecting groups.
When the imine prepared from 4-tolualdehyde and benzyl
amine was used as the electrophilic acceptor, we were
pleased to find that a similar product was obtained.
Interestingly, though, in the 1H NMR spectrum the presence
of an N–H proton was conspicuously lacking. Closer
inspection showed a molecular weight of 277 amu by
GC/MS analysis and a carbonyl stretching vibration of
1638 cmK1 in the FTIR spectrum, which is consistent with
an amide, or its vinylogous analog. Such results are
indicative of the formation of a benzyl-protected aza
Diels–Alder product (Scheme 2).
As can be seen from Table 1, imine substrates bearing
nearly electroneutral or even strongly electron-withdrawing
substituents all worked very well. On the other hand,
attempts at using the imine prepared from 4-anisaldehyde,
which bears the strongly electron-donating methoxy
group, resulted in low conversion and the formation of
only a trace amount of product. Additionally, the use of
benzyl imine prepared from 2-tolualdehyde failed to result
in any product at all, presumably due to unfavorable steric
interactions.
After establishing this protocol for the synthesis of N-benzyl
aza Diels–Alder products, we then turned our attention to
other N-protecting groups in order to explore the generality
of this process. We were pleased to find that a number of
imines with N-aromatic groups all worked well for this
reaction. Furthermore, these imines were found to be more
reactive, giving typically higher yields in shorter reaction
Encouraged by these results, attention was turned to
optimizing this process. Again a variety of potential Lewis
acid catalysts were screened and MgI2 was found to be
optimal. Unfortunately, it was found that substoichiometric
loadings of MgI2 failed to promote the reaction to
NHPg
O
no cat.
I
Pg = Bs
O
NPg
+ TMSI
+
O
MgI2
N
Pg
Pg = Bn
Scheme 2.

C. Timmons et al. / Tetrahedron 61 (2005) 11837–11842
11839
times (12 h rather than 22 h). The results are summarized in
Table 2.
Initial attempts at utilizing the chiral p-tolylsulfinyl
protecting group repeatedly resulted in no reaction. In all
instances starting materials were quantitatively recovered
intact. We then turned our attention to the simpler chiral
imines derived from (S)-a-methylbenzyl amine since this
type of imine bears a strong resemblance to the benzyl
protected imines. Fortunately, when the corresponding
imine prepared from benzaldehyde was utilized, the two
possible diastereomers were isolated in moderate yield.
Furthermore, the two diastereomers, obtained in a 3:1 ratio,
were readily separated and isolated in diastereomerically
pure form by column chromatography.12 In light of these
results, several chiral imines were prepared and subjected to
these conditions. The results are summarized in Table 3.
Table 1. Results of aza Diels–Alder reaction using Bn-protected imines
O
O
MgI2
+
TMSI +
R
NBn
CH2Cl2, N2, 0 °C
N
R
Bn
Entry
R
Product
Yielda
1
2
3
4
5
6
7
Ph–
1a
2a
3a
4a
5a
6a
7a
77
84
91
88
86
85
79
4-Me-C6H4–
4-CF3–C6H4–
4-NO2–C6H4–
4-F–C6H4–
4-Cl–C6H4–
4-Br–C6H4–
Table 3. Results of diastereoselective aza Diels–Alder reaction
O
O
Me
MgI2
+ TMSI +
a Yield of pure product after column chromatography.
CH2Cl2, N2, 0 °C
N
Ph
R
N
R
Table 2. Results of aza Diels–Alder reaction using aromatic protecting
groups
Ph
Me
O
Entry
R
Product
Diastereo-
selectivitya
Yieldb
O
MgI2
+ TMSI +
1
2
3
4
5
6
Ph–
1e
3e
6e
8e
9e
10e
3:1
3:1
3:1
4.5:1
4:1
4:1
61
84
72
62
82
85
R
NAr
CH2Cl2, N2, 0 °C
4-CF3–C6H4–
4-Cl–C6H4–
n-Pr–
3-NO2–C6H4–
2,4-(NO2)2–C6H3–
N
R
Ar
Entry
R
Ar
Product
Yielda
a Determined by 1H NMR analysis of the crude reaction mixture.
b Combined yield of
chromatography.
2 isomers after purification by column
1
2
3
4
Ph–
Ph–
Ph–
4-Br–C6H4–
4-MeO–C6H4–
1b
6b
6c
87
90
94
94
4-Cl–C6H4–
4-Cl–C6H4–
4-Cl–C6H4–
6d
As can be seen from Table 3, a number of electroneutral and
electron-poor substrates are tolerated in this process.
Moderate diastereoselectivities were observed, however, it
is important to note that all products were readily separable
with standard column chromatography techniques. Of
particular interest in Table 3 are entries 4 and 5, in which
aliphatic and meta-substituted aromatic imines were
successfully utilized as substrates for the aza Diels–Alder
reaction. Furthermore, a 2,4-disubstituted substrate (entry 6)
was also found to work well if the groups were strongly
electron withdrawing. Comparison of Tables 1 and 3
demonstrates that these a-methylbenzyl imines are slightly
less reactive than the corresponding benzyl imines,
presumably due to increased steric bulk.
a Yield of pure product after column chromatography.
Due to the large demand for chiral heterocyclic building
blocks, efficient routes to asymmetric dihydropyridones are
quite important in organic chemistry. Several chiral
catalysts were screened with the hopes of developing an
enantioselective aza Diels–Alder reaction. Binol–TiCl2
complex alone failed to produce any desired Diels–Alder
product. Interestingly, both isopropyl-Pybox/MgI2 complex
and isopropyl-Pybox/Cu(OTf)2 complex failed to promote
the aza Diels–Alder reaction with benzyl imines, but both
did effectively promote the reaction with aromatic-protected
imines. Unfortunately, the products from both reactions
were racemic. Interestingly, the use of BinolBOPh2b did
result in the formation of the product in !40% yield, but no
enantioselectivity was observed. With these results in hand,
attention was then turned to focus on chiral auxiliary-
controlled processes.
With regard to mechanism, two possibilities seem plausible.
A [4C2] cycloaddition followed by elimination of iodine
would constitute the typical Diels–Alder pathway. Alter-
natively, it has been shown in similar reactions utilizing
Danishefsky’s diene that such reactions occur via a
Mannich/cyclization pathway.2d,f A mechanistic study is
currently underway and relevant results will be disclosed in
due course.
To date, the majority of diastereomerically controlled aza
Diels–Alder reactions have been performed utilizing chiral
imines derived from sugars,9 amino esters,10 or chiral amino
alcohols.11 Unfortunately, these products often suffer from
the difficulty in removing the protecting group. With this in
mind, we sought to extend the scope of this reaction to
substrates bearing chiral auxiliaries that are easily removed.
In summary, a new method for the synthesis of dihydro-
pyridones has been reported. The reaction is tolerant
of a variety of substrates, including N-benzyl- and

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C. Timmons et al. / Tetrahedron 61 (2005) 11837–11842
N-aryl-protected imines. Attempts at rendering the reaction
asymmetric have been successful. Importantly, this work
represents the first Diels–Alder type reaction with this new
class of iodo-diene.
1H), 2.80 (dd, JZ7.0, 16.5 Hz, 1H), 2.68 (dd, JZ8.5,
16.5 Hz, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3):
190.6, 154.1, 138.1, 136.0, 135.6, 129.7, 128.9, 128.2,
127.7, 127.1, 98.7, 60.5, 57.1, 43.8, 21.1. FTIR:
1638.0 cmK1. GC/MS: m/zZ277 (MC, 91%), 249 (25%),
186 (26%), 118 (74%), 91 (100%). Calculated for
C19H19NO: MCZ277.
3. Experimental
3.1. General methods
3.3.3. N-Benzyl-2,3-dihydro-2-(4-trifluoromethylphenyl)-
4-pyridone (3a). Isolated as an oil. H NMR (500 MHz,
1
All reactions were performed in oven-dried glassware.
Dichloromethane was purified and dried via an Alumina
column immediately prior to use. NMR spectra were
recorded on a Varian Inova NMR spectrometer operating
at 500 MHz (1H) and 125 MHz (13C) or on a Varian
Mercury NMR spectrometer operating at 300 MHz (1H) and
75 MHz (13C). Shift values are reported in ppm and are
referenced based on TMS or solvent for 1H and 13C,
respectively. All spectra were recorded in CDCl3. 19F NMR
spectra, where applicable, were recorded in CDCl3 and
shifts are reported based on an external TFA reference.
Imines were prepared according to standard methods. All
other commercially available chemicals were used without
further purification and stoichiometries were calculated by
the purities reported by the manufacturers. Purification was
performed by flash chromatography on silica gel (Merck 60,
230–400 mesh). IR spectra were recorded as CH2Cl2
deposits on a NaCl disk. Unless otherwise indicated, optical
rotations were performed in CH2Cl2 with a concentration
of 0.5.
CDCl3): 7.63–7.60 (m, 2H), 7.39–7.32 (m, 6H), 7.15–7.13
(m, 2H), 5.11 (d, JZ7.5 Hz, 1H), 4.56 (t, JZ7.5 Hz, 1H),
4.40 (d, JZ15 Hz, 1H), 4.12 (d, JZ15 Hz, 1H), 2.90
(dd, JZ7.0, 16.5 Hz, 1H), 2.62 (dd, JZ7.0, 16.5 Hz, 1H).
19F NMR (212.3 MHz, CDCl3): K63.06 (s). 13C NMR
(125 MHz, CDCl3): 189.5, 153.9, 142.6, 135.5, 130.6
(q, JZ32.1 Hz), 129.1, 128.4, 127.7, 127.4, 126.0 (q, JZ
1.9 Hz), 123.8 (q, JZ270.5 Hz), 99.1, 60.0, 43.3. FTIR:
1638.9 cmK1. HRMS MHC: expected: 332.1257 found:
332.1266.
3.3.4. N-Benzyl-2,3-dihydro-2-(4-nitrophenyl)-4-pyridone
(4a). Isolated as an oil. 1H NMR (500 MHz, CDCl3):
8.23–8.20 (m, 2H), 7.44–7.41 (m, 2H), 7.37–7.34 (m, 4H),
7.15–7.13 (m, 2H), 5.13 (d, JZ7.5 Hz, 1H), 4.61 (t, JZ
7.0 Hz, 1H), 4.44 (d, JZ15 Hz, 1H), 4.12 (d, JZ15 Hz,
1H), 2.93 (dd, JZ7.0, 16.5 Hz, 1H), 2.61 (dd, JZ7.0,
16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): 189.0, 153.8,
147.8, 145.9, 135.2, 129.1, 128.6, 127.9, 127.6, 124.3, 99.4,
59.7, 57.9, 43.0. FTIR: 1637.5 cmK1. HRMS MHC:
expected: 309.1234 found: 309.1224.
3.2. Procedure for the aza Diels–Alder reaction
3.3.5. N-Benzyl-2,3-dihydro-2-(4-fluorophenyl)-4-pyridone
(5a). Isolated as an oil. 1H NMR (500 MHz, CDCl3):
7.38–7.31 (m, 3H), 7.29 (d, JZ7.5 Hz, 1H), 7.23–7.20
(m, 2H), 7.13–7.10 (m, 2H), 7.06–7.01 (m, 2H), 5.09 (d, JZ
7.5 Hz, 1H), 4.48 (t, JZ7.5 Hz, 1H), 4.35 (d, JZ15 Hz,
1H), 4.01 (d, JZ15.5 Hz, 1H), 2.83 (dd, JZ7.0, 16.5 Hz,
1H), 2.64 (dd, JZ7.5, 16.5 Hz, 1H). 19F NMR (212.3 MHz,
CDCl3): K113.86 (m). 13C NMR (125 MHz, CDCl3):
190.1, 162.5 (d, JZ245.9 Hz), 154.1, 135.7, 134.4 (d, JZ
3.4 Hz), 129.0, 128.8, 128.6 (d, JZ68.6 Hz), 127.6, 115.9
Into a dried, N2 flushed vial was added CH2Cl2 (2.0 mL),
3-butyn-2-one (1.1 mmol), and iodotrimethylsilane
(1.0 mmol) at 0 8C. Concurrently, into another dried, N2
flushed vial containing 0.5 mmol MgI2 was added imine
(0.5 mmol) and 2 mL CH2Cl2. Both vials were stirred for
30 min at 0 8C, at which time the contents of the first vial
were transferred to the second via syringe. The reaction was
stirred at 0 8C under N2 atmosphere until completion
1
was observed by H NMR analysis, at which time it was
(d, JZ21.6 Hz), 98.8, 59.9, 57.3, 43.7. FTIR: 1637.9 cmK1
.
quenched with 5 mL 1 M HCl. The mixture was extracted
with CH2Cl2, washed with brine, and dried over anhydrous
Na2SO4. The crude extract was concentrated to dryness
and directly subjected to column chromatography (EtOAc/
hexane, 1:3/3:1) to afford the pure product.
HRMS MHC: expected: 282.1289 found: 282.1290.
3.3.6. N-Benzyl-2,3-dihydro-2-(4-chlorophenyl)-4-pyridone
(6a). Isolated as an oil. 1H NMR (500 MHz, CDCl3):
7.38–7.31 (m, 5H), 7.29 (d, JZ7.5 Hz, 1H), 7.20–7.17
(m, 2H), 7.14–7.11 (m, 2H), 5.09 (d, JZ7.5 Hz, 1H), 4.47
(t, JZ7.5 Hz, 1H), 4.36 (d, JZ15.5 Hz, 1H), 4.10 (d, JZ
15 Hz, 1H), 2.83 (dd, JZ7.0, 16.5 Hz, 1H), 2.62 (dd, JZ
8.0, 16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): 189.9,
154.0, 137.1, 135.6, 134.1, 129.2, 129.0, 128.5, 128.3,
127.7, 99.0, 59.9, 57.4, 43.5. FTIR: 1637.7 cmK1. HRMS
MHC: expected: 298.0993 found: 298.0988.
3.3. Spectroscopic data
3.3.1. N-Benzyl-2,3-dihydro-2-phenyl-4-pyridone (1a).
This is a known compound. 1H NMR spectral data are
consistent with literature values.2b 1H NMR (300 MHz,
CDCl3): 7.40–7.10 (m, 11H), 5.08 (d, JZ7.8 Hz, 1H), 4.50
(t, JZ7.5 Hz, 1H), 4.35 (d, JZ15.3 Hz, 1H), 4.13 (d, JZ
15.0 Hz, 1H), 2.85 (dd, JZ7.2, 16.5 Hz, 1H), 2.68 (dd, JZ
7.8, 16.5 Hz, 1H).
3.3.7. N-Benzyl-2,3-dihydro-2-(4-bromophenyl)-4-pyridone
(7a). Isolated as an oil. 1H NMR (500 MHz, CDCl3):
7.50–7.47 (m, 2H), 7.38–7.33 (m, 3H), 7.29 (d, JZ7.5 Hz,
1H), 7.14–7.11 (m, 4H), 5.09 (d, JZ8.0 Hz, 1H), 4.46
(t, JZ7.5 Hz, 1H), 4.36 (d, JZ15.5 Hz, 1H), 4.10 (d, JZ
15 Hz, 1H), 2.83 (dd, JZ7.0, 16.5 Hz, 1H), 2.62 (dd, JZ
8.0, 16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): 189.9,
3.3.2. N-Benzyl-2,3-dihydro-2-(4-methylphenyl)-4-
pyridone (2a). Isolated as an oil. 1H NMR (500 MHz,
CDCl3): 7.37–7.30 (m, 3H), 7.27 (d, JZ8.0 Hz, 1H),
7.17–7.12 (m, 6H), 5.08 (d, JZ7.5 Hz, 1H), 4.46 (t, JZ
7.5 Hz, 1H), 4.32 (d, JZ15 Hz, 1H), 4.12 (d, JZ15.5 Hz,

C. Timmons et al. / Tetrahedron 61 (2005) 11837–11842
11841
154.0, 137.6, 135.6, 132.2, 129.0, 128.8, 128.3, 127.7,
122.2, 99.0, 60.0, 57.4, 43.5. FTIR: 1637.7 cmK1. HRMS
MHC: expected: 342.0488 found: 342.0477.
CDCl3): 189.5, 151.8, 143.7, 139.5, 130.5 (q, JZ32.6 Hz),
129.0, 128.4, 127.3, 127.2, 126.1 (q, JZ3.9 Hz), 123.8
(q, JZ270.5 Hz), 99.9, 60.5, 59.6, 43.6, 17.9. FTIR:
1637.9 cmK1. [a]D24 K90.4. HRMS MHC: expected:
346.1413 found: 346.1410.
3.3.8. N-Phenyl-2,3-dihydro-2-phenyl-4-pyridone (1b).
This is a known compound. 1H NMR spectral data are
consistent with literature values.2g 1H NMR (500 MHz,
CDCl3): 7.68 (dd, JZ1.0, 7.5 Hz, 1H), 7.34–7.26 (m, 7H),
7.12–7.09 (m, 1H), 7.03–7.01 (m, 2H), 5.30–5.27 (m, 2H),
3.31 (dd, JZ7.5, 16.5 Hz, 1H), 2.79 (ddd, JZ1.0, 3.0,
16.5 Hz, 1H).
3.3.14. (2R)-2,3-Dihydro-N-(S)-a-methylbenzyl-2-(4-
chlorophenyl)-4-pyridone (6e). Isolated as an oil. 1H
NMR (500 MHz, CDCl3): 7.40–7.31 (m, 7H), 7.28–7.26 (m,
2H), 7.09 (d, JZ7.5 Hz, 1H), 5.04 (d, JZ7.5 Hz, 1H), 4.66
(dd, JZ7.0, 7.0 Hz, 1H), 4.44 (q, JZ7.0 Hz, 1H), 2.82 (dd,
JZ7.0, 16.5 Hz, 1H), 2.61 (dd, JZ8.0, 16.5 Hz, 1H), 1.47 (d,
JZ7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): 189.9, 151.8,
139.6, 138.1, 134.1, 129.3, 128.9, 128.3, 1228.2, 127.3, 99.8,
59.83, 59.80, 43.9, 17.7. FTIR: 1637.6 cmK1. [a]D24 K175.5.
HRMS MHC: expected: 312.115 found: 312.1144.
3.3.9. N-Phenyl-2,3-dihydro-2-(4-chlorophenyl)-4-pyridone
(6b). This is a known compound. 1H NMR spectral data are
consistent with literature values.2g 1H NMR (500 MHz,
CDCl3): 7.65 (dd, JZ1.0, 7.5 Hz, 1H), 7.33–7.29 (m, 4H),
7.22–7.19 (m, 2H), 7.14–7.11 (m, 1H), 7.05–6.99 (m, 2H),
5.29 (dd, JZ1.0, 8.0 Hz, 1H), 5.26 (dd, JZ3.0, 7.0 Hz, 1H),
3.29 (dd, JZ7.5, 16.5 Hz, 1H), 2.74 (ddd, JZ1.0, 3.5,
16.5 Hz, 1H).
3.3.15. (2R)-2,3-Dihydro-N-(S)-a-methylbenzyl-2-n-
propyl-4-pyridone (8e). This is a known compound.2b
1H NMR spectral and optical rotation data are consistent
with literature values. 1H NMR (300 MHz, CDCl3):
7.50–7.30 (m, 5H), 6.90 (d, JZ7.2 Hz, 1H), 4.87 (d, JZ
7.2 Hz, 1H), 4.56 (q, JZ6.9 Hz, 1H), 3.51–3.61 (m, 1H),
2.68 (dd, JZ6.6, 16.2 Hz, 1H), 2.32 (dd, JZ2.7, 16.2 Hz,
1H), 2.10–1.90 (m, 1H), 1.66 (d, JZ6.9 Hz, 3H), 1.52–1.20
(m, 3H), 0.92 (t, JZ7.2 Hz, 3H). [a]2D4: lit: C163.1, Found:
C161.8 (c 1.0, CHCl3).
3.3.10. N-(4-Bromophenyl-2,3-dihydro-2-(4-chlorophenyl)-
4-pyridone (6c). Isolated as an oil. H NMR (500 MHz,
1
CDCl3): 7.58 (dd, JZ1.0, 8.0 Hz, 1H), 7.42–7.40 (m, 2H),
7.32–7.29 (m, 2H), 7.19–7.17 (m, 2H), 6.89–6.85 (m, 2H),
5.31 (dd, JZ0.5, 8.0 Hz, 1H), 5.21 (dd, JZ3.0, 7.0 Hz, 1H),
3.27 (dd, JZ7.0, 16.5 Hz, 1H), 2.75 (ddd, JZ1.0, 3.0,
16.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): 189.7, 147.5,
143.5, 136.1, 134.0, 132.6, 129.4, 127.5, 120.1, 117.5,
103.8, 61.2, 43.3. FTIR: 1650.4 cmK1. HRMS MHC:
expected: 361.9942 found: 361.9933.
3.3.16. (2R)-2,3-Dihydro-N-(S)-a-methylbenzyl-2-
(3-nitrophenyl)-4-pyridone (9e). Isolated as an oil.
1H NMR (500 MHz, CDCl3): 8.17–8.15 (m, 2H), 7.69–7.67
(m, 1H), 7.56–7.51 (m, 1H), 7.41–7.33 (m, 3H), 7.29–7.27
(m, 3H), 5.09 (d, 1H, JZ8.0 Hz), 4.77 (dd, 1H, JZ5.5,
7.0 Hz), 4.54 (q, 1H, JZ7.0 Hz), 2.95 (dd, 1H, JZ7.5,
16.5 Hz), 2.55 (dd, 1H, JZ5.5, 16.5 Hz), 1.52 (d, 3H, JZ
7.0 Hz). 13C NMR (125 MHz, CDCl3): 188.8, 151.6, 148.5,
141.8, 139.3, 132.7, 130.2, 129.0, 128.5, 127.1, 123.1,
3.3.11. N-(4-Methoxyphenyl-2,3-dihydro-2-(4-chloro-
phenyl)-4-pyridone (6d). Isolated as an oil. 1H NMR
(500 MHz, CDCl3): 7.52 (dd, JZ1.0, 7.5 Hz, 1H),
7.29–7.26 (m, 2H), 7.21–7.19 (m, 2H), 6.95–6.92 (m, 2H),
6.83–6.80 (m, 2H), 5.23 (dd, JZ1.0, 7.5 Hz, 1H), 5.16 (dd,
JZ4.0, 7.0 Hz, 1H), 3.77 (s, 3H), 3.24 (dd, JZ7.5, 16.5 Hz,
1H), 2.72 (ddd, JZ1.0, 4.0, 16.5 Hz). 13C NMR (125 MHz,
CDCl3): 189.7, 157.0, 149.5, 138.1, 136.8, 133.7, 129.1,
127.8, 121.2, 114.7, 101.8, 61.9, 55.5, 43.3. FTIR:
1646.6 cmK1. HRMS MHC: expected: 314.0942 found:
314.0936.
121.8, 99.9, 61.4, 58.8, 43.2, 18.3. FTIR: 1637.9 cmK1
.
[a]2D4 K69.2. HRMS MClK: expected: 357.1011 found:
357.1017.
3.3.17. (2R)-2,3-Dihydro-N-(S)-a-methylbenzyl-2-(2,4-
dinitrophenyl)-4-pyridone (10e). Isolated as an oil. 1H
NMR (500 MHz, CDCl3): 8.74 (d, 1H, JZ2.5 Hz), 8.32 (dd,
1H, JZ2.5, 9.0 Hz), 7.92 (d, 1H, JZ8.5 Hz), 7.44 (dd, 1H,
JZ1.0, 7.5 Hz), 7.36–7.29 (m, 3H), 7.20–7.19 (m, 2H), 5.48
(dd, 1H, JZ2.5, 9.0 Hz), 5.12 (dd, 1H, JZ1.0, 8.0 Hz), 4.54
(q, 1H, JZ7.0 Hz), 3.13 (dd, 1H, JZ9.0, 17.0 Hz), 2.43 (dd,
1H, JZ2.5, 17.0 Hz), 1.54 (d, 3H, JZ7.0 Hz). 13C NMR
(125 MHz, CDCl3): 180.1, 151.4, 147.4, 147.3, 141.9,
138.9, 130.5, 129.2, 128.8, 127.2, 126.8, 120.7, 99.4, 63.2,
53.9, 41.3, 18.9. FTIR: 1637.8 cmK1. [a]D24 K195.0. HRMS
MHC: expected: 368.1241 found: 368.1232.
3.3.12. (2R)-2,3-Dihydro-N-(S)-a-methylbenzyl-2-phenyl-
4-pyridone (1e). This is a known compound. 1H NMR
spectral and optical rotation data are consistent with
literature values.2b 1H NMR (300 MHz, CDCl3):
7.26–7.45 (m, 10H), 7.04 (d, JZ7.8 Hz, 1H), 5.04 (d, JZ
7.8 Hz, 1H), 4.70 (dd, JZ6.6, 9.0 Hz, 1H), 4.43 (q, JZ
6.9 Hz, 1H), 2.82 (dd, JZ6.9, 16.5 Hz, 1H), 2.71 (dd,
JZ9.0, 16.5 Hz, 1H), 1.47 (d, JZ6.9 Hz, 3H). [a]2D4: lit:
K181.7, Found: K177.8 (c 1.7, CHCl3).
3.3.13. (2R)-2,3-Dihydro-N-(S)-a-methylbenzyl-2-(4-tri-
fluoromethylphenyl)-4-pyridone (3e). Isolated as an oil.
1H NMR (500 MHz, CDCl3): 7.62 (d, JZ8.0 Hz, 2H), 7.49
(d, JZ8.0 Hz, 2H), 7.41–7.38 (m, 2H), 7.36–7.32 (m, 1H),
7.29–7.27 (m, 2H), 7.16 (d, JZ7.5 Hz, 1H), 5.06 (d,
JZ7.5 Hz, 1H), 4.73 (dd, JZ7.0, 7.0 Hz, 1H), 4.47 (q, JZ
7.0 Hz, 1H), 2.89 (dd, JZ7.0, 16.5 Hz, 1H), 2.59 (dd, JZ
7.0, 16.5 Hz, 1H), 1.49 (d, JZ7.0 Hz, 3H). 19F NMR
(212.3 MHz, CDCl3): K63.06 (s). 13C NMR (125 MHz,
Acknowledgements
We gratefully acknowledge financial support from the
National Institutes of Health (CA 99995-1) and the Robert
A. Welch Foundation (D-1361).

11842
C. Timmons et al. / Tetrahedron 61 (2005) 11837–11842
Boersma, A. J.; Minnaard, A. J.; Feringa, B. L. Chem.
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