Intramolecular reactivity of trans [4+4] photodimers of 2-pyridones

Article abstract of DOI:10.1055/s-2007-983793

Photodimers of 2-pyridones are cycloocta-1,5-dienes with two lactam bridges. These, and related structures, undergo halogenation to give rearranged products in which an amide nitrogen has intercepted an initial halonium ion. For the trans isomer, a transi

Full text of DOI:10.1055/s-2007-983793

PAPER
2351
Intramolecular Reactivity of trans [4+4] Photodimers of 2-Pyridones
I
ntramolecular
e
Reactivity
i
of tran
l
s
[4+4
i
]
P
hoto
n
dimers of 2-P
g
yridone
s
Chen,a Patrick J. Carroll,b Scott McN. Sieburth*a
a
Department of Chemistry, Temple University, 1901 N. 13th St., Philadelphia, PA 19122, USA
E-mail: scott.sieburth@temple.edu
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
b
Received 8 March 2007
Dedicated to Paul A. Wender on the occasion of his 60th year
R
O
O
Abstract: Photodimers of 2-pyridones are cycloocta-1,5-dienes
with two lactam bridges. These, and related structures, undergo ha-
logenation to give rearranged products in which an amide nitrogen
has intercepted an initial halonium ion. For the trans isomer, a tran-
sient four-membered azetidinium ion reacts via dealkylation, giving
a dihalide-diamide product in high yield. This readily available in-
termediate reacts with nucleophiles in a process that begins with in-
tramolecular amide N-alkylation, reforming the azetidinium
intermediate. Reaction of this intermediate with the nucleophile
can take two different paths, depending on the reversibility of the
nucleophilic attack, with reversible nucleophiles giving N-dealkyl-
ation and irreversible nucleophiles reacting with the carbonyl
group.
N
N
R
N
≡
≡
N
R
R
N
N
N
O
R
O
O
R
O
R
R
O
2
3
trans
hν
O
N
R
N
N
1
O
O
R
R
cis
Cl
R
O
O
Cl
Cl
Key words: cycloadditions, dimerizations, ketones, photochemis-
try, pyridines
N
R
Cl2
N
N
R
≡
≡
2
3
N
Cl
O
O
R
4
5
Photodimerization of 2-pyridones 1 yields highly func-
tionalized cycloocta-1,5-dienes regioselectively and often
with good stereoselectivity (Scheme 1). This singlet-
mediated [4+4] cycloaddition is selective for head-to-tail
isomers 2 and 3, frequently favoring trans-isomer 2
(Scheme 1).1 Procedures for favoring either trans-2 or cis-
3 have been described.2–4
Cl
O
O
N
Cl
Cl2
R
N
Cl
N
R
Cl
O
N
O
R
Scheme 1 Photodimerization of 2-pyridones and chlorination of the
cis- and trans-dimers
Each of these conformationally rigid structures has been
found to undergo transannular reactions with amide nitro-
gen migration when treated with chlorine (Scheme 1).
Treatment of trans-dimer 2 with chlorine results in a 1,3-
migration of one amide nitrogen to yield 4, whereas a sim-
ilar treatment of 3 leads to participation of both alkenes,
creating a diquinane structure 5, whose formation is also
accompanied by migration of an amide nitrogen
(Scheme 1).
Formation of 4 from 2 involves an intermediate chloroni-
um ion 6, in which the chlorine has been added to the
least-hindered face of one alkene group (Scheme 2). This
chloronium ion is then intercepted by the amide nitrogen
that lies on the other side. The resulting azetidinium amide
7 is reminiscent of a von Braun intermediate, primed to
undergo dealkylation.8,9 Three possible bonds can be bro-
ken in the next step, following paths a, b, and c
(Scheme 2). In terms of orbital overlap, path a initially ap-
peared to be the most likely; however, this potential prod-
uct 8 is not observed, possibly because of the electro-
negative influence of the neighboring chloride. The von
Braun reaction is well known for dealkylation of cyclic
amines. This path b, however, would lead to the frustrated
amide 9, and it also not observed. Path c appears less ob-
vious, but leads to the sole product 4 that is isolated
(Scheme 2). Initially it was believed that the allylic nature
of this position led to this site of reactivity; however, the
actual reason is apparently more subtle (see below).
Diquinane 5 has obvious applications in natural product
synthesis,5,6 but is derived from the less stable dimer 3 and
is formed in moderate yield. In contrast, product 4 forms
in high yield from the most common and most stable
dimer 2. We describe here groundwork for the use of this
readily available intermediate: investigations into the ha-
logenation of trans-2 and related structures, and the reac-
tivity of nucleophiles with product 4, which contains both
an allylic and a non-allylic secondary halide. A prelimi-
nary report on this work has appeared.7
SYNTHESIS 2007, No. 15, pp 2351–2359
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983793; Art ID: C01407SS
© Georg Thieme Verlag Stuttgart · New York
Three N-alkylpyridone dimers have been subjected to ha-
logenation (Scheme 3, Table 1). Addition of chlorine to

2352
P. Chen et al.
PAPER
O
N
O
N
a
Cl
O
Cl
Cl
Cl
O
N
O
N
Cl
Cl
R
Cl
R
n-Bu
n-Bu
NaOEt
c
R
R
Cl2
N
b
N
n-Bu
n-Bu
EtOH
95%
2
N
N
O
O
4a
10a
a
O
O
6
7
4
b
NaOEt
c
O
Cl
Cl
Cl
O
N
O
O
N
Cl
Cl
Cl
n-Bu
H2
Pd/C
N
H2
Pd/C
99%
60%
Cl
R
R
R
N
N
n-Bu
Cl
N
N
N
R
R
O
7a
O
O
O
8
9
O
N
O
N
Cl
O
Scheme 2 Mechanism for chlorination of the trans-dimer 2
n-Bu
n-Bu
NaOEt
Cl
N
N
N
n-Bu
n-Bu
EtOH
99%
the N-butyl dimer 2a gave product 4a in almost quantita-
tive yield, with the structure confirmed by X-ray crystal-
lography.10 The more labile N-benzyl and N-
(methoxymethyl) derivatives also gave the dichlorides 4c
and 4d in high yield. Bromination of 2a smoothly gave the
dibromide 4b.
O
O
11
12
O
N
O
N
Cl
O
Cl
Cl
R
R
NaOEt
EtOH
N
R
R
O
O
4
10
c
d
R = Bn
R = MOM
98%
98%
O
N
O
N
X
R
R
X2
Scheme 4
X
N
R
N
R
O
O
2
4
ethoxide nucleophile attacks only one of several potential
sites.
Scheme 3
Table 1 Yields of Dihalides 4
The reason for the surprising absence of an SN2¢ attack of
the nucleophile on the allylic chloride is revealed in the
crystal structure of 4a (Figure 1).7 The carbon–chloride
bond of the allylic chloride is nearly orthogonal to the p
orbitals of the alkene. In addition, if the allylic chloride
could be twisted to an SN2¢ compatible conformation, an
amide near the alkene face syn to the chloride may also
hinder the SN2¢ approach of the nucleophile.
Product 4
R
X
Yield (%)
4a
4b
4c
4d
n-Bu
n-Bu
Bn
Cl
Br
Cl
Cl
99
70
99
99
MOM
Nevertheless, it was assumed that one influence of the al-
lylic system was the enhancement of reactivity of the al-
lylic bond of the azetidinium ion of intermediate 7. This
role was probed by hydrogenating the alkene of 4a to give
11 (Scheme 4). The clean reduction of this alkene, with-
out loss of the allylic chloride, is another indication of the
conformational disjunction of normal allylic reactivity.
Surprisingly, treatment of 11 with sodium ethoxide gave
a clean conversion into a single product identical with 12,
formed by hydrogenation of 10a.
Dihalides 4 present a unique array of functionality, with a
secondary aliphatic halide and a secondary allylic halide,
flanked by tertiary amides on both sides of the central cy-
clooctene. An initial probe of the reactivity of 4a was con-
ducted by treating this dichloride with sodium ethoxide
(Scheme 4). Inspection of the structure of 4a (Figure 1)
reveals that SN2 attack on both chlorides is blocked by an
amide that straddles the space between them. The allylic
nature of one chloride, however, suggested that SN2¢ dis- Modeling of intermediate 7 found the rather symmetric
placement might be an accessible pathway. This analysis structure shown in Figure 2.12 The azetidinium ion has
proved incorrect, however, with ethoxide 10a as the sole two bonds between carbon and nitrogen that would be
product formed. The nearly identical NMR spectra for 4a broken by nucleophilic attack by paths a and c. In this
and 10a, except for the addition of the ethoxy signals, sug- analysis, the two bonds are nearly identical in length; the
gested analogous structures. Compound 10a, whose struc- bond to be broken in nucleophilic attack via path a is lon-
ture was confirmed by X-ray crystallography,11 is the ger by 0.005 Å. The selectivity for path c is therefore like-
apparent result of a double-inversion process. This pro- ly to be a consequence of the steric and electronic effect
cess would entail an equilibrium between dichloro dia- of the chloride substitution next to the azetidinium ion.
mide 4a and the azetidinium 7a. The rate determining
step, therefore, would likely be the internal displacement
of the allylic chloride. It is notable that, once again, the
Investigation of the chlorination reaction was expanded to
include the pyridone–naphthalene cycloadduct 15,
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York

PAPER
Intramolecular Reactivity of trans [4+4] Photodimers of 2-Pyridones
2353
O
hν
N
O
Me
13
O
O
+
+
+
O
O
N
N
N
N
Me
Me
O
14
16
15
X2
X
O
O
O
N
Me
X
Me
X
17
Figure 1 Partial crystal structure showing the dihedral angle of
the allylic chloride in 4a and the blockage of the SN2 pathways by an
amide
O
O
X
O
N
Me
X
Me
O
X
18
19
a
b
X = Cl
X = Br
17%
35%
23%
14%
Scheme 5 Products 18 and 19 produced by chlorination of 15; both
the amide nitrogen and the phenyl group migrate
range to 19. It is notable that there are two different phenyl
migrations possible for 15, one leading through 17 to 19
(Scheme 5). The alternative phenyl migration isomer is
not observed.
Nucleophilic substitution of the allylic chloride in 4a was
studied with nucleophiles in addition to ethoxide
(Scheme 6). With nucleophiles that can add reversibly to
a carbonyl, substitution of the chloride proceeded smooth-
ly. The reaction with sodium methoxide gave substitution
analogous to that of sodium ethoxide, although with a
slightly reduced yield. Thiophenol and pyrrolidine, both
in the presence of sodium hydride, gave sulfur and nitro-
gen displacement examples. Malononitrile also gave sub-
stitution in good yield.
Figure 2 Calculated structure of azetidinium intermediate 7
formed by irradiation of 13 and produced as a mixture
with the cis-isomer 14 (Scheme 5). Substrate 15 has two
non-equivalent alkenes, and there is little discrimination
between them: two products were formed in this reaction
and both were definitively proven by X-ray crystallogra-
phy.13 One product of this reaction is the equivalent of that
described above, from chloronium ion interception by a
nearby amide nitrogen. The resulting azetidinium ion 16
is then cleaved by chloride to give 18 (Scheme 5).
Cl
Cl
n-Bu
n-Bu
O
O
N
N
Nu–
N
n-Bu
Cl
N
n-Bu
Nu
4a
20
O
O
NuH
yield
a
b
MeOH
PhSH
93%
85%
Where chlorination of the alternative alkene occurs, the
chloronium is intercepted by the nearby aromatic ring, via
cyclobutane 17 (Scheme 5). In this case, the structure of
19 suggests that the chloride opening of intermediate 17
occurs in an SN2¢ fashion to give 19. In this case, however,
a direct SN2 opening of cyclobutane 17 would yield a ter-
tiary allylic chloride, which might be expected to rear-
NH
c
d
88%
80%
NC
NC
H
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York

2354
P. Chen et al.
PAPER
Scheme 6 Substitution of the allylic chloride by soft nucleophiles
product results from internal delivery of a hydride from
the newly formed primary alcohol.
Harder nucleophiles revealed another reaction path, at-
tacking the carbonyl group of the intermediate azetidini-
um 7a (Scheme 7, Table 2). When the amide in 4a
displaces the chloride to give 7a, the amide carbonyl be-
comes susceptible to nucleophilic attack (see arrow,
Scheme 7). In the case of reversible nucleophiles such as
ethoxide, addition to this acyl ammonium carbonyl is of
little consequence. When the nucleophile addition is irre-
versible, however, the addition leads to formation of a ke-
tone or aldehyde, which then suffers a second addition.
Allyl Grignard addition proceeds in good yield, to give es-
sentially one product 21a (Scheme 7, Table 2). Other
Grignard reagents (phenyl, ethyl, phenylethynyl) were
less satisfactory, yielding mixtures of products, although
these reactions were not optimized.
Photocycloaddition of 2-pyridones with themselves, or
with other 1,3-diene equivalents (1,3-dienes, furan, naph-
thalene), yields well-functionalized cycloocta-1,5-dienes,
often in high yield and with good regio- and stereoselec-
tivity. When these cycloocta-1,5-diene products are treat-
ed with chlorine or bromine, transannular participation
leads to novel structures. For the reactions of the trans-cy-
cloadducts described here, capture of the intermediate ha-
lonium ion by the amide nitrogen forms a reactive four-
membered ammonium intermediate that then reacts even
with modest nucleophiles such as chloride, giving the
product in high yield and as a single stereoisomer. When
the halogenation substrate is the achiral pyridone dimer 4,
which has a center of symmetry, the product is chiral, with
six contiguous stereogenic centers. The allylic halide is
readily displaced with relatively soft nucleophiles, but this
reaction is governed by one of the nearby amide nitrogens.
These studies are continuing.
O
N
O
N
Cl
Cl
Cl
Cl
n-
Bu
n-Bu
Nu–
N
n-Bu
Cl
N
n-Bu
Et2O, THF and CH2Cl2 were dried using a Glass Contour (now Seca
Solvent Systems) purification system. Melting points were mea-
sured with a Thomas Hoover capillary melting point apparatus and
are uncorrected. Infrared spectra were recorded on a Perkin-Elmer
1600 FTIR spectrometer. 1H and 13C NMR spectra were recorded
on a Bruker WM-400 spectrometer. Exact mass measurements
were performed with a VG70SE instrument at Drexel University.
O
O
4a
7a
O
O
n-Bu
n-Bu
N
N
N
n-Bu
N
n-Bu
OH
Nu
OH
Nu
H
H
21
22
Nu
Cl
Nu
Nu
1-Benzylpyridin-2(1H)-one (1c)14
O
N
O
N
Cl
To a soln of 2-pyridone (7.1 g, 75 mmol) in MeOH (100 mL) was
added K2CO3 (21 g, 150 mmol) and BnBr (13 mL, 112 mmol). The
mixture was heated to reflux for 2.5 h, filtered, and concentrated.
The residue was diluted with H2O (150 mL) and extracted with
EtOAc (4 × 50 mL). The combined organics were dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash chro-
matography (EtOAc).
n-Bu
n-Bu
O
N
N
n-Bu
n-Bu
O
O
23
10a
Scheme 7 Reaction of 4a with irreversible nucleophiles
Table 2 Products of Reaction of 4a with Irreversible Nucleophiles
Yield: 12.3 g (89%); colorless solid; Rf = 0.42 (hexanes–EtOAc,
1:2); mp 68 °C (Lit.5 72 °C).
Reagent
Nu
Products
Yield (%)
1H NMR (400 MHz, CDCl3): d = ca. 7.28–7.19 (m, 7 H), 6.56 (d,
J = 9.2 Hz, 1 H), 6.08 (dd, J = 6.4, 1.2 Hz, 1 H), 5.09 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 163.0, 139.7, 137.6, 136.7, 129.2,
128.5, 128.3, 121.6, 106.6, 52.4.
21
60
–
22
–
23
–
10a
–
AllMgCl
All
H
21a
NaBH4, EtOH
LiBH4, THF
23b, 10a
21b, 22b
–
30
–
50
–
1-(Methoxymethyl)pyridin-2(1H)-one (1d)15
H
16
35
To a soln of 2-pyridone (5.0 g, 53 mmol) in THF (200 mL) at 0 °C
was added NaH (1.9 g, 79 mmol). After 0.5 h, MOMCl (4.8 mL, 63
mmol) was added, and the mixture was stirred at 0 °C for an addi-
tional 0.5 h. The soln was diluted with sat. NH4Cl (100 mL), extract-
ed with EtOAc (4 × 100 mL), dried (Na2SO4), and concentrated in
vacuo.
With hydride as the nucleophile, the reaction was slower
and produced a range of products (Scheme 7, Table 2).
With sodium borohydride in ethanol at ambient tempera-
ture for eight hours, starting 4a remained, but was fully
consumed after an additional two hours at reflux. In this
case, the major product was 10a, by chloride displacement
by solvent, with a lesser amount of the dechlorinated 23b
formed in substantial amounts (Scheme 7, Table 2). With
lithium borohydride in THF for seven days, only azetidine
products were isolated; however, two-thirds of this prod-
uct included loss of the allylic chloride, to give 22b
(Scheme 7, Table 2). It is tempting to suggest that this
Yield: 7.4 g (100%); oil; Rf = 0.47 (MeOH–CH2Cl2, 1:20).
1H NMR (400 MHz, CDCl3): d = 7.29 (m, 2 H), 6.48 (d, J = 8.4 Hz,
1 H), 6.13 (t, J = 6.4 Hz, 1 H), 5.24 (s, 2 H), 3.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.2, 140.3, 136.4, 121.7, 106.4,
78.5, 57.3.
(1R*,2R*,5S*,6S*)-3,7-Dibenzyl-3,7-diaza-
tricyclo[4.2.2.22,5]dodeca-9,11-diene-4,8-dione (2c)
An 8.0 M soln of 1-benzylpyridin-2(1H)-one (1c; 12.0 g, 64.78
mmol) in MeOH (8 mL) was irradiated with a water-cooled Pyrex-
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York

PAPER
Intramolecular Reactivity of trans [4+4] Photodimers of 2-Pyridones
2355
filtered 450-W medium-pressure mercury lamp for 3 d. The soln
was concentrated in vacuo and the residue was washed with hex-
anes.
13C NMR (100 MHz, CDCl3): d = 165.8, 165.4, 137.3, 127.4, 60.1,
57.8, 50.9, 50.8, 48.4, 47.8, 47.5, 44.8, 29.8, 29.7, 20.4, 20.2, 13.9,
13.8.
Yield: 3.6 g (30%); colorless solid.
HRMS–FAB: m/z [M + H]+ calcd for C18H26N2O2Br2: 463.041879;
found: 463.0410.
1H NMR (400 MHz, CDCl3): d = 7.25 (m, 3 H), 7.07 (m, 2 H), 6.47
(t, J = 6.9 Hz, 1 H), 5.97 (t, J = 8.1 Hz, 1 H), 5.05 (d, J = 15.0 Hz,
1 H), 3.95 (m, 1 H), 3.53 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 174.3, 136.3, 135.4, 130.7, 129.1,
128.4, 128.1, 55.4, 50.9, 50.7.
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibenzyl-7,12-dichloro-
2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione (4c)
To a soln of 2c (3.0 g, 8.10 mmol) in CH2Cl2 (300 mL) was added
a 0.23 M soln of Cl2 in CH2Cl2 (39 mL, 8.9 mmol), and the mixture
was stirred at r.t. for 1 h. The soln was diluted with sat. NaHCO3
(200 mL) and extracted with CH2Cl2 (4 × 100 mL). The combined
organics were dried (MgSO4) and concentrated in vacuo.
(1R*,2R*,5S*,6S*)-3,7-Bis(methoxymethyl)-3,7-diaza-
tricyclo[4.2.2.22,5]dodeca-9,11-diene-4,8-dione (2d)
Neat 1-(methoxymethyl)pyridine-2(1H)-one (1d; 7.3 g, 52.46
mmol) was irradiated with a water-cooled Pyrex-filtered 450-W
medium-pressure mercury lamp for 22 h. The colored impurities
were removed by flash chromatography (MeOH–CH2Cl2, 5:100).
Other impurities were washed out with Et2O; this gave pure 2d.
Yield: quantitative; colorless solid; Rf = 0.71 (hexanes–EtOAc,
1:2); mp 200–201 °C.
IR (KBr): 3475, 3314, 3055, 2980, 2926, 1660, 1452, 1264, 1172,
735 cm–1.
Yield: 700 mg (10%); colorless solid; Rf = 0.42 (MeOH–CH2Cl2,
1:20); mp 200 °C.
IR (KBr): 3054, 2928, 1670, 1265, 739 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.62 (t, J = 6.8 Hz, 1 H), 6.14 (t,
J = 7.2 Hz, 1 H), 4.96 (d, J = 11.2 Hz, 1 H), 4.31 (m, 1 H), 4.15 (d,
J = 10.4 Hz, 1 H), 3.63 (m, 1 H), 3.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 175.3, 134.7, 131.3, 77.7, 56.7,
54.4, 50.5.
1H NMR (400 MHz, CDCl3): d = 7.50–7.30 (m, 10 H), 5.94 (d,
J = 11.4 Hz, 1 H), 5.40 (td, J = 11.1, 2.4 Hz, 1 H), 5.27 (d, J = 13.8
Hz, 1 H), 4.93 (d, J = 14.1 Hz, 1 H), 4.77 (m, 1 H), 4.35 (d, J = 14.4
Hz, 1 H), 4.10–3.90 (m, 4 H), 3.56 (d, J = 10.2 Hz, 1 H), 3.40 (t,
J = 10.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 165, 164, 132, 131, 130.4, 129.7,
129.2, 129.0, 60, 59.9, 58, 57, 53, 52, 51, 45.
HRMS–FAB: m/z [M + H]+ calcd for C24H22N2O2Cl2: 441.1136;
found: 441.1143.
HRMS–FAB: m/z [M + Na]+ calcd for C14H18N2O4: 301.1164;
found: 301.1155.
(1R*,4S*,7S*,8S*,11R*,12R*)-7,12-Dichloro-2,10-bis(meth-
oxymethyl)-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione
(4d)
To a soln of 2d (55 mg, 0.20 mmol) in CH2Cl2 (5 mL) was added
dropwise a 0.63 M soln of Cl2 in CH2Cl2 (0.38 mL, 0.24 mmol), and
the resulting mixture was stirred at 0 °C for 0.5 h. The soln was di-
luted with sat. NaHCO3 (10 mL) and extracted with CH2Cl2 (4 × 10
mL). The combined organics were dried (MgSO4) and concentrated
in vacuo.
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7,12-dichloro-2,10-
diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione (4a)
To a soln of 2a (107 mg, 0.35 mmol) in CH2Cl2 (5 mL) was added
a 0.46 M soln of Cl2 in CH2Cl2 (0.9 mL, 0.41 mmol), and the mix-
ture was stirred at r.t. for 1 h. The soln was diluted with sat.
NaHCO3 (25 mL) and extracted with CH2Cl2 (4 × 30 mL). The
combined organics were dried (MgSO4) and concentrated in vacuo.
Yield: 135 mg (100%); colorless solid; Rf = 0.57 (hexanes–EtOAc,
1:2); mp 165–167.5 °C.
IR (KBr): 2959, 2932, 2872, 1662, 1467, 1176, 753 cm–1.
Yield: quantitative; colorless solid; Rf = 0.54 (MeOH–CH2Cl2,
1:20); mp 58–60 °C.
IR (KBr): 2940, 2834, 1674, 1456, 1173, 1080 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.93 (dt, J = 12.0, 1.6 Hz, 1 H),
5.77 (t, J = 10.8 Hz, 1 H), 4.85 (q, J = 2.0 Hz, 1 H), 4.22 (dd,
J = 4.0, 1.6 Hz, 1 H), 3.91–3.81 (m, 2 H), 3.66–3.58 (m, 3 H), 3.49
(dt, J = 10.0, 1.6 Hz, 1 H), 3.11–2.98 (m, 2 H), 1.56–1.23 (m, 8 H),
0.90 (t, J = 7.2 Hz, 3 H), 0.86 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 6.02 (dt, J = 11.7, 1.5 Hz, 1 H),
5.86 (td, J = 10.8, 2.7 Hz, 1 H), 5.14 (q, J = 2.1 Hz, 1 H), 5.00 (d,
J = 10.8 Hz, 1 H), 4.77 (s, 2 H), 4.52 (d, J = 10.5 Hz, 1 H), 4.38 (dd,
J = 4.2, 1.5 Hz, 1 H), 4.15 (m, 2 H), 3.77 (t, J = 10.5 Hz, 1 H), 3.55
(d, J = 10.2 Hz, 1 H), 3.37 (s, 3 H), 3.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.2, 165.7, 137.1, 127.1, 60.1,
59.7, 58.1, 56.1, 51.1, 48.7, 48.2, 47.5, 30.1, 30.0, 20.7, 20.6, 14.1,
14.0.
13C NMR (100 MHz, CDCl3): d = 167.1, 167.0, 137.1, 127.0, 79.1,
78.2, 59.9, 59.0, 58.1, 57.6, 56.7, 56.2, 50.8, 47.5.
HRMS–FAB: m/z [M + H]+ calcd for C14H18N2O4Cl2: 349.0722;
found: 349.0733.
(1R*,4S*,7S*,8S*,11R*,12R*)-7,12-Dibromo-2,10-dibutyl-2,10-
diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione (4b)
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7-chloro-12-
ethoxy-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione
(10a)
To a soln of 4a (100 mg, 0.27 mmol) in absolute EtOH (5 mL) was
added a 0.16 M soln of NaOEt in EtOH (2 mL, 0.32 mmol), and the
mixture was heated at reflux for 3 h, cooled, and concentrated in
vacuo. The residue was diluted with H2O (20 mL) and extracted
with EtOAc (4 × 30 mL). The combined organics were dried
(MgSO4) and concentrated. The residue was purified by flash chro-
matography (hexanes–EtOAc, 1:10).
To a soln of 2a (50 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added
Br2 (11 mL, 0.22 mmol) in CH2Cl2, and the reaction mixture was
stirred at r.t. for 1 h. The soln was diluted with sat. NaHCO3 (20 mL)
and extracted with CH2Cl2 (4 × 20 mL). The combined organics
were dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography (hexanes–EtOAc, 1:1).
Yield: 53 mg (70%); colorless solid; Rf = 0.57 (1:1 hexanes–
EtOAc); mp 168–170 °C.
IR (KBr): 2958, 2930, 2871, 1661, 1467, 1176, 737 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.07 (d, J = 11.4 Hz, 1 H), 5.70
(td, J = 10.4, 2.4 Hz, 1 H), 4.95 (q, J = 2.4 Hz, 1 H), 4.32 (dd,
J = 4.5, 1.2 Hz, 1 H), 3.92 (d, J = 10.2 Hz, 1 H), 3.87–3.56 (m, 5 H),
3.10 (m, 1 H), 2.91 (m, 1 H), 1.60–1.20 (m, 8 H), 0.88 (m, 6 H).
Yield: 97 mg (95%); colorless solid; Rf = 0.66 (hexanes–EtOAc,
1:5); mp 144–146 °C.
IR (KBr): 3453, 2961, 2930, 2872, 1661, 1265, 738 cm–1.
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York

2356
P. Chen et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 5.85 (d, J = 12.8 Hz, 1 H), 5.75
(td, J = 10.4, 2.8 Hz, 1 H), 4.22 (dd, J = 4.4, 1.6 Hz, 1 H), 4.19 (q,
J = 2.4 Hz, 1 H), 3.85 (m, 2 H), 3.63 (m, 4 H), 3.40 (q, J = 7.2 Hz,
1 H), 3.34 (d, J = 10.4 Hz, 1 H), 3.07 (m, 2 H), 1.37 (m, 2 H), 1.20
(m, 6 H), 1.20 (t, J = 6.8 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H), 0.84 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.1, 166.5, 137.8, 125.4, 65.3,
60.2, 58.9, 58.0, 48.2, 48.1, 47.5, 46.4, 30.1, 30.0, 20.66, 20.59,
15.5, 14.1.
der H2 (1.0 atm) for 5 h. The Pd/C was removed by filtration
through Celite. The filtrate was concentrated in vacuo. The residue
was purified by flash chromatography (hexanes–EtOAc, 1:1).
Yield: 74 mg (60%); colorless solid; Rf = 0.45 (hexanes–EtOAc,
1:1).
1H NMR (400 MHz, CDCl3): d = 4.30 (m, 2 H), 3.85 (m, 2 H), 3.65
(m, 2 H), 3.57 (d, J = 9.9 Hz, 1 H), 3.22–3.00 (m, 3 H), 2.30–1.95
(m, 4 H), 1.62–1.29 (m, 8 H), 0.95 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.6, 167.0, 60.2, 58.9, 58.4,
55.4, 51.6, 49.3, 47.8, 45.1, 32.7, 29.5, 29.4, 26.5, 20.4, 20.3, 13.8,
13.7.
HRMS–FAB: m/z [M + Na]+ calcd for C20H31N2O3Cl: 405.19209;
found: 405.1920.
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibenzyl-7-chloro-12-
ethoxy-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione
(10c)
To a soln of compound 4c (60 mg, 0.14 mmol) in absolute EtOH (10
mL) was added 0.5 M NaOEt in EtOH (0.55 mL, 0.27 mmol), and
the mixture was heated at reflux for 0.5 h. The soln was cooled and
concentrated in vacuo. The residue was diluted with sat. NH4Cl (20
mL) and extracted with EtOAc (4 × 30 mL). The combined organ-
ics were dried (MgSO4) and concentrated. The residue was purified
by flash chromatography (hexanes–EtOAc, 1:1.5).
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7-chloro-12-
ethoxy-2,10-diazatricyclo[6.4.0.04,11]dodecane-3,9-dione (12)
By reduction of 10a: To a soln of 10a (64 mg, 0.16 mmol) in
MeOH (2 mL) was added 10% Pd/C (18 mg). The mixture was
stirred at r.t. under H2 (1 atm) for 6 h. The mixture was filtered
through Celite and concentrated in vacuo to give 12; yield: quanti-
tative.
From 11: To a soln of 11 (50 mg, 0.13 mmol) in absolute EtOH (3
mL) was added 0.5 M NaOEt in absolute EtOH (0.32 mL, 0.16
mmol), and the mixture was heated at reflux for 0.5 h. The soln was
cooled and concentrated in vacuo. The residue was diluted with
H2O (10 mL) and extracted with EtOAc (4 × 20 mL). The combined
organics were dried (MgSO4) and concentrated to give 12; yield:
quantitative.
Yield: 60 mg (98%); colorless solid; Rf = 0.34 (hexanes–EtOAc,
1:1); mp 192–193 °C.
IR (KBr): 3475, 3301, 3032, 2976, 2870, 1659, 1464, 1264, 1169,
1096, 732 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.45–7.30 (m, 10 H), 5.86 (d,
J = 11.4 Hz, 1 H), 5.46 (td, J = 10.5, 2.7 Hz, 1 H), 5.12 (d, J = 14.1
Hz, 1 H), 4.67 (d, J = 13.8 Hz, 1 H), 4.55 (d, J = 14.4 Hz, 1 H), 4.15
(m, 2 H), 4.01 (m, 2 H), 3.90 (m, 1 H), 3.40 (m, 3 H), 3.07 (m, 1 H),
1.19 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.5, 167.0, 137.3, 136.1, 135.7,
130.5, 129.6, 129.5, 128.94, 128.90, 128.4, 125.6, 65.2, 60.3, 58.6,
56.2, 51.8, 51.4, 47.2, 46.3, 15.6.
Colorless solid; Rf = 0.43 (hexanes–EtOAc, 1:2).
1H NMR (400 MHz, CDCl3): d = 4.27 (m, 1 H), 3.85–3.55 (m, 6 H),
3.40–2.88 (m, 5 H), 2.20 (m, 1 H), 1.95 (m, 2 H), 1.75 (m, 1 H), 1.55
(m, 3 H), 1.32 (m, 4 H), 1.15 (t, J = 6.6 Hz, 4 H), 0.90 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.9, 168.5, 76.4, 64.6, 60.6,
58.4, 58.3, 49.1, 47.8, 47.6, 45.5, 29.6, 29.5, 28.6, 24.8, 20.4, 20.3,
15.3, 13.8, 13.7.
HRMS–FAB: m/z [M + H]+ calcd for C26H27N2O3Cl: 451.1788;
Dichlorides 18a and 19a
found: 451.1805.
To a soln of 15 (157 mg, 0.56 mmol) in CH2Cl2 (10 mL) was added
0.46 M Cl2 in CH2Cl2 (1.6 mL, 0.73 mmol), and the mixture was
stirred at 0 °C for 1 h. The soln was diluted with sat. NaHCO3 (30
mL) and extracted with EtOAc (4 × 40 mL). The combined organ-
ics were dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography (hexanes–EtOAc, 2:1). This gave
18a and 19a.
(1R*,4S*,7S*,8S*,11R*,12R*)-7-Chloro-12-ethoxy-2,10-
bis(methoxymethyl)-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-
3,9-dione (10d)
To a soln of compound 4d (69 mg, 0.20 mmol) in absolute EtOH (5
mL) was added 0.5 M NaOEt in EtOH (0.6 mL, 0.30 mmol), and the
mixture was heated at reflux for 1 h. The soln was cooled and con-
centrated in vacuo. The residue was diluted with sat. NH4Cl (10
mL) and extracted with EtOAc (4 × 10 mL). The combined organ-
ics were dried (MgSO4) and concentrated. The residue was purified
by flash chromatography (MeOH–CH2Cl2, 5:100).
Compound 18a
Yield: 33 mg (17%); colorless solid; Rf = 0.65 (hexanes–EtOAc,
1:1); mp 261–263 °C.
IR (KBr): 2924, 2853, 1666, 1478, 1087, 953, 741 cm–1.
Yield: 70 mg (98%); colorless solid; Rf = 0.41 (MeOH–CH2Cl2,
1:20).
IR (KBr): 2934, 2873, 1671, 1456, 1384, 1173, 1083 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.91 (m, 2 H), 4.85 (d, J = 10.8
Hz, 1 H), 4.73 (q, J = 9.6 Hz, 2 H), 4.58 (d, J = 11.1 Hz, 1 H), 4.43
(s, 1 H), 4.32 (d, J = 4.5 Hz, 1 H), 4.15 (m, 2 H), 3.69 (m, 2 H), 3.45
(m, 2 H), 3.36 (s, 3 H), 3.35 (s, 3 H), 1.22 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.4, 167.4, 138.1, 125.2, 78.7,
78.2, 77.5, 65.3, 60.0, 58.13, 58.09, 57.6, 56.6, 47.6, 46.3, 15.4.
1H NMR (400 MHz, CDCl3): d = 7.47 (m, 1 H), 7.31 (m, 2 H), 7.25
(m, 1 H), 5.33 (d, J = 10.8 Hz, 1 H), 5.20 (dd, J = 11.6, 2.4 Hz, 1 H),
5.04 (m, 1 H), 5.00 (dd, J = 9.2, 1.2 Hz, 1 H), 4.51 (d, J = 10.0 Hz,
1 H), 4.35 (s, 1 H), 4.05 (m, 3 H), 3.62 (d, J = 9.2 Hz, 1 H), 3.21 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 168.5, 137.2, 135.6, 133.0, 131.7,
130.3, 128.0, 127.8, 124.2, 78.7, 73.9, 64.8, 61.4, 60.8, 60.5, 58.8,
48.8, 36.1.
HRMS–DCI: m/z [M + H]+ calcd for C18H17Cl2NO2: 350.0714;
found: 350.0722.
HRMS–FAB: m/z [M + H]+ calcd for C16H23N2O5Cl: 359.1373;
found: 359.1356.
Compound 19a
Yield: 45 mg (23%); colorless solid; Rf = 0.49 (hexanes–EtOAc,
1:1); mp 182–184 °C.
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7,12-dichloro-2,10-
diazatricyclo[6.4.0.04,11]dodecane-3,9-dione (11)
To a soln of 4a (125 mg, 0.33 mmol) in MeOH (2 mL) was added
10% Pd/C (36 mg, 0.033 mmol). The mixture was stirred at r.t. un-
IR (KBr): 3052, 2975, 2926, 2843, 1665, 1460, 1266, 1070, 734
cm–1.
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York

PAPER
Intramolecular Reactivity of trans [4+4] Photodimers of 2-Pyridones
2357
1H NMR (400 MHz, CDCl3): d = 7.24–7.14 (m, 2 H), 7.10 (dd,
J = 7.2, 0.8 Hz, 1 H), 6.97 (dd, J = 7.2, 1.2 Hz, 1 H), 5.20 (dt,
J = 7.2, 1.6 Hz, 1 H), 4.93 (d, J = 8.8 Hz, 1 H), 4.64 (td, J = 6.4, 2.0
Hz, 1 H), 4.25 (dd, J = 4.0, 1.2 Hz, 1 H), 4.18 (d, J = 13.2 Hz, 1 H),
3.97 (m, 2 H), 3.75 (dt, J = 12.8, 2.0 Hz, 1 H), 3.65 (d, J = 9.2 Hz,
1 H), 3.11 (s, 3 H), 3.06 (d, J = 2.0 Hz, 1 H).
3.41 (m, 1 H), 3.12–3.01 (m, 2 H), 1.44–1.25 (m, 8 H), 0.94 (t,
J = 7.5 Hz, 3 H), 0.88 (t, J = 7.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.1, 166.6, 137.1, 125.7, 79.8,
60.3, 58.9, 58.3, 57.6, 48.4, 48.1, 47.6, 46.0, 30.1, 30.0, 20.7, 20.6,
14.1.
13C NMR (100 MHz, CDCl3): d = 170.9, 146.8, 141.0, 134.6, 129.2,
128.8, 128.4, 126.3, 117.9, 79.0, 73.9, 64.7, 60.5, 59.8, 55.4, 52.4,
50.3, 40.8.
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7-chloro-12-(phe-
nylsulfanyl)-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-di-
one (20b)
To a suspension of NaH (12 mg, 0.5 mmol) in THF (2 mL) was add-
ed PhSH (35 mL, 0.34 mmol), and the mixture was stirred at 0 °C for
0.5 h. To this was added 4a (106 mg, 0.28 mmol) in THF (2 mL)
and the mixture was warmed to r.t. for 5 h. The soln was diluted
with sat. NH4Cl (10 mL) and extracted with EtOAc (4 × 20 mL).
The combined organics were dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography (hex-
anes–EtOAc, 2:1) to give 20b.
HRMS–FAB: m/z [M + Na]+ calcd for C18H17NO2Cl2: 372.0534;
found: 372.0538.
Dibromides 18b and 19b
To a soln of 15 (72 mg, 0.25 mmol) in CH2Cl2 (10.0 mL) at 0 °C
was added Br2 (14.5 mL, 0.28 mmol) in CH2Cl2, and the mixture was
stirred at 0 °C for 1 h. The soln was diluted with sat. NaHCO3 (20
mL) and extracted with EtOAc (4 × 30 mL). The combined organ-
ics were dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography (hexanes–EtOAc, 2:1); this gave
18b and 19b.
Yield: 107 mg (85%); colorless solid; Rf = 0.56 (hexanes–EtOAc,
1:1); mp 157–158 °C.
IR (KBr): 3460, 3310, 2959, 2930, 2871, 1660, 1470, 1176, 737
cm–1.
Compound 18b
1H NMR (400 MHz, CDCl3): d = 7.40 (m, 2 H), 7.22 (m, 3 H), 5.81
(d, J = 12.0 Hz, 1 H), 5.74 (td, J = 10.0, 2.4 Hz, 1 H), 4.26 (dd,
J = 4.4, 2.0 Hz, 1 H), 4.12 (d, J = 2.0 Hz, 1 H), 3.80 (m, 2 H), 3.62
(t, J = 9.6 Hz, 1 H), 3.48 (m, 2 H), 3.37 (d, J = 9.6 Hz, 1 H), 3.13
(m, 2 H), 1.42 (m, 4 H), 1.27 (m, 4 H), 0.83 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 167.0, 166.6, 136.4, 135.6, 132.4,
129.7, 128.1, 126.8, 60.4, 60.3, 58.0, 48.4, 48.1, 47.9, 30.4, 30.0,
20.7, 20.6, 14.14, 14.10.
Yield: 39 mg (35%); Rf = 0.51 (hexanes–EtOAc, 2:1); mp 225–
227 °C.
1H NMR (400 MHz, CDCl3): d = 7.69 (m, 1 H), 7.44 (m, 2 H), 7.33
(m, 1 H), 5.63 (d, J = 11.7 Hz, 1 H), 5.31 (d, J = 1.5 Hz, 1 H), 5.25
(dd, J = 11.7, 2.4 Hz, 1 H), 5.10 (d, J = 9.0 Hz, 1 H), 4.60 (d,
J = 10.2 Hz, 2 H), 4.28 (d, J = 10.8 Hz, 1 H), 4.20 (d, J = 10.8 Hz,
1 H), 4.08 (d, J = 10.2 Hz, 1 H), 3.74 (d, J = 9.3 Hz, 1 H), 3.32 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 168.0, 138.4, 135.9, 132.7, 132.4,
130.2, 127.5, 127.4, 123.6, 78.7, 74.3, 61.8, 60.4, 58.4, 56.9, 51.7,
48.8, 35.8.
HRMS–FAB: m/z [M + H]+ calcd for C24H31N2O2SCl: 447.187303;
found: 447.1865.
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7-chloro-12-(1-pyr-
rolidino)-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione
(20c)
Compound 19b
Yield: 16 mg (14%); Rf = 0.32 (hexanes–EtOAc, 2:1); mp 105–
To a suspension of NaH (15 mg, 0.62 mmol) in THF (1 mL) was
added pyrrolidine (25 mL, 0.30 mmol), and the mixture was stirred
at 0 °C for 0.5 h. To this was added 4a (75 mg, 0.20 mmol) in THF
(2 mL), and the mixture was warmed to 60–70 °C overnight. The
soln was diluted with H2O (10 mL) and extracted with EtOAc
(4 × 20 mL). The combined organics were dried (Na2SO4) and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (MeOH–CH2Cl2, 5:100) to give 20c.
107 °C.
1H NMR (400 MHz, CDCl3): d = 7.29–7.24 (m, 2 H), 7.15 (dd,
J = 7.6, 1.2 Hz, 1 H), 7.03 (dd, J = 7.6, 1.2 Hz, 1 H), 5.28 (d, J = 6.8
Hz, 1 H), 5.03 (d, J = 8.8 Hz, 1 H), 4.86 (t, J = 5.2 Hz, 1 H), 4.42
(dd, J = 4.4, 1.2 Hz, 1 H), 4.27 (d, J = 12.8 Hz, 1 H), 4.08–3.98 (m,
2 H), 3.85 (dt, J = 12.8, 2.0 Hz, 1 H), 3.73 (d, J = 9.2 Hz, 1 H), 3.27
(s, 1 H), 3.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.1, 146.4, 141.8, 134.9, 129.2,
128.9, 128.4, 126.2, 118.5, 79.4, 73.9, 60.9, 56.8, 55.6, 53.4, 51.0,
49.3, 42.0.
Yield: 72 mg (88%); pale yellow oil; Rf = 0.69 (MeOH–CH2Cl2,
1:16).
IR (KBr): 2959, 2932, 2872, 1659, 1467, 1177, 733 cm–1.
HRMS–FAB: m/z [M + Na]+ calcd for C18H17NO2Br2: 495.9523;
found: 459.9522.
1H NMR (400 MHz, CDCl3): d = 5.93 (d, J = 11.6 Hz, 1 H), 5.75
(td, J = 11.2, 2.8 Hz, 1 H), 4.26 (dd, J = 4.4, 1.2 Hz, 1 H), 3.86 (d,
J = 10.0 Hz, 1 H), 3.80 (m, 1 H), 3.64–3.47 (m, 5 H), 3.03 (m, 2 H),
2.73 (m, 4 H), 1.74 (m, 4 H), 1.52–1.22 (m, 8 H), 0.89 (t, J = 7.2 Hz,
3 H), 0.84 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.2, 166.0, 136.1, 125.6, 62.6,
60.8, 59.9, 57.8, 51.9, 48.5, 48.1, 47.7, 46.3, 30.1, 30.0, 24.0, 20.7,
20.6, 14.1, 14.06.
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7-chloro-12-meth-
oxy-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-dione (20a)
To a soln of 4a (100 mg, 0.27 mmol) in anhyd MeOH (5 mL) was
added 0.16 M NaOMe in MeOH (2 mL, 0.32 mmol), and the mix-
ture was heated at reflux for 30 h. The soln was cooled and concen-
trated in vacuo. The residue was diluted with sat. NH4Cl (20 mL)
and extracted with EtOAc (4 × 30 mL). The combined organics
were dried (MgSO4) and concentrated. The residue was purified by
flash chromatography (hexanes–EtOAc, 1:2) to give 20a.
HRMS–FAB: m/z [M + Na]+ calcd for C22H34N3O2Cl: 430.2237;
found: 430.2234.
Yield: 92 mg (93%); colorless solid; Rf = 0.25 (hexanes–EtOAc,
1:2); mp 63–66 °C.
1H NMR (400 MHz, CDCl3): d = 5.90 (d, J = 12.0 Hz, 1 H), 5.83
(m, 1 H), 4.25 (dd, J = 4.0, 2.0 Hz, 1 H), 4.11 (m, 1 H), 3.93 (d,
J = 10.0 Hz, 1 H), 3.86 (m, 1 H), 3.63 (m, 3 H), 3.42 (s, 3 H), 3.43–
(1R*,4S*,7S*,8S*,11R*,12R*)-2,10-Dibutyl-7-chloro-12-(dicy-
anomethyl)-2,10-diazatricyclo[6.4.0.04,11]dodec-5-ene-3,9-di-
one (20d)
To a suspension of NaH (23 mg, 0.93 mmol) in THF (2 mL) was
added malononitrile (23 mL, 0.35 mmol), and the mixture was
stirred at 0 °C for 0.5 h. To this was added 4a (100 mg, 0.27 mmol)
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York

2358
P. Chen et al.
PAPER
in THF (3 mL), and the mixture was warmed to r.t. overnight. The
soln was diluted with H2O (20 mL) and extracted with EtOAc
(4 × 30 mL). The combined organics were dried (MgSO4) and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (hexanes–EtOAc, 1.5:1) to give 20d.
(m, 1 H), 3.64 (t, J = 6.5 Hz, 2 H), 3.27 (td, J = 7.0, 2.0 Hz, 1 H),
2.96 (q, J = 4.5 Hz, 1 H), 2.70–2.54 (m, 3 H), 1.62–1.20 (m, 8 H),
0.88 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 169.4, 133.1, 131.0, 66.6, 63.8,
61.9, 61.6, 56.5, 56.2, 52.1, 46.4, 44.6, 31.1, 29.2, 20.9, 20.7, 14.2,
14.1.
Yield: 87 mg (80%); colorless solid; Rf = 0.56 (hexanes–EtOAc,
1:1); mp 72–74 °C.
IR (KBr): 2961, 2932, 2874, 2257, 1651, 1473, 1180 cm–1.
HRMS–FAB: m/z [M + H]+ calcd for C18H29N2O2Cl: 339.1839;
found: 339.1833.
1H NMR (400 MHz, CDCl3): d = 5.98 (td, J = 10.4, 2.8 Hz, 1 H),
5.75 (dt, J = 11.6, 1.6 Hz, 1 H), 4.65 (d, J = 12.0 Hz, 1 H), 4.30 (dd,
J = 4.4, 1.6 Hz, 1 H), 3.93 (dt, J = 10.0, 1.2 Hz, 1 H), 3.86 (m, 1 H),
3.73 (t, J = 10.8 Hz, 1 H), 3.60 (m, 1 H), 3.34 (m, 1 H), 3.25 (dt,
J = 11.2, 1.6 Hz, 1 H), 3.14 (m, 3 H), 1.38 (m, 2 H), 1.30 (m, 6 H),
0.92 (t, J = 7.6 Hz, 3 H), 0.86 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.9, 165.6, 130.3, 130.0, 112.9,
112.4, 59.44, 59.41, 57.7, 48.3, 48.2, 47.8, 44.6, 41.5, 30.1, 29.8,
27.7, 20.64, 20.61, 14.1.
Compound 22b
Flash chromatography (MeOH–CH2Cl2, 4:100); yield: 30 mg
(35%); colorless oil; Rf = 0.45 (MeOH–CH2Cl2, 4:100).
1H NMR (400 MHz, CDCl3): d = 7.80 (br, 1 H), 6.12 (dd, J = 10.0,
6.8 Hz, 1 H), 5.55 (dd, J = 10.4, 6.8 Hz, 1 H), 3.91–3.71 (m, 5 H),
3.59 (t, J = 7.2 Hz, 1 H), 3.14 (t, J = 5.6 Hz, 1 H), 2.87 (m, 1 H),
2.55–2.42 (m, 3 H), 2.25–2.21 (m, 1 H), 2.01 (d, J = 11.6 Hz, 1 H),
1.57–1.22 (m, 8 H), 0.90 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 175.7, 133.6, 129.6, 64.4, 64.0,
61.3, 56.1, 48.3, 46.1, 43.3, 33.3, 30.7, 29.7, 20.8, 20.5, 14.2, 14.1.
HRMS–FAB: m/z [M + Na]+ calcd for C21H27N4O2Cl: 425.1720;
found: 425.1723.
(1R*,3R*,6S*,7R*,10S*,11S*)-2,8-Dibutyl-11-chloro-6-(hy-
droxymethyl)-2,8-diazatricyclo[5.3.1.03,10]undec-4-en-9-one
(23b)
(1R*,3R*,6S*,7R*,10S*,11S*)-6-(1-Allyl-1-hydroxybut-3-enyl)-
2,8-dibutyl-11-chloro-2,8-diazatricyclo[5.3.1.03,10]undec-4-en-
9-one (21a)
To a soln of 4a (100 mg, 0.26 mmol) in absolute EtOH (2 mL) at
0 °C was added NaBH4 (14 mg, 0.37 mmol). The mixture was
warmed to r.t. overnight and then heated at reflux for 2 h. The soln
was concentrated, and the residue was diluted with H2O (20 mL)
and then extracted with EtOAc (4 × 30 mL). The combined organ-
ics were dried (MgSO4) and concentrated in vacuo. Flash chroma-
tography (hexanes–EtOAc, 1:2) gave 10a; yield: 51 mg (50%); and
23b; yield: 27 mg (30%).
To a soln of 4a (100 mg, 0.26 mmol) in THF (2 mL) was added 2.0
M AllMgCl (0.30 mL, 0.60 mmol) in THF, and the mixture was
stirred at 0 °C for 0.5 h. The soln was diluted with sat. NH4Cl (20
mL) and extracted with EtOAc (4 × 30 mL). The combined organ-
ics were dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography (hexanes–EtOAc, 3:1) to give
21a. [The structure of 21a was determined by X-ray crystallography
of the hydrochloride salt (mp 173–175 °C).]
Yield: 68 mg (60%); colorless oil; Rf = 0.35 (hexanes–EtOAc,
2.5:1).
IR (KBr): 3052, 2961, 2932, 2864, 1666, 1265, 739 cm–1.
Compound 23b
Rf = 0.23 (hexanes–EtOAc, 1:1).
IR (KBr): 3503, 2961, 2932, 2872, 1653, 1473, 1431 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.72 (s, 1 H), 6.05 (dd, J = 12.5,
7.5 Hz, 1 H), 5.90 (m, 2 H), 5.79 (dd, J = 11.5, 8.5 Hz, 1 H), 5.23–
5.10 (m, 5 H), 4.08 (d, J = 8.5 Hz, 1 H), 3.84–3.77 (m, 3 H), 3.60
(d, J = 7.5 Hz, 1 H), 3.16 (t, J = 8.5 Hz, 1 H), 2.74 (m, 3 H), 2.61
(dt, J = 14.0, 2.0 Hz, 1 H), 2.45 (dd, J = 14.0, 5.0 Hz, 1 H), 2.24 (m,
2 H), 1.52 (m, 2 H), 1.40–1.25 (m, 6 H), 0.90 (m, 6 H)
13C NMR (100 MHz, CDCl3): d = 168.1, 134.6, 134.4, 132.6, 132.2,
118.4, 118.2, 74.5, 64.3, 62.2, 60.7, 57.7, 56.0, 49.7, 46.3, 45.2,
43.7, 37.5, 29.9, 29.3, 20.7, 20.6, 14.2, 14.1.
1H NMR (400 MHz, CDCl3): d = 5.76 (m, 2 H), 4.28 (dd, J = 4.8,
1.6 Hz, 1 H), 3.83–3.78 (m, 1 H), 3.72 (d, J = 10.0 Hz, 1 H), 3.61–
3.53 (m, 2 H), 3.45 (m, 1 H), 3.14–3.04 (m, 3 H), 2.67 (m, 1 H), 2.36
(d, J = 18.4 Hz, 1 H), 1.55–1.25 (m, 8 H), 0.86 (m, 6 H)
13C NMR (100 MHz, CDCl3): d = 169.6, 167.3, 133.0, 126.6, 60.4,
59.9, 58.2, 48.3, 47.9, 43.3, 30.3, 29.9, 29.8, 20.6, 20.6, 14.1
HRMS–FAB: m/z [M + H]+ calcd for C18H28N2O2Cl: 339.1839;
found: 339.1836
HRMS–FAB: m/z [M + H]+ calcd for C24H37N2O2Cl: 421.26218;
found: 421.2634.
Acknowledgment
This work was supported, in part, by Temple University Research
Incentive Grant 16-1313-702.
(1R*,3R*,6S*,7R*,10S*,11S*)-2,8-Dibutyl-6-(hydroxymethyl)-
2,8-diazatricyclo[5.3.1.03,10]undec-4-en-9-one (22b)
To a soln of 4a (106 mg, 0.28 mmol) in THF (5 mL) at 0 °C was
added 2.0 M LiBH4 in THF (0.18 mL, 0.37 mmol). The mixture was
warmed to r.t. and stirred for 1 week. The soln was diluted with sat.
NH4Cl (20 mL) and extracted with EtOAc (4 × 30 mL). The com-
bined organics were dried (MgSO4) and concentrated in vacuo. The
residue was purified by flash chromatography; this gave 21b and
22b.
References
(1) Sieburth, S. McN. CRC Handbook of Organic
Photochemistry and Photobiology; Horspool, W.; Lenci, F.,
Eds.; CRC Press: Boca Raton FL, 2004, Chap. 103, 1–18.
(2) Sieburth, S. McN.; Lin, C.-H. J. Org. Chem. 1994, 59, 3597.
(3) Sieburth, S. McN.; McGee, K. F. Jr.; Al-Tel, T. H. J. Am.
Chem. Soc. 1998, 120, 587.
(4) Sieburth, S. McN.; McGee, K. F. J. Org. Lett. 1999, 1, 1775.
(5) Ader, T. A.; Champey, C. A.; Kuznetsova, L. V.; Li, T.; Lim,
Y.-H.; Rucando, D.; Sieburth, S. McN. Org. Lett. 2001, 3,
2165.
Compound 21b
Flash chromatography (hexanes–EtOAc, 1:3); yield: 15 mg (16%);
colorless oil; Rf = 0.76 (EtOAc).
IR (KBr): 3416, 2959, 2932, 2872, 1643, 1468 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.08 (dd, J = 3.5, 10.5 Hz, 1 H),
5.90 (br, 1 H), 5.61 (dd, J = 3.0, 10.0 Hz, 1 H), 4.57 (q, J = 3.0 Hz,
1 H), 3.95 (m, 1 H), 3.88 (m, 1 H), 3.78 (d, J = 11.5 Hz, 1 H), 3.73
(6) Chen, P.; Chen, Y.; Carroll, P. J.; Sieburth, S. McN. Org.
Lett. 2006, 8, 5413.
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York

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Intramolecular Reactivity of trans [4+4] Photodimers of 2-Pyridones
2359
(7) Lim, Y.; Li, T.; Chen, P.; Schreiber, P.; Kutnetsova, L.;
Carroll, P. J.; Lauher, J. W.; Sieburth, S. McN. Org. Lett.
calculation was performed using WebMO
(www.webmo.net). Images were generated with PyMOL
(pymol.sourceforge.net).
2005, 7, 5413.
(8) Hageman, H. A. Org. React. 1953, 7, 198.
(9) Cooley, J. H.; Evain, E. J. Synthesis 1989, 1.
(10) See ref. 6
(11) Compound 10a crystallized in the rhombohedral space
group R–3, with a = 25.354 (2) Å, b = 25.354 (2) Å,
c = 18.437 (2) Å, and Z = 18. Direct solution using 4159
unique reflections with SHELXL-97 gave a final
R1 = 0.0707 and R2 = 0.1980.
(12) This structure was calculated by initially building a structure
with a carbon atom in place of the positively charged
nitrogen, and minimizing the structure using molecular
mechanics. The resulting structure was then modified by
replacing the carbon with a positively charged nitrogen and
minimizing the structure using PM3 (MOPAC). The
(13) Compound 18a crystallized in the monoclinic space group
P21/n, with a = 8.8752 (11) Å, b = 16.318 (2) Å, c = 13.575
(2) Å, b = 90.9270 (10)°, V = 1965.7 (5) Å3, and Z = 4.
Direct solution using 3180 unique reflections with
SHELXL-97 gave a final R1 = 0.0372 and R2 = 0.0816.
Compound 19a crystallized in the orthorhombic space group
Pca21, with a = 20.5701 (10) Å, b = 9.1456 (4) Å,
c = 16.8463 (8) Å, V = 3169.2 (3) Å3, and Z = 8. Direct
solution using 6546 unique reflections with SHELXL-97
gave a final R1 = 0. 0316 and R2 = 0. 0794.
(14) Giam, C. S.; Hauck, A. E. Org. Prep. Proced. Int. 1977, 9, 5.
(15) Kurita, J.; Yoneda, T.; Kakusawa, N.; Tsuchiy, T. Chem.
Pharm. Bull. 1990, 38, 2911.
Synthesis 2007, No. 15, 2351–2359 © Thieme Stuttgart · New York