Intermolecular photocyclizations of N-(ω-hydroxyalkyl)- tetrachlorophthalimide with alkenes leading to medium- and large-ring heterocycles-reaction modes and regio- and stereoselectivity of the 1,n-biradicals

Article abstract of DOI:10.1002/chem.200902849

A new photocyclization strategy by using intermolecular tandem reactions between N-(ω-hydroxyalkyl)-4,5,6,7-tetrachlorophthalimides (1, 2, and 3) and a series of acyclic and cyclic alkenes is reported. Electron transfer of the triplet-excited phthalimide with the alkene and regioselective trapping of the alkene cation radical by the hydroxyl group at the phthalimide side chain gives a triplet 1,n-biradical, which after intersystem crossing (ISC) leads to regio- and diastereoselective synthesis of polycyclic heterocycles with an N,O-containing medium to large ring. Regio- and diastereoselectivity in the cyclizations are clarified by unambiguous steric structure assignments of the products by X-ray diffraction or extensive 2D NMR measurements. The diastereoselectivity is decided by the stereochemical course of the ISC process of the triplet 1,n-biradicals. These intermolecular photoreactions also furnish a new strategy to generate triplet 1,n-biradicals. Therefore, in photoreactions of 1 and 2 with phenylcyclohexene, the unprecedented stereoselective formation of products by intramolecular hydrogen-atom transfer in the 1,n-biradical intermediate was found (9 and 23). These facts provide direct verification to the reaction pathways of the 1,n-biradicals and give a new insight into the factors deciding reaction-pathway partitioning and stereoselectivity.

Full text of DOI:10.1002/chem.200902849

FULL PAPER
DOI: 10.1002/chem.200902849
Intermolecular Photocyclizations of N-(w-Hydroxyalkyl)-
tetrachlorophthalimide with Alkenes Leading to Medium- and Large-Ring
Heterocycles—Reaction Modes and Regio- and
Stereoselectivity of the 1,n-Biradicals
Yong-Miao Shen,[a, b] Xiao-Liang Yang,[a] Da-Qing Chen,[a] Jie Xue,[a] Liang Zhu,[a]
Hoong-Kun Fun,[c] Hong-Wen Hu,[a] and Jian-Hua Xu*[a]
Abstract: A new photocyclization strat-
egy by using intermolecular tandem re-
actions between N-(w-hydroxyalkyl)-
4,5,6,7-tetrachlorophthalimides (1, 2,
and 3) and a series of acyclic and cyclic
alkenes is reported. Electron transfer
of the triplet-excited phthalimide with
the alkene and regioselective trapping
of the alkene cation radical by the hy-
droxyl group at the phthalimide side
with an N,O-containing medium to
large ring. Regio- and diastereoselec-
tivity in the cyclizations are clarified by
unambiguous steric structure assign-
ments of the products by X-ray diffrac-
tion or extensive 2D NMR measure-
ments. The diastereoselectivity is decid-
ed by the stereochemical course of the
ISC process of the triplet 1,n-biradicals.
These intermolecular photoreactions
also furnish a new strategy to generate
triplet 1,n-biradicals. Therefore, in pho-
toreactions of 1 and 2 with phenylcy-
clohexene, the unprecedented stereose-
lective formation of products by intra-
molecular hydrogen-atom transfer in
the 1,n-biradical intermediate was
found (9 and 23). These facts provide
direct verification to the reaction path-
ways of the 1,n-biradicals and give a
new insight into the factors deciding re-
action-pathway partitioning and stereo-
selectivity.
chain gives
a
triplet 1,n-biradical,
Keywords: biradicals
·
electron
which after intersystem crossing (ISC)
leads to regio- and diastereoselective
synthesis of polycyclic heterocycles
transfer · macrocycles · medium-
sized rings · stereoselectivity
Introduction
The pursuit of new strategies for the construction of
medium and large ring systems is one of the important tasks
in organic synthesis.[1] The formation of medium rings (7–9-
membered rings) is particularly difficult because of a combi-
nation of unfavorable enthalpic and entropic changes during
the cyclization process.[2] Even with the powerful ring-clos-
ing metathesis (RCM) strategy,[3] successful synthesis of
medium-sized rings usually requires rather stringent reaction
conditions, such as high dilution of the reactants, high cata-
lyst loading, and a long reaction time. Furthermore, a con-
formational predisposition in the substrate to bring the two
end groups close together is often required.[3c,4]
In recent years, photoinduced cyclization reactions have
achieved remarkable success in medium and large-ring syn-
thesis[5] and emerged as an important alternative method to
the thermal cyclization reactions. Presently, one of the most
successful photochemical synthetic strategies for medium to
large rings is based on intramolecular cyclizations of the N-
substituted phthalimides initiated by photoinduced electron
[a] Dr. Y.-M. Shen, Prof. X.-L. Yang, D.-Q. Chen, Dr. J. Xue, Dr. L. Zhu,
Prof. H.-W. Hu, J.-H. Xu
Institute of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210093 (China)
Fax : (+86)25-83371161
E-mail: xujh@nju.edu.cn
[b] Dr. Y.-M. Shen
Institute of Chemistry and Chemical Engineering
Shaoxing University, Shaoxing 312000 (China)
[c] Prof. H.-K. Fun
X-ray Crystallography Unit, School of Physics
Universiti Sains Malaysia, George Town 11800 (Malaysia)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902849. It contains copies of
1H NMR spectra for all new compounds, 13C NMR spectra for com-
pounds 6–10, 15, 21–24, 26, and 28, 2D and DEPT NMR spectral
data of compounds 9, 15, and 28, the ionization potential computation
of 17 and 18, CIF files for all X-ray structures, and optimized struc-
tures of compounds 15 and 16.
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transfer (PET) between the excited phthalimide moiety and
a remote electron donor group in the phthalimide side
chain. With a benzyl,[6] dialkylamino,[7] alkylthio,[8] alkoxy,[9]
or trimethylsilyl[10,11] group as the electron donor, the initial
PET event is followed by proton or trimethylsilyl transfer
from the donor cation radical to the oxygen atom of the
ketyl anion radical to give an 1,n-biradical, which then cy-
clizes to the product with the donor group incorporated into
the product. In contrast, when a carboxy anion is used as
the donor group, initial PET is followed by decarboxylation
to give the 1,n-biradical, which on collapse gives a cyclic
product without the donor group incorporation.[12,13] In
these products, the newly formed medium to large ring is
fused with an isoindolone (phthalimidine) skeleton, which is
itself an interesting structural motif[14] because of its wide
biological activity, occurrence in natural products, and its
role as a synthetic intermediate leading to valuable natural
and unnatural products. These photocyclization reactions
can usually be carried out with a rather high reactant con-
centration (0.01–0.1 molLÀ1) without the need for high dilu-
tion conditions. The two terminal groups can be linked by
flexible chains rather than a rigid spacer to fix the substrate
conformation, as in the thermal cyclizations. These advan-
tages, together with a remarkable synthetic versatility by al-
lowing wide changes in the donor group and the side-chain
length and structure make these photoinduced cyclizations
efficient tools for diversity-oriented ring synthesis. Another
useful photocyclization strategy is based on the intramolecu-
lar hydrogen abstraction reaction of a triplet np* excited
systems. These N,O-containing medium and large rings are
noteworthy synthetic targets. The oxazepines[20] and their
fused derivatives[21] have a wide range of biological activity,
and form the basis for the skeletons of the holstiine[22] and
concavine[23] alkaloids. Also, oxazocine derivatives have me-
dicinally important bioactivity.[24] As a result, the synthesis
of oxazepine[25,26] and oxazocine[26f,27] rings and their annu-
lated derivatives has attracted considerable research inter-
est. More importantly, we show that by rendering a new
strategy to generate the triplet 1,n-biradicals by an intermo-
lecular PET process, these photocyclization reactions have
provided a valuable opportunity to gain new insight into the
possible reaction modes of the 1,n-biradicals and the factors
deciding reaction-pathway partitioning and the regio- as
well as stereochemistry in these reaction pathways.
Results
Photocyclizations of N-(2-hydroxyethyl)-4,5,6,7-tetrachloro-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
À
À
carbonyl functionality from a Cg H (Cb H) or a more dis-
[15,16]
À
tant C H bond (the Norrish Type II—Yang reaction).
The resulting triplet 1,4- or 1,n-biradical, after intersystem
crossing (ISC) to the singlet state, cyclizes to the product.
Besides synthetic importance, the mechanistic aspects of
these intramolecular cyclizations have been under intensive
research and have made substantial contributions to our
present understanding of the 1,n-biradical reactivity and the
factors deciding the reaction pathway competition and the
cyclization stereoselectivity.[17]
At the same time, photocyclizations based on intermolec-
ular PET reactions have rarely been investigated. A few
years ago, we reported the first examples on the photochem-
ical medium and large-ring synthesis by intermolecular PET
reactions of N-(w-hydroxyalkyl)-4,5,6,7-tetrachlorophthal-
imide with alkenes.[18] We envision that, intermolecular pho-
tocyclizations offer some special advantages, for example,
high dilution conditions is inherently unnecessary due to the
intermolecular nature of the reaction, and the wide possibili-
ty in changing the phthalimide side chain and the alkene
structure enables them to be versatile in constructing poly-
cyclic heterocycles of various ring sizes and structures. In
our continuous efforts to develop new photocyclization
strategies,[19] we report here photocyclizations of the N-(w-
hydroxyalkyl)-4,5,6,7-tetrachlorophthalimides with several
acyclic and cyclic alkenes to show their applications in the
synthesis of annulated seven-membered oxazepine and the
eight-membered oxazocine derivatives, as well as larger ring
good yields. Photoreactions of 1 (0.025 moldmÀ3) with an
excess amount of styrene in benzene afforded a pair of dia-
stereomeric cyclization products, the cis-6 (1R,11bS; 33%)
and the trans-7 products (1R,11bR; 33%; cis and trans refer
to the steric relationship between the hydroxyl and the
phenyl groups). The steric structures of 6 and 7 were deter-
mined by X-ray crystallographic analyses (Figure 1). The
cyclizations are regioselective, with the alkeneꢁs b-carbon
atom linking to the side-chain oxygen atom in 1 and the al-
keneꢁs a-carbon atom linking to the C-1 atom in 1, leading
to the formation of a 1,4-oxazepine ring. Photocyclizations
of 1 with 1-phenylcyclopentene under similar conditions
proceeded with the same regioselectivity, but this reaction is
also stereoselective giving product
8 (3aR,12bR,12cR)
(71%) as the sole product as evidenced by X- ray crystallo-
graphic analysis.[28] Meanwhile, in the photocyclizations of 1
with 1-phenylcyclohexene, an uncyclized product 9 (13%)
and a cyclized product 10 (4aR,13bR,13cR; 52%) were
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Synthesis of Medium- and Large-Ring Heterocycles
FULL PAPER
Figure 2. ORTEP drawing of product 10.
two enantiomers, as illustrated in Figure 3 with compound
10 as an example. Photoreaction of 1 with the heterocyclic
alkene furan gave the cyclization products 11, 12 (total yield
Figure 3. Packing diagram of product 10.
14%), 13 (16%), and an uncyclized product 14 (33%).
Compounds 11 and 12 were obtained as a mixture of diaste-
reomers in a ratio of ꢀ10:2. In 11 and 12, the furanꢁs C2
and C3 atoms are linked to the side-chain oxygen and C1
atoms in 1, respectively, resulting in an acetal structure. In
compound 13, the two a-carbon atoms in the furan are both
involved in bond formation with 1. The crystal structure of
13 is shown in Figure 4. A control experiment showed that,
14 was formed in a secondary photoreaction of 13 under the
reaction conditions. In the photoreaction of 1 with benzofur-
an, two diastereomeric cyclization products 15 (36%) and
Figure 1. ORTEP drawing of compounds 6 (above) and 7 (below).
formed, with the latter being predominant. A control experi-
ment showed that 10 is a primary product and is not formed
by secondary photoreactions of 9 under irradiation. The
steric structure of 9 was established by a set of DEPT, H-H
COSY, HMQC, HMBC, and NOESY NMR spectroscopic
measurements (see the Supporting Information), which
show that the phenyl and alkoxy groups in the cyclohexane
ring are cis to each other. The steric structure of 10 was es-
tablished by X-ray crystallographic analysis (Figure 2). The
molecular packing diagrams of the crystal samples of 6, 7, 8,
and 10 show that they are all racemates, each consisting of
Figure 4. ORTEP drawing of 13.
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J.-H. Xu et al.
16 (41%) with an acetal structure were formed in compara-
ble yields. DEPT and extensive 2D NMR (H–H COSY,
HMQC, HMBC, and NOESY) spectroscopic studies indicat-
ed that 15 has a relative configuration of (5aR,14bS,14cR),
À
in which the two methine protons (HCACTHNUTRGENNGU(5a) CACHTUNTGREN(NUNG 14c)H) are
cis to each other. Ground-state geometry optimization of
this isomer by DFT/B3LYP/6-31G computation[29] shows
that one of the ortho protons in the benzene ring of the ben-
zofuran is in the anisotropic shielding area of the tetrachlor-
obenzene ring in the phthalimide moiety (see the Support-
ing Information). As a result, its absorption is significantly
moved to the upfield area at d=6.37 ppm. The 1H NMR
spectroscopic coupling constants for the same two protons
in 16 are 6.8 Hz, showing that, in this compound, the furan
ring is also fused to the seven-membered ring in a cis fash-
ion.[30] Therefore, 16 has a (5aR,14bR,14cR) configuration.
Figure 5. ORTEP drawing of 17.
nylcyclopentene gave 22 (3aR,13bR,13cR); 48%) regio- and
diastereoselectively (Figure 6), whereas in a similar photoly-
sis of 2 with 1-phenylcyclohexene, the uncyclized 23 (36%)
and the cyclized 24 (4aR,14bR,14cR; 26%) (Figure 6) were
formed together with a small amount of secondary product
25 (4%).
Photoreactions of N-(3-hydroxypropyl)-4,5,6,7-tetrachloro-
A
2
AHCTUNGTRENNUNG
(24%) and cis-18 (1%; in regard to the steric relationship of
the hydroxyl and the phenyl groups), and an oxazinoisoin-
dole product 19 (9%).[31] The crystal structure of 17 is
shown in Figure 5. Control experiments showed that, both
17 and 18 are photostable, and photolysis of either 17 or 18
in benzene caused no appreciable decomposition. However,
irradiation of cis-18 in the presence of 2 led to the transfor-
mation of 18 into 19. This is why the yield of 18 is low rela-
tive to 17. Similar photoreactions of 2 with a-methylstyrene
gave, in addition to the cyclization product 20 (30%, tempo-
rarily assigned as a (1R,2bR) product by spectral compari-
Figure 6. ORTEP drawing of compounds 22 (above) and 24 (below).
Photocyclizations of 2-{2-[2-(2-hydroxyethoxy)ethoxy]eth-
AHCTUNGERTGoNNUN xy}ethyl 4,5,6,7-tetrachloro-1,3-dihydro-1,3-dioxo-2H-isoin-
dole-2-acetate (3) with alkenes: Photoreactions of 3 with 1-
phenylcyclopentene furnished the trans-fused cyclization
product 26 (3aR, 24bR,24cS) in 17% yield (Figure 7). Simi-
son with 4, 5, 6, 7, and with 17, 18), a dibenz
ACHTUNGTREN[NUNG cd,f]indol-
4(5H)one product 21 (2%). Photoreactions of 2 with 1-phe-
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Synthesis of Medium- and Large-Ring Heterocycles
FULL PAPER
Scheme 1. Proposed photocyclization mechanism.
(SCE, MeCN) as measured by cyclic voltammetry and a
triplet energy (ET) of 67 kcalmolÀ1 as measured by phos-
phorescence spectral measurements. Therefore, TCP is a
stronger excited electron acceptor than triplet excited N-
methylphthalimide (excited reduction potentials are 1.96
and 1.66 V (SCE) respectively). The absorption maxima of 1
in the UV spectrum is at 237 (emax =67937mÀ1 cmÀ1) and
333 nm (emax =2737mÀ1 cmÀ1). The free-energy changes for
electron transfer between 3TCP* and 1,1-diphenylethene
(E1/2 =1.91 V, SCE, MeCN) and a-methylstyrene (E1/2
=
2.13 V, SCE, MeCN) in benzene are slightly endothermic
with DGET of 7.7 and 12.8 kcalmolÀ1, respectively, as esti-
mated by the Weller equation.[32a] The photocyclizations of
N-substituted phthalimides are in most cases in the triplet
reaction channel.[32b–d] In contrast to the weekly fluorescent
N-methylphthalimide, with the internal heavy atom effect of
the four chloro atoms, TCP has no measurable fluorescence.
We have found that in xanthone (ET =74 kcalmolÀ1) sensi-
tized photolysis of 1 with 1-phenylcyclohexene, products 9
(21%) and 10 (33%) are both formed. In the xanthone-sen-
sitized photoreaction of 1 with styrene, the same products 6
and 7 are formed. Therefore, we envisage that these photo-
cyclizations proceed at least predominately by the triplet
channel. In the triplet ion-radical pair formed in the PET
event (Scheme 1), the cation radical of the alkene is inter-
molecularly captured at the b-carbon atom by the hydroxyl
group in the phthalimide side chain, resulting in the forma-
tion of an 1,7-biradical (I in Scheme 1). Because of the trip-
let nature, further transformations of this biradical involving
bond forming or breaking must be preceded by an intersys-
tem crossing (ISC) leading to its singlet state. By analogy
with the much investigated reaction patterns of the triplet
1,4-biradicals typically found in the Norrish Type II–Yang
reactions leading to 1-hydroxybutane-1,4-diyl radicals[15–17]
and in the Paterno–Bꢂchi reactions leading to 2-oxabutane-
Figure 7. ORTEP drawing of 26 (above) and 27 (below).
lar photoreactions of 3 with 1-phenylcyclohexene, on the
other hand, gave the diastereomeric 27 (4aR,25bR,25cS;
7%; Figure 7) and 28 (4aR,25bS,25cR; 21%). The steric
structure of 28 is based on a set of NMR spectroscopic
measurements (DEPT, H–H COSY, HMQC, HMBC, and
NOESY, see the Supporting Information). In these cases, a
19-membered ring is constructed.
Discussion
Photocyclization reaction mechanism: These photocycliza-
tion reactions are proposed to be initiated by photoinduced
electron transfer (PET) of the triplet excited phthalimide
moiety with the alkene (Scheme 1, with the reaction of 1
with 1-phenylcyclohexene as an example). As a model com-
pound for 1, 2, and 3, N-methyl-4,5,6,7-tetrachlorophthal-
imide (TCP) has a half wave reduction potential of À0.95 V
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J.-H. Xu et al.
1,4-diyl radicals,[33] three possible decay pathways for the
singlet 1,7-biradicals formed in the ISC process can be envis-
aged: 1) Intramolecular radical-pair combination to give the
cyclization products. 2) Intramolecular hydrogen-atom trans-
fer to give uncyclized products. 3) b-Cleavage of one of the
s-bonds next to the two radical centers to give fragmenta-
tion products. These transformation pathways for the triplet
1,4-biradicals are now widely accepted. Also, photocycliza-
tion reactions via other 1,n-biradicals such as 1,5-,[34]
1,6-,[34,35] and 1,7-[34,36] biradicals and those with even longer
chains to intervene the two radical centers[16] have been re-
ported. However, there has been no report as yet that re-
flects the whole mechanistic pattern for these 1,n-biradicals
because it is noted that in the Norrish Type II–Yang reac-
tion, the 1,4-biradical is formed by intramolecular hydrogen
abstraction, and a back hydrogen-atom transfer reverts the
1,4-biradical back to the start-
from b-cleavage by either pathway (a) or (b) in Scheme 1.
We envision that these b-cleavage reactions in the 1,7-birad-
icals would not be energetically as favorable as that in the
1,4-biradicals in which in conformations with the radical p
À
orbitals overlapping with the s orbital of the central C C
bond,[40] b-cleavage eliminates the two radical centers to
give closed-shell molecules. In contrast, b-cleavage by either
way in the 1,7-biradical I would give another biACTHNUTRGENUGrN adical (a
1,5-biradical here) together with a neutral molecule as pri-
mary products.
Several byproducts from secondary or side photoreactions
were also found in the photocyclizations. Compound 14 is
derived from the primary product 13 probably by a secon-
dary PET reaction between an excited 1 (or 13) with a
À
ground-state 13 (Scheme 2). C O bond scission in the
formed cation radical of 13 leads to a distal cation radical
ing material, and this process
can only be perceived indirectly
by the less-than-unity quantum
yield for product formation.[37]
In contrast with this situation,
in the photocyclizations of 1
and 2 with the alkenes, the 1,7-
(such as I in Scheme 1) and 1,8-
Scheme 2. Proposed mechanism for the formation of 14.
biradicals have
a
different
origin, and intramolecular dis-
proportionation gives products
(9 and 23) different from the starting materials (1 or 2 and
the alkene). This provides an unprecedented opportunity to
directly verify and examine this reaction pathway in the 1,n-
III. Deprotonation of the cationic furan moiety and back
electron transfer from the anion radical of 1 (or 13) to the
oxygen radical in III followed by protonation afford 14. Al-
ternatively, deprotonation of the cationic furan moiety and
hydrogen abstraction of the oxygen radical also give the
product (Scheme 2), although we have not found any prod-
uct derived from the anion radical of 1 (or 13).
A possible explanation for why the secondary product 19
is only formed from the photolysis of 18 in the presence of
2, but not from 17 is that the thermodynamically less stable
cis-18 might have lower oxidation potential than trans-17.
This is supported by a DFT computation (B3LYP/6-31G)[30]
on their ionization potentials (IP) that shows that the IP of
18 is 0.21 eV lower than that of 17 (see the Supporting In-
formation). SET between exited 2 and 18 leads to the cation
radical of 18 (Scheme 3). Intramolecular nucleophilic attack
of the hydroxyl group to the a-carbon atom of the oxygen-
biradical. The triplet 1,n-bi
ACHTUNGTRNErNUNG adicals are known to have rather
long lifetimes[38] to reach a conformational equilibrium prior
À
À
to ISC by the side-chain C C and C O bond rotations. As a
result, ISC may take place in different conformations suita-
ble for ISC. Since once the 1,n-biradical transforms to the
singlet state, immediate decay by the three competing path-
ways ensures, and each of these pathways has its own con-
formational and stereoelectronic requirements, the partition-
ing of the reaction pathways should be conformation depen-
dent. The cyclization products (4–8, 10, etc.) are formed in
the singlet 1,7-biradicals derived from the triplet precursor
in conformations with the two singly occupied p orbitals
close and oriented suitably to each other within bond-form-
ing distance (ꢀ3 ꢃ).[39] Competitive hydrogen-atom transfer
can also take place in the same singlet biradicals to give the
uncyclized products (9 and 23), although the latter products
may also be derived from other biradical conformations
with the two p orbitals separat-
À
centered cation radical results in C O bond cleavage to give
IV, which on back SET from 2 followed by protonation or
ÀC
on direct hydrogen abstraction gives 19 (Scheme 3).
ed by a longer distance.[39c–e]
Meanwhile, ISC in the triplet
conformations with the two p
orbitals located far apart
beyond bond-forming distance
may result in b-cleavage of the
biradical. However, we have
not found any products derived Scheme 3. Proposed mechanism for the formation of 19.
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Synthesis of Medium- and Large-Ring Heterocycles
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The dibenz
[cd,f]indol-4(5H)one product 21 formed in the
This also gives the most stable radical because computation-
al results show that an allylic radical (as VII in Scheme 5) is
7 KcalmolÀ1 more stable than an a-oxymethylene radical (as
VIII in Scheme 5).[46] This significant difference in radical
stability is also the reason for the regioselectivity found in
Paterno–Buchi reactions of triplet np* carbonyl compounds
with furan, which give oxetane products with an acetal struc-
ture.[47]
photoreaction of 2 with a-methylstyrene is most likely de-
rived from the reaction sequence shown in Scheme 4. It is
Scheme 4. Proposed mechanism for the formation of 21.
Scheme 5. Formation of 11, 12, and 13 from biradical intermediates.
known that the photoreaction of N-methyl-4,5,6,7-tetrachlo-
ACHTUNGTRENNUNGroACHTUNGTRENNUNGphthalimide with styrene derivatives proceeds by the Pa-
terno–Bꢂchi reaction pathway to give spirooxetane prod-
ucts[41] rather than by insertion of the alkene into the phtha-
The delocalized spin distribution in the allylic radical in
VII results in two ways of intramolecular radical-pair combi-
nation to give products 11, 12 (via resonance structure
VIIA), and 13 (via resonance structure VIIB). The regiose-
lectivity in 13 has not been found in previously reported
photocycloaddition reactions and other PET-induced reac-
tions of furan via a triplet biradical intermediate.[47] It is
likely that in such reactions as in the Paterno–Bꢂchi reac-
tion, the short intervening chain between the two radical
centers impedes the 1,5-biradical (as IX in Scheme 6) to
reach an unstrained low energy conformation active for ISC
with the two spin-bearing p orbitals orthogonal within bond
formation distance. As a result, only the oxetane product
(via an 1,4-biradical) is formed. Meanwhile, in the photocyc-
lizations of furan with 1, the long flexible chain linking the
two radical centers allows the occurrence of such an un-
strained ISC conformation.
À
limide C(O) N bond as in the photoreaction of the ring-un-
substituted N-methylphthalimide with alkenes.[42] In the pho-
toreaction of
2
with a-methylstyrene, Paterno–Bꢂchi
reaction competes with the photocyclization to give a spi-
rooxetane product (Scheme 4). Subsequent photoinduced
carbonyl–olefin metathesis of the oxetane product[43] gives
V. Photoinduced conrotatory electrocyclization in V affords
VI with the H and Cl atoms trans to each other. Elimination
of hydrogen chloride in VI furnishes 21.
Regioselectivity in the photocyclization reactions: All the
photocyclizations described above are highly regioselective.
The alkene cation radical is trapped by the hydroxyl group
at the phthalimide side chain in an anti-Markovnikov fash-
ion so that in the cyclized products, the alkeneꢁs b-carbon
atom is bonded to the oxygen atom, whereas the a-carbon
atom is linked to the phthalimide ketyl carbon atom. This
regioselectivity was previously found in cyanoarene-sensi-
tized nucleophilic trapping of the cation radical of aromatic
alkenes by alcohol,[44a] water,[19b] and other nucleophiles[44b]
and in the alcohol trapping of the alkene cation radical in
the intramolecular PET reaction of N-substituted phthal-
imide derivatives.[45] This selective anti-Markovnikov addi-
tion of the alcohol to the alkene in the photocyclizations re-
sults in the formation of a more stable benzyl radical in the
1,n-diradical intermediate (as I in Scheme 1) rather than a
less stable b-phenylmethylene radical (as II in Scheme 1),
which indicates thermodynamic control of the trapping reac-
tion owing to the sufficiently long lifetime of the formed
triplet 1,n-biradical intermediates.[38]
Scheme 6. Biradical intermediates in furanꢁs Paterno–Bꢂchi reaction.
Diastereoselectivity in the photocyclizations: Depending on
the structures of the alkenes, two or three stereogenic cen-
ters are created during these photocyclizations, leading to
diastereomeric cyclization products. The observed degree of
diastereoselectivity, however, is quite different from case to
In the photocyclizations with furan and benzofuran, the
regioselectivity in products 11, 12, 15, and 16 arises from the
trapping of the furan at its a-carbon atom by the hydroxyl
group, giving an acetal structure of the cyclization products.
Chem. Eur. J. 2010, 16, 2873 – 2886
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2879

J.-H. Xu et al.
case. For the acyclic terminal alkenes (styrene and a-methyl-
styrene) in which two new chiral atoms emerge in the cycli-
zation, both diastereomers are formed. In contrast, in the
photocyclizations with the cyclic alkenes (1-phenylcyclopen-
tene and 1-phenylcyclohexene) in which three new chiral
centers are created, the cyclizations are highly diastereose-
lective, with only one out of the four possible diastereomers
actually formed. Many theoretical[48] and experimental[49]
pieces of work have shown that, in a triplet biradical, the
ISC efficiency is highly conformation dependent. In an
active conformation for efficient ISC, the two spin-bearing
p-orbitals should be nearly orthogonal to each other. It is
believed that, in photocyclization reactions via the interme-
diacy of triplet 1,n-biradieals, it is these active ISC confor-
mations of the biradical that decide the product stereochem-
istry because once the biradical is switched to the singlet po-
tential energy surface, immediate radical-pair combination
takes place, and the product is locked in a stereochemistry
inherited from the biradical conformation before ISC, re-
flecting a stereochemical memory to the conformation of its
triplet precursor. This concept has been confirmed in many
cases, not only in reactions via a triplet 1,4-biradical (the
Norrish type II–Yang[17a–d] and Paterno–Bꢂchi re-
is still not sterically hindered. However, ISC in B by inward
rotation of the a-phenylethyl p orbital would bring the
methyl to approach the phthalimide plane closely and cause
significant steric hindrance between them. The resulting
higher energy barrier makes the cis-product 5 the minor
product (trans-4/cis-5 56:22). Two other ISC conformations
of the 1,7-biradicals with the benzyl radical center located
beneath (at the Se face of) the phthalimide carbonyl plane
can also be envisioned, these are enantiomeric to A and B,
respectively, and ISC followed by radical-pair combination
from these two additional ISC conformations gives the
enantiomers of 4, 5, 6, and 7, respectively, to make each of
them a racemate.
In the photocyclizations with the cyclic alkenes 1-phenyl-
cyclopentene and 1-phenylcyclohexene, three new chiral
centers are formed in the products, and four pairs of diaste-
reomeric racemers (RRR–SSS, RRS–SSR, RSS–SR, and
RSR–SRS in terms of the relative configuration of the three
chiral atoms C(3a), C
ACHTUNGERTN(UNGN 12b), and CAHCTUNRTGENN(GUN 12c) and C(4a), CACHTUNGTRENNUNG(13b),
and C(13c) for products from 1-phenylcyclopentene and 1-
AHCTUNGTRENNUNG
phenylcyclohexene, respectively) may be formed. However,
in the reactions of 1 with 1-phenylcyclopentene, only the
RRR–SSS product 8 is actually found. In this case, in the
A
possible
active
conformation
leading
to
this
1,5-,[34] 1,6-,[34,35] and 1,7-[34,36] biradical intermediates.
(3aR,12bR,12cR) product (C in Scheme 8a), in which the
two p orbitals are orthogonal to each other within bond-for-
mation distance (ꢀ3 ꢃ), as a result of the orthogonality of
the two p orbitals, the 2-phenylcyclopentyl plane is orthogo-
nal to the phthalimide framework, with the phenyl situated
upward, and this conformation is not sterically strained.
Also, the ISC process in C via the 1-phenylcyclopentyl p or-
bital inward rotation causes no increase in steric hindrance
and may benefit from the emerging p–p stacking interaction
between the phenyl and the phthalimide framework. The
conformers suitable for ISC to give the RRS and SRS prod-
ucts (conformers D and F in Scheme 8) are rather similar to
conformation B in Scheme 7, with a more sterically demand-
ing cyclopentyl ring here to replace the hydrogen atom and
methyl group in B. Although D and F are not significantly
sterically strained, in these conformers, however, the cyclo-
pentane ring is located above the phthalimide plane. The
ISC process by spin inversion in these cases would bring the
cyclopentane ring to approach the phthalimide Re face and
In the reactions of excited 1 with the alkenes, the initial
intermediate is a triplet 1,7-biradical. For styrene and a-
methylstyrene, the 1,7-biradical has a flexible intervening
chain. By inspection of the molecular models, the two active
conformations for ISC and subsequent product formation
with the benzyl radical placed above (at the Re face of) the
prochiral phthalimide carbonyl plane are shown in
Scheme 7. ISC in conformer A by spin inversion (inward ro-
tation of the benzyl horizontal p orbital) gives the trans-
Scheme 7. Left) ISC conformation leading to product 4 (or 7). Right) ISC
conformation leading to product 5 (or 6).
À
cause severe steric hindrance between the cyclopentane C
(1R,11bR) products 4 and 7,
whereas ISC from conformer B
leads to the cis-(1R,11bS) prod-
ucts 5 and 6, respectively. It is
seen that, for styrene, ISC from
both A and B experiences no
significant steric hindrance.
Therefore, the two products 6
and 7 are formed in similar
Scheme 8. a) ISC conformation leading to product
(3aR,12bR,12cS) product. c) ISC conformation for a (3aS,12bR,12cR) product. d) ISC conformation for a
styrene, ISC from conformer A (3aS,12bR,12cS) product.
8 (3aR,12bR,12cR). b) ISC conformation for a
yields. In the case of a-methyl-
2880
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Chem. Eur. J. 2010, 16, 2873 – 2886

Synthesis of Medium- and Large-Ring Heterocycles
FULL PAPER
H bonds and the phthalimide framework. This explains why
the RRS and SRS products are not found in the photocycli-
zations. In the conformation leading to the SRR product (E
in Scheme 8), similar to C, the phenyl plane is above the
phthalimide ring. However, there is severe steric congestion
À
ation of the active ISC conformations as in the reactions of
1 with the same alkenes can be applied here except that
1) the spacer to link the two spin-bearing p orbitals is slight-
ly more flexible here in the 1,8-biradical and 2) the forma-
tion of an eight-membered ring is less feasible than the
seven-membered ring because of the unfavorable entropic
factor. These two factors explain the parallelism in the dia-
stereoselectivity in the reactions of 1 and 2 with the same
alkene. They also provide a rationalization to the fact that
in the photoreactions of 2 with 1-phenylcyclohexene, the un-
cyclized/cyclized product ratio (23/24 1.38:1) is higher than
in the reactions of 1 (9/10 1:4).
between one of the phenyl CACTHNUTRGENUGN(ortho) H bonds and the imide
À
À
À
side chain (N CH2 CH2 O), which also causes serious
steric hindrance to the ISC process through the 1-phenylcy-
clohexyl p orbital (and the phenyl) rotation. This is likely
the reason for the absence of the SRR product.
Photoreactions of 1 with 1-phenylcyclohexene also give
only one cyclization product 10 (52%) with the same rela-
tive configuration for the three newly formed chiral carbon
atoms (4aR,13bR,13cR). The ISC conformation leading to
this product (G in Scheme 9) is similar to C in Scheme 8.
Conclusion
Intermolecular photocyclization reactions between N-(w-hy-
droxyalkyl-4,5,6,7-tetrachlorophthalimide and alkenes are
achieved by a tandem reaction sequence of photoinduced
electron transfer of triplet phthalimide with the alkene, in-
termolecular nucleophilic trapping of the alkene cation radi-
cal, and intramolecular radical-pair combination of the
formed 1,n-biradical. These photocyclizations lead to the
regio- and diastereoselective synthesis of polycyclic hetero-
cycles with a newly formed medium-to-large ring of various
structures and are especially efficient in constructing the
seven and eight-membered medium-sized rings (oxazepines
and oxazocines) from easily accessible starting materials.
Regio- and diastereoselectivity in these reactions are clari-
fied on the basis of unambiguous steric structure determina-
tion of the products by either X-ray diffraction or extensive
2D NMR spectroscopic measurements. Regioselectivity in
the nucleophilic trapping of the alkene cation radical is dic-
tated by the formation of the most stable radical intermedi-
ate. This results in a selective addition of the hydroxyl at the
b-carbon atom of the styrene derivatives. Diastereoselectiv-
ity in the photocyclizations is, on the other hand, decided by
the stereochemistry in the active ISC conformations of the
triplet 1,n-biradical intermediate, which, in turn, is depen-
dent on the structure of the alkene and the phthalimide side
chain. The stereoselective formation of the uncyclized prod-
ucts 9 and 23 represents the first examples of the formation
of intramolecular hydrogen-atom transfer products that are
structurally different from the starting materials, providing a
direct verification to this process in the 1,n-biradicals. There-
fore, as a new strategy to generate 1,n-biradicals, these pho-
tocyclizations have given new insight into the 1,n-biradical
reactivity concerning possible reaction pathways and the fac-
tors governing the competition and the stereoselectivity in
these reactions. These results also demonstrate the synthetic
potential of the strategy of using electron acceptors with a
side chain bearing a nucleophilic group (such as a hydroxyl)
in PET-induced tandem reactions for the construction of
polycyclic ring systems.
Scheme 9. Left) ISC conformation leading to a (4aR,13bR,13cR) product.
Right) ISC conformation for a (4aS,13bR,13cR) product.
The possible active ISC conformations that would lead to
the RRS, SRS products are similar to D and F in Scheme 8,
which would cause severe steric hindrance during the ISC
process by bringing the cyclohexane ring to approach the
phthalimide plane. The ISC conformation that would lead to
an SRR product (H in Scheme 9) is similar to E in
Scheme 8, which has significant steric congestion in the
static ISC conformation and also causes steric hindrance in
the ISC process. At the same time, since in the uncyclized
product 9, the two methine protons in the cyclohexyl are cis
to each other, this product cannot be formed by hydrogen
transfer in the singlet biradical derived by ISC from confor-
mation G in competition with cyclization. Neither could it
be derived by ISC from a triplet conformation similar to F
in Scheme 8. ISC from these conformations followed by hy-
drogen-atom transfer would lead to an uncyclized product
with the two cyclohexane methine protons trans to each
other. Product 9 can be formed, however, from triplet con-
formations similar to H (Scheme 9) and E (Scheme 8) albeit
with a “looser” geometry with an increased distance be-
tween the two spin-bearing p orbitals[39c–e] to ease the steric
hindrance both in the static ISC conformation and during
the ISC process. ISC followed by hydrogen-atom transfer in
one or both of these two types of low-energy conformations
delivers the hydrogen atom to the cyclohexyl C2 atom from
the opposite side of the alkoxy group to give product 9.
In the photocyclizations of 2 with the alkenes, a triplet
1,8-biradical is formed as an intermediate. Similar consider-
Chem. Eur. J. 2010, 16, 2873 – 2886
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2881

J.-H. Xu et al.
50.5, 67.2, 70.6, 92.6, 126.9, 127.5, 127.8, 128.3, 128.4, 135.3, 137.0, 137.5,
143.2, 163.4 ppm; MS m/z (%): 413 [M+À18] (0.21), 312 (100), 310 (97),
268 (9), 266 (6), 77 (4), 44 (4); elemental analysis calcd (%) for
C18H13Cl4NO3: C 49.92, H 3.03, N 3.23; found: C 49.75, H 3.19, N 3.21.
Experimental Section
General: Melting points were measured on a Keyi XT3A microscopic
melting point apparatus and are uncorrected. 1H NMR spectra were re-
corded on a Bruker DPX 300 spectrometer with CDCl3 as the solvent
unless otherwise specified. 13C NMR spectra were measured on a Bruker
Avance-400 spectrometer at 100 MHz with CDCl3 as the solvent. Chemi-
cal shifts (d) are reported in ppm relative to the residual undeuterated
solvent signal, and coupling constants (J) are given in Hz. DEPT and 2D
NMR measurements were carried out on a Bruker AC-500 spectrometer
X-ray structure analysis: C18H13Cl4NO3; M=433.09; monoclinic; space
group=P21/c; a=9.3322(2), b=9.6937(2), c=20.3059(4) ꢃ; a=90, b=
98.2690(10), g=908; V=1817.85(6) ꢃ; Z=4; 1calcd =1.582 gcmÀ3
AHCTUNGTRENNUNG
;
F-
(000)=880.0; absorption coefficient 0.670 mmÀ1; scan range for data col-
lection=2.21ꢁqꢁ46.458; 34450 measured reflections, 10932 indepen-
dent reflections, 9304 reflections with I>2a(I); Rint =0.0240, 239 refina-
ble parameters, R
[F2>2a(F2)]=0.0303, wR2 (F2)=0.0842.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
with CDCl3 as the solvent. IR spectra were taken with
a Nicolet
Photolysis of 1 with 1-phenylcyclopentene: A solution of 1 (658 mg,
2 mmol) and 1-phenylcyclopentene (1.44 g, 10 mmol) in benzene (80 mL)
was photolyzed for 29 h to reach a 99% conversion of 1. Workup as
before gave recovered 1 (7 mg) and product 8 (668 mg, 71%).
NEXUS870 spectrometer for samples in KBr pellets. Mass spectra (EI)
were recorded with a VG ZAB-HS spectrometer. Elemental analyses
were obtained by using a Heraeus CHN-O-Rapid analyzer. For X-ray
crystallographic analysis, the X-ray diffraction intensities and the unit-
cell parameters were determined on a Brucker SMART APEXII CCD
diffractometer by employing graphite-monochromated (MoKa) radiation
(l=0.71073 ꢃ) and operating in the w/2q scan mode. Data collection and
cell refinement were performed with APEX2 software. Structures were
solved by direct methods and refined by full-matrix least-squares on F2
with SHELXTL. Non-hydrogen atoms were refined by anisotropic dis-
placement parameters, and the positions of all hydrogen atoms were
fixed geometrically and included in estimated positions by using a riding
model.
9,10,11,12-Tetrachloro-12b-hydroxy-12c-phenyl-1,2,3,3a,5,6,12b,12c-octa-
hydro-8H-cyclopentaACHTGNUTREN[NNUG 6,7]ACHTUNRTGENN[GUN 1,4]oxazepinoACHTNUGERTN[NUGN 5,4-a]isoindol-8-one
(3aR,12bR,12cR-8): White block solid from chloroform/petroleum ether;
m.p. 266–2688C; IR (KBr): n˜ =3319, 3086, 2940, 2866, 1690, 1674, 1500,
1414, 751, 727, 703 cmÀ1 1H NMR (300m, 258C, CDCl3): d=1.28–1.40
;
(m, 1H), 1.61–1.73 (m, 1H), 1.91–2.06 (m, 2H), 2.72–2.83 (m, 1H), 2.92
(dd, 1H, J=13.6, 5.8 Hz), 3.71 (td, 1H, J=13.4, 5.0 Hz), 4.05 (td, 1H, J=
12.4, 3.7 Hz), 4.33 (dd, 1H, J=12.5, 4.9 Hz), 4.43 (dd, 1H, J=14.2,
3.4 Hz), 4.57 (s, 1H), 4.52–4.62 (m, 1H), 7.07 (d, 2H, J=5.0 Hz), 7.14–
7.24 ppm (m, 3H); 13C NMR (100 MHz, CDCl3, 258C): d=22.8, 31.7,
33.5, 40.9, 65.8, 72.5, 95.46, 95.54, 126.9, 127.0, 127.5, 128.0, 128.6, 128.8,
134.4, 136.8, 138.3, 144.4, 163.9 ppm; MS m/z (%): 453 [M+À18] (0.16),
298 (77), 296 (58), 268 (6), 144 (100), 129 (88), 128 (46), 115 (33), 44 (4);
elemental analysis calcd (%) for C21H17Cl4NO3: C 53.30, H 3.62, N 2.96;
found: C 53.16, H 3.79, N 2.81.
General procedures for the preparative photolysis of N-(w-hydroxyalkyl)-
4,5,6,7-tetrachlorophthalimide with alkenes in benzene solution: The
light source was a medium-pressure mercury lamp (500 W) in a glass
cooling water jacket to cut off the light of a wavelength shorter than
300 nm. The solution of N-(w-hydroxyalkyl)-4,5,6,7-tetrachlorophthali-
mide and alkene in benzene was purged with N2 for 30 min and then irra-
diated under continuous N2 purging. The reaction course was monitored
by TLC. After the reaction, the solvent was removed under reduced pres-
sure and the residue was separated by flash chromatography on a silica-
gel column with petroleum ether/ethyl acetate as the eluent (gradient
elution).
Photolysis of 1 with 1-phenylcyclohexene: A solution of 1 (658 mg,
2 mmol) and 1-phenylcyclohexene (1.58 g, 10 mmol) in benzene (80 mL)
was photolyzed for 30 h to reach an 89% conversion of 1. Workup as
above gave recovered 1 (71 mg), 9 (109 mg, 13%) and 10 (452 mg, 52%).
N[2-(2-Phenylcyclohexyloxy)ethyl]-4,5,6,7-tetrachlorophthalimide
White solid from ethyl acetate/petroleum ether; m.p. 160–1628C; IR
(KBr): n˜ =3464, 3031, 2926, 2855, 1709, 1406, 1092, 738, 702 cmÀ1
(9):
Photolysis of N-(2-hydroxyethyl)-4,5,6,7-tetrachlorophthalimide (1) with
styrene: A solution of 1 (658 mg, 2 mmol) and styrene (2.08 g, 20 mmol)
in benzene (80 mL) was photolyzed for 28 h to reach a 100% conversion
of 1. The solvent was removed under reduced pressure and the residue
was separated by flash chromatography on a silica-gel column with petro-
leum ether/ethyl acetate as the eluent to give 6 (287 mg, 33%) and 7
(289 mg, 33%).
;
1H NMR (300m, 258C, CDCl3, 500 MHz): d=1.21–1.41 (m, 4H), 1.62–
1.79 (m, 2H), 1.82–1.92 (m, 1H), 2.42–2.51 (m, 1H), 3.37–3.42 (m, 1H),
3.43–3.47 (m, 2H), 3.49–3.57 (m, 1H), 3.77–3.80 (m, 1H), 3.82–3.90 (m,
1H), 6.51 (t, 1H, J=7.5 Hz), 6.87 (t, 2H, J=7.3 Hz), 7.00 ppm (d, 2H,
J=7.3 Hz); 13C NMR (100 MHz, CDCl3, 258C): d=24.86, 25.97, 31.59,
34.87, 38.7, 50.70, 64.44, 81.91, 124.73, 126.87, 127.39, 127.48, 129.39,
139.45, 145.02, 163.01 ppm; MS m/z (%): 487 [M++2] (0.12), 312 (41),
310 (30), 158 (100), 130 (25), 91 (56), 44 (1.3); elemental analysis calcd
(%) for C22H19Cl4NO3: C 54.24, H 3.93, N 2.87; found: C 54.06, H 4.12, N
2.68.
8,9,10,11-Tetrachloro-1,4,5,11b-tetrahydro-11b-hydroxy-1-phenyl-
[1,4]oxazepino
from chloroform/petroleum ether; m.p. 278–2808C; IR (KBr): n˜ =3315,
2955, 2849, 1699, 1686, 1495, 1415, 765, 695 cmÀ1 1H NMR (300m, 258C,
ACHTUNGTRENNUNG[5,4-a]isoindol-7(2H)one (1R,11bS-6): White block solid
;
CDCl3): d=3.44 (brs, 1H), 3.62–3.72 (m, 2H), 3.81–3.94 (m, 2H), 3.99–
4.11 (m, 2H), 4.23 (d, 1H, J=12 Hz), 7.43–7.48 (m, 3H), 7.52–7.55 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3, 258C): d=41.0, 56.5, 69.0, 71.6,
90.4, 127.0, 127.7, 128.4, 128.8, 129.3, 129.4, 131.6, 135.6, 135.7, 137.9,
145.7, 162.3 ppm; MS m/z (%): 413 [M+À18] (0.21), 312 (100), 310 (95),
268 (8), 266 (5), 77 (3), 44 (7); elemental analysis calcd (%) for
C18H13Cl4NO3: C 49.92, H 3.03, N 3.23; found: C 49.63, H 3.22, N 3.18.
10,11,12,13,14-Tetrachloro-2,3,4,4a,6,7,13b,13c-octahydro-13b-hydroxy-
13c-phenyl-1H,9H-cyclohexaCAHTUNGTREN[NGUN 6,7]ACHTUNRTEGG[NNUN 1,4]oxazepinoACHTNUGRTEN[NUGN 5,4-a]isoindol-9-one
(4aR,13bR,13cR-10): White block solid from chloroform/petroleum
ether; m.p. 263–2648C; IR (KBr): n˜ =3327, 2933, 2860, 1688, 1672, 1468,
1414, 727, 705 cmÀ1 1H NMR (300m, 258C, CDCl3): d=1.02–1.21 (m,
;
1H), 1.24–1.41 (m, 1H), 1.61–1.82 (m, 3H), 2.47 (t, 1H, J=13.7 Hz), 3.04
(d, 1H, J=13.6 Hz), 3.73–3.97 (m, 2H), 3.92 (s, 1H), 4.19 (dd, 1H, J=
11.7, 5.1 Hz), 4.29–4.49 (m, 2H), 6.90–7.12 (m, 4H), 7.38–7.41 ppm (m,
1H); 13C NMR (100 MHz, CDCl3, 258C): d=19.6, 22.5, 26.5, 29.7, 41.3,
56.7, 71.1, 85.6, 96.9, 126.2, 127.1, 127.3, 127.7, 128.1, 128.4, 133.9, 136.6,
138.8, 146.2, 164.3 ppm; MS m/z (%): 485 [M+] (0.23), 312 (19), 298 (70),
296 (53), 158 (100), 130 (43), 129 (64), 115 (46), 91 (29), 77 (8); elemental
analysis calcd (%) for C22H19Cl4NO3: C 54.24, H 3.93, N 2.87; found: C
54.16, H 4.02, N 2.79.
X-ray structure analysis: C18H13Cl4NO3; M=433.09; monoclinic; space
group=Pca21; a=23.5432(4), b=10.7804(2), c=13.3435(2) ꢃ; a=90,
b=90, g=908; V=3386.65(10) ꢃ; Z=8; 1calcd =1.699 gcmÀ3; F
ACTHNUTRGNE(NUG 000)=
1760.0; absorption coefficient=0.719 mmÀ1; scan range for data collec-
tion=2.31ꢁqꢁ36.028; 47234 measured reflections, 9201 independent re-
flections, 8861 reflections with I>2a(I); Rint =0.0378, 474 refinable pa-
rameters, R
8,9,10,11-Tetrachloro-1,4,5,11b-tetrahydro-11b-hydroxy-1-phenyl-
[1,4]oxazepino[5,4-a]isoindol-7(2H)one (1R,11bR-7): White block solid
from chloroform/petroleum ether; m.p. 287–2898C; IR (KBr): n˜ =3287,
ACHTUNGTRENNUNG
[F2>2a(F2)]=0.0389, wR2 (F2)=0.1014.
X-ray structure analysis: C22H19Cl4NO3; M=487.18; monoclinic; space
group=P21/c, a=12.7858(6), b=8.9176(4), c=19.5307(9) ꢃ; a=90, b=
104.3210(10), g=908; V=2157.66(17) ꢃ; Z=4; 1calcd =1.500 gcmÀ3; F-
ACHTUNGTRENNUNG
3087, 2958, 2937, 2885, 1689, 1674, 1496, 1419, 1370, 782, 769, 704 cmÀ1
;
AHCTUNGTRENNUNG
(000)=1000.0; absorption coefficient=0.574 mmÀ1; scan range for data
1H NMR (300m, 258C, CDCl3): d=3.62–3.72 (m, 1H), 4.01–4.08 (m, 3H),
4.19–4.33 (m, 2H), 4.37–4.47 (m, 1H), 4.54 (dd, 1H, J=13.3, 3.1 Hz),
7.08–7.13 ppm (m, 5H); 13C NMR (100 MHz, CDCl3, 258C): d=43.8,
collection=2.81ꢁqꢁ24.918; 17683 measured reflections, 5474 indepen-
dent reflections, 3513 reflections with I>2a(I); Rint =0.0350, 275 refina-
ble parameters, R
[F2>2a(F2)]=0.0440, wR2 (F2)=0.1142.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
2882
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2873 – 2886

Synthesis of Medium- and Large-Ring Heterocycles
FULL PAPER
Photolysis of 1 with furan: A solution of 1 (987 mg, 3 mmol) and furan
(4.08 g, 60 mmol) in benzene (120 mL) was photolyzed for 44 h to reach
an 83% conversion of 1. Workup as above gave recovered 1 (166 mg),
11, 12 (139 mg altogether, 14%), 13 (161 mg, 16%), and 14 (325 mg,
33%).
mental analysis calcd (%) for C18H11Cl4NO4: C 48.35, H 2.48, N 3.13;
found: C 48.29, H 2.61, N 3.09.
Photolysis of N-(3-hydroxypropyl)-4,5,6,7-tetrachlorophthalimide (2)
with styrene: A solution of 2 (1.029 g, 3 mmol) and styrene (3.12 g,
30 mmol) in benzene (120 mL) was photolyzed for 28 h to reach a 69%
9,10,11,12-Tetrachloro-12b-hydroxy-3a,5,6,12c-tetrahydrofuro[3’,2’–
6,7,1,4] oxazepinoACHTUNGTRENNUNG[5,4-a]isoindol-8ACHTUNGTNER(NUGN 12bH)ones (11 and 12): White solid
conversion of 2. Workup as above gave recovered
(219 mg, 24%), 18 (8 mg, 1%), and 19 (79 mg, 9%).
2 (317 mg), 17
from ethyl acetate/petroleum ether; m.p. 204–2068C; compound 11 was
not fully separated from 12: IR (KBr): n˜ =3373, 2944, 2882, 1695, 1417,
9,10,11,12-Tetrachloro-1,2,4,5,6,12b-hexahydro-12b-hydroxy-1-phenyl-
[1,5]oxazocino[6,5-a]isoindol-6(2H)one (1R,12bR-17): White block solid
from chloroform/petroleum ether; m.p. 272–2748C; IR (KBr): n˜ =3290,
3084, 2934, 1686, 1673, 1493, 1417, 1117, 763, 706 cmÀ1 1H NMR (300m,
258C, CDCl3): d=2.15–2.21 (m, 1H), 2.41–2.47 (m, 1H), 3.72 (dd, J=
14.7, 11.1 Hz, 1H), 3.96–4.04 (m, 3H), 4.26–4.38 (m, 3H), 5.24 (brs, 1H),
7.09 ppm (s, 5H); MS m/z (%): 370 [M+À75] (0.16), 324 (2), 298 (2), 104
(100), 78 (3); elemental analysis calcd (%) for C19H15Cl4NO3: C 51.04, H
3.38, N 3.13; found: C 50.92, H 3.49, N 3.03.
AHCTUNGTRENNUNG
1077 cmÀ1 1H NMR (300m, 258C, CD3COCD3): d=2.87–2.99 (m, 2H),
;
3.10 (t, 1H, J=10.9 Hz), 3.32–3.43 (m, 2H), 4.07 (d, 1H, J=3.9 Hz),
5.34–5.39 (m, 1H), 6.02 (d, 1H, J=4.0 Hz), 6.57 ppm (d, 1H, J=5.5 Hz);
MS m/z (%): 327 [M+À68] (0.63), 300 (20), 298 (100), 296 (76), 286 (38),
284 (28), 242 (11), 214 (14), 142 (14), 107 (6); elemental analysis calcd
(%) for C14H9Cl4NO4: C 42.35, H 2.28, N 3.53; found: C 42.12, H 2.45, N
3.47.
;
10,11,12,13-Tetrachloro-1,6,7,13b-tetrahydro-13b-hydroxy-1,4-epoxy-
X-ray structure analysis: C19H15Cl4NO3; M=447.12. monoclinic; space
group=P21/c; a=9.6966(3), b=9.1779(2), c=21.2134(6) ꢃ; a=90, b=
[1,4]oxazocino
chloroform/petroleum ether; m.p. 157–1598C; IR (KBr): n˜ =3504, 3425,
3184, 2929, 1688, 1405, 1059,1010, 726 cmÀ1 1H NMR (300m, 258C,
ACHTUNGTRENNUNG[5,4-a]isoindol-9(4H)one (13): White block solid from
95.5040(10), g=908; V=1879.17(9) ꢃ; Z=4; 1calcd =1.580 gcmÀ3
AHCTUNGTRENNUNG
;
F-
;
(000)=912.0; absorption coefficient 0.651 mmÀ1; scan range for data col-
CDCl3): d=3.54–3.62 (m, 1H), 3.77–4.01 (m, 3H), 4.29 (s, 1H), 5.59 (d,
1H, J=6.1 Hz), 5.69 (s, 1H), 5.90 (d, 1H, J=6.0 Hz), 6.25 ppm (s, 1H);
MS m/z (%): 377 [M+À18] (1.2), 312 (10), 298 (19), 214 (5), 142 (6), 68
(100); elemental analysis calcd (%) for C14H9Cl4NO4: C 42.35, H 2.28, N
3.53; found: C 42.12, H 2.45, N 3.47.
lection 2.42ꢁqꢁ41.558; 18408 measured reflections, 3226 independent
reflections, 3016 reflections with I>2a(I); Rint =0.0238, 248 refinable pa-
rameters, R
9,10,11,12-Tetrachloro-1,2,4,5,6,12b-hexahydro-12b-hydroxy-1-phenyl-
[1,5]oxazocino[6,5-a]isoindol-6(2H)-one (1R,12bS-18): White block solid
[F2>2a(F2)]=0.0254, wR2 (F2)=0.0641.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
X-ray structure analysis: C14H9Cl4NO4·H2O; M=415.04; monoclinic;
space group=P21/c; a=7.1888(2), b=8.7775(2), c=23.7045(5) ꢃ; a=90,
b=95.5550(10), g=908; V=1488.72(6) ꢃ; Z=4; 1calcd =1.852 gcmÀ3; F-
from chloroform/petroleum ether; m.p. 213–2158C; IR (KBr): n˜ =3412,
1
1708, 1654, 1430, 727, 696 cmÀ1; H NMR (300m, 258C, CDCl3): d=1.81–
1.93 (m, 3H), 3.47–3.62 (m, 2H), 3.67–3.77 (m, 2H), 4.08–4.19 (m, 1H),
4.26 (d, J=14.7 Hz, 1H), 4.34–4.40 (m, 1H), 7.12–7.14 (m, 2H), 7.34–
7.37 ppm (m, 3H); MS m/z (%): 427 [M+À18] (0.13), 411 (0.72), 324
(40), 298 (23), 296 (18), 104 (100), 77 (9); elemental analysis calcd (%)
for C19H15Cl4NO3: C 51.04, H 3.38, N 3.13; found: C 51.00, H 3.42, N
3.12.
ACHTUNGTRENNUNG
(000)=840.0; absorption coefficient 0.823 mmÀ1; scan range for data col-
lection=2.48ꢁqꢁ45.528; 37534 measured reflections, 9135 independent
reflections, 8061 reflections with I>2a(I); Rint =0.0256, 243 refinable pa-
rameters, RACHTUNGTRENNUNG
[F2>2a(F2)]=0.0316, wR2 (F2)=0.0856.
4,5,6,7-Tetrachloro-3-furan-3-yl-3-hydroxy-2-(2-hydroxyethyl)-2,3-dihy-
droisoindol-1-one (14): White solid from ethyl acetate/petroleum ether;
m.p. 227–2298C; IR (KBr): n˜ =3378, 3258, 1698, 1392, 1033, 753,
7,8,9,10-Tetrachloro-3,4-dihydro-10b-(2-hydroxy-1-phenylethyl)-2H-
[1,3]oxazino
chloroform/petroleum ether; m.p. 199–2018C; IR (KBr): n˜ =3516, 3103,
2965, 2878, 1701, 1396, 1047, 760, 719, 703 cmÀ1 1H NMR (300m, 258C,
ACHUTGTNREN[NUG 2,3-a]isoindol-6ACHTUNGTERN(NUGN 10bH)one (19): White block solid from
731 cmÀ1 1H NMR (300m, 258C, CD3COCD3): d=3.06–3.15 (m, 1H),
;
3.51–3.75 (m, 3H), 6.53 (m, 1H, J=3.1, 1.8 Hz), 6.90 (d, 1H, J=2.7 Hz),
7.50 ppm (brs, 1H); MS m/z (%): 377 [M+À18] (28), 349 (100), 347(72),
323 (42), 321(84), 320(73), 312 (34), 286 (19), 268 (37), 177 (3); elemental
analysis calcd (%) for C14H9Cl4NO4: C 42.35, H 2.28, N 3.53; found: C
42.33, H 2.29, N 3.49.
;
CDCl3): d=1.98–2.29 (m, 3H), 3.15 (td, 1H, J=11.7, 4.9 Hz), 3.61 (m,
1H), 3.96 (dd, 1H, J=10.9, 7.4 Hz), 4.11 (dd, 1H, J=10.4, 7.3 Hz), 4.31
(t, 1H, J=6.7 Hz), 4.54 (dd, J=10.7, 6.5 Hz, 1H), 4.57–4.68 (m, 1H),
6.98–7.00 (m, 2H), 7.11–7.14 ppm (m, 3H); MS m/z (%): 413 [M+À32]
(0.21), 326 (100), 324 (78), 298 (56), 296 (43), 91 (15); elemental analysis
calcd (%) for C19H15Cl4NO3: C 51.04, H 3.38, N 3.13; found: C 50.98, H
3.45, N 3.07.
Photolysis of 1 with benzofuran: A solution of 1 (654 mg, 2 mmol) and
benzofuran (1.18 g, 10 mmol) in benzene (80 mL) was photolyzed for
30 h to reach a 100% conversion of 1. Workup as above gave 15 (320 mg,
36%) and 16 (365 mg, 41%).
Photolysis of 2 with a-methylstyrene: A solution of 2 (0.686 g, 2 mmol)
and a-methylstyrene (2.36 g, 20 mmol) in benzene (80 mL) was photo-
lyzed for 36 h to reach a 60% conversion of 2. Workup as above gave re-
covered 2 (272 mg), 20 (165 mg, 30%), and 21 (8 mg, 2%).
11,12,13,14-Tetrachloro-5a,7,8,14c-tetrahydrobenzofuro
ACHTUNGTRENUN[NG 3’2’:6,7]-
A
R
ACHTUNGTRENNUNG
needles from chloroform/petroleum ether; m.p. 243–2458C; IR (KBr):
n˜ =3320, 1700, 1590, 1410, 1365, 1280, 1210, 1175, 1120, 1080, 1020, 750,
715 cmÀ1 1H NMR (300m, 258C, CDCl3): d=3.41–3.50 (m, 1H), 3.75 (t,
;
9,10,11,12-Tetrachloro-1,2,4,5,6,12b-hexahydro-12b-hydroxy-1-methyl-1-
phenyl
block solid from ethyl acetate/petroleum ether; m.p. 225–2278C; IR
(KBr): n˜ =3294, 3094, 2927, 2875, 1686, 1670, 1412, 729, 697 cmÀ1
A
E
(1R,12bR-20):
White
J=12.6 Hz, 1H), 3.89 (d, J=13.2 Hz, 1H), 4.15 (d, J=14.4 Hz, 1H), 4.26
(brs, 1H), 5.23 (d, J=7.6 Hz,1H), 5.51 (d, J=7.3 Hz, 1H,), 6.34 (d, J=
7.7 Hz, 2H), 6.64 (t, J=7.6 Hz, 1H), 6.87(d, J=7.7 Hz, 1H), 7.13 ppm (t,
J=7.7 Hz, 1H); 13C NMR (100 MHz, 258C, CDCl3): d=29.67, 39.90,
50.76, 62.54, 90.83, 103.48, 109.40, 121.76, 122.01, 122.97, 128.11, 128.55,
129.64, 130.84, 136.84, 138.51, 141.38, 159.66, 162.20 ppm; MS m/z (%):
427 [M+À18] (0.46), 397(1), 296 (3), 268 (3), 118 (100), 89 (10); elemen-
tal analysis calcd (%) for C18H11Cl4NO4: C 48.35, H 2.48, N 3.13; found:
C 48.31, H 2.57, N 3.11.
;
1H NMR (300m, 258C, CDCl3): d=1.06 (s, 3H), 1.82–1.92 (m, 1H), 2.41–
2.49 (m, 1H), 3.67–3.78 (m, 2H), 3.86 (d, 1H, J=12.3 Hz), 4.03 (dd, J=
14.9, 5.1 Hz, 1H), 4.08–4.17 (m, 1H), 4.37 (brs, 1H), 4.44 (d, J=12.3 Hz,
1H), 7.35 ppm (m, 5H); MS m/z (%): 459 [M+] (1), 326 (100), 324 (75),
298 (66), 296 (48), 118 (77), 105 (44), 103 (38), 91(14), 77 (29); elemental
analysis calcd (%) for C20H17Cl4NO3: C 52.09, H 3.72, N 3.04; found: C
52.01, H 3.62, N 2.95.
11,12,13,14-Tetrachloro-5a,7,8,14c-tetrahydrobenzofuro
ACHTUNGTRENUN[NG 3’2’:6,7]-
1,2,3-Tetrachloro-5-(3-hydroxypropyl)-6-methyldibenzACTHNUTRGNEUG[N cd,f]indol-
N
N
ACHTUNGTRENNUNG
4(5H)one (21): White solid from ethyl acetate/petroleum ether; m.p.
210–2118C; IR (KBr): n˜ =3495, 3093, 2964, 1704, 1689, 1628, 748,
needles from chloroform/petroleum ether; m.p. 230–2318C; IR (KBr):
n˜ =3250, 690, 1590, 1480, 1460, 1370, 1250, 1190, 1090, 990, 880, 750,
1
714 cmÀ1; H NMR (300m, 258C, CDCl3): d=2.08 (t, 2H, J=5.7 Hz), 2.89
670 cmÀ1 1H NMR (300m, 258C, CDCl3): d=3.19–3.26 (m, 1H), 3.47–
;
(s, 3H), 3.69 (t, 2H, J=5.4 Hz), 4.43 (t, 2H, J=5.9 Hz), 7.69 (t, 1H, J=
7.6 Hz), 7.77 (t, 1H, J=7.3 Hz), 8.18 (d, 1H, J=8.2 Hz), 9.77 ppm (d,
1H, J=8.2 Hz); 13C NMR (100 MHz, CDCl3, 258C): d=14.4, 32.8, 39.80,
58.8, 117.2, 121.1, 123.1, 125.8, 125.9, 126.5, 126.6, 127.8, 129.0, 129.4,
3.54 (m, 1H), 3.76–3.86 (m, 2H), 4.00 (s, 1H), 4.93 (d, J=6.8 Hz, 1H),
5.58 (d, J=6.8 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H),
7.28 (t, J=7.4 Hz, 1H), 8.02 ppm (d, J=7.6 Hz, 1H); MS m/z (%): 427
[M+À18] (0.46), 310 (1), 297 (9), 266 (3), 213 (2), 118 (100), 89 (4); ele-
Chem. Eur. J. 2010, 16, 2873 – 2886
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2883

J.-H. Xu et al.
131.9, 133.5, 134.2, 136.0, 164.4 ppm; MS m/z (%): 393 [M+] (23), 378
(32), 349 (56), 337 (92), 339 (28), 335 (100), 271 (17), 187 (22), 174 (22),
122 (21), 87 (24); elemental analysis calcd (%) for C19H14Cl3NO2: C
57.82, H 3.58, N 3.55; found C 57.77, H 3.65, N 3.49.
R
int =0.0442, 567 refinable parameters, R
[F2>2a(F2)]=0.0404, wR2 (F2)=
ACHTUNGTRENNUNG
0.1199.
4,5,6,7-Tetrachloro-3-hydroxy-3-benzyl-2-(3-hydroxypropyl)isoindolin-1-
one (25): White block solid from chloroform/petroleum ether; m.p. 215–
2168C; IR (KBr): n˜ =3312, 3032, 2931, 2874, 1691, 1674, 1496, 1421, 1050,
Photolysis of 2 with 1-phenylcyclopentene: A solution of 2 (0.686 g,
2 mmol) and 1-phenylcyclopentene (1.44 g, 10 mmol) in benzene (80 mL)
was photolyzed for 28 h to reach an 84% conversion of 2. Workup as
above gave recovered 2 (108 mg) and product 22 (413 mg, 51%).
716, 705 cmÀ1 1H NMR (300m, 258C, CDCl3): d=1.89–2.02 (m, 1H),
;
2.28–2.49 (m, 1H), 3.40 (d, 1H, J=14.2 Hz), 3.54–3.62 (m, 1H), 3.77–4.08
(m, 4H), 6.73–6.80 (m, 2H), 7.02–7.13 ppm (m, 3H); MS m/z (%): 415
[M+À18] (0.65), 326 (100), 324 (91), 298 (77), 296 (56), 91 (21); elemen-
tal analysis calcd (%) for C18H15Cl4NO3: C 49.68, H 3.47, N 3.22; found:
C 49.62, H 3.53, N 3.23.
10,11,12,13-Tetrachloro-13b-hydroxy-13c-phenyl-2,3,3a,5,6,7,13b,13c-octa-
hydro-1H,9H-cyclopenta[b]ACTHNUTRGNENG[U 1,5]oxazocinoAHCTUNGTRENN[GUN 4,5-a]isoindol-9-one
(3aS,13bS,13cS-22): Colorless plate solid from chloroform/petroleum
ether; m.p. 240–2428C; IR (KBr): n˜ =3364, 3092, 2948, 2869, 1705, 1391,
Photolysis 4,5,6,7-tetrachloro-1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic
acid 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl ester (3) with 1-phe-
nylcyclopentene: A solution of 3 (1.562 g, 3 mmol) and 1-phenylcyclopen-
tene (2.16 g, 15 mmol) in benzene (120 mL) was photolyzed for 32 h to
reach a 74% conversion of 3. Workup as above gave recovered 3
(402 mg) and product 26 (259 mg, 17%).
728, 705 cmÀ1 1H NMR (300m, 258C, CDCl3): d=1.32–1.69 (m, 3H),
;
1.94–2.17 (m, 2H), 2.58–2.72 (m, 2H), 2.96 (dd, 1H, J=13.9, 7.3 Hz),
3.52 (dd, 1H, J=14.7, 11.7 Hz), 3.84–3.98 (m, 2H), 4.37 (dd, 1H, J=14.9,
6.3 Hz), 4.71 (d, 1H, J=4.5 Hz), 5.71 (s, 1H), 6.94–7.22 ppm (m, 5H);
13C NMR (100 MHz, CDCl3, 258C): d=21.4, 27.6, 30.0, 30.7, 38.4, 64.6,
67.5, 85.3, 96.1, 126.7, 127.6, 128.2, 128.6, 129.2, 134.2, 136.6, 137.6, 144.6,
165.6 ppm; MS: m/z (%): 485 [M+] (0.24), 324 (10), 298 (42), 296 (31),
144 (100), 129 (40), 91 (8), 49 (3); elemental analysis calcd (%) for
C22H19Cl4NO3: C 54.24, H 3.93, N 2.87; found: C 54.02, H 4.21, N 2.78.
21,22,23,24-Tetrachloro-1,2,3,3a,5,6,8,9,11,12,14,15,24b,24c-tetradecahy-
dro-24b-hydroxy-24c-phenyl-18H-cyclopenta
pentaoxaazacyclononadecino[16,17-a]isoindole-17,20ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
(3aR,24bR,24cS-26): White solid from ethyl acetate/petroleum ether;
m.p. 215–2178C; IR (KBr): n˜ =3386, 3089, 2897, 1732, 1712, 1387, 1088,
X-ray structure analysis: C22H19Cl4NO3; M=487.18; monoclinic; space
group P21/n; a=12.2563(3), b=9.9236(3), c=17.2503(4) ꢃ; a=90, b=
1
756, 731, 703 cmÀ1; H NMR (300m, 258C, CDCl3): d=1.22–1.47 (m, 2H),
103.2800(10), g=908; V=2041.99(9) ꢃ; Z=4; 1calcd =1.585 gcmÀ3
;
F-
(000)=1000.0; absorption coefficient 0.606 mmÀ1; scan range for data col-
lection=2.38ꢁqꢁ40.338; 41823 measured reflections, 10691 indepen-
dent reflections, 8451 reflections with I>2a(I); Rint =0.0309, 294 refina-
ble parameters, R
[F2>2a(F2)]=0.0389, wR2 (F2)=0.1014.
1.79–1.92 (m, 2H), 2.72–2.91 (m, 2H), 3.62–3.87 (m, 14H), 4.30–4.49 (m,
3H), 4.77 (d, J=11 Hz, 1H), 4.80 (s, 1H), 6.53 (brs, 1H), 6.64 (d, J=
7.9 Hz, 1H), 6.89 (t, J=7.2 Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 7.27 (t, J=
7.2 Hz, 1H), 7.43 ppm (d, J=7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
258C): d=19.3, 25.2, 30.1, 42.8, 64.6, 64.7, 67.2, 68.4, 69.6, 69.9, 70.4, 70.6,
71.0, 88.3, 95.8, 126.0, 127.2, 127.6, 127.7, 128.0, 128.6, 129.0, 134.5, 136.7,
136.9, 144.8, 164.2, 169.0 ppm; MS m/z (%): 661 [M+] (0.02), 520 (2), 372
(29), 370 (56), 368 (58), 334 (12), 298 (51), 296 (54), 145 (100), 129 (50),
91 (47), 45 (42); elemental analysis calcd (%) for C29H31Cl4NO8: C 52.51,
H 4.71, N 2.11; found: C 52.39, H 4.78, N 2.09.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Photolysis of 2 with 1-phenylcyclohexene: A solution of 2 (0.686 g,
2 mmol) and 1-phenylcyclohexene (2.36 g, 20 mmol) in benzene (80 mL)
was photolyzed for 36 h to reach an 88% conversion of 2. Workup as
above gave recovered 2 (79 mg), products 23 (318 mg, 36%), 24 (230 mg,
26%), and 25 (32 mg, 4%).
N-[3-(2-Phenylcyclohexyloxy)propyl]-4,5,6,7-tetrachlorophthalimide (23):
White block solid from chloroform/petroleum ether; m.p. 133–1358C; IR
(KBr): n˜ =3470, 2926, 2854, 1772, 1713, 1449, 1403, 1374, 1095, 750, 735,
X-ray structure analysis: C29H31Cl4NO8; M=663.35; triclinic; space
¯
group= P1; a=9.4640(19), b=10.885(2), c=14.740(3) ꢃ; a=87.38(3),
b=83.27(3), g=80.86(3)8; V=1488.3(5) ꢃ; Z=2; 1calcd =1.480 gcmÀ3; F-
694 cmÀ1 1H NMR (300m, 258C, CDCl3): d=1.23–1.39 (m, 3H), 1.51 (q,
;
AHCTUNGTRENNUNG
(000)=688.0; absorption coefficient=0.449 mmÀ1; scan range for data
J=13.0 Hz, 1H), 1.61–1.77 (m, 3H), 1.86 (d, 2H, J=10.5 Hz), 2.18 (d,
1H, J=10.4 Hz), 2.41 (td, 1H, J=12.6, 3.1 Hz), 2.93–3.00 (m, 1H), 3.24–
3.31 (m, 1H), 3.37 (dd, J=6.9, 13.8 Hz, 1H), 3.44–3.50 (m, 2H), 7.10 (t,
1H, J=7.0 Hz), 7.17 (d, 2H, J=6.9 Hz), 7.24 ppm (t, 2H, J=7.3 Hz);
13C NMR (100 MHz, CDCl3, 258C): d=25.0, 26.0, 28.5, 32.2, 33.7, 36.5,
51.2, 66.8, 82.5, 125.9, 127.7, 127.8, 128.0, 129.4, 139.8, 144.7, 163.4 ppm;
MS m/z (%): 499 [M+] (0.10), 324 (50), 296 (30), 158 (100), 130 (21), 91
(81), 41 (22); elemental analysis calcd (%) for C23H21Cl4NO3: C 55.11, H
4.22, N 2.79; found: C 55.09, H 4.28, N 2.74.
collection=2.97ꢁqꢁ48.458; 6219 measured reflections, 5843 indepen-
dent reflections, 3755 reflections with I>2a(I); Rint =0.0602, 379 refina-
ble parameters, R
[F2>2a(F2)]=0.0725, wR2 (F2)=0.2142.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Photolysis of 3 with 1-phenylcyclohexene: A solution of 3 (1.563 g,
3 mmol) and 1-phenylcyclopentene (2.16 g, 15 mmol) in benzene
(120 mL) was photolyzed for 66 h to reach a 67% conversion of 3.
Workup as above gave recovered 3 (523 mg), products 27 (92 mg, 7%),
and 28 (285 mg, 21%).
11,12,13,14-Tetrachloro-14b-hydroxy-14c-phenyl-1,2,3,4,4a,6,7,8,14b,14c-
decahydro-10H-cyclohexta[b]ACTHNUTRGENNG[U 1,5]oxazocinoAHCTUNGTRENN[GUN 4,5-a]isoindol-10-one
22,23,24,25-Tetrachloro-1,2,3,4,4a,6,7,9,11,12,13,15,16,19,25b,25c-hexade-
cahydro-25b-hydroxy-25c-phenyl-cyclopenta
ACHTUNGTRENNUNG
(4aR,14bR,14cR-24): White block solid from chloroform/petroleum
ether; m.p. 234–2368C; IR (KBr): n˜ =3434, 3091, 2927, 2856, 1700, 1500,
A
U
(4aR,25bR,25cS-27): Block clear solid from ethyl acetate/petroleum
ether; m.p. 199–2008C; IR (KBr): n˜ =3342, 3093, 2939, 1757, 1715, 1384,
;
1202, 1080, 729, 699 cmÀ1 1H NMR (300m, 258C, CDCl3): d=1.22–1.41
1389, 1089, 745, 729, 692 cmÀ1 1H NMR (300m, 258C, CDCl3): d=1.16–
;
1.38 (m, 3H), 1.60–1.78 (m, 3H), 2.04–2.10 (m, 1H), 2.46 (td, J=14.1,
2.6 Hz, 1H), 2.58–2.69 (m, 1H), 3.03 (d, J=14.6 Hz, 1H), 3.53 (t, J=
13.3 Hz, 1H), 3.85–4.01 (m, 2H), 4.27 (dd, J=14.7, 5.0 Hz, 1H), 4.61 (s,
1H), 5.59 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 7.05
(t, J=7.3 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 7.24 ppm (t, J=7.1 Hz, 1H);
13C NMR (100 MHz, CDCl3, 258C): d=19.7, 21.7, 25.9, 26.2, 27.3, 38.7,
56.6, 65.6, 74.9, 98.4, 126.2, 126.4, 126.8, 127.2, 128.1, 128.5, 129.6, 134.0,
136.4, 138.0, 145.0, 166.0 ppm; MS m/z (%): 343 (0.84), 298 (22), 296
(16), 158 (100), 130 (40), 129 (60), 115 (27), 91 (21),41 (5); elemental
analysis calcd (%) for C23H21Cl4NO3: C 55.11, H 4.22, N 2.79; found: C
55.12, H 4.28, N 2.74.
(m, 3H), 1.51 (t, J=13.3 Hz, 1H), 1.67 (d, J=11.4 Hz, 1H), 1.91 (d, J=
11.3 Hz, 1H), 2.61–2.73 (m, 2H), 3.60–3.93 (m, 14H), 4.22–4.32 (m, 1H),
4.40–4.46 (m, 2H), 4.69 (brs, 1H), 4.79 (d, J=16.8 Hz, 1H), 6.55 (d, J=
7.9 Hz, 1H), 6.75 (brs, 1H), 6.88 (t, J=7.2 Hz, 1H), 7.10 (t, J=7.1 Hz,
1H), 7.29–7.37 ppm (m, 2H); MS m/z (%): 675 [M+] (0.01), 518 (0.06),
458 (0.03), 370 (20), 368 (14), 298 (28), 296 (20), 158 (100), 129 (21), 91
(28); elemental analysis calcd (%) for C30H33Cl4NO8: C 53.19, H 4.91, N
2.07; found: C 53.12, H 5.03, N 2.03.
X-ray structure analysis: C30H33Cl4NO8; M=677.37; triclinic, space
group=P21/n, a=18.6856(7), b=9.3008(4), c=19.3476(7) ꢃ; a=90, b=
X-ray structure analysis: C23H21Cl4NO3; M=501.20; triclinic; space
118.183(2), g=908; V=2963.8(2) ꢃ; Z=4; 1calcd =1.518 gcmÀ3; F
ACHTUNGTRENNUNG(000)=
¯
group=P1; a=10.6774(2), b=14.8307(3), c=15.1298(4) ꢃ; a=
1408.0; absorption coefficient=0.453 mmÀ1; scan range for data collec-
tion=2.47ꢁqꢁ25.158; 55576 measured reflections, 8781 independent re-
flections, 5506 reflections with I>2a(I); Rint =0.0788, 379 refinable pa-
95.4770(10), b=109.2210(10), g=106.4500(10)8; V=2122.08(8) ꢃ; Z=2;
1calcd =1.569 gcmÀ3; F(000)=1032.0; absorption coefficient=0.586 mmÀ1
ACHTUNGTRENNUNG ;
scan range for data collection=2.78ꢁqꢁ38.538; 92790 measured reflec-
tions, 22157 independent reflections, 17351 reflections with I>2a(I);
rameters, RACTHNUTRGNEUNG
[F2>2a(F2)]=0.0594, wR2 (F2)=0.1515.
2884
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2873 – 2886

Synthesis of Medium- and Large-Ring Heterocycles
FULL PAPER
22,23,24,25-Tetrachloro-1,2,3,4,4a,6,7,9,11,12,13,15,16,19,25b,25c-hexade-
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cahydro-25b-hydroxy-25c-phenyl-cyclopenta
ACHTUNGTRENNUNG
A
U
(4aR,25bS,25cR-28): White solid from ethyl acetate/petroleum ether;
m.p. 185–1878C; IR (KBr): n˜ =3422, 3261, 2945, 1758, 1718, 1203, 1112,
731, 702 cmÀ1; 1H NMR (300m, 258C, CDCl3): d=1.28–1.93 (m, 6H), 2.13
(d, 1H, J=12.2 Hz), 2.20 (s, 1H), 2.64 (td, J=12.7, 2.8 Hz, 1H), 3.42–
3.59 (m, 4H), 3.71–3.82 (m, 8H), 4.04–4.10 (m, 1H), 4.39 (d, J=17.1 Hz,
1H), 4.39–4.51 (m, 1H), 4.69 (d, J=17.1 Hz, 1H), 5.15 (brs, 1H), 6.40 (d,
J=7.3 Hz, 1H), 6.83 (t, J=7.2 Hz, 1H), 7.07 (t, J=7.2 Hz, 1H), 7.19 (d,
J=7.2 Hz, 1H), 7.26–7.29 (m, 1H), 7.81 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3, 258C): d=18.4, 21.8, 23.4, 25.5, 31.0, 44.8, 57.7, 64.1,
65.6, 68.6, 69.7, 70.5, 70.6, 70.7, 71.7, 97.1, 125.8, 127.1, 127.2, 127.3, 128.2,
128.4, 128.9, 129.3, 133.9, 136.0, 137.5, 148.2, 164.8, 168.7 ppm; MS: m/z
(%): 370 (12), 368 (9), 296 (13), 158 (100), 129 (39), 91 (37); elemental
analysis calcd (%) for C30H33Cl4NO8: C 53.19, H 4.91, N 2.07; found: C
53.03, H 5.13, N 2.01.
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Acknowledgements
This work was supported by the National Natural Science Foundation of
China (NSFC, 20572044), the International Scientific & Technological
Exchange and Cooperation Foundation from the Ministry of Science and
Technology of China (2007DFA41590), and the Zhejiang Provincial Nat-
ural Science Foundation (Y4080395).
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alkene and the phthalimide can be estimated by the equation
ox
1=2
DGET =23.06[E1o=x2ÀE1re=d2+0.38]ÀE* (kcalmolÀ1), in which E
and
red
1=2
E
are the halfwave oxidation potential of the alkene and the re-
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Received: October 15, 2009
Published online: January 19, 2010
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