The Photo-Dehydro-Diels-Alder (PDDA) reaction - A powerful method for the preparation of biaryls

Article abstract of DOI:10.1055/s-2006-958949

The photochemically initiated dehydro-Diels-Alder (PDDA) reaction is an efficient and versatile method for the preparation of biaryls. The ring closure may take place both inter- and intramolecularly, of which the intramolecular variant is more productive

Full text of DOI:10.1055/s-2006-958949

464
FEATURE ARTICLE
The Photo-Dehydro-Diels–Alder (PDDA) Reaction – A Powerful Method for
the Preparation of Biaryls
T
he Photo-D
ea
b
–Alde
r
Reac
l
tion for
o
the Preparation of
W
B
iaryls essig,* Gunnar Müller, Charlotte Pick, Annika Matthes
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937450; E-mail: pablo.wessig@chemie.hu-berlin.de
Received 2 August 2006; revised 17 October 2006
Abstract: The photochemically initiated dehydro-Diels–Alder
(PDDA) reaction is an efficient and versatile method for the prepa-
ration of biaryls. The ring closure may take place both inter- and in-
tramolecularly, of which the intramolecular variant is more
productive from the preparative point of view. A variety of linkers
can be employed to connect the ynone moiety, which acts as the
chromophore, with another acetylene group, thus allowing large
structural versatility. Principles influencing the site selectivity of
the PDDA reaction will also be discussed here.
(a)
(b)
1
3
2
4
Key words: photochemistry, biaryls, alkynes, photo-dehydro-
Diels–Alder reaction, cyclizations
Scheme 1 Comparison of Bergman cyclization (a) with the dehy-
dro-Diels–Alder reaction (b)
Introduction
Nicolaou in 1992.9 Admittedly, there are only few exam-
ples for the preparative utilization of the Bergman cycliza-
tion.10
Acetylenes are intriguing synthetic building blocks for a
vast number of synthetic applications.1 Most of these are
based on substitution reactions at one of the acetylenic
atoms,1a,2 oxidative coupling of two acetylenes,3 addition
reactions,1a,4 as well as alkyne metathesis.5 Compared
with these well-established methods, little has been pub-
lished about preparative applications relying on the addi-
tion of two acetylenic moieties to form one C–C bond in
the initial step.6 Two reactions pursuing this approach,
and that have at first glance little to do with one another,
are the Bergman cyclization7 and the dehydro-Diels–
Alder (DDA) reactions (Scheme 1, reactions a and b, re-
spectively). Both reactions have in common the formation
of highly reactive buta-1,3-diene-1,4-diyl diradicals 2 and
4 as primary intermediates.
The thermally initiated DDA reaction has been known for
a long time, but almost seems to have fallen into oblivion.
Already in 1895 Michael and Bucher reported the dimer-
ization of phenylpropiolic acid upon prolonged heating in
acetic anhydride.11 Twelve years later Pfeiffer and Möller
described a similar reaction of ethyl phenylpropiolate un-
der drastic conditions (200 °C, sealed tube).12 Subse-
quently, some preparative applications have been
published, proving the scope of the reaction.13 In contrast
to these classic examples of the DDA reaction, consider-
able improvement was achieved by transition-metal catal-
ysis. Thus, palladium,14 rhodium,15 and nickel16 catalysts
have been used in the DDA reaction.
The critical difference between these reactions is the for-
mation of an aromatic system in the Bergman cyclization
(Scheme 1, reaction a), which adds a considerable ther-
modynamic driving force to this process. The dehydro-
Diels–Alder reaction, on the other hand, is highly endo-
thermic in the first step (Scheme 1, reaction b).
In connection with our long-standing investigations of the
Norrish–Yang reaction,17 we were interested in structural
modifications of benzoyl chromophores, which up to then
had mostly been used for alleviating oxidative degrada-
tion after photochemical cyclization. To this end, we irra-
diated 1-phenylhex-1-yn-3-one (5a) but obtained, to our
surprise, not the expected Yang product 6 but the naphtha-
lene 7a as product of a photo-dehydro-Diels–Alder (PD-
DA) reaction (Scheme 2).18 We subsequently thoroughly
investigated this interesting cyclization reaction and de-
veloped it into a versatile method for the preparation of bi-
aryls. In this feature article we wish to report
comprehensively on previous and new results towards the
PDDA reaction. (For better clarity, the dienophile moiety
will be colored blue in the graphical representations from
here onwards.)
In the last years, the Bergman cyclization has attracted
considerable attention, because the enediyne moiety (e.g.,
in 1) is often found in natural products and is responsible
for a unique mode of DNA attack.8 Calicheamycin, one of
the most prominent examples, has an extremely high po-
tency against tumor cells, and the research activities in
this area culminated in the fascinating total synthesis by
SYNTHESIS 2007, No. 3, pp 0464–0477
x
x
.
x
x
.2
0
0
7
Advanced online publication: 14.12.2006
DOI: 10.1055/s-2006-958949; Art ID: T12106SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
The Photo-Dehydro-Diels–Alder Reaction for the Preparation of Biaryls
465
OH
Mechanistic Model
Ph
hν
The mechanism of the PDDA reaction was discussed in
detail in our previous publications,18a,19 and here only the
most important points will be summarized. It should be
noted that our present knowledge about the mechanism is
solely based on DFT calculations; short-time spectroscop-
ic investigations are currently underway. The reaction
commences with a photochemical n–p* excitation of 3-
arylalkynones 8 followed by an efficient intersystem
crossing (ISC) to the triplet state (Scheme 3). The triplet
energy of the 3-arylalkynone moiety amounts to about
250 kJ/mol. The approach of one acetylene to the other
proceeds via the transition state 10a (Scheme 3), the ener-
gy of which lies only 13–25 kJ/mol above that of the ex-
cited reactants. (Note that substituents R1 and R2 may be
connected; see the section ‘Intramolecular PDDA Reac-
O
6
O
hν
5a
Ph
O
7a
Scheme 2 Yang cyclization versus photo-dehydro-Diels–Alder
reaction of an ynone
Biographical Sketches
Pablo Wessig (above right), born in (FCI) at the University of Basel, Heisenberg fellow of the DFG at the
Görlitz in 1962, completed his PhD Switzerland, in the group of B. Giese same university. His primary re-
degree at the Humboldt University of in 1993, he obtained his habilitation search interests are focused on pre-
Berlin under the supervision of Prof. degree in the group of G. Szeimies at parative organic photochemistry,
Dr. H.-G. Henning in 1990. After a the Humboldt University in 2000. molecular probes, and rigid molecu-
postdoctoral research fellowship Since 2003 he has been working as a lar sticks.
Gunnar Müller (above left), born in Wessig and is currently working on and the preparative application of the
Salzwedel in 1976, studied chemistry his PhD thesis. His research interests PDDA reaction.
at the Humboldt University of Berlin. include the photochemical prepara-
In 2002 he joined the group of Dr. P. tion of indanones by spin-center shift
Charlotte Pick (below left), born in her diploma in the group of Prof. Dr. PDDA reaction and its synthetic ap-
Bad Soden a. Ts. in 1977, studied U. Koert she joined the group of Dr. plications.
chemistry at the Philipps University P. Wessig in 2005. For her PhD de-
in Marburg. After she had obtained gree she is working in the field of the
Annika Matthes (below right), born chemistry at the Humboldt Universi- group of Dr. P. Wessig to work to-
1980 in Berlin, started her studies in ty in 2000. In 2006 she joined the wards her diploma degree.
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

466
P. Wessig et al.
FEATURE ARTICLE
tion’ below.) As a result, buta-1,3-dien-1,4-diyl diradicals ly, we obtained naphthalenes 7 only in relatively low
9 form in a strongly exothermic process (DE ~ –147 kJ/ yields (Scheme 4).18a
mol). Diradicals 9 seem to play a key role in the mecha-
nism. The DFT calculations with different systems re-
vealed that the triplet and singlet states of 9 have nearly
the same energy, and that activation energies of all possi-
ble consecutive steps are too high at the triplet potential
energy surface (>84 kJ/mol). Consequently, we assume
that at the stage of 9 the electronic state returns to the sin-
glet potential-energy surface. With a relatively low barrier
of 33 kJ/mol, one of the diradical centers now attacks an
ortho position of the opposite aromatic ring and gives, via
transition state 10b, the cyclic allene 11 (Scheme 3). The
last step to the naphthalenes 12 is a formal 1,3-hydrogen
shift, but we found experimentally that this process is al-
ways mediated by the solvent.
O
O
A, B or C
hν
Ph
Ph
R
R
R
13
5
Method
5
7
R
O
C
41% 32%
49% 34%
48% 38%
19% 23%
a
b
c
d
Pr
Me
Et
A
B
A
Ph
7
Scheme 4 Intermolecular PDDA reaction of 5a–d. Reagents and
conditions: Method A: 1. BuLi, 2. RCO2Et, BF3·OEt2; Method B: 1.
BuLi, 2. CdCl2, 3. RCOCl; Method C: 1. BuLi, 2. RCHO, 3. DMP.21
In the preceding discussion it has not yet been mentioned
that the biaryls obtained by the PDDA reaction are poten-
tially axially chiral compounds. It is expected that the in-
troduction of at least one substituent in the ortho position
of the dienophile aryl group should increase the rotational
barrier of the biaryl axis to such an extent that the atrop-
isomers could be resolved at room temperature.22
O
3
O
R1
R2
R1
hν
ISC
R2
R3
R3
EA ~ 13–25 kJ/mol
8
10a
Enantiomerically pure axially chiral biaryls play a very
important role as chiral ligands in asymmetric transition-
metal catalysis23 and as chiral auxiliaries24 for many appli-
cations. Even though the asymmetric synthesis of axially
chiral atropisomers by the PDDA reaction is not a subject
of this article, we will present results that point in this di-
rection. In this connection, the synthesis of axially chiral
dicarboxylic acid derivatives 18 (Scheme 5) is worth
mentioning. It commences with o-iodobenzaldehyde (14),
which was converted in one step and in excellent yields
into the 3-arylpropionic acid 15a25 by treatment with Mel-
drum’s acid26 in a mixture of formic acid and triethyl-
amine.27 After protection of the carboxyl group as a tert-
butyl ester (15b), a Sonogashira coupling28 with but-1-yn-
3-ol afforded the propargyl alcohol 16, which was con-
verted into ketone 17a by Swern oxidation. To investigate
the influence of the ester group, we performed an ex-
change of the protective group in two steps to give the me-
thyl ester 17b. Upon irradiation in tert-butyl alcohol,
esters 17 dimerized into diesters 18 in moderate to good
yields.
3
1
ISC
O
EA ~ 33 kJ/mol
O
R1
R1
R2
R2
H
R3
R3
10b
9
O
O
R1
R1
~ H
R2
R2
H
R3
R3
11
12
Scheme 3 Mechanism of the PDDA reaction
Besides this main reaction path we occasionally observed
a cyclization of diradicals 9 to cyclobutadienes, which re-
acted with the protic solvent, and a cleavage reaction com-
parable with the Norrish type II cleavage.19
Remarkably, the enantiomers of compounds 18 could be
resolved by chiral HPLC, albeit only after extensive opti-
mization of the conditions. The corresponding chromato-
grams as well as the resolution factors are depicted in
Figure 1.
Synthetic Applications
The hitherto discussed PDDA reactions have in common
that ring closure took place between two identical mole-
cules. Bearing in mind that the excited ynones are highly
electrophilic species, we hypothesized that a selective
cross-PDDA reaction should be possible between an
ynone (which is photochemically excited) and a more
electron-rich arylacetylene. Thus, we irradiated com-
pounds 5a,b in the presence of equimolar amounts of phe-
nylacetylene (19a) as well as the electron-rich (4-
Intermolecular PDDA Reaction
As mentioned above, we discovered the PDDA reaction
with the dimerization of 1-phenylhex-1-yn-3-one (5a).20
This reaction could also be observed with some other
ynones 5b–d (Scheme 4),20 which were prepared from
phenylacetylene (13) by different methods. Unfortunate-
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Photo-Dehydro-Diels–Alder Reaction for the Preparation of Biaryls
467
O
O
O
O
O
O
COOR
R1
R1
O
hν
HCOOH, Et3N
84%
I
I
5a,b
isobutene, H+
92%
14
15a (R = H)
15b (R = t-Bu)
19a (R2 = H)
19b (R2 = OMe)
PdCl2(PPh3)2,
CuI, Et3N, 93%
R2
R2
+
19c (R2 = SO2Me)
OH
20
COOR
COOt-Bu
O
(COCl)2
R1
R1
DMSO
94%
O
+
R2
O
OH
O
R1
16
17a (R = t-Bu)
17b (R = Me)
1. TFA,
2. DCCI, DMAP, MeOH, 85%
21
7
R1 R2
Solvent
t-BuOH
MeOH
t-BuOH
MeOH
20
No.
21
4% 20% (7b)
7%
0%
12%
0%
7
Entry
hν
32%
30%
39%
21%
35%
a
a
b
c
d
1
2
3
4
5
Me
Me
Pr
H
H
H
(t-BuOH)
0% (7b)
6% (7a)
0% (7b)
0% (7b)
ROOC
ROOC
O
Me OMe
Me SO2Me MeOH
18a, R = t-Bu; 45%
18b, R = Me; 58%
Scheme 6 Intermolecular cross-PDDA reaction
O
phile component, giving compounds 20 as the main prod-
ucts. We assume that steric hindrance in the intermediate
diradicals is responsible for these results, because com-
pounds 21 are ortho-disubstituted. When we used tert-bu-
tyl alcohol as solvent, the dimerization products 7 were
obtained as minor products (Table in Scheme 6, entries 1,
3).
Scheme 5 Synthesis of diesters 18 by the PDDA reaction
methoxyphenyl)acetylene (19b) and the electron-poor (4-
methylsulfonylphenyl)acetylene (19c) to investigate the
influence of the substituents (Scheme 6).
It should be noted that an excess of arylacetylenes 1929
shortened the irradiation times, but did not influence the
product yields, and complicated their purification. In all
cases we observed a conspicuous preference for the cross-
coupling products 20 and 21 (Scheme 6). Furthermore,
the arylacetylenes 19 acted preferentially as the dieno-
Compared with phenylacetylene (19a), acetylene 19b
containing a donor substituent leads to lower regioselec-
tivity (20/21) (Table in Scheme 6, entry 2 vs entry 4),
whereas the strong electron-withdrawing group in 19c re-
sulted in the formation of only 20 (entry 5).
Intramolecular PDDA Reaction
It is well known from a great variety of organic reactions
that the presence of both reaction centers in the same mol-
ecule, i.e. an intramolecular reaction, is strongly favored
over the intermolecular variant.
This also applies to photochemical reactions, but here it is
not only a consequence of entropic influence. The limited
lifetime of an electronically excited molecule may even
completely prevent an intermolecular reaction if the con-
centration of the reactants is too low. With the intermolec-
ular PDDA reaction we found that the reaction rates are
almost always relatively low and this can, at least partly,
be attributed to these reasons. Therefore we also investi-
gated the intramolecular PDDA reaction, and for this pur-
pose we developed a range of linkers.
In Scheme 7, eight reactant systems 22–29 with different
linker units are summarized. The symmetric diketones
2230 were prepared to investigate the influence of the link-
er length on the yields of the PDDA reactions. Four of the
Figure 1 HPLC resolution [Chiralcel OD (Daicel), hexane–EtOH,
90:10 (18a), 80:20 (18b), flow rate 0.5 mL/min; R = resolution fac-
tor] of enantiomers of diesters 18
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468
P. Wessig et al.
FEATURE ARTICLE
remaining nonsymmetric systems are ketones (23–26),
two are esters (27, 28), and the last one is an amide (29).
The linker chains of nonsymmetric systems 23–29 consist
of three (24, 27, 29) or four (23, 25, 26, 28) atoms result-
ing in the formation of five- or six-membered rings in the
PDDA reaction.
O
O
O
O
A or B
X
X
n
n
Ph
Ph
30a (X = OEt)
30b (X = Cl)
22
(MeOH)
O
hν
We will below briefly discuss the synthetic route to each
system, without going into all details, as well as the pho-
tochemical behavior.
Method
n
2
3
4
7
8
22
31
39% 30%
20%
a
b
c
d
e
A
A
A
A
B
54%
n
19% 32%
15% 0%
41% 8%
O
Ar2
Ph
31
O
O
O
n
Ar1
Ar1
Ar1
Scheme 8 Synthesis and PDDA reaction of diketones 22. Reagents
and conditions: Method A: 1. BuLi, 2. RCO2Et, BF3·OEt2; Method B:
1. BuLi, 2. CdCl2, 3. RCOCl.
23
22 (n = 2–8)
O
Ar2
O
O
Ar1
Ar1
Ar2
24
25
hols and afforded, after renewed oxidation, the target ke-
tones 23 and 24 (Scheme 9).
O
R
N
Ar2
O
In contrast to the case of symmetric diketones 22, two iso-
meric PDDA reaction products can form upon irradiation
of ketones 2333 and 24.33 The results of the irradiation ex-
periments are summarized in Scheme 9 and Table 1. Site
selectivity was low with the parent diphenyl compounds
(Table 1, entries 1, 3) and neither electron-donating
groups (entries 4, 5) nor electron-withdrawing groups
tethered to Ar2 (entries 7, 9) had a significant influence on
the selectivity. On the other hand, if the electron-with-
drawing group is present in the aromatic ring connected to
the ynone moiety, the site selectivity is considerably en-
hanced and reaches a ratio of up to 7:1 (entries 6, 8). Par-
ticularly striking is the photochemical behavior of
reactants bearing a 1-naphthyl group as one of the two aryl
residues. If the naphthyl moiety is attacked at the stage of
the diradicals 9 (see Scheme 3), phenanthrenes 36 or 39
form, otherwise the 1,1¢-binaphthyls 37 or 38 result. The
observed site selectivity was also low if the naphthyl
groups were not substituted in 2-position (entries 2, 10),
but could be enhanced by introduction of a blocking group
(Me or OMe), albeit with low overall yields (entries 12,
13).
O
Ar1
Ar2
Ar1
26
27
O
Ar2
O
N
O
H
Ar1
Ar2
Ar1
28
29
Scheme 7 Systems for the intramolecular PDDA reaction
Symmetric Diketones 22
The symmetric diketones 22a–e (Scheme 8) are accessi-
ble either by reaction of the corresponding diesters 30a
with lithium phenylacetylide in the presence of boron tri-
fluoride diethyl etherate (method A) or from the diacid
dichlorides 30b upon treatment with cadmium phenyl-
acetylide (method B). Unfortunately, the yields were low
with both methods. The irradiation of diketones 22 in
methanol afforded the desired naphthalenes 31 in moder-
ate to good yields if two, three, or four methylene groups
link the two ynone moieties (Scheme 8). Not surprisingly,
the formation of 31d bearing seven methylene groups
failed, because the formed cyclic diketone ring would
have an unfavorable ring size of 11 atoms. A further ex-
tension of the linker group (n = 8) gave the macrocyclic
compound 31e, albeit in low yield (Scheme 8).
We also investigated the reaction of 24 bearing a mesityl
group to find out if methyl groups in the ortho position are
able to prevent attack of the phenyl ring, and found that
alkyl groups are only partly suitable because of their ten-
dency to migrate to the adjacent position.18a
Diynones 25 and 26
Diynones 23 and 24
In view of the synthesis of biaryls fused with a heterocy-
clic ring, we developed ethers 2519 and the protected
amine 26 (Scheme 10). The synthesis of 25a–g commenc-
es with ethyl glycolate 40,19 which was alkylated with
propargyl bromide followed by Sonogashira coupling
with an aryl iodide Ar2I (Scheme 10). The target com-
pounds 25 were accessible via the Weinreb amides 43.19
The nitrogen analogue 26 was prepared similarly, with the
Compounds 23 and 24 were prepared by a similar meth-
odology (Scheme 9). The alcohols 32 play a key role and
were obtained either from arylacetylenes by treatment
with oxetane after lithiation (method A) or by Sonogash-
ira coupling of iodoarenes with appropriate (hydroxy-
alkyl)acetylenes (method B). The aldehydes 33,31
obtained from alcohols 3232 by oxidation, reacted with
lithium arylacetylides to form secondary propargyl alco-
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Photo-Dehydro-Diels–Alder Reaction for the Preparation of Biaryls
469
Table 1 Photochemical Behavior of Compounds 23 and 24
Entry
Starting
material
Methoda
Ar1
Ar2
n
Productsb
Yield (%) Product
ratio
1:1.4
1:1.4
1:2
1
2
23a
23b
24a
24b
24c
24d
24e
24f
B
B
A
A
A
A
A
A
A
B
B
B
B
Ph
Ph
2
2
1
1
1
1
1
1
1
1
1
1
1
34a, 35a
87
30
74
87
87
73
54
69
68
52
67
40
18
Ph
1-naphthyl
36a, 37a34
3
Ph
Ph
34b, 35b18a
34c, 35c18a
4
Ph
PMP
1:1.9
1:1.7
1:4.6
1.5:1
1:7.3
1.7:1
1:1.3
2:1
5
PMP
Ph
34d, 35d18a
34e, 35e18a
6
4-ClC6H4
Ph
7
Ph
4-ClC6H4
34f, 35f18a
8
4-F3CC6H4
Ph
34g, 35g18a
34h, 35h18a
36b, 37b18a
38a (R = H), 39a18a
38b (R = Me)
38c (R = OMe)34
9
24g
24h
24i
Ph
4-F3CC6H4
10
11
12
13
Ph
1-naphthyl
1-naphthyl
Ph
Ph
Ph
24j
2-methyl-1-naphthyl
2-methoxy-1-naphthyl
–
24k
–
a Preparation of 23 and 24: Reagents and conditions: Method A: 1. BuLi, 2. oxetane; Method B: Sonogashira coupling.
b Analytical data of the new compounds are collected in Table 5.
difference that the 3-phenylpropargyl moiety was intro- the two facing phenyl groups in 55, which partly compen-
duced in one step.
sates the steric repulsion (Table 3, entry 2). An isopropyl
group enhances the selectivity to 1:2.3 (Table 3, entry 3)
and with a tert-butyl group only product 54k formed
(Table 3, entry 4).
To explore the influence of substituents in the linker on
the site selectivity, we also prepared compounds 25h–k
following a slightly different approach (Scheme 10).
Thus, aldehydes 4719 were converted into propargyl alco- The irradiation of N-tosylamide 26 in methanol gave
hols 4819 by treatment with lithium phenylacetylide fol- products 56 and 57 in 39% yield and in an isomeric ratio
lowed by alkylation with bromoacetic acid (49). The of 1.6:1 (Scheme 11).
remaining steps are the same as for 25a–g (Scheme 10).
We initially expected the photochemical behavior of 25 to
be very similar to that of 23 and 24. To our surprise, the
seemingly slight structure modification caused apprecia-
ble changes in the PDDA reaction (Scheme 11, Table 2).
In contrast to compounds 24, the introduction of the same
electron-withdrawing groups (Cl, CF3) has only a margin-
al influence on the site selectivity of the PDDA reaction
(Table 2, entries 2–4). To our delight, the even stronger
electron-withdrawing mesyl group, as indicated by the
higher Hammett-constant,35 considerably enhanced the
selectivity in favor of 52 (Table 2, entry 5). The photo-
chemical behavior of 25f,g bearing a 1-naphthyl group
was also unexpected. Instead of the PDDA reaction, only
the cleavage products formed.19
Esters 27 and 28
In the preceding sections, the chromophoric group was al-
ways an ynone, and we assumed for the moment that this
would be a structural prerequisite for the PDDA reaction.
On the other hand, these ketones required relatively labo-
rious syntheses, as discussed above. Furthermore, linkers
bearing a keto group cannot be cleaved easily after ring
closure, and this is a disadvantage with regard to further
synthetic modifications of the biaryls prepared by the
PDDA reaction. For these reasons we decided to investi-
gate whether ester groups can be used instead of ketones
as linkers.
Esters 27 and 28 are easily accessible (Scheme 12,
Table 4) from propargyl alcohols 5834 and homopropargyl
alcohols 59,34 respectively, either by direct esterification
with the appropriate 3-arylpropiolic acids in the presence
of DCC/DMAP (method A) or by conversion with phos-
gene into the chloroformates and treatment with lithium
arylacetylides (method B).
A second approach to influencing the site selectivity is
based on steric repulsion, and was investigated with com-
pounds 25h–k (Scheme 11). Even the introduction of a
methyl group inverts the site selectivity in favor of 54 (cf.
Table 2, entry 1 and Table 3, entry 1), albeit marginally.
The considerably larger phenyl group has nearly the same
effect, presumably owing to a p-stacking effect between
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470
P. Wessig et al.
FEATURE ARTICLE
Ar2
A
i
O
COOEt
ii
OH
O
HO
COOEt
DMP
R
40
41 (R = H)
42 (R = Ar2)
n
n
Ar2
Ar2
Li
I
Ar2
32
33
Ar1
B
iii, iv
Ar1
O
N
1.
2. DMP
v
O
O
R
R1
Ar1
Ar2
=
=
Ar2
O
or
or
Ar2
O
25a–g
O
43
(23, 24a–h)
(24i–k)
n
Ar1
Ar2
vi
N
COOMe
R2
HN
Ts
COOMe
23 (n = 2)
24 (n = 1)
Ph
Ts
(23b, 24h)
(23a, 24a–g, 24i–k)
45
44
vii, iv
Ar2
O
N
Ph
R1
hν
viii
23a, 24a–g
N
N
n
n
R2
+
Ph
Ts
O
Ph
R
Ts
26
O
O
Ar1
35
34
O
46
R
R
viii
ix
O
COOH
OH
O
Ph
Ph
48
50
iv
47
n
hν
+
23b, 24h
n
O
Ar1
R
O
N
R
Ph
viii
36
37
O
O
Ar2
O
Ph
O
Ph
O
25h–k
51
n
n
hν
24i–k
Scheme 10 Synthesis of compounds 25 and 26. Reagents and con-
ditions: (i) Propargylbromide, NaH; (ii) Ar2I, PdCl2(PPh3)2, CuI
(cat.), (i-Pr)2NH; (iii) NaOH; (iv) H(Me)NOMe·HCl, TBTU, (i-
Pr)2NEt; (v) Ar1C≡CLi; (vi) PhC≡CCH2OMs, NaH; (vii) KOH; (viii)
PhC≡CLi; (ix) BrCH2CO2H (49), NaH.
O
R
+
O
39
38
Scheme 9 Synthesis and PDDA reaction of compounds 23 and 24
The substituents Ar1 and Ar2 in esters 27 and 28 were cho-
sen according to two main criteria. On the one hand, the
goal was to elucidate the influence of blocking groups in
the ortho positions of aryl groups on site selectivity. On
the other hand, we wanted to prepare the interesting sub-
stance class of 1,1¢-binaphthyls.34
Our first irradiation experiments with esters 27 and 28 un-
der the previously employed conditions were disappoint-
ing. The compounds showed very low photochemical
reactivity in various solvents and unselective decomposi-
tion upon prolonged irradiation times. The supposition
that the esters absorb UV light at wavelengths too short
Table 2 PDDA Reaction of Ketones 25a–g19
Entry
Starting material Ar1
Ar2
Solvent
t-BuOH
MeCN
MeOH
t-BuOH
t-BuOH
MeCN
MeCN
Yielda (%)
Ratio 52/53
1.3:1
1.7:1
1.2:1
2.4:1
6.6:1
–
1
2
3
4
5
6
7
25a
25b
25c
25d
25e
25f
Ph
Ph
77
42
52
34
46
–
4-ClC6H4
Ph
Ph
4-ClC6H4
4-F3CC6H4
4-MsC6H4
1-naphthyl
Ph
Ph
Ph
Ph
25g
1-naphthyl
–
–
a Yield of products 52 and 53 combined.
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Photo-Dehydro-Diels–Alder Reaction for the Preparation of Biaryls
471
R1
O
A
B
O
method A or B
n
n
HO
O
Ar2
58 (n = 1)
59 (n = 2)
Ar1
Ar2
(see table 4)
R1
hν
25a–g
27 (n = 1)
28 (n = 2)
O
+
O
O
OMe
R2
OMe
R2
MON =
DMOP =
52
54
53
55
O
R
R
Ph
OMe
Ar2
hν
O
25h–k
+
n
n
hν
27a,d,e
28a,f
O
O
+
Ph
Ph
O
O
N
O
Ar1
O
Ph
60
61
Ts
Ts
hν
N
26
+
R
O
O
56
57
n
n
hν
27b,c
28b,d
+
O
O
Scheme 11 PDDA reactions of ketones 25 and 26
O
Ar1
O
62
63
for our equipment (see experimental part) could soon be
ruled out.
Ar2
n
O
Therefore we hypothesized that the efficiency of intersys-
tem crossing to the triplet state, necessary for the PDDA
reaction, is too low, compared with the above-discussed
ketones. To prove this, we irradiated esters 27 and 28 in
acetone as triplet sensitizer37 and observed, to our delight,
a dramatically increased reactivity.
n
+
hν
O
27f
28c,e
O
R
O
64
65
The results are summarized in Scheme 12 and Table 4.
Not surprisingly, in the absence of blocking groups both
isomeric PDDA reaction products always formed in near-
ly the same amounts (Table 4, entries 1, 2, 7–9). Replace-
ment of both o-hydrogen atoms of phenyl (entry 4, 12) or
of the hydrogen atom in the 2-position of naphthyl (entries
3, 6, 10, 11) by a methoxy group suppressed the formation
of one isomer. The photochemical behavior of 27e (entry
5) verified that methyl groups are also suited to protect a
phenyl ring from attack in the PDDA reaction. Although
it is obviously possible to prevent the formation of mix-
tures of isomers in the course of the PDDA reaction by
blocking groups, the yields never exceed 50%. We pre-
sume that undesirable attack at blocked positions takes
Scheme 12 Synthesis and PDDA reactions of esters 27 and 28
place nevertheless, but that this results in the molecules
undergoing undefined decomposition.
Amides 29
The usability of the last linker system, the secondary
amides 29, was demonstrated with the parent compound
29a, the synthesis and PDDA reaction of which is depict-
ed in Scheme 13. The very short and simple route to 29a
consists of the coupling of 3-phenylpropiolic acid (66)38
with propargylamine (67),38 followed by Sonogashira
coupling of the resulting amide 6839 with iodobenzene.
Upon irradiation, amide 29a40 cyclized to a mixture of the
two isomeric PDDA reaction products 69a40 and 70a,40 in
49% yield and in an isomeric ratio of 1:1.8 (Scheme 13).
Table 3 PDDA Reaction of Ketones 25h–k
Entry
Starting material
R
Yielda (%) Ratio 54/55
1
2
3
4
25h
25i
Me
Ph
68
55
62
41
1:1.5
1:1.6
1:2.3
–
Summary and Outlook
We have demonstrated that the PDDA reaction is a pow-
erful method for the preparation of various biaryls. The re-
action can be performed intermolecularly as dimerization
of ynones or addition of ynones to acetylenes, but this
gives products in relatively low yields. Considerable im-
25j
25k
i-Pr
t-Bu
a Yield of products 54 and 55 combined.
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

472
P. Wessig et al.
FEATURE ARTICLE
Table 4 Synthesis and PDDA Reactions of Esters 27 and 28a
Entry
Starting
material
Ar1
Ar2
n
Methodb Yieldc (%) of PDDA
Yielde Ratioe
27 or 28
productsd
(%)
68
79
46
34
38
1
2
27a36
27b34
27c34
27d
Ph
Ph
1
1
1
1
1
1
2
2
2
2
2
2
A
A
A
A
A
A
A
A
B
A
B
A
90
96
60a + 61a
62a + 63a
63b
1:1.1
Ph
1-naphthyl
1:1.1
3
Ph
2-methoxy-1-naphthyl
40
–
4
2,6-(MeO)2C6H3
Mes
Ph
Ph
100
100
100
88
60b
–
5
27e
60c
–
6
27f34
28a
2-methoxy-1-naphthyl Ph
64a (R = OMe) 36
–
7
Ph
Ph
60d + 61b
62b + 63b
64b + 65a
81
71
59
1:1.4
1.4:1
1:1.6
–
8
28b34
28c34
28d34
28e34
28f
Ph
1-naphthyl
98
9
1-naphthyl
Ph
Ph
46
10
11
12
2-methoxy-1-naphthyl
91
63c (R = OMe) 38
64c (R = OMe) 28
2-methoxy-1-naphthyl Ph
2,6-(MeO)2C6H3 Ph
54
–
91
60e
28
–
a Analytical data of new compounds are given in Table 5.
b Preparation of 27 and 28 from 58 or 59. Reagents and conditions: Method A: 58 or 59, Ar1C≡CCO2H, DCC/DMAP; Method B: 1. 58 or 59,
COCl2, 2. Ar1C≡CLi.
c Yield of product 27 or 28 from 58 or 59.
d PDDA reaction products; see Scheme 12. Irradiation was performed in acetone.
e Yields and ratios of PDDA reaction products.
O
O
are possible by the PDDA reaction (with the exception of
dimerization and cyclization of symmetric reactants). We
have, fortunately, learnt to influence this outcome by the
introduction of blocking or shielding groups in the reac-
tants.
+
OH H2N
N
i
H
Ph
Ph
68
67
66
Ph
ii
One of the most fascinating properties of biaryls is their
potential atropisomerism. Therefore, our future efforts
will be focused on the stereoselective synthesis of enan-
tiomerically pure biaryls on the basis of the results pre-
sented in this article.
O
NH
hν
N
O
H
69a
70a
Ph
Ph
+
29a
NH
The irradiations of the appropriate acetylenes or diacetylenes were
performed in MeOH, t-BuOH, or MeCN (ketones) or acetone (es-
ters and amides) at concentrations of 0.01 mmol/mL. A high-
pressure mercury arc lamp (150 W) was used. Light of wavelength
<300 nm was absorbed by a Pyrex glass jacket between the lamp
and the reaction vessel. The reactions were monitored by TLC to de-
termine when the reactants had completely disappeared. The solns
were concentrated under reduced pressure and the crude residues
were purified by flash chromatography to give the pure photoprod-
ucts. 1H NMR (300 MHz) and 13C NMR (75.5 MHz) spectra were
recorded on a Bruker DPX-300 spectrometer. CDCl3 was used as
the solvent for NMR measurements and TMS was used as internal
reference. The ESI-HRMS and EI-HRMS were carried out on a
MSI Concept 1H mass spectrometer. The analytical data of the new
compounds described here are given in Table 5.
O
Ph
Scheme 13 Synthesis and PDDA reaction of amide 29a. Reagents
and conditions: (i) DCC (1.1 equiv), DMAP (6 mol%); (ii) PhI,
Pd(PPh3)2Cl2 (3 mol%), CuI (10 mol%), i-Pr2NH (1 equiv).
provement can be achieved by connecting these two moi-
eties by a linker. For this purpose, we have developed
eight linker systems, each associated with special charac-
teristics regarding synthesis and photochemistry. A disad-
vantage at first glance is that almost always two isomers
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Photo-Dehydro-Diels–Alder Reaction for the Preparation of Biaryls
473
Table 5 Analytical Data of New Compounds
Compound
1H NMR (300 MHz, CDCl3): d
13C NMR (75.5 MHz, CDCl3): d
HRMS: m/z
15b
7.75–6.79 (m, 4 H), 2.96–2.91 (t, 2 H, 171.8 (Cq/COO), 143.3 (Cq/Ar), 139.5 (CHAr), 129.4 (ESI) calcd for
3J = 7.8 Hz, CH2), 2.49–2.44 (t, J = 7.8 (CHAr), 128.33 (CHAr), 128.0 (CHAr), 100.4 (Cq/Ar), C13H17O2INa [M+ + Na]:
Hz, 2 H, CH2), 1.37 (s, 9 H, t-Bu)
80.5 (Cq/tBu), 36.1 (CH2), 35.5 (CH2), 28.1
(CH3/t-Bu
355.0165; found:
355.0165
)
16
7.31–7.06 (m, 4 H, Ar), 4.73–4.66 (m, 1 172.9 (Cq/COO), 142.8 (Cq/Ar), 132.0 (CHAr), 128.7 (EI) calcd for C17H22O3
H, CH), 3.24–3.18 (s, 1 H, OH), 3.00 (t, (CHAr), 128.4 (CHAr), 126.2 (CHAr), 122.2 (CHAr), [M+]: 274.1569; found:
3J = 8 Hz, 2 H, CH2), 2.51–2.46 (t, 3J = 95.8 (Cq/acetylene), 82.0 (Cq/acetylene), 80.7 (Cq/t-Bu),
8 Hz, 2 H, CH2), 1.50–1.48 (d, 3J = 6.6, 58.6 (CH), 36.2 (CH2), 30.42 (CH2), 28.1
274.1569
3 H, CH3), 1.35 (s, 9 H, t-Bu)
(CH3/t-Bu), 24.4 (CH3)
17a
17b
7.35–7.00 (m, 4 H, Ar), 3.46 (s, 3 H,
184.4 (Cq/CO), 172.9 (Cq/COO), 144.4 (Cq/Ar), 134.0 (EI) calcd for C14H14O3
(CHAr), 131.1 (CHAr), 129.1 (CHAr), 126.7 (CHAr), [M+]: 230.0943; found:
OCCH3), 2.96–2.91 (t, 2 H, CH2, 3J =
7.8 Hz), 2.94–2.44 (t, 3J = 7.8 Hz, 2 H, 119.3 (Cq/Ar), 92.1 (Cq/acetylene), 88.6 (Cq/acetylene
CH2) 2.26 (s, 3 H, CH3)
)
230.0943
51.7 (CH3), 34.7 (CH2), 32.8 (CH3), 29.7 (CH2)
7.50–7.17 (m, 4 H, Ar), 3.08–3.02 (d, 3J 184.4 (Cq/CO), 171.8 (Cq/COO), 144.8 (Cq/Ar), 133.9 (EI) calcd for C17H20O3
= 7.7 Hz, 2 H, CH2), 2.56–2.51 (d, 3J = (CHAr), 131.0 (CHAr), 129.1 (CHAr), 126.5 (CHAr), [M+]: 272.1412; found:
7.7 Hz, 2 H, CH2), 2.15 (s, 3 H, CH3),
1.36 (s, 9 H, t-Bu)
119.3 (Cq/Ar), 92.1 (Cq/acetylene), 88.9 (Cq/acetylene),
80.5 (Cq/t-Bu), 36.0 (CH2), 32.8 (CH3), 29.9 (CH2),
272.1412
28.0 (CH3/t-Bu
)
18a
18b
8.70 (s, 1 H), 7.46–7.13 (m, 7 H), 2.802 205.5 (Cq/CO), 198.8 (Cq/CO), 172.3 (Cq/COO), 140.2 (ESI) calcd for C34H41O6
(s, 3 H), 2.60–2.51 (m, 4 H), 2.36–2.29 (Cq/Ar), 138.6 (Cq/Ar), 135.8 (Cq/Ar) 134.9 (Cq/Ar),
[M+ + H]: 545.2903;
found: 545.2898
(m, 4 H), 1.46 (s, 9 H), 1.34 (s, 9 H)
131.0 (CHAr), 129.1 (CH), 128.7 (CHAr), 128.6
(CHAr), 127.4 (CHAr), 127.1 (CHAr), 126.0 (CHAr),
125.6(CHAr), 80.9 (Cq/t-Bu), 80.2 (Cq/t-Bu), 36.5
(CH2), 35.2 (CH2), 31.6 (CH3) 28.1 ((CH3)3), 28.0
((CH3)3), 27.0 (CH3)
8.62 (s, 1 H), 7.03–7.38 (m, 7 H), 3.65 198.7 (Cq/CO), 173.4 (Cq/COO), 173.2 (Cq/COO), 139.9 (EI) calcd for C28H28O6
(s, 3 H), 3.46 (s, 3 H), 2.75–2.80 (t, 2J = (Cq/Ar), 130.9 (CHAr), 130.24 (Cq/Ar), 129.2 (CHAr), [M+]: 460.1886; found:
7.8 Hz, 2 H), 2.72 (s, 3 H), 2.31–2.65
(m, 6 H), 2.07 (s, 3 H)
125.7 (CHAr), 51.9 (CH3), 51.45 (CH3), 35.1
(CH2), 33.9 (CH2), 31.6 (CH3), 27.9 (CH2), 27.9
(CH2), 27 (CH3)
460.1886
20a
21a
8.48 (s, 1 H), 8.05–8.02 (m, 1 H), 7.99 198.1 (Cq/CO), 140.9 (Cq/Ar), 139.9 (Cq/Ar), 133.9
(EI) calcd for C18H14O
(d, 4J = 1.9 Hz, 1 H), 7.95–7.92 (m, 1
(Cq/Ar), 133.0 (Cq/Ar), 129.9 (CHAr), 129.6 (CHAr), [M+]: 246.1045; found:
H), 7.58–7.50 (m, 7 H), 2.75 (s, 3 H)
128.6 (CHAr), 128.4 (CHAr), 127.6 (CHAr), 126.6
(CHAr), 126.1 (CHAr), 124.8 (CHAr), 26.7 (CH3)
246.1045
7.91 (d, 3J = 8.3 Hz, 2 H), 7.69 (dd, 3J = 204.9 (Cq/CO), 138.4 (Cq/Ar), 138.3 (Cq/Ar), 138.1
(EI) calcd for C18H14O
[M+]: 246.1045; found:
8.7, 8.7 Hz, 2 H), 7.58–7.37 (m, 7 H),
1.94 (s, 3 H)
(Cq/Ar), 134.4 (Cq/Ar), 131.9 (Cq/Ar), 130.6 (CHAr),
128.5 (CHAr), 128.2 (CHAr), 128.0 (CHAr), 127.24 246.1045
(CHAr), 127.22 (CHAr), 126.7 (CHAr), 124.3
(CHAr), 30.7 (CH3)
20b
8.49 (s, 1 H), 8.05–8.02 (m, 1 H), 7.99 200.4 (Cq/CO), 140.8 (Cq/Ar), 140.0 (Cq/Ar), 138.81
(ESI) calcd for C20H19O
[M+ + H]: 275.1436;
found: 275.1434
(d, 4J = 1.5 Hz, 1 H), 7.95–7.89 (m, 1
(Cq/Ar), 138.78 (Cq/Ar), 133.0 (Cq/Ar), 129.94
H), 7.58–7.51 (m, 7 H), 3.11 (t, 3J = 7.2 (CHAr), 129.92 (CHAr), 129.0 (CHAr), 128.42
Hz, 2 H), 1.85 (tq, 3J = 7.2, 7.5 Hz, 2 H), (CHAr), 128.35 (CHAr), 127.6 (CHAr), 126.6
1.06 (t, 3J = 7.5 Hz, 3 H)
(CHAr), 126.1 (CHAr), 124.8 (CHAr), 40.6 (CH2),
17.9 (CH2), 13.9 (CH3)
20c
21c
8.45 (s, 1 H), 8.04–7.94 (m, 3 H), 7.59– 198.2 (Cq/CO), 159.2 (Cq/Ar), 140.6 (Cq/Ar), 134.1
7.52 (m, 2 H), 7.45–7.40 (m, 2 H), (Cq/Ar), 134.0 (Cq/Ar), 133.1 (Cq/Ar), 132.3 (Cq/Ar),
7.07–7.02 (m, 2 H), 3.90 (s, 3 H), 2.74 131.1 (CHAr), 130.0 (CHAr), 129.4 (CHAr), 128.5
(EI) calcd for C19H16O2
[M+]: 276.1150; found:
276.1150
(s, 3 H),
(CHAr), 126.6 (CHAr), 126.2 (CHAr), 124.8 (CHAr),
113.9 (CHAr), 55.4 (CH3), 26.8 (CH3)
7.83 (d, 3J = 8.3 Hz, 1 H), 7.81 (d, 3J = 205.1 (Cq/CO), 158.2 (Cq/Ar), 138.7 (Cq/Ar), 138.5
(EI) calcd for C19H16O2
[M+]: 276.1150; found:
276.1150
8.9 Hz, 1 H), 7.53–7.49 (m, 4 H), 7.40– (Cq/Ar), 136.9 (Cq/Ar), 133.9 (Cq/Ar), 133.2 (Cq/Ar),
7.37 (m, 2 H), 7.21 (dd, 3J = 8.9 Hz,
130.4 (CHAr), 129.9 (CHAr), 129.5 (CHAr), 128.6
4J = 2.5 Hz, 1 H), 6.99 (d, 4J = 2.5 Hz, 1 (CHAr), 128.1 (CHAr), 127.7 (CHAr), 122.0 (CHAr),
H), 3.71 (s, 3 H), 1.94 (s, 3 H),
119.6 (CHAr), 105.6 (CHAr), 55.1 (CH3), 30.7
(CH3)
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

474
P. Wessig et al.
FEATURE ARTICLE
Table 5 Analytical Data of New Compounds (continued)
Compound
1H NMR (300 MHz, CDCl3): d
13C NMR (75.5 MHz, CDCl3): d
HRMS: m/z
20d
8.53 (s, 1 H), 8.11–8.06 (m, 3 H), 7.98 197.7 (Cq/CO), 145.8 (Cq/Ar), 139.8 (Cq/Ar), 138.7
(EI) calcd for C19H16O3S
[M+]: 324.0820; found:
324.0818
(d, 4J = 1.7 Hz, 1 H), 7.82–7.79 (m, 1
H), 7.73–7.69 (m, 2 H), 3.16 (s, 3 H),
2.76 (s, 3 H)
(Cq/Ar), 133.9 (Cq/Ar), 133.3 (Cq/Ar), 131.0 (CHAr),
130.7 (CHAr), 130.2 (CHAr), 129.2 (CHAr), 127.5
(CHAr), 127.1 (CHAr), 125.4 (CHAr), 124.9 (CHAr),
44.6 (CH3), 26.6 (CH3)
23a
24j
7.59–7.56 (m, 2 H), 7.48–7.35 (m, 5 H), 187.3 (Cq/CO), 133.1 (CHAr), 131.6 (CHAr), 130.7
(ESI) calcd for C21H16O
7.29–7.26 (m, 3 H), 2.89 (t, 3J = 7.4 Hz, (CHAr), 128.7 (CHAr), 128.2 (CHAr), 127.7 (CHAr), [M+ + H]: 273.1279;
2 H), 2.53 (t, 3J = 6.8 Hz, 2 H), 2.04
(quin, 3J = 7.2 Hz, 2 H)
123.6 (Cq/Ar), 119.9 (Cq/Ar), 90.9 (Cq), 88.8 (Cq),
87.8 (Cq), 81.6 (Cq), 44.3 (CH2), 23.0 (CH2), 18.8
(CH2)
found: 273.1278
8.30 (d, 3J = 8.7 Hz, 1 H), 7.86 (d, 3J = 185.4 (Cq/CO), 143.0 (Cq/Ar), 131.6 (CHAr), 131.4
(EI) calcd for C24H17O
8.3 Hz, 1 H), 7.82 (d, 3J = 6.8 Hz, 1 H), (Cq/Ar), 131.1 (CHAr), 128.3 (CHAr), 128.2 (CHAr), [M+ – H]: 322.1279;
7.59 (ddd, 3J = 8.3, 6.8 Hz, 4J = 1.5 Hz, 127.9 (CHAr), 127.8 (CHAr), 126.0 (CHAr), 125.4
1 H), 7.49 (ddd, 3J = 7.9, 6.8 Hz, 4J =
(CHAr), 123.4 (Cq/Ar), 94.7 (Cq), 87.8 (Cq), 44.5
found: 322.1280
1.3 Hz, 1 H), 7.41–7.37 (m, 3 H), 7.29– (CH2), 21.5 (CH3), 14.5 (CH2)
7.25 (m, 4 H), 3.17–3.11 (m, 2 H),
2.93–2.86 (m, 2 H), 2.72 (s, 3 H)
26
7.75–7.69 (m, 2 H), 7.58–7.51 (m, 2 H), 182.3 (Cq/CO), 143.9 (Cq/Ar), 136.1 (Cq/Ar), 133.4
(EI) calcd for
7.50–7.38 (m, 1 H), 7.37–7.29 (m, 2 H), (CAr), 131.6 (CAr), 131.2 (CAr), 129.7 (CAr), 128.7 C26H21NO3S [M+]:
7.26–7.13 (m, 5 H), 7.11–7.06 (m, 2 H), (CAr), 128.6 (CAr), 128.2 (CAr), 127.6 (CAr), 121.9 427.1242; found:
4.42 (s, 2 H, NCH2C≡), 4.29 (s, 2 H,
NCH2CO), 2.30 (s, 3 H, TsCH3)
(Cq/Ar), 119.4 (Cq/Ar), 94.6 (PhC≡CCO), 86.4
(PhC≡CCO), 86.1 (PhC≡CCH2), 81.3
(PhC≡CCH2), 56.4 (NCH2CO), 38.6 (NCH2C≡),
21.5 (TsCH3)
427.1241
27d
27e
7.48–7.42 (m, 2 H), 7.36–7.29 (m, 4 H), 163.2 (Cq/Ar), 153.6 (Cq/CO), 132.8 (CHAr), 132.4
(EI) calcd for C20H16O4
6.52 (d, 3J = 8.5 Hz, 2 H), 5.05 (s, 2 H), (CHAr), 131.9 (CHAr), 131.6 (CHAr), 128.7 (CHAr), [M+]: 320.1049; found:
3.88 (s, 6 H)
128.3 (CHAr), 122.1 (Cq/Ar), 103.2 (CHAr), 98.0
(Cq/Ar), 88.0 (Cq), 86.9 (Cq), 82.4 (Cq), 81.6 (Cq),
56.1 (CH3), 53.9 (CH2)
320.1048
7.50–7.47 (m, 2 H), 7.34–7.32 (m, 3 H), 153.7 (Cq/CO), 142.7 (Cq/Ar), 140.8 (Cq/Ar), 131.9
(EI) calcd for C21H18O2
6.89 (s, 2 H), 5.06 (s, 2 H), 2.46 (s, 6 H), (CHAr), 128.8 (CHAr), 128.3 (CHAr), 127.9 (CHAr), [M+]: 302.1307; found:
2.30 (s, 3 H)
122.0 (Cq/Ar), 116.2 (Cq/Ar), 87.4 (Cq), 87.0 (Cq),
86.1 (Cq), 82.3 (Cq), 53.9 (CH2), 21.5 (CH3), 20.8
(CH3)
302.1307
28a
28f
7.62–7.59 (m, 2 H), 7.49–7.35 (m, 5 H), 153.8 (Cq/CO), 133.0 (CHAr), 131.7 (CHAr), 130.7
(EI) calcd for C19H14O2
7.32–7.27 (m, 3 H), 4.43 (t, 3J = 6.8 Hz, (CHAr), 128.6 (CHAr), 128.2 (CHAr), 128.0 (CHAr), [M+]: 274.0994; found:
2 H), 2.85 (t, 3J = 6.8 Hz, 2 H)
123.2 (Cq/Ar), 119.5 (Cq/Ar), 86.8 (Cq), 84.8 (Cq),
82.3 (Cq), 80.4 (Cq), 63.7 (CH2), 19.8 (CH2)
274.0992
7.42–7.40 (m, 2 H), 7.34 (t, 3J = 8.5 Hz, 163.1 (Cq/Ar), 154.0 (Cq/CO), 132.6 (CHAr), 131.6
(EI) calcd for C21H18O4
1 H), 7.30–7.27 (m, 3 H), 6.52 (d, 3J = (CHAr), 128.2 (CHAr), 127.9 (CHAr), 123.3 (Cq/Ar), [M+]: 334.1205; found:
8.5 Hz, 2 H), 4.42 (t, 3J = 7.3 Hz, 2 H), 103.3 (CHAr), 98.0 (Cq/Ar), 88.4 (Cq), 84.9 (Cq),
3.88 (s, 6 H), 2.85 (t, 3J = 7.3 Hz, 2 H) 82.2 (Cq), 81.0 (Cq), 63.5 (CH2), 56.1 (CH3), 19.8
(CH2)
334.1205
29a
34a
7.49–7.44 (m, 2 H), 7.38–7.20 (m, 8 H), 152.9 (Cq/CO), 132.5 (CAr), 131.7 (CAr), 130.2 (CAr), (EI) calcd for C18H13NO
6.22 (br s, 1 H, NH), 4.31 (d, 3J = 5.5
128.6 (CAr), 128.5 (CAr), 128.3 (CAr), 122.3 (Cq/Ar), [M+]: 259.0997; found:
Hz, 2 H, CH2)
120.0 (Cq/Ar), 85.5 (PhC≡CCH2), 83.9
(PhC≡CCH2), 83.7 (PhC≡CCO), 82.4
(PhC≡CCO), 30.4 (CH2)
259.0997
7.81 (d, 3J = 8.3 Hz, 1 H), 7.75 (s, 1 H), 199.1 (Cq/CO), 142.8 (Cq/Ar), 140.3 (Cq/Ar), 139.6
(EI) calcd for C20H16O
7.55–7.44 (m, 5 H), 7.32 (ddd, 3J = 8.3, (Cq/Ar), 135.0 (Cq/Ar), 132.3 (Cq/Ar), 128.80 (CHAr), [M+]: 272.1201; found:
8.3 Hz, 4J = 1.4 Hz, 1 H), 7.21–7.19 (m, 128.78 (Cq/Ar), 128.5 (CHAr), 128.1 (CHAr), 127.9 272.1202
2 H), 3.17 (t, 3J = 6.2 Hz, 2 H), 2.66 (t, (CHAr), 126.9 (CHAr), 126.7 (CHAr), 126.6 (CHAr),
3J = 6.7 Hz, 2 H), 2.20–2.14 (m, 2 H)
125.7 (CHAr), 41.1 (CH2), 31.2 (CH2), 22.9 (CH2)
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

FEATURE ARTICLE
The Photo-Dehydro-Diels–Alder Reaction for the Preparation of Biaryls
475
Table 5 Analytical Data of New Compounds (continued)
Compound
1H NMR (300 MHz, CDCl3): d
13C NMR (75.5 MHz, CDCl3): d
HRMS: m/z
35a
8.71 (s, 1 H), 8.01–7.99 (m, 1 H), 7.55– 199.1 (Cq/CO), 138.7 (Cq/Ar), 138.3 (Cq/Ar), 136.7
7.37 (m, 6 H), 7.28–7.26 (m, 2 H), (Cq/Ar), 135.1 (Cq/Ar), 131.4 (Cq/Ar), 130.4 (Cq/Ar),
2.79–2.72 (m, 4 H), 2.10–2.04 (m, 2 H) 130.04 (CHAr), 130.00 (CHAr), 128.62 (CHAr),
128.60 (CHAr), 128.4 (CHAr), 127.4 (CHAr), 126.2
(CHAr), 125.8 (CHAr), 39.4 (CH2), 28.5 (CH2), 23.0
(CHAr)
(EI) calcd for C20H16O
[M+]: 272.1201; found:
272.1202
38b
8.01 (s, 1 H), 7.95 (d, 3J = 8.3 Hz, 1 H), 205.4 (Cq/CO), 148.2 (Cq/Ar), 137.5 (Cq/Ar), 136.9
7.91 (d, 3J = 8.1 Hz, 1 H), 7.88 (d, 3J = (Cq/Ar), 133.9 (Cq/Ar), 132.9 (Cq/Ar), 132.3 (Cq/Ar),
7.9 Hz, 1 H), 7.56 (ddd, 3J = 8.1, 8.1 Hz, 132.0 (Cq/Ar), 131.9 (Cq/Ar), 128.5 (CHAr), 128.4
4J = 1.5 Hz, 1 H), 7.50 (d, 3J = 8.5 Hz, 1 (CHAr), 128.00 (CHAr), 127.98 (CHAr), 127.9
H), 7.38–7.23 (m, 4 H), 7.13 (ddd, 3J = (CHAr), 127.8 (CHAr), 126.3 (CHAr), 125.8 (CHAr),
8.3, 8.3 Hz, 4J = 1.3 Hz, 1 H), 6.83 (dd, 125.2 (CHAr), 124.6 (CHAr), 37.2 (CH2), 25.0
3J = 7.9 Hz, 5J = 0.6 Hz, 1 H), 3.41–3.36 (CH2), 20.2 (CH3)
(EI) calcd for C24H18O
[M+]: 322.1358; found:
322.1358
(m, 2 H), 2.72–2.67 (m, 2 H), 1.99 (s, 3
H)
45
7.80–7.74 (m, 2 H), 7.31–7.24 (m, 5 H), 168.9 (Cq/CO), 143.8 (Cq/Ar), 136.0 (Cq/Ar), 131.6
7.18–7.12 (m, 2 H), 4.48 (s, 2 H,
(ESI) calcd for
(CAr), 129.6 (CAr), 128.6 (CAr), 128.2 (CAr), 127.6 C19H19NNaO4S [M+ +
NCH2C≡), 4.16 (s, 2 H, CH2), 3.72 (s, 3 (CAr), 113.8 (Cq/Ar), 86.1 (PhC≡C), 81.3 (PhC≡C), Na]: 380.0927; found:
H, CO2CH3), 2.37 (s, 3 H, TsCH3)
52.3 (NCH2CO), 47.0 (CO2CH3), 38.4 (NCH2C≡), 380.0922
31.5 (TsCH3)
46
7.75–7.69 (m, 2 H), 7.24–7.16 (m, 5 H), 168.5 (Cq/CO), 143.5 (Cq/Ar), 136.3 (Cq/Ar), 131.5
7.12–7.06 (m, 2 H), 4.45 (s, 2 H,
(ESI) calcd for
(CAr) 129.5 (CAr), 128.4 (CAr), 128.1 (CAr), 127.6 C20H22N2NaO4S [M+ +
NCH2C≡), 4.26 (s, 2 H, NCH2CO), 3.64 (CAr), 122.1 (Cq/Ar), 85.7 (PhC≡C), 82.0 (PhC≡C), Na]: 409.1198; found:
(s, 3 H, OCH3), 3.11 (s, 3 H, NCH3),
2.29 (s, 3 H, TsCH3)
61.4 (OCH3), 46.4 (NCH2CO), 38.2 (NCH2C≡),
32.3 (NCH3), 21.4 (TsCH3)
409.1193
56/57
8.26 (s, 1 H, 57), 7.91–7.84 (m, 1 H),
192.0 (Cq/CO, 57), 191.4 (Cq/CO, 56), 144.05 (CHAr) (ESI) calcd for
C26H21NO3S [M+ + H]:
(Cq/Ar), 136.6 (Cq/Ar), 135.12(Cq/Ar), 135.07 (CHAr), 428.1320;
7.78 (d, 3J = 8.1 Hz, 2 H), 7.68 (s, 1 H, 144.0 (Cq/Ar), 143.7 (Cq/Ar), 138.6 (CHAr), 137.2
56), 7.56 (d, 3J = 8.1 Hz, 2 H), 7.53–
7.51 (m, 2 H), 7.51–7.48 (m, 2 H),
133.8 (Cq/Ar), 133.2 (CHAr), 132.7 (Cq/Ar), 131.7
found: 428.1315
7.46–7.44 (m, 1 H), 7.43–7.41 (m, 2 H), (Cq/Ar), 130.4 (Cq/Ar), 130.0 (Cq/Ar), 129.7 (CHAr),
7.40–7.39 (m, 3 H), 7.38–7.36 (m, 3 H), 129.62 (CHAr), 129.55 (CHAr), 129.3 (Cq/Ar), 129.1
7.33 (d, 3J = 1.1 Hz, 1 H), 7.31 (d, 3J = (CHAr), 128.7 (Cq/Ar), 128.6 (CHAr), 128.3 (Cq/Ar),
1.1 Hz, 1 H), 7.22–7.16 (m, 2 H), 7.10 128.0 (CHAr), 127.8 (CHAr), 127.5 (CHAr), 127.3
(d, 3J = 7.9 Hz, 2 H), 7.00 (d, 3J = 7.9
Hz, 2 H), 4.63 (s, 2 H, NCH2CAr, 56),
(CHAr), 127.2 (CHAr), 126.7 (CHAr), 126.3 (Cq/Ar),
125.2 (CHAr), 55.8 (COCH2N, 56), 54.6
4.33 (s, 2 H, NCH2CAr, 57), 4.10 (s, 2 H, (COCH2N, 57), 49.2 (NCH2CAr, 56), 47.0
COCH2N, 57), 3.91 (s, 2 H, COCH2N, (NCH2CAr, 57), 21.4 (CH3, 56), 15.2 (CH3, 57)
56), 2.25 (s, 3 H, CH3, 56), 2.19 (s, 3 H,
CH3, 57)
60b
60c
60d
7.94 (d, 3J = 8.3 Hz, 1 H), 7.87 (s, 1 H), 169.6 (Cq/CO), 158.1 (Cq/Ar), 140.2 (Cq/Ar), 136.2
(EI) calcd for C20H16O4
[M+]: 320.1048; found:
320.1049
7.72 (d, 3J = 8.5 Hz, 1 H), 7.60 (ddd,
(Cq/Ar), 135.4 (Cq/Ar), 132.8 (Cq/Ar), 130.3 (CHAr),
3J = 8.3, 7.9 Hz, 4J = 1.3 Hz, 1 H), 7.49– 128.3 (CHAr), 128.2 (CHAr), 127.7 (CHAr), 126.3
7.41 (m, 2 H), 6.74 (d, 3J = 8.5 Hz, 2 H), (CHAr), 121.3 (Cq/Ar), 120.1 (CHAr), 111.8 (Cq/Ar),
5.43 (d, 4J = 1.1 Hz, 2 H), 3.62 (s, 6 H) 104.1 (CHAr), 68.2 (CH2), 55.9 (CH3)
7.98 (d, 3J = 8.3 Hz, 1 H), 7.92 (s, 1 H), 169.5 (Cq/CO), 141.4 (Cq/Ar), 140.2 (Cq/Ar), 137.5
7.65 (dd, 3J = 8.1, 7.0 Hz, 1 H), 7.58 (d, (Cq/Ar), 136.3 (Cq/Ar), 135.8 (Cq/Ar), 132.3 (Cq/Ar),
3J = 8.3 Hz, 1 H), 7.45 (dd, 3J = 8.1, 7.0 131.0 (Cq/Ar), 128.8 (CHAr), 128.3 (CHAr), 128.2
(EI) calcd for C21H18O2
[M+]: 302.1307; found:
302.1307
Hz, 1 H), 7.04 (s, 2 H), 2.40 (s, 3 H),
1.80 (s, 6 H)
(CHAr), 127.0 (CHAr), 126.9 (CHAr), 120.4 (Cq/Ar),
120.0 (CHAr), 68.4 (CH2), 21.3 (CH3), 20.1 (CH3)
7.84 (d, 3J = 7.9 Hz, 1 H), 7.73–7.70 (m, 145.5 (Cq/Ar), 138.8 (Cq/Ar), 134.92 (Cq/Ar), 134.87 (EI) calcd for C19H14O2
1 H), 7.59–7.44 (m, 5 H), 7.41–7.35 (m, (Cq/Ar), 132.6 (Cq/Ar), 130.9 (CHAr), 129.1 (CHAr), [M+]: 274.0994; found:
1 H), 7.28–7.25 (m, 2 H), 4.54 (t, 3J =
128.8 (CHAr), 128.5 (CHAr), 128.3 (CHAr), 127.9
274.0994
5.5 Hz, 2 H), 3.24 (t, 3J = 5.5 Hz, 2 H) (CHAr), 127.3 (CHAr), 127.2 (CHAr), 126.2 (CHAr),
125.3 (CHAr), 121.5 (Cq/Ar), 66.9 (CH2), 29.7 (CH2)
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

476
P. Wessig et al.
FEATURE ARTICLE
Table 5 Analytical Data of New Compounds (continued)
Compound
1H NMR (300 MHz, CDCl3): d
13C NMR (75.5 MHz, CDCl3): d
HRMS: m/z
61b
8.75 (s, 1 H), 8.00–7.96 (m, 1 H), 7.54– 166.0 (Cq/CO), 137.4 (Cq/Ar), 137.3 (Cq/Ar), 134.9
(EI) calcd for C19H14O2
7.43 (m, 6 H), 7.27–7.23 (m, 2 H), 4.45 (Cq/Ar), 132.2 (CHAr), 131.9 (Cq/Ar), 130.0 (CHAr), [M+]: 274.0994; found:
(t, 3J = 6.0 Hz, 2 H), 2.88 (t, 3J = 6.0 Hz, 129.7 (CHAr), 128.9 (CHAr), 128.7 (CHAr), 127.8
274.0993
2 H)
(CHAr), 126.3 (CHAr), 122.8 (Cq/Ar), 60.4 (CH2),
26.8 (CH2)
60e
7.84–7.81 (m, 1 H), 7.70 (s, 1 H), 7.57– 163.6 (Cq/CO), 157.4 (Cq/Ar), 138.5 (Cq/Ar), 135.0
7.52 (m, 2 H), 7.43–7.36 (m, 2 H), 6.73 (Cq/Ar), 134.9 (Cq/Ar), 132.3 (Cq/Ar), 129.2 (CHAr),
(d, 3J = 8.3 Hz, 2 H), 4.51 (t, 3J = 5.3 Hz, 128.2 (CHAr), 127.6 (CHAr), 127.3 (CHAr), 126.0
2 H), 3.62 (s, 6 H), 3.23 (t, 3J = 5.3 Hz, (CHAr), 125.2 (CHAr), 122.9 (Cq/Ar), 116.1 (Cq/Ar),
(EI) calcd for C21H18O4
[M+]: 334.1205; found:
334.1205
2 H)
104.3 (CHAr), 67.0 (CH2), 55.9 (CH3), 29.8 (CH2)
69a/70a
8.14 (s, 1 H, 69a), 8.03–7.97 (m, 1 H), 185.4 (Cq/CO), 149.4 (CHAr), 139.5 (Cq/Ar), 138.6
(EI) calcd for C18H13NO
7.88 (s, 1 H, 70a), 7.85 (s, 2 H), 7.71– (CHAr), 135.1 (CHAr), 133.1 (CHAr), 132.6 (CHAr), [M+]: 259.0997; found:
7.65 (m, 2 H), 7.55–7.50 (m, 2 H),
131.7 (CHAr), 130.6 (Cq/Ar), 130.0 (Cq/Ar), 129.6
259.0997
7.49–7.47 (m, 1 H), 7.45–7.44 (m, 2 H), (Cq/Ar), 128.7 (Cq/Ar), 128.6 (CHAr), 128.3 (CHAr),
7.44–7.41 (m, 2 H), 7.40–7.39 (m, 1 H), 127.9 (CHAr), 127.7 (CHAr), 127.5 (CHAr), 127.2
7.38–7.36 (m, 1 H), 7.36–7.30 (m, 3 H), (Cq/Ar), 126.1 (CHAr), 125.6 (Cq/Ar), 125.0(Cq/Ar),
7.25–7.23 (m, 1 H), 7.04 (br s, 1 H, NH, 121.6 (CHAr), 48.1 (CH2, 69a), 44.3 (CH2, 70a)
70a), 5.81 (br s, 1 H, NH, 69a), 4.51 (s,
2 H, CH2, 70a), 4.25 (d, 3J = 5.3 Hz, 2
H, CH2, 69a)
(9) (a) Smith, A. L.; Hwang, C.-K.; Pitsinos, E. N.; Scarlato, G.
R.; Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 3134.
(b) Nicolaou, K. C.; Hummel, C. W.; Pitsinos, E. N.;
Nakada, M.; Smith, A. L.; Shibayama, K.; Saimoto, H. J.
Am. Chem. Soc. 1992, 114, 10082.
Acknowledgment
We thank the DFG (We1850/5-1,3, Heisenberg fellowship to P.W.)
for financial support.
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Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York

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The Photo-Dehydro-Diels–Alder Reaction for the Preparation of Biaryls
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M.; Taga, T.; Fuji, K. J. Am. Chem. Soc. 1995, 117, 12159.
(e) Tanaka, K.; Ahn, M.; Watanabe, Y.; Fuji, K.
(28) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
(29) Compound 19a is commercially available. For the
preparation of compound 19b, see: (a) Ipaktschi, J.;
Hosseinzahed, R.; Schlaf, P.; Eckert, T. Helv. Chim. Acta
2000, 83, 1224. For the preparation of compound 19c, see:
(b) Rao, P. N. P.; Uddin, J.; Knaus, E. E. J. Med. Chem.
2004, 47, 3972.
(30) Compounds 22a–c have already been prepared by other
methods. For 22a, see: (a) Freeman, F.; Kim, D. S. H. L.;
Rodriguez, E. J. Org. Chem. 1992, 57, 1722. For 22b,c,
see: (b) Foud, F. S.; Wright, J. M.; Plourde, G.; Purohit, A.
D.; Wyatt, J. K.; El-Shafy, A.; Hyad, G.; Crasto, C. F.; Lin,
Y.; Jones, G. B. J. Org. Chem. 2005, 70, 9789. For 22d,e, see
ref. 18a.
(31) Compounds 33 were used without further purification.
(32) Compounds 32 have already been described in the literature.
For 32, Ar2 = Ph, n = 1, see: (a) Molinaro, C.; Jamison, T. F.
J. Am. Chem. Soc. 2003, 125, 8076. For 32, Ar2 = PMP,
n = 1, see: (b) Campi E. M., Chong J. M., Jackson W. R.,
van der Schoot M.; Tetrahedron; 1994, 50: 2533. For 32,
Ar2 = 4-ClC6H4 and Ar2 = 4-F3CC6H4, n = 1, see ref. 18a.
For 32, Ar2 = 1-naphthyl, n = 1, see: (c) Feuerstein, M.;
Berthiol, F.; Doucet, H.; Santelli, M. Synthesis 2004, 1281.
For 32, Ar2 = Ph, n = 2, see: (d) Roesch, K. R.; Larock, R.
C. J. Org. Chem. 2001, 66, 412; For Ar2 = 1-naphthyl, n = 2,
see ref. 34.
(33) Analytical data of 23a and 24j are given in Table 5. For 23b
and 24k, see ref. 34. For 24a–i, see ref. 18a.
(34) Wessig, P.; Müller, G. Chem. Commun. 2006, 4524.
(35) March, J. Advanced Organic Chemistry, 4th ed.; Wiley:
New York, 1992, 280.
(36) Klemm, L. H.; Hsu Lee, D.; Gopinath, K. W.; Klopfenstein,
C. E. J. Org. Chem. 1966, 31, 2376.
(37) Yamaji, M.; Kobayashi, J.; Tobita, S. Photochem.
Tetrahedron: Asymmetry 1996, 7, 1771. (f) Ahn, M.;
Tanaka, K.; Fuji, K. J. Chem. Soc., Perkin Trans. 1 1998,
185. (g) Tada, M.; Nishiiri, S.; Zhixiang, Y.; Imai, Y.;
Tajima, S.; Okazaki, N.; Kitano, Y.; Chiba, K. J. Chem. Soc.,
Perkin Trans. 1 2000, 2657.
Photobiol. 2005, 4, 294.
(38) Compounds 66 and 67 are commercially available.
(39) Compound 68 has already been described in the literature,
see: Choualeb, A.; Braunstein, P.; Rose, J.; Welter, R. Inorg.
Chem. 2004, 43, 57.
(25) Larock, R. C.; Tu, C.; Pace, P. J. Org. Chem. 1998, 63, 6859.
(26) (a) Bonifacio, V. D. B. Synlett 2004, 1649. (b) Chen, B. C.
Heterocycles 1991, 323, 529.
(27) (a) Toth, G.; Koever, K. E. Synth. Commun. 1995, 25, 3067.
(b) Kawasaki, N.; Goto, M.; Kawabata, S.; Kometani, T.
Tetrahedron: Asymmetry 2001, 12, 585. (c) Englert, H. C.;
Gerlach, U.; Goegelein, H.; Hartung, J.; Heitsch, H.; Mania,
D.; Scheidler, S. J. Med. Chem. 2001, 44, 1085.
(40) The 1H NMR data of 29a, 69a and 70a have already been
published, see: Klemm, L. H.; McGuire, T. M.; Gopinath, K.
W. J. Org. Chem. 1976, 41, 2571. The 13C NMR and MS
data are given in Table 5.
Synthesis 2007, No. 3, 464–477 © Thieme Stuttgart · New York