Photocycloaddition of arenes and allenes

Article abstract of DOI:10.1021/jo4002307

In this work, we report on a new intramolecular para cycloaddition of arenes with allenes, yielding attractive rigid scaffolds bearing several reactive functionalities to build in further diversity. Bicyclo[2.2.2]octadiene- type products and benzoxepine acetals are formed in this reaction, in ratios and yields depending on the substitution pattern on the aromatic ring, the nature of the chromophore, and the tether. This unprecedented reaction has remarkable features that distinguish it from many other photochemical transformations: it is particularly robust with respect to substituents, it can be scaled up without a notable loss of efficiency, and it can lead to structures with a high degree of complexity in low to good yields. All photochemical precursors could be synthesized readily in three steps. We confirmed the compatibility of the nitrogen atom in the photocycloaddition step, which gives access to a bicyclo[2.2.2]octadiene scaffold with two points that allow further diversification. This reaction was scaled up to multigram quantities without erosion of the typically high yields in photocycloadducts. Sequential deprotection of the N- or C-terminus of bicyclic amino acids gave access to two conformationally constrained unnatural amino acids with different dispositions of the two anchor points.

Full text of DOI:10.1021/jo4002307

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Article
The photocycloaddition of arenes and allenes.
Ursula Streit, Frederic Birbaum, Anna Quattropani, and Christian G. Bochet
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4002307 • Publication Date (Web): 03 May 2013
Downloaded from http://pubs.acs.org on May 4, 2013
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The photocycloaddition of arenes and allenes.
#
Ursula Streit, Frédéric Birbaum, Anna Quattropani and Christian G. Bochet*
Department of Chemistry University of Fribourg, Chemin du Musée 9, CH-1700 Fribourg,
#
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Switzerland, and Merck Serono S.A., Chemin des Mines 9, CH-1202 Geneva, Switzerland.
christian.bochet@unifr.ch
TOC Graphic
R
O
R
R
O
R
X
hν
X
CH Cl2
X
O
2
O
X=O, NPG
+
•
up to 92%
X
•
Br
very rapid increase in complexity !
Abstract
In the present work, we report on a new intramolecular para-cycloaddition of arenes with allenes,
yielding attractive rigid scaffolds bearing several reactive functionalities to build in further diversity.
Bicyclo[2.2.2]octadiene-type products and benzoxepine acetals are formed in this reaction, in ratios
and yields depending on the substitution pattern on the aromatic ring, the nature of the chromophore
and the tether. This unprecedented reaction has remarkable features that distinguishes it from many
other photochemical transformations: it is particularly robust with respect to substituents, it can be
scaled up without notable loss of efficiency, and it can lead to structures with high complexity in low to
good yields. All photochemical precursors could be synthesized readily in three steps. We confirmed
the compatibility of the nitrogen atom in the photocycloaddition step, which gives access to
bicyclo[2.2.2]octadiene scaffold with two points that allow further diversification. This reaction was
scaled up to multigram quantities without erosion of the typically high yields in photocycloadducts.
Sequential deprotection of the N- or the C-terminus of bicyclic amino acids gave access to two
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conformationally constrained unnatural amino acids with different disposition of the two anchor
points.
INTRODUCTION
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Cycloadditions are very powerful and versatile synthetic tools. They are, by essence, atom-economical,
and may lead to the simultaneous formation of several bonds, thus allowing a rapid increase in
molecular complexity. Aromatic rings are, however, remarkably resistant to cycloadditions, and very
few reactions are capable to exploit them in such processes. Activation by transition metal complexes is
one way of conferring an alkene or diene character to aromatic rings, but the main approach is the
1,2,3,4,5
photochemical excitation.
6
,7
While the meta photocycloaddition is very well established and has been applied many times in
8
9,10
11
organic synthesis, the ortho-
and particularly the para- versions have not yet gained much
attention as they occur rarely and usually with low yield. However, these two modes also have the
potential to create significant complexity, with the formation of a new ring and up to four new
stereocenters.
Among the few examples leading to para products in high yield, the benzil-sensitized intramolecular
photocycloaddition of a cinnamoylamide and a benzamide moiety leads quantitatively to a
12
bicyclo[2.2.2]octadiene core. The proposed mechanism involves the reaction of the olefininic partner
with the ipso position of the aromatic ring, leading to a spiro biradical intermediate, which then
recombines towards the final compound. Interestingly, similar enamides with a naphthyl moiety
13
undergo preferably an ortho photocycloaddition. There are earlier reports on the para cycloadditions
of benzene with allene and 1,2-cyclononadiene, but no yields were mentioned, and the reaction, to the
1
4
best of our knowledge, was neither further studied nor exploited in synthesis, to the notable exception
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of the reaction of 1,1-dimethylallene with 2-phenyl-1-pyrrolium cation reported by Mariano et al.
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which gave significant yields of cycloadducts.
In a preliminary communication, we reported on a very robust intramolecular para-cycloaddition of
aromatic aldehydes with allenes, which is remarkably tolerant of a variety of substituents on either the
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allene or the arene partners (Scheme 1). In the present work, we explore the scope and limitation of
this reaction, in particular by studying the influence of the chromophore and the nature of the allene
tether. This reaction was used to prepare a series of rigid and highly complex cores, bearing several
branching points and reactive functionalities, different features that are attractive for diversity-oriented
1
7
synthesis (DOS).
H
H
O
H
hν (350nm)
R
R
R
CH Cl
O
O
2
2
O
+
•
O
O
1
2
3
Scheme 1. Intramolecular photocycloadditions of allenyl salicylaldehydes.
RESULTS AND DISCUSSION
Preparation of the substrates
The allene bromide 6 was prepared according to a known two-step sequence (Scheme 2), starting from
but-2-yne-1,4-diol which was monochlorinated with thionyl chloride into 4 and then isolated by
1
8
distillation. Reduction with lithium aluminium hydride gave the allenyl alcohol 5, which was
19
converted to the allenyl bromide 6 by reaction with phosphorous tribromide.
OH
OH
SOCl2
LiAlH4
PBr3
Et O, py
PhH, py
Et O
2
2
HO
Br
•
•
3
6%
63%
53%
OH
Cl
4
5
6
Scheme 2.
Preparation of allenyl bromide 6.
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6
The salicylaldehydes 7a-p were either commercially available or prepared from the corresponding
20
phenol precursor by a highly selective tin tetrachloride-catalyzed ortho-formylation (Table 1).
Table 1. Preparation of salicylaldehydes.
R
[H CO]
R
2
n
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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9
0
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9
0
1
2
3
4
5
6
7
8
9
0
O
SnCl , Bu N
4
3
OH
OH
7b,d,k,m
37-62%
Product
R=
isolated yield
52 %
7
7
7
b
d
k
3-Me
t
3- Bu
62 %
3,5-Me
2
2
37 %
7m
3,6-Me
42 %
The allenyl bromide 6 was then coupled to variously substituted salicylaldehyde derivatives 7a-p by a
simple nucleophilic displacement in the presence of a weak base, to give the 2-(buta-2,3-
dienyloxy)benzaldehyde derivatives 1a-p in moderate to excellent yields (Table 2).
Table 2. Synthesis of allenyloxybenzaldehydes.
R
1
K CO
R
1
2
3
O
DMF, rt
O
Br
+
•
•
2
2
O
OH
40-94%
7a-p
6
1a-p
Entry Product
R=
H
isolated yield
86 %
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
3-Me
3-OMe
70 %
100 %
51 %
t
3- Bu
4-Me
60 %
4-OMe
67 %
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1g
1h
1i
5-Me
55 %
75 %
59 %
88 %
63 %
67 %
84 %
89 %
40 %
94 %
5-OMe
t
5- Bu
1
0
1
2
3
1j
5-Cl
10
11
12
13
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1
1
1
1k
1l
3,5-Me
2
t
3,5- Bu
2
1m
1n
1o
1p
3,6-Me
2
14
2 2
4,5-CH O
1
1
5
6
4-OAc, 5-OMe
4-OMe, 5-OAc
This two-component synthetic route is attractive because of its simplicity, which makes it amenable to
the rapid production of an array of photocycloaddition precursors. However, its scale up would require
large amounts of bromoallene 6, the preparation of which is quite cumbersone and globally low-
yielding (12% over three steps). Thus we looked for an alternative route, taking advantage of the
21
Crabbé homologation. The salicylic aldehyde 7a was first alkylated in high yield with propargyl
bromide (Scheme 3), and subsequently homologated into allene 1a. This latter reaction was carried out
twice starting with 40 g of 8 yielding in total 36.6 g of photocycloaddition precursor 1a. Likewise, the
methyl ester derivative 10a was synthesized on a 22 g scale from methyl salicylate by nearly
quantitative propargylation, followed by the Crabbé homologation.
[
H CO]n
2
K CO
2
3
CuBr, HN(iPr)2
BrCH C H
2
2
O
O
O
DMF
Dioxane reflux
•
OH
O
O
95 %
4
6 %
7
a
8
1a
3
6.6 grams
[
2
H CO]n
OMe
O
OMe
O
K CO
OMe
O
2
3
CuBr, HN(iPr)2
Dioxane reflux
BrCH C H
2
2
DMF rt
•
OH
O
O
9
8 %
46 %
9
10a
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6
Scheme 3. Multigram scale preparation of the allene precursors
As nitrogen is a central element in biologically active molecules, we were interested in including it in
our cycloaddition precursor, and to further explore the scope and limitation of this new reaction,
considering other types of heteroatoms in the tether. Of particular interest were sulfur and the
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frequently photochemistry-unfriendly nitrogen atom. If the latter would be compatible, non natural
polycyclic amino acids could be obtained in one step from the simple allenylic precursors. Very
recently, the thermal counterpart of this reaction was exploited by Vanderwal et al. with an amide-
tethered allene, exploiting the pioneering work of Himbert et al., who reported intramolecular thermal
2
3
arene-allene cycloadditions. Thus, the N-Boc analogue of allene 1 was prepared in a three-steps
sequence starting from aniline (Scheme 3). Protection of the amine with tert-butyl dicarbonate into 6
2
4
was followed by a quite low-yielding monoformylation, and subsequent allenylation with allenyl
bromide, led to the photocycloaddition precursor 14a. The ester analogue 14b was prepared by a
closely related route, but without the problematic formylation step, taking advantage of the
2
5,26
commercially available methyl anthranilate 12b, which was protected and allenylated (Scheme 4).
OMe
Boc O
O
2
Toluene
NHBoc
N
NH2 88 %
11
Boc
1
. NaH
2. BrCH2CCH
2%
15
1
. t-BuLi (2.1eq)
18%
CuBr, [H CO]
n
2. DMF, THF
2
iPrOH, 1,4-dioxane
9
63%
R
R
R
. basea
1
Boc O
O
2
2
.BrCH CHCCH2
O
O
2
•
42-93 %
N
NH2
NHBoc
33-67 %
Boc
12b R=OMe
2c R=Ph
13a R=H (18%)
13b R=OMe (93%)
3c R=Ph (42%)
14a R=H (67%)
14b R=OMe (33%)
14c R=Ph (52%)
1
1
2 3
Scheme 4. Preparation of the cycloaddition precursors. a) K CO for 14a, NaH for 14b,c.
Surprisingly, the allenylation of 13b failed to proceed with the reaction conditions applied earlier for
the benzaldehyde 13a. Hypothesizing that potassium carbonate was a too weak base, we first
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successfully used cesium carbonate and activation of the bromide by the addition of sodium iodide.
However, we finally settled for sodium hydride at lower temperature, as a comparable efficiency was
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1
1
1
1
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1
1
1
1
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5
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5
6
observed but for a significantly lower cost. As we had developed an alternative route amenable to scale
Error! Bookmark not defined.
up,
we also prepared 14b by a Crabbé homologation of alkyne 15, itself obtained
0
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8
9
0
1
2
3
4
5
6
7
8
9
0
by direct propargylation of carbamate 13b. The overall yield of this sequence is satisfactory, and it was
carried out up to a scale of 30 grams. The benzophenone derivative 14c was also prepared by the
protection of 12c, followed by allenylation.
Photochemistry with an oxygen-containing tether
®
The allenylsalicylaldehyde derivatives 1a-o were irradiated at 350 nm (Rayonet , quartz glassware) in
dry and degassed dichloromethane at room temperature, and the benzoxepine and dihydrofuran-fused
bicyclo[2.2.2]octadiene products 2a-p and 3a-p were observed in varying proportions (Table 3).
Table 3. Spectroscopic and isolated yields of irradiation products.
hν (350nm)
R
R 6
R
1
O
CH Cl
O
5
4
2
2
O
+
O
•
2
O
O
3
1a-p
2a-p
3a-p
Spectroscopic experiments
Preparative experiments
a
a
a
b
b
b
Entry
1
1
2
3
Time
2
3
Time
6 h
2
3
1a
110 min
40 min
38%
52%
21%
20%
19%
10%
15%
13%
2
3
1b
1c
8 h
19 min
40 min
67%
84%
19%
0%
1.3 h
3 h
67%
65%
24%
4
1d
0%
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
5
6
7
1e
1f
200 min
525 min
80 min
0%
0%
19%
21%
15%
18 h
27 h
16 h
0%
0%
14%
21%
11%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1g
56%
34%
8
9
1h
1i
60 min
60 min
58%
58%
0%
12.5 h
13.5 h
23%
63%
0%
c
11%
20%
1
0
1
1j
120 min
30 min
30%
73%
34%
20%
2.5 h
3 h
28%
61%
40%
12%
1
1
1k
2
1l
30 min
84%
13%
0%
1 h
4 h
94%
14%
0%
1
3
4
1m
120 min
90 min
36%
35%
0%
1
1
1o
1p
86%
0%
0%
1.5 h
48 h
69%
0%
c
5
380 min
19%
15%
a
1
b
c
1
1mM solution, yields determined by H-NMR. Preparative scale and isolated yields. Isolated
1
product not totally pure, yield corrected by H-NMR.
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In order to better compare the values, small scale irradiation under normalized conditions (11 mM in
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
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4
4
4
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4
4
5
5
5
5
5
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5
5
5
5
6
27
dichloromethane) were performed, and the conversion was monitored by NMR analysis. The
reactions were not performed directly in the NMR tube, as deuterated solvents express a different
vibrational pattern and may therefore show a non-negligible influence on the non-radiative relaxation
0
1
2
3
4
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5
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0
1
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
8
of the excited state and may alter the outcome of photochemical reactions. The reaction was also
carried out on a preparative scale (0.15-0.79 mmol), and the identity of the products were established
by full spectroscopic analyses; the identity of the core structures was confirmed by X-ray analysis of 2l
1
6
and 3b.
Substitution on position 3 of the aromatic ring with electron releasing substituents (Table 3, entries 2-4)
accelerates the reaction considerably and enhances the formation of the para-photocycloaddition
product, whereas the substituents on the position 4 show an opposite effect. For example irradiation of
the 4-methyl- or 4-methoxy-substituted analogue leads to remarkably longer reaction times and no
formation of the bicyclo[2.2.2]octadiene product (Table 3, entries 5 and 6). On the other hand,
substitution at position 5 with electron donating groups leads to shorter reaction times and higher yields
of bicyclo[2.2.2]octadienes (Table 3, entries 7 - 9). However the effect is not as strong as for the same
substituents on position 3. Interestingly, 5-chloro and 3,6-dimethyl (Table 3, entries 10 and 13) are the
only substituents which could enhance the formation of the benzoxepine product. For the substitution
with a tert-butyl group at position 3 a counterintuitive sterical influence is observed, completely
suppressing the formation of the benzoxepine product (Table 3, entries 4 and 12). Additionally, the
reaction time is considerably decreased; the bicyclo[2.2.2]octadiene compound 2l is obtained in a very
high yield in one hour on a 100 mg scale. On the other hand, irradiation of 1n does not yield any
photocycloaddition compounds and leads to complete decomposition of the starting material.
Throughout this study Rayonet lamps have been used and replaced as their intensity considerably
weakens over their lifetime. Thus, since the irradiation intensity was not consistent, actinometric
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
measurements were not made and quantum yields are not accessible. However clear trends emerged
from these experiments, since overall efficiency varied by a factor up to 50.
The UV-Vis spectra of the derivatives substituted at position 5 show also red-shifted absorptions
(Figure 1, supplementary information). This bathochromic shift could also account for the shorter
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
irradiation times. As the precursors 1 usually show weak absorbance at long wavelength, the 350 nm-
centered emission of the fluorescent lamps overlaps only with the tail of the band.
Shortening the irradiation wavelength does not, however, lead to a substantial increase in yield, as
shown by the individual monitoring of each compounds arising from 1a under irradiation at 254 nm
(Figure 2, supplementary information). The benzoxepine compound 3a is relatively photostable at this
wavelength, to the contrary of the bicyclo-octadiene derivative 2a. This experiment also confirms that
both compounds are not precursors of each other.
The reaction was nominally carried out in dichloromethane, but we studied the influence of various
3 6 4 6 8
solvents, such as acetonitrile-d , acetone-d , methanol-d , benzene-d and toluene-d (Figure 3,
supplementary information). Dichloromethane, acetonitrile and methanol showed the best results with
similar conversion and reaction times; however, dichloromethane shows in all cases the highest yields
for the benzoxepine. The photocycloaddition does also take place in acetone, but slower conversion and
considerably lower yields for the benzoxepine compound are observed. Benzene and toluene are poor
solvents for this photocycloaddition as yields of the benzoxepine compound are low and the
bicyclo[2.2.2]octadiene does not form at all in toluene. Deuteration of dichloromethane has no apparent
effect on the conversion, at least for 1a.
This cycloaddition is compatible with multigram scale execution; 1a was irradiated in 5 batches
containing each 9.1 g of starting material in 1.5 L of dichloromethane. Overall, more than 10 g of the
final compound 2a could be produced. The reaction was usually stopped at a conversion of around 60
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2
%, at which point ca 20 % of the bicyclo[2.2.2]octadiene product 2a was formed; further irradiation
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
usually did not lead to a significant increase of product. From each batch, ca 30 % of starting material
1a could be recovered, together with ca 10 % of the benzoxepine 3a. The isolation of 2a at this scale
needed special care, as the bicyclo[2.2.2]octadiene 2a tends to form its dimer 16 by an apparent hetero-
Diels-Alder reaction. The dimerization was observed when the crude reaction mixture was stored at 4
°C overnight, when the monomer was concentrated from a mixture of hexane and ethyl acetate in the
rotatory evaporator, or when the monomer was heated in isopropanol.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
O
16
This side reaction can however be avoided if the crude mixture is purified immediately after the
irradiation by flash chromatography with dichloromethane and ether as solvent mixture. The pure
compound can be stored in a freezer over several months without observable dimerization. On the other
hand, this high reactivity can be exploited for further modification of the core; this will be published in
due course.
Thermal reaction
In order to confirm the photochemical nature of the reaction, it was also attempted under thermal
conditions. Therefore the starting material was heated in a microwave oven (Biotage Initiator, single
mode, sealed vessel). The starting material 1a is thermally stable up to 190°C, and some conversion to
the product 17 as well as the cleavage of the allenyl to the salicylic aldehyde 7a is observed above
2
9
2
00°C (Scheme 5). Product 17a is formed by an apparent Claisen rearrangement, which has already
30
been observed with arylallenyl ethers.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MeCN, Δ
µW >200°C
O
O
O
+
OH
•
OH
O
5
:
1
1
a
17a
7a
Scheme 5. Thermal reaction of 1a.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Other chromophores
The reaction is not limited to benzaldehyde derivatives, and other functional groups were examined
Table 4). The Y substituent is an intrinsic part of the chromophore, thus it has a considerable influence
(
on the absorbance (Figure 4, supplementary information); on the other hand, due to the sensitivity of
the bicyclo[2.2.2]octadiene to shorter wavelentgths, the change of the irradiation towards more
energetic light is detrimental. Therefore three different groups were probed: ester, nitrile and ketone
were chosen, taking into account the previously mentioned constrains.
Table 4. Synthesis and photolysis of other precursors.
•
X
6, K CO
DMF, rt
hν
Y
2
3
Y
O
Y
CH Cl
2
2
O
+
O
+
40-86%
•
23-75%
O
O
HO
OH
1a Y=CHO
0a Y=CO CH3
0b Y=COCH3
0c Y=COPh
0d Y=CN
2a Y=CHO
18a Y=CO CH3
18b Y=COCH3
3a X=H
9 X=Me
20
1
1
1
1
1
2
2
18d Y=CN
Entry
Y=
allene
bicyclo[2.2.2]octadiene benzoxepine
other
1
2
3
4
5
CHO
1a (86%)
2a (19%)
18b (21%)
-
3a (15%)
COMe 10b (40%)
COPh 10c (46%)
19 (45%)
-
-
20 (75%)
CO
2
Me 10a (48%)
10d (65%)
18a (24%)
18d (32%)
CN
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As the UV spectra of the methyl benzoate 10a shows a hypsochromic shift the irradiation was carried
out at 300 nm instead of 350 nm and the product 18a was isolated in 24 % of yield (Table 4, entry 4;
this product rapidly degrades after isolation). The para photocycloaddition product is the major formed
compound and no benzoxepine-like structure was observed. Along with the main compound, a side
product could also be isolated from the crude mixture in 6 % yield, and was tentatively identified by
proton-NMR as the Claisen-rearranged product 17b.
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OMe
O
O
OH
OH
17a
17b
Figure 5. The Claisen rearrangement side products.
Likewise, an analoguous side product, tentatively assigned to 17a was also isolated from the irradiation
of 2-(buta-2,3-dienyloxy)-benzaldehyde 1a at 254 nm in 6 % yield as well as in the thermal conversion
of 1a upon heating above 200 °C (vide supra). The formation of this product could be explained by a
3
1
photoinduced Claisen rearrangement, but to our knowledge, there are no earlier reports on such
reactions with allenes.
The benzonitrile 10d, as it was already the case for the methyl benzoate 10a, absorbs at shorter
wavelengths than the benzaldehydes. Therefore the irradiation was carried out at 300 nm instead of 350
nm, leading to the isolation of 18d in 32 % yield. No other photocycloaddition product could be
detected. However, traces of the byproduct arising from the Claisen rearrangement were also observed
in the crude reaction mixture.
The UV spectra of the acetophenone 10b shows a slight shift of the absorption to shorter wavelengths,
but this effect is less pronounced than for the former two examples. Therefore the starting material can
still be excited in the Rayonet reactor at 350 nm, and the benzoxepine 19 was isolated in 45 %, together
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2
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4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with the bicyclo[2.2.2]octadiene 18b in a 21 % yield. The ketone and the aldehyde are the only
functional group for which we could isolate the benzoxepine products.
As more substituted aliphatic ketones would be prone to Norrish-type I reactions, we turned our
attention to the benzophenone analogue 10c. Photolysis of this substrate would not only open the
access to new products but also converges with the work of Griesbeck et al., where the
photocycloaddition of allyloxy-substituted benzophenone undergo intramolecular photocycloadditions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
32
upon irradiation, leading to a benzoxepine and a diastereoisomeric mixture of dihydrobenzofurans.
Surprisingly, none of our previously observed compounds were formed. On the other hand, the reaction
is very fast and completely regioselective towards a diastereoisomeric mixture of dihydrobenzofurans
1
5 in high yield (75%). The advantage of the ester and nitriles is the formation of single photoproducts,
the bicyclo[2.2.2]octadiene derivatives (Table 5, entries 4 and 5).
Photochemistry with a nitrogen-containing tether
These results motivated us to further explore the scope and limitation of this new reaction, considering
other types of heteroatoms in the tehter, in particular the frequently photochemistry-unfriendly nitrogen
22,33
atom.
The UV spectrum of the N-Boc precursor 14a is slightly shifted towards shorter wavelengths
with respect to its oxygen-containing analogue 1. The photocycloaddition step was nevertheless carried
1
out at 350 nm, yielding the two photocycloaddition products 21a and 22 (Scheme 6). However, H-
NMR spectra of both cycloadducts are poorly resolved and suggest the presence of rotamers. This
1
hypothesis could unfortunately not be confirmed by H-NMR spectroscopy at higher temperature (up to
3
4
6
0 °C). On the other hand, when 14a was irradiated at 300 nm for 2 hours in dichloromethane, the
bicyclo[2.2.2]octadiene product 21a was obtained in good yield, without other regioisomer. Likewise,
irradiation of 14b gave smoothly the cycloadduct 21b in very high yield, which shows a similar
rotamer pattern as for 21a. This reaction is compatible with larger scale experiments; thus, irradiation
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of up to 20 g of compound 14b in 1.5 L of dichloromethane lead to the isolation of the
photocycloadduct 21b in very high yield (92 %).
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
R
Boc
hν (300 nm)
N
R
O
2
CH Cl2
O
•
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Boc
N
N
66-90%
Boc
1
1
4a R=H
4b R=OMe
21a R=H (66%)
21b R=OMe (92%)
22 (traces, only observed
for irradiation at 350nm)
up to 20 grams
Scheme 6. Photocycloaddition of nitrogen-containing allenes
Since we suspected that the rotamers arise from the N-Boc group, we subjected the products to acidic
hydrolysis (Scheme 7).
The deprotection of 21a in trifluoroacetic acid seems to proceed well by TLC analysis; however the
isolation of the free amine failed, despite attempts of chromatography on neutral alox, on silica gel
eluted with dichloromethane and basified with ammonia saturated methanol, by ion exchange or
extraction. Formation of the hydrochloride led to complete decomposition. On the other hand, the
cycloadduct 21b contains two different protecting groups that may be removed to open the access for
further diversification (scheme 7). In this case, either trifluoroacetic acid (in presence of anisole as tert-
3
5
36
37
butyl carbocation scavenger) or hydrogen chloride were used. With trifluoroacetic acid, the parent
amine 23 is obtained in very high yield after neutralisation of the acid. The hydrochloride salt 25 is
obtained by reaction with hydrochloric acid and filtration of the precipitate, or by simple evaporation of
the solvent. These procedures give the desired compounds in high purity and yields without further
purification. However the solid hydrochloride 25 is easier to handle than the oily amine 23, and seems
to be more stable for storage. At this stage, the NMR spectra were well-resolved, even at room
temperature.
The saponification of the methyl ester 21b was easily achieved by reaction with a sodium hydroxide
solution, affording the carboxylic acid 24 in high yield. Purification of this compound by flash
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
8
chromatography, recrystallization or by catch and release on solid phase extraction (SPE) did not
improve the initial purity. However, further transformation of the compound showed that this purity is
sufficient for the generation of a library of amides, which will be reported elsewhere. Therefore, no
further purification attempts were tried and the compound was used as extracted from the reaction
mixture.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
OMe
OMe
O
NaOH, EtOH
85%
HCl, Et O
2
O
O
Boc
91 %
N
PG
N
HCl
NH
2
4
25
2
2
1b PG=Boc
TFA
9%
9
3
PG=H
Scheme 7. Deprotection at both termini
Other regiochemistries
An alternative way to avoid the formation of benzoxepine derivatives is to move the allenyloxy tether
away from the aldehyde. Thus, we intended to carry out this photocycloaddition with compounds
having the allenyloxy tether attached at the meta or para position with respect to the aldehyde. The
precursors 26 and 27 were readily synthesized via our usual route (Scheme 8). While the ortho-
substituted 1a and meta-substituted 26 were quite stable, the para-substituted analogue 27 is
susceptible to oxidation to the carboxylic acid, and therefore should be kept in the absence of air.
Irradiation of the meta-precursor 26 failed to give identifiable photoproducts, whereas the para-
substituted 27 formed the desired bicyclo[2.2.2]octadiene compound 28 in moderate yield (33%). It is
worth mentioning that a single regioisomer was formed from precursor 27 and the absence of
conjugated double bond prevent product 28 from dimerization, observed for 2a. The difference in
reactivity of the meta vs ortho/para isomers is worth noting, and probably arise from the direct
conjugation between donor and acceptor subsitutents.
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2
3
4
5
6
7
8
9
O
O
K CO
DMF, rt, 16h
hν (350 nm)
2
3
CH Cl
2
2
•
+
no reaction
Br
•
5
7 %
O
OH
6
26
hν (350 nm)
K CO
2
3
CH Cl
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DMF, rt, 16h
2
2
O
O
•
O
+
•
Br
8
9 %
33 %
OH
O
6
27
28
Scheme 8. meta and para substitution.
In order to verify whether the para substitution is also compatible with nitrogen on the tether, we
prepared another series of precursors, along the lines of the ortho substituted compounds (scheme 9).
Thus, the anilines 29a,b were protected as N-Boc (30a,b) and propargylated (31a,b). The alkynes were
then converted into the allenes 32a,b via a Crabbé homologation.
O
Br
O
O
Boc O
2
NaH, DMF
R
R
R
42-98%
4
7-60%
NH2
9a R=Me
N
NHBoc
Boc
2
2
30a R=Me (98%)
9b R=OMe
30b R=OMe (42%)
31a R=Me (47%)
3
1b R=OMe (60%)
[H CO]
CuBr, HN(iPr)2
Dioxane reflux
2
n
O
O
R
O
hν
R
(
254 or 300 nm)
HCl
74-76%
R
•
4
6-61%
N
3
2-69%
NH
NBoc
Boc
HCl
32a R=Me (46%)
2b R=OMe (61%)
33a R=Me (69%)
33b R=OMe (32%)
34a R=Me (76%)
34b R=OMe (74%)
3
Scheme 9. para-product
The precursor 32a was subsequently irradiated at 300 nm in a Rayonet reactor, and the
bicyclo[2.2.2]octadiene 33a was obtained in good yield (69%). The compound is not very stable but
can be easily deprotected into the more stable hydrochloride salt 34a. Similarly, the photolysis was
carried out with the methyl ester 32b. This compound has a lower absorption at 300 nm, but we
nevertheless suceeded in obtaining 33b by irradiation at 254 nm (32%). Acidic deprotection gave 34b
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
in good yield. This amino acid ester has similar potential as 25 as a diversification platform, with a
different disposition of the two anchor points, and no chirality.
Intermolecular tests
In order to check whether this photocycloaddition is limited to its intramolecular version, we prepared
the compound 35, by the coupling of the bromoallene 6 with phenol (Scheme 10). It was irradiated at
350 nm as a 1 M solution in dichloromethane with 1 equivalent of o-anisaldehyde. We did not observe
the formation of any new compounds even after a prolonged irradiation (44 hours), despite a decrease
of the anisaldehyde concentration over time.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
K CO
2
3
Br
+
DMF, rt, 16 h
•
OMe
•
no reaction
OH
O
hν (350 nm)
6
6 %
6
35
CH Cl , (1M)
2
2
Scheme 10 Irradiation of 35 in presence of o-anisaldehyde.
CONCLUSION
The unprecedented photoreaction described in this work has remarkable features that distinguishes it
from many other photochemical transformations: it is particularly robust with respect to substituents,
type and location of the chromophore and the nature of the heteroatom in the tether, it can be scaled up
without notable loss of efficiency, and it can lead to structures with high complexity in moderate to
excellent yields. The mechanism, either a stepwise radical cyclization or a concerted cycloaddition is
currently under investigation, and will be reported in due course. We have confirmed the compatibility
of nitrogen atom in the photocycloaddition step, which gives access to bicyclo[2.2.2]octadiene
scaffolds with two points that allow further diversification. This reaction was scaled up to multigram
quantities without erosion of the typically high yields in photocycloadducts. Sequential deprotection of
the N- or the C-terminus of bicyclic amino acids gave access to two conformationally constrained
unnatural amino acids with different disposition of the two anchor points. Thus, the presence of several
branching points and reactive functionalities gives the opportunity to further diversify these structures
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into a wide variety of compounds that could be useful for different applications such as drug discovery;
similar substrates with other heteroatom-containing tethers are being investigated. This potential is
currently under evaluation.
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EXPERIMENTAL SECTION
General Information. Unless otherwise indicated, all starting materials were obtained from standard
suppliers and were used without further purification. The deuterated chloroform was dried and
neutralized over basic alumina prior to use. Analytical thin layer chromatography was performed on
Kieselgel F-254 pre-coated aluminium sheets TLC plates. Visualization was performed with either a
2
54 nm ultraviolet lamp, or a potassium permanganate staining solution. Silica gel column
chromatography was carried out with silica gel (32–63, 60 Å). Solid phase extractions were carried out
1
13
on Isolute SPE columns NH2, SAX or SCX from Biotage. The H and C NMR spectra were recorded
on Fourier transform spectrometers at 500 MHz, 400 MHz, 360 MHz or 300 MHz. Chemical shifts (δ)
are expressed in parts per million using residual solvent protons as reference: chloroform (δ = 7.27 ppm
1
13
1
13
for H, δ = 77.0 ppm for C), acetonitrile (δ = 1.94 ppm for H, δ = 118.69 ppm for C),
1
13
1
dichloromethane (δ = 5.30 ppm for H, δ = 54.00 ppm for C), benzene (δ = 7.16 ppm for H, δ =
1
3
1
13
128.39 ppm for C), methanol (δ = 3.31 ppm for H, δ = 49.15 ppm for C), water (δ = 4.75 ppm for
1
1
13
H), acetone (δ = 2.05 ppm for H, δ = 29.92 ppm or 206.68 ppm for C), DMSO (δ = 2.50 ppm for
1
13
H, δ = 39.51 ppm for C). Coupling constant (J) are reported in Hz. Splitting patterns are designated
as s (singlet), d (doublet), t (triplet), q (quartet), quint. (quintet), m (multiplet), br s (broad signal).
Combination gas chromatography and mass spectroscopy were obtained using a Zebron ZB-1, 30 m x
0.25 mm, 100 % methylpolysiloxane column, mass detection by EI. Combination HPLC and mass
spectroscopy were obtained using a photodiode array detector and an ESI mass spectrometer detector.
Gradient: A: H
2
O + 7 mM formic acid and B: MeCN + 5 mM formic acid. 0 min 5 % B; 4 min 100 %
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B; 7 min 100 % B. Flow 0.5 ml/min. Column InterChrom Strategy 3um C18 – 2 50 x 2.0 mm equipped
with a precolumnm InterChrom Strategy 3. ESI-HRMS mass spectra were determined by FTMS. FT-
IR spectroscopy was performed in chloroform, neat on a NaCl cell or in KBr. Alternatively FT-IR
spectra were also recorded using a Golden Gate Single Reflection ATR System. The intensity of the
absorption is indicated with w (weak), m (medium) and s (strong). UV–Vis and optical rotation were
recorded with standard instruments. Melting points were measured without correction. Photochemical
irradiations were carried out in a LUMOS 43 photoreactor (Atlas Photonics Inc.), in a quartz vessel,
with 1 diode at 365, 375, 385, 405 or 430 nm, or in a Srinivasan-Griffin (Rayonet-RPR-100)
0
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photoreactor, in a quartz vessel, with 16 lamps at 254, 300, 350 or 420 nm.
General procedure for nucleophilic substitution to obtain photocycloaddition precursors 1a-1p.
To a suspension of K
salicylaldehyde 7a-7p (0.7 – 12 mmol) at rt. 4-Bromo-1,2-butadiene 6 (1 – 2.5 equiv) was added
dropwise over 1 h and the reaction mixture was stirred for 16 h at rt. Et O was added (50 – 300 mL)
and the organic layer was washed with an aq. sol. of K CO (three times) and with HCl 1N (three
times). The organic layer was washed with brine dried over MgSO and evaporated.
-(Buta-2,3-dienyloxy)-benzaldehyde 1a. Prepared according to the general procedure from
salicylaldehyde 7a (8.58 ml, 82 mmol, 1 equiv) and 4-bromo-1,2-butadiene 6 (12.52 g, 94 mmol, 1.1
equiv) with K CO (14.71 g, 106 mmol, 1.3 equiv) in DMF (50 ml). The crude product was purified by
flash column chromatography (Si: 250 g) with hexane and EtOAc as solvents (10:1) to afford 2-(buta-
,3-dienyloxy)-benzaldehyde 1a (12.209 g, 70.1 mmol, 86 % yield) as a yellow liquid, analysis
2 3
CO (1.2-1.8 equiv) in DMF (0.16 – 2 M) was added the corresponding
2
2
3
4
2
2
3
2
4
0 1
3
according to literature. H NMR (360 MHz, CDCl ) δ ppm 4.67 - 4.74 (m, 2 H) 4.92 (dt, J = 6.58,
2.72 Hz, 2 H) 5.34 - 5.49 (m, 1 H) 6.96 - 7.09 (m, 2 H) 7.50 - 7.60 (m, 1 H) 7.85 (dd, J = 7.72, 1.82 Hz,
13
1
3
H) 10.52 (s, 1 H). C NMR (91 MHz, CDCl ) δ ppm 66.1, 77.1, 86.5, 113.0, 120.9, 125.1, 128.4,
-
1
135.7, 160.7, 189.9, 209.5. IR (NaCl thin film) νmax [cm ] 3077, 2865, 2760, 1957, 1862, 1692, 1599,
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484, 1458, 1399, 1377, 1285, 1237, 1161, 1102, 1041, 1002, 851, 758, 654. UV-VIS (MeCN, c = 2.8
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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5
5
5
5
5
5
5
6
-
5
x 10 mol/l): λmax 215 nm (ε = 22710); 251 nm (ε = 10443); 316 nm (ε = 4789). EI-MS [m/z] (%)
174.4 (7.5), 145.4 (13), 122.4 (48), 121.3 (100), 120.4 (17), 92.4 (14), 53.3 (11).
2
-(Buta-2,3-dienyloxy)benzaldehyde 1a on multigram scale via Crabbé homologation.
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Paraformaldehyde (17.25 g, 574 mmol), copper(I) bromide (16.12 g, 112 mmol) and 2-(prop-2-
ynyloxy)benzaldehyde 8 (40 g, 250 mmol) were suspended under argon atmosphere in dry dioxane
(
600 mL). Diisopropylamine (96 mL, 674 mmol) (distilled from KOH before use) was added and the
reaction mixture was heated to a gentle reflux for 4 h. The reaction mixture was cooled down and
added to HCl 1N (1 L). The organics were extracted with DCM (4x 300 mL), dried over MgSO and
4
evaporated. The crude product was purified by flash column chromatography (Si: 500 g) with hexane
and EtOAc as solvents (8:1) to afford 2-(buta-2,3-dienyloxy)benzaldehyde 1a (19.98 g, 115 mmol, 45.9
%
yield) as a yellow liquid. Spectral data as described previously.
2
-(Buta-2,3-dienyloxy)-3-methyl-benzaldehyde 1b. Prepared according to the general procedure from
-hydroxy-3-methyl-benzaldehyde 7b (1.66 g, 12.2 mmol, 1.0 equiv) and 4-bromo-buta-1,2-diene 6
2
(
2.2 g, 16.5 mmol,1.35 equiv) with K
2 3
CO (3.0 g, 22 mmol, 1.8 equiv) in DMF (35 mL). The crude
product was purified over a plug of silica gel to afford 2-(buta-2,3-dienyloxy)-3-methyl-benzaldehyde
4
0 1
1
b (1.6 g, 8.5 mmol, 70 % yield), analysis according to literature. H NMR (360 MHz, CDCl
3
) δ ppm
2
.31 (s, 3H), 4.45 (dt, J = 7.3, 2.1 Hz, 2H), 4.77 (dt, J = 6.6, 2.1 Hz, 2H), 5.40 (quint, J = 6.6 Hz, 1H),
1
3
7.10 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 10.35 (s, 1H). C NMR (90
MHz, CDCl ) δ ppm 15.8, 73.0, 76.2, 86.3, 124.3, 126.1, 129.4, 132.3, 137.5, 159.8, 190.3, 209.8. IR
3
-
1
(
NaCl thin film) νmax [cm ] 3352, 3069, 2928, 2863, 2749, 1956, 1694, 1588, 1470, 1368, 1247, 1198,
-
5
1
1
086, 975, 850, 767. UV-VIS (MeCN, c = 3.1 x 10 mol/l): λmax 209 nm (ε = 37123); 254 nm (ε =
+
5038); 304 nm (ε = 3543). ESI-HRMS [m/z] calculated for C12
H
12NaO
2
[M+Na] 211.0730, found
211.0732.
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2
-(Buta-2,3-dienyloxy)-3-methoxy-benzaldehyde 1c. Prepared according to the general procedure
from 2-hydroxy-3-methoxy-benzaldehyde 7c (500 mg, 3.3 mmol, 1.3 equiv) and 4-bromo-buta-1,2-
diene 6 (350 mg, 2.6 mmol, 1.0 equiv) with K CO (545 mg, 3.9 mmol, 1.5 equiv) in DMF (20 mL).
The crude product was purified by flash column chromatography on silica gel with Et O and pentane as
solvents (1:2) to afford 2-(buta-2,3-dienyloxy)-3-methoxy-benzaldehyde 1c (530 mg, 2.6 mmol,
2
3
2
0
1
2
3
4
5
6
7
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2
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0 1
quant.), analysis according to the literature. H NMR (360 MHz, CDCl
3
) δ ppm 3.89 (s, 3H), 4.69 (dt,
J = 7.3, 1.8 Hz, 2H), 4.76 (dt, J = 6.4, 1.8 Hz, 2H), 5.38 (quint, J = 6.4 Hz, 1H), 7.13 (d, J = 5.0 Hz,
1
3
2
8
2
H), 7.40 (quint, J = 4.1 Hz, 1H), 10.44 (s, 1H). C NMR (90 MHz, CDCl3) δ ppm 56.4, 72.3, 76.4,
-
1
7.1, 118.3, 119.4, 124.7, 130.7, 151.1, 153.4, 191.0, 210.5. IR (NaCl thin film) νmax [cm ] = 3078,
957, 2840, 1955, 1691, 1584, 1481, 1441, 1390, 1368, 1310, 1251, 1205, 1067, 972, 910, 851. UV-
-
5
VIS (MeCN, c = 3.96 x 10 mol/l): λmax 219 nm (ε = 21925); 259 nm (ε = 8723); 320 nm (ε = 3114).
+
ESI-HRMS [m/z] calculated for C12
H12NaO
3
[M+Na] 227.0679, found 227.0678.
2-(Buta-2,3-dienyloxy)-3-tert-butyl-benzaldehyde 1d. Prepared according to the general procedure
from 2-hydroxy-3-tert-butyl-benzaldehyde 7d (1 g, 5.61 mmol, 1 equiv) and 4-bromo-1,2-butadiene 6
(
0.746 g, 5.61 mmol, 1 equiv) with K
product was purified by flash column chromatography (Si:25 g) with hexane and Et
10:1) to afford 2-(buta-2,3-dienyloxy)-3-tert-butyl-benzaldehyde 1d (654.6 mg, 2.84 mmol, 51 %
2
CO
3
(1.008 g, 7.29 mmol, 1.3 equiv) in DMF (18 mL). The crude
2
O as solvents
(
1
yield) as a yellow oil. H NMR (400 MHz, CDCl
3
) δ ppm 1.44 (s, 9 H) 4.51 (dt, J = 6.69, 2.65 Hz, 2 H)
4
.91 (dt, J = 6.63, 2.62 Hz, 2 H) 5.44 - 5.58 (m, 1 H) 7.17 (t, J = 7.71 Hz, 1 H) 7.60 (dd, J = 7.83, 1.77
1
3
Hz, 1 H) 7.72 (dd, J = 7.58, 1.77 Hz, 1 H) 10.34 (s, 1 H). C NMR (101 MHz, CDCl
3
) δ ppm 30.8,
3
5.2, 76.1, 76.8, 86.9, 124.0, 127.7, 130.2, 133.5, 143.9, 161.4, 190.4, 209.6. IR (NaCl thin film) νmax
-
1
[cm ] 2962 (m), 2872 (w); 1958 (w); 1687 (s); 1583 (m); 1471 (w); 1430 (m), 1369 (m), 1252 (m)
-
5
1
213 (m), 1179 (m), 977 (m). UV-VIS (MeCN, c = 2 x 10 mol/l): λmax 211 nm (ε = 23196); 257 nm (ε
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+
=
8504); 304 nm (ε = 2244). ESI-HRMS [m/z] calculated for C15
53.1192.
2-(Buta-2,3-dienyloxy)-4-methyl-benzaldehyde 1e. Prepared according to the general procedure from
-hydroxy-4-methyl-benzaldehyde 7e (0.7 g, 5.14 mmol, 1 equiv) and 4-bromo-1,2-butadiene 6 (0.684
g, 5.14 mmol, 1 equiv) with K CO (0.924 g, 6.68 mmol, 1.3 equiv) in DMF (15 ml). The work-up
2
H18NaO [M+Na] 253.1199 found
3
4
5
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9
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
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5
5
5
6
2
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1
2
3
4
5
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7
8
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4
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8
9
0
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2
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4
5
6
7
8
9
0
2
3
afforded 2-(buta-2,3-dienyloxy)- 4-methyl-benzaldehyde 1e (0.583 g, 3.1 mmol, 60 % yield) as a
1
yellow solid, which was used without further purification. H NMR (360 MHz, CDCl
3
) δ ppm 2.40 (s,
3 H) 4.62 - 4.72 (m, 2 H) 4.86 - 4.96 (m, 2 H) 5.38 - 5.49 (m, 1 H) 6.80 (s, 1 H) 6.85 (d, J = 7.72 Hz, 1
13
3
H) 7.74 (d, J = 7.72 Hz, 1 H) 10.44 (s, 1 H). C NMR (91 MHz, CDCl ) δ ppm 22.3, 66.1, 76.9, 86.6,
-
1
113.6, 121.9, 123.0, 128.3, 147.1, 160.8, 189.4, 209.5. IR (KBr) νmax [cm ] 3436 (br, w), 2879 (m),
1
8
1
2
953 (m), 1681 (s), 1607 (s), 1499 (m), 1381 (m), 1257 (s), 1207 (m), 1166 (m), 1113 (m), 1000 (m),
-
5
52 (m), 819 (m). UV-VIS (MeCN, c = 2.7 x 10 mol/l): λmax 219 nm (ε = 21899); 259 nm (ε =
+
3267); 316 nm (ε = 5702). ESI-HRMS [m/z] calculated for C12
H
12NaO
2
[M+Na] 211.0730 found
11.0728. mp 49 °C.
2-(Buta-2,3-dienyloxy)-4-methoxy-benzaldehyde 1f. Prepared according to the general procedure
from 2-hydroxy-4-methoxy-benzaldehyde 7f (1.25 g, 8.22 mmol, 1 equiv) and 4-bromo-1,2-butadiene
6
2 3
(1.093 g, 8.22 mmol, 1 equiv) with K CO (1.476 g, 10.68 mmol, 1.3 equiv) in DMF (18 ml). The
crude product was purified by flash column chromatography (Si: 25 g) with hexane and DCM as
solvents (2:1) to afford 2-(buta-2,3-dienyloxy)-4-methoxy-benzaldehyde 1f (1.1298 g, 5.53 mmol, 67.3
1
% yield) as a white-off solid. H NMR (360 MHz, CDCl
3
) δ ppm 3.87 (s, 3 H) 4.62 - 4.71 (m, 2 H)
4
7
9
1
.89 - 4.95 (m, 2 H) 5.36 - 5.47 (m, 1 H) 6.47 (d, J = 1.82 Hz, 1 H) 6.56 (dd, J = 8.63, 1.82 Hz, 1 H)
1
3
3
.83 (d, J = 8.63 Hz, 1 H) 10.33 (s, 1 H). C NMR (91 MHz, CDCl ) δ ppm 55.6, 66.2, 77.1, 86.5,
-
1
9.1, 106.2, 119.3, 130.5, 162.5, 166.0, 188.4, 209.5. IR (Golden Gate) νmax [cm ] 2991, 2867, 2774,
953, 1661, 1596, 1596, 1576, 1439, 1253, 1200, 1168, 1096, 997, 826. UV-VIS (MeCN, c = 2.35 x
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5
5
5
5
5
6
-
5
1
0 mol/l): λmax 208 nm (e = 14277); 233 nm (e = 16844); 272 nm (e = 14025); 310 nm (e = 8927).
+
ESI-HRMS [m/z] calculated for C12
H12NaO
3
[M+Na] 227.0679 found 227.0679. mp 62 °C.
2-(Buta-2,3-dienyloxy)-5-methyl-benzaldehyde 1g. Prepared according to the general procedure from
-hydroxy-3-methyl-benzaldehyde 7g (0.83 g, 6.1 mmol, 1.0 equiv) and 4-bromo-buta-1,2-diene 6 (1.1
g, 7.7 mmol, 1.3 equiv) with K CO (1.5 g, 11 mmol, 1.8 equiv) in DMF (20 mL). The crude product
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
was purified over a silica gel plug to afford 2-(buta-2,3-dienyloxy)-5-methyl-benzaldehyde 1g (630 mg,
40 1
3
3
.35 mmol, 55% yield). Analysis according to the literature. H NMR (360 MHz, CDCl ) δ ppm 2.31
(s, 3H), 4.66 (dt, J = 6.4, 2.7 Hz, 2H), 4.90 (dt, J = 6.6, 2.7 Hz, 2H), 5.41 (quint, J = 6.6 Hz, 1H), 6.90
1
3
(
d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4, 2.0 Hz, 1H), 7.64 (s, 1H), 10.48 (s, 1H). C NMR (90 MHz,
CDCl ) δ ppm 20.3, 66.3, 76.9, 86.7, 113.1, 124.9, 128.4, 130.4, 136.4, 158.8, 190.1, 209.5. IR (NaCl
thin film) νmax [cm ] 3352, 3066, 2925, 2864, 2760, 1957, 1863, 1686, 1609, 1582, 1494, 1396, 1284,
3
-
1
-
5
1
243, 1161, 1114, 1003, 941, 851, 811, 727, 649. UV-VIS (MeCN, c = 4.5 x 10 mol/l): λmax 218 nm
(ε = 27375); 254 nm (ε = 12495); 327 nm (ε = 5545). EI-MS [m/z] (%) 188.3 (7.1), 145.4 (20), 136.4
100), 135.5 (87), 118.4 (11), 107.3 (25), 77.4 (11).
-(Buta-2,3-dienyloxy)-5-methoxy-benzaldehyde 1h. Prepared according to the general procedure
from 2-hydroxy-5-methoxy-benzaldehyde 7h (0.626 ml, 4.80 mmol, 1 equiv) and 4-bromo-1,2-
butadiene 6 (0.638 g, 4.80 mmol, 1 equiv) with K CO (0.862 g, 6.24 mmol, 1.3 equiv) in DMF (15
(
2
2
3
ml). The work-up afforded 2-(buta-2,3-dienyloxy)-5-methoxy-benzaldehyde 1h (738.8 mg, 3.62
1
mmol, 75 % yield) as a yellow solid, which was used without further purification. H NMR (360 MHz,
CDCl
.08 Hz, 1 H) 7.13 (dd, J = 8.86, 2.95 Hz, 1 H) 7.34 (d, J = 3.18 Hz, 1 H) 10.48 (s, 1 H). C NMR
101 MHz, CDCl ) δ ppm 55.7, 67.0, 76.9, 86.7, 110.2, 115.2, 123.3, 125.6, 153.9, 155.5, 189.6, 209.5.
3
) δ ppm 3.82 (s, 3 H) 4.62 - 4.70 (m, 2 H) 4.85 - 4.94 (m, 2 H) 5.35 - 5.46 (m, 1 H) 6.97 (d, J =
1
3
9
(
3
-
1
IR (KBr) νmax [cm ] 3450 (br s), 3063 (w), 2990 (w), 2874 (m), 1961 (m), 1854 (w), 1679 (s), 1619
-
(
m), 1585 (m), 1501 (s), 1433 (m), 1384 (m), 805 (m), 736 (m), 649 (w). UV-VIS (MeCN, c = 3.0 x 10
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2
5
mol/l): λmax 225 nm (ε = 19728); 254 nm (ε = 8524); 352 nm (ε = 4582). ESI-HRMS [m/z] calculated
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
for C12
H
12NaO
3
[M+Na] 227.0679 found 227.06815. mp 49 °C.
2-(Buta-2,3-dienyloxy)- 5-tert-butyl-benzaldehyde 1i. Prepared according to the general procedure
from 2-hydroxy-5-tert-butyl-benzaldehyde 7i (1.1 g, 6.17 mmol, 1 equiv) and 4-bromo-1,2-butadiene 6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
0.821 g, 6.17 mmol, 1 equiv) with K
product was purified by flash column chromatography (Si: 70 g) with hexane and Et
10:1) to afford 2-(buta-2,3-dienyloxy)-5-tert-butyl-benzaldehyde 1i (0.8336 g, 3.62 mmol, 58.7 %
2
CO
3
(1.109 g, 8.02 mmol, 1.3 equiv) in DMF (18 ml). The crude
2
O as solvents
(
1
yield) as a yellow oil. H NMR (360 MHz, CDCl
3
) δ ppm 1.32 (s, 9 H) 4.63 - 4.73 (m, 2 H) 4.86 - 4.94
(
m, 2 H) 5.36 - 5.48 (m, 1 H) 6.95 (d, J = 8.63 Hz, 1 H) 7.58 (dd, J = 8.63, 2.72 Hz, 1 H) 7.86 (d, J =
1
3
2.72 Hz, 1 H) 10.50 (s, 1 H). C NMR (91 MHz, CDCl
3
) δ ppm 31.3, 34.2, 66.3, 77.2, 86.7, 112.8,
13
1
24.5, 124.8, 133.0, 143.8, 158.8, 190.2, 209.5. C NMR (75 MHz, DMSO-d ) δ ppm 31.0, 33.9, 65.8,
6
-
1
77.2, 86.8, 114.0, 123.5, 123.8, 133.5, 143.1, 158.5, 189.2, 208.6. IR (Golden Gate) νmax [cm ] 2961,
2
868, 1957, 1681, 1606, 1492, 1364, 1262, 1187, 1136, 1097, 1002, 848, 818. UV-VIS (MeCN, c = 3.0
-
5
x 10 mol/l) λmax 219 nm (ε = 22517); 254 nm (ε = 9057); 325nm (ε = 3772). ESI-HRMS [m/z]
+
calculated for C15
H18NaO
2
[M+Na] 253.1199 found 253.1196.
2
-(Buta-2,3-dienyloxy)-5-chloro-benzaldehyde 1j. Prepared according to the general procedure from
5-chloro-2-hydroxy-benzaldehyde 7j (650 mg, 4.2 mmol, 1.2 equiv) and 4-bromo-buta-1,2-diene 6
450 mg, 3.4 mmol, 1.0 equiv) with K CO (545 mg, 3.9 mmol, 1.1 equiv) in DMF (20 mL). The work-
up afforded 2-(buta-2,3-dienyloxy)-5-chloro-benzaldehyde 1j (624.0 mg, 3.0 mmol, 88 % yield) which
(
2
3
4
0 1
was used without further purification. Analysis according to literature. H NMR (360 MHz, CDCl
3
) δ
ppm 4.69 (dt, J = 6.6, 2.5 Hz, 2H), 4.91 (dt, J = 6.6, 2.5 Hz, 2H), 5.40 (quint, J = 6.6 Hz, 1H), 6.96 (d,
1
3
J = 9.1 Hz, 2H), 7.48 (dd, J = 8.6, 2.3 Hz, 1H), 7.79 (d, J = 2.7 Hz, 1H), 10.43 (s, 1H). C NMR (90
MHz, CDCl ) δ ppm 66.6, 77.3, 86.3, 114.7, 126.1, 126.6, 128.0, 135.2, 159.1, 188.5, 209.6. IR (NaCl
3
-
1
thin film) νmax [cm ] = 3019, 2882, 1956, 1682, 1596, 1477, 1394, 1269, 1215, 1128, 1001, 903, 853,
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
5
7
56, 669. UV-VIS (MeCN, c = 2.87 x 10 mol/l) λmax 221nm (ε = 8477); 249 nm (ε = 3066); 330 nm
+
(
ε = 1276). ESI-HRMS [m/z] calculated for C11
H
9
ClNaO
2
[M+Na] 231.0183, found 231.0185.
2
-(Buta-2,3-dienyloxy)-3,5-di-methyl-benzaldehyde 1k. Prepared according to the general procedure
from 3,5-di-methyll-2-hydroxy-benzaldehyde 7k (861.5 mg, 5.74 mmol, 1 equiv) and bromo-1,2-
butadiene 6 (763 mg, 5.74 mmol, 1 equiv) with K CO (1031 mg, 7.46 mmol, 1.3 equiv) in DMF
17ml). The crude product was purified by flash column chromatography (Si: 50g) with hexane and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
(
DCM as solvents (5:3) to afford 2-(buta-2,3-dienyloxy)-3,5-di-methyl-benzaldehyde 1k (730.7 mg,
1
3
4
.61 mmol, 63 % yield) as a yellow liquid. H NMR (360 MHz, CDCl
3
) δ ppm 2.29 - 2.36 (m, 6 H)
.47 (d, J = 7.27 Hz, 2 H) 4.83 (d, J = 6.36 Hz, 2 H) 5.33 - 5.60 (m, 1 H) 7.27 (s, 1 H) 7.49 (s, 1 H)
1
3
10.37 (s, 1 H). C NMR (91 MHz, CDCl
3
) δ ppm 210.0; 190.7; 158.0; 138.4; 134.1; 132.1; 129.1;
-1
1
26.2; 86.5; 76.3; 73.3; 20.6; 15.9. IR (NaCl thin film) νmax [cm ] 2928 (w); 2861 (w); 2740 (w); 1957
(m); 1686 (s); 1606 (w); 1591 (w); 1476 (s); 1392 (m); 1368 (m); 1297 (w); 1249 (m); 1249 (m); 1200
-5
(
s); 1144 (m); 976 (m); 851 (m). UV-VIS (MeCN, c = 2.93 x 10 mol/l): λmax 212 nm (ε = 23371); 257
+
nm (ε = 8940); 313 nm (ε = 2102). ESI-HRMS [m/z] calculated for C13
H14NaO
2
[M+Na] 225.0886
found 225.0884.
2
-(Buta-2,3-dienyloxy)-3,5-di-tert-butyl-benzaldehyde 1l. Prepared according to the general
procedure from 3,5-di-tert-butyl-2-hydroxy-benzaldehyde 7l (1.0 g, 4.2 mmol, 1.2 equiv) and bromo-
,2-butadiene 6 (450 mg, 3.4 mmol, 1.0 equiv) with K CO (550 mg, 4 mmol, 1.2 equiv) in DMF (20
1
2
3
mL). The crude product was purified by flash column chromatography (Si: 25g) with pentane and
DCM as solvents (5:2) to afford 2-(buta-2,3-dienyloxy)-3,5-di-tert-butyl-benzaldehyde 1l (650.7 mg,
40 1
2
3
.3 mmol, 67 % yield) as a yellow solid, analysis according to literature. H NMR (360 MHz, CDCl )
δ ppm 1.33 (s, 9 H) 1.44 (s, 9 H) 4.43 - 4.53 (m, 2 H) 4.85 - 4.96 (m, 2 H) 5.43 - 5.57 (m, 1 H) 7.63 (d,
13
3
J = 2.7 Hz, 1 H) 7.71 (d, J = 2.7 Hz, 1 H) 10.30 (s, 1 H). C NMR (91 MHz, CDCl ) δ ppm 209.6,
190.9, 159.4, 146.5, 143.0, 130.9, 129.3, 124.0, 87.0, 76.8, 76.1, 35.3, 34.7, 31.3, 30.9. IR (NaCl thin
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2
-
1
film) νmax [cm ] 2962, 2871, 2746, 1959, 1689, 1596, 1478, 1395, 1364, 1237, 1202, 1163, 980, 849.
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
5
UV-VIS (MeCN, c = 5.2 x 10 mol/l): λmax 216 nm (ε = 24614); 261 nm (ε = 9821); 306 nm (ε =
+
2
930). ESI-HRMS [m/z] calculated for C19
H26NaO
2
[M+Na] 309.1825, found 309.1826.
2
-(Buta-2,3-dienyloxy)-3,6-dimethyl-benzaldehyde 1m. Prepared according to the general procedure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
from 2-hydroxy-3,6-dimethyl-benzaldehyde 7m (0.75 g, 4.99 mmol, 1 equiv) and 4-bromo-1,2-
butadiene 6 (0.664 g, 4.99 mmol, 1 equiv) with K CO (0.897 g, 6.49 mmol, 1.3 equiv) in DMF (15
2
3
ml). The work-up afforded 2-(buta-2,3-dienyloxy)-3,6-dimethyl-benzaldehyde 1m (0.85 g, 4.21 mmol,
1
84 % yield) as a yellow liquid, which was used without further purification. H NMR (360 MHz,
3
CDCl ) δ ppm 2.31 (s, 3 H) 2.56 (s, 3 H) 4.31 - 4.54 (m, 2 H) 4.75 - 4.93 (m, 2 H) 5.33 - 5.55 (m, 1 H)
1
3
6
2
ν
.93 (d, J = 7.72 Hz, 1 H) 7.30 (d, J = 7.72 Hz, 1 H) 10.57 (s, 1 H). C NMR (91 MHz, CDCl
3
) δ ppm
09.9, 193.0, 161.3, 139.3, 136.3, 129.4, 127.9, 127.5, 86.6, 76.4, 73.2, 21.0, 15.8. IR (NaCl thin film)
-
1
max [cm ] 2978 (w); 2927 (w); 2876 (w); 2363 (w); 1957 (w); 1689 (s); 1571 (m); 1484 (m); 1380
(w); 1362 (m); 1261 (w); 1217 (m); 1074 (m); 984 (m); 938 (w); 852 (m); 818 (w); 782 (w). UV-VIS
-5
(
MeCN, c = 2.5 x 10 mol/l): λmax 211 nm (ε = 26646); 255 nm (ε = 10274); 306 nm (ε = 2508). ESI-
+
HRMS [m/z] calculated for C13
H
14NaO
2
[M+Na] 225.0886 found 225.0887.
6
-(Buta-2,3-dienyloxy)benzo[d][1,3]dioxole-5-carbaldehyde 1n. Prepared according to the general
procedure from 6-hydroxy-3,4-methylenedioxybenzaldehyde 7n (441.1 mg, 2.66 mmol, 1 equiv) and 4-
bromo-1,2-butadiene 6 (494 mg, 3.72 mmol, 1.4 equiv) with K CO (514 mg, 3.72 mmol, 1.4 equiv) in
DMF (4 ml). The work-up afforded 6-(Buta-2,3-dienyloxy)benzo[d][1,3]dioxole-5-carbaldehyde 1n
2
3
(
514.9 mg, 2.360 mmol, 89 % yield) as a white-off solid, which was used without further purification.
1
6
H NMR (360 MHz, DMSO-d ) δ ppm 4.64 - 4.73 (m, 2 H) 4.97 - 5.04 (m, 2 H) 5.45 - 5.61 (m, 1 H)
1
3
6
8
.11 (s, 2 H) 6.98 (s, 1 H) 7.08 (s, 1 H) 10.16 (s, 1 H). C NMR (91 MHz, CDCl
3
) δ ppm 67.2, 77.1,
-
1
6.4, 95.6, 102.1, 105.8, 119.2, 142.3, 154.0, 159.0, 187.9, 209.5. IR (Golden Gate) nmax [cm ] 3063
(
w), 2990 (w), 2894 (w), 1957 (w), 1669 (s), 1619 (s), 1497 (s), 1442 (s), 1402 (m), 1391 (m), 1354
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
m), 1325 (w), 1263 (s), 1227 (s), 1159 (s), 1117 (w), 1076 (m), 1032 (s), 994 (s), 925 (s), 874 (s), 865
-
5
(s), 797 (s), 776 (m), 714 (w), 636 (m), 610 (m). UV-VIS (MeCN, c = 3.4 x 10 mol/l): λmax 273 nm (ε
+
=
3761); 341 nm (ε = 4044). ESI-HRMS [m/z] calculated for C12
H
10NaO
4
[M+Na] 241.0471 found
2
41.0472. mp 90 °C.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5-(Buta-2,3-dien-1-yloxy)-4-formyl-2-methoxyphenyl acetate 1o. Prepared according to the general
procedure from 4-formyl-5-hydroxy-2-methoxyphenyl acetate 7o (148.6 mg, 0.707 mmol, 1 equiv) and
4
2 3
-bromo-1,2-butadiene 6 (188 mg, 1.414 mmol, 2 equiv) with K CO (127 mg, 0.919 mmol, 1.3 equiv)
in DMF (0.5 mL). The crude product was purified by flash column chromatography (Si: 10 g) with
hexane and EtOAc as solvents (3:1) to afford 5-(buta-2,3-dien-1-yloxy)-4-formyl-2-methoxyphenyl
1
acetate 1o (73.6 mg, 0.281 mmol, 39.7 % yield) as a white-off solid. H NMR (360 MHz, CDCl
3
) δ
ppm 2.39 (s, 3 H) 3.93 (s, 3 H) 4.68 - 4.75 (m, 2 H) 4.87 - 4.94 (m, 2 H) 5.42 (quin, J = 6.81 Hz, 1 H)
1
3
6
8
3
1
3
.70 (s, 1 H) 7.34 (s, 1 H) 10.02 (s, 1 H). C NMR (75 MHz, CDCl ) δ ppm 20.8, 56.3, 67.1, 77.1,
-
1
5.9, 107.6, 110.0, 120.7, 147.56, 147.59, 153.4, 169.4, 186.9, 210.0. IR (Golden Gate) νmax [cm ]
728 (w), 3704 (w), 3627 (w), 3598 (w), 2988 (w), 2943 (w), 2852 (w), 1956 (w), 1754 (m), 1676 (s),
605 (s), 1508 (s), 1474(w), 1418 (m), 1376 (m), 1276 (s), 1204 (s), 1161 (s), 1110 (s), 1025 (s), 1009
(s), 981 (s), 912 (m), 873 (m), 854 (m), 834 (s), 739 (s), 677 (m), 614 (m), 592 (m), 570 (s), 538 (s).
-
5
UV-VIS (MeCN, c = 2.86 x 10 mol/l): λmax 315 nm (ε = 1853); 275 nm (ε = 2798); 233 nm (ε =
+
4
860); 203 nm (ε = 4455). ESI-HRMS [m/z] calculated for C14
285.07351.
-(Buta-2,3-dien-1-yloxy)-5-formyl-2-methoxyphenyl acetate 1p. Prepared according to the general
procedure from 5-formyl-4-hydroxy-2-methoxyphenyl acetate 7p (144.3 mg, 0.687 mmol, 1 equiv) and
4-bromobuta-1,2-diene 6 (228 mg, 1.716 mmol, 2.5 equiv) with K CO (123 mg, 0.893 mmol, 1.3
H14NaO
5
[M+Na] 285.07334 found
4
2
3
equiv) was dissolved in dry DMF (3 ml). The crude product was purified by flash column
chromatography (Si: 15 g) with hexane and DCM as solvents (1:5 to pure DCM) to afford 4-(buta-2,3-
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2
dien-1-yloxy)-5-formyl-2-methoxyphenyl acetate 1p (168.5 mg, 0.642 mmol, 94 % yield) as a white-
off solid. 1H NMR (300 MHz, CDCl ) δ ppm 2.30 (s, 13 H) 3.90 (s, 14 H) 4.71 (dt, J = 6.75, 2.48 Hz,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
8 H) 4.92 (dt, J = 6.61, 2.55 Hz, 8 H) 5.42 (quin, J = 6.66 Hz, 4 H) 6.56 (s, 4 H) 7.53 (s, 4 H) 10.32 (s,
13
4
3
H). C NMR (75 MHz, CDCl ) δ ppm 20.5, 56.2, 67.0, 77.1, 86.5, 97.5, 118.4, 122.1, 134.0, 157.2,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1
160.6, 169.0, 187.6, 209.7. IR (Golden Gate) νmax [cm ] 2929(w), 2876 (w), 2783 (w), 1981 (w), 1957
(w), 1744 (m), 1666 (s), 1606 (s), 1512 (m), 1478 (m), 1440 (m), 1369 (m), 1333 (m), 1290 (s),
-
5
1257(m), 1226 (s), 1199 (s), 1180 (s), 1116 (s), 1007 (s). UV-VIS (MeCN, c = 2.7 x 10 mol/l): λmax
3
17 nm (ε = 11480); 269 nm (ε = 17749); 233 nm (ε = 27587); 206 nm (ε = 18895). ESI-HRMS [m/z]
+
calculated for C14
H14NaO
5
[M+Na] 285.07334 found 285.07314. mp 97 °C.
General procedure for photocycloaddition to obtain the bicyclo[2.2.2]octadienes 2a-2p and the
benzoxepines 3a-3p. The corresponding allenyloxy benzaldehyde 1a-1o (0.15 – 0.74 mmol, 1 equiv)
was dissolved in dry DCM (0.03 – 0.04 M) in a quartz tube equipped with a magnetic stir bar and a
rubber septum. The reaction mixture was purged with argon for 15 min and irradiated under argon
atmosphere at 350 nm at rt for the time indicated in Table 3. The reaction mixture was then evaporated.
1
,5
2
-Oxa-tricyclo[5.2.2.0 ]undeca-4,8,10-triene-9-carbaldehyde 2a and 8-Methylene-11,12-dioxa-
2,7
tricyclo[7.2.1.0 ]dodeca-2,4,6-triene 3a. Prepared according to the general procedure from 2-(buta-
2
,3-dienyloxy)-benzaldehyde 1a (129.4 mg, 0.743 mmol)in dry DCM (20 ml). The crude mixture was
purified by flash column chromatography (Si: 30 g) with pentane and DCM as solvents (5:3 to pure
1,5
DCM) to afford 2-oxa-tricyclo[5.2.2.0 ]undeca-4,8,10-triene-9-carbaldehyde 2a (25.2 mg; 19 %
2
,7
yield) as a yellow solid and 8-methylene-11,12-dioxa-tricyclo[7.2.1.0 ]dodeca-2,4,6-triene 3a (20.0
4
0
mg; 15
%
yield) as
a
white-off solid, analysis according to literature.
2-Oxa-
1
,5
1
tricyclo[5.2.2.0 ]undeca-4,8,10-triene-9-carbaldehyde 2a; H NMR (500 MHz, CDCl
3
) δ ppm 2.15 (q,
J = 15.44 Hz, 2 H) 3.97 (br. s., 1 H) 5.41 (s, 1 H) 6.18 (t, J = 6.81 Hz, 1 H) 6.59 (d, J = 7.72 Hz, 1 H)
13
7
.08 (d, J = 5.90 Hz, 1 H) 9.70 (s, 1 H). C NMR (91 MHz, CDCl
3
) d ppm 187.4, 148.6, 146.5, 138.9,
29
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