Photocycloaddition of arenes and allenes.

TL;DR: A new intramolecular para cycloaddition of arenes with allenes, yielding attractive rigid scaffolds bearing several reactive functionalities to build in further diversity, and was scaled up to multigram quantities without erosion of the typically high yields in photocycloadducts.

Abstract: 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 wa...

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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,
Switzerland, and
#
Merck Serono S.A., Chemin des Mines 9, CH-1202 Geneva, Switzerland.
christian.bochet@unifr.ch
TOC Graphic
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
O
X
•
hν
CH
2
Cl
2
up to 92%
O
X
R
R
O
X
•
R
Br
very rapid increase in complexity !
X=O, NPG
X
O
R
+
1
Published in "The Journal of Organic Chemistry doi: 10.1021/jo4002307, 2013"
which should be cited to refer to this work.
http://doc.rero.ch

conformationally constrained unnatural amino acids with different disposition of the two anchor
points.
INTRODUCTION
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
photochemical excitation.
1,2,3,4,5
While the meta photocycloaddition is very well established
6,7
and has been applied many times in
organic synthesis,
8
the ortho-
9,10
and particularly the para- versions
11
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
bicyclo[2.2.2]octadiene core.
12
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
undergo preferably an ortho photocycloaddition.
13
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
best of our knowledge, was neither further studied nor exploited in synthesis,
14
to the notable exception
2
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of the reaction of 1,1-dimethylallene with 2-phenyl-1-pyrrolium cation reported by Mariano et al.
which gave significant yields of cycloadducts.
15
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
allene or the arene partners (Scheme 1).
16
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
synthesis (DOS).
17
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
distillation. Reduction with lithium aluminium hydride gave the allenyl alcohol 5,
18
which was
converted to the allenyl bromide 6 by reaction with phosphorous tribromide.
19
Scheme 2.
Preparation of allenyl bromide 6.
O
O
•
hν (350nm)
CH
2
Cl
2
O
O
O
O
+
1
23
R
R
R
H
H
H
OH
OH
SOCl
2
PhH, py
36%
OH
Cl
LiAlH
4
Et
2
O
63%
HO
•
PBr
3
Et
2
O, py
53%
Br
•
45
6
3
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The salicylaldehydes 7a-p were either commercially available or prepared from the corresponding
phenol precursor by a highly selective tin tetrachloride-catalyzed ortho-formylation (Table 1).
20
Table 1. Preparation of salicylaldehydes.
Product R= isolated yield
7b 3-Me 52 %
7d 3-
t
Bu 62 %
7k 3,5-Me
2
37 %
7m 3,6-Me
2
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.
Entry Product R= isolated yield
1 1a H 86 %
2 1b 3-Me 70 %
3 1c 3-OMe 100 %
4 1d 3-
t
Bu 51 %
5 1e 4-Me 60 %
6 1f 4-OMe 67 %
OH
[H
2
CO]
n
SnCl
4
, Bu
3
N
37-62%
O
OH
R
R
7b,d,k,m
O
OH
K
2
CO
3
DMF, rt
40-94%
O
O
•
1a-p
Br
•
+
6
1
2
1
2
R
R
7a-p
4
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7 1g 5-Me 55 %
8 1h 5-OMe 75 %
9 1i 5-
t
Bu 59 %
10 1j 5-Cl 88 %
11 1k 3,5-Me
2
63 %
12 1l 3,5-
t
Bu
2
67 %
13 1m 3,6-Me
2
84 %
14 1n 4,5-CH
2
O
2
89 %
15 1o 4-OAc, 5-OMe 40 %
16 1p 4-OMe, 5-OAc 94 %
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
Crabbé homologation.
21
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.
O
OH
O
O
O
•
O
K
2
CO
3
BrCH
2
C
2
H
DMF
95 %
[H
2
CO]
n
CuBr, HN(iPr)
2
Dioxane reflux
46 %
81a
36.6 grams
OH
O
OMe
O
O
OMe
O
•
O
OMe
K
2
CO
3
BrCH
2
C
2
H
DMF rt
98 %
[H
2
CO]
n
CuBr, HN(iPr)
2
Dioxane reflux
46 %
9
10a
7a
5
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Frequently asked questions

Q1. What are the contributions mentioned in the paper "The photocycloaddition of arenes and allenes" ?

In the present work, the authors report on a new intramolecular para-cycloaddition of arenes with allenes, yielding attractive rigid scaffolds bearing several reactive functionalities to build in further diversity. 2. 2 ] octadiene scaffold with two points that allow further diversification. 

Q2. How many mL of diisopropylamine was added to the reaction mixture?

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. 

Q3. How many mmol of benzonitrile was added to the reaction mixture?

4-Bromo-1,2butadiene 6 (1.116 g, 8.39 mmol, 1 equiv) was added dropwise within 1 h and the reaction mixture was stirred for 16 h at rt. 

Q4. How many mmol of the corresponding salicylaldehyde were added?

To a suspension of K2CO3 (1.2-1.8 equiv) in DMF (0.16 – 2 M) was added the corresponding salicylaldehyde 7a-7p (0.7 – 12 mmol) at rt. 

Q5. How long was the reaction mixture stirred at rt?

The reaction mixture was stirred at rt for 20 h, then dry DMF (8.78 mL, 113 mmol, 2.5 equiv) was added dropwise at 0 °C for 1.5 h and the reaction mixture was stirred for 20 h at rt. 

Q6. How many mL of methyl salicylate was added to the reaction mixture?

Diisopropylamine (87.3 mL, 613 mmol, 2.6 equiv) (distilled from KOH before use) was added and the reaction mixture was heated to a gentle reflux for 17 h. 

Q7. What is the way to keep the para-substituted analogues?

While the orthosubstituted 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. 

Q8. how much is a tert-butyl 5-methyl ethenoind?

The solvent was evaporated and the crude product was purified by flash column chromatography (Si: 10g) with DCM and Et2O (95% DCM) as solvent to afford 1-tert-butyl 5-methyl 4,5-dihydro-5,7a-ethenoindole-1,5(2H)-dicarboxylate 33b (33 mg, 0.109 mmol, 32 % yield) as a yellow solid. 

Q9. What is the chemistry of tert-butyl 2-benzoylc?

The crude product was purified by flash column chromatography (Si: 25g) with hexane and EtOAc as solvents (7:1) to afford tert-butyl-buta-2,3-dienyl(2formylphenyl)carbamate 14a (500.7 mg, 1.832 mmol, 68 % yield) as a yellow oil. 

Q10. What substitutions could enhance the formation of the benzoxepine product?

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. 

Q11. What is the chemical composition of the tert butyl(11-aza-8-?

The solvent was evaporated and the crude mixture was purified by flash column chromatography (Si: 25g) with hexane and EtOAc as solvents (3:1) to afford tert-butyl-(11-aza-8-methylene-12-oxa[7,2,1,02,7]dodeca-2,4,6triene)carboxylate 22 (10.5 mg, 0.038 mmol, 9 % yield) as a translucent oil and tert butyl-(2-azatricyclo[5,2,2,01,5]undeca-4,8,10-triene-9-carbaldehyde)carboxylate 21a (74.1 mg, 0.271 mmol, 60 % yield) as a white solid.