Synthesis of fluorinated tricyclic scaffolds by intramolecular [2+2] photocycloaddition reactions

Article abstract of DOI:10.1002/anie.201204080

Fabulous Fluorine: The synthesis of fluorinated products 1 and 2 by [2+2] photocycloaddition was readily feasible after optimization of the irradiation conditions. The electron-deficient trifluoroolefin unit reacted intramolecularly to products 1 (nine ex

Full text of DOI:10.1002/anie.201204080

Angewandte
Chemie
DOI: 10.1002/anie.201204080
Photochemistry
Synthesis of Fluorinated Tricyclic Scaffolds by Intramolecular
[2+2] Photocycloaddition Reactions**
Diego A. Fort, Thomas J. Woltering, Matthias Nettekoven, Henner Knust, and Thorsten Bach*
Dedicated to Professor George A. Olah on the occasion of his 85th birthday
In recent years, fluorinated compounds have attracted con-
siderable synthetic interest and they have gained an impor-
tant position among heteroatom-substituted hydrocarbon
analogues.[1] First and foremost, this interest has been kindled
by the success that fluorinated compounds have encountered
in several areas of medicinal chemistry.[2] Furthermore, many
Scheme 1. Structure of 1, which is the product of an intramolecular
[2+2] photocycloaddition of a tetronate, and of its fluorinated ana-
logues A, which are potentially accessible from fluorinated precursors
B.
other useful and intriguing properties of fluorinated com-
pounds have been elucidated,[1,3] which has further intensified
the efforts towards their selective synthesis. In this regard, it is
surprising to note that the use of fluorinated compounds in
[2+2] photocycloaddition reactions[4] has not been studied
systematically to date. There are scattered reports on the
preparation of fluorinated cage compounds and C6F10 valence
isomers,[5] on the use of fluorinated ethylenes in intermolec-
ular [2+2] photocycloaddition reactions,[6] and on the syn-
thesis of fluoro- and trifluoromethyl-substituted uracil deriv-
atives.[7] A monofluorinated olefin has recently been used
successfully as reaction partner in an intramolecular enone
[2+2] photocycloaddition.[8] Apart from that, the use of
fluorinated compounds in [2+2] photocycloaddition chemis-
try has remained essentially unexplored.
3-enyl bromide. Despite the fact that the trifluoro-substituted
alkene is extremely electron-poor,[10] it did successfully add to
the photoexcited tetronate at l = 254 nm in isopropanol as the
solvent (Table 1, entry 1). A further modification of the
solvent revealed that diethyl ether (Table 1, entry 5) was
superior to tert-butanol (entry 2), dichloromethane (entry 3),
or acetonitrile (entry 4). In the latter solvents the reaction
remained incomplete after an irradiation time of six hours,
while severe product decomposition was found to occur in
tert-butanol.
Given the potential use of fluorinated compounds as new
scaffolds for medicinal chemistry we have now studied
a modification of the known tricyclic skeleton 1[9] by fluorine
substitution (Scheme 1). Products of general structure A
seemed accessible from precursors B, in which the carbon
atoms at positions 2, 3, and 4 should carry fluorine atoms.
Particular interest was directed to the question whether
electron-deficient trifluoro-substituted olefins could serve as
intramolecular reaction partners in a [2+2] photocycloaddi-
tion and whether any facial diastereoselectivity would be
exerted by a fluorine atom at the stereogenic center C2.
Preliminary results of these studies are disclosed herein.
An initial set of experiments was performed with tetro-
nate 2 derived from commercially available 3,4,4-trifluorobut-
The fact that the reaction can be successfully sensitized by
acetone (Table 1, entries 6 and 7) at l = 300 nm supports the
Table 1: Optimization of reaction conditions for the intramolecular
[2+2] photocycloaddition of tetronate 2 to the tricyclic product 3.
Entry[a]
l [nm]
Solvent
t [h][b]
Yield [%][c]
1
2
3
4
5
6
7
254
254
254
254
254
300
300[g]
iPrOH
tBuOH
CH2Cl2
MeCN
Et2O
4
4
6
6
4
4
4
24
<5
53[d]
62[e]
78
[*] Dr. D. A. Fort, Prof. Dr. T. Bach
acetone
acetone
14[f]
11[h]
Lehrstuhl fꢂr Organische Chemie I
Technische Universitꢃt Mꢂnchen
Lichtenbergstr. 4, 85747 Garching (Germany)
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home_en/
[a] All reactions were conducted using a RPR-100 reactor with 16 Rayonet
RPR-2540 ꢀ lamps or RPR-3000 ꢀ lamps (quartz apparatus) as the
irradiation source in deaerated solvent (c=5 mm). [b] Elapsed reaction
time to achieve 100% conversion of the starting material. [c] Yield of
isolated product after chromatographic purification. [d] The reaction was
not complete after 6 h. 25% of starting material was recovered. [e] The
reaction was not complete after 6 h. 15% of starting material was
recovered. [f] Paternꢁ–Bꢂchi reaction products (41%) were obtained as
major products. [g] Duran filter. [h] Paternꢁ–Bꢂchi reaction products
(36%) were obtained as major products.
Dr. T. J. Woltering, Dr. M. Nettekoven, Dr. H. Knust
Discovery Chemistry, PRCB, F. Hoffmann-La Roche AG
Grenzacherstrasse 124, 4070 Basel (Switzerland)
[**] D.A.F. wishes to acknowledge funding by the Roche Postdoc
Fellowship (RPF) Program.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204080.
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Table 3: Intramolecular [2+2] photocycloaddition of N-Boc-protected
3,4,4-trifluorobut-3-enylamino-substituted enones 6 to the respective
trifluorinated products 7.
previously postulated intermediacy of a triplet species in the
[2+2] photocycloaddition of tetronates.[9b] The major reaction
in acetone as the solvent was however the addition of the
photoexcited ketone (Paternꢀ–Bꢁchi reaction) to the tri-
fluoro-substituted double bond.
Since there is no precedence for a successful addition
reaction of a trifluoro-substituted olefin to a photoexcited
enone, it was investigated whether the reaction is feasible with
other substrates but tetronates. To this end, the enones 4a and
4c (Table 2) were prepared by condensation of the respective
1,3-dicarbonyl compounds with 3,4,4-trifluorobut-3-enol.[11]
Tetramate 4b was synthesized by alkylation of N-Boc-
protected tetramic acid[12] with the respective bromide and
subsequent deprotection using trifluoroacetic acid (TFA; see
the Supporting Information).
Entry[a]
Substrate
n
Y
Product
Yield [%][b]
1
2
3
6a
6b
6c
1
1
2
O
CH2
CH2
7a
7b
7c
73
69
68
[a] All reactions were conducted using a RPR-100 reactor with 16 Rayonet
RPR-2540 ꢀ lamps (quartz apparatus) as the irradiation source in
deaerated solvent (c=5 mm). [b] Yield of isolated product after chro-
matographic purification.
Table 2: Intramolecular [2+2] photocycloaddition of 3,4,4-trifluorobut-3-
enyloxy-substituted enones 4 to the respective trifluorinated products 5.
fashion. Formation of the six-membered tetrahydropyran ring
proceeded readily and [2+2]-photocycloaddition products 9
were obtained in 72% and 70% yield (Scheme 2).
Entry[a]
Substrate
n
Y
Product
Yield [%][b]
1
2
3
4a
4b
4c
1
1
2
CH2
NH
CH2
5a
5b
5c
95
75
83
[a] All reactions were conducted using a RPR-100 reactor with 16 Rayonet
RPR-2540 ꢀ lamps (quartz apparatus) as the irradiation source in
deaerated solvent (c=5 mm). [b] Yield of isolated product after chro-
matographic purification.
Scheme 2. Intramolecular [2+2] photocycloaddition of 4,5,5-trifluoro-
but-4-enyloxy-substituted enones 8 to the respective trifluorinated
products 9.
The influence of a difluorosubstitution in position C2 of
the side chain was probed with tetronate 10 (Scheme 3). The
compound was available from its nonfluorinated analogue[9b]
by allylic oxidation and subsequent transformation of the
carbonyl group into a difluorinated carbon center. Under the
previously established conditions the [2+2] photocycloaddi-
tion proceeded smoothly and delivered tricyclic product 11 as
a single diastereoisomer in 71% yield.
If a 3-butenyl tetronate with a single fluorine atom in
position 2 undergoes a [2+2] photocycloaddition, the ques-
tion of facial diastereoselectivity arises, because the carbon
atom at this position is a stereogenic center. The respective
compound 12 (Scheme 4) was prepared from alcohol 13 by
treatment with diethylaminosulfur trifluoride (DAST) in
dichloromethane as the solvent. Alcohol 13 in turn was
prepared by SeO2 oxidation[13] of 3-butenyl tetronate[9b] (68%
To our delight, the [2+2] photocycloaddition of com-
pounds 4 proceeded equally well under the optimal con-
ditions, which had been established with substrate 2. Cyclo-
pentenone 4a delivered the respective tricyclic product 5a in
a yield of 95% (Table 2, entry 1). The tetramic acid derivative
4b reacted smoothly (Table 2, entry 2) as did the six-
membered cyclohexenone 4c (entry 3). In all cases, the
products 5 were obtained as single regio- and diastereoiso-
mers. The relative configuration of the three stereogenic
centers was established by NOE studies.
By varying the linker between the enone and the
trifluorovinyl group it was checked whether the intramolec-
ular [2+2] photocycloaddition of trifluoroalkenes is generally
applicable. The b-amino-substituted enone substrates 6
(Table 3) were prepared by condensation of 3,4,4-trifluoro-
but-3-enylamine with the respective ketones and subsequent
tert-butoxycarbonyl (Boc) protection of the secondary amine
group (see the Supporting Information). The desired photo-
chemical reaction proceeded cleanly upon irradiation at l =
254 nm and delivered products 7 in diastereomerically pure
form. The reaction was complete in one hour.
A longer tether between the enone and the olefin was
employed in the reaction of substrates 8, which are homo-
logous to 4a and 4c and which were prepared in the same
Scheme 3. Intramolecular [2+2] photocycloaddition of 2,2-difluorobut-
3-enyl tetronate (10) to the respective difluorinated product 11.
2
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Scheme 5. Diastereoselective preparation of fluoride 14b and of its
diastereoisomer 14a.
Scheme 4. Facial diastereoselectivity in the intramolecular [2+2] photo-
cycloaddition of 2-fluorobut-3-enyl tetronate (12) and 2-hydroxybut-3-
enyl tetronate (13).
[2+2] photocycloaddition reaction of appropriately substi-
tuted tetronates. Regarding the use of fluorinated compounds
in this type of chemistry, the most significant results are:
1) The electron-withdrawing character of fluorine atoms that
are directly attached to a double bond does not impair the
ability of the double bond to undergo an enone photo-
cycloaddition reaction. Under optimized reaction condi-
tions, trifluoro-substituted olefins linked to an enone
chromophore smoothly underwent the desired reaction in
yields of 68–95%.
2) Fluorine substitution in a position adjacent to a double
bond is compatible with intramolecular [2+2] photocy-
cloaddition chemistry. Both difluoro- and monofluoro-
substituted substrates 10 and 12 reacted cleanly.
3) A fluoro-substituted stereogenic center in a-position to an
olefin does not induce a notable facial diastereoselectivity.
As observed in other photochemical processes,[16] stereo-
electronic effects have a minor impact on the facial
diastereoselectivity. In thermal reactions, however, they
often govern the facial diastereoselectivity in acylic
substrates.[17]
yield). Both compounds were subjected to an intramolecular
[2+2] photocycloaddition at l = 254 nm in diethyl ether as the
solvent. The conversion was complete after five hours and the
reaction delivered two diastereoisomeric products 14 and 15
in either case. While the reaction of fluorinated substrate 12
was unselective (d.r. = 14a/14b = 50:50), alcohol 13 delivered
a major product, to which structure 15a was assigned based on
extensive one- and two-dimensional NMR spectroscopy
studies.
An interpretation of this outcome is relatively straightfor-
ward when considering the favored conformation for either
substrate (Scheme 4). If the heteroatom substituent X is in
a pseudoequatorial position (depicted on the bottom left)
product diastereoisomers a will be formed. If it is positioned
pseudoaxially (bottom right) the diastereoisomers b will be
the products.
Apparently, the small fluorine atom (X = F) does not
exhibit a preference for either position and the conformations
are populated equally. As a consequence, products 14 are
obtained in a ratio of 1:1. In the case of the alcohol (X = OH),
the conformation with a pseudoequatorial hydroxy group is
favored and leads via the respective 1,4-biradical[14] to product
15a. Stereoelectronic effects do not seem to play a role in the
stereodifferentiation process.
The compatibility of fluorine substitution with typical
[2+2] photocycloaddition chemistry, as shown in this study, is
expected to stimulate future work towards the preparation of
cyclobutane-based fluorinated scaffolds. Research along
these lines continues in our laboratories.
Access to diastereomerically pure monofluorinated pho-
tocycloaddition products was achieved by conventional sub-
stitution reactions, which proceeded stereospecifically under
inversion of configuration. The major diastereoisomer 15a
obtained from the [2+2] photocycloaddition of alcohol 13 was
converted with DAST into monofluorinated product 14b
(Scheme 5).
In an analogous fashion its diastereoisomer 14a was
synthesized. Access to ketone 16 was possible either by
oxidation of products 15 or—in low yields—by direct
[2+2] photocycloaddition of a 2-oxo-3-butenyl tetronate.
The Meerwein–Ponndorf–Verley reduction[15] of this ketone
proceeded chemo- and diastereoselectively to alcohol 15b
(62% yield), which in turn was converted to monofluoride
14a by treatment with DAST (74%).
Received: May 25, 2012
Revised: August 3, 2012
Published online: && &&, &&&&
Keywords: cycloaddition · diastereoselectivity · fluorine ·
.
photochemistry · strained molecules
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Photochemistry
D. A. Fort, T. J. Woltering, M. Nettekoven,
H. Knust, T. Bach*
&&&& — &&&&
Synthesis of Fluorinated Tricyclic
Scaffolds by Intramolecular
[2+2] Photocycloaddition Reactions
Fabulous Fluorine: The synthesis of fluo-
rinated products 1 and 2 by [2+2] photo-
cycloaddition was readily feasible after
optimization of the irradiation condi-
tions. The electron-deficient trifluoro-
olefin unit reacted intramolecularly to
products 1 (nine examples, d.r.>95:5).
The reaction was also investigated after
modification of position 2 of the side
chain both with one or two fluoro sub-
stituents (e.g. to yield product 2).
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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