Photochemical Doyle-Kirmse Reaction: A Route to Allenes

Article abstract of DOI:10.1021/acs.orglett.9b04560

This Letter describes the metal-free, blue-light-induced [2,3]-sigmatropic rearrangement of sulfonium ylides generated from donor/acceptor diazoalkanes and propargyl sulfides. The reaction furnishes highly functionalized allenes from a broad range of starting materials in decent yield. Mechanistic experiments supported by the literature data suggest singlet carbenes as intermediates in this reaction.

Full text of DOI:10.1021/acs.orglett.9b04560

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photochemical Doyle−Kirmse Reaction: A Route to Allenes
†,§
Katarzyna Orłowska,†,§ Katarzyna Rybicka-Jasinska,
Piotr Krajewski,†,‡ and Dorota Gryko*,†
́
†Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
‡Department of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
S
* Supporting Information
ABSTRACT: This Letter describes the metal-free, blue-light-
induced [2,3]-sigmatropic rearrangement of sulfonium ylides
generated from donor/acceptor diazoalkanes and propargyl
sulfides. The reaction furnishes highly functionalized allenes
from a broad range of starting materials in decent yield.
Mechanistic experiments supported by the literature data
suggest singlet carbenes as intermediates in this reaction.
Scheme 1. Metal-Catalyzed and Photochemical Reactions of
Donor/Acceptor Diazoalkanes
he unique reactivity of the 1,2-diene moiety and its
Tpresence in a number of natural products have attracted
considerable attention over the last several decades.1−3 Allenes
undergo a wide variety of reactions including cycloisomeriza-
tion,4,5 cycloaddition,6−8 and cross-coupling9−11 reactions
furnishing a valuable collection of small and complex molecules
with impressive regio- and diastereoselectivities.12,13 As a
result, this functionality has often been installed in biologically
active molecules, such as steroids14 or nucleosides,15 to tune
their pharmacological properties.
The appealing chemistry of allenes results in a variety of
synthetic methods for their preparation, starting from classical
procedures16 to more recent reports on enantioselective
methods promoted by metal catalysts (e.g., copper,17
palladium,18 or gold19). Prominent among these are rearrange-
ment reactions involving sulfonium or oxonium propargyl
ylides. Typically, these reactive intermediates are generated
from propargyl sulfides or alcohols and extremely electrophilic
metal carbenes derived from diazocarbonyl compounds.20−24
Unlike carbene chemistry induced by metal catalysts,25,26
photolytic reactions are less explored, with only a few examples
being promoted by visible light.27 Our group developed
photocatalytic procedures for the functionalization of alde-
hydes,28 ketones,29 and indoles,30 evidencing that in the
presence of blue light, α-diazo esters can act as efficient
alkylating reagents. On the contrary, the decomposition of aryl
diazoacetates to free carbenes under blue-light irradiation
proved to be feasible because these compounds absorb light in
the wavelength region of 400−500 nm.31,32 As a consequence,
the reactivity of donor/acceptor diazo compounds under blue-
light irradiation has been extensively studied. Indeed, visible-
light-induced cyclopropanation,33 cyclopropenation,34 benzan-
nulation,35 and cross-coupling36 as well as C−H,32 O−H,32
and N−H32,37 insertion reactions have been recently reported.
Photochemically generated carbenes react with propargyl
tertiary alcohols,38 giving cyclopropenes in contrast with metal-
catalyzed [2,3]-sigmatropic rearrangement involving ylide
intermediates (Scheme 1A).24
Such ylides, in general, can undergo either [1,2]- or [2,3]-
sigmatropic rearrangements, but for allyl sulfides, the Doyle−
Kirmse reaction predominates (Scheme 1B).39,40,34
In this line, we questioned whether in the presence of blue
light propargyl sulfides would follow a pattern of propargyl
alcohols and undergo a photochemical cyclopropenation
reaction or rather furnish [2,3]-sigmatropic rearrangement
products, as reported by Kirmse41 and Doyle42 in metal-
catalyzed reactions.
Herein we report that under blue-light irradiation the
Doyle−Kirmse reaction of propargyl sulfides with donor/
acceptor diazoalkanes leads to allenes, valuable building blocks
toward complex molecules (Scheme 1C).
Received: December 19, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b04560
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a
Table 1. Background and Optimization Studies
Scheme 2. Scope of Reaction: Aryl Diazocarbonyl
Compounds
a
b
entry
light
blue
no light
blue
green
green
UV
yield (%)
1
2
3
76
0
c
70
45
65
12
22
80
4
d
5
e
6
ef
,
7
UV
blue
g
8
a
Reaction conditions: 1 (0.15 mmol), 2 (9 equiv), DCM (0.5 mL),
b
c
single blue LED, 24 h, rt. Isolated yields. Methylene blue (1 mol %)
d
e
was added. Eosin Y (1 mol %) was added. Reaction time: 8 h.
f
g
Benzophenone (20 mol %) was added. Reaction was started with 1
(0.075 mmol) in DCM (0.25 mL); a second portion of 1 (0.075
mmol) in DCM (0.25 mL) was added after 3 h.
Taking into consideration the optical properties of donor/
acceptor diazo compounds (see the SI), specifically, the local
absorbance maximum for the lowest energy absorption, we
selected methyl (4-cyano)phenyl diazoacetate (1) as a model
diazoalkane and reacted it with phenyl propargyl sulfide (2)
under blue-light irradiation (Table 1). To our delight, the
reaction furnished allene 3 in 76% yield (entry 1). Control
experiments demonstrated the crucial role of light (entry 2)
and revealed that the addition of a photosensitizer to the
reaction performed under blue light did not significantly affect
the reaction yield (entry 3). Consequently, because some diazo
compounds absorb in the wavelength around 500 nm, the
model reaction was irradiated with green light. The desired
product 3 formed, however, in diminished yield. Keeping in
mind that suitable sensitizers induce the generation of
carbenes, we examined whether the addition of eosin Y, an
organic photocatalyst, improved the reaction outcome. The
yield indeed increased up to 65% (entry 5). On the contrary,
reactions with and without the addition of benzophenone (a
photosensitizer) under high-energy UV light were less efficient
and led to the decomposition of starting materials just after 8 h
(entries 6 and 7). Presumably, in these cases, the photo-
excitation of not only diazo ester 1 but also propargyl sulfide 2
contributed to the loss of reaction selectivity. Dichloromethane
(DCM) ensured the formation of product in the highest yield.
Notably, there was no need to use dry, degassed solvents. (For
details, see the SI.) The yield further improved when diazo
compound 1 was added portionwise to the solution of 9 equiv
of sulfide 2 in DCM (second portion after 3 h, entry 8).
With the optimal conditions in hand, we investigated the
scope of aryl diazoacetates (Scheme 2) and propargyl sulfides
(Scheme 3). The visible-light-induced Doyle−Kirmse reaction
works well for a broad range of aryl diazo compounds
regardless of the position and electronic effects of a substituent
in the phenyl ring. In the case of electron-donating substituents
(allenes 15−17), as compared with those with electron-
withdrawing groups (products 3−6), yields slightly decrease as
a result of the lower electrophilicity of carbenes generated from
diazo reagents. Halogen substituents on the phenyl ring within
the diazo compound structure (7−11) are also well tolerated,
a
Reaction conditions: diazoalkane (0.15 mmol, added in two
portions), phenyl propargyl sulfide (2, 9 equiv), DCM (0.5 mL),
single blue LED, 24 h. Reaction performed on a 1 mmol scale.
b
with the 4-fluoro derivative giving the best result (9, 88%).
Furthermore, the substitution position does not strongly affect
the reaction yield; for two- and three-substituted products 10
and 11, yields decrease to some extent, as compared with four-
substituted diazoalkane derivative 9.
The reaction is also efficient for diazoacetates bearing
unsubstituted aryl and naphthyl aromatic rings, affording
products 12−14 in good yield. Even allene 18 bearing a
heteroaromatic moiety can be synthesized in satisfactory yield,
in contrast with allene bearing the pyridine unit.
Various esters of aryl diazoacetate including (−)-menthyl are
well tolerated with benzyl diazoester (λmax = 430 nm) giving
allene 20 in the highest yield. Additionally, the reaction is
easily scalable, and the synthesis of compound 4 on a 1 mmol
scale gives product 4 in even slightly better yield (4, 84%
compared with 78% on the 0.15 mmol scale).
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DOI: 10.1021/acs.orglett.9b04560
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a
giving allenes 23−25 in good yield but also nitrogen-
containing heteroaromatics, for example, pyridine, tetrazole,
quinolone (26−29), and aliphatic sulfides, for which products
form (30−32) in only slightly diminished yield (Scheme 3). A
valuable example is allene 33 bearing the cysteine moiety,
which was obtained in 58% yield with, as expected, no
diastereoselectivity. The effect of substitution on the propargyl
moiety was also examined, and due to steric hindrance, allenes
34 and 35 were obtained but in moderate yield.
Scheme 3. Scope of Reaction: Propargylic Sulfides
On the basis of recent reports on the reactivity of aryl
diazoacetates under blue-light irradiation,32 we assume that the
photoexcitation of an aryl diazocarbonyl compound is also the
initial step in their reaction with propargyl sulfides (Scheme 4).
Scheme 4. Plausible Mechanism of the Photochemical
Doyle−Kirmse Reaction
Under light irradiation, nitrogen extrusion occurs, leading to a
singlet carbene that can either undergo intersystem crossing to
the triplet state or, as such, react with a propargyl sulfide,
generating a sulfonium ylide. The subsequent [2,3]-sigma-
tropic rearrangement furnishes the desired allene. Exploring
the mechanistic aspects of the reaction, we questioned the
nature of carbene species involved in the visible-light-induced
Doyle−Kirmse reaction. Our recent studies on the porphyrin-
photocatalyzed α-alkylation of ketones with α-diazo esters
suggest the generation of triplet carbenes detected as an adduct
with TEMPO.28 Concurrently, the reported reaction is not
halted by the addition of TEMPO, and no adducts with
carbenes can be observed. (See the SI.) Taking into
consideration the fact that direct photolysis of diazo
compounds leads to the generation of singlet carbenes,
whereas photosensitization furnishes triplet carbenes,43,44 we
performed the reaction with and without the addition of a
triplet sensitizer, tetraphenyl porphyrin (TPP, Scheme 5A).
When TPP was added, a decrease in the yield was indeed
observed compared with the porphyrin-free reaction. More-
a
Reaction conditions: diazoalkane 1 (0.15 mmol, added in two
portions), propargylic sulfide (9 equiv), DCM (0.5 mL), single blue
LED, 24 h.
It is noteworthy that under developed conditions, aryl
diazoketone also absorbing blue light gives allene 22 in 43%
yield (Figure 1). In contrast, methyl 2-diazo-3-phenyl-
propionate (λmax = 410 nm, Figure 1) is not reactive under
developed conditions, suggesting that the absorption of light in
the blue region is not the only prerequisite for an efficient
reaction.
As far as propargyl sulfides are concerned, the reaction
tolerates not only derivatives with substituted phenyl rings
Scheme 5. Mechanistic Experiments
Figure 1. Absorption spectra of various diazoalkanes (6 μmol·mL−1 in
DCM) and phenyl propargyl sulfide 2 (3.6 μmol·mL−1 in DCM). For
UV−vis spectra of other aryl diazocarbonyl compounds, see the SI.
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Letter
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This outcome is typical for singlet carbene species, as
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method enables the synthesis of a broad range of highly
functionalized allenes in good to excellent yield under mild
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Mechanistic considerations support the involvement of
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04560.
Full description of optimization and mechanistic studies,
general procedure for [2,3]-sigmatropic rearrangement
to allenes, UV−vis spectra of aryl diazocarbonyl
compounds, compound characterization (NMR,
HRMS, AE), and NMR spectra (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dorota.gryko@icho.edu.pl.
ORCID
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Katarzyna Orłowska: 0000-0003-2172-7789
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(29) Rybicka-Jasinska, K.; Orłowska, K.; Karczewski, M.; Zawada,
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Katarzyna Rybicka-Jasinska: 0000-0002-9018-7846
K.; Gryko, D. Eur. J. Org. Chem. 2018, 2018, 6634.
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2018, 554, 86.
Dorota Gryko: 0000-0002-5197-4222
Author Contributions
§K. O. and K.R.-J. contributed equally.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support for this work was supported by the Ministry
of Science and Higher Education (K.O., grant no. 0132/DIA/
2017/46) and the Foundation for Polish Sciences (D.G., grant
no. FNP TEAM POIR.04.04.00-00-4232/17-00). We extend
our gratitude to Dr. Olga Staszewska-Krajewska (Institute of
Organic Chemistry, PAS) for NOE experiments.
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DOI: 10.1021/acs.orglett.9b04560
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