Visible-light sensitization of vinyl azides by transition-metal photocatalysis

Article abstract of DOI:10.1002/anie.201308820

Irradiation of vinyl and aryl azides with visible light in the presence of Ru photocatalysts results in the formation of reactive nitrenes, which can undergo a variety of C-N bond-forming reactions. The ability to use low-energy visible light instead of UV in the photochemical activation of azides avoids competitive photodecomposition processes that have long been a significant limitation on the synthetic use of these reactions. Rock and pyrrole: Irradiation of vinyl and aryl azides with visible light in the presence of Ru photocatalysts results in the formation of reactive nitrenes, which can undergo a variety of C-N bond-forming reactions. The ability to use low-energy visible light instead of UV in the photochemical activation of azides (see picture) avoids competitive photodecomposition processes. Copyright

Full text of DOI:10.1002/anie.201308820

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DOI: 10.1002/anie.201308820
Photocatalysis Very Important Paper
Visible-Light Sensitization of Vinyl Azides by Transition-Metal
Photocatalysis**
Elliot P. Farney and Tehshik P. Yoon*
Abstract: Irradiation of vinyl and aryl azides with visible light
in the presence of Ru photocatalysts results in the formation of
À
reactive nitrenes, which can undergo a variety of C N bond-
forming reactions. The ability to use low-energy visible light
instead of UV in the photochemical activation of azides avoids
competitive photodecomposition processes that have long been
a significant limitation on the synthetic use of these reactions.
T
he use of visible-light-activated transition metal catalysts in
synthesis is presently receiving increased attention.[1] These
methods are attractive both because visible light is easier to
handle than high-energy UV light and because complex
organic molecules are more stable towards photodecomposi-
tion under lower-energy visible light irradiation. Almost all of
the reactions reported to date have involved activation by
photoinduced electron-transfer processes. Recently, we
reported that the same class of transition metal photocatalysts
can also promote cycloaddition reactions using a complemen-
tary energy transfer process.[2,3] The ability to generate
electronically excited organic molecules using visible light
suggested to us that a much broader diversity of reactions
traditionally conducted with high-energy UV light might be
made more operationally accessible and more tolerant of
complex functionality using transition metal photocatalysis.
As a demonstration of this concept, we report herein the
facile, room-temperature generation and rearrangement of
vinyl nitrenes by visible light photocatalytic activation of
azides.
Scheme 1. Photoreduction versus energy transfer photocatalysis for
activation of organic azides.
using Ru(bpy)3 as a photocatalyst [Scheme 1, Eq. (1)].[9]
2+
The key intermediate in this reaction, however, was proposed
to be a nitrene radical anion generated by one-electron
reduction of the azide, and these intermediates do not exhibit
the characteristic reactivity of neutral nitrenes.[10] We won-
dered, therefore, if we might be able to access the powerful
À
C N bond-forming reactivity of nitrenes using visible light
activation by employing transition-metal photocatalysts as
triplet sensitizers of azide decomposition.
As a test of this hypothesis, we investigated the photo-
catalytic transformation of dienyl azides into pyrroles
[Scheme 1, Eq. (2)]. Driver has reported that this overall
transformation can be achieved by Lewis acid catalysis,[11]
although the method is limited to a-azidoesters and does not
tolerate strongly Lewis basic substituents. Driver has pro-
posed a mechanism involving chelate-controlled Schmidt-like
cyclization rather than a discrete nitrene intermediate. This
transformation thus offered an interesting opportunity to test
our mechanistically distinct ideas about photocatalytic acti-
vation of azides. Dienyl azide 1 is insufficiently electron-
deficient to be easily reduced by ruthenium photocatalysts;
Nitrenes are involved in a wide range of carbon–nitrogen
bond-forming reactions, including several that produce het-
erocycles such as aziridines,[4] indoles,[5] and pyrroles.[6] The
photochemical generation of nitrenes from azides is an
attractive strategy that liberates only dinitrogen as a stoichio-
metric byproduct;[7] however, the photolysis of azides with
UV light generally results in poor functional group tolerance
and competitive photodecomposition processes that can
diminish the yield of these reactions.[8] Liu has recently
reported visible-light-induced photoreduction of aryl azides
2+
the reduction potentials of Ru*(bpy)3 and 1, respectively,
are À0.89[12] and À1.81 V[13] versus the saturated calomel
electrode (SCE). On the other hand, we calculated that the
first electronically excited triplet state of 1 (ET = 45.4 kcal
molÀ1)[14] was energetically well poised for sensitization by the
[*] E. P. Farney, Prof. T. P. Yoon
Department of Chemistry, University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
E-mail: tyoon@chem.wisc.edu
long-lived Ru*(bpy)3 triplet state (ET = 46 kcalmolÀ1).
2+
Indeed, irradiation of 1 with blue light in the presence of
several ruthenium polypyridyl photocatalysts (3a–e) resulted
in formation of pyrrole 2 along with a nonisolable compound
we assigned as azirine 4 (Table 1). Despite the fact that the
excited state reduction potentials of the photocatalysts
assayed span almost a volt (À0.05 and À0.94 V vs. SCE for
3b and 3c, respectively),[15] similar levels of conversion were
Homepage: http://yoon.chem.wisc.edu
[**] This research was conducted using funds from the NIH (grant
number GM095666) and the Sloan Foundation. The NMR facilities
at UW-Madison are funded by the NSF (grant number CHE-
1048642).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308820.
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Table 1: Initial investigations on triplet sensitization of dienyl azide 1.
Control experiments demonstrated that both the
photocatalyst and light are required (entries 13 and
14). On the other hand, the reaction can be
conveniently conducted using a variety of visible-
light sources; although blue light-emitting diode
(LED) strips provided somewhat faster rates, reac-
tions irradiated with household light bulbs also
provide good yields (entry 15). Direct photoreac-
tions of 2 using 254 nm UV light suffered from
significant photodecomposition, resulting in much
lower yields and poor overall mass balance
(entry 16), verifying our contention that the ability
to use visible light in these reactions indeed provides
a significant synthetic advantage.
Table 2 summarizes our investigations into the
scope of this transformation. Both electron-rich and
electron-poor aryl substituents can be present on the
dienyl unit, and the corresponding pyrroles can be
isolated in nearly quantitative yields (entries 1–5).
Although heterocyclic substituents are not well
tolerated in Driverꢀs Lewis acid catalyzed process,
these substrates were smoothly transformed to
pyrroles 6d and 6e under photocatalytic conditions.
As expected, aliphatic dienyl azides were compatible
with the reaction conditions (entries 6–8). Vinyl
substitution was also tolerated, affording 6h con-
taining a versatile handle for further synthetic
elaboration (entry 9). Tricyclic fused heterocycles
were accessible from g-substituted azidoacrylates
(entry 10).
Dienyl azides lacking an a-ester substituent are
also readily transformed into pyrroles (entries 11–
13). We found that this class of substrates does not
react under Lewis acid catalyzed conditions, even
after prolonged reaction times, presumably due to
the lack of the chelating moiety involved in the
Schmidt-type activation of the azide. Conversely, 1-
azido-4-phenylbutadiene (5j) undergoes cyclization
to afford pyrrole 6j in excellent yield after 4 h of
irradiation. Aliphatic dienyl azide 5k also underwent
Entry[a]
Catalyst
(loading [mol%])
Solvent
(concentration [m])
t [h]
Yield 2 [%]
(yield 4 [%])[b]
1
2
3
4
5
6
7
8
3a (2.5)
3b (2.5)
3c (2.5)
3d (2.5)
3e (2.5)
3e (2.5)
3e (2.5)
3e (2.5)
3e (2.5)
3e (2.5)
3e (2.5)
3e (1)
MeCN (0.4)
MeCN (0.4)
MeCN (0.4)
MeCN (0.4)
MeCN (0.4)
DMSO (0.4)
acetone (0.4)
CH2Cl2 (0.4)
CHCl3 (0.4)
CHCl3 (0.1)
CHCl3 (0.1)
CHCl3 (0.1)
CHCl3 (0.1)
CHCl3 (0.1m)
CHCl3 (0.1)
MeCN (0.1)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
5
12 (31)
9 (22)
21 (48)
17 (28)
25 (39)
22 (48)
21 (41)
28 (32)
30 (27)
34 (24)
94 (0)
91 (0)
0 (0)
9
10
11
12
13
14c
15d
16e
5
5
5
5
none
3e (1)
3e (1)
none
0 (0)
73 (12)
49 (0)
5
[a] Reactions conducted using 0.25 mmol of 1 under air-free conditions with
irradiation from a blue LED strip unless otherwise noted. [b] Yields determined by
1H NMR analysis using an internal standard. [c] Reaction conducted in the dark.
[d] Reaction irradiated with a 23 W compact fluorescent lightbulb. [e] Reaction
irradiated at 254 nm in a Rayonet reactor.
observed in each case (entries 1–5). This observation would
be surprising for a mechanism involving photoinduced
reduction of 1. On the other hand, it is consistent with
a triplet energy transfer process, as the excited-state triplet
energies of these five photocatalysts are quite similar (45–
47 kcalmolÀ1).[15] We also observed little dependence on
solvent polarity; reactions in chloroform (e = 4.81) and
acetonitrile (e = 36.6) gave similar results (entries 5–9).
These data, too, support an energy transfer mechanism, as
charged radical ion intermediates would be strongly destabi-
lized in nonpolar media. We observed a modest increase in
conversion upon decreasing the concentration of the reaction
(entry 10), and a 5 h reaction time provided complete
conversion to pyrrole 2 (entry 11), which confirmed that 4 is
fully converted to 2 over the course of the reaction. Lowering
the catalyst loading to 1 mol% had little effect on the yield of
the reaction (entry 12), and under these optimized conditions,
irradiation of dienyl azide 1 cleanly produced pyrrole 2 in
91% yield after 5 h of irradiation.
cyclization, although the conversion to pyrrole was modest
after extended irradiation. We attribute the slow rate of
reaction to the higher triplet energy of the less conjugated
dienyl azide, which we computed to be 52 kcalmolÀ1.[14] This
value is somewhat higher than the triplet excited state of
Ru*(dtbbpy)3 (ET = 47 kcalmolÀ1), which would be consis-
2+
tent with inefficient triplet energy transfer. However, the
[Ir(dF(CF3)ppy)2(dtbbpy)]+ complex we had found to be
optimal for visible light triplet sensitization of styrenes has
a
significantly higher-energy triplet state (ET = 61 kcal
molÀ1),[16] and using this photocatalyst, the cyclized pyrrole
product is formed in 70% yield after 12 h. Furthermore,
sensitization of aryl azides proceeded smoothly to afford
indoles (entries 14 and 15). This is noteworthy because direct
photolysis of aryl azides often produces complex mixtures of
products from multiple reaction manifolds.[17] Indeed, direct
irradiation of 5m at 350 nm resulted in complete consumption
of the starting azide within 1 h but produced only 51% yield
of indole 6m as a part of a complex, inseparable mixture.
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Table 2: Study of the substrate scope in the synthesis of pyrroles.
adding 1 equivalent of cyclopentadiene to a photosen-
t [h] Yield [%][a]
sitized reaction of 1, which produced the hetero-Diels–
Entry Substrate
Product
Alder cycloadduct expected from interception of the
=
highly reactive C N moiety in 71% isolated yield and
1
3
4
99
99
as a single diastereomer (Scheme 2). Notably, this
trapping experiment, too, is markedly more efficient
under photocatalytic conditions; the same experiment
conducted by direct UV photolysis at 254 nm produced
only 40% of the trapped hetero-Diels–Alder cyclo-
adduct along with numerous inseparable decomposi-
tion products.
5a
6a
6b
2
5b
3
2.5 95
The azirine can be isolated in cases where subse-
quent ring expansion to the five-membered heterocycle
is slow. For example, irradiation of the aryl-substituted
vinyl azide 8 generates azirine 9 in 90% yield. Azirines
are highly reactive intermediates that can be used in the
synthesis of a variety of heterocyclic compounds.[19] To
highlight the utility of azirines generated under these
conditions, we converted 9 to a variety of substituted
aziridines by addition of nucleophiles and radicals to
5c
6c
6d
4
4
3
98
86
5d
5
5e
6e
2
6
8
11
14
2
93
89
86
89
=
the C N bond (10–12). Hetero-Diels–Alder cycloaddi-
1
tion with cyclopentadiene to afford cycloadduct 13 is
also rapid and high-yielding. Finally, we found that 9
can be easily converted to highly substituted pyrrole 14
by reaction with a stabilized phosphonium ylide.
Scheme 3 outlines our working mechanism for the
photocatalytic generation of pyrrole 2. Irradiation of
Ru(dtbbpy)32+ with visible light produces its long-lived
excited state; exergonic energy transfer to dienyl azide
1 produces triplet 1*, which expels dinitrogen to
produce a nitrene intermediate. Ring-closure affords
azirine 4, which undergoes slow but high-yielding
rearrangement to pyrrole 2.
One of the most intriguing implications of these
investigations is the possibility that visible light photo-
catalysis might provide convenient access to the diverse
reactivity of free nitrenes under exceptionally mild
conditions. As a preliminary demonstration of the
generality of this approach, we examined the photo-
catalytic activation of azidonaphthalene 15 [Eq. (3)].
We calculated the triplet excited-state energy of 15 to
be 62.0 kcalmolÀ1,[14] which suggested that it could be
efficiently sensitized by [Ir(dF(CF3)ppy)2(dtbbpy)]+.
Indeed, visible light irradiation of 15 for 5 h in the
presence of this Ir photocatalyst resulted in the clean
production of aziridine 16, which presumably arises
from intramolecular reaction of the photogenerated
nitrene with the pendant allyl substituent.
7
5 f
6 f
6g
6h
8
5g
9
5h
10
4
96
5i
6i
6j
11
3
92
47
5j
12
36
5k
6k
6l
13b
12
20
70
75
14
5l
15
6
93
In conclusion, we have demonstrated that photo-
catalytic activation of aryl and vinyl azides with visible
light provides a convenient method to access the
chemistry of nitrenes. The ability to use low-energy
5m
6m
[a] Data represent the averaged isolated yields from two reproducible experi-
ments. [b] Conducted using [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1 mol%) as photo-
catalyst.
We were intrigued by the appearance of transitory
intermediate 4 at partial conversions of dienyl azide 1. We
assigned this intermediate as azirine 4 based upon analogy to
the photochemical production of azirines by UV irradiation of
b-styrenyl azides.[18] The identity of azirine 4 was confirmed by
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a broad range of methods for the construction of heterocycles
À
and C N bonds, we anticipate that this approach could be
useful in synthesis, drug discovery, and all of the various fields
in which such structures are important.
Received: October 9, 2013
Published online: November 26, 2013
Keywords: azides · energy transfer · nitrenes ·
.
nitrogen heterocycles · photocatalysis
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visible light in this application minimizes complications
arising from photodecomposition and thus provides uni-
formly higher yields than direct photoexcitation with UV
light. Given the importance of nitrene intermediates in
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