Cyclopentene Annulations of Alkene Radical Cations with Vinyl Diazo Species Using Photocatalysis

Article abstract of DOI:10.1002/anie.201805732

A direct (3+2) cycloaddition between alkenes and vinyl diazo reagents using either Cr or Ru photocatalysis is described. The intermediacy of a radical cation species enables a nucleophilic interception by vinyl diazo compounds, a departure from their trad

Full text of DOI:10.1002/anie.201805732

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Cyclopentene Annulations of Alkene Radical Cations with Vinyl
Diazo Species Using Photocatalysis
Authors: Francisco J. Sarabia, Qiankun Li, and Eric M. Ferreira
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805732
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10.1002/anie.201805732
Angewandte Chemie International Edition
COMMUNICATION
Cyclopentene Annulations of Alkene Radical Cations with Vinyl
Diazo Species Using Photocatalysis
Francisco J. Sarabia,+ Qiankun Li,+ and Eric M. Ferreira*
Abstract: A direct (3+2) cycloaddition between alkenes and vinyl
diazo reagents using Cr or Ru photocatalysis is described. The
intermediacy of a radical cation species enables a nucleophilic
interception by vinyl diazo compounds, a departure from their
traditional electrophilic behavior. A variety of cyclopentenes are
synthesized using this method, and experimental insights implicate a
direct cycloaddition instead of a cyclopropanation/rearrangement
cascade process.
engender direct and single-step reactivity with the less
nucleophilic vinyl diazo species. Toward this goal of developing
valuable (3+2) cycloaddition methods, herein we report a novel
cyclopentene annulation process of vinyl diazo reagents
mediated by Cr and Ru photoredox catalysis, with evidence
implicating
a
direct
cycloaddition
instead
of
a
cyclopropanation/rearrangement cascade.
Previous Work
a. Carbene/carbenoid-based cycloaddition
Cycloadditions represent one of the most widely employed
strategies for efficient molecule synthesis, emblematic of their
strengths in convergency and regio- and stereocontrol. In
comparison to the venerable Diels-Alder (4+2) cycloaddition for
cyclohexene construction, the formation of cyclopentenes via
CO2R
RO2C
RO2C
[M]
RO
OR
N2
[M]
electrophilic
intermediate
b. Enone cyclopentannulation
OTBS
OTBS
R
O
O
O
CO2Me
O
O
[Cu]
(3+2)
pathways
is
more
limited
in
prominence.[1]
R
MeO
R
TBSOTf
MeO
OTBS
N2
enol diazoacetate
Stereochemically and functionally diverse five-membered
carbocycles are common cores in many bioactive and functional
molecules (e.g., rocaglamide, chromodorolide B, merrilactone
A),[2] and developments for their direct and convergent
N2
This Work - Direct Radical Cation-Based [3+2] Cycloaddition
[Cr] or [Ru]
photocatalytic
[O]
RO2C
CO2R
R
N2
R
R
R
R
diazo reagent
as nucleophile
light
construction can be highly enabling.
Vinyl and enol
R
diazocarbonyl compounds are one such reagent that can serve
as the 3-carbon component of a (3+2) cycloaddition.[3] These
species have engaged in reactivity generally through metal
carbene/carbenoid intermediacy. Here, diazo decomposition
using Rh, Cu, or Au catalysis generates an electrophilic carbene
species that can undergo the addition with alkenes.[4,5]
Consequently, the electrophilic activation has generally
necessitated the use of nucleophilic C=C partners, such as enol
ethers, indoles, or vinyl azides (Figure 1a).[6,7] An alternative
cyclopentene (3+2) approach would utilize a vinyl diazo reagent
as a nucleophile. There have been isolated reports of vinyl
diazo nucleophilicity with activated C=X and X=Y systems (e.g.,
oxocarbenium, iminium, LA-activated iodosyl).[8,9] Guerrero and
coworkers demonstrated cycloaddition reactivity in principle in a
cyclopentannulation pairing enol diazoacetates with conjugate
acceptors (Figure 1b).[10] This net transformation involves a two-
step sequence of TBSOTf-mediated conjugate addition, and
cyclopropanation/ring opening to access the cyclopentene unit.
A direct cyclopentene annulation using vinyl diazocarbonyl
compounds as nucleophiles, however, has not been
Figure 1. Cyclopentene formations from vinyl diazo (3+2) cycloadditions.
The emergence of photoredox catalysis has sparked broad
interest in their diverse transformations and their intriguing
mechanistic pathways.[11] Diazo reagents in these processes
have seen limited use thus far.[12] As part of our program toward
developing earth-abundant metals in photoredox catalysis, we
recently described a Cr-catalyzed cyclopropanation between
diazocarbonyl compounds and alkenes.[12c]
This reaction
proceeds via alkene oxidation to a radical cation intermediate by
the excited state Cr complex.[13] We were curious whether vinyl
diazo species would be able to undergo similar reactions to give
cyclopentene compounds;[14] the process could be conceived to
proceed
via
initial
cyclopropanation,
followed
by
vinylcyclopropane rearrangement.[15]
Alternative, direct
processes could also be possible, which would in turn raise
further questions of regioselectivity in the cyclopentene
formation (vide infra).
demonstrated.
We hypothesized that generating a more
Our initial study of this reaction is outlined in Scheme 1.
Using vinyl diazoacetate 2a with trans-anethole (1a) as the
alkene substrate, we found that our catalytic chromium
reactive electrophilic 2-carbon partner (i.e., a radical cation) may
conditions (Cr: [Cr(Ph2phen)3](BF4)3, CH3NO2, 23
indeed provided cyclopentene 3aa in excellent yield. Notably,
W CFL)
[*]
F. J. Sarabia, Dr. Q. Li, Prof. Dr. E. M. Ferreira
Department of Chemistry
University of Georgia
Athens, GA 30602 (USA)
E-mail: emferr@uga.edu
this product was observed as a single diastereomer and with
exclusive regioselectivity.
Some deviations from these
conditions were relevant, while others had minimal effects.
Fewer than 2 equiv of the vinyl diazo reagent was detrimental to
yield. Near UV irradiation was acceptable, but both blue and
white LEDs afforded diminished yields. Both light and the
[+]
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201805732
Angewandte Chemie International Edition
COMMUNICATION
CO2Et
R1
Cr or Ru
(1.5 – 3 mol %)
R1
R2
photoredox catalyst were essential to reactivity; the simple CrCl3
salt did not catalyze the cyclopentene annulation. Interestingly,
Ar
R3
EtO2C
>19:1 dr
(unless
noted
Ar
R2
N2
CH3NO2/CH2Cl2
23 W CFL
R3
otherwise)
the
highly
oxidizing
ruthenium
photocatalyst
Ru
1
2aa (~2–4 equiv)
3
3aa[b] (R = Me)
Cr: 92% yield
([Ru(bpz)3](PF6)2) was also effective, with considerably shorter
reaction times. Substantially lower catalyst loadings (0.2 mol %)
were detrimental for Cr, but less so for Ru. In comparison to the
photocatalytic systems, reactions that proceed through
carbene/carbenoid manifolds[3-5] were inferior (0-23% yield).
Given the previously observed differential behavior of these two
oxidizing photocatalysts,[16] we decided to pursue both in the
subsequent reaction scope studies.
3ba (R = n-Pr)
Cr: 69% yield
(3 equiv, 2 mol %, 41 h)
Ru: 85% yield,
(3 equiv, 2.5 mol %, 6 h)
3ca (R = i-Pr)
Cr: 37% yield
(3 equiv, 2 mol %, 60 h)
Ru: 56% yield,
(4 equiv, 3 mol %, 25 h)
CO2Et
PMP
R
(2 equiv, 1.5 mol %, 16 h)
Cr: 91% yield
(2 equiv, 2 mol %, 25 h[c]
)
3da[d] (R = cyclopropyl)
Cr: 17% yield
(4 equiv, 3 mol %, 49 h)
Ru: 60% yield
Ru: 93% yield
(2 equiv, 1.5 mol %, 1 h)
(4 equiv, 3 mol %, 28 h)
3ga (p-OMOM)
3fa (R = p-OTBS)
Cr: 57% yield
(3 equiv, 2 mol %, 47 h)
Ru: 72% yield
3ea (R = p-OBn)
Cr: 66% yield
(3 equiv, 2 mol %, 39 h)
Ru: 79% yield
(2 equiv, 1.5 mol %, 16 h)
Cr: 69% yield
(3 equiv, 2 mol %, 31 h)
Ru: 67% yield
R
CO2Et
(3 equiv, 2.5 mol %, 8 h) (3 equiv, 2.5 mol %, 8 h)
3ha (p-Me)
Cr: 16% yield
(3 equiv, 2 mol %, 45 h)
Ru: 0% yield
(2 equiv, 1.5 mol %, 19 h)
3ia (o-OMe)
Cr: 57% yield
(3 equiv, 2 mol %, 41 h)
Ru: 58% yield
(4 equiv, 3 mol %, 24 h)
Standard Conditions:
CO2Et
Me
PMP
EtO2C
PMP
Cr (1.5 mol %)
+
N2
2a
(2 equiv)
CH3NO2/CH2Cl2 (~5:1)
23 W CFL, 18 h
Me
Me
3aa (>19:1 dr)
1a
MeO
O
CO2Et
CO2Et
CO2Et
H
NMR yield
(%)[a]
NMR yield
(%)[a]
Deviation from
Standard Conditions
Deviation from
Standard Conditions
CO2Et
N
NONE
89 (92[b,c]
)
MeO
99 (93[b]
)
1.5 mol % Ru, 1 h
Me
Me
3ma
Cr: 55% yield
(3 equiv, 2 mol %, 44 h)
Ru: 47% yield
H
1 equiv 2a
57
84
0.2 mol % Ru, 1.5 h
88
3 equiv 2a
NUV[d]
3ka[b]
Cr: 10% yield
(3 equiv, 2 mol %, 48 h)
Ru: 52% yield
(4 equiv, 3 mol %, 24 h)
3ja
3la
Cr: 87% yield
5 mol % [IPr(CH3CN)Au]BF4
CH2Cl2, 23 °C, 24 h
23
Cr: 66% yield
(4 equiv, 2 mol %, 48 h)
Ru: 69% yield
87
75
74
86
(3 equiv, 2 mol %, 17 h)
Ru: 71% yield
(2 equiv, 1.5 mol%, 1 h)
blue LED, 37 h
white LED, 37 h
1 mol % Cr
2 mol % Rh2(OAc)4
CH2Cl2, 40 °C, 5 h
0
(4 equiv, 3 mol %, 4 h)
(4 equiv, 3 mol %, 24 h)
10 mol % AgSbF6
CH2Cl2, 40 °C, 4 h[e]
19
0.2 mol % Cr, 42 h
24
0
0
PMP
CO2Et
3oa[b] (n = 2)
Cr: 70% yield
(3 equiv, 2 mol %, 35 h)
Ru: 64% yield
3pa (n = 3)
Cr: 71% yield
(2 equiv, 1.5 mol %, 9 h)
Ru: 65% yield
(2 equiv, 1.5 mol %, 4 h)
3na (n = 1)
Cr: 38% yield
10 mol % CrCl3
no catalyst
no light
[f]
1.5 mol % Cu(t-BuSal)2
DCE, 84 °C, 4 h
(3 equiv, 2 mol %, 41 h)
Ru: 59% yield
(2 equiv, 1.5 mol %, 4 h)
0
0
PMP: para-methoxyphenyl. [a] 1H NMR yields determined using 2-naphthaldehyde as a standard.
n
(2 equiv, 1.5 mol %, 3 h)
H
[b] Isolated yield in parentheses. [c] 16 h. [d] Near-UV light (bulbs at 300, 350, and 419 nm). [e] 4.9:1
stoichiometry of 1a:2a used. [f] Cu(t-BuSal)2: copper bis(N-t-butylsalicylaldimine).
3qa[b,e]
3ra[b]
PMP
CO2Et
CO2Et
PMP
Ph
Cr: 69% yield, 6.6:1 dr
(3 equiv, 2 mol % 26 h)
Ru: 81% yield, 7.1:1 dr
(2 equiv, 1.5 mol %, 4 h)
Cr: 76% yield
Cr
[Cr(Ph2phen)3](BF4)3
Ph
Ru
[Ru(bpz)3](PF6)2
N
Me
(2 equiv, 1.5 mol %, 14 h)
Ru: 89% yield
(2 equiv, 1.5 mol %, 2 h)
(BF4
)
3
(PF6
)
2
Ph
N
N
N
N
Me
t-Bu
H
N
N
N
N
N
N
N
Cr
Ru
N
[a] Acyclic alkene substrates were pure E-isomers. PMP: para-methoxyphenyl. [b] Relative stereochemistry
confirmed by NOE. [c] Gram scale reaction. [d] Alkene substrate 1.5:1 E/Z. [e] Major diastereomer drawn.
N
N
N
N
N
Ph
Ph
Ph
Scheme 2. Photocatalyzed (3+2) cycloaddition - Alkene scope.
Scheme 1. Reaction optimization.
Diazo variation was also examined (Scheme 3). Other
diazoesters were largely effective to afford cyclopentenoates,
including activated phenyl ester 3ad. Ketones were tolerated
with the Ru system (3ae). β-Alkyl and β-aryl substitutions on the
diazo reagent were also tolerated.
A variety of cyclopentenes could be synthesized via this
(3+2) cycloaddition. We found that 1.5-3 mol % catalyst loading,
and ~2-4 equiv of the diazo reagent were sufficient for effective
reactivity across several substrates evaluated (Schemes 2 and
3). Alkene variation is presented in Scheme 2. The main
requirement is an electron rich substituent to facilitate single
electron oxidation of the alkene species. Acyclic disubstituted
alkenes afforded the trans-substituted cyclopentene compounds.
Oxygenated arenes were optimal for this requirement, as the
aromatic group could be substituted with alkyl ethers, silyl ethers,
and acetals. An alkyl arene was only modestly reactive with the
COR1
R2
Cr or Ru
(1.5 – 3 mol %)
R2
O
PMP
PMP
Me
R1
CH3NO2/CH2Cl2
23 W CFL
Me
N2
1a
CO2t-Bu
2 (2–4 equiv)
3, >19:1 dr
CO2Bn
CO2Ph
COPh
PMP
Me
PMP
PMP
Me
PMP
Me
Me
3ab
3ac
3ad
Cr: 46% yield
(4 equiv, 3 mol %, 72 h) (2 equiv, 1.5 mol %, 25 h)
Ru: 74% yield
(2 equiv, 1.5 mol %, 1 h)
3ae
Cr: <5% yield
Cr complex and unreactive with the Ru catalyst (3ha).
A
Cr: 94% yield
(2 equiv, 1.5 mol %, 17 h)
Ru: 99% yield
Cr: 78% yield
(4 equiv, 2 mol %, 48 h)
Ru: 78% yield
carbazole-based enamine could engage in the cycloaddition to
afford nitrogenated cyclopentene 3ja. Both spirocyclic and
fused ring systems can also be synthesized via this
cycloaddition (3ka-3qa). In both families of ring systems, very
Ru: 61% yield
(4 equiv, 3 mol %, 24 h)
(3 equiv, 2.5 mol %, 19 h)
(2 equiv, 1.5 mol %, 1 h)
CO2Et
PMP
CO2Et
CO2Et
CO2Et
PMP
PMP
Me
PMP
Me
Me
Ph
CF3
high diastereoselectivities can be achieved.[17]
Acyclic
Me
Me
Me
3ag
3af
3ai
3ah
Cr: 62% yield
(3 equiv, 2 mol %, 8 h)
Ru: 92% yield
Cr: 56% yield
(2 equiv, 2 mol %, 46 h)
Ru: 90% yield
Cr: <5% yield
Cr: 34% yield
(4 equiv, 3 mol %, 41 h)
Ru: 96% yield
trisubstituted alkenes are also competent reactants (3ra).
(2 equiv, 1.5 mol%, 25 h)
Ru: 68% yield
(4 equiv, 3 mol %, 24 h)
(2 equiv, 1.5 mol %, 4 h) (3 equiv, 2.5 mol %, 4 h) (2 equiv, 1.5 mol %, 4 h)
PMP: para-methoxyphenyl
Scheme 3. Photocatalyzed (3+2) cycloaddition - Diazo scope.
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10.1002/anie.201805732
Angewandte Chemie International Edition
COMMUNICATION
A few additional constraints were noted in our evaluation
(Scheme 4). Tetrasubstituted alkene 1s and stilbene (1t) were
unreactive, likely due to steric hindrance. Enol diazoacetate 2j
was not productive, presumably because of competitive enol
oxidation by the catalyst. Finally, γ-substitution on the diazo
reagent was not tolerated. This limitation could also be due to
steric considerations, although we also found background
pyrazole formation mediated by heat/light (eq 1)[18] was
particularly fast in these cases.[19] Adding the diazo reagent in
up to three portions over the course of the reaction was
generally beneficial to minimize background processes.[20]
Information toward mechanistic elucidation was accrued
experimentally. We subjected two vinylcyclopropanes, from
potential direct (5) or vinylogous (6) addition, to the reaction
conditions (eq 2). From either compound, there was no
formation of the cyclopentene product (3aa), thereby eliminating
this potential pathway. When cis-anethole (1acis) is subjected to
the standard catalytic conditions, the trans product (3aa) is the
only diastereomer observed (eq 3). Trans-anethole was not
recovered when this transformation was run partway, suggestive
that a bond rotation occurs along the reaction pathway that
ultimately leads to the single diastereomer. This observed
stereoconvergency validates the likely intermediacy of species 7,
where the second bond forming event then establishes the high
stereoselectivity. Figure 3 depicts the favorability of the trans-
substituted product via intermediate 7; in the favored conformer
the PMP group has only one gauche interaction instead of two.
Finally, when we subjected independently-synthesized diazo
cyclobutane 11 to the photocatalytic conditions, cyclopentene
3aa was formed in essentially quantitative yield (eq 4).[26] We
have not observed this cyclobutane compound in reaction
mixtures, but given the comparatively rapid formation of 3aa
from 11 it could exist as an off-cycle product. We presently
favor the 5-endo pathway due to the formation of a less strained
intermediate;[27] further experimentation will elucidate whether
either (or both) of these pathways are indeed viable.[28]
O
OTBS
O
O
PMP
Me
Me
Me
Ph
CO2Et
Ph
EtO
EtO
EtO
Ph
N2
N2
2k
N2
1s
1t
EtO2C
2j
2l
R
EtO2C
R
heat/light
(1)
N2
N NH
Scheme 4. Observed reaction constraints.
Mechanistic possibilities considered for this transformation
are depicted in Figure 2, using trans-anethole and ethyl vinyl
diazoacetate as model reagents. The excited state catalyst
oxidizes the alkene to form radical cation 4, consistent with
measured reduction potentials.[21,22] At this stage, one scenario
would involve cyclopropanation on C(α) or C(γ) of the diazo
reagent, followed by vinylcyclopropane rearrangement and
isomerization to the enoate. We have ruled out this possibility
(vide infra). Alternatively, the vinyl diazo reagent can attack
electron deficient intermediate 4 as a nucleophile.[8,23] Benzylic
radical stabilization of the resulting intermediate (7) would offer a
rationale for the observed high regioselectivity.[24,25] A 5-endo
radical cyclization generates intermediate 8. Reduction of this
species and loss of N2 produces the observed cyclopentene.
Another possible pathway from intermediate 7 would involve a 4-
exo cyclization to species 9. Ring expansion with concomitant
loss of N2, and reduction would afford the observed
cyclopentene. If expansion is not immediate, an off-cycle
reduction of intermediate 9 would yield cyclobutane 11.
CO2Et
PMP
Me
PMP
Me
CO2Et
PMP
Me
Cr or Ru (1.5 mol %)
(2)
or
CH3NO2/CH2Cl2
23 W CFL
CO2Et
5
6
3aa
not observed
Cr (2 mol %) or
Ru (1.5 mol %)
CO2Et
PMP
Me
EtO2C
PMP
Me
+
(3)
(4)
N2
2a
CH3NO2/CH2Cl2, 23 W CFL
Cr: 58% yield, 56 h
Ru: 66% yield, 1.5 h
1acis
3aa
(2-3 equiv)
N2
CO2Et
Cr or Ru (1.5 mol %)
PMP
Me
PMP
Me
CO2Et
CH3NO2/CH2Cl2, 23 W CFL
Cr: 99% yield, 6 h / Ru: >99% yield, 1 h
11
3aa
CO2Et
H
PMP
Me
PMP
Me
CO2Et
CO2Et
PMP
H
H
H
N2
N2
Me
CO2Et
N2
disfavored
7
favored
3aa
(trans-isomer)
PMP
Me
PMP
Me
CO2Et
2a
or
cyclopropanation
vinylcyclopropane
rearrangement/
isomerization
CO2Et
[M]
light
5
6
Figure 3. Conformational analysis of intermediate 7.
CO2Et
N2
CO2Et
N2
CO2Et
PMP
PMP
N2
[M]*
PMP
PMP
Me
2a
PMP
CO2Et
- N2
[M]
nucleophile
attack
5-endo
cyclization
Me
Me
N2
reduction
8
Me
3aa
Me
7
1a
4
In general, the cycloaddition reaction times for the ruthenium
catalyst were shorter than those for the chromium catalyst.
Reduction potentials for the two metal catalyst excited states
4-exo
cyclization
cyclobutyl carbinyl
fragmentation
N2
[M]
reduction
CO2Et
[M]
reduction
PMP
PMP
- N2
ring
PMP
CO2Et
CO2Et
[M]
oxidation
suggest similar reactivity would be expected.[21]
In the
expansion
Me
Me
11
9
10
Me
3+
]
E*1/2 = +1.33 V
E*1/2 = +1.45 V
1a
2a
Eox = +1.13 V
Eox = +1.57 V
previously studied radical cation (4+2) cycloadditions, there have
been observed mechanistic differences that appear to reflect
radical chain (Ru) vs. photocatalyst turnover (Cr) processes,[16,29]
that may extrapolate to observed differences here. We have
observed reactivity distinctions between the Cr-catalyzed (4+2)
and these (3+2) reactions;[30] further studies will seek to
establish photocatalyst roles in both the Ru and Cr systems.
[Cr(Ph2phen)3
Red. potentials (vs. SCE)
2+
]
[Ru(bpz)3
Figure 2. Proposed mechanism for cyclopentene annulation.
This article is protected by copyright. All rights reserved.

10.1002/anie.201805732
Angewandte Chemie International Edition
COMMUNICATION
The cycloaddition products can also be readily diversified;
representative transformations of compound 3aa are shown in
Scheme 5. Enoate cyclopropanation and epoxidation both occur
Acknowledgements
This work was supported by the NSF and EPA through the
Catalysis Collaboratory for Light-Activated Earth Abundant
Reagents (C-CLEAR) (CHE-1339674). F.J.S. is supported by
the NSF Graduate Research Fellowship Program (038550-02).
Mass spectrometry data was acquired on an instrument
supported by the NIH (S10RR028859). We thank Prof. Todd
Harrop and Phan Truong for assistance with electrochemical
measurements.
with
excellent
diastereoselectivity.
Both
allylic
halogenation/azidation and oxidation[31] functionalize the γ-
methylene. Michael additions and deconjugative alkylations
were also successful, both in high diastereoselectivity. Diol 18
can be attained in excellent dr, and it can be further transformed
into piperidine 19 via oxidative cleavage and reductive amination.
Cycloaddition with TMS-diazomethane[32] works well, and a
further desilylative elimination yields aminonitrile 21. Reduction
to alcohol 22 followed by Johnson orthoester Claisen
Keywords: chromium • cycloaddition • diazo compound •
rearrangement affords alkene 23.
Diastereoselective
photocatalysis • ruthenium
hydrogenation affords ester 24;[33] importantly, the electron-rich
arene can be oxidatively converted to carboxylic acid 25,
illustrating substrate requirements we observe in radical cation
formation are ultimately not restrictive in accessing product
diversity.
[1]
[2]
[3]
N. Iwasawa, Thermal and Metal-Induced [3+2] Cycloadditions. In
Comprehensive Organic Synthesis II (Eds.: P. Knochel, G. A.
Molander), Elsevier, Amsterdam, 2014; vol. 5, pp 273-350.
For
a recent review of cyclopentane natural product synthesis
approaches, see: Ferreira, A. J.; Beaudry, C. M. Tetrahedron 2017, 73,
965.
CO2Et
CO2Et
CO2Et
X
PMP
Me
PMP
Me
For recent reviews on the use of vinyl and enol diazocarbonyl
compounds, see: a) Q. -Q. Cheng, Y. Deng, M. Lankelma, M. P. Doyle,
Chem. Soc. Rev. 2017, 46, 5425; b) E. López, S. González-Pelayo, L.
A. López, Chem. Rec. 2017, 17, 312; c) Q. -Q. Cheng, Y. Yu, J.
Yedoyan, M. P. Doyle, ChemCatChem 2018, 10, 488.
PMP
Me
12 (X = O)
66%, >19:1 dr
13 (X = CH2)
61%, >19:1 dr
14, 45%
1.3:1 dr
15, 51%
N3
O
(a) or (b)
(d)
(c)
CO2Et
CO2Et
EtO2C
PMP
[4]
For seminal examples using vinyl diazocarbonyls, see: a) H. M. L.
Davies, B. Hu, Tetrahedron Lett. 1992, 33, 455; b) H. M. L. Davies, B.
Hu, E. Saikali, P. R. Bruzinski, J. Org. Chem. 1994, 59, 4535; c) H. M. L.
Davies, B. Xiang, N. Kong, D. G. Stafford, J. Am. Chem. Soc. 2001,
123, 7461; d) Y. Lian, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132,
440; e) J. F. Briones, H. M. L. Davies, J. Am. Chem. Soc. 2013, 135,
13314; f) E. López, G. Lonzi, J. González, L. A. López, Chem. Commun.
2016, 52, 9398; g) E. López, J. González, L. A. López, Adv. Synth.
Catal. 2016, 358, 1428; h) E. López, L. A. López, Angew. Chem. Int. Ed.
2017, 56, 5121; Angew. Chem. 2017, 129, 5203; i) E. López, G. Lonzi,
L. A. López, Synthesis 2017, 49, 4461.
PMP
Ph
PMP
(e)
(f)
NO2
(g)
Me
Me
Me
17, 99%, >19:1 dr
(m)
3aa
16, 76%
(i)
(k)
H
N
CO2Et
OH
CH2OH
CO2Et
EtO2C
N
H
PMP
Me
PMP
Me
PMP
Me
PMP
OH
TMS
22, 97%
24, 99%
Me
18, 87%
20, 98%
11:1 dr
1.4:1 dr
(h)
(j)
(l)
(n)
CO2Et
CO2Et
NH2
CO2Et
[5]
For seminal examples using enol diazocarbonyls, see: a) A. G. Smith,
H. M. L. Davies, J. Am. Chem. Soc. 2012, 134, 18241; b) X. Xu, J. S.
Leszczynski, S. M. Mason, P. Y. Zavalij, M. P. Doyle, Chem. Commun.
2014, 50, 2462; c) Y. Deng, M. V. Yglesias, H. Arman, M. P. Doyle,
Angew. Chem. Int. Ed. 2016, 55, 10108; Angew. Chem. 2016, 128,
10262; d) C. Jing, Q. -Q. Cheng, Y. Deng, H. Arman, M. P. Doyle, Org.
Lett. 2016, 18, 4550; e) Y. Deng, L. A. Massey, Y. A. Rodriguez Núñez,
H. Arman, M. P. Doyle, Angew. Chem. Int. Ed. 2017, 56, 12292; Angew.
Chem. 2017, 129, 12460.
PMP
Me
PMP
Me
HO2C
Me
PMP
N
Ph
CN
CO2Et
Me
19, 24% (+12%)
21, 99%
23, 87%, 2.1:1 dr
25, 78%, 13:1 dr
Scheme 5. Cycloaddition product diversification. Reagents: a) m-CPBA; b)
Me3S(O)I, NaH; c) NBS, AIBN, then NaN3; d) Pd(OH)2/C, TBHP, K2CO3; e)
CH3NO2, DBU; f) KHMDS, BnBr, HMPA; g) OsO4, NMO; h) Pb(OAc)4, then
NaBH3CN, BnNH2, AcOH; i) Me3SiCHN2, n-BuLi; j) TsOH; k) DIBAL; l)
MeC(OEt)3, PivOH; m) Pd/C, H2; n) RuCl3·3H2O, NaIO4.
[6]
C=O and C=N bonds have also been utilized as the 2-atom component
to form heterocycles. For examples, see: a) M. P. Doyle, W. Hu, D. J.
Timmons, Org. Lett. 2001, 3, 3741; b) M. P. Doyle, M. Yan, W. Hu, L. S.
Gronenberg, J. Am. Chem. Soc. 2003, 125, 4692; c) J. Barluenga, G.
Lonzi, L. Riesgo, L. A. López, M. Tomás, J. Am. Chem. Soc. 2010, 132,
13200.
In summary, we have developed a photocatalyzed (3+2)
cycloaddition between alkenes and vinyl diazo compounds.
Both Ru and Cr complexes catalyze this reactivity, and the
transformation appears to proceed via vinyl diazo nucleophilic
interception of a radical cation. High diastereoselectivities are
obtained in the transformation, and the cycloadducts are readily
diversified. To our knowledge, this is the first report of a vinyl
diazo species reacting with a radical cation electrophile. We
anticipate this reaction can serve as an excellent platform for
accessing an array of cyclopentane-based compounds; further
mechanistic studies, expansions toward enantioselective
variants, and applications in chemical synthesis are currently
underway.
[7]
[8]
For a related (3+2) cycloaddition between aryl diazoacetates and
alkynes, see: E. J. Park, S. H. Kim, S. Chang, J. Am. Chem. Soc. 2008,
130, 17268.
For isolated cases of vinyl diazo nucleophilicity, see: a) ref 6b; b) J.
Barluenga, G. Lonzi, L. Riesgo, M. Tomás, L. A. López, J. Am. Chem.
Soc. 2011, 133, 18138; c) A. M. Jadhav, V. V. Pagar, R. -S. Liu, Angew.
Chem. Int. Ed. 2012, 51, 11809; Angew. Chem. 2012, 124, 11979; d) V.
V. Pagar, A. M. Jadhav, R. -S. Liu, J. Org. Chem. 2013, 78, 5711; e) V.
V. Pagar, R. -S. Liu, Org. Biomol. Chem. 2015, 13, 6166; f) G. Xu, C.
Zhu, W. Gu, J. Li, J. Sun, Angew. Chem. Int. Ed. 2015, 54, 883; Angew.
Chem. 2015, 127, 897.
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[9]
The enol subunit of an enol diazocarbonyl has been invoked as a
[19] Pyrazole formation was also observed in minute amounts in reactions
using non-γ-substituted vinyl diazo compounds.
nucleophile (e.g., Mukaiyama aldol-type, etc.).
discussion and references.
See ref 3a for
[20] See the Supporting Information for details.
[10] a) M. Del Bel, A. Rovira, C. A. Guerrero, J. Am. Chem. Soc. 2013, 135,
12188; b) For a related example in synthesis, see, S. -H. Hou, Y. -Q. Tu,
L. Liu, F. -M. Zhang, S. -H. Wang, X. -M. Zhang, Angew. Chem. Int. Ed.
2013, 52, 11373; Angew. Chem. 2013, 125, 11583.
[21] Measurements: [Cr(Ph2phen)3]3+ in CH3NO2 (ref 17); [Ru(bpz)3]2+ in
CH3CN (ref 11a); 1a in CH3NO2 (ref 17); 2a in CH3NO2 (Supporting
Information).
[22] Interestingly, the (3+2) could also be mediated using Bauld’s oxidizing
triarylaminium catalyst, albeit in moderate yield (47%). See the
Supporting Information.
[11] For select reviews, see: a) C. K. Prier, D. A. Rankic, D. W. C.
MacMillan, Chem. Rev. 2013, 113, 5322; b) J. Xuan, W. -J. Xiao,
Angew. Chem. Int. Ed. 2012, 51, 6828; Angew. Chem. 2012, 124,
6934; c) J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev.
2011, 40, 102; d) R. A. Angnes, Z. Li, C. R. D. Correia, G. B. Hammond,
Org. Biomol. Chem. 2015, 13, 9152; e) T. P. Yoon, ACS Catal. 2013, 3,
895.
[23] The scheme depicts the nucleophile attack on the alkene radical cation
by 2a as a 2-electron process, consistent with analogous proposed 2-
electron attacks on similar species. For example, see, F. Wu, L. Wang,
J. Chen, D. A. Nicewicz, Y. Huang, Angew. Chem. Int. Ed. 2018, 57,
2174; Angew. Chem. 2018, 130, 2196.
[12] a) X. Huang, R. D. Webster, K. Harms, E. Meggers, J. Am. Chem. Soc.
2016, 138, 12636; b) K. Rybicka-Jasinska, L. W. Ciszewski, D. Gryko,
Adv. Synth. Catal. 2016, 358, 1671; c) F. J. Sarabia, E. M. Ferreira, Org.
Lett. 2017, 19, 2865.
[24] Vinyldiazo 2a could also be conceived as a 1-electron reactant, which
has been invoked for non-vinyl diazo esters and other diazo
compounds. This radical mode of nucleophilic attack essentially yields
resonance forms of intermediate 7/8, which may or may not be more
significant contributors to the hybrid depending on specific substitution
patterns. For isolated examples invoking non-vinyl diazo esters and
other diazo compounds as 1-electron reactants, see: a) ref 12b; b) H. -
S. Dang, B. P. Roberts, J. Chem. Soc., Perkin Trans. 1 1996, 769; c) Y.
Li, C. Chen, F. Li, L. Liao, L. Liu, Polym Chem. 2017, 8, 2881; d) Y.
Wang, X. Wen, X. Cui, L. Wojtas, X. P. Zhang, J. Am. Chem. Soc. 2017,
139, 1049.
[13] For reports of this process using triarylaminium catalysts, see: a) G.
Stufflebeme, K. T. Lorenz, N. L. Bauld, J. Am. Chem. Soc. 1986, 108,
4234; b) N. L. Bauld, G. W. Stufflebeme, K. T. Lorenz, J. Phys. Org.
Chem. 1989, 2, 585; c) W. Yueh, N. L. Bauld, J. Am. Chem. Soc. 1995,
117, 5671.
[14] For
a
photoredox-catalyzed
(3+2)
cycloaddition
between
acylcyclopropanes and alkenes, see: Z. Lu, M. Shen, T. P. Yoon, J. Am.
Chem. Soc. 2011, 133, 1162.
[25] This regioselectivity could not be forced in the other direction via
intramolecular tethering. See the Supporting Information for details.
[26] Both catalyst and light were necessary for this rearrangement.
[27] 5-endo radical cyclizations are rare but have been reported.
[28] For additional mechanistic discussion, see the Supporting Information.
[29] M. A. Cismesia, T. P. Yoon, Chem. Sci. 2015, 6, 5426.
[30] In contrast to the Cr-catalyzed (4+2) cycloadditions, O2 was not
beneficial for this reaction.
[15] a) For a review, see: J. E. Baldwin, Chem. Rev. 2003, 103, 1197; b)
For an example of a radical-cation based VCP rearrangement, see, J. P.
Dinnocenzo, D. A. Conlon, J. Am. Chem. Soc. 1988, 110, 2324.
[16] R. F. Higgins, S. M. Fatur, S. G. Shepard, S. M. Stevenson, D. J.
Boston, E. M. Ferreira, N. H. Damrauer, A. K. Rappé, M. P. Shores, J.
Am. Chem. Soc. 2016, 138, 5451.
[17] The diastereoselectivity observed in spirocycles 3la and 3ma likely
arises due to similar principles as those in the 1,2-trans substituted
alkenes. The diastereoselectivity of 3qa presumably arises from
preferential facial attack opposite the large t-Bu group.
[31] J. -Q. Yu, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 3232.
[32] M. O’Connor, C. Sun, D. Lee, Angew. Chem. Int. Ed. 2015, 54, 9963;
Angew. Chem. 2015, 127, 10101.
[18] a) E. C. Taylor, I. J. Turchi, Chem. Rev. 1979, 79, 181; b) R. Huisgen,
Angew. Chem. Int. Ed. Engl. 1980, 19, 947; Angew. Chem. 1980, 92,
979.
[33] Mg/MeOH reduction afforded a ~1:1 mixture of diastereomers, and the
other diastereomer could then be obtained pure after ester cleavage.
See the Supporting Information for details.
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Francisco J. Sarabia, Qiankun Li, and
Eric M. Ferreira*
Page No. – Page No.
Cyclopentene Annulations of Alkene
Radical Cations with Vinyl Diazo
Species Using Photocatalysis
A radical departure: A direct (3+2) cycloaddition between alkenes and vinyl diazo
reagents using Cr or Ru photocatalysis is described. The intermediacy of a radical
cation species enables a nucleophilic interception by vinyl diazo compounds, a
significant deviation from their traditional electrophilic behavior.
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