Metalloradical approach to 2H -chromenes

Article abstract of DOI:10.1021/ja4111336

Cobalt(III)-carbene radicals, generated through metalloradical activation of salicyl N-tosylhydrazones by cobalt(II) complexes of porphyrins, readily undergo radical addition to terminal alkynes to produce salicyl-vinyl radical intermediates. Subsequent hydrogen atom transfer (HAT) from the hydroxy group of the salicyl moiety to the vinyl radical leads to the formation of 2H-chromenes. The Co(II)-catalyzed process can tolerate various substitution patterns and produces the corresponding 2H-chromene products in good isolated yields. EPR spectroscopy and radical-trapping experiments with TEMPO are in agreement with the proposed radical mechanism. DFT calculations reveal the formation of the salicyl-vinyl radical intermediate by a metalloradical-mediated process. Unexpectedly, subsequent HAT from the hydroxy moiety to the vinyl radical leads to formation of an o-quinone methide intermediate, which dissociates spontaneously from the cobalt center and easily undergoes an endocyclic, sigmatropic ring-closing reaction to form the final 2H-chromene product.

Full text of DOI:10.1021/ja4111336

Article
pubs.acs.org/JACS
Metalloradical Approach to 2H‑Chromenes
Nanda D. Paul,† Sutanuva Mandal,† Matthias Otte,† Xin Cui,‡ X. Peter Zhang,‡ and Bas de Bruin*,†
†Homogeneous Catalysis Group, van ’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH
Amsterdam, The Netherlands
‡Department of Chemistry, University of South Florida, Tampa, Florida 33620-5250, United States
S
* Supporting Information
ABSTRACT: Cobalt(III)−carbene radicals, generated through metallo-
radical activation of salicyl N-tosylhydrazones by cobalt(II) complexes of
porphyrins, readily undergo radical addition to terminal alkynes to
produce salicyl−vinyl radical intermediates. Subsequent hydrogen atom
transfer (HAT) from the hydroxy group of the salicyl moiety to the vinyl
radical leads to the formation of 2H-chromenes. The Co(II)-catalyzed
process can tolerate various substitution patterns and produces the
corresponding 2H-chromene products in good isolated yields. EPR
spectroscopy and radical-trapping experiments with TEMPO are in
agreement with the proposed radical mechanism. DFT calculations
reveal the formation of the salicyl−vinyl radical intermediate by a
metalloradical-mediated process. Unexpectedly, subsequent HAT from
the hydroxy moiety to the vinyl radical leads to formation of an o-
quinone methide intermediate, which dissociates spontaneously from the cobalt center and easily undergoes an endocyclic,
sigmatropic ring-closing reaction to form the final 2H-chromene product.
synthesis over the past decades.4,5 Synthetic methods developed
INTRODUCTION
■
so far include Pd-catalyzed ring closure of 2-isoprenyl phenols,5a
Claisen rearrangement of propargyl phenol ethers,5b Ru-
catalyzed ring-closing methathesis protocols,5c−f nucleophilic
substitution of chromene acetals (e.g., with allylsilanes, trialkyl−
tin compounds,5f and Grignard reagents5g,h), and Petasis-like
reactions using vinylic boronate esters, boronic acids, and
trifluoroborates.5i−k All of these routes involve multistep reaction
sequences, and many of them require the use of complicated
prefunctionalized fragments, show a limited degree of functional
group tolerance, and lead to formation of regioisomeric product
mixtures.5l Therefore, the development of shorter, more efficient,
and broadly applicable synthetic routes toward 2H-chromenes is
certainly in demand. Herein we describe a novel metalloradical
approach.
2H-Chromenes (2H-1-benzopyran derivates)1 are important
structural motifs that exist in numerous natural products (e.g.,
tannins and polyphenols found in teas, fruits, and vegetables) and
medicines possessing interesting biological activities (Figure 1).
As stable metalloradicals with well-defined open-shell doublet
d7-electronic configuration, cobalt(II) complexes of porphyrins,
[CoII(Por)], have emerged as a new class of catalysts capable of
carbene-transfer6 reactions proceeding via radical mechanisms
involving discrete CoIII−carbene radical intermediates (species C
in Scheme 1 is a relevant example for the reactions described in
this study).7 In comparison with classical electrophilic Fischer-
type carbenes, these carbene radical intermediates have a reduced
tendency to undergo undesirable carbene dimerization reactions.
Furthermore, they reveal discrete catalytic radical-type reactions.
For example, cyclopropanation reactions mediated by
[CoII(Por)] catalysts proceed via “carbene radical” addition to
Figure 1. Selected examples of pharmacologically active and photo-
chromic compounds based on 2H-chromene and related scaffolds.
For example, the 2H-chromene is a crucial substructure of a wide
variety of known pharmaceutical agents and drug candidates with
antitumor, antibacterial, antiviral, antioxidative, antidepressant,
antihypertensive, antidiabetic, fungicidal, insecticidal, and
antiviral activities.2 Furthermore, 2H-chromenes find interesting
applications as photochromic materials and in the synthesis of
dyes.3 As a result, considerable efforts have been made for their
Received: November 5, 2013
© XXXX American Chemical Society
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Scheme 1. Simplified Representation of the [CoII(Por)]-
Catalyzed Metalloradical Coupling−Cyclization Protocol
Using Alkynes and Salicyl Tosylhydrazones To Produce 2H-
Chromenes
observations, control experiments, labeling experiments, EPR
spectroscopy, and computational studies (DFT).
RESULTS AND DISCUSSION
■
Initial studies focused on the reaction between tosylhydrazone 1a
and phenylacetylene 2a to produce 2H-chromene 3a (Table 1).
Table 1. Conditions of [CoII(Por)]-Catalyzed 2H-Chromene
Synthesis Using Salicyl N-Tosylhydrazone and
a
Phenylacetylene
b
entry
1
catalyst
base
solvent
yield (%)
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P2)]
[CoII(P3)]
[CoII(P2)]
[CoII(P3)]
[CoII(P2)]
CoIICl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KHCO3
K3PO4
PhMe
45
c
2
THF
35
3
dioxane
DCE
25
c
4
40
c
5
MeCN
DMF
<5
0
6
7
PhCl
70
8
1,2-PhCl2
PhCl
70
9
20
10
11
12
13
14
15
16
17
18
19
PhCl
<10
20−25
75
PhCl
NaOMe
LiOtBu
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
PhCl
the olefinic substrate, thus allowing conversion of electron-
deficient olefins.6,7 In addition, the metalloradical-catalyzed
approach was successfully applied for highly enantioselective
alkyne cyclopropenation8 as well as regioselective synthesis of
furans.9
PhCl
20
PhCl
60−65
77
PhCl
PhCl
75
PhCl
77
Recently, we developed a metalloradical-catalyzed carbene
carbonylation protocol to synthesize ketenes, using N-tosyl-
hydrazones as “carbene precursors”.10 The use of N-tosyl-
hydrazones11 as diazo precursors in [CoII(Por)]-based metallo-
radical catalysis was thus far unprecedented, and may open up a
new area to bring about new chemical transformations using in
situ generated unstable diazo precursors that are otherwise
difficult to handle.11
To explore the use of metalloradical catalysis in other radical-
induced cyclization reactions, we envisioned the possibility of a
new catalytic pathway for the construction of 2H-chromenes
from salicyl tosylhydrazones and alkynes (Scheme 1). In this
process, we anticipated formation of vinyl radical intermediates
D through radical addition of Co(III)−carbene radical C to the
alkyne substrate.8,9 Subsequent hydrogen atom transfer (HAT)
from the ortho-hydroxy group to the vinyl radical moiety of D is
then expected to generate the 2H-chromene product. In addition
to its fundamental importance, such catalytic tandem radical
addition-cyclization processes are synthetically attractive, as they
enable the direct synthesis of multi-substituted chromenes from
N-tosylhydrazones and acetylenes.
1,2-PhCl2
1,2-PhCl2
1,2-PhCl2
1,2-PhCl2
1,2-PhCl2
1,2-PhCl2
1,2-PhCl2
77
78
d
20
70
21
22
23
24
<5
<5
0
CoII(OAc)2
RhII2(OAc)4
none
0
a
Stoichiometry: N-tosylhydrazone (1a) (0.3 mmol; 1.0 equiv) and
b
alkyne (2a) (1.0 mmol; 3.0 equiv). Isolated yields after column
chromatography. Reaction temperature: 60 °C. Reaction temper-
ature: 55 °C.
c
d
Various reaction conditions were screened to optimize the
catalytic process and to explore the potential of asymmetric
induction. Three different [CoII(Por)] catalysts (Figure 2) were
employed: [CoII(P1)], [CoII(P2)], and the chiral catalyst
Herein, we report a general and regioselective protocol for the
one-pot synthesis of 2H-chromenes involving intermolecular
radical-induced 6π-electrocyclization of acetylenes with salicyl
tosylhydrazones using cobalt(II)-based metalloradical catalysis.
This unprecedented tandem addition-cyclization pathway of
Co(III)−carbene radicals has a broad substrate scope and can be
applied to various combinations of tosylhydrazones and terminal
acetylenes, including challenging and electron-deficient alkynes.
Furthermore, we disclose a plausible reaction mechanism for
these reactions based on a combination of experimental
Figure 2. Structures of cobalt(II) complexes of porphyrins: P1 =
tetraphenylporphyrin; P2 = 3,5-DitBu-IbuPhyrin; P3 = 3,5-DitBu-
ChenPhyrin.
B
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[CoII(P3)]. The catalysts [CoII(P2)] and [CoII(P3)] were
previously reported,6 being excellent cyclopropanation catalysts
due to the cooperative effect of the H-bond donor motifs in the
second coordination sphere.7,13 Initial experiments were focused
on the evaluation of ligand and solvent effects on the possibility
of catalytic 2H-chromene formation from salicyl tosylhydrazone
1a and phenylacetylene (2a), using the above-mentioned
[CoII(Por)] catalysts at 90 °C (Table 1).
cyclic functionalities (Table 2). The reaction was not significantly
affected by the substituents on the aromatic ring of the terminal
Table 2. Reaction of N-Tosylhydrazone 1a with Various
a b
,
Terminal Alkynes Catalyzed by [CoII(P2)]
Optimization of the reaction conditions revealed that the
reaction proceeded most efficiently in nonpolar solvents such as
toluene, chlorobenzene, or 1,2-dichlorobenzene, whereas
reactions in solvents of high polarities such as THF, dioxane,
MeCN, and DMF afforded poor yields (Table 1, entries 1−8).
Among the series of bases examined such as K3PO4, K2CO3,
Cs2CO3, LiOtBu, NaOtBu, KOtBu, and NaOMe, the best results
were obtained with KOtBu (Table 1, entries 7−15). Lowering
the reaction temperature decreased the yield of 3a slightly (Table
1, entry 20).
Control experiments showed that no product was obtained in
the absence of a [CoII(Por)] catalyst (Table 1, entry 24). While
other cobalt(II) sources like CoCl2 and Co(OAc)2 (Table 1,
entries 21 and 22) only afforded the 2H-chromene product in
trace amounts (<5%), other typical carbene-transfer catalysts
such as Rh2(OAc)4 proved to be essentially ineffective (Table 1,
entry 23). Interestingly, CuBr2 produced benzofurans in high
yield instead of chromenes, as was recently reported by Wang
and co-workers.12 Notably, these CuBr2-catalyzed benzofuran
formation reactions were proposed to proceed via completely
different, nonradical allene intermediates (Scheme 2).
Scheme 2. Proposed Nonradical CuBr2-Catalyzed
Cyclizations (Top) versus Radical-Type [CoII(Por)]-
Catalyzed Cyclizations (Bottom) of Terminal Alkynes with
Salicyl Carbenes Generated from the Corresponding
Tosylhydrazones
The catalysts [CoII(P1)], [CoII(P2)], and [CoII(P3)] showed
similar activities (Table 1, entries 15−20). However, for salicyl
tosylhydrazone substrates containing electron-withdrawing
groups, the catalysts [CoII(P2)] and [CoII(P3)] performed
better than [CoII(P1)] (for example, see Table 3, entry 6).
Unexpectedly, reactions with the chiral catalyst [CoII(P3)] did
not result in any significant enantioselectivity (chiral HPLC)
under the various reaction conditions applied. In all further
catalytic studies, we therefore focused on reactions with
[CoII(P2)] in 1,2-dichlorobenzene at 90 °C. To explore the
versatility of the metalloradical-catalyzed tandem vinylation−
cyclization coupling protocol, several reactions employing a
variety of terminal alkynes and N-tosylhydrazones were
performed using the above optimized reaction conditions. The
reaction proved to be tolerant of alkynes 2 containing various
functional groups, including aryl, alkyl, naphthyl, and hetero-
a
Stoichiometry: N-tosylhydrazone (1a) (0.3 mmol; 1.0 equiv) and
b
alkyne (2a−j) (1.0 mmol; 3.0 equiv). Isolated yields after
chromatography.
alkyne; both electron-rich (Table 2, entries 2−5) and electron-
deficient arylalkynes (Table 2, entries 6−8) were effective.
Reactions of naphthyl alkyne and 3-thienylacetylene with N-
tosylhydrazone 1a furnished the corresponding 2H-chromenes
in moderate yields (Table 2, entries 9 and 10). Alkyl alkynes such
as 4-phenyl-1-butyne proved also to be suitable reaction partners,
generating the corresponding 2H-chromene in moderate yield
(Table 2, entry 11). Reactions with 1,2-disubstituted alkynes did
C
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not lead to chromene formation (Table 2, entry 12). Instead,
carbene dimerization was observed, along with some other
unidentified products, while most of the 1,2-disubstituted alkyne
could be recovered from the reaction mixture. Carbene
dimerization was also observed for reactions of 1a in the absence
of alkynes.
To further expand the scope of the reaction, various
substituted salicyl N-tosylhydrazones were employed as
substrates to test the catalytic formation of 2H-chromenes
using phenylacetylene as a reaction partner.
As shown in Table 3, hydrazones with electron-donating
groups at the meta-, para-, or disubstituted at both meta- and
para-positions were all effective, affording the corresponding 2H-
chromenes 3m, 3n, and 3o in good yields (Table 3, entries 1−3).
Reactions also proceeded with electron-withdrawing groups on
the hydrazone moiety, albeit leading to lower yields (Table 3,
entries 4−7). For example, the use of the salicyl hydrazone 1e
having an electron-withdrawing fluoro atom at the ortho-
position led to the corresponding chromene in a moderate
yield (Table 3, entry 4). Similarly, salicyl hydrazones substituted
with bromo atoms are also tolerated in the chromene formation
reaction (Table 3, entries 5 and 6).
It is noteworthy that substrate 1h, having a strong electron-
withdrawing nitro group at its para-position, produced the
corresponding chromene 3s in moderate yield (Table 3, entry 7).
However, the presence of strong electron-withdrawing groups on
the aromatic ring of the hydrazones made the reactions sluggish,
and hence longer reaction times were needed. The naphthalene-
based tosylhydrazone 1i gave access to 2H-chromene 3t (Table
3, entry 8), which is of interest in the field of photochromic
materials (see also Figure 1).3
To shed more light on the catalytic reaction mechanism, we
performed a set of control experiments, labeling studies, and EPR
spectroscopic investigations. Additionally, we explored the
mechanism computationally.
EPR spectroscopic analysis of the reaction mixture using salicyl
tosylhydrazone (1a), phenylacetylene (2a), and [CoII(P1)]
(sample taken from a solution under the applied catalytic
reaction conditions, EPR spectrum recorded at RT) reveals a
strong EPR signal indicating the formation of an organic radical
or ligand radical species (see Figure 3). An identical EPR signal
Table 3. [CoII(P2)]-Catalyzed Reaction of N-
Tosylhydrazones 1b−i with Phenylacetylene
a b
,
Figure 3. X-band EPR spectrum recorded from a reaction mixture of
salicyl tosylhydrazone 1a, phenylacetylene, KOtBu, and cobalt catalyst
[CoII(P1)] in toluene solution. Spectrum recorded at RT. Frequency =
9.360420 GHz, modulation amplitude = 2 Gauss, microwave power = 20
mW.
was detected in absence of phenylacetylene. Some hyperfine
structure is visible, but the pattern is poorly resolved (spectral
simulations show a maximum isotropic proton hyperfine splitting
iso
AHiso < 12 MHz; in the case of cobalt hyperfine splitting, ACo
<
8 MHz). The species detected may stem from carbene radical C
(see Scheme 1), but detection of a stable free organic radical or a
ligand radical species formed from C as a side product cannot be
excluded. The detection of an identical signal, of roughly the
same intensity, in the presence and absence of excess
phenylacetylene makes it actually rather unlikely that the signal
detected stems directly from species C (DFT calculations shown
in Scheme 3 suggest that species C should rapidly react with
phenylacetylene to form the more stable species D or H).
However, irrespective of the exact interpretation of the EPR
signal detected, these data are clearly indicative for formation of
radicals upon reacting [CoII(Por)] catalyst with diazo com-
pounds.7 In good agreement, no 2H-chromene formation was
observed when the catalytic reaction was performed in the
a
Stoichiometry: N-tosylhydrazone (1a−i) (0.3 mmol; 1.0 equiv) and
b
alkyne (2a) (1.0 mmol; 3.0 equiv). Isolated yields after
c
d
chromatography. Reaction time 40 h. Yield with [CoII(P1)].
D
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Scheme 3. [CoII(Por)]-Catalyzed Metalloradical Coupling−
C formed should be in rapid equilibrium with “bridging carbene”
C′ according to these calculations. Related species were
previously detected with EPR spectroscopy in frozen solutions.7a
Radical addition of C to the phenylacetylene substrate
produces “vinyl radical” species D in an exergonic process
(ΔG° = −22.99 kcal mol−1) via a low barrier (ΔG⧧ = +5.04 kcal
mol−1) transition state TS2. Spin density plots reveal that both C
and D are substrate-centered radicals (Figure 4). The unpaired
a
Cyclization of Alkynes and Salicyl Tosylhydrazones
Figure 4. (a) Spin density plots of the DFT-optimized “carbene radical”
species C (left) and vinyl radical species D (right).
electron in carbene radical C has a high spin density at the
“carbene carbon” and is further delocalized over the adjacent
hydroxyl−phenyl moiety. The unpaired electron of vinyl radical
species D has a high spin density at the expected vinyl position
and is further delocalized over the adjacent phenyl moiety
(Figure 4).
Two conceivable reaction pathways from species D were
considered in the DFT calculations (Scheme 3): productive
formation of 2H-chromene G and nonproductive formation of
cyclopropene I (Scheme 3). Overall 2H-chromene formation is
much more exergonic (ΔG° = −73.56 kcal mol−1) than
cyclopropene formation (ΔG° = −38.94 kcal mol−1). The
productive 2H-chromene formation pathway involves hydrogen
atom transfer from the hydroxyl moiety of D to its vinyl radical
moiety.
The rate-limiting transition state barrier for HAT via TS3
(ΔG⧧ = +17.47 kcal mol−1) is easily accessible under the applied
reaction conditions. In agreement with these DFT calculations,
experimental data reveal a small but significant KIE of 1.3 0.1.
This value was determined from the 3a/3a-D product ratio
obtained in an internal competition experiment using 1a and 1a-
D in a 1:1 ratio. Note that the absolute value of the KIE
determined in this manner should be treated with some care. It is
based on deuterium labeling of a rather acidic C−H bond of
product 3a in a reaction performed under basic conditions at
elevated temperatures. Under these conditions, H/D scrambling
between 3a and unreacted 1a-D cannot be excluded and is even
likely. Hence, the measured KIE value puts a lower limit to the
intrinsic KIE for HAT.
a
DFT-D3 calculated (Turbomole BP86, def2-TZVP) free energies
(ΔG298K° in kcal mol−1 (DFT free energies without dispersion
corrections between brackets). All energies, including the transition
states, are reported with respect to species A as the reference point.
presence of an excess of the radical scavenger TEMPO (∼10
equiv with respect to the catalyst; TEMPO = 2,2,6,6-tetramethyl
piperidinoxyl). These data clearly support a radical-type
mechanism (for the proposed mechanism, see Scheme 3).
Furthermore, isotope-labeling experiments using N-tosyl-
hydrazone 1a-D, containing a deuterium-substituted phenoxyl
moiety (70% ArO-D based on 1H NMR spectrocopy), produce
the corresponding 2H-chromenes with a deuterium atom at the
expected 2-position (60% based on 1H NMR). This is suggestive
for direct hydrogen atom transfer from the phenoxyl moiety to
the vinyl radical in intermediate D (Scheme 3).
The mechanism was further investigated computationally
using DFT methods (see Experimental Section and Supporting
Information for details). Plausible radical-type pathways were
investigated at the BP86 and def2-TZVP level, using the
nonfunctionalized [CoII(Por)] system as a simplified catalyst
model (Scheme 3). The choice of the computational method is
in line with our previous computational studies, dealing with
closely related catalytic group-transfer reactions mediated by
[CoII(Por)] systems proceeding via similar carbene7,10 and
nitrene radical intermediates.13 We evaluated the mechanism
both at the uncorrected DFT level and with DFT-D3 to include
Grimme’s dispersion corrections.
As expected, dispersion corrections have a profound influence
on the substrate binding affinity of the cobalt center, making
formation of diazo adduct B exergonic rather than endergonic.
However, the corrections have little influence on the relative
transition state barriers of the subsequent steps, and overall, the
DFT-D3 and DFT reaction profiles are very similar. Further
discussion is focused on the calculated DFT-D3 relative free
energies (ΔG298K°).
Unexpectedly, the HAT process does not produce a stable
phenoxyl radical species according to DFT. Instead, spontaneous
dissociation of the substituted trans-configured o-quinone
methide E is observed, as a result of simultaneous Co−C bond
homolysis during HAT via TS3.
Formation of E is exergonic (ΔG° = −20.32 kcal mol−1).
Rotation about the C−C single bond in E produces the cis-
configured o-quinone methide F, which easily undergoes
endocyclic ring closure via TS4 (ΔG⧧ = +6.09 kcal mol−1) to
form the final 2H-chromene product G. Related thermal
(noncatalyzed) sigmatropic rearrangements of other (proposed)
o-quinone methide intermediates, prepared via entirely different
routes, have previously been reported to produce 2H-
Elimination of N2 from B via TS1 (barrier: ΔG⧧ = +8.47 kcal
mol−1) is exergonic (ΔG° = −14.75 kcal mol−1), producing the
key cobalt(III)−carbene radical intermediate C (Scheme 3)
similar to carbene radical formation in the previously reported
cyclopropanation mechanism with [CoII(Por)] species.7 Species
E
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chromenes.4a,14 Hence, according to DFT, the final ring-closing
steps required for 2H-chromene formation occur outside the
coordination sphere of cobalt, far away from the chiral influence
of the catalyst. Considering that these ring-closing steps
determine the enantioselectivity of the reaction, the computa-
tional results are in line with the experimental observations
showing 2H-chromene formation without asymmetric induction,
despite using the chiral [CoII(P3)] catalyst (Figure 2) known to
be a highly enantioselective carbene-transfer catalyst in other
reactions.6−9
Besides 2H-chromene formation, intermediate D is also
expected to undergo easy formation of a cyclopropene ring
(Scheme 3). Considering that the same catalysts as used in the
present study were previously shown to be active for alkyne
cyclopropanation,8 these reactions should proceed via similar
intermediates. However, aryl cyclopropenes similar to I tend to
be (very) unstable,15 and thus far, only acceptor-type carbenes
have been reported as suitable reaction partners in [CoII(Por)]-
catalyzed cyclopropanation reactions of aryl acetylenes.8 In
agreement with the reported cyclopropenation activity, for-
mation of I is feasible. In fact, the TS5 barrier for ring closure
toward I is even lower than the rate-limiting TS3 barrier for HAT
in the productive pathway for 2H-chromene formation.
However, cyclopropanation is much less exergonic and is
calculated to be reversible under the applied reaction conditions.
The same transition state TS5 allows for regeneration of
intermediate D to re-enter into the productive, much more
exergonic pathway leading to 2H-chromenes. Hence, 2H-
chromene formation rather than cyclopropene formation is a
thermodynamically controlled feature, made kinetically possible
by the catalyst. The calculations are in excellent agreement with
the experimental observations, showing only 2H-chromene
formation without cyclopropene side products.
used for catalysis were dried over and distilled from sodium (toluene) or
CaH2 (dichloromethane, hexane, ethyl acetate, methanol). All the
cobalt−porphyrin catalysts [CoII(P1)], [CoII(P2)], and [CoII(P3)] and
N-tosylhydrazone sodium salts were synthesized according to published
procedures.7a,8,11 All the alkynes were used as purchased from Aldrich.
All other chemicals were purchased from commercial suppliers and used
without further purification. NMR spectra (1H and 13C) were measured
on a Varian INOVA 500 MHz (125 MHz for 13C), a Bruker AV400 (100
MHz for 13C), or a Varian MERCURY 300 MHz (75 MHz for 13C)
spectrometer. Mass spectra of the newly synthesized compounds were
recorded in Agilent-5973 GC-MS spectrometer, and the corresponding
HRMS data were recorded on JEOL AccuTOF 4G via direct injection
probe. Elemental analysis of the newly synthesized complexes was
performed by the Mikroanalytisches Laboratorium Kolbe, Germany.
EPR spectra were recorded on a Bruker EMXplus spectrometer.
General Procedure for Cyclization of Salicyl Tosylhydrazones
and Terminal Alkynes. Under a nitrogen atmosphere, the respective
([CoII(Por)] catalyst (2 mol %) and salicyl tosylhydrazone (1a−i) (0.3
mmol) were added to a flame-dried Schlenk tube. The tube was capped
with a Teflon screw cap, evacuated, and backfilled with nitrogen. The
screw cap was replaced with a rubber septum. Base KOtBu (3 equiv; 0.9
mmol) and the terminal alkyne (2a−l) (3 equiv; 1 mmol) dissolved in 4
mL of 1,2-dichlorobenzene (anhydrous) were added at once via a
syringe. The Schlenk tube was then placed in an oil bath and heated to
the desired temperature for a set period. After the reaction finished, the
resulting mixture was concentrated and the residue was purified by flash
chromatography (silica gel) or preparative TLC to give the products
(3a−t). Up to 40% of the starting alkyne could be recovered from the
reaction mixture.
Deuterium-Labeling Experiment and KIE Measurement.
Deuterium-labeled salicyl tosylhydrazone (1b) was synthesized by
stirring the corresponding nonlabeled tosylhydrazone in a DMSO-d6−
D2O mixture for 24 h. Then, 70% of deuterium incorporation, as
determined by 1H NMR spectroscopy, was found in the resulting
deuterated N-tosylhydrazone. The catalytic reaction with the
deuterium-labeled (70%) tosylhydrazone (1a) and phenylacetylene
(2a) was performed in absolutely inert atmosphere using deuterated
CONCLUSIONS
■
1
In summary, we have developed a new one-pot protocol for the
regioselective synthesis of 2H-chromenes. These reactions
proceed via radical-induced addition−cyclization of terminal
alkynes with carbene radicals. Salicyl N-tosylhydrazones are used
as convenient carbene radical precursors in these new cobalt-
(II)−metalloradical-mediated reactions. This straightforward
methodology has a broad substrate scope and can be applied
for various salicyl N-tosylhydrazone compounds with different
substituents and terminal alkynes. The cobalt(II)-mediated
process provides a direct method for diastereoselective synthesis
of 2H-chromenes from simple and readily available organic
building blocks. To the best of our knowledge, the reactions
described in this paper are the first examples of cobalt(II)-based
metalloradical transformations leading to formation of six-
membered heterocyclic ring structures. The catalytic processes
proceed via remarkably selective tandem radical addition−
cyclization reactions, involving radical addition of unusual
carbene radical intermediates to alkynes, followed by HAT and
subsequent ring closure. The successful development of this new
catalytic reaction is expected to open a heretofore unexplored
research avenue, which hopefully triggers the further develop-
ment of catalytic radical-induced (6π-electro)cyclization pro-
cesses for selective syntheses of diverse and unusual heterocycles
that are difficult to prepare otherwise.
bromobenzene as the solvent. H NMR spectroscopy revealed 60%
deuterium incorporation (85% wrt starting deuterium-labeled N-
tosylhydrazone) at the C2-position of the 2H-chromene product in
the crude reaction mixture. The KIE was calculated from the 3a/3a-D
product ratio (deuterated 2D-chromene vs nondeuterated 2H-
1
chromene product, as determined by H NMR integration) obtained
in an internal competition experiment using nondeuterated salicyl
tosylhydrazone 1a and deuterated 1a-D in a 1:1 ratio (1 equiv of alkyne)
under the optimized reaction conditions described above.
EPR Spectra of Catalytic Reaction Mixtures. A reaction mixture
consisting of salicyl tosylhydrazone 1a (0.5 mmol), phenylacetylene (1.5
mmol), KOtBu (1 mmol), and cobalt catalyst [CoII(P1)] (Co(TPP))
(15 mol %) in 5 mL of toluene was heated to 90 °C for a short while
before recording an EPR spectrum at RT. The spectrum (Figure 3)
revealed an intense signal at g = 2.0044.
Computational Details. Geometry optimizations were carried out
with the Turbomole program package16 coupled to the PQS Baker
optimizer17 via the BOpt package,18 at the spin-unrestricted ri-DFT level
using the BP8619 functional and the resolution-of-identity (ri)
method.20 We optimized the geometries of all stationary points at the
def2-TZVP basis set level,21 both with and without Grimme’s dispersion
corrections (disp3 version).22 The identity of the transition states was
confirmed by following the imaginary frequency in both directions
(IRC). All minima (no imaginary frequencies) and transition states (one
imaginary frequency) were characterized by calculating the Hessian
matrix. ZPE and gas-phase thermal corrections (entropy and enthalpy,
298 K, 1 bar) from these analyses were calculated. The relative (free)
energies obtained from these calculations are reported in Scheme 3 and
in Table S1 (Supporting Information).
EXPERIMENTAL SECTION
General Considerations. All manipulations were performed under
a nitrogen atmosphere using standard Schlenk techniques. All solvents
■
F
dx.doi.org/10.1021/ja4111336 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(i) Walkinshaw, A. J.; Xu, W.; Suero, M. G.; Gaunt, M. J. J. Am. Chem.
Soc. 2013, 135, 12532. (j) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
(k) Liu, F.; Evans, T.; Das, B. C. Tetrahedron Let. 2008, 49, 1578.
(l) Moquist, P. N.; Kodama, T.; Schaus, S. E. Angew. Chem., Int. Ed.
2010, 49, 7096.
ASSOCIATED CONTENT
* Supporting Information
NMR data, absolute energies (atomic units), and the coordinates
of the DFT-optimized structures are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(6) (a) Doyle, M. P. Angew. Chem. 2009, 121, 864; Angew. Chem., Int.
Ed. 2009, 48, 850. (b) Huang, L. Y.; Chen, Y.; Gao, G. Y.; Zhang, X. P. J.
Org. Chem. 2003, 68, 8179. (c) Penoni, A.; Wanke, R.; Tollari, S.; Gallo,
E.; Musella, D.; Ragaini, F.; Demartin, F.; Cenini, S. Eur. J. Inorg. Chem.
2003, 1452. (d) Chen, Y.; Zhang, X. P. J. Org. Chem. 2007, 72, 5931.
(e) Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007, 129,
12074. (f) Zhu, S. F.; Ruppel, J. V.; Lu, H. J.; Wojtas, L.; Zhang, X. P. J.
Am. Chem. Soc. 2008, 130, 5042. (g) Zhu, S. F.; Perman, J. A.; Zhang, X.
P. Angew. Chem., Int. Ed. 2008, 47, 8460. (h) Fantauzzi, S.; Gallo, E.;
Rose, E.; Raoul, N.; Caselli, A.; Issa, S.; Ragaini, F.; Cenini, S.
Organometallics 2008, 27, 6143. (i) Ruppel, J. V.; Gauthier, T. J.; Snyder,
N. L.; Perman, J. A.; Zhang, X. P. Org. Lett. 2009, 11, 2273. (j) Zhu, S. F.;
Xu, X.; Perman, J. A.; Zhang, X. P. J. Am. Chem. Soc. 2010, 132, 12796.
(k) Chen, Y.; Zhang, X. P. J. Org. Chem. 2004, 69, 2431. (l) Xu, X.; Zhu,
S.; Cui, X.; Wojtas, L.; Zhang, X. P. Angew. Chem., Int. Ed. 2013, 52,
11857.
(7) (a) Dzik, W. I.; Xu, X.; Zhang, X. P.; Reek, J. N. H.; de Bruin, B. J.
Am. Chem. Soc. 2010, 132, 10891. (b) Lu, H.; Dzik, W. I.; Xu, X.; Wojtas,
L.; de Bruin, B.; Zhang, X. P. J. Am. Chem. Soc. 2011, 133, 8518. (c) Dzik,
W. I.; Zhang, X. P.; de Bruin, B. Inorg. Chem. 2011, 50, 9896. (d) Dzik,
W. I.; Reek, J. N. H.; de Bruin, B. Chem.Eur. J. 2008, 14, 7594.
(e) Lyaskovskyy, V.; de Bruin, B. ACS Catal. 2012, 2, 270.
(8) Cui, X.; Xu, X.; Lu, H.; Zhu, S.; Wojtas, L.; Zhang, X. P. J. Am.
Chem. Soc. 2011, 133, 3304.
AUTHOR INFORMATION
Corresponding Author
b.debruin@uva.nl
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the European Research
Council (ERC Grant Agreement 202886-CatCIR; B.dB.), The
Netherlands Organization for Scientific Research (NWO-VICI
Grant 016.122.613; B.dB.), the University of Amsterdam
(B.dB.), the National Science Foundation (CHE-1152767;
X.P.Z.), and the National Institutes of Health (R01-
GM098777; X.P.Z.). M.O. gratefully acknowledges the AvH
Foundation for a Feodor Lynen postdoctoral fellowship.
REFERENCES
■
(1) (a) Covington, A. D. Chem. Soc. Rev. 1997, 111. (b) Ellis, G. P., Ed.
Chromenes, Chromanones, and Chromones. In The Chemistry of
Heterocyclic Compounds; Wiley-Interscience: New York, 1977; Vol. 31.
(c) Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds. Comprehensive
Heterocyclic Chemistry II; Pergamon: Oxford, 1996; Vol. 2.
(9) Cui, X.; Xu, X.; Wojtas, L.; Kim, M. M.; Zhang, X. P. J. Am. Chem.
Soc. 2012, 134, 19981.
(10) Paul, N. D.; Chirila, A.; Lu, H.; Zhang, X. P.; de Bruin, B. Chem.
(2) (a) Schneider, P.; Hawser, S.; Islam, K. Bioorg. Med. Chem. Lett.
2003, 13, 4217. (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 9074. (c) Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A.-L.;
Tillequin, F.; Koch, M.; Pierre, A.; Guilbaud, N.; Leonce, S.; Kraus-
Berthier, L.; Rolland, Y.; Atassi, G. J. Med. Chem. 1996, 39, 4762.
(d) Jankun, J.; Selman, S. H.; Swiercz, R.; Skrzypczak-Jankun, E. Nature
1997, 387, 56. (e) Mukai, K.; Okabe, K.; Hosose, H. J. Org. Chem. 1989,
54, 557. (f) Lago, J. H. G.; Ramos, C. S.; Casanova, D. C. C.; Morandim,
A. D.; Bergamo, D. C. B.; Cavalheiro, A. J.; Bolzani, V. D.; Furlan, M.;
Guimaraes, E. F.; Young, M. C. M.; Kato, M. J. J. Nat. Prod. 2004, 67,
1783. (g) Gauthier, S.; Caron, B.; Cloutier, J.; Dory, Y. L.; Favre, A.;
Larouche, D.; Mailhot, J.; Ouellet, C.; Schwerdtfeger, A.; Leblanc, G.;
Martel, C.; Simard, J.; Merand, Y.; Belanger, A.; Labrie, C.; Labrie, F. J.
Med. Chem. 1997, 40, 2117. (h) Bauer, D. J.; Selway, J. W. T.; Batchelor,
J. F.; Tisdale, M.; Caldwell, I. C.; Young, D. A. B. Nature 1981, 292, 369.
(i) Terregroza, I.; Evans, T.; Das, B. C. Chem. Biol. Drug. Des. 2009, 73,
339. (j) Xu, G.; Yang, G.; Wang, C.; Fan, S.; Xie, L.; Gao, Y. Molecules
2013, 18, 11964. (k) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q.
Angew. Chem., Int. Ed. 2000, 39, 734. (l) Nicolaou, K. C.; Cao, G.-Q.;
Pfefferkorn, J. A. Angew. Chem., Int. Ed. 2000, 39, 739. (m) Thomas, N.;
Zachariah, S. N. Asian J. Pharm. Clin. Res. 2013, 6/2, 11.
(3) (a) Bamfield, P.; Hutchings, M. G. Chromic Phenomena: The
Technological Applications of Colour Chemistry; The Royal Society of
Chemistry: Cambridge, UK, 2010. (b) Pina, F.; Melo, M. J.; Laia, C. A.
T.; Parola, J.; Lima, J. C. Chem. Soc. Rev. 2012, 41, 869.
(4) (a) Majumdar, N.; Korthals, K. A.; Wulff, W. D. J. Am. Chem. Soc.
2012, 134, 1357. (b) Graham, T. J. A.; Doyle, A. G. Org. Lett. 2012, 14,
1616.
(5) (a) Iyer, M.; Trivedi, G. R. Synth. Commun. 1990, 20, 1347.
(b) Hlubeck, J.; Ritchie, E.; Taylor, W. C. Tetrahedron Lett. 1969, 1369.
(c) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864. (d) Harrity, J.
P. A.; La, D. S.; Cefalo, D. R.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem.
Soc. 1998, 120, 2343. (e) Brimble, M.; Jay-Smith, M.; Furkert, D.;
Sperry, J. Synlett 2011, 1395. (f) Doodeman, R.; Rutjes, F. P. J. T.;
Hiemstra, H. Tetrahedron Lett. 2000, 41, 5979. (g) Li, X.; Reuman, M.;
Russell, R. K.; Adams, R.; Ma, R.; Branum, S.; Youells, S.; Roberts, J.;
Jain, N.; Kanojia, R.; Sui, Z. Org. Process Res. Dev. 2007, 11, 414.
(h) Grese, T. A.; Pennington, L. D. Tetrahedron. Lett. 1995, 36, 8913.
Eur. J. 2013, 19, 12953.
(11) (a) Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem.
2005, 1479. (b) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46,
236. (c) Xia, Y.; Liu, Z.; Xiao, Q.; Qu, P.; Ge, R.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2012, 51, 5714. (d) Ye, F.; Ma, X.; Xiao, Q.; Li, H.;
Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2012, 134, 5742.
(12) Zhou, L.; Shi, Y.; Xiao, Q.; Liu, Y.; Ye, F.; Zhang, Y.; Wang, J. Org.
Lett. 2011, 13, 968.
́
(13) (a) Lyaskovskyy, V.; Olivos Suarez, A. I.; Lu, H.; Jiang, H.; Zhang,
X. P.; de Bruin, B. J. Am. Chem. Soc. 2011, 133, 12264. (b) Olivos Suarez,
A. I.; Jiang, H.; Zhang, X. P.; de Bruin, B. Dalton Trans. 2011, 40, 5697.
(c) Olivos Suarez, A. I.; Lyaskovskyy, V.; Reek, J. N. H.; van der Vlugt, J.
I.; de Bruin, B. Angew. Chem., Int. Ed. 2013, 52, 12510.
(14) Parker, K. A.; Mindt, T. L. Org. Lett. 2001, 3, 3875.
(15) (a) Sheshenev, A. E.; Baird, M. S.; Croft, A. K.; Bolesov, I. G.
Tetrahedron 2009, 65, 10036 and references therein. (b) Xu, X.; Zavalij,
P. Y.; Doyle, M. P. J. Am. Chem. Soc. 2013, 135, 12439.
(16) Ahlrichs, R. Turbomole Version 6.4; Theoretical Chemistry Group,
University of Karlsruhe.
(17) PQS, version 2.4, 2001, Parallel Quantum Solutions, Fayetteville,
Arkansas (USA) (the Baker optimizer is available separately from PQS
upon request): Baker, I. J. Comput. Chem. 1986, 7, 385.
(18) Budzelaar, P. H. M. J. Comput. Chem. 2007, 28, 2226.
(19) (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098. (b) Perdew, J. P.
Phys. Rev. B 1986, 33, 8822.
(20) Sierka, M.; Hogekamp, A.; Ahlrichs, R. J. Chem. Phys. 2003, 118,
9136.
(21) Schaefer, A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571.
(22) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010,
132, 154104.
G
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