Synthesis of Benzodihydrofurans by Asymmetric C?H Insertion Reactions of Donor/Donor Rhodium Carbenes

Article abstract of DOI:10.1002/chem.201701630

Metal carbenes appended with two electron-donating groups, known as “donor/donor” carbenes, undergo diastereo- and enantioselective rhodium-catalyzed C?H insertion reactions with ether substrates to form benzodihydrofurans. Unlike the reactions of metal carbenes with electron-withdrawing groups attached, the attenuated electrophilicity enables these reactions to be conducted in Lewis basic solvents (e.g., acetonitrile) and in the presence of water. The diazo precursors for these species are prepared in situ from hydrazone using a mild and chemoselective oxidant (MnO₂). Although this sequence often can be performed in one-pot, control experiments have elucidated why a “two-pot” process is often more efficient. A thorough screening of achiral catalysts demonstrated that sterically encumbered catalysts are optimal for diastereoselective reactions. Although efficient insertion into allylic and propargylic C?H bonds is observed, competing dipolar cycloaddition processes are noted for some substrates. The full substrate scope of this useful method of benzodihydrofuran synthesis, mechanisms of side reactions, and computational support for the origins of stereoselectivity are described.

Full text of DOI:10.1002/chem.201701630

A Journal of
Accepted Article
Title: Synthesis of Benzodihydrofurans by Asymmetric C-H Insertion
Reactions of Donor/Donor Carbenoids
Authors: Jared Thomas Shaw, Kellan N. Lamb, Richard A. Squitieri,
Srinivasa R. Chintala, Ada J. Kwong, Edward I. Balmond,
Cristian Soldi, Olga Dmytrenko, Marta Castiñeira Reis, Ryan
Chung, J. Bennett Addison, James C. Fettinger, Jason C.
Hein, Dean J. Tantillo, and Joseph M. Fox
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To be cited as: Chem. Eur. J. 10.1002/chem.201701630
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Synthesis of Benzodihydrofurans by Asymmetric C–H Insertion
Reactions of Donor/Donor Rhodium Carbenes
Kellan N. Lamb,†∞ Richard A. Squitieri,†∞ Srinivasa R. Chintala,‡ Ada J. Kwong,† Edward I. Balmond,†
Cristian Soldi,† Olga Dmytrenko,‡ Marta Castiñeira Reis,† Ryan Chung,§ J. Bennett Addison,† James C.
Fettinger,† Jason E. Hein,§ Dean J. Tantillo,† Joseph M. Fox,*,‡ Jared T. Shaw*,†
†Department of Chemistry, One Shields Ave, University of California, Davis, CA, 95616
∞These authors contributed equally to this work.
‡Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United
States
§Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z1,
Canada
Abstract: Metal carbenes appended with two electron-
donating groups, known as “donor/donor” carbenes,
undergo diastereo- and enantioselective rhodium-catalyzed
C–H insertion reactions with ether substrates to form
benzodihydrofurans. Unlike the reactions of metal carbenes
with electron-withdrawing groups attached, the attenuated
electrophilicity enables these reactions to be conducted in
Lewis basic solvents (e.g., acetonitrile) and in the presence
of water. The diazo precursors for these species are
prepared in situ from hydrazone using
a mild and
chemoselective oxidant (MnO2). Although this sequence
often can be performed in one-pot, control experiments have
elucidated why a “two-pot” process is often more efficient. A
thorough screen of achiral catalysts demonstrates that
sterically-encumbered
catalysts
are
optimal
for
diastereoselective reactions. Although efficient insertion into
allylic and propargylic C–H bonds is observed, competing
dipolar cycloaddition processes are noted for some
substrates. The full substrate scope of this useful method of
benzodihydrofuran synthesis, mechanisms of side reactions,
Figure 1. Structure of metal carbenes.
and
computational
support
for
the
origins
of
stereoselectivity are described.
The key intermediate in a C–H insertion is a metal carbene,
typically derived from a diazo compound. The reactivity of
metal carbenes is controlled by the functional groups
adjacent to the carbene center. An electron-withdrawing
group, such as a carbonyl, sulfonyl, or cyano is classified as
an acceptor, whereas an electron-donating group, such as an
aryl or vinyl group, is considered a donor (in a π-sense;
Figure 1). Acceptor- and acceptor/acceptor carbene have
found great utility in the formation of lactones and cyclic
ketones via intramolecular C–H insertion.4 However, the high
reactivity of acceptor- and acceptor/acceptor carbenes can
present challenges for achieving high chemoselectivity in C–
H insertion reactions.5 When one of the acceptor groups is
replaced with a donor group, resulting in a “donor/acceptor”
carbene, the reactivity is attenuated, allowing for highly
Introduction
In the area of enantioselective catalysis, metal-catalyzed C–H
insertions are well known as useful and versatile reactions to
promote C-C and C-heteroatom bond formation with high
levels of selectivity. The bulk of C–H insertion research over
the past 30 years has focused on rhodium (II) as an effective
catalyst for both inter- and intramolecular reactions.
Pioneering work 1 , 2 has led to the development of highly
effective ligands that have solidly established the utility of
rhodium-(II)-catalyzed C–H insertions in organic synthesis3.
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selective intermolecular insertions to take place6. While C–H
insertion reactions have been published extensively for the
three aforementioned carbene categories, examples of metal-
catalyzed C–H insertion reactions of donor/donor carbine are
few7 , 8 , 9 and no enantioselective reactions were published
prior to our first entry into this area10. Subsequent to our initial
report, Fürstner published X-ray crystal structures of several
rhodium carbenes, which have helped illuminate the origin of
their reactivity.11
enantiomerically pure resveratrol derivatives. We noticed an
opportunity to develop the C–H insertion reaction of
donor/donor carbenes for application in natural product
synthesis. C–H insertion has been previously used in the total
synthesis of BDF natural products such as (-)-ephedradine A,
(orantine) . (-)-serotobenine and (-)-decursivine , (-)-
aperidine21, and (+)-lithospermic acid22 (Figure 3). In most
cases, enantioselectivity is imparted by both a chiral rhodium
catalyst and a chiral auxiliary. The diazo species in all cases
is donor/acceptor. While donor-acceptor carbenes have been
19
20
We initially explored the C–H insertion reactions of donor-
donor carbenes as an entry into the enantioselective
synthesis of benzodihydrofurans (BDFs)12. This heterocyclic
core is found widely in natural products, most notably in the
shown to undergo a wide variety of highly selective
intermolecular reactions6, these natural product syntheses
demonstrate that the selectivities are often lower for
intramolecular reactions.
oligomers of resveratrol. Resveratrol is
a polyphenolic
phytoalexin produced by plants in response to infection or
injury, often oligomerizing to form complicated structures.
Studies suggest that resveratrol itself is partly responsible for
the health benefits of drinking red wine13, whereas some of
the oligomers derived from resveratrol also possess
interesting bioactivities (Figure 2).14, 15
Figure
2.
Target
resveratrol-derived
molecules
featuring
benzodihydrofuran and indane core structures.
Figure 3. Previous examples of C–H insertion in BDF synthesis.
Resveratrol dimers have been previously accessed through
16
17
cyclization,
metal-catalyzed cross couplings,
and
enzymatic transformations.18 Enzymatic transformations are
challenging to control for a single target and often provide a
complex product mixture. Synthetic methods provide
excellent product control, however, much of the work has
been focused on carbocycles such as indane and indanones
and very little has been done to address heterocyclic targets
containing a benzodihydrofuran core. Additionally, none of
the synthetic methods applied to resveratrol derivative
synthesis are enantioselective. The natural products are
isolated as both racemates and single enantiomers, thus
there is a need for a robust method to synthesize
Recently, we reported our initial study of the intramolecular
C–H insertion of donor/donor Rh(II) carbenes10. Derivatives of
2-hydroxybenzophenone were converted to a diaryl diazo
compounds and were effective in forming benzodihydrofurans
via C–H insertion. We also demonstrated the utility of our
method by synthesizing 2 (Figure 2) for the first time as a
single enantiomer. Herein, we report our full study including
an expanded scope and exploration of side reactions, as well
as mechanistic and kinetic studies.
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Table 1. Screening of dirhodium tetracarboxylate catalysts to optimize
yield and diastereoselectivity
investigated a series of dirhodium carboxylate catalysts,
including several catalysts that have not been described
previously (Table 1, entries 8, 12, 15, 16, 17, 19). Catalysts
with bulky carboxylate ligands, e.g. Rh2(O2CPh3)4, resulted in
excellent diastereoselectivity and yield with no observable
imine formation (Table 1, entries 7, 8, 15, 17). Although
Rh2(O2CPh)4 (entry 11) gave good
Results and Discussion
Method Development. Our initial investigation into the C–H
insertion of diaryl Rh (II) carbenes was conducted with diazo
29 (Scheme 1). Initially, diazo compound 29 was prepared
and isolated using Swern conditions as reported by Brewer23.
This substrate was added to a solution of Rh2(OAc)4 using a
syringe pump and produced 12 in high yield and with modest
diastereoselection for the syn isomer. After investigating a
few other oxidants, MnO2 emerged as the most operationally
simple24. After isolation, a small quantity of Rh2(OAc)4 was
added to the solution of diazo intermediate 29 and again, high
yield for the product was observed. Finally, in an attempt to
streamline the process, the oxidant (MnO2) and catalyst were
sequentially added to a solution of the hydrazone, once again
resulting in a high level of conversion to the product. With
these conditions in hand, we investigated additional achiral
rhodium catalysts. Commercially available Rh2(TFA)4 and
Rh2(esp)2 were unable to improve on the preliminary result
(Table 1, entries 2 and 3). Initially, we attributed the lower
yields to lower catalyst efficiency. Upon closer inspection of
the 1H NMR of the crude reaction, it was clear that in the case
of Rh2(esp)2 there was a significant byproduct present.
Isolation and characterization of this byproduct revealed its
identity as imine 13 (Table 1). Subsequent experiments
revealed that the formation of imine is increased at lower
temperature (Table 1, entry 4) and is negated entirely when
the oxidant was filtered away prior to catalyst addition (Table
1, entry 5). To obtain insight in to steric and electronic effects
of ligand structure on selectivity for C–H insertion, we
Scheme 1. Initial investigation of diaryl rhodium (II) carbenes in C–H
insertion.
chemoselectivity for C–H insertion, the diastereoselectivity
was low and could be improved by replacing the phenyl ring
with either mesityl or 9-anthracenyl (Table 1, entries 12 and
15). Alkyl substitutions showed an increased preference for
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imine formation and generally suffered from lower isolated
yields as a result (entries 6, 13, 18 and 19). Rh2(cap)4 was a
unique catalyst for this screen as the only non-
C–H insertion. Three hydrazones were selected for this study
(eq 1). Rates of oxidation for unsubstituted 39a and p-
methoxy substituted 39b hydrazones were similar, while the
cyano substituted hydrazone (39c) was slower (Figure 4A).
After the rhodium catalyst was added, C–H insertion
proceeded rapidly in all cases (<10 minutes), as inferred from
the disappearance of the diazo signal. We observe only slight
differences in the rate of C–H insertion as a function of the
aryl substituent. The variability in rates of oxidation based on
the electronic nature of the hydrazone paired with the rapid
and near constant rate of carbene formation and subsequent
C–H insertion account for varying levels of imine formation
from different substrates. Although the relative rates were not
examined with different catalysts, it can be inferred that faster
or slower catalytic rates would also have an impact on the
imine formation pathway.
tetracarboxylate
ligand
and
afforded
excellent
chemoselectivity for C–H insertion, though both the dr and
yield were modest (entry 14).
Although imine 13 would appear to be
hydrogenolysis of the hydrazone, the oxidative nature of the
reaction conditions ruled out this pathway. control
a product of
A
experiment with benzophenone hydrazone 30 suggests that
the imine is a product of hydrazone reacting with carbene.
When a mixture of hydrazone (30) and diphenyldiazomethane
31 is combined with a rhodium catalyst, rapid conversion to
benzophenone imine is observed (Scheme 2A). In the
absence of catalyst, trace imine 32 is formed along with
products of decomposition. In other contexts, we have also
seen the formation of azines, which are known to arise from
reaction of Rh-carbenes with diazo compounds.25 Treatment
of diphenyldiazomethane with a rhodium catalyst results in
rapid formation of azine 34, presumably by nucleophilic attack
of the hydrazone amino group on the carbene intermediate.
These two control experiments suggest that substrates prone
to either slow oxidation or slow insertion may lead to
undesirable by-products (Scheme 2B).
Scheme 2. A) Control reactions to determine side products of C–H
insertion, B) Conditions for side product formation.
Figure 4. Reaction progress curves of conversion vs. time of (A)
hydrazone oxidation and (B) C–H insertion as determined by ReactIR
monitoring. The hydrazone oxidatinos were carried out with 8 equiv of
MnO2 in CH3CN at 01 M in 39a-c at 25 °C.
The relative rates of hydrazone oxidation and C–H insertion
were studied using real-time FTIR spectroscopy. We were
interested in learning how the electronic nature of the aryl ring
of the hydrazone would affect the rates of both oxidation and
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Computational studies are consistent with the hypothesis that
imine is formed by the reaction of the hydrazone with a
rhodium carbene intermediate. The process was modeled at
the B3LYP/6-31G(d) [C,H,N,O], LANL2DZ [Rh] level of
theory26, using Rh(HCO2)4 as a model catalyst. Addition of
the hydrazone to the rhodium carbene complex is predicted
to be endothermic by 3.1 kcal/mol, but proton transfer to form
the precursor to fragmentation is predicted to be exothermic
by 3.6 kcal/mol. The free energy barrier to fragmentation, via
the transition state structure shown in Figure 5, is predicted to
be only 4.1 kcal/mol (3.5 kcal/mol from separate hydrazone
and carbene). The results of these calculations suggest that
the process shown is indeed facile and a reasonable
mechanism for imine formation is shown in Scheme 3.
C–H insertion is slow, then the diazo intermediate can
dimerize to azine. Although this pathway is rarely seen for
intramolecular processes, we have observed azine formation
when we have attempted intermolecular reactions (not
shown).
After exploring achiral catalysts, we turned our attention to
controlling enantioselectivity with the hope of improving
diastereoselectivity at the same time. The oxazolidinone
catalyst Rh2(4S-MPPIM)4 41 resulted in no observable
conversion to the C–H insertion product 12 (Table 2, entry 1).
Rh2(R-DOSP)4 gave rapid conversion to the desired product
with a high level of diastereoselectivity (94:6) and modest
enantioselectivity (36:64) (Table 2, entry 2). Finally, use of the
phthalimide
catalyst
Rh2(R-PTAD)4
43
produced
benzodihydrofuran 12 with excellent yield, enantioselectivity
and diastereoselectivity. Although reasonable effort is made
to exclude water from these reactions by the use of oven-
dried glassware and anhydrous solvent, the presence of
water does not have a significant impact on the reaction
selectivity and only slightly reduced yield is observed (Table 2,
entry 6). Similar results are observed when the reaction is
conducted in alcoholic solvents. These results are consistent
with the greatly reduced electrophilicity of donor/donor
carbene (when compared to those appended with an
electron-withdrawing group), which slows down nucleophilic
attack by oxygen nucleophiles such as water.
Table 2. Chiral catalysts for C–H insertion of benzyl ether 11.
Figure 5. Fragmentation transition state structure for the formation of
32 from 30. Selected distances in Å.
Scheme 3. Proposed mechanism of imine formation.
Together, these results provide a mechanistic basis for the
variable reactivity that is observed in the case of the PMB
ether and in other substrate classes discussed later. If both
the imine oxidation and the C–H insertion are slow, then
under “one-pot” conditions where all reagents are added at
once, the remaining hydrazone can consume carbene
intermediate to form imine, thus decreasing the yield of
insertion product. This unproductive pathway can be
suppressed by filtering away the MnO2 prior to addition of the
catalyst (“two-pot” conditions shown in Table 1, entry 5), or by
simply allowing full conversion of the hydrazone to the diazo
intermediate before treating with catalyst, i.e., the presence or
absence of MnO2 is irrelevant. If the oxidation is fast but the
Although the reaction with Rh2(PTAD)4 worked with
exceptional selectivity with the PMB ether in CH2Cl2, this was
not the case as we started to explore other substrate classes.
When we subjected n-butyl ether 44 to our one-pot conditions
in CH2Cl2, we observed that enantioselectivity was high, yet
there was no diastereoselectivity (Table 3, entry 1). When
coupled with the poor yield, this provided us with an ideal
substrate for solvent optimization. Nonpolar solvents pentane
and toluene did little to improve this ratio (entries 2-3). Polar
solvents THF and ethyl acetate provided significant boosts to
the dr (entries 4-5). Finally, acetonitrile was found to be
superior (entry 6) by offering the highest dr while also
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doubling the yield and only slightly compromising the er. In
contrast, polar solvents are seldom used for the reactions of
acceptor-substituted carbenes. 27 One caveat is that the
solubility of Rh2(PTAD)4 in acetonitrile is relatively low, which
puts an upper limit on the catalyst loading. Based on the
results of this screen, we opted to run the bulk of our
substrate scope studies in acetonitrile.
Table 3. Optimization of solvent.
C–H Insertion of Allyl Ethers. Allylic ethers are attractive
substrates, given their ease of synthesis and flexibility with
regard to subsequent functionalization. For this substrate
category, we were interested in the effects of substitution on
the insertion reaction, and also the product outcome.
Although a rhodium carbene with a pendant allylic ether can,
in theory, undergo either C–H insertion or cyclopropanation,
we only observe insertion with most substrates (Table 5).
Yields are generally very high, although lack of alkene
substitution and substitution close to the insertion site appear
to lead to a decrease (entries 1 and 2). Enantio- and
diasteroselectivities are high in all cases. Also, E/Z
isomerization is not observed (entries 3 and 4). These
substrates were all run with conditions A - our “one-pot”
method.
C–H Insertion of Benzyl Ethers. With our catalyst, solvent,
and procedure set, we proceeded to examine substrate
scope. Given our interest in resveratrol-derived natural
products containing phenyl-substituted benzodihydrofurans,
we were particularly interested benzyl ether substrates. We
were pleased to observe that Rh2(R-PTAD)4 was useful for
the C–H insertion of a variety of substituted benzyl ethers
(Table 4). Products were isolated as a single diastereomer by
NMR in each case, and enantioselectivities were excellent
and appear to be unaffected by the presence of strong
electron-donating or electron-withdrawing groups on any of
the three aryl rings. A strong withdrawing group adjacent to
the benzylic insertion site causes a reduction in yield (entries
2 and 4), but the same substitution on the pendant aryl ring
has no effect (entry 9). The bulk of the substrates worked well
when exposed to our one-pot conditions A, but some
experienced a boost in yield, er and/or dr when exposed to
our two-pot conditions B. Overall, the reaction of benzylic
ethers is robust and amenable to varying electronic
environments and functional groups.
Table 5. Enantioselective C–H insertion reactions of substituted allyl
ethers.
Table 4. Enantioselective C–H insertion reactions of substituted benzyl
ethers.
Attempted insertion reactions of cinnamyl ether 50 revealed
an alternate, non-catalytic reaction pathway. When insertion
of 50 was first attempted with conditions A, formation of the
expected benzodihydrofuran 51 was observed with modest
yield and enantioselectivity (Scheme 4). When conditions B
were used in an attempt to boost yield and selectivity, rapid
conversion to fused pyrrazoline 52 by an intramolecular
dipolar cycloaddition (DPC) was observed. Following this
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result, the hydrazone was subjected to MnO2 with no catalyst
present, also resulting in the DPC product. DPC reactions of
diazo compounds with alkenes are well-documented28 and a
recent report from the Zard group provides close precedent
for our results29 . Full characterization of 52 proved to be
elusive due to its rapid thermal nitrogen extrusion30, resulting
in cyclopropane product 53, whose structure was determined
unambiguously by X-ray crystallography. Chemical shift and
splitting values from a full set of 2-D NMR spectroscopy
(COSY, HSQC, HMBC, NOESY, TOCSY, 1H-15N HSQC)
were consistent with NMR chemical shifts and coupling
The attempted insertion of unsubstituted propargyl ether 63
led primarily to the DPC product. Hydrazone 63 was
subjected to our standard one-pot conditions with Rh2(R-
PTAD)4 in CH2Cl2. The major product was pyrazole 64 from
1,3-dipolar cycloaddition, in analogy to the competing
1
pathway for allylic substrates (eq 2). Some signals in the H
NMR spectrum of the unpurified reaction mixture suggest that
insertion product 65 was formed in small quantities. Stirring
hydrazone 63 with only MnO2 afforded the DPC product as
the sole product. Phenyl substitution of an alkene accelerated
the formation of DPC. In contrast, phenyl substitution of the
analogous alkyne caused a reduction in rate of DPC
formation, potentially due to increased sterics and less
flexibility in the substrate.
constants computed with density functional theory (DFT)31
.
Two additional allylic ethers were cyclized to produce
pyrrazolines 55a and 55b. The cyclization product 54b was
formed previously with a similar method by Zard, and the
spectral data is consistent with theirs29. Given three potential
pathways of reactivity, these results demonstrate that
rhodium-catalyzed C–H insertion outpaces intramolecular
DPC in most cases, and direct cyclopropanation is never
observed.
Table 6. Enantioselective C–H insertion reactions of propargyl ether 56.
H2N
conditions A
Ph
O
N
O
(one pot)
Ph
Ph
Ph
51, 54% yield
50
>95:5 dr, 86:14 er
-OR-
conditions B
(two pot)
50:50 er
MnO2, CH2Cl2
(no catalyst!)
Ph
H
H
O
O
Ph
N
N
Ph
Ph
53, >95:5 dr
100% conversion
52, >95:5 dr
73% yield
X-ray structure of 53
H
H2N
R
MnO2
CH3CN
N
O
O
N
N
R
54a (R=Ph)
54b (R=CH3)
55a (R=Ph), 64% yield, >95:5 dr
55b (R=CH3), 36% yield, >95:5 dr
Scheme 4. Competing insertion and uncatalyzed 1,3-dipolar cycloaddition
pathways for cinnamyl ether 50.
C–H Insertion of Propargyl Ethers. Alkyne substitution on
the C–H insertion substrate presented an opportunity for
catalyst optimization. Phenylpropargyl ether 56 underwent
substitution with high diastereoselectivity and yield, yet the
enantiomer ratio was among the lowest observed (Table 6,
entry 1). Although the er was improved greatly by running the
reaction in CH2Cl2, the yield was halved (entry 2). Additional
PTAD-like catalysts were tested in the hope of improving
these two areas. Rh2(S-PTTL)4 (58), Rh2(S-TCPTTL)4 (59),
and Rh2(S-BPTTL)4 (entries 3, 4, and 7) afforded roughly the
same yield and lower enantioselectivities than Rh2(S-PTAD)4.
A large increase in yield was noted for Rh2(S-NTTL)4 (60) and
When phenyl substituted alkyne 56 was revisited, it was
revealed that the DPC product is formed to varying degrees.
With Rh2(PTAD)4 as the catalyst, the major product is C–H
insertion (Table 7, entry 1), highlighting the high reactivity of
this catalyst. With Rh2(OAc)4, dipolar cycloaddition is the
major pathway (entry 2). Although reduced temperature shifts
Rh2(S-PhenTTL)4 (61) (entries
5 and 6), however the
enantioselectivity was diminished in both cases.
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the reaction toward C–H insertion, cycloaddition is still the
dominant pathway. As with 63, omission of the catalyst yields
the DPC product 66 in high yield.
outcomes of C–H insertion events. Based on DFT
calculations, intermolecular cyclopropanation reactions have
34
also been proposed to follow a concerted pathway
.
However, our more recent experimental studies on
intramolecular cyclopropanation reactions to form
Table 7. Reactions of propargyl ether 56.
bicyclobutanes led us to propose a stepwise mechanism
involving an ylide intermediate35 . Similarly, we considered
that a zwitterionic pathway might also prove relevant to
intramolecular C–H insertion reactions, where geometric
constraints would render difficult a mechanism involving
concerted C–H insertion.
A mechanistic model for the intramolecular C–H insertion
reaction was developed computationally as shown in Figure 6.
For carbene 69, a transition state structure (TS1) was located
for hydride transfer to give ylide intermediate 70. This same
transition state structure was observed from several starting
geometries, including one where the C–H bond and the Rh=C
were aligned as in Nakamura’s transition state for concerted
C–H insertion32. With a very low barrier ( H‡ = 4.0 kcal
kcal/mol with M06-2X/LANL2DZ [6-311+G(d,p)]; 2.4 kcal/mol
with B3LYP/LANL2DZ[6-31G(d)]), ylide 70 proceeds to the
formal C–H insertion product via a second transition state
C–H Insertion of Alkyl Ethers. Alkyl ethers were challenging
substrates that demonstrated the limits of this methodology.
Although conditions B worked well for several branched
ethers, the er was slightly diminished in the case of isopropyl
ether 67d (Table 8). Methyl ether 67e proceeded with poor
conversion and modest er. The yield could be improved with
a shorter oxidation time (entry 6). The low reactivity is
expected, because hydride transfer is believed to be the first
event in a concerted, asynchronous reaction that is followed
by rapid collapse of the metal-bound anion and pendant
cation32. The poor enantioselectivity is not surprising due to
the low steric demand of the methyl ether, especially when
viewed in comparison to our computational results for more
substituted reactants (see below).
structure (TS2).
The predicted barrier for the highly
exothermic conversion of ylide 70 into product 12 is much
lower than the expected barrier for isomerization of the
oxonium of intermediate 70.36 Because TS2 represents the
barrier to a stereospecific process, the diastereoselectivity
should be governed by TS1. Moreover, this very low barrier is
consistent with many previous examples in which C–H
insertion at stereocenters has been shown to be
stereospecific, as the conversion of ylide 70 into product 12 is
expected to be fast and hence stereospecific.
Table 8. C–H insertion reactions of alkyl ethers.
Origin of Stereoselectivity. Computation was used to query
the mechanism of the intramolecular C–H insertion reaction
to form dihydrobenzofuran products. A concerted mechanism
for reactions of Rh-carbenes has been proposed based on
DFT calculations by Nakamura and co-workers32.
A
concerted mechanism had also been proposed for
intramolecular C–H insertion reactions by Taber and co-
workers based on semi-empirical calculations 33 . Taber’s
model proved very effective for predicting stereochemical
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10.1002/chem.201701630
Chemistry - A European Journal
FULL PAPER
A. Syn: Lower Energy (TS1a)
A
CH3
H3C
O
CH3
H3C
CH3
H3C
O
O
O
O
O
O
O
O
O
O
O
Rh
Rh
Rh
Rh
Rh
Rh
H
H
H
H
O
O
O
O
O
O
O
O
O
H
H
O
O
O
O
O
O
H3C
H3C
CH3
CH3
H3C
CH3
TS1
carbene (69)
O
O
H3C
O
H3C
CH3
H3C
O
560.7i cm-1
79.2i cm-1
H3C
CH3
H3C
O
O
O
O
O
m062x/LANL2DZ [6-311+G(d,p)]: DH‡ 6.5 kcal/mol
B3LYP/LANL2DZ[6-31G(d)]: DH‡ 8.1 kcal/mol
O
O
–
–
Rh
Rh
Rh
Rh
H
H
H
O
O
O
O
O
O
H
O
+
O
O
B. Anti: Higher Energy (TS1b)
+
O
H3C
CH3
CH3
H3C
O
H3C
CH3
O
O
O
TS2
O
ylide (70)
O
H3C
Rh
Rh
H3C
H
H
O
O
O
O
B
O
TS1
6.5 (8.1)
TS2 7.9 (5.9)
H3C
CH3
O
ylide (70)
3.9 (3.5)
H3C
516.4i cm-1
193.7i cm-1
m062x/LANL2DZ [6-311+G(d,p)]: DH‡ 7.9 kcal/mol
B3LYP/LANL2DZ[6-31G(d)]: DH‡ 10.1 kcal/mol
carbene (69)
H = 0.0
~
~
Figure 7. Transition state structures for initial hydride transfer step
leading to (A) syn- and (B) anti- diastereomers.
product (12)
–42.8 (–32.9)
Figure 6. (A) Proposed mechanism for C–H insertion involving an ylide
intermediate (70) that proceeds to dihydrobenzofuran product with a very
low barrier (TS2). (B) Enthalpy vs reaction coordinate for the conversion of
carbene 69 into product 12 via ylide 70. Enthalpies are in kcal/mol.
Energies at the M06-2X/LANL2DZ [6-311+G(d,p)] level are shown first,
with enthalpies at the B3LYP/LANL2DZ[6-31G(d)] level in parentheses.
The Rh2(OAc)4–derived transition state structures were used
to develop
a model to rationalize the high levels of
enantioselectivity and diastereoselectivity observed with
Rh2(S-PTAD)4 catalyzed C–H insertion reactions. This model
assumes that Rh2(S-PTAD)4 adopts
a
‘chiral crown’
structure,37 similar to that observed for Rh2(S-PTTL)4, where
all of the phthalimido groups are projected on the same face
of the catalyst (the chiral crown structure has recently been
observed in a Rh2(S-PTTL)4[=C(Ar)COOMe).38 Starting with
the known structure of Rh2(S-PTTL)439 and the core structure
of Rh2(OAc)4–derived transition state structure TS1a, we
were able to locate the transition state structure shown in
Computation was also used to probe the diastereoselectivity
for the transformation of carbene 69 into ylide 70. As shown
in Figure 7, two transition state structures were located—
TS1a, which leads to the syn-diastereomer, and TS1b, which
leads to the anti-diastereomer. For TS1b, the enthalpic
barrier was 1.4 kcal/mol higher at the M06-2X/LANL2DZ [6-
311+G(d,p)] level, and 2.0 kcal/mol higher at the
Figure 8.
Calculations were carried out at the
B3LYP/LANL2DZ[6-31G(d)] level.
Similar differences
B3LYP/LANL2DZ[6-31G(d)] level. In this transition state
structure, which leads to syn-(R)-12, the chiral crown
structure of the catalyst is maintained without incurring any
offensive steric interactions. An attractive C–H π interaction40
(2.82 Å) between the substrate-derived phenyl group and a
ligand phthalimido was observed. We also located transition
state structures that would lead to the diastereomeric product
anti-(S)-12 as well as the enantiomeric product syn-(S)-12,
which were higher in energy by 4.7 and 6.1 kcal/mol,
respectively, relative to the transition state structure leading
to syn-(R)-12 (Supporting Information). These transition state
structures both incurred significant interactions between
substrate and ligand fragments. While the large size and
between the two transition states were observed when
E‡,,E(ZPE)‡ and G‡ were compared (Supporting
Information). These computational findings are consistent
with the experimental finding that the syn-diastereomer is
favored.
conformational flexibility of these complexes makes
a
complete comprehensive analysis nearly impossible, we were
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10.1002/chem.201701630
Chemistry - A European Journal
FULL PAPER
under an atmosphere of argon in oven-dried glassware with magnetic
stirring. Dry solvent was dispensed from a solvent purification system
that passes solvent through two columns of dry neutral alumina. 1H
NMR spectra and proton-decoupled 13C NMR spectra were obtained
on a 400 MHz Bruker or a 600 MHz Varian NMR spectrometer.
Chemical shifts (δ) are reported in parts per million (ppm) relative to
TMS (s, δ 0). Multiplicities are given as: s (singlet), d (doublet), t
(triplet), q (quartet), p (pentet), h (hextet), and m (multiplet). Complex
splitting will be described by a combination of these abbreviations, i.e.
dd (doublet of doublets). 13C NMR chemical shifts are reported
relative to CDCl3 (t, δ 77.4) unless otherwise noted. High-resolution
mass spectra were recorded on positive ESI mode unless otherwise
noted. Melting points were taken on an EZ-melting apparatus and
were uncorrected. Infrared spectra were taken on a Bruker Tensor 27
spectrometer. Chromatographic purifications were performed by flash
chromatography with silica gel (Fisher, 40–63 μm) packed in glass
columns. The eluting solvent for the purification of each compound
was determined by thin-layer chromatography (TLC) on glass plates
coated with silica gel 60 F254 and visualized by ultraviolet light.
Abbreviations for frequently used chemicals will be seen as follows:
dichloromethane (CH2Cl2), ethanol (EtOH), ethyl acetate (EtOAc),
methanol (CH3OH), tetrahydrofuran (THF), acetonitrile (CH3CN).
Diastereoselectivity of the C–H insertion reactions was measured
primarily by crude 1H NMR (compounds listed as >95:5), with some
substrates measured by GC-MS (compounds listed as >99:1). In situ
FT-IR monitoring was conducted with a Mettler-Toledo ReactIR 15
equipped with a DiComp (Diamond) ATR probe connected via an AgX
(silver halide) 6 mm x 1.5 m fiber optic cable. Reaction temperatures
were monitored using an internal thermistor in the IR probe.
Sampling was carried out over 2000–800 cm–1 at 4 wavenumber
resolution with 1x gain. The formation and consumption of the diazo
intermediate was performed by tracking the IR peak height at 1316 or
1280 cm–1 over time relative to a signal point baseline.
not able to locate alternate transition state structures that
maintain the chiral crown structure of Rh2(S-PTTL)4 without
incurring such steric interactions.
2.82 Å
H•••C
OCH3
O
N
O
O
tBu
tBu
N
H
O
H
Rh
O
O
H
N
tBu
O
tBu
N
O
O
General Procedure A for the Synthesis of Benzophenones:
In a flame-dried flask, 2-hydroxybenzophenone (0.5 g, 2.5 mmol) and
anhydrous Cs2CO3 (2.44 g, 7.5 mmol) were dissolved in anhydrous
acetonitrile (25 mL, 0.1 M). The desired alkyl bromide (3 mmol) was
added slowly, and the reaction was heated at 50 °C for 3-18 hours.
Following completion (determined by TLC), the Cs2CO3 was removed
via filtration, then the solvent was removed in vacuo to give the crude
product. Purification using column chromatography with 10-20%
EtOAc/hexanes as the eluent afforded the desired alkylated product.
Figure 8. Transition state for the initial hydride transfer step in the
reaction leading to syn-(R)-12. The carbene is derived from Rh2(S-
PTTL)4, a structurally similar analog to Rh2(S-PTAD)4 with t-Bu groups
instead of adamantyl groups. The t-Bu groups are not shown for
clarity. Calculations were carried out at the B3LYP/LANL2DZ[6-
31G(d)] level.
Conclusions
In summary, we have developed the C–H insertion reaction of
donor/donor diaryl rhodium carbenes for the enantioselective
synthesis of benzodihydrofurans. Our method enables the
rapid assembly of enantioenriched benzodihydrofuran cores
in one step from diaryl hydrazones. The reaction is robust
and amenable to the presence of water, varying functional
groups and steric factors. Computation has led to a robust
mechanistic model and provides an explanation for the high
enantio- and diastereoselectivity observed. Several side
pathways have been thoroughly investigated and
characterized. This synthetic method should be valuable in
the future synthesis of natural products and other compounds
with a benzodihydrofuran core.
General Procedure B for the Synthesis of Benzophenones:
To a flask was added 2-hydroxybenzophenone (0.5 g, 2.5 mmol), the
desired alcohol (2.5 mmol) along with anhydrous THF (25 mL, 0.1 M).
After cooling to 0 °C, PPh3 (0.787 g, 3 mmol) and diisopropyl
azodicarboxylate (DIPAD) (0.589 mL, 3 mmol) were added and the
reaction was stirred overnight while coming to room temperature. The
solvent was evaporated, and careful purification using column
chromatography with 5-10% EtOAc/hexanes as the eluent afforded
the desired alkylated product.
General Procedure C for the Synthesis of Dibenzyl Alcohols:
In a flame-dried flask purged with argon, aryl bromide (1 equiv.) was
dissolved in THF (0.24M) and cooled to -78 °C. Butyllithium solution
(1.1 equiv., 2.5 M in hexanes) was added dropwise, and the reaction
was stirred at -78 °C for 20-40 minutes. The desired aldehyde (1.05
equiv., 0.37 M in THF) was then added dropwise, and the reaction
was stirred for an hour before it was allowed to warm slowly to room
temperature over an additional three to four hours. The reaction was
quenched with a volume of saturated ammonium chloride solution
equal to the volume of aryl bromide solution and diluted with an
equivalent amount of water. The aqueous layer was extracted three
Experimental Section
Materials and Instrumentation:
Unless otherwise specified, all commercially available reagents were
used as received. All reactions using dried solvents were carried out
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10.1002/chem.201701630
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FULL PAPER
times with EtOAc, and the combined organic layers were washed one
time each with water and brine. The organic layer was then dried over
Na2SO4, filtered and concentrated in vacuo to afford the crude product.
alumina.
Tetrahydrofuran
was
freshly
distilled
from
sodium/benzophenone. Anhydrous chlorobenzene was purchased
from Acros. Rh2(OAc)4 was purchased from Pressure Chemicals.
Chromatography was performed on silica gel (Silicycle Siliaflash 40-
63μm, 60Å). Reagents were used directly as purchased from
commercial sources without further purification. For 13C NMR,
multiplicities were distinguished using an ATP pulse sequence: typical
quaternary and methylene carbon appears ‘up’ (C or CH2); methane
and methyl carbons appears ‘down’ (CH or CH3). High-resolution
mass spectrometry (HRMS) was performed using Liquid Injection
Field Desorption Ionization (LIFDI) coupled with a time of flight (TOF)
detector. Dirhodium tetrakis(tri(4-fluorophenyl)acetate (16),
dirhodium tetrakisbenzoate (19),
fluorophenyl)-2-methylpropanoate (24), and dirhodium tetrakis (2-
methy-2-phenyl)propanoate (26),43 were prepared by methods in the
literature.
Purification
using
column
chromatography
with
20-30%
EtOAc/hexane solution provided the desired product.
General Procedure D for the Synthesis of Benzophenones:
To a flame-dried flask purged with argon was added the alcohol from
General Procedure D (1.0 equiv), solid NaHCO3 (10 equiv.) and dry
CH2Cl2 (0.13M). Dess-Martin periodinane (1 equiv.) was added and
the reaction was stirred at room temperature for 2-4 hours. The
reaction was quenched with a volume of saturated Na2SO3 equal to
half the volume of CH2Cl2 and was stirred for 5 minutes. An equal
volume of saturated NaHCO3 solution was then added, and the
aqueous layer was extracted with EtOAc three times. The combined
organic layers were washed one time each with water and brine, then
dried over Na2SO4, filtered and concentrated in vacuo to afford the
desired ketone product. This product was carried forward without
further purification. The ketone (1 equiv.) was taken up in dry CH2Cl2
(0.1M) and cooled to 0 °C. BCl3 (1.5 equiv., 1.0 M in CH2Cl2) was
added dropwise, and the reaction was stirred at 0 °C for one hour.
The reaction was quenched with a volume of saturated ammonium
chloride equal to the volume of CH2Cl2. The aqueous layer was
extracted three times with CH2Cl2, and then the combined organics
were washed one time each with water and brine. The organic layer
was dried over Na2SO4, filtered and concentrated to afford crude
product. This product was taken immediately into the next reaction
without further purification. The phenol (1 equiv.) was dissolved in
acetonitrile (0.1M) under argon. To the flask was added Cs2CO3 (3
equiv.) and PMBCl (1.2 equiv.) and the reaction was heated at 50 °C
overnight. The Cs2CO3 was filtered off, and the filtrate was
concentrated in vacuo to afford crude product. Purification using
column chromatography with 20-30% EtOAc/hexane solution afforded
the desired product.
41
42
dirhodium tetrakis(2-(4-
General Procedure G for the synthesis of Tetrakis dirhodium (II)
complexes:
To a flame dried round-bottomed flask equipped with a pressure
equalizing addition funnel containing a plug of cotton and Na2CO3 (for
removal of acetic acid) and a reflux condenser was charged with
dirhodium tetraacetate (50 mg, 0.113 mmol, 1.0 equiv) and the
appropriate carboxylic acid (1.13 mmol, 10 equiv) and the apparatus
was evacuated and filled with nitrogen. Anhydrous chlorobenzene
was added and the mixture was heated to reflux for 12 h. The solvent
was subsequently distilled off and the green residue was dissolved in
CH2Cl2, washed three times with aqueous saturated sodium
bicarbonate, dried over anhydrous MgSO4, filtered, concentrated, and
chromatographed on silica gel to give the title compound as a green
solid.
General Procedure
benzodihydrofurans:
H
for the synthesis of racemic
General Procedure E for the Synthesis of Hydrazones:
The desired hydrazone (1 eq) was dissolved in acetonitrile or CH2Cl2
(0.016M) under argon atmosphere. The flask was wrapped in foil,
then MnO2 (8 eq.) was added followed by Rh2(OAc)4 (0.01 eq). The
reaction was stirred from 3-18 hours at room temperature. Following
reaction completion, the MnO2 was removed by passing the crude
reaction through a plug of celite or silica and rinsing several times with
CH2Cl2. The solvent was removed in vacuo to give the crude product.
Column chromatography using 2-5% EtOAc/hexanes as the eluent
afforded the desired product.
To a flame-dried flask was added anhydrous EtOH (0.06 M) along
with the desired alkylated benzophenone (1 equiv.) from General
Procedure A, B, or D. Glacial acetic acid (1.2 equiv) was added
followed by anhydrous hydrazine (6 equiv.), and the reaction was
heated to 80 °C overnight. After the EtOH was removed in vacuo, the
residue was taken up in Et2O and water. The layers were separated
and the organic layer was washed with water (2 x 20 mL). The
combined organic layers were dried using anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The crude material was purified
using column chromatography (15-25% EtOAc/hexanes) to afford the
desired product. Yields were typically seen between 60-90%.
General
Procedure
I
for
the
synthesis
of
chiral
benzodihydrofurans (Method A):
In a flame-dried flask, the desired hydrazone (1 equiv.) was dissolved
in acetonitrile (0.016 M) under argon atmosphere. The flask was
placed in an ice bath wrapped in foil, then MnO2 (8 equiv.) was added
followed by Rh2(R-PTAD)4 (0.01 eq). The reaction was stirred from 3-
18 hours while coming to room temperature. Following reaction
completion, the MnO2 was removed by passing the crude reaction
through a plug of silica or celite and rinsing several times with CH2Cl2.
The solvent was removed in vacuo to give the crude product. Column
chromatography using 2-5% EtOAc/hexanes as the eluent afforded
the desired product.
General Procedure F for the screening of achiral catalysts:
To a vial was added hydrazone 11 (25.0 mg, 0.075 mmol) and the
desired rhodium catalyst (7.5 X 10-4 mmol, 1 mol%). The vial was
flushed with Ar and CH2Cl2 (4.7 mL, 0.016M) was added. MnO2 (52.1
mg, 0.6 mmol) was added last, and the vial was capped and covered
with foil. The reaction was run overnight at room temperature, filtered
through celite and concentrated to afford the crude product.
Diastereoselectivity and product ratios were assessed by 1H NMR.
The residue was purified by flash column chromatography (10:90
EtOAc/hexanes) to provide insertion product.
General
Procedure
J
for
the
synthesis
of
chiral
benzodihydrofurans (Method B):
General Considerations for the Synthesis of Novel Achiral
Catalysts:
In a flame-dried flask, the desired hydrazone (1 equiv.) was dissolved
in acetonitrile (0.1 M) under argon atmosphere. The flask was
wrapped in foil, and MnO2 (8 equiv.) was added. The oxidation was
allowed to stir for 1 hour, then reaction was filtered through celite into
a new flame-dried flask. The bright orange diazo compound was
All reactions were carried out in glassware that was flame-dried under
vacuum and cooled under nitrogen. Dichloromethane, toluene and
hexanes were dried with columns packed with activated neutral
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10.1002/chem.201701630
Chemistry - A European Journal
FULL PAPER
diluted to 0.015 M, cooled to -20 or 0 °C, and the Rh2(R-PTAD)4
catalyst was added. The insertion reaction was stirred for 3-18 hours.
The solvent was then evaporated to give the crude product. Column
chromatography using 2-5% EtOAc/hexanes afforded the desired
product.
[2]
[3]
Doyle, M. P.; Brandes, B. D.; Kazala, A. P.; Pieters, R. J.; Jarstfer,
M. B.; Watkins, L. M.; Eagle, C. T. Tetrahedron Lett. 1990, 31,
6613-6616.
For comprehensive reviews on C–H insertion, see: a) Doyle, M. P.;
Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704-724; b)
Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061-
3071; c) Santiago, J. V.; Machado, A. H. L. Beilstein J. Org. Chem.
2016, 12, 882-902.
General Procedure K for the in-situ monitoring of the C–H
insertion reaction
[4]
a) Taber, D. F.; Petty, E. H. J. Org. Chem. 1982, 47, 4808-4809; b)
Taber, D. F.; Ruckle, R. E. J. Am. Chem. Soc. 1986, 108, 7686-
7693; c) Doyle, M. P.; Van Oeveren, A.; Westrum, L. J.;
Protopopova, M. N.; Clayton, T. W. J. Am. Chem. Soc. 1991, 113,
8982-8984
A flame-dried three-necked round bottom flask and magnetic stir bar
was fitted with two rubber septa (left and right ports) and a glass
stopper (center port). Through one of the side septa a hole was
bored through which the IR probe was inserted. The resulting setup
was cooled under argon and placed into a preheated water bath set at
25 ºC. After configuring the IR acquisition parameters, acetonitrile (5
mL) was then added and the instrument was blanked. The spectral
acquisition was initiated and a baseline signal was acquired. After a
stable signal was achieved, hydrazone (.5 mmol, 0.1 M) was added
through the center port and was allowed to stir for ~20 min to allow for
thermal equilibration. MnO2 (348 mg, 4 mmol, 8 equiv.) was then
added in one portion and the resulting suspension was allowed to stir
vigorously until there was no noticeable change in the diazo signals.
For the cyclization, an additional 5 mL aliquot of acetonitrile was
added to the stirring reaction to obtain a nominal concentration of 0.5
M. The water bath was then replaced with an ice bath. After the
reaction temperature become constant (~30 min), Rh2(R-PTAD)4
(7.80 mg, 0.005 mmol, 0.01 equiv.) was added.
[5]
[6]
a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091-1160; b)
Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911-936.
a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075-
9076; b) Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38,
3061-3071; c) Davies, H. M. L.; Pelphrey, P. M. Organic Reactions
(Hoboken, NJ, United States) 2011, 75, 75-212.
[7]
[8]
a) Zhu, D.; Ma, J.; Luo, K.; Fu, H.; Zhang, L.; Zhu, S. Angew. Chem.,
Int. Ed. 2016, 55, 8452-8456; b) Ma, X.; Wu, F.; Yi, X.; Wang, H.;
Chen, W. Chem. Commun. 2015, 51, 6862-6865; c) Zhang, Y.;
Wang, D.; Cui, S. Org. Lett. 2015, 17, 2494-2497.
Examples of metal-catalyzed reactions of diaryldiazomethanes
include: a) Mehrotra, K. N.; Singh, G. S. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1985, 24B, 773-774. b) Werner, H.;
Schneider, M. E.; Bosch, M.; Wolf, J.; Teuben, J. H.; Meetsma, A.;
Troyanov, S. I. Chem. Eur. J. 2000, 6, 3052-3059. e) Petursson, S.
Carbohydr. Res. 2001, 331, 239-245. f) Petursson, S.; Jonsdottir, S.
Tetrahedron Asymmetry 2012, 23, 157-163; g) Qiu, L.; Huang, D.;
Xu, G.; Dai, Z.; Sun, J. Org. Lett. 2015, 17, 1810-1813; h) Zhang,
Y.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 2494-2497.
Acknowledgements
KNL acknowledges support from the Department of
Education GAANN Fellowship, the Department of Chemistry
Borge Fellowship, and the UC Davis Graduate Research
Award. AJK thanks UC Davis Provost Undergraduate
Fellowship (PUF) and the Arnold and Mabel Beckman
Foundation. CS thanks CAPES (Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior) and the
Brazilian Ministry of Education for a postdoctoral fellowship.
JH gratefully acknowledge Mettler-Toledo Autochem for the
donation of an EasyMax 402 Process Reaction Platform.
Additionally, we thank Merck Research Labs for student
research fellowships (to R.C.). MCR would like to
acknowledge the Ministerio de Educación y Ciencia for the
FPU fellowship and to the Fundación Pedro Barrié de la
Maza for a fellowship to visit the Tantillo lab and professors
Carlos Silva López and Olalla Nieto Faza for helpful
comments.
[9]
a) Ma, X. J.; Wu, F. F.; Yi, X. F.; Wang, H. X.; Chen, W. Z. Chem.
Comm. 2015, 51, 6862-6865; b) Zhu, D.; Ma, J.; Luo, K.; Fu, H. G.;
Zhang, L.; Zhu, S. F. Angew. Chem. Int. Ed. 2016, 55, 8452-8456.
c) W. H. Cheung, S. L. Zheng, W. Y. Yu, G. C. Zhou, C. M. Che,
Org. Lett. 2003, 5, 2535-2538; d) X. L. Dai, T. H. Warren, J. Am.
Chem. Soc. 2004, 126, 10085-10094. e) M. P. Doyle, K. G. High, S.
M. Oon, A. K. Osborn, Tetrahedron Lett. 1989, 30, 3049-3052; f) M.
A. Garcia-Garibay, H. Dang, Org. Biomol. Chem. 2009, 7, 1106-
1114; g) Y. Li, J. S. Huang, Z. Y. Zhou, C. M. Che, X. Z. You, J. Am.
Chem. Soc. 2002, 124, 13185-13193; h) H. Werner, M. E.
Schneider, M. Bosch, J. Wolf, J. H. Teuben, A. Meetsma, S. I.
Troyanov, Chem. Eur. J. 2000, 6, 3052-3059; i) S. L. Zheng, W. Y.
Yu, M. X. Xu, C. M. Che, Tetrahedron Lett. 2003, 44, 1445-1447.
[10] Soldi, C.; Lamb, K. N.; Squitieri, R. A.; González-López, M.; Di
Maso, M. J.; Shaw, J. T. J. Am. Chem. Soc. 2014, 136, 15142-
15145.
[11] a) Werlé, C.; Goddard, R.; Fürstner, A. Angew. Chem., Int. Ed. 2015,
54, 15452-15456; b) Werlé, C.; Goddard, R.; Philipps, P.; Farès, C.;
Fürstner, A. J. Am. Chem. Soc. 2016, 138, 3797-3805
[12] Sun, X. X.; Zhang, H. H.; Li, G. H.; Meng, L.; Shi, F. Chem.
Commun. 2016, 52, 2968-2971.
[13] Resveratrol in Health and Disease; Aggarwal, B. B., Shishodia, S.,
Eds.; CRC Press, Taylor and Francis Group: Boca Raton, FL, 2006.
[14] Pezet, R.; Perret, C.; Jean-Denis, J. B.; Tabacchi, R.; Gindro, K.;
Viret, O. J. Agric. Food. Chem. 2003, 51, 5488-5492.
Keywords: keyword 1 • keyword 2 • keyword 3 • keyword 4 •
keyword 5
[15] Sato, M.; Tsuchiya, H.; Miyazaki, T.; Ohyama, M.; Tanaka, T.;
Iinuma, M. Lett. Appl. Microbiol. 1995, 21, 219-222.
[16] a) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y. Q.; Zografos,
A. L. J. Am. Chem. Soc. 2009, 131, 1753-1765; b) Jia, Y.; Li, T.; Yu,
C.; Jiang, B.; Yao, C. Org. Biomol. Chem. 2016, 14, 1982-1987; c)
Matsuura, B. S.; Keylor, M. H.; Li, B.; Lin, Y.; Allison, S.; Pratt, D. A.;
Stephenson, C. R. J. Angew. Chem. 2015, 127, 3825-3828.
[17] a) Jeffrey, J. L.; Sarpong, R. Org. Lett. 2009, 11, 5450-5453; b)
Klotter, F.; Studer, A. Angew. Chem., Int. Ed. 2014, 53, 2473-2476;
c) Kim, I.; Choi, J. Org. Biomol. Chem. 2009, 7, 2788-2795; d) Kim,
K.; Kim, I. Org. Lett. 2010, 12, 5314-5317.
[1]
a) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8,
3437-3440; b) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong,
N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897-6907.
This article is protected by copyright. All rights reserved.

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FULL PAPER
[18] Li, C.; Lu, J.; Xu, X.; Hu, R.; Pan, Y. Green Chemistry 2012, 14,
3281-3284.
[19] Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125,
8112-8113.
[20] Koizumi, Y.; Kobayashi, H.; Wakimoto, T.; Furuta, T.; Fukuyama, T.;
Kan, T. J. Am. Chem. Soc. 2008, 130, 16854-16855.
[21] Wakimoto, T.; Miyata, K.; Ohuchi, H.; Asakawa, T.; Nukaya, H.;
Suwa, Y.; Kan, T. Org. Lett. 2011, 13, 2789-2791.
[22] Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 5767-5769.
[23] Javed, M. I.; Brewer, M. Org. Synth. 2008, 85, 189-195.
[24] a) Morrison, H.; Yates, P.; Danishefsky, S. J. Org. Chem. 1961, 26,
2617−2618; b) Severin, T.; Pehr, H. Chem. Ber. 1979, 112,
3559−3565.
[25] For precedent for the formation of azines in Rh-catalyzed reactions
of diazocompounds, see Panish, R.; Selvaraj, R.; Fox, J. M. Org.
Lett. 2015, 17, 3978–3981, and references therein.
[26] Computations were carried out using Gaussian09 (Frisch, M. J., et
al.; Gaussian, Inc.
: Wallingford, CT, 2009; full reference in
Supporting Information) and the B3LYP functional (A. D. Becke, J.
Chem. Phys. 1993, 98, 1372-1377; A. D. Becke, J. Chem. Phys. 1993, 98,
5648-5652; C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785-789; P. J.
Stephens, F. J. Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys. Chem. 1994,
98, 11623-11627; J. Tirado-Rives, W. L. Jorgensen, J. Chem. Theory
Comput. 2008, 4, 297-306), along with the 6-31G(d) basis set for C, H,
N and O and the LANL2DZ basis set for Rh. Energies discussed in
the text are free energies at 298K.
[27] Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861-
2904
[28] Taber, D. F.; Guo, P. J. Org. Chem. 2008, 73, 9479-9481
[29] Quiclet-Sire, B.; Zard, S. Z. Chem. Commun. 2006, 1831-1832.
[30] a) Slates, H. L.; Wendler, N. L. J. Am. Chem. Soc. 1959, 81, 5472-
5475; b) Kocsis, K.; Ferrini, P. G.; Arigoni, D.; Jeger, O. Helv. Chim.
Acta 1960, 43, 2178-2181; c) Adam, W.; Diedering, M.; Trofimov, A.
V. J. Phys. Org. Chem. 2004, 17, 643-655.
[31] See supporting information.
[32] Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002,
124, 7181-7192.
[33] a) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc.
1996, 118, 547-556; b) Hare, S. R.; Tantillo, D. J. Chem. Sci. 2017,
8, 1442-1449..
[34] a) Nowlan, D. T.; Singleton, D. A. J. Am. Chem. Soc. 2005, 127,
6190-6191; b) DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J.
M. J. Am. Chem. Soc. 2009, 131, 7230-7231; c) DeAngelis, A.;
Dmitrenko, O.; Fox, J. M. J. Am. Chem. Soc. 2012, 134, 11035-
11043.
[35] Panish, R.; Chintala, S. R.; Boruta, D. T.; Fang, Y.; Taylor, M. T.;
Fox, J. M. J. Am. Chem. Soc. 2013, 135, 9283-9286.
[36] Miller, S. R.; Krasutsky, S.; Kiprof, P. J. Mol. Struct. (Theochem)
2004, 674, 43–47
[37] DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am. Chem.
Soc. 2009, 131, 7230-7231
[38] Werlé, C.; Goddard, R.; Philipps, P.; Farès, C.; Fürstner, A. Angew.
Chem., Int. Ed. 2016, 55, 10760-10765
[39] DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am. Chem.
Soc. 2009, 131, 7230-7231
[40] a) Nishio, M. PCCP 2011, 13, 13873-13900; b) Takahashi, O.;
Kohno, Y.; Nishio, M. Chem. Rev. 2010, 110, 6049-6076; c) Steiner,
T. Angew. Chem., Int. Ed. 2002, 41, 48-76.
[41] DeAngelis, A. (2011). Rhodium(II)-catalyzed intermolecular
reactions of -alkyl--diazoesters: Selectivity over -hydride
elimination (Doctoral dissertation).
[42] Melník, M.; Progress in Coordination and Bioinorganic Chemistry;
Slovak Techn. University Press, 2003, 213.
[43] Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1992,
33, 2709-2712.
This article is protected by copyright. All rights reserved.