Reactivity Profiles of Diazo Amides, Esters, and Ketones in Transition-Metal-Free C-H Insertion Reactions

Article abstract of DOI:10.1021/jacs.8b12420

Vinyl cations derived from diazo ketones participate in transition-metal-free C-H insertion reactions, but the corresponding amide and ester analog exhibit divergent reactivity profiles. Whereas cations formed from diazo ketones undergo a rearrangement and C-H insertion sequence, those from diazo amides do so less efficiently and tend to be competitively trapped before the insertion step occurs. Diazo esters undergo several rearrangement steps and fail to insert. DFT calculations reveal that this disparity stems from two factors: differing levels of electrostatic stabilization of the initially formed vinyl cation by the adjacent carbonyl oxygen and predistortion of the ketone and amide systems toward C-H insertion. The computational data is in strong agreement with experimental results, and this study explains how structural and electronic factors determine the outcome of reactions of diazo carbonyl-derived vinyl cations.

Full text of DOI:10.1021/jacs.8b12420

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Reactivity Profiles of Diazo Amides, Esters, and Ketones in
Transition-Metal-Free C−H Insertion Reactions
Sarah E. Cleary,†,⊥,¶ Xin Li,‡,⊥ Li-Cheng Yang,‡ K. N. Houk,§ Xin Hong,*,‡
and Matthias Brewer*,†
‡Department of Chemistry, Zhejiang University, Hangzhou 310027, China
†Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States
§Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: Vinyl cations derived from diazo ketones
participate in transition-metal-free C−H insertion reactions,
but the corresponding amide and ester analog exhibit
divergent reactivity profiles. Whereas cations formed from
diazo ketones undergo a rearrangement and C−H insertion
sequence, those from diazo amides do so less efficiently and
tend to be competitively trapped before the insertion step
occurs. Diazo esters undergo several rearrangement steps and
fail to insert. DFT calculations reveal that this disparity stems
from two factors: differing levels of electrostatic stabilization of the initially formed vinyl cation by the adjacent carbonyl oxygen
and predistortion of the ketone and amide systems toward C−H insertion. The computational data is in strong agreement with
experimental results, and this study explains how structural and electronic factors determine the outcome of reactions of diazo
carbonyl-derived vinyl cations.
through a Lewis-acid-mediated vinyl cation formation,
rearrangement, and C−H insertion sequence.
INTRODUCTION
■
C−H insertion reactions have become important methods in
organic synthesis because their strategic use can provide
efficient and atom-economical ways to prepare organic
molecules.1−5 Intramolecular variants of these bond-forming
reactions have found application in the synthesis of a wide
variety of carbocyclic and heterocyclic scaffolds. For example,
metal carbenes (i.e., 2) and metal nitrenes are useful
intermediates for the synthesis of carbocycles, lactones, and
lactams, as well as other nitrogen heterocycles (3, Scheme
1a).1−3,6,7 C−H insertion reactions that do not rely on
transition metals are also known but are more limited in
prominence despite their potential cost and environmental
advantages. For example, we have shown that 1-aza-2-
azoniallene salts (5) can act as nitrenium ion equivalents
that undergo intramolecular C−H insertion to form pyrazo-
lines (6, Scheme 1b).8,9 Vinyl and aryl cations, which are
electron-deficient carbene equivalents, can also undergo C−H
insertion reactions.10−19 However, the use of vinyl cations as
carbene surrogates for C−H insertion has been limited by the
lack of mild and selective ways to generate these highly reactive
and unstable intermediates. Our use of β-hydroxy-α-diazo
ketones14 and Nelson’s use of vinyl triflates15 as vinyl cation
precursors that lead to C−H insertion reactions address these
challenges and broaden the scope and usefulness of vinyl
cation C−H insertions. For example, we formed cyclo-
pentenone products (11 and 12; Scheme 1c) in good yields
We have now explored the extension of this C−H insertion
strategy to the synthesis of α,β-unsaturated butenolides and γ-
lactams (i.e., 15) using β-hydroxy-α-diazo esters or β-hydroxy-
α-diazo amides (i.e., 13) as starting materials (Figure 1a).
Butenolides and γ-lactams are common scaffolds in biologically
active molecules (Figure 1b), and these unsaturated hetero-
cyclic structures are not directly accessible by metal carbene
C−H insertion. We describe experiments to effect these
transformations and computational studies that elucidate the
differing reactivity profiles observed for each of these starting
materials.
RESULTS AND DISCUSSION
■
In prior work, we assessed a variety of reaction conditions for
the conversion of β-hydroxy-α-diazo ketones to cyclo-
pentenones. We discovered that C−H insertion occurs more
readily at a methyl group than a methylene position (11 and
12, respectively, Scheme 1c) and that (C6F5)3B and SnCl4 are
more effective Lewis acids for this transformation than BF3·
OEt2 or Sc(OTf)3 (Scheme 1c). In contrast, Pellicciari20 and
Padwa21 reported that treating β-hydroxy-α-diazo ethyl esters
(e.g., 16, Scheme 2) with BF3·OEt2 in pentane or benzene gave
products (e.g., 17, 18, 19) derived from the capture of cation
Received: November 19, 2018
© XXXX American Chemical Society
A
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H insertion conditions. Our studies focused on diazo ester 20
(Scheme 3), which we prepared by adding lithiated methyl
diazoacetate to cyclohexanone.
Scheme 1. C−H Insertions Leading to 5-Membered
Carbocycles and Heterocycles
Scheme 3. Reaction of Methyl Diazo Ester 20 with SnCl4 or
Sc(OTf)3
a
1
Yield determined by H NMR (4-chlorobenzaldehyde as internal
b
c
standard). Not detected. Conditions: (a) SnCl4, (b) Sc(OTf)3.
Treating diazo ester 20 with (C6F5)3B in CH2Cl2 led to a
complex mixture of inseparable products. However, switching
the Lewis acid to SnCl4 led to the formation of three major
products: vinyl chloride 25 (7% yield), lactone 18 (14% yield),
and primary alkyl chloride 27 (66% yield, Scheme 3). Vinyl
chloride 25 would form from the reaction of the initially
formed vinyl cation (21) with chloride anion, which is
analogous to vinyl fluoride 17 that was observed by Padwa and
Pellicciari21 (Scheme 2). Lactone 18 and chloride 27 would be
derived from allyl cation 23, which aligns with the earlier
observation of 18 and 19. When Sc(OTf)3 was used as the
Lewis acid, lactone 18 was observed as the major product
(24% yield) and diene 24 was detected as a minor product
(17% yield). Diene 24 would result from a 1,3-hydride transfer
of vinyl cation 21, followed by deprotonation. The lack of any
C−H insertion products (i.e., 26) is consistent with what
Padwa and Pellicciari observed despite our adjustment to the
substrate and reaction conditions. It is noteworthy that none of
the diazo ketones examined returned any products derived
from an allyl cation similar to 23.
With these results in hand, we were interested to investigate
amide analogs, e.g., 28. We prepared β-hydroxy-α-diazo amide
28 by adding lithiated 2-diazo-N,N-dimethylacetamide to
cyclohexanone. Treating this material with (C6F5)3B gave a
complex mixture of products (Table 1, entry 1). SnCl4
provided vinyl chloride 30a as the major isolable product
(33% yield, entry 2). Analysis of the crude reaction mixture by
NMR indicated the presence of small quantities of bicyclic
lactam 29, but this product could not be isolated cleanly.
Encouraged by these results, we screened Sc(OTf)3,
In(OTf)3, and TMSOTf for their potential to facilitate the
insertion (Table 1). Sc(OTf)3 returned bicyclic lactam 29 in
24% yield (entry 3), but the NMR of the crude reaction
mixture showed that vinyl triflate 30b was the major product
present. This material proved to be unstable to silica gel
chromatography; quantitative 19F NMR of the crude reaction
mixture showed a 47% yield of vinyl triflate 30b, but
purification by silica gel flash column chromatography returned
only 25% yield (entry 3). When Sc(OTf)3 was used in
acetonitrile, the bicyclic lactam was observed in comparable
yield (entry 4). In(OTf)3 did not prove any more effective
than Sc(OTf)3 (entry 5). Finally, in an attempt to reduce the
Figure 1. Unsaturated heterocycles not directly accessible from metal
carbene C−H insertion.
Scheme 2. Reaction of β-Hydroxy-α-diazo Ester 16 with
BF3·OEt2 from Padwa and Pellicciari21
intermediates, rather than C−H insertion. To see if this
divergent reactivity was due to a difference in the reaction
conditions or was inherent to the substrates, we reevaluated
the reactivity of β-hydroxy-α-diazo methyl esters under our C−
B
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Table 1. Reaction of Diazo Amide 28 with Lewis Acids
entry
Lewis aAcid (1 equiv)
solvent
temp (°C)
yield lactam 29 (%)
compound
yield (%)
a
1
2
3
4
5
6
(C6F5)3B
SnCl4
Sc(OTf)3
Sc(OTf)3
ln(OTf)3
TMSOTf
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
rt
rt
rt
40 °C
rt
n.d.
inseparable mixture
30a
30b
30b
30b
30b
33%
25% (47%)
0%
28%
62%
b
24%
24%
17%
6%
0 °C
a
b
Not detected. Yield in parentheses was determined by 19F NMR using 4-fluorobenzophenone as an internal standard. For the full list of Lewis
acids screened, see Table S2 (ESI).
Figure 2. DFT-computed free energy profile of the C−H insertion of β-hydroxy-α-diazo ketone.
formation of vinyl trifilate 30b by reducing the number of
equivalents of triflate anion in the reaction, we treated β-
hydoxy-α-diazo amide 28 with TMSOTf. Interestingly, this
had the undesired effect of giving the vinyl triflate in an
increased isolated yield of 62% (entry 6). Importantly, these
reactions of diazo amide 28 did not produce any products that
would be derived from an allyl cation similar to ester 27.
These experimental results show that the three classes of
diazo carbonyl starting materials (ketone, ester, and amide)
react in distinct ways when treated with Lewis acids. On the
basis of the observed products, the initial steps of the reaction
sequence, which lead to the formation of a destabilized vinyl
cation (i.e., 9 and 21, Schemes 1 and 3), appear to be
operational for each of the substrates tested. However, at this
point the reactivity of the substrates diverges and the differing
results indicate that the rate of various steps in the reaction
sequence change depending on which carbonyl variant is
present. In all cases, the initially formed vinyl cation can
rearrange via a 1,2-shift across the alkene to give a second
(cyclic) vinyl cation (i.e., 10 and 22). This rearrangement
seems facile for diazo ketones and esters, whereas diazo amides
tend to react by capture of the destabilized vinyl cation prior to
rearrangement to give vinyl triflate 30. Once rearrangement
occurs, the ketone and amide substrates undergo a productive
C−H insertion reaction to give cyclopentenone or γ-lactam
products (e.g., 11, 12, and 29), whereas the ester undergoes
another 1,2-shift to generate an allyl cation, which is then
captured either inter- or intramolecularly to give 18 and 27.
Importantly, ketone and amide substrates did not return any
products derived from allyl cations. Since insertion and allyl
cation formation are competing events, these results indicate
that ketone and amide substrates undergo insertion faster than
ring contraction, whereas ester substrates undergo ring
contraction more quickly than insertion.
C
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Figure 3. Optimized geometries of selected intermediates and transition states for β-hydroxy-α-diazo ketone.
Figure 4. DFT-computed free energy profile of the C−H insertion of β-hydroxy-α-diazo ester.
To understand the differing reactivity profiles, we studied
these transformations with density functional theory (DFT)
calculations. The DFT-computed free energy profile of the C−
H insertion of the β-hydroxy-α-diazo tert-butyl ketone, which
gave the highest levels of insertion, is shown in Figure 2. The
optimized geometries of key intermediates and transition states
are shown in Figure 3. The diazonium 31 undergoes an initial
dissociation of nitrogen gas via TS32, generating the linear
vinyl cation 33. Intermediate 33 has very low barriers for the
subsequent ring expansion (via TS34) and C−H insertion (via
TS36 and TS38), leading to the bicyclic intermediate 39. In
contrast, the competing ring contraction via TS40 requires a
barrier of 9.6 kcal/mol, making it much less favorable
compared to the C−H insertion pathway (TS36 vs. TS40).
Although we located the primary carbocation intermediate 37,
the overall C−H insertion process from 37 to TS38 has no free
energy barrier to the CH insertion reaction (this process has a
0.5 kcal/mol electronic energy barrier based on the method of
optimization). The lack of free energy barrier for C−C bond
formation suggests that the sequential hydrogen abstraction
and C−C bond formation can occur through a dynamically
concerted fashion. The overall C−H insertion process from 35
to 39 proceeds without a long-lived primary carbocation
intermediate. This finding is related to our previous dynamics
study of the C−H insertion of heteroallene cations.9
Therefore, the intramolecular C−H insertion of vinyl cation
can be similarly characterized as an energetically stepwise but
dynamically concerted process. Detailed dynamics studies of
this transformation are ongoing in our laboratories.
D
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Figure 5. Optimized geometries of selected intermediates and transition states for β-hydroxy-α-diazo ester.
Figure 6. DFT-computed free energy profile of the C−H insertion of β-hydroxy-α-diazo amide.
We next investigated the free energy changes of the same
transformations for a β-hydroxy-α-diazo ester. The DFT-
computed free energy profile is shown in Figure 4, and the
optimized geometries of selected intermediates and transition
states are shown in Figure 5. After nitrogen dissociation, the
energy barrier for ring expansion of vinyl cation 21 to vinyl
cation 45 via TS44 is only 2.4 kcal/mol, indicating a low
lifetime of the linear vinyl cation intermediate. This is similar
to the ketone compound (33 to TS34, Figure 2), which is
consistent with the experimental observations that reactions of
both compounds showed only little trapping of the linear vinyl
cation species. The ring expansion leads to the seven-
membered ring vinyl cation 45, and 45 can undergo the C−
H insertion (via TS46 and TS48) or ring contraction (via
TS50). Our calculations suggested that the ring contraction is
3.9 kcal/mol more favorable than the hydrogen abstraction
(TS46 vs TS50). This trend is in a nice agreement with the
experimental results that the major products for β-hydroxy-α-
diazo ester are derived from the allyl cation (Scheme 3).
For the β-hydroxy-α-diazo amide, the computed free energy
profile is shown in Figure 6 and the optimized geometries of
selected intermediate and transition states are included in
Figure 7. The computed results indeed corroborate the
experimental observations. From the linear vinyl cation
E
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Figure 7. Optimized geometries of selected intermediates and transition states for β-hydroxy-α-diazo amide.
intermediate 53, the ring expansion barrier via TS54 is 8.1
kcal/mol. This ring expansion barrier is significantly higher
than those of the ketone and ester (1.8 and 2.4 kcal/mol,
respectively); thus, the lifetime of 53 is considerably longer
than the lifetimes of 33 and 21. This explains why the vinyl
triflate product forms in the reaction of the β-hydroxy-α-diazo
amide (Table 1). Subsequent to the ring expansion, either the
C−H insertion (via TS56 and TS58) or the ring contraction
(via TS60) can occur. TS56 is 4.3 kcal/mol more favorable
than TS60; thus, as observed experimentally, ring contraction
is unlikely to occur for β-hydroxy-α-diazo amides.
The vinyl cation model provides a reasonable approach to
study the reactivity profiles of diazo amides, esters, and
ketones. However, we want to emphasize that the counter-
anion and solvent molecules can potentially interact with the
vinyl cation to affect the free energy profile. To address the
affects of counteranion and solvent molecules, we also
performed DFT calculations on a vinyl cation−triflate anion
pair model and a vinyl cation−DCM complex model. Our
calculations indicate that the presence of the triflate anion
indeed affects the shape of free energy surface but has limited
affects on the chemoselectivities of ketone, ester, and amide
reactions (Figures S1−S3). In addition, the DCM solvent
molecule can interact with the carbonyl group of the vinyl
cation species, leading to a vinyl cation−DCM complex.
However, the DCM solvent molecule interacts with the
carbonyl group in a similar fashion for all explored cationic
species (Figures S4−S6). Thus, the inclusion of an explicit
DCM solvent molecule has limited affects on the shape of the
free energy surfaces or the chemoselectivities.
The computational results provide a mechanistic basis for
the experimental observations of the distinctive reactivities.
The intrinsic barriers of the key elementary transformations
that account for the reactivity changes are compared in Figure
8. For the ring expansion of linear vinyl cation species, the
electrostatic interaction between the carbonyl oxygen and the
vinyl cation differentiate the three types of substrates. In the
ketone and ester, there is only a weak electrostatic interaction
between the carbonyl and the vinyl cation. The O−C distance
is 2.06 and 2.17 Å, respectively (highlighted in Figure 8a). The
strong electron-donating amino substituent in the amide
results in a much stronger electrostatic interaction, and the
same O−C distance is 1.89 Å. This O−C electrostatic
interaction no longer exists in the ring expansion transition
state because of the redistribution of positive charge.
Therefore, the linear vinyl cation of the amide is stabilized
and has a higher barrier for ring expansion than the ketone and
ester variants.
For the C−H insertion step, the predistortion of the seven-
membered ring vinyl cation controls the reactivity. Both the
ketone and the amide have a methyl group proximal to the
vinyl cation. This conformation is predistorted toward C−H
insertion; thus, the C−H insertion barriers are exceptionally
low (0.4 and 1.0 kcal/mol, respectively, Figure 8b). However,
the most stable conformation for the ester substrate has the
methyl group oriented away from the vinyl cation. Here,
significant conformational change must occur prior to the C−
H insertion, and the barrier is increased to 7.6 kcal/mol.
For the ring contraction step, the stabilizing interaction
between the methyl group and the vinyl cation differentiates
the three compounds. The ketone has a highlighted H−C
distance of 1.92 Å (Figure 8c), and this interaction stabilizes
the seven-membered ring vinyl cation and increases the barrier
of ring contraction. The same interaction does not exist for the
ester substrate, and this interaction is weaker in the amide due
to the inductive effects of the amino substituent. Therefore, the
ketone has the highest barrier for ring contraction, the amide is
slightly lower, and the ester would contract most easily.
CONCLUSIONS
■
In conclusion, we have described experimental results showing
that three classes of β-hydroxy-α-diazo carbonyls (ketone,
ester, and amide) react in distinct ways when treated with
Lewis acids. The initial steps of the reaction sequence, which
lead to the formation of a destabilized vinyl cation, appear to
be operational for each of the substrates tested. However, at
this point the reactivity of the substrates diverges, and to
explain these results we completed computational studies that
provide insight into the mechanistic differences. In all cases,
the initially formed linear vinyl cation can rearrange via a 1,2-
shift across the alkene to give a second (cyclic) vinyl cation.
This rearrangement is facile for the diazo ketone and ester but
slow for the diazo amide. Computational results indicate that
this difference in reactivity is due to the differing degree of
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Figure 8. Intrinsic barriers of key elementary transformations of vinyl cation for ketone, ester, and amide substrates.
electrostatic interaction between the carbonyl oxygen and the
linear vinyl cation. The amide has a strong electrostatic
interaction which slows the migration step. Once rearrange-
ment occurs, the ketone and amide substrates are both
predistorted toward C−H insertion, whereas the ester adopts a
low-energy conformation that makes insertion less favorable. A
subsequent ring contraction leading to an allyl cation occurs
readily for the ester substrate but is less favorable in the ketone
and amide examples due to stabilizing electrostatic interactions
that are present in these cases. This is in line with experimental
results where ketone and amide substrates failed to return any
products derived from allyl cations, whereas the ester substrate
gave these products in significant yield. With a better
understanding of what causes the different reaction outcomes,
we now seek to devise ways to bias the reactions to promote
the formation of α,β-unsaturated butenolides and γ-lactams.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b12420.
Experimental details, procedures, compound character-
ization data, computational details, energies, enthalpies,
free energy of calculated structures, Cartesian coor-
1
dinates for optimized structures, and copies of H and
13C NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*hxchem@zju.edu.cn
*matthias.brewer@uvm.edu
ORCID
Sarah E. Cleary: 0000-0001-8876-1696
K. N. Houk: 0000-0002-8387-5261
G
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Xin Hong: 0000-0003-4717-2814
Matthias Brewer: 0000-0003-4250-7195
Present Address
¶Department of Chemistry, University of Oxford, Inorganic
Chemistry Laboratory, South Parks Rd, Oxford, OX1 3QR,
UK.
Author Contributions
⊥S. E. C. and X. L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation of the
USA (CHE-1665113 for M.B. and CHE-1764328 for K.N.H.)
and the National Scientific Foundation of China (21702182
and 21873081 for X.H.) is gratefully acknowledged. Mass
spectrometry data was acquired by Bruce O’Rourke on
instruments purchased through instrumentation grants pro-
vided by the National Institutes of Health (NIH) (S10
OD018126). Calculations were performed on the super-
computer cluster at the Department of Chemistry, Zhejiang
University.
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