Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed Intramolecular Diazo Group Transfer from Azide to Alkene

Article abstract of DOI:10.1002/chem.201805904

Alkenes can be cleaved by means of the (3+2) cycloaddition and subsequent cycloreversion of 1,3-dipoles, classically ozone (O₃), but the azide (R?N₃) variant is rare. Chemoselectivity for these azide to alkene diazo group transfers (DGT) is typically disfavored, thus limiting their synthetic utility. Herein, this work discloses a palladium-catalyzed intramolecular azide to alkene DGT, which grants chemoselectivity over competing aziridination. The data support a catalytic cycloreversion mechanism distinct from other known metal-catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2) cycloadditions. Kinetics experiments reveal an unusual mechanistic profile in which the catalyst is not operative during the rate-controlling step, rather, it is active during the product-determining step. Catalytic DGT was used to synthesize N-heterocyclic quinazolinones, a medicinally relevant structural core. We also report on the competing aziridination and subsequent ring expansion to another N-heterocyclic core structure of interest, benzodiazepinones.

Full text of DOI:10.1002/chem.201805904

A Journal of
Accepted Article
Title: Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed
Intramolecular Diazo Group Transfer from Azide to Alkene
Authors: Grant B. Frost, Michaela K. Mittelstaedt, and Christopher J.
Douglas
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To be cited as: Chem. Eur. J. 10.1002/chem.201805904
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Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed
Intramolecular Diazo Group Transfer from Azide to Alkene
Grant B. Frost, Michaela K. Mittelstaedt and Christopher J. Douglas*
Dedicated to all organic azide chemists
Abstract: Alkenes can be cleaved via the (3+2) cycloaddition and
subsequent cycloreversion of 1,3-dipoles, classically ozone (O3), but
the azide (R–N3) variant is rare. Chemoselectivity for these azide to
alkene diazo group transfers (DGT) is typically disfavored, thus
limiting their synthetic utility. Herein, we disclose a palladium-
catalyzed intramolecular azide to alkene DGT, which grants
chemoselectivity over competing aziridination. Our data support a
catalytic cycloreversion mechanism distinct from other known metal-
catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2)
cycloadditions. Kinetics experiments reveal an unusual mechanistic
profile in which the catalyst is not operative during the rate-controlling
step, rather, it is active during the product-determining step. Catalytic
DGT was used to synthesize N-heterocyclic quinazolinones, a
medicinally relevant structural core. We also report on the competing
aziridination and subsequent ring expansion to another N-heterocyclic
core structure of interest, benzodiazepinones.
Nitrogen is found extensively in organic molecules: natural
products, pharmaceuticals, and materials. Thus, the construction
of C–N bonds is a continual core goal of synthetic organic
chemists. Organic azide (R–N3) reactions are a common strategy
for incorporating nitrogen into target molecules of various sizes
and complexities. This broad utility is due to the immense diversity
of azide reactivity: 1,3 dipole, nitrene, nucleophile, electrophile,
and radical.[1] Although this grants organic azides synthetic
versatility, it also necessitates the development of methods to
control selectivity. In the context of thermolytic azide/alkene
reactions, the chemoselectivity challenge is two-fold (Scheme 1,
a, top). There is an initial divergence of mechanistic paths: nitrene
formation versus (3+2) cycloaddition. Nitrenes often react with
alkenes to form aziridines, but are so energetic they tend to
indiscriminately aminate at C–H bonds as well.[2] (3+2)
cycloadditions form triazolines, some of which are isolable, but
most rearrange to form imines and aziridines with the expulsion
of N2.[3] However, Huisgen et al. observed that triazolines can also
rearrange via N–N bond cleavage,[4] and Fusco et al. discovered
that both N–N and C–C bond cleavage can occur.[5] Regitz et al.
categorized these mechanisms as azide to alkene DGT, as imines
and diazos (R–N2) result.[6] This is analogous to alkene ozonolysis
in which a carbonyl and carbonyl oxide (R–O2) form. However,
cleavage of the alkene C–C bond subsequent to azide (3+2)
[*]
G. B. Frost, M. K. Mittelstaedt, Prof. Dr. C. J. Douglas
Department of Chemistry
University of Minnesota Twin Cities
Smith Hall, 207 Pleasant St SE, Minneapolis, MN 55455 (USA)
E-mail: cdouglas@umn.edu
Homepage: http://www1.chem.umn.edu/groups/douglas/
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Chemoselectivity challenge of azide/alkene reactions, metal
catalysis solutions and this work
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Table 1. Thermolysis reaction and catalyst optimization
cycloaddition is usually disfavored, in contrast to the ozonolysis of
C–C bonds. Chemoselectivity for azide to alkene DGT with C–C
bond cleavage has thus far been based solely on substituent
effects. DGT may be favored over other pathways with sufficiently
electron poor azide diazo donors (R = SO2R3 or POR3 ) and
2
electron rich alkene diazo acceptors (R1 = N or O).[6a,7] Catalyst-
based chemoselectivity for DGT is desirable, as it could allow for
reactivity comparable to ozonolysis, but with the incorporation of
nitrogen into the products, namely imines and potentially
synthetically versatile diazos.
Significant strides have been made in controlling the
chemoselectivity of azide/alkene reactivity with metal catalysts
(Scheme 1, a, bottom). It is well established that catalysts (M =
Co, Fe, Ru, Rh) can selectively cleave azides to
nitrenoids/metalloradicals and impose control for aziridination
(Scheme 1, a, left).[8] Although a vast amount of research has
been aimed at metal-catalyzed azide/alkyne (3+2) cycloadditions
(M = Cu, Ru, Ag),[9] there are few reports of metal-catalyzed
azide/alkene (3+2) cycloaddition reactions. Rare earth metals, Ce
and Sm, are thought to catalyze cycloadditions with subsequent
decomposition of the triazolines to imines (Scheme 1, center).[10]
PdII-catalysts can also affect azide/alkene reactivity, however it is
unclear if there is a consistent mechanism involved. Migita et al.
reported the PdCl2(PhCN)2-catalyzed allylic ether isomerization
with subsequent azide cycloaddition and rearrangement to
imines.[11] Recently, Ramasastry et al. reported Pd(OAc)2 altered
the chemoselectivity of a thermal azide/alkene ring closing
reaction to form the pyridine ring of β-carbolines.[12] However, all
of these transformations involve only the expulsion of N2. Herein
we report a PdII-catalyzed cycloreversion to achieve azide to
alkene DGT with C–C bond cleavage (Scheme 1, right).
2a[a]
3a
4a
5a
entry
catalyst
1
2
3
4
5
6
7
8
9
none[b]
none
PdCl2(PhCN)2
Pd(OAc)2
29%
31%
19%
16%
27%
54%
68%
59%
62%
48%
<1%
27%
27%
20%
2%
1%
2%
1%
<1%
46%
1%
1%
1%
10%
9%
4%
4%
5%
4%
3%
6%
PdCl2
17%
10%
5%
6%
6%
PdCl2(PPh3)2
PEPPSITM-IPr
PEPPSITM-IPr[c]
PEPPSITM-IPr[d]
[a] product yields. [b] time = 14 hours [c] 5 mol % [d] 20 mol %
We centered our studies of catalytic azide to alkene DGT on
consumed and surprisingly, a mixture of primarily 2a (29%)
and 3a (48%) was observed with quantitative H NMR (qNMR)
the reactions of carbamoyl azides 1 with PdII-complex PEPPSITM
-
1
IPr. (Scheme 1, b). The kinetics of catalytic DGT are fascinating
in that the reaction is overall zeroth order in Pd, indicating that the
catalyst effects the product-determining step and not the rate-
controlling step. Based on our evidence and literature precedence
we propose the plausible key mechanistic step to be a PdII-
promoted β-carbon elimination/cycloreversion from an
intermediate cycloadduct. Through this, we chemoselectively
synthesized quinazolinones 2. Under noncatalyzed thermolytic
conditions we synthesized benzodiazepinones 3 via the ring
expansion of azirinoquinazolinones 4. Our synthetic focus was in
accordance with the noteworthy strategy of employing
azide/alkene cycloadditions/rearrangements for the synthesis of
other N-heterocyclic targets.[12-13] Both quinazolinones and
benzodiazepinones are core structures of many bioactive
molecules of interest and new methods for their construction are
continually sought.[14]
along with a very minor quantity of imine 5a (Table 1, entry 1).
Formation of 2a could be rationalized as the carbamoyl azide is
still an electron poor diazo group donor and the alkene is ortho to
the secondary aniline and therefore could still serve as a relatively
electron rich diazo acceptor. Rationale for the formation of 3a
remained elusive.
Next, we reacted 1a for just 2 hours and in this case 1a was
already 94% consumed, and a mixture of 2a (31%) and aziridine
4a (46%) was obtained (Table 1, entry 2). Since an approximately
equimolar quantity of 4a formed prior to 3a we proposed that 3a
results from the ring expansion of 4a. Indeed, Woerner et. al.
reported a single example of an analogous thermal aziridine ring
expansion.[16] Subsequent attempts to isolate 4a with silica gel
column chromatography were unsuccessful. Instead, we isolated
urea 6a,
a plausible hydrolysis product (see supporting
information).[17] Thus, our structural assignment of 4a as the
azirinoquinazolinone was predicated on both the observed ring
expansion to 3a, as well as the isolation of 6a. Also, the overall
mass balance of identifiable products was non-ideal, thus we
hypothesized a Curtius rearrangement was diverting a minor
portion of 1a to unidentified side products (see supporting
information).[18]
Our studies commenced with heating a solution of 1a in
toluene-d8 to 130 °C in an NMR tube. (Table 1, a, entry 1). We
were initially not hypothesizing any of the DGT product 2a to form
as this was neither
a sulfonyl/phosphoryl azide nor an
enamine/enol ether reaction. Nor were we expecting enamine
product 3a as this would appear to indicate an unlikely vinylic C–
H nitrene amination. A thermolytic Curtius rearrangement of an
acyl azide should be a concerted process that does not involve
an intermediate nitrene.[15] However, after 14 hours 1a was fully
With the relevant products of the thermolysis reaction
identified we began testing PdII catalysts for their effect on
chemoselectivity (Table 1, b). PdCl2(PhCN)2 (Migita’s
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conditions)[11] altered the product distribution significantly,
decreasing 2a and promoting formation of 3a from 4a or
producing 3a via an alternative mechanism (Table 1, entry 3).
Interestingly, the yield of 5a also increased considerably.
Pd(OAc)2, (Ramasastry’s conditions)[12] produced
a similar
product distribution to PdCl2(PhCN)2 (Table 1, entry 4). PdCl2
improved the mass balance compared to the first two PdII
catalysts (Table 1, entry 5). However, no significant
chemoselectivity was achieved with the initial entries.
PdCl2(PPh3)2 was selective for DGT, producing 2a in 54% yield,
favoring it over the aziridination/ring expansion pathway 4.5:1
(2a:(3a + 4a)) (Table 1, entry 6). PEPPSITM-IPr improved the yield
and chemoselectivity for 2a (68%, 11.3:1) (Table 1, entry 7).
Altering the loading of PEPPSITM-IPr to 5% and 20% each
decreased the yield and selectivity slightly (Table 1, entries 8-9).
We performed reaction progress kinetics with qNMR to
assess the general kinetic behavior of these unique catalytic and
thermolytic reactions (Figure 1). The PEPPSITM-IPr-catalyzed
and the thermolysis reactions were monitored until maximum
yields of 2a were observed. This occurred between 120 and 150
minutes for both reactions, at ~95-97% conversion of 1a, as we
observed a minor degradation of 2a at further time points. The
plot illustrates the stark chemoselectivity achieved with
PEPPSITM-IPr, but interestingly we did not observe a change in
the rate of 1a consumption. Rather, the rate of 2a formation
drastically increased while the rate of 4a formation decreased.
We expanded our kinetic analysis by performing a series of
initial rate measurements. The initial rates of 1a conversion for the
Figure 1. Reaction progress kinetics
Table 2. Initial rates kinetics experiments
thermolysis reaction (ν1a) and the PEPPSITM-IPr reaction (ν1a(Pd)
)
were approximately equal, as observed with reaction progress
kinetics (Table 2, entries 1-2). Halving [PEPPSITM-IPr] produced
an initial rate within error of ν1a and ν1a(Pd), supporting an overall
zeroth order in Pd (Table 2, entry 3). The presence of catalyst
only affected the initial rates of formation of 2a (ν2a) and 4a (ν4a).
Halving [1a] resulted in an approximately two-fold reduction in
ν1a(Pd), supporting an expected first order reaction in azide (Table
2, entry 4). We synthesized azide 7 with no alkene as a proxy for
measuring the rate of the hypothesized Curtius rearrangement
that may compete with productive (3+2) cycloaddition. The initial
rate of conversion of 7 (ν7) under thermolytic conditions was
measured (Table 2, entry 5). Remarkably, the sum of ν7 with the
rates of product formation ν2a and ν4a was within error of ν1a (-
2.64e-6 ± 1.16e-7 M/s ≈ -2.61e-6 ± 1.46e-7) This accounts for the
full mass balance. When 7 was reacted in the presence of
PEPPSITM-IPr the rate of conversion increased slightly (Table 2,
entry 6). This may indicate that some nonproductive interaction of
Pd and azide could occur prior to cycloaddition.
Next, we broadened our studies to other azide 1 substrates
(Scheme 2). We first targeted derivatives substituted para to the
alkene with groups of varying electronic character. Substrates 1b-
1f were subjected to both sets of reaction conditions. Yields were
measured with qNMR at two timepoints (2 and 2.5 hours) to
gauge if a significant change in rate or decomposition occurred.
The duration of the thermolysis reactions was then extended
(overnight) to observe the ring expansion of 4 to 3. Strikingly, the
chemoselectivity for the thermolysis of 1 was greatly influenced
by the electronic character of the ring. More electron rich
substrates 1b and 1c had decreased preference for DGT and
entry
[1a]
ν1a (M/s)
ν2a (M/s)
[Pd]
1[a]
2[b]
3
[0.01]
[0.01]
[0.01]
[0.005]
-
-2.61e-6 ± 1.46e-7
-2.51e-6 ± 7.90e-8
-2.59e-6 ± 5.77e-8
-1.31e-6 ± 6.26e-8
8.14e-7 ± 5.46e-8
1.74e-6 ± 2.65e-7
1.79e-6 ± 2.38e-7
9.63e-7 ± 5.52e-8
[0.001]
[0.0005]
[0.001]
4
entry
[7]
ν7 (M/s)
[Pd]
-
5
6
[0.01]
[0.01]
-
-5.42e-7 ± 3.24e-8
-6.89e-7 ± 3.21e-8
-
-
[0.001]
[a] ν4a = 1.28e-6 ± 9.70e-8 [b] ν4a(Pd) below detection threshold for Pd-
catalyzed reactions
more electron poor substrates 1d-1f had increased
preference for DGT products. 1f, the most electron poor substrate
tested, favored DGT over aziridination 1.5:1. We established a
Hammett linear free energy relationship (LFER) that illustrates
this electronic bias for chemoselectivity (Figure 2). σpara
correlated very well with the observed chemoselectivity (R2
0.99) and ρ = 0.68. Despite the increased electronic bias for
aziridination with more electron rich substrates, PEPPSITM-IPr still
=
catalyzed the formation of 2b to
a yield of 65% and
chemoselectivity 6.4:1. 2c-2f yields were also good (67-71%) and
good chemoselectivity was achieved. For the reaction of 1f, 2f
was the sole observed product.
We synthesized 1g with an electron deficient p-NO2 benyzl-
group as well as 1h with N-Me group to test if the N-Bn protecting
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group has a role in catalyst activity. Both substrates
behaved similarly to 1a. PEPPSITM-IPr catalyzed the formation of
2g and 2h, and ring expansion products 3g and 3h were obtained
in the uncatalyzed reaction. Next, we synthesized derivatives with
alterations to the alkene; butenyl azide 1i and styrenyl azide 1j.
Azide 1i reacted in an analogous manner to 1a, however the
catalyzed reaction gave slightly reduced yield of 2i (46%). Under
thermolytic conditions 1j selected significantly for the H-shift
product 5j instead of 2j and 4j. 2j was speculated to have formed
in only a minor quantity based on the 1H NMR spectrum (see
supporting information). However, PEPPSITM-IPr was still slightly
active and increased the yield and chemoselectivity for DGT
product 2j.
We propose the following mechanisms to account for our
kinetic data and synthetic results. Under thermolysis conditions
rate-controlling (3+2) cycloaddition (A) leads to intermediate
triazoline I and competing Curtius rearrangement (B) leads to
intermediate aminoisocyanate II (Scheme 3, a). I is favored 3.9:1
over II based on our initial rates measurements of 1a. Based on
reported triazoline decomposition mechanisms, I ring opens (C)
to the diazonium III, at which point the chemoselectivity
divergence of interest occurs.[6a] C–C bond cleaving DGT (D)
leads to quinazolinone 2a with elimination of CH2N2, which may
further decompose under the reaction conditions.[19] However, III
favors 3-exo-tet aziridination (E) with expulsion of N2 to form 4a,
which
undergoes
relatively
slow
rearrangement
to
benzodiazepinone 3a via a plausible 1,2-hydride shift (F).[16] Since
the product ratios for our Hammett LFER analysis were calculated
as (2:(3 + 4)) and ρ = 0.68, it indicates that negative charge builds
as 2 forms (Scheme 3, b). Therefore, the electronic influence on
chemoselectivity arises from the rings’ ability to stabilize or
destabilize the negative charge that builds at the benzylic position,
which alters the barrier of DGT. On the other hand, 3-exo-tet
aziridination should be less impacted by changes to the ring
electronics (Scheme 3, c). Thus, the σpara LFER observed is likely
a reflection of mostly the ΔΔG‡ for DGT.
In the presence of PEPPSITM-IPr, we propose an interaction
between either intermediate I or III and Pd alters the ΔΔG‡
between the DGT path and aziridination. Since the reaction is
zeroth order overall in Pd, kinetics data is unable to lend evidence
as to how this process works. Presumably, rate-controlling
cycloaddition produces minute concentrations of I, and then I or
III reacts with Pd in a bimolecular process. If Pd irreversibly traps
I or III then the ΔΔG‡ between the two paths may result either from
the barrier of aziridination increasing, the barrier of DGT
decreasing, or a combination of both. If the Curtin-Hammett
principle is operative, and binding between an intermediate and
Pd is reversible, then the barrier for DGT from the Pd-bound
intermediate may be lower relative to the noncatalyzed DGT.
(Scheme 3, d). We propose this to be most plausible and
triazoline I exchanges reversibly with 3-chloro-pyridine binding to
Pd at the once terminal nitrogen of the azide to form I●Pd (G).[20]
Scheme 2. Substrate Scope [a] yields assessed at both 2 h and 2.5 h, and
maximum yield is reported [b] see supporting information for specific substrate
reaction time [c] chemoselectivity ratios calculated with maximum yields from
any timepoint [d] 2 h [e] 2.5 h [f] yield same at both timepoints [g] 9% 4e
remained [h] 14% likely 5h obtained [i] 12% 4i remained [j] timepoints taken at
2 h and 20 h due to slower reaction, 2j not isolated but downfield 1H NMR peak
at δ = 8.54 indicative of quinazolinone product.[k] ratio given is 2j:5j, 5j being
the H-shift product equivalent to 1a
From this species
a β-carbon elimination may initiate a
cycloreversion process to cleave the C–C bond and eliminate 2a
from the complex (H)(Scheme 3, e).[21] This forms IV with CH2N2
bound to the Pd which may either exchange with the pyridine to
reform PEPPSITM-IPr (I) or the cycle continues by exchange of
CH2N2 with I (J).[22]
Figure 2. Chemoselectivity Hammett LFER
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Scheme 3. Plausible PEPPSITM-IPr catalysis and thermolysis mechanisms
PdII-catalyzed
[1]
Reviews: a) S. Bräse, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem.
2005, 117, 5320; Angew. Chem. Int. Ed. 2005, 44, 5188; b) D. Huanga,
G. Yana, Adv. Synth. Catal. 2017, 359, 1600.
In summary, we have presented
a
intramolecular DGT from azides to alkenes. Catalyst based
chemoselectivity is achieved after the rate-controlling step,
plausibly through interaction with the intermediate triazoline. This
represents a new mode of metal-catalyzed chemoselective
control in azide/alkene reactions. We applied the DGT reaction to
synthesize medicinally relevant N-heterocyclic quinazolinones
and demonstrated the competing aziridination may be a useful
method to synthesize benzodiazepinones.
[2]
[3]
a) W. Lwowski, Angew. Chem. Int. Ed. 1967, 6, 897; b) R. Belloli
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R. Huisgen, Angew. Chem. 1963, 75, 604; Angew. Chem. Int. Ed. 1963,
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Acknowledgements
Thank you to the National Institutes of Health (R01 GM095559).
Thank you to Prof. S. R. Kass (UMN) for instrument use as well
as insightful conversation. Thanks to Dr. N. R. Rondla for
mentorship and disscussions.
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Conflicts of Interest
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a) M. S. Ziegler, K. V. Lakshmi, T. D. Tilley, J. Am. Chem. Soc. 2017,
139, 5378; b) J. R. Johansson, T. Beke-Somfai, A. S. Stꢀlsmeden, N.
Kann, Chem. Rev. 2016, 116, 14726; c) W. D. G. Brittain, B. R. Buckley,
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Chem. 2012, 5462
The authors declare no conflicts of interest
Keywords: palladium • azide • cycloreversion • diazo group
transfer • alkene cleavage
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10.1002/chem.201805904
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Grant B. Frost, Michaela K. Mittelstaedt
and Christopher J. Douglas*
Page No. – Page No.
Chemoselectivity for Alkene Cleavage
by Palladium-Catalyzed
Intramolecular Azide to Alkene Diazo
Group Transfer
Promoting Reversion: Palladium-catalyzed intramolecular azide to alkene diazo group
transfer enables the synthesis of N-heterocyclic quinazolinones. Our data support a new
mode of azide/alkene metal-catalysis, a cycloreversion mechanism which grants
chemoselectivity over competing aziridination.
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