C-H Insertion by Alkylidene Carbenes to Form 1,2,3-Triazines and Anionic [3 + 2] Dipolar Cycloadditions to Form Tetrazoles: Crucial Roles of Stereoelectronic and Steric Effects

Article abstract of DOI:10.1021/acs.orglett.9b04548

The synthesis of 1,2,3-triazines and bicyclic tetrazoles from α-azido ketones is described. The common intermediate generated from lithiated trimethylsilyldiazomethane and α-azido ketones diverges depending on the steric bulk of the substituents. The form

Full text of DOI:10.1021/acs.orglett.9b04548

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
C−H Insertion by Alkylidene Carbenes To Form 1,2,3-Triazines and
Anionic [3 + 2] Dipolar Cycloadditions To Form Tetrazoles: Crucial
Roles of Stereoelectronic and Steric Effects
Fa-Jie Chen,‡ Yongjia Lin,† Man Xu,† Yuanzhi Xia,*,† Donald J. Wink,‡ and Daesung Lee*,‡
†College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang Province 325035, P. R. China
‡Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
S
* Supporting Information
ABSTRACT: The synthesis of 1,2,3-triazines and bicyclic
tetrazoles from α-azido ketones is described. The common
intermediate generated from lithiated trimethylsilyldiazo-
methane and α-azido ketones diverges depending on the steric
bulk of the substituents. The formation of 1,2,3-triazines via a
C−H insertion of alkylidene carbene to form 3-azidocyclopro-
pene, followed by its rearrangement, is supported by density
functional theory calculations. Tetrazole formation proceeds
via a facile anionic [3 + 2] dipolar cycloaddition between a
lithiated diazo moiety and an azido group facilitated by the
chelation of a lithium ion.
zwitterion C, which ultimately generates 1,2,3-triazine B via
the formation of the intermediate D and its 1,3-H shift (eq 6).
In addition, we surmised that the steric bulk of the R
substituent would further gear the carbenic carbon closer to
the C−H bond via the bond angle (∠) compression.8 To test
these hypotheses, we systematically investigated the reactions
of α-azido ketones, and herein we describe the formation of
novel bicyclic tetrazoles and α-insertion to form azido
cyclopropenes that rearrange to generate 1,2,3-triazines.
We commenced our exploration by comparing the reactivity
of a pair of ketones with significantly different steric factors at
the α-carbon. The initial reaction was carried out with α-azido
ketone 1a (R = Ph)9 and LTMSD (THF, −78 °C to rt), which
afforded 3a (22%) and 3a′ (32%), whereas under identical
conditions, ketone 1b (R = t-Bu) provided only bicyclic
tetrazole 2b in 71% yield (Scheme 2). These results indicate
that depending on the steric bulk of the R substituent, IN1 can
directly cyclize to generate 2b, it survives until the reaction is
quenched by a proton to generate 3a,6 or it undergoes the
elimination of LiOSiMe3 to generate IN2, which then
rearranges to propargyl azide 3a′.10
he reactivity of alkylidene carbenes has been exploited in
1
Tvarious synthetic transformations (Scheme 1).
Most
prototypic transformations of alkylidene carbenes are insertion
reactions into C−H, N−H, O−H, and O−Si bonds to form
five-membered carbo- and heterocycles (eq 1).2 Alkylidene
carbenes also undergo a 1,2-shift of a hydride or a π-functional
group (alkene, arene, alkyne) to generate alkynes3 or
participate in an addition reaction with alkenes to generate
alkylidene cyclopropanes (eq 2).4 Also, the site-selective
insertion into a bridgehead C−H bond relying on the
conformation-dependent electronic effect of oxygen was
exploited for the synthesis of the platensimycin skeleton (eq
3).2q In the context of expanding the scope of alkylidene-
carbene-mediated transformations,5 we have demonstrated
that acyclic and cyclic ketones containing a heteroatom
functional group at the α-position react with lithiated
trimethylsilyldiazomethane (LTMSD) to generate the corre-
sponding alkylidene carbenes, which showed unusual reactivity
profiles depending on the nature of the α-substituent (eq 4).6
In light of the crucial role of the α-substituent in steering the
reactivity of the nearby alkylidene carbene moiety, we turned
our attention to the alkylidene carbene containing an α-azido
substituent. On the basis of the electron-donating nature of an
azide functionality, the n → σ* (C−H) hyperconjugation
would activate the corresponding C−H bond toward α-
insertion by alkylidene carbene to generate cyclopropene A,
which, because of its high ring strain, would spontaneously
rearrange to form 1,2,3-triazine B (eq 5).7 On the contrary, the
polar azido group can directly interact with the empty p orbital
of the alkylidene carbene to form a six-membered ring
At this juncture, we reasoned that the steric bulk of the R
substituent might promote the formation of 1,2,3-triazine 4
from IN2 by exerting the exo-Thorpe−Ingold effect.11 Also,
the increased steric bulk will facilitate the elimination of
LiOSiMe3 to generate alkylidene carbene IN2 more efficiently
over cyclization product 2. With these hypotheses in mind, we
Received: December 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04548
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Scheme 1. Representative Transformations of Alkylidene
Carbenes
Table 1. Reactions of α-Azido Ketones Containing
a b
,
Noncyclic Alkyl Substituents
Scheme 2. Reactivity Dependency on a Steric Factor
a
Reaction conditions: trimethylsilyldiazomethane (1.2 equiv), n-BuLi
(1.3 equiv), azido ketone 1 (1.0 equiv) in THF, under N2 at −78 °C
b
for 1 h, then at rt for x h. Isolated yield.
explored various ketones 1 containing a quaternary carbon at
the α′-position of α-azido ketones. It was found that
intermediate IN1 could remain in the reaction mixture, even
at room temperature, but in most cases, it can cyclize to
tetrazole12 compound 2. With a narrow range of the structural
space of the quaternary carbon-containing R substituent,
eventually 1,2,3-triazine13 4 could be generated.
Upon recognition of the crucial role of the steric effect in
controlling the reaction pathways we decided to examine the
steric effect of the alkyl substituent with α-azido ketones, with
a systematic variation of the steric factors (Table 1). gem-
Dimethyl-containing α-azido ketones 1b and 1c reacted with
LTMSD smoothly and afforded tetrazoles 2b and 2c in 71 and
88% yield, respectively (entries 1 and 2). The structure of
tetrazole 2c was confirmed by an X-ray crystallographic
analysis. With 1d as the substrate, tetrazole 2d and
homologated ketone 3d were obtained in 35 and 13% yield
(entry 3) by running the reaction for 0.5 h, but only tetrazole
2d was obtained in 74% yield when the reaction was carried
out for 3 h (entry 4). An alkyne at a remote position from the
carbonyl group did not affect the formation of tetrazole, and
thus 2e was obtained in good yield (75%), although a relatively
longer reaction time was required (entry 5). Surprisingly,
substrate 1f with an ester functionality at the α′-position
provided product 3f (69%), which is derived from the
protonation of the diazo moiety, followed by the substitution
+
of N2 with water (entry 6). Interestingly, when the gem-
dimethyl group in 1c was replaced with a gem-diethyl (1g) and
a gem-dipropyl group (1h), only triazines 4g and 4h were
generated, both in 53% yield (entries 7 and 8). Similarly,
diethylpropyl-containing substrate 1i afforded triazine 4i in
slightly lower yield (41%) (entry 9). These outcomes suggest
that the formation of tetrazole 2 and 1,2,3-triazine 4 highly
depends on the steric effect of the substituent around the
reaction center.
These results prompted us to further explore the reactivity
and selectivity of other α-azido ketones containing cycloalkyl
substituents (Table 2). A variety of α-azido ketones containing
a cyclohexyl substituent provided tetrazoles in moderate to
good yield. α-Azido ketones 1j and 1k containing an α-silyloxy
group reacted with LTMSD to provide tetrazoles 2j and 2k in
80 and 94% yield, respectively (entries 1 and 2). Similarly,
B
DOI: 10.1021/acs.orglett.9b04548
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Letter
provided only triazines 4t and 4u in 42 and 44% yield,
respectively, without forming the corresponding tetrazoles.
It was found that the α-azido group is crucial for the
addition of LTMSD sterically hindered ketones (Scheme 3).
Table 2. Reactions of α-Azido Ketones Containing
Cycloalkyl Substituents
a
Scheme 3. Activating Role of α-Azido Group for the
Carbonyl Addition of a Bulky Nucleophile
The corresponding ketones 1t′ and 1u′ are inert to LTMSD,
and these ketones were recovered intact under identical
conditions. For α-azido ketones, most likely the lithium-
chelated ketone is more active toward the nucleophile, which
can overcome the severe steric hindrance, whereas ketones 1t′
and 1u′ do not have this activating mechanism to compensate
the steric hindrance.14 Furthermore, the α-azido group
stabilizes the intermediate IN1 such that in most cases the
elimination of LiOSiMe3 from IN1 is relatively slow compared
with the corresponding adduct lacking the azido group.
The effect of structural change was further examined. For
example, α-azido ketone 1v containing a quaternary center at
the β-position generated only C−H insertion product 5v,
which is in equilibrium with an allylic transposed azide
(Scheme 4). The additional methyl group in 1w at the carbon
Scheme 4. Effect of Different Substituent Patterns
a
Reaction conditions: trimethylsilyldiazomethane (1.2 equiv), n-BuLi
(1.3 equiv), azido ketone 1 (1.0 equiv) in THF, under N2 at −78 °C
b
c
d
e
for 1 h, then rt for 1 h. Isolated yield. 2 h. 0.5 h. 60 °C, 16 h.
bearing an azide did not change its reactivity compared with
1c, providing tetrazole 4w as a 7:1 mixture of diastereomers.
On the contrary, structurally similar ketones 1x and 1y only
lead to the decomposition of the starting material. These
results clearly indicate the importance of the right position and
balance of the steric factors on the α,α′-carbons of the ketone
for the formation of tetrazoles.15
To gain insight into the mechanism for the formation of
bicyclic tetrazoles 2 and 1,2,3-triazines 4, density functional
theory (DFT) calculations were carried out.16 For tetrazole
formation, the initial adduct IN1 rearranges to IN2, which can
undergo an anionic [3 + 2] dipolar cycloaddition6c,17 with a
relatively low activation barrier (9.4 kcal/mol) via a lithium-
ion-chelated transition state TS2 (Figure 1). The initial
cycloadduct IN3 then rearranges to a more stable aromatic
form IN4, the protonation of which ultimately leads to
tetrazoles 2l and 2m also were obtained in 66 and 62% yield,
respectively (entries 3 and 4). Although seemingly not
significantly different from the others in the series, only ketone
1n containing a propyl group provided triazine 4n in 31% yield
along with tetrazole 2n in 33% yield (entry 5). α-Azido ketone
1o containing an adamantyl group afforded tetrazole 2o in 86%
yield (entry 6), whereas azido cyclopentyl-containing ketone
1p mainly afforded 3p (78%), a protonated product of the
corresponding intermediate, along with triazine 4p in 22%
yield (entry 7). Also, structurally similar azido ketones 1q and
1r provided tetrazoles 2q and 2r in 70 and 69% yield (entries 8
and 9). A moderate yield of tetrazole 2s was generated (58%)
from cyclobutyl-containing substrate 1s (entry 10). Adaman-
tane-based α-silyloxy and α-alkoxy azido ketones 1t and 1u
C
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and α-azido ketones. The selectivity and efficiency for these
reactions crucially depend on the hypersensitive steric effect of
the substituents on α-azido ketones. DFT calculations show
that the formation of tetrazole is the consequence of a facile
anionic [3 + 2] dipolar cycloaddition between a lithiated diazo
moiety and an azido group, which is due to the chelation of a
lithium ion with the nitrogen-based dipole and dipolarophile.
DFT calculations also bolster that the formation of 1,2,3-
triazines involves an initial C−H bond insertion by the
alkylidene carbene at the carbon bearing an azido group to
form 3-azidocyclopropenes, which subsequently rearrange to
more stable 1,2,3-triazines. The generality of the anionically
activated [3 + 2] dipolar cycloaddition of diazo-compound-
based dipoles will be further investigated in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04548.
Experimental procedures, characterization data, X-ray
crystallographic data, and DFT calculations data (PDF)
Figure 1. DFT-calculated reaction mechanism for the formation of
tetrazole 2c.
Accession Codes
tetrazoles 2. For the formation of 1,2,3-triazine 4, it is expected
that two different mechanistic pathways are plausible, as shown
in Scheme 1.18
The calculations show that the C−H insertion pathway from
alkylidene carbine IN5 has a relatively low barrier via TS4 (3.5
kcal/mol) to generate azido cyclopropene IN6, which
rearranges to 1,2,3-triazine 4 via TS5 (Figure 2). Although
CCDC 1957606 and 1959780 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dsunglee@uic.edu (D.L.).
*E-mail: xyz@wzu.edu.cn (Y.X.).
ORCID
Fa-Jie Chen: 0000-0002-0421-3885
Yuanzhi Xia: 0000-0003-2459-3296
Donald J. Wink: 0000-0002-2475-2392
Daesung Lee: 0000-0003-3958-5475
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1764141, D.L.) and the NSFC
(21873074 and 21572163, Y.X.) for financial support. The
Mass Spectrometry Laboratory at UIUC is acknowledged.
Figure 2. DFT-calculated reaction mechanism for 1,2,3-triazine
formation via the C−H insertion pathway.
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D
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