Synthesis of Bridged Azacycles and Propellanes via Nitrene/Alkyne Cascades

Article abstract of DOI:10.1021/acs.orglett.0c00798

A nitrene/alkyne cascade reaction terminating in C-H bond insertion to form functionalized bridged azacycles from carbonazidates is presented. Due to an initial Huisgen cyclization, all carbonazidates reacted with the alkyne in an exo mode in contrast to the use of sulfamate esters, which react predominately in an endo mode. Substrates with different ring sizes as well as different aryl and heteroaryl groups were also explored. Variation of the nitrene tether showed that 7-membered rings were the maximum ring size to be formed by nitrene attack on the alkyne. Examples incorporating stereocenters on the carbonazidate's tether induced diasteroselectivity in the formation of the bridged ring and two new stereocenters. Additionally, propellanes containing aminals, hemiaminals, and thioaminals formed from the bridged azacycles in the same reaction via an acid-promoted rearrangement.

Full text of DOI:10.1021/acs.orglett.0c00798

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Letter
Synthesis of Bridged Azacycles and Propellanes via Nitrene/Alkyne
Cascades
Qinxuan Wang and Jeremy A. May*
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ABSTRACT: A nitrene/alkyne cascade reaction terminating in C−H bond insertion to form functionalized bridged azacycles from
carbonazidates is presented. Due to an initial Huisgen cyclization, all carbonazidates reacted with the alkyne in an exo mode in
contrast to the use of sulfamate esters, which react predominately in an endo mode. Substrates with different ring sizes as well as
different aryl and heteroaryl groups were also explored. Variation of the nitrene tether showed that 7-membered rings were the
maximum ring size to be formed by nitrene attack on the alkyne. Examples incorporating stereocenters on the carbonazidate’s tether
induced diasteroselectivity in the formation of the bridged ring and two new stereocenters. Additionally, propellanes containing
aminals, hemiaminals, and thioaminals formed from the bridged azacycles in the same reaction via an acid-promoted rearrangement.
xygen- and nitrogen-containing polycycles are common
structural motifs present in natural products, many of
based nitrenes almost exclusively reacted in an exolike mode
with alkynes.
O
which possess significant biological activities.1,2 Strategies for
the construction of bridged polycycles that have been explored
in total syntheses include cycloadditions,3 cyclizations,4
carbocation rearrangements,5 and multistep reactions. A
substrate-controlled, general strategy to construct bridged
polycyclic isomers from easily accessible precursors would
facilitate the rapid construction of these targets. To that end,
many research groups, including our own, are in pursuit of
carbene/alkyne and nitrene/alkyne cascades to build multiple
C−C and C−N bonds and multiple rings of the target
polycycles in a single transformation.6,7
The exo-cyclization of alkynyl nitrenes to form α-
iminocarbenes like 16 has been significantly more difficult to
implement. Instead, α-diazoimines and α-iminocarbenes were
generated via triazole formation and subsequent ring opening
in the presence of transition metal catalysts (see 14 and 15).10
Our group reported that intermediates 10 were generated from
silyl alkynylcarbonazidates 9 via triazole formation, and
dediazotization provided the exolike product of nitrene/alkyne
cyclization (Scheme 1c).6f Unfortunately, azasilacyclopentenes
11 were formed as the major products via an unusual α-silyl
C−H bond insertion due to triplet carbene reactivity. The
targeted bridged tricyclic product 12 was observed only as a
minor product, and to the best of our knowledge, no group has
successfully selectively synthesized nitrogen-containing bridged
tricycles via nitrene/alkyne cascades.
Nitrene/alkyne cascades could be utilized for the formation
of polycyclic azacycles. For example, Blakey’s group developed
a series of metallonitrene/alkyne cascade reactions initiated by
endocyclization with Rh-nitrenes to generate cation/metal-
loenamine intermediate 2, followed by intramolecular cyclo-
propanation, aromatic substitution, or oxygen-ylide formation
followed by [2,3]-Wittig rearrangement to build the fused
bisheterocyclic products 3 (Scheme 1a).8 Recently, Shi and co-
workers reported a substrate-dependent cascade reaction of
alkynyl-tethered sulfamates 5 (Scheme 1b).9 In the case of
sulfamates bearing a cyclopropyl or cyclobutyl group, oxidative
amination and cyclization formed cyclobutane-containing
heterocycles 7 and 8. Alternatively, with 5- or 6-membered
cyclic sulfamates, only a direct C−H bond insertion reaction
occurred to give the fused bicyclic products 4.9a Sulfamate-
To avoid α-silyl C−H bond insertion in the cascade
reaction, phenylethynyl carbonazidate 19 was prepared in just
two steps from the parent ketone 18 (80% yield overall). A
Received: March 2, 2020
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© XXXX American Chemical Society
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A

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Scheme 1. Nitrene-Initiated Cascade Reactions
Table 1. Formation of Bridged Azacycle
a
Yield based on 1H NMR peak integration relative to methyl-4-
nitrobenzoate. See the Supporting Information for more details.
range of aprotic solvents were examined at 0.01 M. Saturated
hydrocarbon solvents provided better yields than benzene or
1,4-dioxane (Table 1, entries 1−4). Isopropyl acetate (i-
PrOAc) was also examined due to its common use in industry
as well as in carbene reactions. To our delight, it afforded a
better yield (35%) than that from nonpolar solvents (entry 5).
To reduce side reactions, a rhodium(II) catalyst was added to
promote intramolecular C−H insertion. Gratifyingly, after
adding Rh2(esp)2, the yield of the bridged azacycle 20
increased significantly. As a result, i-PrOAc with Rh2(esp)2
(1 mol %) provided the best conditions for this nitrene/alkyne
cascade reaction and gave the bridged azacycle 20 in 55% yield
(entry 6). With different ester solvents, the yields were less
than those from i-PrOAc (entries 7−9). Dimethyl carbonate
was also examined, but the yield was not improved (entry 10).
Some other dirhodium catalysts were also examined (entries
11−13),11 but did not improve the yields.
The scope of carbonazidate reactivity was then explored
(Scheme 2). For carbonazidates containing a heteroatom-
activated methylene, bridged products 20 and 21−24 were
formed in useful isolated yields. Similar yields of 20 and 21
illustrated that the electron-withdrawing group on the alkynyl
phenyl ring had little effect on the outcome. Introducing a
methoxy group in the meta position of the phenyl ring
decreased the yield to 45% of 22, which could be due to
inductive effects. Electron-rich naphthyl-substituted 23 suc-
cessfully produced product in 41% yield. N-Toluenesulfonyl
amide (N-Ts) 24 showed similar reactivity as N-Boc amide 20.
Sulfur-containing substrate provided less of the bridged
azacycle than amides, affording the corresponding product
25 in a lower yield (34%). This could be due to decreased
activation of the adjacent C−H bond by sulfur relative to an
amide nitrogen. Alternatively, sulfur could also react with the
intermediate carbene to form a sulfur ylide,12 which could
potentially shut down the cascade reaction. Interestingly, by
introducing a phenyl group in the cyclohexyl 4-position, the
conformation of the cyclohexane ring can be controlled. With
the alkyne cis to the phenyl group, bridged tricycle 26 was
produced. However, with the alkyne trans to the phenyl group,
no bridged product was produced. Incorporation of a ketal in
the 4-position provided no activation for product formation,
giving 27 with only a 29% yield. For the carbonazidates
containing tertiary, benzylic, or allylic C−H bonds for
insertion, the yields were generally higher than those with an
α-heteroatom activated methylenes (see 28−31). Benzylic C−
H bonds showed the highest activity for C−H insertion, giving
enamine 28 in 84% yield. Both methoxy-activated and methyl-
activated tertiary C−H bonds were highly reactive and
provided higher yields of product than did C−H insertion at
an allylic C−H bond (compare 29−31).
Many pyridine derivatives have intriguing activities against
important biological targets.13 Impressively, when using a
cyclohexyl carbonazidate bearing 3-pyridinyl alkynyl substitu-
tion, bridged tricycle 32 was obtained in 59% yield.
Introducing a methyl group at the 3 position in the ring
improved the yield, giving 33 in 68% yield. However, when a 2-
pyridinyl alkynyl carbonazidate was tested, only pyridotriazole
34 was formed with or without Rh2(esp)2 via an electro-
cyclization from the corresponding diazo intermediate (formed
in the first mechanistic cyclization).14 This product was very
thermally stable (tested to 175 °C), and no further
transformation was observed.
B
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a
Scheme 2. Formation of Bridged Azacycles
Scheme 3. Boc Protection of Bridged Azacycles and
a
Propellane Formation
a
b
All yields are isolated yields (average of 2 runs). Trifluoroacetic acid
used instead of acetic acid.
a
Scheme 4. Variation of Tether Length and Ring Sizes
a
b
All yields are isolated yields (average of 2 runs). Overall yield of
two steps from the propargylic alcohol. See the Supporting
c
Information for more details. ORTEP diagram for 34. Thermal
ellipsoids are shown at the 50% probability level. Hydrogen atoms
d
have been omitted for clarity. Without Rh2(esp)2.
In general, the rearrangement of the bridged tricyclic
products with heteroatoms such as oxygen, nitrogen, or sulfur
connected to the newly formed bridgehead carbon occurs fairly
easily, even as a purified solid. Therefore, those bridged
products were difficult to purify by chromatography. In
particular, oxacycles such as 35 could not be isolated despite
multiple techniques attempted (Scheme 3). To avoid
rearrangement and isolate these products in a form with a
significantly longer shelf life, the relatively more stable N-Boc
protected bridged tricycles 36−39 were synthesized by a one-
pot sequence (Scheme 3a). Furthermore, by simply adding
acetic acid (AcOH) after the cascade reaction and before any
workup, the propellane products 40−43 could be generated
from bridged tricycles via rearrangement (Scheme 3b).
A larger ring fused to the bridged tricycle could be accessed
by lengthening the tether to the carbonazidate (Scheme 4).
Both 6- and 7-exo-dig cyclizations produced cyclourethane
fused bridged tricycles (45 and 57), and no fused bicycles were
formed via direct C−H insertion into the cyclohexyl or pyran
ring of 44 or 56, respectively. It appears that 6- and 7-exo-dig
cyclization were both more facile than 5-exo-dig cyclizations as
evidenced by higher isolated yields (compare 45 and 57 to
a
b
All yields are isolated yields. General conditions: 0.01 M of
c
carbonazidate in i-PrOAc with 1 mol % Rh2(esp)2, 100 °C, 12 h. 1:2
AcOH/i-PrOAc, rt, 3 h. Yield is calculated for two steps from 56,
with a 95% yield from 57.
d
36), which would be an unusual scenario.15 Alternatively, the
conformation of the carbene intermediates after the 6- and 7-
exo-dig cyclizations might be more favorable for the
C
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subsequent C−H insertion than the conformation of the 5-exo-
dig product. These outcomes are important, because even with
the larger rings the initial [3 + 2] cycloaddition to form the
triazole intermediate controls the sense of cyclization to give
exocyclization-derived carbene reactivity, whereas sulfamate-
derived nitrenes give endocyclization-derived carbene reac-
tivity. Unsurprisingly, further extension of the carbonazidate-
bearing side chain resulted in only direct C−H insertion on the
tether rather than medium ring formation. The cyclization
generally favored the formation of a 6-membered ring over a 5-
membered ring. This produced a ratio of about 1.5:1 when the
tether between the alkyne and the carbonazidate was extended
to three atoms (see 47 and 48), and a ratio of ∼6:1 for an
oxygenated four atom tether (see 50 and 51). The improve-
ment in the selectivity in the latter example was likely due to
the oxygen activating the adjacent C−H bonds. Cycloheptane
52 produced the bicyclo[4.2.1]nonane core in 53 in 71% yield,
and no bicyclo[3.2.2]nonane 55 was detected. A minor
amount of the fused bicyclic product 54 was also observed.
Impressively, when methyl substituted secondary carbonazi-
date 56 was tested, diastereomer 57 was obtained with greater
than 10:1 dr. Rearrangement to the propellane was also
performed, producing the corresponding diastereomer 58 in
64% overall yield from 56. The ability to control the
stereoselectivity of C−C bond formation via easy to access
enantioenriched secondary alcohols16 will be highly useful in
stereocontrolled synthesis.
The excellent diastereoselectivity from 56 inspired further
exploration. Another α-methyl ether in a shorter tether was
examined (see carbonazidate 59). Unfortunately, after 6-exo-
dig cyclization, the final C−H insertion gave bridged product
60 with only 1.3:1 dr (Scheme 5). A larger substituent like a
phenyl group did increase the diastereoselectivity to be greater
than 10:1 dr (62). Removing the pyranyl oxygen in 56 to give
substrate 63 caused the diastereoselectivity to drop to 3.3:1 dr.
These results indicated that the conformation imposed by the
tether substituent on the postalkyne-cyclization intermediate
could control the stereoselectivity of C−H insertion.
The diastereoselectivity above may be explained by
considering the carbene intermediate immediately prior to
C−H bond insertion (Scheme 6). Huisgen cyclization of
Scheme 6. Potential Origins of Diastereoselectivity
carbonazidates 56 or 63 to form a triazole fused to a 7-
membered ring, followed by electrocyclative ring opening to a
diazo imine and Rh-catalyzed dediazotization (Scheme 1d),
would give carbene intermediates 65. Similarly, carbonazidates
59 and 61 would give Rh carbenes 66. Minimizing the
conformational energy of the substituted carbamate rings as
shown in 65b and 66b places the ring substituent in a
pseudoequatorial disposition.3a In these conformations, the
carbene would be placed closer to the methylene on the
pseudoequatorial side of the tetrahydropyran ring. In
considering 65b, apparently having a smaller ether oxygen
(X = O) allows for a more discriminating carbene approach
than the larger methylene (X = CH2), consequently providing
higher disasteroselectivity as well as a higher yield. The control
found in conformation 66b is likely dependent on the size of
the R group due to the influence it would exert on the twist-
chair conformation, which then controls subsequent insertion
selectivity.
In conclusion, nitrene/alkyne cascades synthesized bridged
polycyclic compounds chemoselectively from carbonazidates in
useful yields. In contrast to our previous approach where
bridged products were the minor product, Rh2(esp)2 catalysis
and the use of aromatic alkynes improved the chemoselectivity
and gave useful yields of bridged heterocyclic [n.2.1] cores.
Aryl and heteroaryl substituents are both readily tolerated.
With the abundance of heterocycles in natural and medicinal
compounds, this bridged azacycle formation could serve both
synthetic and medicinal chemists. By simple modification of
the reaction conditions, we were also able to promote
rearrangement in the same reaction to propellane structures,
which are also present in a considerable number of natural
products and medicinally interesting compounds. While endo
cyclizations prevailed with the sulfonamide-based substrates,
this work shows that 5-, 6-, and 7-exo-dig cyclizations readily
occur from carbonazidates as controlled by the initial Huisgen
cyclization. Up to 7-membered rings fused to the bridged
bicycle can be incorporated. The impact of chiralilty in the
carbonazidate tethers on the diastereoselectivity of the cascade
reaction has also been explored, with promising transmission of
the stereochemistry to the products in several cases.
Applications of this methodology to the synthesis of complex
targets and additional mechanistic investigations are ongoing.
a
Scheme 5. Diastereoselectivity in the Cascade Reaction
a
b
All yields are isolated yields. General conditions: 0.01 M of
carbonazidate in i-PrOAc with 1 mol % Rh2(esp)2, 100 °C, 12 h.
D
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00798.
Experimental details and compound spectral data (PDF)
Accession Codes
CCDC 1981686 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Jeremy A. May − Department of Chemistry, University of
Houston, Houston, Texas 77204-5003, United States;
orcid.org/0000-0003-3319-0077; Email: jmay@uh.edu
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the NSF
(Grant CHE-1352439) and the Welch Foundation (Grant E-
1744).
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