Divergent, Strain-Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation

Article abstract of DOI:10.1002/anie.202100583

The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain-release reactions upon N-activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3-substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.

Full text of DOI:10.1002/anie.202100583

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Azetidines Hot Paper
Divergent, Strain-Release Reactions of Azabicyclo[1.1.0]butyl
Carbinols: Semipinacol or Spiroepoxy Azetidine Formation
Charlotte H. U. Gregson, Adam Noble, and Varinder K. Aggarwal*
[
5b]
[5d]
Abstract: The azetidine moiety is a privileged motif in
medicinal chemistry and new methods that access them
efficiently are highly sought after. Towards this goal, we have
found that azabicyclo[1.1.0]butyl carbinols, readily obtained
from the highly strained azabicyclo[1.1.0]butane (ABB), can
undergo divergent strain-release reactions upon N-activation.
Treatment with trifluoroacetic anhydride or triflic anhydride
triggered a semipinacol rearrangement to give keto 1,3,3-
substituted azetidines. More than 20 examples were explored,
enabling us to evaluate selectivity and the migratory aptitude of
different groups. Alternatively, treatment of the same alcohols
with benzyl chloroformate in the presence of NaI led to
iodohydrin intermediates which gave spiroepoxy azetidines
upon treatment with base. The electronic nature of the
activating agent dictates which pathway operates.
me 1b)
or organocuprates
to enable rapid access to
diverse 1,3-substituted azetidines. We recently reported the
preparation of azabicyclo[1.1.0]butyllithium (ABB-Li, 2) by
the facile lithiation of 1 at the bridgehead position with
[8a]
TMEDA-ligated sec-butyllithium (Scheme 1b).
ABB-Li
resembles a carbenoid as it is a nucleophile with inherent
electrophilicity due to the strained structure. We subsequently
employed 2 in reactions with boronic esters to give boronate
complexes 3 that underwent strain-release 1,2-rearrange-
ment upon activation of the ABB nitrogen with acetic acid.
This alternative umpolung-type reactivity of ABB enabled
the synthesis of 1,3,3-substituted azetidines (4) bearing
a versatile tertiary boronic ester.
We wanted to further develop the use of 2 as a synthon for
1,3,3-substituted azetidines by exploring alternative electro-
philes which could also trigger strain-release reactivity and
considered the use of ketones and aldehydes (Scheme 1c). We
envisaged that after formation of azabicyclo[1.1.0]butyl
carbinols (ABB-carbinols, 5), subsequent N-activation by
a suitable electrophile could trigger a pinacol-type rearrange-
[
8]
Introduction
The past decade has seen a surge in the application of
[1]
azetidines in pharmaceutical drug candidates. This is due in
part to their improved pharmacokinetics in comparison to
their larger ring analogues: molecules with the azetidine motif
were shown to exhibit greater metabolic stability and
[
2]
increased bioavailability. 1,3-Substituted azetidines also
benefit from having 3D character, which has been shown to
[
3]
improve clinical success, but without introducing chirality
and so are more amenable to synthesis. This specific
substitution pattern is featured on the azetidine scaffold of
[4]
[1a]
the marketed drugs azelnidipine, cobimetinib and barici-
tinib (Scheme 1a).
[
1b]
An emerging method for the construction of 1,3-substi-
tuted azetidines is the use of azabicyclo[1.1.0]butane (ABB,
[
5,6]
[7]
1).
First prepared in 1969, the highly strained building
block was shown to react with electrophiles such as tosyl
[
5a]
chloride, through activation of the ABB nitrogen, followed
by nucleophilic addition at the bridgehead carbon (Sche-
me 1b). More recently, it was demonstrated that ABB could
react with strong nucleophiles such as turbo amides (Sche-
[
*] C. H. U. Gregson, Dr. A. Noble, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100583.
ꢀ
2021 The Authors. Angewandte Chemie International Edition
Scheme 1. a) Marketed drugs containing 1,3-substituted azetidine scaf-
folds. b) Electrophilic activation of ABB, nucleophilic addition to ABB
and lithiation of ABB followed by reaction with boronic esters.
c) Reaction of ABB-Li with carbonyls and subsequent divergent reac-
tivity.
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
7
360
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1
ment, cleaving the bridging CÀN bond and releasing ring
products were determined by H NMR. Presumably, the
[
9,10]
strain.
Such a pinacol-type rearrangement is analogous to
electron-withdrawing nature of the CF group present in 5r
reduces the basicity of the nitrogen and minimizes acid-
mediated decomposition.
Having gained access to a range of ABB-carbinols, their
reactivity with different activating agents was investigated.
Firstly, the addition of benzyl chloroformate (CbzCl) to 5a
resulted in the formation of chlorohydrin 10 in 83% yield
(Scheme 3a). This result is consistent with previous reports of
3
[11]
the semipinacol rearrangement of a-hydroxy epoxides. This
would lead to azetidines bearing a quaternary centre (6/7).
Alternatively, N-activation of ABB-carbinols could result in
a nucleophilic addition of the alcohol to form spiroepoxy
[1a,12,13]
azetidines (8)
which would be interesting synthetic
targets as they could display further strain-release reactiv-
[12]
ity. In this paper, we report our success in discovering two
divergent pathways from a common ABB-carbinol inter-
mediate that lead to either 1,3,3-substituted azetidines, via
a semipinacol rearrangement, or spirocyclic epoxides.
[15]
the 1,3-functionalisation of ABB with chloroformates.
However, when trifluoroacetic anhydride (TFAA) was em-
ployed as the activating agent, the desired semipinacol
rearrangement occurred to form keto azetidine 6a in 71%
yield (Scheme 3b).
Results and Discussion
The divergent reactivity of 5a can be rationalised by the
extent of positive charge build-up at the electrophilic bridge-
head carbon. When TFAA is used as an activator, the
trifluoroacetyl group, being more electron-withdrawing than
the Cbz group, results in a greater build-up of positive charge,
thereby favouring the semipinacol reaction pathway. We
postulated that the different counterions could also play a role
in determining the outcome of the reaction, therefore, we
investigated whether product formation was determined by
the nucleophilicity of the counterion or by the nature of the
activating group. This was achieved by performing the
reactions in the presence of NaI in order to keep the
We began our investigation by studying the reaction of
ABB-Li with acetophenone (Scheme 2).
formed in situ by the sequential reaction of amine salt 9 with
[14]
ABB-Li was
[8a]
phenyllithium and sec-butyllithium, and subsequently re-
acted with acetophenone at À788C to form ABB-carbinol 5a
in good yield. This procedure was successfully applied to
a wide range of ketones and aldehydes. The alcohol products
were stable to aqueous work-up and could be stored at À188C
with no evidence of degradation. However, apart from the
trifluoromethylated example 5r, the ABB-carbinols were
found to partially decompose on silica gel and so yields of the
[16]
counterion (iodide) constant (Scheme 3c).
Once again,
with CbzCl, nucleophilic addition dominated to give exclu-
sively iodohydrin 11 via the nucleophilic addition pathway.
With TFAA, both nucleophilic addition and semipinacol
rearrangement occurred to give 12 and 6a in 40% and 49%
Scheme 2. Synthesis of ABB-carbinols by the reaction of ABB-Li with
carbonyl compounds. Reactions performed on 2.0 mmol scale at
1
0
4
.31 M initial concentration. Yields determined by H NMR. [a]
.0 mmol scale. [b] 1.0 mmol scale. [c] Purified by flash column
Scheme 3. Divergent reactivity of 5a with a) CbzCl vs. b) TFAA. c) In-
chromatography.
vestigations into the cause of divergence.
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yield, respectively. Finally, when moving to an even more
7h–k were obtained after ring expansions from ABB-
electrophilic activating agent, triflic anhydride (Tf O), the
carbinols bearing 4-, 5-, 6-, and 7-membered rings in yields
2
semipinacol rearrangement dominated to give sulfonamide
of 27–54% using TFAA (method A) and 50–87% using Tf O
2
7
a in 50% yield with no nucleophilic addition observed. Thus,
(method B). The lower yields when using TFAA were
attributed to competing nucleophilic addition of trifluoro-
acetate due to the lower migratory aptitude of alkyl groups.
the outcome of the reaction is predominantly determined by
the electronic nature of the activating group on nitrogen: the
more electron-withdrawing it is the more the semipinacol
pathway is favored.
We sought to optimise the semipinacol pathway and found
that, in the absence of NaI, the reaction yields with TFAA and
Tf O were improved by switching the solvent to CH Cl and
[17]
The semipinacol rearrangement of ABB-carbinol 5l gave
azetidines 6/7l with an intriguing 2,6-diazaspiro[3.4]octane
[18]
core in 48% and 63% yields, respectively. This example is
particularly noteworthy as a Reaxys search identified this
motif in > 250 patents with > 1300 unique examples where
pharmacological data is presented. Furthermore, it is easily
prepared in just two steps from N-Boc azetidinone. In order
to further probe the selectivity over which group migrates,
a non-symmetrical alcohol bearing two different alkyl groups
(a cyclohexyl and a methyl group) was explored. Using both
2
2
2
performing the reaction at À788C (conditions A and B; see
Supporting Information for optimisation study). In the case of
Tf O, the yield was further increased by the addition of 2,6-
2
lutidine. We then explored the scope of the reaction using
both sets of conditions (A and B) with a broad range of ABB-
carbinols (Scheme 4).
TFAA (method A) and Tf O (method B), exclusive migration
2
[11b]
For non-symmetrical alcohols bearing an aryl and methyl
group, in all cases, and under both sets of conditions, we found
exclusive migration of the aryl group to give azetidines 6/7a–c
in good yields, even in the cases of electron-poor aryl groups.
Furthermore, electron-rich and electron-deficient heteroar-
omatic groups (indolyl and 3-pyridyl) also worked well, giving
compounds 6/7d–f in good yields—again exclusive migration
of the aryl group was observed. However, 4-pyridyl carbinol
of the more substituted alkyl group
was observed, giving 6/
7m, the latter in almost quantitative yield.
We subsequently compared the migration of a Ph group
over other substituents, including more substituted alkyl
groups and other functional groups. Comparing Ph with H, we
found that the Ph group migrated exclusively to give
[9]
aldehydes 6/7n in 51% and 84% yields, respectively.
Comparing Ph/ethyl and Ph/alkynyl, again resulted in exclu-
sive migration of the Ph group, giving azetidines 6/7o,p in
excellent yields. However, comparing Ph/Cy resulted in high
5
g was found to be a poor substrate, as the reaction was
unsuccessful with TFAA and low yielding with Tf O.
2
Cyclic ketones were also explored as the semipinacol
rearrangement would result in a ring expansion to give
valuable spirocyclic azetidine scaffolds. Azetidines 6h–k and
selectivity but only in the case of TFAA to give 6q; Tf O gave
a 1:1.5 ratio of products 7q/7q’, now in favour of Cy
migration. In both cases, the yield of the ketone was low. In
2
Scheme 4. Scope of ABB-carbinols employed in the semipinacol rearrangement reaction. Reactions performed on 0.25 mmol scale at 0.1 M. [a]
Reaction also performed on 1.0 mmol scale to give 6a in 90% yield. [b] Reactions stirred for 15 min at À788C then 30 min at 08C. [c] Product
1
isolated after reduction by NaBH to the primary alcohol. [d] From purified 5r. [e] Formed under conditions B and yield determined by H NMR.
4
7
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fact, the main component of the latter reaction was spirocyclic
epoxide 13, formed in 66%. Trifluoromethyl carbinol 5r was
[19]
tested and as expected, exclusive migration of the Ph group
was observed. This substrate was substantially less reactive
than the others, requiring 08C to trigger the semipinacol
rearrangement. Azetidine 6r was formed in only 25% yield
with competing nucleophilic addition of trifluoroacetate
observed. Selectivity for the semipinacol rearrangement was
much higher with Tf O (conditions B), giving azetidine 7r in
2
7
2% yield.
Azetidines 6s and 7s were obtained from ABB-carbinol
s derived from benzophenone in 42% and 90% yields under
5
conditions A and B, respectively. In the case of 6s, the lower
yield observed was due to competing nucleophilic addition.
Finally, comparing Ph/p-MeOC H , we found that the more
6
4
[20]
electron-rich aryl group migrated preferentially, but not by
much: a 3.2:1 ratio of 6t/6t’ and 1.3:1 ratio of 7t/7t’ were
obtained under conditions A and B, respectively.
The commonly observed relative migratory aptitude in
[9,17,20]
semipinacol rearrangements
of aryl > alkenyl > hydride
>
substituted alkyl > less substituted alkyl is mirrored here in
Scheme 5. Scope of ABB-carbinols employed in the epoxide formation
reactions using TFAA. A similar pattern is seen with the more
reaction. Reactions performed on 0.25 mmol scale and 0.1 M initial
concentration. [a] Reaction also performed on 1.0 mmol scale to give
electron-withdrawing Tf O, but the selectivity is lower since it
2
8
a in 93% yield. [b] Intermediate iodohydrin purified before second
induces a faster reaction. In the case of the especially
hindered substrate 7q, containing both phenyl and cyclohexyl
migrating groups, no selectivity is observed. Here, CÀC bond
step. [c] Stirred for 42 h after addition of K CO . [d] 0.05 M initial
2
3
concentration. [e] From purified 5r. [f] Semipinacol reaction also
occurred in 36% yield. [g] After addition of Boc O, heated at 808C for
2
rotation of the hindered substrate is likely to have a higher
1
8 h without K CO .
2 3
[21]
barrier than 1,2-migration, which results in migration of
whichever group is antiperiplanar to the central CÀN upon
reaction with Tf O.
yield (86%). Due to its instability on silica gel (as with 8d),
purification of the intermediate iodohydrin was necessary in
order to isolate analytically pure 8p.
2
The formation of spirocyclic epoxide 13 from 5q under
conditions B was intriguing, and we were keen to establish
whether this pathway could be promoted more generally. We
reasoned that iodohydrin 11, formed from the reaction of 5a
with CbzCl and NaI (Scheme 3c), could potentially serve as
an intermediate in the selective synthesis of spiroepoxy
azetidines. Indeed, addition of potassium carbonate to
a solution of 11 in methanol resulted in the quantitative
In the case of trifluoromethyl ABB-carbinol 5r, CbzCl
was found to be unreactive, but treatment with TFAA in the
presence of NaI led to selective formation of the iodohydrin
intermediate. After the addition of potassium carbonate,
epoxide 8r was isolated in 49% yield. The high selectivity for
iodohydrin formation from 5r contrasts with the reactivity of
5a, where treatment with TFAA in the presence of NaI
resulted in the formation of both iodohydrin 12 and the
semipinacol product 6a. This is a result of the slower rate of
the semipinacol rearrangement with the trifluoromethyl
ABB-carbinol 5r. Despite the reaction of 5a with TFAA/
NaI leading to a mixture of 12 and 6a, treating this mixture
with potassium carbonate led to the formation of epoxide 14
in 38% yield. Interestingly, other activators could also be
employed with NaI. Tosyl chloride (TsCl) behaved similarly
to CbzCl to give sulfonamide 15 in 87% yield, whereas di-tert-
[22]
formation of epoxy azetidine 8a after 15 minutes.
This
method was telescoped to a one-pot procedure, and ABB-
carbinol 5a was converted to 8a in 96% yield (Scheme 5).
We then extended this protocol to produce a range of
spirocyclic epoxides from selected ABB-carbinols
(
Scheme 5). Employing ABB-carbinols with heteroaryl
groups (indolyl and pyridyl) gave 8d and 8 f in good yields
of 62% and 66%, respectively. Electron-rich indolyl epoxide
8
d was found to be unstable on silica gel, which complicated
purification. However, we found that if the intermediate
iodohydrin was purified prior to base-induced cyclization, no
further purification of 8d was necessary. Dispiro compounds
butyl dicarbonate (Boc O) was slower to react and required
2
heating to activate ABB-carbinol 5a. Under these conditions
8
j and 8l were obtained from ABB-carbinols 5j and 5l in
with Boc O, cyclization of the iodohydrin occurred without
2
excellent yields of 90% and 91%, respectively. Compound 8l
is particularly interesting, as the nitrogen protecting groups
are orthogonal and serve to desymmetrize the molecule.
additional base to give epoxide 16 in 57% yield.
Trisubstituted epoxide 8n was also accessible in 80% yield Conclusion
from benzaldehyde derived 5n. We found that with less
substitution, the rate of cyclization was much slower and
required 42 hours to reach completion. We were also able to
synthesize the sensitive propargylic epoxide 8p in excellent
We have discovered novel, divergent reactivity of
azabicyclo[1.1.0]butyl carbinols, which are themselves easily
obtained from the reaction of azabicyclo[1.1.0]butyllithium
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[
[
pinacol rearrangement in ABB-carbinols to give either amide
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Keywords: azabicyclo[1.1.0]butane · azetidines · epoxides ·
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Manuscript received: January 13, 2021
Accepted manuscript online: February 8, 2021
Version of record online: February 26, 2021
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7365