Reaction of Vinyl Aziridines with Arynes: Synthesis of Benzazepines and Branched Allyl Fluorides

Article abstract of DOI:10.1002/chem.201904727

We report the cycloaddition between vinyl aziridines and arynes. Depending on the reaction conditions and the choice of the aryne precursor, the aziridinium intermediate can be trapped through two distinct mechanistic pathways. The first one proceeds through a formal [5+2] cycloaddition to furnish valuable multi-substituted benzazepines. In the second pathway, the aziridinium is intercepted by a fluoride ion to afford allylic fluorides in good yields. Both reactions proceed stereospecifically and furnish enantiopure benzazepines and allylic fluorides.

Full text of DOI:10.1002/chem.201904727

A Journal of
Accepted Article
Title: Reaction of Vinylaziridines with Arynes: Synthesis of
Benzazepines and Branched Allyl Fluorides
Authors: Sherif Kaldas, Eva Kran, Christian Mück-Lichtenfeld, Andrei
Yudin, and Armido Studer
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To be cited as: Chem. Eur. J. 10.1002/chem.201904727
Link to VoR: http://dx.doi.org/10.1002/chem.201904727
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COMMUNICATION
Reaction of Vinylaziridines with Arynes: Synthesis of
Benzazepines and Branched Allyl Fluorides
a
b
b
a,
b,
Sherif J. Kaldas, Eva Kran, Christian Mück-Lichtenfeld, Andrei K. Yudin * and Armido Studer *
Abstract: We report the cycloaddition between vinylaziridines and
arynes. Depending on the reaction conditions and the choice of the
aryne precursor, the aziridinium intermediate can be trapped through
two distinct mechanistic pathways. The first one proceeds through a
formal [5+2] cycloaddition to furnish valuable multi-substituted
benzazepines. In the second pathway, the aziridinium is intercepted
by fluoride ion to afford allylic fluorides in good yields. Both reactions
proceed stereospecifically and furnish enantiopure benzazepines and
allylic fluorides.
The ongoing resurgence in aryne chemistry can be attributed to
the development of modern methodologies that enable the
efficient generation of arynes in situ under mild reaction
conditions.[ This advancement has allowed the scope of aryne
chemistry to expand significantly into the areas of transition metal
catalysis and multicomponent reactions, among others.[2]
Amination reactions are an area in which aryne chemistry has
been particularly successful. As a result, aminations of arynes
have found great utility in the total synthesis of alkaloids.[3]
1]
As a part of our ongoing programs in aryne chemistry[4] and the
synthesis of aza-heterocycles from aziridines,[5] we were
interested in exploring the reactivity of vinylaziridines toward
arynes. We envisioned that the [5+2] cycloaddition between an
aryne and
a vinylaziridine could proceed through formal
[
6]
cycloaddition reaction to furnish valuable benzazepines (Figure
[
7]
1
a). The 7-membered aza-heterocycle is an important scaffold
in medicinal chemistry and is found in a wide range of bioactive
compounds,[8] natural products,[9] dipeptide mimics,[10] and
dyes[11] (Figure 1b). Due to the importance of this class of
Figure 1. (a) Reaction of vinylaziridines with arynes. (b) Examples of
benzazepine-containing pharmaceuticals, natural products and dyes.
heterocycle, several methods have been developed for the
synthesis of this and similar scaffolds.[12]
We initiated our study by screening different conditions for
benzyne generation in the presence of 1-benzyl-2-vinylaziridine
(
2a) as a model vinylaziridine (Scheme 1). Utilizing the conditions
[
13]
developed by Kobayashi we only observed a trace amount of
the desired benzazepine 3a. However, we did record the
formation of allylic fluoride 6a, which is most likely formed from an
attack of the fluoride anion onto the internal allylic position of the
electrophilic aziridinium cation. This led us to screen methods for
fluoride-free aryne generation. Utilizing aryne precursor 1b and
iPrMgCl•LiCl[14] we only recovered 2a. It has been reported that
magnesiated 1b is highly reactive and decomposes to the aryne
at -78 °C, presumably before nucleophilic attack of 2a. We were
pleased to see that by utilizing the same conditions, but switching
to the more stable aryne precursor 1c,[15] we were able to observe
the formation of benzazepine 3a in encouraging 45% yield.[16]
[
[
a]
b]
Prof. Dr. A. Studer, E. Kran, Dr. C. Mück-Lichtenfeld
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster, Germany
E-mail: studer@uni-muenster.de
S. J. Kaldas, Prof. Dr. A. K. Yudin
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St. George St. Toronto, ON, Canada, M5S 3H6
E-mail: ayudin@chem.utoronto.ca
Supporting information for this article is given via a link at the end of
the document.
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Chemistry - A European Journal
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COMMUNICATION
2
3
4
5
1
1
1
1
4-ClC
4-ClC
4-ClC
4-ClC
6
H
6
H
6
H
6
H
4
4
4
4
Et
Et
2
O
O
iPrMgClc
iPrMgCld
0
0
2
THF
iPrMgCld
30
41
PhMe
iPrMgCl•LiCl
4
:1
O:1,2-
DME
6
1
4-ClC
6
H
4
Et
2
iPrMgCl•LiCl
36
7
8
9
1
1
2
3
4
4
4
4-ClC
4-ClC
4-ClC
6
6
6
H
H
H
4
4
4
Et
Et
Et
Et
Et
2
O
2
O
2
O
2
O
2
O
iPrMgCl•LiCl
iPrMgCl•LiCl
iPrMgCl•LiCl
iPrMgCl•LiCl
iPrMgCl•LiCl
0
0
80
73
65
0
6 4
4-FC H
1e
4-ClC
6 4
H
Procedure 1: A solution of vinylaziridine was added after stirring Grignard
reagent with aryne precursor at -78 °C for 30 min. Procedure 2: Aryne solution
was added to vinylaziridine solution at 0 °C. Procedure 3: Vinylaziridine in
solution was added at room temperature after stirring Grignard reagent with
aryne precursor at -78 °C for 30 min. Procedure 4: Grignard reagent added to
solution of vinylaziridine and aryne precursor at -78 °C before warming to
Scheme 1. Initial reaction screen utilizing various aryne precursors with
vinylaziridine 2a.
With the initial hit in hand, we began optimization of the annulation
a
b
c
d
room temperature. NMR yield. 1.3 M in THF. 2.0 M in Et
Reaction carried out at room temperature.
2
O. 2.0 M in THF.
reaction (Table 1). Switching the solvent from Et
deleterious effect (34%, Entry 1). Exchanging iPrMgCl•LiCl for
iPrMgCl (2.0 M in Et O or THF) resulted in the recovery of both
2
O to THF had a
e
After optimization, the scope of the reaction was investigated
Scheme 2). Overall, a variety of aryne precursors and vinyl
2
(
starting materials (Entries 2 and 3), while a combination of THF
aziridines could be matched to furnish benzazepines (3a – 3p).
Electron-rich arynes such as those substituted by o-methoxy and
m-methoxy engaged efficiently in the reaction (3b, 3d, 3m and
as solvent and iPrMgCl (2.0 M in THF) furnished 3a in modest
3
0% yield (Entry 4). Toluene or a 4:1 mixture of Et
2
O/1,2-
dimethoxyethane[17] resulted in the formation of 3a in 41% and
3o). This is likely due to the increased nucleophilicity of the aryne
36% yield, respectively (Entries 5 and 6). We then explored the
aiding in the second step of cyclization. Electron-poor arynes such
as o-fluorinated and m-carboxymethyl ester-substituted
derivatives also reacted with a variety of vinylaziridines (3c, 3e,
order of addition. Mixing Grignard reagent and 1c at -78 °C
followed by taking up the resulting solution and adding it dropwise
to 2a at room temperature was unsuccessful (Entry 7). Likewise,
adding 2a to a pre-mixed solution of Grignard reagent and 1c at
room temperature did not form the desired product (Entry 8).
Gratifyingly, adding Grignard reagent to a solution of 1c and 2a at
3g, 3j, 3k and 3n). However, highly electron-deficient aryne
precursors such as those substituted by trifluoromethyl, nitro or
nitrile groups were not tolerated, likely due to the poor aryne
generation from the corresponding stabilized anions.[ Electron-
neutral arynes also furnished the desired benzazepines in good
yields (3a, 3f, 3h, 3i, 3l and 3p). Selected ortho-substituted
18]
-
78 °C before warming to room temperature significantly
improved the yield to 80% (Entry 9). Changing the leaving group
on the arene to 4-FC (Entry 10) or adding the Grignard reagent
6
H
4
arynes reacted to form benzazepines (3b, 3e, 3g, 3i, 3k and 3m
–
at room temperature to a mixture of 1c and 2a (Entry 11) resulted
in slightly lower yield. To determine the stability of vinylaziridine to
3o) in greater than 20:1 regioselectivity.[ As expected, meta-
19]
substituted arynes provide both product regioisomers without any
selectivity (3c, 3d and 3j), indicating the free aryne is generated
in solution. Various groups such as benzyl (3a – 3f, 3i, 3o and 3p),
cyclohexyl (3g) and p-methoxybenzyl (PMB) (3h, 3j, 3k and 3l –
basic conditions, 2a was treated with
iPrMgCl•LiCl at room temperature. After 24 hours, only minimal
decomposition of the vinylaziridine was observed.
2 equivalents of
2
Table 1. Optimization of the reaction between aryne precursors (1c or 1d) and
vinylaziridine 2a.
3n) were tolerated on the vinylaziridine nitrogen (R ) without
significant impact on the yield or regioselectivity. Furthermore, the
4
reaction also proceeded when R was replaced by a methyl group
5
(
3f – 3h, 3j and 3k). The reaction also proceeded when R was
substituted with a phenyl group (1:1 E/Z mixture) to furnish
benzazepines 3l – 3n. Utilizing enantiopure trans-vinylaziridine
2b, the reaction proceeded with complete stereoretention to
afford chiral benzazepines 3o and 3p in 99% ee. On the other
hand, the corresponding cis-vinylaziridine stereoisomer was
unreactive. Finally, the reaction was amenable to scale up with
compound 3a being isolated in 69% yield on a 1 mmol scale.[20]
Entry
1
Proced
ure
Solvent
(0.05 M)
Grignard
reagent
Yield
(%)a
Ar
1
4-ClC
6
H
4
THF
iPrMgCl•LiClb
34
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COMMUNICATION
DFT calculations were conducted next using 2a and benzyne as
model components to elucidate whether the transformation
proceeds as a formal sequential cycloaddition (see Figure 1a) or
as a concerted [5+2] cycloaddition (Figure 2).[ The vinylaziridne
22]
2a exists as cis and trans-isomer, with the latter being slightly
more stable (2.1 kcal/mol). Both isomers can engage in the
reaction with benzyne to form the corresponding zwitterions A and
B which have similar free energies (-10 kcal/mol). We have
identified two transition structures of nucleophilic addition of the
aryl anion to the terminal carbon atom of the vinyl group. We could
not locate a stable secondary alkyl anion as intermediate of the
addition, opening of the aziridinium ring proceeds without
additional barrier. In the cis-2a derived intermediate A, the aryl
anion moiety and the double bond are distal (trans with respect to
the aziridinium plane) and the barrier for reaction to 3a is high (TS-
‡
A, ΔG =40.9 kcal/mol). In intermediate
B
the reacting
functionalities are close to each other (cis) and nucleophilic
addition/aziridinium ring opening proceeds with a remarkably low
‡
barrier (TS-B, ΔG =11.7 kcal/mol) to afford 3a. Therefore, we
assume that addition of cis-2a to benzyne is reversible and
product formation proceeds exclusively via intermediate B. We
could not identify a direct reaction pathway of benzyne and 2a
leading to 3a via a concerted [5+2] cycloaddition.
We have also looked at nucleophilic ring opening of intermediate
B with fluoride anion (see SI). The free energy of this transition
structure is below the intermediate by almost 4 kcal/mol,
indicating that this process (initiated by formation of a pre-reactive
complex) is competitive with the benzazepine formation. Hence,
under appropriate conditions the ring-opening leading to valuable
allylic fluorides[23-25] might become the dominant process.
6 4
Scheme 2. Preparation of benzazepines 3a – 3p (Ar = 4-ClC H ). Yield refers
to isolated yield after column chromatography. Reactions were carried out in
0
.05 M Et
2
O with 1.50 equiv of aryne precursor and 1.65 equiv of iPrMgCl•LiCl
a
(1.3 M in THF). Reaction was warmed to 0 °C and stirred until completion.
Isolated yield reported. Ratio of regioisomers determined by analysis of crude
NMR mixture.
For the development of bioactive molecules, it is important to have
substrates that are easily modified as this simplifies the synthesis
of analogues and allows one to rapidly probe the outcome of
various structural modifications on bioactivity. Along these lines,
we were able to derivatize 3a through a Sharpless dihydroxylation
furnishing the diol 4. Reduction of the double bond and
concomitant benzyl deprotection with Pd/C and H furnished the
2
tetrahydrobenzazepine 5 (Scheme 3). Both 4 and 5 are cores of
compounds that have been explored as anti-parasitics and 5-
R modulators.[
21]
Figure 2. DFT calculated free energies of the reaction of aziridine 2a with 1,2-
benzyne (PW6B95-D3//PBE0-D3/def2-TZVP).
HT
2
Along these lines, we found after screening conditions that
utilizing 3.0 equivalents of TBAF (1.0 M in THF) in combination
with 1.0 equivalent of vinylaziridine and 2.0 equivalents of aryne
precursor in wet acetonitrile (0.1 M) at -10 °C to be optimal for this
transformation. The transformation is rapid, with complete
consumption of the vinylaziridine within 60 minutes. The reaction
is also completely regioselective for the branched regioisomer.[
26]
Scheme 3. Derivatization of 3a through dihydroxylation (4) and hydrogenation
a
(
5). 12% ee, without chiral ligand the yield dropped to 25%.
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Chemistry - A European Journal
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COMMUNICATION
Table 2. Preparation of allyl fluorides 6a – 6i.
Scheme 4. Enantioselective synthesis of allyl fluorides through a stereospecific
reaction between arynes and enantiopure vinylaziridine 2b.
In conclusion, we have demonstrated a highly effective reaction
between vinylaziridines and arynes. Depending on the choice of
reaction conditions, either benzazepines or allyl fluorides can be
obtained
with
excellent
stereoselectivity.
Downstream
DFT
functionalization of the benzazepine scaffold and
a
investigation of the mechanism were also presented. The present
methodology presents advantages over previous work in that it is
highly divergent and furnishes enantiopure products. This work
also highlights the continuously expanding scope of aryne
chemistry and facilitates the exploration of these compounds as
biologically active molecules and synthetic intermediates.
Acknowledgements
We thank the Natural Science and Engineering Research Council
(
NSERC) for funding. We would also like to acknowledge the
Deutsche Forschungsgemeinschaft (DFG) for financial support.
S.J.K thanks NSERC for CGS-D funding and the University of
Toronto for Special Opportunity Travel Grant funding. We also
acknowledge NSERC and the Canadian Foundation for
Innovation, Project Number 19119, and the Ontario Research
Fund for funding of the Centre for Spectroscopic Investigation of
Complex Organic Molecules and Polymers.
Reaction carried out at -10 °C to minimize amount of cycloaddition product.
Reactions were carried out in 0.1 M MeCN with 1.5 equivalents of vinylaziridine
and 2.0 equivalents of TBAF (1.0 M in THF) at room temperature overnight.
aIsolated yield after column chromatography. bReaction ran at -20 °C.
Utilizing the optimized conditions, we were able to synthesize a
number of allylic fluorides in good isolated yields (Table 2). The
electron-neutral aryne precursor 1a reacted cleanly with benzyl,
cyclohexyl and p-methoxybenzyl protected vinylaziridines (6a –
Keywords: arynes • vinyl aziridines • aryl anions • strained rings
•
DFT calculations
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10.1002/chem.201904727
COMMUNICATION
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Chemistry - A European Journal
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S. J. Kaldas, E. Kran, C. Mück-
Lichtenfeld, A. K. Yudin*, A. Studer*
Page No. – Page No.
Reaction of Vinylaziridines with
Arynes: Synthesis of Benzazepines
and Branched Allyl Fluorides.
Chemodivergent and enantiospecific! The addition of vinylaziridines to in situ
generated arynes provides depending on the reaction conditions and the choice of
aryne precursor multi-substituted benzazepines or allylic fluorides. Both reactions
proceed stereospecifically and furnish enantiopure products.
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