Tetrahydro-1,3-oxazepines via Intramolecular Amination of Cyclopropylmethyl Cation

Article abstract of DOI:10.1021/acs.orglett.5b01014

An efficient synthesis of tetrahydro-1,3-oxazepines was developed involving the regioselective intramolecular amination of cyclopropylmethyl cation. The cation was generated by the abstraction of one imidate group in bis-imidate bearing a carbocation-stabilizing substituent. Using 1,1,2,3-tetrasubstituted cyclopropane substrates, highly diastereoselective intramolecular amination to trans-tetrahydro-1,3-oxazepines was achieved. The resulting tetrahydro-1,3-oxazepines were transformed to the homoallylamine derivatives in high yields.

Full text of DOI:10.1021/acs.orglett.5b01014

Letter
pubs.acs.org/OrgLett
Tetrahydro-1,3-oxazepines via Intramolecular Amination of
Cyclopropylmethyl Cation
Marija Skvorcova, Liene Grigorjeva, and Aigars Jirgensons*
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia
S
* Supporting Information
ABSTRACT: An efficient synthesis of tetrahydro-1,3-oxaze-
pines was developed involving the regioselective intra-
molecular amination of cyclopropylmethyl cation. The cation
was generated by the abstraction of one imidate group in bis-
imidate bearing a carbocation-stabilizing substituent. Using
1,1,2,3-tetrasubstituted cyclopropane substrates, highly diaster-
eoselective intramolecular amination to trans-tetrahydro-1,3-
oxazepines was achieved. The resulting tetrahydro-1,3-oxazepines were transformed to the homoallylamine derivatives in high
yields.
tructural investigations of cyclopropylmethyl cation 1 have
shown that it exists as an equilibrating mixture of πσ-
imidates are convenient systems for amination of carbocations.
In bis-imidates, one of the imidates serves as the leaving group
when activated with an acid catalyst while the other acts as an
N-nucleophile. Following this approach, it was explored
whether carbenium ion 6C derived from readily available bis-
imidate 5 can be regioselectively aminated depending on the
cyclopropane substituent (Table 1).
S
delocalized bisected cyclopropylmethyl cation 1A and non-
classical bicyclobutonium ion 1B (Figure 1).1,2 The carbocation
Initial studies showed that substrate 5a containing phenyl
substituent selectively forms homoallyl carbocation amination
product 7a when exposed to Lewis acid catalyst (Table 1, entry
1). Screening of catalysts revealed that relatively weak Lewis
acids such as Cu(OTf)2 and (CuOTf)2·C6H6 were the optimal
catalysts for the reaction. Stronger Lewis acids or acids
containing nucleophilic counterions led to decomposition of
product 7 (see the Supporting Information for details). Further,
the substrate scope with respect to the cyclopropane
substituent was explored. Bis-imidates 5 bearing aryl substituent
with electron donating groups (entries 2, 3, and 5) afforded
tetrahydro-1,3-oxazepines in excellent yields. Amination of bis-
imidates 5 having electron-poor aryl groups (entries 4 and 15)
gave satisfying results only for substrate 5d (entry 4). Bis-
imidates 5 bearing electron-rich heteroaryl substituents also
provided the expected product 7 (entries 6 and 9−11). The
reaction was not limited only to aryl carbocation stabilizing
groups. Substrates bearing vinyl substituent (entries 7 and 8)
gave high product yield. Bis-imidates 5b containing groups with
lower carbocation stabilizing ability such as ethyl (entry 13) or
alkynyl (entry 14) led to the formation of a product mixture.
However, if the alkyl group contained a silyl group as a β-
cation-stabilizing substituent, the amination product was
obtained in good yield (entry 12).
Figure 1. Regioselectivity in cyclopropylmethyl cation reaction with
nucleophiles.
1 is often represented as 1C which is a hybrid of the proposed
discrete structures 1A and 1B. The reaction of cyclo-
propylmethyl cation 1C with nucleophiles can occur at any of
the three possible sites bearing partial positive charge leading to
homoallyl,3 cyclopropylmethyl,2a,3a,j,4 or cyclobutyl4,5 deriva-
tives 2−4. Several regioselective reactions of cyclopropylmethyl
cation 1 with nucleophiles have been reported as a useful
approach to products based on structures 2−4.3−5
Although not systematically studied, the available exper-
imental data suggest that regioselectivity of intramolecular
cyclization is mainly controlled by the geometric constraints
and/or effects of cyclopropane substituents. A carbocation
stabilizing group can be used to direct the addition of
nucleophile to cyclopropylmethyl cation 1C presumably via
inducing electron distribution in favor of the classical
carbocation.
Tetrahydro-1,3-oxazepine derivatives 7 are masked unsatu-
rated amino alcohols which are valuable multifunctional
Few studies have been reported for amination reactions of
cyclopropylmethylcarbocation.3j,l,5e The reason for that could
be the limited range of amine nucleophiles compatible with
acidic conditions typically used to initiate the reaction.
Previously, we6 as well as others7 have demonstrated that bis-
Received: April 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Substrate Scope for the Cyclization of Bis-imidates
5 to Tetrahydro-1,3-oxazepines 7
Scheme 1. Chirality Transfer in the Cyclization of
Enanatioenriched Substrate S-5a
a
To determine if the racemization is associated with
unselective abstraction of the imidate group, substrates cis-d2-
5a and trans-d2-5a with deuterium labeling at the methylene
position were prepared (Scheme 2). In both substrates, the
entry
R
product, yield (%)
1
2
3
4
5
6
7
8
9
Ph
7a, 85
7b, 96
7c, 87
7d, 83
7e, 90
7f, 94
7g, 96
7h, 91
7i, 89
7j, 64
7l, 79
7k, 81
Scheme 2. Selective Abstraction of trans-Imidate Function in
Deuterium-Labeled Bis-imidate 5a
4-MeOC6H4
4-Me2NC6H4
4-FC6H4
1-naphthyl
3-(N-tosyl)indolyl
(E)-C6H5CHCH
vinyl
2-thienyl
b
10
2-(N-methyl)pyrrolyl
3-furyl
c
11
12
Ph(Me)2SiCH2
Et
d
13
d
14
C6H5CC
d
15
3,5-(di-Cl)-C6H3
a
imidate group trans to the phenyl group was selectively
abstracted to give the corresponding deuterium labeled
regioisomers d2-rac-7a′ and d2-rac-7a″, respectively (only one
Bis-imidate (0.5 mmol), Cu(OTf)2 (0.05 mmol), CH2Cl2 (5 mL).
Yields are isolated yields. Please see the Supporting Information for
b
c
details. Cu(OTf)2 (0.005 mmol). (CuOTf)2·C6H6 (0.05 mmol).
d
1
Mixture of products.
isomer in each case was detected by H NMR). The exclusive
trans-imidate elimination would be difficult to explain by the
accessibility of the sterically less hindered imidate group to the
catalyst. More likely, these results point to specific stereo-
electronic requirement for the leaving group to facilitate the
formation of cyclopropylmethyl cation/homolallyl cation.
Having established that abstraction of the imidate is selective,
the partial loss of enantioselectivity in the product 7a formation
obviously stems from the availability of both faces of
carbocation 6C/6C′. Nevertheless, the chirality was preserved
to some extent which is difficult to explain. This could be
related to a partial nature of nonclassical carbocation
intermediate since the planar homoallyl cation would lead to
complete racemization.
intermediates. However, there is a limited number of methods
available to access this type of amino alcohol.8 In order to
demonstrate the utility of tetrahydro-1,3-oxazepines 7, several
examples were transformed to amino alcohol derivatives 9
(Table 2). The one-pot, two-step procedure involved cleavage
of cyclic imidate function with acetic acid followed by
methanolysis of the intermediate 8.
The cyclization studies with enantioenriched bis-imidate S-5a
showed that tetrahydro-1,3-oxazepine 7a forms with consid-
erable degree of racemization (Scheme 1).
Diastereoselective amination of carbocation 6C/6C′ bearing
an additional substituent was explored (Scheme 3). Bis-imidate
11 was prepared from readily accessible stereochemically
defined dicarboxylic acid derivative 10.9 Amination of bis-
imidate 11 gave trans-substituted tetrahydro-1,3-oxazepine 12
as the only detectable isomer. Configuration of the reaction
product 12 was determined by X-ray analysis of the
derivatization product−diol 13.
In summary, we have demonstrated that a cyclopropylmethyl
cation generated by the abstraction of one imidate group in bis-
imidates undergoes regioselective intramolecular amination. A
homoallylamine derivative was formed selectively if cyclo-
propane contained a carbocation stabilizing substituent. The
resulting tetrahydro-1,3-oxazepines were transformed to
unsaturated amino alcohol derivatives. It was demonstrated
that highly diastereoselective cyclization to trans-substituted
tetrahydrooxazepine could be achieved starting from 1,1,2,3-
tetrasubstituted cyclopropane substrates.
Table 2. Transformation of Tetrahydro-1,3-oxazepines 7 to
Amino Alcohols 9
a
entry
R
product, yield (%)
1
2
3
4
5
Ph
9a, 94
9b, 96
9i, 91
9h, 89
9k, 89
4-MeOC6H4
2-thienyl
vinyl
Ph(Me)2SiCH2
a
Key: (1) tetrahydro-1,3-oxazepine (1.0 mmol), Ac2O (1 mL), AcOH
(1 mL); (2) K2CO3 (3.0 mmol), MeOH (2 mL). Yields are isolated
yields. Please see the Supporting Information for details.
B
DOI: 10.1021/acs.orglett.5b01014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data for
new compounds. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01014.
■
S
Eriksson, L.; Stalbrand, H.; Cumpstey, I. Tetrahedron: Asymmetry
2009, 20, 795.
̊
AUTHOR INFORMATION
■
(8) (a) Trost, B. M.; Bonk, P. J. J. Am. Chem. Soc. 1985, 107, 1778.
(b) Van der Louw, J.; van der Baan, J. L.; Stichter, H.; Out, G. J. J.; de
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Corresponding Author
*E-mail: aigars@osi.lv.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Latvian Council of Science (Grant
No. 593/2014) is gratefully acknowledged. We thank Dmitrijs
Stepanovs (Latvian Institute of Organic Synthesis) for
perfoming X-ray analysis and Kristaps Jaudzems (Latvian
Institute of Organic Synthesis) for assistance with 2D NMR
spectra.
(9) Marcoux, D.; Charette, A. B. Angew. Chem., Int. Ed. 2008, 47,
10155.
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DOI: 10.1021/acs.orglett.5b01014
Org. Lett. XXXX, XXX, XXX−XXX