Stereoselective Dynamic Cyclization of Allylic Azides: Synthesis of Tetralins, Chromanes, and Tetrahydroquinolines

Article abstract of DOI:10.1021/jacs.7b11299

This report describes the stereoselective synthesis of 3-azido-tetralins, -chromanes, and -tetrahydroquinolines via a tandem allylic azide rearrangement/Friedel-Crafts alkylation. Exposure of allylic azides with a pendant trichloroacetimidate to catalytic quantities of AgSbF₆ proved optimal for this transformation. This cascade successfully differentiates the equilibrating azide isomers, providing products in excellent yield and selectivity (>25 examples, up to 94% yield and >25:1 dr). In many cases, the reactive isomer is only a trace fraction of the equilibrium mixture, keenly illustrating the dynamic nature of these systems. We demonstrate the utility of this process via a synthesis of hasubanan.

Full text of DOI:10.1021/jacs.7b11299

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Communication
Stereoselective Dynamic Cyclization of Allylic Azides:
Synthesis of Tetralins, Chromanes, and Tetrahydroquinolines
Matthew R. Porter, Rami M. Shaker, Cristian Calcanas, and Joseph J. Topczewski
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11299 • Publication Date (Web): 05 Jan 2018
Downloaded from http://pubs.acs.org on January 5, 2018
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Journal of the American Chemical Society
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Stereoselective Dynamic Cyclization of Allylic Azides: Synthesis of
Tetralins, Chromanes, and Tetrahydroquinolines
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Matthew R. Porter, Rami M. Shaker, Cristian Calcanas, and Joseph J. Topczewski*
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, Minnesota, 55455, United States
Supporting Information Placeholder
approach that combines the use of proximal functionality with a
ABSTRACT: This report describes the stereoselective synthesis
complexity generating cyclization. By merging these tactics (Figꢀ
ure 2c), we obtain selectivity on unꢀsymmetric systems and acꢀ
complished a tandem FriedelꢀCrafts alkylation (Figure 2d). This
reaction results in the highest combined yield and diastereoselecꢀ
tivity reported to date for a dynamic allylic azide functionalizaꢀ
tion. We demonstrate the utility of this chemistry through a sucꢀ
cinct synthesis of hasubanan.
of 3ꢀazidoꢀtetralins, ꢀchromanes, and ꢀtetrahydroquinolines via a
tandem allylic azide rearrangement/FriedelꢀCrafts alkylation.
Exposure of allylic azides with a pendant trichloroacetimidate to
catalytic quantities of AgSbF6 proved optimal for this transforꢀ
mation. This cascade successfully differentiates the equilibrating
azide isomers, providing products in excellent yield and selectiviꢀ
ty (>25 examples, up to 94% yield and >25:1 dr). In many cases,
the reactive isomer is only a trace fraction of the equilibrium mixꢀ
ture, keenly illustrating the dynamic nature of these systems. We
demonstrate the utility of this process via a synthesis of hasuꢀ
banan.
Our strategy incorporated a second proximal allylic
functional group. When the azide is proximal (Figure 2c, OIM
group, isomers i E and iv Z), the second group would be primary.
However, when the azide is distal (Figure 2c, ii trans isomer), the
second group would be allylic and therefore substantially more
reactive. We chose a trichloroacteimidate because it could be
readily activated under electrophilic conditions, such as those for
glycosylation,38,39 rearrangement,40–45 or substitution.46–50 A penꢀ
dent arene might intercept the putative electrophile in a Friedelꢀ
Crafts alkylation. Ring closure could potentially proceed from
either allylic terminus and the tether would enforce regioselectiviꢀ
ty. Imposing selectivity by these combined approaches could afꢀ
ford a highly chemoꢀ, siteꢀ, regioꢀ, and diastereoselective protocol
Tetralins, chromanes, and tetrahydroquinolines represent priviꢀ
leged structural motifs present in pharmaceuticals, agrochemicals,
and natural products. Many feature an amino substituent at the Cꢀ
3 position (Figure 1). These molecules display a wide range of
activity including treatments or potential treatments for cancer,
pain, depression, thrombosis, Parkinson’s disease, and malaria.1–9
Due to this rich history, numerous synthetic methods can generate
these systems including cyclization,10–15 annulation,16,17 cycloadꢀ
dition,18,19 partial reduction,20,21 and others.6,22–24 Presented herein
is a distinctive carbonꢀcarbon bond forming reaction that generꢀ
ates these privileged motifs with the required 3ꢀaminoꢀ
functionality by manipulating the allylic azide rearrangement.
for the synthesis of 3ꢀazidoꢀtetralins, ꢀchromanes, and
tetrahydroquinolines (X = CH2, O, or NꢀPG, respectively; Figure
2d).
ꢀ
We began with allylic azide 1a (Table 1). This allylic
azide exists as an equilibrium mixture (1.3:1.0:0.7:trace
E:trans:Z:cis, representations shown in Figure 2c). The reactive
trans isomer is only ~30% of the mixture. We exposed azide 1a to
a number of activators, including Lewis acids (entries 1ꢀ3),
Brønsted acids (entries 4ꢀ7), and transition metal complexes (enꢀ
tries 8ꢀ10). Most conditions led to decomposition (entry 1), poor
selectivity (entries 2,3), or poor reactivity (entries 3ꢀ5, 8, and 9).
Control experiments, conducted after an initial hit with cationic
gold(I) (entry 10), provided encouraging results with silver salts.
Silver salts with nonꢀcoordinating counter ions were efficacious
(entries 12ꢀ14) and those with more lipophilic counter ions proꢀ
vided superior results. Conditions with catalytic AgSbF6 are mild,
high yielding, and highly stereoselective (entry 14). In a control
experiment, 2,6ꢀdiꢀtertꢀbutyꢀ4ꢀmethylꢀpyridine inhibited the reacꢀ
tion (entry 15). The reaction is slow in ethanol stabilized chloroꢀ
form (entry 16) or in the presence of deliberately added water
(entry 17). These observations implicate general acid catalysis.51
The reaction was tolerant to ambient conditions (entry 18).
Figure 1. Representative Biologically Active Compounds
Allylic azides exist as an equilibrating mixture of isoꢀ
mers. This was first noted by Winstein, who documented the rate
of isomerization for prenyl and crotyl azides.25 Since then, chemꢀ
ists have struggled to exploit this rearrangement synthetically
because of difficulty differentiating the azide isomers.26–33 Only a
few reports accomplish selective elaboration. The Craig lab reꢀ
ported a tandem Claisen rearrangement (Figure 2a).34 Selectivity
was achieved by orchestrating a second irreversible sigmatropic
process. The Aubé lab reported a tandem Schmidt reaction that
attained selectivity through cyclization and achieved diastereꢀ
ocontrol via chairꢀlike intermediates (Figure 2b).35 Recently, we
initiated a program to explore the allylic azide rearrangement’s
potential.36 We reported the first example of enantioselective resoꢀ
lution of symmetric systems.37 Herein, we report a synergistic
Figure 2. Selectivity for Allylic Azide Functionalization
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Table 1. Optimization of Tandem Rearrangement Friedel-
Crafts Alkylation
1
2
3
4
5
6
7
entrya
1
catalyst
yield %b
35
drc
BF3·OEt2
28:1
8
9
2
Cu(OTf)2
Zn(OTf)2
TFA
75
58
4
9:1
9:1
4:1
7:1
13:1
7:1
nd
3
10
11
12
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60
4
5
TsOH
4
6
Tf2NH
80
49
0
7
TfOH
8
PdCl2
9
[(COP)PdCl]2
JohnPhosAuSbF6
AgOTs
0
nd
10
11
12
13
14
15d
16e
17f
18g
75
0
21:1
nd
AgClO4
AgOTf
81
80
92
3
7:1
7:1
21:1
3:1
16:1
21:1
20:1
We explored the scope of this cyclization with a series
of allylic azides (Scheme 1). Common substituents on the aryl
ring were tolerated (H, OMe, Cl, or Br, 2aꢀ2d). Conveniently,
derivative 2d provided diffraction quality crystals. Analysis unꢀ
ambiguously demonstrated the relative configuration of 2d. Other
compounds were assigned by analogy to compound 2d. Different
tethers were tolerated. The 3ꢀmethyl group is not required for
diastereoselectivity (2e). Azide 2e maps onto biologically active
3ꢀaminoꢀtetralins (Figure 1). Interestingly, imidate 1f exists alꢀ
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
55
71
77
a0.10 mmol substrate at 0.1 M in CHCl3 for 24 h. b Determined by GCꢀFID analysis
using naphthalene as an internal standard. Values are the average of duplicate trials.
cDetermined by GCꢀFID analysis. d20 mol% 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylpyridine was
added. nd = not determined. eThe reaction was conducted in CHCl3 stabilized with
EtOH. f5 equivalents of water were deliberately added. gThe reaction was conducted
under ambient conditions.
1
most exclusively as the unreactive isomers by H NMR analysis
(>99% E and Z). The reactive trans isomer is destabilized by synꢀ
pentane interactions with the geminal methyl groups. However,
this does not inhibit reactivity and compound 2f was isolated in
acceptable yield. This observation supports CurtinꢀHammett kiꢀ
netics with rate limiting aromatic substitution. Moving the methyl
group to the center of the allylic system eroded the dr (1.7:1 for
compound 2g). We propose a putative stereochemical model
based on chair like transition states (Figure 3). The pathways difꢀ
fer in the orientation of the vinyl group. The major diastereomer
could arise from the pseudoꢀequatorial orientation. When the hyꢀ
drogen atom is replaced with a methyl (1g), then the relative enꢀ
ergy approaches unity and diastereoselectivity is reduced (2g).
Lastly, a group larger than methyl was permitted in the backbone
(2h).
Figure 3. Putative Cyclic Stereochemical Model
Incorporating a heteroatom into the system would genꢀ
erate valuable heterocycles. A number of ethereal allylic azides
were converted into chromanes in high yield and selectivity
(Scheme 2, 4a). Activating groups such as methyl (4b) or methꢀ
oxy (4c) were competent as were compounds with a halogen subꢀ
stituent (entries 4dꢀ4f). Polyꢀsubstituted aromatics were tolerated
(entries 4gꢀ4i). These results are gratifying because the heteroaꢀ
tom is a basic site that could slow catalysis. The proximal oxygen
would inductively reduce the stability of a cationic intermediate
and could disrupt the azide equilibrium.52 These substrates also
indicate limitations in this method. The formation of 4j was slow
and imidate decomposition occurred. Chromane 4k was isolated
as a mixture of regioisomers (1.4:1).
We explored aniline derived allylic azides that lead to
azidoꢀtetrahydroquinolines (Scheme 3). Several azides were preꢀ
pared with varying arene substitution and Nꢀprotecting group. All
imidate precursors in this class contained less than 10% of the
reactive trans isomer at equilibrium. Gratifyingly, these azides
readily afforded tetrahydroquinolines in good yield with high dr.
A number of arylꢀsubstituents were tolerated (entries 6aꢀ6f).
We conducted the reaction on a gram scale (Scheme 4).
Using >1 g of imidate 1a provided tetralin 2a in 82% yield. The
product could be oxidized under the Upjohn protocol53 to afford
diol 7. Reduction using palladium on carbon provided amine 8.
Selective reduction of the azide with LiAlH4 afforded amine 9.
The protocol of Evans54 was used to form pyrrolidine 10. Cyꢀ
cloaddition provided triazole 11.
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closure with dicyclohexyl borane.54 This last step clearly illusꢀ
trates the advantage of using an allylic azide in this synthesis beꢀ
cause the final amine functionality was established with concurꢀ
rent CꢀN bond formation.
1
2
3
Scheme 1. Formation of Tetralins 2a-g by Tandem Process
In conclusion, we report a tandem allylic azide rearꢀ
rangementꢀFriedel Crafts alkylation. This dynamic cyclization
process resolves a mixture of equilibrating allylic azide isomers
by exploiting the enhanced reactivity of the allylic electrophile.
We demonstrated that this process is general and leads to valuable
3ꢀazidoꢀtetralin, –chromane, and –tetrahydroquinoline heterocyꢀ
cles. Furthermore, the products of this reaction are readily diversiꢀ
fiable.
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Scheme 3. Formation of Tetrahydroquinolines 5a-f
Yields reported for isolated material as the average of duplicate trials. The dr was
determined by 1H NMR.
Scheme 2. Formation of Chromanes 3a-k by Tandem Process
Yields reported for isolated material as the average of duplicate trials. The dr was
determined by 1H NMR.
Scheme 4. Gram Scale Reaction and Diversification of Prod-
uct
Scheme 5. Synthesis of Hasubanan by Tandem Process
Me3S
MeOSO3
NaN3
Yields reported for isolated material as the average of duplicate trials. The dr was
determined by 1H NMR.
NaOH
93%
76%
X
O
N3
(+)-14
(+)-15
O
We were emboldened to attempt a synthesis of hasuꢀ
banan (Scheme 5). Hasubanan is the parent structure of the hasuꢀ
banan alkaloids, a large family of botanical natural products.
Members of this family have been studied synthetically and disꢀ
play diverse biological activities.55–60 The vicinal tetrasubstituted
centers in the core provide a significant synthetic challenge. To
the best of our knowledge, there are no prior reported syntheses of
the parent molecule hasubanan. We began with ester 12, which is
directly available from commercial material.61–63 Reduction and
partial reꢀoxidation afforded aldehyde 13, which was elaborated
by CoreyꢀChaykovsky epoxidation. Epoxide 14 was opened regiꢀ
oselectively with NaN3 in acetone/water yielding allylic azide 15.
Imidate 16 was isolated after activation with trichloroacetonitrile.
The key cyclization proceeded as expected to establish the necesꢀ
sary stereochemical relationship and the quaternary carbon center.
The minor diastereomer was not observed. The final functional
group manipulation was accomplished through reduction and ring
OH
1) LiAlH4
12
13
X = OEt
X = H
2) TPAP, NMO
84% (2 steps)
CCl3CN
86%
DBU
10 mol%
AgSbF6
N3
NH
HBCy2
71%
80%
N3
OIM
(+)-Hasubanan
(+)-17
(+)-16
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data (PDF)
Crystallographic data for compound 2d (CIF)
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Page 4 of 6
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Gagneuz, A.; Winstein, S.; Young, W. G. J. Am. Chem. Soc.
1960, 82, 5956.
AUTHOR INFORMATION
Corresponding Author
1
2
3
4
Gagnon, D.; Lauzon, S.; Godbout, C.; Spino, C. Org. Lett. 2005,
7, 4769.
*jtopczew@umn.edu
Notes
The authors declare no competing financial interests.
Lauzon, S.; Tremblay, F.; Gagnon, D.; Godbout, C.; Chabot, C.;
MercierꢀShanks, C.; Perreault, S.; DeSeve, H.; Spino, C. J. Org.
Chem. 2008, 73, 6239.
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Vekariya, R. H.; Liu, R.; Aubé, J. Org. Lett. 2014, 16, 1844.
ACKNOWLEDGMENT
We thank Ryan Daley for assistance in the analysis of compound
2d. Madeline Newcomb for creating the cover art associated with
this manuscript. Financial support was provided by the University
of Minnesota and The American Chemical Society’s Petroleum
Research Fund (PRF # 56505ꢀDNI1). This research was supported
by the National Institute of General Medical Sciences of the Naꢀ
tional Institutes of Health under Award Number R35GM124718.
We also acknowledge NIH Shared Instrumentation Grant
#S10OD011952.
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