Enoldiazosulfones for Highly Enantioselective [3 + 3]-Cycloaddition with Nitrones Catalyzed by Copper(I) with Chiral BOX Ligands

Article abstract of DOI:10.1021/acs.orglett.8b03421

Enoldiazosulfones undergo [3 + 3]-cycloaddition with nitrones when catalyzed by copper(I) catalysts, but not with dirhodium(II) catalysts. Under mild reaction conditions with chiral bisoxazoline ligands, copper(I) catalysts produce 1,2-oxazine-sulfone derivatives in high yields and enantioselectivities. Dirhodium(II) catalysts form stable donor-acceptor cyclopropenes that undergo uncatalyzed [3 + 2]-cycloaddition reactions with nitrones.

Full text of DOI:10.1021/acs.orglett.8b03421

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enoldiazosulfones for Highly Enantioselective [3 + 3]-Cycloaddition
with Nitrones Catalyzed by Copper(I) with Chiral BOX Ligands
Frady G. Adly,†,‡ Kostiantyn O. Marichev,† Joseph A. Jensen,† Hadi Arman,†
and Michael P. Doyle*,†
†Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas 78249, United States
‡Faculty of Science and Technology, University of Canberra, Canberra, Australian Capital Territory 2601, Australia
S
* Supporting Information
ABSTRACT: Enoldiazosulfones undergo [3 + 3]-cyclo-
addition with nitrones when catalyzed by copper(I) catalysts,
but not with dirhodium(II) catalysts. Under mild reaction
conditions with chiral bisoxazoline ligands, copper(I) catalysts
produce 1,2-oxazine-sulfone derivatives in high yields and
enantioselectivities. Dirhodium(II) catalysts form stable
donor−acceptor cyclopropenes that undergo uncatalyzed [3
+ 2]-cycloaddition reactions with nitrones.
Scheme 1. Metal-Catalyzed [3 + 3]-Cycloaddition Reaction
of Enoldiazo Compounds with Stable Dipoles
rganosulfones are a valuable class of sulfur containing
Omolecules owing to their versatility as useful intermediates
in organic synthesis.1 They have a wide spectrum of biological
properties that are recognized in natural products, pharmaceut-
icals, and agrochemicals.2 However, despite their availability for
more than 50 years,3 diazosulfones have not been widely used in
catalytic reactions involving metal carbenes.4 Although the
construction of these structures extends from tosyldiazo-
methanes to β-keto-α-diazosulfones, only two examples of
cycloaddition reactions have been reported in which a
vinyldiazosulfone has been used for the preparation of
We have successfully employed silyl-protected enoldiazoace-
tates,7 -acetamides,8 and -ketones9 in [3 + 3]-cycloaddition
reactions with a variety of stable dipolar reactants (Scheme 1).
These reactions occur with competitive formation of the
donor−acceptor cyclopropene generated intramolecularly by
dinitrogen extrusion.10 In previous studies the donor−acceptor
cyclopropene was found to be a resting state for the vinylcarbene
that, once regenerated, undergoes [3 + 3]-cycloaddition.11 High
enantioselectivities were achieved using chiral dirhodium(II)11
and, more recently, copper(I)8 catalysts. We were intrigued with
the possible application of enoldiazosulfones to [3 + 3]-
cycloaddition reactions. We expected that they would be
conveniently available from β-keto-α-diazosulfones by silyl
transfer to the enolate,12 but we were uncertain of their viability
for [3 + 3]-cycloaddition because of the anticipated stability of
the donor−acceptor cyclopropene.6 We now report that the
sulfonyl-bearing frameworks (eq 1 and 2), and one of them
the probable uncatalyzed [4 + 2]-cycloaddition by the donor−
acceptor TBSO-cyclopropenesulfone formed from the diazo
compound by dinitrogen extrusion.5,6
Received: October 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03421
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Table 1. Metal-Catalyzed Divergent Addition Reactions of
Enoldiazosulfone 1a and Nitrone 2a: Catalyst Screening
Table 2. Copper(I)-Catalyzed [3 + 3]-Cycloaddition of
a
Enoldiazosulfone 1a and Nitrone 2a: Chiral Ligand
a
Optimization
yield (%)
entry
catalyst (x mol %)
Rh2(OAc)4 (2)
Rh2(oct)4 (2)
[Cu(CH3CN)4]BF4 (5)
Cu(OTf)·Tol1/2 (5)
[Au(JohnPhos)(CH3CN)]SbF6 (5)
AgSbF6 (5)
3a
4
5
b
1
2
3
4
5
6
7
73
74
b
c
77
33
trace
b
b
b
c
14
37
92
76
c
b
b
b
c
d
Pd(PhCN)2Cl2 (5)
15
41
entry
ligand
3a yield (%)
3a ee (%)
4 yield (%)
a
All reactions were carried out on a 0.20 mmol scale in 4.0 mL of
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
40
42
82
85
83(92)
84(88)
80
82
81
85
72
28
32
66
79
96(99)
97(98)
59
85
72
87
97
17
<10
b
1
DCM: 2a (0.20 mmol) and 1a (0.30 mmol). Determined by H
NMR analysis using 1,3,5-trimethoxybenzene as the internal standard.
c
Isolated yield after flash-chromatography.
e
ef
,
e
e
sulfone group stabilizes the cyclopropene formed by dinitrogen
extrusion, rendering dirhodium(II) catalysts ineffective to
reform the metal-carbene. Chiral copper(I) catalysts, however,
are able to overcome this limitation to effect [3 + 3]-
cycloaddition in high yields and excellent enantiocontrol.
Silyl-protected enoldiazosulfones were prepared in high yields
from the corresponding β-ketosulfones by diazo transfer and
subsequent enolization/silyl transfer.12 To determine metal
catalyst suitability tert-butyldimethylsilyl (TBS)-protected
enoldiazosulfone 1a was treated with N,α-diphenylnitrone 2a
in dichloromethane (DCM) at room temperature (Table 1).
Dirhodium(II) catalysts generated the product from [3 + 2]-
cycloaddition (4) between the nitrone and the donor−acceptor
cyclopropene formed from 1a (entries 1 and 2), whereas
copper(I) tetrafluoroborate [Cu(CH3CN)4]BF4 formed the
product from [3 + 3]-cycloaddition (3a) in 77% isolated yield
(entry 3). Unlike previously documented [3 + 3]-cycloaddition
reactions of enoldiazo compounds with nitrones,9,13 where a
slight molar excess of nitrone over the diazo compound provided
optimum results, reactions with 1a required an excess of the
enoldiazosulfone over nitrone to achieve optimum yields. The
yield of 3a decreased with increasing the amounts of nitrone
[copper(I) catalysis]: 0.7 equiv of 2a (77% 3a), 1.0 equiv of 2a
(37% 3a), and 2.0 equiv of 2a (19% 3a). This was due to a facile
silyl transfer from the donor−acceptor cyclopropene to the
nitrone that was competitive with cycloaddition (see Supporting
Information for NMR spectra) and probable subsequent ring
opening of cyclopropene.6 Other catalysts that are known to
form metal carbenes from diazo compounds, specifically,
gold(I) hexafluoroantimonate [Au(JohnPhos)(CH3CN)]-
SbF614 and silver(I) hexafluoroantimonate,7b completely shifted
the reaction chemoselectivity to the formation of the
Mukaiyama−Mannich addition product affording 5 in 92%
and 76% yields, respectively (entries 5 and 6). Use of copper(I)
triflate [Cu(OTf)·Tol1/2] and bis(benzonitrile)palladium(II)
chloride [Pd(PhCN)2Cl2], however, resulted in a mixture of 3a,
9
10
11
trace
26
a
All reactions were carried out on a 0.20 mmol scale in 4.0 mL of
DCM: the copper(I) catalyst consisting of 5 mol % of [Cu-
(CH3CN)4]BF4 and 6 mol % of chiral ligand was stirred in 1.0 mL of
DCM at room temperature for 1 h, and the 2a (0.20 mmol) and 1a
b
(0.30 mmol) were added in sequence. Isolated yield after flash-
c
chromatography. Enantiomeric excesses were determined by chiral
d
HPLC analysis. Determined by 1H NMR spectral analysis using
e
1,3,5-trimethoxybenzene as the internal standard. Results in DCE as
reaction solvent are shown in parentheses. Lowering the catalyst
loading from 5.0 to 2.0 to 1.0 mol % showed minimal effect on
enantioselectivity.
f
4, and 5 (entries 4 and 7). In the absence of nitrone
[Cu(CH3CN)4]BF4, Rh2(OAc)4, and Rh2(oct)4 formed the
hydrolytically unstable donor−acceptor cyclopropene 6 quanti-
tatively within 10 min (eq 3).
Control experiments were conducted with preformed donor−
acceptor cyclopropene 6 to confirm the role of the catalysts in
the formation of 3a and 4. When cyclopropene 6 was treated
with an equivalent amount of nitrone 2a in the absence of
catalyst, the [3 + 2]-cycloaddition product 4 was obtained in a
yield comparable with that from the dirhodium(II)-catalyzed
reactions (Table 1). However, when cyclopropene 6 was added
to a solution of nitrone 2a and Cu(CH3CN)4BF4 under standard
reaction conditions, the [3 + 3]-cycloaddition product 3a was
obtained in 71% yield without evidence for the formation of 4.
These results are consistent with initial metal−carbene
formation with the enoldiazosulfone, followed by irreversible
formation of the donor−acceptor cyclopropene with
dirhodium(II) catalysts but either direct [3 + 3]-cycloaddition
B
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a
Scheme 2. Copper-Catalyzed [3 + 3]-Cycloaddition of Enoldiazosulfones 1 with Nitrones 2: Substrate Scope
a
All reactions were carried out on a 0.2 mmol scale in 4.0 mL of DCE: copper(I) catalyst (5 mol % of [Cu(CH3CN)4]BF4 and 6 mol % of chiral
b
ligand stirred in 1.0 mL of DCE at room temperature for 1 h; 2 (0.20 mmol), 1 (0.30 mmol). Reaction was carried out on a 2.0 mmol scale of 2g.
a
However, promising results were provided by ligands L3 and L4,
which gave improved yields of 3a without observable formation
of 4. Further ligand screening was carried out with side-armed
bisoxazoline (sabox) ligands in which substituents at the
bridgehead carbon are known to influence catalyst selectivity.9,15
Ligands L5 and L6 gave further enhancements with
enantioselectivities of 96% and 97% ee, respectively. Although
L11 gave the desired product with 97% ee, its yield did not
exceed 72% due to formation of 4 (26% yield).
Scheme 3. TBS-Group Removal from 3a and 3l
Solvent variation using ligand L5 showed minimal effect on
reaction outcome (see Supporting Information), although
modest increases in both yield and ee values were observed in
1,2-dichloroethane (DCE). Using L5 in DCE as a solvent gave
3a in 92% yield and 99% ee (entry 5), while ligand L6 in DCE
afforded 3a in 88% yield and 98% ee (entry 6). Thus, ligand L5 in
DCE was selected to extend the scope of the reaction. Lowering
the catalyst loading from 5.0 to 2.0 to 1.0 mol % showed minimal
effect on enantioselectivity; however, prolonged reaction time
(48 h) was required for 1.0 mol % catalyst loading to achieve a
yield comparable to that for 5.0 mol % loading.
a
X-ray structure of 8 with 50% thermal ellipsoid probability.
of the metal carbene or reversible formation of the donor−
acceptor cyclopropene with copper(I) catalysts.
Enantiocontrol in the copper(I)-catalyzed cycloaddition
process was examined with a set of chiral BOX ligands L1−11
(Table 2). L1 and L2 were unsuitable due to low conversion to
products and competing formation of 4 (entries 1 and 2).
A diverse set of N,α-disubstituted nitrones was employed to
investigate the scope of the reaction with 1 in the presence of
[Cu(CH3CN)4]BF4/L5 in DCE (Scheme 2). In all cases, the
C
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catalytic system generated the corresponding [3 + 3]-cyclo-
addition products 3a−o in good yields and excellent
enantioselectivities. Neither electron withdrawing nor electron
donating substituents at ortho-, meta-, or para-positions of the α-
phenyl affected the outcome of the reaction. Also, nitrones with
2-furyl (3f), 2-thiophenyl (3g), 2-naphthyl (3h), or even
cyclopropyl (3i) at the α-positions, as well as those with the p-
MeO-substituent on the N-phenyl ring (3j and 3k), gave the 1,2-
oxazine cycloaddition products in good yields with high
enantiocontrol. Replacing the phenyl group of the enoldiazo-
sulfone with a methyl group also resulted in the corresponding
[3 + 3]-cycloaddition product (3b), which occurred in 86%
yield with 96% ee. The substrate scope also highlighted the
important influence of the nitrone N-group to affect optimal
enantioselectivity (Scheme 2). Compared to the N-phenyl
group, N-benzyl and N-diphenylmethyl variants afforded lower
enantioselectivities when L5 was employed (86% and 65% ee for
3l and 3o, respectively). However, ligand screening showed that
high enantiocontrol toward 3l can be restored by using either L6
or L10, returning excellent yields with 98% and 96% ee,
respectively. Enantioselectivity for the reactions of nitrone with
a bulkier N-diphenylmethyl group was enhanced to 83% ee only
by switching from L5 to L10. The absolute configuration of the
newly created stereocenter in 3l by (4R,4′R,5S,5′S)- and
(4R,4′R)-bisoxazoline ligands was confirmed to be (S) by X-
ray crystallographic analysis after removal of the TBS-protecting
group (Scheme 3).
Michael P. Doyle: 0000-0003-1386-3780
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The financial support of this research from the National Science
Foundation (CHE-1559715) is gratefully acknowledged. The
NMR spectrometer used in this research was supported by a
grant from U.S. National Science Foundation (1625963). F.G.A.
acknowledges financial support from Australia Awards-Endeav-
our Fellowship 2018 program, Australian Federal Government
(ERF_PDR_6425_2018).
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03421.
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2011, 133, 16402. (b) Xu, X.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem.,
Int. Ed. 2012, 51, 9829. (c) Xu, X.; Zavalij, P. J.; Doyle, M. P. Chem.
Commun. 2013, 49, 10287. (d) Xu, X.; Zavalij, P. Y.; Doyle, M. P. J. Am.
Chem. Soc. 2013, 135, 12439. (e) Xu, X.; Zavalij, P. Y.; Doyle, M. P.
Angew. Chem., Int. Ed. 2013, 52, 12664. (f) Deng, Y.; Massey, L. A.;
Screening tables, experimental procedures, compound
characterization data, NMR spectra, and HPLC traces
(PDF)
Accession Codes
́
̃
Rodriguez Nunez, Y. A.; Arman, H.; Doyle, M. P. Angew. Chem., Int. Ed.
2017, 56, 12292.
CCDC 1863663 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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Soc. 2016, 138, 44.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michael.doyle@utsa.edu.
ORCID
Frady G. Adly: 0000-0002-7279-276X
Kostiantyn O. Marichev: 0000-0001-7674-950X
(12) Qian, Y.; Shanahan, C. S.; Doyle, M. P. Eur. J. Org. Chem. 2013,
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