Organoiodine-Catalyzed Enantioselective Intermolecular Oxyamination of Alkenes

Article abstract of DOI:10.1021/jacs.0c11440

Metal-free, catalytic enantioselective intermolecular oxyamination of alkenes is realized by use of organoiodine(I/III) chemistry. The protocol is applicable toward aryl- and alkyl-substituted alkenes with high enantioselectivity and electronically controlled regioselectivity. The oxyaminated products can be easily deprotected in one step to reveal free amino alcohols in high yields without loss of enantioselectivity. A key to our success is the discovery of a virtually unexplored chemical entity, N-(fluorosulfonyl)carbamate, as a bifunctional N,O-nucleophile.

Full text of DOI:10.1021/jacs.0c11440

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Communication
Organoiodine-Catalyzed Enantioselective Intermolecular
Oxyamination of Alkenes
Chisato Wata and Takuya Hashimoto*
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ABSTRACT: Metal-free, catalytic enantioselective intermolecular oxyamination of alkenes is realized by use of organoiodine(I/III)
chemistry. The protocol is applicable toward aryl- and alkyl-substituted alkenes with high enantioselectivity and electronically
controlled regioselectivity. The oxyaminated products can be easily deprotected in one step to reveal free amino alcohols in high
yields without loss of enantioselectivity. A key to our success is the discovery of a virtually unexplored chemical entity, N-
(fluorosulfonyl)carbamate, as a bifunctional N,O-nucleophile.
β-Amino alcohol is a common structural motif in natural
products and pharmaceuticals,1 and also in asymmetric
synthesis as chiral auxiliaries, ligands, and catalysts.2 One
ideal way to access enantioenriched β-amino alcohols is
catalytic enantioselective intermolecular oxyamination of
alkenes given its ease of synthesis planning and the availability
of a vast number of alkenes.3 The standard procedure for this
purpose has long been the osmium-catalyzed Sharpless
asymmetric aminohydroxylation (AA),4 while it is plagued
with poor regioselectivity,5 and the toxicity and cost of
osmium,6 hampering its more comprehensive application.
A handful of reports have emerged to address this challenge
by using transition metal catalysis,7 although few offer ways to
transform alkenes to unprotected β-amino alcohols. Yoon and
co-workers have described the iron-catalyzed enantioselective
oxyamination of vinylarenes and terminal dienes with an N-
nosyl oxaziridine which reveals free β-amino alcohols after two-
step deprotection.7b The Arnold group has disclosed the
engineered hemeprotein-catalyzed enantioselective aminohy-
droxylation of vinylarenes which directly affords unprotected
β-amino alcohols.7f It is of note that these two studies are not a
Figure 1. Organoiodine(I/III)-catalyzed enantioselective intermolec-
ular difunctionalization of alkenes.
direct replacement of the Sharpless AA, as these methodologies
exhibit complementary regioselectivity. Outside transition
metal catalysis, Denmark and co-workers have reported the
regard to the use of organoiodine chemistry for the
selenium-catalyzed syn-oxyamination of a single 1,2-diaryl-
oxyamination of alkenes,15 the fully intramolecular, stoichio-
ethylene without referring to deprotection.8 Even with these
metric oxyamination using a chiral organoiodine(III) reagent
advances, aliphatic alkenes remain a very challenging substrate
remains the state-of-the-art as reported by the Wirth
class in catalytic enantioselective intermolecular oxyamina-
group.16,29
tion.9
Herein, we report the realization of an organoiodine(I/III)-
catalyzed enantioselective intermolecular oxyamination of
Chiral organoiodine(I/III) catalysis has become a reliable
tool to difunctionalize alkenes in a stereocontrolled manner
alkenes, capitalizing on the discovery of a novel carbamate as
without the need for transition metals,10 owing to the rapid
development of this field in the past 15 years.11 However, two
Received: November 3, 2020
Published: January 22, 2021
identical functionalities are inevitably incorporated into an
alkene (Figure 1a),12 unless at least one of the nucleophiles is
preinstalled in the substrate.13 An unmet challenge in this field
is, therefore, intermolecular heterodifunctionalization of
alkenes with high regio- and stereocontrol,14 which will enable
valuable synthetic transformations like oxyamination. With
https://dx.doi.org/10.1021/jacs.0c11440
J. Am. Chem. Soc. 2021, 143, 1745−1751
© 2021 American Chemical Society
1745

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Communication
a b
,
Table 1. Optimization of Stoichiometric Oxyamination
Table 2. Scope of Stoichiometric Oxyamination
ab
,
entry
change from the standard conditions
yield (%)
c
1
2
3
4
5
none
without 1a·Li
without 1a
CDCl3 as solvent
TsNHCO2Bn and TsN(Li)CO2Bn
instead of 1a and 1a·Li
73 (72)
45
5
55
0
d
6
1b and 1b·Li instead of 1a and 1a·Li
7 instead of PhI(OAc)2
76
e
7
(72%, 93% ee)
a
b
c
0.10 mmol scale. NMR yield (isolated yield). 0.3 mmol scale.
d
e
PhI(OAc)2 (0.20 mmol), 1b (0.20 mmol), 1b·Li (0.12 mmol). 7
(0.12 mmol), CH3CN (0.5 M), −20 °C, 48 h.
Scheme 1. Deprotection and Reagent Synthesis
a
b
0.30 mmol scale. Isolated yield of single regioisomer, see the SI for
c
regioselectivity of each reaction. 1a (0.72 mmol), 1a·Li (0.72 mmol).
d
PhI(OAc)2 (0.60 mmol), 1b (0.60 mmol), 1b·Li (0.36 mmol).
e
f
PhI(OAc)2 (0.90 mmol), 1b (0.90 mmol), 1b·Li (0.36 mmol). 0.10
mmol scale with 7 (0.12 mmol), 1a (0.12−0.24 mmol), 1a·Li (0.12−
0.24 mmol), see the SI for details.
a bifunctional N,O-nucleophile. The oxyamination and
successive deprotection are conducted without needs for
transition metals, harsh conditions, or inert atmosphere.
Compared with the Sharpless AA, the equal level of
enantioselectivities and higher regioselectivities are achieved
over a broad range of vinylarenes.17 Furthermore, the first
highly regio- and enantioselective intermolecular oxyamination
of aliphatic alkenes is accomplished.
Our conceptual blueprint is the use of a carbamate
reagent,8,18 which acts as a bifunctional nitrogen and oxygen
nucleophile sequentially toward an alkene (Figure 1b). A
suitable carbamate reagent needs to have two seemingly
opposite properties: one is high acidity to facilitate the
generation of a reactive alkene-coordinated iodonium inter-
mediate; the other is high nucleophilicity toward the activated
alkene. For the successful implementation of this protocol, the
amide nitrogen, not the carbonyl oxygen, of the carbamate
must attack at the alkene carbon with more positive charge. At
the same time, facile deprotection of the oxyaminated products
must be taken into consideration to reveal free β-amino
alcohols without loss of stereochemical integrity and overall
yield.
We first sought to identify a carbamate reagent which fulfills
all these criteria, in a stoichiometric oxyamination of trans-β-
methylstyrene using PhI(OAc)2. A crucial breakthrough in this
attempt was the discovery of benzyl N-(fluorosulfonyl)-
carbamate 1a, a chemical entity that has never been used
before in organic synthesis,19 as a bifunctional N,O-
nucleophile (Table 1). Under the optimized conditions,
trans-β-methylstyrene reacted with 1a and its lithium salt 1a·
Li under air at 25 °C to give trans-oxazolidinone 2 in 73%
yield. The observed syn-stereospecificity and high regioselec-
tivity (>95:5) are consistent with our proposed mechanism
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Communication
Table 3. Scope of Catalytic Enantioselective Intermolecular Oxyamination of Alkenes
a
b
c
0.10 mmol scale with MMPP (0.10 mmol) at −10 °C. 0.10 mmol scale with Selectfluor (0.15 mmol) at 10 °C. Isolated yield of single
d
regioisomer; see the SI for regioselectivity of each reaction. Performed with 25b.
group are crucial for the generation of the iodonium
Scheme 2. One-pot Oxyamination−Deprotection
intermediate and the successive attack of the nitrogen atom,
respectively. In this reaction, the benzyl moiety of 1a was
trapped by acetonitrile and the carbamate reagent, generating
byproducts 3−5. Without lithium salt 1a·Li, the yield was
reduced, and aldehyde 6, which stemmed from competitive
addition of water, became the major byproduct (entry 2).20
Essentially no reaction took place when lithium salt 1a·Li alone
was used in the absence of 1a (entry 3). Acetonitrile is the
solvent of choice, considering its ability to scavenge the benzyl
group of the carbamate and dissolve 1a·Li (entry 4). The
exquisite reactivity of N-(fluorosulfonyl)carbamate was under-
lined by the reaction using TsNHCO2Bn and its lithium salt
instead of 1a and 1a·Li,8,18a which gave no desired product
(entry 5). In the evaluation of substrate scope (vide infra), we
noticed that byproducts 4 and 5 occasionally became an
(see Figure 1b). We assume that the strong electron-
withdrawing nature and small size of the fluorosulfonyl
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Communication
obstacle for the isolation of the products. Accordingly, tert-
butyl carbamate 1b (see Scheme 1b) was introduced as an
alternative, which forms volatile isobutene as the byproduct.
This traceless strategy worked equally well to give 2 in 76%
yield by modifying the stoichiometry of the reagents (entry 6).
At this stage, we also optimized an enantioselective oxy-
amination using a stoichiometric amount of a chiral
organoiodine(III) reagent. By examining several lactate-based
reagents developed by Fujita and Ishihara,21 we found out that
the oxyamination with chiral reagent 7 furnished (4S,5S)-2 in
72% yield and 93% ee (entry 7).22
The N-fluorosulfonyl group of the carbamate reagent also
plays a vital role in deprotection of the oxyaminated product
(Scheme 1a), building on the labile sulfur−fluorine bond in
protic media.23 Acid hydrolysis of (4S,5S)-2 furnished the
corresponding free amino alcohol in one step, which was
isolated as N-Boc protected form 8 in 83% yield without
erosion of its stereochemical integrity. Examination of the
reaction solution revealed formation of sulfamic acid 9 as the
intermediate. The carbamate reagent synthesis was also
optimized to secure its availability on a large scale (Scheme
1b). The procedure is column chromatography free and
routinely carried out on a 100 mmol scale in the lab, and
carbamates 1 and lithium salts 1·Li are obtained in good yields
as bench-stable, crystalline solids.
Transforming unactivated trans- and cis-alkenes to the
corresponding β-amino alcohols with reliable regio- and
diastereoselectivities is still a daunting challenge even in
racemic fashion, although considerable progress has been
achieved in both stoichiometric and catalytic racemic oxy-
aminations.18,24 Accordingly, we initially evaluated the scope of
stoichiometric oxyamination (Table 2), with a focus on
difficult substrates for our catalytic oxyamination (vide infra).
Styrene, o- and p-methoxystyrenes reacted to afford 10−12
in good yields and >95:5 regioselectivities. TBS-protected
cinnamyl alcohol reacted to give amino diol 13 with perfect
syn-stereospecificity. The oxyamination of a cinnamyl alcohol
derivative with an α-chiral center took place from the
congested side of the alkene to give all syn amino diol 14
with good diastereoselectivity. Acyclic aryl-substituted cis-
alkenes, which are prone to give a mixture of diastereomers in
other oxyaminations,7d,18a,24a,d,k,n,v were converted to 15 and
16 in moderate yields without compromising syn-stereo-
specificity (>95:5 dr). Indene was also a viable substrate to
give 17 in good yield.
The oxyamination of a terminal aliphatic alkene provided 18
with electronically controlled regioselectivity, as in the case of
vinylarenes, forging the C−N bond at the internal carbon. It is
of note that, in preceding oxyaminations, deterioration or
reversal of the regioselectivity is frequently observed by
switching from aryl- to alkyl-substituted alkenes.18b,24b,h,v
Symmetrical, trans- and cis-aliphatic alkenes were also tolerated
to give 19−21 in moderate yields. While unsymmetrical
internal aliphatic alkenes present a challenge due to lack of a
strong electronic and steric bias required for regioselective
oxyamination,25 trans- and cis-allylic silyl ethers underwent
oxyamination to generate 22 and 23 with high regioselectivity
and syn-stereospecificity. The oxyamination of a terminal diene
also gave product 24 in moderate yield.26
enantioselectivities. The reactions with cis-aryl alkenes and
aliphatic alkenes, except for cis-aliphatic alkenes, led to
moderate enantioselectivities.
We next shifted focus on our final goal of achieving an
organoiodine(I/III)-catalyzed enantioselective intermolecular
oxyamination of alkenes (Table 3). By investigating catalyst
structures, reaction conditions, and external oxidants (see the
SI), we reached to a couple of principles to implement catalytic
highly enantioselective oxyamination. Chiral organoiodine
catalysts based on a 5-methylresorcinol core with N,N-
diisopropylamide side arms 25, introduced by Mun
̃
iz,12f are
indispensable to attain good turnover and high enantioselec-
tivity. Catalyst 25a with pendant benzyl groups worked well for
a broad range of alkenes, while methyl-substiuted catalyst 25b
performed better for ortho-substituted vinylarenes in terms of
both the yield and ee.
The judicious choice of an oxidant depending on the
electronic properties of vinylarenes is also an important factor.
For electronically neutral and slightly electron-poor vinyl-
arenes, magnesium monoperoxyphthalate hexahydrate
(MMPP) was found to be optimal (Table 3a).27 The
conditions were applicable to halogenated (26−28), alkylated
(29 and 30), oxygenated (31−33), and fused (34) vinylarenes
with excellent enantioselectivities. Concomitantly, ring-opened
byproducts were obtained in 10−15% yields with moderate ee
(Table 3b). We have confirmed the byproducts could stem
from vinylarenes via epoxidation and ring opening with 1a in
the absence an organoiodine catalyst.12f The observed
moderate enantioselectivity implies hydrolysis of the reaction
intermediate as the second pathway.10c
As for electron-deficient or ortho-halogenated vinylarenes,
the use of Selectfluor as an oxidant constantly gave the
products in good yields and high enantioselectivities (Table
3c). Typical electron-withdrawing functionalities such as nitro,
alkoxycarbonyl, cyano, acyl, trifluoromethyl, and sulfonyl
groups were all tolerated as showcased in products 35, 38-
43. The substitution pattern of the aromatic ring was examined
with nitrostyrenes, generating 35−37 with excellent enantio-
selectivities. In the oxyamination of o-nitrostyrene, catalyst 25b
was selected to give product 37 which contained a small
amount of the regioisomer. The catalytic oxyamination with
trans- and cis-β-methylstyrenes led to poor yields irrespective
of the reaction conditions. Meanwhile, cinnamyl benzoates
reacted to give 47−49 as a single diastereomer with high
enantioselectivities using Selectfluor.12d Catalytic enantiose-
lective intermolecular oxyamination of aliphatic alkenes is an
unsolved challenge in synthetic organic chemistry.28 Accord-
ingly, we were delighted that the catalytic oxyamination using
Selectfluor tolerated terminal aliphatic alkenes, giving 18, 50−
54 having different functionalities in good yields and
enantioselectivities over 80%.
Finally, we developed one-pot reactions that give unpro-
tected amino alcohols straightforwardly (Scheme 2). By use of
the stoichiometric oxyamination with PhI(OAc)2, styrene was
converted to (rac)-N-Boc-phenylglycinol 55 in 83% overall
yield (eq 1). The catalytic enantioselective oxyamination/
deprotection sequence was implemented on 3 mmol scale
using p-nitrostyrene to give 56 in 67% overall yield and 96% ee
(eq 2).
These substrates were then subjected to chiral organoiodine-
(III)-mediated oxyamination (see Table 1, entry 7). Styrene, p-
methoxystyrene, TBS-protected cinnamyl alcohol, and 1,3-
nonadiene reacted to afford 10, 11, 13, and 24 with high
In conclusion, we have realized the organoiodine(I/III)-
catalyzed, highly enantioselective intermolecular oxyamination
of alkenes which generates enanitoenriched β-amino alcohols
from aryl- and alkyl-substituted alkenes. A critical element in
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(3) (a) Karjalainen, O. K.; Koskinen, A. M. P. Diastereoselective
synthesis of vicinal amino alcohols. Org. Biomol. Chem. 2012, 10,
4311−4326. (b) Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Lacy, A.
R.; Rathi, A. H. Recent developments in methodology for the direct
oxyamination of olefins. Chem. - Eur. J. 2011, 17, 58−76.
the successful achievement is the discovery of N-(fluoro-
sulfonyl)carbamates as a new reagent in synthetic organic
chemistry.29
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11440.
■
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Accession Codes
CCDC 1963253, 1963807−1963808, and 2036171−2036172
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
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AUTHOR INFORMATION
Corresponding Author
■
Takuya Hashimoto − Chiba Iodine Resource Innovation
Center and Department of Chemistry, Graduate School of
Science, Chiba University, Chiba 263-8522, Japan;
orcid.org/0000-0002-6963-4322; Email: takuya.hash@
chiba-u.jp
̈
Z.-J.; Zhang, R. K.; Gorbe, T.; Arnold, F. H. Enantioselective
Author
aminohydroxylation of styrenyl olefins catalyzed by an engineered
hemoprotein. Angew. Chem., Int. Ed. 2019, 58, 3138−3142.
(8) Tao, Z.; Gilbert, B. B.; Denmark, S. E. Catalytic, enantioselective
syn-diamination of alkenes. J. Am. Chem. Soc. 2019, 141, 19161−
19170.
Chisato Wata − Chiba Iodine Resource Innovation Center and
Department of Chemistry, Graduate School of Science, Chiba
University, Chiba 263-8522, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11440
(9) Coombs, J. R.; Morken, J. P. Catalytic enantioselective
functionalization of unactivated terminal alkenes. Angew. Chem., Int.
Ed. 2016, 55, 2636−2649.
Notes
̈
̃
(10) (a) Romero, R. M.; Woste, T. H.; Muniz, K. Vicinal
difunctionalization of alkenes with iodine(III) reagents and catalysts.
The authors declare no competing financial interest.
́
Chem. - Asian J. 2014, 9, 972−983. (b) Molnar, I. G.; Thiehoff, C.;
ACKNOWLEDGMENTS
In memory of Prof. Kilian Mun
■
Holland, M. C.; Gilmour, R. Catalytic, vicinal difluorination of olefins:
Creating a hybrid, chiral bioisostere of the trifluoromethyl and ethyl
groups. ACS Catal. 2016, 6, 7167−7173. (c) Fujita, M. Mechanistic
aspects of alkene oxidation using chiral hypervalent iodine reagents.
Tetrahedron Lett. 2017, 58, 4409−4419. (d) Li, X.; Chen, P.; Liu, G.
Recent advances in hypervalent iodine(III)-catalyzed functionaliza-
tion of alkenes. Beilstein J. Org. Chem. 2018, 14, 1813−1825.
̃
iz. We thank Yamato Omatsu,
Prof. Yoshiyuki Mizuhata, and Prof. Norihito Tokitoh for X-ray
crystallography of 14 and TBDPS analog of 22, and Prof. Keiji
Maruoka for the access to ESI-MS. This work was supported
by JSPS KAKENHI Grant Number JP18H04256 in Precisely
Designed Catalysts with Customized Scaffolding, Grant-in-Aid
for Scientific Research (B) JP19H02710, the Society of Iodine
Science, Ube Industries Foundation and Toyo Gosei Memorial
Foundation.
(11) (a) Dohi, T.; Kita, Y. Hypervalent iodine reagents as a new
entrance to organocatalysts. Chem. Commun. 2009, 2073−2085.
(b) Uyanik, M.; Ishihara, K. Conformationally-flexible chiral hyper-
valent organoiodine catalysts for enantioselective oxidative trans-
formations. Yuki Gosei Kagaku Kyokaishi 2012, 70, 1116−1122.
(c) Singh, F. V.; Wirth, T. Hypervalent iodine-catalyzed oxidative
functionalizations including stereoselective reactions. Chem. - Asian J.
2014, 9, 950−971. (d) Claraz, A.; Masson, G. Asymmetric iodine
catalysis-mediated enantioselective oxidative transformations. Org.
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