O2-Assisted Four-Component Reaction of Vinyl Magnesium Bromide with Chiral N-tert-Butanesulfinyl Imines To Form syn-1,3-Amino Alcohols

Article abstract of DOI:10.1002/anie.202109566

An O₂-assisted, four-component reaction has been developed to synthesize a wide range of syn-1,3-amino alcohols in one step. The reaction proceeds by oxygenation of vinyl magnesium bromide (component-I) with O₂ (component-II) to give

Full text of DOI:10.1002/anie.202109566

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: O2-Assisted Four-component Reaction of Vinyl Magnesium
Bromide with Chiral N-tert-Butanesulfinyl Imines To Form syn-1,
3-Amino Alcohols
Authors: Zhen Lei Song, Runping Wang, Jingfan Luo, Chunmei Zheng,
Lu Gao, and Hongyun Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202109566
Link to VoR: https://doi.org/10.1002/anie.202109566

10.1002/anie.202109566
Angewandte Chemie International Edition
RESEARCH ARTICLE
O2-Assisted Four-component Reaction of Vinyl Magnesium
Bromide with Chiral N-tert-Butanesulfinyl Imines To Form syn-1,
3-Amino Alcohols**
Runping Wang,† Jingfan Luo,† Chunmei Zheng, Hongyun Zhang, Lu Gao and Zhenlei Song*
R. P. Wang,† J. F. Luo,† C. M. Zheng, H. Y. Zhang, Prof. Dr. L. Gao, Prof. Dr. Z. L. Song
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced
Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
E-mail: zhenleisong@scu.edu.cn
†These two authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: An O2-assisted, four-component reaction has been
developed to synthesize a wide range of syn-1,3-amino alcohols in
one step. The reaction proceeds by oxygenation of vinyl magnesium
bromide (component-I) with O2 (component-II) to give a magnesium
enolate of acetaldehyde, which undergoes addition to a chiral N-tert-
butanesulfinyl imine (component-III) followed by a sequential addition
with excess vinyl magnesium bromide (component-IV). The approach
allows diastereoselective synthesis of anti/syn- and syn/syn-3-amino-
1,5-diols in good yields with high diastereoselectivity. The method was
illustrated in an efficient, four-step synthesis of piperidine alkaloid (-)-
2'-epi-ethylnorlobelol.
diastereo- and enantioselective manner has remained an active
and important research area in organic synthesis.
Diastereoselective access to 1,3-amino alcohols typically involve
reduction of 1,3-amino ketones,[4] 1,3-hydroxy imines[5] or 2,3-
dihydroisoxazoles,[6] or the addition of organometallic reagents to
1,3-amino aldehydes and ketones (Scheme 1-I).[7] Palladium-
catalyzed intramolecular allylic amination of N-tosyl carbamate,[8]
hemiaminal[9] or trichloroacetimidates [10] derived from 2-pentene-
1,5-diol enables a cyclization strategy for the synthesis of 1,3-
amino alcohol variants (Scheme 1-II). Recent elegant progresses
in transition-metal-catalyzed aliphatic C−H amination[11] with
nitrenes,[12] allylic C−H amination (Scheme 1-III)[13] and
hydroamination of homoallenyl carbamate (Scheme 1-IV)[14] are
emerging as straightforward and atom-economical route to this
motif.
Introduction
1,3-Amino alcohols are important motifs in many pharmaceuticals
and natural products (Scheme 1, upper) either within an open
chain (e.g. lopinavir[1]) or embedded in a ring structure (e.g.
andrachamine and pseudohygroline[2]). Additionally, 1,3-amino
alcohols are useful chiral building blocks in asymmetric synthesis
functioning as chiral ligands and auxiliaries.[3] In this context,
developing efficient approaches towards 1,3-amino alcohols in a
Scheme 2. (a) General profile of oxygenation of Grignard reagents. (b) Urabe’s
work: air-assisted addition of Grignard reagents to olefins. (c) This work: O2-
assisted four-component reaction of vinyl magnesium bromide and (S)-N-tert-
butanesulfinyl imines 1 to form syn-1, 3-amino alcohols 2.
Grignard reagents (RMgX) are well-known to oxygenate with
O2 to give the corresponding magnesium alkoxide (ROMgX)
(Scheme 2a).[15] The reaction is proposed to proceed via a radical
Scheme 1. Representative bioactive molecules and natural products containing
syn-1,3-amino alcohol, and general strategies towards this motif.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202109566
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 1. Screening of Reaction Conditions[a]
Entry
CH2CHMgBr
(equiv.)
R
Air or O2 t1 [b]
t2 [b]
Additives
(1.1 equiv.)
Solvent
/mL (I+II) [c]
Yield
(2) [d]
dr
(2) [e]
Yield
(3) [e]
1
3.0
5.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
t-Bu (1a)
4-MeC6H4 (1b)
/
/
3 h
/
THF/4.5 (1.5+3)
THF/5.5 (2.5+3)
THF/6 (3+3)
5%
75:25
75:25
75:25
75:25
75:25
75:25
/
79%
22%
44%
45%
40%
51%
N.R.
34%
N.R.
32%
35%
/
2
air
air
O2
O2
O2
O2
O2
O2
O2
O2
O2
12 h
12 h
12 h
1 h
/
17%
35%
45%
52%
30%
N.R.
53%
N.R.
55%
62%
32%
3
12 h
/
4
3 min
5 min
10 min
5 min
5 min
5 min
5 min
5 min
5 min
/
THF/6 (3+3)
5
1 h
/
THF/6 (3+3)
6
1 h
/
THF/6 (3+3)
7
1 h
AlMe3
THF/6 (3+3)
8
1 h
ZnMe2
THF/6 (3+3)
75:25
/
9
1 h
ZnCl2
THF/6 (3+3)
10
11
12
15 min
15 min
15 min
/
/
/
THF/CH2Cl2/6 (3+3)
THF/CH2Cl2/7 (3+4)
THF/CH2Cl2/7 (3+4)
90:10
90:10
≥95:5
[a] Reaction conditions: 1 (0.5 mmol), vinyl magnesium (1.0 M in THF) at -78 ºC. [b] t1: passing air or O2 (1 atm) through the solution; t2: addition with imine 1. [c]
solvent I: THF to dissolve vinyl magnesium; solvent II: THF or CH2Cl2 to dissolve imine 1. [d] Isolated yields. [e] The ratios were determined by 1H NMR of crude
products.
mechanism to yield a peroxide species (ROOMgX). Then
reduction of the peroxide with RMgX generates ROMgX.[16] The
overall yield of this reaction is good in the case of alkyl Grignard
reagents, but poor in the case of aryl ones. Although this
chemistry was discovered almost 120 years ago, its synthetic
utility has barely been explored, with exception of work by Urabe
and co-workers in 2005 (Scheme 2b).[17] They took advantage of
the radical species (R•) generated by oxidation of Grignard
reagents in air to develop a one-pot, three-component coupling
of Grignard reagent, olefin, and O2, which directly afforded
alcohols.
Here we report another synthetically valuable utility of
Grignard reagent oxygenation in a four-component coupling
process (Scheme 2c). Oxygenation of vinyl magnesium bromide
(component-I) with O2 (component-II) gives the corresponding
magnesium enolate intermediate (CH2=CHOMgX), which
undergoes addition to chiral N-tert-butanesulfinyl imine 1[18]
(component-III) followed by addition with excess vinyl
magnesium bromide (component-IV). The reaction enables an
efficient one-step approach to diverse syn-1,3-amino alcohols 2
predominantly, while normal addition to give allylic sulfonamide
3 proceeds as a minor pathway. Our approach showcases a
strategically distinct method toward syn-1,3-amino alcohols in
constrat to those shown in Scheme 1, and has substantial utility
in organic synthesis.
aldehydes (1.0 equiv.) in anhydrous CH2Cl2 at room temperature
affords a variety of (S)-N-tert-butanesulfinyl imines 1 in good
yields with complete E-selectivity (see Supplementary
Information on pages S3-S23 for details). Our studies began
after we observed that during the addition of vinyl
magnesiumbromide to (S)-N-tert-butanesulfinyl imine 1a in THF
at -78 ºC under argon, the normal addition product allylic
sulfinamide 3a was obtained in 79% yield, while the synthetically
more valuable syn-1,3-amino alcohol 2a was also obtained in 5%
yield with 75:25 dr (Table 1, entry 1). The origin of 2a was unclear,
but its secondary hydroxyl group led us to speculate that oxygen
was involved. Thus, we repeated the reaction in dry air to favor
the formation of 2a. As expected, the yield of 2a increased to
17% after 12 h of reaction (entry 2). Increasing the loading of
vinyl magnesium bromide to 6.0 equiv. gave 2a in a higher yield
of 35% (entry 3), along with 44% of 3a. An even higher yield of
2a was obtained by passing pure oxygen gas through the
solution of vinyl magnesium bromide in THF, and then removing
the oxygen balloon before the addition of 1a. The duration of the
sparging proved important: sparging with oxygen for 5 min gave
higher yield (52%, entry 5) than sparging for shorter or longer
(entries 4 and 6). Of various Lewis acids as additives, only ZnMe2
provided comparable yield of 53% (entry 8), while other Lewis
acids completely inhibited formation of 2a and 3a (entries 7 and
9). Using the mixed solvent system containing THF and non-
coordinating
solvent
CH2Cl2
significantly
improved
diastereoselectivity (entry 10), leading to 2a in an optimal yield
of 62% with a syn/anti ratio of 90:10 (entry 11). Reaction of (S)-
N-p-toluenesulfinyl imine 1b[19] gave the corresponding syn-1,3-
amino alcohol 2b with complete syn-selectivity but only 32%
yield (entry 12), indicating lower overall efficiency than with (S)-
N-tert-butanesulfinyl imine 1a.
Results and Discussion
Optimization of Reaction Conditions. (S)-N-tert-butanesulfinyl
imines 1 were synthesized by the procedure developed by
Ellman and co-workers in 1999.[18a] In the presence of Ti(Oi-Pr)4
(2.8 equiv.) as the Lewis acidic dehydrating agent, direct
condensation of (S)-N-tert-butylsulfenamide (1.1 equiv.) with
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202109566
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 2. Scope of (S)-N-tert-butanesulfinyl Imines 1 and Vinyl Magnesium Bromides[a]
[a] Reaction conditions: O2 (1 atm in balloon) and vinyl magnesium (3.0 mmol, 1.0 M in THF), 5 min, -78 ºC; then addition of imine 1 (0.5 mmol) in CH2Cl2 (4 mL),
15 min, -78 ºC. [b] Isolated yields. [c] The ratios were determined by 1H NMR of crude products. [d] Scaled-up to 4 mmol of imine. [e] sparging O2 for 5.5 min, and
vinyl magnesium bromide (5.0 equiv.).
Scope of Imines. The scope of (S)-N-tert-butanesulfinyl imine 1
was examined using vinyl magnesium bromide (Table 2). The
yield differences among the ethyl group-substituted 2c, 2f
containing a geminal bis(silyl)group[20] and 2g bearing a much
bulkier adamantyl group indicated a steric bias that bulkier
substituents on the imine reduced the yield. The reaction
tolerated a silyl alkynyl group (2h), which could be converted into
other functionalities via a variety of transformations, such as
Hiyama-Denmark cross-coupling.[21] Imines containing various
heteroatom-functionalities such as ether, sulfonamide,
azide,halogen, sulfide or acetal served as good substrates,
giving 2j-2p in good yields with generally high
diastereoselectivities. No oxidation of the sulfide group was
observed in the formation of 2o. The reaction proved suitable for
a large-scale synthesis of 2n using 4 mmol of imine, which
provided a comparable yield of 53%. Good applicability was also
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202109566
Angewandte Chemie International Edition
RESEARCH ARTICLE
addition (dr = 90:10), leading to anti/syn-isomer 2al in 53% yield
from (R, S)-1al, and to syn/syn-isomer 2am in 64% yield from (R,
R)-1al. The predominant syn-addition in both cases indicated
that the tert-butanesulfinyl moiety controlled the stereochemical
outcome, with minimal influence from the β-stereogenic center in
the imine.
Scheme 4. Comparison of the synthesis of 2m via the step-wise method and
our method.
Comparison of Traditional Step-wise Method and Our
Method. Our approach was more efficient at synthesizing syn-
1,3-amino alcohols 2 (e.g. 2m) than the typical step-wise process
shown in Scheme 4, which requires three steps: (1) Mannich-
type addition of the sodium enolate of methyl acetate to imine
1m, (2) reduction of the ester group with DIBAL-H, and (3)
addition of vinyl magnesium bromide to the resulting 1,3-amino
aldehyde 5. While this three-step process provided 1,3-amino
alcohol 2m with the desired syn-stereocontrol, the overall yield
was only 27% and dr was poor at 70:30. Our method, in contrast,
required only one step and led to 2m in much higher yield of 69%
and better dr of 90:10 (Table 2).
Scheme 3. Synthesis of anti/syn-3-amino-1,5-diol 2al and syn/syn-3-amino-
1,5-diol 2am.
observed for imines containing cyclopropane, cyclobutane, or N-
heterocycles with 4-7 members (2q-2v). The reaction functioned
well with a wide range of alkyl imines bearing a phenyl ring
substituted with electron-donating or -withdrawing groups, or
alkyl imines bearing a heterocyclic group such as 2-thiophene or
3-indole at the terminal position of the alkyl chain (2w-2af).
Suitable substrates also included α,β-unsaturated imines, which
gave 2ag and 2ah, useful precursors to form cyclic 1,3-amino
alcohols via the ring closing metathesis (RCM) reaction.[22]
In contrast to alkyl imines, aryl imines were much more
challenging substrates for this transformation. The reaction gave
allylic sulfinamide 3 as the predominant product via the normal
addition, while the desired syn-1,3-amino alcohols were obtained
in only moderate or poor yields (e.g. 2ai, 2aj). Ketimine was less
reactive than aldimine, failing to undergo either normal or
sequential addition. We exploited the reactivity difference
between ketimine and aldimine to synthesize 2ak in 40% yield:
the aldimine reacted selectively, while the ketimine remained
untouched. The reaction appears suitable only for unsubstituted
vinyl magnesium bromide: reaction with either 1-methyl- or 3,3-
dimethyl vinyl magnesium bromide gave complex mixtures
lacking the desired 1,3-amino alcohol products.
Scheme 5. Mechanistic studies.
Mechanistic Studies. In mechanistic studies, we ruled out the
possibility that syn-1,3-amino alcohol 2a formed from the normal
addition product 3a (Scheme 5a). We also clarified the likely role
of radicals in the reaction by conducting two experiments with the
radical trapping reagent TEMPO. Sparging O2 gas into a solution
of vinyl magnesium bromide and 3.0 equiv. of TEMPO in THF,
then adding imine 1a gave the normal adduct 3a in 75% yield
without any 1,3-amino alcohol 2a (Scheme 5b-i). In the second
Synthesis of 3-Amino-1,5-diol. To demonstrate the synthetic
utility of this sequential addition, we applied it to synthesis of 3-
amino-1,5-diol synthons (Scheme 3). Condensation of TBS-
protected 3-hydroxyl aldehyde (R)-4 with (S)-or (R)-N-tert-
butylsulfenamide gave rise to the respective diastereomers (R,
S)-1al and (R, R)-1al. Both served as good substrates under the
optimal reaction conditions to undergo predominantly syn-
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202109566
Angewandte Chemie International Edition
RESEARCH ARTICLE
experiment, adding the solution of imine 1a and TEMPO in
CH2Cl2 to O2-saturated vinyl magnesium bromide gave 2a in
49% yield, with 15% yield of 3a (Scheme 5b-ii). The results from
these two experiments suggest that the radical process
participates in the reaction of vinyl magnesium bromide with O2,
but not in the addition to imine.
Application to Synthesis of (-)-2'-epi-Ethylnorlobelol. We
applied our approach to the rapid synthesis of (-)-2'-epi-
ethylnorlobelol (Scheme 7).[26] Cyclization of syn-1,3-amino
alcohol 2m (Table 2) with NaH via intramolecular N-substitution
delivered 11 in 85% yield. Removal of the N-tert-butanesulfinyl
auxiliary of 11 under acidic conditions, followed by hydrogenation
of the alkene, gave rise to the target (-)-2'-epi-ethylnorlobelolin
an overall yield of 80%. Because several piperidine alkaloids,
such as sedum and related alkaloids,[2] contain syn-1,3-amino
alcohol fragment, our method should be useful for the synthesis
of many compounds.
Based on these observations and the well-known fact that
alkyl or phenyl Grignard reagents (RMgX) can react with O2 via
a radical pathway to give the corresponding alcohols,[15] we
proposed that our reaction might involve a similar oxidation of
vinyl magnesium bromide, leading to a magnesium enolate
intermediate (Scheme 5c). One-electron transfer from the
Grignard reagent to oxygen generates a vinyl radical and anionic
oxygen radical. Peroxide 6[23] then forms through either a radical
chain or a non-radical chain process. Vinyl magnesium bromide
reduces the peroxide, leading to a magnesium enolate 7.
Formation of 7 was supported by a trapping experiment using (n-
Bu)3SiCl, which afforded the corresponding silyl enol ether 8.
This mechanism explains why the duration of O2-sparging
influences efficiency: times shorter than 5 min cannot provide
sufficient magnesium enolate, while longer times consume more
vinyl magnesium bromide. In order to determine the ratio of
magnesium enolate to vinyl magnesium bromide, we used an
excess of imine 1a to trap these two magnesium nucleophiles.
The reaction gave rise to 0.37 mmol of 2a and 1.3 mmol of 3a,
indicating a ratio of magnesium enolate to vinyl magnesium
bromide of roughly 1:4.6 (Scheme 5d, see Supplementary
Information on pages S45-S46 for details).
Scheme 7. Application of sequential addition to the synthesis of (-)-2'-epi-
ethylnorlobelol.
Conclusion
In summary, we have developed an O2-assisted, four-
component reaction to synthesize syn-1,3-amino alcohols in one
step. The reaction proceeds by oxygenation of vinyl magnesium
bromide with O2 to give the magnesium enolate of acetaldehyde,
which undergoes addition to the imine followed by a sequential
addition with excess vinyl magnesium bromide, leading to 1,3-
amino alcohols with predominant syn-stereocontrol. The
approach tolerates a wide range of functionality, and also allows
the diastereoselective synthesis of anti/syn- and syn/syn-3-
amino-1,5-diols. The reaction efficacy was demonstrated in an
efficient synthesis of (-)-2'-epi-ethylnorlobelol, suggesting its
utility for preparing bioactive molecules bearing a 1,3-amino
alcohol motif. This work showcases a new and valuable utility of
Grignard reagent oxygenation. We are exploring more synthetic
applications of the scenario in organic synthesis.
Scheme 6. Model of sequentail addition of imine 1 with the magnesium enolate
of acetaldehyde and vinyl magnesium bromide.
Based on these results, we propose a mechanistic model of
sequential addition to form syn-1,3-amino alcohol 2 (Scheme 6).
Imine 1 undergoes the first addition with the magnesium enolate
of acetaldehyde, which appears more reactive than vinyl
magnesium bromide. According to Davis[24] and Ellman’s
model,[25] a Zimmerman-Traxler-type six-membered transition
state 9 is suggested to favor approach of the enolate from the re-
face of imine, that is consistent with the observed stereochemical
outcome at the amino moiety in 2. The resulting 1,3-amino
aldehyde intermediate might adopt a six-membered chelated
conformation 10-syn predominantly, as 10-anti suffers a 1,3-
diaxial interaction between the R and H groups. In this way, 10-
syn is quickly trapped by excess vinyl magnesium bromide,
leading to attack on the re-face of the carbonyl moiety to form
syn-1,3-amino alcohol 2. In some cases, a by-product forms from
10 via sequential addition of the enolate and vinyl magnesium
bromide, that was observed in only trace amounts.
Acknowledgements
We are grateful to financial support from the National Natural
Science Foundation of China (21921002), Ministry of Science
and Technology of the People′s Republic of China
(2018ZX09711001-005-004), the Open Research Fund of
Chengdu University of Traditional Chinese Medicine Key
Laboratory of Systematic Research of Distinctive Chinese
Medicine Resources in Southwest China (2020LF2003), and the
Science and Technology Department of Sichuan Province
(2020YFS0186) for financial support. We acknowledge Dr. D. B.
Luo and Dr. D. C. Ma in Analytical Undefined Testing Center of
Sichuan University for conducting X-ray crystallographic analysis.
Keywords: oxygenation • multi-component reaction • 1,3-amino
alcohol • N-tert-butanesulfinyl imines • vinyl magnesium bromide
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202109566
Angewandte Chemie International Edition
RESEARCH ARTICLE
[1] E. J. Stoner, A. J. Cooper, D. A. Dickman, L. Kolaczkowski, J. E. Lallaman,
J. H. Liu, P. A. Oliver-Shaffer, K. M. Patel, J. B. Paterson, D. J. Plata, D. A.
Riley, H. L. Sham, P. J. Stengel, J.-H. J. Tien, Org. Process Res. Dev. 2000,
4, 264.
Z.-S. Su, C.-W. Hu, P.-H. Xiao, Y.-Y. He, Z.-L. Song, J. Am. Chem. Soc.
2016,138, 1877; d) Y. Chen, X.-Y. Song, L. Gao, Z.-L. Song, Org. Lett. 2021,
23, 124.
[21] a) W.-T. T. Chang, R. C. Smith, C. S. Regens, A. D. Bailey, N. S. Werner, S.
E. Denmark, Org. React. 2011, 75, 213; b) Y. Nakao, T. Hiyama, Chem. Soc.
Rev. 2011, 40, 4893.
[2] R. W. Bates, K. Sa-Ei, Tetrahedron 2002, 58, 5957.
[3] S. M. Lait, D. A. Rankic, B. A. Keay, Chem. Rev. 2007, 107, 767.
[4] a) G. E. Keck, A. P. Truong, Org. Lett. 2002, 4, 3131; b) F. A. Davis, P. M.
Gaspari, B. M. Nolt, P. Xu, J. Org. Chem. 2008, 73, 9619; c) R. A. Pilli, D.
Russowsky, L. C. Dias, J. Chem. Soc., Perkin Trans. 1, 1990, 1213; e) J.
Barluenga, E. Aguilar, S. Fustero, B. Olano, A. L. Viado, J. Org. Chem. 1992,
57, 1219.
[22] F. A. Davis, Y.-Z. Wu, Org. Lett. 2004, 6, 1269.
[23] Caution: Despite magnesium peroxide was not produced in an isolable
amount and was quickly consumed by excessive vinyl magnesium bromide,
care must be taken in the formation of peroxides particularly in a large-scale
preparation.
[5] a) N. Koichi, U. Yutaka, Y. Shigeru, Bull. Chem. Soc. Jpn. 1986, 59, 525; b)
D. R. Williams, M. H. Osterhout, J. Am. Chem. Soc. 1992, 114, 8750; c) S.
J. Veenstra, S. S. Kinderman, Synlett 2001, 1109; d) T. Kochi, T. P. Tang, J.
A. Ellman, J. Am. Chem. Soc. 2003, 125, 11276.
[24] F. A. Davis, P. Zhou, G. V. Reddy, J. Org. Chem. 1994, 59, 3243.
[25] a) D. A. Cogan, G.-C. Liu, J. Ellman, Tetrahedron 1999, 55, 8883. b) T. P.
Tang, J. A. Ellman J. Org. Chem. 1999, 64, 12.
[26] a) C. Schöpf, T. Kauffmann, P. Berth, W. Bundschuh, G. Dummer, H. Fett,
G. Habermehl, E. Wieters, W. Wüst, Justus Liebigs Annalen der Chemie
1957, 608, 88; b) D. Passarella, A. Barilli, F. Belinghieri, P. Fassi, S. Riva,
A. Sacchetti, A. Silvania, B. Danieli, Tetrahedron: Asymmetry 2005, 16,
2225; c) L.-J. Chen, D.-R. Hou, Tetrahedron: Asymmetry 2008, 19, 715; d)
C. Bhat, S. G. Tilve, Tetrahedron 2013, 69, 6129; e) S. T. Bugde, P. S.
Volvoikara, S. G. Tilve, Synthesis 2018, 50, 1113.
[6] P. Aschwanden, L. Kværnø, R. W. Geisser, F. Kleinbeck, E. M. Carreira, Org.
Lett. 2005, 7, 5741.
[7] J.-L. Toujas, L. Toupet, M. Vaultier, Tetrahedron 2000, 56, 2665.
[8] a) G. Broustal, X. Ariza, J.-M. Campagne, J. Garcia, Y. Georges, A. Marinetti,
R. Robiette, Eur. J. Org. Chem. 2007, 4293. b) Y. Tamaru, T. Bando, Y.
Kawamura, K. Okamura, Z. Yoshida, M. Shiro, J. Chem. Soc., Chem.
Commun. 1992, 1498; c) L. E. Overman, T. P. Remarchuk, J. Am. Chem.
Soc. 2002, 124, 12; d) B. M. Trost, A. R. Sudhakar, J. Am. Chem. Soc. 1987,
109, 3792.
[9] B. Tang, L. Wang, D. Menche, Synlett 2013, 24, 625.
[10] Y.-Z. Xie, K. Yu, Z.-H. Gu, J. Org. Chem. 2014, 79, 1289.
[11] A. Trowbridge, S. M. Walton, M. J. Gaunt. Chem. Rev. 2020, 120, 2613.
[12] a) J. L. Roizen, M. E. Harvey, J. D. Bois, J. Acc. Chem. Res. 2012, 45, 911;
b) C. G. Espino, P. M. Wehn, J. Chow, J. D. Bois, J. Am. Chem. Soc. 2001,
123, 6935; c) D. N. Zalatan, J. D. Bois, J. Am. Chem. Soc. 2008, 130, 9220;
d) E. Milczek, N. Boudet, S. Blakey, Angew. Chem. Int. Ed. 2008, 47, 6825;
Angew. Chem. 2008, 120, 6931; e) Y.-G. Liu, X.-G. Guan, E. L.-M. Wong, P.
Liu, J.-S. Huang, C.-M. Che, J. Am. Chem. Soc. 2013, 135, 7194; f) S. M.
Paradine, J. R. Griffin, J.-P. Zhao, A. L. Petronico, S. M. Miller, M. C. White,
Nat. Chem. 2015, 7, 987; g) S. M. Paradine, M. C. White, J. Am. Chem. Soc.
2012, 134, 2036; h) F. Collet, C. Lescota, P. Dauban, Chem. Soc. Rev. 2011,
40, 1926.
[13] a) G. T. Rice, M. C. White, J. Am. Chem. Soc. 2009, 131, 11707; b) X.-B. Qi,
G. T. Rice, M. S. Lall, M. S. Plummer, M. C. White, Tetrahedron 2010, 66,
4816; c) R. Ma, J. Young, R. Promontorio, F. M. Dannheim, C. C. Pattillo, M.
C. White, J. Am. Chem. Soc. 2019, 141, 9468; d) F. Nahra, F. Liron, G.
Prestat, C. Mealli, A. Messaoudi, G. Poli, Chem. Eur. J. 2009, 15, 11078.
[14] P. A. Spreider, A. M. Haydl, M. Heinrich, B. Breit, Angew. Chem. Int. Ed.
2016, 55, 15569; Angew. Chem. 2016, 128, 15798.
[15] For review, see: a) B. J. Wakefield, Organomagnesium Methods in Organic
Synthesis, Academic Press: London, 1995, pp. 197–199; b) R. C. Lamb, P.
W. Ayers, M. K. Toney, J. F. Garst, J. Am. Chem. Soc. 1966, 88, 4261; c) C.
Walling, S. A. Buckler, J. Am. Chem. Soc. 1953, 75, 4372; d) M. S. Kharasch,
W. B. Reynolds, J. Am. Chem. Soc. 1943, 65, 501.
[16] a) M. K. Schwaebe, R. D. Little, Tetrahedron Lett. 1996, 37, 6635; b) S.
Kyasa, R. N. Meier, R. A. Pardini, T. K. Truttmann, K. T. Kuwata, P. H.
Dussault, J. Org. Chem. 2015, 80, 12100; c) R. Willand-Charnley, B. W.
Puffer, P. H. Dussault, J. Am. Chem. Soc. 2014, 136, 5821; d) C. Fattorusso,
M. Persico, N. Basilico, D. Taramelli, E. Fattorusso, F. Scala, O. Taglialatela-
Scafati, Bioorg. Med. Chem. 2011, 19, 312; e) S.-O. Lawesson, N. C. Yang,
J. Am. Chem. Soc. 1959, 81, 4230; f) D. T. Longone, A. H. Miller,
Tetrahedron Lett. 1967, 8, 4941.
[17] Y. Nobe, K. Arayama, H. Urabe, J. Am. Chem. Soc. 2005, 127, 18006.
[18] a) G.-C. Liu, D. A. Cogan, T. D. Owens, T. P. Tang, J. A. Ellman, J. Org.
Chem. 1999, 64, 1278; b) D. A. Cogan, G.-C. Liu, K.-J. Kim, B. J. Backes, J.
A. Ellman, J. Am. Chem. Soc. 1998, 120, 8011.
[19] a) F. A. Davis, A. J. Friedman, E. W. Kluger, J. Am. Chem. Soc. 1974, 96,
5000; b) F. A. Davis, R. E. Reddy, J. M. Szewczyk, G. V. Reddy, P. S.
Portonovo, H.-M. Zhang, D. Fanelli, R. T. Reddy, P. Zhou, P. J. Carroll, J.
Org. Chem. 1997, 62, 2555; c) F. A. Davis, P. Zhou, B. C. Chen. Chem. Soc.
Rev. 1998, 27, 13.
[20] a) Z. Lei, L. Gao, X. Wu, L.-J. Li, Z.-L. Song, Org. Lett. 2010, 12, 5298; b) J.
Lu, Y.-B. Zhang, Z.-B. Gan, H.-Z. Li, Z.-L. Song, Angew. Chem. Int. Ed. 2012,
51, 5367; Angew. Chem. 2012, 124, 5463; c) Z.-J. Liu, X.-L. Lin, N. Yang,
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202109566
Angewandte Chemie International Edition
RESEARCH ARTICLE
“Old reagent with a new use”: Vinyl magnesium bromide, a
widely used Grignard reagent, can be oxygenated with O2 to
give a magnesium enolate intermediate. This enables a four-
component reaction that efficiently converts chiral N-tert-
butanesulfinyl imine into a wide range of syn-1,3-amino
alcohols in one step.
7
This article is protected by copyright. All rights reserved.