Stereocontrolled Addition of Scrambling ortho-Sulfinyl Carbanions: Easy Access to Homopropargylamines and α-Allenylamines

Article abstract of DOI:10.1021/acs.orglett.0c00625

An unprecedented behavior of ortho-sulfinylpropargyl carbanions in the presence of optically active sulfinylimines affords two different families of compounds: This peculiar chemodivergency is importantly affected by the nature of the employed base, and a

Full text of DOI:10.1021/acs.orglett.0c00625

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Letter
Stereocontrolled Addition of Scrambling ortho-Sulfinyl Carbanions:
Easy Access to Homopropargylamines and α‑Allenylamines
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Balu Cruz-Delgado, Ricardo I. Rodríguez, Anielka Rosado-Abon, Ruben Sanchez-Obregon,
Francisco Yuste,* and Jose Aleman*
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ABSTRACT: An unprecedented behavior of ortho-sulfinylpropargyl carbanions in the presence of optically active sulfinylimines
affords two different families of compounds: this peculiar chemodivergency is importantly affected by the nature of the employed
base, and assisted by the configuration of the electrophile, displaying no alteration in the stereocontrol of both reactions. α-
Allenylamines are formed exclusively, using R-sulfinyl aldimines as electrophiles, while homopropargylamines result when S-sulfinyl
aldimines are employed.
In a different context, the use of optically active sulfoxides as
chiral auxiliaries has been exploited over the last decades; this
exploitation is due to their great stability and high stereo-
control in several synthetic transformations. Over the last
years, our group has highlighted the peculiar behavior of the
ortho-sulfinyl carbanions generated by the use of bases, such as
LDA or diverse MHMDS, toward the stereocontrolled
generation of new C−C single bonds between sterically
hindered nucleophile−electrophile pairs.9 Taking this informa-
tion into account, we considered the possibility of taking
advantage of the delicate equilibrium of ortho-sulfinyl propargyl
carbanions, designing a chemodivergent procedure based on a
remotely controlled activation, to selectively achieve the γ-
functionalization (Scheme 1, pathway A, top) or the ε-
functionalization (Scheme 1, pathway B, bottom) of the
described benzyl-propargyl scaffolds in the presence of the
same electrophile. Sulfinyl aldimines10 were chosen as the
amino source in this process, considering (a) its easy
preparation, (b) their successful use in numerous asymmetric
transformations, (c) the latent possibility of modulating the
chiral information at the S atom, and (d) the facile reported
omopropargyl amines hold a preferred position in
Horganic synthesis, because of their versatility as building
blocks in the synthesis of terpenoid derivatives and other
biologically active compounds.1 Meanwhile, allenyl derivatives
in their optically active form have received great attention in
the synthetic chemistry community, because of their
ubiquitous presence among different natural products and
pharmaceuticals.2 However, the asymmetric construction of
axially chiral allene derivatives and the design of acyclic
molecules containing vicinal quaternary carbon centers
represent some of the most challenging modern synthetic
transformations. Unsurprisingly, a powerful arsenal of strat-
egies that lead to these architectures continuously enriches the
synthetic chemist’s toolbox, as a consequence of its trending
demand. According to the literature,3a the most invoked
methodologies that enable the synthesis of enantio-enriched
allenes consist of the resolution of racemates3 and chirality
transfer from optically pure propargyl derivatives,4 among
others.5 Related to the present work, Yin and co-workers have
described an asymmetric copper-catalyzed alkynylogous aldol
addition of propargyl esters to aldehydes, giving access to the
corresponding enantio-enriched α-allenyl alcohols.6 Regarding
the preparation of homopropargyl amines,7 the most
frequently employed procedures rely on the use of Schiff
bases in the presence of propargyl or allenyl moieties.7 In this
regard, earlier this year, Qiu and Hu8 reported an
enantioselective multicomponent strategy, enabling the prep-
aration of optically active homopropargyl amines.
Received: February 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00625
© XXXX American Chemical Society
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NHMDS, afforded 3a in lower yields (Table 1, entries 2 and
3). In order to gather more information about the role of the
cation (Li, Na, K), 12-crown-4 ether was evaluated as an
additive, recovering the entire unreacted starting materials
(Table 1, entry 4). Interestingly, the use of HMPA afforded 3a,
along with the corresponding allene, as a major product for the
first time (Table 1, entry 5). This result suggested an
important contribution from a plausible association between
the base and the recently generated carbanion,9 favoring the
generation of one product over another. Subsequently, we
decided to change the configuration of the aldimine to the
corresponding (R)-2a, rendering 4a with high diastereoselec-
tivity when LHMDS or KHMDS were used (Table 1, entries 7
and 8), while no conversion with LDA was observed (Table 1,
entry 6). Nevertheless, NHMDS was remarkably efficient, in
terms of yield and diastereomeric ratio (dr) (compare entries 3
and 9 in Table 1), and, to our delight, complete suppression of
3a was observed, showing a synergistic behavior between the
base and the configuration of the imine. With these optimized
conditions in our hands, we proceeded to explore the scope of
the propargylation reaction (see Scheme 2).
As expected, the reaction was proven to work faster when
electron-poor aromatic rings were present in the aldimines (3c,
3d, and 3g), in contrast to electron-rich ones. The
experimental trials disclosed that, when bulkier substituents
were used (3e and 3j), the yield severely diminished,
enhancing the formation of the allenyl adducts. Nonetheless,
the diastereoselectivity remained unaltered in the desired
products. Conversely, the use of a tert-butyl substituted
aldimine suppressed the formation of the target amine. The
reaction conditions also proved to be successful when using an
aliphatic aldimine (n-Pr) leading to 3f, and heterocyclic
substrates also gave good results, giving rise to the products 3h
and 3i. To our delight, compound 3a resulted to be a
crystalline solid that allowed its study by X-ray diffraction
(XRD) in order to elucidate the absolute configuration of the
two stereogenic centers, wherein the α-amino center has the R
configuration and S at the benzylic position. Considering that
the products were obtained under the same reaction conditions
(see the Supporting Information for further details), we
Scheme 1. Proposed Strategy
procedures to remove the chiral auxiliary after transformation,
leading to two different families of amine derivatives.
Despite the brilliant strategies that are currently employed to
synthesize α-allenylamines and homopropargyl amines, the
lack of a general procedure that enables the selective
preparation of each of these skeletons, starting from a common
substrate, encouraged us to design a tunable methodology to
tackle this challenge in a stereoselective fashion. Herein, we
present the first chemodivergent functionalization of aryl
propargyl moieties remotely controlled by a chiral sulfoxide to
the best of our knowledge, which provides efficient access to
two different families of amine-bearing compounds exhibiting
high stereocontrol in both cases.
We started our studies with the optimization of the addition
of alkyne 1 to aldimines 2. In previous reports,9 we have
established the use of LDA as an efficient deprotonating
reagent, triggering the formation of the corresponding benzyl
carbanion. Therefore, we performed the reaction of 1 in front
of aldimine (S)-2a, observing the formation of 3a as the only
product with an extraordinary diastereomeric ratio (Table 1,
entry 1). Considering this result, and aiming to improve the
yield, the temperature was increased. Despite multiple efforts,
any attempt led to complete degradation of the starting
materials, as −78 °C proved to be the optimal temperature to
perform this reaction. Screening different metal−organic bases
with lower coordinative character, namely, KHMDS and
a
Table 1. Optimization of the Reaction
b
Yield (%)
entry
base
LDA
KHMDS
NHMDS
LDA
LDA
LDA
LHDMS
KHMDS
NHMDS
2
additive
3a
67
<20
40
<10
22
0
0
0
0
4a
diastereomeric ratio, dr
1
2
3
4
5
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(S)-2a
(R)-2a
(R)-2a
(R)-2a
(R)-2a
−
−
−
0
0
>98:<2
−
>98:<2
−
90:10
−
90:10
90:10
>98:<2
c
15
0
d
12-crown-4
HMPA
−
−
−
−
e
c
43
0
6
7
8
9
18
45
73
a
b
Reaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), base (0.12 mmol), 0.15 M. Isolated yield is shown in all cases. The diastereomeric ratio of
c
d
e
the major product is indicated and calculated by NMR crude. Epimer of 4a at the sulfur atom (N-S). 12-crown-4 (0.4 mmol). HMPA (0.4
mmol),
B
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a
a
Scheme 2. Scope of the Propargylation Reaction
Scheme 3. Scope of the Allenylation Reaction
a
Reaction conditions: 1 (0.1 mmol), (R)-2 (0.12 mmol), NHMDS
(0.15 mmol), 0.015 M. Isolated yields are shown in all cases, unless
otherwise noted. Diastereomeric ratio (dr) values were measured by
NMR, and the regioisomer ratio (rr) is not indicated; in all cases,
these values were observed to be >50:1. bThe reaction was run in 1.2
mmol scale.
a
Reaction conditions: 1 (0.1 mmol), (S)-2 (0.12 mmol), LDA (0.15
mmol), 0.015 M. Isolated yields shown in all cases, unless otherwise
noted. Diastereomeric ratio (dr) and regioisomer ratio (rr) were
measured via NMR. bReaction was run in 1.2 mmol scale. Yield
c
measured by NMR crude.
In addition, to fulfill the role of the chiral auxiliaries in the
described transformations, the treatment of 3a and 4a
(independently) with t-BuLi furnished the cleavage of the
sulfoxide at the aromatic ring, leading to 5a and 7a,
respectively, in good yield (Scheme 4). Subsequently, the
assumed the same stereocourse of the reaction, and stereo-
chemical outcome for the compounds.
After studying the synthetic scope of the above-described
homopropargylation reaction, we replaced the chiral informa-
tion of the electrophile by inverting the configuration from the
(S)-p-tolylsulfinyl aldimines to their enantiomeric forms: (R)-
p-tolylsulfinyl aldimines. Taking into account the previously
screened parameters, we formed the diastereomeric enriched
allenes. Various aromatic aldimines were shown to undergo the
desired transformation, affording the products with high levels
of diastereoselectivity (Scheme 3). In addition, substrates
containing electron-donating substituents (4b) and electron-
withdrawing substituents (4c and 4g) were tested, proving that
the reaction works smoothly, regardless of the electronic
nature of the aryl motif. Moreover, the use of thienyl and
pyridyl aldimines led to the corresponding allenes 4h and 4i,
showing efficient results overall. Unfortunately, aliphatic
aldimines were found to be unsuitable in this transformation
(4f and 4k), affording only complex reaction crudes. As
previously stated, the use of bulky substituted aromatic rings
produced deleterious results under the quaternization con-
ditions. Therefore, in order to gather more information about
this trend, a 2,6-disubstituted aromatic ring under these
reaction conditions was tested, furnishing product 4j in low
yield, although maintaining high stereocontrol. To our
convenience, suitable crystals of compound 4g were obtained,
allowing the determination of the architecture at the axially
chiral allenes (Ra) and absolute configuration of the new
stereogenic center via X-ray analysis.
Scheme 4. Removal of the Chiral Auxiliaries
acidolysis of the N-sulfinyl group gave the corresponding free
amino group in each case: the homopropargylamine 6a and the
α-allenylamine 8a in excellent yield, without observing erosion
of the optical purity.11
In light of the experimental data presented herein, and
taking into account previously described theoretical eviden-
ce,9c,d we propose a plausible mechanism for the present
asymmetric transformations. The chemodivergent behavior of
the generated benzyl carbanions derived from 1 may be
correlated with the nature of the employed base (LDA vs
NHMDS), unshackling a different disposition of the ortho-
sulfinyl motif at an early transition state, and a “match−
C
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Letter
mismatch” relationship with the N-sulfinylimines. When
lithium diisopropylamide is used, the resulting planar sp2
benzyl carbanion is stabilized by an intramolecular association
with the oxygen atom of the sufoxide (Scheme 5, Pathway A),
the bottom face, avoiding any type of steric hindrance.
Moreover, a plausible π−π stabilization could be contributing
to this model (not feasible in intermediate B), leading to the
formation of diastereoisomer I. This proposal is in accordance
with the observed diminished yields when a bulkier substituent
was employed (see Scheme 2, 3g) and the failure when using
the 2,6-disubstituted aromatic ring 3j and the aliphatic tert-Bu
3k. Regarding the allenylamines, the stereoselectivity can be
explained mainly by a desymmetrization process of the two π-
bonds forming the triple bond produced by the conjugation
with the recently generated carbanion, because only the π-
bond oriented in parallel, with respect to the orbital containing
the lone electron pair, will be suitable to perform a nucleophilic
attack. In order to avoid steric interactions between the
nucleophile and the electrophile, the approach is favored by
the re face of the imine (Scheme 5, intermediate C), leading to
the observed diastereoisomer II. As a complementary reactivity
test, both procedures were performed using the racemic
sulfinylimine ( )-2a as an electrophile. When LDA was used,
the yield of 3a decreased from 67% (as depicted in Scheme 3)
to 30%, isolating unreacted starting material 1 and optically
enriched N-sulfinylimine (−)-2a. In agreement with the
previous observation, NHMDS conducted to the formation
of 4a in 33% yield,12 and, in this case, obtaining optically
enriched (+)-2a with opposite configuration. This fact displays
the importance of the right base−imine combination to
achieve the targeted amine selectively.
Scheme 5. Proposed Stereochemical Outcome of the
Reactions
To conclude, we have developed a stereocontrolled
chemodivergent strategy that selectively enables the generation
of propargylic or allenylic intermediates, starting from a
common substrate in front of optically active sulfinylimines.
The nature of the employed base proved to be crucial to
trigger one activated species over another, because the
configuration of the imine played a synergistic role to enhance
the diastereoselectivity in the presented transformations. This
method represents an elegant approach for the synthesis of two
different families of amino compounds and is intended to
inspire the development of new procedures to extend its scope
and complete its limitations.
thus generating a coordination through the O[LDA]+
benzyl carbanion, that blocks the upper face of the planar
system, favoring the approachment of the aldimines from the
bottom face, as it was previously supported by DFT
calculations.9c In the case where NHMDS is used, the resulting
“naked” anion, is prompted to delocalize more easily
(compared to the coordination proposal) throughout the
aromatic ring and the triple bond system (Scheme 5, Pathway
B). Therefore, the more compromised the charge is, the less
reactive the anion will be. Because of this high conjugation
phenomenom, the so-called “scrambling” anion is observed,
enabling two activated sites, the propargylic C(sp3) and the
alkynylic Cβ(sp), with the latter one being more prompt to
perform the nucleophilic attack on the “matched” imine. This
previous statement can be supported with the fact that, when
using HMPA as an additive and LDA as a base, the major
product of the reaction was the allenyl derivative. However, the
dr was not entirely satisfactory, because of the “mismatched”
imine used (recall Table 1, entry 5).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00625.
Experimental details, supplementary figures, character-
1
ization of H and 13C spectra for all compounds and X-
ray data for 3a and 4g (PDF)
Accession Codes
CCDC 1969083 and 1969084 contain 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.
AUTHOR INFORMATION
Corresponding Authors
■
Regarding the high stereoselectivity observed for both
families of products, we propose that, in the case of the
homopropargyl amines (as shown in Scheme 5, intermediate
A), the nucleophilic attack is executed by the si face of the
aldimine, as the tolyl group of the electrophile is oriented at
́
Francisco Yuste − Instituto de Quımica, Universidad Nacional
́
́
Autonoma de Mexico, Circuito Exterior, Cd. Universitaria,
́
04510 Mexico City, Mexico; orcid.org/0000-0002-0145-
0009; Email: yustef@unam.mx
D
https://dx.doi.org/10.1021/acs.orglett.0c00625
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
assisted conditions. Chem. Commun. 2010, 46, 213−215. (d) Yang,
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́
́
́
́
Jose Aleman − Departamento de Quımica Organica (Modulo-
1) and Institute for Advanced Research in Chemical Sciences
́
(IAdChem), Universidad Autonoma de Madrid, 28049
Madrid, Spain; orcid.org/0000-0003-0164-1777;
Email: jose.aleman@uam.es; www.uam.es/jose.aleman
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Authors
́
́
Balu Cruz-Delgado − Instituto de Quımica, Universidad
Nacional Autonoma de Mexico, Circuito Exterior, Cd.
Universitaria, 04510 Mexico City, Mexico
Ricardo I. Rodríguez − Departamento de Quımica Organica
(Modulo-1), Universidad Autonoma de Madrid, 28049
Madrid, Spain; orcid.org/0000-0003-3846-8154
Anielka Rosado-Abon − Instituto de Quımica, Universidad
Nacional Autonoma de Mexico, Circuito Exterior, Cd.
Universitaria, 04510 Mexico City, Mexico
Ruben Sanchez-Obregon − Instituto de Quımica, Universidad
Nacional Autonoma de Mexico, Circuito Exterior, Cd.
Universitaria, 04510 Mexico City, Mexico
́
́
́
́
́
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M.; Bannwarth, C. Catalytic Deracemization of Chiral Allenes by
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00625
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank DGAPA-UNAM (Project No. PAPIIT-IN205319)
for financial support. B.C.D. thanks CONACYT for a graduate
■
́
fellowship (Grant No. 335839) and R.I.R. thanks Fundacion
Carolina for a graduate fellowship. We also thank M. C. Garcia
́
́
Gonzalez, R. Gavino, R. Patino, M. A. Pena, and R. A. Toscano
̃ ̃ ̃
for their technical assistance (all from UNAM). We are grateful
to the Spanish Government (No. RTI2018-095038-B-I00),
“Comunidad de Madrid” and European Structural Funds (No.
S2018/NMT-4367).
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(11) Steps order of the transformation was inverted, looking for the
best global yield from 3a and 4a to 6a and 8a, respectively. It was
found that the most suitable order is the one presented in the
manuscript in terms of yield. Note that, in both cases, the
diastereoselectivity is preserved.
(12) Standard conditions were employed when performing these
tests (0.1 mmol of 1, and 0.12 mmol of rac-2a). It was possible to
recover the unreacted 2a after flash column chromatography, in both
cases with optical rotation nearly to the optically pure N-sulfinylimine,
indicating that a kinetic resolution process has occurred. See: Davis, F.
A.; Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S. Tetrahedron Lett.
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