Stereoinversion of Unactivated Alcohols by Tethered Sulfonamides

Article abstract of DOI:10.1002/anie.201812894

The direct, catalytic substitution of unactivated alcohols remains an undeveloped area of organic synthesis. Moreover, catalytic activation of this difficult electrophile with predictable stereo-outcomes presents an even more formidable challenge. Described herein is a simple iron-based catalyst system which provides the mild, direct conversion of secondary and tertiary alcohols to sulfonamides. Starting from enantioenriched alcohols, the intramolecular variant proceeds with stereoinversion to produce enantioenriched 2- and 2,2-subsituted pyrrolidines and indolines, without prior derivatization of the alcohol or solvolytic conditions.

Full text of DOI:10.1002/anie.201812894

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Accepted Article
Title: Stereoinversion of Unactivated Alcohols by Tethered
Sulfonamides
Authors: Silas Cook, Paul T. Marcyk, Latisha R. Jefferies, Deyaa I.
AbuSalim, Maren Pink, and Mu-Hyun Baik
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812894
Angew. Chem. 10.1002/ange.201812894
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10.1002/anie.201812894
Angewandte Chemie International Edition
COMMUNICATION
Stereoinversion of Unactivated Alcohols by Tethered
Sulfonamides
Paul T. Marcyk, Latisha R. Jefferies, Deyaa I. AbuSalim, Maren Pink, Mu-Hyun Baik* and Silas P.
Cook*
Abstract: The direct, catalytic substitution of unactivated alcohols
remains an undeveloped area of organic synthesis. Moreover,
catalytic activation of this difficult electrophile with predictable
stereooutcomes presents an even more formidable challenge.
Described here is a simple iron-based catalyst system which provides
a mild, direct conversion of secondary and tertiary alcohols to
sulfonamides. Starting from enantioenriched alcohols, the
intramolecular variant proceeds with stereoinversion to produce
enantioenriched 2- and 2,2-subsituted pyrrolidines and indolines—
without prior derivatization of the alcohol or solvolytic conditions.
be substituted with a wide range of nucleophiles,[12] unactivated
alcohols remain a significant challenge.[13] Recently, we reported
an iron-catalyzed intramolecular Friedel-Crafts arylation of
unactivated secondary alcohols that proceeds with chirality
transfer.[14] We sought to translate this system into a general
conceptual framework for the direct amination of alcohols.
Scheme 1. An Ion-Pair Approach to Enantioselective Substitution.
The interconversion of functional groups represents an
archetypal operation in organic synthesis. These transformations
can leverage the reactivity of a common functional group to install
a new, more valuable motif. Classic examples include the SN2 and
SN1 reactions (Scheme 1). While the SN2 proceeds
stereospecifically with inversion of configuration,[1] the SN1
reaction, due to the carbocation intermediate, generally proceeds
with loss of stereochemistry.[2] Chemists have gone to great
lengths to control the facial selectivity of nucleophile attack on the
carbocation through the use of enantioenriched catalysts.[3]
Transferring the stereochemical information of the starting
electrophile that undergoes an ionization event remains a
challenge.[4] Here we demonstrate that secondary and tertiary
alcohols can be used directly as electrophiles with inversion of
stereochemistry when displaced with tethered sulfonamides.
Due to their ubiquity and stability, aliphatic alcohols are
attractive electrophiles for functional group interconversion. The
2018 ACS Green Chemical Institute Pharmaceutical Roundtable
highlighted the activation of alcohols for nucleophilic substitution
as a key reaction in need of development.[5] Conventional
methods for alcohol substitution often involve converting the
In certain limited cases, enantioenriched secondary
alcohols can be utilized directly to transfer chiral information to
new carbon-heteroatom bonds. For example, Samec and co-
workers used a Brønsted acid catalyst to control the facial
approach of the nucleophile for a stereoinvertive dehydrative
cyclization.[15] Inverting free tertiary alcohols for this type of
substitution, however, remains problematic. Solvolysis represents
the only successful approach to transfer the chirality of tertiary
electrophiles to the substituted product.[16] Moreover, the starting
alcohol to
a halide or pseudohalide before nucleophilic
alcohols must be activated as
a
nitrobenzoyl ester,[17]
substitution or employ the Mitsunobu reaction.[6][7] Direct, catalytic
activation of alcohols for substitution is an attractive approach to
form carbon-heteroatom bonds because water is the only
stoichiometric byproduct. One approach is the Lewis or Brønsted
acid-promoted SN1 substitution[8] of benzylic,[9] allylic,[10] and
propargylic[11] alcohols. While π-activated or tertiary alcohols can
alkoxydiphenyl phosphine,[18] or trifluoroacetate[4] to permit
ionization. While a substitution of an unactivated tertiary alcohol
exists, in studies of α-tocopherol, this too proceeds under
solvolytic conditions.[19] The direct substitution of unactivated
tertiary alcohols with nitrogen nucleophiles would represent a
major advance in this field; providing access to α-tertiary chiral
amine products—an amine class that currently necessitates
lengthy synthetic sequences.[20] Here, we report an iron-catalyzed
system capable of directly substituting aliphatic alcohols as well
as the stereoinvertive, intramolecular substitution of chiral
secondary and tertiary alcohols by sulfonamide nucleophiles.
To gain insight into the reactivity of unactivated alcohols in
an amination reaction, we began our investigation by treating
cyclohexanol with p-toluenesulfonamide in the presence of select
acid catalysts (see Supporting Information). Iron(II) or iron(III)
salts alone proved ineffective in this difficult transformation.
Consistent with the enhanced Lewis acidity of Fe(III) salts
containing “non-coordinating” counterions,[14, 21] the combination
[a]
[b]
P.T. Marcyk, Dr. L. R. Jefferies, D. I. AbuSalim, Dr. M. Pink, Prof.
Dr. S. P. Cook
Department of Chemistry, Indiana University
800 East Kirkwood Avenue, Bloomington, IN 47405 (United States)
E-mail: sicook@indiana.edu
D. I. AbuSalim, Prof. Dr. M.-H. Baik
Department of Chemistry,Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141 (Republic of Korea)
and
Center for Catalytic Hydrocarbon Functionalizations, Institute
forBasic Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail:mbaik2805@kaist.ac.kr
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201812894
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of iron(III) chloride with AgSbF6 in 1,2-dichloroethane at 80 °C for
24 hours afforded the desired amination product in 78% yield (see
SI). Three equivalents of AgSbF6 relative to iron proved superior
to fewer equivalents, consistent with the exchange of all three
chlorides for hexafluoroantimonate ions. Brønsted acids,
including HSbF6, produced low yield, thereby providing support
and consumption of alkene, suggesting an E1 elimination
followed by hydroamination of the alkene as an alternative and
competing pathway to the substitution.[23] In addition to p-
toluenesulfonamide, p-nitrobenzenesulfonamide also functioned
well as the nucleophile, providing an easily removable nosyl
protecting group in product 2g, while methanesulfonamide
for an iron-based Lewis acid as the primary activator of the alcohol. provided 2h in 71% yield. Efforts to extend this methodology to
However, select bases (e.g., Cs2CO3, K2CO3, and 2,6-di-tert-
butyl-4-methylpyridine) did measurably lower the yield,
suggesting some background Brønsted acid catalysis (see SI).
other nitrogen nucleophiles such as carbamates, amides, anilines,
and aliphatic amines were unsuccessful potentially due to
competitive iron coordination to nitrogen. Primary alcohols proved
difficult. While phenethylalcohol (1k) functions well in the reaction,
likely through anchimeric assistance,[24] other primary alcohols
resulted in low yields (data not shown). Conversely, tertiary
alcohols were excellent substrates, affording the amination
products in good (2l-m)-to-near quantitative yields (2n). Contrary
to primary and secondary alcohols, tertiary alcohols worked better
at lower temperature or without the use of AgSbF6.
Table 1. Substrate Scope for the Intermolecular Alcohol
Substitution with Sulfonamides.
While the intermolecular amination of secondary alcohols
resulted in racemic products, we hypothesized that an
intramolecular amination of enantioenriched alcohols would
proceed rapidly to provide access to stereodefined pyrrolidines
and indolines, a motif present in many natural products and bio-
active molecules.[25] Current methods to set this difficult
stereocenter[26] involve enantioselective hydroaminations,[27]
asymmetric hydrogenation,[28] and kinetic resolutions,[29] all of
which rely on chiral catalysts. Other approaches required the
prefunctionalization of chiral alcohols[30] We found that the
intramolecular substitution of enantioenriched secondary alcohols
proceeded with high yield and enantiospecificity, transferring
chirality to the formed pyrrolidine ring (Table 2). The reactions did
not proceed with Brønsted acids instead of iron and were not
inhibited by exogenous bases, in contrast to the intermolecular
variants.
The scope of the intramolecular substitution of chiral
secondary alcohol was explored by varying the alcohol sidechain.
Simple chains such as methyl in 3a and n-propyl in 3b formed the
2-substituted pyrrolidine with excellent yield and 96% es. Alcohols
with larger sidechains, such as 2-methylpropyl in 3c, performed
better with complete chirality transfer to form 4c. The benzylic
alcohol in 3d formed the desired pyrrolidine product 4d as a
racemic mixture due to formation of the stabilized benzylic
carbocation. Enantioenriched 2-substituted indolines were also
accessible with this method, Once again, simple alkyl groups such
as methyl in 3e and ethyl in 3f proved high yielding with high levels
of enantiospecificity even on gram scale. The electronic
properties of the nitrogen nucleophile could be modified with
electron-donating or -withdrawing groups on the aniline without
reducing the enantiospecificity of the reaction. The reaction
tolerated remote functional groups. For example, the inclusion of
a primary bromide in 3i or tosylate in 3j proceeded well to provide
a synthetic handle for further functionalization. Furthermore, the
tosyl group can be efficiently removed affording the deprotected
indoline product without racemization (see SI).[31] Extending this
methodology to six-membered piperadine rings produced an
inseparable mixture of six- and five-membered products—arising
from a rapid carbocation rearrangement (see SI).
[a] Isolated yields. [b] 4-Nitrobenzenesulfonamide nucleophile used. [c]
Methanesulfonamide nucleophile used. [d] 1:1 Mixture of 2 and 3 substituted
product. [e] FeCl3 only.
With suitable conditions for the amination of cyclohexanol
1b, we next evaluated the performance of the intermolecular
reaction across a variety of aliphatic alcohols. We were pleased
to find that cyclic and symmetric acyclic secondary alcohols
resulted in the desired amination products in moderate-to-good
yields (2a-f, Table 1). Unfortunately, 2-hexanol (1j) resulted in a
1:1 mixture of 2 and 3 substituted products 2j, suggesting a facile
carbocation rearrangement.[22] To test whether the intermolecular
reaction proceeds with stereoinversion, enantioenriched (R)-2-
butanol (1i) was subjected to the reaction conditions and provided
racemic product 2i, possibly due to background Brønsted acid
catalysis. Reaction monitoring by GC/MS indicated the formation
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10.1002/anie.201812894
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Table 2. Intramolecular Stereoinvertive Substitution of Secondary Alcohols.
with the reactions conditions. While the triisopropylsilyl (TIPS)
group in 5h group proved stable to the reaction conditions, the
tert-butyldimethyl silyl (TBS) group for 5i was partially deprotected
over the course of the reaction. In all, Table 3 presents an
expeditious route to 2,2-disubstituted indolines with serviceable
ee and good yields—a previously challenging and labor-intensive
synthetic endeavor.
Table 3. Intramolecular Stereoinvertive Substitution of Tertiary Alcohols.
[a] Isolated yields. Enantiomeric excess determined by chiral HPLC analysis.
Since the intramolecular substitution of secondary alcohols
proceeded in high yield and enantiospecificity, we suspected that
enantioenriched tertiary alcohols could be substituted via a non-
racemic mechanism. We reasoned that the developing tertiary
carbocation could be attacked from the face opposite of the
departing alcohol, resulting in chirality transfer. To intercept a
tertiary carbocation with minimal racemization under non-
solvolytic conditions, the iron-ate/carbocation ion pair needs to be
tightly associated to block one face of the carbocation (Scheme
2b).[32] We reasoned that a solvent with lower dielectric constant
combined with decreased reaction temperature would fortify the
ion pair and favor stereoinversion. To our delight, decreasing the
reaction temperature to –40 ºC and switching the solvent to
toluene produced the enantioenriched 2,2-disubstituted indoline
products (Table 3). Indoline 6a with alkyl side chains was formed
in 79% ee—transferring 89% of the chiral information from starting
alcohol 5a. The electronic properties of the sulfonamide
nucleophile could be altered by placing an electron-withdrawing
or -donating group at the para position of the aniline ring.
Attenuating the nucleophilicity with electron-withdrawing groups,
such as CF3 in 5c or F in 5d, decreased both the yield and the
enantiospecificity of the reaction. The more electron-rich
nucleophile in 5e had little effect on the reaction. In addition to
alkyl side chains, electron-rich aromatic rings (5f and 5g) also
proceeded with good es. Silyl protected phenols were compatible
[a] Isolated yields. Enantiomeric excess determined by chiral HPLC analysis. [b]
Reaction run in (5:1) toluene:DCE. [c] Phenol of 5i is protected with TBS. Reaction
yielded a mixture of TBS protected and deprotected phenol. Mixture converted to
the 6i with TBAF (1 equiv).
To determine whether the reaction proceeds with inversion
of stereochemistry, the absolute configuration of enantioenriched
alcohol 3i and the resulting indoline ring 4i were assigned by X-
ray crystallography (Scheme 2a). Alcohol 3i crystalized readily
and assigned the (R) configuration. Pentabromophenol-derived
indoline 7, however, had the (S) configuration, thereby confirming
that the intramolecular substitution of secondary alcohols
proceeds with stereoinversion. For the intramolecular substitution
of tertiary alcohols, our model predicts stereoinversion. The
departing iron-hydroxide would block the front face of the
carbocation favoring rapid attack of nitrogen from the opposite
face (Scheme 2b). The stereochemistry of tertiary alcohol 5a was
confirmed (R)- configuration by X-ray crystallography. However,
since an X-ray-suitable crystal for indoline product 6a remains
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unrealized, an asymmetric benzylation of D-alanine derivative 8
followed by a seven-step sequence produced (R)-6a (Scheme 2c
and SI),[33] a testament to the limitations of current methods to
prepare α-tertiary chiral amines. Indoline product 6a was
determined to be in the (S) configuration, thereby confirming the
intramolecular substitution of tertiary alcohols also proceeds with
stereoinversion.
steps than current technology allows. By rapidly intercepting ion
pairs, we have leveraged an unconventional tactic to form the
Csp3–N bond with predictable stereochemical outcomes.
Scheme 3. Computed Free-Energy Diagram for the Intramolecular Substitution
of 3a.
Acknowledgements
We acknowledge Indiana University for partial support. We also
acknowledge the NSF CAREER Award (CHE-1254783), Lilly
Grantee Award, and Amgen Young Investigator Award. P.T.M. was
supported by the Graduate Training Program in Quantitative and
Chemical Biology (T32 GM109825).
Scheme 2. Stereochemical model and absolute configuration for the
intramolecular substitution of (a) secondary alcohols (b) tertiary alcohols. (c)
Absolution configuration determination for indoline product 6a via an asymmetric
benzylation of D-alanine derivative 8.
To help elucidate whether Fe(SbF6)3 is the active iron
catalyst, we employed density functional theory calculations
(Scheme 3 and SI). We focused on the stereoinversion step for
3a with the alcohol bound to FeCl3, Fe(SbF6)Cl2, Fe(SbF6)2Cl,
and Fe(SbF6)3. The lowest barrier for C–N bond formation (I-TS)
was 26.4 kcal/mol with Fe(SbF6)3. This finding is consistent with
our experimental data—where no reaction occurs in the absence
of AgSbF6, and the best yields were obtained with three
equivalents relative to Fe (see SI). These calculations show that
the residual reactivity observed with fewer than three equivalents
of AgSbF6 is likely due to an equilibrium that includes Fe(SbF6)3—
the relevant, active catalyst.
In conclusion, we have developed a mild and efficient iron-
catalyzed substitution of unactivated alcohols with sulfonamide
nucleophiles. This methodology allows efficient access to
secondary and tertiary alkyl sulfonamides from readily available
alcohols. Furthermore, the intramolecular variant of the reaction
proceeds with inversion of stereochemistry. By employing the
concept of tight-ion pairing as a solution to cation facial
selectivity, this method represents a rare example where
secondary and even tertiary alcohols react with an achiral
catalyst to transfer the chiral information to the products under
non-solvolytic conditions. This method enables efficient access
to enantioenriched 2,2-disubstiuted indoline products in far fewer
Conflicts of Interest
The authors declair no conflicts of interest.
Keywords: Alcohol Substitution • Indoline • Iron • Asymmetric •
Sulfonamide
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Employing a simple
iron catalyst, the
direct conversion of
secondary and tertiary
alcohols to
Paul T. Marcyk, Latisha R. Jefferies, Deyaa I. AbuSalim,
Maren Pink, Mu-Hyun Baik* and Silas P. Cook*
Page No. – Page No.
Stereoinversion of Unactivated Alcohols by Tethered
Sulfonamides
sulfonamides is
reported. Starting
from enantioenriched
alcohols, the
intramolecular variant
proceeds with
stereoinversion to
produce
enantioenriched 2-
and 2,2-subsituted
pyrrolidines and
indolines—without
prior derivatization of
the alcohol or
solvolytic conditions.
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