Intramolecular substitutions of secondary and tertiary alcohols with chirality transfer by an iron(III) catalyst
Intramolecular substitutions of secondary and tertiary alcohols with chirality transfer by an iron (III) catalyst
Rahul A. Watile
Anon Bunrit Srijit Biswas
Joseph S.M. Samec
Optically pure alcohols are abundant in nature and attractive as feedstock for organic synthesis but challenging for further transformation using atom efficient and sustainable methodologies, particularly when there is a desire to conserve the chirality. Usually, substitution of the OH group of stereogenic alcohols with conservation of chirality requires derivatization as part of a complex, stoichiometric procedure. We herein demonstrate that a simple, inexpensive, and environmentally benign iron(III) catalyst promotes the direct intramolecular substitution of enantiomerically enriched secondary and tertiary alcohols with O-, N-, and S-centered nucleophiles to generate valuable 5-membered, 6-membered and arylfused 6-membered heterocyclic compounds with chirality transfer and water as the only byproduct. The power of the methodology is demonstrated in the total synthesis of (+)-lentiginosine from D-glucose where iron-catalysis is used in a key step. Adoption of this methodology will contribute towards the transition to sustainable and bio-based processes in the pharmaceutical and agrochemical industries.
F substituting the OH group in stereogenic alcohols is a major
inding efficient and atom-economical strategies for directly
challenge in synthetic organic chemistry1–4. Traditional
methods are usually multistep and rely on the use of hazardous
reagents in stoichiometric amounts, often leading to tedious
purifications5,6. An example of the state-of-the-art
transformations is the Mitsunobu reaction7, which is based on the
stoichiometric use of an azodicarboxylate and triphenylphosphine.
Alternative methodologies are, therefore, searched for and
particularly the direct substitution of non-derivatized alcohols has
long been viewed as one of the most desired chemical
transformations for which pharmaceutical companies want greener
alternatives8–10. As potential applications for direct substitution
of alcohols are found in both pharmaceutical and agricultural
products, where only one of the enantiomers has the desired
biological effect, a special emphasis on stereoselective and
stereospecific substitutions has been given10. The main benefits with
a direct substitution are atom economy, one-step procedure, less
reagents, and non-derivatized intermediates.
Whereas direct substitutions of the OH group in alcohols has
been achieved through an SN1-type mechanism and these
reactions have been thoroughly explored in the past decades11,
reports on plausible highly stereoselective SN2-like reactions are
relatively rare11–13. Only recently have SN2′-type reactions been
reported for gold-catalyzed and palladium-catalyzed
intramolecular amination and etherification reactions of stereogenic allylic
alcohols (Fig. 1a)14–21. However, these reactions are substrate
dependent and if the double bond and OH group was
juxtapositioned, the reactivity collapsed (Fig. 1b)22,23. In this context, we
recently achieved direct intramolecular SN2-like reaction of
underivatized stereogenic alcohols to generate heterocycles by
using a phosphinic acid catalyst, that reaction was limited to
secondary alcohols, strong nucleophiles, and substrates giving
kinetically and thermodynamically favored five-membered
products (Fig. 1c)1,24.
The substitution of the OH group in enantioenriched tertiary
alcohols with chirality transfer is even more challenging,
nevertheless very important as many biologically active compounds
have tertiary structures25,26. As state of the art, a substitution with
transfer of chirality was only achieved via in situ derivatization of
alcohols to trifluoro acetate derivatives (Fig. 1d) (Terminology of
such transformation is not settled by the community and both
stereospecific and chirality transfer are used. In this article,
chirality transfer will be used.) Interestingly, it was found that the
protocol was chemoselective for tertiary alcohols over secondary
and primary alcohols27.
Despite these recent advances emphasized above, there are no
reported methods on either the synthesis of non-allylic
sixmembered heterocyclic compounds through intramolecular
substitution of the OH group or the direct intramolecular substitution
of tertiary alcohols with chirality transfers, or the use of substrates
containing weak nucleophiles (such as phenolic OH)28. In order to
offer a synthetic route to overcome these limitations, we continued
our efforts on acid-catalyzed transformations and report herein a
Au and Pd catalysis
Limited substrate scope
cat. Fe(OTf)3, MS (3Å)
R1 = aryl, alkyl, propargyl, alkyl
R2 = aryl, alkyl, H
X = –NAr,–O, –S
up to 99% yield
80–99% chirality transfer
Fe(OTf)3-catalyzed intramolecular substitution of enantioenriched
secondary and tertiary alcohols by N-, O- and S-centered
nucleophiles with high degree of chirality transfer. Accordingly,
this approach gives a high yield route to enantioenriched
pyrrolidine, tetrahydrofuran, tetrahydrothiophene,
1,2,3,4-tetra-hydroquinoline, and chromane derivatives that are core structures found
in several biologically active compounds important for
pharmaceutical and agricultural industries (Fig. 1e).
Screening of Lewis acid catalysts and reaction conditions. For
the initial screening of chirality transfer, we selected
4-((4-methoxyphenyl)amino)-1-phenylbutan-1-ol (1a) (Table 1) as a model
substrate for the intramolecular substitution reaction to yield
1-(4methoxyphenyl)-2-phenylpyrrolidine (2a). The p-methoxyphenyl
(PMP) group was introduced on the nitrogen to enhance its
nucleophilicity and thus facilitate the substitution reaction. In
addition, the PMP has further synthetic advantages because it can
be removed after the reaction if desired (Fig. 2)29,30.
Initially, the catalytic reactivity and chirality transfer of
different Lewis acids were screened with model compound 1a,
from those oxophilic iron-based catalysts gave higher yields and
chirality transfers than other Lewis acids in this series
(Supplementary Table 2). (Chirality transfer is determined as
percentage of conserved ee.) In further studies, the most Lewis
acidic complex, Fe(OTf)3, was found to be the most efficient
catalyst for the transformation, and it gave desired pyrrolidine 2a
in 62% yield (Table 1, entry 12). Accordingly, high Lewis acidity
is crucial for activating the C–O bond towards nucleophilic attack
and the counter ion had a profound effect on both the yield and
the chirality transfer (Table 1, entries 1–12). To further improve
the efficiency of the reaction, different additives were studied. As
a result, the addition of molecular sieves (MS) (3 Å) improved
both the yield and chirality transfer of the transformation (Table
1, entry 14). A control reaction showed that the MS did not
promote the reaction in the absence of Fe(OTf)3 (Table 1, entry
15). The role of the MS is to suppress hydrolysis of Fe(OTf)3
species by generated water and thus prevent catalyst deactivation.
The influences of solvent and reaction temperature were also
studied. The optimal solvent was found to be 1,2-dichloroethane
(DCE) in terms of both reactivity and chirality transfer
(Supplementary Table 3). We observed a correlation between
conversion and the reaction temperature up to 90 °C, but further
increases in the temperature decreased the chirality transfer
(Table 1, entry 13). Thus, using 10 mol% Fe(OTf)3 in DCE at
90 °C generated 2a in a quantitative yield with 99% chirality
transfer (Table 1, entry 14). Based on the results above, the Fe
(OTf)3 catalyst have a well-tuned reactivity where the C–O bond
is activated for nucleophilic attack. Notably, under optimized
conditions the C–O bond is cleaved in the presence of an
intramolecular nucleophile leading to chirality transfer.
Synthesis of (+)-lentiginosine. After determining the optimized
reaction conditions, we investigated the substrate scope. N-, O-,
and S-centered nucleophiles were utilized in the intramolecular
substitution of various enantioenriched benzylic alcohols with
chirality transfer to generate five-membered heterocyclic
derivatives (Fig. 3). Substrates with N-, O-, and S-centered nucleophiles
generated products in excellent yields and with high chirality
transfers (Fig. 3a, entries 2a–2j). We extended our studies to
nonbenzylic alcohols. As mentioned in the “Introduction” section,
allylic alcohols, where the nucleophile cannot protonate
the leaving OH group, were not tolerated by previous protocols
(Fig. 1b)24,25. Overcoming the restrictions of previous strategies,
using the iron catalyst we found allylic alcohol 1k furnished 2k in
79% yield and 89% chirality transfer with the iron catalyst (Fig.
3a, entry 2k). Interestingly, the present method was appropriate
for less reactive propargyl alcohol 1l, generating enantioenriched
2-(phenylethynyl)tetrahydrothiophene (2l) in a 98% yield and
91% chirality transfer (Fig. 3a, entry 2l).
Next, we examined non-activated alkyl alcohols. For the reaction
to proceed with less reactive aliphatic alcohols, the reaction
temperature was increased to 100 °C. The N-centered nucleophiles
1m and 1n generated enantioenriched
2-methyl-1phenylpyrrolidine (2m) and 2-ethyl-1-phenylpyrrolidine (2n),
respectively, in good yields and with high degrees of chirality
transfer (Fig. 3a, entries 2m and 2n). This result is notable as to
date, only a few methods are available for direct nucleophilic
substitution of non-activated aliphatic alcohols, and those reactions
proceed through SN1 pathways to give racemic products31–37. One
challenge with aliphatic alcohols compared to π-activated alcohols is
that competing elimination processes can occur.
To demonstrate the utility of the intramolecular substitution
reaction with chirality transfer, we completed the total synthesis
of (+)-lentiginosine38 (8, Fig. 2) from optically pure D-glucose.
The key step in the synthesis was the intramolecular substitution
of 4 in the presence of Fe(OTf)3 to furnish 5 (Fig. 2) in 99% yield
with complete inversion of configuration (100% chirality
transfer). The removal of PMP from optically pure 5 using
CAN gave 6 in 82% yield without erosion of the enantiomeric
excess. Subsequent N-allylation afforded 7, which smoothly
underwent ring closing metathesis. The metathesis product was
hydrogenated to afford (+)-lentiginosine (8). Thereby, we have
prepared (+)-lentiginosine in only 10 steps from the most
available natural building block D-glucose and thus we have
shortened the synthetic route considerably from previously
reported (18 steps)39.
Formation of six-membered heterocycles. Although with the
substrates above, there was only gradual improvement in
Intramolecular substitution of secondary alcohols with chirality transfer; 6-membered
Intramolecular substitution of tertiary alcohols with chirality transfer
Intramolecular substitution of secondary alcohols with chirality transfer; 5-membered
EtOH, 70 °C
NaCNBH3, 70 °C
i) Grubbs (II), p-TsOH,
toluene, 100 °C, 70%
ii) Pd(OH)2, H2, 3N HCI
MeOH, rt, 75%
reactivity and selectivity in comparison to our previous
phosphinic acid studies, with Fe(OTf)3 catalyst we were able to extend
the substrate scope markedly. In the present study, six-membered
and aryl-fused six-membered heterocyclic compounds can be
generated in excellent yields with good chirality transfers. This
class of heterocyclic compounds are prevalent in pharmaceuticals
and agrochemicals and their synthesis through direct catalytic
substitution with chirality transfer is not reported in literature. In
these cases, longer reaction times were required to obtain good
yields and chirality transfers (Fig. 3b, entries 2o–2p).
Furthermore, substrates containing poor nucleophiles (phenolic-O
nucleophiles) showed full conversion and good chirality transfers
(Fig. 3b, entries 2q–2r). Notably, this is the first time a
nonactivated phenol has been used as a nucleophile in the
substitution of an OH group with transfer of chirality.
Substitution reactions of underivatized tertiary alcohols.
Prompted by the good results achieved with secondary alcohols,
the more challenging tertiary alcohols were next examined.
Substitution reactions of tertiary alcohols with chirality transfer
have all, to date, required a stoichiometric-activating agent to
promote the substitution5,6, and furthermore, the substitution
reactions have been restricted with respect to nucleophiles. We
report here a range of six-membered heterocyclic compounds
produced from underivatized tertiary alcohols in excellent yield
and with high chirality transfer (see Fig. 3c).
We initially performed the intramolecular substitution of
Ncentered enantioenriched tertiary alcohol 1s using the same
reaction conditions as were used for secondary alcohols. While
the yield of 2s was quantitative, the chirality transfer was low
(Supplementary Table 3, entry 1, c.t. 9%). The key to achieving
high chirality transfer turned out to be decreasing the polarity of
the solvent system. By using a mixture of n-hexane and DCE, as
well as optimizing the temperature and time (Supplementary
Table 3) the chirality transfer was increased to 98% (Fig. 3c, entry
4a). This is the first example of a substitution reaction of the OH
group of a tertiary alcohol with chirality transfer without prior
We were also able to apply this protocol to tertiary alcohols
containing weak nucleophiles. Substrate 1t, having a phenolic
Onucleophile, provided full conversion, albeit initially only
moderate chirality transfer. Lowering the temperature of the
reaction to −15 °C increased the chirality transfer of the reaction
while still providing full conversion (Fig. 3c, entry 2t). Finally, we
investigated sterically hindered and easily dehydrated aliphatic
tertiary alcohols in the intramolecular nucleophilic substitution
reaction (Fig. 3c, entries 2u and 2v). These are very challenging
substrates known to undergo elimination reactions and chosen to
demonstrate any limitations of the reaction. Aliphatic tertiary
alcohols 1u and 1v generated 2-methyl-2-(4-methylpentyl)
chromane (2u) in 92% yield and 85% chirality transfer and
(S)2-methyl-2-(4-methylpentyl)thiochromane (2v) in 90% yield and
99% chirality transfer, respectively (Fig. 3c, entries 2u and 2v).
This is noteworthy where for substrate 2u, the combination of a
tertiary alcohol prone to undergo elimination with an extremely
poor nucleophilic phenol generates products in high chirality
transfers. The product resembles the core of Vitamin E, and thus
has biological significance. As shown above, the inherent property
of Fe(OTf)3 to activate underivatized and tertiary alcohols opens
a truly attractive and general approach to synthesize
fivemembered, six-membered, and aryl-fused six-membered
heterocyclic compounds in excellent yield and with high chirality
Mechanistic studies. The intramolecular substitution reactions
reported here could, theoretically, proceed by a spectra of SN1- or
SN2-like reaction mechanisms, but to distinguish them is
challenging. The electrophile, or the nucleofuge in this work, can
directly be substituted in an SN2-like pathway or can be ionized in
a rate-limiting step without nucleophilic assistance proceeding
through an SN1 pathway. In addition, a substitution of
nucleofuges can occur with different pathways, including
nucleophileassisted ionization, contact ion pair, solvent-separated ion pair,
and free carbocation40. As a result, mechanistic spectra can be
very complex.41–46 In general, rate order and chirality transfer are
used to distinguish between SN1 and SN2 reaction pathways1,47,
but the intramolecular substitution reactions set inherent
limitations. Firstly, the rate order is not possible to measure because
the electrophile and nucleophile are present in the same molecule,
and therefore, it is impossible to vary the concentration of the
individual species. To meet this challenge, we synthesized
substrate analogs with two equivalent nucleophiles in the molecule,
as detailed below. Secondly, using the chirality transfer to draw
conclusions about the reaction mechanism is not straightforward,
as an SN1 reaction that proceeds through a tight ion pair can give
a substituted product with perfect transfer of chirality.
Kinetic studies. To elucidate the reaction mechanism of the
present transformations, we studied the rate order of the Fe
(OTf)3 catalyst. The rate-order was determined by varying the
concentration of catalyst in the transformation of 1a–2a, and a
Rate order determination
first-order dependence on catalyst concentration was found
(Supplementary Fig. 1).
The overall rate in an SN1 reaction is only dependent on the
concentration of the electrophile due to the rate-limiting
generation of the carbenium ion, whereas an SN2 reaction is
dependent on both the electrophile and nucleophile. As we
could not vary the concentration of the electrophile and
nucleophile, we prepared substrates with two nucleophiles
present instead of only one (1d′ and 1u′, Fig. 4). Even though
this does not show the rate-order, it might give useful
information whether the kinetics are governed by the
nucleophile. It should be noted that this experimental set-up
does not follow first principles and the results should be
interpreted with care. As a result, we found that the reaction
rate was doubled when two nucleophiles were present on the
molecule (1d′) instead of only one (1d) (Fig. 4a, b). Similarly,
the reaction rate with a substrate with two electrophilic moieties
was twice that of the standard substrate (Supplementary Fig. 2).
Moreover, rate constant and deuterium kinetic isotope effect
(KIE) was also measured for substrates 1b and 1b′ (Fig. 4e, f
and Supplementary Fig. 4). A deuterium KIE (KIE = kH/kD =
0.91) was observed when the hydrogen atom on 1b is replaced
by deuterium and the reactions were performed under similar
conditions. This inverse KIE also support an SN2-like pathway.
Even though the full rate-order is not elucidated, these
observations support an SN2-like reaction mechanism for
secondary alcohols where one equivalent of iron is responsible
for the catalysis47.
To continue our mechanistic investigations, we introduced
tertiary alcohols 1u and its derivative 1u′ with two nucleophiles
for comparison (Fig. 4c, d). Now the reaction rate did not show a
rate increase for 1u′ and indicates that the reaction mechanism
for the tertiary alcohol is different than for secondary alcohols,
likely following an SN1 pathway.
In our previous report on phosphinic acid-catalyzed
intramolecular substitution of alcohols24, it was found that, in the absence
of an internal nucleophile, iron(III) promotes an SN1-type
reaction, yielding a racemic mixture of the corresponding
product. In other words, iron promotes C−O bond cleavage;
however, in the absence of an internal nucleophile, a
solventseparated carbenium ion is generated before being attacked by
another molecule of the substrate via an SN1-type reaction. In the
present case, the tethering of the nucleophile to the molecule
enables the reaction to proceed through an SN2-like mechanism,
inducing the high chirality transfer.
Clarification of the mechanism by theoretical calculations. On
the basis of the experimental results, an SN2-like mechanism
seems to be feasible for secondary benzylic alcohols. To get
further insights to the reaction mechanisms we decided to study the
reaction involving substrates 1a, c, and d representing the three
nucleophiles and secondary benzyl alcohol used in this study by
DFT calculations (B3LYP/6-31+G**/LANL2DZ). Since first-row
transition metals have partially occupied d-orbitals, several spin
states might be energetically accessible, depending on the
oxidation state of the metal and its coordination sphere. Furthermore,
the most favorable spin state can change during the course of the
reaction48,49. Hence, we studied the transformation of 1d to 2d by
initially considering all three possible spin states for iron (III)
(doublet, quartet, and sextet). FeCl3 was chosen as a model to
mimic the Fe(OTf)3 used in the experiments as it also was found
to promote the substitution (Table 1, entry 9) and FeCl3 gave
more coherent results as compared to Fe(OTf)3.
The sextet spin state was found to be preferred over the quartet
and doublet spin states by 20 and 40 kcal/mol, respectively, for all
computed structures (Supplementary Fig. 5). The energy profile
for the intramolecular nucleophilic substitution of 1d is depicted
in Fig. 5a. First, Lewis acidic FeCl3 can coordinate to the hydroxyl
group attached the benzylic position giving Fe species C1d or to
the primary alcohol group giving Fe species B1d. They are both in
similar energy but only C1d can facilitate the nucleophilic attack
in an SN2 fashion that leads to transition state TS1d with an
activation free energy of 17.6 kcal/mol. Finally, product 2d and
water are released, regenerating the iron (III) catalyst. A third
possible Fe species A1d, where both alcohol groups coordinate to
FeCl3 is 5 kcal/mol more stable than B1d and C1d and can be
considered rather as a resting state of the catalysis.
We next studied the transformation of substrates 1a and 1c
(Fig. 5, Supplementary Fig. 6). The energy profiles for both
substrates are similar to those obtained for 1d (Supplementary
Fig. 6). However, in the resting state, the p-methoxyamino group
prefers the non-coordinating mode, probably due to steric
hindrance (Supplementary Fig. 6, intermediate C1a). The
transition states found for each substrate are shown in Fig. 5b;
substrate 1a shows a substantially higher energy barrier than
either 1c or 1d, which is consistent with the much higher reaction
temperature required for 1a (90 °C) than for 1c, and d (30 and 0 °
Both the experimental data and DFT calculations support an
SN2-type mechanism for secondary alcohols. However, an SN1
pathway through the formation of an ion pair still cannot be
completely ruled out. Due to charge separation in the transition
state of an SN1 reaction mechanism, calculations cannot be used
for comparison. Accordingly, attempts to find transition states
comprising tight-ion pairs failed. In the case of tertiary alcohols,
the experimental results suggest that the coordination of iron to
the nucleofuge would lead to C–O bond cleavage to generate a
tight ion-pair intermediate. In nonpolar solvent mixtures, the ion
pair remains tight, and nucleophilic attack generates the
substitution products with high chirality transfer. However, in a
polar solvent, the ion pairing is loosened, and nucleophilic attack
can occur from either side, leading to a product with lower
chirality transfer. This is in accordance with our experimental
results and we propose that the reaction of secondary alcohols
with poor nucleophiles that generate six-membered ethers and
tertiary alcohols proceeds through an SN1-like mechanism in
which the preservation of chirality from the substrate to the
product is governed by the solvent polarity.
Therefore, the mechanistic picture of the present transformation
is complex and substrate dependent, and for substrates that have
less drive to promote an SN2-like mechanism, the reaction media
can be altered to govern both the yield and enantiomeric purity of
the product. Due to the favorable energetics of internal ring
closures, the system is tunable for a wide range of nucleophiles and
secondary and tertiary alcohols that can provide intermediates and
products of pharmaceutical and agrochemical relevance.
We report herein a substitution of both secondary and tertiary
alcohols leading to enantioenriched five-membered,
six-membered, and aryl-fused six-membered heterocyclic compounds.
Notably, this direct substitution method works for
enantioenriched tertiary alcohols, where the chirality is preserved to the
product and water is generated as the only by-product. The
transformation is catalyzed by an abundant, inexpensive,
nontoxic iron catalyst, with substrates comprising non-activated alkyl
alcohols and poor uncharged nucleophiles can successfully be
used. These advancements have enabled a green transformation
of readily available alcohols as raw material in the synthesis of
important motifs found in biologically active compounds
important in pharmaceutical and agrochemical industries. We
demonstrate the power of the substitution in 22 substrates with
chirality transfer and as a key step in the total synthesis of
(+)-lentiginosine, where all the three stereocenters in the natural
product are derived from glucose. Mechanistic studies support
that the reaction with secondary alcohols to generate
fivemembered heterocycles proceed through an SN2-like mechanism,
while with tertiary alcohols, an SN1-type reaction mechanism
comprising a tight ion pair would occur in less polar solvent
mixtures. Overall, our approach provides an efficient and
atomeconomic strategy for substitution of non-derivatized stereogenic
alcohols with transfer of chirality, thereby filling a major gap in
the methodology of organic chemistry.
General procedure. To an oven-dried 5-ml vial equipped with a magnetic stir bar,
the substrate amino alcohol 1a (135.5 mg, 0.5 mmol), MS (3 Å; 300 mg), and Fe(OTf)3
(25.05 mg, 0.05 mmol) were added. The tube was sealed with a Teflon-lined cap,
connected to a vacuum and backfilled with argon three times by piercing with a
needle attached to a Schlenk line. Then, DCE (2.0 ml; anhydrous) was added by
syringe, and the mixture was stirred at 90 °C for 24 h. After this, the reaction was
cooled to room temperature, and the crude material was concentrated under vacuum.
The crude residue was purified by column chromatography with ethyl acetate and
hexanes (1:20) to obtain pure product 2a (99%, 133 mg). Full experimental details and
characterization of compounds are given in the Supplementary Information.
The data that support the plots within this paper and other findings of this study, such as
1H NMR, 13C NMR, and HPLC spectra, as well as experimental procedures and
quantum chemical calculations are available in the Supplementary Information.
Emer, E. et al. Direct nucleophilic SN1-type reactions of alcohols. Eur. J. Org.
Chem. 647–666 (2011).
J.S.M.S. thanks the Swedish Research Council, FORMAS and Stiftelsen Olle Engkvist
Byggmästare for financial support. The simulations were performed on resources
provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX and
NSC. We are grateful to Prof. F. Himo for advising us with the DFT calculations.
S.B. and J.S.M.S. designed the project. R.A.W., A.B., E.L., and R.A performed the
experiments. S.A. synthesized the natural product, J.M. performed DFT calculations, R.A.
W, T.R., and J.S.M.S. co-wrote the manuscript, analyzed the data, discussed the results,
and commented on the manuscript.
Supplementary Information accompanies this paper at
Competing interests: The authors declare no competing interests.
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