A direct and stereoretentive synthesis of amides from cyclic alcohols

Article abstract of DOI:10.1002/ejoc.201101165

Chlorosulfites prepared in situ using thionyl chloride react with nitrile complexes of titanium(IV) fluoride to give a one-pot conversion of alcohols into amides. For the first time, amides are obtained from cyclic alcohols with stereoretention. Critical to the design of these new Ti^IV reactions has been the use of little-explored Ti^IV nitrile complexes that are thought to chelate chlorosulfites in the transition state tocreate a carbocation that is rapidly captured by the nitrile nucleophile through a front-side attack mechanism.

Full text of DOI:10.1002/ejoc.201101165

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101165
A Direct and Stereoretentive Synthesis of Amides from Cyclic Alcohols
Deboprosad Mondal,[a] Luca Bellucci,[b] and Salvatore D. Lepore*[a]
Keywords: Amides / Alcohols / Titanium / Chirality / Hyperconjugation
Chlorosulfites prepared in situ using thionyl chloride react
with nitrile complexes of titanium(IV) fluoride to give a one-
pot conversion of alcohols into amides. For the first time,
been the use of little-explored TiIV nitrile complexes that are
thought to chelate chlorosulfites in the transition state to
create a carbocation that is rapidly captured by the nitrile
amides are obtained from cyclic alcohols with stereoreten- nucleophile through a front-side attack mechanism.
tion. Critical to the design of these new TiIV reactions has
leaving group,[10] we fortuitously discovered a more direct
Introduction
stereospecific Ritter-type amidation reaction for cyclic
Amides are among the most abundant functional groups
alcohols. This initial observation involved the reaction of
in nature and, understandably, decades of creative research
an 8-quinoline sulfonate (quisylate, QsO) with titanium(IV)
have been devoted towards their efficient synthesis with the
fluoride in the presence of alkyl or aryl nitriles (Scheme 1).
majority of these studies centering on the dehydrative cou-
We next thought to extend the concept of chelating leaving
pling of amines with carboxylic acids.[1] For the past few
groups to chlorosulfites, which can be generated in situ. To
years, we have been in engaged in the development of meth-
the best of our knowledge, chlorosulfites have not been ex-
ods to directly transform chiral secondary alcohols into new
ploited as leaving groups and are primarily relegated to use
compound classes with retention of configuration, espe-
as intermediates in the classic SOCl2 chlorination reaction.
cially since non-racemic alcohols have become increasingly
In this communication, we report our success in utilizing
more available thanks to the development of recent power-
chlorosulfites for one-pot, two-step reactions of cyclic
ful catalytic methods.[2] Recently, a metal-free procedure for
alcohols to yield amide products with predominant reten-
the transformation of phenols into amides has been de-
tion of configuration (Scheme 1). Importantly, these find-
scribed with the use of a radical cascade reaction.[3] Primary
ings appear to be the first experimental verification of sec-
alcohols have also been converted into amides via hemi-
ondary hyperconjomers,[11] a theory of non-planar carbo-
aminal intermediates under catalytic dehydrogenation con-
cations developed by Sorensen and Schleyer.[12,13]
ditions.[4] As a tool for the direct conversion of alcohols to
amides, the Ritter reaction has received substantial atten-
tion over the years. Excluding anchimeric assistance[5] or
diastereomeric control,[6] this reaction is well known to pro-
ceed by a non-stereospecific carbocation mechanism and is
often limited to alcohols where such intermediates are stabi-
lized. However, two examples describing unexpectedly
stereospecific Ritter amidations have been reported.[7]
Nevertheless, most stereoselective approaches to amides
from chiral alcohols require multistep procedures.[8]
As a complementary technique, we have previously re-
Scheme 1. One-pot, stereoretentive amidation reaction of cyclic
ported a stereoretentive reaction by using a nucleophile-
alcohols.
assisting leaving group (NALG) to position a TiIV azidation
reagent for a front-face attack.[9] Using a designed chelating
[a] Department of Chemistry, Florida Atlantic University
Results and Discussion
Boca Raton, Florida 33431, USA
Fax: +1-561-297-2759
E-mail: slepore@fau.edu
The initial inclination to use titanium(IV) fluoride in re-
actions with chelating leaving groups was based on our de-
sire to develop a stereoretentive fluorination reaction as a
follow-up to our success with chlorinations[14] and bromina-
tions[9] by using the corresponding TiIV halogen reagents.
[b] Dipartimento Farmaco Chimico Tecnologico,
Università degli Studi di Siena,
via Aldo Moro-2, 53100 Siena, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101165.
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D. Mondal, L. Bellucci, S. D. Lepore
SHORT COMMUNICATION
Although currently under study by various groups for use Table 2. Nitrile generality for stereoretentive amidation.
in dental varnishes,[15] titanium(IV) fluoride has received
only modest attention from the organic synthesis com-
munity[16] probably due to its moderate complexing abil-
ity,[17] propensity for oligomer complex formation, and
sparing solubility in typical reaction solvents. Following up
on a report indicating that TiF4 can be solubilized as nitrile
complexes,[18] we hypothesized that a fluorination reaction
might still be possible with added nitrile. To our surprise,
the subsequent reaction of this solubilized reagent with the
chlorosulfite ester of l-menthol failed to give the expected
fluoride but instead afforded amide product 1a after aque-
ous workup with complete retention of configuration
(Table 1). The major side product in this reaction was chlo-
ride 2. Interestingly, the chlorosulfite of menthol failed to
yield product 2 at a reaction temperature of 0 °C, except in
the presence of the TiIV reagent. Indeed, our subsequent
studies revealed that a number of TiIV species can be used
to catalyze halosulfite reactions leading to alkyl halides in
excellent yields under mild conditions with nearly exclusive
retention of configuration.[19] On the basis of previous stud-
ies,[18] we suspected that multiple equivalents[20] of TiF4 and
[a] Isolated yield. [b] Reactions 1.0 m in TiF4.
nitrile would be necessary for our amidation reaction. In-
deed, the optimal ratio of benzonitrile/TiF4 appears to be
4:1. Using 10 equivalents of TiF4 (2.5 m) led to an 84% (Table 3, Entries 1–4). In some cases, a significant amount
yield of amide 1a.[21] Further studies with the l-menthol of inversion product (≈25%) was observed under these reac-
substrate revealed that the stereoretentive amidation reac- tion conditions (Table 3, Entry 5). In particular, the reac-
tion is successful with both aromatic and aliphatic nitriles tion outcome of cholestanol (a saturated derivative of 5) led
(Table 2). The primary limitation appears to be with to a mixture of retention/inversion products (not shown).
strongly electron-deficient nitriles such as trichloroacetoni- This attracted our attention, because others have com-
trile (Table 2, Entry 5) presumably due to their poor li- mented that this substrate should proceed by a different
ganding ability. We note that acetamide product 1g was pro- mechanism in our system due to the absence of a nearby
duced in an excellent yield of 92% (Table 2, Entry 6).
double bond.[22] We recently achieved a high-yielding chlo-
rination of cholestanol by using a closely related TiIV reac-
tion with exclusive retention of configuration.[19,23] Never-
theless, this less stereospecific result with the present amid-
ation reaction prompted us to further examine our mechan-
istic hypotheses for these titanium(IV) reactions as dis-
cussed below.
Table 1. Effect of TiIV concentration on amidation yields.
In general, this amidation reaction gives high-yielding re-
sults with cycloalkanols of varying ring sizes under mild
conditions (Table 3, Entries 6–9). However, with the excep-
tion of 1-adamantanol (Table 3, Entry 10), our conditions
failed to yield amides with tertiary alcohol substrates, giv-
ing the chloride products instead. Given the preference of
our reaction for secondary substrates, we deem this reactiv-
ity profile complementary to that of the classic Ritter reac-
tion, which is generally only useful in easily ionized systems
such as tertiary alcohols. In light of our emerging mechan-
istic conception for this reaction (discussed below), we were
not surprised to observe that the stereospecificity of the
present amidation reaction does not extend to acyclic sys-
Entry
PhCN
[equiv.]
TiF4
[equiv.]
Conc. of TiF4
Yield [%][a]
1a
[m]
2[b]
1
2
3
4
5
6
7
8
4
4
8
2
2
4
4
4
6
8
10
0.2
1.0
1.0
2.5
2.5
2.5
2.5
2.5
30
45
52
56
62
67
75
84
55
43
35
33
25
22
13
5
8
16
24
32
40
[a] Isolated yield. [b] Chlorides formed with complete stereoreten-
tion.
Using benzonitrile as a convenient coupling partner, a tems. We conducted a study of acyclic alcohols by using
variety of substrate alcohols were examined by using our (S)-2-octanol and (S)-1-phenylethanol.[22] In a reaction of
optimized amidation conditions (Table 3). Very similar to the non-racemic phenylethanol with benzonitrile and TiF4,
the previously mentioned menthol example, we observed amide 13 was obtained entirely as the racemate (Scheme 2).
that a number of cyclic chiral alcohols were converted into It should be noted that the chlorosulfite of phenylethanol
amide products with complete retention of configuration readily converts into the chloride product at 0 °C. Accord-
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Stereoretentive Synthesis of Amides from Cyclic Alcohols
Table 3. Substrate generality for stereoretentive amidation.
Scheme 2. Amidation of acyclic alcohols.
mediates whose nucleophilic capture is under dia-
stereomeric control. They further point out that, in some
cases, carbocations are not completely dissociated from the
leaving group, leading to tight ion-pair formation and thus
attack is favored from the less-hindered backside.
To help distinguish between the various mechanistic pos-
sibilities in the present amidation reaction, we closely exam-
ined trans- and cis-3-methylcyclohexanol. If the reactions
of these isomeric alcohols proceed through a classical SN1
mechanism they should form the same carbocation inter-
mediate. Attack of this intermediate should then lead to the
same product outcome. This was not the case. Instead, we
observed a clear preference for retention products in these
amidation reactions (Scheme 3). Thus cis-3-methylcyclohex-
anol (16) led primarily to cis product 18 (4:1) and the trans
substrate (i.e., 17) led to mainly trans product 19 (3:1).
Though no hydride shift product was observed for cis-3-
methylcyclohexanol, the chlorosulfite of trans-3-methylcy-
clohexanol (17) gave hydride-shift product 20 with the
amide group exclusively as the trans isomer.
[a] Yield of retention product only. [b] Intermediate chlorosulfite
prepared at –78 °C with TiF4 concentration maintained at 1.0 m.
[c] Inversion product produced in 26% yield.
Scheme 3. Amidation in cis- and trans-3-methylcyclohexanol.
ingly, the chlorosulfite was prepared at –78 °C and then
Our experimental results with other cyclic alcohols
added to a TiIV solution. The amidation reaction with 2- (Tables 1–3) also suggest that amidation reactions giving
octanol produced a mixture of direct substitution product predominantly retention of configuration may not proceed
14 and hydride-shifted product 15 (2.9:1). Polarimetry mea- by a classical SN1 mechanism. Indeed, amidation studies of
surements of purified hydride-shifted product 15 indicated l-menthol under typical Ritter conditions (well known to
that it was essentially racemic. However, direct substitution proceed via classical carbocation intermediates) afforded
product 14 gave an enantiomeric excess of 28% favoring amide products arising from a tertiary carbocation.[21] Such
inversion (Scheme 2).[24] Finally, primary alcohols (Table 3, products have never been observed in our studies of 2-sub-
Entry 11) reacted very slowly, which is consistent with our stituted cyclic alcohols. Instead, we suggest that our amid-
previous work with titanium(IV)-mediated reactions.[9]
ation reactions may involve a fast front-side attack of a
In our previous communications involving titanium(IV) carbocation intermediate such as 21 possessing pyramidal
reagents, we suggested that stereoretentive products are geometry, as theorized by Sorensen and Schleyer
likely achieved through an SNi mechanism.[9,14] However, (Scheme 4).[12,13] Importantly, the cationic center in 21 is
the recent work of Braddock (Imperial College London) expected to maintain its configuration (as a single hyper-
and Burton (Oxford) provide convincing evidence that an conjomer) through hyperconjugative stabilization.[25] By
SN1-type mechanism may also be operative in NALG/TiIV contrast, there appears to be less of a barrier to carbocation
reactions.[22] Specifically, the British researchers argue that planarization in acyclic systems, possibly explaining the
these TiIV-mediated reactions proceed via carbocation inter- lack of stereospecificity in their amidation reactions.
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D. Mondal, L. Bellucci, S. D. Lepore
SHORT COMMUNICATION
support. We also thank Dr. Songye Li, Prof. Andrea Tafi, and Prof.
Salvatore Guccione for helpful discussions.
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Scheme 4. Proposed mechanism and intermediates for the observed
amidation reaction.
Conclusions
We have discovered an exciting variation of the Ritter
reaction by using an inexpensive and unexplored TiIV/nitrile
reagent to prepare amides directly from cyclic secondary
alcohols. Critical to the design of this new reaction is the
first-ever use of chlorosulfites, formed by the well-known
reaction of alcohols and thionyl chloride, as in situ formed
chelating leaving groups. Further mechanistic studies on
this system are currently underway especially with a view
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[10] S. D. Lepore, D. Mondal, Tetrahedron 2007, 63, 5103–5122.
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Experimental Section
General Procedure for Stereoretentive Amidation Reactions: To an
ice-cold solution of alcohol (1.0 equiv.) in dichloromethane (1.0 m)
was added thionyl chloride (1.5 equiv.) followed by stirring for 1 h
to form the chlorosulfite. In a separate reaction vessel, nitrile
(40 equiv.) was added to a TiF4 (10 equiv.) suspension in dichloro-
methane (4.0 m) and allowed to stir at room temperature until com-
plete dissolution (≈15 min). Because TiF4 is fairly moisture sensi-
tive, it was quickly transferred to a reaction vessel under an atmo-
sphere of argon and then weighed. The amount of each remaining
reagent was then based on the weight of TiF4. The titanium/nitrile
solution was then cooled to 0 °C, and to this solution was added
the previously prepared chlorosulfite, transferring by cannula under
argon pressure. The chlorosulfite-containing vessel was further
washed with an amount of dichloromethane necessary to bring the
final concentration of TiF4 in the other vessel to the desired con-
centration (2.5 m). After stirring for 2 h, the reaction was quenched
with deionized water and stirred (≈30 min) until the organic layer
became clear. The organic layer was removed, and the aqueous
layer was extracted with dichloromethane (2ϫ). All organic layers
were combined, dried with anhydrous sodium sulfate, and concen-
trated in vacuo. The crude product was purified by silica gel flash
chromatography (ethyl acetate/hexane).
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for compounds 1a–e, 1g, 3–7, and 5α-
[19] D. Mondal, S. Y. Li, L. Bellucci, A. Tafi, S. Guccione, S. D.
Lepore, manuscript in preparation.
[20] Although a large excess of TiF4 is used in this reaction, we
note that the reagent is very inexpensive (≈1 USD/g) and envi-
ronmentally benign.
1
cholestan-3β-chloride; copies of the H and 13C NMR spectra for
compounds 1, 3–7, and 8, 10, and 11; NMR spectra of product
mixtures for variously substituted cyclohexanols.
[21] For perspective, this yield represents a sixfold increase over the
highest yield achieved in the literature by using a Lewis acid
assisted Ritter reaction with menthol, which is considered a
problematic substrate: P. B. Shrestha-Dawadi, J. Jochims, Syn-
thesis 1993, 426–432.
Acknowledgments
We thank the National Institutes of Mental Health (087932–01)
and National Science Foundation (NSF) (0311369) for financial
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Stereoretentive Synthesis of Amides from Cyclic Alcohols
[22]
[24] A rotation value –4.4 (c = 5.5, CHCl3). Pure inversion product
was made by an alternative route in four steps from (S)-2-oc-
tanol through an SN2 mechanism, giving an optical rotation of
–15.7 (c = 3.55, CHCl3).
[25] I. V. Alabugin, K. M. Gilmore, P. W. Peterson, WIREs Comput.
Mol. Sci. 2011, 1, 109–141.
D. C. Braddock, R. H. Pouwer, J. W. Burton, P. J. Broadwith,
J. Org. Chem. 2009, 74, 6042–6049.
[23] Starting from the in situ formed chlorosulfite of cholestanol
(0.1 m in CH2Cl2) and using TiCl4 (5 equiv.) at 0 °C, the direct
substitution chloride product was formed in 15 min as a single
product in 80% yield with complete retention of configuration
(see the Supporting Information).
Received: August 8, 2011
Published Online: October 27, 2011
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