Stereoretentive copper(II)-catalyzed ritter reactions of secondary cycloalkanols

Article abstract of DOI:10.1002/adsc.201300233

A Ritter-like coupling reaction of cyclic alcohols and both aryl and alkyl nitriles to form amides catalyzed by copper(II) triflate is described. These reactions proceed in good yields under mild and often solvent-free conditions. With 2-and 3-substituted

Full text of DOI:10.1002/adsc.201300233

UPDATES
DOI: 10.1002/adsc.201300233
Stereoretentive Copper(II)-Catalyzed Ritter Reactions of
Secondary Cycloalkanols
Mohammed H. Al-hunitia and Salvatore D. Leporea,*
a
Department of Chemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, Florida 33431, USA
Fax : (+1)+561-297-2759; e-mail: slepore@fau.edu
Received: March 19, 2013; Revised: August 11, 2013; Published online: October 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300233.
Abstract: A Ritter-like coupling reaction of cyclic
alcohols and both aryl and alkyl nitriles to form
amides catalyzed by copper(II) triflate is described.
These reactions proceed in good yields under mild
and often solvent-free conditions. With 2- and 3-
substituted cycloalkanols, amide products are
formed with near complete retention of configura-
tion. This is likely due to fast nucleophilic capture
of non-planar carbocations (hyperconjomers) stabi-
lized by ring hyperconjugation. A critical aspect of
this novel catalytic cycle is the in situ activation of
the alcohol substrates by thionyl chloride to form
chlorosulfites.
vated alcohols.[8] Nevertheless, this classic reaction
continues to be the subject of continued investigation,
especially for diastereoselective amide formation[9]
with very recent successes using benzylic alcohols.[10,11]
Recently, our group developed a new method for
a one-pot stereoretentive amidation reaction of cyclic
alcohols (Scheme 1).[12] In this method, thionyl chlo-
Keywords: amides; carbocations; catalytic reaction;
hyperconjomers; Ritter reaction; stereoretentive re-
action
Scheme 1. Stereoretentive amidation via a non-planar hyper-
conjomer-stabilized carbocation intermediate.
Introduction
The dehydrative coupling of an amine with a carboxyl-
ic acid continues to be the method of choice for ride was used for the first time for the in situ genera-
amide bond formation. Such a step is usually achieved tion of a chlorosulfite leaving group for a non-chlori-
through activation of the acid;[1] however, due to the nation reaction. The absolute stereochemistry of the
reactivity of acid derivatives and other issues, numer- resultant amide is that of the alcohol substrate; the
ous alternative strategies have been developed.[2] Ex- reaction proceeds with retention of configuration.
amples include the use of azides as an amine precur- Such selectivity was suggested to be the first experi-
sor as in the modified Staudinger reaction,[3] the mental verification of cyclohexyl cation hyperconjom-
Schmidt reaction,[4] and the Beckmann rearrange- ers,[13] achieved via the formation of non-planar car-
ment.[5] More recently, oxidative amidation, a highly bocations, a theory developed by Sorensen and
atom-economical approach, has been developed al- Schleyer.[14,15] Although the method is fairly general
lowing the formation of amides from readily available with respect to nitriles and cyclic alcohols substrates,
starting materials.[6] This promising approach usually the use of large excess of nitrile (40 equiv.) and the
requires the use of heat, a stoichiometric amount of TiF4 coupling agent (10 equiv.) greatly limits its utility.
oxidant, and relatively expensive reagents.[7] The well- In the present communication, we detail our develop-
known Ritter reaction affords amides from the cou- ment of a catalytic version of this unique stereoreten-
pling of nitriles with alcohols and alkenes. However, tive amidation reaction.
this method is practically limited to tertiary and acti-
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Mohammed H. Al-huniti and Salvatore D. Lepore
UPDATES
Table 2. A survey of metal salt reactivity.
Results and Discussion
We began our investigation by examining the effec-
tiveness of various leaving groups using our previous-
ly developed titanium(IV) fluoride conditions
(Table 1).[12] Interestingly, our previously described
Table 1. Leaving group study using TiF4.
[a]
Isolated yields.
reacts rapidly with chlorosulfites to give exclusively
halide products in high yields.[17] Martin and co-work-
ers have reported similar results using FeACTHNURTGNEU(GN III) halides
in related systems.[18] Accordingly, we choose to study
metal salts possessing non-nucleophilic ligands. The
readily available triflate salts of copper(II) and
scandium
a high catalyst loading of 50%. Copper(II) carbonate
gave a significantly lower yield than Cu(OTf)2 al-
ACHTUNGTRENUN(NG III) afforded amide product, albeit with
AHCTUNGTRENNUNG
though this result may be due to poor solubility. To
rule out the role of triflate as anything other than
a spectator ion, KOTf was used (entry 6); however,
no amide product was observed.[19] We also observed
product formation with other metal salts including
those of Co(II) and Ag(I) which afforded only
modest yields (entries 4 and 5). We proceeded to fur-
ther study the present amidation reaction using cop-
per(II) triflate due to its lower toxicity and cost rela-
tive to the scandium reagent.
[a]
Isolated yields.
Ratio determined using H NMR
[b]
1
We chose to proceed with copper(II) triflate despite
nucleophile assisting leaving group (NALG) contain- some drawbacks. Literature evidence suggests that
ing a diethylene oxide chelating arm (compound 2)[16] copper(II) is destroyed in the presence of sulfur diox-
gave a similar diastereoselectivity but much poorer ide gas which is a by-product of the present reac-
yield than other chelating leaving groups such as tion.[20] Furthermore, this metal salt is relatively in-
chlorosulfite 1 and 8-sulfonylquinoline 3. Poorer re- soluble in all but coordinating solvents; however, ster-
sults were observed with other leaving groups (en- eoretention is only observed in non-coordinating sol-
tries 4–8). Surprisingly, substrate 9 containing the tri- vents such as dichloromethane.
fluoromethanesulfonate (triflate) leaving group gave
This led us to try reactions in which the nitrile cou-
the inverted amide product as the major diastereomer pling partner would serve as both reagent and solvent
under the action of TiF4 (entry 9). Our leaving group in this system (virtually solvent-free conditions). This
study clearly suggested that the in situ formed chloro- approach also allowed for easier removal of SO2
sulfite 1 would be the optimal starting point in our likely generated during the course of the reaction by
goal to develop a catalytic form of this stereoretentive flushing the head-space in the reaction vessel with
Ritter reaction.
argon. In some cases, a small amount of CH2Cl2 (1M)
We next examined various metal salts (Table 2) in was used to further solubilize the reactants. These
an attempt to realize catalytic conditions for this ami- minimal-solvent conditions with 20% catalyst afford-
dation reaction. In our previous work, TiF4 was ed a 71% of amide 10 from trans-2-methylcyclohexan-
chosen due to its modest Lewis acidity and essentially
ACHTUNGTRENoNGNU l with complete retention of configuration. Catalyst
non-reactive fluoride ligands. However, this reagent load and nitrile stoichiometry studies were then per-
formed oligomeric complexes requiring the use of formed under solvent-free conditions (Table 3). Not
large excesses to bring about reasonable yields. By surprisingly, no product was observed when the reac-
contrast, catalytic TiCl4 (and its bromide analog) tion was performed in the absence of catalyst
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Stereoretentive Copper(II)-Catalyzed Ritter Reactions of Secondary Cycloalkanols
Table 3. Study of catalyst loading and nitrile equivalents.
leading to the synthetically useful yields described in
the previous section (Table 3).
Previous reports indicate that l-menthol is a prob-
lematic substrate in Ritter reactions owing to its pro-
pensity to undergo cation rearrangements.[23] Thus we
proceeded to perform a nitrile generality study with
this substrate to further probe the limits of our cata-
lytic reaction. Our studies revealed that both aliphatic
and aromatic nitriles afford amides 13 in moderate to
good yields with no detectable hydride shift products
(Table 4). Importantly, the amide products were
Table 4. Nitrile generality study.
[a]
No product was observed after 24 h.
(entry 1). However, after 7 days a very small amount
of product was observed. Importantly, this product
mixture gave little selectivity.[21]
In terms of product yield, a catalyst loading of 20%
appears to be optimal especially with 4 to 5 equiva-
lents of nitrile (entries 6 and 7). However, these addi-
tional equivalents of nitrile also lowered the ratio of
retention to inversion (10:11). Taking into account
yield and stereoselectivity, we selected 20% CuACTHNUTRGNEUNG(OTf)2
and 1.9 or 2.0 equivalents nitrile as optimal conditions
for our generality studies.
From our initial experiments involving catalytic
Cu(II), dialkyl sulfite 12 was observed as a minor by-
product in the amidation reaction of l-menthol
(Scheme 2). This is expected to arise from the chloro-
sulfite.[22] In separate experiments, we observed that
CuACHTUNGTRENNUNG(OTf)2 catalyzed the reaction of this alcohol with
its chlorosulfite to give dialkyl sulfite 12. In addition,
dialkyl sulfite 12 was prepared and subjected to our
reaction conditions but amide product 10 was ob-
served only after long reaction times (>24 h). Based
on these findings, we sought to minimize dialkyl sul-
fite formation by altering the sequence of reagent ad-
[a]
Isolated yields for 1.2 and 1.9 equiv, of nitrile.
dition. Thus
a 1M CH2Cl2 solution of nitrile,
Cu(OTf)2, and alcohol were added slowly to thionyl formed with complete retention of configuration. In-
ACHTUNGTRENNUNG
chloride. This approach was ultimately successful terestingly, the reaction tolerates a phenolic hydroxy
group (entry 4). The primary limitation appears to be
with reactions involving electron-deficient nitriles
such as p-chlorobenzonitrile (entry 3) and especially
trichloroacetonitrile (entry 7). For optimal yield, two
equivalents of nitrile were used; however, in most
cases, reasonable yields were also obtained with as
little as 1.2 equivalents.
We next examined a range of saturated cyclic alco-
hols to explore substrate generality (Table 5). Very
similar to the previously mentioned menthol example,
we observed the formation of amide products with
complete retention of configuration with a number of
cyclic alcohols (entries 1 and 3–6). One exception was
cis-2-methylcyclohexanol which underwent rapid
Scheme 2. Dialkyl sulfite by-product formation.
chlorination and no amidation. However, other
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Mohammed H. Al-huniti and Salvatore D. Lepore
UPDATES
Table 5. Substrate generality study.
chemistry was clearly demonstrated by X-ray crystal
structure analysis to be the inversion product.[25]
Ritter reactions of bornyl and isobornyl chloride in
the presence of SbCl5 in acetonitrile have been shown
to give the same exo-amide product[26] suggesting
a common carbocation intermediate and a preference
for exo-attack.[27] In the case of isoborneol (entry 4),
the present method gave only the stereoretentive
amide (exo-product) product 15 albeit in low yield
(21%). However, the main by-product is the chloride
but, here as well, we observe a preference for stereo-
retention (i.e., isobornyl chloride).
A variety of ring sizes also afforded good product
yields under the present conditions (entries 7–10). In-
terestingly, poor yields of amide were observed with
cyclododecanol which gave almost exclusive elimina-
tion product (entry 11). Carbocations involving simi-
lar macrocyclic substrates are known to form transan-
nular m-hydrido bridges.[28] Perhaps these non-classical
carbocation intermediates alter the course of the pres-
ent amidation reaction with this large ring substrate.
As in our previous studies,[12] tertiary and primary al-
cohols gave little or no yields in this reaction except
in the case of 1-adamantanol (entry 13).
The high degree of stereoretention in the present
reaction argues against a classical SN1 mechanism in-
volving a planar cation. In such systems, stereocenters
nearby the planar carbocation center should influence
facial preference in nucleophilic attack. Such a mecha-
nism explains previously reported Ritter reactions of
borneol and isoborneol which led to product mixtures
favoring the exo-product. Based on our recent exten-
sive computational study of a related system,[17] we
argue that cyclic carbocations in the present reaction
retain their configuration due to stabilization by hy-
perconjugation.[15] In this scenario, the copper(II) cat-
alyst chelates to both chlorosulfite and the nitrile cou-
pling partner to give complex A (Scheme 3). This che-
lation to chlorosulfite increases its leaving group abili-
[a]
For entries 1 and 3–6, yields are for isolated amide prod-
ucts which were obtained as single diastereomers with re-
tention of configuration at the carbinol carbon center.
Only chlorination and minor elimination products ob-
served.
[b]
[c]
Chlorination with retention of configuration (5:1) was
the major by-product.
methyl cyclohexanol isomers (entries 5 and 6) also
gave the expected stereoretentive amide product in
reasonable yields although a small amount of hydride
shift product was observed in each case.
The case of (À)-borneol (entry 3) presents an inter-
esting opportunity to compare the present method
with previously reported Ritter modifications. In our
case, (À)-borneol was converted to amide product 14
in 69% yield with complete retention of configuration
(endo product). This outcome stands in contrast with
virtually all reported Ritter reactions involving this
substrate.[24] Using a recently developed iodine-cata-
lyzed Ritter reaction performed at a 1208C, (À)-bor-
Scheme 3. Proposed mechanism and intermediates for the
neol led to an amide product whose relative stereo- observed amidation reaction.
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Stereoretentive Copper(II)-Catalyzed Ritter Reactions of Secondary Cycloalkanols
the desired concentration (2.5M). After stirring for 2 h, the
reaction was quenched with deionized water and stirred
AHCTUNGTREG(NNNU ~30 min) until the organic layer became clear. The organic
layer was removed and the aqueous layer was extracted
twice with dichloromethane. All organic layers were com-
bined, dried over anhydrous sodium sulfate, and concentrat-
ed under vacuum.
ty leading to rapid cation formation under mild condi-
tions. This configurationally “frozen” carbocation is
then trapped by nitrile delivered to the front face in
ion pair B to form a nitrilium salt which is converted
to amide upon aqueous work-up.
Conclusions
General Copper(II) Triflate Procedure
Nitrile (1.9 mmol) and copper(II) triflate (0.15 mmol) were
added with stirring to an oven-dried vial under an argon at-
mosphere containing anhydrous dichloromethane (1 mL).
Alcohol (1.0 mmol) was then added and the mixture was
stirred at room temperature (15–228C) until a homogenous
mixture is observed. This solution was then transferred
(over >45 min) through cannula to an oven-dried flask con-
taining thionyl chloride (1.7 mmol) under argon at room
temperature. Headspace gases were replaced with argon
We have previously disclosed a stereoretentive Ritter
reaction involving chlorosulfites conveniently formed
in situ. However, this earlier work entailed large
excess of TiF4 and the use of the nitrile coupling part-
ner as a cosolvent. In the present work, we have dra-
matically increased the atom economy of this stereo-
selective reaction through a systematic evaluation of
various metal catalysts and reaction conditions. As
a result of these improvements, it is now possible to several times in the first 1 hour. The reaction was monitored
for the disappearance of alcohol by TLC using an aqueous
potassium permanganate staining solution. After comple-
tion, the reaction mixture was cooled, diluted and poured
into cooled aqueous KOH solution (20% w:v; 25 mL) and
stirred for several hours. The aqueous layer was then ex-
tracted several times with dichloromethane followed by
drying and evaporation. The crude mixture was purified
using silica chromatography (in EtOAc/hexanes).
directly convert non-activated cyclic secondary alco-
hols directly to the corresponding amide with a high
degree of retention of configuration.
Experimental Section
General Information
All reaction mixtures were purified using flash silica gel 40–
63m. Analytical thin layer chromatography was performed
on 0.25 mm silica gel 60-F plates. Visualization was accom-
plished with UV light and aqueous potassium permanganate
solution staining. 1H NMR spectra were recorded on
a Varian Mercury 400 (400 MHz) spectrometer and are re-
ported in ppm using solvent as an internal standard (CDCl3
at 7.26 ppm). Coupling constants were reported in Hz and
13C NMR spectra were recorded on a Varian Mercury 400
(100 MHz) spectrometer. Chemical shifts are reported in
ppm, with solvent resonance employed as the internal stan-
dard. High-resolution mass spectra were obtained from Uni-
versity of Florida Mass Spectrometry Laboratory. All re-
agents were used without any further purification. Solvents
were dried with activated molecular sieves.
Acknowledgements
We thank the National Institutes of Mental Health (087932-
01) and NSF (0311369) for financial support.
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