Mechanism of SmI2/amine/H2O-promoted chemoselective reductions of carboxylic acid derivatives (esters, acids, and amides) to alcohols

Article

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Mechanism of SmI₂/Amine/H₂O‑Promoted Chemoselective

Reductions of Carboxylic Acid Derivatives (Esters, Acids, and Amides)

to Alcohols

Michal Szostak,*^,†Malcolm Spain,^‡Andrew J. Eberhart,^‡and David J. Procter*^,‡

^†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States

^‡School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom

S

* Supporting Information

ABSTRACT: Samarium(II) iodide−water−amine reagents

have emerged as some of the most powerful reagents (E° =

−2.8 V) for the reduction of unactivated carboxylic acid

derivatives to primary alcohols under single electron transfer

conditions, a transformation that had been considered to lie

outside the scope of the classic SmI₂reductant for more than

30 years. In this article, we present a detailed mechanistic investigation of the reduction of unactivated esters, carboxylic acids,

and amides using SmI₂−water−amine reagents, in which we compare the reactivity of three functional groups. The mechanism

has been studied using the following: (i) kinetic, (ii) reactivity, (iii) radical clock, and (iv) isotopic labeling experiments. The

kinetic data indicate that for the three functional groups all reaction components (SmI₂, amine, water) are involved in the rate

equation and that the rate of electron transfer is facilitated by base assisted deprotonation of water. Notably, the mechanistic

details presented herein indicate that complexation between SmI₂, water, and amines can result in a new class of structurally

diverse, thermodynamically powerful reductants for eﬃcient electron transfer to a variety of carboxylic acid derivatives. These

observations will have important implications for the design and optimization of new processes involving Sm(II)-reduction of

ketyl radicals.

preferred reagent system (Figure 1A).¹⁰In 2002, Dahlen

́

and

INTRODUCTION¹

■

Hilmersson¹¹reported a breakthrough ﬁnding on the synergistic

eﬀect of water and amines on the reduction of simple dialkyl

ketones using a reagent system previously described by Cabri and

co-workers¹²and demonstrating a striking acceleration of the

reaction rate in kinetic studies (Figure 1B). In 2004, Flowers and

co-workers reported a study on the role of diﬀerent alcohols in

the reduction of acetophenone (Figure 1C).¹³In 2011, as an

extension of mechanistic studies on the role of alcohols as

additives to SmI₂in the reduction of α,β-unsaturated nitriles,

Hoz and co-workers reported a detailed investigation of the role

of alcohols in the reduction of a sterically demanding ketone,

norcamphor (Figure 1D).^14,15In 2014, we reported mechanistic

investigations on the reduction of six-membered lactones using

SmI₂−H₂O with the key ﬁnding being the unusual eﬀect of water

on the stabilization of ketyl radical intermediates (Figure 1E).¹⁶

The stabilizing eﬀect of water as the Sm(II) additive was also

demonstrated in a mechanistic study on the reduction of

Meldrum’s acids to β-hydroxy acids using SmI₂−H₂O as the key

reagent system.¹⁷Recent work has also shown that alcohols serve

as crucial additives to lanthanides(II) in several related processes

involving ketyl radicals or equivalents.¹⁸

Samarium(II) iodide-mediated generation of ketyl radicals from

aldehydes and ketones has been the focus of intensive research

eﬀort for more than three decades.²In particular, the use of SmI₂

enables synthesis of alcohols under conditions orthogonal to

other reagents operating via single- and two-electron pathways,³

and this process has been featured as a key step in numerous

synthetic applications in which the exceptional chemoselectivity

of SmI₂proved beneﬁcial over other available reductants.⁴The

vast majority of processes involving generation of ketyl radicals

with Sm(II) requires precomplexation of the lanthanide center

with alcohol cosolvent to increase the redox potential of the

system⁵or to promote protonation of the ketyl radical by a

proton source placed in close proximity to the short-lived

radical.⁶Numerous mechanistic studies have indicated the role of

alcohols as crucial SmI₂-additives in reactions involving ketyl

radicals (Figure 1).

Speciﬁcally, the pioneering ﬁndings by Kagan and co-workers

on the reduction of 2-octanone with SmI₂−H₂O,⁷and the

subsequent studies by Curran⁸and by Kamochi and Kudo⁹on

the role of water in promoting reductions of dialkyl and aryl

ketones, respectively, suggested that water may be a key additive

to Sm(II) for the reduction of simple ketones (not shown). In

1999, Keck and co-workers systematically examined the eﬀect of

alcohol stoichiometry on the formation of Sm(II)−ROH

complexes as demonstrated in a highly stereocontrolled

reduction of β-hydroxy ketones using SmI₂−MeOH as the

Special Issue: Mechanisms in Metal-Based Organic Chemistry

Received: August 11, 2014

A

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Article

these studies are almost exclusively limited to processes

proceeding via an outer-sphere electron transfer.^26a,bIt is clear

that a better mechanistic understanding of the role of the

additives in the reduction of carboxylic acid derivatives could

aﬀord key insights for the development of new reductive

processes (e.g., chemoselective reductions of complex functional

groups, development of reductive bond forming reactions) and

contribute to the progression of the rich carbonyl chemistry of

SmI₂(e.g., reduction, cross-coupling, tandem bond forming

events) to acyl-type radicals generated from carboxylic acid

derivatives under mild and chemoselective reaction conditions

(Figure 2).²⁻⁴

Figure 2. Accepted and proposed mechanism of SmI₂-mediated

electron transfer to aldehydes, ketones, and carboxylic acid derivatives.

Herein, we present systematic kinetic and radical clock studies

on the reduction of unactivated esters, acids and amides using

SmI₂(Chart 1). We demonstrate that for the three functional

Figure 1. Previous mechanistic studies on electron transfer to carbonyl

groups using Sm(II)-based reagents.

While the reduction of ketones and aldehydes to give the

corresponding ketyl radicals is one of the useful reactions

mediated by Sm(II),²⁻⁴until 2011 it had been thought that

unactivated carboxylic acid derivatives (e.g., esters, carboxylic

acids, amides) were outside the reducing range of Sm(II).¹⁹In

2011, we reported that the Sm(II) reagent produced from SmI₂,

amine, and water is capable of reducing unactivated esters via

radical intermediates, thus for the ﬁrst time expanding the

carbonyl chemistry of SmI₂beyond the reduction of ketones and

aldehydes.²⁰In 2012, we reported the ﬁrst general reduction of

carboxylic acids with SmI₂as an alternative to the classical

hydride-mediated reductions.²¹In 2014, we reported the ﬁrst

general reduction of all types of amides (primary, secondary,

tertiary) to the corresponding primary alcohols under mild

conditions using the SmI₂−amine−water reagent.²²Prior to our

report, only a few methods for the reduction of amides to

alcohols had been reported.²³The excellent C−N/C−O

cleavage chemoselectivity of this reaction (>90:10 in all cases

examined) was proposed to result from complexation of the

Lewis acidic Sm(III) to the nitrogen atom in the carbinolamine

intermediate as well as from the mildly basic conditions of the

reagent system favoring the carbinolamine intermediate collapse

via alkoxide. The chemoselective reduction of nitriles²⁴and cyclic

esters²⁵using SmI₂−amine−water²⁶has also been reported.

The growing importance of SmI₂in the reduction of carboxylic

acid derivatives^{20−22,24,25}prompted us to undertake a thorough

mechanistic study of the formation of primary alcohols from

unactivated esters, carboxylic acids, and amides using the SmI₂−

amine−water system. In the literature, the vast majority of

mechanistic studies on Sm(II) implicate the role of alcohols;⁷⁻¹⁷

however, mechanistic studies on the synergistic eﬀect of amine

and water additives to Sm(II), including studies on the critical

role of amine and water additives, are rare.^26a,b,eFurthermore,

Chart 1. Methods Employed in the Current Study To

Determine the Mechanism of the Reduction of Carboxylic

Acid Derivatives Using Sm(II)

groups all reaction components (SmI₂, amine, water) are

involved in the rate equation and that the rate of electron

transfer is facilitated by base assisted deprotonation of water.

Moreover, we demonstrate that the reactions occur via fast,

reversible ﬁrst electron transfer and that the electron transfer

from simple SmI₂−water complexes (i.e., in the absence of

amine) to carboxylic acid derivatives is rapid. In addition, we

utilize reactivity studies to demonstrate that electronic

(Hammett) and steric (Taft) eﬀects signiﬁcantly inﬂuence the

rate of the reductions. Furthermore, we employ kinetic isotope

eﬀect experiments and ¹⁸O labeling experiments to determine

that proton transfer to carbon and hydrolysis (esters and amides)

are not involved in the rate-determining step of the reductions.

Overall, the data suggest that reactions of esters, carboxylic

acids, and amides proceed via a uniﬁed mechanism, in which the

key step involves the second electron transfer step with amine

B

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serving as an intramolecular base. The mechanistic details

presented herein indicate that complexation between SmI₂,

water, and amines results in a new class of structurally diverse,

thermodynamically powerful reductants for eﬃcient electron

transfer to a variety of carboxylic acid derivatives. Importantly,

these mechanistic studies provide substantial insights into the

fundamental steps of the SmI₂-mediated reduction of carboxylic

acid derivatives and could be critical for the design and

optimization of processes involving reduction of ketyl radicals

as a key step.

attempts to conduct kinetics to higher conversions, we have

detected signiﬁcant background reactions due to oxidation to

Sm(III) or miscibility problems. Within experimental error, the

reduction of 1 in the presence of SmI₂−Et₃N−H₂O was found to

be ﬁrst order in all components of the reaction (Table 1). The

rate constant of (1.4 0.1)× 10 M⁻³s⁻¹was determined for the

reduction of 1 under these reaction conditions. Taken together,

these results suggested that all reaction components were

involved in the rate equation and that the reduction of 1 was a fast

process.

At this stage of the investigation into the reaction mechanism,

we learned from a related reduction of six-membered lactones

using SmI₂−H₂O,^16,17a process concurrently under inves-

tigation in our laboratory, that the rate of the latter reaction is

signiﬁcantly dependent on the concentration of water cosolvent.

Accordingly, we further explored the impact of H₂O on the

reduction rate of 1 by monitoring the rate of the reduction over a

20-fold concentration range as depicted in Figure 3. In this study,

RESULTS AND DISCUSSION

■

Mechanism of Ester Reduction (Section A). In 2011, we

reported the ﬁrst general reduction of unactivated esters using

SmI₂−amine−water.²⁰This study provided a valuable founda-

tion for the development of reductive processes involving other

functional groups with SmI₂−amine−water;^21,22,24,25however,

the mechanistic details of this process, including the critical role

of amine and water additives, remained unclear.

To gain preliminary insight into the mechanism of the

reduction of carboxylic acid derivatives with SmI₂, we conducted

a range of kinetic studies (Table 1). tert-Butyl 3-phenyl-

Table 1. Rate Constant and Reaction Orders for the

Reduction of tert-Butyl 3-Phenylpropanoate Using SmI₂−

Et₃N−H₂O

rate order

a

b

c

d

k

[M⁻³s⁻¹

]

substrate

0.96 0.10

SmI₂

1.09 0.10

Et₃N

1.18 0.10

H₂O

0.92 0.10

1.4 × 10

a

[SmI₂] = 75 mM, [H₂O] = 250 mM, [Et₃N] = 150 mM, [ester] = 5−

b

20 mM. [SmI₂] = 50−100 mM, [H₂O] = 250 mM, [Et₃N] = 150

mM, [ester] = 12.5 mM. [SmI₂] = 75 mM, [H₂O] = 250 mM, [Et₃N]

= 75−250 mM, [ester] = 12.5 mM. [SmI₂] = 75 mM, [H₂O] = 75−

300 mM, [Et₃N] = 150 mM, [ester] = 12.5 mM. T = 23 °C.

c

d

Figure 3. Plot of k_obsversus concentration of H₂O for the reduction of 1.

[H₂O] = 0.075−1.2 M. [SmI₂] = 75 mM, [Et₃N] = 150 mM, [ester] =

12.5 mM, T = 23 °C.

propanoate (1) was selected as a model substrate because its

rate of reduction was found to be in a convenient range for kinetic

studies and there was ample precedent for Sm(II) reduction

conditions available for this substrate from our previous

studies.²⁰The reduction of 1 displayed a well-behaved kinetic

proﬁle throughout the course of the reduction. Kinetic proﬁles

have been followed under the closest possible kinetic conditions

relevant to the experimental conditions employed in synthetic

studies.^{20−22,24,25}The rates were determined by monitoring

alcohol formation via GC or GC-MS analysis (cf., SmI₂decay as

in other studies) at low conversions to prevent signiﬁcant

background reactions due to oxidation to Sm(III)^5,6and

miscibility problems in heterogeneous reaction mixtures. The

kinetics under pseudo-ﬁrst-order conditions were determined by

plotting ln[concentration] vs time, and the rate orders were

determined by plotting ln(rate) vs ln(concentration). A similar

procedure was followed for determining kinetics of the reduction

of unactivated carboxylic acids²¹and amides²²(vide infra). The

selection of substrates for mechanistic studies was based on the

reaction rate in order to determine kinetics under experimentally

relevant reaction conditions.^{20−22,24,25}Under the relevant

experimental conditions, reactions mediated by Sm(II) and

other lanthanides(II) cannot be monitored to higher conversions

due to the sensitive nature of this class of reagents.^1−3,5,6In

a nonlinear rate dependence on H₂O was found. At lower

concentrations (up to 300 mM), the rate was found to increase

linearly with a slope corresponding to the rate order of 1,

consistent with saturation behavior (300 mM). However, at

higher concentrations (300−1200 mM), the rate decreased

dramatically, consistent with substrate displacement from the

inner coordination sphere of Sm(II). In agreement with previous

studies, H₂O is expected to show high aﬃnity for Sm(II) and

compete for coordination to Sm(II) with the carboxylic acid

derivative.^13,14Interestingly, the concentration of H₂O at which

the decrease in the reaction rate is observed correlates with

iodide displacement from the Sm(II) coordination sphere.^13c

To further elucidate the role of the amine component, the

reduction rate of 1 was measured in the presence of a wide range

of amines with varying steric and electronic properties

(morpholine, n-Bu₃N, Et₃N, n-BuNH₂, pyrrolidine: v_initial= 2.4

× 10⁻⁴; 3.9 × 10⁻⁵; 5.0 × 10⁻⁴; 6.8 × 10⁻³; 8.8 × 10⁻³mM s⁻¹,

respectively).²⁷Remarkably, a dramatic change in the reaction

rate of over 2 orders of magnitude was found by simply using

diﬀerent amines for the reduction. Considering steric properties

exerted by these amines, our ﬁndings bode well for the

C

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chemoselective ﬁne-tuning of Sm(II)−amine reductants to

speciﬁc functional groups.

To elucidate the productivity diﬀerence in the SmI₂−amine−

H₂O mediated reduction of esters, we utilized intermolecular

competition studies (Table 2).^18cRemarkably, in the series of

Table 2. Role of Steric and Electronic Eﬀects on the Relative

Rates for the Reduction of Esters

Figure 4. Plot of log k vs σ and σ⁺for the reduction of 4-phenylacetic

acid methyl esters with SmI₂−Et₃N−H₂O. [Ester] = 0.025 M. [SmI₂] =

0.050 M. [Et₃N] = 0.60 M. [H₂O] = 0.60 M. T = 23 °C.

a

Relative reactivity values determined from product distribution by ¹H

b

NMR or GC of crude reaction mixtures. Relative reactivity values vs

the corresponding ethyl esters are shown in parentheses. All data

represent the average of at least two experiments.

eight methyl esters a reactivity range of over 3 orders of

magnitude was observed, depending on steric and electronic

properties of the α-carbon substituent at the ester group

undergoing the reduction (entries 1−8). This eﬀect is consistent

with both electronic stabilization of ketyl-type radicals (entries

1−4) and steric inhibition of coordination to Sm(II) (entries 4−

8). Moreover, several substrates with enhanced leaving group

ability compared with the methyl ester were examined (entries

9−14). These results support the importance of electronic

stabilization of ketyl radical intermediates in the reduction.²⁸The

data presented in Table 2 indicate high levels of chemoselectivity

in the reduction of esters with SmI₂−Et₃N−H₂O.^2j

Evidence for the electronic and steric stabilization of ketyl-type

radical intermediates was further substantiated by Hammett

(Figure 4)²⁹and Taft correlation studies (Figure 5).³⁰The

Hammett correlation study, employing methyl esters of 4-

phenylacetic acid (note that 4-substituted benzyl alcohols

undergo reductive cleavage of benzyl heteroatom bonds),^26e

showed a large positive ρ-value of 0.43 (R²= 0.98), which can be

Figure 5. Plot of log k vs E_Sfor the reduction of hydrocinnamic acid

esters with SmI₂−Et₃N−H₂O. [Ester] = 0.025 M. [SmI₂] = 0.050 M.

[Et₃N] = 0.60 M. [H₂O] = 0.60 M. T = 23 °C.

compared with the ρ-value of 0.49 for ionization of phenylacetic

acids in H₂O at 25 °C.²⁹In addition, a good correlation was

obtained by plotting log(k_obs) vs Hammet−Brown σ⁺con-

stants,³¹which may suggest that resonance eﬀects are involved in

stabilization of the reactive center. The Taft correlation study,

obtained by plotting log(k_obs) vs E_Sin a series of aliphatic esters

of hydrocinnamic acid showed a large positive slope of 0.83 (R²=

0.97). Overall, these results suggest that an anionic intermediate

D

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is formed in the transition state of the reaction and that a

conformational change is taking place in the rate-determining

step of the reaction. Note that the geometry and conformational

preferences of ketyls, hydroxyalkyl radicals, and hydroxyalkyl

carbanions indicate that ketyl radicals are planar.³²As suggested

by the Taft plot, the overall transformation from ketyl to

hydoxyalkyl carbanion can be compared with a change in

geometry similar to the ester hydrolysis (sp²to sp³).³³

observed with other Sm(II) reagents, including systems with

higher redox potential (SmI₂−MeOH, SmI₂−LiCl, SmI₂−

HMPA, and SmI₂−Et₃N). The reductive opening of cyclopropyl

carbinol does not occur under the reaction conditions (Scheme

2a). (3) The reduction of the methyl ester of cyclo-

Scheme 2. Additional Control Experiments: (a) Reductive

Opening of Cyclopropyl Carbinol; (b) Reduction Using

SmI₂−NaOH−H₂O (Kamochi−Kudo Conditions)

Next, to gain independent evidence on the nature of the

electron transfer steps, we carried out several studies employing

mechanistic probes³⁴and labeling experiments (Scheme 1 and

Scheme 1. Experiments Designed To Investigate Mechanism

of the Reduction of Unactivated Esters using SmI₂−Et₃N−

H₂O: (a) Radical Clock Studies; (b) Racemization Studies;

(c) ¹⁸O Incorporation Studies

propanecarboxylic acid (Scheme 1a, Table 3, entries 9−11, R =

H, approximated unimolecular rate constant k_frag= ca. 9.4 × 10⁷

s⁻¹at 25 °C) with SmI₂−amine−H₂O aﬀorded the correspond-

ing acyclic alcohol and cyclopropyl carbinol in 96:4 ratio. This

allows us to estimate the rate of reduction of ketyl-type radicals

with Sm(II) to be comparable to a unimolecular reaction with k

of about 10⁸s⁻¹.³⁴⁻³⁶(4) Experiments utilizing chiral probe 10

(Scheme 1b) demonstrate that enolization does not occur in the

process despite basic reaction conditions. (5) Control experi-

ments using H₂¹⁸O (Scheme 1c) show that the reduction does

not proceed via sequential ester hydrolysis/acid reduction

mechanism. (6) Control experiments with a SmI₂−base system

(Scheme 2b, modiﬁed Kamochi−Kudo conditions)³⁸demon-

strate that under optimized reaction conditions SmI₂−NaOH−

H₂O reduces aliphatic esters in high yield. Overall, these ﬁndings

strongly suggest that reductions of unactivated esters with SmI₂−

amine−H₂O occur via fast, reversible electron transfer³⁹and

indicate that electron transfer using simple SmI₂−H₂O

complexes (i.e., without amine) to aliphatic esters is rapid.⁴⁰

Mechanism of Carboxylic Acid Reduction (Section B).

Following our successful use of the SmI₂−amine−H₂O reagent

for the reduction of unactivated esters,²⁰in 2012, we reported the

ﬁrst general reduction of unactivated carboxylic acids using

Table 3): (1) Most importantly, trans-cyclopropane-containing

radical clock (R₁= Ph, approximated unimolecular rate constant

k

_frag= ca. 3 × 10¹¹s⁻¹at 25 °C)^35,36was selected and subjected to

the reaction conditions with a limiting amount of SmI₂(Scheme

1a and Table 3, entries 1). The reaction resulted in rapid

cyclopropyl ring opening to give acyclic ester 7 and alcohol 8 in

94:6 ratio. Cyclopropyl carbinol 9 was not detected in the

reaction. (2) Several control experiments were performed

(Scheme 1a, Table 3, entries 2−8).³⁷The reaction with SmI₂−

H₂O resulted in a facile opening, with no over-reduction to 8 or 9

observed. The reductive opening of radical clock was not

Table 3. Radical Clock Experiments in the Reduction of Esters Using SmI₂−Et₃N−H₂O and SmI₂−H₂O Reagents

a

b

entry

R₁

SmI₂(equiv)

Et₃N (equiv)

H₂O (equiv)

time

conv (%)

7

(%)

8

(%)

5

9

(%)

<2

1

2

3

4

5

Ph

H

4

8

4

2

8

24

48

24

48

<1 min

2 h

80

>98

53

75

<2

53

>98

<2

2.0

6.4

<2

200

2 h

c

48

2 h

<2

72 h

2 h

<2

dec.

<2

d

6

e

7

2 h

f

8

2 h

<2

g

9

24

48

24

48

2 h

62.8

>98

<2

34.2

<2

26.6

93.6

g

10

H

2 h

h

11

H

200

2 h

a

b

1

Quenched with air after the indicated time. Determined by H NMR or GC-MS of crude reaction mixtures and comparison with authentic

samples. In all entries, >90% combined yield of 7 and 8 based on the recovered starting material. In all entries, when <2% is indicated, 9 was not

c

d

e

f

g

detected. 66:34 ratio of ester to acid. HMPA, 24 equiv, was used. LiCl, 48 equiv, was used. MeOH, 370 equiv, was used (4/1 v/vol). Morpholine

h

was used instead of Et₃N. <2% conv. using SmI₂, 8 equiv and H₂O, 800 equiv at rt for 2 h.

E

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SmI₂.²¹It should be noted that in contrast to other functional

groups addressed in this study, the reduction of unactivated

carboxylic acids had been previously described by Kamochi and

Kudo using SmI₂−base systems;³⁸however, this process was low

yielding and limited in scope. The successful application of

Sm(II) systems other than SmI₂−amine−water to the reduction

of carboxylic acids suggested the following: (1) this functional

group is more accessible to eﬃcient electron transfer from

Sm(II) than other carboxylic acid derivatives; and (2) high

chemoselectivity in the reduction of carboxylic acids can be

achieved using Sm(II). This proved to be the case in our

synthetic studies.²¹

higher concentrations (112−225 mM). As such, the reduction of

carboxylic acids is signiﬁcantly more sensitive to changes in the

concentration of water than the reduction of esters (vide

supra),^6,13−15which can be explained by the higher Lewis basicity

of the carboxylic acid/carboxylate ligand in the transition state of

the reaction.⁴¹This eﬀect is consistent with substrate displace-

ment from the inner coordination sphere of Sm(II) and previous

studies.^13c,26d,16The rate dependence on the amine component

in the reduction of 12 was found to follow a similar order as the

rate of the reduction of esters (n-Bu₃N, Et₃N, pyrrolidine: v_initial

=

9.1 × 10⁻³; 1.3 × 10⁻²; 1.6 × 10⁻²mM s⁻¹, respectively).²⁷The

kinetic data are consistent with the role of the steric and

electronic properties of the amines in enhancing the redox

potential of the Sm(II) reductant, as well as with the increased

negative charge of the reductant by coordination of an anionic

carboxylate ligand. Finally, control experiments indicated that

water is required for the reduction of carboxylic acids under these

conditions (<2% conversion in the absence of water), which rules

out the role of carboxylic acid acting as a proton source in the

reduction.⁴²However, the recent ﬁndings should also be

considered.⁴³

As in the studies on the mechanism of the reduction of esters

with SmI₂−amine−water, we started our investigation by

conducting kinetic experiments (Table 4). The reduction of 2-

Table 4. Rate Constant and Reaction Orders for the

Reduction of 2-Butyloctanoic Acid Using SmI₂−Bu₃N−H₂O

Having determined kinetics of the reduction of carboxylic

acids, we turned our attention to intermolecular competition

studies to gain insight into the productivity diﬀerence in the

SmI₂−amine−water mediated reduction of carboxylic acids

using a set of eight carboxylic acids as a benchmark for

comparison with the reduction of esters under otherwise

identical reaction conditions (Table 5; cf. Table 2).^18c

rate order

a

b

c

d

k

[M⁻⁴s⁻¹

]

substrate

0.93 0.10

SmI₂

1.93 0.10

Bu₃N

0.94 0.10

H₂O

1.01 0.10

2.5 × 10²

a

[SmI₂] = 75 mM, [H₂O] = 250 mM, [Bu₃N] = 150 mM, [acid] = 5−

b

20 mM. [SmI₂] = 50−75 mM, [H₂O] = 200 mM, [Bu₃N] = 125 mM,

c

[acid] = 10.5 mM. [SmI₂] = 75 mM, [H₂O] = 250 mM, [Bu₃N] =

d

75−250 mM, [acid] = 12.5 mM. [SmI₂] = 75 mM, [H₂O] = 75−112

mM, [Bu₃N] = 150 mM, [acid] = 12.5 mM. Negative rate order

(−0.48) for [H₂O] = 112−225 mM. T = 23 °C.

Table 5. Role of Steric and Electronic Substitution on the

Relative Rates of Reduction of Carboxylic Acids

butyloctanoic acid (12) using Bu₃N as the amine ligand was

selected as a model reaction because the rate of reduction of 12

was found to be in a convenient range for kinetic studies under

these conditions. It should be noted that all kinetic experiments

in this study were performed under experimental conditions

similar to those employed in synthetic studies to gain insight into

the mechanism under experimentally relevant condi-

tions.^{20−22,24,25}Variations between kinetics performed under

pseudo-ﬁrst-order and preparative experimental conditions

under have been reported.^16,33,39Reaction conditions available

for the reduction of unactivated carboxylic acids with a variety of

SmI₂−amine−water systems have been published.²¹

Within experimental error, the reduction of 12 with SmI₂−

Bu₃N−H₂O was found to be ﬁrst order in acid, second order in

SmI₂, ﬁrst order in amine, and ﬁrst order in water at lower

concentration of water (Table 4). The rate constant of (2.5

0.1) × 10²M⁻⁴s⁻¹was determined for the reduction of 12 under

these conditions. In summary, these results suggested that all

reaction components were involved in the rate equation. The rate

order of two for SmI₂most likely results from the formation of a

dimeric SmI₂complex with a dimerization process promoted by

water or amine,^26a,bor formation of the Sm(III) carboxylate

under the reaction conditions.³⁸The rate order of two for SmI₂

may also suggest that the reduction proceeds in two steps with

the latter being rate determining.³⁹The rate order of one for

amine, acid, and water indicates that the mechanism of the

reduction of carboxylic acids bears similarities to the mechanism

of the reduction of esters under these reaction conditions.

Interestingly, the reduction of 12 was found to display a

nonlinear rate dependence on water concentration (linear

increase up to 112 mM) with a dramatic decrease of the rate at

a

Relative reactivity values determined from product distribution by ¹H

NMR and/or GC of crude reaction mixtures. All data represent the

average of at least two experiments.

Remarkably, in the series of eight derivatives a change of the

reactivity range from 3 orders of magnitude (esters, Table 2) to 1

order of magnitude (acids, Table 5) was observed, consistent

with the ﬂattening out eﬀect in the reduction rate of carboxylic

acids using SmI₂−amine−water observed during the kinetic

studies. Moreover, the reduction of 4-phenylacetic acids using

SmI₂−amine−water (Hammett study, Table 6)²⁹showed a ﬂat

k_X/k_Hof 1.10 0.02, providing further evidence for the relative

insensitivity of the reduction rate of carboxylic acids to electronic

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Table 6. Eﬀect of Substitution on the Relative Rates for the

Reduction of 4-Phenylacetic Acids Using SmI₂−Et₃N−H₂O

Scheme 3. Experiments Designed To Investigate the

Mechanism of the Reduction of Unactivated Carboxylic Acids

a

using SmI₂−Et₃N−H₂O: (a) Radical Clock Studies; (b)

a

Racemization Studies

b

entry

R

σ

RV

1

2

3

4

5

CF₃

Cl

0.54

0.23

0.06

0

1.08

1.09

1.12

1.00

1.10

F

H

MeO

−0.27

a

Conditions: [acid] = 0.025 M. [SmI₂] = 0.050 M. [Et₃N] = 0.60 M.

b

[H₂O] = 0.60 M. T = 23 °C. Relative reactivity values determined

from product distribution by ¹H NMR or GC of crude reaction

mixtures.

a

Conditions: A: Et₃N (48 equiv), H₂O (48 equiv); B: NaOH(aq) (16

equiv, 4 N).

performed (Scheme 3a, Table 8, entries 2−7).³⁷The reaction

with excess of SmI₂resulted in a full reduction to 8 (entry 2). The

reaction with SmI₂−H₂O resulted in a facile opening, with no

over-reduction to 8 or 9 observed (entry 3), and the rate

dependence on water concentration was consistent with the

previous studies (entry 5).^16,17The reductive opening of the

radical clock was not observed with SmI₂, SmI₂−amine, or

SmI₂−MeOH systems (entries 4−5, 7). (3) Experiments

utilizing chiral probe 17 (Scheme 3b) demonstrate that

enolization does not occur to a signiﬁcant extent in the reduction

(the rate of ET is faster than the rate of enolization); however,

note that the presence of a chiral α-stereocenter is not

compatible with the reduction using SmI₂−NaOH (Scheme

3b, conditions B). The data in Table 8 strongly suggest that the

reaction proceeds via reversible electron transfer and indicate

that electron transfer using simple SmI₂−H₂O complexes (i.e.,

without amine) to aliphatic acids is rapid. In summary, these

ﬁndings strongly suggest that reductions of unactivated acids

with SmI₂−amine−H₂O occur via a similar mechanism to the

reduction of unactivated esters with the major diﬀerence being a

ﬂattening out of the reaction rate due to the presence of a

negatively charged carboxylate intermediate.

and steric components on the substrate, consistent with the

formation of a negatively charged intermediate and strong

coordination to Sm(II) during the transition state of the reaction.

Finally, to test the role of electronic activation in the relative rates

of the reduction of carboxylic acids, we performed competition

experiments with electronically diﬀerentiated esters and

aldehydes (Table 7). The data in Table 7 indicate that the

Table 7. Eﬀect of Electronic Activation on the Relative Rates

of Reduction of Esters, Carboxylic Acids, and Aldehydes

Using SmI₂−Et₃N−H₂O

a

Relative reactivity values determined from product distribution by ¹H

NMR or GC of crude reaction mixtures. All data represent the average

Mechanism of Amide Reduction (Section C). Building

upon our experience in using Sm(II) reagents,^20,21in 2014 we

reported the ﬁrst general reduction of amides to alcohols with

SmI₂−amine−water.²²The reaction was particularly signiﬁcant

because of the uncommon C−O/C−N cleavage selectivity for all

types of amides (primary, secondary, tertiary) and the excep-

tionally mild reaction conditions that allow direct conversion of

amides to alcohols under standard laboratory conditions.⁴⁵Prior

to our report, only a few methods for the reduction of amides to

alcohols had been reported, and none of them displayed the

generality of the SmI₂-mediated process.²³Perhaps not

surprisingly in light of the low electrophilicity of amide

bonds,⁴⁶during the development of the reaction we found that

the reduction of amides is signiﬁcantly more challenging than the

reduction of other carboxylic acid derivatives. We hypothesized

that detailed mechanistic studies would shed light on this process

and allow for further optimization of the reaction conditions

reported in our initial communication. From the outset, we

realized that the key question pertained to the generality of the

reduction mechanism, an answer to which could potentially

provide insights into the use of similar reaction conditions to

maximize the synthetic eﬃciency of the process. For comparison

purposes, the discussion on the mechanism of amide reduction

of at least two experiments.

chemoselectivity of the reduction of esters and carboxylic acids

can be signiﬁcantly inﬂuenced by a judicious choice of the

electronics of the substrate, which may have important

consequences from a synthetic perspective. Moreover, the data

in Table 7 suggest that the reduction of aldehydes under these

conditions is under thermodynamic control, which could be due

to the reversibility of the ﬁrst electron transfer or formation of

hydrated hemiacetals.⁴⁴Relative rates for the reduction of

carboxylic acids,²¹esters,²⁰and aldehydes¹¹have been published.

Next, experiments employing mechanistic probes were carried

out to establish reversibility of the electron transfer^34,40in the

reduction of carboxylic acids with SmI₂−amine−water and the

potential for racemizaton of a chiral α-stereocenter under the

reaction conditions (Scheme 3 and Table 8): (1) Most

importantly, trans-cyclopropane-containing radical clock 15

was subjected to the reaction conditions with a limiting amount

of SmI₂(Scheme 3a and Table 8, entry 1).^35,36The reaction

resulted in rapid cyclopropyl ring opening to give acyclic acid 16

and alcohol 8 in 78:22 ratio. Cyclopropyl carbinol 9 was not

detected in the reaction. (2) Several control experiments were

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Table 8. Radical Clock Experiments in the Reduction of Carboxylic Acids Using SmI₂−Et₃N−H₂O and SmI₂−H₂O Reagents

a

b

entry

SmI₂(equiv)

Et₃N (equiv)

H₂O (equiv)

time

conv (%)

16 (%)

8

(%)

9.5

96

9

(%)

<2

yield (%)

1

2

3

4

5

6

2

8

24

48

24

48

<1 min

2 h

44

>98

15

34

15

44

96

15

<2

8

<2

200

2 h

<2

48

2 h

<2

48

2 h

8.3

d

7

615 (MeOH)

2 h

<2

a

b

1

Quenched with air after the indicated time. Determined by H NMR or GC-MS of crude reaction mixtures and comparison with authentic

d

samples. In all entries, when <2% is indicated, 9 was not detected. MeOH instead of H₂O was used (4/1 v/vol).

follows the same format as the discussion of the reduction of

unactivated esters and carboxylic acids.

We started our investigation by conducting a range of kinetic

studies (Table 9). N,N-Diethyldecanamide (18) was selected as a

follows a similar order as for the reduction of esters and acids

(Et₃N, pyrrolidine: v_initial= 5.4 × 10⁻⁴; 5.6 × 10⁻³mM s⁻¹,

respectively).²⁷Taken together, these results strongly suggest

that the role of amine and water components in the reduction of

esters, acids, and amides in this Sm(II) reducing system shares

signiﬁcant similarities between the substrates and is not

signiﬁcantly inﬂuenced by the relative redox potentials and

coordination abilities of the substrates. Considering steric

Table 9. Rate Constant and Reaction Orders for the

Reduction of N,N-Diethyldecanamide using SmI₂−Et₃N−

H₂O

properties of amines with varying pK_BHvalues,²⁷these

+

observations suggest that chemoselective ﬁne-tuning of Sm-

(II)−amine reductants to speciﬁc functional groups should be

possible.^2jThe relative reactivity of functional groups with

SmI₂−amine−water systems has been published.²⁰⁻²²

To elucidate how steric and electronic parameters inﬂuence

the rate of amide reduction, we conducted a set of intramolecular

competition experiments across a selected series of benchmark

substrates with varying electronic and steric properties (Table

10).^18cAll values presented in Table 10 are normalized versus

rate order

a

b

c

d

k [M⁻¹s⁻¹

]

substrate

0.50 0.10

SmI₂

0.93 0.10

Et₃N

0.94 0.10

H₂O

0.84 0.10

1.7 × 10⁻¹

a

[SmI₂] = 75 mM, [H₂O] = 250 mM, [Et₃N] = 150 mM, [amide] =

5−20 mM. [SmI₂] = 50−75 mM, [H₂O] = 200 mM, [Et₃N] = 125

mM, [amide] = 10.5 mM. [SmI₂] = 75 mM, [H₂O] = 250 mM,

[Et₃N] = 75−250 mM, [amide] = 12.5 mM. [SmI₂] = 75 mM,

[H₂O] = 75−112 mM, [Et₃N] = 150 mM, [amide] = 12.5 mM.

Negative rate order (−0.37) for [H₂O] = 112−225 mM. T = 23 °C.

b

c

d

Table 10. Eﬀect of Steric and Electronic Substitution on the

Relative Rates of Reduction of Amides Using SmI₂−Et₃N−

H₂O

model substrate because its rate of reduction was found to be in a

convenient range for kinetic studies. The reduction of N,N-

diethyldecanamide displayed a well-behaved kinetic proﬁle

throughout the course of the reaction. Reaction conditions for

the reduction of amides using SmI₂−amine−water have been

published.²²Within experimental error, the reduction of 18 with

SmI₂−Et₃N−H₂O was found to be ﬁrst order in SmI₂, ﬁrst order

in amine, and ﬁrst order in H₂O at low concentration of water.

The reaction displayed half-order dependence on amide

concentration. The rate constant of (1.7 0.1) × 10⁻¹M⁻¹

s⁻¹was determined for the reduction of 18 under these reaction

conditions. The observed rate order for the amide most likely

results from the formation of a complex between the Lewis basic

substrate and the reagent,^26e,41in which the amide competes for

coordination with amine/water at the Sm(II) center; however,

formation of amide dimers could also contribute to the observed

rate order.⁴⁷The rate order of one for SmI₂, amine, and water

indicates that the mechanism of the reduction of amides bears

signiﬁcant similarities to the reduction of unactivated esters and

carboxylic acids under these reaction conditions. In addition, the

reduction of 18 also displays a nonlinear rate dependence on

water concentration (linear increase up to 112 mM) with a

dramatic decrease of the rate at higher concentrations (112−225

mM), which is analogous to the eﬀect of the concentration of

water on the rate of the reduction of carboxylic acids (vide

supra).^6,13−15This eﬀect is consistent with the coordination of

the substrate to the Sm(II) center. Moreover, the rate

dependence on the amine component in the reduction of 18

a

Relative reactivity values determined from product distribution by ¹H

NMR or GC of crude reaction mixtures. All values are normalized vs

C₉H₁₉COR.

decanamides. Interestingly, the study revealed signiﬁcant

diﬀerences in the reduction rate between primary (10-fold

diﬀerence in reactivity), secondary, and tertiary amides (>100-

fold diﬀerence in reactivity across the ﬁve benchmark substrates),

with the largest relative diﬀerence observed for secondary

amides. This eﬀect is similar to the ﬂattening out eﬀect observed

in the reduction of unactivated carboxylic acids under the same

reaction conditions.

Next, Taft³⁰and Hammett²⁹correlation studies were carried

out to gain additional insight into the mechanism of amide

reduction (Figures 6−9). Taft correlation (Figure 6) was

obtained by plotting log(k_obs) vs E_Sin a series of N-mono and

N,N-disubstituted 3-phenylpropanamides and showed large

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Figure 7. Plot of log k vs σ and σ⁺for the reduction of 2-

phenylacetamides with SmI₂−Et₃N−H₂O. [Amide] = 0.025 M.

[SmI₂] = 0.050 M. [Et₃N] = 0.60 M. [H₂O] = 0.60 M. T = 23 °C.

Figure 6. Plot of log k vs E_Sfor the reduction of N-mono and N,N-

disubstituted 3-phenylpropanamides with SmI₂−Et₃N−H₂O. [Amide]

= 0.025 M. [SmI₂] = 0.050 M. [Et₃N] = 0.60 M. [H₂O] = 0.60 M. T = 23

°C.

positive slopes of 0.92 (R²= 0.99) and of 3.25 (R²= 0.94) for the

reduction of secondary and tertiary amides, respectively. This can

be compared with a positive slope of 0.97 determined earlier for

the reduction of aliphatic esters of hydrocinnamic acid. Taken

together, these ﬁndings indicate that steric factors play a

signiﬁcant role in the reduction of carboxylic acid derivatives

with SmI₂−amine−water. The slow reaction rate caused by

inhibition of Sm(II)-coordination to carbonyl groups due to

steric factors has been previously reported.^16b

Hammett correlation studies (Figures 7−9) were conducted

for various para-substituted 2-phenylacetamides and showed

large positive ρ-values of 0.52 (R²= 0.98) (Figure 7) and of 0.60

(R²= 0.90) (Figure 9) for the reduction of primary and tertiary

amides, respectively, which can be compared with the ρ-value of

0.43 determined for the reduction of methyl esters of 4-

phenylacetic acid determined earlier, and a small positive ρ-value

of 0.13 (R²= 0.99) (Figure 8) for the reduction of secondary

amides under identical reaction conditions. Previously, it has

been shown that 4-substituted benzyl alcohols undergo reductive

cleavage of benzyl heteroatoms.^26eIn the reduction of para-

triﬂuoromethyl-substituted primary amides, a competing de-

ﬂuorination reaction was observed under these reaction

conditions,^26fand these substrates were not included. In

addition, typically good correlations were obtained by plotting

log(k_obs) vs Hammet−Brown σ⁺constants for the reduction of

amides with SmI₂−amine−water,³¹which suggests that reso-

nance eﬀects are involved in stabilization of the reactive center. In

summary, Hammett correlation studies in the reduction of

amides suggest the following: (1) an anionic intermediate is

formed in the transition state of the reaction; (2) the reaction of

primary and tertiary amides bears analogies to the reduction of

unactivated esters under the SmI₂−amine−water conditions in

terms of electronic stabilization of the anionic intermediate in the

Figure 8. Plot of log k vs σ and σ⁺for the reduction of N-alkyl 2-

phenylacetamides with SmI₂−Et₃N−H₂O. [Amide] = 0.025 M. [SmI₂]

= 0.050 M. [Et₃N] = 0.60 M. [H₂O] = 0.60 M. T = 23 °C.

transition state of the reaction; and (3) the reaction of secondary

amides bears similarities to the reduction of unactivated

carboxylic acids under the SmI₂−amine−water conditions in

that an additional negative charge is present in the transition state

of the reaction (i.e., N−H deprotonation or formation of

carboxylate occurs prior to the rate-determining step of the

reaction).

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SmI₂resulted in a full (primary and secondary) and signiﬁcant

(tertiary) reduction to 8 (entries 4−6). The reaction with SmI₂−

H₂O resulted in cyclopropyl opening, with no over-reduction to

8 or 9 observed (entries 7−9); note that reactions in entries 4−

10 have not been optimized. The reductive opening of the radical

clock was not observed with the SmI₂−THF system (entries 10−

12). (3) Experiments utilizing chiral probe 24 (Scheme 4b)^22,23c

demonstrate that enolization does not occur in the reduction

despite basic reaction conditions. (4) Control experiments using

H₂¹⁸O (Scheme 4c) show that amide and/or iminium hydrolysis

are not the major reaction pathways with the extent of ¹⁸O

incorporation consistent with the relative stability of the iminium

intermediates.⁴⁸

The data in Table 11 strongly suggest that the reduction of

amides proceeds via a reversible electron transfer and indicate

that electron transfer using simple SmI₂−H₂O complexes (i.e.,

without amine) to unactivated amides is feasible, but this process

is slower than that from Sm(II) to the corresponding esters and

carboxylic acids as would be expected on the basis of the relative

electrophilicity of the carbonyl groups. In summary, these

ﬁndings demonstrate that reductions of unactivated amides with

SmI₂−amine−H₂O occur via a similar mechanism to the

reduction of unactivated esters and carboxylic acids with the

major diﬀerence being a ﬂattening out of the reaction rate due to

steric factors (primary amides), the presence of a negatively

charged intermediate (secondary amides), and inhibition of

coordination of Sm(II) center (tertiary amides).

Additional Radical Clock Experiments. Previous studies

have shown that diﬀerent Sm(II)-based reducing systems are

capable of eﬃciently promoting electron transfer to the carbonyl

groups of carboxylic acid derivatives.^{20−22,24,25}As shown in

Tables 3, 8, and 11, SmI₂−water was one of the examined

systems that promoted the reductive opening of cyclopropyl

radical clocks; however, under the reaction conditions, further

reduction to the alcohol was not observed, consistent with the

higher chemoselectivity of the reagent (cf., SmI₂−Lewis base−

water reagents).^2j

Figure 9. Plot of log k vs σ and σ⁺for the reduction of N,N-dialkyl 2-

phenylacetamides with SmI₂−Et₃N−H₂O. [Amide] = 0.025 M. [SmI₂]

= 0.050 M. [Et₃N] = 0.60 M. [H₂O] = 0.60 M. T = 23 °C.

Studies employing mechanistic probes^34,40and labeling

experiments were conducted to elucidate the nature of the

electron transfer steps and to probe the potential for

racemization and hydrolysis under the reaction conditions

(Scheme 4 and Table 11): (1) Most importantly, trans-

Scheme 4. Experiments Designed To Investigate the

Mechanism of the Reduction of Unactivated Amides Using

SmI₂−Et₃N−H₂O: (a) Radical Clock Studies; (b)

Racemization Studies; (c) ¹⁸O Incorporation Studies

To compare the reactivity of SmI₂−water and SmI₂−amine−

water reagents and to gain insights into the relative rates of the

ﬁrst electron transfer^34,35a set of competition studies was

designed and carried out (Table 12). The relative reactivity

values were determined from the product distribution of the C−

C cleavage products.^18cIn these experiments, further reduction

to the alcohol is typically not observed or results from the

reduction of the more reactive carboxylic acid derivative as

shown in Tables 2, 5, and 10. The studied substrates do not

participate in alternative reaction pathways. This method allows

us to accurately measure the relative energy barriers for the ﬁrst

electron transfer to carboxylic acid derivatives and stability of the

resulting radicals using various Sm(II)-based systems.

As shown in Table 12 (entries 1−4), comparison of the relative

reactivity toward the ﬁrst electron transfer of esters with varying

steric (entries 1−2) and electronic (entries 3−4) properties

reveals the following: (1) the radical formed from a tert-butyl

ester is signiﬁcantly less stable than the radical formed from a

methyl ester using SmI₂−amine−water (entry 1); however, the

stability of these radicals is similar when using SmI₂−water (entry

2); (2) the stability of radicals formed from a methyl and a pfp

ester is similar when using SmI₂−amine−water (entry 3);

however, the radical formed from a methyl ester is signiﬁcantly

less stable when using SmI₂−water (entry 4). These eﬀects are

consistent with the stabilization of ketyl radicals with SmI₂−

amine−water relative to SmI₂−water and the fact that SmI₂−

cyclopropane-containing radical clock 22 was subjected to the

reaction conditions with a limiting amount of SmI₂(Scheme 4a

and Table 11, entries 1−3).^35,36The reaction resulted in rapid

cyclopropyl ring opening to give acyclic amides 23 and alcohol 8

in 78:22, 85:15, and 92:8 ratio (primary, secondary, and tertiary

amides, respectively). Cyclopropyl carbinol 9 was not detected in

the reaction. (2) Several control experiments were performed

(Scheme 4a, Table 11, entries 4−12).³⁷The reaction with excess

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Table 11. Radical Clock Experiments in the Reduction of Amides Using SmI₂−Et₃N−H₂O and SmI₂−H₂O Reagents

a

b

entry

22

SmI₂(equiv)

Et₃N (equiv)

H₂O (equiv)

time

conv (%)

23 (%)

8

(%)

yield (%)

1

22a

22b

22c

22a

22b

22c

22a

22b

22c

22a

22b

22c

2

8

24

72

24

<1 min

18 h

2 h

54

50

78

85

22

15

8

54

50

51

99

97

99

39

4

2

3

24

51

92

4

72

>98

39

<2

>98

5

72

3

97

41

<2

6

72

59

7

200

>98

8

2 h

4

9

2 h

10

<5

10

11

12

18 h

<5

a

b

1

Quenched with air after the indicated time. Determined by H NMR or GC-MS of crude reaction mixtures and comparison with authentic

samples. In all entries, 9 was not detected (<2.0%). Combined yield of 23 and 8. Conversion = (100 − SM).

type radical formed from the acid; (3) using SmI₂−NaOH, the

Table 12. Radical Clock Experiments Designed To Investigate

the Rate of Initial Electron Transfer to Sterically and

Electronically Diﬀerentiated Carboxylic Acid Derivatives

Using SmI₂−Et₃N−H₂O and SmI₂−H₂O Reductants

ketyl-type radical formed from the ester is signiﬁcantly less stable

than the ketyl-radical formed from the acid, which indicates that

the formation of an anion stabilizes the ketyl. This in turn

indicates that under SmI₂−amine−water conditions the

carboxylic acid is partially deprotonated during the ﬁrst electron

transfer step (cf. Hammett studies and kinetic experiments in

Table 5).

Finally, comparison of the relative rates for the ﬁrst electron

transfer to amides versus esters (entries 8−9) and acids (entries

10−11) using SmI₂−amine−water and SmI₂−water systems

reveals the following features: (1) the stability of ketyl radicals

formed from amides is much higher than that of radicals formed

from esters using SmI₂−amine−water (entry 8); however, these

radicals are similar in stability when using SmI₂−water (entry 9);

(2) radicals formed from carboxylic acids are similar in stability to

radicals formed from amides using SmI₂−amine−water (entry

10) and SmI₂−water systems (entry 11). These observations are

consistent with the stabilization of ketyl-type radicals with SmI₂−

amine−water and the Lewis basicity of the carboxylic acid

derivative. Overall, the ﬁndings presented in Table 12 are

consistent with the thermodynamic nature of the ﬁrst electron

transfer step under the examined reaction conditions.

b

28

29

8

a

entry

R₁

R₂

conditions

(%)

k_26/27

1

OMe

OH

OtBu

Opfp

OH

A

B

A

B

A

B

C

A

B

A

B

42

82

7.5

<2

29

60

21

3

4

41

8.5

26

24

6

<5

8.5

20

<5

20

<5

16

<5

11.5

2.0

2

3

0.44

<0.04

1.25

10.3

0.31

0.04

1.35

0.52

0.57

4

5

6

OH

7

OH

67

44

40

29

34

8

NH₂

9

54

15

19

10

11

OH

a

Conditions: A, SmI₂(2 equiv), Et₃N (24 equiv), H₂O (24 equiv); B,

SmI₂(8 equiv), H₂O (200 equiv); C, SmI₂(2 equiv), NaOH (12

equiv), H₂O (24 equiv). Quenched with air after the indicated time. In

all entries, preformed Sm(II) system was used. Determined by H

NMR or GC-MS of crude reaction mixtures and comparison with

authentic samples. In all entries, 9 was not detected (<2.0%).

Kinetic Isotope Eﬀects.⁴⁹Several types of deuteration and

kinetic isotope studies with carboxylic acid derivatives using

SmI₂−amine−water have been conducted.²⁰⁻²²A summary of

these studies is presented in Table 13. Deuteration and KIE

studies suggest that anions are protonated in a series of electron

transfers and that proton transfer to carbon is not involved in the

b

1

amine−water systems are typically more sterically encumbered

than SmI₂−alcohol reagents. Moreover, these ﬁndings demon-

strate that the diﬀerence in rates in the reduction of methyl and

pfp esters with SmI₂−amine−water may result from a decreased

energy of activation (favoring the pfp ester) for the second

electron transfer.

Table 13. Summary of Deuterium Incorporation and Kinetic

Isotope Eﬀect Studies in the Reduction of Esters, Carboxylic

Acids, and Amides Using SmI₂−Et₃N−H₂O

entry

substrate

D²[%]

k_H/k_D

Examination of the relative rates for the ﬁrst electron transfer

to carboxylic acids (entries 5−7) reveals dramatic diﬀerences in

reactivity between SmI₂−amine−water (entry 5), SmI₂−water

(entry 6), and SmI₂−NaOH (entry 7) systems. The results are

summarized as follows: (1) using SmI₂−amine−water, the ketyl

radical formed from the ester is slightly more stable than the ketyl

radical formed from acid; however after deprotonation to

carboxylate, the ketyl stability signiﬁcantly increases via inductive

eﬀect (cf. Table 7); (2) using SmI₂−water, the ketyl-type radical

formed from the ester is signiﬁcantly more stable than the ketyl-

a

1

PhCH₂CH₂CO₂i-Pr

PhCH₂CH₂CO₂H

>97

96.0

83.2

94.7

96.9

1.4

1.1

1.4

1.3

b

2

c

3

PhCH₂CH₂CONH₂

PhCH₂CH₂CONHn-Bu

PhCH₂CH₂CONEt₂

c

4

c

5

a

b

c

Reference 20. Reference 21. Reference 22. KIE determined from

intramolecular competition experiments or parallel runs. D²

incorporation determined from reactions using D₂O instead of H₂O.

See ref 16a for additional details.

K

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rate-determining step of the reduction of unactivated esters,

carboxylic acids, and amides with SmI₂−amine−water.^16,20−22

Proposed Mechanism. The mechanistic studies presented

in this manuscript indicate that reductions of unactivated esters,

carboxylic acids, and amides with SmI₂−amine−water proceed

via a generalized mechanism featuring the following steps: (1)

reversible coordination, protonation, and ﬁrst electron transfer

steps; (2) rate-limiting second electron transfer step; (3) rapid

hemiacetal/hemiaminal collapse and reduction to the alcohol

product (Scheme 5). Several other features of the presented

6).^16aA summary of determined mechanistic parameters for the

reduction of all three functional groups is presented in Chart 2.

1

d[alcohol]/dt = k[SmI₂] [H₂O] [Et₃N] [ester]

d[alcohol]/dt = k[SmI₂]²[H₂O]¹[Et₃N]¹[acid]¹

(1)

(2)

(3)

(4)

1

d[alcohol]/dt = k[SmI₂] [H₂O] [Et₃N] [amide]^0.5

d[RH]/dt = k[SmI₂]²[H₂O]⁰[Et₃N]¹[RX]¹

d[RCH₂H]/dt = k[SmI₂]¹[H₂O]¹[Et₃N]¹

[RCH₂OH]¹

Scheme 5. (a) Proposed Mechanism for the Reduction of

Carboxylic Acid Derivatives Using SmI₂−H₂O−Amine

Complexes and (b) Mechanism Describing the Final Step of

the Electron Transfer to Carboxylic Acid Derivatives Using

SmI₂−Et₃N−H₂O

(5)

(6)

d[1, 5‐diol]/dt = k[SmI₂]¹[H₂O]²[lactone]²

Chart 2. Summary of Methods Employed in the Current Study

To Determine the Mechanism of Reduction of the Three

Functional Groups

a

b

Flat correlation was observed. “−” sign indicates that ¹⁸O

c

mechanism are noteworthy: (i) inner-sphere electron transfer

process that is inhibited by large concentrations of water and

facilitated by Brønsted basic amines in the case of all three

functional groups; (ii) rate-determining step that can be ﬁne-

tuned by steric and electronic properties of the carboxylic acid-

derived substrate; (iii) change of the substrate ground state redox

potential by coordination of the carbonyl group to the Lewis

acidic SmI₂-reductant allowing eﬃcient electron transfer.

incorporation was not observed. nd = not determined. D₂

incorporation was observed. “−” sign indicates that a signiﬁcant

primary KIE to carbon was not observed.

d

Recent ﬁndings demonstrate that reductions of carboxylic

acids (SmI₂−amine−water)²⁰⁻²²and other carbonyl derivatives

(SmI₂−water)¹⁶using distinct Sm(II) reductants share common

mechanistic features, the most important being the thermody-

namic character of the ﬁrst electron transfer step and a nonlinear

rate dependence on the water concentration.^2j,40The recent

advances in the understanding of processes mediated by SmI₂−

amine−water complexes²⁶should be considered in conjunction

with other recent studies on the mechanisms of SmI₂-mediated

reactions¹³⁻¹⁵in the future development of new SmI₂-promoted

transformations.

The synthetic and mechanistic experiments indicate that in the

reductions of carboxylic acid derivatives with SmI₂−amine−

water, the reactive complex between SmI₂, water, and amine

must be present in signiﬁcant quantities.^26aWithin this complex,

one molecule of amine participates in partial deprotonation of

water, resulting in a formal negative charge at oxygen and an

overall increase of the redox potential of the Sm(II) reductant in

the transition state. The use of SmI₂−amine−water is advanta-

geous over other Sm(II) systems due to the high redox potential

of the reagent, which allows the reduction of traditionally

unreactive functional groups under single electron transfer

CONCLUSIONS

■

We have described a detailed investigation into the mechanism of

the SmI₂-mediated reduction of carboxylic acid derivatives

(esters, acids, and amides) to alcohols. With minor diﬀerences

noted in the manuscript, the overall mechanism for the

transformation of all three functional groups is similar. Our

data are consistent with the formation of distinct Sm(II)

reductants by complexation between Sm(II), amine, and H₂O.

The reduction appears to proceed after deprotonation of a

molecule of H₂O by amine and to involve a reversible ﬁrst

electron transfer step. Our data demonstrate that a set of novel

conditions.^2jFrom a practical point of view, the pK_BHdependent

+

deprotonation of H₂O in SmI₂−amine−H₂O complexes can

have a profound impact on achieving high levels of chemo-

selectivity in the reductions of various substrates.

A summary of observed reaction orders for the reduction of

carboxylic acid derivatives using SmI₂−H₂O−Et₃N is presented

in eqs 1−3, which can be compared with the reduction of alkyl

halides using SmI₂−H₂O−Et₃N (eq 4),^26bdeoxygenation of

benzyl alcohols using SmI₂−H₂O−Et₃N at low concentrations of

substrate and water (eq 5),^26eand the reduction of six-membered

lactones using SmI₂−H₂O at low concentration of water (eq

+

Sm(II) reductants that can be ﬁne-tuned by the pK_BHof the

amine component is available for challenging electron transfer

L

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iodide (THF solution, 0.20−0.80 mmol, 2.0−8.0 equiv, 0.10 M) was

added followed by Et₃N and H₂O with vigorous stirring, which resulted

in the formation of the characteristic dark brown color of the SmI₂−

Et₃N−H₂O complex. A solution of substrate (0.10 mmol, 1.0 equiv,

stock solution in THF) was added, and the reaction mixture was stirred

for the indicated time. The excess of Sm(II) was oxidized by bubbling air

through the reaction mixture. Workup and analysis was performed as

described for method B. In all other cases, the Sm(II) reagent was

preformed by adding the speciﬁed additive to the SmI₂solution

prepared as described above and stirring until the color characteristic to

a particular Sm(II) complex had appeared (SmI₂−H₂O, burgundy red;

SmI₂−MeOH, dark brown; SmI₂−HMPA, purple; SmI₂−LiCl, green;

SmI₂−Et₃N, dark blue).

Procedure D. Epimerization Studies. An oven-dried vial containing a

stir bar was placed under a positive pressure of argon and subjected to

three evacuation/backﬁlling cycles under high vacuum. Samarium(II)

iodide (THF solution, 0.80 mmol, 8.0 equiv, 0.10 M) was added

followed by Et₃N and H₂O with vigorous stirring, which resulted in the

formation of the characteristic dark brown color of the SmI₂−Et₃N−

H₂O complex. A solution of substrate (0.10 mmol, 1.0 equiv, stock

solution in THF) was added, and the reaction mixture was stirred for 2−

18 h. The excess of Sm(II) was oxidized by bubbling air through the

reaction mixture. Workup and analysis was performed as described for

method B. Enantiomeric excess was determined after chromatographic

puriﬁcation on silica gel. HPLC analysis: ester and acid reduction

(chiralpak IA 28C, hexanes/i-PrOH 99/1, 1.0 mL/min, 220 nm), t_R

(minor) = 18.42 min, t_R(major) = 19.48 min; amide reduction, R

(chiracel OD-H, hexanes/i-PrOH 95/5, 1.0 mL/min, 220 nm), t_R

(minor) = 8.75 min, t_R(major) = 10.39 min; amide reduction, S

(chiracel OD-H, hexanes/i-PrOH 95/5, 1.0 mL/min, 220 nm), t_R

(major) = 9.23 min, t_R(minor) = 11.12 min.

reactions to carboxylic acid derivatives. Most crucially, this work

is one of the few studies showing that Sm(II) additives (e.g.,

H₂O, amine−H₂O) contribute to the stabilization of ketyl radical

intermediates rather than to simply increasing the redox

potential of the Sm(II) reductant. We fully expect that these

ﬁndings will contribute to the development of new electron

transfer reactions. The work in this direction is ongoing in our

laboratories, and these results will be reported shortly.

EXPERIMENTAL SECTION

■

General Methods. All products and staring materials used in this

study are commercially available or have been previously reported.²⁰⁻²²

The products were identiﬁed using ¹H NMR, GC, and GC-MS analysis

and comparison with authentic samples. The reaction progress was

quantiﬁed by ¹H NMR or GC-MS analysis using internal standards after

workup unless stated otherwise. Characterization data for all alcohol

products have been previously reported. All experiments were

performed using standard Schlenk techniques under argon atmosphere.

All solvents were purchased at the highest commercial grade and used as

received or after puriﬁcation by passing through activated alumina

columns or distillation from sodium/benzophenone under nitrogen. All

solvents were deoxygenated by freeze−pump−thawing or sparging with

argon prior to use. Samarium(II) iodide was prepared as described

previously.⁴⁵Samarium metal was purchased as −40 mesh and stored at

room temperature in a closed container on a bench prior to use. 1,2-

Diiodoethane was stored at 4 °C and used after puriﬁcation as described

previously.⁴⁵All other chemicals were purchased at the highest

commercial grade and used as received. Reaction glassware was oven-

dried at 140 °C for at least 24 h or ﬂame-dried prior to use, allowed to

cool under vacuum, and purged with argon (three cycles). Other general

methods have been published.^5b

Procedure E. H₂¹⁸O Incorporation Studies. An oven-dried vial

containing a stir bar was placed under a positive pressure of argon and

subjected to three evacuation/backﬁlling cycles under high vacuum.

Samarium(II) iodide (THF solution, 0.80 mmol, 8.0 equiv, 0.10 M) was

added followed by Et₃N and H₂O with vigorous stirring, which resulted

in the formation of the characteristic dark brown color of the SmI₂−

Et₃N−H₂O complex. A solution of substrate (0.10 mmol, 1.0 equiv,

stock solution in THF) was added, and the reaction mixture was stirred

for 2−18 h. The excess of Sm(II) was oxidized by bubbling air through

the reaction mixture. Workup and analysis was performed as described

for method B. ¹⁸O incorporation was determined by HRMS analysis

after workup.

Procedure F. Reagent Stoichiometry Studies. An oven-dried vial

containing a stir bar was placed under a positive pressure of argon and

subjected to three evacuation/backﬁlling cycles under high vacuum.

Samarium(II) iodide (THF solution, 0.45 mmol, 4.5 equiv, 0.10 M) was

added followed by Et₃N (4−24 equiv) and H₂O (4−24 equiv) with

vigorous stirring, which resulted in the formation of the characteristic

dark brown color of the SmI₂−Et₃N−H₂O complex. A solution of

substrate (0.10 mmol, 1.0 equiv, stock solution in THF) was added, and

the reaction mixture was stirred for 24 h. The excess of Sm(II) was

oxidized by bubbling air through the reaction mixture; a small aliquot

(1.0 mL) was removed from the reaction mixture, diluted with diethyl

ether (2 mL) and HCl (0.1 N, 0.25 mL), and analyzed by GC-MS to

obtain product distribution using correction for response factors

obtained by analyzing known quantities of the starting materials and

products.

Procedure G. Reductions Using SmI₂−NaOH. An oven-dried vial

containing a stir bar was charged with sodium hydroxide, placed under a

positive pressure of argon, and subjected to three evacuation/backﬁlling

cycles under high vacuum. Samarium(II) iodide (THF solution) was

added followed by substrate (0.10 mmol, 1.0 equiv, stock solution in

THF) and H₂O with vigorous stirring, which resulted in the formation

of the characteristic dark green color of the SmI₂−NaOH−H₂O

complex. A solution of substrate (0.10 mmol, 1.0 equiv, stock solution in

THF) was added, and the reaction mixture was stirred for the indicated

time. The excess of Sm(II) was oxidized by bubbling air through the

reaction mixture, and the reaction mixture was diluted with CH₂Cl₂(30

mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with

Procedure A. Kinetic Studies. An oven-dried vial containing a stir bar

was placed under a positive pressure of argon and subjected to three

evacuation/backﬁlling cycles under high vacuum. Samarium(II) iodide

(THF solution, 0.10 M) was added followed by Et₃N and H₂O with

vigorous stirring, which resulted in the formation of the characteristic

dark brown color of the SmI₂−Et₃N−H₂O complex. A solution of

substrate (stock solution in THF) was added, and the reaction mixture

was vigorously stirred under argon. Small aliquots (typically, 0.25 mL)

were removed from the reaction mixture at set time intervals,

immediately quenched by bubbling air through the reaction mixture,

diluted with diethyl ether (2.0 mL) and HCl (0.1 N, 0.25 mL), and

analyzed by GC or GC-MS to obtain yield and product distribution

using internal standard and comparison with authentic samples: Agilent

HP-5MS (19091S-433) (length 30 m, internal diameter 0.25 mm, ﬁlm

0.25 μm), He as the carrier gas, ﬂow rate 1 mL/min, initial oven temp 90

°C, 10 °C/min ramp, after 90 °C hold for 3 min to 220 °C, then hold at

220 °C for 5 min. Ester kinetics: product = 11.50 min; starting material =

12.55 min; standard = 12.45 min. Acid kinetics: product = 14.73 min;

starting material = 16.09 min; standard = 14.94 min. Amide kinetics:

product = 9.39 min; starting material = 15.29 min; standard = 13.69 min.

Procedure B. Relative Reactivity Studies. An oven-dried vial

containing a stir bar was placed under a positive pressure of argon and

subjected to three evacuation/backﬁlling cycles under high vacuum.

Samarium(II) iodide (THF solution, 0.20 mmol, 2.0 equiv, 0.10 M) was

added followed by Et₃N (0.33 mL, 24 equiv) and H₂O (0.043 mL, 24

equiv) with vigorous stirring, which resulted in the formation of the

characteristic dark brown color of the SmI₂−Et₃N−H₂O complex. A

preformed solution of two substrates (each 0.10 mmol, 1.0 equiv, stock

solution in THF) was added, and the reaction mixture was stirred until

decolorization to white had occurred. The reaction mixture was diluted

with CH₂Cl₂(30 mL) and HCl (1 N, 30 mL). The aqueous layer was

extracted with CH₂Cl₂(3 × 30 mL); the organic layers were combined,

dried over Na₂SO₄, ﬁltered, and concentrated. The sample was analyzed

by ¹H NMR (CDCl₃, 500 MHz) and GC-MS to obtain conversion and

yield using internal standard and comparison with authentic samples.

Procedure C. Radical Clock Studies. An oven-dried vial containing a

stir bar was placed under a positive pressure of argon and subjected to

three evacuation/backﬁlling cycles under high vacuum. Samarium(II)

M

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1

CH₂Cl₂(3 × 30 mL); the organic layers were combined, dried over

2-(4-Methoxyphenyl)ethanol (Figure 4, entry 4). H NMR (300

MHz, CDCl₃) δ 1.55 (br, 1 H), 2.84 (t, J = 6.6 Hz, 2 H), 3.82 (s, 3 H),

3.85 (t, J = 6.6 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.17 (d, J = 8.7 Hz, 2

H); ¹³C NMR (75 MHz, CDCl₃) δ 38.3, 55.3, 63.8, 114.1, 130.0, 130.4,

158.3.

1

Na₂SO₄, ﬁltered, and concentrated. The sample was analyzed by H

NMR (CDCl₃, 500 MHz) and GC-MS to obtain conversion and yield

using internal standard and comparison with authentic samples.

Procedure H. Determination of Deuterium Incorporation and

Kinetic Isotope Eﬀect. An oven-dried vial containing a stir bar was

placed under a positive pressure of argon and subjected to three

evacuation/backﬁlling cycles under high vacuum. Samarium(II) iodide

(THF solution, 0.80 mmol, 8.0 equiv, 0.10 M) was added followed by

Et₃N and D₂O (deuterium incorporation) or an equimolar mixture of

D₂O and H₂O (kinetic isotope eﬀect) with vigorous stirring, which

resulted in the formation of a characteristic dark brown color of the

SmI₂−Et₃N−H₂O complex. A solution of substrate (0.10 mmol, 1.0

equiv, stock solution in THF) was added, and the reaction mixture was

stirred for 2−18 h. The excess of Sm(II) was oxidized by bubbling air

through the reaction mixture. Workup and analysis was performed as

described for Method B. Deuterium incorporation was determined after

chromatographic puriﬁcation on silica gel (¹H NMR, 500 MHz, CDCl₃).

Characterization Data. Characterization data for all alcohol

products have been previously reported.²⁰⁻²²¹H and ¹³C NMR data

for the alcohol products used in the current study are presented below

for characterization purposes.

1

4-Phenylbutan-1-ol (Scheme 1, entry 1, 8). H NMR (300 MHz,

CDCl₃) δ 1.44−1.67 (m, 4 H), 1.71 (br, 1 H), 2.56 (t, J = 7.8 Hz, 2 H),

3.55 (t, J = 6.6 Hz, 2 H), 7.06−7.13 (m, 3 H), 7.16−7.23 (m, 2 H); ¹³C

NMR (75 MHz, CDCl₃) δ 27.6, 32.3, 35.7, 62.8, 125.8, 128.3, 128.5,

142.4.

rac-((1R,2R)-2-Phenylcyclopropyl)methanol (Scheme 1a, 9). ¹H

NMR (500 MHz, CDCl₃) δ 0.82−0.91 (m, 2 H), 1.34−1.41 (m, 1 H),

1.65 (br, 1 H), 1.72−1.76 (m, 1 H), 3.49−3.57 (m, 2 H), 6.99 (dd, J =

1.5, 7.5 Hz, 2 H), 7.07 (tt, J = 1.5, 7.0 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 2 H);

¹³C NMR (125 MHz, CDCl₃) δ 13.9, 21.3, 25.3, 66.6, 125.7, 125.9,

128.4, 142.5.

1

(R)-2-Phenylpropan-1-ol (Scheme 1b, 11). H NMR (500 MHz,

CDCl₃) δ 1.21 (d, J = 7.0 Hz, 3 H), 1.33 (br, 1 H), 2.84−2.91 (m, 1 H),

3.63 (d, J = 7.0 Hz, 2 H), 7.14−7.18 (m, 3 H), 7.24−7.28 (m, 2 H); ¹³C

NMR (125 MHz, CDCl₃) δ 17.6, 42.5, 68.7, 126.7, 127.5, 128.7, 143.7.

(R)-2-Methyl-3-phenylpropan-1-ol (Scheme 4b, 25). ¹H NMR (500

MHz, CDCl₃) δ 0.85 (d, J = 6.5 Hz, 3 H), 1.36 (br, 1 H), 1.84−1.93 (m,

1 H), 2.36 (dd, J = 8.0, 13.0 Hz, 1 H), 2.69 (dd, J = 6.5, 13.5 Hz, 1 H),

3.39−3.49 (m, 2 H), 7.09−7.14 (m, 3 H), 7.19−7.23 (m, 2 H) ; ¹³C

NMR (125 MHz, CDCl₃) δ 16.5, 37.8, 39.7, 67.7, 125.9, 128.3, 129.2,

140.6.

1

Benzyl Alcohol (Table 2, entry 1). H NMR (500 MHz, CDCl₃) δ

1.75 (br, 1 H), 4.60 (s, 2 H), 7.19−7.24 (m, 1 H), 7.26−7.31 (m, 4 H);

¹³C NMR (125 MHz, CDCl₃) δ 65.4, 127.0, 127.7, 128.6, 140.9.

Phenethyl Alcohol (Table 2, entry 2). ¹H NMR (500 MHz, CDCl₃) δ

1.65 (br, 1 H), 2.78 (t, J = 7.0 Hz, 2 H), 3.76 (t, J = 6.5 Hz, 2 H), 7.13−

7.17 (m, 3 H), 7.21−7.25 (m, 2 H); ¹³C NMR (125 MHz, CDCl₃) δ

39.2, 63.7, 126.5, 128.6, 129.1, 138.5.

ASSOCIATED CONTENT

* Supporting Information

■

S

3-Phenylpropan-1-ol (Table 2, entry 3). ¹H NMR (400 MHz,

CDCl₃) δ 1.32 (br, 1 H), 1.79−1.87 (m, 2 H), 2.64 (t, J = 7.6 Hz, 2 H),

3.61 (t, J = 6.4 Hz, 2 H), 7.09−7.24 (m, 5 H); ¹³C NMR (100 MHz,

CDCl₃) δ 32.1, 34.3, 62.3, 125.9, 128.4, 128.5, 141.8.

Kinetic plots, ¹H and ¹³C NMR spectra, and HPLC traces. This

material is available free of charge via the Internet at http://pubs.

acs.org.

Decan-1-ol (Table 2, entry 4). ¹H NMR (500 MHz, CDCl₃) δ 0.81

(t, J = 6.9 Hz, 3 H), 1.15−1.33 (m, 15 H), 1.47−1.53 (m, 2 H), 3.57 (t, J

= 6.6 Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃) δ 14.1, 22.7, 25.8, 29.3,

29.5, 29.6, 29.7, 31.9, 32.8, 63.1.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: michal.szostak@rutgers.edu.

■

1

rac-((1S,4R)-4-Pentylcyclohexyl)methanol (Table 2, entry 5). H

*E-mail: david.j.procter@manchester.ac.uk.

Notes

NMR (300 MHz, CDCl₃) δ 0.75−0.91 (m, 7 H), 1.02−1.27 (m, 10 H),

1.38 (br, 1 H), 1.71 (d, J = 8.7 Hz, 4 H), 3.37 (d, J = 6.4 Hz, 2 H); ¹³C

NMR (75 MHz, CDCl₃) δ 14.1, 22.7, 26.6, 29.5, 32.2, 32.7, 37.4, 37.8,

40.7, 68.8.

The authors declare no competing ﬁnancial interest.

1-Adamantanemethanol (Table 2, entry 6). ¹H NMR (400 MHz,

CDCl₃) δ 1.26 (br, 1 H), 1.43−1.46 (m, 6 H), 1.55−1.70 (m, 6 H),

1.90−1.95 (m, 3 H), 3.13 (s, 2 H); ¹³C NMR (75 MHz, CDCl₃) δ 28.2,

34.5, 37.2, 39.0, 73.9.

ACKNOWLEDGMENTS

■

We thank the EPRSC and the Leverhulme Trust for support.

M.S. thanks Rutgers University for support during the

preparation of this manuscript.

1

2-Methyl-3-phenylpropan-1-ol (Table 2, entry 7). H NMR (300

MHz, CDCl₃) δ 0.85 (d, J = 6.9 Hz, 3 H), 1.33 (br, 1 H), 1.79−1.94 (m,

1 H), 2.36 (dd, J = 8.0, 13.5 Hz, 1 H), 2.69 (dd, J = 6.2, 13.4 Hz, 1 H),

3.37−3.50 (m, 2 H), 7.07−7.25 (m, 5 H); ¹³C NMR (75 MHz, CDCl₃)

δ 16.5, 37.8, 39.7, 67.7, 125.9, 128.3, 129.2, 140.6.

REFERENCES

■

(1) For a preliminary communication on the mechanism of ester

reduction, see: Szostak, M.; Spain, M.; Procter, D. J. Chem.Eur. J.

2014, 20, 4222.

(2) (a) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis

using Samarium Diiodide: A Practical Guide; RSC Publishing: Cam-

bridge, U.K., 2010. Recent reviews on SmI₂: (b) Molander, G. A.;

Harris, C. R. Chem. Rev. 1996, 96, 307. (c) Kagan, H. B. Tetrahedron

2003, 59, 10351. (d) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem.

2-Butyloctan-1-ol (Table 2, entry 8). ¹H NMR (500 MHz, CDCl₃) δ

0.79−0.85 (m, 6 H), 1.09−1.14 (br, 1 H), 1.16−1.29 (m, 16 H), 1.35−

1.42 (m, 1 H), 3.47 (d, J = 5.5 Hz, 2 H); ¹³C NMR (100 MHz, CDCl₃) δ

14.1, 22.7, 23.1, 26.9, 29.1, 29.8, 30.6, 30.9, 31.9, 40.5, 65.8.

2-(4-(Triﬂuoromethyl)phenyl)ethanol (Figure 4, entry 1). ¹H NMR

(300 MHz, CDCl₃) δ 1.51 (br, 1 H), 2.95 (t, J = 6.6 Hz, 2 H), 3.92 (t, J =

6.6 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H), 7.59 (d, J = 8.1 Hz, 2 H); ¹³C

NMR (75 MHz, CDCl₃) δ 38.9, 63.2, 122.5, 125.5 (q, J³= 3.8 Hz), 129.3

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2-(4-Chlorophenyl)ethanol (Figure 4, entry 2). ¹H NMR (300 MHz,

CDCl₃) δ 1.48 (br, 1 H), 2.86 (t, J = 6.6 Hz, 2 H), 3.87 (t, J = 6.6 Hz, 2

H), 7.19 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H); ¹³C NMR (75

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Article Doi

Mechanism of SmI2/amine/H2O-promoted chemoselective reductions of carboxylic acid derivatives (esters, acids, and amides) to alcohols

DOI: 10.1021/jo5018525

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Article abstract of DOI:10.1021/jo5018525

Full text of DOI:10.1021/jo5018525

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