Reduction of activated carbonyl groups using alkylphosphanes as reducing agents: A mechanistic study

Article abstract of DOI:10.1002/ejoc.201200019

A comprehensive mechanistic investigation on the reduction of activated carbonyl groups using alkylphosphanes as reducing agents has been conducted through a combination of experimental as well as computational studies. Both approaches show that this kind of reduction proceeds either through proton transfer from alkylphosphanes and cleavage by water during work-up or through another reaction pathway involving the participation of water at the initial stage and a two-fold proton transfer to afford the product. The reaction mechanism of the reduction of activated carbonyl groups using alkylphosphanes has been studied both experimentally and theoretically. The reduction was shown to proceed either through proton transfer from alkylphosphanes and cleavage by water during work-up or through the participation of water at the initial stage and a two-fold proton transfer.

Full text of DOI:10.1002/ejoc.201200019

FULL PAPER
DOI: 10.1002/ejoc.201200019
Reduction of Activated Carbonyl Groups Using Alkylphosphanes as Reducing
Agents: A Mechanistic Study
Yin Wei,[a] Xu-Guang Liu,[b] and Min Shi*[a,b]
Keywords: Aldehydes / Ketones / Reduction / Phosphanes / Reaction mechanisms
A comprehensive mechanistic investigation on the reduction
through proton transfer from alkylphosphanes and cleavage
of activated carbonyl groups using alkylphosphanes as re- by water during work-up or through another reaction path-
ducing agents has been conducted through a combination of
experimental as well as computational studies. Both ap-
proaches show that this kind of reduction proceeds either
way involving the participation of water at the initial stage
and a two-fold proton transfer to afford the product.
(Scheme 1).[5] Subsequently, the scope of this reduction pro-
cess was extended to other compounds including activated
Introduction
Organophosphorus compounds have proven to be particu-
larly versatile as catalysts or reagents in many types of reac-
tions, and are extensively applied in organic synthesis. The
common applications of organophosphorus compounds in-
clude the use of phosphonium ylides in the Wittig reac-
tion,[1] the use of phosphanes in the Staudinger and Mitsu-
nobu reactions,[2] and the use of phosphanes as ligands in
transition-metal-mediated processes.[3] In the recent decade,
phosphanes have been intensively used as nucleophilic cata-
lysts in Morita–Baylis–Hillman/aza-Morita–Baylis–Hill-
man reactions, and Michael addition reactions and their
related reactions.[4] However, the use of phos-
phanes as reductants accompanied by a proton transfer has
rarely been seen. In 2006, we first reported an interesting
reduction of activated carbonyl groups using alkylphos-
phanes as reducing agents that provides a convenient method
to afford α-hydroxyl esters, ketones, and phosphonates
Scheme 1. Reduction of activated carbonyl groups by alkylphos-
phanes.
Scheme 2. Proposed mechanism for reduction of α-keto esters by phosphanes.
carbonyl groups such as 2,2,2-trifluoro-1-arylethanones,
[a] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Science,
345 Lingling Road, Shanghai 200032, China
[b] Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science & Technology,
130 Mei Long Road, Shanghai 200237, China
and reductive coupling of acyl cyanides was also achieved
(Scheme 1).[6] Recently, our group also demonstrated that
the C=C double bond in isatin-derived electron-deficient
alkenes could be exclusively reduced in the presence of alk-
ylphosphanes and water.[7] Based on the preliminary results
of deuterium and 18O labeling experiments, the mechanism
E-mail: mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200019.
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Reduction of Activated Carbonyl Groups
for reduction of α-keto esters by alkylphosphanes was pro-
posed to proceed as shown in Scheme 2, which involves pro-
ton transfer from alkylphosphanes and cleavage by water
during work-up.[5]
To the best of our knowledge, a comprehensive mechan-
istic investigation into this reduction process has not been
reported, and several intricacies involved in the reaction
mechanism are unclear. Herein, we wish to elucidate the
mechanistic details of this interesting reduction through
combined experimental as well as computational studies.
Results and Discussion
Scheme 3. Reduction of 1 using alkylphosphanes as reducing
agents.
Experimental Studies on Mechanism
Our investigation began with a series of deuterium label-
ing experiments to examine which proton sources were
transferred to the products in this reduction reaction in the
presence of alkylphosphanes. The reduction of 1-(4-chloro-
phenyl)-2,2,2-trifluoroethanone (1) was initially carried out
in the absence of water using P(CD3)3 as a reducing agent,
affording the product 2 in 58% yield with relatively low
deuterium content (33%) at the C-1 position [Scheme 3,
Equation (1)]. This observation agreed with our previous
findings that the proton was directly transferred from the
alkylphosphane to the product 2, however, the low deute-
rium content implied that the proton comes not only from
phosphane, but also from other sources. Presumably, water
may be another proton source that could directly partici-
pate in the reaction. Subsequently, we examined the same
reduction reaction using PBu3 with water at the initial stage.
The reduction of 1 took place smoothly within three hours
at room temperature in the presence of PBu3 and D2O,
leading to the corresponding product 2 in 99% yield with
high deuterium content (87%) at the C-1 position
[Scheme 3, Equation (2)]. This result indicated that the pro-
ton in water was indeed transferred into the product,
namely, water is another proton source in the reduction re-
action using alkylphosphane as a reducing agent. It should
be mentioned here that this reduction does not occur when
only 1 and H2O are mixed in the absence of alkylphos-
phane. Presumably, there are two reaction pathways for the
reduction reaction of activated carbonyl compounds in the
presence of alkylphosphanes, which includes our previously
suggested reaction pathway through the proton transfer
from alkylphosphanes and cleavage by H2O during work-
up, and another reaction pathway involving water partici-
pation in the reaction at the initial stage.
reduction of 1, suggesting that there are also two reaction
pathways for the reduction reaction of α-keto ester 3 and
the proton transferred in the reduction process is either
from alkylphosphanes or from water.
Scheme 4. Reduction of 3 using alkylphosphanes as reducing
agents.
To examine the scope of this reduction reaction pro-
moted by alkylphosphanes, we further investigated the re-
duction of o-nitrobenzaldehyde (5) under similar reaction
conditions; the results are presented in Scheme 5. The reac-
tion still occurred in the presence of P(CD3)3, however, di-
mer 7 was formed as the main product in moderate yield
(39%) along with the reduced product 6 in very low yield
We then conducted similar reduction reactions of α-keto
ester 3 without water using P(CD3)3 as reducing agent and
with D2O in the presence of PBu3, respectively. The results
are shown in Scheme 4. The product 4 was obtained in 65%
yield with 64% deuterium content at the C-1 position when
the reaction was conducted without water in the presence
of P(CD3)3. The same product was also acquired in 65%
yield with high deuterium content (92%) when the reaction
was conducted in the presence of D2O and PBu3. These
Scheme 5. Reduction of 5 using alkylphosphanes as reducing
results are consistent with the above observations for the agents.
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(17%), which indicated that some other reactions proceeded Int 3 is thermodynamically much less stable (58.7 kJ/mol),
when aldehydes were employed as substrates [Scheme 5, indicating that this reaction pathway (Path 1) is less likely
Equation (a)]. Surprisingly, no deuterium was detected in to occur than Path 2 shown in Scheme 6. Because the ex-
the products, indicating that the transferred proton during periments were conducted at room temperature, we ex-
the reaction does not stem from the alkylphosphane. These cluded this thermodynamically unfavorable reaction path-
results implied that the reaction pathway through proton way (Path 1) and focused our attention on another reaction
transfer from alkylphosphane and cleavage by H2O during pathway (Path 2). We found that the phosphane can ap-
work-up does not proceed when aldehydes are used as sub- proach the carbonyl group to give intermediate Int 4 with-
strates. The reaction was also carried out in the presence of out an energy barrier. One hydrogen atom from PMe3 is
D2O and PBu3, affording the dimeric product 7 in 72% transferred to afford intermediate Int 5, which is thermody-
yield without deuterium content, and the reduced product namically more stable, by passing through transition state
6 in 8% yield with 100% deuterium content. These results TS4–5 (90.6 kJ/mol). Then, one water molecule is induced
show that water must be required to start the reduction re- at this stage, giving the relaxed complex Int 6. The O–H
action; however, it is not the main reaction in this system.
bond in water is then cleaved over transition state TS6–7,
leading to the more stable intermediate Int 7, which un-
dergoes a second hydrogen transfer to afford product com-
plex Int 8 via transition state TS7–8. Cleavage of this com-
Theoretical Investigations on the Reaction Pathways
We first computationally explored possible reaction path- plex to yield the separate components 2 and O=PMe3 is
ways using the reduction reaction of 1 with PMe3 as a therefore endothermic by approximately 136 kJ/mol. The
model system. As aforementioned, this kind of reduction results of these calculations show that the hydrogen atom
reaction may proceed through two pathways, thus, we inves- from PMe3 could be transferred to give thermodynamically
tigated several possible reaction pathways at the B2PLYP- stable intermediates that undergo hydrolysis to afford a
M2/6-31+G(2d)//mPW1K/6-31+G(d) level of theory.[8] We more stable product, which are in line with the aforemen-
first examined the possible reaction pathways using 1 and tioned experimental findings.
PMe3 without H2O at the initial stage. The attack of PMe3
Subsequently, we also investigated the possible reaction
on the carbonyl group of 1 initiates the reaction, which re- pathways at the B2PLYP-M2/6-31+G(2d)//mPW1K/6-
sults in a relaxed complex Int 1 of 1 and PMe3 or zwitter- 31+G(d) level using 1 and PMe3 with H2O present at the
ionic intermediate Int 2. After crossing a barrier through initial stage. Thus, the attack of PMe3 on the carbonyl
transition state TS2–3 of 61.5 kJ/mol, intermediate Int 3 is group of 1 initiates the reaction and is associated with one
formed (Path 1 shown in Scheme 6). However, intermediate water molecule, leading to two kinds of intermediates
Scheme 6. Energy profiles for the reduction of 1 using PMe3 without water at the initial stage.
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Reduction of Activated Carbonyl Groups
Scheme 7. Energy profiles for the reduction of 1 using PMe3 with water at the initial stage.
Int W1 and Int W2. The formation of intermediate Int W1 pathway for the reduction of 3 in the presence of PMe3
is slightly endothermic by 6.0 kJ/mol with respect to the without H2O at the initial stage. Thus, attack of PMe3 to
separated reactants. In contrast, the formation of interme- the carbonyl group of 3 initiates the reaction, which results
diate Int W2 is more exothermic by 53.4 kJ/mol with respect in a relaxed complex Int 9 of compound 3 and PMe3 or
to the separated reactants, indicating that intermediate zwitterionic intermediate Int 9Ј (Scheme 8). Because the re-
Int W2 is much more stable. We then investigated two pos- action starting from Int 9Ј leads to the more thermodynam-
sible reaction pathways (see Scheme 7) starting from inter- ically unfavorable intermediate (for details, see the Support-
mediates Int W1 and Int W2, respectively. Starting from in- ing Information), we focused our investigations on the reac-
termediate Int W1, the O–H bond of water is cleaved and tion pathway starting from the relaxed complex Int 9. When
the hydrogen is first transferred to the carbon center, lead- PMe3 further approaches the carbonyl group, either inter-
ing to the formation of intermediate Int W3 through a five- mediate Int 10, which was proposed previously,[5] or inter-
membered cyclic transition structure TSW1–W3 with an en- mediate Int 10Ј, which is similar to Int 4, could be formed
ergy barrier of 10.4 kJ/mol. Subsequently, intermediate without an energy barrier. Intermediate Int 10 is more
Int W3 undergoes another proton transfer via a second stable than intermediate Int 10Ј by approximately 20 kJ/
four-membered ring transition structure TSW3–W5, leading mol. Thus, we examined the next step from intermediate
to the product complex Int W5, which then affords the sep- Int 10, which is thermodynamically more stable. One hydro-
arated products. Another possible reaction pathway starts gen atom from PMe3 is transferred to give intermediate
from intermediate Int W2; in this case the O–H bond of Int 11 by passing through transition state TS10–11 (72.0 kJ/
water is cleaved and the hydrogen is transferred to the oxy- mol). At this stage, one water molecule is induced into the
gen center, leading to the formation of intermediate Int W4 reaction, giving the relaxed complex Int 12. The O–H bond
through
a five-membered cyclic transition structure in water is then cleaved over transition state TS12–13, leading
TSW2–W4 with an energy barrier of 42.1 kJ/mol. Sub- to the more stable intermediate Int 13, which undergoes a
sequently, the second proton is also transferred via another second hydrogen transfer process to afford product complex
four-membered cyclic transition structure TSW4–W6, leading Int 14 via transition state TS13–14. Cleavage of this complex
to the product complex Int W6, which then affords the sep- to yield the separate components 4 and O=PMe3 is there-
arated products. Because the formation of the intermediate fore endothermic by approximately 47.5 kJ/mol. The results
Int W2 is exothermic, the initial steps of the reaction take of these calculations show that the hydrogen atom from
place easier at room temperature. Thus, we propose that the PMe3 could also be transferred to α-keto ester, giving ther-
reaction takes place following the Path 4.
modynamically stable intermediates that subsequently un-
We further investigated the reduction reaction of 3 theo- dergo hydrolysis to afford the more stable reduction prod-
retically using PMe3 as reducing agent with and without uct, which are in line with the aforementioned experimental
water at the initial stage. First, we investigated the reaction findings.
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Scheme 8. Energy profile for the reduction of 3 using PMe3 without water at the initial stage.
We subsequently investigated the reaction pathway at the the stable zwitterionic intermediate similar to Int 2 could
B2PLYP-M2/6-31+G(2d)//mPW1K/6-31+G(d) level using 3 not be generated in this case. We found that another inter-
and PMe3 with H2O at the initial stage. The reaction is mediate, Int 16, could be formed from a relaxed complex
initiated by attack of PMe3 on the carbonyl group of 3 and Int 15 without an energy barrier. One hydrogen atom from
association with one water molecule, leading to two kinds PMe3 is transferred to afford intermediate Int 17, which is
of intermediates Int W7 and Int W7Ј. Because intermediate thermodynamically more stable than intermediate Int 16, by
Int W7Ј is less stable than intermediate Int W7 by approxi- passing through transition state TS16–17 (105.0 kJ/mol).
mately 43.0 kJ/mol (for details, see the Supporting Infor- However, intermediate Int 17 is thermodynamically less
mation), we focused on the reaction pathway starting from stable with respect to the separated reactants, indicating
intermediate Int W7, which is more stable by 20.0 kJ/mol that this process is thermodynamically unfavorable. More-
with respect to the separated reactants. We then investigated over, the reaction energy barrier of 123.7 kJ/mol is certainly
the possible reaction pathway from intermediate Int W7 too high for a room temperature reaction. Thus, the re-
(see Scheme 9). Starting from intermediate Int W7, the O– duction reaction of compound 5 without water at the initial
H bond of water is cleaved and the hydrogen is first trans- stage cannot occur under the standard experimental condi-
ferred to the carbon center, leading to the formation of in- tions shown above. This result is in line with experimental
termediate Int W8 through a five-membered cyclic transi- findings that no H/D exchange takes place during the
tion structure TSW7–W8 with an energy barrier of 10.4 kJ/ course of the reaction using 5 and P(CD3)3 without water
mol. Subsequently, intermediate Int W8 undergoes a second at the initial stage.
proton transfer via a second five-membered ring transition
structure TSW8–W9, leading to the product complex Int W9, B2PLYP-M2/6-31+G(2d)//mPW1K/6-31+G(d) level using 5
which then affords the separated products. and PMe3 with H2O at the initial stage. Thus, attack of
Subsequently, we investigated the reaction pathway at the
We also investigated the reduction of ο-nitrobenzalde- PMe3 on the carbonyl group of compound 3 initiates the
hyde 5 using PMe3 as a reducing agent with and without reaction and is associated with one water molecule, leading
water at the initial stage. First, we investigated the reaction to two kinds of intermediates, Int W10 and Int W10Ј. Be-
pathway at the B2PLYP-M2/6-31+G(2d)//mPW1K/6- cause the formation of intermediate Int W10Ј is slightly
31+G(d) level using 5 and PMe3 without H2O at the initial exothermic by 15.6 kJ/mol with respect to the separated re-
stage (Scheme 10). The attack of PMe3 on the carbonyl actants (for details, see the Supporting Information), we fo-
group of 5 initiates the reaction, leading to a relaxed com- cused on the reaction pathway starting from intermediate
plex Int 15 of 5 and PMe3. It should be mentioned here that Int W10, which is more stable by 52.2 kJ/mol with respect
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Reduction of Activated Carbonyl Groups
Scheme 9. Energy profile for the reduction of 3 using PMe3 with water at the initial stage.
Scheme 10. Energy profile for the reduction of 5 using PMe3 without water at the initial stage.
to the separated reactants. We then investigated the possible ture TSW10–W11 with an energy barrier of 38.1 kJ/mol. Sub-
reaction pathway (see Scheme 11) starting from intermedi- sequently, intermediate Int W11 undergoes a second proton
ate Int W10. Starting from this intermediate, the O–H bond transfer via the second five-membered cyclic transition
of water is cleaved and the hydrogen is first transferred to structure TSW11–W12, leading to the product complex
the carbon center, leading to the formation of intermediate Int W12, and then to the separated products. These compu-
Int W11 through a five-membered cyclic transition struc- tational results suggest that there is only one reaction path-
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Scheme 11. Energy profile for generation of 6 in the reduction reaction of 5 using PMe3 with water at the initial stage.
used without further purification. All reactions were monitored by
way for the reduction reaction of ο-nitrobenzaldehyde 5 and
that the proton transferred during the course of reaction is
only from water. According to the aforementioned experi-
mental results, the main product obtained for this reaction
was the dimeric diol product 7, which was probably formed
by initial benzoin condensation, followed by reduction of
the hydroxy ketone.
TLC with Huanghai GF254 silica gel coated plates. Flash column
chromatography was carried out using 300–400 mesh silica gel at
increased pressure. Reactions were performed under argon.
P(CD3)3 was prepared by the reaction of tri-o-tolyl phosphite with
CD3MgI, which was prepared from CD3I (D content Ͼ90%) with
magnesium, under standard conditions.[8]
Typical Reaction Procedure for the Preparation of 2: A mixture of
1-(4-chlorophenyl)-2,2,2-trifluoroethanone (0.5 mmol) and PBu3
(0.5 mmol) in solvent was stirred under an argon atmosphere at
room temperature for the required time. After the reaction, the
solution was concentrated under reduced pressure and the residue
was purified by flash chromatography on silica gel (EtOAc/petro-
leum ether, 1:20) to afford pure 2.
Conclusions
We have performed a detailed investigation into the
mechanism for reduction of activated carbonyl groups using
alkylphosphanes as reducing agents through computational
analysis and deuterium labeling experiments. Both theoreti-
cal and experimental studies show that this kind of re-
duction reaction proceeds either through proton transfer
from alkylphosphanes and cleavage by water during work-
up, or through another reaction pathway involving water
participation from the initial stage and through double pro-
ton transfer to afford the product. These two reaction path-
ways may exist simultaneously during the course of the re-
action.
Computational Details: The geometries of all systems were opti-
mized at the mPW1K/6-31+G(d) level of theory. Subsequent fre-
quency calculations on the stationary points were carried out at
the same level of theory to ascertain the nature of the stationary
points as minima or first-order saddle points on the respective po-
tential energy surfaces. All transition states were characterized by
one and only one imaginary frequency pertaining to the desired
reaction coordinate. The intrinsic reaction coordinate (IRC) calcu-
lations were carried out at the same level of theory to further au-
thenticate the transition states. The conformational space of flexi-
ble systems was first searched using the MM3 force field and the
systematic search routine in the TINKER program. All stationary
points located at force field level were then reoptimized at the
mPW1K/6-31+G(d) level as described before.[9] Thermochemical
corrections to 298.15 K were calculated for all minima from un-
scaled vibrational frequencies obtained at the same level. The ther-
mochemical corrections were combined with single-point energies
calculated at the B2-PLYP-M2/6-31+G(2d)//mPW1K/6-31+G(d)
level to yield free energy G298 at 298.15 K. In conformationally flex-
ible systems, enthalpies were calculated as Boltzmann-averaged val-
ues over all available conformers. All quantum mechanical calcula-
tions were performed with the Gaussian 03[10] software.
Experimental Section
General Remarks: Melting points were obtained with a Yanagimoto
micro melting point apparatus. H and 13C NMR spectra were re-
1
corded for a solution in CDCl3 with tetramethylsilane (TMS) as
internal standard; J values are given in Hertz. Mass spectra were
recorded with a HP-5989 instrument and HRMS were measured
with a Finnigan MA+ mass spectrometer. Solid compounds re-
ported in this paper gave satisfactory CHN microanalyses with a
Carlo–Erba 1106 analyzer. Commercially obtained reagents were
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Reduction of Activated Carbonyl Groups
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We thank the Shanghai Municipal Committee of Science and Tech-
nology (11JC1402600), the National Basic Research Program of
China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (21072206, 20472096,
20872162, 20672127, 20821002, and 20732008).
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Received: January 9, 2012
Published Online: March 7, 2012
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