Mechanistic study of samarium diiodide-HMPA initiated 5-exo-trig ketyl-olefin coupling: The role of HMPA in post-electron transfer steps

Article abstract of DOI:10.1021/ja802448x

The mechanistic importance of HMPA and proton donors (methanol, 2-methyl-2-propanol, and 2,2,2-trifluoroethanol) on SmI₂-initiated 5-exo-trig ketyl-olefin cyclizations has been examined using stopped-flow spectrophotometric studies. In the pres

Full text of DOI:10.1021/ja802448x

Published on Web 05/15/2008
Mechanistic Study of Samarium Diiodide-HMPA Initiated 5-exo-trig
Ketyl-Olefin Coupling: The Role of HMPA in Post-Electron Transfer Steps
†
†
Dhandapani V. Sadasivam, P. K. Sudhadevi Antharjanam, Edamana Prasad, and
Robert A. Flowers, II*
Department of Chemistry, Lehigh UniVersity, Bethlehem, PennsylVania 18015
Received April 3, 2008; E-mail: rof2@lehigh.edu
One of the most important follow-up steps in the reduction of
ketones by samarium diiodide (SmI ) is addition of a ketyl radical
Table 1. Rate Orders for Substrate, SmI2, and HMPA
2
rate order
to an olefin. Intramolecular ketyl-olefin and related coupling events
-
1 a
)
b
c
d
system
kobs(s
substrate
SmI
2
HMPA
1
provide routes to a range of important intermediates and are critical
-
-
1
2
2
1
2
6.0 ( 0.1 × 10
3.9 ( 0.1 × 10
1.0 ( 0.1
0.9 ( 0.1
1.0 ( 0.1
1.0 ( 0.1
1.08 ( 0.03
1.0 ( 0.1
2
in a number of tandem bond-forming events initiated by SmI .
Proton donors and hexamethylphosphoramide (HMPA) are often-
times vital components in these and related reactions, but their
mechanistic role is poorly understood. To elucidate the mechanistic
role of these additives, a series of proton donors in the presence of
HMPA were examined to study their impact on the rate and
mechanism of ketyl-olefin coupling. The data described herein
show two important features: (1) HMPA plays an important
mechanistic role in ketyl-olefin coupling after the initial reduction
of a ketone through the formation of a solvent-separated ion pair
from the metal-coordinated ketyl intermediate, and (2) in the
presence of HMPA, proton donors do not play a mechanistic role
in the rate-determining step of the reaction.
a
[SmI ] ) 5 mM, HMPA ) 40 mM, [substrate] ) 60 mM, [ROH]
2
b
) 125 mM. [SmI2] ) 5 mM, HMPA ) 40 mM, [substrate] ) 50-90
c
d
mM, [t-BuOH] ) 125 mM. From ref 4. [SmI2] ) 5 mM, HMPA )
1
0-240 mM, [substrate] ) 60 mM, [t-BuOH] ) 125 mM.
Although the mechanism of SmI
2
-initiated ketyl-olefin coupling
3
has not been investigated in detail, the seminal studies of Curran
2h
and Molander have probed the mechanistic aspects of this reaction
through careful product studies and other experimental observations.
Curran proposed that ketone reduction by SmI
2
is a relatively fast,
reversible process with the equilibrium lying to the side of unreacted
3
ketone and SmI
2
. This hypothesis was based on the observation
to produce diols are
relatively slow, while ketones containing an appropriately placed
pendant olefin are reduced and subsequently cyclize at a faster rate.
In a series of elegant product studies, Molander proposed that the
that reactions between ketones and SmI
2
Figure 1. Equivalents of HMPA versus kobs for reduction of 1. The inset
shows equivalents of HMPA versus kobs for reduction of 2. [SmI2] ) 5
mM.
sterically encumbered SmI
2
-HMPA reductant was responsible for
of HMPA and product studies showed that they had no impact on
the diastereoselectivity of the reaction. The kobs and rate order data
for all other reaction components are contained in Table 1. The
rate order of 1 for HMPA was surprising since previous studies on
the reduction of dialkyl ketones provided a rate order of 0 for
the observed products and diastereoselectivities of 5- and 6-exo
2
h
ketyl-olefin cyclizations.
To analyze the hypotheses of Molander and Curran, detailed
studies were performed to elucidate the mechanistic role of HMPA
and three proton donors (methanol, trifluoroethanol, and 2-methyl-
4
HMPA. Examination of parent ketones 3-pentanone and cyclo-
2
1
-propanol) in the reductive coupling of 2-but-3-enylcyclohexan-
-one (1) and 4-methyloct-7-en-3-one (2) shown below. A series
hexanone under the conditions employed for the rate studies of 1
and 2 confirmed these findings (Supporting Information). To further
explore the impact of HMPA on the cyclization process, the reaction
rate for the reduction of 1 and 2 was monitored over a broad
concentration range, as shown graphically in Figure 1. In the
absence of HMPA, the reaction rate is on the order of the natural
2
decay of SmI under the conditions of our study. After addition of
at least 4 equiv of HMPA, the rate was accelerated substantially.
A subsequent increase in the rate was observed as the concentration
of HMPA was increased, and the rate of the reaction did not begin
to level off until addition of a large excess. The data obtained from
this experiment are consistent with saturation behavior.
of rate experiments were initiated, and the rate orders for each
component of the reaction were determined. Rate studies were
performed under pseudo-first-order conditions with substrate in
excess by monitoring the decay of the Sm absorption at 555 nm.
In all cases, the rate order of proton donors was zero in the presence
Elegant studies by Daasbjerg and Skrydstrup have shown that
2 4 2
addition of 4-10 equiv of HMPA produces [Sm(THF) (HMPA) ]I ,
†
and further addition beyond 10 equiv likely produces
[Sm(HMPA) ]I through the equilibrium shown in Scheme 1. A
6 2
Present address: Department of Chemistry, Indian Institute of Technology
5
Madras, Chennai, India.
7
228 9 J. AM. CHEM. SOC. 2008, 130, 7228–7229
10.1021/ja802448x CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
When k-1 . k
, the equation simplifies to that shown in eq 2:
2
d[SmI2]
)
kobs[Sm(HMPA) ][HMPA][1]
(2)
n
dt
indicating that the rate will exhibit a first-order dependence on
SmI ], [substrate], and [HMPA]. At modest concentrations of
HMPA, these conditions are met for both substrates examined in
this study.
[
2
further consequence of HMPA coordination to Sm(II) is the
production of a more powerful reductant. Taken together, these
6
studies are consistent with HMPA playing an important role in
accelerating the rate of reactions and providing increased stereo-
selectivity through the formation of a sterically encumbered
The results described herein are consistent with a broader role
for HMPA beyond production of a more powerful, sterically
crowded Sm(II) reductant in 5-exo-trig ketyl-olefin cyclizations.
The mechanism derived from rate studies shows that HMPA is
important not only in increasing the reduction potential of the Sm(II)
reductant but also in enhancing the inherent reactivity of the radical
anion through conversion of a sterically congested contact ion pair
to a solvent-separated ion pair, allowing cyclization to occur. The
absence of an influence on the stereoselectivity and rate expression
by proton donors is consistent with proton transfer occurring after
the rate and stereoselection steps, suggesting that the ability of
HMPA to coordinate strongly to Sm prevents coordination of proton
donors to the inner-sphere, distancing them from the vicinity of
1,4
reductant. Recently, Hoz has provided evidence that HMPA plays
a mechanistic role in the reduction of diaryl ketones after initial
7
reduction to the ketyl radical anion. In Hoz’s study, HMPA was
shown to slow the rate of bimolecular coupling through complex-
ation of Sm(III) required to bridge two colligating radical anions.
Although the present work shows that HMPA accelerates ketyl-olefin
cyclization beyond concentrations required to increase the reducing
2
power of SmI , the question remains whether the additive could
be mechanistically important in a post-electron transfer step.
To elucidate the mechanistic role of HMPA, it is important to
keep a number of points in mind: (1) The formation of the
Sm-HMPA complex is required for initiation of ketyl-olefin
thereactingcenters.ThemechanisticcomplexityoftheSmI -HMPA-
2
initiated ketyl-olefin cyclization shows that simple empirical
models based on structural knowledge of ground-state reductants
are likely to contain a high degree of uncertainty.
cyclization. (2) Addition of successive amounts of HMPA to SmI
2
in THF likely drives the equilibrium shown in Scheme 1 to the
saturated Sm(II)-HMPA complex while simultaneously increasing
the polarity of the solvent milieu. (3) The rate law describing the
reaction provides the stoichiometry of the activated complex relative
Acknowledgment. R.A.F. is grateful to the National Science
Foundation (CHE-0413845) for support of the work at Lehigh
University. We thank Professors Shmaryahu Hoz and Rebecca S.
Miller for insightful comments on the manuscript.
8
to the reactants. (4) Since the ketyl-olefin cyclization is fast, it is
reasonable to assume that the rate-limiting step of the reaction
9
occurs before the cyclization event.
Supporting Information Available: General experimental methods,
spectroscopic and rate data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 2
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1
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1
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(1)
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2
JA802448X
J. AM. CHEM. SOC. 9 VOL. 130, NO. 23, 2008 7229