A mild, palladium-catalyzed method for the dehydrohalogenation of alkyl bromides: Synthetic and mechanistic studies

Article abstract of DOI:10.1021/ja306323x

We have exploited a typically undesired elementary step in cross-coupling reactions, β-hydride elimination, to accomplish palladium-catalyzed dehydrohalogenations of alkyl bromides to form terminal olefins. We have applied this method, which proceeds in excellent yield at room temperature in the presence of a variety of functional groups, to a formal total synthesis of (R)-mevalonolactone. Our mechanistic studies have established that the rate-determining step can vary with the structure of the alkyl bromide and, most significantly, that L₂PdHBr (L = phosphine), an intermediate that is often invoked in palladium-catalyzed processes such as the Heck reaction, is not an intermediate in the active catalytic cycle.

Full text of DOI:10.1021/ja306323x

Article
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A Mild, Palladium-Catalyzed Method for the Dehydrohalogenation of
Alkyl Bromides: Synthetic and Mechanistic Studies
Alex C. Bissember,†,‡ Anna Levina,† and Gregory C. Fu*,†,‡
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
ABSTRACT: We have exploited a typically undesired elementary step in cross-
coupling reactions, β-hydride elimination, to accomplish palladium-catalyzed
dehydrohalogenations of alkyl bromides to form terminal olefins. We have applied
this method, which proceeds in excellent yield at room temperature in the presence of
a variety of functional groups, to a formal total synthesis of (R)-mevalonolactone. Our
mechanistic studies have established that the rate-determining step can vary with the structure of the alkyl bromide and, most
significantly, that L2PdHBr (L = phosphine), an intermediate that is often invoked in palladium-catalyzed processes such as the
Heck reaction, is not an intermediate in the active catalytic cycle.
(Me2PhSiCH2MgCl).8 Although this investigation focused on
the regioselective synthesis of terminal olefins from secondary
INTRODUCTION
The elimination of HX to form an olefin is one of the most
■
elementary transformations in organic chemistry (eq 1).1,2
alkyl bromides, Oshima also applied his method to two primary
alkyl halides, which provided good yields of the terminal olefin
(79−96%) along with small amounts of the internal olefin (2−
8%). Furthermore, while our study was underway, Frantz
reported that Pd(P(t-Bu)3)2 catalyzes the elimination/isomer-
ization of certain enol triflates to 1,3-dienes.9
The development of new mild methods for the elimination
However, harsh conditions, such as the use of a strong
of HX to generate an olefin, a fundamental transformation in
Brønsted acid, a strong Brønsted base, or a high temperature
organic synthesis, persists as a worthwhile endeavor. In this
(which can lead to poor functional-group compatibility and
olefin isomerization) are often necessary for this seemingly
straightforward process. For example, many classical methods
for the dehydration of alcohols, such as the Chugaev
elimination via a xanthate ester,3 require elevated temperatures
(e.g., 100−250 °C). More recently, through the development of
sophisticated derivatizing agents such as the Burgess4 and
Martin5 reagents, some of the deficiencies of the older
approaches have been remedied; however, while these
report, we describe the use of a palladium catalyst to achieve
elimination reactions of primary alkyl electrophiles and furnish
terminal olefins in excellent yield at room temperature (eq 2).
particular methods are effective for net dehydrations of
RESULTS AND DISCUSSION
■
secondary and tertiary alcohols, they are not generally useful
In recent years, we and others have pursued the development of
for primary alcohols.
metal-catalyzed cross-coupling reactions of alkyl electrophiles
For the dehydration of primary alcohols, the Sharpless−
Grieco reaction, wherein the alcohol is converted into a
that contain β-hydrogens.10 Historically, it was believed that
two substantial impediments to accomplishing this objective
selenide and then a selenoxide prior to elimination, is a
particularly effective approach.6 Because of the mildness of the
were slow oxidative addition and, if oxidative addition could be
achieved, rapid β-hydride elimination in preference to trans-
conditions (e.g., elimination at room temperature or below),
this method has been widely used in organic synthesis.7
metalation (Figure 1).
Having made progress in the development of palladium-
However, drawbacks of this reaction include the generation of a
based catalysts for cross-coupling of alkyl electrophiles,10d,f we
sought to exploit these advances to devise a mild method for
HX elimination of alkyl electrophiles to form olefins, since the
oxidative addition challenge had presumably been solved and
stoichiometric amount of a toxic arylselenol byproduct and
difficulties in separating the desired olefin from selenium-based
impurities.
With respect to metal-catalyzed methods for HX elimination,
Oshima reported in 2008 that CoCl2/IMes·HCl effects the
formation of olefins from alkyl halides (but not sulfonates) in
Received: June 28, 2012
Published: August 20, 2012
the presence of 2 equiv of a Grignard reagent
© 2012 American Chemical Society
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Pd2(dba)3 and P(t-Bu)2Me (entry 10), and a lower loading of
Pd(P(t-Bu)2Me)2 can be employed with only a small loss in
yield (entry 11).
We have determined that this Pd(P(t-Bu)2Me)2-catalyzed
method can be applied to the room-temperature dehydroha-
logenation of a range of primary alkyl bromides, furnishing the
desired terminal olefins in generally high yields [Table 2; for
each reaction, essentially no product (<2%) is formed in the
absence of Pd(P(t-Bu)2Me)2].14 Through the use of a higher
catalyst loading (compare entries 1−3), more hindered (γ- and
β-branched) electrophiles can be converted to olefins nearly
quantitatively. Allylbenzene can also be generated in excellent
yield and with no isomerization to β-methylstyrene (entry 4). A
wide array of functional groups are compatible with this mild
method for elimination of HBr, including a silyl ether (entry 5),
a carbamate (entry 6), esters (entries 7−12), an aryl chloride
(entry 8), heteroaromatic substituents (oxygen, sulfur, and
nitrogen; entries 9−13), and a ketone (entry 14). On the other
hand, preliminary studies indicate that the presence of a
primary alcohol, an aldehyde, or a nitroarene can be
problematic.15 A primary alkyl bromide reacts exclusively in
the presence of a secondary bromide (entry 15),16 a primary
tosylate (entry 16), or a primary chloride (entry 17). For most
of these elimination processes, virtually no isomerization to the
internal olefin (<2%) is observed.
When 1-iodododecane is subjected to the method developed
for the dehydrohalogenation of alkyl bromides (Table 1), only
a small amount of 1-dodecene (20% yield) is generated; N-
alkylation of dicyclohexylamine is the major product.
Furthermore, under the same conditions, essentially no
elimination is observed with a primary alkyl chloride or
tosylate, presumably because of the relatively high barrier for
oxidative addition to Pd(P(t-Bu)2Me)2.17 On the other hand, at
elevated temperature, elimination of a primary tosylate to give
the desired terminal olefin proceeds in excellent yield (eq 3). It
Figure 1. Outline of a possible pathway for (and impediments to)
palladium-catalyzed cross-coupling of an alkyl electrophile.
the “deleterious” β-hydride elimination process (Figure 1)
would now be the desired pathway. Indeed, in our earlier efforts
to achieve cross-coupling reactions of alkyl electrophiles, we
had noted that significant, although not synthetically useful,
quantities of the olefin were sometimes observed as undesired
side products (e.g., up to 31% in the case of a Suzuki
coupling11).
After examining an array of reaction parameters, we have
been able to develop a palladium-catalyzed method for olefin
synthesis that accomplishes the dehydrohalogenation of a
primary alkyl bromide at room temperature with excellent
efficiency (Table 1, entry 1). The ligand of choice is P(t-
Table 1. Palladium-Catalyzed Elimination of an Alkyl
Bromide To Generate an Olefin: Influence of Reaction
Parameters
a
entry
variation from the “standard” conditions
none
yield (%)
1
2
98 (91)
no Pd(P(t-Bu)2Me)2
3
3
no KOt-Bu
95 (81)
4
no Cy2NH
13
5
Pd(P(t-Bu)3)2, instead of Pd(P(t-Bu)2Me)2
Pd(PCy3)2, instead of Pd(P(t-Bu)2Me)2
Pd(PPh3)4, instead of Pd(P(t-Bu)2Me)2
Cy2NMe, instead of Cy2NH
Cs2CO3, instead of Cy2NH
3
6
12
7
3
8
42
is worth noting that alkyl tosylates are not suitable substrates
for Oshima’s cobalt-catalyzed elimination, likely because of the
difficulty in achieving homolytic cleavage of the C−O bond;8 in
contrast, under our conditions, C−O scission is probably
accomplished through an SN2 pathway.12a,c
9
28
10
3% Pd2(dba)3 + 12% P(t-Bu)2Me, instead of
Pd(P(t-Bu)2Me)2
96 (76)
11
3%, instead of 6%, Pd(P(t-Bu)2Me)2
90 (75)
a
Determined via gas chromatography with the aid of a calibrated
Palladium-catalyzed eliminations of more hindered (γ- and β-
branched) primary alkyl tosylates also proceed in excellent yield
(Table 3, entries 2 and 3). Interestingly, a secondary alkyl
tosylate undergoes elimination, predominantly generating the
internal 2-alkene (2:1 internal:terminal; entry 4). Furthermore,
not only an alkyl tosylate, but also a mesylate, can be eliminated
to form an olefin with good efficiency (entry 5). Perhaps in part
because of the elevated reaction temperature, small amounts of
olefin isomerization are sometimes observed in eliminations of
alkyl sulfonates (entries 1 and 5), and preliminary experiments
indicate that the functional-group tolerance of the method is
limited. For each elimination illustrated in Table 3, essentially
no olefin is produced in the absence of Pd(P(t-Bu)2Me)2
(<2%).
internal standard (averages of two experiments); yields after 4 h are
given in parentheses.
Bu)2Me, which we have previously established to be useful for
palladium-catalyzed Suzuki reactions of alkyl electrophiles.12
Essentially no 2-dodecene is detected (<1%).13
In the absence of Pd(P(t-Bu)2Me)2, virtually no olefin is
formed (Table 1, entry 2). Although KOt-Bu is not necessary
(entry 3), a poor yield is obtained in the absence of Cy2NH
(entry 4). Palladium complexes bearing other hindered
trialkylphosphines (entries 5 and 6) or PPh3 (entry 7) are
comparatively ineffective, as are other Brønsted bases (entries 8
and 9). An active catalyst can be generated in situ from
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Table 2. Palladium-Catalyzed Elimination Reactions of Alkyl
Bromides
Table 3. Palladium-Catalyzed Elimination Reactions of Alkyl
Sulfonates
a
Percent yields of isolated products (averages of two experiments) are
provided. For each elimination in which a >2% yield of the internal
olefin was generated, the terminal:internal olefin ratio (determined via
1H NMR spectroscopy) is given in brackets.
described the preparation of this bioactive compound from
nerol via alcohol A, which was transformed into olefin C via a
Sharpless−Grieco sequence (top pathway in Figure 2).18
Spencer noted that the conversion of the alcohol to the
selenide “proved to be the only difficult step in the synthesis”.19
Figure 2. Conversions of an alcohol to an olefin en route to (R)-
a
Both values are percentages. Isolated yields (averages of two
mevalonolactone: (top) Spencer;18 (bottom) this study.
experiments) are provided. In all cases, >98% of the unpurified
elimination product is the terminal olefin, with the exception of entries
11 and 16, for which the terminal:internal olefin ratios (determined via
b
1H NMR spectroscopy) are given in brackets. Because of the volatility
We effected the transformation of alcohol A into olefin C in
78% overall yield through our palladium-catalyzed elimination
process (bottom pathway in Figure 2). Thus, treatment of A
with Ph3PBr2 furnishes primary alkyl bromide B, and
subsequent palladium-catalyzed dehydrohalogenation under
our standard conditions at room temperature affords the
desired olefin in excellent yield (93%). Finally, removal of the
of allylbenzene, the yield was determined via gas chromatography vs a
calibrated internal standard (average of two experiments). KOt-Bu
loading: 2.5%. KOt-Bu loading: 20%.
c
d
We applied our palladium-catalyzed elimination process to a
formal total synthesis of (R)-mevalonolactone. Spencer
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1-ethoxyethyl protecting group generates Spencer’s intermedi-
ate C.
Mechanism. Our current hypothesis is that these
palladium-catalyzed elimination reactions follow the pathway
outlined in Figure 3 [throughout this section, L = P(t-Bu)2Me].
at higher concentration) with respect to the alkyl bromide, and
zeroth order with respect to Cy2NH. According to 31P NMR
spectroscopy, L2Pd(CH2CH2R)Br is the predominant resting
state of palladium during the early stages of the reaction (small
amounts of L2Pd and L2PdHBr are also present; as the reaction
progresses, the proportion of L2PdHBr increases). These data
are consistent with oxidative addition and a subsequent step
each being partially rate-determining.
For the stoichiometric chemistry of L2Pd, we have
established that β-hydride elimination is impeded by the
addition of excess P(t-Bu)2Me (eq 5); we have similarly
determined that the palladium-catalyzed dehydrohalogenation
of 1-bromododecane is inhibited by added P(t-Bu)2Me.
Furthermore, we observe a modest kinetic isotope effect
when comparing the rate of elimination of 1-bromododecane
with that of 1-bromo-2,2-dideuteriododecane (kH/kD = 1.5; eq
6). Collectively, these data are consistent with β-hydride
elimination being the other partially rate-determining step.
Figure 3. Outline of a possible mechanism for Pd(P(t-Bu)2Me)2-
catalyzed dehydrobromination reactions.
Thus, oxidative addition of the alkyl bromide to L2Pd proceeds
via an SN2 process to generate L2Pd(CH2CH2R)Br (D).12a,c
Dissociation of one phosphine furnishes 14-electron palladium
adduct E, which undergoes β-hydride elimination to provide
palladium olefin−hydride intermediate F. In the presence of
base (Cy2NH) and L, palladium complex F affords [Cy2NH2]-
Br, the olefin, and L2Pd.
To make our mechanistic study more tractable, we chose to
focus our investigation on palladium-catalyzed dehydrobromi-
nations in the absence of KOt-Bu, a process that also occurs in
excellent yield (Table 1, entry 3).20 With regard to the oxidative
addition step of the proposed catalytic cycle, we previously
established that L2Pd reacts with 1-bromo-3-phenylpropane in
Et2O at 0 °C and crystallographically characterized the Pd(II)
adduct.12b Here we examined the reaction of 1-bromododecane
with L2Pd in dioxane at room temperature and determined that
oxidative addition is complete within 1.5 h, affording a mixture
of L2Pd(CH2CH2R)Br and L2PdHBr21 (eq 4). After an
In a previous study, we demonstrated that oxidative addition
of a primary alkyl electrophile to Pd/P(t-Bu)2Me preferentially
proceeds through an SN2 pathway.12a,c If oxidative addition is
indeed partially rate-determining for the dehydrohalogenation
of 1-bromododecane, then one might anticipate that, in the
case of a more hindered alkyl bromide, oxidative addition
would be entirely rate-determining. We determined the rate law
for the dehydrobromination of a β-branched primary alkyl
bromide and established that it is first order in the alkyl
bromide, first order in L2Pd, and zeroth order in Cy2NH (eq
7). Furthermore, 31P NMR spectroscopy revealed that L2Pd is
additional 1.5 h, this mixture proceeds to form L2PdHBr
quantitatively. Taken together, these data indicate that oxidative
addition and then β-hydride elimination are chemically and
kinetically competent initial steps of the catalytic cycle.
We also investigated the impact of added P(t-Bu)2Me on the
reaction of 1-bromododecane with L2Pd (eq 5). The rate of
consumption of L2Pd is unaffected by the additional ligand,
whereas the formation of L2PdHBr is inhibited, consistent with
the suggestion that L2Pd (rather than L1Pd or L3Pd) is the
species undergoing oxidative addition and that ligand
dissociation precedes β-hydride elimination.22
the predominant resting state of the catalyst. Taken together,
these observations are consistent with oxidative addition being
the rate-determining step for the palladium-catalyzed elimi-
nation of this more hindered alkyl bromide.
Interestingly, L2PdHBr is not an intermediate in the primary
catalytic cycle. Thus, treatment of 1-bromododecane with 6%
The rate law for the palladium-catalyzed dehydrobromination
of 1-bromododecane is first order with respect to L2Pd,
fractional order (first order at lower concentration, zeroth order
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L2PdHBr, rather than L2Pd, produces essentially no 1-dodecene
(eq 8).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
gcfu@caltech.edu
■
Notes
The authors declare no competing financial interest.
We have established that Cy2NH is not a sufficiently strong
Brønsted base to drive the acid−base equilibrium illustrated in
eq 9 to the right, thereby producing L2Pd from L2PdHBr.23,24
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, Grant R01-
GM62871), an American Australian Association Merck
Company Foundation Fellowship (A.C.B.), the Paul E. Gray
(1954) Endowed Fund for the Undergraduate Research
Opportunities Program (A.L.), and the John Reed Fund (A.L.).
REFERENCES
Thus, it appears that, during our palladium-catalyzed
dehydrobromination process, a palladium hydride other than
L2PdHBr undergoes reductive elimination to regenerate Pd(0).
Because each turnover of the catalyst generates [Cy2NH2]Br,
a question arises as to why this ammonium salt does not
protonate L2Pd to form L2PdHBr, thereby deactivating the
palladium catalyst. In fact, during the course of the
dehydrobromination process, we do observe a slow accumu-
lation of L2PdHBr. Fortunately, however, the poor solubility of
[Cy2NH2]Br in dioxane impedes this deleterious protonation
(i.e., [Cy2NH2]Br precipitates faster than it protonates L2Pd).25
Although we previously postulated that the formation of a
relatively stable L2PdHCl (L = PCy3) complex could be the
origin of the low catalyst activity in a Heck reaction of an aryl
chloride,23 we had not fully appreciated the importance of
avoiding the formation of L2PdHBr in developing a mild Pd/
P(t-Bu)2Me-catalyzed method for the dehydrohalogenation of
alkyl bromides. The fortuitous solubility properties of
[Cy2NH2]Br, combined with the unanticipated regeneration
of Pd(0) prior to the formation of L2PdHBr (L = phosphine),
are likely critical to the success of this process. The latter
observation regarding the timing of reductive elimination is
worth considering when contemplating the mechanism of Heck
reactions.26
■
(1) (a) McMurry, J. Organic Chemistry; Thomson: Belmont, CA,
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(2) Kostikov, R. R.; Khlebnikov, A. F.; Sokolov, V. V. Sci. Synth.
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(3) (a) Chugaev, L. Ber. Dtsch. Chem. Ges. 1899, 32, 3332−3335.
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(11) Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem.
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3910−3912. (b) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G.
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5752.
CONCLUSIONS
■
Although the elimination of HX to form an olefin is a classic
transformation in organic chemistry, there remains a need for
new mild methods to accomplish this fundamental process.
Herein we have exploited a generally undesired elementary step
in cross-coupling reactions, β-hydride elimination, to achieve
palladium-catalyzed dehydrohalogenations of alkyl bromides.
This method, which we have applied to a formal total synthesis
of (R)-mevalonolactone, enables the efficient synthesis of
terminal olefins at room temperature in the presence of a
variety of functional groups, including heterocycles. Our
mechanistic studies have established that the rate-determining
step can vary with the structure of the alkyl bromide. Most
significantly, we have determined that L2PdHBr (L =
phosphine), an intermediate that is often invoked in
palladium-catalyzed processes such as the Heck reaction, is
not an intermediate in the active catalytic cycle.
̈
(13) Isomerization of the initially generated olefin by a palladium
hydride intermediate is a well-established side reaction in Heck
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couplings. For recent examples of isomerizations of olefins catalyzed
by palladium hydrides, including Pd(P(t-Bu)3)2HCl, see: Gauthier, D.;
Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J. Am.
Chem. Soc. 2010, 132, 7998−8009.
(14) The proportion of internal olefin does not increase as the
reaction progresses, and treatment of 1-dodecene with L2PdHBr in
dioxane at room temperature does not lead to the generation of
internal olefins (although isomerization is observed at elevated
temperatures).
(15) Under our standard conditions (Table 1), in the presence of 1
equiv of a primary-amine additive, the dehydrobromination of 1-
bromododecane proceeded in ∼95% yield. The dehydrobromination
was slightly inhibited (55−70% yield, with the balance being unreacted
1-bromododecane) by the addition of 1 equiv of an unprotected indole
or a nitrile.
(16) The relative rate of dehydrobromination of 1-bromododecane vs
1-bromo-2-methylpentadecane (a β-branched alkyl bromide) is ∼13.
(17) For a study of the relative rates of oxidative addition of n-
nonyl−X (X = I, Br, Cl, F, OTs) to Pd(P(t-Bu)2Me)2 in THF, see ref
12c.
(18) Ray, N. C.; Raveendranath, P. C.; Spencer, T. A. Tetrahedron
1992, 48, 9427−9432.
(19) Spencer also noted that the selenide was “tenaciously
contaminated” by a selenium-containing impurity.
(20) Because of the slow accumulation of L2PdHBr during the course
of the palladium-catalyzed dehydrobromination (as discussed later),
we focused our mechanistic studies on the early stages of the reaction.
(21) Throughout this discussion, L2PdHBr refers to trans-L2PdHBr.
(22) This contrasts with Yamamoto’s studies of thermal decom-
position of trans-L2PdEt2, wherein β-hydride elimination proceeds
predominantly without ligand dissociation. See: Ozawa, F.; Ito, T.;
Yamamoto, A. J. Am. Chem. Soc. 1980, 102, 6457−6463.
(23) Treatment of L2Pd with [Cy2NH2]Br in dioxane at room
temperature leads to very slow formation of L2PdHBr. For related
observations with a different ligand (PCy3), halide (Cl), and base
(Cy2NMe), see: Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126,
13178−13179.
(24) On the other hand, KOt-Bu does react with L2PdHBr to
generate L2Pd in quantitative yield. However, when KOt-Bu rather
than Cy2NH is employed as the stoichiometric base, the elimination
does not proceed cleanly, and there is a considerable background
reaction (E2).
(25) The decreased efficiency of Cy2NMe relative to Cy2NH (Table
1, entry 8 vs entry 1) may be due to the greater solubility in dioxane of
[Cy2NHMe]Br compared with [Cy2NH2]Br, which leads to more
protonation of L2Pd to form inactive L2PdHBr.
(26) The Mizoroki−Heck Reaction; Oestreich, M., Ed.; Wiley: New
York, 2009.
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