NHC-copper hydrides as chemoselective reducing agents: Catalytic reduction of alkynes, alkyl triflates, and alkyl halides

Article abstract of DOI:10.1016/j.tet.2014.04.004

The NHC-copper-catalyzed Z-selective semi-reduction of terminal and internal alkynes, as well as the NHC-copper-catalyzed reduction of primary alkyl triflates and primary and secondary alkyl iodides and bromides are described. The high chemoselectivity demonstrated in these examples illustrates the mild nature of copper hydride complexes as reducing agents, which have applications in synthetic chemistry beyond their traditional role in the reduction of activated alkenes and carbonyl compounds.

Full text of DOI:10.1016/j.tet.2014.04.004

Tetrahedron 70 (2014) 4219e4231
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Tetrahedron
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NHCecopper hydrides as chemoselective reducing agents: catalytic
reduction of alkynes, alkyl triflates, and alkyl halides
,
Nick Cox a, Hester Dang a, Aaron M. Whittaker b, Gojko Lalic a
*
a Department of Chemistry, University of Washington, Seattle, WA 98195-1700, United States
b Department of Chemistry, University of California, Irvine, CA 92697-2025, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The NHCecopper-catalyzed Z-selective semi-reduction of terminal and internal alkynes, as well as the
NHCecopper-catalyzed reduction of primary alkyl triflates and primary and secondary alkyl iodides and
bromides are described. The high chemoselectivity demonstrated in these examples illustrates the mild
nature of copper hydride complexes as reducing agents, which have applications in synthetic chemistry
beyond their traditional role in the reduction of activated alkenes and carbonyl compounds.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 16 January 2014
Received in revised form 1 April 2014
Accepted 2 April 2014
Available online 12 April 2014
Keywords:
Alcohol deoxygenation
Alkyne semi-reduction
Halide reduction
N-Heterocyclic carbene copper hydride
Sulfonate reduction
1. Introduction
Copper hydride complexes have been used extensively as mild
reducing reagents in the reduction of activated alkenes and car-
bonyl compounds.1e3 Although a number of copper hydride com-
plexes had been studied as early as the 1970s,4,5 the use of copper
hydride complexes became popular following a report by Stryker in
1988.6 He demonstrated the use of a triphenylphosphine copper
hydride hexamer 2, better known as Stryker’s reagent, in the re-
duction of a,b-unsaturated carbonyl compounds (Scheme 1, Eq. 1).
Stryker’s reagent exhibited remarkable chemoselectivity, and is
much less reactive toward unactivated olefins. Further de-
velopments by Stryker led to the use of catalytic amounts of 2 for
the reduction of activated alkenes under high pressures of H2.7 In
1998, Lipshutz showed that a much more efficient catalytic reaction
could be achieved with the use of silanes as the hydride source in
the reduction of enones catalyzed by 2 (Scheme 1, Eq. 2).8 Lipshutz
also described the use of Stryker’s reagent as a catalyst for the 1,2-
hydrosilylation of ketones and aldehydes.9
Enantioselective reactions of phosphine-supported copper hy-
dride complexes have also been explored. The copper-catalyzed
asymmetric reduction of activated alkenes was first developed by
Buchwald and used chiral bidentate phosphine ligands, such as (7)
Scheme 1. Phosphine copper hydrides as mild reducing agents.
(Scheme 1, Eq. 3) and polymethylhydrosiloxane (PMHS) (8) as the
hydride source.10 This highly enantioselective reaction was used to
reduce
a,b-unsaturated esters, lactams, and cyclic enones. Many
* Corresponding author. Tel.: þ1 206 616 8493; fax: þ1 206 685 8665; e-mail
addresses: gojko.lalic@gmail.com, lalic@chem.washington.edu (G. Lalic).
other examples of enantioselective reductions1 drew inspiration
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.004

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N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
from work by Lipshutz and Carreira, who demonstrated the
asymmetric conjugate reduction of acyclic enones11 and nitro-
alkenes,12 respectively.
The next stage in the development of copper hydride complexes
as reducing reagents saw the introduction of electron-rich N-het-
erocyclic carbene ligands in place of phosphines, as a way of en-
hancing reactivity. The first use of NHCecopper complexes as
catalysts in the reduction of activated alkenes was reported by
Buchwald and Sadighi.13 In this reaction, IPrCuCl used as a pre-
catalyst, displayed remarkable catalytic efficiency and functional
group tolerance, in the presence of PMHS (8) as the hydride source
(Scheme 2, Eq. 4). The greater electron-donating ability of the NHC
ligand resulted in increased reactivity of the copper hydride in-
termediate, allowing for catalyst loading as low as 0.1 mol %.
Scheme 3. NHCecopper-catalyzed reduction of alkynes, triflates, and halides.
(1) the over-reduction of the desired alkene to the alkane,27,28
and (2) the Z/E isomerization of the desired alkene to afford
a mixture of stereoisomers.29,30 Both of these complications ne-
cessitate careful monitoring of the reaction in order to minimize
the formation of undesired byproducts. These difficulties are fur-
ther magnified by challenges associated with the separation of any
unreacted alkyne, over-reduced alkane, and E-alkene isomer from
the desired Z-alkene. Although some progress in this area has been
made,31e35 at the time we began our investigation there was no
generally applicable procedure for alkyne semi-reduction that fully
mitigated these problems.
Scheme 2. Previous examples of NHCecopper hydrides as reducing agents.
Later, Nolan showed that strong
s-donating NHC ligands
ð6Þ
allowed the efficient copper-catalyzed hydrosilylation of sterically
hindered, electron-rich ketones,14,15 illustrating the greater re-
activity of NHCecopper hydride complexes as compared to those
supported by phosphine ligands (Scheme 2, Eq. 5).
Despite all of these developments, copper hydride complexes
are commonly recognized only for their use in the reduction of
activated alkenes and carbonyl compounds, as illustrated in
Schemes 1 and 2. We were interested in expanding the scope of
copper hydride chemistry and exploring the use of copper hydride
complexes in catalytic reduction of other classes of organic mole-
cules. At the same time, we were hoping that the unique reactivity
and the mild nature of copper hydride complexes will allow us to
address two long standing problems in organic synthesis: selective
semi-reduction of alkynes and mild deoxygenation of primary al-
cohols. In this paper, we highlight recent progress our group has
made in this area. We describe the development of the copper-
catalyzed semi-reduction of internal and terminal alkynes to af-
ford Z-alkenes,16 and the development of the mild reduction of
primary alkyl sulfonates and primary and secondary alkyl halides17
(Scheme 3).
Our initial investigation into the use of NHCecopper complexes
as catalysts in reduction reactions drew inspiration from a report by
Sadighi,36 who showed that an unactivated alkyne in the presence
of complex 15 underwent rapid syn-hydrocupration at room tem-
perature to form NHCecopper alkenyl complex 16 (Eq. 6).
Drawing on Sadighi’s work, we proposed the catalytic reaction
depicted in Scheme 4, in which the hydrocupration reaction is
followed by protonation of the alkenyl copper intermediate using
an alcohol, releasing the desired Z-alkene and regenerating
2. Results and discussion
2.1. Copper-catalyzed semi-reduction of alkynes
The most common procedure for the reduction of alkynes to
alkenes is the use of molecular hydrogen in the presence of the
Lindlar catalyst.18,19 Although much effort has been devoted to the
development of new techniques for achieving this important
transformation,20e26 the Lindlar catalyst is still the reagent of
choice despite its many drawbacks. There are two persistent
problems with existing methodologies for alkyne semi-reduction:
Scheme 4. Proposed Cu-catalyzed semi-reduction of alkynes.

N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
4221
a catalytically active copper alkoxide species. This approach to the
semi-reduction of alkynes by the delivery of a hydride and a proton
has rarely been exploited,37 and is distinct from traditional metal-
catalyzed alkyne semi-reductions, in which hydrogen is delivered
by a metal dihydride complex. Unlike metal dihydride complexes,
NHCecopper hydrides are known to be unreactive toward simple
alkenes.13 As a result, we anticipated that our approach would re-
sult in minimal over-reduction and isomerization of the alkene
products, and could provide a general solution to two of the most
persistent problems in the semi-reduction of alkynes.
2.1.1. Terminal alkynes. Our initial efforts at the reduction of ter-
minal alkynes using methods based on Sadighi’s work were un-
successful (Scheme 5, Eq. 7); yield of the desired alkene was only
19%, and incomplete conversion of the alkyne starting material was
observed. Through the systematic study of the reactivity of the
catalytic intermediates, we were able to identify three side re-
actions responsible for low yield. The first involved the catalytic,
unproductive consumption of the silane and alcohol. The
NHCecopper complex 18 rapidly catalyzed the formation of H2 and
silyl ether 20 when exposed to silane and alcohol (Scheme 5, Eq. 8).
We found that by changing the NHC ligand from ICy to IPr, the rate
of this reaction was suppressed significantly (Scheme 5, Eq. 9).
Scheme 6. Competing formation of catalytically inactive copper acetylide.
in Table 1. Using these conditions, we were able to selectively re-
duce terminal alkynes in the presence of a variety of functional
groups that are incompatible with traditional techniques for alkyne
semi-reduction. Some of the most notable examples are internal
alkynes (23), strained alkenes (24), conjugated dienes (25), aryl
halides (26, 27), ketones (28), and nitroarenes (29). The reaction
also performs well in the presence of polar functional groups such
as sulfonates (31), alcohols (32), esters (33), imides (36), and car-
bamates (37e38), as well as silyl-protected alcohols (34). Moreover,
in no case were we able to detect over-reduction of the desired
alkenes to the corresponding alkanes, and allenes were not detec-
ted in the reduction of a propargylic alcohol and several of its
Table 1
NHCecopper-catalyzed semi-reduction of terminal alkynesa
Scheme 5. Competing protonation of copper hydride by alcohol.
In addition, we found that there were two other competing
reactions that contributed to deactivation of the catalyst. The first
involved the deprotonation of the alkyne by copper alkoxide
complex 14 to form copper acetylide complex 21, which is cata-
lytically inactive (Scheme 6, Eq. 10).
We were able to overcome this competing reaction by finding
conditions, which increased the rate of silicon-to-copper hydride
transmetallation. As shown in Scheme 6, Eq. 11, substituting trie-
thylsilane for the more-reactive polymethylhydrosiloxane (PMHS)
resulted in a dramatic increase in the yield of alkenyl copper
complex 22. The second competing reaction, which resulted in
catalyst deactivation (Scheme 6, Eq. 12) again involved deproto-
nation of the alkyne, this time by alkenyl copper complex 22 to
form the inactive copper acetylide 21. Although this reaction is
slow, we found that it is responsible for the incomplete conversion
of the alkyne in reactions performed with a low catalyst loading
(Scheme 6, Eq. 13). In order to find conditions, which could out-
compete this reaction, we explored the use of more-acidic alco-
hols. We found that with the more-acidic yet sterically hindered
isobutanol we can achieve complete conversion even with
0.5 mol %, and a significantly higher rate of the reaction.
Combining these observations, we were able to find optimal
conditions for the semi-reduction of terminal alkynes as illustrated

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N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
derivatives (32e35). To demonstrate that careful monitoring of the
reaction is unnecessary, we showed that terminal alkene 39 is
completely unreactive, and formation of alkane 40 was not ob-
served even with prolonged exposure to these reaction conditions
(Eq. 14).
suggests that the semi-reduction is completely selective for overall
syn-addition, with no isomerization of the alkene products.
ð18Þ
Finally, we attempted to identify the resting state of the catalyst
at partial conversion by 1H NMR (Scheme 8). When tert-butanol
was used as the proton source, we found that the reaction was
sufficiently slow so as to allow for convenient monitoring by 1H
NMR at room temperature. At roughly 25% conversion, we were
able to clearly identify IPrCu-alkenyl species 22 as the sole resting
state of the catalyst. Considering that the subsequent protonation
step is irreversible, this strongly suggests that the turnover-limiting
step of the catalytic cycle is protonation of alkenyl copper. This
conclusion is also consistent with the rate enhancement observed
when using more-acidic proton sources.
ð14Þ
In order to make this method for semi-reduction of terminal
alkynes more practical and to increase its ease of use, we developed
a procedure, which can be carried out on a multi-gram scale, using
commercially available IPrCuCl as a pre-catalyst, and without the
need for an inert-atmosphere glovebox. As shown in Eq. 15, these
modifications allowed us to prepare alkene 37 on a 14 mmol scale
in 90% yield.
2.1.2. Internal alkynes. Our attempts at the semi-reduction of in-
ternal alkynes using the techniques optimized for terminal alkyne
semi-reduction were unsuccessful, resulting in incomplete con-
version and only 15% yield of the desired alkene (Scheme 9, Eq. 19).
Furthermore, we observed complete consumption of the silane and
alcohol, strongly suggesting that a reaction similar to that shown in
Scheme 5, Eq. 8 was out-competing hydrocupration of the internal
alkyne. To test this hypothesis, we carried out the competition
experiment shown in Scheme 9, Eq. 20, in which a stoichiometric
amount of IPrCuH was exposed to equal amounts of alkyne 43 and
isobutanol. We observed minimal conversion of the alkyne to the
alkene, along with vigorous bubbling, confirming that the un-
productive formation of H2 was out-competing the desired reaction
pathway.
To address this competing reaction, we explored the use of tert-
butanol as the proton source. Indeed, repeating the competition
experiment with the less-acidic alcohol significantly increased
yield of the desired alkene (Scheme 9, Eq. 21). This prompted fur-
ther investigation of the reaction mechanism in an effort to un-
derstand the differences in reactivity between internal and
terminal alkynes.
ð15Þ
Particular emphasis was placed on developing a procedure,
which allowed for convenient purification of the desired product.
The major difficulty was the removal of the polymer byproducts
formed from PMHS. We found that a treatment of the crude re-
action mixture with acids, bases, or oxidants did not facilitate the
purification of the desired product. However, we also found that
these nonpolar byproducts could be easily separated by filtering the
reaction mixture through a plug of alumina. The separation of the
polymer byproducts was also facilitated by the use of 2-methyl-1-
pentanol (Eq. 15) as the proton source, in place of isobutanol.
All of the elementary steps in the mechanism depicted in
Scheme 4 are supported by experiments reported by Sadighi36 and
Tsuji.35 To provide further rationale for the mechanism depicted in
Scheme 4, we carried out the series of reactions shown in Scheme 7.
As demonstrated in Eqs. 16 and 17, we were able to show that both
IPrCuH complex 15, as well as the alkenyl copper species 22 are
both viable catalysts in the semi-reduction of alkyne 17. These re-
sults support the notion that both complex 15 and an alkenyl
copper intermediate lie on the catalytic cycle.
In situ monitoring of the reaction by 1H NMR revealed that no
alkenyl copper species could be observed. However, we were able
to detect a resonance at 2.67 ppm, which is in agreement with the
characteristic hydride resonance of IPrCuH dimer 15 first reported
by Sadighi36 (Scheme 10). This, together with the lack of any ob-
served resonances characteristic of alkenyl copper, suggests that
the major catalyst resting state in the reduction of internal alkynes
is a copper hydride species rather than alkenyl copper. This further
implies that the turnover-limiting step for internal alkyne semi-
reduction is hydrocupration of the alkyne rather than protonation
of alkenyl copper. Given that the alcohol is not likely involved in the
hydrocupration step, the use of more-acidic alcohols, such as iso-
butanol, can only enhance the rate of the competing copper hydride
protonation reaction. This is also consistent with our observations
in the competition experiments described in Scheme 9, in which
the use of less-acidic alcohols has a beneficial effect on yield of the
desired alkene.
Guided by these observations of the reaction mechanism, we
were able to achieve the selective semi-reduction of internal al-
kynes with only slight variations to the reaction conditions used for
terminal alkyne semi-reduction. As shown in Table 2, we were able
to selectively reduce internal alkynes in the presence of polar
functional groups such as esters (45), carbamates (46), alcohols
(47), and alkyl chlorides (48). Propargylic alcohol derivatives could
be reduced without any observed elimination or allene formation
Scheme 7. Catalytic competency of proposed intermediates 9 and 16.
We also carried out the deuterium labeling experiment depicted
in Eq. 18, where deuterium-labeled tert-butanol was used in lieu of
isobutanol, resulting in the formation of a single isomer of
deuterium-labeled alkene 42. This provides additional evidence for
the alkenyl copper protonation step of the catalytic cycle, and

N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
4223
Scheme 8. Determination of catalyst resting state as alkenyl copper by 1H NMR at ca. 25% conversion of the alkyne starting material.
Scheme 9. Competing protonation of 15 in reduction of internal alkynes.
(49e51). Finally, functional groups that are easily reduced using
traditional techniques for alkyne semi-reduction, such as benzo-
nitriles (52), nitroarenes (53), and aryl halides (54) are well-
tolerated under these conditions. Most importantly, the reaction
was completely selective for the formation of the Z isomer. No
isomerization of the alkene products was detected, and no over-
reduction to the alkane was observed.
Scheme 10. Resting state experiment for internal alkyne reduction.
Similar to the adaptations we made to the reduction of terminal
alkynes in order to increase its ease of use, we developed a variant to
the procedure for internal alkyne semi-reduction, which allows for
the multi-gram preparation of Z internal alkenes using a commer-
Eq. 22 depicts the semi-reduction of alkyne 55 on a 25 mmol
scale, affording alkene 56 in 87% yield. An added convenience of
this adapted procedure is the substitution of tert-butanol (which
can solidify at room temperature, complicating addition by syringe)
with tert-amyl alcohol (2-methyl-2-butanol), which has a melting
point of ꢀ12 ꢁC.
cially available pre-catalyst and without the need for a glovebox.
We have developed a catalytic system, which exploits the mild
nature of copper hydride complexes in order to achieve the Z-se-
lective semi-reduction of alkynes without any over-reduction to the
alkane, providing an attractive alternative to the Lindlar catalyst.
Additionally, the high chemoselectivity, scalability, and ease of use
ð22Þ

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N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
Table 2
NHCecopper-catalyzed semi-reduction of internal alkynesa
Scheme 11. Optimization of the NHCeCu-catalyzed reduction of triflates.
of this procedure offer a practical solution to alkyne semi-
reduction.
2.2. Copper-catalyzed reduction of primary alkyl triflates
24). This further demonstrates the mild nucleophilic character of
copper hydride as a reducing agent. Additionally, we were sur-
prised to find that TMDSO (58) was a more reactive source of hy-
dride as compared to PMHS in this reaction (Scheme 11, Eq. 25).
Finally, while alkoxide additives are commonly used to aid in cat-
alyst turnover in related reactions,63,64 we found that they resulted
in unproductive competing reactions, which consumed the triflate
starting material (Scheme 11, Eq. 26). These competing reactions
could be avoided by using the much less basic CsF additive.
As depicted in Table 3, we were able to develop a practical, two-
step triflation/reduction procedure for primary alcohol de-
oxygenation that proceeds with high overall yield from the starting
alcohols. This technique was found to be compatible with a variety
of functional groups that are commonly reduced when using tra-
ditional techniques for alcohol deoxygenation, including aryl ha-
lides (61e64), benzonitriles (65), and nitroarenes (67). Esters (68),
silyl-protected alcohols (69, 70), and alkenes (71) were also toler-
ated. Remarkably, primary triflates can be reduced selectively in the
presence of both alkyl tosylates (72) and alkyl bromides (73).
We propose the catalytic cycle depicted in Scheme 12, which is
based on experiments demonstrating the validity of each elemen-
tary step of the reaction. The experiment shown in Scheme 13, Eq.
27 illustrates rapid fluoride/hydride exchange between silicon and
copper to form IPrCuH complex 15. We also found that when
NHCecopper hydride complex 15 is exposed to 5.0 equiv of alkyl
triflate 57, the complete and rapid disappearance of complex 15 can
be observed by 1H NMR. While we were unable to visualize the
formation of IPrCuOTf complex 75 in the same NMR experiment,
this can be rationalized based on its insolubility in 1,4-
dioxanedindeed, a crystalline precipitate is observed in the NMR
tube upon addition of alkyl triflate. In a separate reaction of triflate
57 and copper hydride 15, we were able to detect formation of al-
kane 59 by GC (Scheme 13, Eq. 28), indicating that IPrCuH 15 is
a competent reducing agent in the reduction of triflates. Finally,
IPrCuF complex 74 was formed in 97% yield in the reaction of IPr-
CuOTf 75 and CsF (Scheme 13, Eq. 29).
The selective reduction of alcohols and their derivatives to al-
kanes plays an important role in the synthesis of complex organic
molecules, as it is often the case that an unwanted oxygen-
containing functional group must be removed in the late stages
of a multi-step synthesis.38 While numerous methods for the de-
oxygenation of alcohols exist,39e47 the most widely used approach
for alcohol deoxygenation involves a two-step process in which the
alcohol is converted into either a halide or Barton ester48e50 prior to
a separate reduction step using stoichiometric amounts of a tin
hydride reagent.51,52 These approaches work well for the selective
deoxygenation of tertiary and secondary alcohols, and are known to
be tolerant of a variety of functional groups. However, because
these reactions typically involve the formation of alkyl radical in-
termediates, they are much less effective in the selective de-
oxygenation of primary alcohols.48 Instead, the most commonly
used methods for primary alcohol deoxygenation involve con-
verting the primary alcohol to a halide or sulfonate ester prior to
reduction with strong borohydride reagents.53e57 Given the high
reactivity of these reducing reagents, we considered that an alter-
native approach involving copper hydride could provide a more
practical technique for the selective deoxygenation of primary al-
cohols. Although several examples of stoichiometric reduction of
halides and sulfonates by copper hydrides were known,58e60 there
were no examples of catalytic reactions at the time our work in this
area began.
Sulfonate esters are easy to prepare from primary alcohols and
commercially available sulfonyl chlorides and anhydrides,61 and
their reactivity as leaving groups can be easily modulated.62 As
shown in Scheme 11, Eq. 23, we found that primary alkyl triflate 57
could be reduced using the IPrCuOt-Bu catalyst 14, tetramethyldi-
siloxane (TMDSO) (58) as the stoichiometric source of hydride, and
CsF, which facilitates catalytic turnover. In the course of the re-
action optimization, we determined that the highly-reactive triflate
leaving group was essential for maintaining reactivitydindeed,
even with prolonged reaction times, tosylate leaving groups (60)
only achieved 10% conversion to the desired alkane (Scheme 11, Eq.
Overall, this approach to primary alcohol deoxygenation offers
a practical alternative to existing techniques, owing to the high

N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
4225
Table 3
functional group tolerance and mild nature of the copper hydride
reducing agent.
Two-step deoxygenation of 1ꢁ alcohols via Cu-catalyzed reduction of triflatesa
2.3. Copper-catalyzed reduction of alkyl halides
Similar to the reduction of alkyl sulfonates, the reduction of
alkyl halides is commonly used as part of a strategy for the two-step
deoxygenation of alcohols, as alcohols can be easily converted into
the corresponding halides. Additionally, a number of recent ex-
amples in natural product synthesis involve the reduction of alkyl
halides in the late stages of a multi-step synthesis.65e69 As dis-
cussed previously, this transformation is most often achieved using
a stoichiometric quantity of tin hydride.
2.3.1. Secondary alkyl halides. In our initial attempts to reduce
secondary halides using the conditions optimized for the reduction
of primary triflates, we observed a competing elimination reaction,
as exemplified by the reduction of iodide 76 (Scheme 14, Eq. 30). To
solve this problem, we explored the use of different solvents,
turnover additives, and hydride sources. Eventually, we found that
by changing the hydride source to a more reactive silane (Ph2SiH2)
and the turnover additive to potassium 2-tert-butylphenoxide (79),
we were able to suppress the competing elimination reaction
(Scheme 14, Eq. 31).
Scheme 14. Competing elimination in the reduction of 2ꢁ iodides.
Using these reaction conditions, we were able to selectively
reduce a variety of secondary iodides in good to excellent yield, and
in the presence of functional groups that are often reactive when
using traditional methods for halide reduction (Table 4). This in-
cludes aryl chlorides (80), aryl bromides (81), and benzonitriles
(82). Carbamates (83), esters (84, 86), ethers (85), and silyl-
protected alcohols (87) are also tolerated. In addition to second-
ary alkyl iodides, we found that secondary alkyl bromides con-
taining aryl chloride (80), aryl bromide (81), carbamate (83), ester
(84), and alkene (88) substituents can also be reduced selectively
using these conditions. However, yields of the alkane products are
typically lower in these cases as compared with the reduction of the
corresponding secondary iodides, which can be rationalized based
on the higher reactivity of alkyl iodides as compared to alkyl
bromides.
Scheme 12. Catalytic cycle for the NHCeCu-catalyzed reduction of triflates.
2.3.2. Primary alkyl halides. We found that the same conditions
used for the reduction of primary alkyl triflates was highly effective
in the reduction of primary alkyl iodides, although the reaction
time had to be increased to 24 h to achieve full conversion. As
shown in Table 5, we were able to selectively reduce primary alkyl
iodides in the presence of aryl halides (61, 63, 64), benzonitriles
Scheme 13. Experiments demonstrating feasibility of elementary steps in the pro-
posed mechanism for the Cu-catalyzed reduction of triflates.

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N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
Table 4
NHCecopper-catalyzed reduction of 2ꢁ alkyl halidesa
Scheme 15. Catalytic cycle for the NHCeCu-catalyzed reduction of halides.
distinguish paths A and B, which involve two-electron process,
from path C, which involves single-electron transfer.
Based on the strength of the carboneoxygen bond,70 and the
fact that sulfonates are not known to stabilize oxygen radicals, it is
highly unlikely that the reduction of triflates discussed earlier in-
volves the formation of a free radical intermediate. Alkyl halides,
however, are common radical precursors, and a recent example of
an iridium-catalyzed reduction of alkyl iodides occurs through
a radical mechanism.71 Ultimately, we found evidence that the
dominant mechanism of the copper-catalyzed reduction of alkyl
halides is unlikely to involve the formation of free radical in-
termediates. This conclusion is supported by the series of experi-
ments depicted in Scheme 16.
Table 5
NHCecopper-catalyzed reduction of 1ꢁ alkyl halidesa
Scheme 16. Demonstration that a radical mechanism is not dominant.
When the reduction of primary alkyl iodide 91 was conducted in
the presence of 1.0 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy
free radical (TEMPO) (92), a reagent commonly used as a radical
trap, formation of the desired alkane was not inhibited (Scheme 16,
Eq. 32). Additionally, no adduct of 91 and TEMPO was detected. To
provide additional support for the notion that a radical mechanism
is not the dominant pathway, we carried out a competition ex-
periment using iodide 93 (Scheme 16, Eq. 33). Iodides of type 93
have been shown to engage in a fast radical cyclization reaction
after the homolytic cleavage of the carboneiodide bond.71 We
observed that the desired linear product 95 was formed in 87%
yield, while the product resulting from reductive cyclization (96)
was minor.72 When 1.0 equiv of TEMPO was added, the radical
cyclization reaction was completely inhibited, and the desired re-
duction product was formed in 81% yield. Finally, when the same
(65), amides (89), esters (90), silyl-protected alcohols (70), and al-
kenes (71). We were also quite surprised to find that primary io-
dides can be selectively reduced in the presence of alkyl tosylates
(72).
The catalytic cycle depicted in Scheme 15 describes the pro-
posed mechanism for the NHCecopper-catalyzed reduction of alkyl
halides. The silicon-to-copper transmetallation step,16,36 as well as
the additive-assisted turnover step64 are both well-precedented,
and so we focused our investigation of the reaction mechanism of
the proposed step in which the halide leaving group is reduced by
copper hydride complex 15. This step is likely to occur through one
of three possible pathways: (A) an oxidative-addition/reductive-
elimination process, (B) nucleophilic substitution, or (C) the for-
mation of an alkyl radical intermediate. We initially sought to

N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
4227
experiment was repeated using bromide 94 (which is less pre-
disposed to undergo homolytic cleavage of the carbonehalide
bond), no cyclization product was formed even in the absence of
TEMPO, and the desired product was formed in quantitative yield.
Altogether, these results suggest that the reduction step is likely to
involve a two-electron process.
In summary, these procedures provide means for the removal of
halogens from primary and secondary alkyl halides with chemo-
selectivity that is complementary to the most common techniques
for achieving this transformation, such as reduction with tin hy-
drides. The approach we have developed for the reduction of alkyl
halides further supports the notion that NHCecopper hydrides
possess greater reactivity than phosphine copper hydrides, such as
Stryker’s reagent, while still maintaining much of the functional
group tolerance of such mild reducing agents.
Materials: THF, CH2Cl2, toluene, and Et2O were degassed and
dried on columns of neutral alumina. 1,4-Dioxane was distilled
ꢀ
from purple Na/benzophenone ketyl, and stored over 4 A molec-
ular sieves. Deuterated solvents were purchased from Cambridge
Isotope Laboratories, Inc. and used as received. All terminal al-
kynes, internal alkynes, primary alcohols, and secondary alcohols
were prepared according to standard techniques found in litera-
ture. All other commercially available reagents were purchased
from AK Scientific, Inc., GFS Chemicals, Oakwood Products, Inc.,
SigmaeAldrich Co., STREM Chemicals, Inc., Tokyo Chemical In-
dustry Co., Ltd., or VWR international, LLC. and were used as
received.
4.2. General procedure for the reduction of terminal alkynes
In a nitrogen-filled glovebox, a 1-dram vial was charged with
a stir bar followed by the alkyne (1.00 equiv, 1.00 mmol), PMHS 8
(1.20 equiv, 71.7 mg, 1.20 mmol), and isobutanol (1.00 equiv,
88.9 mg, 1.20 mmol). This mixture was diluted in toluene (10 mL)
before adding IPrCuOt-Bu 14 (0.0050 equiv, 2.6 mg, 0.0050 mmol).
The reaction mixture was stirred at 25 ꢁC until complete conver-
sion of the starting material was achieved (1 h). The mixture was
then diluted with hexanes (20 mL), and filtered through a silica gel
plug using a 1:1 ethyl acetate/hexane solution (100 mL). The fil-
trate was concentrated under vacuum, and the crude reaction
products were purified either by using a 10 g silica gel column,
distillation, and/or an aqueous workup. The aqueous workup was
carried out by stirring the crude reaction products in a solution of
NaOH (10 mL, 0.1 M in tetrahydrofuran/H2O 5:1) for 30 min. The
solution was then extracted with diethyl ether (3ꢂ20 mL), and the
combined organic layers were washed with brine (20 mL), and
dried over MgSO4 before filtration and concentration under vac-
uum. See examples below for details on the purification procedure
used.
3. Conclusion
Copper hydride complexes have historically been used as mild
reagents for reduction of carbonecarbon multiple bonds that are
activated by an electron-withdrawing group, and for reduction of
carbonyls. We have shown that NHCecopper complexes can cata-
lyze the reduction of unactivated internal and terminal alkynes
with remarkable chemoselectivity. Furthermore, we have ex-
panded the use of copper hydride complexes to the catalytic re-
duction of other classes of organic molecules, such as alkyl
sulfonates and halides. Importantly, we have shown that the in-
herently mild nature of the copper hydride reagent allows these
transformations to be carried out with chemoselectivity that is
often complementary or superior to the selectivity of commonly
used reducing reagents. As such, these new transformations offer
attractive alternatives to traditional approaches to the semi-
reduction of alkynes, the deoxygenation of primary alcohols, and
the reduction of primary and secondary alkyl halides.
4. Experimental
4.1. General
4.2.1. Selected examples
4.2.1.1. (ꢃ)-Pent-4-en-1-yl bicyclo[2.2.1]hept-5-ene-2-
carboxylate (24). Compound was isolated as a colorless liquid
(196 mg, 95% yield) after purification by silica gel chromatography
(0e10% Et2O/hexanes with a 5% benzene additive over eight col-
Additional spectral data for compounds not listed here are
available in:
General: All reactions were performed under a nitrogen atmo-
sphere, using a nitrogen-filled glovebox or flame-dried glassware
unless otherwise indicated. Column chromatography was per-
umn volumes). 1H NMR (300 MHz, CDCl3)
d
6.19 (dd, J¼5.7, 3.1 Hz,
1H), 5.92 (dd, J¼5.4, 2.8 Hz, 1H), 5.88e5.72 (m, 1H), 5.13e4.93 (m,
2H), 4.03 (td, J¼6.6, 2.1 Hz, 2H), 3.31e3.11 (m, 1H), 3.04e2.82 (m,
2H), 2.13 (dt, J¼6.8, 2.3 Hz, 2H), 1.97e1.84 (m, 1H), 1.80e1.63 (m,
2H), 1.43 (d, J¼9.7 Hz, 2H), 1.38e1.16 (m, 1H). 13C NMR (126 MHz,
formed on a Biotage Iso-1SV flash purification system using silica
gel (Agela Technologies Inc., 60 A, 40e60
ꢀ
mm, 230e400 mesh).
Infrared (IR) spectra were recorded on a PerkineElmer Spectrum
RX I spectrometer. IR peak absorbencies are represented as follows:
s¼strong, m¼medium, w¼weak, br¼broad. 1H, 13C, and 31P NMR
spectra were recorded on a Bruker AV-300 or AV-500 spectrometer.
CDCl3) d 174.9, 137.9, 137.7, 132.5, 115.4, 63.7, 49.8, 45.9, 43.5, 42.7,
30.2, 29.3, 28.0. HRMS calculated for [MþNa]þ 229.1204, found
229.1215. FTIR (neat, cmꢀ1): 3063 (w), 2975 (m), 1732 (s), 1336 (s),
1186 (s).
1H NMR chemical shifts (
d) are reported in parts per million (ppm)
downfield of TMS and are referenced relative to residual CHCl3
(7.26 ppm), C6H6 (7.16 ppm), CH2Cl2 (5.32 ppm), or CH3CN
(1.94 ppm). 13C chemical shifts are reported in parts per million
downfield of TMS and are referenced to the carbon resonance of the
4.2.1.2. 1-(4-(Pent-4-en-1-yloxy)phenyl)ethanone (28). Compound
was isolated as a colorless oil (189 mg, 93% yield) after purification
by silica gel chromatography (0e5% Et2O/hexanes with a 5% ben-
zene additive, over eight column volumes). 1H NMR (300 MHz,
solvent CDCl3 (
d
77.2 ppm), C6D6 (128.1), or CD2Cl2 (54.0). Data are
CDCl3)
d
7.93 (d, J¼8.9 Hz, 2H), 6.92 (d, J¼8.9 Hz, 2H), 5.91e5.89 (m,
represented as follows: chemical shift, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br s¼broad singlet),
integration, and coupling constants in Hertz (Hz). Mass spectra
were collected on a JEOL HX-110 High Resolution Mass Spectrom-
eter, an Applied Biosystems Inc. QStar XL High Resolution Mass
Spectrometer, a Bruker Esquire 1100 Liquid ChromatographeIon
Trap Mass Spectrometer, or a Hewlett Packard 5971A Gas Chro-
matographeMass Spectrometer. GC analysis was performed on
a Shimadzu GC-2010 with a flame ionization detector and an
1H), 5.18e4.95 (m, 2H), 4.03 (t, J¼6.4 Hz, 2H), 2.56 (s, 3H),
2.43e2.17 (m, 2H), 2.09e1.79 (m, 2H). 13C NMR (126 MHz, CDCl3)
d
196.9, 163.1, 137.7, 130.7, 130.3, 115.6, 114.3, 67.5, 30.1, 28.4, 26.5.
HRMS calculated for [MþH]þ 205.1228, found 205.1233. FTIR (neat,
cmꢀ1): 3076 (w), 2944 (m), 1675 (s), 1255 (s), 1019 (s).
4.2.1.3. 2-(Pent-4-en-1-yl)isoindoline-1,3-dione (36). Compound
was isolated as a white solid (196 mg, 91% yield) after a THF/NaOH
workup followed by silica gel chromatography (0e20% Et2O/hex-
SHRXI-5MS column (15 mꢂ0.25 mmꢂ0.25
mm).
anes over eight column volumes). 1H NMR (300 MHz, CDCl3)
d 7.84

4228
N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
(dd, J¼5.3, 3.1 Hz, 2H), 7.71 (dd, J¼5.5, 3.0 Hz, 2H), 5.94e5.68 (m,
1H), 5.16e4.90 (m, 2H), 3.88e3.57 (m, 2H), 2.12 (dt, J¼14.1, 7.3 Hz,
4.4.1. Selected examples
4 . 4 .1.1. ( Z ) - 2 , 4, 7 , 9 -Te t ra m e t hyld e c - 5 - e n e - 4, 7- di ol
(47). Compound was isolated as a white solid (227 mg, 99% yield)
after a THF/NaOH workup followed by silica gel chromatography
(0e40% ethyl acetate/hexanes over eight column volumes). 1H NMR
2H), 1.94e1.68 (m, 2H). 13C NMR (126 MHz, CDCl3)
d 168.6, 137.5,
134.0, 132.3, 123.3, 115.5, 37.7, 31.1, 27.7. HRMS calculated for
[MþNa]þ 238.0843, found 238.0852. FTIR (neat, cmꢀ1): 3061 (w),
2938 (m), 1712 (s), 1397 (m).
(300 MHz, CDCl3)
d
5.30 (s, 2H), 4.32 (s, 2H), 1.83 (qt, J¼12.9, 6.4 Hz,
2H), 1.51 (d, J¼6.0 Hz, 4H), 1.34 (s, 6H), 0.96 (d, 4.7 Hz, 6H), 0.94 (d,
J¼6.6, 6H). 13C NMR (126 MHz, CDCl3)
d 135.4, 74.1, 52.8, 31.0, 24.9,
4.2.1.4. N,N-Di(tert-butylcarbamate)-N-(pent-4-en-1-yl) amine
(38). Compound was isolated as a white solid (240 mg, 84% yield)
after purification by silica gel chromatography (0e10% ethyl ace-
tate/hexanes over eight column volumes, then 0e5% Et2O/hexanes
with a 5% chloroform additive over eight column volumes). 1H NMR
24.8, 24.7. HRMS calculated for [MþNa]þ 251.1987, found 251.1991.
FTIR (neat, cmꢀ1): 3219 (br), 3004 (w), 2954 (s), 1158 (s).
4 . 4 .1. 2 . ( Z ) - ( 3 - ( B e n z yl ox y ) n o n - 4 - e n - 1 - yl ) b e n z e n e
(51). Compound was isolated as a colorless liquid (283 mg, 92%
yield) after a THF/NaOH workup followed by silica gel chromatog-
raphy (0e15% ethyl acetate/hexanes over eight column volumes).
(300 MHz, CDCl3)
d 5.91e5.71 (m, 1H), 5.16e4.86 (m, 2H),
3.67e3.44 (m, 2H), 2.06 (q, J¼7.2 Hz, 2H), 1.68 (dd, J¼14.9, 7.4 Hz,
2H), 1.52 (d, J¼10.1 Hz, 18H). 13C NMR (126 MHz, CDCl3)
d 152.8,
138.0, 115.1, 82.2, 46.2, 31.1, 28.2, 28.1. HRMS calculated for [MþH]þ
286.2018, found 286.2010. FTIR (neat, cmꢀ1): 3077 (w), 2980 (m),
1785 (m), 1700 (s), 1128 (s).
1H NMR (300 MHz, MeOD)
d
7.59e6.88 (m, 10H), 5.64 (dt, J¼11.1,
7.5 Hz, 1H), 5.35 (dt, J¼11.0, 7.1 Hz, 1H), 4.56 (d, J¼11.8 Hz, 1H), 4.31
(d, J¼11.8 Hz, 1H), 4.15 (dt, J¼13.7, 8.3 Hz, 1H), 2.80e2.55 (m, 2H),
2.08e1.81 (m, 3H), 1.77e1.60 (m, 1H), 1.39e1.15 (m, 4H), 0.86 (t,
J¼6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 142.3, 139.1, 133.9, 130.7,
4.3. Glovebox-free, multi-gram scale reduction of terminal
alkyne
128.6, 128.4, 128.3, 127.9, 127.5, 125.8, 73.6, 70.0, 37.5, 32.0, 31.9,
27.7, 22.5, 14.1. HRMS calculated for [MþNa]þ 331.2037, found
331.2030. FTIR (neat, cmꢀ1): 3026 (w), 2955 (m), 1603 (m), 1453
(m), 1068 (s).
A flame-dried reaction flask was pressurized with dry nitrogen
then charged with
0.070 mmol, 0.0050 equiv), THF (7 mL), and anhydrous potassium
tert-butoxide (1 M solution in tert-butanol, 70 L, 0.070 mmol,
a stir bar followed by IPrCuCl (34 mg,
m
4 . 4 .1. 3 . ( Z ) - 1 - N i t r o - 4 - ( o c t - 3 - e n - 1 - yl o x y ) b e n z e n e
(53). Compound was isolated as a yellow liquid (218 mg, 87% yield)
after purification by silica gel chromatography (0e10% ethyl ace-
tate/hexanes with a 5% chloroform additive over eight column
0.0050 equiv). This mixture was allowed to stir at ambient tem-
perature for 15 min before adding a solution of PMHS (1.01 mL,
16.8 mmol, 1.20 equiv relative to hydride), carbamic acid, N-(pent-
4-ynyl)-1,1-dimethylethyl ester 41 (2.69 mL, 14.0 mmol,1.00 equiv),
and 2-methyl-1-pentanol (2.08 mL, 16.8 mmol, 1.20 equiv) in tol-
uene (70 mL). The reaction mixture was allowed to stir at ambient
temperature for 2 h. At this point, the reaction mixture was filtered
through a 30 g plug of silica gel with a 1:1 ethyl acetate/hexanes
solution (100 mL). The filtrate was concentrated under vacuum,
then loaded onto a 30 g plug of neutral alumina as a solution in
hexanes (15 mL). The plug was then washed with 100 mL of hex-
anes, and the filtrate was discarded. This was followed by a 1:4
Et2O/hexanes solution (200 mL), with eluents collected in 20 mL
fractions. Once the desired alkene began to elute from the plug
based on TLC, the plug was rinsed with 100 mL EtOAc to recover the
remaining product. The product-containing fractions were col-
lected then concentrated under vacuum to afford carbamic acid, N-
(pent-4-enyl)-1,1-dimethylethyl ester 37 as a colorless liquid (2.3 g,
volumes). 1H NMR (500 MHz, CDCl3)
d
8.20 (d, J¼9.0 Hz, 2H), 6.94
(d, J¼9.1 Hz, 2H), 5.57 (dt, J¼17.2, 8.0 Hz,1H), 5.43 (dt, J¼17.0, 7.7 Hz,
1H), 4.05 (t, J¼6.8 Hz, 2H), 2.58 (dt, J¼7.5, 6.7 Hz, 2H), 2.18e2.02 (m,
2H), 1.40e1.25 (m, 4H), 0.91 (t, J¼6.7 Hz, 3H). 13C NMR (126 MHz,
CDCl3)
d 164.2, 141.5, 133.6, 126.1, 123.9, 114.6, 68.5, 31.9, 27.3, 27.2,
22.5, 14.1. HRMS calculated for [MþNa]þ 272.1262, found 272.1274.
FTIR (neat, cmꢀ1): 3011 (w), 2955 (m), 1513 (s), 1342 (s), 1021 (s).
4.5. Glovebox-free, multi-gram scale reduction of internal
alkyne
A flame-dried reaction flask was pressurized with dry nitrogen
then charged with a stir bar followed by IPrCuCl (507 mg,
1.04 mmol, 0.0400 equiv), toluene (6.5 mL), and anhydrous potas-
90% yield). 1H NMR (300 MHz, C6D6)
(m, 2H), 4.02 (br s, 1H), 3.06e2.78 (m, 2H), 1.91e1.65 (m, 2H), 1.46
(s, 9H), 1.32e1.11 (m, 2H). 13C NMR (75 MHz, C6D6)
156.0, 138.3,
d
5.70e5.48 (m,1H), 5.02e4.79
sium tert-butoxide (1 M solution in tert-butanol, 1.30 mL,
1.30 mmol, 0.0500 equiv). This mixture was allowed to stir at am-
bient temperature for 15 min before adding PMHS (4.69 mL,
78.0 mmol, 3.00 equiv relative to hydride) followed immediately by
anhydrous methyl 4-(oct-3-ynyloxy)benzoate 55 (6.45 mL,
26.0 mmol, 1.00 equiv) as a solution in toluene (30 mL). After stir-
ring for 5 min, tert-amyl alcohol (7.03 mL, 65.0 mmol, 2.50 equiv)
was added, and the reaction mixture was allowed to stir for 6 h at
45 ꢁC. At this point, the reaction mixture was filtered through a 30 g
plug of silica gel with a 1:1 ethyl acetate/hexanes solution (200 mL).
The filtrate was concentrated under vacuum, then loaded onto
a 300 g plug of neutral alumina as a solution in hexanes (40 mL).
The plug was then washed with 500 mL of hexanes, and the filtrate
was discarded. This was followed by a 1:4 Et2O/hexanes solution
(600 mL), with eluents collected in 60 mL fractions. Once the de-
sired alkene began to elute from the plug based on TLC, the plug
was rinsed with 400 mL EtOAc to recover the remaining product.
The product-containing fractions were collected then concentrated
under vacuum to afford (Z)-methyl 4-(oct-3-enyloxy)benzoate 56
as a colorless liquid (5.9 g, 87% yield). 1H NMR (300 MHz, C6D6)
d
115.0, 78.3, 40.3, 31.3, 29.6, 28.6. HRMS calculated for C10H19NNaO2
[MþNa]þ: 208.1313, found: 208.1305. FTIR (neat, cmꢀ1): 3349 (s),
3078 (w), 2932 (s), 1696 (s), 1522 (s), 1252 (s), 1177 (s), 994 (m), 912
(m), 781 (w).
4.4. General procedure for the reduction of internal alkynes
In a nitrogen-filled glovebox, a 1-dram vial was charged with
a stir bar followed by the alkyne (1.00 equiv, 1.00 mmol), PMHS 8
(2.00 equiv, 120 mg, 2.00 mmol), and tert-butanol (2.50 equiv,
185 mg, 2.50 mmol). This mixture was diluted in toluene (2 mL)
before adding IPrCuOt-Bu 14 (0.020 equiv, 11 mg, 0.020 mmol). The
reaction mixture was stirred at 40 ꢁC until complete conversion of
the starting material was achieved (8 h). The mixture was then
diluted with hexanes (20 mL), and filtered through a silica gel plug
using a 1:1 ethyl acetate/hexane solution (100 mL). The filtrate was
concentrated under vacuum, and the crude reaction products were
purified using a 10 g silica gel column (see selected examples below
for mobile phase used).
d
8.15 (d, J¼9.0 Hz, 2H), 6.69 (d, J¼9.0 Hz, 2H), 5.58e5.42 (m, 1H),
5.42e5.26 (m, 1H), 3.54 (s, 3H), 3.49 (t, J¼6.8 Hz, 2H), 2.41e2.19 (m,

N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
4229
2H), 1.96 (t, J¼6.5 Hz, 2H), 1.37e1.10 (m, 4H), 0.87 (t, J¼7.0 Hz, 3H).
13C NMR (75 MHz, C6D6)
166.5, 163.1, 132.8, 132.0, 124.9, 123.3,
J¼6.7 Hz, 3H). 13C NMR (126 MHz, C6D6)
d
164.1, 141.9, 125.9, 114.4,
d
68.7, 32.3, 30.0, 30.0, 29.8, 29.7, 29.2, 26.2, 23.1, 14.4. HRMS calcu-
lated for C16H26NO3 [MþH]þ: 280.1912, found: 280.1911. FTIR (neat,
cmꢀ1): 3053 (m), 2928 (s), 1593 (s), 1521 (s), 1342 (s), 1264 (s), 1172
(m), 1111 (m), 845 (m).
114.4, 67.6, 51.4, 32.1, 27.6, 27.4, 22.7, 14.2. HRMS calculated for
C
16H22NaO3 [MþNa]þ: 285.1466, found: 285.1460. FTIR (neat,
cmꢀ1): 3011 (w), 2955 (s),1918 (w),1720 (s),1606 (s),1511 (m),1435
(m), 1278 (s), 1169 (s), 1105 (s), 1028 (m), 847 (m), 771 (s), 696 (w).
4.6.1.5. Methyl 4-(dec-1-yl)oxybenzoate (68). Compound was
isolated as a white solid (142 mg, 97% yield). 1H NMR (300 MHz,
4.6. General triflation/reduction procedure for primary alco-
hol deoxygenation
C6D6)
d
8.14 (d, J¼8.9 Hz, 2H), 6.73 (d, J¼8.9 Hz, 2H), 3.67e3.41 (m,
5H),1.65e1.43 (m, 2H), 1.40e1.11 (m, 14H), 0.92 (t, J¼6.7 Hz, 3H). 13
C
NMR (126 MHz, CD2Cl2) d 167.2, 163.6, 132.0, 123.0, 114.6, 68.9, 52.2,
A flame-dried reaction flask was pressurized with dry nitrogen
then charged with a stir bar, a primary alcohol (2.0 mmol,
1.0 equiv), and CH2Cl2 (5.0 mL). The flask was placed in a dry ice/
acetone bath at ca. ꢀ78 ꢁC, and while stirring vigorously, 2,6-
32.5, 30.2, 30.2, 30.0, 29.9, 29.7, 26.6, 23.3,14.5. HRMS calculated for
C
3053 (m), 2926 (s), 1715 (s), 1605 (s), 1511 (s), 1435 (s),1258 (s),1010
(m), 647 (w).
18H29O3 [MþH]þ: 293.2116, found: 2293.2112. FTIR (neat, cmꢀ1):
lutidine (370 mL, 3.2 mmol, 1.6 equiv) was added, followed by the
drop-wise addition of triflic anhydride (460
mL, 2.4 mmol,
4.6.1.6. 1-Hexyloxy-2-methoxy-4-(prop-2-en-1-yl)benzene
1.2 equiv). The reaction mixture was allowed to stir for 15 min at
ꢀ78 ꢁC before adding HCl (15 mL, 1 M solution in H2O). The flask
was then removed from the dry ice/acetone bath, and after slightly
thawing, the reaction mixture was transferred to a separatory
funnel and extracted with CH2Cl2 (5ꢂ15 mL). The organic layers
were combined then dried over Na2SO4 before filtration and con-
centration under vacuum. The resulting crude reaction products
were then filtered through a 10 g plug of silica gel, which was rinsed
with a 1:9 solution of ethyl acetate/hexanes until all of the desired
alkyl triflate was recovered based on TLC of the eluent. The product-
containing fractions were combined and concentrated under vac-
uum, and the alkyl triflate products were used immediately with-
out further purification. In a nitrogen-filled glovebox, a dry 20 mL
vial was charged with a stir bar, followed by cesium fluoride (76 mg,
0.50 mmol, 1.0 equiv), IPrCuOt-Bu 14 (13 mg, 0.025 mmol,
0.050 equiv), and 1,4-dioxane (1.67 mL). While stirring at ambient
(71). Compound was isolated as a colorless liquid (102.3 mg, 82%
yield). 1H NMR (300 MHz, C6D6)
d
6.75 (d, J¼2.8 Hz, 2H), 6.65 (s,1H),
6.10e5.81 (m, 1H), 5.26e4.98 (m, 2H), 3.77 (t, J¼6.5 Hz, 2H), 3.45 (s,
3H), 3.26 (d, J¼6.6 Hz, 2H), 1.82e1.56 (m, 2H), 1.53e1.31 (m, 2H),
1.31e1.05 (m, 4H), 0.85 (t, J¼6.8 Hz, 3H). 13C NMR (75 MHz, C6D6)
d
150.6, 148.3, 138.4, 132.7, 121.0, 115.5, 114.1, 113.4, 69.2, 55.6, 40.2,
32.0, 29.9, 26.2, 23.0, 14.3. HRMS calculated for C16H25O2 [MþH]þ:
249.1854, found: 249.1849. FTIR (neat, cmꢀ1): 3059 (w), 2932 (s),
2280 (m),1639 (m),1590 (s),1466 (s),1260 (s),1141 (s),1040 (s), 914
(m), 812 (s).
4.6.1.7. p-Toluenesulfonic acid, hexyl ester (72). Compound was
isolated as a colorless liquid (122.5 mg, 96% yield). Spectral data
match reported literature values.75
4.7. General procedure for the reduction of secondary halides
temperature, tetramethyldisiloxane (58 mL, 0.33 mmol, 0.65 equiv)
was added, followed by a solution of alkyl triflate (0.50 mmol,
1.0 equiv) in 1,4-dioxane (1.67 mL). The reaction mixture was stir-
red at ambient temperature for 4 h, at which point it was filtered
through a 10 g plug of silica gel, which was then rinsed with Et2O
(20 mL). The filtrate was concentrated under vacuum and the crude
reaction products were purified by chromatography on silica gel
(25 g) using a solvent gradient of 0e10% ethyl acetate/hexanes over
eight column volumes.
In a nitrogen-filled glovebox, a dry 20 mL vial was charged with
stir bar, potassium 2-tert-butylphenoxide 79 (104 mg,
0.550 mmol, 1.10 equiv), IPrCuOt-Bu 14 (13 mg, 0.025 mmol,
0.050 equiv), and 1,4-dioxane (3.33 mL). While stirring, diphe-
a
nylsilane (130 mL, 0.70 mmol, 1.4 equiv) was added, followed im-
mediately by a solution of alkyl iodide or bromide (0.50 mmol,
1.0 equiv) in 1,4-dioxane (3.33 mL). The reaction mixture was stir-
red at ambient temperature for 24 h, at which point it was filtered
through a 10 g plug of activated alumina, which was rinsed with
Et2O (20 mL). The filtrate was concentrated, and the desired alkane
product was purified by chromatography on activated alumina
(25 g) using a solvent gradient of 0e10% ethyl acetate/hexanes over
eight column volumes.
4.6.1. Selected examples
4.6.1.1. 1-(4-Bromophenyl)oxyhexane (63). Compound was iso-
lated as a colorless liquid (108.9 mg, 85% yield). Spectral data
match reported literature values.73
4.6.1.2. 1-(4-Iodophenyl)oxyhexane (64). Compound was iso-
lated as a colorless liquid (128.1 mg, 84% yield). Spectral data
match reported literature values.74
4.7.1. Selected examples of 2ꢁ iodide reduction
4.7.1.1. 1-(4-Bromophenyl)oxypentane (81). Compound was
isolated as a colorless liquid (102.8 mg, 85% yield). Spectral data
match reported literature values.76,77
4.6.1.3. 1-(4-Cyanophenyl)oxyhexane (65). Compound was iso-
lated as a colorless liquid (90.2 mg, 89% yield). 1H NMR (500 MHz,
CDCl3)
d
7.57 (d, J¼8.6 Hz, 2H), 6.93 (d, J¼8.6 Hz, 2H), 3.99 (t,
4.8. General procedure for the reduction of primary halides
J¼6.5 Hz, 2H), 1.87e1.70 (m, 2H), 1.51e1.40 (m, 2H), 1.39e1.29 (m,
4H), 0.91 (t, J¼6.4 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d
162.6, 134.1,
In a nitrogen-filled glovebox, a dry 20 mL vial was charged with
a stir bar, followed by cesium fluoride (76 mg, 0.50 mmol,1.0 equiv),
IPrCuOt-Bu 14 (13 mg, 0.025 mmol, 0.050 equiv), and 1,4-dioxane
(1.67 mL). While stirring at ambient temperature, tetramethyldi-
119.5, 115.3, 103.8, 68.5, 31.6, 29.1, 25.7, 22.7, 14.1. HRMS calculated
for C13H18NO [MþH]þ: 204.1388, found: 204.1383. FTIR (neat,
cmꢀ1): 3054 (m), 2932 (s), 2225 (s), 1899 (w), 1606 (s), 1506 (s),
1264 (s), 1171 (s), 1017 (m), 835 (s).
siloxane (58 mL, 0.33 mmol, 0.65 equiv) was added, followed by
a solution of alkyl iodide (0.50 mmol, 1.0 equiv) in 1,4-dioxane
(1.67 mL). The reaction mixture was stirred at ambient tempera-
ture for 24 h, at which point it was filtered through a 10 g plug of
silica gel, which was then rinsed with Et2O (20 mL). The filtrate was
concentrated under vacuum and the crude reaction products were
4.6.1.4. 1-(4-Nitrophenyl)oxydecane (67). Compound was iso-
lated as a yellow liquid (100.3 mg, 72% yield). 1H NMR (300 MHz,
CDCl3)
d
8.19 (d, J¼9.3 Hz, 2H), 6.94 (d, J¼9.3 Hz, 2H), 4.04 (t,
J¼6.5 Hz, 2H), 1.91e1.69 (m, 2H), 1.51e1.16 (m, 14H), 0.88 (t,

4230
N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
9. Lipshutz, B. H.; Chrisman, W.; Noson, K. J. Organomet. Chem. 2001, 624,
367e371.
10. Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald, S. L. J. Am.
purified by chromatography on silica gel (25 g) using a solvent
gradient of 0e10% ethyl acetate/hexanes over eight column
volumes.
Chem. Soc. 1999, 121, 9473e9474.
11. Lipshutz, B. H.; Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42, 4789e4792.
12. Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793e4795.
13. Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003, 5, 2417e2420.
14. Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P. Organometallics 2004, 23,
1157e1160.
4.8.1. Selected examples
4.8.1.1. 1-(4-Bromophenyl)oxyhexane (63). Compound was iso-
lated as a colorless liquid (119.1 mg, 93% yield). Spectral data
match reported literature values.73
ꢁ
15. Díez-Gonzalez, S.; Scott, N. M.; Nolan, S. P. Organometallics 2006, 25,
2355e2358.
16. Whittaker, A. M.; Lalic, G. Org. Lett. 2013, 15, 1112e1115.
17. Dang, H.; Cox, N.; Lalic, G. Angew. Chem., Int. Ed. 2014, 53, 752e756.
18. Lindlar, H. Helv. Chim. Acta 1952, 35, 446e450.
19. Lindlar, H.; Dubuis, R. Org. Synth. Coll. 1973, 5, 880e883.
20. Yabe, Y.; Yamada, T.; Nagata, S.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Adv. Synth.
Catal. 2012, 354, 1264e1268.
4.8.1.2. 1-(4-Iodophenyl)oxyhexane (64). Compound was iso-
lated as a colorless liquid (133.9 mg, 88% yield). Spectral data
match reported literature values.74
€
€
21. Armbruster, M.; Kovnir, K.; Behrens, M.; Teschner, D.; Grin, Y.; Schlogl, R. J. Am.
4.8.1.3. 1-(4-Cyanophenyl)oxyhexane (65). Compound was iso-
lated as a colorless liquid (87.1 mg, 84% yield). Spectral data
match values reported previously for compound 65.
Chem. Soc. 2010, 132, 14745e14747.
22. Weerachawanasak, P.; Mekasuwandumrong, O.; Arai, M.; Fujita, S.-I.; Pra-
serthdam, P.; Panpranot, J. J. Catal. 2009, 262, 199e205.
23. Hori, J.; Murata, K.; Sugai, T.; Shinohara, H.; Noyori, R.; Arai, N.; Kurono, N.;
Ohkuma, T. Adv. Synth. Catal. 2009, 351, 3143e3149.
4.8.1.4. N-Methyl-N-(4-(hex-1-yl)oxyphenyl)acetamide
(89). Compound was isolated as a colorless liquid (124.6 mg, 98%
24. Dominguez-Dominguez, S.; Berenguer-Murcia, A.; Pradhan, B. K.; Linares-Sol-
ano, A.; Cazorla-Amoros, D. J. Phys. Chem. C. 2008, 112, 3827e3834.
25. Panpranot, J.; Phandinthong, K.; Sirikajorn, T.; Arai, M.; Praserthdam, P. J. Mol.
Catal. Chem. 2007, 261, 29e35.
yield). 1H NMR (300 MHz, C6D6)
d
6.63 (d, J¼9.0 Hz, 2H), 6.58 (d,
J¼9.0 Hz, 2H), 3.55 (t, J¼6.4 Hz, 2H), 3.14 (s, 3H), 1.77 (s, 3H),
26. Nishio, R.; Sugiura, M.; Kobayashi, S. Org. Biomol. Chem. 2006, 4, 992e995.
27. van Laren, M. W.; Elsevier, C. J. Angew. Chem., Int. Ed. 1999, 38, 3715e3717.
28. Kluwer, A. M.; Koblenz, T. S.; Jonischkeit, T.; Woelk, K.; Elsevier, C. J. J. Am. Chem.
Soc. 2005, 127, 15470e15480.
1.64e1.49 (m, 2H), 1.42e1.11 (m, 6H), 0.87 (t, J¼6.9 Hz, 3H). 13C NMR
(126 MHz, CDCl3)
d 171.1, 158.5, 137.4, 128.2, 115.4, 68.4, 37.4, 31.7,
29.3, 25.8, 22.7, 22.5, 14.1. HRMS calculated for C15H24NO2 [MþH]þ:
250.1807, found: 250.1806. FTIR (neat, cmꢀ1): 3461 (w), 3298 (w),
3050 (m), 2931 (s), 2537 (w), 2305 (w), 2055 (w),1885 (w),1655 (s),
1512 (s), 1025 (m).
ꢁ
ꢁ
ꢁ ꢁ
29. Molnar, A.; Sarkany, A.; Varga, M. J. Mol. Catal. Chem. 2001, 173, 185e221.
30. Ulan, J. G.; Maier, W. F.; Smith, D. A. J. Org. Chem. 1987, 52, 3132e3142.
31. Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1985, 50, 1147e1149.
32. Hauwert, P.; Maestri, G.; Sprengers, J. W.; Catellani, M.; Elsevier, C. J. Angew.
Chem., Int. Ed. 2008, 47, 3223e3226.
33. Trost, B. M.; Braslau, R. Tetrahedron Lett. 1989, 30, 4657e4660.
34. Belger, C.; Neisius, N. M.; Plietker, B. Chem.dEur. J. 2010, 16, 12214e12220.
35. Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Adv. Synth. Catal. 2012, 354,
1542e1550.
4.8.1.5. 1-(tert-Butyldimethylsilyl)oxyhexane
(70). Compound
was isolated as a colorless liquid (90.9 mg, 84% yield). Spectral data
match reported literature values.78
36. Mankad, N. P.; Laitar, D. S.; Sadighi, J. P. Organometallics 2004, 23, 3369e3371.
37. Tsuji reported the semi-reduction of aryl acetylenes using an approach similar
to our own. However, this technique was not effective for the reduction of
simple alkenes. See Ref. 35.
4.8.1.6. 1-Hexyloxy-2-methoxy-4-(prop-2-en-1-yl)benzene
(71). Compound was isolated as a colorless liquid (120.1 mg, 97%
yield). Spectral data match values reported previously for com-
pound 71.
€
38. Herrmann, J. M.; Konig, B. Eur. J. Org. Chem. 2013, 2013, 7017e7027.
39. Schlaf, M.; Thibault, M. E.; Di Mondo, D.; Taher, D.; Karimi, E.; Ashok, D. Int. J.
Chem. React. Eng. 2009, 7, http://dx.doi.org/10.220/1542650.1905.
40. Gevorgyan, V.; Liu, J.-X.; Rubin, M.; Benson, S.; Yamamoto, Y. Tetrahedron Lett.
1999, 40, 8919e8922.
4.8.1.7. p-Toluenesulfonic acid, hexyl ester (72). Compound was
isolated as a colorless liquid (111.6 mg, 87% yield). Spectral data
match reported literature values.75
41. Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 2000,
65, 6179e6186.
42. Dobmeier, M.; Herrmann, J. M.; Lenoir, D.; Koenig, B. Beilstein J. Org. Chem. 2012,
8, 330e336 No. 36.
43. Hendrickson, J. B.; Singer, M.; Hussoin, M. S. J. Org. Chem. 1993, 58, 6913e6914.
44. Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66,
7741e7744.
Acknowledgements
45. Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838e1841.
46. Mirza-Aghayan, M.; Boukherroub, R.; Rahimifard, M. Tetrahedron Lett. 2009, 50,
5930e5932.
47. Kobiro, K.; Sumoto, K.; Okimoto, Y.; Wang, P. J. Supercrit. Fluids 2013, 77, 63e69.
48. McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. Org. React. (Hoboken, NJ, U.S.)
2012, 77, 161e591.
49. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574e1585.
50. Barrett, A. G. M.; Prokopiou, P. A.; Barton, D. H. R. J. Chem. Soc., Chem. Commun.
1979, 1175.
51. Menapace, L. W.; Kuivila, H. G. J. Am. Chem. Soc. 1964, 86, 3047e3051.
52. Kuivila, H. G. Acc. Chem. Res. 1968, 1, 299e305.
53. Hutchins, R. O.; Kandasamy, D.; Dux, F., III; Maryanoff, C. A.; Rotstein, D.;
Goldsmith, B.; Burgoyne, W.; Cistone, F.; Dalessandro, J.; Puglis, J. J. Org. Chem.
1978, 43, 2259e2267.
The financial support by NSF (_501100000930) (NSF CAREER
Award 1254636) is gratefully acknowledged.
Supplementary data
Additional spectral data including 1H and 13C NMR for products
not reported in the experimental section are provided. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2014.04.004.
54. Hutchins, R. O.; Kandasamy, D.; Maryanoff, C. A.; Masilamani, D.; Maryanoff, B.
References and notes
E. J. Org. Chem. 1977, 42, 82e91.
55. Rolla, F. J. Org. Chem. 1981, 46, 3909e3911.
56. Santaniello, E.; Fiecchi, A.; Manzocchi, A.; Ferraboschi, P. J. Org. Chem. 1983, 48,
3074e3077.
1. Riant, O. Copper(I) Hydride Reagents and Catalysts, Pt. 2nd ed.; John Wiley &
Sons Ltd.: New York, 2009.
2. Lipshutz, B. H. Modern Organocopper Chemistry; Wiley-VCH GmbH: Weinheim,
Germany, 2002; pp 167e187.
3. Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916e2927.
4. Churchill, M. R.; Bezman, S. A.; Osborn, J. A.; Wormald, J. J. Am. Chem. Soc. 1971,
93, 2063e2065.
5. Churchill, M. R.; Bezman, S. A.; Osborn, J. A.; Wormald, J. Inorg. Chem. 1972, 11,
1818e1825.
6. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110,
291e293.
7. Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111, 8818e8823.
8. Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett. 1998, 39,
4627e4630.
57. Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1983, 48, 3085e3091.
58. Yoshida, T.; Negishi, E.-i. J. Chem. Soc., Chem. Commun. 1974, 762e763.
59. Ashby, E. C.; Goel, A. B.; Lin, J. J. Tetrahedron Lett. 1977, 3695e3698.
60. Ashby, E. C.; Lin, J.-J.; Goel, A. B. J. Org. Chem. 1978, 43, 183e188.
61. Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85e126.
62. Lepore, S. D.; Mondal, D. Tetrahedron 2007, 63, 5103e5122.
63. Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. (Washington, DC, U.S.) 2008,
108, 2916e2927.
64. Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed. 2007, 46, 498e504.
65. Burch, P.; Binaghi, M.; Scherer, M.; Wentzel, C.; Bossert, D.; Eberhardt, L.;
Neuburger, M.; Scheiffele, P.; Gademann, K. Chem.dEur. J. 2013, 19, 2589e2591.

N. Cox et al. / Tetrahedron 70 (2014) 4219e4231
4231
66. Peng, F.; Danishefsky, S. J. J. Am. Chem. Soc. 2012, 134, 18860e18867.
67. Crane, E. A.; Zabawa, T. P.; Farmer, R. L.; Scheidt, K. A. Angew. Chem., Int. Ed. 2011,
50, 9112e9115.
68. Canham, S. M.; France, D. J.; Overman, L. E. J. Am. Chem. Soc. 2010, 132,
7876e7877.
72. Experiment was conducted in the absence of light. In the absence of catalyst,
radical cyclization proceeded much more slowly (trace amount after 24 h).
73. Niu, J.; Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73, 7814e7817.
74. Wadumethrige, S. H.; Rathore, R. Org. Lett. 2008, 10, 5139e5142.
75. Asano, K.; Matsubara, S. Org. Lett. 2009, 11, 1757e1759.
69. Zurwerra, D.; Gertsch, J.; Altmann, K.-H. Org. Lett. 2010, 12, 2302e2305.
70. Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; John Wiley
& Sons: New York, NY, 2001.
71. Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat. Chem.
2012, 4, 854e859.
76. Belloni, M.; Manickam, M.; Ashton, P. R.; Kariuki, B. M.; Preece, J. A.; Spencer, N.;
Wilkie, J. Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A 2001, 369, 17e35.
77. An, P.; Shi, Z.-F.; Dou, W.; Cao, X.-P.; Zhang, H.-L. Org. Lett. 2010, 12, 4364e4367.
78. Lebel, H.; Ladjel, C. J. Org. Chem. 2005, 70, 10159e10161.