Synthesis of Allylic Alcohols via Cu-Catalyzed Hydrocarbonylative Coupling of Alkynes with Alkyl Halides

Article abstract of DOI:10.1021/jacs.7b12582

We have developed a modular procedure to synthesize allylic alcohols from tertiary, secondary, and primary alkyl halides and alkynes via a Cu-catalyzed hydrocarbonylative coupling and 1,2-reduction tandem sequence. The use of tertiary alkyl halides as electrophiles was found to enable the synthesis of various allylic alcohols bearing α-quaternary carbon centers in good yield with high 1,2-reduction selectivity. Mechanistic studies that suggested a different pathway was operative with tertiary alkyl halides compared with primary and secondary alkyl halides for generating the key copper(III) oxidative adduct. For tertiary electrophiles, an acyl halide likely forms via radical atom transfer carbonylation. The preference for 1,2-reduction over 1,4-reduction of α,β-unsaturated ketones bearing tertiary substituents was rationalized using density functional theory transition state analysis. On the basis of this computational model, the coupling method was extended to primary and secondary alkyl iodide electrophiles by using internal alkynes with aryl substituents, providing trisubstituted allylic alcohols in high yield with good regioselectivity.

Full text of DOI:10.1021/jacs.7b12582

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Article
Synthesis of Allylic Alcohols via Cu-Catalyzed
Hydrocarbonylative Coupling of Alkynes with Alkyl Halides
Li-Jie Cheng, Shahidul M Islam, and Neal P. Mankad
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12582 • Publication Date (Web): 26 Dec 2017
Downloaded from http://pubs.acs.org on December 26, 2017
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Synthesis of Allylic Alcohols via Cu-Catalyzed Hydrocarbonylative
Coupling of Alkynes with Alkyl Halides
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LiꢀJie Cheng, Shahidul M. Islam, and Neal P. Mankad*
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, IL 60607
ABSTRACT: We have developed a modular procedure to synthesize allylic alcohols from tertiary, secondary, primary alkyl halꢀ
ides and alkynes via a Cuꢀcatalyzed hydrocarbonylative coupling and 1,2ꢀreduction tandem sequence. The use of tertiary alkyl halꢀ
ides as electrophiles was found to enable synthesis of various allylic alcohols bearing ꢀquaternary carbon centers in good yield
with high 1,2ꢀreduction selectivity. Mechanistic studies suggested a different pathway was operative with tertiary alkyl halides
compared to primary and secondary alkyl halides for generating the key copper(III) oxidative adduct. For tertiary electrophiles, an
acyl halide likely forms via radical atom transfer carbonylation (ATC). The preference for 1,2ꢀreduction over 1,4ꢀreduction of ͕,ꢀꢀ
unsaturated ketones bearing tertiary substituents was rationalized using DFT transition state analysis. Based on this computational
model, the coupling method was extended to primary and secondary alkyl iodide electrophiles by using internal alkynes with aryl
substituents,
providing
triꢀsubstituted
allylic
alcohols
in
high
yield
with
good
regioselectivity.
other motifs with quaternary carbon centers10 due to versatile transꢀ
formations of both alkene and hydroxyl functional groups.
Scheme 1. Synthesis of allylic alcohols from alkynes
INTRODUCTION
Allylic alcohols are common structural motifs in many
complex organic molecules and, moreover, are versatile synꢀ
thetic building blocks due to their dual alkene/alcohol funcꢀ
tionalities. In the past decades, numerous approaches have
been developed for the preparation of allylic alcohols.1 Among
them, the use of alkynes as substrates has received significant
interest due to their wide availability. The conventional methꢀ
od for synthesis of allylic alcohols involves the preparation of
stoichiometric metalꢀalkyne complexes2 or metalꢀalkenyl reaꢀ
gents3 from alkynes, followed by nucleophilic addition to carꢀ
bonyl compounds (Scheme 1a). However, the use of stoichioꢀ
metric organometallic reagents can be undesirable due to their
possible sensitivity toward air/water, poor functional group
tolerance, and necessity to be purified before use. Therefore,
much effort has been devoted to the transient generation of the
alkenyl metal reagent in catalytic quantities.4 For example, the
Niꢀcatalyzed reductive coupling of aldehydes and alkynes has
been well developed for the synthesis of allylic alcohols
(Scheme 1b).5 In addition, the electrophiles can be extended
from aldehyde to alcohols via a redox coupling process.6 Furꢀ
thermore, Rhꢀcatalyzed coupling of terminal alkynes with
carboxylic acids to synthesize branched allylic esters via a
redoxꢀneutral propargylic CꢀH activation was also reported
(Scheme 1c).7
However, despite these impressive successes, several challenges
still remain. These established coupling methods rely on electrophilic
partners where the carbonyl group is preꢀinstalled, while the use of
electrophiles such as alkyl halides has not been reported for the synꢀ
thesis of allylic alcohols. Moreover, these current methods are norꢀ
mally applied to prepare allylic alcohols bearing primary or secondary
carbon centers at the position. There is no general approach to synꢀ
thesize the allylic alcohols bearing ꢀquaternary carbon centers,8 even
though these structures not only exist in many pharmaceuticals and
natural products9 but also are ideal precursors to access a variety of
On the other hand, transitionꢀmetalꢀcatalyzed carbonylative CꢀC
coupling of organic electrophiles with organometallic reagents repreꢀ
sent one of most efficient methods to construct carbonyl compounds
due to its modularity and use of cheap and abundant CO as a C1 feedꢀ
stock.11 Although carbonylative coupling reactions have long been
established for C(sp2)ꢀhybridized electrophiles, use of unactivated
C(sp3)ꢀhybridized electrophiles is far less developed12ꢀ13 due to their
slow rate of oxidative addition14 as well as competitive ꢀꢀhydride
elimination under carbonylative conditions.15 In particular, while
carbonylative CꢀC coupling with tertiary alkyl halide electrophiles is
known to enable the synthesis of ketones with quaternary carbon
centers, reported examples invariably suffer from requiring induction
1
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by photoirradiation, use of preciousꢀmetal Pd catalysts, and limited
3
MeIPrCuCl instead of ClIPrCuCl
IMesCuCl instead of ClIPrCuCl
tButylꢀI instead of tButylꢀBr
tButylꢀCl instead of tButylꢀBr
NaOMe instead of KOMe
LiOMe instead of KOMe
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0
4:1
1:1
6:1
ꢀꢀ
scope.12a, 12e
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In this context, our group recently developed a Cuꢀcatalyzed hyꢀ
drocarbonylative CꢀC coupling of terminal alkynes with unactivated
primary or secondary alkyl iodides16 based on established Cuꢀ
catalyzed hydrofunctionalization of alkynes.17ꢀ18 Dialkyl ketone prodꢀ
ucts were formed via 1,4ꢀreduction of ͕,ꢀꢀunsaturated ketone interꢀ
mediates generated by hydrocarbonylative CꢀC coupling. We wonꢀ
dered whether 1,2ꢀreduction could be preferred over 1,4ꢀreduction
under controlled conditions,19 providing allylic alcohols instead of
ketones as products. Herein, we reported a general method for highly
regioselective synthesis of allylic alcohols from tertiary, secondary,
primary alkyl halides and alkynes via a Cuꢀcatalyzed hydrocarbonylaꢀ
tive coupling and 1,2ꢀreduction tandem sequence (Scheme 1d). Notaꢀ
bly, the use of tertiary alkyl halides enables the synthesis of various
allylic alcohols bearing ꢀquaternary carbon centers. It is noteworthy
that despite great achievements in the coupling of primary and secꢀ
ondary alkyl electrophiles,20 the construction of all carbon quaternary
centers via catalytic CꢀC coupling with tertiary alkyl electrophiles
remains a challenge.21
5
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3:1
ꢀꢀ
8
9
KOtBu instead of KOMe
0
ꢀꢀ
10
11
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15
(EtO)3SiH instead of PMHS
(Me2HSi)2O instead of PMHS
(EtO)2MeSiH instead of PMHS
3.0 equiv PMHS instead of 6.0
1,4ꢀdioxane instead of THF
Toluene instead of THF
0
ꢀꢀ
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10
90
78
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1:2
14:1
5:1
ꢀꢀ
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ꢀꢀ
16
3 atm CO instead of 6 atm
58
5:1
a
b
The reaction was performed on 0.1 mmol scale. Yield and
RESULTS AND DISCUSSION
the ratio of 3a/4a were determined by 1H NMR integration
against an internal standard.
Using our previously established conditions,16 we did not observe
formation of either allylic alcohol or ketone products when tertꢀbutyl
iodide was used as the electrophilic partner. However, after intensive
investigation, we found that the desired allylic alcohol 3a could be
obtained in 94% yield when ClIPrCuCl was used as the catalyst and
tertꢀbutyl bromide as the electrophile in the presence of KOMe as the
base and polymethylhydrosiloxane (PMHS) as the reducing reagent at
room temperature (Table 1, entry 1). The saturated alcohol 4a was
also obtained as a minor product. Control experiments established that
4a arose from the competitive 1,4ꢀreduction of the relevant enone
intermediate followed by reduction of the resulting saturated ketone,
not from reduction of 3a.22 We also investigated different NHC ligꢀ
ands, and ClIPr was found to be superior to other ligands (Table 1,
entry 2ꢀ4). The use of more reactive tertꢀbutyl iodide could also give
the product in slightly lower yield with moderate selectivity, whereas
the less reactive tertꢀbutyl chloride did not react at all (Table 1, entry
5ꢀ6). Use of NaOMe as the base gave significantly decreased yield,
and other bases such as LiOMe and KtOBu did not afford the desired
product (Table 1, entry 7ꢀ9). We also evaluated different silanes as
reducing reagents. While (EtO)3SiH and (Me2HSi)2O gave no product
or trace product, the use of (EtO)2MeSiH could afford the product in
comparable yield and slightly higher selectivity (Table 1, entry 10ꢀ
12). Considering that PMHS is a cheap, easyꢀtoꢀhandle, and environꢀ
mentally friendly as a reducing agent, we decided to continue using
PMHS in all the reactions. Reducing the amount of PMHS to 3.0
equivalents led to a decreased yield and lower selectivity (Table 1,
entry 13). Changing the solvent to either 1,4ꢀdioxnae or toluene reꢀ
sulted in no product formation (Table 1, entry 14ꢀ15). Finally, we
found that keeping the CO pressure at 6 atm is necessary to obtain
high yield and excellent selectivity (Table 1, entry 16).
Table 2. Hydrocarbonylative Coupling of Unactivated Ter-
tiary Alkyl Bromides: Scope with Respect to Alkynesa
a The reaction was performed on 0.2 mmol scale. All yields are
combined isolated yields of product 3 and saturated alcohols 4.
Table 1. Hydrocarbonylative Coupling of an Unactivated
Tertiary Alkyl Bromide: Selected optimization studiesa
1
The ratios of 3/4 (in parentheses) were determined by H NMR
analysis after purification. b IPrCuCl was used as catalyst and the
reaction was conducted at 45°C.
With the optimal conditions in hand, we next investigated the subꢀ
strate scope with respect to alkynes (Table 2). In most cases, the alꢀ
lylic alcohols were obtained in good yield with excellent selectivity
(>10:1). The mild reaction conditions allow the use of a variety of
alkynes containing different functional groups, such as benzyl ether
(3c), chloroalkyl (3d), indolyl (3e), terminal alkene (3f) and ester
(3g). Aryl bromide, ester, and cyanide groups also survived the reacꢀ
tion (3hꢀ3j). Moreover, we were delighted to find that internal alꢀ
kynes are also applicable, providing triꢀsubstituted allylic alcohols
with ͕ꢀquaternary carbons as single products in good yields (3kꢀ3m).
Use of IPrCuCl as a catalyst at 45°C was required for the reaction of
less reactive 5ꢀdecyne (3l). Satisfactory regioselectivity was obtained
when an unsymmetrical internal alkyne was used as substrate (3m).
variations from “standard” conꢀ 3a yield
ditions
entry
3a/4ab
(%)b
94
1
2
None
12:1
4:1
IPrCuCl instead of ClIPrCuCl
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Inspired by Ryu’s work,23 we next sought to probe whether the ͕,ꢀꢀ
unsaturated ketone was formed via coupling of an alkenyl copper
intermediate with an acyl halide generated through an atom transfer
carbonylation (ATC) pathway. We conducted the stoichiometric couꢀ
pling of alkenyl copper 5 with pivaloyl bromide 7, and the ͕,ꢀꢀ
unsaturated ketone 6 was obtained in 86% isolated yield (Scheme 2d).
This is distinct from hydrocarbonylative coupling with primary alkyl
electrophiles,16 where an ATC pathway can be ruled out because no
product could be generated from stoichiometric coupling of an
alkenyl copper complex with a primary acyl iodide.
We also evaluated the scope with respect to different tertiary alkyl
bromides (Table 3). A tertiary bromide with a benzyl group was also
applicable in the coupling reaction (3o). Cyclic tertiary alkyl iodides
are also suitable substrates (3pꢀ3q). Ether functional groups within
the cyclic electrophile are tolerated (3q). Although the steric bulky 1ꢀ
bromoadamantane only gave the product in poor yield (36%), the
more reactive 1ꢀiodoadamantane afforded the product (3r) in good
yield with excellent selectivity.
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Table 3. Hydrocarbonylative Coupling of Unactivated Ter-
tiary Alkyl Bromides: Scope with Respect to Electrophilesa
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Based on the above results, we hypothesize a mechanism for hyꢀ
drocarbonylative coupling with tertiary alkyl electrophiles that diꢀ
verges from the previous work with primary and secondary alkyl
electrophiles (Scheme 3). First, an alkyl radical A is likely generated
from the reaction between a silyl radical24 and the alkyl halide. The
alkyl radical A then undergoes carbonylation with CO to give an acyl
radical B, which reacts with alkyl halide to afford acyl halide C and
propagate the radical chain. Then, the oxidative addition of acyl halꢀ
ide C to the alkenyl copper D forms the copper(III) complex E. Finalꢀ
ly, the desired ͕,ꢀꢀunsaturated ketone F is obtained via reductive
elimination of E. In the next part of the tandem sequence, intermediꢀ
ate F undergoes Cuꢀcatalyzed 1,2ꢀreduction to provide the ultimate
allylic alcohol product upon workup of G.
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Scheme 2. Mechanistic studies
a The reaction was performed on 0.2 mmol scale. All yields are
combined isolated yields of product and saturated alcohols 4. The
ratios of 3/4 (in parentheses) were determined by 1H NMR analyꢀ
sis after purification. b 1ꢀiodoadamantane was used as the electroꢀ
phile.
Next, we conducted several experiments to investigate the mechaꢀ
nism. No product was observed when TEMPO was added to the reacꢀ
tion (Scheme 2a), which is indicative of radical activation of the alkyl
halide. A radical mechanism also was found to be operative in our
previous hydrocarbonylative CꢀC coupling reaction with primary and
secondary alkyl iodides.16 We also attempted the stoichiometric couꢀ
pling of alkenylcopper 5 with tertꢀbutyl bromide under the CO atꢀ
mosphere (Scheme 2b). To our surprise, the ͕,ꢀꢀunsaturated ketone 6
was not observed, indicating that tertiary alkyl halides have a different
radical initiation pathway than what was discovered for primary and
secondary alkyl halides previously.16 Further studies revealed the
allylic alcohol product was obtained only in the presence of PMHS,
which suggests that the silane plays a vital role to initiate alkyl radical
generation. We also synthesized ͕,ꢀꢀunsaturated ketone 6 and subꢀ
jected it to the same conditions in the absence of CO. Results mirrorꢀ
ing the catalytic experiments were obtained, with the allylic alcohol
resulting from 1,2ꢀreduction being observed as a major product
(Scheme 2c). This observation is consistent with the ͕,ꢀꢀunsaturated
ketone being an intermediate in a tandem coupling/reduction process.
Scheme 3. Hypothetical mechanism
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Because the relative preferences for enones F to undergo 1,2ꢀ
reactivity. The hydrocarbonylative coupling of 1ꢀphenylꢀ1ꢀhexyne
8a with 1ꢀiodooctane 9a could afford the triꢀsubstituted alcohol 10a
in high yield with excellent regioselectivity when the IPrCuCl was
used as catalyst (Table 4, entry 1). Briefly screening the NHC ligꢀ
ands showed the commercial available IPr is superior to other NHC
ligands (Table 4, entry 2ꢀ5).
reduction when R1 is tertiary and to undergo 1,4ꢀreduction when R1
is primary/secondary was initially counterintuitive to us based on
sterics, we decided to conduct a DFT analysis. Using a model CuꢀH
complex supported by the small N,N’ꢀdimethylimidazolꢀ2ꢀylidene
carbene, reactions with a methyl enone and a tertꢀbutyl enone were
examined. Transition states for 1,2ꢀreduction and 1,4ꢀreduction
were located for both substrates (Figure 1). For reduction of the
methyl enone, the 1,4ꢀreduction pathway was calculated to have a
lower barrier than the 1,2ꢀreduction pathway by 4.9 kcal/mol, which
is consistent with previous calculations on phosphineꢀligated CuꢀH
systems.19c For the tertꢀbutyl enone, the activation barrier for 1,2ꢀ
reduction was lower than that for 1,4ꢀreduction by 13.7 kcal/mol,
consistent with our experimental observations. In examining the two
transition states for the tertꢀbutyl enone substrate, we can rationalize
that the 1,2ꢀreduction transition state is actually less crowded due to
the approach trajectory of the CuꢀH reductant. In the 1,4ꢀreduction
pathway, the CuꢀH species approaches the enone with a trajectory
that places the carbene substituents over the tertꢀbutyl group. In
contrast, in the 1,2ꢀreduction pathway the CuꢀH species approaches
the enone with a trajectory for which the carbene substituents are
rotate away into a plane that is orthogonal to the C(O)–tꢀBu plane.
Table 4. Hydrocarbonylative Coupling of an Unactivated
primary Alkyl iodide: Effect of Catalystsa
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entry catalyst
10a yield (%)b
10a/11ab
20:1
4:1
1
2
3
4
5
IPrCuCl
98
85
69
69
0
SIPrCuCl
ClIPrCuCl
MeIPrCuCl
IMesCuCl
15:1
3:1
ꢀꢀ
N
a The reaction was performed on 0.1 mmol scale. b Yield and
N
N
1
N
the ratio of 10a/11a were determined by H NMR integration
Cu
Cu
against an internal standard.
O
O
H
H
Table 5. Hydrocarbonylative Coupling of Unactivated
Primary and Secondary Alkyl iodidesa
R
R
1,2-reduction
1,4-reduction
R = Me (42.3)
R = t-Bu (30.9)
R = Me (37.4)
R = t-Bu (44.6)
For R = t-Bu:
favored
disfavored
Figure 1. Transition states (DFT, B3LYP/6ꢀ311G(d,p), THF
PCM model) for 1,2ꢀ and 1,4ꢀreduction of enones by a model
CuꢀH species. Transition state barriers (in parentheses) are given
as Gibbs free energies in units of kcal/mol.
Next, we questioned whether 1,2ꢀreduction of the enone intermeꢀ
diate could be amenable to primary and secondary alkyl electroꢀ
philes, thus providing a general method to synthesize allylic alcoꢀ
hols. The computational studies indicated that the steric effect adjaꢀ
cent to the carbonyl group of the enone intermediate plays a vital
role in controlling the regioselectivity between 1.2ꢀreduction and
1,4ꢀreduction. We reasoned the introduction of a substitute at the ͕
position of the enone intermediate would substantially increase the
steric hindrance near the carbonyl group, making the 1,2ꢀreduction
more favorable regardless of the alkyl halide electrophile’s identity.
This would require the use of internal alkynes as substrates. While
in our previous work we observed that dialkylꢀsubstituted alkynes
such as 5ꢀdecyne did not react at all,16 we are delighted to find that
replacing one of the alkyl substitutes with an aryl group enhanced
a
The reaction was performed on 0.2 mmol scale. All yields
are isolated yields. b Determined by 1H NMR analysis after puriꢀ
fication.
Under the optimized reaction conditions, the substrate scope was
tested. While low regioselectivity was found when replacing the
butyl group with sterically less demanding methyl group (10c),
good and excellent regioselectivities were obtained with the ethyl
(10b) and cyclohexyl groups (10d), respectively. Diphenylacetyꢀ
lenes are also suitable substrate (10e). Diaryl acetylenes bearing
either electronꢀdonating or electronꢀwithdrawing groups gave the
corresponding products (10fꢀ10g) in good yields. We also investiꢀ
gated the substrate scope with alkyl iodides. A terminal alkene moiꢀ
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ety (10h) remained intact under the present conditions. The alkyl
ACKNOWLEDGMENT
electrophile scope can also be extended from primary alkyl iodides
to secondary alkyl iodides (10i). Increasing the steric hindrance of
secondary alkyl iodide has no effect on the yield and good diastereꢀ
oselectivity was successfully achieved during the 1,2ꢀreduction
process (10j). Cyclic alkyl iodides are also suitable substrates (10kꢀ
10m). Both of ether (10l) and NꢀBoc functional groups (10m) withꢀ
in the electrophile are well tolerated. It is noteworthy that neither
saturated ketone nor alcohol side products were detected under
these conditions, indicating that the 1,4ꢀreduction pathway was fully
suppressed.
1
2
3
4
5
6
7
8
Funding was provided by the NSF (CHEꢀ1664632). This reꢀ
search was supported in part through the computational reꢀ
sources provided by the Advanced Cyberinfrastructure for Eduꢀ
cation and Research (ACER) at UIC.
REFERENCES
1
Recent book and review: (a) Montgomery, J.; Sormunen. G. J.
9
Scheme 4. Competition experiment between primary and
tertiary alkyl halides
In Metal Catalyzed Reductive CꢀC Bond Formation: A Departure
from Preformed Organometallic Reagents; Krische, M. J., Ed.;
Springer: Berlin, 2007; Vol. 279, pp 1ꢀ23. Skucas, E.; (b) Lumbroꢀ
so, A.; Cooke, M. L.; Breit, B. Angew. Chem., Int. Ed. 2013, 52,
1890.
10
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2
(a) Buchwald, S. L.; Watson, B. T.; Huffman, J. C. J. Am.
Chem. Soc. 1987, 109, 2544. (b) Van Wagenen, B. C.; Livinghouse,
T. Tetrahedron Lett. 1989, 30, 3495. (c) Takai, K.; Kataoka, Y.;
Utimoto, K. J. Org. Chem. 1990, 55, 1707. (d) Takagi, K.; Rousset,
C. J.; Negishi, E. J. Am. Chem. Soc. 1991, 113, 1440. (e) Kataoka,
Y.; Miyai, J.; Oshima, K.; Takai, K. Utimoto, K. J. Org. Chem.
1992, 57, 1973. (f) Takayanagi, Y.; Yamashita, K.; Yoshida, Y.;
Sato, F. J. Chem. Soc., Chem. Commun. 1996, 1725.
A competition experiment was conducted to compare the relative
reaction rate of primary iodide and tertiary alkyl bromide (Scheme
4). Interestingly, the product 10e derived from the primary alkyl
halide was formed as the major product, which contrasts with previꢀ
ous studies in which tertiary alkyl halide are more reactive due to
the generation of more thermodynamically stable tertiary alkyl radiꢀ
cals.25 Our observation clearly supports the two distinct mechanisms
we proposed for the primary and tertiary alkyl halides, respectively.
We attributed our results to generation of the tertiary alkyl radical
by atom transfer carbonylation (ATC) being slow relative to primaꢀ
ry alkyl radical generation by a Cuꢀmediated pathway.
3
(a) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75,
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For recent reviews, see: Skucas, E.; Ngai, M.ꢀY.; Komanduri,
V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394. (b) Lumbroso,
A.; Cooke, M. L.; Breit, B. Angew. Chem., Int. Ed. 2013, 52, 1890
and references therein.
5
For selected examples, see: (a) Huang, W.ꢀS.; Chan, J.;
SUMMARY
Jamison, T. F. Org. Lett. 2000, 2, 4221. (b) Mahandru, G. M.; Liu,
G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (c) Miller,
K. M.; Huang, W.ꢀS.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125,
3442. (d) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997,
119, 9065. (e) Miller, K. M.; Huang, W.ꢀS.; Jamison, T. F. J. Am.
Chem. Soc. 2003, 125, 3442. (f) Mahandru, G. M.; Liu, G.; Montꢀ
gomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (g) Patman, R. L.;
Chaulagain, M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 2066. (h) Malik, H. A.; Sormunen, G. J.; Montgomꢀ
ery, J. J. Am. Chem. Soc. 2010, 132, 6304. (i) Leung, J. C.; Patman,
R. L.; Sam, B.; Krische, M. J. Chem. Eur. J. 2011, 17, 12437. (j)
Chaulagain, M. R.; Sormunen, G.; Montgomery, J. J. Am.
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Y.; Zhou, Q.ꢀL. J. Am. Chem. Soc. 2008, 130, 14052.
In summary, we have developed a modular procedure to syntheꢀ
size allylic alcohols from tertiary, secondary, and primary alkyl
halides and alkynes via a Cuꢀcatalyzed hydrocarbonylative coupling
and 1,2ꢀreduction tandem sequence. The reaction tolerates a variety
of functional groups under mild reaction conditions, affording corꢀ
responding allylic alcohol in good yield with excellent selectivity.
The use of tertiary alkyl halide enables the synthesis of various
allylic alcohols bearing ꢀquaternary carbon centers, which are still
challenging using the previous catalytic methods. Mechanistic studꢀ
ies suggest a different pathway was involved with the tertiary alkyl
halide and a tertiary acyl halide was formed via radical atom transꢀ
fer carbonylation (ATC) pathway. The preference for 1,2ꢀreduction
over 1,4ꢀreduction of this intermediate was supported by DFT analꢀ
ysis. By employing internal alkynes with one aryl substituent, priꢀ
mary and secondary alkyl electrophiles are also applicable under the
similar reaction conditions, providing triꢀsubstituted allylic alcohols
in high yield with good
6 For selected examples, see: (a) McInturff, E. L.; Nguyen, K. D.;
Krische, M. J. Angew. Chem., Int. Ed. 2014, 53, 3232. (b) Nakai,
K.; Yoshida, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2014, 136, 7797. (c) Patman, R. L.; Chaulagain, M. R.; Williams,
V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066. (d)
Williams, V. M.; Leung, J. C.; Patman, R. L.; Krische, M. J.
Tetrahedron 2009, 65, 5024.
ASSOCIATED CONTENT
Supporting Information
7 Lumbroso, A.; Koschker, P.; Vautravers, N. R.; Breit, B. J. Am.
Chem. Soc. 2011, 133, 2386.
The Supporting Information is available free of charge on the
ACS Publications website.
8
For one isolated example, see: Ohashi, M.; Saijo, H.; Arai,
T.; Ogoshi, S. Organometallics 2010, 29, 6534.
9
Experimental procedures & spectral data (PDF)
For selected examples, see: R. Schäckel, B. Hinkelmann, F.
Sasse, M. Kalesse, Angew. Chem. Int. Ed. 2010, 49, 1619. Wipf, P.;
Graham, T. H. J. Am. Chem. Soc. 2004, 126, 15346. (c) Kiꢀ
noshita, A.; Higashino, M.; Aratani , Y.; Kakuuchi , A.; Matsuꢀ
ya , H.; Ohmoto, K. Bioorg. Med. Chem. Lett. 2016, 26, 1016.
AUTHOR INFORMATION
10
Corresponding Author
For selected examples, see: (a) Herzon, S. B.; Myers, A. G. J.
Am. Chem. Soc. 2005, 127, 5342. (b) Ding, C.; Zhang, Y.; Chen, H.;
Wild, Ch.; Wang, T.; White, M. A.; Shen, Q.; Zhou, J. Org. Lett.
* npm@uic.edu
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22 When a mixture of 3a and 4a (3a/4a = 12:1) was subjected to
the same conditions, the ratio between 3a and 4a did not change.
The corresponding saturated ketone was reduced to 4a in 90% yield
under the same conditions.
2013, 15, 3718. (c) Fournier, J.ꢀF.; Mathieu, S.; Charette, A. B. J.
Am. Chem. Soc. 2005, 127, 13140.
11 For selected book and reviews, see: (a) Beller, M.; Wu, X.ꢀF.
Transition Metal Catalyzed Carbonylation Reactions: Carbonylative
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Berlin, 2013. (b) Wu, X.ꢀF.; Neumann, H.; Beller, M. Chem. Soc.
Rev. 2011, 40, 4986. (c) Brennführer, A.; Neumann, H.; Beller, M.
Angew. Chem. Int. Ed. 2009, 48, 4114.
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Reviews on radical carbonylation: (a) Schiesser, C. H.; Wille,
U.; Matsubara, H.; Ryu, I. Acc. Chem. Res. 2007, 40, 303. (b) Suꢀ
mino, S.; Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014,
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Pd catalysis: (a) Ishiyama, T.; Miyaura, N.; Suzuki, A. Tetraꢀ
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Patai, S. The Chemistry of the MetalꢀCarbon Bond; Stille, J.
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For selected papers on copperꢀcatalyzed 1,2ꢀreduction of
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For selected reviews, see (a) Terao, J.; Kambe, N. Acc. Chem.
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For selected examples, see: (a) Tsuji, T.; Yorimitsu, H.;
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