Cobalt-Catalyzed Carbonylative Cross-Coupling of Alkyl Tosylates and Dienes: Stereospecific Synthesis of Dienones at Low Pressure

Article abstract of DOI:10.1021/jacs.7b07983

Despite advances in organometallic cross-coupling of alkyl electrophiles, there are few stereoselective reactions of chiral, nonracemic substrates. Herein we report a stereospecific carbonylative coupling of alkyl tosylates and dienes producing enantioenriched dienones. This catalytic process proceeds under low pressure and mild conditions using a simple cobalt catalyst and extends to diverse tosylate and diene coupling partners. The transformation constitutes a unique, convergent approach to the asymmetric synthesis of valuable carbonyl compounds from easily accessed starting materials.

Full text of DOI:10.1021/jacs.7b07983

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Communication
Cobalt-Catalyzed Carbonylative Cross Coupling of Alkyl Tosylates
and Dienes: Stereospecific Synthesis of Dienones at Low Pressure
Brendon T. Sargent, and Erik J. Alexanian
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07983 • Publication Date (Web): 22 Aug 2017
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Cobalt-Catalyzed Carbonylative Cross Coupling of Alkyl Tosylates
and Dienes: Stereospecific Synthesis of Dienones at Low Pressure
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Brendon T. Sargent and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
Supporting Information Placeholder
ABSTRACT: Despite advances in organometallic cross cou-
pling of alkyl electrophiles, there are few stereoselective reac-
tions of chiral, non-racemic substrates. Herein, we report a ste-
reospecific carbonylative coupling of alkyl tosylates and dienes
producing enantioenriched dienones. This catalytic process
proceeds under low pressure and mild conditions using a sim-
ple cobalt catalyst and extends to diverse tosylate and diene
coupling partners. The transformation constitutes a unique,
convergent approach to the asymmetric synthesis of valuable
Figure 1. Stereospecific, carbonylative cross couplings of alkyl
carbonyl compounds from easily accessed starting materials.
tosylates.
1
in good yield and enantiospecificity (84% H NMR yield, 93%
es, entry 1). Substituting 10 mol % Na[Co(CO)4] (entry 2) or 5
mol % of the dimeric Co2(CO)8 as catalyst (entry 3) led to de-
creased yield. A palladium-based catalytic system we previously
used in the esterification of unactivated secondary alkyl bro-
mides provided no product (entry 4).8 Lowering the catalyst
loading to 5 mol % (entry 5) had a minor effect on chemical
yield. Decreasing the CO pressure to 1 atm (entry 6) led to de-
creased reaction conversion and enantiospecificity. The use of
higher pressures of CO (5 atm, entry 7) provided no improve-
ment over 2 atm CO. The inorganic base Cs2CO3 was inferior
to the organic base TMP and completely racemized the product
(entry 8). Reaction in the absence of ambient light proceeded
with only a slight decrease in yield and enantiospecificity (78%
1H NMR yield, 90% es, entry 9),7d and no reaction occurred in
the absence of catalyst (entry 10).
Catalytic cross couplings of secondary alkyl electrophiles are
powerful transformations for the stereoselective construction of
C–C bonds.1 Enantioconvergent transformations of racemic
electrophiles facilitate access to an array of important chemo-
types, but these transformations often utilize proximal coordi-
nating functionality to promote enantioselective transfor-
mations.2 An alternative, though less common, approach is to
utilize chiral, non-racemic electrophiles in stereoselective cross
couplings.3 This approach capitalizes on the array of methods
available for preparing simple building blocks stereoselectively
(e.g., chiral, non-racemic secondary alcohols).4 Despite the po-
tential for such processes, they are currently limited in scope.
An early example of a carbonylative, stereoselective cross
coupling of a chiral, non-racemic secondary electrophile is the
Fe-mediated ketone synthesis developed by Collman (Figure 1).5
While this strategy extends to a variety of carbonyl compounds,
the requirement for stoichiometric Na2Fe(CO)4, an air and
water sensitive, highly reactive reagent, is a significant draw-
back. Alternatively, anionic cobalt carbonyl complexes have
been shown to catalyze several carbonylative processes involving
alkyl electrophiles.6 Stereoselective applications have not ap-
peared, however. We were intrigued by prior reports demon-
strating cobalt-catalyzed couplings with dienes, albeit with pri-
mary or activated electrophiles.7 Herein, we report a catalytic,
stereospecific carbonylative cross coupling of alkyl electrophiles
using an easily accessed anionic cobalt catalyst. This mild, cata-
lytic process enables the stereoselective synthesis of valuable
dienones from chiral, non-racemic secondary alkyl tosylates and
dienes in a convergent manner.
Table 1. Cobalt-catalyzed cross coupling of an unactivated
alkyl tosylate with a terminal diene.
yield
(%)a
es
(%)b
93
entry
variation from standard conditions above
1
2
3
(S)-1
84
62
72
91
94
10 mol % Na[Co(CO)4] instead of K[Co(CO)4]
5 mol % Co2(CO)8 instead of K[Co(CO)4]
5 mol % Pd(PPh3)2Cl2/10 mol % IMes instead of
K[Co(CO)4]
4
< 2
93
70
90
4
5
6
5 mol % instead of 10 mol % K[Co(CO)4]
1 atm (balloon) CO instead of 2 atm CO
5 atm CO instead of 2 atm CO
Cs2CO3 instead of TMP
67
53
84
36
78
< 2
7
8
90
9
no ambient light
Our studies commenced with the carbonylative cross cou-
pling of unactivated secondary alkyl tosylate (S)-1 and diene 2
(Table 1). A catalytic system comprised of 10 mol %
10
no K[Co(CO)4]
a
Reactions were performed with [2]0 = 0.5 M. Yields determined
by H NMR spectroscopy of crude reaction mixture using an inter-
1
K[Co(CO)4]
and
1.1
equiv
of
TMP
(2,2,6,6-
tetramethylpiperidine)
provided
dienone
3
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b
nal standard. Enantiospecificity (es) = (eeproduct/eesubstrate) x 100%,
See Table 1 for conditions. aIsolated yields unless otherwise not-
ed. Enantiospecificity (es) = (eeproduct/eesubstrate) x 100%, determined
1
2
3
determined by chiral HPLC.
b
1
by chiral HPLC. Reaction yield determined by H NMR spectros-
Table 2. Stereospecific, low-pressure catalytic cross couplings
of alkyl tosylates and dienes.a
c
copy of crude reaction mixtures using an internal standard. Reac-
tion time 16 h. dReaction performed at 10 atm CO and 90 °C.
4
5
6
7
10 mol % K[Co(CO)4]
O
We next applied the catalytic system to the carbonylative
cross couplings of a range of dienes using (S)-1 as substrate (Ta-
ble 2). Electron-rich and electron-poor dienes were well tolerat-
ed under the reaction conditions (4-7). In addition, cross cou-
pling with a substituted diene provided dienone 8 in good
yield. The carbonylative cross couplings of heterocyclic dienes
and aliphatic dienes also proceeded efficiently (9-10). Im-
portantly, the reaction is not limited to acyclic dienes, as the
coupling with 1,3-cyclohexadiene delivered dienone 11 in 60%
yield with good stereocontrol (89% es).
2 atm CO
R1
R1
OTs
R3
R3
R2
1.2 equiv
R2
1.1 equiv TMP
t-amyl-OH
70 °C, 24 h
8
9
O
O
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Ph
Ph
CF3
F
4
5
71% yield
69% yield
90% es
90% es
O
O
An initial survey of diverse chiral, non-racemic alkyl tosylates
supports the generality of this method. Pendant functionality
including alkenes and alkyl halides were well tolerated provid-
ing dienones 12 and 13, respectively, in good yields and high
enantiospecificities. The reactions of substrates derived from
enantioenriched 1,3-diols efficiently provided g-alkoxy dienones
with good stereospecificity, and demonstrated tolerance of aryl
ester and chloride substitution (14-16). Cycloalkyl tosylates are
also viable coupling partners, as demonstrated by the carbonyla-
tive cross coupling of cyclopentyl tosylate (17). The reaction is
not limited to acyclic secondary tosylates with methyl branch-
ing; the transformation of the tosylate of (S)-3-octanol yielded
18 with good enantiospecificity (92%) and larger branching
groups were tolerated with similar reaction efficiency (19). Fur-
thermore, primary tosylates were competent substrates in the
reaction, as a phthalimide protected amino alcohol derivative
containing an a-chiral center delivered dienone 20 in moderate
yield with minimal racemization.
Ph
Ph
Ph
Ph
OMe
MeO
6
7
77% yield
93% es
76% yield
95% es
O
O
Ph
O
8
9
61% yield
92% es
82% yield
94% es
O
O
Ph
n-Pent
10
11
60% yieldb
89% es
52% yield
86% es
Cl
O
O
O
Ph
Ph
The asymmetric synthesis of non-symmetrical ketones con-
taining a-chiral centers remains a significant synthetic chal-
lenge. Common approaches generally involve long linear se-
quences and the use of chiral auxiliaries, as there are very lim-
ited strategies for the asymmetric a-alkylation of ketones.9 We
envisioned a concise, convergent route to these compounds via
the stereospecific carbonylative cross coupling of tosylates, fol-
lowed by simple reduction of the dienone. As an initial demon-
stration, we targeted naturally occurring ketone 22 (eq 1).10 The
stereospecific coupling of the tosylate of (R)-butan-2-ol (21) with
(E)-nona-1,3-diene was followed by hydrogenation to provide
ketone 22 in 54% yield over two steps, with 94% es. This strat-
egy offers a powerful approach to non-symmetrical ketones with
a-chiral centers, capitalizing on the availability of chiral, non-
racemic secondary alcohols. Additionally, applications of the
product dienones in selective 1,4- or 1,6-conjugate additions, or
Diels-Alder cycloadditions, are easily envisioned.11
12
13
54% yield
93% es
62% yield
97% es
O
O
PhO
O
Ph
Ph
Cl
14
15
58% yield
94% es
43% yieldc
95% es
O
O
O
Ph
Ph
MeO
O
16
17
48% yield
49% yield
93% es
O
O
Me
Me
Ph
Ph
Me
Me
19
40% yield
18
38% yieldb
92% es
O
O
N
Ph
O
20
46% yieldd
94% ee
A mechanistic outline for the carbonylative cross coupling is
depicted in Scheme 1. The cobalt catalyst first engages with the
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Journal of the American Chemical Society
This work was supported by Award No. R01 GM107204 from the
National Institute of General Medical Sciences.
alkyl tosylate in an SN2 displacement to provide an alkylcobalt
intermediate.12 This species undergoes migratory insertion of
CO with retention of configuration, followed by acylmetalla-
tion of the diene substrate to provide an allylcobalt. b-hydride
elimination or b-elimination of the cobalt yields the dienone
product and the catalyst is regenerated.
1
2
3
4
5
6
7
8
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Scheme 1. Plausible catalytic cycle for the stereospecific, car-
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O
9
X
[Co(CO)4]
R1
OTs
R1
R2
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racemic dienones and derivatives under mild, catalytic condi-
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AUTHOR INFORMATION
Corresponding Author
*eja@email.unc.edu
(12) See supporting information for determination of absolute ste-
reochemistry.
ACKNOWLEDGMENT
10 mol % K[Co(CO)4]
O
Ph
OTs
2 atm CO
Ph
+
Ph
1.1 equiv TMP
Ph
t-amyl-OH, 70 oC
1.2 equiv
84% yield, 93% es
stereospecific, carbonylative
cross couplings of alkyl tosylates
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