Exploiting ancillary ligation to enable nickel-catalyzed c-o cross-couplings of aryl electrophiles with aliphatic alcohols

Article abstract of DOI:10.1021/jacs.8b01800

The use of (L)Ni(o-tolyl)Cl precatalysts (L = PAd-DalPhos or CyPAd-DalPhos) enables the C(sp²)-O cross-coupling of primary, secondary, or tertiary aliphatic alcohols with (hetero)aryl electrophiles, including unprecedented examples of such nickel-catalyzed transformations employing (hetero)aryl chlorides, sulfonates, and pivalates. In addition to offering a competitive alternative to palladium catalysis, this work establishes the feasibility of utilizing ancillary ligation as a complementary means of promoting challenging nickel-catalyzed C(sp²)-O cross-couplings, without recourse to precious-metal photoredox catalytic methods.

Full text of DOI:10.1021/jacs.8b01800

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Exploiting Ancillary Ligation to Enable Nickel-Catalyzed C-O
Cross-Couplings of Aryl Electrophiles with Aliphatic Alcohols
Preston M. MacQueen, Joseph P. Tassone, Carlos Diaz, and Mark Stradiotto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01800 • Publication Date (Web): 30 Mar 2018
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Exploiting Ancillary Ligation to Enable Nickel-Catalyzed C-O
Cross-Couplings of Aryl Electrophiles with Aliphatic Alcohols
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Preston M. MacQueen,‡ Joseph P. Tassone,‡ Carlos Diaz, and Mark Stradiotto*
a Department of Chemistry, Dalhousie University, 6274 Coburg Road, P.O. 15000, Halifax, Nova Scotia B3H 4R2, Canada
Supporting Information Placeholder
βꢀhydrogen elimination for nickel versus palladium,13 and in light
ABSTRACT: The use of (L)Ni(oꢀtolyl)Cl preꢀcatalysts (L =
of the utility of nickel in C(sp2)ꢀN14 crossꢀcouplings.15 Nonetheꢀ
less, no examples of such nickelꢀcatalyzed transformations emꢀ
ploying (hetero)aryl chlorides have been reported. In an effort to
address difficult C(sp2)ꢀO bond reductive elimination within a
presumptive Ni(0/II) cycle (Scheme 1A), MacMillan and coꢀ
workers16 employed (dtbbpy)NiCl2 (5 mol%), in combination
with an iridium photocatalyst17 (1 mol%) and quinuclidine (10
PAdꢀDalPhos or CyPAdꢀDalPhos) enables the C(sp2)ꢀO crossꢀ
coupling of primary, secondary, or tertiary aliphatic alcohols with
(hetero)aryl electrophiles, including unprecedented examples of
such nickelꢀcatalyzed transformations employing (hetero)aryl
chlorides, sulfonates, and pivalates. In addition to offering a comꢀ
petitive alternative to palladium catalysis, this work establishes
the feasibility of utilizing ancillary ligation as a complementary
means of promoting challenging nickelꢀcatalyzed C(sp2)ꢀO crossꢀ
couplings, without recourse to preciousꢀmetal photoredox catalytꢀ
ic methods.
mol%),
whereby
oxidation
of
putative
(dtbbpy)Ni2+(aryl)(alkoxide) intermediates to Ni(III) facilitates
C(sp2)ꢀO bond formation (Scheme 1C). While useful in the crossꢀ
coupling of primary or secondary aliphatic alcohols, the electroꢀ
phile scope is limited to (hetero)aryl bromides.16
Scheme 1. Catalyst Design to Promote the Crossꢀcoupling of
Aliphatic Alcohols and (Hetero)aryl Halides (ArX).
Interest in the synthesis of aromatic ethers of primary and secꢀ
ondary aliphatic alcohols arises from the ubiquity of C(sp2)ꢀOꢀ
C(sp3) linkages in a range of compounds of interest, including
natural products and active pharmaceutical ingredients.1 Whereas
some ethers of this type can be prepared from phenols and alkyl
electrophiles by way of SN2 chemistry (Williamson ether syntheꢀ
sis2), complementary methods employing (hetero)aryl electroꢀ
philes are soughtꢀafter, in that they enable alternative disconnecꢀ
tion strategies in which readily accessed aliphatic alcohols can be
employed. Only limited success has been achieved in the preparaꢀ
tion of alkyl (hetero)aryl ethers by use of SNAr chemistry or copꢀ
per catalysis (Ullmann ether synthesis3);4 such protocols typically
suffer from the requirement of activated (hetero)aryl bromides or
iodides and forcing reaction conditions. Conversely, some particuꢀ
larly useful palladium catalysts for the crossꢀcoupling of (hetꢀ
ero)aryl electrophiles with primary or secondary aliphatic alcohols
have emerged,1a, 5 which enable transformations of comparatively
inexpensive and abundant (hetero)aryl chlorides.6 The successful
development of such challenging palladium catalysis can be atꢀ
tributed to the judicious selection of ancillary ligand to promote
productꢀforming C(sp2)ꢀO bond reductive elimination over unꢀ
wanted βꢀhydrogen elimination in catalytic intermediates of the
type LnPd(aryl)(alkoxide) (Scheme 1A), with the electronꢀrich
and sterically demanding phosphines RockPhos,7 AdꢀBippyPhos,8
and JosiPhos CyPFꢀtBu9 proving particularly effective (Scheme
1B).10 Notwithstanding such progress, the high cost and scarcity
of palladium provides motivation for the development of related
methodologies employing more Earthꢀabundant metals.11
The breakthroughs that have been achieved in palladium crossꢀ
coupling catalysis via rational ancillary ligand design18 suggest
that a similar approach holds promise in nickel chemistry. Noneꢀ
theless, reports documenting the design of ancillary ligands for
use in enabling nickelꢀcatalyzed crossꢀcouplings are rare.19 Our
group recently developed the PAdꢀDalPhos ancillary ligand class
(Scheme 1D), which has proven to be useful in otherwise chalꢀ
lenging nickelꢀcatalyzed C(sp2)ꢀN crossꢀcoupling applications.20
The application of nickel12 catalysis in the crossꢀcoupling of alꢀ
iphatic alcohols with (hetero)aryl chlorides is attractive, given the
more facile C(sp2)ꢀCl bond oxidative addition and less favorable
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Unlike the bulky, electronꢀrich ancillary ligands that have proven
conducted in the presence of, or with rigorous exclusion of, ambiꢀ
optimal for use with palladium, the relatively electronꢀpoor phosꢀ
phaadamantane cage in PAdꢀDalPhos was strategically incorpoꢀ
rated so as to facilitate productꢀforming, C(sp2)ꢀN bond reductive
elimination. In expanding on this work, we sought to evaluate the
viability of utilizing PAdꢀDalPhos ligation as an alternative to
iridium/nickel photoredox catalysis in enabling nickelꢀcatalyzed
C(sp2)ꢀO crossꢀcouplings (Scheme 1A).
ent light.
1
2
3
4
5
6
Table 1. Catalyst Screening and Reaction Optimization.a
7
8
9
Herein we report on the successful application of PAdꢀDalPhos
and CyPAdꢀDalPhos (Scheme 1D) in the nickelꢀcatalyzed C(sp2)ꢀ
O crossꢀcoupling of primary, secondary, or tertiary aliphatic alcoꢀ
hols with (hetero)aryl (pseudo)halides, in the absence of photoꢀ
chemical activation. The use of these ancillary ligands allows for
a diverse electrophile scope to be accommodated, including (hetꢀ
ero)aryl chlorides, under conditions that are competitive with the
best palladium catalysts known for such transformations.
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R
OH
b
Entry Preꢀcat.
Base
3a/4a b 1a b C10H8
We initially examined the crossꢀcoupling of 1ꢀ
chloronaphthalene (1a) with 4ꢀmethylpentanꢀ1ꢀol (2a) or 2ꢀ
propanol (2b), employing nickel preꢀcatalysts that had proven
useful in alternative crossꢀcoupling applications, including:
(L)Ni(oꢀtolyl)Cl21 (L = CyPAdꢀDalPhos,20e C1; L = PAdꢀ
DalPhos,20a C2; L = dppf,22 C3); (IPr)Ni(styrene)2,23C4; and
(PAdꢀDalPhos)NiCl,20d C5 (Table 1). In focusing on reactions of
2a, we were pleased to observe that the use of C1 (5 mol%) in
combination with NaOtBu enabled high conversion (80%) to the
NaOt
<
1
80
50
<5
<5
50
10
55d
50
25
50
60 f
10
<5
<5
65
75
10
40
75
75
20
5
C1
C2
C3
C4
C1
C1
C2
C2
C2
C5
C1
C2
C3
C4
C1 g
C1
2a
Bu
NaOt
Bu
NaOt
Bu
NaOt
Bu
LiOt-
Bu
5
5
5
5
<
<
<
2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
3
4
◦
target alkyl aryl ether 3a after 18 h at 110 C (entry 1). Inferior
selectivity for 3a versus reduction to naphthalene was observed
with C2 (entry 2), and naphthalene formation was predominant
with C3 or C4 under these conditions (entries 3 and 4). Whereas
the use of bases other than NaOtBu with C1 proved less effective
(entries 5 and 6), in reactions employing C2 the use of K2CO3 or
Cs2CO3 (entries 7 and 8) afforded yields of 3a similar to that
achieved using NaOtBu, with the benefit of reduced naphthalene
formation. Comparison of the Ni(II) and Ni(I) PAdꢀDalPhos preꢀ
catalysts C2 and C5 revealed only minimal variation in perforꢀ
mance (entry 7 versus entry 10).
5
5
6
Cs2CO
6
c
5
5
0
0
0
5
5
5
5
5
5
3
3
Cs2CO
3
4
6
4
<
<
1
<
<
<
7
<5
<5
10
10
30
85
80
80
25
20
8
K2CO3
9
K3PO4
Cs2CO
Given the efficacy of C1, we sought to evaluate the perforꢀ
mance of CyPAdꢀDalPhos relative to ancillary ligands that had
proven useful in related palladium catalysis (Scheme 1B). Using
the conditions in entry 1, with the exception of employing
Ni(COD)2 (10 mol%) and either CyPAdꢀDalPhos, RockPhos, Adꢀ
BippyPhos, or CyPFꢀtBu (10 mol% each), full conversion of 1a
was observed in all cases. However, only CyPAdꢀDalPhos affordꢀ
ed product formation (45% 3a), with reactions employing the
other ligands producing naphthalene (>70%) and other unidentiꢀ
fied byꢀproducts. These observations highlight the emerging trend
that ‘repurposing’ ligands from palladium chemistry is not a
broadly effective strategy in nickel catalyst development.20a Furꢀ
thermore, the superior performance of C1 relative to
Ni(COD)2/CyPAdꢀDalPhos underscores the benefits of preꢀ
catalyst usage,21 and the possible inhibitory effect of COD on the
transformations reported herein.
10
11
12
13
14
15
16
3
NaOt
Bu e
NaOt
Bu
NaOt
Bu
NaOt
Bu
NaOt
Bu
NaOt
Bu
2b
2b
h
Crossꢀcouplings employing 2b were more challenging than
those involving 2a, with C1 proving superior to C2ꢀC4 (entries
11ꢀ14), and where NaOtBu outꢀperformed each of LiOtBu,
KOtBu, K3PO4, or Cs2CO3. The use of 1ꢀbromonaphthalene afꢀ
forded similar results (entry 11 versus entry 15). Improved selecꢀ
tivity for 4a was achieved by using a larger excess of 2b (entry 11
versus entry 16).
a Conditions: 1ꢀChloronapthalene (0.12 mmol), alcohol (2a, 1.1 equiv; 2b,
3 equiv), base (1.5 equiv), toluene (1 mL). Estimated percent converꢀ
b
sions on the basis of calibrated GC data, with the remaining mass balance
corresponding to unidentified byꢀproducts (C10H8 = naphthalene). c <15%
conversion to 3a using K3PO4 (3.0 equiv; 65% 1a, 10% C10H8) or K2CO3
(3.0 equiv; 85% 1a, 5% C10H8). d 65% using 10 mol% C2. e < 5% converꢀ
sion to 4a using LiOtBu (1.5 equiv; <5% 1a, 65% C10H8), KOtBu (1.5
equiv; 60% 1a, 35% C10H8), K3PO4 (3.0 equiv; 90 % 1a, 10% C10H8), or
The benefit of additives was examined under conditions preꢀ
sented in Table 1 (entries 1, 2, 6, and 7). In all cases, the addition
f
Cs2CO3 (3.0 equiv; 85% 1a, 10% C10H8). Negligible conversion of 1a at
80 ◦C after 18 h, and 40% conversion to 4a (40% 1a, 10% C10H8) employꢀ
ing 3 mol% C1 (110 ◦C, 18 h). g Using 1ꢀbromonaphthalene. h 5 equiv 2b.
24
of PhBPin20d (0.15 equiv), PhB(OH)2 (0.15 equiv), triethylaꢀ
mine7 (1 equiv), or quinuclidine16 (0.10 equiv) afforded no signifꢀ
icant improvement. Furthermore, no significant change in catalyst
performance was observed for C1 or C2 when reactions were
We then turned our attention to testing MacMillan’s
(dtbbpy)NiCl2/quinuclidine catalyst system16 in the crossꢀcoupling
of an aliphatic alcohol with an aryl chloride in the absence of
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photochemical activation. 4ꢀChlorobenzotrifluoride (1b) was
chosen given the successful crossꢀcoupling of 1ꢀhexanol and 4ꢀ
bromobenzotrifluoride using (dtbbpy)NiCl2/quinuclidine under Irꢀ
photoredox conditions.16 Whereas high conversion to 3b was
achieved with C1 (90%), a mixture of products was generated by
use of (dtbbpy)NiCl2/quinuclidine, with low conversion to 3b
(20%, Scheme 2).
1
2
3
4
5
6
7
8
Scheme 2. Comparing C1 and (dtbbpy)NiCl2/quinuclidine in the
C(sp2)ꢀO CrossꢀCoupling of an Aryl Chloride with 2a.a
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a Estimated conversion to 3b on the basis of calibrated GC data.
The substrates successfully accommodated by use of C1 or C2
in the C(sp2)ꢀO crossꢀcoupling of aliphatic alcohols with (hetꢀ
ero)aryl (pseudo)halides (Schemes 3 and 4) is competitive with
the best catalysts known for such transformations (i.e., Pd,7ꢀ9 Ni,16
or other), with nickelꢀcatalyzed reactions of this type employing
(hetero)aryl chlorides or phenolꢀderived electrophiles being disꢀ
closed herein for the first time.25 Beyond the formation of 3a
(Scheme 3), methanol(ꢀd4) was employed successfully, providing
a route to anisole derivatives (3c, 3d, 3d-d3). Primary aliphatic
alcohols featuring branched/benzylic structures (3e, 3g, 3h), as
well as pendant chloro (3f), amino (3i), thiophenꢀ2ꢀyl (3j), silyl
(3k), 2ꢀpyridyl (3l), and alkenyl (3m) groups were also accomꢀ
modated. The successful use of cyclopropanemethanol leading to
3h is notable, given the propensity of such fragments to undergo
ringꢀopening,26 and for nickel to engage in radical chemistry.13b
The chemoselective crossꢀcoupling of 3ꢀmethylꢀ1,3ꢀbutanediol
leading to 3n is in keeping with our competition experiments
(vide infra). Secondary aliphatic alcohols were also accommodatꢀ
ed (Scheme 4), including 2ꢀpropanol (4aꢀ4c), 1ꢀphenylethanol
(4d), 1ꢀmethoxyꢀ2ꢀpropanol (4e), 2ꢀbutanol (4f), 3,3ꢀdimethylꢀ2ꢀ
butanol (4g), 3ꢀhydroxyoxetane (4h), and cyclohexanol derivaꢀ
tives (4iꢀ4k). The first successful nickelꢀcatalyzed C(sp2)ꢀO crossꢀ
couplings involving tertiary aliphatic alcohols (4l and 4m) were
also achieved. The ability to conduct crossꢀcouplings on synthetiꢀ
cally useful scales was confirmed in the synthesis of 3a (0.89 g,
75%) from 1a (5.3 mmol), and 4m (1.09 g, 83%) from 6ꢀ
chloroquinoxaline (6.5 mmol).
a
Conditions: (Hetero)aryl (pseudo)halide (1.0 equiv), alcohol (1.1ꢀ5.0
a
b
equiv). Isolated yields reported. Using C1 and NaOtBu (1.5 equiv).
Using C2 and Cs2CO3 (3.0 equiv).
Scheme 4. Substrate Scope for the CrossꢀCoupling of (Hetꢀ
ero)aryl Electrophiles and Secondary or Tertiary Aliphatic Alcoꢀ
hols.a
The crossꢀcouplings featured in Schemes 3 and 4 encompass a
range of electrophile classes, with electronꢀpoor substrates being
favored. While not explored exhaustively, inferior conversion was
achieved with electronꢀrich electrophiles such as 4ꢀbromoanisole
or 4ꢀphenoxyphenyl methanesulfonate under the optimized condiꢀ
tions. Throughout, quinoline, quinoxaline, quinaldine, and pyridyl
core structures, as well as trifluoromethyl, aldehyde, ketone, ether,
and nitrile addenda (including in orthoꢀpositions) proved compatꢀ
ible, whereby C2 was employed with alternative bases only in
cases where suitable catalytic performance with C1/NaOtBu was
not achieved. While our (hetero)aryl scope focused primarily on
a
Conditions: (Hetero)aryl (pseudo)halide (1.0 equiv), alcohol (1.1ꢀ5.0
a
b
equiv). Isolated yields reported. Using C1 and NaOtBu (1.5 equiv).
Using C2 and Cs2CO3 (3.0 equiv).
nitrogenꢀcontaining
substrates,
we
found
that
5ꢀ
chlorobenzo[b]thiophene, 5ꢀchloroꢀ2ꢀmethylbenzothiazole, and 5ꢀ
chlorobenzofurazan were not suitable electrophiles under our
conditions. The use of sulfonates and pivalates was also successꢀ
fully demonstrated, complementing the Williamson ether syntheꢀ
sis involving phenol nucleophiles and alkyl (pseudo)halides.
Scheme 5. Competition Experiments in C(sp2)ꢀO CrossꢀCoupling
Chemistry Using C1 or C2.
Scheme 3. Substrate Scope for the CrossꢀCoupling of (Hetꢀ
ero)aryl Electrophiles and Primary Aliphatic Alcohols.a
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Corresponding Author
1
2
Corresponding author: mark.stradiotto@dal.ca
ORCID: 0000ꢀ0002ꢀ6913ꢀ5160
3
4
5
Author Contributions
‡These authors contributed equally.
6
7
Notes
The authors declare the following competing financial interests:
Dalhousie University has filed patents on the DalPhos ancillary
ligands and derived nickel preꢀcatalysts used in this work, from
which royalty payments may be derived.
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ACKNOWLEDGMENT
We are grateful to the NSERC of Canada (Discovery and I2I
Grants for M.S.; CGSꢀD for P.M.Q.), the Government of Canada
(Vanier CGS for J.P.T.), the Killam Trusts, and Dalhousie Uniꢀ
versity for their support of this work. Cytec (Solvay) is thanked
for the donation of phosphatrioxaadamantane. We also thank Dr.
Michael Lumsden and Mr. Xiao Feng (Dalhousie) for technical
assistance in the acquisition of NMR and MS data.
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C(sp2)ꢀO bond cleavage, see: Tobisu, M.; Chatani, N. Acc. Chem. Res.
2015, 48, 1717ꢀ1726.
(16) Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D.
W. C. Nature 2015, 524, 330ꢀ334.
(17) (a) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116,
10035ꢀ10074; (b) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R.
W.; MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 0052.
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Chemistry: Reactivity and Catalysis. John Wiley & Sons: Hoboken, NJ,
2016, 1ꢀ405.
◦
(Scheme 5A), at both 25 and 110 C. The relative difficulty of
C(sp2)ꢀO crossꢀcoupling was further illustrated in competitions
involving secꢀbutylamine to give 5b (Scheme 5B), whereby C1
retained a modest preference for C(sp2)ꢀN crossꢀcoupling, even
with this more hindered alkylamine nucleophile. The formation of
3a over 4a (Scheme 5C) is consistent with our chemoselective
synthesis of 3n (Scheme 3). Finally, the nickelꢀcatalyzed crossꢀ
coupling of 4ꢀchlorobenzonitrile (1c) with cyclopropylamine (to
give 5c) or 2ꢀpropanol (to give 4c), each featuring secondary alkyl
substitution, was examined (Scheme 5D); whereas complete seꢀ
lectivity for the formation of 5c was observed with C1,20e C2
proved less selective.
In summary, the use of nickel preꢀcatalysts featuring PAdꢀ
DalPhos or CyPAdꢀDalPhos ligation enables the C(sp2)ꢀO crossꢀ
coupling of primary, secondary, or tertiary aliphatic alcohols with
(hetero)aryl electrophiles, including hitherto unknown examples
of such nickelꢀcatalyzed transformations employing (hetero)aryl
chlorides, sulfonates, and pivalates. Beyond offering a competiꢀ
tive alternative to palladium catalysis, this work establishes, for
the first time, the feasibility of employing ancillary ligation as a
complementary means of promoting challenging nickelꢀcatalyzed
C(sp2)ꢀO crossꢀcouplings, without recourse to photoredox catalytꢀ
ic methods. We are currently exploring mechanistic aspects of the
transformations disclosed herein, and will report on the results of
these studies in due course.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: XX.XXXX/XXXXXX.
Synthetic protocols and product characterization data including
NMR spectra (PDF).
(19) For some noteworthy examples in CꢀC crossꢀcoupling chemistry,
see: (a) Hansen, E. C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J.
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(25) While some substrate pairings reacted in the absence of a Ni
catalyst (e.g., those involving 2ꢀchloropyrimidine), control experiments
confirmed that <10% conversion is achieved in the absence of Ni for the
pairings presented in Schemes 3 and 4.
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