Site-selective catalytic deaminative alkylation of unactivated olefins

Article abstract of DOI:10.1021/jacs.9b07489

A catalytic deaminative alkylation of unactivated olefins is described. The protocol is characterized by its mild conditions, wide scope - including the use of ethylene as substrate -, and exquisite site-selectivity pattern for both a-olefins and internal olefins, thus unlocking a new catalytic platform to forge sp³-sp³ linkages, even in the context of late-stage functionalization.

Full text of DOI:10.1021/jacs.9b07489

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Communication
Site-selective catalytic deaminative alkylation of unactivated olefins
Shang-Zheng Sun, Ciro Romano, and Ruben Martin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07489 • Publication Date (Web): 29 Sep 2019
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Journal of the American Chemical Society
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Site-Selective Catalytic Deaminative Alkylation of Unactivated Olefins
Shang-Zheng Sun,† Ciro Romano,† and Ruben Martin†§*
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†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Cata-
lans 16, 43007 Tarragona, Spain
§ ICREA, Passeig Lluís Companys, 23, 08010, Barcelona, Spain
Supporting Information Placeholder
Therefore, at the outset of our investigations it was un-
clear whether a site-selective catalytic deaminative alkyl-
ation could ever be implemented with unactivated a-ole-
fins or even internal olefins, chemical feedstocks derived
from the petroleum processing. If successful, such un-
charted territory might not only provide an unrecognized
opportunity to explore currently inaccessible chemical
spaces in both olefin functionalization and deamination
events, but also offer a new strategic approach for rapidly
and reliably generate structural diversity via unconven-
tional sp3–sp3 bond-disconnections.8 In our continuing in-
terest in Ni-catalyzed reactions,9 we report herein the suc-
cessful realization of this goal (Scheme 1). The salient
features of this process are the mild conditions, high
chemoselectivity profile, and exquisite site-selectivity for
both a-olefins and internal olefins, even at late-stages.
While anti-Markovnikov selectivity was found in the for-
mer,10 the use of the latter results in bond-formation at re-
mote sp3 C–H sites enabled by chain-walking scenarios.11
ABSTRACT: A catalytic deaminative alkylation of unac-
tivated olefins is described. The protocol is characterized
by its mild conditions, wide scope – including the use of
ethylene as substrate –, and exquisite site-selectivity pat-
tern for both a-olefins and internal olefins, thus unlocking
a new catalytic platform to forge sp3–sp3 linkages, even
in the context of late-stage functionalization.
The recent years have witnessed an emerging demand for
forging C–C bonds via functionalization of unactivated
olefin feedstocks.1 Among various scenarios, the catalytic
addition of metal hydride species across an unactivated
olefin constitutes an active frontier of contemporary ca-
talysis research, as it formally generates a latent carbo-
genic nucleophile that can further be elaborated in the
presence of an appropriate electrophilic partner.2
Scheme 1. Catalytic Deaminative sp3–Alkylation of Olefins.
alkyl amines
unactivated alkenes
Me Me
Table 1. Optimization of the Reaction Conditions.a
Me
O
Me
OH
O
2a
Me
Ph
Ph
Ph
O
Et
NiBr2·glyme (10 mol%)
Ph
O
N
L4 (15 mol%)
NH2
Linalool
(-)-β-Pinene
BocN
R2
BF4
H
(EtO)2MeSiH, Na2HPO4
NMP/dioxane, 40 ºC
Ph
N
drug-type molecules
chemical feedstocks
Boc
1a
3a
H-source
entry deviation standard conditions
3a (%)b
R2
81 (80)c
66
52
58
3
1
NH2
none
Ni
Ha
R
n
2
L1 instead of L4
L2 instead of L4
L3 instead of L4
L5 instead of L4
L6 instead of L4
using Ni(cod)2
this work
remote sp3 C–H sites
N
N
3
1,2-hydroalkylation
R1
R1
4
R
R1=H; R2=OMe (L1)
R1=H; R2=CF3 (L2)
R1=R2=H (L3)
R1=H; R2=tBu (L4)
R1=Me; R2=tBu (L5)
n = 0
n ≠ 0
5
mild conditions
site- & chemoselective
sp3 C–C bond-linkages
n
6
11
H
R
H
from internal olefins
7
33
32
41
51
6
from α-olefins
8
using (EtO)3SiH
using K2CO3 as the base
NMP as solvent
dioxane as solvent
no Ni, L4, Na2HPO4 or silane
9
Driven by the prevalence of alkyl amines in pharmaceu-
ticals and preclinical candidates,3 chemists have recently
been challenged to design catalytic sp3 C–N cleavage
techniques as a new tactic for lead generation in drug dis-
covery.4 Despite the elegant advances realized, C–C
bond-forming scenarios remain currently confined to the
use of well-defined organometallic reagents,5 organic hal-
ide counterparts6 or biased electron-deficient olefins.7
O
10
11
12
N
N
Me
0
L6
a 1a (0.20 mmol), 2a (0.60 mmol), NiBr2·glyme (10 mol%),
L4 (15 mol%), (EtO)2MeSiH (0.60 mmol), Na2HPO4 (0.40
mmol), NMP/dioxane (4:1) at 40 ºC for 14 h. b GC yields
using 1-decane as internal standard. c Isolated yield.
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We began our work by evaluating the deaminative alkyl-
Page 2 of 6
(3j, 3k, 3v) were perfectly tolerated. Notably, organo-
borons (3g), alkyl halides (3e, 3f, 3k) or aryl halides (3h,
3l, 3w) could all be well-accommodated, thus providing
ample opportunities for further derivatization via conven-
tional cross-coupling reactions.16 Even free alcohols do
not interfere with productive sp3–sp3 bond-formation (3i,
3w). As expected, the deaminative alkylation of sub-
strates possessing multiple unsaturation motifs occurred
exclusively at the less-substituted olefin (3q, 3r). As
shown for 3q, the reaction could be executed on a 2 mmol
scale without significant erosion in yield. Importantly,
1,1-disubstituted alkenes as substrates posed no problems
(3s-3u). Likewise, the targeted sp3–sp3 bond-formation
could be extended to cyclic analogues other than 1a (3j-
k, 3n-o and 3p) and to aliphatic congeners (3v, 3w).
1
2
3
4
5
6
7
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ation of pyridinium salt 1a – readily prepared from the
corresponding alkyl amine congener on a large scale –
with unactivated olefin 2a (Table 1).12 After careful eval-
uation of all reaction parameters,13 we found that a com-
bination of NiBr2·glyme (10 mol%), L4 (15 mol%),
(EtO)2MeSiH, Na2HPO4 in NMP/dioxane at 40 ºC pro-
vided the best results, affording 3a in 80% isolated yield
with an exquisite anti-Markovnikov selectivity. Among
all of the ligands analyzed, 2,2’-bipyridine motifs turned
out to be particularly suited for the targeted transfor-
mation (entries 2-6); unlike related reductive coupling re-
actions, an intimate interplay of electronic effects on the
ligand backbone and the presence of substituents adjacent
to the nitrogen atom were not critical for the reaction to
occur.14 Subtle changes on the nickel precatalyst, hydride
source, inorganic base or solvent, however, had a delete-
rious effect on reactivity, invariably obtaining lower
yields of 3a, if any (entries 7-11). As anticipated, control
experiments revealed that all of the parameters were es-
sential for forging the sp3–sp3 linkage (entry 12).15
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Table 3. Deaminative Alkylation with Internal Olefins.a,b
Ha
n
R1
Ph
Ph
NiI2 (10 mol%)
L6 (15 mol%)
N
n
BF4
(EtO)3SiH, Na2HPO4
R1
Ph
Me
1
DMSO/dioxane, 35 ºC
3 or 4
a,b
a
Table 2. Deaminative Alkylation with -Olefins.
R
Me
R2
BocN
2
BocN
BocN
4c (R = Me), 57%
3c (R = OTBS), 50%
3e ( R = Cl), 47%
4a, 58%
Me
4b, 65%
Ph
Ph
BF4
NiBr2·glyme (10 mol%)
R2 R1
L4 (15 mol%)
O
N
(EtO)2MeSiH, Na2HPO4
NMP/dioxane, 40 ºC
Me
N
O
R1
1
3
Ph
O
H
Me
3a (R = Bn), 76%
3b (R = OBn), 64%
3c (R = (CH2)3OTBS), 74%
Me
BocN
BocN
BocN
O
2
R
4e, 50%
4d, 48%
4f, 53%
Me
3d (R = (CH2)2CN), 69%
3e (R = (CH2)3Cl), 66%
3f (R = (CH2)3Br), 73%
3g (R = BPin), 57%
X
R
BocN
3j (X = CH2), 56%
3k (X = CF2), 68%
Boc
N
3h (R = (CH2)2OCOpC6H4F), 77%
3i (R = (CH2)2OH, 61%
BocN
X
Ph
Ph
BocHN
BocN
4k, 57%c
4g (R = (CH2)2
), 55%
Me
R
N
BocN
4i (X = O), 66%
4j (CF2), 62%
X
4h (R = Me), 79%
3n (X = (CH)NHBoc), 50%c
3o (X = O), 69%
3l (R = CH2m-C6H4Cl), 63%
3m (R = tBu), 60%
3p, 76%
a As Table 1 (entry 1). b Isolated yields, average of two inde-
pendent runs. c dr = 1.5:1.
X
BocN
Me
2
3s (X = NBoc), 60%e
3t (X = H), 59%e
The lower binding affinity of unactivated internal olefins
to metal centers17 and the inherent difficulty in discrimi-
nating both ends of the double bond left a reasonable
doubt to whether our deaminative alkylation could be ex-
tended to internal olefins. Indeed, no sp3–sp3 formation
was observed upon exposure of 2-heptene to 1a under the
Ni/L4 regime shown in Table 2. Interestingly, however,
the inclusion of substituents adjacent to the nitrogen atom
on the ligand backbone enabled a deaminative sp3–alkyl-
ation at remote sp3 C–H sites.11,18 After judicious evalua-
tion of the reaction parameters, a combination of NiI2 (10
mol%), L6 (20 mol%), (EtO)3SiH (0.40 mmol), Na2HPO4
(0.80 mmol) in DMSO/1,4-dioxane afforded 4c in 57%
yield with > 36:1 selectivity (Table 3).19,20 As shown, the
reaction could also accommodate silyl ethers (3c),
BocN
3q, 69%, 56%d
BocN
3r, 48%
Ph Me
RO
O
Et
HO
Me
BocN
3u, 61%e
3w (R = COpC6H4F), 50%
3v, 43%
a As Table 1 (entry 1). b Isolated yields, average of two inde-
pendent runs. c dr = 1.5:1. d 2.0 mmol scale. e NiI2 (10 mol%),
L6 (20 mol%) in DMSO/dioxane (3:1) at 35 oC.
As evident from the results compiled in Table 2, our cat-
alytic deaminative alkylation of a-olefins showed an ex-
cellent chemoselectivity profile, and nitriles (3d), esters
(3h, 3w), carbamates (3n, 3s), silyl ethers (3c) or ketones
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phthalimides (4e), aldehydes (4f), alkyl halides (3e), car-
With a reliable set of conditions in hand for both a-olefins
and internal olefins, we wondered whether our protocol
could be applied within the context of late-stage function-
alization.22 As shown in Scheme 2, this turned out to be
the case. Although modest yields were obtained in certain
cases, these results should be interpreted against the chal-
lenge that is addressed, particularly with substrates pos-
sessing multiple functional groups derived from linalool
(5), paclonbutrazol (7), galactose (10) or valencene (11),
with C–C bond-formation taking place exclusively at the
least substituted olefin site. Similarly, b-pinene (8), cam-
phene (9) or estrone derivatives (6) posed no problems.
The reaction could also be extended to amino acid deriv-
atives (12-15), either using primary alkyl amines (12-13)
or their secondary congeners (14, 15).23 The ability to ob-
tain 15 as a single regioisomer is particularly noteworthy,
thus indicating that late-stage deaminative alkylation is
not limited to a-olefins. As shown for 14-19, our tech-
nique could be used to derivatize mexiletine, isoxepac or
indomethacin via sp3 C–N bond-cleavage with simple
olefin counterparts. Even drug-type molecules such as 20-
21 could be employed for forging sp3–sp3 linkages.
1
2
3
4
5
6
7
8
bamates (4i, 4j) or nitrogen-containing heterocycles
(4g).15 Importantly, excellent site-selectivity for sp3–sp3
bond-formation at distal primary sp3 C–H sites was found
regardless of the position of the double bond, even at
long-range (4f). Even branched substituents or trisubsti-
tuted olefins (4d) do not compete with the efficacy of the
reaction,21 with deaminative alkylation invariably occur-
ring at the less-sterically hindered primary sp3 C–H site.
9
Scheme 2. Advanced Synthetic Intermediates.a,b
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N
N
O
Cl
O
Me
N
Me
Me
Me
Me
H
Me
Me
OH
H
H
O
3
BocN
NBoc
BocN
5, 40%
6, 75%
7, 51%
from Linalool
from Estrone
from Paclonbutrazol
Me
Me
Me
Me
O
O
O
Me
Me
BocN
O
O
O
Scheme 3. Synthetic Application.a
Me Me
BocN
8, 75%c
from (-)-β-Pinene
9, 46%c
from Camphene
10, 58%
from α-D-Galactose
one-pot deaminative alkylation without isolation of pyridinium salts
BocN
Ph
BocN
R
H
Ph
Me
Me
NH2
O
Ph
Ph
Ph
as Table 1
(entry 1)
BF4
Ph
Me
1a
MeO2C
EtOH, 80 ºC
N
Boc
22
3a
N
Me
Me
76% yield (from 1a)
52% yield (from 22)
Boc
MeO2C
Me
from Glycine
11, 46%c
12 (R = Ph), 55%d
14, 50%
from (±)-Leucine
O
13 (R = (CH2)2Br), 49%d
from (+)-Valencene
regioconvergent deaminative alkylation cross-coupling reactions
1a
Me
Me
Me
Me
Me
Me
Me
NiI2 (10 mol%)
O
O
O
Et
NBoc
Me
L6 (15 mol%)
statistical mixtures
BocN
O
(EtO)3SiH, Na2HPO4
Me
R
Ar
DMSO/dioxane, 35 ºC
4a, 67%
MeO2C
Me
from Mexiletine
Me
15, 51%
from (±)-Leucine
MeO
16 (R = Ph), 61%
17 (R = (CH2)2Br), 55%
18 (Ar = 3-ClC6H4), 70%
utilization of ethylene as coupling partner
from Isoxepac
Cl
ethylene
Me Me
as Table 1
(entry 1)
BocN
+
H
1a
O
O
O
MeO
23
(1 bar)
61% yield
O
N
N
Me
O
O
Et
O
Me
O
Me
Me
The results shown in Scheme 3 further illustrates the syn-
thetic value of our deaminative alkylation. Interestingly,
3a was within reach from N-Boc 4-aminopiperidine (22)
without the need for isolating pyridinium 1a (top).13 Alt-
hough in an unoptimized 52% yield, this result shows that
telescoping the formation of the latter might be a viable
alternative for forging sp3–sp3 linkages. In addition, re-
gioconvergent scenarios could be implemented from sta-
tistical mixtures of olefins, invariably leading to 4a as sin-
gle regioisomer (middle). Even ethylene – the largest-vol-
ume chemical produced in industry–24 could be employed
as substrate under atmospheric pressure en route to 23
(bottom). Taken together, the data shown in Tables 2-3
and Schemes 2-3 serve as a testament to the prospective
O
O
( )3
Et
O
Ph
O
Cl
19, 60%
20, 56%
from Indomethacin & α-D-Galactose
from Indomethacin
Et
Cl
O
t-Bu
O
4
O
N
N
O
N
O
21, 30%e
from Isoxepac & Paclonbutrazol
a a-Olefin: as Table 1 (entry 1); internal olefins: as Table 3.
b Isolated yields, average of two runs. 8 (dr = 97:3); 9 (dr =
c
46:40:7:7); 11 (dr = 9:1). d 80 oC. e NiBr2·glyme (15 mol%).
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Page 4 of 6
graphical journey of innovative organic architectures that
impact of our deaminative alkylation of unactivated ole-
fins, offering a counterintuitive new approach to forge
sp3–sp3 bonds while expanding our ever-growing arsenal
of olefin functionalization and deaminative events.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, crys-
tallographic data and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* rmartinromo@iciq.es
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
We thank ICIQ and FEDER/MICIU –AEI/PGC2018-
096839-B-100 for financial support. S.–Z. S. sincerely thank
MINECO for a predoctoral fellowship.
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tin, R. Ni-catalyzed site-selective dicarboxylation of 1,3-
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biphilic α-bromoalkyl boronic esters. Angew. Chem., Int. Ed.
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alyzed hydroamidation of alkynes with isocyanates. J. Am.
Chem. Soc. 2016, 138, 15531. (e) Serrano, E.; Martin, R.
Nickel-catalyzed reductive amidation of unactivated alkyl
bromides. Angew. Chem. Int. Ed. 2016, 11207.
9
(10) For a recent catalytic hydroalkylation of unactivated olefins
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R.; McCourt, R. O.; van der Puyl, V.; Shenvi, R. A. Hydroal-
kylation of olefins to form quaternary carbons. J. Am. Chem.
Soc. 2019, 141, 7709.
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Mazet, C. Well-defined transition metal hydrides in catalytic
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mote sp3 C–H functionalization via Ni “chain-walking” reac-
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(20) The reaction temperature did not have a profound influence
on the deaminative alkylation of internal olefins, obtaining
similar results at T = 40 ºC. It is worth noting, however, that
the utilization of a-olefins at T = 35 ºC (Table 2) led to ~10%
erosion in yield of the targeted products.
(21) 4d was obtained from E/Z mixtures of 2w, thus indicating
that the geometry of the starting olefin does not have a nega-
tive influence on product formation.
(22) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska,
S. W. The medicinal chemist’s toolbox for late stagefunction-
alization of drug-like molecules. Chem. Soc. Rev., 2016, 45,
546.
(23) Although 14 and 15 were obtained from racemic Leucine, we
found that the deaminative alkylation of L-Alanine (99% ee)
with 2c resulted in a racemate. This observation is consistent
with a C–N scission occurring via single-electron transfer
(SET). For preliminary mechanistic discussions and control
experiments performed with either cyclopropyl derivatives as
radical clocks or 3,4-dihydropyrrole derivatives as substrates,
see Supporting information.
(13) For details, see Supporting Information
(14) For recent reviews on catalytic reductive cross couplings: (a)
Gu, J.; Wang, X.; Xue, W.; Gong, H. Nickel-catalyzed reduc-
tive coupling of alkyl halides with other electrophiles: con-
cept and mechanistic considerations. Org. Chem. Front.
2015, 3, 1411. (b) Weix, J. D. Methods and mechanisms for
cross-electrophile coupling of Csp2 halides with alkyl elec-
trophiles. Acc. Chem. Res. 2015, 48, 1767. (c) Moragas, T.;
Correa, A.; Martin, R. Metal-catalyzed reductive coupling re-
actions of organic halides with carbonyl-type compounds.
Chem. - Eur. J. 2014, 20, 8242. (d) Knappke, C. E. I.; Grupe,
S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Jacobi von Wange-
lin, A. Reductive cross-coupling reactions between two elec-
trophiles. Chem. - Eur. J. 2014, 20, 6828.
(15) The mass balance accounts for hydrogenolysis, homocou-
pling and recovered starting material.
(16) De Meijere, A.; Brase, S.; Oestreich, M. Metal-Catalyzed
Cross-Coupling Reactions; Wiley-VCH: Weinheim, Ger-
many, 2004.
(17) Stradiotto, M.; Lundgren, R. J. Ligand design in metal chem-
istry: reactivity and catalysis. John Wiley & Sons, 2016.
(18) The utilization of L5 resulted in 8% yield of 4c, thus showing
the superior performance of pyrox-type ligands such as L6 in
the targeted deaminative alkylation at remote sp3 centers.
(19) For selected Ni-catalyzed chain-walking C–C bond-for-
mations, see: (a) Sahoo, B.; Bellotti, P.; Juliá-Hernández, F.;
(24) Stechel, E. B.; Miller, J. E. Re-energizing CO2 to fuels with
the sun: Issues of efficiency, scale and economics. J. CO2
Utilization. 2013, 1, 28.
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1,2-hydroalkylation
Ph
O
Ph
1
2
olefin feedstocks
natural products
Ph
BF4
then
R
Ha
n
Me
from α-olefins (n = 0)
Me
3
4
5
Me
OH
O
NH2
Ni
or
Me
R
Me
Me
NH2
remote sp3 C–Ha sites
mild conditions
site- & chemoselective
sp3 C–C bond-linkages
R
n
6
from internal olefins (n ≠ 0)
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