Nickel-catalyzed allylation of α-amido sulfones to form protected homoallylic amines

Article abstract of DOI:10.1055/s-0034-1379539

The allylation of stable, protected imine precursors, α-amido sulfones, with allylic acetates to form homoallylic amines is catalyzed by nickel under mild reducing conditions. Aliphatic and aryl imines are tolerated, as are substituted allylic acetates. I

Full text of DOI:10.1055/s-0034-1379539

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Nickel-Catalyzed Allylation of α-Amido Sulfones To Form Protect-
ed Homoallylic Amines
NiCl2(dme) (2 mol%)
dtbbpy (2 mol%)
Et3N (2 mol%)
Jill A. Caputo
PG
Marina Naodovic
Daniel J. Weix*
PG
HN
HN
+
OAc
R
Mn0 (2 equiv)
DMA, 40 °C
R
SO2Ph
Department of Chemistry, University of Rochester, Rochester,
NY, 14627-0216, USA
+
1
5
(
8
5
2
)
7
6
0
2
0
5
R = Ar; 1°, 2°, 3° alkyl
PG = Boc, Cbz
daniel.weix@rochester.edu
Received: 02.09.2014
Accepted after revision: 21.10.2014
Published online: 07.01.2015
imines had not previously been reported. We present here a
nickel-catalyzed allylation of aliphatic imines (Scheme 1)
that starts from simple, stable precursors (allylic acetates
and α-amido sulfones) and forms N-Boc and N-Cbz homoal-
lylic amine products under mild conditions (40 °C, mild re-
ductant, catalytic base). The imine is presumably generated
in situ from the α-amido sulfone16 by added base (Cs2CO3 or
Et3N) or by the Mn(OAc)2 generated during the reaction (Ta-
ble 1).
DOI: 10.1055/s-0034-1379539; Art ID: st-2014-r0733-c
Abstract The allylation of stable, protected imine precursors, α-amido
sulfones, with allylic acetates to form homoallylic amines is catalyzed by
nickel under mild reducing conditions. Aliphatic and aryl imines are tol-
erated, as are substituted allylic acetates. In the case of substituted al-
lylic acetates, high diastereoselectivity and regioselectivity is observed
in some cases and the branched product is obtained almost exclusively.
Key words nickel, allylation, amines, imines, reduction
PG
PG
HN
[Ni]
HN
+
OAc
[Ni]
R
base
Mn0
Homoallylic amines are useful synthetic intermediates
due to their latent functionality. For example, homoallylic
amines were key intermediates in the recent syntheses of
(+)-preussin1 and (–)-aphanorphine.2 Despite this utility,
fewer methods exist for the allylation of imines than for the
analogous allylation of aldehydes.3 The major challenges as-
sociated with imine allylation are the low reactivity of
imines, competing decomposition of the imine, and the fre-
quent need for a protecting/activating group on the nitro-
gen.4 Aliphatic imines are particularly challenging to handle
because of the potential for hydrolysis, and the most gener-
al strategies rely upon the use of more stable imines
(sulfinyl imines, hydrazones) or synthesis and immediate
use of less stable imines (N-Boc, N-Dpp, N-Ts).5
The majority of approaches have used allyl metal re-
agents (zinc,6 silicon,5,7 tin,8 or boron9), either preformed or
generated in situ, as the allyl donor. In some cases, highly
enantioselective reactions have been developed. The use of
allyl electrophiles has been limited to the use of allyl ha-
lides and stoichiometric indium6b,9g,h,10 or palladium11 catal-
ysis with a diboron or indium reductant.12 The cobalt-
catalyzed allylation of N-aryl aryl imines with allyl acetate
was reported by Gosmini,13 but aliphatic imines were not
explored.
R
SO2Ph
PG
N
and
via
R
Scheme 1 Nickel-catalyzed allylation of α-amido sulfones
We began by exploring the use of stoichiometric
amounts of base for imine formation (Table 1, entries 1 and
2). While cesium carbonate resulted in a higher yield at
higher nickel catalyst loadings, at lower catalyst loadings
triethylamine afforded equivalent yields (Table 1, entries 1–
3). Even though the yield was slightly higher with stoichio-
metric cesium carbonate, we chose to focus on triethyl-
amine due to its low cost and low molecular weight. The
use of a catalytic amount of triethylamine resulted in no
significant change in yield compared to stoichiometric tri-
ethylamine (Table 1, entries 3 and 4) and, when using allyl
acetate, reactions proceeded in high yield without any tri-
ethylamine (Table 1, entry 5). However, reactions of more
substituted allylic acetates conducted without added base
took much longer to reach completion (data not shown). In
addition, use of 4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-terpyridine
resulted in a good yield for a reaction with simple allyl ace-
tate, but poor yields for substituted allylic acetates (data not
shown). An excess of allyl acetate improved yields slightly
Although it had previously been shown that the allyla-
tion of ketones14 and, more recently, aldehydes15 by allylic
acetates could be catalyzed by nickel, the allylation of
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324
J. A. Caputo et al.
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(Table 1, entry 4 vs. 6) and the use of benzotriazole17 as the
leaving group instead of benzenesulfinate resulted in a low-
er yield (Table 1, entry 4 vs. 7). Finally, only trace amounts
of product were formed in the absence of nickel, a ligand, or
manganese (Table 1, entries 8–10). We chose to explore the
scope of the reaction using the conditions reported in entry
6 (Table 1) due to the low catalyst loading that was
achieved.
regioselectivity was lower (3:1 branched/linear, Table 2, en-
try 9). Crotyl acetate formed a 1:1 mixture of the syn- and
anti-branched products (results not shown).20
Table 2 Substrate Scope for the Allylation Reaction
NiCl2(dme) (2 mol%)
dtbbpy (2 mol%)
PG
PG
HN
Et3N (2 mol%)
HN
+
OAc
(1.1 equiv)
Table 1 Allylation of α-Amido Sulfones with Allyl Acetate
R
Mn0 (2 equiv)
DMA, 40 °C
R
SO2Ph
(1.0 equiv)
NiCl2(dme) (2 mol%)
Boc
Boc
dtbbpy (2 mol%)
base (2 mol%)
HN
HN
Entry Allylic acetate
Product
Yield
(%)a
+
OAc
(1.0 equiv)
Cy
SO2Ph
Mn0 (2 equiv)
DMA, 40 °C
Boc
(1.0 equiv)
HN
1
85
OAc
Entry
Modifications
Yield (%)a
1
2
3
4
5
6
7
8
9
10
10 mol% Ni and dtbbpy,b 1 equiv Cs2CO3
94
76
89
83
93
88
46
1
Boc
10 mol% Ni and dtbbpy, 1 equiv Et3N
HN
1 equiv Et3N
2
3
4
87
OAc
OAc
OAc
2 mol% Et3N
no Et3N
Boc
1.1 equiv allyl acetate, 2 mol% Et3N
HN
49b
benzotriazole substrate,c 2 mol% Et3N
no Ni
no dtbbpy
no Mn0
1
Boc
HN
HN
2
48b,c
a Yields are corrected GC yields vs. internal standard (dodecane).
b 4,4′-Di-tert-butyl-2,2′bipyridine (dtbbpy).
c tert-Butyl {(1H-Benzo[d][1,2,3]triazol-1-yl)(cyclohexyl)methyl}carbamate;
ca. 7% (uncorrected GC yield) allyl acetate remaining at 48 h.
Boc
Application of these conditions to a variety of allylic
acetates and α-amido sulfones is reported in Table 2. Alkyl
α-amido sulfones substituted with primary and secondary
alkyl groups adjacent to the nitrogen (R in Table 2) were
allylated in high yield (Table 2, entries 1 and 2), but sulfones
substituted with tertiary alkyl and aryl groups resulted in
lower yield (Table 2, entries 3 and 4).18 A number of substi-
tuted allylic acetates are tolerated (Table 2, entries 5–9).
In cases where a mixture of branched and linear ho-
moallylic amines could be formed, the branched product
was formed almost exclusively. The diastereoselectivity was
excellent for cinnamyl acetate derivatives (Table 2, entries
5–8). The relative stereochemistry of the major product
from cinnamyl acetate was determined to be syn by single-
crystal X-ray analysis.19 Similarly good regioselectivity and
diastereoselectivity was obtained with 3-phenylbut-3-enyl
acetate (Table 2, entry 8). Although 1,1-diacetoxyprop-2-
ene also resulted in high diastereoselectivity (14:1 dr), the
OAc
5
6
75d
Boc
HN
OAc
88
Boc
HN
OAc
7
84e
MeO
OMe
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J. A. Caputo et al.
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Ni(cod)2 (110 mol%)
dtbbpy (110 mol%)
Et3N (2 mol%)
Boc
Entry Allylic acetate
Product
Yield
(%)a
HN
Boc
HN
Boc
+
OAc
HN
Cy
SO2Ph
Mn0 (2 equiv)
DMA, 40 °C
60% corrected
GC yield
(1.0 equiv)
8
OAc
57e
(1.1 equiv)
Scheme 2 Stoichiometric allylation of an α-amido sulfone
Boc
In closing, we have demonstrated the first allylation of
N-carbamoyl imines with allylic acetates.24 The reaction
works best with aliphatic imines, in contrast to the majori-
ty of other methods in the literature, and the use of α-ami-
do sulfones avoids the handling of reactive imines. This
report sets the stage for further development of stereose-
lective and even enantioselective reactions.3a,15
HN
HN
OAc
OAc
9
77f
82
OAc
Cbz
10
OAc
Acknowledgment
a Isolated yield after column chromatography (SiO2).
b Low yield is due to dimerization of allyl acetate.
c The reaction did not reach full conversion after an extended reaction time.
d Relative configuration confirmed by single-crystal X-ray analysis.
e Relative configuration assigned by analogy to entry 5.
This work was supported by the Alfred P. Sloan Foundation through a
Fellowship to D.J.W. We thank Dr. William W. Brennessel (University
of Rochester) for X-ray analysis of tert-butyl (1-cyclohexyl-2-phenyl-
but-3-en-1-yl)carbamate (Table 2, entry 6) and Stephanie Dorn (Uni-
versity of Rochester) for help with data analysis.
f The isolated product was obtained as a mixture of isomers. Based upon GC
analysis, this mixture was a 14:5:1 ratio of major branched diastereo-
mer/linear product/minor branched diastereomer.
Although we have not yet investigated the mechanism
of this reaction in detail, it is clear from control experi-
ments that nickel is required and it is likely that an N-Boc
imine is formed in situ. This leaves two possible pathways:
allylation of the imine by an allylnickel intermediate or
nickel-catalyzed formation of an allylmanganese reagent
that subsequently reacts with the imine. Two pieces of evi-
dence support the allylnickel pathway. First, the reactions
proceed in high yield in the presence of mild acids (NH,
AcOH, Et3N·AcOH) with only one equivalent of allylic ace-
tate, but allylmanganese reagents are sensitive to acid.21
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379539.
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References and Notes
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preference for forming the same branched syn product from
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(24) Typical Procedure for the Allylation of α-Amido Sulfones
On the benchtop, an oven-dried 1-dram vial equipped with a
Teflon-coated stir bar was charged with 4,4′-di-tert-butyl-2,2′-
bipyridine (2.7 mg, 0.0100 mmol), NiCl2(dme) (2.0 mg, 0.0100
mmol), tert-butyl cyclohexyl(phenylsulfonyl)methylcarbamate
(177 mg, 0.500 mmol, 1.00 equiv), N,N-dimethylacetamide
(DMA) (1.00 mL), a solution of cinnamyl acetate (91.8 μL, 0.550
mmol, 1.10 equiv in 1.00 mL DMA), Et3N (1.40 μL, 0.0100
mmol), dodecane (10.0 μL), and Mn0 (54.9 mg, 1.00 mmol). The
reaction vial was then capped with a screw cap fitted with a
PTFE-faced silicone septum and stirred (1200 rpm) at 40 °C.
After 19 h, the reaction mixture was then filtered through a
short silica pad (1.5 cm wide × 2 cm high), and the pad was
washed with Et2O (75 mL) before the filtrate was concentrated
in vacuo. The residue was then purified by flash chromatogra-
phy (hexanes–acetone, 95:5) to afford the pure homoallylic
amine (Table 2, entry 5) as a white solid (124 mg, 75% yield).
X-ray crystallography confirmed that the syn isomer was
obtained; mp 101–103 °C. Due to the existence of rotamers at
ambient temperature, the 1H NMR spectrum was obtained at
55 °C: 1H NMR (400 MHz, CDCl3, 55 °C): δ = 7.28–7.15 (m, 5 H),
6.03 (dt, J = 17.1, 8.8 Hz, 1 H), 5.09–5.05 (m, 2 H), 4.06 (br s, 1
H), 3.86 (br s, 1 H), 3.43 (t, J = 8.2 Hz, 1 H), 1.29 (s, 9 H), 1.75–
0.86 (series of m, 11 H). 13C NMR (126 MHz, CDCl3): δ = 155.9,
141.6, 139.8, 128.5, 128.4, 126.5, 115.9, 78.8, 57.7, 52.9, 39.4,
31.2, 28.4, 28.3, 26.5, 26.4, 26.3. IR: 3341, 2924, 1678, 1535,
1173 cm–1. LRMS (ESI+): m/z = 352.3 [M + Na+]. HRMS (ESI+): m/z
[M + H+] calcd for C21H32NO2: 330.243; found: 330.244. X-ray
quality crystals were grown by slow evaporation of acetone.
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(18) We get substantially the same results with a preformed imine.
(19) Crystallographic data for the compound reported in Table 2,
entry 5 has been deposited with the Cambridge Crystallo-
graphic Data Centre (CCDC 1022004). This data can be obtained
free of charge from the CCDC at http://www.ccdc.cam.ac.uk/
data_request/cif.
(20) Gong observed similar diastereoselectivity with crotyl acetate
for the reductive allyation of aldehydes using nickel. See ref. 15.
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