Photoredox α-vinylation of α-amino acids and N -aryl amines

Article abstract of DOI:10.1021/ja506094d

A new coupling protocol has been developed that allows the union of vinyl sulfones with photoredox-generated α-amino radicals to provide allylic amines of broad diversity. Direct C-H vinylations of N-aryl tertiary amines, as well as decarboxylative vinylations of N-Boc α-amino acids, proceed in high yield and with excellent olefin geometry control. The utility of this new allyl amine forming reaction has been demonstrated via the syntheses of several natural products and a number of established pharmacophores.

Full text of DOI:10.1021/ja506094d

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Communication
Photoredox-Mediated #-Vinylation of #-Amino Acids and N-Aryl Amines
Adam Noble, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja506094d • Publication Date (Web): 14 Jul 2014
Downloaded from http://pubs.acs.org on July 17, 2014
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Photoredox-Mediated α-Vinylation of α-Amino Acids and N-Aryl Amines
Adam Noble and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544
dmacmill@princeton.edu
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RECEIVED DATE
Scheme 1. Proposed Mechanism for the Vinylation Reaction.
Abstract. A new coupling protocol has been developed that
allows the union of vinyl sulfones with photoredox-generated α-
SO2Ph
R'
R'
N
R
R'
N
R
amino radicals to provide allylic amines of broad diversity.
Direct C–H vinylations of N-aryl tertiary amines, as well as
decarboxylative vinylations of N-Boc α-amino acids, proceed in
high yield and with excellent olefin geometry control. The utility
of this new allyl amine forming reaction has been demonstrated
via the syntheses of several natural products and a number of
established pharmacophores.
vinyl
SO2Ph
sulfone
6
allylic amine
PhSO2
IrII (7)
reductant
N
R
SET
5
PhSO2
α-amino radical
Visible light photoredox catalysis has recently emerged as a
powerful activation strategy for the discovery and invention of
new chemical transformations.1 The capacity of metal-to-ligand
charge transfer (MLCT) catalysts to simultaneously act as strong
reductants and oxidants under the influence of low energy
photon sources has enabled the design of many novel reaction
mechanisms that can be chemoselectively triggered using visible
light. One emerging application of photoredox catalysis is its
use in the direct functionalization of unactivated sp3 C–H bonds,2
an area of research that has become a fundamental goal of
modern organic chemistry.3 In this context, our laboratory has
become interested in the activation of C–H bonds to generate α-
amino radicals, which are versatile intermediates that can
participate in radical–radical couplings4 to afford benzylic
amines (Eq 1) or be trapped with radical acceptors to forge α-N-
alkylation adducts.5,6 Generation of α-amino radicals under
photoredox conditions typically proceeds via single-electron
oxidation of an amine and subsequent deprotonation of the
resulting radical cation.4,5 Recently, our group has also reported
– H+ (for 3)
Photoredox
IrIII (1)
SET
– H+, – CO2 (for 4)
Catalytic Cycle
*IrIII (2)
H
CO2H
oxidant
N
R
N
R
3
4
household
light bulb
α-amino radical precursors
an alternative strategy for α-amino radical formation via the
decarboxylation of N-tert-butoxycarbonyl (N-Boc) α-amino
acids,7,8 a CO2-extrusion mechanism that has implications for the
use of biomass feedstocks in conjugate additions and
organometallic couplings.
Allylic amines have long been attractive targets for new
reaction development due to their importance as (i)
functionalized building blocks9 and (ii) versatile intermediates in
the production of medicinal agents.10 Indeed, over the last three
decades, numerous methods have been developed for the
preparation of allyl amines, typically proceeding through the
addition of vinyl metal reagents to C=N bonds11 or the direct
amination of allylic substrates.12 Moreover, deprotonation-based
methods for the direct α-vinylation of nitrogen centers have been
reported via the α-lithiation, transmetallation of tertiary
carbamates, followed by metal-catalyzed cross-couplings with
vinyl halides.3d,13
Direct C−H and Decarboxylative Arylation of Amines (Eq 1)
CN
H
N
N
R
X
Ar
photoredox
catalyst
X
N-aryl amine
benzylic amine
OR
Taking inspiration from our previously developed photoredox
arylation protocols (Eq 1),4,7 we sought to extend the utility of α-
amino radicals to the direct synthesis of allylic amines from N-
aryl amines or α-amino acids. Specifically, we hypothesized
that allyl amines should be accessible via exposure of α-amino
radicals to olefins that can generically participate in radical-
based vinylation mechanisms (i.e. incorporate leaving groups
that are susceptible to single-electron β-elimination pathways).
As an overarching goal of this work we hoped to demonstrate
■ versatile intermediate
CO2H
N
N
R
via:
■
radical–radical couplings
Boc
■
addition across π systems
α-amino radical
amino acid
Direct C−H and Decarboxylative Vinylation of Amines (Eq 2)
R'
N
PhO2S
N
R
R'
R
that photoredox-generated α-amino radicals provide
a
photoredox
catalyst
complementary approach to allyl amine production in
comparison to stoichiometric metal-based technologies. Herein,
we describe the successful execution of these ideals and present
allylic amine
α-amino radical
vinyl sulfone
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Table 1. Initial Studies Towards the C–H Vinylation Reaction.
photocatalytic cycle would then be accomplished via reduction
•
red
1
2
3
4
of the sulfinyl radical (For PhSO2 /PhSO2Na, E1/2 = +0.50 V
vs. SCE)19 with IrII 7 (E1/2 [IrIII/II] = –1.37 V vs. SCE)17 to give a
sulfinate anion while reconstituting the photocatalyst 1.
With this mechanistic hypothesis in mind, we set out to
explore the feasibility of our proposed vinylation reaction (Table
1 mol% photocatalyst
SO2Ph
Ph
N
N
Ph
2.0 equiv. base
solvent (0.25 M), rt, 24 h
26 W CFL
Ph
Ph
amine 8
vinyl sulfone 9
allylic amine 10
5
6
1).
Our initial investigations began by exposure of N-
base
solvent
yielda
E:Z
entry
photocatalyst
phenylpyrrolidine (8) to (E)-(2-(phenylsulfonyl)vinyl)benzene
(9), in the presence of Ir(ppy)3, NaOAc, and a 26 W household
fluorescent light bulb. To our delight, the desired allylic amine
product 10 was observed under these new photocatalytic
conditions, albeit in modest yield and stereoselectivity (entry 1,
28%, 21:79 E:Z). The efficiency of this vinylation protocol was
improved by changing to less polar solvents, with toluene
providing higher yield and selectivity compared to N,N-
dimethylacetamide (DMA) (entry 2, 57% yield, 91:9 E:Z).
Moreover, evaluation of a number of different photocatalysts
revealed that less reducing photocatalysts, such as
Ir(ppy)2(dtbbpy)PF6 (11) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1),
provided enhanced E-selectivities (entries 3 and 4, ≥95:5
E:Z).20,21 The choice of base was also found to have a dramatic
effect on the yield while maintaining the high E-selectivity, with
CsOAc proving to be optimal (entry 5, 81% yield). Finally, the
use of 1,2-dichloroethane (DCE) as the reaction medium was
found to provide slightly higher yields than toluene, delivering
allyl amine 10 in 91% yield and with a 98:2 E:Z ratio (entry 7).
The required participation of both the photocatalyst and light
were confirmed via control experiments (entries 8 and 9).
Having identified optimal reaction conditions, we next
examined the scope of the C–H vinylation reaction with respect
to the amine substrate. As shown in Table 2, this protocol is
successful with a range of tertiary N-aryl amines (products 10
and 12–24, 64–98% yield, 94:6 to >98:2 E:Z). A variety of
cyclic amines are well tolerated, with five-, six-, and seven-
membered rings giving their respective products in excellent
yields (products 10, 12, and 13, 84–98% yield, ≥97:3 E:Z). This
vinylation protocol is relatively unaffected by the nature of the
7
8
9
1
Ir(ppy)3
21:79
91:9
NaOAc
NaOAc
NaOAc
NaOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
DMA
toluene
toluene
28%
57%
33%
40%
81%
87%
91%
<5%
0%
2
Ir(ppy)3
>98:2
3
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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4
1
1
toluene
toluene
toluene
DCE
95:5
96:4
97:3
98:2
-
5
6b
7b
8b
9b,c
1
1
none
1
DCE
DCE
-
aDetermined by 1H NMR analysis using an internal standard. bPerformed with 3.0
equiv. base and at 0.1 M in solvent. cPerformed in the absence of light. 1 =
Ir[dF(CF3)ppy]2(dtbbpy)PF6, 11 = Ir(ppy)2(dtbbpy)PF6.
the first direct C–H vinylation of N-aryl tertiary amines and the
first decarboxylative olefination of N-Boc α-amino acids using
vinyl sulfones in the presence of iridium-based MLCT catalysts
(Eq 2).
Reaction Design. Critical to our proposal of generating allylic
amines from α-amino radicals was the identification of an
appropriate alkene SOMO-phile, an olefinic coupling partner
that would be susceptible to radical addition yet could further
participate in single-electron β-elimination to deliver the
required vinylation adduct.
In this context, Nozaki and
coworkers, among others, have ingeniously demonstrated that
unsaturated sulfones can generically react with alkyl radicals to
produce a wide variety of olefin containing products.14,15 For our
purposes, we presumed that vinyl sulfones should be useful
substrates for the proposed photoredox vinylation given that (i)
they are electron-deficient olefins which should readily couple
with nucleophilic α-amino radicals and (ii) the radical C–C bond
forming step should be rapidly followed by β-sulfone
elimination to produce a sulfinyl radical, a species that should
rapidly undergo single-electron reduction via the reduced state of
the photocatalyst. Furthermore, with respect to substrate
availability, we recognized that vinyl sulfones are easily
prepared in one step from aldehydes using Horner–Wadsworth–
Emmons reactions16a or via direct sulfonylation of olefins.16b
The specific mechanistic details of our proposed photoredox
vinylation reaction are outlined in Scheme 1. It has been
established that irradiation of Ir[dF(CF3)ppy]2(dtbbpy)PF6
[dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine,
dtbbpy = 4,4'-di-tert-butyl-2,2'-bipyridine] (1, depicted as IrIII in
Scheme 1) with visible light will generate the excited state IrIII
species 2, which is a strong oxidant (E1/2 [*IrIII/II] = +1.21 V vs.
SCE in MeCN).17 This photoexcited complex should readily
undergo single-electron transfer (SET) with a tertiary amine 3
Table 2. Direct C–H Vinylation: Amine Scope.a
R2
R3
R2
R3
1 mol% photocat. 1
PhO2S
Ph
N
N
Ph
CsOAc, DCE, rt
26 W CFL
R1
R1
amine
vinyl sulfone
allylic amine
product
yield E:Z
product
yield
E:Z
X
n
Ph
N
Ph
N
Ph
Ph
(±)-10 n = 1
(±)-12 n = 2
(±)-13 n = 3
84% >98:2
(±)-19 X = O
79% 94:6
74% 94:6
84%
97:3
(±)-20 X = NBoc
98% >98:2
R
N
Ph
R
Ph
Ph
N
(±)-21 R = H
(±)-22 R = Me
73% >98:2
80% >98:2
R
(e.g. N-phenylpyrrolidine (R = Ph), E1/2 = +0.70 V vs. SCE)18
to form a radical cation that upon deprotonation will deliver the
α-amino radical 5 (for R = Ph). Similarly, the excited state IrIII
species 2 could also undergo SET with the carboxylate formed
red
(±)-14 R = p-OMe
67% >98:2
n
(±)-15 R = p-CO2Me 75% >98:2
Ph
N
red
(±)-16 R = p-F
(±)-17 R = p-Br
(±)-18 R = o-Br
76% >98:2
75% >98:2
65% >98:2
Bn
by deprotonation of α-amino acid 4 (e.g. Boc-Pro-OCs, E1/2
=
+0.95 V vs. SCE)7a to generate a carboxyl radical, which upon
loss of CO2 would deliver α-amino radical 5 (for R = Boc).
Reaction of 5 with a vinyl sulfone would then generate the β-
sulfonyl radical 6, which after elimination of a sulfinyl radical
would provide the allylic amine product. Completion of the
(±)-23 n = 1
(±)-24 n = 2
64% >98:2
84% >98:2
aAll reactions performed with 0.50 mmol vinyl sulfone, 2.5 equiv. amine, 3.0 equiv.
CsOAc, and 1.0 mol% photocatalyst 1 in DCE (5.0 mL). Yields are of isolated
products. E:Z ratio determined by 1H NMR analysis.
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Table 3. Direct C–H Vinylation: Vinyl Sulfone Scope.a
N-aryl group, with substrates possessing electron donating or
1
2
3
4
5
6
7
8
withdrawing functionalities demonstrating good efficiency
(products 14–18). Heteroatom-containing cyclic amines were
also found to be suitable (products 19 and 20) along with acyclic
substrates (products 21 and 22). Vinylation of a number of
pharmacologically important fused nitrogen heterocycles such as
N-benzyl-protected indolines and tetrahydroquinolines was
demonstrated to be possible, with excellent regioselectivity for
the α-methylene ring position over the benzylic α-amino site
(products 23 and 24).
We next sought to establish the scope of the vinyl sulfone in
this direct C–H olefination reaction. As shown in Table 3, β-
sulfonyl styrenes were found to be excellent substrates
regardless of the electronic nature of the aryl substituent
(products 25–31, 74–85% yield, 92:8 to >98:2 E:Z). Moreover,
vinyl sulfones that incorporate heteroaromatic substituents were
found to be viable, including electron deficient pyridines and
electron rich indoles (products 32–34, 68–83% yield, 93:7 to
>98:2 E:Z). The reaction is not limited to styrenyl reagents, as
exemplified by the use of a conjugated dienyl sulfone to generate
an α-amino diene product (35, 60% yield). Trisubstituted alkene
adducts could also be delivered via the use of β,β-disubstituted
vinyl sulfones that incorporate alkyl–aryl and aryl–aryl groups
(products 36 and 37, 84% yield). Perhaps most notable,
R1
R1
1 mol% photocat. 1
R2
N
PhO2S
N
CsOAc, DCE, rt
26 W CFL
R2
vinyl sulfone
product
yield
Ph
Ph
amine
allylic amine
yield E:Z
E:Z
product
N
N
R
9
Ph
Ph
N
(±)-33
Me 68% 82:18b
(>98:2)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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42
43
44
45
46
47
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60
(±)-25 R = p-Me
(±)-26 R = p-Cl
80% >98:2
80% >98:2
N
(±)-27 R = p-CO2Me 74%
(±)-28 R = p-OMe 78%
93:7
97:3
O
Ph
(±)-34
(±)-35
83%
60%
93:7
93:7
(±)-29
(±)-30
R = o-F
82% >98:2
85% >98:2
Me
R = m-CF3
Me
N
Ph
N
R
Ph
N
77%
92:8
(±)-31
(±)-32
Ph
(±)-36 R = Me
(±)-37 R = Ph
84% >98:2
N
unsaturated sulfones bearing
a β-heteroatom were also
-
84%
N
Ph
successful in this protocol, allowing direct access to enamine
functionality (product 38, 79% yield). Unfortunately, extension
of this methodology to the synthesis of tetrasubstituted α-amino
olefins could not be realized as α-substituted vinyl sulfones have
proven to be non-reactive under our optimized conditions.
To further extend the utility of this photoredox-mediated
vinylation reaction, we next turned our attention to the
decarboxylative olefination of N-carbamoyl α-amino acids.
Importantly, the use of readily cleavable carbamate protecting
(±)-38 R = NPhth
78% >98:2
79% 15:85
aAll reactions performed with 0.50 mmol vinyl sulfone, 2.5 equiv. amine, 3.0 equiv.
CsOAc, and 1.0 mol% photocatalyst 1 in DCE (5.0 mL). Yields are of isolated
products. E:Z ratio determined by 1H NMR analysis. bIsomerization from 82:18 E:Z
(crude ratio) to >98:2 E:Z occurred during the mildly acidic purification conditions.
NPhth = Phthalimidoyl.
(products 39 and 40, 76 and 75% yield, respectively). Unnatural
cyclic amino acids are readily employed to create the
corresponding α-amino olefins (product 42, 74% yield, >98:2
E:Z). Importantly, this decarboxylative vinylation may also be
applied to a range of acyclic α-amino acids that incorporate a
variety of functional groups including aliphatic, aromatic,
sulfide, and indolic functionalities (products 41 and 43–45, 68–
77% yield, >98:2 E:Z).
We next examined the scope of the vinyl sulfone coupling
partner in this decarboxylative olefination (Table 5). It is clear
that a range of vinyl sulfones can be successfully employed in
this CO2-extrusion mechanism without loss in yield or olefin
geometry control (entries 1–4, 69–84% yield, 94:6–97:3 E:Z).
Again, unsaturated sulfones bearing electron-withdrawing
functional groups react efficiently (entries 1 and 2, 79 and 84%
yield, 94:6 E:Z), as do those possessing electron-donating groups
(entry 3, 69% yield, 97:3 E:Z). Finally, heteroaryl rings are also
groups provides
a valuable synthetic handle for further
elaboration. To our delight, we found that Ir(ppy)2(dtbbpy)PF6
(11), in the presence of 26 W light and CsHCO3, rapidly
promoted the decarboxylative coupling of Boc-Pro-OH with
sulfone 9 to generate the desired allylic amine 39 in 76% yield
and with excellent olefin geometry control (Table 4, 94:6 E:Z).22
Intriguingly, we discovered that while this CO2-extrusion,
vinylation mechanism is efficiently catalyzed by photocatalyst 1,
the use of photocatalyst 11 was necessary to achieve high levels
of E-olefin selectivity.23 As demonstrated in Table 4, these
optimized conditions could be applied to a wide range of α-
amino acids, to generate allylic amines in high yield and olefin
geometry control (products 39–45, 68–77% yield, 92:8 to >98:2
E:Z). Modification of the α-amino acid protecting group is well
tolerated, allowing incorporation of different carbamate systems
Table 4. Decarboxylative Vinylation: Amino Acid Scope.a
product, yield (E:Z)
product, yield (E:Z)
product, yield (E:Z)
amino acid
amino acid
amino acid
MeS
CO2H
NHBoc
MeS
Ph
CO2H
Ph
N
R
N
R
N
CO2H
N
Ph
NHBoc
Boc
Boc
Boc-Pro-OH (R = Boc)
Cbz-Pro-OH (R = Cbz)
(±)-39 76% (94:6)
(±)-40 75% (92:8)
Boc-Pip-OH
(±)-42 74% (>98:2)
Boc-Met-OH
(±)-44 70% (>98:2)
Me
Me
CO2H
Ph
CO2H
NHBoc
Ph
CO2H
Ph
Me
Me
NHBoc
NHBoc
NHBoc
HN
NHBoc
NHBoc
HN
Boc-Phe-OH
(±)-41 77% (>98:2)
Boc-Val-OH
(±)-43 73% (>98:2)
Boc-Trp-OH
(±)-45 68% (>98:2)
aAll reactions performed with 0.50 mmol vinyl sulfone, 1.2 equiv. amino acid, 2.0 equiv. CsHCO3, and 0.5 mol% photocatalyst 11 at 50 °C in 1,4-dioxane (30 mL). Yields are
of isolated products. E:Z ratio determined by 1H NMR analysis.
3
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Table 5. Decarboxylative Vinylation: Vinyl Sulfone Scope.a
(2) (a) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C.
Science 2013, 339, 1593. (b) Petronijević, F. R.; Nappi, M.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2013, 135, 18323. (c) Qvortrup, K.; Rankic, D. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 626. (d) Terrett, J. A.;
Clift, M. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 6858. (e)
Xia, J.-B.; Zhu, C.; Chen, C. J. Am. Chem. Soc. 2013, 135, 17494.
1
2
3
4
5
6
7
8
0.5 mol% photocat. 11
PhO2S
CO2H
R
N
N
R
CsHCO3, 1,4-dioxane
50 °C, 26 W CFL
Boc
Boc
(3) (a) Bergman, R. G. Nature 2007, 446, 391. (b) Godula, K.; Sames, D. Science
2006, 312, 67. (c) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (d)
Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069.
Boc-Pro-OH
vinyl sulfone
allylic amine
entry
product, yield (E:Z)
entry
product, yield (E:Z)
(4) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011, 334, 1114.
(5) (a) Kohls, P.; Jadhav, D.; Pandey, G.; Reiser, O. Org. Lett. 2012, 14, 672. (b)
Miyake, Y.; Nakajima, K.; Nishibayashi, Y. J. Am. Chem. Soc. 2012, 134,
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Commun. 2012, 48, 6966. (d) Zhu, S.; Das, A.; Bui, L.; Curran, D. P.;
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E. M.; Yoon, T. P. J. Org. Chem. 2013, 78, 4107. (f) Mizoguchi, H.; Oikawa,
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Eur. J. 2012, 18, 16473. (i) Singh, A.; Arora, A.; Weaver, J. D. Org. Lett.
2013, 15, 5390.
1
2
CF3
N
N
Boc
F
Boc
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(±)-46 84% (94:6 E:Z)
(±)-47 79% (94:6 E:Z)
3
4
OMe
N
N
N
Boc
Boc
(6) For reviews on functionalization of α-amino C–H bonds using photoredox
catalysis, see: (a) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687. (b) Hu, J.;
Wang, J.; Nguyen, T. H.; Zheng, N. Beilstein J. Org. Chem. 2013, 9, 1977.
(7) (a) Zuo, Z.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014, 136, 5257. (b) Zuo,
Z.; Ahneman, D.; Chu, L.; Terrett, J.; Doyle, A. G.; MacMillan, D. W. C.
Science 2014, 10.1126/science.1255525.
OMOM
(±)-48 69% (97:3 E:Z)
(±)-49 69% (95:5 E:Z)
aAll reactions performed using the conditions described in Table 4. Yields are of
isolated products. E:Z ratio determined by 1H NMR analysis.
(8) For
a
photoredox-mediated generation of α-amino radicals from
N-aryl α-amino acids, see: Chen, L.; Chao, C. S.; Pan, Y.; Dong, S.; Teo, Y.
C.; Wang, J.; Tan, C.-H. Org. Biomol. Chem. 2013, 11, 5922.
(9) Nag, S.; Batra, S. Tetrahedron 2011, 67, 8959.
(10) (a) Skoda, E. M.; Davis, G. C.; Wipf, P. Org. Process Res. Dev. 2012, 16, 26.
(b) Stütz, A. Angew. Chem. Int. Ed. Engl. 1987, 26, 320.
(11) (a) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res.
2007, 40, 1394. (b) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P.
M. P. Chem. Rev. 2010, 110, 6169.
(12) (a) Cheikh, R. B.; Chaabouni, R.; Laurent, A.; Mison, P.; Nafti, A. Synthesis
1983, 685. (b) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689.
(c) Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1. (c) Collet, F.;
Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926. (d) Ramirez, T. A.;
Zhao, B.; Shi, Y. Chem. Soc. Rev. 2012, 41, 931.
(13) For selected examples, see: (a) Dieter, R. K.; Li, S. J. Org. Chem. 1997, 62,
7726. (b) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu, K.;
Watson, R. T. J. Org. Chem. 2004, 69, 3076. (c) Beng, T. K.; Gawley, R. E.
Org. Lett. 2011, 13, 394. (h) Barker, G.; McGrath, J. L.; Klapars, A.; Stead,
D.; Zhou, G.; Campos, K. R.; O’Brien, P. J. Org. Chem. 2011, 76, 5936. (i)
Millet, A.; Dailler, D.; Larini, P.; Baudoin, O. Angew. Chem. Int. Ed. 2014,
53, 2678.
(14) For selected examples of the use of vinyl sulfones as radical vinylating agents,
see: (a) Miyamoto, N.; Fukuoka, D.; Utimoto, K.; Nozaki, H. Bull. Chem. Soc.
Jpn. 1974, 47, 503. (b) Russell, G. A.; Ngoviwatchai, P.; Tashtoush, H.; Pla-
Dalmau, A.; Khanna, R. K. J. Am. Chem. Soc. 1988, 110, 3530. (c) Xiang, J.;
Jiang, W.; Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1997, 119, 4123. (d)
Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem. Int. Ed. 1999, 38,
1943. (e) Schaffner, A.-P.; Darmency, V.; Renaud, P. Angew. Chem. Int. Ed.
2006, 45, 5847. (f) Poittevin, C.; Liautard, V.; Beniazza, R.; Robert, F.;
Landais, Y. Org. Lett. 2013, 15, 2814.
(15) After submission of this article, a related photochemical vinylation was
reported: Amaoka, Y.; Nagatomo, M.; Watanabe, M.; Tao, K.; Kamijo, S.;
Inoue, M. Chem. Sci. 2014, doi: 10.1039/c4sc01631a.
(16) (a) Lee, W. J.; Oh, D. Y. Synth. Commun. 1989, 19, 2209. (b) Sawangphon,
T.; Katrun, P.; Chaisiwamongkhol, K.; Pohmakotr, M.; Reutrakul, V.;
Jaipetch, T.; Soorukram, D.; Kuhakarn, C. Synth. Commun. 2013, 43, 1692.
(17) Lowry, M. S.; Goldsmith, J. I.; Slinker, J. D.; Rohl, R.; Pascal Jr., R. A.;
Malliaras, G. G.; Bernhard, S. Chem. Mater. 2005, 17, 5712.
readily tolerated in this coupling protocol, as demonstrated by
the synthesis of drug-like pyridinyl-pyrrolidine adduct 49 (entry
4, 69% yield, 95:5 E:Z).
With the scope of the C–H and decarboxylative vinylation
reactions shown to be broad across a range of substrates, we next
turned our attention to synthetic applications of this
methodology.
As shown in Figure 1, a variety of
pharmacophores were readily accessible via an intramolecular
Heck reaction (50), an acid-promoted cyclization (51), and an
alkene reduction (52). Furthermore, the decarboxylative and C–
H vinylation reactions were applied to enable the concise total
syntheses of the natural products (±)-norruspoline (53)24 and (±)-
galipinine (54),25 respectively (see Supporting Information for
details).
Figure 1. Derivatization of Allylic Amine Products.
Ph
Ph
N
Ph
N
N
50
(±)-51
(±)-52
87% from 18
72% (95:5 dr) from 10
80% from 10
OMe
OH
O
O
N
H
N
Me
(±)-53 (norruspoline)
76% from 48
(±)-54 (galipinine)
3 steps from commercial
(18) Liu, W.; Ma, Y.; Yin, Y.; Zhao, Y. Bull. Chem. Soc. Jpn. 2004, 79, 577.
(19) Persson, B. Acta Chem. Scand. 1977, 31B, 88.
(20) The lower E-selectivities with Ir(ppy)3 were found to be a result of post
reaction isomerization. Post-reaction isomerization was also promoted by
photocatalysts 1 and 11, although this only became apparent after prolonged
reaction times. For a related isomerization process, see: Singh, K.; Staig, S. J.;
Weaver, J. D. J. Am. Chem. Soc. 2014, 136, 5275.
(21) For discussions regarding the stereoselectivity of radical additions to vinyl
sulfones see references 14b and 14c.
(22) See Supporting Information for optimization studies.
(23) Using photocatalyst 1 instead of 11 gave comparable yields of 39 but with an
E:Z ratio of 1:1. Using photocatalyst 1 in combination with KOAc as the base
led to improved Z-selectivity (≥3:1 Z:E).
(24) Roessler, F.; Ganzinger, D.; Johne, S.; Schöpp, E.; Hesse, M. Helv. Chim.
Acta 1978, 61, 1200.
Acknowledgement. Financial support was provided by
NIHGMS (R01 GM103558-03) and kind gifts from Merck and
Amgen.
Supporting Information Available. Experimental procedures
and spectral data are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) For recent reviews, see (a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem.
2010, 2, 527. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev.
2011, 40, 102. (c) Tucker, J. W.; Stephenson, C. R. J. J. Org. Chem. 2012, 77,
1617. (d) Xuan, J.; Xiao, W.-J. Angew. Chem. Int. Ed. 2012, 51, 6828. (e)
Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
(f) Xie, J.; Jin, H.; Xu, P.; Zhu, C. Tetrahedron Lett. 2014, 55, 36. (g) Schultz,
D. M.; Yoon, T. P. Science 2014, 343, 1239176.
(25) (a) Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.; Fouraste, I.; Moulis,
C. Phytochemistry 1999, 51, 1167. (b) Jacquemond-Collet, I.; Benoit-Vical,
F.; Mustofa; Valentin, A.; Stanislas, E.; Mallié, M.; Fourasté, I. Planta Med.
2002, 68, 68.
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