Anti-Markovnikov Radical Hydro- and Deuteroamidation of Unactivated Alkenes

Article abstract of DOI:10.1002/chem.201901566

Radical anti-Markovnikov hydro- and deuteroamidation of unactivated alkenes was achieved by merging photoredox and thiol catalysis. Reactions proceed by addition of the electrophilic CbzHN-radical (Cbz=carbobenzyloxy), readily generated by single-electron-transfer (SET) oxidation of an α-Cbz-amino-oxy acid to an alkene. The adduct radical is reduced by thiophenol added as an organic polarity reversal cocatalyst, which mediates the H transfer from H₂O to the alkyl radical intermediate. Accordingly, deuteroamidation of alkenes was realized with excellent D incorporation by using D₂O as the stoichiometric formal radical-reducing reagent. The reaction features low redox catalyst loading, excellent anti-Markovnikov selectivity, and the use of a large alkene excess is not required. Diverse Cbz-protected primary amines, including β-deuterated amines, can be obtained by applying this method.

Full text of DOI:10.1002/chem.201901566

A Journal of
Accepted Article
Title: Anti-Markovnikov Radical Hydro- and Deuteroamidation of
Unactivated Alkenes
Authors: Heng Jiang and Armido Studer
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To be cited as: Chem. Eur. J. 10.1002/chem.201901566
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COMMUNICATION
Anti-Markovnikov Radical Hydro- and Deuteroamidation of
Unactivated Alkenes
Heng Jiang and Armido Studer*
Abstract:
Radical
anti-Markovnikov
hydro-
and
precursor is challenging with existing methodology.[3a] Notably,
D-labelling is important for analysis of metabolic pathways of
drug candidates and for studying reaction mechanisms by using
NMR and mass spectrometry techniques.[7] Moreover,
selectively deuterated bioactive molecules are promising
pharmaceuticals by enhancing their pharmacokinetic and
pharmacodynamic properties.[8] Therefore, the development of
practical alkene deuteroamination methods for the synthesis of
β-deuterated amines with high D incorporation is of importance.[9]
deuteroamidation of unactivated alkenes is achieved by merging
photoredox and thiol catalysis. Reactions proceed by addition of
the electrophilic CbzHN-radical, readily generated by SET
oxidation of an -Cbz-amino-oxy acid, to an alkene. The adduct
radical is reduced by thiophenol added as an organic polarity
reversal cocatalyst which mediates the H-transfer from H2O to
the alkyl radical intermediate. Accordingly, deuteroamidation of
alkenes is realized with excellent D-incorporation by using D2O
as the stoichiometric formal radical reducing reagent. The
reaction features low redox catalyst loading, excellent anti-
Markovnikov selectivity, and the use of a large alkene excess is
not required. Diverse Cbz-protected primary amines including β-
deuterated amines can be obtained by applying this method.
Bioactive
natural
products,
pharmaceuticals
and
agrochemicals often contain a primary amine functionality. Such
amines also serve as precursors for structurally more complex
N-containing compounds. Regarding their preparation, the
hydroamination of an alkene is an ideal synthetic strategy, since
the CC double bond can be readily accessed from various
functional groups which themselves are difficult to be transferred
to the amino functionality.[1] Considering transition-metal
catalysed hydroamination, most methods use secondary amines
as N-donors providing the corresponding tertiary amines as
products in Markovnikov-type selectivity.[2] Recently, radical
hydroamidation has emerged as a promising approach for the
preparation of N-protected primary amines from the
corresponding alkenes (Scheme 1a).[3] In contrast to transition-
metal mediated processes, radical alkene hydroamidation that
generally proceeds via electrophilic amidyl radicals delivers the
anti-Markovnikov products.[4] However, the use of a large excess
of the alkene component (in general 10 equivalents)[3a],[3c-e] or
sulfonyl protecting groups that have to be removed under harsh
conditions restricts their synthetic potential,[3b],[3f] especially for
late-stage modification of structurally complex alkenes.
Consequently, an efficient and practical method for the
preparation of protected primary amines by intermolecular
radical anti-Markovnikov hydroamidation is demanded.[5],[6]
Scheme 1. anti-Markovnikov hydro- and deuteroamidation of alkenes (PG =
protecting group).
We report herein cooperative photoredox[10] and thiol
catalyzed
anti-Markovnikov
hydroamidation
and
deuteroamidation of alkenes by using an Ir-complex as a
photocatalyst and catalytic thiophenol as the H or D-transfer
mediator using an -amido-oxy acid as N-radical precursor
(Scheme 1b).[11] Compared to previous methods for radical
hydroamidation, our process uses only two equivalents of the
alkene component and a small amount of both photocatalyst and
thiophenol polarity reversal catalyst.[12] Notably, the Cbz-group
used herein is a common N-protecting group in organic
synthesis.[13] Considering the alkene deuteroamidation,
satisfactory D-incorporation of diverse alkenes can be achieved,
demonstrating the high efficiency of thiophenol acting as a
radical deuteration reagent in combination with D2O.
The proposed catalytic cycle of the anti-Markovnikov
hydroamidation and deuteroamidation is presented in Scheme 2.
The sequence starts by photo-excitation of the Ir(III)-complex
upon visible light irradiation to generate the excited Ir(III)*-
complex, which is SET-reduced by the -Cbz-amino-oxy
carboxylate, formed by deprotonation with Na2CO3, to generate
the carboxyl radical along with the reduced Ir(II)-complex. The
carboxyl radical sequentially fragments CO2 and acetone to
Amides or their derivatives used in established anti-
Markovnikov radical hydroamidations generally serve as both
amidyl radical precursors and as H-donors.[3] Since D-labelled
amidyl radical precursors are more difficult to prepare, radical
alkene deuteroamidation by using a D-labelled amidyl radical
[*]
Dr. H. Jiang, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Corrensstraß 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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generate the N-centered radical (CbzHN•), which then adds to
the terminal position of the alkene to give the corresponding
adduct alkyl radical.[11],[14] The high regioselectivity of this
addition step explains the anti-Markovnikov selectivity.[4] The
hydroamidation product is eventually formed by reduction of the
alkyl radical with PhSH. This step also delivers the phenylthiyl
radical, that undergoes SET-reduction by the Ir(II)-complex to
regenerate the ground state Ir(III)-complex along with the
thiolate anion.[15] NaHCO3 or H2CO3, that readily exchange their
protons with H2O, serve as the proton donor to regenerate
thiophenol. Thus, H2O is the formal H-donor for the reduction
step and by simply replacing H2O with D2O, the process will
deliver the corresponding deuteroamidation product. A pitfall in
this dual catalytic cycle is the direct reduction of CbzHN• by
PhSH to give CbzNH2. However, considering polar effects, the
reduction of the electrophilic amidyl radical by the “electrophilic”
H-donor PhSH should be rather slow.[12,16] As an additional
problem, radical thiol-ene reaction would consume the thiol
cocatalyst.[16]
systems 4-CzIPN (PC-Ⅳ) and Mes-Acr-Me (PC-Ⅴ) provided
worse results (entries 12–15).
Table 1. Reaction optimization.
Entry[a]
Deviation from above
Yield%[b]
1
none
83 (81)
2
w/o photocatalyst Ⅰ
n.d.
3
w/o PhSH S-Ⅰ
5
4
w/o Na2CO3
n.d.
51
5
w/o H2O
6
conducted in the dark
S-Ⅱ instead of S-Ⅰ
S-Ⅲ instead of S-Ⅰ
S-Ⅳ instead of S-Ⅰ
S-Ⅴ instead of S-Ⅰ
S-Ⅵ instead of S-Ⅰ
Ru(bpy)3(PF6)2 instead of Ⅰ
Ru(bpz)3(PF6)2 instead of Ⅰ
4-CzIPN instead of Ⅰ
Mes-Acr-Me instead of Ⅰ
n.d.
73
7
8
29
9
70
10
11
12
13
14
15
22
17
n.d.
n.d.
trace[c]
6[c]
Scheme 2. Proposed catalytic cycle.
We commenced the study by using the amidyl radical
precursor 1 in combination with 2-ethylbutene 2a to provide 3a
with complete regiocontrol. Extensive experimentation revealed
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1 equiv), 2a (0.4 mmol, 2
equiv), photocatalyst (0.002 mmol, 1 mol%), thiol (0.01 mmol, 5 mol%),
Na2CO3 (0.2 mmol, 1 equiv), H2O (2 mL) and DCM (2 mL) was irradiated by a
20 W blue LEDs at 25 ℃ for 16 h. [b] The yield was determined by 1H NMR
analysis using CH2Br2 as an internal standard. [c] 5 mol% photocatalyst was
used.
that
the
hydroamidation
is
best
conducted
with
Ir(dFCF3ppy)2(dtbbpy)PF6 as the photocatalyst (PC-Ⅰ, 1 mol%)
in combination with PhSH (5 mol%) as the thiol cocatalyst,
Na2CO3 as the base in dichloromethane (DCM) and water (1:1)
at room temperature for 16 hours under blue light irradiation.
Targeted 3a was isolated in 81% yield. Control experiments
revealed the necessity of photocatalyst, thiol, base and light
irradiation (entries 2-4 and 6). The yield was diminished in the
absence of H2O due to the lower solubility of the -amido-oxy
acid carboxylate (entry 5). PhSH was demonstrated to be the
best thiol cocatalyst, since the use of other thiols including aryl
thiols (entries 7-9), an alkyl thiol (entry 10) and a silyl thiol (entry
11) gave lower yields. Other photoredox catalysts such as
Ru(bpy)3(PF6)2 (PC-Ⅱ), Ru(bpz)3(PF6)2 (PC-Ⅲ) and the organic
To explore the reaction scope, various alkenes were
examined (Table 2). A series of unactivated radical acceptors
including 1,1-disubstituted alkenes (3b and 3c), an internal non-
cyclic alkene (3d), trisubstituted alkenes (3e and 3f) and
terminal alkenes (3h and 3i) engaged in the radical
hydroamidation. Amazingly, even a tetrasubstituted alkene could
be hydroamidated with the novel method providing 3g in a very
good yield (80%). Moreover, cyclic alkenes were readily
converted to the N-protected amines 3j-3n in 63-85% yields.
Next, we examined functional group tolerance and found that
different functionalities including free alcohols (3o and 3t),
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ethers (3p), esters (3q and 3r), silyl ethers (3s), ketones (3u and
3v), amines (3w and 3x), halides (3y) and silanes (3z) are all
tolerated and the corresponding Cbz-protected primary amines
were isolated in moderate to very good yields (43-85%).
products were employed to evaluate the synthetic potential of
this hydroamidation. Reaction of -pinene provided the ring-
opening product 3ak in 59% yield. This result clearly supported
the radical nature of the transformation. Camphene afforded the
corresponding amide 3al with excellent diastereoselectivity and
very high yield (90%). The relative configuration was assigned
by NOE-experiments (see Supporting Information). It is notable
that the hydroamidation of linalool occurred with complete
regioselectivity at the more electron rich internal double bond
(3am). Menthol (3an) and sclareol (3ao) derivatives also
engaged in the hydroamidation reaction to provide structurally
more complex Cbz-protected amines in good yields.
Table 2. Alkene hydroamidation – reaction scope.[a],[b]
Table 3. Radical deuteroamidation of various alkenes.[a],[b]
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1 equiv), 2 (0.4 mmol, 2
equiv), PC-Ⅰ (0.001 mmol, 0.5 mol%), PhSH (0.006 mmol, 3 mol%), Na2CO3
(0.2 mmol, 1 equiv), D2O (1 mL) and DCM (1 mL) was irradiated by a 20 W
blue LEDs at 25 °C for 16 h. [b] Isolated yields are provided. [c] PC-Ⅰ (0.002
mmol, 1 mol%), PhSH (0.01 mmol, 5 mol%), K3PO4 (0.2 mmol, 1 equiv), D2O
(2 mL) and DCM (2 mL) were used.
[a] Reaction conditions: A mixture of 1 (0.2 mmol, 1 equiv), 2 (0.4 mmol, 2
equiv), PC-Ⅰ (0.002 mmol, 1 mol%), PhSH (0.01 mmol, 5 mol%), Na2CO3 (0.2
mmol, 1 equiv), H2O (2 mL) and DCM (2 mL) was irradiated by a 20 W blue
LEDs at 25 °C for 16 h. [b] Isolated yields are provided. [c] K3PO4 (0.2 mmol, 1
equiv) was used instead of Na2CO3.
By simply replacing H2O with D2O under otherwise identical
conditions, various β-deuterated amides could be prepared via
photoredox and thiol co-catalyzed deuteroamidation. As shown
in Table 3, a 1,1-disubstituted alkene (4a), a trisubstituted
alkene (4b), a tetrasubstituted alkene (4c) and cyclic alkenes
including cyclopentene (4d), cyclohexene (4e) and cycloheptene
(4f) provided the targeted β-deuterated N-Cbz-protected amines
in good yields (62-81%) and excellent D incorporation (90-97%).
A terminal alkene (4g) was also efficiently deuteroamidated in
As expected considering polar effects, electron-rich alkenes
such as vinyl ethers, silyl enol ethers, enol esters, enamides and
vinyl silanes underwent this hydroamidation reaction smoothly,
affording N-protected β-amino alcohols 3aa-3ah, the 1,2-
diamine derivative 3ai and the β-amido alkylsilane 3aj in
moderate to good yields (34-87%), further enlarging the scope of
this method. In addition, several alkene containing natural
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[3]
For intermolecular alkene anti-Markovnikov hydroamidation proceeding
via amidyl radicals, see: a) S. W. Lardy, V. A. Schmidt J. Am. Chem.
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as the alcohol- (4h), ether- (4i), ester- (4j), silyl ether- (4k),
ketone- (4l), imide- (4m), halide- (4n) and silane-moiety (4o) are
well tolerated to afford diverse β-deuterated Cbz-protected
amines in satisfactory yields (60-75%) and very high D content
(88-97%). Electron-rich alkenes including vinyl ethers (4p and
4q), enol esters (4r), silyl enol ethers (4s), enamides (4t) and
vinyl silanes (4u) worked smoothly, providing β-deuterated N-
protected primary amines in good yields and excellent D
incorporation (93-97%). Notably, the deuteroamidation of enol
ethers and enamides gives access to primary amines containing
a deuterium atom adjacent to a heteroatom (O or N), offering a
promising approach for the preparation of D-labelled bioactive
compounds and drug candidates with increased metabolic
stability.[9]
In conclusion, we have established a photoredox and thiol
co-catalyzed method for radical hydroamidation and
deuteroamidation of various unactivated as well as electron rich
alkenes. Diverse Cbz-protected primary amines and the
corresponding β-deuterated congeners were obtained in good
yields and high D incorporation using practical and mild
conditions. Importantly, the Cbz-group used in these
transformations is a common N-protecting group in synthetic
organic chemistry.
[4]
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Acknowledgements
This work was supported by the Alexander von Humboldt
Foundation (postdoctoral fellowship to H. J.) and the European
Research Council (ERC Advanced Grant agreement
No.692640).
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Conflict of Inerest
The authors declare no conflict of interest.
Keywords: hydroamination • deuteroamination • photoredox
catalysis• thiol catalysis • primary amines
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Layout 2:
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H. Jiang, A. Studer*
Page No. – Page No.
Anti-Markovnikov Radical Hydro- and
Deuteroamidation of Unactivated
Alkenes
CN and CD bond formation is achieved by mild and highly practical radical
deuteroamidation of alkenes. The method uses a readily accessed -amido-oxy
acid as an N-radical precursor and D2O as a formal radical reducing reagent
applying iridium/thiol cocatalysis. Replacing D2O by H2O provides the
corresponding hydroamidation products.
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