Arylphosphonylation and arylazidation of activated alkenes

Article abstract of DOI:10.1002/anie.201311241

Two radical-mediated processes of activated alkenes, namely arylphosphonylation and arylazidation, are described. The difunctionalization of alkenes by a tandem process that involves radical addition, 1,4-aryl migration, and desulfonylation generates α-ar

Full text of DOI:10.1002/anie.201311241

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DOI: 10.1002/anie.201311241
Alkene Difunctionalization
Hot Paper
Arylphosphonylation and Arylazidation of Activated Alkenes**
Wangqing Kong, Estꢀbaliz Merino, and Cristina Nevado*
Dedicated to Professor Max Malacria on the occasion of his 65th birthday
Abstract: Two radical-mediated processes of activated alkenes,
namely arylphosphonylation and arylazidation, are described.
The difunctionalization of alkenes by a tandem process that
involves radical addition, 1,4-aryl migration, and desulfonyla-
tion generates a-aryl-b-heterofunctionalized amides bearing
a quaternary stereocenter when the substituent on the nitrogen
atom is an aryl group. Alternatively, heterooxindoles or
spirobicycles can be obtained with excellent regioselectivity in
the presence of an alkyl substituent on the nitrogen atom.
Scheme 1. Arylheterofunctionalization of activated alkenes.
Alkenes represent privileged motifs in organic synthesis.
Their accessibility, robust nature, and broad functionalization
potential has triggered the development of novel methods to
incorporate functional groups across the C = C p system.
Following the pioneering work of Sharpless and co-workers,[1]
alternative methods to enable the introduction of two func-
tional groups across alkenes in a catalytic, regio- and
stereocontrolled manner have been intensively studied.[2]
Both metal-free as well as transition-metal-mediated dioxy-
genation,[3] aminooxygenation,[4] diamination,[5] aminohalo-
genation,[6] fluoroamination,[7] azidooxygenation,[8] and
amino- and oxotrifluoromethylation[9] reactions of alkenes
have been reported. In contrast, the carbo- and heterofunc-
tionalization of alkenes involving the incorporation of arenes
has been more limited and mostly restricted to the formation
of oxindoles and related heterocycles.[10] In this context,
phosphonyl[11] and azido[12] oxindoles have recently been
described. Our group has reported the addition of a CF3
radical to the double bond of tosyl acrylamides as a way to
trigger an aryl migration/desulfonylation sequence.[13] We
envisioned that, under the right set of conditions, diverse
heteroatom-centered radicals could be engaged in such
a cascade process, enabling the simultaneous formation of
carbon–carbon and carbon–heteroatom bonds across alkenes
beyond the well-established oxindole synthesis (Scheme 1).
Herein, we report the successful realization of this concept
with the introduction of azido and phosphonyl radicals for the
flexible synthesis of unprecedented a-aryl-b-heterofunction-
alized amides with a quaternary stereocenter. Furthermore,
phosphorylated oxindoles and spirobicycles could also be
obtained in a completely regioselective manner.
The optimization of the reaction conditions was per-
formed with acryl sulfonamides 1 (Table 1).[14] It is well
established that Ph2P(O)H reacts with silver salts to form
the corresponding [Ph2P(O)Ag] complexes, which can sub-
sequently add to alkenes.[11a,b,15] Different salts were explored
in combination with substrate 1a, with AgNO3 showing the
best performance (entries 1–3). The reaction seems not to be
influenced by the presence of base and, in contrast to previous
methods,[11a,b] the addition of other Lewis acids, such as
Mg(NO3)·6H2O, leads to decomposition of the starting
material (entries 4 and 5). The amount of silver could be
reduced, and with 10 mol% of AgNO3, the desired product
2a could be isolated in 67% yield (entry 6). Next, we
attempted the introduction of an azide group with iodine(III)
reagent 4.[8c] Its reaction with 1b in toluene at 608C furnished
the desired product, but as part of a complex reaction mixture
(entry 7). The reaction was found to be cleaner in dichloro-
methane, and 2b could be isolated in 56% yield (entry 8). To
increase the conversion of the starting material, different
additives were used: Copper iodide (30 mol%) in the
presence or absence of 2,2’-bipyridine as a ligand furnished
complex mixtures (entry 9).[12] In contrast, the addition of
NaHCO3 (1 equiv) improved the conversion of the starting
material (entry 10). After a small screening of bases,[14] the
use of phenanthroline (phen) enabled us to isolate the desired
a-aryl-b-azido amide 3b in 71% yield (entry 11).
With the optimized reaction conditions for both processes
in hand, we then set out to explore the scope of these
transformations. Tosyl amide substrates that bear electron-
donating or electron-withdrawing groups at the para position
of the aromatic ring that is directly bound to the nitrogen
atom (R1; Table 2) produced the corresponding b-phosphonyl
and b-azido amides 2b–e and 3b–e in good yields (entries 3–
10). The presence of ortho substituents seemed to reduce the
reaction efficiency (entries 11 and 12). The substitution
[*] Dr. W. Kong, Dr. E. Merino, Prof. Dr. C. Nevado
Department of Chemistry
Universitꢀt Zꢁrich (Switzerland)
E-mail: cristina.nevado@chem.uzh.ch
[**] The European Research Council (ERC; Starting grant 307948) is
kindly acknowledged for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311241.
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Table 1: Optimization of the reaction conditions.[a]
Scheme 2).[14] The presence of
a more nucleophilic nitrogen atom
in the molecule triggers, upon phos-
phonylation of the alkene, not only
an 1,4-aryl migration/desulfonyla-
tion cascade, but also the formation
2
À
of a new C(sp ) N bond in the ortho
position relative to the original
sulfonyl group in a formal 1,3-
N migration process. This method
enables the synthesis of meta-sub-
stituted oxindoles 6b–d in a com-
pletely regioselective fashion. Pre-
viously reported silver-catalyzed
arylphosphonylations with acrylam-
ide substrates only furnished an
inseparable mixture of regioisomers
of these products, as two possible
sites for arylation of the double
bond are present in the correspond-
ing starting materials, thus high-
lighting the synthetic potential of
this new method.[11a] Finally, when
the arylsulfonyl moiety was
replaced with an electron-rich ben-
zoate group as in substrate 7, phos-
Entry
Substrate
Solvent
Additives
Product
Yield[b] [%]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
AgBF4 (30%)
AgOTf (30%)
AgNO3 (30%)
AgNO3 (30%), NaHCO3 (1 equiv)
AgNO3 (30%), Mg(NO3)2·6H2O (50%)
AgNO3 (10%)
–
–
2a
2a
2a
2a
32
19
58
58
[c]
–
2a
3b
3b
69 (67)
80[c]
59 (56)
[c]
9
10
11
CuI (30%), with or without bipy (30%)
NaHCO3 (1 equiv)
phen (1 equiv)
–
3b
3b
75
78 (71)
[a] Reaction conditions A (used for substrate 1a): HPOPh2 (2 equiv), MeCN (0.05m), 1008C, 14 h.
Reaction conditions B (used for substrate 1b): 4 (1.5 equiv), solvent (0.05m), 608C, 14 h. [b] Yield
determined by H NMR spectroscopy using 1,2-dibromoethane as the internal standard. The value in
brackets corresponds to the yield of isolated product after column chromatography on silica gel.
[c] Complex reaction mixture.
1
phonylated
spirobicyclic
com-
pattern on the aromatic ring of the sulfona-
mide group was further explored (R2;
Table 2). m-Methyl, p-methoxy-, and p-
phenyl benzosulfonamide substrates were
efficiently transformed into the correspond-
ing b-functionalized amides 2i, 2j, 3h, and 3j
(entries 13–16). The reaction is completely
regioselective so that the 1,4-migration of the
aryl group takes place exclusively through the
carbon atom that is bound to the SO2 group in
the substrate.
More elaborate arylsulfonyl substituents
were also investigated. Substrates bearing 1,4-
dioxolane, indane, or dibenzofurane sulfonyl
moieties (1k–m) were transformed into the
corresponding linear amides in good yields
(entries 17–20). Finally, we also investigated
different substituents on the alkene. Substrate
1n, which bears a phenyl ring at the propene
moiety, efficiently gave the corresponding
amides 2n and 3n in 65 and 62% yield,
respectively (entries 21–22). In contrast, tri-
Scheme 2. Scope of the silver-catalyzed arylphosphonylation reaction. Yields of isolated
products after column chromatography on silica gel are given. [a] HPOR2 (2 equiv),
AgNO3 (50 mol%), MeCN (0.05m), 1008C, 14 h. [b] Small quantities of Ph2P(O)OMe (9)
were also detected in the reaction mixture. [c] Diastereoisomers could be separated by
crystallization.
substituted olefin 1o was found to be unreactive under
reaction conditions A, but decomposed under reaction con-
ditions B (entry 23).
The influence of the nitrogen substitution pattern on the
reaction was further evaluated. In contrast to the results that
are summarized in Table 2, N-methyl-N-tosyl amide 5a
furnished phosphonyl oxindole 6a in 58% yield in the
presence of an increased amount of AgNO3 (50 mol%;
pounds 8a–c were obtained in good yields and with moderate
selectivities. The different reactivity of N-aryl- and N-alkyl-
substituted substrates (1 vs. 5) was further explored: When an
ester group was introduced at the ortho position of the
arylsulfonamide moiety, the more nucleophilic alkyl-substi-
tuted nitrogen atom reacts with the ester furnishing
the corresponding isoquinolinedione 6 f in 66% yield
(Scheme 3a). In sharp contrast, the analogous N-aryl-sub-
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Table 2: Scope of the arylphosphonylation and the arylazidation reaction.
stituted substrate 1p provided
a mixture of both amide 2p and
isoquinolinedione 6p in a 5:1 ratio
(Scheme 3b).
Control
experiments
were
designed to investigate the mecha-
nism of these transformations.[14]
The efficiency of the reactions of
1a and 5a under the standard con-
ditions was strongly affected by the
presence of 2,2,6,6-tetramethyl-1-
Entry Cond.[a]
Substrate R1
R2
Product[b]
Yield[c] [%]
1
A
B
A
B
A
B
A
B
A
B
A
B
B
A
A
B
A
B
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1 f
1g
1h
1i
H
H
H
H
2a
3a
2b
3b
67
73
61
71
68
75
72
72
68
80
60
55
84
66
80
75
73
80
2
3
4
5
piperidinyloxy
2,6-di-tert-butyl-4-methylphenol
(BHT), which points towards a rad-
ical mechanism (Scheme 4a,
(TEMPO)
and
p-Cl
p-Cl
p-Me
p-Me
p-Br
p-Br
H
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
m-Me
p-OMe
p-Ph
p-Ph
2c (X=OMe)
3c
2d (X=OMe)
3d
6
7
8
9
left).[14] When the [Ph2P(O)Ag]
complex was used in a stoichiomet-
ric fashion,[15] in the presence or
absence of AgNO3, no conversion
of 1a was observed. The same result
was obtained when [Ph2P(O)Ag]
was used in a catalytic fashion in
the presence of P(OMe)2OH, thus
suggesting that the silver additive is
needed to generate the reactive
2e
3e
10
11
12
13
14
15
16
17
18
H
o-Cl
o-F
H
2 f (X=OMe, R3 =nC6H13)
3g
3h
H
2i (X=OMe)
2j
3j
2k
3k
1j
1j
1k
1k
p-Cl
p-Cl
p-Cl
p-Cl
phosphonyl
radical
from
Ph2P(O)H, but, in contrast to pre-
viously reported examples,[11a,b] that
the [Ph2P(O)Ag] complex is not an
active intermediate in our reaction
(Scheme 4a, right).
Deuterium labelling experi-
ments were also carried out. The
lack of a primary intermolecular
kinetic isotope effect (KIE) in the
reaction of 5a and [D5]-5a con-
19
20
A
B
1l
p-Cl
p-Cl
2l (X=OEt)
64
51
1m
3m
21
22
A
B
1n
1n
p-OMe p-Me
p-OMe p-Me
2n (R3 =Ph)
3n (R3 =Ph)
65
62
À
firmed that the rupture of the C H
23
A, B
1o:
–
–
bond on the arylsulfonyl group is
not involved in the rate-determin-
ing step. A similar normal secon-
dary KIE (KIE = 1.3) was mea-
sured in an intramolecular experi-
ment with [D]-5a as the substrate
(Scheme 4b,c).[16] We also aimed to
determine the source of hydrogen
[a] Reaction conditions A: HPOPh2 (2 equiv), AgNO3 (10%), MeCN (0.05m), 1008C, 14 h. Reaction
conditions B (used for substrate 1b): 4 (1.5 equiv), phen (1 equiv), CH2Cl2 (0.05m), 608C, 14 h.
[b] Unless otherwise stated, R3 =Me and X=Ph. [c] The values correspond to the yield of isolated
product after column chromatography on silica gel.
that generates the amide moiety in the final products.[17]
Ph2P(O)H seems to be the key hydrogen source in these
reactions,[18] whereas in the reaction with azide-transfer
reagent 4, adventitious traces of water in the medium seem
À
to be responsible for the formation of the N H bond
(Scheme 4d).[17] With these results in hand, the following
mechanism can be proposed for these transformations
(Scheme 5): In the first step, the phosphorus- or azide-
centered radical interacts with the activated alkene to give
3
3
À
À
a new C(sp ) P or C(sp ) N bond and an a-alkyl radical
intermediate I. A 5-ipso cyclization then takes place on the
aromatic ring generating aryl radical II, which leads to amidyl
radical III upon rearomatization with concomitant desulfo-
nylation. In the case of the arylphosphonylation reaction and
Scheme 3. [a] Reaction conditions: HPOPh2 (2 equiv), AgNO3
(10 mol%), MeCN (0.05m), 1008C, 14 h.
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according to the deuterium labelling experiments, the hydro-
gen is abstracted from R2P(O)H, so that a self-propagating
radical cycle operates without the need to further invoke
a metal or a [Ph2POAg] complex, which is in contrast to
previously described oxidative phosphonylation reac-
tions.[11,19] The presence of an alkyl group on the nitrogen
atom generates a more nucleophilic amidyl radical (see
Scheme 2 and Scheme 3a), thus triggering a subsequent
2
À
C(sp ) N bond formation. The intermediate aryl radical IV
will be oxidized at the expense of AgNO3, which, in this case,
needs to be regenerated in the reaction mixture, thus
explaining the need for a higher silver loading in these
transformations. Functionalized oxindoles 6 were obtained in
a completely regioselective fashion. The normal secondary
kinetic isotope effect (sKIE) that is described in Scheme 4b,c
could either indicate a C(sp3) to C(sp2) rehybridization in the
À
transition state (a-sKIE) or an involvement of the C H bond
in hyperconjugation (b-sKIE). As no rehybridization of
3
2
À
À
C(sp ) H/D to C(sp ) H/D can occur for the formation of
products 6, we rationalized that the observed effect in terms
of a b-sKIE is due to a more efficient hyperconjugation by the
À
C H bond in intermediate II, which would point towards the
ipso-cyclization/desulfonylation (I to III) being the rate-
determining step of these transformations.[20]
Finally, the replacement of the sulfonyl group by a ben-
zoate moiety with increased electron density furnished the
corresponding spirobicycles 8 from an intermediate analo-
gous to II.
In summary, two radical-mediated transformations of
activated alkenes, namely arylphosphonylation and arylazi-
dation, have been developed. a-Aryl-b-azido and a-aryl-b-
phosphonyl amides could be obtained for the first time in
excellent yields and also in a highly regioselective fashion.
Control experiments suggest that a 5-exo-dig ipso cyclization
of an a-alkyl-b-heterofunctionalized radical onto the aro-
Scheme 4. Mechanistic study. [a] Reaction conditions: HPOPh2
(2 equiv), AgNO3 (10 mol%), MeCN (0.05m), 1008C, 14 h. [b] Reac-
tion conditions: 4 (1.5 equiv), phen (1 equiv), CH2Cl2 (0.05m), 608C,
14 h. [c] Reaction conditions: HPOPh2 (2 equiv), AgNO3 (50 mol%),
MeCN (0.05m), 1008C, 14 h.
2
3
À
matic ring for the formation of the new C(sp ) C(sp ) bond is
followed by a desulfonylation process as the turnover-limiting
step for these reactions. Further studies to introduce other
radicals into these transformations are currently underway.
Received: December 27, 2013
Revised: March 3, 2014
Published online: April 1, 2014
Keywords: alkenes ·
.
aryl migration ·
desulfonylation ·
difunctionalization · radicals
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