O-allylated pudovik and passerini adducts as versatile scaffolds for product diversification

Article abstract of DOI:10.1021/acs.joc.0c01721

The palladium-catalyzed O-allylation of α-hydroxyphosphonates and α-hydroxyamides obtained from Pudovik and Passerini multicomponent reactions has allowed interesting and highly straightforward access to a variety of building blocks for product diversific

Full text of DOI:10.1021/acs.joc.0c01721

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Article
O-Allylated Pudovik and Passerini Adducts as
Versatile Scaffolds for Product Diversification
Mansour Dolé KERIM, Tania Katsina, Martin Cattoen,
Nicolas Fincias, Stellios Arseniyadis, and Laurent El Kaim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01721 • Publication Date (Web): 26 Aug 2020
Downloaded from pubs.acs.org on August 29, 2020
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The Journal of Organic Chemistry
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O-Allylated Pudovik and Passerini Adducts as Versatile Scaffolds for
Product Diversification
Mansour Dolé Kerim,‡ Tania Katsina,† Martin Cattoen,† Nicolas Fincias,‡,† Stellios Arseniyadis,†,* and
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Laurent El Kaïm‡,*
‡ Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech, UMR 7652, Université Paris-Saclay,
828 Bd des Maréchaux, 91128 Palaiseau (France)
† Queen Mary University of London, School of Biological and Chemical Sciences, Mile End Road, London, E1 4NS (UK)
O-Allylated Pudovic and Passerini adducts: Platform molecules for further diversification
Me
OCOMe
RuH cat
O
O
OH
R1
R1
X
Pd
R1
X
O
R1
X
O
RCM
DBU, NuH
Nu
X
X
=PO(OR2)2, CONHR3
Nu =OR4, NHR5R6, SR7
ABSTRACT: The palladium-catalyzed O-allylation of α-hydroxyphosphonates and α-hydroxyamides obtained from Pudovik and
Passerini multicomponent reactions has allowed an interesting and highly straightforward access to a variety of building blocks for
product diversification. These post-functionalizations include a selective base- or ruthenium hydride-mediated isomeriza-
tion/Claisen rearrangement cascade and a ring-closing metathesis that allows access to a variety of diversely functionalized
phosphono-oxaheterocycles.
Palladium-catalyzed O-allylation of Pudovic and Passerini adducts
Pudovik
! INTRODUCTION
Diethyl phosphite (1 equiv.)
NEt3 (0.5 equiv.), 50 °C
OCOMe
For several decades now, metal-catalyzed reactions have
become an increasingly important subset of synthetic tools to
assemble molecules. Among them, the palladium-catalyzed
allylic alkylation, also referred to as the Tsuji-Trost reaction,
has been recognized as an essential tool for the construction of
C−C bonds. Indeed, this reaction allows to easily incorporate
an allyl group onto an in situ generated C-centered nucleophile
under mild conditions.1 Another interesting application is the
construction of C−O bonds, however this approach has been
much less explored.2,3 In our quest to implement the
palladium-catalyzed allylic alkylation to new substrates,4 we
became interested in applying this chemistry to
α-hydroxyphosphonates, also known as Pudovik adducts
(Figure 1). Indeed, we were intrigued by the possibility of the
alkoxide intermediate to undergo either a direct O-allylation or
O
OH
O
4
R1
H
R1
R1
X
X
Passerini
R2NC, H3BO3 (1 equiv.)
DMF, 50 °C
Pd
1
2 [X = PO(OR2)2]
3 [X = CONHR3
5 [X = PO(OR2)2]
6 [X = CONHR3
]
]
O-Allylated Pudovik and Passerini adducts: Platform molecules for further diversification
Me
RuH cat
O
O
R
R
X
RCM
O
O
R
X
PO(OEt)2
DBU, NuH
Nu
X
=PO(OR1)2, CONHR2
Nu =OR3, NHR4R5, SR6
Figure 1. O-Allylated Passerini and Pudovik adducts: Useful
platforms for product diversification.
a
competing C-allylation resulting from a preliminary
phospha-Brook rearrangement that is know to occur under
basic conditions, and which would afford a mixture of C- and
O-allylated products. Our seminal investigation led to the
conclusion that the phospha-Brook rearrangement did not
occur under the palladium conditions and that the O-allylation
product was formed exclusively, thus offering an interesting
solution to an unaddressed synthetic challenge, namely the
alkylation of α-hydroxyphosphonates.5 Since then, we have
applied this palladium-catalyzed O-allylation to a wider range
of α-hydroxyphosphonate derivatives and eventually extended
the method to yet another interesting family of compounds,
namely α-hydroxyamides, also referred to as Passerini
adducts. In addition, we have showcased the synthetic utility
of the resulting products by subjecting them to various key
post-transformations as a mean to access valuable building
blocks. We report here in full the results of our efforts.
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acidic allylic proton, with the styryl group further activating
! RESULTS AND DISCUSSION
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the electron-withdrawing character of the amide and the
phosphonate, as well as an allylic position that can potentially
be activated by a metal. As such, a base-mediated process
would trigger an isomerization of the cinnamyl double bond,8
while a ruthenium-,9,10 rhodium11 or iridium-based12 catalyst
would selectively promote the isomerization of the other non
styrenyl double bond. In both cases, the resulting allyl vinyl
ethers can undergo subsequent Claisen rearrangement to
generate two very different 1,4-alkenyl carbonyl derivatives
via a chair-like transition state (Schemes 2 and 4).13 This
one-pot 1,2-H isomerization/Claisen rearrangement sequences
have been repeatedly implemented to build structurally
complex products from simpler, more accessible diallyl
ethers,14 however, this strategy is not without challenges as
both double bonds are susceptible to isomerization, resulting
in possible mixtures.
With this in mind, we first started by evaluating the base-
mediated isomerization/Claisen rearrangement cascade on the
O-allylated Passerini adducts 6a-d. The results are depicted in
Scheme 3. When O-allylamide 6a was heated in the
presence of triethylamine or Cs2CO3 and toluene at 120 °C
under microwave irradiation, unreacted starting material was
recovered. Interestingly, switching to DBU (0.5 equiv.) under
otherwise identical conditions led to the desired α-ketoamide
7a in 65% yield.8 These conditions were eventually applied to
the allyloxy amides 6b-d affording the desired α-ketoamides
7b-d in 76-88% yield (Scheme 2).
This DBU-mediated isomerization was eventually applied
to the Pudovik adducts 5p-r. To our surprise, when the
corresponding phosphonate ethers were exposed to our
optimized conditions, intractable mixtures of products were
obtained. Replacing toluene with acetonitrile or DMF did not
improve the result. In an effort to analyze the potential
issues associated with the formation of α-ketophosphonates
under these conditions, we reasoned that the latter could
potentially be decomposing under basic conditions or even
undergo ketene formation. Indeed, ketophosphonates are
known for their behavior as acylating agents with the
phosphonyl group being easily displaced by various nucleo-
philes. To validate our hypothesis, we ran the reactions in the
presence of various primary amines. To our delight, the corre-
sponding amides 9a-d were formed, albeit in moderate yields
ranging from 56 to 77%. Piperidine was found to be less
reactive affording amide 9e in only 38% isolated yield.
NH indoles could also be used as showcased by the formation
of the acylated indoles 9f-g. Unfortunately, attempts to direct
the reaction towards C-acylated indoles using N-methyindole
led to unidentified mixtures. The reaction can also be run in a
nucleophilic solvent such as ethanol or trifluoroethanol to
afford the corresponding esters 9i and 9j in 89% and 53%
yields respectively. The reaction was eventually extended to
the formation of thioesters by running the reaction in a 2:1
toluene/thiol solution and heating at 150 °C under microwave
irradiation; the corresponded thioester 9k was formed in 67%
yield (Scheme 3).
To begin this endeavour, a first α-hydroxyphosphonate (2a)
was synthesized using standard Pudovik conditions [diethyl
phosphite (1 equiv.), NEt3 (0.5 equiv.), 50 °C, 24 h] and sub-
jected to slightly optimized palladium-catalyzed allylic alkyla-
tion conditions [Pd2dba3 (2.5 mol %), PPh3 (10 mol %),
Cs2CO3 (0.25 equiv.), toluene, 50 °C, 30 min] using allyl
methyl carbonate as an allyl donor (Scheme 1). Interestingly,
the C-allylated product was not observed, but instead the
reactions led to the formation of the corresponding O-allylated
product 5a. Considering the difficulty in making this type of
compounds under more traditional alkylating conditions which
favor the phospha-Brook rearrangement, we decided to further
investigate this reaction.A set of diversely substituted
α-hydroxyphosphonates were therefore synthesized. As a
general trend, all the Pudovik adducts (2a-q) were obtained in
excellent yields after simple evaporation and filtration over a
pad of silica gel to remove any traces of phosphite, which
were found to inhibit the subsequent allylation step. The reac-
tion proved to be compatible with different phosphites (2a-c)
as well as a wide range of aldehydes, including aromatic
(2a-g) and α,β-unsaturated aldehydes (2p-r), albeit some
phosphonates were obtained in slightly lower yields such as
the heteroaromatic (2h-n) and the aliphatic derivatives (2o).
Going forward, the conditions established for the allylation of
2a efficiently provided a set of structurally diverse α-allyloxy-
phosphonates. The influence of the phosphite was minimal,
though the smaller dimethyl phosphite 5b was obtained in a
slightly higher yield (94%) than the diethyl and diisopropyl
analogues 5a (90%) and 5c (90%). Both electron-rich and
electron-poor aryls substituents were well-tolerated (78-97%
yield, 5a-g). Similarly, heteroaryl-containing substrates also
led to high yields (71-98% yield, 5h-n), although the
formation of the 3-pyridyl derivative 5h required a longer
reaction time (12 h vs 30 min). This lower reactivity was also
observed with the aliphatic precursor 2o, which required a
slightly higher temperature (100 °C) to generate the desired
product 5o (67%). The influence of the allyl moiety was
also evaluated. Interestingly, while the use of the branched
methallyl carbonate did not hamper the reaction (5s, 88%),
we observed slightly lower yields when using the linear
cinnamyl carbonate instead (60-64% for 5t and 5u vs 85-96%
for 5g and 5i). Finally, the more hindered quaternary
α-hydroxyphosphonates 2s and 2t derived from the
corresponding methyl ketone precursors6 led to the α-allylated
products 5v and 5w, albeit in 27% and 21% yield respectively.
To extend the scope of the palladium-catalyzed allylic
alkylation, we next turned our attention towards a related
family of compounds, namely α-hydroxyamides. The latter
were prepared via a Passerini multicomponent reaction by
reacting various cinnamaldehydes with the corresponding
isocyanate in the presence of boric acid.7 The resulting
Passerini adducts were then subjected to the same allylic
alkylation conditions as previously with the exception that
Cs2CO3 was not used as it appeared to be unnecessary. To our
delight, the corresponding O-allylated products 6a-e were all
obtained in high yields ranging from 77 to 84%.
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Having prepared a number of α,α-diallyloxyphosphonates,
we then evaluated the possibility of reorganizing their
structure using a metal-catalyzed approach.15 Treating 5q with
RuClH(CO)(PPh3)3 in toluene under microwave irradiation
(120 °C, 30 min) led to the formation of the Claisen
With these O-allylated products in hand, we next set out to
demonstrate their synthetic utility by running several diversifi-
cations.
The first one that came into our mind involved the
O-allylated cinnamyl derivatives 5p-r and 6a-d. Indeed, these
two families of bis-allyl ethers have in common a relatively
rearrangement product 10a in 41% yield and
a 2:1
diastereomeric ratio (Scheme 4). We then applied our initial
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reaction conditions [RuClH(CO)(PPh3)3 (5 mol %), 120 °C the yield to 62% (Scheme 5). These conditions were
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(MW), toluene, 30 min] to the O-allyl Passerini adducts 6a-c.
The latter were readily converted to the corresponding
α,β-unsaturated amides 10b-d in moderate to good yields
ranging from 69 to 85% albeit in a roughly 1:1 mixture of
diastereoisomers.
When the ruthenium-catalyzed isomerization conditions
were applied to compound 5i, we observed the formation of
the disubstituted heterocycle 11a. After slightly optimizing the
reaction conditions (reaction run in chloroform at 180 °C for
10 min under microwave irradiation), we were able to increase
eventually applied to a series of heterocyclic O-allylated
derivatives (5j-n and 6e), resulting in the formation of the
corresponding disubstituted heterocycles 11b-g in yields
ranging from 29 to 62%. The conditions were also applied to
the quinoline derivative 5x (structure not shown), affording
the disubstituted quinoline 11h in 45% yield.
Finally, we turned our attention to the synthesis of
phosphono-oxaheterocycles by subjecting various Pudovik
adducts bearing a pendent olefin to ring-closing metathesis
(RCM) conditions (Scheme 6).16 To this end, we prepared
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Scheme 1. Sequential DBU-mediated isomerization/Claisen rearrangement.
Step 1
Step 2
Pudovik
Diethyl phosphite (1 equiv.)
O
O
R3
OH
NEt3 (0.5 equiv.), 50 °C
Pd2dba3, PPh3, Cs2CO3
Toluene, 50 °C, 30 min
+
R1
R2
MeOOCO
4a (R3 = H)
R3
R1
R2
R1 R2
X
X
Passerini
R2CN, H3BO3 (1 equiv.)
DMF, 50 °C
1a-p (R2 = H)
1q (R2 = Me)
2a-s [X = PO(OEt)2, PO(i-Pr)2, PO(OMe)2]
3a-e [X = CONHt-Bu,CONHCy]
5a-v
6a-e
4b (R3 = Ph)
Pudovik Adductsa
O
O
O
O
O
PO(OEt)2
PO(OMe)2
PO(OMe)2
PO(OEt)2
PO(Oi-Pr)2
Cl
Cl
Cl
O2N
NO2
Step 1
Step 2
2a (quant.)
5a (90%)
2d (91)b
2b (quant.)
5b (94%)
2c (quant.)
5c (90%)
2e (quant.)
5e (97%)
5d (78%)
(gram scale)
O
O
O
O
O
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
O
S
N
Br
MeO
Step 1
Step 2
2f (quant.)
5f (79%)c
2g (quant.)
5g (85%)
2h (71%)
5h (78%)c
2i (quant.)
5i (95%)
2j (92%)
5j (72%)
O
O
O
O
O
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
Ph
PO(OEt)2
S
O
S
S
Step 1
Step 2
2k (85%)
5k (89%)
2m (69%)
5m (98%)
2n (73%)
5n (98%)
2o (81%)
5o (67%)d,e
2l (81%)
5l (71%)
O
Ph
PO(OEt)2
O
O
O
O
Ph
PO(OEt)2
Me
Me
PO(OEt)2
PO(OEt)2
PO(OEt)2
R
O
MeO
MeO
R = H
R = p-OMe R = o-OMe
Step 1 2p (quant.)
2g (quant.)
5t (64%)
2i (quant.)
2s (77%)g
5v (21%)h,i
2q (quant.)
5q (77%)
2r (quant.)
5r (72%)e
2q (quant.)
5s (88%)f
Step 2
5p (73%)
5u (60%)
Passerini Adductsj
O
O
O
O
O
CONHt-Bu
CONHCy
CONHt-Bu
CONHCy
CONHCy
O
O
MeO
MeO
Step 1
3a (86%)
6a (81%)
3b (82%)
6b (80%)
3c (82%)
6c (77%)
3d (71%)
6d (83%)
3e (81%)
6e (84%)
Step 2
a All the reactions were run on a 1 mmol scale (yields reported are isolated yields). b Reaction run under mechanical stirring. c Reaction ran at 50 °C for 2 h (5f) and 12 h
(5h). d Reaction ran at 100 °C. e Reaction ran for 1.5 h. f Reaction ran for 2 h. g Prepared from acetophenone. h 50% starting ketone recovered. i Reaction ran for 1 h in the
absence of Cs2CO3. j All the reactions were run on a 5 mmol scale.
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Scheme 2. Sequential DBU-mediated isomerization/Claisen rearrangement.
1
2
Sequential DBU-mediated isomerization/Claisen rearrangement
3
4
5
6
O
DBU (0.5 equiv.)
O
O
R
CONHR'
R
CONHR'
Toluene, 120 °C (MW)
R
CONHR'
7a-d
6a-d
7
8
Passerini adduct modificationa
9
O
O
O
O
CONHt-Bu
CONHCy
CONHt-Bu
CONHCy
10
11
12
13
14
15
16
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20
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22
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O
MeO
MeO
7a
65%
7b
7c
7d
79%
88%
76%
All the reactions were run on a 0.5 mmol scale. a Yields reported are isolated yields.
Scheme 3. Sequential DBU-mediated isomerization/Claisen rearrangement.
Sequential DBU-mediated isomerization/Claisen rearrangement/nucleophilic addition
Nu
H
O
O
DBU (0.5 equiv.)
8 (1.5 equiv.)
O
R
R
Nu
PO(OEt)2
R
PO(OEt)2
Toluene, 130-150 °C (MW)
9a-k
5p-r
Pudovik adduct modificationa
O
OMe
O
O
O
O
N
N
N
N
H
N
H
H
H
MeO
MeO
MeO
9a
60%b
9b
66%b
9c
64%b
9d
77%b
9e
38%b
(gram scale)
O
OMe
O
OMe
O
O
O
N
N
OEt
OCH2CF3
SEt
MeO
MeO
MeO
R
9f (R = H, 63%)c
9g (R = CO2Me, 41%)c
9i
9j
9k
9h
61%c
89%c
53%c
67%d
All the reactions were run on a 0.5 mmol scale. a Yields reported are isolated yields. b Reaction ran at 130 °C. c Reaction ran at 140 °C. d Reaction ran at 150 °C.
Scheme 4. Sequential Ru-catalyzed isomerization/Claisen rearrangement.
Sequential RuClH(CO)(PPh3)3-catalyzed isomerization/Claisen rearrangement
Me
CHO
RuClH(CO)(PPh3)3 (5 mol %)
O
O
R
X
R
R
X
Toluene, 120 °C (MW)
X
5q [X = PO(OEt)2]
10a-d
6a-c [X = CONHt-Bu,CONHCy]
Pudovik and Passerini adduct modificationa
O
O
O
O
H
H
H
H
NHt-Bu
NHCy
NHt-Bu
PO(OEt)2
O
O
O
MeO
MeO
MeO
10a
41% (dr = 1:1)
66% (dr = 1:1)b
10b
10d
10c
85% (dr = 1:1)
78% (dr = 1:1)
69% (dr = 1:1)
All the reactions were run on a 0.5 mmol scale. a Yields reported are isolated yields). b Reaction run in DMF at 140 °C
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Scheme 5. Pudovik and Passerini adduct modification: Sequential Ru-catalyzed isomerization/Claisen rearrangement.
1
2
Sequential RuClH(CO)(PPh3)3-catalyzed isomerization/Claisen rearrangement
3
4
5
X
X
X
RuClH(CO)(PPh3)3 (5 mol %)
CHCl3, 180 °C (MW), 10 min
Y
Y
Y
O
O
CHO
6
7
5i-n, 5t [X = PO(OEt)2, Y = O/S]
6e [X = CONHCy, Y = O]
11a-g
8
Pudovik adduct modificationa
9
(EtO)2OP
(EtO)2OP
S
Me
Me
10
11
12
13
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CHO
PO(OEt)2
CHO
PO(OEt)2
CHO
Me
CHO
Me
O
O
S
11a (62% from 5i)
11b (48% from 5j)
11c (29% from 5k)
11d (54% from 5l)
(EtO)2OP
Me
CHO
Me
CHO
PO(OEt)2
CHO
CHO
PO(OEt)2
N
S
S
CONHCy
O
Me
11e (56% from 5m)
11f (29% from 5n)
11g (63% from 6e)
11h (45% from 5x)
All the reactions were run on a 0.1 mmol scale. a Yields reported are isolated yields.
Scheme 6. Pudovik adduct modification: Sequential O-allylation/RCM.
OCOMe
GII (4 mol %)
OH
N
N
Pd2dba3, PPh3, Cs2CO3
Toluene, T (°C), t (h)
O
O
Cl
(
)
n
Ru
PO(OEt)2
( )
n
PO(OEt)2
( )
n
CH2Cl2, 40 °C
PO(OEt)2
Ph
Cl
PPh3
GII
12a-g
13a-g
14a-g
Pudovik and Passerini adduct modification
O
O
O
O
O2N
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
13c
13a
13b
40% (50 °C then 100 °C, 12 h)
13d
58% (80 °C, 12 h)
82% (100 °C, 5 h)
91% (50 °C, 2 h)
O
O
(
)
6
O
(
)
6
O
O
(
)
6
(EtO)2OP
O
PO(OEt)2
(EtO)2OP
O
13e
13f
97% (50 °C, 4 h)
13g
82% (50 °C, 4 h)
74% (50 °C, 4 h)
Pudovik and Passerini adduct modification
O
O
6
O
5
7
7
O2N
O
PO(OEt)2
PO(OEt)2
PO(OEt)2
(EtO)2OP
14c
81%
14a
14b
14d
89%
82%
92%
O
(
)
4
O
O
O
14
15
16
(EtO)2OP
O
(
)
5
O
(EtO)2OP
(EtO)2OP
O
14g
14e
14f
69%a (E/Zb = 77:23)
92%a (E/Zb = 83:17)
99%a (E/Zb = 78:22)
All the reactions were run on a 1 mmol scale (yields reported are isolated yields). aRequired 6 mol % catalyst loading. bDetermined by NMR analysis on the crude reaction
mixture.
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Page 6 of 14
a range of dienes of various length 13a-g and subjected them stirred at room temperature or 50 °C for the indicated time.
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to standard RCM conditions using Grubbs’ second-generation
catalyst, GII (4 mol %) in refluxing CH2Cl2 (100 mM
concentration). Under these conditions, the smaller rings, such
as the dihydrofuran 14a (89%), the dihydropyrane 14b (82%)
and the oxepin 14c (81%) were obtained in high yields.
Benzooxepin 14d was obtained with an even higher yield of
92%. The larger derivatives such as the 14-, 15- and
16-phosphono-oxaheterocycles could also be effectively
accessed, however they required more dilute conditions
(1 mM) to avoid any undesired oligomerization. Of note is the
efficient formation of [12] and [13]metacyclophanes 14f and
14g which were obtained in 69 and 99% yield, respectively.
All three macrocycles were obtained as a mixture of E/Z
isomers in a consistent ratio of 4:1 as assessed by 13C NMR.
This selectivity is in agreement with previous results observed
with the widely available Grubbs' second-generation cata-
lyst.17
The reaction mixture was then diluted with chloroform and
concentrated under reduced pressure to remove NEt3.
Dimethyl [hydroxy(4-nitrophenyl)methyl]phosphonate
(2d). Compound 2d was prepared by mechanically stirring
4-nitrobenzaldehyde (831 mg, 5.5 mmol, 1.1 equiv.),
dimethylphosphite (0.46 mL, 5.0 mmol, 1.0 equiv.) and
triethylamine (0.35 mL, 2.5 mmol, 0.5 equiv.). The title
compound was obtained as an orange solid (1.2 g, 4.6 mmol,
91%) after a very fast reaction completed in five minutes and
immediately purified by flash column chromatography over
silica gel (CH2Cl2/EtOAc, 100:0 to 0:100). Spectral data
matched those reported in the literature.5 1H NMR (400 MHz,
CDCl3) δ 8.23 (d, J = 8.7 Hz, 2H), 7.67 (dd, J = 8.7, 2.2 Hz,
2H), 5.22 (d, J = 12.3 Hz, 1H), 4.79 (brs, 1H), 3.78 (d,
J = 8.9 Hz, 3H), 3.75 (d, J = 9.0 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 147.8 (d, J = 3.7 Hz), 143.9, 127.7 (d,
J = 5.3 Hz, 2C), 123.6 (d, J = 2.6 Hz, 2C), 70.1 (d, J = 158.6
Hz), 54.6 (d, J = 7.1 Hz), 53.9 (d, J = 7.6 Hz). IR (thin film):
3246, 2958, 2854, 1518, 1347, 1236, 1027, 864 cm-1. HRMS
(ESI) m/z: [M]+ calcd for C9H12NO6P 261.0402; Found
261.0396.
Diethyl [(allyloxy)(benzo[b]thiophen-2-yl)methyl]phos-
phonate (2m). Colourless oil, 208 mg, 69X% isolated yield.
Rf = 0.45 (PE/Et2O = 1:5). 1H NMR (400 MHz, CDCl3) δ 7.82
(dd, J = 4.6, 3.9 Hz, 1H), 7.75 (dd, J = 8.4, 6.4 Hz, 1H), 7.42
(d, J = 3.4 Hz, 1H), 7.37-7.29 (m, 2H), 5.31 (ddd, J = 11.7,
5.5, 1.0 Hz, 1H), 4.22-4.10 (m, 4H), 3.29 (dd, J = 9.2, 5.5 Hz,
1H), 1.36-1.25 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 140.1 (dd, J = 15.4, 2.1 Hz), 124.6 (d, J = 9.2 Hz), 123.9,
122.8 (d, J = 8.2 Hz), 122.5, 67.9 (d, J = 164.3 Hz), 63.8 (d,
J = 7.0 Hz), 63.8 (d, J = 10.6 Hz), 16.6. IR (thin film): 3250,
2985, 1439, 1205 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C13H17O4PSNa 323.0483; Found 323.0506.
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! CONCLUSION
In summary, we have developed orthogonal catalytic
conditions for a cascade isomerization/Claisen rearrangement
starting from O-allyl Pudovik and Passerini adducts. The
presence of the amido or phosphono substituents is highly
beneficial as it increases the acidity of the starting materials
thus allowing a more efficient isomerization/Claisen cascade
under basic conditions. The applicability of the method is
further demonstrated by trapping the acylphosphonate
intermediates of Pudovik adducts with various oxygen or
nitrogen nucleophiles, allowing to access diverse compounds.
A switch in the selectivity of the isomerization was achieved
when a ruthenium hydride catalyst was used.
! EXPERIMENTAL SECTION
Diethyl [(allyloxy)(benzo[b]thiophen-3-yl)methyl]phos-
phonate (2n). Colorless oil, 218 mg, 73% isolated yield.
Rf = 0.45 (PE/Et2O = 1:5). 1H NMR (400 MHz, CDCl3)
δ 7.93-7.89 (m, 1H), 7.88-7.84 (m, 1H), 7.74 (dd, J = 3.4,
0.5 Hz, 1H), 7.42-7.33 (m, 2H), 5.42 (ddd, J = 11.0, 5.8,
0.8 Hz, 1H), 4.17-3.86 (m, 4H), 3.70 (dd, J = 8.6, 5.8 Hz, 1H),
1.27 (tt, J = 2.3, 1.2 Hz, 3H), 1.14 (tt, J = 5.3, 2.7 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 140.5, 137.5 (d,
J = 5.9 Hz), 131.8, 125.6 (d, J = 7.4 Hz), 124.7, 124.3, 122.8
(d, J = 16.2 Hz), 66.4 (d, J = 164.2 Hz), 63.5 (d, J = 7.1 Hz),
63.4 (d, J = 7.2 Hz), 16.5 (dd, J = 12.3, 5.6 Hz). IR (thin film):
3200, 2980, 1430, 1203 cm-1. HRMS (ESI) m/z: [M + Na]+
calcd for C13H17O4PSNa 323.0483; Found 323.0506.
Diethyl (1-hydroxy-1-phenyl)ethylphosphonate (2s).
n-BuLi (as a 2.5 M solution in hexanes, 2.1 µL, 5.3 µmol) and
diethyl phosphite (822 µL, 6.38 mmol, 1.2 equiv.) were mixed
under dry nitrogen. The mixture was stirred for 5 min before
acetophenone (0.62 mL, 5.0 mmol, 1.0 equiv.) was added at
0 °C. The resulting mixture was allowed to stir at the same
temperature for 5 min and the reaction was quenched by
addition of EtOAc (3 mL) and H2O (2 mL). The layers were
separated and the aqueous phase was extracted with EtOAc
(2 x 5 mL). The combined organic phases were dried over
anhydrous MgSO4 and concentrated under reduced pressure.
The crude residue was co-evaporated with toluene several
times to remove traces of phosphite and purified by flash
column chromatography over silica gel with a gradient of
EtOAc in petroleum ether (50/50 to 70/30). The title
compound 2s was obtained as white crystals (1,3 g, 5.2 mmol,
98%). Rf = 0.31 (CH2Cl2/EtOAc = 7:3). mp = 77-78 °C.
1H NMR (400 MHz, CDCl3) δ 7.63-7.58 (m, 2H), 7.35 (t,
General methods. All reactions were carried out in sealed
tubes. Column chromatography was carried out on silica gel.
1H NMR spectra were obtained with tetramethylsilane
(δ = 0 ppm) as an internal standard in CDCl3 using a Bruker
AVANCE 400 spectrometer (400 MHz). Data are reported as
follows: chemical shift in ppm, apparent multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, p = pentet,
m = multiplet or overlap of non-equivalent resonances),
coupling constants, integration. 13C NMR spectra were record-
ed at 100 MHz and residual solvent peaks were used as an
internal reference (CHCl3 δ 77.16). Data are reported as
follows: chemical shift in ppm, multiplicity deduced from
DEPT experiments (CH3, CH2, CH, Cq), apparent multiplicity,
coupling constants and integration where relevant. IR spectra
were recorded on a Perkin Elmer Spectrum 65 FT-IR Spec-
trometer. Melting points were measured on a Stuart SMP3
melting point apparatus and are uncorrected. Low-resolution
mass spectra were recorded on an Agilent 1100 series LC-MS
(with a 6310 ion trap) under electrospray ionization (ESI). For
compounds containing bromine, the mass of 79Br was used.
All commercially available compounds were used without
further purification. Compounds 2a-l, 2o-r, 2t, 5a-i, 5o, 5q,
5t-u, 5w, 12a-g, 13a-g and 14a-g have already been reported
and therefore won’t be described here; the spectral data
matched those reported in the literature. Compounds 2r and
2u were prepared and engaged in the allylation step without
further purification.
General procedure for the synthesis of the α-hydroxy-
phosphonates. A mixture of aldehyde (1.01 equiv.), diethyl
phosphite (1.00 equiv.) and triethylamine (0.50 equiv.) was
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J = 7.3 Hz, 2H), 7.28 (dd, J = 7.3, 1.7 Hz, 1H), 4.15-3.80 (m, N-Cyclohexyl-4-(furan-2yl)-2-hydroxyacetamide
(3e).
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5
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7
8
4H), 3.66 (brs, 1H, OH), 1.82 (d, J = 15.5 Hz, 3H), 1.25 (t,
J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 141.1, 128.1 (d, J = 2.5 Hz), 127.5 (d,
J = 2.9 Hz), 126.0 (d, J = 4.3 Hz), 73.6 (d, J = 158.6 Hz), 63.4
(d, J = 4.3 Hz), 63.4 (d, J = 4.4 Hz), 26.1 (d, J = 3.9 Hz), 16.5
(d, J = 5.7 Hz), 16.4 (d, J = 6.0 Hz). IR (thin film): 3580,
3382, 2997, 2932, 1496, 1247, 970 cm-1. HRMS (ESI) m/z:
[M]+ calcd for C12H19O4P 258.1021; Found 258.1016.
General procedure for the synthesis of α-hydroxyamides
(3a-e). A mixture of aldehyde (5 mmol), isocyanide (5 mmol)
and boric acid (5 mmol) in DMF (1 mL) was stirred at 50 °C
using a heating mantle for 24 h. The crude solution was then
diluted with 100 mL of Et2O and washed two times with 10
mL of water. After evaporation of the solvent under reduced
pressure, the crude residue was purified by flash chromatog-
raphy over silica gel.
(E)-N-(tert-Butyl)-2-hydroxy-4-(4-methoxyphenyl)but-3-
enamide (3a). Yellow solid, 1.13 g, 86% isolated yield.
Rf = 0.38 (PE/Et2O = 3:7). mp = 135-137 °C. 1H NMR
(400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz, 2H), 6.84 (d,
J = 8.6 Hz, 2H), 6.65 (d, J = 15.8 Hz, 1H), 6.10 (dd, J = 15.8,
7.1 Hz, 1H), 6.07 (brs, 1H), 4.54 (ddd, J = 7.1, 3.7, 1.0 Hz,
1H), 3.80 (s, 3H), 3.67 (brs, 1H), 1.36 (s, 9H). 13C{1H} NMR
(101 MHz, CDCl3) δ 171.4, 159.7, 133.1, 128.9, 128.1, 125.0,
114.1, 73.2, 55.4, 51.6, 28.8. IR (thin film): 3364, 2964, 2932,
2836, 1644, 1605, 1510, 1454, 1364, 1245, 1173, 1029, 978,
828, 788 cm-1. HRMS (ESI) m/z: [M]+ calcd for C15H21NO3
263.1521; Found 263.1521.
Brown solid, 910 mg, 81% isolated yield. Rf = 0.3
(PE/Et2O = 2:8). mp = 85-87 °C. H NMR (400 MHz, CDCl3)
1
δ 7.36 (dd, J = 1.8, 0.8 Hz, 1H), 6.42 (br, 1H), 6.33-6.31 (m,
2H), 5.02 (d, J = 2.7 Hz, 1H), 4.30 (brs, 1H), 3.99-3.34 (m,
1H), 1.95-1.79 (m, 2H), 1.74-1.51 (m, 3H), 1.40-1.26 (m, 2H),
1.23-1.05 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.1,
152.2, 142.9, 110.6, 108.4, 67.7, 48.6, 32.9, 32.8, 25.5, 24.9,
24.8. IR (thin film): 3288, 2929, 1853, 1647, 1529, 1450,
1252, 1223, 1150, 1059, 1012, 809, 739 cm-1. HRMS (ESI)
m/z: [M]+ calcd for C12H17NO3 223.1208; Found 223.1208.
General procedure for the Pd-catalyzed O-allylation of
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α-hydroxyphosphonates.
To
a
solution
of
α-
hydroxyphosphonate (1.0 mmol) in toluene (0.5 M solution)
was added Pd2(dba)3 (0.025 mmol), allyl methyl carbonate
(1.0 mmol), triphenylphosphine (0.1 mmol) and Cs2CO3
(0.25 mmol). The resulting mixture was stirred at the
indicated temperature using a heating mantle for the indicated
amount of time. The reaction mixture was then filtered over a
pad of Celite and concentrated under reduced pressure.
Diethyl[(allyloxy)(thiophen-2-yl)methyl]phosphonate
(5j). Yellow oil, 210 mg, 72% isolated yield. Rf = 0.55
1
(PE/EtOAc = 1:3). H NMR (400 MHz, CDCl3) δ 7.33 (dt,
J = 5.1, 1.4 Hz, 1H), 7.18-7.10 (m, 1H), 7.01 (ddd, J = 5.0,
3.5, 0.6 Hz, 1H), 5.87 (dddd, J = 17.1, 10.4, 6.6, 5.1 Hz, 1H),
5.25 (dddd, J = 10.4, 3.9, 3.0, 1.4 Hz, 2H), 4.95 (d,
J = 15.7 Hz, 1H), 4.22-3.93 (m, 6H), 1.32-1.22 (m, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 137.6 (d, J = 2.0 Hz),
133.7, 127.8 (d, J = 8.1 Hz), 126.9 (d, J = 2.5 Hz), 126.7 (d,
(E)-N-Cyclohexyl-2-hydroxy-4-(4-methoxyphenyl)but-3-
enamide (3b). Yellow solid, 1.18 g, 82% isolated yield.
Rf = 0.23 (PE/Et2O
J = 3.4 Hz), 118.7, 72.9 (d,
J = 176.9 Hz), 71.2 (d,
J = 12.9 Hz), 63.5 (d, J = 7.0 Hz), 63.4 (d, J = 6.8 Hz), 16.6
(d, J = 5.7 Hz), 16.5 (d, J = 5.8 Hz). IR (thin film): 2989,
1717, 1262, 1028 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C12H19O4PSNa 313.0639; Found 313.0685.
= 3:7). mp =
95-97 °C. 1H NMR
(400 MHz, CDCl3) δ 7.33 (d, J = 8.8 Hz, 2H), 6.86 (d,
J = 8.8 Hz, 2H), 6.70 (d, J = 15.9 Hz, 1H), 6.50 (brs, 1H), 6.18
(dd, J = 15.9, 6.5 Hz, 1H), 4.69 (d, J = 6.5 Hz, 1H), 4.30 (br,
1H), 3.83 (s, 3H), 3.81-3.70 (m, 1H), 1.98-1.86 (m, 2H), 1.78-
1.57 (m, 3H), 1.45-1.29 (m, 2H), 1.26-1.08 (m, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.5, 159.5, 132.3,
128.9, 128.0, 124.9, 114.0, 72.9, 55.3, 48.4, 33.0, 25.5, 24.8.
IR (thin film): 3393, 3052, 2934, 2856, 1645, 1607, 1511,
1264, 1249, 1174, 1033, 825, 732 cm-1. HRMS (ESI) m/z:
[M]+ calcd for C17H23NO3 289.1678; Found 289.1685.
(E)-N-(tert-Butyl)-2-hydroxy-4-phenylbut-3-enamide
(3c). Yellow solid, 961 mg, 82% isolated yield. Rf = 0.30
(PE/Et2O = 4:6). mp = 95-97 °C. 1H NMR (400 MHz, CDCl3)
δ 7.35-7.29 (m, 2H), 7.28-7.16 (m, 3H), 6.65 (dd, J = 15.9,
0.8 Hz, 1H), 6.19 (dd, J = 15.9, 6.9 Hz, 1H), 6.01 (brs, 1H),
4.51 (dd, J = 6.9, 2.6 Hz, 1H), 3.61 (brs, 1H), 1.29 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 136.1, 133.4,
128.7, 128.3, 127.3, 126.9, 73.1, 51.6, 28.9. IR (thin film):
3384, 3055, 2970, 1658, 1649, 1525, 1454, 1366, 1264, 1223,
966, 909, 732 cm-1. HRMS (ESI) m/z: [M]+ calcd for
C14H19NO2 233.1416; Found 233.1409.
(E)-N-Cyclohexyl-4-(furan-2yl)-2-hydroxybut-3-enamide
(3d). Red oil 887 mg, 71% isolated yield. Rf = 0.33
(PE/Et2O = 2:8). 1H NMR (400 MHz, CDCl3) δ 7.32 (d,
J = 1.8 Hz, 1H), 6.55 (dd, J = 15.8, 1.4 Hz, 1H), 6.44 (br, 1H),
6.34 (dd, J = 3.3, 1.8 Hz, 1H), 6.29-6.13 (m, 2H), 4.64 (brs,
1H), 4.13 (br, 1H), 3.87-3.46 (m, 1H), 1.95-1.81 (m, 2H),
1.75-1.05 (m, 3H), 1.40-1.24 (m, 2H), 1.22-1.02 (m, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 152.0, 142.4,
125.7, 120.7, 111.5, 109.0, 72.4, 48.5, 33.0, 25.5, 24.9.
IR (thin film): 3302, 2964, 2932, 2855, 1642, 1526, 1450,
1264, 1013, 959, 731, 702 cm-1. HRMS (ESI) m/z: [M]+ calcd
for C14H19NO3 249.1365; Found 249.1622.
Diethyl[(allyloxy)(furan-3-yl)methyl]phosphonate (5k).
Yellow oil, 242 mg, 89% isolated yield. Rf
= 0.36
1
(PE/EtOAc = 1:3). H NMR (400 MHz, CDCl3) δ 7.51-7.47
(m, 1H), 7.41 (t, J = 1.7 Hz, 1H), 6.56-6.51 (m, 1H), 5.86
(dddd, J = 16.8, 10.4, 6.4, 5.2 Hz, 1H), 5.24 (ddq, J = 18.8,
10.4, 1.4 Hz, 2H), 4.67 (d, J = 14.8 Hz, 1H), 4.19-4.03 (m,
5H), 4.00-3.93 (m, 1H), 1.36-1.18 (m, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 143.5, 141.8 (d, J = 11.2 Hz), 134.0,
119.7 (d, J = 1.4 Hz), 118.4, 110.4 (d, J = 3.6 Hz), 71.0 (d,
J = 12.3 Hz), 69.6 (d, J = 175.5 Hz), 63.3 (d, J = 6.9 Hz), 63.1
(d, J = 6.7 Hz), 17.8-15.1 (m). IR (thin film): 2980, 1727,
1242, 1048 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C12H19O5PNa 297.0867; Found 297.0855.
Diethyl[(allyloxy)(thiophen-3-yl)methyl]phosphonate
(5l). Yellow oil, 210 mg, 71% isolated yield. Rf = 0.55
1
(PE/EtOAc = 1:3). H NMR (400 MHz, CDCl3) δ 7.33 (dddd,
J = 12.0, 8.0, 3.1, 1.8 Hz, 2H), 7.19 (dt, J = 4.9, 1.1 Hz, 1H),
5.87 (dddd, J = 16.9, 10.4, 6.4, 5.1 Hz, 1H), 5.23 (ddq,
J = 17.7, 10.4, 1.4 Hz, 2H), 4.82 (d, J = 15.1 Hz, 1H), 4.18-
3.91 (m, 6H), 1.29-1.20 (m, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 135.9 (d, J = 1.4 Hz), 134.0, 127.5 (d, J = 3.7 Hz),
126.1 (d, J = 1.3 Hz), 124.3 (d, J = 9.4 Hz), 118.3, 73.4 (d,
J = 172.5 Hz), 71.3 (d, J = 12.9 Hz), 63.3 (d, J = 6.9 Hz), 63.1
(d, J = 6.8 Hz), 16.6 (d, J = 5.7 Hz), 16.5 (d, J = 5.8 Hz).
IR (thin film): 2985, 1372, 1257, 1048 cm-1. HRMS (ESI) m/z:
[M + Na]+ calcd for C12H19O4PSNa 313.0639; Found
313.0685.
Diethyl[(allyloxy)(benzo[b]thiophen-2-yl)methyl]-
phosphonate (5m). Yellow oil, 334 mg, 98% isolated yield.
Rf = 0.47 (PE/EtOAc = 1:5). 1H NMR (400 MHz, CDCl3)
δ 7.85-7.80 (m, 1H), 7.77-7.72 (m, 1H), 7.39-7.30 (m, 3H),
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5.91 (dddd, J = 17.1, 10.4, 6.6, 5.1 Hz, 1H), 5.34-5.22 (m, 128.1 (d, J = 1.8 Hz, 2C), 120.2 (d, J = 4.4 Hz), 114.2 (2C),
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5
6
7
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2H), 5.04 (dd, J = 16.2, 0.7 Hz, 1H), 4.29-4.00 (m, 6H), 1.33-
1.25 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.4,
139.5 (d, J = 2.4 Hz), 139.0 (d, J = 2.6 Hz), 133.6, 124.5 (d,
J = 18.5 Hz), 124.3 (d, J = 8.9 Hz), 123.8, 122.5, 119.0, 73.6
(d, J = 175.1 Hz), 71.6 (d, J = 12.9 Hz), 63.7 (d, J = 7.0 Hz),
63.5 (d, J = 6.8 Hz), 16.7-16.4 (m). IR (thin film): 2985, 1728,
1261, 1048 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C16H21O4PSNa 363.0795; Found 363.0802.
113.6, 75.9 (d, J = 170.8 Hz), 73.8 (d, J = 12.1 Hz), 63.2 (d,
J = 7.0 Hz), 62.9 (d, J = 6.9 Hz), 55.5, 19.7, 16.7 (t,
J = 5.5 Hz, 2C). IR (thin film): 3469, 2979, 2838, 1644, 1292,
1077, 963 cm-1. HRMS (ESI) m/z: [M]+ calcd for C18H27O5P
354.1596; Found 354.1601.
Diethyl [1-(allyloxy)-1-phenylethyl]phosphonate (5v).
Colorless oil, 15 mg, 27% isolated yield. Rf = 0.63
1
(CH2Cl2/EtOAc = 7:3). H NMR (400 MHz, CDCl3) δ 7.55-
Diethyl[(allyloxy)(benzo[b]thiophen-3-yl)methyl]
7.48 (m, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (dd, J = 7.4,
1.7 Hz, 1H), 5.94 (ddt, J = 17.0, 10.4, 5.2 Hz, 1H), 5.31 (dq,
J = 17.0, 1.7 Hz, 1H), 5.14 (ddd, J = 10.4, 3.0, 1.4 Hz, 1H),
4.16-3.92 (m, 5H), 3.80 (dd, J = 12.5, 4.8 Hz, 1H), 1.88 (d,
J = 15.9 Hz, 3H), 1.23 (t, J = 6.1 Hz, 3H), 1.20 (t, J = 6.1 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 138.7, 135.0, 128.2
(d, J = 2.4 Hz), 127.9 (d, J = 3.2 Hz), 127.8 (d, J = 4.5 Hz),
116.2, 79.5 (d, J = 169.9 Hz), 64.1 (d, J = 12.7 Hz), 63.4 (d,
J = 7.1 Hz), 63.3 (d, J = 6.9 Hz), 19.8, 16.5 (d, J = 5.1 Hz),
16.5 (d, J = 5.2 Hz). IR (thin film): 3403, 3065, 2993, 1446,
1249, 1057, 1029, 839 cm-1. HRMS (ESI) m/z: [M]+ calcd for
C15H23O4P 298.1334; Found 298.1336.
9
phosphonate (5n). Yellow oil, 334 mg, 98% isolated yield.
Rf = 0.45 (PE/EtOAc = 1:5). 1H NMR (400 MHz, CDCl3)
δ 8.01-7.97 (m, 1H), 7.88-7.83 (m, 1H), 7.61 (d, J = 3.6 Hz,
1H), 7.37 (pd, J = 7.1, 1.4 Hz, 2H), 5.88 (dddd, J = 17.0, 10.4,
6.4, 5.1 Hz, 1H), 5.31-5.12 (m, 3H), 4.21-3.85 (m, 6H), 1.28-
1.21 (m, 3H), 1.18-1.10 (m, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 140.6, 137.9 (d, J = 4.3 Hz), 133.9, 130.1, 126.6 (d,
J = 8.5 Hz), 124.7, 124.3, 123.2, 122.8, 118.5, 72.7 (d,
J = 174.6 Hz), 71.3 (d, J = 13.5 Hz), 63.3 (d, J = 6.8 Hz), 63.1
(d, J = 6.8 Hz), 16.6 (d, J = 13.9, 5.8 Hz), 16.5 (d, J = 5.8 Hz).
IR (thin film): 2985, 2868, 1430, 1257 cm-1. HRMS (ESI) m/z:
[M + Na]+ Calcd for C16H21O4PSNa 363.0795; Found
363.0802.
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12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
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Diethyl
[(allyloxy)(quinolin-3-yl)methyl]phosphonate
(5x). Yellow oil, 212 mg, 63% isolated yield. Rf = 0.2
1
(E)-Diethyl (1-(allyloxy)-3-phenylallyl)phosphonate (5p).
(EtOAc = 100%). H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H),
Yellow oil, 225 mg, 73% isolated yield. Rf
=
0.35
8.24 (t, J = 2.4 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.81 (d,
J = 8.1 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.0 Hz,
1H), 5.98-5.72 (m, 1H), 5.27-5.19 (m, 2H), 4.89 (d,
J = 16.1 Hz, 1H), 4.31-3.70 (m, 6H), 1.23 (t, J = 7.1 Hz, 3H),
1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 150.2 (d, J = 5.0 Hz), 148.1 (d, J = 2.1 Hz), 135.4 (d,
J = 6.5 Hz), 133.4, 129.9, 129.3, 128.2 (d, J = 1.6 Hz), 128.1,
127.7 (d, J = 2.5 Hz), 127.0, 118.9, 75.16 (d, J = 170.5 Hz),
71.7 (d, J = 13.0 Hz), 63.4 (d, J = 7.1 Hz), 63.2 (d,
J = 7.0 Hz), 16.5 (d, J = 5.3 Hz), 16.4 (d, J = 5.3 Hz). IR (thin
film): 3052, 2982, 2932, 1496, 1253, 1046, 1020, 963, 788,
731, 700 cm-1. HRMS (ESI) m/z: [M]+ calcd for C17H22NO4P
335.1286; Found 335.1281.
General procedure for the Pd-catalyzed O-allylation of
α-hydroxyamides. To a solution of α-hydroxyamide
(2.0 mmol) in toluene (0.5 M solution) were added Pd2(dba)3
(0.05 mmol), allyl methyl carbonate (2.0 mmol) and
triphenylphosphine (0.2 mmol) and the resulting mixture was
stirred at 50 °C using a heating mantle for 30 min. The reac-
tion mixture was then filtered over a pad of Celite and concen-
trated under reduced pressure. After evaporation of the solvent
under reduced pressure, the crude residue was purified by
flash column chromatography over silica gel.
(E)-2-(Allyloxy)-N-(tert-butyl)-4-(4-methoxyphenyl)but-
3-enamide (6a). Yellow oil, 492 mg, 81% isolated yield.
Rf = 0.33 (PE/Et2O = 6:4). 1H NMR (400 MHz, CDCl3) δ 7.33
(d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.64 (dd,
J = 15.9, 0.7 Hz, 1H), 6.50 (brs, 1H), 6.02 (dd, J = 15.9,
6.6 Hz, 1H), 5.99-5.87 (m, 1H), 5.42-5.06 (m, 2H), 4.29 (dd,
J = 6.6, 1.3 Hz, 1H), 4.23-3.94 (m, 2H), 3.80 (s, 3H), 1.37 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.9, 159.6, 134.0,
133.1, 129.1, 128.1, 122.9, 117.8, 114.0, 80.9, 70.4, 55.4,
51.0, 28.9. IR (thin film): 3406, 2966, 2934, 2868, 1675, 1606,
1510, 1454, 1364, 1249, 1174, 1032, 967, 734 cm-1. HRMS
(ESI) m/z: [M]+ calcd for C18H25NO3 303.1834; Found
303.1843.
(CH2Cl2/EtOAc = 9:1). 1H NMR (400 MHz, CDCl3) δ 7.41 (d,
J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.29-7.22 (m, 1H),
6.71 (dd, J = 16.0, 4.1 Hz, 1H), 6.23(ddd, J = 16.0, 7.3, 5.1
Hz, 1H) 5.95-5.85 (m, 1H), 5.27 (dddd, J = 10.4, 3.9, 2.9,
1.4 Hz, 2H), 4.36 (ddd, J = 16.2, 7.4,1.2 Hz, 1H), 4.26-4.14
(m, 5H), 4.07 (ddt, J = 12.9, 6.3, 1.1 Hz, 1H), 1.32 (t,
J = 7.1 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 136.2 (d,
J = 2.7 Hz), 134.6 (d, J = 13.3 Hz), 134.0, 128.7, 128.2,
126.8(d, J = 1.6 Hz), 122.6 (d, J = 4.3 Hz), 118.3, 76.0 (d,
J = 169.2 Hz), 71.25 (d, J = 12.0 Hz), 63.3 (d, J = 7.0 Hz), 63.0
(d, J = 6.9 Hz), 16.7 (d, J = 3.9 Hz), 16.6 (d, J = 3.9 Hz).
IR (thin film): 3027, 2980, 2907, 1645, 1241, 1097, 1017,
963 cm-1. HRMS (ESI) m/z: [M]+ calcd for C16H23O4P
310.1334; Found 310.1345.
(E)-Diethyl[1-(allyloxy)-3-(2-methoxyphenyl)allyl]
phosphonate (5r). Yellow oil, 246 mg, 72% isolated yield.
1
Rf = 0.4 (CH2Cl2/EtOAc = 8:2). H NMR (400 MHz, CDCl3)
δ 7.45 (d, J = 7.6 Hz, 1H), 7.24 (m, 1H), 7.02 (dd, J = 16.1,
4.4 Hz, 1H), 6.92 (t, J = 7.6 Hz), 6.86 (d, J = 8.3 Hz, 1H), 6.23
(m, 1H), 5.91 (m, 1H), 5.33-5.20 (m, 2H), 4.36 (dd, J = 15.6,
7.8 Hz, 2H), 4.25-4.03 (m, 6H), 3.83 (s, 3H), 1.32 (t,
J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 157.0 (d, J = 1.2 Hz), 134.1, 130.1 (d,
J = 13.8 Hz), 129.3, 127.3 (d, J = 1.1 Hz), 125.2 (d,
J = 2.2 Hz), 123.0 (d, J = 4.2 Hz), 120.7, 118.2, 111.0, 76.6 (d,
J = 170.1 Hz), 71.0 (d, J = 12.7 Hz), 63.2 (d, J = 6.9 Hz), 63.0
(d, J = 6.9 Hz), 55.5, 16.6 (d, J = 4.9 Hz), 16.5 (d, J = 5.0 Hz).
IR (thin film): 3469, 2979, 2838, 1644, 1292, 1077, 963 cm-1.
HRMS (ESI) m/z: [M]+ calcd for C17H25O5P 340.1440; Found
340.1445.
Diethyl (E)-{3-(4-methoxyphenyl)-1-[(2-methylallyl)oxy]
allyl}phosphonate (5s). Yellow oil (208 mg, 88% isolated
1
yield. Rf = 0.4 (CH2Cl2/EtOAc = 4:1). H NMR (400 MHz,
CDCl3) δ 7.39-7.31 (m, 2H), 6.90-6.83 (m, 2H), 6.64 (ddd,
J = 15.9, 4.5, 1.2 Hz, 1H), 6.07 (ddd, J = 15.9, 7.7, 5.3 Hz,
1H), 4.99 (s, 1H), 4.94 (s, 1H), 4.30 (ddd, J = 15.5, 7.7,
1.2 Hz, 1H), 4.24-4.12 (m, 4H), 4.11 (d, J = 12.7 Hz, 1H),
3.97 (d, J = 12.7 Hz, 1H), 3.81 (s, 3H), 1.76 (s, 3H), 1.31 (td,
J = 7.1, 3.5 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 159.8, 141.5, 134.5 (d, J = 13.5 Hz), 129.1 (d, J = 2.6 Hz),
(E)-2-(Allyloxy)-N-cyclohexyl-4-(4-methoxyphenyl)but-
3-enamide (6b). Yellow solid, 525 mg, 80% isolated yield.
Rf = 0.33 (PE/Et2O = 4:6). mp = 83-85 °C. 1H NMR
(400 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 6.81 (d,
J = 8.7 Hz, 2H), 6.63 (d, J = 15.6 Hz, 1H), 6.55 (br, 1H), 6.02
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The Journal of Organic Chemistry
(dd, J = 15.6, 6.6 Hz, 1H), 5.97-5.83 (m, 1H), 5.34-5.17 (m,
1641, 1612, 1453, 1365, 1245, 1225, 1177, 1082, 1035, 991,
916 cm-1. HRMS (ESI) m/z: [M]+ calcd for C18H25NO3
303.1834; Found 303.1840.
1
2
3
4
5
6
7
8
2H), 4.37 (dd, J = 6.6, 1.3 Hz, 1H), 4.20-3.91 (m, 2H), 3.85-
3.63 (m, 1H), 3.76 (s, 3H), 1.97-1.79 (m, 2H), 1.77-1.51 (m,
3H), 1.46-1.27 (m, 2H), 1.23-1.07 (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 169.7, 159.4, 133.8, 132.9, 128.9, 127.9,
122.7, 117.8, 113.9, 80.3, 70.3, 55.2, 47.7, 33.1, 33.0, 25.5,
24.8. IR (thin film): 3409, 3312, 2930, 2854, 1667, 1606,
1509, 1450, 1249, 1032, 823, 733 cm-1. HRMS (ESI) m/z:
[M]+ calcd for C20H27NO3 329.1991; Found 329.1997.
N-Cyclohexyl-3-(4-methoxybenzyl)-2-oxohex-5-enamide
(7b). Yellow oil, 131 mg, 79% isolated yield. Rf = 0.33
(PE/Et2O = 8:2). 1H NMR (400 MHz, CDCl3) δ 7.07 (d,
J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 6.72 (br, 1H), 5.82-
5.56 (m, 1H), 5.08-4.83 (m, 2H), 4.06-3.89 (m, 1H), 3.76 (s,
3H), 3.73-3.61 (m, 1H), 2.92 (dd, J = 13.9, 7.3 Hz, 1H), 2.68
(dd, J = 13.9, 7.1 Hz, 1H), 2.44-2.364(m, 1H), 2.31-2.20 (m,
1H), 1.93-1.78 (m, 2H), 1.74-1.56 (m, 3H), 1.42-1.07 (m, 5H).
13C{1H} NMR (101 MHz, CDCl3) δ 201.7, 159.0, 158.2,
135.1, 130.9, 130.2, 117.3, 114.0, 55.3, 48.5, 45.9, 35.7, 34.9,
32.7, 25.5, 24.8 IR (thin film): 3370, 2930, 2854, 1714, 1668,
1611, 1510, 1449, 1244, 1177, 1106, 1034, 915 cm-1. HRMS
(ESI) m/z: [M]+ calcd for C20H27NO3 329.1991; Found
329.1990.
3-Benzyl-N-(tert-butyl)-2-oxohex-5-enamide (7c). Yellow
oil, 121 mg, 88% isolated yield. Rf = 0.4 (PE/Et2O = 9:1).
1H NMR (400 MHz, CDCl3) δ 7.29-6.93 (m, 5H), 6.63 (brs,
1H), 5.74-5.43 (m, 1H), 5.06-4.73 (m, 2H), 4.14-3.75 (m, 1H),
2.88 (dd, J = 13.8, 7.4 Hz, 1H), 2.65 (dd, J = 13.8, 7.1 Hz,
1H), 2.44-1.95 (m, 2H), 1.26 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 202.2, 159.1, 139.0, 135.0, 129.2, 128.5,
126.4, 117.3, 51.3, 45.1, 36.6, 35.0, 28.3. IR (thin film): 3394,
3064, 2970, 2930, 1714, 1682, 1641, 1515, 1454, 1365, 1225,
1072, 915, 741 cm-1. HRMS (ESI) m/z: [M]+ calcd for
C17H23NO2 273.1729; Found 273.1733.
N-Cyclohexyl-3-(furan-2-ylmethyl)-2-oxohex-5-enamide
(7d). Yellow solid, 110 mg, 76% isolated yield. Rf = 0.31
(PE/Et2O = 9:1). mp = 63-65 °C. 1H NMR (400 MHz, CDCl3)
δ 7.25 (dd, J = 1.9, 0.8 Hz, 1H), 6.75 (br, 1H), 6.23 (dd,
J = 3.2, 1.9 Hz, 1H), 5.98 (dd, J = 3.2, 0.7 Hz, 1H) 5.84-5.52
(m, 1H), 5.17-4.79 (m, 2H), 4.07-3.94 (m, 1H), 3.79-3.64 (m,
1H), 2.99 (dd, J = 15.2, 7.8 Hz, 1H), 2.89 (dd, J = 15.2, 6.1
Hz, 1H), 2.47-2.36 (m, 1H), 2.34-2.24 (m, 1H), 1.96-1.82 (m,
2H), 1.77-1.66 (m, 3H), 1.67-1.54 (m, 2H), 1.44-1.30 (m, 2H),
1.26-1.09 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 201.1,
158.9, 152.9, 141.5, 134.6, 117.8, 110.3, 106.7, 48.5, 43.4,
35.1, 32.8, 28.6, 25.5, 24.8. IR (thin film): 3371, 3318, 2930,
1717, 1667, 1517, 1450, 1372, 1147, 1108, 1011, 917,
728 cm-1. HRMS (ESI) m/z: [M]+ calcd for C17H23NO3
289.1678; Found 289.1668.
(E)-2-(Allyloxy)-N-(tert-butyl)-4-phenylbut-3-enamide
(6c). Yellow oil, 437 mg, 77% isolated yield. Rf = 0.35
9
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(PE/Et2O = 7:3). H NMR (400 MHz, CDCl3) δ 7.43-7.26 (m,
5H), 6.72 (dd, J = 16.0, 1.1 Hz, 1H), 6.52 (brs, 1H), 6.21 (dd,
J = 16.0, 6.4 Hz, 1H), 6.08-5.79 (m, 1H), 5.45-5.14 (m, 2H),
4.34 (dd, J = 6.4, 1.4 Hz, 1H), 4.25-3.93 (m, 2H), 1.39 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 169.7, 136.3, 133.9,
133.3, 128.6, 128.0, 126.8, 125.3, 117.9, 80.8, 70.6, 51.1,
28.9. IR (thin film): 3407, 3026, 2967, 2868, 1677, 1514,
1451, 1364, 1225, 1071, 1044, 966, 734 cm-1. HRMS (ESI)
m/z: [M]+ calcd for C17H23NO2 273.1729; Found 273.1716.
(E)-2-(Allyloxy)-N-cyclohexyl-4-(furan-2-yl)but-3-
enamide (6d). Yellow oil, 240 mg, 83% isolated yield.
Rf = 0.33 (PE/Et2O = 1:1). 1H NMR (400 MHz, CDCl3) δ 7.34
(d, J = 1.6 Hz, 1H), 6.53 (dd, J = 15.9, 1.3 Hz, 1H), 6.50 (brs,
1H), 6.36 (dd, J = 3.3, 1.6 Hz, 1H), 6.27 (d, J = 3.3 Hz, 1H),
6.13 (dd, J = 15.9, 6.3 Hz, 1H), 5.98-5.83 (m, 1H), 5.37-5.17
(m, 2H), 4.38 (dd, J = 6.3, 1.3 Hz, 1H), 4.20-3.96 (m, 2H),
3.84-3.69 (m, 1H), 1.97-1.79 (m, 2H), 1.75-1.53 (m, 3H),
1.46-1.27 (m, 2H), 1.26-1.05 (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 169.4, 152.1, 142.4, 133.8, 123.9, 121.3,
118.1, 111.5, 108.9, 80.0, 70.6, 47.8, 33.3, 33.1, 25.6, 24.9.
IR (thin film): 3405, 3312, 2930, 2854, 1656, 1517, 1450,
1264, 1151, 1013, 927, 731, 701 cm-1. HRMS (ESI) m/z: [M]+
calcd for C17H23NO3 289.1678; Found 289.1685.
2-(Allyloxy)-N-cyclohexyl-2-(furan-2-yl)acetamide (6e).
Yellow oil, 442 mg, 84% isolated yield. Rf
= 0.40
(PE/Et2O = 3:7). 1H NMR (400 MHz, CDCl3) δ 7.39 (dd,
J = 1.9, 0.8 Hz, 1H), 6.74 (br, 1H), 6.39 (d, J = 3.2 Hz, 1H),
6.34 (dd, J = 3.2, 1.9 Hz, 1H), 6.00-5.71 (m, 1H), 5.38-5.10
(m, 2H), 4.83 (s, 1H), 4.14-3.91 (m, 2H), 3.90-3.68 (m, 1H),
2.02-1.84 (m, 2H), 1.82-1.52 (m, 3H), 1.49-1.30 (m, 2H),
1.29-1.09 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.3,
150.1, 143.3, 133.5, 118.5, 110.5, 110.5, 74.7, 70.3, 48.0,
33.1, 25.6, 24.9. IR (thin film): 3318, 2932, 2855, 1730, 1658,
1533, 1451, 1349, 1260, 1151, 1094, 892, 749 cm-1. HRMS
(ESI) m/z: [M]+ calcd for C15H21NO3 263.1521; Found
263.1514.
General procedure for the sequential DBU-mediated isom-
erization/Claisen rearrangement/amine addition on the O-
allylated Pudovik adducts. A solution of the O-allylated Pu-
dovik adduct (0.5 mmol,
1 equiv.), DBU (0.04 mL,
General procedure for the sequential DBU-mediated
isomerization/Claisen rearrangement of the O-allylated
Passerini adducts. A mixture of the O-allylated Passerini
adduct (1 equiv, 0.5 mmol), DBU (0.5 equiv, 0.25 mmol,
0.04 mL), and toluene (2 mL, 0.25 M) was stirred at 120 °C
for 30 min under microwave irradiation. After evaporation of
the solvent under reduced pressure, the crude residue was
purified by flash column chromatography over silica gel.
N-(tert-Butyl)-3-(4-methoxybenzyl)-2-oxohex-5-enamide
(7a). Yellow oil, 99 mg, 65% isolated yield. Rf = 0.35
(PE/Et2O = 9:1). 1H NMR (400 MHz, CDCl3) δ 7.08 (d,
J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.70 (brs, 1H), 5.81-
5.51 (m, 1H), 5.12-4.85 (m, 2H), 4.08-3.88 (m, 1H), 3.76 (s,
3H), 2.89 (dd, J = 13.8, 7.4 Hz, 1H), 2.68 (dd,
J = 13.8, 7.1 Hz, 1H), 2.50-2.08 (m, 2H), 1.33 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 202.4, 159.2, 158.2,
135.1, 130.9, 130.2, 117.3, 113.9, 55.3, 51.3, 45.4, 35.8, 35.0,
28.3. IR (thin film): 3394, 2968, 2933, 2836, 1714, 1681,
0.25 mmol, 0.5 equiv.), and the amine (0.75 mmol, 1.5 equiv.)
in toluene (1 mL, 0.5 M) was stirred at 130 °C for 30 min
under microwave irradiation. After evaporation of the solvent
under reduced pressure, the crude residue was purified by
flash column chromatography over silica gel.
2-Benzyl-N-(2-methylallyl)pent-4-enamide (9a). White
solid, 73 mg, 60% isolated yield. Rf = 0.31 (PE/Et2O = 7:3).
1
mp = 45-47 °C. H NMR (400 MHz, CDCl3) δ 7.33-7.07 (m,
5H), 5.83-5.70 (m, 1H), 5.36 (brs, 1H), 5.10 (ddd, J = 17.0,
3.2, 1.4 Hz, 1H), 5.13-5.02 (m, 2H), 4.70-4.68 (m, 1H), 4.55-
4.53 (m, 1H), 3.68 (d, J = 5.9 Hz, 2H), 2.93 (dd,
J = 13.5, 9.3 Hz, 1H), 2.76 (dd, J = 13.5, 5.3 Hz, 1H), 2.51-
2.42 (m, 1H), 2.37 (ddd, J = 18.0, 9.0, 5.2 Hz, 1H) 2.30-2.21
(m, 1H), 1.56 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 174.1, 141.9, 139.8, 135.8, 129.1, 128.5, 126.4, 117.2,
111.0, 50.4, 44.9, 38.8, 37.0, 20.3. IR (thin film): 3444, 3045,
2919, 1675, 1604, 1516, 1454, 1202 cm-1. HRMS (ESI) m/z:
[M]+ calcd for C16H21NO 243.1623; Found 243.1615.
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2-(2-Methoxybenzyl)-N-(2-methylallyl)pent-4-enamide 1H), 7.31 (d, J = 3.8 Hz, 1H), 7.29-7.24 (m, 1H), 7.10 (d,
1
2
3
4
5
6
7
8
(9b). White solid, 90 mg, 66% isolated yield. Rf = 0.37
(PE/Et2O = 7:3). mp = 69-71 °C. 1H NMR (400 MHz, CDCl3)
δ 7.18 (td, J = 7.9, 1.7 Hz, 1H), 7.10 (dd, J = 7.4, 1.5 Hz, 1H),
6.87-6.82 (m, 2H), 5.89-5.79 (m, 1H), 5.42 (brs, 1H), 5.16-
5.04 (m, 2H), 4.76-4.74 (m, 1H), 4.64-4.62 (m, 1H), 3.82 (s,
3H), 3.73 (d, J = 6.0 Hz, 2H), 2.87-2.80 (m, 2H), 2.56-2.39
(m, 2H), 2.29-2.15 (m, 1H), 1.57 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 174.6, 157.4, 142.2, 136.2, 131.2, 128.0,
127.8, 120.6, 116.7, 110.9, 110.3, 55.4, 47.7, 44.8, 36.9, 33.7,
20.3. IR (thin film): 3044, 3045, 2986, 2839, 1674, 1602,
1515, 1466, 1241, 1031 cm-1. HRMS (ESI) m/z: [M]+ calcd for
C17H23NO2 273.1729; Found 273.1727.
2-(4-Methoxybenzyl)-N-(2-methylallyl)pent-4-enamide
(9c). White solid, 88 mg, 64% isolated yield. Rf = 0.25
(PE/Et2O = 6:4). mp = 63-65 °C. 1H NMR (400 MHz, CDCl3)
δ 7.06 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 5.76 (ddt,
J = 17.1, 10.1, 6.9 Hz, 1H), 5.55 (brs, 1H), 5.10-5.00 (m, 2H),
4.69 (s, 1H), 4.56 (s, 1H), 3.75 (s, 3H), 3.67 (d, J = 5.9 Hz,
1H), 2.85 (dd, J = 13.6, 9.1 Hz, 1H), 2.68 (dd, J = 13.6,
5.3 Hz, 1H), 2.49-2.29 (m, 2H), 2.28-2.15 (m, 1H), 1.56 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 174.2, 158.1, 141.9,
135.8, 131.8, 130.0, 117.0, 113.9, 110.9, 55.3, 50.3, 44.8,
37.8, 36.9, 20.3. IR (thin film): 3444, 3055, 2986, 2921, 2852,
1671, 1613, 1515, 1452, 1232, 1035 cm-1. HRMS (ESI) m/z:
[M]+ calcd for C17H23NO2 273.1729; Found 273.1730.
J = 8.6Hz, 2H), 6.76 (d, J = 8.6Hz, 2H), 6.55 (dd, J = 3.8,
0.6 Hz, 1H), 5.84-5.75 (m, 1H), 5.13-5.01 (m, 2H), 3.74 (s,
3H), 3.45-3.40 (m, 1H), 3.14 (dd, J = 13.8, 8.1 Hz, 1H), 2.89
(dd, J = 13.8, 6.1 Hz, 1H), 2.68-2.61 (m, 1H), 2.46-2.40 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.9, 158.4, 135.8,
134.8, 130.9, 130.6, 130.0, 125.2, 124.6, 123.8, 120.8, 117.9,
117.1, 114.1, 109.2, 55.34, 47.3, 37.6, 36.8. IR (thin film):
3074, 2997, 2835, 1697, 1583, 1300, 1203, 1033, 920,
818 cm-1. HRMS (ESI) m/z: [M]+ calcd for C21H21NO2
319.1572; Found 319.1584.
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
Methyl 1-[2-(4-methoxybenzyl)pent-4-enoyl]-1H-indole-
3-carboxylate (9g). White solid, 77 mg, 41% isolated yield.
1
Rf = 0.29 (PE/Et2O = 8:2). mp = 85 °C. H NMR (CDCl3,
400 MHz) δ 8.50 (d, J = 7.4 Hz, 1H), 8.12 (d, J = 6.8 Hz, 1H),
7.95 (s, 1H), 7.46-7.32 (m, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.74
(d, J = 8.6 Hz, 2H), 5.83-5.78 (m, 1H), 5.21-4.90 (m, 2H),
3.93 (s, 3H), 3.72 (s, 3H), 3.48-3.41 (m, 1H), 3.10 (dd,
J = 13.8, 8.5 Hz, 1H), 2.94 (dd, J = 13.8, 5.8 Hz, 1H), 2.68-
2.61 (m, 1H), 2.52-2.38 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 174.2, 164.5, 158.5, 136.1, 134.2, 130.6, 130.4,
129.9, 127.5, 126.0, 125.0, 121.5, 118.4, 116.9, 114.2, 113.7,
55.3, 51.7, 47.5, 37.7, 36.8. IR (thin film): 2949, 2835, 1704,
1640, 1550, 1245, 1185, 1102 cm-1. HRMS (ESI) m/z: [M]+
calcd for C23H23NO4 377.1627; Found 377.1630.
1-(1H-Indol-1-yl)-2-(2-methoxybenzyl)pent-4-en-1-one
(9h). Brown oil, 98 mg, 61% isolated yield. Rf = 0.4
N-Butyl-2-(4-methoxybenzyl)pent-4-enamide
(9d).
1
Yellow oil, 106 mg, 77% isolated yield. Rf = 0.35
(PE/Et2O = 1:1). 1H NMR (400 MHz, CDCl3) δ 7.07 (d,
J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.82-5.69 (m, 1H),
5.13 (brs, 1H), 5.11-5.00 (m, 2H), 3.77 (s, 3H), 3.22-3.01 (m,
2H), 2.84 (dd, J = 13.6, 9.2 Hz, 1H), 2.69 (dd, J = 13.6,
5.0 Hz, 1H), 2.50-2.36 (m, 1H), 2.30-2.13 (m, 2H), 1.34-1.22
(m, 2H), 1.21-1.07 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 174.2, 158.2, 136.0, 132.0, 130.0,
117.0, 113.9, 55.4, 50.5, 39.1, 38.0, 36.9, 31.7, 20.0, 13.8. IR
(thin film): 3292, 2956, 2931, 1639, 1549, 1511, 1242, 1176,
1036, 912 cm-1. HRMS (ESI) m/z: [M]+ calcd for C17H25NO2
275.1885; Found 275.1877.
2-(4-Methoxybenzyl)-1-(piperidin-1-yl)pent-4-en-1-one
(9e). Yellow oil, 55 mg, 38% isolated yield. Rf = 0.35
(PE/Et2O = 1:1). 1H NMR (400 MHz, CDCl3) δ 7.01 (d,
J = 8.6 Hz, 2H), 6.72 (d, J = 8.6 Hz, 2H), 5.78-5.51 (m, 1H),
5.06-4.79 (m, 2H), 3.70 (s, 3H), 3.56-3.28 (m, 2H), 3.19-2.98
(m, 2H), 2.94-2.85 (m, 1H), 2.80 (dd, J = 13.0, 9.3 Hz, 1H),
2.61 (dd, J = 13.0, 5.1 Hz, 1H), 2.44-2.35 (m, 1H), 2.23-2.07
(m, 1H), 1.48-1.18 (m, 5H), 0.96-0.83 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 172.9, 158.1, 136.1, 132.1, 130.1, 116.6,
113.7, 55.3, 46.7, 43.2, 42.9, 38.2, 37.2, 26.3, 25.8, 24.6.
IR (thin film): 2936, 2856, 1624, 1511, 1442, 1243, 1035,
732 cm-1. HRMS (ESI) m/z: [M]+ calcd for C18H25NO2
287.1885; Found 287.1818.
(PE/Et2O = 9.5:0.5). H NMR (400 MHz, CDCl3) δ 8.57 (d,
J = 8.3 Hz, 1H), 7.61-7.45 (m, 2H), 7.41-7.33 (m, 1H), 7.27
(td, J = 7.5, 1.1 Hz, 1H), 7.20 (td, J = 7.9, 1.7 Hz, 1H), 7.14
(dd, J = 7.5, 1.4 Hz, 1H), 6.86-6.82 (m, 2H), 6.56 (dd, J = 3.8,
0.6 Hz, 1H), 5.83-5.78 (m; 1H), 5.10-4.97 (m, 2H), 3.81 (s,
3H), 3.65-3.60 (m, 1H) 3.21 (dd, J = 13.3, 6.6 Hz, 1H), 2.90
(dd, J = 13.3, 7.5 Hz, 1H), 2.73-2.68 (m, 1H), 2.38-2.31 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 157.5, 135.8,
135.4, 131.5, 130.6, 128.3, 126.9, 125.0, 124.9, 123.7, 120.7,
120.6, 117.2, 117.1, 110.4, 108.7, 55.3, 44.4, 36.0, 34.6.
IR (thin film): 3074, 2997, 2836, 1700, 1493, 1314, 1205,
1050, 919, 897 cm-1. HRMS (ESI) m/z: [M]+ calcd for
C21H21NO2 319.1572; Found 319.1573.
General procedure for the sequential DBU-mediated
isomerization/Claisen rearrangement/nucleophilic addi-
tion. A mixture of the O-allylated Pudovik adduct (0.5 mmol),
DBU (0.04 mL, 0.25 mmol, 0.5 equiv.) and the corresponding
alcohol (1 mL, 0.5 M) or a 2:1 toluene/thiol mixture was
stirred at 140 °C for 30 min under microwave irradiation.
After evaporation of the solvent under reduced pressure, the
crude residue was purified by flash column chromatography
over silica gel.
Ethyl 2-(2-methoxybenzyl)pent-4-enoate (9i). Colourless
oil, 111 mg, 89% isolated yield. Rf = 0.3 (PE/Et2O = 9.5:0.5).
1H NMR (400 MHz, CDCl3) δ 7.19 (td, J = 7.9, 1.7 Hz, 1H),
7.10 (dd, J = 7.3, 1.5 Hz, 1H), 6.87-6.82 (m, 2H), 5.80-5.72
(m, 1H), 5.09-5.00 (m, 2H), 4.04 (qd, J = 7.1, 2.0 Hz, 2H),
3.82 (s, 3H), 2.87-2.81 (m, 3H), 2.38 (m, 1H), 2.27 (m, 1H),
1.13 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 175.4, 157.7, 135.7, 130.9, 127.8, 127.7, 120.3, 116.8,
110.3, 60.2, 55.3, 45.3, 36.5, 33.0, 14.3. IR (thin film): 2978,
2936, 2361, 1729, 1601, 1289, 1176, 1050, 917, 855 cm-1.
HRMS (ESI) m/z: [M]+ calcd for C15H20O3 248.1412; Found
248.1414.
General procedure for the sequential DBU-mediated isom-
erization/Claisen rearrangement/indole addition on the O-
allylated Pudovik adducts. A solution of the O-allylated Pu-
dovik adduct (0.5 mmol), DBU (0.04 mL, 0.25 mmol,
0.5 equiv.) and the indole (0.5 mmol,
1 equiv.) in
toluene (1 mL, 0.5 M) was stirred at 140 °C for 30 min under
microwave irradiation. After evaporation of the solvent under
reduced pressure, the crude residue was purified by flash
column chromatography over silica gel.
1-(1H-Indol-1-yl)-2-(4-methoxybenzyl)pent-4-en-1-one
(9f). Colorless oil, 101 mg, 63% isolated yield. Rf = 0.34
(PE/Et2O = 9:1). 1H NMR (CDCl3, 400 MHz) δ 8.53 (d,
J = 8.3 Hz, 1H), 7.53 (dd, J = 7.8, 0.6 Hz, 1H), 7.38-7.33 (m,
2,2,2-Trifluoroethyl-2-(4-methoxybenzyl)pent-4-enoate
(9j). Colourless oil, 80 mg, 53% isolated yield. Rf = 0.35
(PE/Et2O = 9:1). 1H NMR (400 MHz, CDCl3) δ 7.08 (d,
J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.80-5.70 (m, 1H),
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
5.81-5.54 (m, 1H), 5.32 (brs, 1H), 3.77 (s, 3H), 3.65-3.56 (m,
5.11-5.06 (m, 2H), 4.49-4.29 (m, 2H), 3.79 (s, 3H), 2.94-2.76
(m, 3H), 2.44-2.29 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 173.4, 158.4, 134.6, 130.6, 129.9, 123.1(q, J = 277.1
Hz), 114.0, 60.2 (q, J = 36.6 Hz), 55.3, 47.4, 36.8, 35.9.
IR (thin film): 2949, 2835, 1704, 1640, 1550, 1245, 1185,
1102 cm-1. HRMS (ESI) m/z: [M]+ calcd for C15H17F3O3
302.1130; Found 302.1142.
1H), 2.89-2.67 (m, 1H), 1.33 (s, 9H), 0.91 (d, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 203.9, 164.6, 158.7,
143.6, 143.0, 132.1, 131.5, 129.4, 129.2, 126.3, 125.8, 114.4,
114.3, 55.4, 51.5, 50.6, 48.4, 28.9, 12.4. IR (thin film): 3316,
2968, 2934, 2838, 1722, 1670, 1634, 1610, 1511, 1422, 1392,
1364, 1264, 1250, 1179, 1034, 981, 731 cm-1. HRMS (ESI)
m/z: [M]+ calcd for C18H25NO3 303.1834; Found 303.1843.
(E)-N-Cyclohexyl-4-(4-methoxyphenyl)-5-methyl-6-
1
2
3
4
5
6
7
8
S-Ethyl 2-(4-methoxybenzyl)pent-4-enethioate (9k).
Yellow oil, 88 mg, 67% isolated yield. Rf = 0.35
(PE/Et2O = 9.5:0.5). H NMR (400 MHz, CDCl3) δ 7.06 (d,
1
oxohex-2-enamide (10c). It was unfortunately impossible to
separate and precisely distinguish the syn from the anti isomer
(dr = 1:1). Brown solid, 140 mg, 85% isolated yield. Rf = 0.3
9
J = 8.6 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 5.74 (ddt, J = 17.1,
10.2, 7.0 Hz, 1H), 5.28-4.71 (m, 2H), 3.78 (s, 3H), 2.99-2.77
(m, 4H), 2.70 (dd, J = 13.0, 6.1 Hz, 1H), 2.48-2.34 (m, 1H),
2.31-2.15 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 202.4, 158.3, 135.0, 131.0, 130.2, 117.4,
113.9, 56.0, 55.3, 37.5, 36.5, 23.3, 14.9. IR (thin film): 3045,
2933, 2840, 1680, 1613, 1513, 1448, 1299, 1230, 1179, 1035,
925 cm-1. HRMS (ESI) m/z: [M]+ calcd for C15H20O2S
264.1184; Found 264.1186.
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
(PE/Et2O = 2:8). mp
=
146 °C. First diasteroisomer:
1H NMR (400 MHz, CDCl3) δ 9.69 (d, J = 2.4 Hz, 1H), 7.10
(d, J = 8.7 Hz, 2H), 7.00-6.90 (m, 1H), 6.85 (d, J = 8.7 Hz,
2H), 5.71 (dd, J = 15.1, 1.1 Hz, 1H), 5.45 (br, 1H), 3.83-3.72
(m, 1H), 3.78 (s, 3H), 3.66-3.56 (m, 1H), 2.86-2.77 (m, 1H),
1.94-1.81 (m, 2H), 1.73-1.54 (m, 3H), 1.40-1.27 (m, 2H), 1.13
(d, J = 7.0 Hz, 3H), 1.18-1.00 (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 204.0, 164.3, 158.7, 144.0, 143.4, 132.0,
131.4, 129.4, 129.2, 125.5, 125.0, 114.4, 114.3, 55.4, 50.6,
49.0, 48.4, 33.2, 25.6, 24.9, 12.5, 12.4. Second diasteroiso-
General procedure for the sequential [Ru-H]-catalyzed
isomerization/Claisen rearrangement. A solution of the
O-allylated Pudovik or Passerini adduct (0.5 mmol),
RuClH(CO)(PPh3)3 (0.025 mmol, 0.05 equiv.) in toluene
(1 mL, 0.5M) was heated under microwave irradiation at the
indicated temperature for 30 min. After evaporation, the crude
residue was purified by flash column chromatography over
silica gel.
1
mer: H NMR (400 MHz, CDCl3) δ 9.50 (d, J = 2.4 Hz, 1H),
7.07 (d, J = 8.7 Hz, 2H), 7.00-6.90 (m, 1H), 6.83 (d, J = 8.7
Hz, 2H), 5.71 (dd, J = 15.1, 1.1 Hz, 1H), 5.45 (br, 1H), 3.83-
3.72 (m, 1H), 3.76 (s, 3H), 3.66-3.56 (m, 1H), 2.86-2.77 (m,
1H), 1.94-1.81 (m, 2H), 1.73-1.54 (m, 3H), 1.40-1.27 (m, 2H),
1.18-1.00 (m, 3H), 0.91 (d, J = 7.1 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 203.9, 164.3, 158.7, 144.0, 143.4, 132.0,
131.4, 129.4, 129.2, 125.5, 125.0, 114.4, 114.3, 55.4, 50.6,
49.0, 48.3, 33.2, 25.6, 24.9, 12.5, 12.4. IR (thin film): 3287,
2952, 2854, 1722, 1665, 1625, 1511, 1264, 1249, 1179, 1033,
981, 732 cm-1. HRMS (ESI) m/z: [M]+ calcd for C20H27NO3
329.1991; Found 329.2000.
(E)-Diethyl (3-(4-methoxyphenyl)-4-methyl-5-oxopent-1-
en-1-yl)phosphonate (10a). It was unfortunately impossible
to separate and precisely distinguish the syn from the anti
isomer (dr = 1:1). Yellow oil, 112 mg, 66% 41% isolated
yield. Rf = 0.43 (CH2Cl2/AcOEt = 6:4). First diasteroisomer:
1H NMR (400 MHz, CDCl3) δ 9.68 (d, J = 2.4 Hz, 1H), 7.09
(d, J = 8.7 Hz, 2H), 6.95-6.79 (m, 3H), 5.81-5.44 (m, 1H),
4.10-3.91 (m, 8H), 3.78 (s, 3H), 3.70-3.59 (m, 1H), 2.95-2.62
(m, 1H), 1.37-1.19 (m, 6H), 0.93 (d, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 203.3, 158.9, 153.1 (d,
J = 5.0 Hz), 131.1, 129.5, 119.6 (d, J = 62.8 Hz), 114.5, 70.0
(d, J = 5.0 Hz), 55.4, 51.0 (d, J = 21.7 Hz), 50.3, 16.5 (d,
J = 3.8 Hz), 12.6. Second diasteroisomer: 1H NMR
(400 MHz, CDCl3) δ 9.49 (d, J = 2.3 Hz, 1H), 7.05 (d,
J = 8.7 Hz, 2H), 6.95-6.79 (m, 3H), 5.81-5.44 (m, 1H), 4.10-
3.91 (m, 8H), 3.77 (s, 3H), 3.70-3.59 (m, 1H), 2.95-2.62 (m,
1H), 1.37-1.19 (m, 6H), 1.14 (d, J = 7.0 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 203.2, 158.9, 152.4 (d, J = 5.1
Hz), 130.5, 129.2, 117.7 (d, J = 62.9 Hz), 114.4, 61.9 (d,
J = 5.6 Hz), 55.4, 50.2, 50.1 (d, J = 21.7 Hz), 16.4 (d,
J = 3.2 Hz), 12.4. IR (thin film): 2980, 2934, 2906, 2837,
1722, 1608, 1511, 1246, 1177, 1018, 962, 833, 722 cm-1.
HRMS (ESI) m/z: [M]+ calcd for C17H25O5P 340.1440; Found
340.1439.
(E)-N-(tert-Butyl)-5-methyl-6-oxo-4-phenylhex-2-
enamide (10d). It was unfortunately impossible to separate
and precisely distinguish the syn from the anti isomer
(dr = 1:1). Yellow oil, 107 mg, 78% isolated yield. Rf = 0.28
1
(PE/Et2O = 4:6). First diasteroisomer: H NMR (400 MHz,
CDCl3) δ 9.70 (d, J = 2.4 Hz, 1H), 7.43-7.07 (m, 5H), 6.98-
6.91 (m, 1H), 5.71 (d, J = 15.1 Hz, 1H), 5.47 (br, 1H), 3.69-
3.60 (m, 1H), 2.92-2.76 (m, 1H), 1.33 (s, 9H), 1.13 (d,
J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 203.9,
164.6, 143.2, 140.2, 139.5, 129.0, 129.0, 128.4, 128.1, 127.3,
126.6, 126.1, 51.4, 50.6, 49.6, 28.8, 12.5. Second diastero-
1
isomer: H NMR (400 MHz, CDCl3) δ 9.50 (d, J = 2.2 Hz,
1H), 7.43-7.07 (m, 5H), 6.98-6.91 (m, 1H), 5.71 (d, J = 15.1
Hz, 1H), 5.47 (br, 1H), 3.69-3.60 (m, 1H), 2.92-2.76 (m, 1H),
1.32 (s, 9H), 0.90 (d, J = 7.1 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 203.7, 164.5, 142.5, 140.2, 139.5, 129.0,
129.0, 128.4, 128.1, 127.3, 126.6, 126.1, 51.4, 50.4, 49.2,
28.8, 12.4. IR (thin film): 3295, 3062, 2968, 2932, 1721, 1666,
1628, 1538, 1453, 1362, 1265, 1222, 981, 910, 734 cm-1.
HRMS (ESI) m/z: [M]+ calcd for C17H23NO2 273.1729; Found
273.1737.
General procedure for the sequential [Ru-H]-catalyzed
isomerization/Claisen rearrangement of the heteroaromatic O-
allylated Passerini and Pudovik adducts. To
solution of the O-allylated Pudovik or Passerini adduct
(0.1 mmol) in CHCl3 (0.1M) was added RuClH(CO)(PPh3)3
(0.005 mmol, 0.05 equiv.) and the resulting mixture was
heated at 180 °C for 10 min under microwave irradiation. The
reaction mixture was filtered through Celite, concentrated
under reduced pressure and the crude residue was purified by
flash column chromatography over silica gel.
(E)-N-(tert-butyl)-4-(4-methoxyphenyl)-5-methyl-6-
oxohex-2-enamide (10b). It was unfortunately impossible to
separate and precisely distinguish the syn from the anti isomer
(dr = 1:1). Yellow oil, 105 mg, 69% isolated yield. Rf = 0.3
(PE/Et2O = 3:7). First diasteroisomer: 1H NMR (400 MHz,
CDCl3) δ 9.70 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H),
6.98-6.88 (m, 1H), 6.85 (d, J = 8.7 Hz, 2H), 5.81-5.54 (m,
1H), 5.32 (brs, 1H), 3.78 (s, 3H), 3.65-3.56 (m, 1H), 2.89-2.67
(m, 1H), 1.34 (s, 9H), 1.14 (d, J = 7.0 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 204.1, 164.6, 158.8, 143.6, 143.0, 132.1,
131.5, 129.4, 129.2, 126.3, 125.8, 114.4, 114.3, 55.4, 51.5,
50.7, 48.9, 28.9, 12.5. Second diasteroisomer: 1H NMR
(400 MHz, CDCl3) δ 9.50 (d, J = 2.3 Hz, 1H), 7.07 (d,
J = 8.7 Hz, 1H), 6.98-6.88 (m, 1H), 6.84 (d, J = 8.7 Hz, 2H),
a
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Diethyl[(3-(1-oxopropan-2-yl)furan-2-yl)methyl]-
[M + Na]+ calcd for C16H21O4PSNa 363.0795; Found
363.0802.
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phosphonate (11a). Yellow oil, 17 mg, 62% isolated yield.
Rf = 0.32 (PE/EtOAc = 1:3). 1H NMR (400 MHz, CDCl3)
δ 9.63 (d, J = 1.2 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 6.39 (d,
J = 1.8 Hz, 1H), 4.09-3.99 (m, 4H), 3.81-3.73 (m, 1H), 2.89
(d, J = 20.8 Hz, 2H), 1.41 (d, J = 7.2 Hz, 3H), 1.28-1.23 (m,
Diethyl[(2-(1-oxopropan-2-yl)benzo[b]thiophen-3-yl)me-
thyl]phosphonate (11f). Yellow oil, 7 mg, 29% isolated yield.
Rf = 0.43 (PE/EtOAc = 1:3). 1H NMR (400 MHz, CDCl3)
δ 9.81 (s, 1H), 7.81-7.77 (m, 1H), 7.53-7.48 (m, 1H), 7.32
(ddd, J = 5.8, 4.3, 1.9 Hz, 2H), 4.15-4.05 (m, 5H), 3.51-3.38
(m, 2H), 1.54 (d, J = 7.1 Hz, 3H), 1.34-1.26 (m, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 201.7 (d, J = 3.0 Hz),
139.2 (d, J = 1.9 Hz), 138.4 (d, J = 3.6 Hz), 131.3 (d,
J = 11.3 Hz), 130.3 (d, J = 9.6 Hz), 124.6 (d, J = 0.7 Hz),
124.5 (d, J = 1.4 Hz), 122.6 (d, J = 1.1 Hz), 122.3 (d,
J = 1.3 Hz), 62.9 (d, J = 6.8 Hz), 62.7 (d, J = 6.8 Hz), 46.7 (d,
J = 2.0 Hz), 27.6 (d, J = 143.5 Hz), 16.6 (d, J = 1.4 Hz), 16.5
(d, J = 1.4 Hz), 13.0 (d, J = 2.2 Hz). IR (thin film): 2990,
2925, 1728, 1030 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C16H21O4PSNa 363.0795; Found 363.0802.
6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 200.8 (d,
J = 3.6 Hz), 142.7 (d, J = 12.2 Hz), 142.3 (d, J = 3.8 Hz),
118.8 (d, J = 8.8 Hz), 110.2 (d, J = 3.6 Hz), 62.4 (dd, J = 6.6,
5.0 Hz), 43.2 (d, J = 1.9 Hz), 25.4 (d, J = 144.0 Hz), 16.3 (d,
J = 5.9 Hz), 14.1 (d, J = 2.0 Hz). IR (thin film): 2960, 1743,
1420, 1247 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C12H19O5PNa 297.0867; Found 297.0855.
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Diethyl[(3-(1-oxopropan-2-yl)thiophen-2-
yl)methyl]phosphonate (11b). Yellow oil, 14 mg, 48%
isolated yield. Rf = 0.33 (PE/EtOAc = 1:3). 1H NMR
(400 MHz, CDCl3) δ 9.65 (d, J = 1.2 Hz, 1H), 7.22 (dd,
J = 5.3, 2.5 Hz, 1H), 6.81 (d, J = 5.3 Hz, 1H), 4.11-4.03 (m,
4H), 3.90 (q, J = 7.1 Hz, 1H), 3.37 (d, J = 2.1 Hz, 1H), 3.32
(d, J = 2.1 Hz, 1H), 1.40 (d, J = 7.0 Hz, 3H), 1.28 (d,
J = 7.3 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 200.7 (d,
J = 2.9 Hz), 136.1 (d, J = 8.8 Hz), 129.1 (d, J = 10.7 Hz),
126.9 (d, J = 3.8 Hz), 124.7 (d, J = 4.2 Hz), 62.7 (d,
J = 6.9 Hz), 62.6 (d, J = 6.9 Hz), 46.4, 26.6 62.7 (d, J = 144.7
Hz), 16.5 (d, J = 5.9 Hz), 14.7. IR (thin film): 2985, 2935,
1728, 1030 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C12H19O4PSNa 313.0639; Found 313.0685.
N-Cyclohexyl-2-[3-(1-oxopropan-2-yl)furan-2-
yl]acetamide (11g). Yellow oil, 83 mg, 63% isolated yield.
Rf = 0.33 (PE/Et2O = 2:8). 1H NMR (400 MHz, CDCl3) δ 9.60
(d, J = 1.1 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 6.22 (d,
J = 1.8 Hz, 1H), 5.78 (br, 1H), 3.74-3.62 (m, 1H), 3.57-3.43
(m, 3H), 1.86-1.75 (m, 2H), 1.67-1.50 (m, 3H), 1.41-1.22 (m,
5H), 1.17-1.00 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 201.0, 167.2, 146.2, 142.5, 118.8, 110.3, 48.5, 43.3, 34.9,
32.9, 32.9, 25.5, 24.8, 14.1 IR (thin film): 3296, 2929, 2854,
1644, 1538, 1450, 1350, 1249, 892, 736 cm-1. HRMS (ESI)
m/z: [M]+ calcd for C15H21NO3 263.1521; Found 263.1526.
Diethyl[(2-(1-oxopropan-2-yl)furan-3-yl)methyl]-
phosphonate (11c). Yellow oil, 8 mg, 29% isolated yield.
Rf = 0.30 (PE/EtOAc = 1:3). 1H NMR (400 MHz, CDCl3)
δ 9.63 (d, J = 1.2 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 6.39 (s,
1H), 4.07-4.01 (m, 4H), 3.77 (q, J = 7.2 Hz, 1H), 2.89 (d,
J = 20.8 Hz, 2H), 1.41 (d, J = 7.2 Hz, 3H), 1.26 (td, J = 7.1,
3.2 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 198.8 (d,
J = 3.4 Hz), 148.2 (d, J = 11.2 Hz), 142.3 (d, J = 1.4 Hz),
112.9 (d, J = 3.0 Hz), 112.3 (d, J = 9.7 Hz), 62.8 (t,
J = 7.1 Hz), 45.0 (d, J = 1.9 Hz), 23.3 (d, J = 144.2 Hz), 16.5
(d, J = 5.9 Hz), 12.3 (d, J = 1.9 Hz). IR (thin film): 2960,
2935, 1420, 1247 cm-1. HRMS (ESI) m/z: [M + Na]+ calcd for
C12H19O5PNa 297.0867; Found 297.0855.
Diethyl[(2-(1-oxopropan-2-yl)thiophen-3-yl)methyl]pho-
sphonate (11d). Yellow oil, 16 mg, 54% isolated yield.
Rf = 0.32 (PE/EtOAc = 1:3). 1H NMR (400 MHz, CDCl3)
δ 9.62 (d, J = 1.6 Hz, 1H), 7.24 (s, 1H), 7.04 (dd, J = 5.2,
1.4 Hz, 1H), 4.08-3.99 (m, 4H), 3.72 (q, J = 7.0 Hz, 1H), 3.17
(d, J = 5.9 Hz, 1H), 3.12 (d, J = 5.9 Hz, 1H), 1.49 (d,
J = 7.1 Hz, 3H), 1.27-1.24 (m, 7H). 13C{1H} NMR (101 MHz,
CDCl3) δ 199.3, 132.1 (d, J = 9.9 Hz), 130.2, 128.5 (d,
J = 12.1 Hz), 124.3, 62.4, 46.2, 27.6 (d, J = 141.6 Hz), 16.4 (d,
J = 5.9 Hz), 15.8. IR (thin film): 2980 2925, 1748, 1060 cm-1.
HRMS (ESI) m/z: [M + Na]+ calcd for C12H19O4PSNa
313.0639; Found 313.0685.
Diethyl[(3-(1-oxopropan-2-yl)benzo[b]thiophen-2-yl)me-
thyl]phosphonate (11e). Yellow oil, 9.5 mg, 56% isolated
yield. Rf = 0.42 (PE/EtOAc = 1:3). 1H NMR (400 MHz,
CDCl3) δ 9.82 (s, 1H), 7.82-7.77 (m, 1H), 7.54-7.47 (m, 1H),
7.34-7.29 (m, 2H), 4.16-4.04 (m, 6H), 3.45 (dq, J = 21.5,
15.7 Hz, 2H), 1.54 (d, J = 7.1 Hz, 3H), 1.34-1.25 (m, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 201.7 (d, J = 3.0 Hz),
139.2, 138.4 (d, J = 3.5 Hz), 131.3 (d, J = 11.3 Hz), 130.3 (d,
J = 9.7 Hz), 124.6, 124.5, 122.6, 122.2, 62.9 (d, J = 6.8 Hz),
62.7 (d, J = 6.8 Hz), 46.7 (d, J = 2.0 Hz), 27.7 (d,
J = 143.5 Hz), 16.6 (d, J = 4.5 Hz), 13.0 (d, J = 2.2 Hz).
IR (thin film): 2995, 2910, 1748, 1045 cm-1. HRMS (ESI) m/z:
Diethyl
[(4-(1-oxopropan-2-yl)quinolin-3-yl)methyl)-
phosphonate (11h). Yellow oil, 75 mg, 45% isolated yield.
Rf = 0.10 (AcOEt = 100%). 1H NMR (400 MHz, CDCl3)
δ 9.89 (s, 1H), 8.81 (d, J = 1.6 Hz, 1H), 8.12 (d, J = 8.3 Hz,
1H), 7.74-7.60 (m, 2H), 7.58-7.43 (m, 1H), 4.33 (q,
J = 7.0 Hz, 1H), 4.18-3.92 (m, 4H), 3.41 (dd, J = 21.7,
12.2 Hz, 2H), 1.66 (d, J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz,
3H), 1.21 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 202.2 (d, J = 2.2 Hz), 152.9 (d, J = 4.4 Hz), 148.1
(d, J = 2.8 Hz), 143.3 (d, J = 7.6 Hz), 130.8 (d, J = 1.3 Hz),
129.2 (d, J = 1.2 Hz), 127.5 (d, J = 0.9 Hz), 126.6 (d,
J = 3.2 Hz), 124.7 (d, J = 9.7 Hz), 124.2 (d, J = 1.0 Hz), 62.9
(d, J = 7.0 Hz), 62.6 (d, J = 6.8 Hz), 48.8 (d, J = 1.6 Hz), 29.9
(d, J = 139.1 Hz), 16.5 (d, J = 5.6 Hz), 16.5 (d, J = 5.6 Hz),
14.0 (d, J = 1.1 Hz). IR (thin film): 2981, 2931, 2908, 1723,
1703, 1572, 1504, 1242, 1162, 1048, 1016, 958, 795,
763 cm-1. HRMS (ESI) m/z: [M]+ calcd for C17H22NO4P
335.1286; Found 335.1296.
General procedure for the ring-closing metathesis. To a
solution of diene (0.2 mmol) in CH2Cl2 (4 mL) was added
second generation Grubbs catalyst (0.01 mmol) and the
resulting mixture was stirred at the indicated temperature
using a heating mantle for the indicated amount of time. The
reaction mixture was then filtered over a pad of Celite,
concentrated under reduced pressure and the crude residue
was purified by flash column chromatography.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
1H and 13C NMR spectra for all new compounds (PDF)
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monosubstituted allyl substrates with benzyl alcohols. Tetrahedron:
Asymmetry 2010, 21, 1176-1178.
AUTHOR INFORMATION
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Corresponding Authors
(4) (a) Fournier, J.; Arseniyadis, S.; Cossy, J. A modular and
scalable one-pot synthesis of polysubstituted furans. Angew. Chem.
Int. Ed. 2012, 51, 7562-7566. (b) Fournier, J.; Lozano, O.; Menozzi,
C.; Arseniyadis, S.; Cossy, J. Palladium-catalyzed asymmetric allylic
alkylation of cyclic dienol carbonates: Efficient route to
enantioenriched γ-butenolides bearing an all-carbon α-quaternary
stereogenic center. Angew. Chem. Int. Ed. 2013, 52, 1257-1261.
(c) Elhachemia, H.; Cattoen, M.; Cordier, M.; Cossy, J.;
Arseniyadis, S.; Ilitki, H.; El Kaïm, L. Selective Tsuji-Trost type
C-allylation of hydrazones: A straightforward entry into 4,5-dihydro
pyrazoles. Chem. Commun. 2016, 52, 14490-14493. (d) Nascimento
de Oliveira, M.; Fournier, J.; Arseniyadis, S.; Cossy, J. A Pd-AAA
approach to α-quaternary γ-butyrolactones. Org. Lett. 2017, 19, 14-
17. (e) Nascimento de Oliveira, M.; Arseniyadis, S.; Cossy, J.
Palladium-catalyzed asymmetric allylic alkylation of 4-substituted
isoxazolidin-5-ones: A straightforward access to β2,2-amino acids.
Chem. Eur. J. 2018, 24, 4810-4814. (f) Song, T.; Arseniyadis, S.;
Cossy, J. Highly enantioselective, base-free synthesis of α-quaternary
succinimides through catalytic asymmetric allylic alkylation. Chem.
Eur. J. 2018, 24, 8076-8080. (g) Song, T.; Arseniyadis, S.; Cossy, J.
Asymmetric synthesis of α-quaternary γ-lactams through palladium-
catalyzed asymmetric allylic alkylation. Org. Lett. 2019, 21, 603-607.
(h) Aubert, S.; Katsina, T.; Arseniyadis, S. A sequential Pd-
AAA/CM/Cope rearrangement strategy for the stereoselective synthe-
sis of γ-butenolides. Org. Lett. 2019, 21, 2231-2235. (i) Katsina, T.;
Sharma, S.; Buccafusca, R.; Quinn, D. J.; Moody, T. S.; Arseniyadis,
Stellios Arseniyadis – Queen Mary University of London,
School of Biological and Chemical Sciences, Mile End Road,
London, E1 4NS, UK; Email: s.arseniyadis@qmul.ac.uk
Laurent El Kaïm – Laboratoire de Synthèse Organique,
CNRS, Ecole Polytechnique, ENSTA ParisTech, UMR 7652,
Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau,
France; Email: laurent.elkaim@ensta-paristech.fr
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Mansour Dolé Kerim – Laboratoire de Synthèse Organique,
CNRS, Ecole Polytechnique, ENSTA ParisTech, UMR 7652,
Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau,
France
Tania Katsina – Queen Mary University of London, School
of Biological and Chemical Sciences, Mile End Road, London,
E1 4NS, UK
Martin Cattoen – Queen Mary University of London,
School of Biological and Chemical Sciences, Mile End Road,
London, E1 4NS, UK
Nicolas Fincias – Queen Mary University of London, School
of Biological and Chemical Sciences, Mile End Road, London,
E1 4NS, UK
Notes
S.
A
Sequential palladium-catalyzed allylic alkylation/retro-
The authors declare no competing financial interest.
Dieckmann fragmentation strategy for the synthesis of α-substituted
acrylonitriles. Org. Lett. 2019, 21, 9348-9352.
ORCID
(5) (a) Kerim, M. D.; Cattoen, M.; Fincias, N.; Dos Santos, A.;
Arseniyadis, S.; El Kaïm, L. Palladium-catalysed O-allylation of
α-hydroxyphosphonates: An expedient entry into phosphono-
oxaheterocycles. Adv. Synth. Catal. 2018, 360, 449-454. For exam-
ples of retro-Abramov reactions on aldehydes, see: (b) Agnel, G.;
Negishi, E.-I. Highly stereo- and regiocontrolled cyclopentannulation
via allylphosphonate conjugate addition and hydroboration-oxidation-
elimination. Synthesis of pentalenic acid with virtually complete
stereo- and regiocontrol. J. Am. Chem. Soc. 1991, 113, 7424-7426.
(c) Rowe, B. J.; Spilling, C. D. Stereospecific Pd(0)-catalyzed aryla-
tion of an allylic hydroxy phosphonate derivative: Formal synthesis of
(S)-(+)-ar-turmerone. J. Org. Chem. 2003, 68, 9502-9505; For similar
reactions with ketones, see: (d) Gancarz, R.; Gancarz, I. Failure of
aminophosphonate synthesis due to facile hydroxyphosphonate -
phosphate rearrangement. Tetrahedron Lett. 1993, 34, 145-148.
(e) Sekine, M.; Nakajima, M.; Kume, A.; Hashizume, A.; Hata, T.
Silyl phosphites. XVIII. Versatile utility of α-(trimethylsilyloxy)
alkylphosphonates as key intermediates for transformation of
aldehydes into several carbonyl derivatives. Bull. Chem. Soc. Jpn.
1982, 55, 224-238.
(6) Liu, C.; Zhang, Y.; Qian, Q.; Yuan, D.; Yao, Y. n-BuLi as a
highly efficient precatalyst for hydrophosphonylation of aldehydes
and unactivated ketones. Org. Lett. 2014, 16, 6172-6175.
(7) Kumar, J. S.; Jonnalagadda, S. C.; Mereddy, V. R. An efficient
boric acid-mediated preparation of α-hydroxyamides. Tetrahedron
Lett. 2010, 51, 779-782.
(8) Reid, J. P.; McAdam, C. A.; Johnston, A. J. S.; Grayson, M. N.;
Goodman, J. M.; Cook, M. J. Base-mediated cascade rearrangements
of aryl-substituted diallyl ethers. J. Org. Chem. 2015, 80, 1472-1498.
(9) Reuter, J. M.; Salomon, R. G. Ruthenium(II) catalyzed
Martin Cattoen: 0000-0002-9343-5948
Stellios Arseniyadis: 0000-0001-6831-2631
Laurent El Kaïm: 0000-0001-5729-8010
ACKNOWLEDGMENT
We would like to thank Ecole Polytechnique, ENSTA ParisTech,
Queen Mary University of London and the Islamic Development
Bank for financial support.
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