Palladium-catalyzed intermolecular [4 + 2] formal cycloaddition with (Z)-3-iodo allylic nucleophiles and allenamides

Article abstract of DOI:10.1039/C8OB03072C

A highly chemo- and regioselective [4 + 2] formal cycloaddition of (Z)-3-iodo allylic nucleophiles and allenamides catalyzed by palladium is reported. The methodology proceeds under mild reaction conditions and is tolerant of alkyl and aryl functional groups. The S_N2′ substitution at the proximal C═C bond performed against the Heck or S_N2 pathway delivered a variety of 2-amino-dihydropyrans and 2-amino-tetrahydropiperidines in moderate to satisfactory yields. The [4 + 2] formal cycloaddition derivatives are convertible to interesting scaffolds 2,6,7,7a-tetrahydropyrano[2,3-b]pyrrole and 2,6,7,7a-tetrahydro-1H-pyrrolo[2,3-b]pyridine derivatives via ring-closing metathesis (RCM) with Grubbs catalyst II.

Full text of DOI:10.1039/C8OB03072C

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DOI: 10.1039/C8OB03072C
Journal Name
COMMUNICATION
Palladium-Catalyzed Intermolecular [4 + 2] Formal Cycloaddition
with (Z)-3-Iodo Allylic Nucleophiles and Allenamides
Received 00th January 20xx,
Accepted 00th January 20xx
‡a
‡a
a
a
a
a
b
Fachao Yan, Hanbing Liang, Bing Ai, Wenjing Liang, Luyang Jiao, Shuzhi Yao, Pingping Zhao,
a
a
a
Qing Liu,* Yunhui Dong, and Hui Liu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly chemo- and regioselective [4 + 2] formal cycloaddition of
Z)-3-iodo allylic nucleophiles and allenamides catalyzed by
palladium is reported. The methodology proceeds under mild
Recently, our group has demonstrated efficient synthetic
methodologies for five- and six-membered heterocycles via
(
1
0
transition-metal-catalyzed ring-closing metathesis cyclization. For
example, we successfully developed an intermolecular cyclization-
Heck reaction of allenamides to access functionalized
reaction conditions and is tolerant of alkyl ， aryl founctional
group. The S
against Heck or S
N
2’ substitution at proximal C=C bond performed
2 pathway, delivered a variety of 2-amino-
1
3
tetrahydropyridine derivatives, where π-allyl
η
and
η
N
1
1
intermediates were proposed (I, Scheme 1). Allenic scaffold N-
dihydropyrans and 2-amino-tetrahydropiperidines in moderate to
satisfactory yields. The [4 + 2] formal cycloaddition derivatives are
convertible to interesting scaffolds 2,6,7,7a-tetrahydropyrano[2,3-
allenamide has emerged a versatile building block in numerous
b]pyrrole
and
2,6,7,7a-tetrahydro-1H-pyrrolo[2,3-b]pyridine
MeO
Me
O
H3C
Me
Me
N
H
H
H
derivatives via ring-closing metathesis (RCM) with Grubbs catalyst
II.
Me
CH3
O
O
O
H
HO
HO
O
O
O
N
N
O
N
H
O
O
N
4
H
H
N
Me
S
N
O
CH3
O
Treament of malaria neosporsis
PCT: WO 2000004026 A1, 2000
Antitumor agents
PCT: WO 2007077543 A2, 2007
Functionalized
2-amino-dihydropyrans
and
2-amino
'Upenamide
Antimalarial Activity
OEt
tetrahydropiperidines are prevalen structural motifs, commonly
observed in an array of pharmaceuticals and biologically active
natural products, such as the representative bioactive moleculers in
antitumor, antimalarial, anticancer, treatment of Parkinson’s
Me
OH OH
HO
O
HN
N
H
N
NH2
O
N
N
H
H
H
F3C
O
N
N
1
Treament of Parkinson's diease
PCT: WO 2016038379 A1
disease, and so on (Figure 1). As a consequence, these important
Anticancer and Antidiabeticagents
PCT: WO 2000039140 A1, 2000
H
Antiasthmatics Agents
MAO-B inhibitor BAYER: WO2003/76405 A1, 2003
2
016
building blocks have received considerable attention in recent years.
Their preparation relies mainly on multiple-step synthesis while
direct procedures for building these core structures are less
Fig. 1 Biologically-active natural products featuring pyrans and
piperidines.
2
explored. Current methods for the construction of dihydropyrans
Previous Work: Cyclization-Heck Reaction via π -allylic palladium intermediate
and tetrahydropiperidines scaffolds have been developed through
η 1
η 3
Ln
II
3
4
5
7
[Pd0]
Diels-Alder reaction, Michael addition, Prins cyclization,
R
Pd
R
R-X
R
Heck reaction
dehalogenation coupling,6 cross-coupling domino reaction,
dehalogenated carbonylation coupling as well as multicomponent
reactions. However, synthetic challenges remains in installing the
PdII
(I)
N
Ts
R = Aryl, Alkene
N
N
N
8
Ts
Ts
Ts
9
A
Current Work:
amino group at 2 position of dihydropyran ring. Due to the
importantance bioactivities of these valuable bioactive molecules,
the development of new synthetic strategies to functionalized 2-
amino-dihydropyrans and 2-amino-tetrahydropiperidines is
indispensable.
a: SN2
Untouched
b: Heck
Ln
Pd
II
R
[Pd0]
R
SN2'
R
I
(II)
HX
N
X
N
N
XH
X = N, O
Ts
Ts
Ts
c: SN2'
η 1
B
*
*
Highly chemoselectivty: Substituion VS Heck Reaction
Highly regioselectivity: SN2' Substitution reaction
a. School of Chemistry and Chemical Engineering, Shandong University of
Scheme 1 Previous work and proposal for this work.
Technology, 266 West Xincun Road, Zibo 255049, P. R. China. E-mail:
huiliu1030@sdut.edu.cn.
College of Chemical and Environmental Engineering, Shandong University of
transformations including [m + 2] cycloadditions with suitable
synthons. Applying our design to form η intermediate (A), a
b
1
2
1
Science and Technology, 579 Qianwangang Road, Huangdao District, Qingdao,
2
66590, P.R.China
nucleophilic group was introduced to vinyl iodides that could
further react with allenamide to generate the η intermediate (B)
‡
These authors contributed equally to this work.
1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
Table 2 Substrate scope of [4 + 2] oxyheterocycles cyclization of
under palladium(0) catalysis (II, Scheme 1). However, in this case
a,b
View Article Online
allenamides
N
there are many competing reactions pathways: a) S 2 substitution
DOI: 10.1039/C8OB03072C
2
R2
R
at distal C=C bond; b) Heck reaction; c) S 2’ substitution at proximal
N
Pd(PPh3)4 (10 mol%)
R1
R1
C=C bond. Herein, we would like to report a highly chemo- and
regioselective [4 + 2] cycloaddition of N-allenamides with (Z)-3
iodide allylic nucleophiles to construct 2-amino-dihydropyran and 2-
amino-tetrahydropiperidine derivatives.
I
R3
R3
DMAP (2.0 equiv.)
dioxane, 50 oC, 2.5 h
N
O
3
N
R4
OH
2
4
R
1
Me
iPr
In our initial investigations, we tested the reaction of allenamide
O
N
O
N
n = 1, 2
O
N
n = 1, 2
Ts
Ts
Ts
n = 1 3ac, 88%
n = 2 3ac', 92%
1
a with 3-iodo-2-phenyl allylic alcohol 2a in the presence of 10 mol%
3
aa, 97%
n = 1 3ab, 78%
n = 2 3ab', 90%
o
PdCl
2
(PPh
3
)
2
and 2.0 equivalents of K
2
CO
3
at 80 C in dioxane under
MeO
Cl
nitrogen atmosphere. To our delight, the reaction progressed with
high chemo- and regioselectivity via S 2’ substitution way to
generate 2-amino-3-methylene-3, 6-dihydro-pyran 3aa as a single
product in 46% yield (Table 1, entry 1). In order to optimize the
reaction conditions, we screened other Pd catalysts and commonly
used bases and solvents. For instance, we found that the use of
MeO
N
O
N
O
N
O
N
Ts
Ts
Ts
3
ad, 82%
3ae, 77%
3af, 72%
F
Et
Et
nBu
O
N
O
N
O
N
Ts
Ts
Ts
Pd
the effect of several bases on the reaction, K
Cy NMe in the presence of Pd(OAc) /PPh , and found that that
organic bases were better suited compared to inorganic bases
entries 3-6). Dioxane was identified a more efficient solvent
compared to MeCN and DMF (entries 6-8). Subsequently, when
Pd(PPh was applied as catalyst instead of Pd(OAc) /PPh there
was an increase in yield of 3aa to 70% in dioxane and with Cy NMe
as base (entry 10). Further optimization of the reaction conditions
2 3
(dba) /PCy
3
as catalyst was ineffective (entry 2). We examined
3
ag, 65%
3ah, 65%
3ai, 59%
2
CO , K PO , TEA, and
3
3
4
C12H25
Et
2
2
3
O
N
O
N
O
N
Ts
Boc
Ms
3ch, 55%
3
aj, 72%
3bh, 67%
(
F
Me
3
)
4
2
3
,
O
N
O
N
O
N
2
Ms
Ms
Ts
3
ca, 58%
3cg, 75%
3da, 70%
MeO
resulted in Pd(PPh
3
)
4
(10 mol%) and DMAP (2.0 equiv.) in dioxane at
C12H25
Me
o
5
0
C, affording the desired product in excellent yield of 97%
O
N
O
N
O
N
Ts
(entries 11-16). Meanwhile, both catalyst and base were
Ts
Ts
3
dd, 69%
3ea, 50%
3ej, 40%
Et
Table 1. Optimization of reaction conditions.a
O
N
Ts
3ak, 63%
cat, base
I
o
ligand, solvent, t/ C
N
O
N
Me
Ts
OH
2a
Et
Et
Et
Ts
1a
3aa
O
N
O
N
O
N
Ts
Ts
Ms
entry
catalyst
ligand
base
solvent
t(oC) yield (%)b
3
ek, 38%
3dk, 67%
3ck, 58%
1
2
PdCl2(PPh3)2
Pd2(dba)3
-
K2CO3
TEA
dioxane
dioxane
80
80
46
40
aReaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), Pd(PPh
3 4
)
PCy3
(0.02 mmol), DMAP (0.4 mmol), dioxane (2.0 mL), N
2
, 2.5 h.
b
3
4
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
Cy2NMe
K2CO3
dioxane
dioxane
80
80
53
5
Isolated yields.
5
6
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
K3PO4
TEA
dioxane
dioxane
80
80
13
62
established as necessary inputs for this transformation (entries 17
and 18).
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
PPh3
TEA
MeCN
DMF
80
80
80
80
33
30
58
70
With the optimized conditions in hand, we embarked testing the
substrate scope of this procedure (Table 2). First, we examined the
PPh3
TEA
-
-
TEA
dioxane
dioxane
1
functional groups effect of R substituent of 3-iodo allylic alcohols.
1
1
0
1
2
Cy NMe
1
The allylic aryl R substituent bearing electron-donating groups (Me,
Pd(PPh3)4
Pd(PPh3)4
-
-
2
Cy NMe
MeCN
80
80
15
47
iPr, and OMe) exhibited excellent tolerance in this transformation,
delivering the desired products in good to excellent yields (3aa-3ae).
The reactions of substrates with aryl bearing electron-withdrawing
halogens provided the 2-amino-dihydropyran derivatives with
1
1
2
3
Cy2NMe
toluene
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
-
-
-
DIPEA
DMAP
DMAP
dioxane
dioxane
dioxane
80
80
50
53
79
97
1
4
1
5
1
1
6
Pd(PPh )
-
-
-
DMAP
dioxane
dioxane
dioxane
100
80
69
NR
NR
slightly lower yields (3af-3ag). While aryl groups at R may engage
3
4
-
1
1
7
8
DMAP
-
in conjugation with positive effect for this transformation, the alkyl
Pd(PPh3)4
80
1
group allylic substituents at R such as Et, nBu and C12
H25 have not
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [Pd] (0.02
significantly influence the reaction, affording 2-amino-dihydropyran
derivatives in moderate yields (3ah-3aj). N-protected allenamides
with Boc or Ms transformed smoothly to the corresponding
b
mmol), base (0.4 mmol), solvent (2.0 mL), N
yields.
2
, 2.5 h. Isolated
2
| J. Name., 2012, 00, 1-3
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Table 3 Substrate scope of [4 + 2] nitrogen heterocycles cyclization
Table 4 Applications of the 2-amino-dihydropyrans and 2-amino-
View Article Online
of allenamides
piperidines
DOI: 10.1039/C8OB03072C
R1
R1
R1
R1
Pd2(dba)3 (5 mol%)
PPh3 (20 mol%)
Grubbs catalyst II (5 mol%)
DCM, 30 oC, N , 1.5 h
n = 1, 2
I
R3
R3
N
NHTs
TEA (2.0 equiv)
dioxane , 80 oC , 5 h
N
N
X
N
R4
N
R4
n = 1, 2
X
6
Ts
Ts Ts
2
1
4
5
3
iPr
MeO
Me
MeO
N
N
N
O
O
O
Ts
Ts
Ts
N
N
N
N
N
N
Ts Ts
Ts Ts
Ts Ts
6
aa, 83%
6ac, 73%
6ad, 91%
5aa, 71%
5ab, 63%
5ac, 60%
nBu
C12H25
Et
C12H25
Et
C12H25
N
N
N
O
N
O
Ts
Ts Ts
Boc
N
N
N
N
N
N
Ts Ts
ad, 78%
Ts Ts
Ts Ts
6ai, 94%
6aj, 56%
6bh, 93%
5
5ae, 79%
5ed, 46%
a
Reaction conditions: 1 (0.3 mmol), 4 (0.2 mmol), Pd
2
(dba)
3
(0.01
Me
b
Et
mmol), TEA (0.4 mmol), dioxane (2.0 mL), N
2
, 5 h. Isolated yields.
N
O
Ms
O
N
products in good yields (3bh, 3ch, 3ca and 3cg). Furthermore,
coordinating effects of allylic tether of allenamides were
Ts
6ab', 80%
6
ch, 54%
a
investigated for 2-Me allylic, phenyl and 1-butenyl groups. We
Reaction conditions: 3 (1.0 equiv), Grubbs-II (5 mol%), DCM (1
3
b
found that R substituent, 2-Me allylic group can perform efficiently mL), N
2
, 1.5 h. Isolated yields.
as well as the allylic group, having corresponding products with
homoallylic allenamides obtained in high yields (3ab’ and 3ac’). In delivered tetrahydropyridine derivatives efficiently in good
contrast, the phenyl group substituent impacted by decreased yields (5ab-5ae). Moreover, phenyl-protected allenamide 1e
yields for 3ea and 3ej under 50% and with the transformation can also furnish 5ed in 46% yield.
requiring longer reaction time. This result shows that the
To demonstrate the significance of this methodology, the formed
coordination of the allylic group was essential to this 2-amino-dihydropyrans and tetrahydropyridines were converted
into
2,6,7,7a-tetrahydropyrano[2,3-b]pyrrole
and
2,6,7,7a-
transformation and in accord with our proposed mechanism (The
screening of the reaction conditions for the N-phenyl allenamide,
see Supporting Information).
Subsequently, the tetrasubstituted vinyl iodides were reacted
with N-protected allenamides under standard conditions, delivering
the corresponding products in moderate yields (3ak, 3dk and 3ck).
It is noteworthy to mention that a relatively lower yield of 38% was
obtained from allenamide substrate-bearing phenyl group,
tetrahydro-1H-pyrrolo[2,3-b]pyridine derivatives via ring-closing
metathesis (RCM) using Grubbs catalyst II (Table 4). The 2-amino-
1
4
3
-methylene-3, 6-dihydro-pyran 3aa was subjected to 5 mol% of the
o
Grubbs catalyst II in DCM, at 30 C for 1.5 h, delivering 3-phenyl-7-
tosyl-2,6,7,7a-tetrahydropyrano[2,3-b]pyrrole 6aa in 83% yield.
Subsequently, more examples were examined to generate the
corresponding products in good to excellent yields (6ac-6aj).
Notably, the substrate bearing strong electron-donating group OMe
highlighting the importance of the double bond for metal can
coordination (3ek). Despite of the products 3ea, 3ej, and 3ek were dihydropyrano[2,3-b]pyrrole
produce
the
3-(4-methoxyphenyl)-7-tosyl-2,7-
via dehydrogenation and
produced without allylic double bond, we believe that the π-system aromatization (6ad) . Furthermore, the 5-dodecyl-1,7-ditosyl-
1
5
2
,6,7,7a-tetrahydro-1H-pyrrolo[2,3-b]pyridine 6aj can also be
of the phenyl may act as a weak ligand for the intermediate
transition state. In general, the results confirmed that presence of
double bond was a better group for the transformation. We
managed to obtain suitable crystals for compound 3ak and
determined the structure by X-ray diffraction analysis (Table 2).
To further explore the substrate scope of this strategy, 3-
iodo allylamines were applied instead of 3-iodo vinyl alcohol to
obtained in 56% yield. Specifically, the boc-protected 2,6,7,7a-
tetrahydropyrano[2,3-b]pyrrole 6bh was obtained in 93% yield. The
2
6
yield. The unique fused heterocyclic molecules are registered for
the first time. These compounds are potential candidates for bio-
activity testing and therapeutic applications in pharmaceuticals.
According to the above experimental results, we suggest a
plausible mechanism of this [4 + 2] transformation as shown in
Scheme 2. The reaction is initiated from the oxidative addition
-amino-dihydropyrans bearing homoallylic group can generate
,7,8,8a-tetrahydro-2H-pyrano[2,3-b]pyridine derivatives 6ab’ in 80%
1
3
prepare
derivatives (Table 3). After a series of condition screening,
optimized conditions were determined as 5 mol% Pd (dba)
2-amino-3-methylene-1,2,3,6-tetrahydropyridine
2
o
3
,
2
3
0 mol% PPh and 2.0 equivalents TEA in dioxane at 80 C for 5
of Pd(PPh
)
3 4
to 2a, generating the five-membered vinyl
h under nitrogen atmosphere. Meanwhile, We observed that
vinyl amine substrate 4 was not completely consumed,
presumably because of the lower nucleophilicity of N-
tosylated amine. Hence, in this instance the substrates ratio of
16
palladium complex 8 in the presence of a base. Then,
allenamide 1a is inserted forming a seven-membered ring
intermediate 9. Subsequently, intermediate
intramolecular ligand exchange with double bond to form
intermediate 10, releasing the oxygen nucleophile.
9 undergo
1
a: 4a was adjusted to 1.5:1 providing 5aa in 71% yield. The
reaction with both phenyl and alkyl substituted vinyl iodides
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Journal Name
Michels, H. Schirok, K.-H. Schlemmer, J. Bell, M.VFie.wFAirttzicgleeOranllinde,
Ph
S. Dodd, and A. Gill, WO200376405A1, 2003; (g) G. H. Braun,
I
DOI: 10.1039/C8OB03072C
Pd(0)Ln
D. M. M. Jorge, H. P. Ramos, V. B. da Silva, S. Giuliatti, S. V.
Sampaio, C. A. Taft, and C. H. T. P. Silva, J. Bioml. Struct. Dyn.,
2008, 25, 347-355.
Ph
OH
2a
O
N
HI Base
.
Ts
3aa
2
(a) S. S. Sonar, S. A. Sadaphal, R. U. Pokalwar, B. B. Shingate,
and M. S. Shingare, J. Heterocycl. Chem., 2010, 47, 441-445;
(b) M. Rubiralta, A. Diez, I. Reig, J. Castells, J.-L. Bettiol, D. S.
Grierson, and H.-P. Husson, Heterocycles, 1990, 31, 173-186;
Ph
PdII Ln
O
Ln
II
8
Ph
Pd
(c) F. Benington, R. D. Morin, and L. C. Clark, J. Org. Chem.,
O
N
Ts
1960, 25, 1912-1916; (d) N. Dieltiens, D. D. Claeys, B. Allaert,
F. Verpoort, and C. V. Stevens, Chem. Commun., 2005, 0,
1
0
4
477-4478; (e) Y.-X. Wang, and N. Castagnoli Jr, Tetrahedron
O
Ln
Pd
N
Ligand Exchanging
II
Lett., 1995, 36, 3981-3984; (f) A. I. Meyers, D. A. Dickman,
and T. R. Bailey, J. Am. Chem. Soc., 1985, 107, 7974-7978; (g)
S. Zhang, J. Zhen, M. E. A. Reith, and A. K. Dutta, J. Med.
Chem., 2005, 48, 4962-4971.
Ts
1a
Ph
N
Ts
9
3
4
(a) B. B. Touré, and D. G. Hall, Chem. Rev., 2009, 109, 4439-
Scheme 2 Proposed mechanism.
4
5
486; (b) D. Yadagiri, and P. Anbarasan, Chem. Sci., 2015, 6,
847-5852; (c) A. G. Dossetter, T. F. Jamison, and E. N.
Finally, product 3aa is formed through high selectivity
proximal S 2’ substitution, with no distal S 2 substitution at
the N-allenamides detected. Notably, no Heck-type product
was observed, indicating the high chemoselectivity to S 2’
substitution but not insertion to the double bond. According to
this transformation, the double bond is not only plays an
important role on the ligand exchange, but also easily
converted to more valuable molecules.
In summary, we have developed a palladium-catalyzed,
highly chemo- and regioselective [4 + 2] formal cycloaddition
involving (Z)-3-iodo allylic nucleophiles and allenamides. The
corresponding products were produced in moderate to good
yields. The approach provided a straightforward access to 2-
amino-dihydropyrans and 2-amino-tetrahydropiperidines.
Moreover, the [4 + 2] formal cycloaddition derivatives
underwent an intramolecular ring-closing reaction by means of
Grubbs catalyst II. The proposed mechanism confirmed that
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