Palladium-Catalyzed Umpolung Type-II Cyclization of Allylic Carbonate-Aldehydes Leading to 3-Methylenecycloalkanol Derivatives

Article abstract of DOI:10.1002/adsc.201900450

Palladium-catalyzed umpolung type-II cyclization of allylic carbonate-aldehydes leading to 3-methylenecycloalkanol derivatives was developed. The formate reductant was effective for the cyclization without causing a reduction of the η³-allylpalladium intermediate. One-pot decarboxylative allylation of aldehyde-containing malonate with 2-[(acetyloxy)methyl]-2-propenyl methyl carbonate followed by the cyclization of the allyl acetate-aldehyde formed in situ was also achieved. The high diastereoselectivities observed in the cyclization of branched substrates indicates that a chair-chair transition state should be involved. Based on the presumed transition state, we could predict the enantioselectivity of the cyclization using SEGPHOS as a chiral diphosphine ligand and obtain optically active alcohols in up to 95:5 er. (Figure presented.).

Full text of DOI:10.1002/adsc.201900450

Title: Palladium-Catalyzed Umpolung Type-II Cyclization of Allylic
Carbonate-Aldehydes Leading to 3-Methylenecycloalkanol
Derivatives
Authors: Hirokazu Tsukamoto, Kawase Ayumu, and Takayuki Doi
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10.1002/adsc.201900450
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Umpolung Type-II Cyclization of Allylic
Carbonate-Aldehydes Leading to 3-Methylenecycloalkanol
Derivatives
Hirokazu Tsukamoto,*a, b Ayumu Kawasea and Takayuki Doia
a
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai 980-8578,
Japan. Phone and Fax: +81-22-795-6867.
Department of Pharmaceutical Sciences, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama
b
245-0066, Japan. Phone: +81-45-859-1300. Fax: +81-45-859-1301. E-mail: hirokazu.tsukamoto@hamayaku.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
contrast to type-I metallo-carbonyl ene cyclization,[9]
Abstract.
Palladium-catalyzed
umpolung
type-II
cyclization of allylic carbonate-aldehydes leading to 3- type-II one involving six-membered ring formation
methylenecycloalkanol derivatives was developed. The
formate reductant was effective for the cyclization without
causing a reduction of the 3-allylpalladium intermediate.
One-pot decarboxylative allylation of aldehyde-containing
malonate with 2-[(acetyloxy)methyl]-2-propenyl methyl
carbonate followed by the cyclization of the allyl acetate-
aldehyde formed in situ was also achieved. The high
diastereoselectivities observed in the cyclization of
branched substrates indicates that a chair-chair transition
state should be involved. Based on the presumed transition
state, we could predict the enantioselectivity of the
cyclization using SEGPHOS as a chiral diphosphine ligand
and obtain optically active alcohols in up to 95:5 er.
and its asymmetric variant has hardly been explored
(Scheme 1).[10–14] Then, we direct our attention to the
palladium-catalyzed umpolung type-II cyclization of
allylic carbonate (or acetate)-aldehyde
demonstrate the following three matters: 1) the
reaction conditions to afford 3-
methylenecyclohexanol derivatives 2 without causing
both Tsuji-Trost reaction[15] and reduction of 3-
allylpalladium intermediate[16]; 2) diastereoselectivity
to give important information about its uncertain
transition state (chair-chair, chair-boat, etc.)[17–19]; 3)
enantioselectivity, which has scarcely been achieved.
1
to
Keywords: allylic carbonate; diastereoselectivity;
enantioselectivity; one-pot; palladium; umpolung
cyclization
O
R
R
HO
Type I cyclization
previous report
X
P
P
X
H
X
Pd+
O
OAc
R
An allylpalladium species usually generated by
oxidative addition of an allylic acetate or carbonate to
a palladium(0) catalyst is one of the most versatile
R1
h 2
X
PR2
R1
X
P
HO
R3
Pd+
P
h 2
O
intermediates
in
organic
synthesis.[1]
The
P
R1
X
O
R3
R2
allylpalladium exists in an equilibrium between an
electrophilic 3-complex and nucleophilic 1-one
which strongly biases toward the former. Therefore it
is mainly utilized as an electrophile and an
incorporation of chiral ligands enables the
enantioselective allylation of various nucleophiles.[2]
Type II
cyclization
2
chair-chair TS 3
h 2
P
P
this report
R1
X
HO
R3
R1
R2
RO
Pd+
X
P
R3
R2
h 2
O
P
1: R=CO2Me or Ac
R3
chair-boat TS 3'
R2
2'
It is also possible to make use of the intermediate as a
4]
nucleophile,[3,
particularly in an intramolecular
Scheme 1. Type-I and II Pallado-Carbonyl Ene Reactions
process, because the thermodynamically unstable 1-
complex is more effectively captured by an adjacent
electrophile rather than external one. We have
recently reported the palladium-catalyzed asymmetric
umpolung type-I cyclization of allylic acetate-
aldehydes using a combination of formate reductant[5]
and commercially available chiral diphosphine
ligands, i.e., SEGPHOS[6] or DM-SEGPHOS.[7, 8] In
Prior to the development of the asymmetric
cyclization, we ascertained whether the reaction
conditions for the type-I cyclization using achiral
diphosphine, i.e., 1,2-bis(diphenylphosphino)ethane
(dppe), instead of SEGPHOS was applicable to the
1
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10.1002/adsc.201900450
Advanced Synthesis & Catalysis
unexplored six-membered ring formation (Table 1).
To our delight, the combination of formic acid and
tributylamine also worked well for the cyclization of
allylic acetate 1a or carbonate 1b tethered by p-
toluenesulfonamide to afford 2a in excellent yields
(Entries 1 and 2). In the case of carbonate 1b, the
amine could be omitted owing to the basicity of the
methoxide ion in situ formed from the leaving group
(Entry 3).
Table 2. Substrate Scope[a]
Substrate[b]
Entry
Temp
Product
Time
14 h
Yield[c]
73%[d]
O
Me
HO
Me
NTs
NTs
1
50 °C
RO
RO
RO
2c
2d
1c
O
HO
NTs
Me
NTs
Me
2
3
50 °C
13 h
92%[d]
77%[d]
91%
Table 1. Effect of Leaving Groups and Reductant.
1d
O
HO
O
10 mol% Pd[P(o-tolyl)3]2
HO
15 mol% dppe
NTs
Me
NTs
NTs
NTs
50 °C
8 h
Reductant
CH3CN (0.05 M), 50 °C
Me
RO
1a: R = Ac
2e
2f
1e
2a
1b: R = CO2Me
O
HO
O
O
4
5
6
7
50 °C
50 °C
50 °C
80 °C
5 h
10 h
5 h
Time Yield
Entry
R
Reductant
RO
(h)
(%)[c]
1f
HCO2H-Bu3N[a]
9
20
8
96
99
84
O
Me
O
HO
Me
O
1
2
3
Ac (1a)
CO2Me (1b) HCO2H-Bu3N[a]
71%
(dr 10:1)
CO2Me (1b)
[a] 3 equiv. [b] 1 equiv. [c] Isolated yield.
HCO2H[b]
RO
[e]
2g
1g
O
HO
O
O
84%
(dr 4:1)
Next, substrate scope was explored (Table 2).
Introduction of a methyl group at either -position of
p-toluenesulfonamide group led the exclusive
formation of trans-adducts 2c and 2d (Table 2,
RO
O
Me
Me
2h[e]
1h
1i
HO
CO2Et
CO2Et
CO2Et
CO2Et
8 h
95%
Entries 1 and 2). As seen in the related compounds[20]
,
OR
2i
2j
NOESY spectra of these adducts with two trans-
substituents at 5,6- and 2,5-positions showed that
both of the substituents occupied pseudoaxial
positions to prevent unfavorable gauche interactions
between the methyl and N-tosyl groups (Figure 1).
The reaction of secondary allylic carbonate 1e
resulted in the regio- and diastereoselective
cyclization to give cis-adduct 2e in high yield (Entry
3 and Figure 1). Oxygen-tethered substrates 1f–h also
underwent the reductive cyclization to give
O
HO
CO2Et
CO2Et
8
80 °C
9 h
89%[d]
OR
1j
O
HO
9
80 °C
50 °C
12 h
30 h
9 h
45%
78%
59%
65%
40%
RO
2k
1k
O
HO
tetrahydro-5-methylene-2H-pyran-3-ols
2f–h in
NTs
NTs
10
11
12
13
excellent yields (Entries 4–6). Although the
predominant formation of cis-substituted pyrans 2g
and 2h seems to contrast with the stereoselectivity
observed in the cyclization of sulfonamide-tethered
substrates 1c and 1d, all of the hydroxyl groups are
oriented in the common pseudoaxial positions in 2c-d
and 2g-h to minimize the 1,3-diaxial interactions
(Entries 1 vs. 5 and 2 vs. 6 and Figure 1).[21] In
contrast to piperidin-3-ols 2c and 2d, trans-
substituted pyrans 2g' and 2h' as minor diastereomers
obtained from 1g and 1h adopted di-pseudoequatorial
conformation (See Supporting Information).
RO
1l
2l
Me
Me
O
HO
NTs
NTs
100 °C
RO
2m
1m
O
OH
50 °C
9 h
O
O
OR
RO
1n
2n
O
HO
100 °C
20 h
2o
1o
[a] 1 equiv HCO2H was used as a reductant. [b] R = CO2Me
(entries 1–11 and 13) and R = CO2Et (entry 12). [c] Isolated
yield. [d] A single diastereomer was obtained. [e] Only major
isomer is shown.
2
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10.1002/adsc.201900450
Advanced Synthesis & Catalysis
HO
H
HO
H
HO
H
H
NTs
H
in 1j occupying pseudoequatorial positions in TS-3
(Scheme 1 and Table 1, Entries 5, 6, and 8). In the
case of 1c and 1d, the methyl substituent would be
oriented in the pseudoaxial position of TS-3 to avoid
unfavorable gauche interactions between the methyl
and N-tosyl groups. Cis-diastereoselective cyclization
of 1e should be derived from thermodynamically
more stable anti-3-allypalladium.[25] Electron-
withdrawing hetero atoms in the tether would
increase the electrophilicity of the carbonyl groups by
the inductive effect and accelerate the reaction. Rigid
sp2 aromatic ring in the tether moiety may cause the
strain in the transition state leading to the low product
yields.
NTs
NTs
Me
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
2c
2d
2e
H
ArCOO
ArCOO
HO
H
H
O
H
Me
O
CO2Et
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
p-nitrobenzoate
of 2g(major)
p-nitrobenzoate
of 2h (major)
2j
Ar = C6H4-p-NO2
Figure 1. NOESY Correlations of 2c–e, j and p-
Nitrobenzoates of 2g and 2h (major isomer) and Their
Conformations.
Finally, we investigated the asymmetric type-II
cyclization reaction with SEGPHOS ligand (Scheme
3 and Table 3). The reaction of oxygen-tethered
substrate 1f with (S)-SEGPHOS ligand instead of
dppe led to the formation of 2f in 70:30 er in favor of
(R)-isomer (Table 3, Entry 1).[26] The moderate
enantiomeric ratio of 2f indicates that the activation
energy of transition state 7 (TS-7) leading to (R)-2 is
slightly lower than that of TS-7' leading to (S)-2
(Scheme 3). The difference in the activation energy
between TS-7 and 7' can be enhanced by introduction
of dialkyl groups at the allylic position as R2, which
generate more severe steric repulsion with the
pseudoequatorial phenyl group on the right
phosphorus atom in TS-7' rather than TS-7. As we
expected, dimethyl-substituted substrate 1p (R1=H,
R2=Me) successfully underwent the enantioselective
cyclization to afford (R)-2p in 95:5 er (Table 3, entry
2). On the other hand, the major enantiomer of the
product was switched by shifting the position of
geminal dimethyl groups to the -position of
carbonyl group in 1q (R1=Me, R2=H) (Table 3, entry
3). The identical selectivity was also observed in the
cyclization of sulfonamide-tethered substrate 1r
(Table 3, entry 4). The predominant formation of (S)-
2q and (S)-2r should be ascribed to more severe
steric repulsion between R1 groups and the pseudo-
equatorial phenyl group of SEGPHOS in TS-7 rather
than TS-7' (Scheme 3).
The cyclization of carbon-tethered ones 1i–k required
higher reaction temperature to complete conversion
to give 2i–k in moderate to excellent yields (Table 2,
Entries 7–9). It is noteworthy that the product 2i
could also be obtained in good yield by one-pot
sequence consisting of decarboxylative allylation of
diethyl 2-oxoethylmalonate (5) with 2-[(acetyloxy)
methyl]-2-propenyl methyl carbonate (4) under
Pd(PPh3)4 catalysis in THF[22] followed by reductive
cyclization of the allylic acetate-aldehyde
intermediate 6 with the aid of diphosphine ligand and
acetonitrile solvent (Scheme 2). The stereocenter in
the tether carbon in 1j induced perfect trans-
diastereoselectivity leading to 2j (Entry 8). These
diastereoselectivities gave us information about the
transition state as a hint for the asymmetric variant
(vide infra). The reaction of homolog 1l also
proceeded well to give seven-membered ring 2l in
high yield (Entry 10).[23] Tertiary alcohol 2m was
obtained in moderate yield when ketone 1m was
heated at 100 °C under the similar reaction conditions
(Entry 11).[24] The planar benzene tether in 1n and 1o
seemed to cause lowering yields of six-membered
heterocycle 2n and five-membered carbocycle 2o
(Entries 12 and 13).
O
CO2Et
O
HO
CO2Et
CO2Et
CO2Et
5
CO2Et
OCO2Me
4
CO2Et
10 mol% Pd(PPh3)4
THF, rt, 1 h;
15 mol% dppe,
3 equiv Bu3N-HCO2H
CH3CN, 80 °C, 12 h
OAc
2i (61%)
R1
6
OAc
HO
R1
R1
P
X
R2
Pd+
X
P
R1
O
R2
H
R2
R2
Scheme 2. One-Pot Reaction between 4 and 5 Leading to
2i.
R1
O
(R)-2
R1
transition state 7 for (R)-2
X
R2
R2
Based on the diastereoselectivity shown in Table 2,
the cyclization would proceed through Zimmerman-
Traxler chair-like transition state 3 (TS-3) where the
other six-membered ring also exists in a chair
conformation rather than a boat conformation (TS-3')
(Scheme 1). Except for toluenesulfonamide-tethered
substrates 1c and 1d, the high diastereoselectivities
can be rationalized by not only the methyl substituent
in 1g and 1h but also the ethoxycarbonyl substituent
OCO2Me
R2
R2
1f: X=O, R1=R2=H
R2
P
1p: X=O, R1=H, R2=Me
1q: X=O, R1=Me, R2=H
1r: X=NTs, R1=Me, R2=H
X
R1
X
Pd+
P
R2
R1
R1
O
R1
(S)-2
HO
H
transition state 7´ for (S)-2
Scheme
3.
(S)-SEGPHOS-Ligated
Pd-Containing
Transition States 7 and 7' Leading to (R)- and (S)-2.
3
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10.1002/adsc.201900450
Advanced Synthesis & Catalysis
To a test tube containing a solution of 1f·p–r (1.0 equiv) in
anhydrous CH3CN (0.05 M) were added Pd[P(o-tolyl)3]2
(10 mol%), (S)-SEGPHOS (15 mol%), and HCO2H (1.0
equiv) under argon. The resulting mixture was sealed with
a screw cap and stirred at 80 °C for the time described in
Table 3. Then the mixture was concentrated in vacuo. The
residue was purified by silica gel chromatography (11%
Et2O/hexane) for 2f·p·q or preparative TLC (20%
EtOAc/toluene, developed 2 times) for 2r to afford 2f·p–r.
Except for 2r, the enantiomeric ratio (er) of the products
was determined by chiral HPLC after conversion of the
products to their p-nitrobenzoates (p-NO2BzCl, Et3N,
DMAP and DCM). The absolute configurations were
determined by modified Mosher’s method[27] using major
and minor diastereomers of (R)-MTPA esters, which were
obtained by condensation of the products (DCC, DMAP
and DCM) with (R)-Mosher’s acid and subsequent
separation with preparative TLC. In the case of 2r, the
enantiomeric ratio was directly determined by chiral HPLC
and the absolute configuration was determined by modified
Mosher’s method using major diastereomers of its (R)- and
(S)-MTPA esters.
Table 3. Effect of Substituents on the Asymmetric
Cyclization of 1f and 1p–r.
R1
R1
R2
O
HO
R1
R1
R2
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-SEGPHOS
X
X
X
+
1.0 equiv HCO2H
R2
R2
R1
CH3CN (0.05 M), 80 °C
R2
R2
R1
(S)-2
HO
OCO2Me
(R)-2
1f: X=O, R1=R2=H
1p: X=O, R1=H, R2=Me
1q: X=O, R1=Me, R2=H
1r: X=NTs, R1=Me, R2=H
Isolated
Er
Entry
1
2
Time (h)
(R):(S)[a]
yield (%)
1
2
3
4
19
8
72
36
49
83
74
60
70:30
95:5
27:73
12:88
1f
1p
1q
1r
2f
2p
2q
2r
[a] Enantiomeric ratio (er) was determined by chiral HPLC.
Acknowledgements
This work was partly supported by The Research Foundation for
Pharmaceutical Sciences, SUNTRY FOUNDATION for LIFE
SCIENCES, Platform Project for Supporting Drug Discovery and
Life Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research (BINDS)) from AMED
under Grant Number JP18am0101095 and JP18am0101100, and
JSPS KAKENHI Grant Numbers JP24590004 and JP15H05837
in Middle Molecular Strategy.
In summary, we developed palladium-catalyzed
umpolung type-II cyclization of allylic carbonate-
aldehydes leading to 3-methylenecycloalkanol
derivatives. The high diastereoselectivities observed
in the cyclization of branched substrates indicates that
a chair-chair transition state should be involved.
Based on the presumed transition state, we designed
some substrates for its asymmetric variant using
SEGPHOS as a chiral diphosphine ligand, which
were converted into optically active alcohols in up to
95:5 er.
References
[1] a) P. W. Jolly, Angew. Chem. Int. Ed. Engl. 1985, 24,
283–295; b) J. Tsuji, in Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 2 (Eds.: E.
Negishi), WILEY, New York, 2002, pp. 1669–1687; c)
L. Acemoglu, J. M. J. Williams, in Handbook of
Organopalladium Chemistry for Organic Synthesis, Vol.
2 (Eds.: E. Negishi), WILEY, New York, 2002, pp.
1689–1705; d) G. Poli, G. Prestat, F. Liron, C.
Kammerer-Pentier, Top. Organomet. Chem. 2012, 38,
1–64.
Experimental Section
General procedure for umpolung cyclization of allylic
carbonate-carbonyls 1b–o (Table 1 and 2)
To a test tube containing a solution of 1b–o (1.0 equiv) in
anhydrous CH3CN (0.05 M) were added Pd[P(o-tolyl)3]2
(10 mol%), dppe (15 mol%) and HCO2H (1.0 equiv) under
argon. The resulting mixture was sealed with a screw cap
and stirred at the temperature for the time described in
Table 1 and 2. Then the mixture was concentrated in vacuo.
The residue was purified by preparative TLC or silica gel
chromatography to afford 2b–o.
[2] a) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996,
96, 395–422; b) B. M. Trost, D. R. Fandrick,
Aldrichimica Acta 2007, 40, 59–72; c) B. M. Trost, M.
L. Crawley, Chem. Rev. 2003, 103, 2921–2943; d) B.
M. Trost, Top. Organomet. Chem. 2012, 38, 321–340;
e) T. Hayashi, J. Organomet. Chem. 1999, 576, 195–
202; f) T. Hayashi, Acc. Chem. Res. 2000, 33, 354–362.
General procedure for one-pot Tsuji-Trost reaction
and umpolung cyclization between 4 and 5 (Scheme 2)
To a test tube containing a solution of 4 (18.6 mg, 0.099
mmol) and 5 (20.0 mg, 0.099 mmol) in anhydrous THF
(2.0 mL) was added Pd(PPh3)4 (11.5 mg, 0.010 mmol)
under argon. The resulting mixture was sealed with a
screw cap and stirred at room temperature for 1 h. To the
mixture were added dppe (5.9 mg, 0.015 mmol), HCO2H-
Bu3N (11.2 µL/ 70.5 µL, 0.30 mmol) and anhydrous
CH3CN (2.0 mL). The resulting mixture was stirred at
80 °C for 12 h and then treated with water. The aqueous
layer was extracted with EtOAc twice. The combined
organic layers were washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by
silica gel chromatography (14% EtOAc/hexane) to afford
2i (15.5 mg, 0.060 mmol, 61%).
[3] a) Y. Tamaru, J. Organomet. Chem. 1999, 576, 215–
231; b) J. A. Marshall, Chem. Rev. 2000, 100, 3163–
3185; c) K. J. Szabó, Chem. Eur. J. 2004, 10, 5268–
5275; d) Y. Yamamoto, I. Nakamura, Top. Organomet.
Chem. 2005, 14, 211–239; e) H. C. Malinakova, Lett.
Org. Chem. 2006, 3, 82–90; f) G. Zanoni, A. Pontiroli,
A. Marchetti, G. Vidari, Eur. J. Org. Chem. 2007,
3599–3611; g) M. Jeganmohan, C.-H. Cheng, Chem.
Commun. 2008, 3101–3117; h) K. Spielmann, G. Niel,
R. M. de Figueiredo, J.-M. Campagne, Chem. Soc. Rev.
2018, 47, 1159–1173.
General procedure for asymmetric umpolung
cyclization of allylic carbonate-aldehydes 1f·p–r (Table
3)
4
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10.1002/adsc.201900450
Advanced Synthesis & Catalysis
[4] Iridium-catalyzed umpolung allylations, see S. W. Kim,
W. Zhang, M. J. Krische, Acc. Chem. Rev. 2017, 50,
2371–2380.
[16] J. Tsuji, T. Mandai, Synthesis 1996, 1–24.
[17] Chair-transition state for type-II carbonyl-ene
cyclizations: M. I. Johnston, J. A. Kwass, R. B. Beal, B.
B. Snider, J. Org. Chem. 1987, 52, 5419–5424.
[5] The first use of a non-metallic reductant in umpolung
allylation of allylic acetates and aldehydes, see I. S.
Kim, M.-Y. Ngai, M. J. Krische, J. Am. Chem. Soc.
2008, 130, 6340–6341.
[18] Boat-transition state for type-II carbonyl-ene
cyclizations: D. C. Braddock, K. K. Hii, J. M. Brown,
Angew. Chem. Int. Ed. 1998, 37, 1720–1723.
[6] H. Shimizu, I. Nagasaki, K. Matsumura, N. Sayo, T.
[19] Open transition state for type-II carbonyl-ene
cyclizations: a) K. Maruoka, T. Ooi, H. Yamamoto, J.
Am. Chem. Soc. 1990, 112, 9011–9012; b) T. Ooi, K.
Maruoka, H. Yamamoto, Tetrahedron 1994, 50, 6505–
6522.
Saito, Acc. Chem. Res., 2007, 40, 1385–1393.
[7] For Pd(0)-catalyzed umpolung type-I cyclizations of
allylic acetate-aldehydes using formate reductant, see H.
Tsukamoto, A. Kawase, T. Doi, Chem. Commun., 2015,
51, 8027–8030.
[20] 2-Alkyl-substituted N-tosyl-piperidines are reported
to adopt 2-pseudoaxial conformations: a) B. M. Trost,
J.-P. Surivet, F. D. Toste, J. Am. Chem. Soc. 2004, 126,
15592–15602; b) S. J. Hedley, W. J. Moran, A. H. G. P.
Prenzel, D. A. Price, J. A. A. Harrity, Synlett 2001,
1596–1598; c) A. Kennedy, A. Nelson, A. Perry,
Beilstein J. Org. Chem. 2005, 1, 1–12; d) M. Y.
Kawamura, A. G. Talero, J. V. Santiago, E. Garambel-
Vilca, I. G. Rosset, A. C. B. Burtoloso, J. Org. Chem.
2016, 81, 10569–10575; e) R. F. de la Pradilla, C.
Simal, R. H. Bates, A. Viso, L. Infantes, Org. Lett.
2013, 15, 4936–4939; f) L.-X. Liao, Z.-M. Wang, H.-X.
Zhang, W.-S. Zhou, Tetrahedron: Asymmetry 1999, 10,
3649–3657; g) J. C. Hopman, E. van den Berg, L. O.
Ollero, H. Hiemstra, W. N. Speckamp, Tetrahedron
Lett. 1995, 36, 4315–4318.
[8] For related Pd(II)-catalyzed umpolung cyclizations of
allenic aldehydes with arylboronic acids, see a) H.
Tsukamoto, T. Matsumoto, Y. Kondo, Org. Lett. 2008,
10, 1047–1050; b) X. Zhang, X. Han, X. Liu, Org. Lett.
2015, 17, 3910–3913.
[9] a) W. Oppolzer, V. Snieckus, Angew. Chem. Int. Ed.
Engl. 1978, 17, 476–486; b) M. L. Clarke, M. B.
France, Tetrahedron 2008, 64, 9003–9031.
[10] Palladium-catalyzed cyclizations of allylic acetate-
carbonyls in the presence of metallic reagents leading
to 3-methylene-cyclopentanols, cycloheptanols, and -
cyclooctanols: a) Y. Masuyama, Y. Nimura, Y. Kurusu,
Tetrahedron Lett. 1992, 33, 6477–6478; b) T. Ahiko, T.
Ishiyama, N. Miura, Chem. Lett. 1997, 811–812; c) R.
Mukai, Y. Horino, S. Tanaka, Y. Tamaru, M. Kimura, J.
Am. Chem. Soc. 2004, 126, 11138–11139; d) V. C.
Nguyen, Y.-T. Kim, Y.-K. Yu, H.-Y. Kang, Bull.
Korean Chem. Soc. 2005, 26, 711–712.
[21] Because tetrahydro-5-methylene-2H-pyran-3-ols 2f–h
were volatile, full structure determinations based on
NMR spectra were carried out after conversion of them
to their p-nitrobenzoates.
[11] Barbier-type cyclizations of allylic halide-carbonyls
leading to 3-methylenecyclopentanols: a) J. Nokami, S.
Wakabayashi, R. Okawara, Chem. Lett. 1984, 869–870;
b) G. A. Molander, J. B. Etter, P. W. Zinke, J. Am.
Chem. Soc. 1987, 109, 453–463; c) A. Kinoshita, M.
Miwako, Chem. Lett. 1994, 1475–1478; (d) Y.-Q. Lu,
C.-J. Li, Tetrahedron Lett. 1996, 37, 471–474; (e) G. A.
Molander, Y. L. Huérou, G. A. Brown, J. Org. Chem.
2001, 66, 4511–4516;
[22] J. Tsuji, I. Shimizu, I. Minami, Y. Ohashi,
Tetrahedron Lett. 1982, 23, 4809–4812.
[23] Type-II carbonyl-ene cyclizations leading to seven-
membered ring: a) N. H. Andersen, H.-S. Uh, S. E.
Smith, P. G. M. Wuts, J. Chem. Soc., Chem. Commun.
1972, 956–957; b) N. H. Andersen, F. A. Golec, Jr.,
Tetrahedron Lett. 1977, 3783–3786; c) K. Mikami, M.
Terada, E. Sawa, T. Nakai, Tetrahedron Lett. 1991, 32,
6571–6574.
[12] Palladium(0)-catalyzed annulation between ortho-
aldehyde-containing aryl halides and allene leading to
3-methylenecyclopentanols or cyclohexanols: a) U.
Anwar, R. Grigg, M. Rasparini, V. Savlc, V. Sridharan,
Chem. Commun. 2000, 645–646; b) X. Gai, R. Grigg, S.
Collard, J. E. Muir, Chem. Commun. 2000, 1765–1766.
[24] Type-II carbonyl-ene cyclizations of ketones: a) L. E.
Overman, D. Lesuisse, Tetrahedron Lett. 1985, 26,
4167–4170; b) C.-M. Cheung, D. Craig, R. S. Todd,
Synlett 2001, 1611–1613.
[25] a) J. W. Faller, M. E. Thomsen, M. J. Mattina, J. Am.
Chem. Soc. 1971, 93, 2642–2653; b) J. W. Faller, M. T.
Tully, K. J. Laffey, J. Organomet. Chem. 1972, 37,
193–199.
[13] Palladium(II)-catalyzed annulation between 2-
formylarylboronic acids and allenoates leading to
indenol derivatives: X. Yu, X. Lu, Org. Lett. 2009, 11,
4366–4369. In this paper, a single example of its
asymmetric reaction is shown.
[26] The moderate enantioselectivity observed in the
cyclization of 1f may stem from a lean of the
Zimmerman-Traxler transition states where allylic R1
group in 7' is closer to the pseudoequatorial phenyl
group on the right phosphorus atom than R2 group at
the carbonyl alpha-position in 7. Similar tendency is
also observed in type I cyclization.
[14] K. Mikami, E. Sawa, M. Terada, Tetrahedron
Asymmetry 1991, 2, 1403–1412.
[15] a) M. E. Krafft, M. C. Lucas, Chem. Commun. 2003,
1232–1233; b) J. Bian, M. Van Wingerden, J. M.
Ready, J. Am. Chem. Soc. 2006, 128, 7428–7429.
5
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10.1002/adsc.201900450
Advanced Synthesis & Catalysis
[27] a) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J.
Am. Chem. Soc. 1991, 113, 4092–4096; b) J. A. Dale,
D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543–2549; c) J. A. Dale, H. S. Mosher, J. Am. Chem.
Soc. 1973, 95, 512–519.
6
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10.1002/adsc.201900450
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium-Catalyzed Umpolung Type-II
Cyclization of Allylic Carbonate-Aldehydes
Leading to 3-Methylenecycloalkanol Derivatives
R1
h 2
R1
X
R1
X
O
P
HO
R3
X
PR2
10 mol% Pd[P(o-tolyl)3]2
Pd+
15 mol% dppe
P
h 2
O
P
1 eq. HCO2H
MeCN, 50–80 °C
Adv. Synth. Catal. Year, Volume, Page – Page
R2
R2
R3
MeO2CO
chair-chair TS
R3
Type II cyclization
40–95% yield
18 examples
X = NTs, O, CR2 et. al.
R1, R2, R3 = H or Me
Hirokazu Tsukamto*, Ayumu Kawase, Takayuki
Doi
7
This article is protected by copyright. All rights reserved.