Palladium-Catalyzed Sequential Twofold Nucleophilic Substitution on 3-Bromopenta-2,4-dienyl Phosphate: Preparation of C1- And C2-Symmetric Doubly Functionalized Allenes

Article abstract of DOI:10.1021/acs.joc.9b01933

Readily available 3-bromopenta-2,4-dienyl esters (1x, acetate; 1y, benzoate; 1z, diethyl phosphate) were applied to the palladium-catalyzed reaction with various soft nucleophiles. The reaction proceeded through the twofold nucleophilic substitution via formal S_N2′- and S_N2-processes, giving the various doubly functionalized allenes 2 in good yields. In the reactions of carboxylates 1x and 1y, the first substitution took place at the C-Br bond to form (allenyl)methyl ester intermediates 3. Because the second substitution on 3 proceeded faster than the first substitution on 1x or 1y, 3 was not isolable, and C₂-symmetric allenes 2 were obtained even in the presence of remaining 1x and 1y. On the other hand, the phosphate moiety was more reactive than the C-Br moiety in 1z. The initial products from 1z were 5-Nu-3-bromopenta-1,3-dienes 4, which were less reactive than 1z. Monosubstitution products 4 were isolable, and the stepwise introduction of two different Nu groups in C₁-symmetric allenes 2 was realized starting with 1z under the controlled reaction conditions. By the use of a chiral palladium catalyst, axially chiral doubly functionalized allenes were obtained up to 95% ee.

Full text of DOI:10.1021/acs.joc.9b01933

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Article
Palladium-Catalyzed Sequential Twofold Nucleophilic
Substitution on 3-Bromopenta-2,4-dienyl Phosphate: Preparation
of C1- and C2-Symmetric Doubly Functionalized Allenes
Yen-Chou Chen, and Masamichi Ogasawara
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01933 • Publication Date (Web): 09 Sep 2019
Downloaded from pubs.acs.org on September 9, 2019
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Palladium-Catalyzed Sequential Twofold Nucleophilic
Substitution on 3-Bromopenta-2,4-dienyl Phosphate:
Preparation of C1- and C2-Symmetric Doubly
Functionalized Allenes
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Yen-Chou Chen†,‡ and Masamichi Ogasawara*,†
†Department of Natural Science, Graduate School of Science and Technology and Research Cluster on
"Innovative Chemical Sensing", Tokushima University, Tokushima 770-8506, Japan
‡Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan
ogasawar@tokushima-u.ac.jp
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted)
Table of Contents/Abstract Graphic
+ Nu–
+ Nu'–
(EtO)2PO
O
Nu
Nu
•
Pd (cat.)
Pd (cat.)
Nu'
Br
Br
isolable
Abstract. Readily available 3-bromopenta-2,4-dienyl esters (1x, acetate; 1y, benzoate; 1z, diethyl
phosphate) were applied to the palladium-catalyzed reaction with various soft nucleophiles. The
reaction proceeded through the twofold nucleophilic substitution via formal SN2'- and SN2-processes
giving the various doubly functionalized allenes 2 in good yields. In the reactions of carboxylates 1x
and 1y, the first substitution took place at the C-Br bond to form (allenyl)methyl ester intermediates 3.
Because the second substitution on 3 proceeded faster than the first substitution on 1x or 1y, 3 were not
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isolable and C2-symmetric allenes 2 were obtained even in the presence of remaining 1x and 1y. On the
other hand, the phosphate moiety was more reactive than the C-Br moiety in 1z. The initial products
from 1z were 5-Nu-3-bromopenta-1,3-dienes 4 which were less reactive than 1z. Monosubstitution
products 4 were isolable, and the stepwise introduction of two different Nu groups in C1-symmetric
allenes 2 was realized starting with 1z under the controlled reaction conditions. By the use of a chiral
palladium catalyst, axially chiral doubly functionalized allenes were obtained in up to 95% ee.
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Introduction
Development of novel and efficient methods of preparing allenic compounds has been an important
subject due to synthetic usefulness of allenes in organic chemistry.1 In 2000, we reported a palladium-
catalyzed reaction for preparing various functionalized allenes starting with an easily accessible 1-
hydrocarbyl- or 1-silyl-2-bromo-1,3-diene and a soft nucleophile (Scheme 1, top).2 By the use of an
appropriate chiral palladium species as a precatalyst, the reaction could provide enantiomerically
enriched axially chiral allenes in up to 94% ee.3 A key intermediate of the palladium-catalyzed process
is an (alkylidene-p-allyl)palladium species,4 that is somewhat similar to the widely accepted
intermediates in the Tsuji-Trost reaction.5 Addition of an allenylmethyl ester to a zero-valent palladium
species also provides an analogous (alkylidene-p-allyl)palladium species,6 and its reaction with soft
nucleophiles gives comparable allenic products (Scheme 1, bottom).7 As shown in Scheme 1, the two
Pd-catalyzed processes are closely related to each other.
Scheme 1. Palladium-Catalyzed Nucleophilic Substitution on 2-Bromo-1,3-dienes and Allenylmethyl
Esters.
R
+
Br
Nu
+ Pd0Ln
+ Nu–
•
R
R = alkyl, aryl, silyl
R
PdLn
OE
•
R
E = Ac or
P(O)(OR')2
In 2012, we introduced 3-bromopenta-2,4-dienyl acetate (1x) as a unique bifunctional electrophile in
the palladium-catalyzed reaction.8 Compound 1x possesses properties and substructures of both 2-
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bromo-1,3-dienes and allylic acetates, and it undergoes the "twofold Pd-catalyzed nucleophilic
substitution" to give doubly functionalized C2-symmetric allenes 2 in high yields with excellent
regioselectivity. The vinylic C-Br bond in 1x is more reactive than the allylic acetate moiety in the
addition to Pd(0), and thus the primal intermediary product is allenylmethyl acetate 3. Whereas
monosubstituted intermediate 3 is more reactive than 1x in the palladium-catalyzed reaction, generated
3 is consumed faster than 1x. Accordingly, 3 is not isolable nor detectable, and C2-symmetric doubly
substituted allene 2 is obtained preferentially even in the presence of remaining 1x (Scheme 2). In other
words, stepwise introduction of two different Nu-groups in the doubly substituted allenes is not possible
by the palladium-catalyzed reaction of 1x.
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Scheme 2. Palladium-Catalyzed Double Nucleophilic Substitution on 3-Bromo-2,4-pentadienyl Acetate
1x.
AcO
Nu
+ 2 Nu–
•
Pd-cat.
Nu
Br
1x
2
slower
+ Nu–
faster
+ Pd0
+ Nu–
+ Pd0
AcO
•
Nu
AcO
Nu
3
not isolable
Br–
AcO–
[Pd]+
[Pd]+
In this article, we examine the effects of acyl groups in 3-bromopenta-2,4-dienyl esters in the
palladium-catalyzed reaction. It is found that the reactivity of 3-bromopenta-2,4-dienyl diethyl
phosphate (1z) is different from that of the corresponding carboxylates. The allylic phosphate moiety is
the better leaving group than the vinylic bromide in 1z, and the monosubstituted intermediates,
bromodienes 4, can be isolated starting with 1z. That is, stepwise introduction of two different Nu
groups is realized starting with 1z leading to various doubly substituted unsymmetric (C1-symmetric)
allenic products 2 (Scheme 3).
Scheme 3. Palladium-Catalyzed "Sequential" Double Nucleophilic Substitution on 3-Bromo-2,4-
pentadienyl Diethyl Phosphate 1z.
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O
1
2
+ Nu–
Pd-cat.
+ Nu'–
Nu
Nu
(EtO)2PO
•
Nu'
Pd-cat.
Br
3
4
5
Br
1z
4
2
isolable
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Results and Discussion
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Preparation of 3-Bromopenta-2,4-dienyl Esters 1. The substrates for this study, 3-bromopenta-2,4-
dienyl benzoate (1y), phosphate (1z), and carbonate (1w), were prepared as depicted in Scheme 4
starting with O-TBS-protected (Z)-3-bromopenta-2,4-dienol (5).9 The fluoride-induced desilylation of 5
followed by reactions with benzoyl chloride, diethyl chlorophosphate, or ethyl chlorocarbonate afforded
(Z)-1w-z in 77-89% yields. Whereas unprotected 3-bromopenta-2,4-dienol was susceptible to
polymerization, it was applied to the esterification without extensive purification/isolation. Among the
three bromopentadienyl esters, carbonate 1w was found to be unstable and polymerize easily under the
ambient conditions. Accordingly, 1w was eliminated from further studies, and 1y and 1z were examined
in the palladium-catalyzed reactions (vide infra).
Scheme 4. Preparation of 3-Bromopenta-2,4-dienyl Esters (1w-z).
TBSO
Br
TBSO
EO
ref. 9
1) TBAF
2) E-Cl, pyridine
Br
Br
Br
1w-z
5
E = PhC(=O)- (y); 89%
(EtO)2P(=O)- (z); 88%
(EtO)C(=O)- (w); 77%
Preparation of C2-Symmetric Allenes by Palladium-Catalyzed Nucleophilic Double Substitution
of 1. At the outset, substrates 1x-z were applied in the Pd-catalyzed reaction in the presence of excess
(2.5 equiv with respect to 1) prototypical malonate pronucleophiles 6a or 6b (Table 1). All the three
substrates reacted with 6a smoothly with a palladium catalyst (2.0 mol %) generated in situ from
[PdCl(p-allyl)]2 and dpbp. The substrates were consumed completely within 12 hours and doubly
functionalized C2-symmetric allene 2aa was isolated in 83-89% yields (entries 1-3). Under the similar
conditions, the reactions with phenylmalonate 6b provided the corresponding C2-symmetric allene 2bb
in good yields ranging 81% to 86% irrespective of the choice of the substrates (entries 4-6).
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Table 1. Palladium-Catalyzed Reactions of 1x-z with Excess Pronucleophile 6a or 6b.a
4
5
6
7
8
[Pd(π-allyl)Cl]2 (1.0 mol %)
dpbp (2.2 mol %)
EO
Nu
+ Nu-H
(2.5 equiv)
•
base, THF
40 °C, 12 h
Nu
Br
1x-z
6
2
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6a: CHMe(CO2Me)2
6b: CHPh(CO2Et)2
dpbp =
Ph2P PPh2
entry
substrate 1
Nu-H 6
6a
base
NaH
yield of 2 (%)b
83 (2aa)
1c
2
1x
1y
1z
1x
1y
1z
6a
NaH
89 (2aa)
3
6a
NaH
87 (2aa)
4c
5
6b
tBuOK
tBuOK
tBuOK
84 (2bb)
81 (2bb)
86 (2bb)
6b
6
6b
a
The reaction was carried out with 1 (0.50 mmol) and 6 (1.25 mmol) in THF in the presence of an
appropriate base and a Pd-catalyst (2 mol %) generated from [PdCl(p-allyl)]2 and dpbp. b Isolated yield
by silica gel chromatography. c Taken from ref. 8.
Palladium-Catalyzed Nucleophilic Single Substitution of 1z. While all three substrates 1x-z
showed the similar results in the palladium-catalyzed reaction with an excess (2.5 equiv. to 1) soft
nucleophile (Table 1), the carboxylates and the phosphate exhibited different reactivities in the reaction
with a stoichiometric soft nucleophile.
Treatment of the carboxylate, 1x or 1y, with an equimolar mixture of 6a and NaH (1 equiv with
respect to 1) in THF in the presence of the Pd/dpbp catalyst (2 mol %) afforded C2-symmetric allene
2aa in ca. 50% yield together with ca. 50% unreacted 1 (Scheme 5).8 This result indicated that presumed
intermediate 3 was more reactive than 1x and 1y in the palladium-catalyzed nucleophilic substitution
(see Scheme 2).
Scheme 5. Palladium-Catalyzed Reactions of Carboxylates 1x and 1y with Stoichiometric 6a.
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RCO
O
1
2
3
4
5
6
7
Br
R = Me (1x)
Ph (1y)
Pd/dpbp (2.0 mol %)
NaH, THF
40 °C, 12 h
(MeO2C)2CMe
+ 1 (~50%)
•
CMe(CO2Me)2
+
2aa (~50%)
CHMe(CO2Me)2 (6a)
(1.0 equiv to 1)
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On the other hand, the palladium-catalyzed reactions of phosphate 1z with stoichiometric soft
nucleophiles provided the corresponding "single substitution" products, 5-(nucleophile-substituted)-3-
bromopenta-1,3-dienes 4, predominantly. The results of the nucleophilic single substitution of 1z are
listed in Table 2 with the detailed reaction conditions. The reactions of 1z with methylmalonate (6a) or
acetoamidomalonate (6c) were conducted using the Pd/dpbp precatalyst (5 mol %). The reactions
proceeded with good selectivity under the optimized conditions, and the corresponding single
substitution products 4a and 4c were obtained in 88% and 83% yields, respectively (entries 1 and 2). In
both cases, the formation of the double substitution products, C2-symmetric allenes 2, was minor. On the
other hand, the reaction with bissulfone pronucleophile 6d was much less selective in the presence of
the Pd/dpbp precatalyst irrespective of the bases (entries 3 and 4). Although expected single-substitution
product 4d was obtained in modest yields, the concomitant formation of C2-symmetric allene 2dd was
detected together with unreacted 1z. It was found that the palladium precatalyst coordinated with a
bulkier bis(triarylphosphine) ligand (DTBM-bp) showed the much better selectivity of the mono-
substitution, and 4d was obtained in up to 88% selectivity under the optimized conditions (entries 5 and
6). The relatively low isolated yield (50%) of 4d was ascribed to the instability of the compound that
polymerized/oligomerized slowly during chromatographic purification on silica gel. The reaction with
N-pronucleophile 6e also took place in excellent selectivity with the Pd/dpbp precatalyst, and the
corresponding (boc)2N-substituted bromodiene 4e was isolated in 91% yield (entry 7). All 5-Nu-3-
bromopenta-1,3-dienes 4 were obtained as mixtures of the two geometric isomers with the E-isomers
predominant in 82-88%.
Table 2. Palladium-Catalyzed Reactions of 1z with Stoichiometric Pronucleophiles 6.a
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O
Pd2(dba)4 (2.5 mol %)
P–P (5.2 mol %)
(EtO)2PO
Nu
+ Nu-H
(1.1 equiv)
6
+ 2
base, THF
temp., 24 h
Br
Br
4
5
1z
4
6
7
8
9
6d:
O2S
6a: CHMe(CO2Me)2
6c: CH(NHAc)(CO2Et)2
6e: NH(boc)2
P–P =
CHMe
SO2
Ar2P PAr2
dpbp: Ar = Ph
DTBM-bp: Ar = -C6H2-3,5-tBu2-4-OMe
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entry Nu-H
base
NaH
temp.
P–P
dpbp
1z/4/2b
7/90/3
yield of 4c E/Z in 4b
1
2
3
4
5
6
7
6a
6c
6d
6d
6d
6d
6e
0 °C
88% (4a)
83% (4c)
––––
84/16
82/18
––––
––––
––––
88/12
88/12
KOtBu
NaH
23 °C
23 °C
40 °C
40 °C
60 °C
40 °C
dpbp
4/84/12
70/19/11
18/48/34
48/49/3
12/88/0
6/94/0
dpbp
LiCH2SiMe3
LiCH2SiMe3
LiCH2SiMe3
KOtBu
dpbp
––––
DTBM-bp
DTBM-bp
dpbp
––––
50% (4d)
91% (4e)
a
The reaction was carried out with 1z (0.20 mmol) and 6 (0.22 mmol) in THF in the presence of an
appropriate base (0.22 mmol) and a Pd-catalyst (5 mol %) generated from Pd2(dba)4 and a bisphosphine.
b Determined by the 1H-NMR measurements. c Isolated yield by silica gel chromatography.
Palladium-Catalyzed Synthesis of C1-Symmetric Allenes 2. Single substitution products 4, obtained
from 1z and a soft nucleophile Nu– as in Table 2, were excellent substrates in the palladium-catalyzed
"second" nucleophilic substitution to give doubly functionalized allenes 2. When a nucleophile Nu'– in
the second palladium-catalyzed reaction was different from a Nu group in 4, doubly substituted
unsymmetric (C1-symmetric) allenes 2 were obtained selectively (except for the reactions of 4e; vide
infra). These C1-symmetric allenes 2 could not be prepared starting with acetate 1x or benzoate 1y (see
Schemes 2 and 5). The results of preparing the C1-symmetric allenes are listed in Table 3. Both
methylmalonate- or acetoamidomalonate-tethered bromodienes 4a and 4c were equally reactive and the
treatments with an appropriate 6 gave the corresponding C1-symmetric allenes in high yields ranging
72–94% (entries 1-6). Allenes 2ad and 2cd, which possess a malonate and a bissulfone moieties within
the molecules, were also accessed by the reverse introduction of the two functional groups. That is, the
reactions of bissulfone-tethered 4d with a malonate pronucleophile 6a or 6c provided 2ad or 2cd in 84%
and 77% yields, respectively (entries 7 and 8). While the palladium-catalyzed reactions of 4a, 4c, and
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4d proceeded with excellent chemoselectivity to give the corresponding C1-symmetric allenes
exclusively, the products from 4e comprised of the two allenic species. For example, the reaction
between 4e and 6a afforded C1-symmetric allene 2ae in 21% yield together with C2-symmetric allene
2aa in 46% yield (entry 9). The reactions of 4e with the other pronucleophile showed a similar trend
(entries 10 and 11).
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Table 3. Palladium-Catalyzed Synthesis of C1-Symmetric Doubly Functionalized Allenes 2 from 4.a
[Pd(π-allyl)Cl]2 (2.5 mol %)
Nu
dpbp (5.2 mol %)
Nu
Nu'
+ Nu'-H
+
•
•
base, THF
40 °C, 24 h
Nu'
Nu'
(1.5 equiv)
Br
6
C1-2
C2-2
4
entry
bromodiene 4
Nu'-H 6
base
tBuOK
NaH
yield of C1-2 (%)b yield of C2-2 (%)b
1
2
4a
6c
6d
6e
6a
6d
6e
6a
6c
6a
6c
6d
87 (2ac)
91 (2ad)
78 (2ae)
94 (2ac)
72 (2cd)
93 (2ce)
84 (2ad)
77 (2cd)
21 (2ae)
15 (2ce)
33 (2de)
––––
––––
3
tBuOK
NaH
––––
4
4c
––––
5
NaH
––––
6
tBuOK
NaH
––––
7
4d
4e
––––
8
tBuOK
NaH
––––
9
46 (2aa)
44 (2cc)
59 (2dd)
10
tBuOK
NaH
11
a
The reaction was carried out with 4 (0.10 mmol) and 6 (0.15 mmol) in THF in the presence of an
appropriate base and a Pd-catalyst (5 mol %) generated from [PdCl(p-allyl)]2 and dpbp. b Isolated yield
by silica gel chromatography.
The C2-symmetric allenes obtained from (boc)2N-tethered 4e do not possess the (boc)2N group. These
observations implied that the (boc)2N moieties in 2ae, 2ce, and 2de functioned as leaving groups under
the palladium catalysis. Indeed, this possibility was confirmed by the reaction of 2ae with excess 6a in
the presence of the Pd/dpbp species, which provided 2aa in 75% yield (Scheme 6). The results in Table
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3 and Scheme 6 clearly indicated that the (boc)2N group needed to be introduced at the second step in
1
2
3
the preparation of mono-N(boc)2 C1-symmetric allenes such as 2ae and 2ce.
4
5
6
7
Scheme 6. Palladium-Catalyzed Substitution at N(boc)2 Moiety in 2ae.
8
9
(MeO2C)2CMe
•
[Pd(π-allyl)Cl]2 (2.5 mol %)
N(boc)2
2ae
dpbp (5.5 mol %)
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(MeO2C)2CMe
•
+
CMe(CO2Me)2
NaH, THF
40 °C, 24 h
CHMe(CO2Me)2 (6a)
2aa (75%)
(1.5 equiv)
The C1-symmetric doubly functionalized allenes could be prepared by the "one-pot" procedure
directly from 1z as outlined in Table 4. After the treatment of 1z with slight excess pronucleophile 6 and
an appropriate base (1.1 equiv. to 1z) in the presence of the Pd/dpbp precatalyst until the total
consumption of 1z (checked by TLC), a second nucleophile, which was generated from 6 (typically
different from the first one) and a base, was added to the reaction mixture without an additional
palladium catalyst. Stirring the reaction mixtures for 24 h at 40 °C gave the corresponding C1-symmetric
allenes in 60-81% yields. Although the yields by the one-pot procedure are competitive with or slightly
lower than the combined yields from the two step sequence via 4, the operational simplicity of the
procedure provided easier access to doubly substituted unsymmetric allenes 2.
Table 4. Preparation of C1-Symmetric Allenes 2 from 1z by "One-Pot" Procedure.a
Pd2(dba)4 (2.5 mol %)
P–P (5.2 mol %)
Nu'-H 6
O
(1.5 equiv)
Nu
(EtO)2PO
+
Nu-H
•
base-1, THF
temp., time
Nu'
base-2
40 °C, 24 h
(1.1 equiv)
Br
C1-2
1z
6
entry Nu-H 6 base-1
temp
0 °C
time
48 h
Nu'-H 6 base-2 yield of 2 (%)b
1
2
3
4
5
6
6a
6c
NaH
6c
6d
6e
6a
6d
6e
tBuOK
NaH
60 (2ac)
76 (2ad)
81 (2ae)
62 (2ac)
64 (2cd)
60 (2ce)
tBuOK
NaH
tBuOK
23 °C
24 h
NaH
tBuOK
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a The reaction was carried out starting with 1z (0.20 mmol) in THF in the presence of a Pd-catalyst (5
mol %) generated from Pd2(dba)4 and dpbp. b Isolated yield by silica gel chromatography.
1
2
3
4
5
6
7
8
Palladium-Catalyzed Asymmetric Synthesis of Axially Chiral Allenes 2. Allenes 2 obtained in this
study are axially chiral, and application of an appropriate chiral palladium species to the reaction may
furnish 2 in enantiomerically enriched forms. Three malonate pronucleophiles 6a-c were chosen, and
their asymmetric reactions with bromopentadienyl esters 1x-z were examined using a palladium
precatalyst (5 mol %) generated from Pd2(dba)4 and (R)-segphos according to our previous studies
(Table 5).3 The enantioselective reactions with 6a provided axially chiral allene 2aa in excellent yields
ranging 87% to 92% irrespective of the choice of substrates 1x-z, and the highest enantioselectivity of
88% ee was observed in the reaction of phosphate 1z (entries 1-3). The best result in the asymmetric
synthesis of 2bb was obtained in the reaction of 1y in 99% yield and 85% ee (entry 5). Among the three
pronucleophiles examined, 6c showed the highest enantioselectivity (entries 7-9). The highest
9
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t
enantioselectivity of 95% ee was recorded in the reaction between 1y and 6c using BuOCs as a base
(entry 8). All the axially chiral allenes obtained in Table 5 were levorotatory and their absolute
configurations were deduced to be (R) by the Lowe-Brewster rule.10
Table 5. Palladium-Catalyzed Asymmetric Synthesis of Axially Chiral Allenes 2.a
Pd2(dba)4 (2.5 mol %)
Nu H
EO
(R)-segphos (5.5 mol %)
+ Nu-H
(2.5 equiv)
•
base, THF
40 °C, 24 h
O
Br
1x-z
Nu
6a-c
(R)-(–)-2
O
O
PPh2
PPh2
(R)-segphos
O
entry
substrate 1
Nu-H 6
base
yield of 2 (%)b
87 (2aa)
ee of 2 (%)c
1
2
3
4
5
6
1x
1y
1z
1x
1y
1z
6a
NaH
79
61
88
80
85
81
92 (2aa)
91 (2aa)
6b
tBuOCs
79 (2bb)
99 (2bb)
77 (2bb)
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7
8
9
1x
1y
1z
6c
tBuOCs
72 (2cc)
86
95
86
1
2
3
4
5
6
7
8
9
74 (2cc)
77 (2cc)
a
The reaction was carried out with 1 (0.20 mmol) and 6 (0.60 mmol) at 40 °C for 24 h in THF (1.5
mL) in the presence of an appropriate base and a chiral Pd-catalyst (5 mol %) generated from Pd2(dba)4
and (R)-segphos. b Isolated yield by alumina chromatography c Determined by chiral HPLC analysis.
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Consideration to Relative Reactivity between Carboxylate, Phosphate, and Bromide in 1.
Substrates 1x-z possesses two different sites susceptible to activation with palladium catalysis, and the
carboxylates and the phosphate show different reactivity toward the palladium-catalyzed nucleophilic
substitution. Because the bromo substituents are more reactive than the carboxylate moieties in 1x and
1y, the initially formed monosubstitution intermediates should be 3. The carboxylate moieties in 3 are
more reactive than the bromide substituents in 1x and 1y, and intermediates 3 are consumed faster than
1 (Scheme 7, top). Accordingly, 3 are not isolable and C2-symmetric allenes 2 are preferentially
obtained even in the presence of remaining 1x and 1y.8 On the other hand, the phosphate substituent is
more reactive than the C-Br moiety in 1z. Accordingly, the initial products from 1z are bromodienes 4
which are less reactive than 1z. Therefore monosubstitution products 4 are isolable, and the introduction
of two different Nu groups in allenes 2 is realized starting from 1z under the controlled reaction
conditions (Scheme 7, bottom).
Scheme 7. Proposed Reaction Pathways from 1 to 2.
slower
faster
RCO
O
Nu–; Pd0 (cat.)
Nu–; Pd0 (cat.)
RCO
O
Nu
•
•
Nu
Nu
Br
RCO
Nu
Br–
RCO2
–
1x (R = Me)
1y (R = Ph)
3
2
[Pd]+
[Pd]+
O
not isolable
faster
slower
(EtO)2PO
O
Nu–; Pd0 (cat.)
Nu–; Pd0 (cat.)
Nu
Nu
Br–
•
Nu
Br
Br
Nu
–
1z
4
2
(EtO)2PO2
[Pd]+
[Pd]+
Br
isolable
Conclusions
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In summary, we have demonstrated that readily available 3-bromopenta-2,4-dienyl esters 1x-z are
excellent precursors to a variety of doubly functionalized allenes 2. The reaction of 1 and soft
nucleophile 6 is catalyzed by the Pd/dpbp complex, and 1 undergoes the twofold nucleophilic
substitution via formal SN2' and SN2 processes to give the allenic products in high yields. Stepwise
introduction of two different Nu groups can be realized by the reaction starting with phosphate 1z
leading to the C1-symmetric allenes, which are not accessible from carboxylates 1x and 1y. By the use
of a chiral palladium catalyst, axially chiral doubly functionalized allenes were obtained in up to 95% ee.
1
2
3
4
5
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Experimental Section
General. All anaerobic and/or moisture-sensitive manipulations were carried out with standard
1
Schlenk techniques under predried nitrogen or with glovebox techniques under prepurified argon. H
NMR (at 400 MHz) and 13C{1H} NMR (at 101 MHz) chemical shifts are reported in ppm downfield of
internal tetramethylsilane. 31P{1H} NMR (at 162 MHz) chemical shifts are externally referenced to 85%
H3PO4. Tetrahydrofuran was distilled from benzophenone−ketyl under nitrogen prior to use.
Dichloromethane was distilled from CaH2 under nitrogen prior to use. O-TBS-protected (Z)-3-
bromopenta-2,4-dienol (5),9 1,3-benzodithiole-1,1,3,3-tetraoxide,11 dpbp,12 and (R)-segphos13 were
prepared as reported. DTBM-bp was reported previously,14 however, no characterization data were
given. Synthetic procedure and characterization data of DTBM-bp are described in Supporting
Information. All other chemicals were obtained from commercial sources and used without additional
purification.
(Z)-3-Bromopenta-2,4-dienyl Benzoate (1y). To a stirred solution of 5 (3.00 g, 10.8 mmol) in THF
(40 mL) was added a solution of tetrabutylammonium fluoride (1.0 M in THF, 10.8 mL, 10.8 mmol)
dropwise at 0 °C. After stirring the solution for 30 min at room temperature, the reaction mixture was
quenched with saturated NH4Claq (100 mL). The organic layer was separated, and the aqueous layer was
extracted with ether three times. The combined organic layer was washed with brine, dried over MgSO4,
then concentrated under reduced pressure. The residue, crude (Z)-3-bromopenta-2,4-dienol, was
dissolved in dichloromethane (40 mL), and to this were added pyridine (2.14 g, 27.1 mmol) and benzoyl
chloride (3.04 g, 21.6 mmol) at 0 °C. The solution was allowed to warm to room temperature and kept
stirred for 1 h. The solution was diluted with dichloromethane (40 mL) and washed successively with
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water, saturated CuSO4aq twice, water, and brine. The organic layer was dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by silica gel chromatography
(hexane/ethyl acetate = 20/1) followed by vacuum transfer to give 1y as a pale-yellow oil. Yield: 2.59 g
1
2
3
4
5
6
7
1
(89%). H NMR (CDCl3): d 5.10 (d, J = 6.0 Hz, 2H), 5.34 (d, J = 10.4 Hz, 1H), 5.69 (d, J = 16.3 Hz,
8
9
1H), 6.28 (t, J = 6.0 Hz, 1H), 6.37 (dd, J = 16.3 and 10.4 Hz, 1H), 7.41-7.49 (m, 2H), 7.53-7.62 (m, 1H),
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8.03-8.10 (m, 2H). C{1H} NMR (CDCl3): d 64.4, 120.3, 128.25, 128.28, 128.6, 129.8, 130.0, 133.3,
13
135.1, 166.5. ESI-HRMS Calcd for C12H11BrO2Na (M + Na): 288.9840. Found: 288.9849.
(Z)-3-Bromopenta-2,4-dienyl Diethyl Phosphate (1z). This compound was prepared essentially in
the same way of the synthesis of 1y using diethyl phosphoryl chloride (3.73 g, 21.6 mmol) instead of
benzoyl chloride. The crude product was purified by silica gel chromatography (benzene/EtOAc/Et3N =
1
75/25/1) followed by vacuum transfer to give 1z as a pale-yellow oil. Yield: 2.86 g (88%). H NMR
(CDCl3): d 1.31-1.40 (m, 6H), 4.08-4.20 (m, 4H), 4.81 (dd, J = 8.6, 5.9 Hz, 2H), 5.33 (d, J = 10.4 Hz,
1H), 5.67 (d, J = 16.3 Hz, 1H), 6.21 (t, J = 5.9 Hz, 1H), 6.34 (dd, J = 16.3 and 10.4 Hz, 1H). C{1H}
13
NMR (CDCl3): d 16.3 (d, JCP = 6.4 Hz), 64.2 (d, J = 5.7 Hz), 66.6 (d, JCP = 5.2 Hz), 120.5, 127.5, 128.8
(d, JCP = 7.5 Hz), 134.9. 31P{1H} NMR (CDCl3): d –0.28. EI-HRMS Calcd for C9H16BrO4PNa (M + Na):
320.9867. Found: 320.9875.
(Z)-3-Bromopenta-2,4-dienyl Ethyl Carbonate (1w). This compound was prepared essentially in
the same way of the synthesis of 1y using ethyl chloroformate (2.35 g, 21.6 mmol) instead of benzoyl
chloride. The crude product was purified by silica gel chromatography (hexane/CHCl3 = 3/1) followed
by vacuum transfer to give 1w as a pale-yellow oil. Yield: 1.95 g (77%). 1H NMR (CDCl3): d 1.32 (t, J
= 7.1 Hz, 3H), 4.22 (q, J = 7.1 Hz, 2H), 4.90 (d, J = 6.1 Hz, 2H), 5.33 (d, J = 10.5 Hz, 1H), 5.67 (d, J =
16.2 Hz, 1H), 6.17 (t, J = 6.1 Hz, 1H), 6.34 (dd, J = 16.2 and 10.5 Hz, 1H). C{1H} NMR (CDCl3): d
13
14.4, 64.5, 66.9, 120.5, 127.7, 128.2, 135.0, 155.1. EI-HRMS Calcd for C8H11BrO3Na (M + Na):
256.9789. Found: 256.9783.
2-Methyl-1,3-benzodithiole 1,1,3,3-Tetraoxide (6d). To a suspension of 1,3-benzodithiole-1,1,3,3-
tetraoxide (3.00 g, 13.8 mmol) and NaH (0.40 g, 16.5 mmol) in THF (30 mL) was added a THF solution
(20 mL) of iodomethane (2.34 g, 16.5 mmol) at room temperature under nitrogen, and then the mixture
was refluxed overnight. The mixture was filtered through a short pad of silica gel to remove precipitated
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inorganic salts. The silica gel pad was washed with a small amount of CHCl3 three times, and the
combined solution was evaporated to dryness under reduced pressure. The residue was purified by
column chromatography on silica gel (CHCl3/hexane/benzene/Et2O = 9/2/2/1) to give the title
1
2
3
4
5
6
7
8
9
compound as a white solid. Yield: 2.95 g (92%). 1H NMR (CDCl3): d 1.87 (d, J = 6.8 Hz, 3H), 4.47 (q, J
= 6.8 Hz, 1H), 7.90-7.98 (m, 2H), 8.01-8.07 (m, 2H). 13C{1H} NMR (CDCl3): d 6.9, 70.3, 122.9, 135.4,
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137.7. ESI-HRMS Calcd for C8H8O4S2Na (M + Na): 254.9762. Found: 254.9752.
Preparation of C2-Symmetric Allenes 2 by Palladium-Catalyzed Double Substitution of 1. The
reactions were conducted according to a reported procedure.8 The reaction conditions and the results are
summarized in Table 1. A mixture of [PdCl(p-allyl)]2 (1.8 mg, 10 µmol/Pd), dpbp (5.7 mg, 11 µmol),
and 1 (0.50 mmol) was dissolved in THF (5 mL) and the solution was added to a mixture of 6 (1.25
mmol) and base (1.25 mmol) via cannula under nitrogen. The mixture was stirred for 12 h at 40 °C, then
filtered through a short pad of silica gel to remove precipitated inorganic salts. The silica gel pad was
washed with a small amount of Et2O three times and the combined solution was evaporated to dryness
under reduced pressure. The yellow residue was chromatographed on silica gel to give allene 2 in pure
form. The 1H- and 13C-NMR spectra of 2aa and 2bb were consistent with those reported previously.8
Palladium-Catalyzed Nucleophilic Single Substitution of 1z. The reaction conditions and the
results are summarized in Table 2. A mixture of Pd2(dba)4 (5.8 mg, 5.0 μmol), a bisphosphine ligand
(10.5 μmol), and 1z (60 mg, 0.20 mmol) was dissolved in THF (2 mL), and the solution was added to a
mixture of 6 (0.22 mmol) and an appropriate base (0.22 mmol) via a cannula under nitrogen. The
mixture was stirred for 24 h, and then filtered through a short pad of silica gel to remove precipitated
inorganic salts. The silica gel pad was washed with a small amount of EtOAc three times, and the
combined solution was evaporated to dryness under reduced pressure. The yellow residue was
chromatographed on silica gel to give bromodiene 4 in pure form. The characterization data of
bromodiene products 6 are listed below.
Dimethyl 2-(3-Bromopenta-2,4-dienyl)-2-methylmalonate (4a). Colorless oil. Yield: 52 mg (88%)
starting with 1c (60 mg; 0.20 mmol). E/Z = 84/16. (E)-4a: 1H NMR (CDCl3): d 1.45 (s, 3H), 2.92 (d, J =
7.2 Hz, 2H), 3.74 (s, 6H), 5.23 (d, J = 10.4 Hz, 1H), 5.57 (d, J = 16.3 Hz, 1H), 5.92 (t, J = 7.2 Hz, 1H),
6.31 (dd, J = 16.3 and 10.4 Hz, 1H). C{1H} NMR (CDCl3): d 20.4, 37.9, 52.9, 53.7, 118.8, 128.9,
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1
129.0, 135.8, 172.2. (Z)-4a: H (CDCl3): d 1.44 (s, 1H), 2.80 (d, J = 8.4 Hz), 3.73 (s, 6H), 5.38 (d, J =
1
2
3
4
5
10.8 Hz), 5.69 (d, J = 16.4 Hz), 6.00 (t, J = 8.4 Hz), 6.58 (dd, J = 16.4 and 10.8 Hz). ESI-HRMS Calcd
for C11H15BrO4Na (M + Na): 313.0051. Found: 313.0062.
6
7
Diethyl 2-Acetamido-2-(3-bromopenta-2,4-dienyl)malonate (4c). Pale-yellow oil. Yield: 60 mg
8
9
(83%) starting with 1c (60 mg; 0.20 mmol). E/Z = 82/18. (E)-4c: 1H NMR (CDCl3): d 1.26 (t, J = 7.1 Hz,
6H), 2.04 (s, 3H), 3.39 (d, J = 7.4 Hz, 2H), 4.26 (q, J = 7.2 Hz, 4H), 5.23 (d, J = 10.4 Hz, 1H), 5.57 (d, J
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= 16.3 Hz, 1H), 5.81 (t, J = 7.4 Hz, 1H), 6.29 (dd, J = 16.3 and 10.4 Hz, 1H), 6.78 (s, 1H). C{1H}
13
NMR (CDCl3): d 14.1, 23.2, 35.5, 63.0, 65.6, 119.2, 127.4, 129.3, 135.7, 167.6, 169.3. (Z)-4c: 1H NMR
(CDCl3): d 1.26 (t, J = 7.2 Hz, 6H), 2.02 (s, 3H), 3.29 (d, J = 8.8 Hz, 2H), 4.25 (qd, J = 7.1 and 1.2 Hz,
5H), 5.37 (d, J = 10.8 Hz, 1H), 5.67 (d, J = 16.0 Hz, 1H), 5.84 (t, J = 8.8 Hz, 1H), 6.53 (ddd, J = 16.0,
10.8, and 0.8 Hz, 1H), 6.78 (s, 1H). 13C{1H} NMR (CDCl3): d 14.1, 23.1, 32.7, 63.1, 65.9, 122.1, 126.5,
128.0, 129.7, 167.3, 169.5. ESI-HRMS Calcd for C14H20BrNO5Na (M + Na): 384.0423. Found:
384.0431.
2-(3-Bromopenta-2,4-dienyl)-2-methylbenzodithiole 1,1,3,3-Tetraoxide (4d). White solid. Yield:
1
38 mg (50%) starting with 1c (60 mg; 0.20 mmol). E/Z = 88/12. (E)-4d: H NMR (CDCl3): d 1.76 (s,
3H), 3.35 (d, J = 7.2 Hz, 2H), 5.36 (d, J = 10.4 Hz, 1H), 5.68 (d, J = 16.3 Hz, 1H), 6.19 (t, J = 6.9 Hz,
1H), 6.43 (dd, J = 16.3 and 10.4 Hz, 1H), 7.90-7.97 (m, 2H), 8.00-8.08 (m, 2H). 13C{1H} NMR (CDCl3):
d 16.7, 31.6, 76.3, 120.6, 123.4, 124.0, 132.0, 135.3, 135.5, 135.8. (Z)-4d: 1H NMR (CDCl3): d 1.76 (s,
3H), 3.18 (d, J = 8.4 Hz, 2H), 5.51 (d, J = 10.4 Hz, 1H), 5.80 (d, J = 16.0 Hz, 1H), 6.19 (t, J = 6.9 Hz,
1H), 6.66 (d, J = 16.0 and 10.4 Hz, 1H), 7.90-7.97 (m, 2H), 8.00-8.08 (m, 2H). ESI-HRMS Calcd for
C13H13BrO4S2Na (M + Na): 398.9336. Found: 398.9350.
N,N-Di(tert-butoxycarbonyl)-N-(3-bromopenta-2,4-dienyl)amine (4e). Pale-yellow oil. Yield: 66
mg (91%) starting with 1c (60 mg; 0.20 mmol). E/Z = 88/12. (E)-4e: 1H NMR (CDCl3): d 1.50 (s, 18H),
4.46 (d, J = 5.6 Hz, 2H), 5.24 (d, J = 10.4 Hz, 1H), 5.59 (d, J = 16.4 Hz, 1H), 5.99 (t, J = 5.6 Hz, 1H),
6.31 (dd, J = 16.4 and 10.4 Hz, 1H). C{1H} NMR (CDCl3): d 28.2, 47.8, 82.9, 118.9, 125.7, 131.3,
13
135.2, 152.3. (Z)-4e: 1H NMR (CDCl3): d 1.50 (s, 18H), 4.35 (d, J = 7.3 Hz, 2H), 5.40 (d, J = 10.6 Hz,
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1H), 5.69 (d, J = 16.1 Hz, 1H), 6.12 (t, J = 6.7 Hz, 1H), 6.31 (dd, J = 16.2 and 10.5 Hz, 1H). ESI-HRMS
Calcd for C15H24BrNO4Na (M + Na): 384.0786. Found: 384.0775.
1
2
3
4
5
Preparation of C1-Symmetric Allenes 2 by Palladium-Catalyzed Substitution of 4. The reaction
6
7
conditions and the results are summarized in Table 3. A mixture of [PdCl(p-allyl)]2 (1.0 mg, 2.5 μmol),
8
9
dpbp (2.9 mg, 5.5 μmol), and 4 (0.10 mmol) was dissolved in THF (1 mL), and the solution was added
to a mixture of 6 (0.15 mmol) and an appropriate base (0.15 mmol) via a cannula under nitrogen. The
mixture was stirred for 24 h, and then filtered through a short pad of silica gel to remove precipitated
inorganic salts. The silica gel pad was washed with a small amount of EtOAc three times, and the
combined solution was evaporated to dryness under reduced pressure. The yellow residue was
chromatographed on silica gel to give allene 2 in pure form. The characterization data of C1-symmetric
allenes 2 are listed below.
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1
Dimethyl 2-[6-Acetamido-6,6-di(ethoxycarbonyl)hexa-2,3-dienyl]-2-methylmalonate (2ac). H
NMR (CDCl3): d 1.26 (t, J = 7.1 Hz, 6H), 1.42 (s, 3H), 2.04 (s, 3H), 2.52 (dd, J = 7.9 and 2.3 Hz, 2H),
2.82-3.09 (m, 2H), 3.72 (d, J = 2.7 Hz, 6H), 4.22-4.26 (m, 4H), 4.85-5.00 (m, 2H), 6.81 (s, 1H). 13C{1H}
NMR (CDCl3): d 14.1, 19.9, 23.0, 32.6, 35.8, 52.7, 53.8, 62.7, 66.4, 84.1, 85.6, 167.6, 169.1, 172.2,
207.7. ESI-HRMS Calcd for C20H29NO9Na (M + Na): 450.1740. Found: 450.1745.
2-[6,6-Di(methoxycarbonyl)hepta-2,3-dienyl]-2-methylbenzodithiole 1,1,3,3-Tetraoxide (2ad). 1H
NMR (CDCl3): d 1.45 (s, 3H), 1.77 (s, 3H), 2.62 (dd, J = 7.8 and 2.3 Hz, 2H), 2.94 (dd, J = 7.8 and 2.1
Hz, 2H), 3.74 (s, 6H), 5.13-5.27 (m, 2H), 7.88-7.96 (m, 2H), 7.98-8.05 (m, 2H). 13C{1H} NMR (CDCl3):
d 16.8, 20.0, 29.9, 35.4, 52.75, 52.78, 53.9, 76.2, 82.2, 87.1, 123.25, 123.26, 135.32, 135.33, 136.08,
136.10, 172.12, 172.15, 208.8. ESI-HRMS Calcd for C19H22O8S2Na (M + Na): 465.0654. Found:
465.0654.
Dimethyl 2-[5-{N,N-Di(tert-butoxycarbonyl)amino}penta-2,3-dienyl]-2-methylmalonate (2ae). 1H
NMR (CDCl3): d 1.44 (s, 3H), 1.50 (s, 18H), 2.58 (dd, J = 7.8 and 2.3 Hz, 2H), 3.72 (d, J = 2.1 Hz, 6H),
4.01-4.25 (m, 2H), 4.98-5.23 (m, 2H). 13C{1H} NMR (CDCl3): d 19.9, 28.2, 35.8, 45.0, 52.6, 52.7, 53.9,
82.5, 87.5, 88.3, 152.3, 172.2, 172.3, 206.2. ESI-HRMS Calcd for C21H33NO8Na (M + Na): 450.2104.
Found: 450.2096.
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2-[6-Acetamido-6,6-di(ethoxycarbonyl)hexa-2,3-dienyl]-2-methylbenzodithiole
1,1,3,3-
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Tetraoxide (2cd). H NMR (CDCl3): d 1.26 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.75 (s, 3H),
2.05 (s, 3H), 2.81-2.99 (m, 2H), 2.99-3.14 (m, 2H), 4.01-4.41 (m, 4H), 4.92-5.11 (m, 1H), 5.11-5.32 (m,
1H), 7.87-7.96 (m, 2H), 7.98-8.05 (m, 2H). 13C{1H} NMR (CDCl3): d 14.11, 14.13, 16.7, 23.1, 29.8,
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32.4, 62.85, 62.89, 66.35, 76.1, 82.5, 86.0, 123.26, 123.29, 135.3, 135.4, 136.05, 136.12, 167.5, 167.6,
169.2, 208.8. ESI-HRMS Calcd for C22H27NO9S2Na (M + Na): 536.1025. Found: 536.1037.
Diethyl 2-Acetamido-2-[5-{N,N-di(tert-butoxycarbonyl)amino}penta-2,3-dienyl]malonate (2ce).
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1H NMR (CDCl3): d 1.25 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.51 (s, 18H), 2.05 (s, 3H), 2.94-
3.11 (m, 2H), 4.05-4.16 (m, 2H), 4.16-4.30 (m, 4H), 4.98-5.01 (m, 1H), 5.14-5.17 (m, 1H), 6.89 (s, 1H).
13C{1H} NMR (CDCl3): d 14.10, 14.11, 23.0, 28.2, 32.5, 45.1, 62.6, 62.7, 66.5, 82.6, 86.2, 88.6, 152.4,
167.6, 167.7, 169.3, 206.2. ESI-HRMS Calcd for C24H38N2O9Na (M + Na): 521.2475. Found: 521.2468.
2-[5-{N,N-Di(tert-butoxycarbonyl)amino}penta-2,3-dienyl]-2-methylbenzodithiole
1,1,3,3-
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Tetraoxide (2de). H NMR (CDCl3): d 1.51 (s, 18H), 1.79 (s, 3H), 2.86-3.05 (m, 2H), 4.09-4.27 (m,
2H), 5.26-5.42 (m, 2H), 7.87-7.94 (m, 2H), 7.97-8.05 (m, 2H). 13C{1H} NMR (CDCl3): d 16.7, 28.2,
30.0, 44.6, 76.3, 82.8, 84.6, 89.9, 123.26, 123.28, 135.29, 135.31, 136.11, 136.14, 152.3, 207.2. ESI-
HRMS Calcd for C23H31NO8S2Na (M + Na): 536.1389. Found: 536.1389.
Palladium-Catalyzed Substitution of N(boc)2 Moiety in 2ae with Malonate. A mixture of [PdCl(p-
allyl)]2 (0.73 mg, 2.0 μmol), dpbp (2.3 mg, 4.4 μmol), and 2ae (34.0 mg, 79.5 μmol) was dissolved in
THF (1 mL), and the solution was added to a mixture of 6a (20 mg, 0.12 mmol) and NaH (3.0 mg, 0.13
mmol) via a cannula under nitrogen. The mixture was stirred at 40 °C for 24 h and then filtered through
a short pad of silica gel to remove precipitated inorganic salts. The silica gel pad was washed with a
small amount of EtOAc three times, and the combined solution was evaporated to dryness under
reduced pressure. The yellow residue was chromatographed on silica gel to give allene 2aa (21 mg;
75% yield).
Palladium-Catalyzed "One-Pot" Synthesis of C1-Symmetric Allenes 2. The reaction conditions
and the results are summarized in Table 4. A mixture of Pd2(dba)4 (5.8 mg, 5.0 μmol), dpbp (5.8 mg, 11
μmol), and 1c (60 mg, 0.20 mmol) was dissolved in THF (2 mL), and the solution was added to a
mixture of first pronucleophile 4 (0.22 mmol) and an appropriate base (0.22 mmol) via a cannula under
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nitrogen. The reaction progress was monitored by TLC. When 1z was consumed completely, a solution
of second pronucleophile 2 (0.30 mmol) and an appropriate base (0.30 mmol) in THF (1.5 mL) was
added to the reaction mixture via a cannula under nitrogen. The mixture was stirred for 24 h at 40 °C,
and then filtered through a short pad of silica gel to remove precipitated inorganic salts. The silica gel
pad was washed with a small amount of EtOAc three times, and the combined solution was evaporated
to dryness under reduced pressure. The yellow residue was chromatographed on silica gel to give allene
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2 in pure form. The H- and C-NMR analyses clarified that the allenic products obtained here were
identical with those prepared from 4 (see Table 3).
Pd-Catalyzed Asymmetric Synthesis of (R)-(–)-2. To a mixture of Pd2(dba)4 (5.8 mg, 5.0 μmol),
(R)-segphos (6.7 mg, 11 µmol), 6 (0.60 mmol), and an appropriate base (0.50 mmol) in THF (3 mL)
was added 1 (0.20 mmol) by means of syringe under nitrogen. After stirring the mixture for 24 h at
40 °C, the mixture was filtered through a short pad of Al2O3 to remove precipitated inorganic salts. The
Al2O3 pad was washed with a small amount of a hexane/EtOAc (1:1) mixture, and the combined organic
solution was evaporated to dryness under reduced pressure. The residue was purified by
chromatography on Al2O3 to give (R)-(–)-2 in pure form. The absolute configurations were deduced to
be (R) by the Lowe-Brewster rule10 from the signs of optical rotation. Axially chiral allenes 2aa, 2bb,
and 2cc were reported previously as racemates.8 The conditions for the chiral HPLC analyses are listed
below. (R)-(–)-2aa: [a]29 = –21.5 (c 3.03, CHCl3 for the sample of 88% ee). Chiral HPLC Analysis
D
Conditions: Chiralpak OZ-H; eluent, hexane/iPrOH = 10/1; flow rate: 0.5 mL/min; t1 [(S)-enantiomer] =
20.1 min, t2 [(R)-enantiomer] = 21.8 min. (R)-(–)-2bb: [a]31 = –22.5 (c 4.77, CHCl3 for the sample of
D
85% ee). Chiral HPLC Analysis Conditions: Chiralpak AD-H; eluent, hexane/iPrOH = 20/1; flow rate,
0.8 mL/min; t1 [(R)-enantiomer] = 33.5 min, t2 [(S)-enantiomer] = 42.1 min. (R)-(–)-2cc: [a]21D = –51.8
(c 0.49, CHCl3 for the sample of 95% ee). Chiral HPLC Analysis Conditions: Chiralpak AD-H; eluent,
hexane/iPrOH = 10/1; flow rate, 0.8 mL/min; t1 [(S)-enantiomer] = 29.7 min, t2 [(R)-enantiomer] = 31.9
min.
1
Supporting Information Available. Preparation of DTBM-bp, H-, 13C{1H}-, and 31P{1H}-NMR
spectra for all the new compounds, and chiral HPLC chromatograms. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Acknowledgment. This work was supported by a Grant-in-Aid for Challenging Exploratory Research
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(16K13989) to M.O. from JSPS, Japan.
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References and Footnotes.
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(8) Ogasawara, M.; Suzuki, M.; Takahashi, T. Preparation of C2-Symmetric Allenes by Palladium-
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