Enantioselective synthesis of butadien-2-ylcarbinols via (silylmethyl)allenic alcohols from chromium-catalyzed additions to aldehydes utilizing chiral carbazole ligands

Article abstract of DOI:10.1016/j.tet.2010.07.065

The synthesis of chiral, nonracemic butadienylcarbinols by employing intermediate (trimethylsilyl)methylallenic alcohols is described. Allenic alcohols are obtained by treatment of aldehydes with (4-bromobut-2-ynyl) trimethylsilane in the presence of a ca

Full text of DOI:10.1016/j.tet.2010.07.065

Tetrahedron 66 (2010) 7707e7719
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Enantioselective synthesis of butadien-2-ylcarbinols via (silylmethyl)allenic
alcohols from chromium-catalyzed additions to aldehydes utilizing chiral
carbazole ligands
*
María Durán-Galván, Shilpa A. Worlikar, Brian T. Connell
Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77842-3012, US
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2010
Received in revised form 22 July 2010
Accepted 22 July 2010
Available online 30 July 2010
The synthesis of chiral, nonracemic butadienylcarbinols by employing intermediate (trimethylsilyl)
methylallenic alcohols is described. Allenic alcohols are obtained by treatment of aldehydes with
(4-bromobut-2-ynyl)trimethylsilane in the presence of a catalytic amount of CrCl3 or CrCl2. Several new
tridentate bis(oxazolinyl)carbazole ligands were synthesized and evaluated as the source of chirality. The
synthesis of chiral allenic alcohols can be achieved in good yields (58e88%) and enantioselectivities
(55e78% ee). Allenic alcohols may be treated with TBAF or 2 M HCl to provide the desired dienes in
43e86% yields. Alternatively, the (trimethylsilyl)methyl allenic alcohols afford iodobutadienyl carbinols
when treated with N-iodosuccinimide.
Keywords:
Asymmetric catalysis
Regioselectivity
Chromium
Ó 2010 Elsevier Ltd. All rights reserved.
Dienes
Carbazole ligands
1. Introduction
Unfortunately, these procedures require the preparation of non-
readily available organometallic starting materials as well as the use
1,3-Butadien-2-ylcarbinols are highly functionalized molecules
that are attractive to organic chemists due to their versatility as
building blocks in organic synthesis.1 As a result, a number of
methodologies have been developed for the synthesis of these
molecules. Early protocols include addition of Grignard2 and lithium3
reagents to aldehydes or epoxides. The majority of these methods
gave low regioselectivity, providing mixtures of 1,3-butadien-
2-ylcarbinols and allenic alcohols (Eq. 1). Therefore, methodologies
involving the use of different organometallic reagents, such as tin,4
boron,5 and silicon1d,e compounds were developed to overcome
regioselectivity problems. These methods have achieved modest to
high enantioselectivities.
of considerable amounts of toxic reagents. Recently, new approaches
have emerged to avoid these drawbacks.1a,6 For instance, Chan
developed an indium-mediated coupling in aqueous media where
the active organoindium intermediate is formed in situ.6d In other
approaches, Alcaraz reported the homologation of chiral epoxy
bromides while Diver developed an alkyne-ethylene cross-metath-
esis protocol to provide the corresponding 1,3-butadien-2-ylcarbi-
nols.6b,e More recently, Yamamoto et al. reported an enantioselective
protocol, which allows the formation of 1,3-butadien-2-ylcarbinols
with high enantioselectivity and moderate yields by directly cou-
pling aldehydes with 4-bromobuta-1,2-diene.6f
Although the methods recently developed have overcome many
of the limitations presented by early approaches, only a few enan-
tioselective synthetic procedures are known and which present
various drawbacks including limited functional group tolerance or
low reactivity that results in modest yields. Hence, there is an interest
in developing an alternate method for the synthesis of 1,3-butadien-
2-ylcarbinols. (Allenylmethyl)silanes are powerful syntheticreagents
capable of reacting with a wide variety of electrophiles to afford
1,3-dienyl-2-yl compounds.4d,7 It is known that (trimethylsilyl)
methyl allenic alcohols provide the corresponding 1,3-butadien-
2-ylcarbinols by treatment with hydrofluoric acid.4d Therefore, we
focused on the synthesis of these chiral (silylmethyl)allenic alcohols,
which could be directly converted to the desired dienes (Eq. 2).
* Corresponding author. Tel.: þ1 979 845 5746; fax: þ1 979 458 2969; e-mail
address: connell@chem.tamu.edu (B.T. Connell).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.065

7708
M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
Br
attention because they proved to be an excellent source of chi-
rality for these asymmetric NozakieHiyama type reactions.8a,9
We envisioned that the chiral (trimethylsilyl)methyl allenic al-
cohols can be prepared by the chromium-catalyzed allenylation of
aldehydes with (4-bromobut-2-ynyl)trimethylsilane (A) utilizing
the bis-oxazoline carbazole ligands. Herein, we describe the race-
mic and enantioselective synthesis of (trimethylsilyl)methyl allenic
alcohols and its transformation to 1,3-butadien-2-ylcarbinols.10
OH
OH
O
A
TMS
(2)
R
TMS
R
R
H
cat. CrCl3
A Cr/Mn redox system catalyzes the enantioselective alleny-
lation of aldehydes with propargyl bromides or 4-bromobuta-1,2-
diene (Eq. 3).8 The asymmetric allenylation utilizing tridentate bis
(oxazoline) carbazole ligands 1 (Fig. 1) developed by Nakada et al.
is among these reports. These carbazole ligands attracted our
OH
Br
O
CH3
CH3
R
(3)
Cr2+/Mn0
chiral carbazole ligand
R
H
Ph
Ph
2. Results and discussion
1aa (R1 = Me)
1ab (R1 = i-Pr)
1ac (R1 = t-Bu)
N
H
The propargylic bromide (4-bromobut-2-ynyl) trimethylsilane
(A) was prepared from but-2-yn-1-ol by a known procedure.11
Benzaldehyde was combined with A in the presence of a catalytic
amount of CrCl3, 2 equiv Mn0 and 1.1 equiv TMSCl inTHF. The desired
allenic alcohol 2a was formed in 75% yield after 16 h with excellent
regioselectivity (Table 1, entry 1). The corresponding propargylic
O
O
N
N
R1
R1
1
Figure 1. Tridentate bis(oxazoline)carbazoles.
Table 1
Scope of the chromium-catalyzed allenylation reactiona
OH
O
i) CrCl3 (20 %), Mn0
Br
R
TMS
TMS
Yieldb (%)
75
TMSCl, THF, rt.
R
H
A
ii) 1 M HCl
2
Entry
1
Product
Entry
6
Product
Yieldb (%)
OH
OH
TMS
TMS
2a
2f
56
Br
OH
OH
TMS
TMS
2
2b
2c
70
54
7d
2g
81
59
H3C
OH
CH3 OH
H3C
TMS
c
TMS
TMS
3
8
2i
CH3
Br
OH
OH
4
2d
2e
77
83
9c
2j
60
56
TMS
OH
OH
TMS
TMS
5
10e
2k
F3C
MeO
a
Reaction conditions: (4-bromobut-2-ynyl)trimethylsilane (A) (1.1 equiv), CrCl3 (20 mol %), Mn0 (2 equiv), TMSCl (1.1 equiv), THF, 16 h; 2 mL of 1 M HCl.
Isolated yields.
Reaction time: 48 h.
Reaction time: 12 h.
CrCl2 (10 mol %).
b
c
d
e

M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
7709
Table 3
alcohol was not observed. To explore the scope of the reaction, var-
Screening of basesa
ious aldehydes were examined as substrates. Aromatic aldehydes
containing para substituents are excellent substrates for this reaction
and afford the corresponding product in good yields (entry 2).
However, more sterically hindered aldehydes required a longer re-
action time, but the desired product was obtained in good yield after
48 h (entries 3 and 9). Allenic alcohol 2d was obtained after only 16 h
despite the presence of an o-bromo substituent (entry 4). The for-
mation of allenic alcohols proceeds rapidly with good yields with
aromatic aldehydes containing electron-withdrawing substituents
(entries 4e6) and aliphatic aldehydes (entry 7). When meta
substituted aldehydes are used, the product is obtained with 59%
yield (entry8). Inthe case ofp-methoxybenzaldeyde only, the desired
product isobtained whenCrCl2 isutilizedfor theallenylationreaction
(entry 10).
Encouraged by these results, we directed our attention to the
development of a method for the asymmetric synthesis of (tri-
methylsilyl)methyl allenic alcohols. We chose to examine the
effect of ligand 1ab under various conditions.10 When 1ab was
utilized in THF (Table 2, entry 1), the desired alcohol 2aa was
obtained after 20 h in 31% ee. The %ee increased to 46% when
CrCl2 was used (entry 2). To optimize the reaction conditions,
different solvents were explored (entries 3e6). No product was
observed when 1,2-dimethoxyethane was used, while DMF and
EtCN8a afforded the desired product with poor to moderate
enantiomeric excess (entries 4 and 5). MeCN became the solvent
of choice, increasing the %ee to 73%. Next, the effect of catalyst
loading was studied (entries 7 and 8). Decreasing the loading of
CrCl2 and ligand to 5 mol % had virtually no effect on the %ee
(entries 6 and 7) but when the loading was further reduced to
2.5 mol % the %ee decreased considerably (entry 8). A slight
increase in the %ee was observed with 5 mol % of the catalyst and
2 equiv Mn0 (entry 9). Under these conditions, the starting ma-
terial was completely consumed after 36 h (entry 10). Additional
Mn0 (5 equiv) reduced the %ee (entry 11).12
Br
TMS
A
OH
O
i) CrCl2, 1ab, Mn0, base
Ph
TMS
Ph
H
TMSCl, MeCN, rt, 20 h
ii) 1 M HCl, 30 min
2aa
Entry
Base
i-Pr2Et
Conversion (%)
eeb (%)
1
2
3
4
5
6
7
8
91
97
99
85
99
86
95
99
99
98
95
78
74
68
26
40
52
52
45
29
24
11
2,6-Lutidine
Pyridine
4-tert-Bupyridine
2,6-di-tert-Bupyridine
2-Chloropyridine
2-Bromopyridine
1,8-Bis(dimethyl amino)naphthalene
DBU
9
10c
11
DABCO
K2CO3
a
Reaction conditions: (4-bromobut-2-ynyl)trimethylsilane (A) (1.5 equiv), CrCl2
(5 mol %), ligand 1ab (5 mol %), Mn0 (2 equiv), TMSCl (1.1 equiv), i-Pr2NEt
(0.3 equiv), 20 h 2 mL of 1 M HCl.
b
Enantiomeric excess and conversion determined by chiral HPLC.
After the reaction conditions were optimized with respect to
solvent, catalyst loading, Mn0 and base, different carbazole ligands
were explored. Ligands 1aaeac were synthesized by known pro-
cedures (Fig. 1).9b,13 It was observed that the substituent R1 plays an
importantroleinthe%eeofthereaction. SmallerR1 substituents, such
as Me or i-Pr afforded the product with higher %ee values (Table 4,
entries 1 and 2), while the bulkier t-Bu-substituted ligand decreased
the %ee and considerably slowed the reaction rate (entry 3).
Table 4
Initial screening of carbazole ligandsa
Br
TMS
A
OH
i) CrCl2, Ligand, Mn0, i-Pr2NEt
O
Ph
TMS
Table 2
TMSCl, MeCN, rt, 18-20 h
ii) 1 M HCl, 30 min
Ph
H
Optimization of enantioselective reaction conditionsa
2aa
Br
A
TMS
OH
Entry
Ligand
Conversion (%)
eeb (%)
i) CrCl2, 1ab, Mn0, i-Pr2NEt
O
Ph
TMS
1
1aa (R1¼Me)
1ab (R1¼i-Pr)
1ac (R1¼t-Bu)
92
91
86
74
78
20
TMSCl, rt, 20 h
Ph
H
2
ii) 1 M HCl, 30 min
3c
2aa
a
Reaction conditions: (4-bromobut-2-ynyl)trimethylsilane (A) (1.5 equiv), CrCl2
(5 mol %), ligand (5 mol %), Mn0 (2 equiv), TMSCl (1.1 equiv), i-Pr2NEt (0.3 equiv),
20 h; 2 mL of 1 M HCl.
Entry
CrCl2 (%)
Mn0(equiv)
Solvent
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
10% CrCl3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
THF
THF
DME
DMF
99
99
0
31
46
0
b
Enantiomeric excess and conversion determined by chiral HPLC.
Reaction time: 4 days.
10
10
10
10
10
5
2.5
5
5
c
74
95
99
d
d
91
99
d
8
EtCN
48
73
72
51
75
78
21
With the results of Table 4 in hand, we felt that a more thorough
investigation of the effects of carbazole ligand substitution on re-
action yield and enantioselectivity was warranted. Unfortunately,
the known methods of synthesizing substituted carbazoles cannot
be broadly applied to a range of analogues of ligand 1, therefore
modified synthetic routes to these molecules were explored. Our
strategy for a more general synthesis of ligands 1 can be described
as a cross-coupling of dihalocarbazoles with boronic acids, followed
by halogenation, carbonylative amidation, and cyclization.13 3,6-
Disubstituted carbazoles 4aec, 4e, and 4f were prepared by Suzuki
coupling of 3,6-diiodo-9H-carbazole with the corresponding bo-
ronic acid 3 using Pd(OAc)2 catalyst, P(o-tol)3 ligand, and Ba
(OH)2$8H2O base in DME/H2O (Table 5). Known carbazoles 4a, 4b,
and 4f were obtained with excellent yield.9b,14 While carbazole 4c
was obtained with moderate yield, carbazole 4d was not obtained
under these conditions. However, when Pd(PPh3)4 was used as
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10c
11
2
5
5
a
Reaction conditions: (4-bromobut-2-ynyl)trimethylsilane (A) (1.5 equiv), ligand
1ab (5 mol %), TMSCl (1.1 equiv), i-Pr2NEt (0.3 equiv), 20 h; 2 mL of 1 M HCl.
b
Enantiomeric excess determined by chiral HPLC.
Reaction time: 36 h.
c
The reaction rate is not dependent on the base employed. On the
other hand, the %ee is higher when i-Pr2NEt, 2,6-lutidine or pyri-
dine is used (Table 3, entries 1e3) compared to bases with more
steric hindrance, such as 2,6-di-tert-butylpyridine, DBU or DABCO
(entries 5, 9, and 10).

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M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
Table 5
Table 7
Suzuki coupling of 3,6-diiodo-9H-carbazole with boronic acids 3a
Alternative route to obtain 1,8-dihalo-9H-carbazoles
R1
R1
Br Br
R1
R1
R1B(OH)2 (3)
I
I
Pd(OAc)2, P(o-tol)3
R1B(OH)2 (3)
Ba(OH)2•8H2O
DME/H2O
N
H
N
H
Conditions
N
H
N
H
a or b
Br
Br
Br
Br
4
5
6
Entry
Boronic acid
Product
Yieldb (%)
Entry
Boronic acid
Conditions
a
Product
Yieldc (%)
1
2
3a (R1¼Ph)
4a
4b
4c
4d
4e
4f
84
79
23
<10
96
91
1
2
3
3d (R1¼9-Anthracenyl)
3e (R1¼2,6-Dimethylphenyl)
3f (4-Methoxyphenyl)
5d
5e
5f
0
0
40
3b (R1¼
a
-Naphthyl)
a,b
a
3
3c (R1¼
b-Naphthyl)
4c
5
3d (R1¼9-Anthracenyl)
3e (R1¼2,6-Dimethylphenyl)
3f (4-Methoxyphenyl)
a
Pd(PPh3)4 (10 mol %), satd NaHCO3, PhMe, EtOH, reflux, 5 h.
Pd(OAc)2 (5 mol %), P(o-tol)3(10 mol %), Ba(OH)2$8H2O (3.0 equiv), DME/H2O,
6
b
80 ꢀC, 8 h.
a
R1B(OH)2 3 (3.0 equiv), Pd(OAc)2 (5 mol %), P(o-tol)3 (10 mol %), Ba(OH)2$8H2O
c
(3.0 equiv), DME/H2O, 80 ꢀC, 8 h.
Isolated yields.
b
Isolated yields.
c
R1B(OH)2 (3.0 equiv), Pd(PPh3)4 (10 mol %), satd NaHCO3, PhMe, EtOH, reflux,
solubility problems. Sterically hindered boronic acid 3e failed to
give the desired carbazole 5e upon coupling with 1,3,6,8-tetra-
bromo-9H-carbazole using either Pd(OAc)2 or Pd(PPh3)4 catalysts.
The bulky nature of boronic acid 3e renders the oxidative addition
of Pd to the CeBr bond difficult.16 The electron-rich boronic acid 3f
gave the desired carbazole 5h in 40% yield upon Suzuki coupling
with 1,3,6,8-tetrabromo-9H-carbazole using Pd(PPh3)4 as the cat-
alyst. With a view to improve the solubility of the product obtained
by coupling 6 with boronic acid 3d, we tried to introduce polar
groups in the molecule before the SuzukieMiyaura coupling step
(Eq. 4). All attempts to protect the amino group of 1,3,6,8-tetra-
bromo-9H-carbazole with the Boc group failed, likely due to the
steric hindrance surrounding the amine.
overnight.
catalyst, carbazole 4d was obtained albeit with poor yield (Table 5,
entry 4). Although TLC indicated completion of the reaction and
a peak for the desired product was observed in the mass spectrum,
we believe the limited solubility of carbazole 4d lead to problems in
purification and an ultimately low yield.
Next, substituted carbazoles 4 were halogenated to complete
the preparation of the carbonylative amidation substrates (Table 6).
Carbazole 5a was obtained by the known procedure.9b Iodination of
carbazole 4b with benzyltrimethylammonium dichloroiodide
(BTMA$ICl2) afforded 3,6-di-a-naphtyl carbazole 5b in 40% yield
(Table 6, entry 2). Carbazole 5c was obtained in 80% crude
yield after iodination with a KI/KIO4 mixture. Unfortunately, the
yield decreases considerably after recrystallization from PhMe and
the pure compound is obtained in only 18% yield (Table 6, entry 3).
Carbazole 4d, with bulky anthracenyl groups as 3,6-substituents,
failed to give the desired halogenated carbazole. Although TLC in-
dicated the formation of a new product, this compound was highly
insoluble and could not be readily purified. Carbazoles 4e and 4f
failed to give the desired iodinated product upon attempted io-
dination with either BTMA$ICl2 or KI/KIO4 as iodinating reagents.
Br
Br
Br
Br
(Boc)2O, DMAP,
acetone, reflux, 24 h
(4)
or
N
N
H
(Boc)2O, DMAP,
MeCN, rt, 2 days
Br
Br
Br
Br
Boc
6
After obtaining the desired 1,8-dihalo precursors 5, we carried
out Pd-catalyzed carbonylative amidation with amino alcohols 7
derived by reduction of the corresponding chiral amino acids.17 The
bisamides were partially purified by passing through a short silica
plug followed by immediate subjection to dehydrative cyclization.
First, we focused on the variation of the substituent on the oxazoline
group. Bisamide 8aa was obtained from the Pd(PPh3)4 catalyzed
coupling of carbazole 5a and amino alcohol 7a in the presence of
Et3N and under a CO atmosphere (Table 8). The desired ligand 1aa
was notobtained in goodyields when subjected toBF3$OEt2 induced
cyclization, but it was isolated in 48% yield after two steps and high
purity when subjected to MeSO2Cl cyclization followed by refluxing
in 5% alcoholic KOH (Table 8, entry 1). Bisamides 8ad and 8ae pro-
vided 27% and 25% yields of the corresponding bis(oxazolinyl)car-
bazole, respectively (entries 2 and 3) after BF3$OEt2 induced
cyclization. Carbonylative amidation of 5a with amino alcohol 7f18
provided bisamide 8af, which failed to give the desired ligand 1af
when subjected to BF3$OEt2 cyclization. MeSO2Cl cyclization of 8af
gave the desired ligand 1af in 61% yield from 5a (entry 4).
Table 6
Iodination of 3,6-disubstituted carbazoles 4
R1
R1
R1
R1
Conditions
a or b
N
H
N
H
I
I
4
5
Entry
Carbazole
Conditions
Product
Yieldc (%)
a
b
a
1
2
3
4a (R1¼Ph)
5a
5b
5c
38
40
18
4b (R1¼
a
-Naphthyl)
b-Naphthyl)
4c (R1¼
a
KI, KIO4,$2H2O, AcOH, H2SO4, H2O, 5 h.
b
c
BnMe3N$ICl2 (2.2 equiv), AcOH, H2SO4, 60 ꢀC, overnight.
Isolated yields.
An alternative route was considered to obtain the desired 1,8-
dihalocarbazoles, which were unattainable by the previous method.
It was envisioned that 1,3,6,8-tetrabromo-9H-carbazole 615 could be
functionalized to afford the desired carbazoles 5dee (Table 7).
However, when 6 was combined with boronic acid 3d under
Suzuki coupling conditions, the desired 3,6edi(anthracen-9-yl)-
1,8-dibromo-9H-carbazole 5d was not obtained (entry 1). As ob-
served previously for iodination, TLC suggested the formation of
a coupled product but it was not isolated it due to extreme
Next, we turned our attention to the synthesis of ligands 1 with
different substituents in the carbazole nucleus. For this purpose,
halogenated carbazoles 5 were subjected to carbonylative amida-
tion with amino alcohol 7b. Bisamides 8bb and 8cb gave the cor-
responding ligands by BF3$OEt2 cyclization in 35% and 25% yields,
respectively, starting with the corresponding 1,8-diiodo-9H-car-
bazoles 5b and 5c (Table 9, entries 1 and 2). Bisamide 8fb failed to
give the desired ligand when subjected to BF3$OEt2 cyclization, but

M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
7711
Table 8
Synthesis of bis(oxazolinyl)carbazoles from 5aa
Ph
Ph
Ph
O
Ph
O
R1
Ph
Ph
OH
b) or c)
OH
7
NH2
a)
N
H
N
H
HN
R1
NH
R1
N
H
HO
O
O
N
N
I
I
5a
8
1
R1
R1
Entry
Amino alcohols
Bisamide
Cyclization method
Product
Yieldd (%)
c
1
7a (R1¼Me)
7d(R1¼Ph)
7e(R1¼Bn)
8aa
8ad
8ae
8af
1aa
1ad
1ae
1af
48
27
25
61
b
b
c
2e
3
4e
7f(R1¼(R)-1-Methoxyethyl)
a
Amino alcohol 7 (2.5 equiv) CO (1 atm), Pd(PPh3)4 (20 mol %), NEt3 (4.0 equiv), DMF, 60 ꢀC, 8 h.
b
c
BF3$Et2O, 120 ꢀC, 6 h.
(i) MeSO2Cl (2.5 equiv), NEt3 (2.0 equiv), CH2Cl2, 0 ꢀC to rt, 12 h. (ii) 5% alc KOH, reflux, 4 h.
d
e
Isolated yields.
The absolute configuration is as indicated, except for compounds containing amino alcohols 7d or 7f, for which the absolute configuration is (R).
Table 9
Synthesis of bis(oxazolinyl)carbazoles by coupling with 7ba
R1
R1
R1
R1
O
i-Pr
R1
R1
OH
7b
b) or c)
OH
NH2
a)
N
H
N
H
HN
NH
O
N
H
HO
O
O
N
N
X
X
i-Pr
i-Pr
8
1
5
i-Pr
i-Pr
Entry
Carbazole
R1
X
Bisamide
Cyclization method
Product
Yieldd (%)
b
b
c
1
2
3
4
5
5b
5c
5f
5g
5g
a
b
-Naphthyl
-Naphthyl
I
I
Br
Br
Br
8bb
8cb
8fb
8gb
8gb
1bb
1cb
1fb
1gb
1gb
35
25
55
26
51
4-Methoxyphenyl
tert-Butyl
tert-Butyl
b
c
a
Amino alcohol 7 (2.5 equiv) CO (1 atm), Pd(PPh3)4 (20 mol %), NEt3 (4.0 equiv), DMF, 60 ꢀC, 8 h.
b
c
BF3$Et2O, 120 ꢀC, 6 h.
(i) MeSO2Cl (2.5 equiv), NEt3 (2.0 equiv), CH2Cl2, 0 ꢀC to rt, 12 h. (ii) 5% alc KOH, reflux, 4 h.
Isolated yields.
d
provided a 55% yield of 1fb when subjected to MeSO2Cl cyclization
Interestingly, a decrease in the temperature of the reaction from
rt to 10 ꢀC results in a slight decrease in the %ee observed from 75%
ee to 70% ee (Table 11, entries 1 and 2). However, %ee was drastically
reduced to 30% ee when the reaction temperature was further
lowered to 0 ꢀC. The same effect was also observed when ligand
1ab was utilized for the reaction. When allenic alcohol 2aa is
resubmitted to the reaction conditions at 0 ꢀC a decrease in the ee
value from 72% to 62% ee occurs. These results implicate that a ra-
cemization process is occurring under the lower temperature re-
action conditions. When 2aa is resubmitted to the reaction
conditions at rt, no racemization is observed.
After optimizing the reaction conditions, the scope of the asym-
metric reaction was examined by studying a variety of aldehydes as
electrophiles (Table 12). para-Substituted or unsubstituted aromatic
aldehydes are excellent substrates and afforded the desired product
in highyields and good enantioselectivities (Table 12, entries 1 and 2).
When more sterically hindered o-methyl benzaldehydewas used, the
reaction is slower and the ee dropped to 59% ee (entry 3). Electron
deficient aldehydes gave the desired product with good ee values
(entries 4e6). As is the case with no chiral ligands present, aliphatic
aldehydes undergo reaction more quickly than aromatic aldehydes.
The products derived from addition to aliphatic aldehydes afford the
corresponding allenes in good yields and modest enantioselectivities.
The absolute configuration of all products in Table 12 was established
(entry 3). 1,8-Dibromo-3,6-di-tert-butyl-9H-carbazole (5g)19 was
prepared by the literature method. When bisamide 8gb was sub-
jected to BF3$OEt2 cyclization, ligand 1gb was isolated with poor
yield (entry 5). The yield improved to 51% when MeSO2Cl was used
for the dehydrative oxazoline formation (entry 6).
Due to solubility-related difficulties with the purification of
diiodo-9H-carbazole 5d, we subjected the unpurified Suzuki-cou-
pled product to Pd-catalyzed carbonylative amidation and then,
separately, BF3$OEt2 and MeSO2Cl induced cyclization. No desired
ligand was obtained in either case. Additionally, no desired ligand
was isolated upon subjecting unpurified 9H-carbazole 4d to io-
dination followed by carbonylative amidation and cyclization.
Having obtained several additional bis(oxazolinyl)carbazoles 1
withvarying substitutionpatterns(Tables8 and9), wenowelectedto
examine their efficacy in promoting the asymmetric allenylation
reaction. Following the same trends as shown inTable 4, thepresence
of a small R1 substituent such as a benzyl group afforded the 2aawith
higher enantiomeric excess than when a phenyl group was used
(Table 10, entries 1 and 2). The %ee of the product decreased slightly
with R1¼(R)-1-methoxyethyl, which is not as bulky as a Ph or a t-Bu
group (entry 3). Phenyl was the best substituent at the R2 position,
other aliphatic or aromatic R2 substituents, including t-Bu,
thyl, and -naphthyl, did not increase the %ee observed (entries 4e6).
a-naph-
b

7712
M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
Table 10
Table 11
Effect of ligand substituents on enantiomeric excessa
Effect of temperature on enantiomeric excessa
R2
Br
R2
TMS
A
OH
i) CrCl2, 1ae, Mn0, i-Pr2NEt
O
Ph
2aa
TMS
TMSCl, MeCN, rt, 20 h
ii) 1 M HCl, 30 min
Ph
H
N
H
O
O
N
N
Entry
Temperature (ꢀC)
eeb (%)
R1
R1
TMS
1
2
3
rt
10
0
75
70
30
Br
A
OH
a
i) CrCl2, Ligand 1, Mn0, i-Pr2NEt
O
Reaction conditions: (4-bromobut-2-ynyl)trimethylsilane (A) (1.5 equiv), CrCl2
(5 mol %), ligand 1ae (5 mol %), Mn0 (2 equiv), TMSCl (1.1 equiv), i-Pr2NEt
(0.3 equiv), 20 h; 2 mL of 1 M HCl.
Ph
2aa
TMS
TMSCl, MeCN, rt, 18-20 h
ii) 1 M HCl, 30 min
Ph
H
b
Enantiomeric excess determined by chiral HPLC.
after conversion of the (trimethylsilyl)methyl allenic alcohols to the
corresponding diene and comparison of the sign of optical rotation to
the known compounds.4d
Entry
Ligand
Conversion (%)
eeb (%)
1
2
3
1ad (R1¼Ph, R2¼Ph)
99
68
32
99
99
86
31
75
68
57
21
20
1ae (R1¼Bn, R2¼Ph)
1af (R1¼(R)-1-Methoxyethyl, R2¼Ph)
Having the (trimethylsilyl)methyl allenic alcohols in hand, we
explored the synthesis of 1,3-butadien-2-ylcarbinols. It is knownthat
treatment of (trimethylsilyl)methyl allenic alcohols with a mixture of
hydrofluoric acid and hydrochloric acid affords the desired diene.4d
In search of milder reaction conditions that would allow the use of
this methodology in sensitive substrates, we explored the use of
various fluoride sources. We found TBAF can be utilized for the clean
desilylation of the (silylmethyl)allenic alcohols to afford the corre-
sponding dienes. When 2aa was treated with TBAF in THF for 36 h,
diene 9a was obtained in 54% yield (Table 13, entry 1). These reaction
4
1bb (R1¼i-Pr, R2¼
a-naphthyl)
b-Naphthyl)
5c
6
1cb(R1¼i-Pr,R2¼
1gb (R1¼i-Pr, R2¼t-Bu)
a
Reaction conditions: (4-bromobut-2-ynyl)trimethylsilane (A) (1.5 equiv), CrCl2
(5 mol %), ligand (5 mol %), Mn0 (2 equiv), TMSCl (1.1 equiv), i-Pr2NEt (0.3 equiv),
20 h; 2 mL of 1 M HCl.
b
Enantiomeric excess and conversion determined by chiral HPLC.
CrCl2 (3 mol %), 1cb (3 mol %).
c
Table 12
Scope of the asymmetric chromium-catalyzed allenylation reactiona
OH
i) CrCl2, 1ab, Mn0, i-Pr2NEt
O
Br
R
TMS
TMS
TMSCl, CH3CN, rt,
ii) 1 M HCl, rt
R
H
A
2
Entry
1
Product
Yieldb (%)
eec (%)
Entry
Product
Yieldb (%)
eec (%)
72
OH
OH
TMS
TMS
2aa
2bb
2cc
2dd
88
78
70
59
68
5
2ee
2ff
88
F3C
OH
OH
TMS
TMS
2
75
77
82
6
7e
8e
60
67
58
74
68
55
H3C
Br
OH
CH3 OH
3d
2gg
2hh
TMS
TMS
Br
OH
OH
TMS
Ph
TMS
4
a
Reaction conditions: (4-bromobut-2-ynyl)trimethylsilane (A) (1.5 equiv), CrCl2(5 mol %), 1ab (5 mol %), Mn0 (2 equiv), TMSCl (1.1 equiv), i-Pr2NEt (0.3 equiv), 48 h; 2 ml of
1 M HCl.
b
c
Isolated yields.
Enantiomeric excess determined by chiral HPLC.
(4-Bromobut-2-ynyl)trimethylsilane (3 equiv), 50 h.
Reaction time: 36 h.
d
e

M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
Table 13 (continued)
7713
Table 13
Conversion of allenic alcohols to 1,3-butadien-2-ylcarbinolsa
Entry
Product
Yieldb (%)
OH
OH
OH
TBAF (1 equiv)
R
TMS
R
THF, rt, 36 h
11
9k
75
2
9
MeO
Entry
1
Product
Yieldb (%)
54
a
Reaction conditions: TBAF (1 equiv), THF, rt, 36 h.
Isolated yields.
b
OH
9a
conditions were tolerant of several functional groups and the (silyl-
methyl)allenic alcohols synthesized were successfully transformed
to 1,3-butadien-2-ylcarbinols in good to excellent yields.
OH
For most of the substrates, no regioselectivity issues were en-
countered and racemization was avoided. However, for the syn-
thesis of compound 9c, byproduct vinylsilane 10 was obtained,
albeit in less than 5% yield (Eq. 5). The vinylsilane was also ob-
served as a very minor byproduct in the synthesis of compounds
2
3
9b
9c
86
79
H3C
CH3 OH
9a, 9b, and 9d (Table 13, entries 1, 2, and 4). The a,b-unsaturated
aldehyde cinnamaldehyde affords TMS-protected allenic alcohols
(Eq. 6). Bisdesilylation with TBAF in THF affords the desired adduct
9l in 35% yield.
Br
OH
CH3 OH
4
5
9d
9e
82
59
CH3 OH
9c
TBAF
TMS
(5)
THF, rt,
OH
36 h
CH3 OH
84%
(18:1)
TMS
2cc
F3C
Br
10
OH
The synthesis of 1,3-butadien-2-ylcarbinols can be achieved
under basic conditions (TBAF) but also under acidic conditions.
When aliphatic allenic alcohols are treated with HCl, desilylation
occurs and the corresponding dienes are obtained. The formation of
1,3-butadien-2-ylcarbinol 9h from 3-phenylpropionaldehyde in
one pot is illustrated in Eq. 7. After the aldehyde was treated with A
under our reaction conditions, 2 M HCl was added to the reaction
mixture and 9h was obtained after 5 h in 56% yield.
6
9f
72
OH
7
8
9g
9h
84
43
O
Br
OTMS
TMS
A
OH
CrCl2, 1ab, Mn0, i-Pr2NEt
Ph
H
Ph
TMS
Ph
(6)
OH
TBAF
THF
OH
Ph
35% overall
H3C
9l
9
9i
9j
81
74
CH3
Br
TMS
A
Ph
OH
Ph
O
OH
i)
CrCl2 (5 mol%), 1ab
(7)
Mn0, i-Pr2NEt, TMSCl,
10
H
CH3CN, rt, 36 h
9h
ii) 2 M HCl, 5 h, rt
44% ee
56%

7714
M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
To illustrate the versatility of (trimethylsilyl)methyl allenic al-
rich aryl substituents at the 3,6-positions of the carbazole nucleus,
which could not be obtained by previous methods. After Pd-cata-
lyzed carbonylative amidation of the substituted 1,8-dihalocarba-
zoles, the desired ligands are obtained by dehydrative oxazoline
formation induced by either BF3$OEt2 or MeSO2Cl.
Bis(oxazoline) carbazoles are reasonable ligands for this chro-
mium-catalyzed addition reaction, affording chiral alcohols in
generally good yields and enantioselectivities. These versatile ad-
ducts can be converted to 1,3-butadien-2-ylcarbinols by desilyla-
tion using TBAF or iodinated for further functionalization. Aliphatic
aldehydes can also be converted to 1,3-butadien-2-ylcarbinols in
one pot under acidic conditions.
cohols, 2g was treated with NIS to give the iodinated adduct 11 in
60% yield (Eq. 8). During this process, the alcohol was protected in
situ and a 1:1 mixture of the free alcohol and the silyl ether was
obtained.4d TBAF was added after 1 h and the free alcohol 11 was
obtained in 60% yield. The synthesis of 2-iodo-1,3-dienes can also
be accomplished by treatment with I2.7c Furthermore, (trime-
thylsilyl)methyl allenic alcohols may also be reacted with other
4d
electrophiles including Br2 and Selectfluor7e to afford the corre-
sponding halogenated derivatives.
OH
OH
I
i) NIS, CH2Cl2
0 °C to rt, 1 h
ii) TBAF, 2 h, rt
60%
Cy
TMS
(8)
Cy
4. Experimental section
4.1. General information
2g
11
All reactions were performed under an argon atmosphere in
oven-dried glassware with magnetic stirring. Acetonitrile, propio-
nitrile, DME, TMSCl, and DIPEA were distilled from CaH2 before use.
THF was dried with a solvent purification system. Liquid aldehydes
were distilled under reduced pressure and stored refrigerated.
Carbazole ligands 1aaeac were prepared according to previously
reported procedures.9,13 Other commercially available reagents
were used as received. Reactions were monitored by analytical thin
layer chromatography using 0.25 mm glass-backed silica gel plates.
Flash column chromatography was performed using silica gel
(230e400 mesh). Visualization was accomplished by UV light and
potassium permanganate or p-anisaldehyde stains.
The absolute configuration of the chiral alcohols was assigned
by comparing the optical rotations of known compounds 9a, 9g,
and 9h with the values reported in the literature.1d,5a The absolute
configuration of 9f was established by debromination to afford 9a
and comparison with the known compound (Eq. 9).
OH
OH
n-BuLi (2 equiv)
(9)
THF;
then H2O
93%
Br
9f
9a
1H NMR spectra were recorded at 300 MHz and referenced to
CDCl3 (d
7.27). 1H NMR coupling constants (J) are reported in hertz
(Hz) and multiplicities are indicated by: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), dt (doublet of triplets), td
(triplet of doublets) br (broad), dd (doublet of doublets). Proton-
decoupled 13C NMR spectra were recorded at 75 MHz and reported
A plausible transition state that rationalizes the observed ste-
reochemical outcome is depicted in Figure 2. Thepropargylmoiety is
in the apical, less hindered position, avoiding stericinteractions with
the oxazoline substituents. The aldehyde coordinates to chromium
with a trans geometry and occupies the less encumbered equatorial
position. Addition to the aldehyde takes place from the Si-face,
affording the R-alcohol. This is comparable with the observations
made by Nakada and Inoue.8a Nonetheless, as previously dis-
relative to CDCl3 (d 77). Infrared Spectra were obtained as thin film
on NaCl plates. High performance liquid chromatography was
performed on a system equipped with a wavelength detector and
chiral stationary columns (0.46ꢁ25 cm).
cussed,8a,d the formation of
a dinuclear complex or an in-
termolecular mechanism cannot be ruled out at this time.20
4.2. General method for the preparation of allenic alcohols
Inside a nitrogen atmosphere drybox, a mixture of CrCl3 (10 mg,
0.06 mmol) and Mn powder (325 mesh, 33 mg, 0.6 mmol) were
added to a 2-dram vial. Then, the vial was capped with a Teflon lid
and it was removed from the drybox. THF (2 mL) was added via
syringe and a purple suspension resulted. This was followed by
addition of (4-bromo-2-butyn-1-yl)trimethylsilane
0.33 mmol), the aldehyde (0.3 mmol) and TMSCl (42
A
(88 mg,
L,
m
0.33 mmol). The mixture was stirred at rt until the reaction was
completed as judged by TLC. HCl (1 M) was added to the gray so-
lution and it was stirred until the alcohol is completely deprotected
as judged by TLC. The mixture was then extracted with EtOAc. The
mixed organic phases were washed with brine, dried with MgSO4,
and concentrated under reduced pressure to give dark yellow oil.
The residue was purified by flash chromatography using EtOAc/
hexanes (1:50 to 1:9) as eluent.
Figure 2. Proposed transition state.
3. Conclusion
In summary, we have executed asymmetric syntheses of (tri-
methylsilyl)methylallenic alcohols and shown their further trans-
formation into 1,3-butadien-2-ylcarbinols. Several analogues of the
bis(oxazoline) carbazole ligand 1 were synthesized. An alternative
route was also developed via the intermediate 3,6-disubstituted-
1,8-dibromo-9H-carbazoles 5def, which are produced in one step
by selective cross-coupling of tetrabromide 6. This route is espe-
cially useful for synthesis of analogues of ligand 1 with electron-
4.2.1. 1-(3,5-Dimethylphenyl)-2-((trimethylsilyl)methyl)buta-2,3-
dien-1-ol (2i). Obtained as a yellow oil (47 mg, 0.18 mmol, 59%).
1H NMR (CDCl3, 300 MHz)
d 6.98 (s, 2H), 6.94 (s, 1H), 5.03 (q,
J¼3.0 Hz, 2H), 4.90 (m, 1H), 2.33 (s, 6H), 2.21 (d, J¼4.8 Hz 1H),
1.30e1.22 (dt, J¼15, 2.30 Hz 1H), 1.04e0.96 (dt, J¼14.8, 2.8 Hz,
1H), 0.02 (s, 9H). 13C NMR (75 MHz, CDCl3)
d 205.6, 142.9, 139.0,
130.7, 126.0, 106.3, 81.0, 75.9, 22.4, 18.0, 0.5; IR (thin film) 3417,

M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
7715
2953, 1953, 1248 cmꢂ1; HRMS (ESI) calcd for C16H24OSi (MþH)
film) 3408, 2953, 1953, 1247 cmꢂ1; HRMS (ESI) calcd for C15H22OSi
(MþLi) 253.1600, found 253.1596. Enantiomeric excess determined
by HPLC (250 nm) using a ChiralPAK AD-H column (hexanes/iso-
261.1675, found 261.1668.
4.2.2. 1-(Naphthalen-2-yl)-2-((trimethylsilyl)methyl)buta-2,3-dien-
propanol¼98:2, flow rate¼0.6 ml/min) retention time¼17.8 min
18
1-ol (2j). Obtained as a light yellow oil (51 mg, 0.18 mmol, 60%). 1H
(major), 14.0 (minor). [
a
]
e106.7 (c 1.0, CHCl3).
D
NMR (CDCl3, 300 MHz)
d
8.24(d, J¼8.3 Hz, 1H), 7.88 (d, J¼8.3 Hz,
1H), 7.82 (d, J¼8.3 Hz, 1H), 7.64 (d, J¼6.2 Hz, 1H), 7.51 (m, 3H), 5.78
(m, 1H), 5.01 (q, J¼2.8, 2.8 Hz, 2H), 2.31 (d, J¼4.5 Hz 1H), 1.43e1.36
(dt, J¼15.1, 2.9 Hz, 1H), 1.13e1.05 (dt, J¼15.1, 2.9 Hz, 1H), 0.0 (s, 9H).
4.3.3. (R)-1-o-tolyl-2-((trimethylsilyl)methyl)buta-2,3-dien-1-ol
(2cc). Obtained as a clear oil (38 mg, 0.15 mmol, 77%, 59% ee) 1H
NMR (CDCl3, 300 MHz)
d 7.41 (m, 1H), 7.18 (m, 3H), 5.24 (m, 1H),
13C NMR (75 MHz, CDCl3)
d
207.0, 137.1, 134.2, 131.6, 128.9, 128.8,
4.94 (q, J¼3.0 Hz, 2H), 2.37 (s, 3H), 2.07 (d, J¼4.8 Hz 1H), 1.36e1.28
126.3, 125.8, 125.4, 125.1, 124.2, 104.8, 79.6, 73.0, 17.0, ꢂ0.8. IR (thin
film) 3386, 3061, 2953, 1952, 1248, 1056 cmꢂ1; HRMS (ESI) calcd for
C18H22OSi (MþLi) 289.1600, found 289.1594.
(dt, J¼2.9, 15.1 Hz, 1H), 1.06e0.99 (dt, J¼2.9, 15.1 Hz, 1H), 0.02 (s,
9H). 13C NMR (75 MHz, CDCl3)
d 205.4, 139.5, 136.3, 130.5, 127.6,
126.7, 125.9, 104.1, 79.2, 72.1, 19.3, 16.5, ꢂ1.1 IR (thin film) 3358,
2953, 1955, 1247 cmꢂ1; HRMS (ESI) calcd for C15H22OSi (MþLi)
253.1600, found 253.1597. Enantiomeric excess determined by
HPLC (210 nm) using a ChiralPAK AD-H column (hexanes/iso-
4.2.3. 1-(4-Methoxyphenyl)-2-((trimethylsilyl)methyl)buta-2,3-dien-
1-ol (2k). Obtained as yellow oil (30 mg, 0.11 mmol, 56%). 1H NMR
(CDCl3, 300 MHz)
d
7.32e7.28(d, J¼8.8 Hz, 2H), 6.91e6.87 (d,
propanol¼98:2, flow rate¼0.6 ml/min) retention time 12.8 min
19
J¼8.8 Hz, 2H), 5.01 (q, J¼2.8 Hz, 2H), 4.94 (m, 1H), 3.82 (s, 3H), 2.23
(major), 11.3 (minor). [
a]
ꢂ49.3 (c 1.0, CHCl3).
D
(br s, 1H), 1.31e1.23 (dt, J¼15.0, 2.9 Hz, 1H), 1.06e0.98 (dt, J¼15.0,
2.9 Hz, 1H), 0.02 (s, 9H). 13C NMR (75 MHz, CDCl3)
d
204.6, 159.5,
4.3.4. (S)-1-(2-Bromophenyl)-2-((trimethylsilyl)methyl)buta-2,3-
134.3, 128.5, 113.9, 105.6, 80.1, 74.6, 55.5, 17.3, ꢂ0.8; IR (thin film)
3428, 2954, 1953, 1248, 1118 cmꢂ1; HRMS (ESI) calcd for C15H22O2Si
(Mþ Li) 269.1549, found 269.1543.
dien-1-ol (2dd). Obtained as a yellow oil (44 mg, 0.14 mmol, 72%,
68% ee) 1H NMR (CDCl3, 300 MHz)
d 7.52e7.44 (m, 2H), 7.33 (td,
J¼1.57, 7.67 Hz, 1H), 7.33 (td, J¼1.92, 7.67 Hz, 1H), 5.42 (m, 1H), 4.94
(q, J¼3.09 Hz, 2H), 2.29 (d, J¼6.95 Hz 1H), 1.39e1.33 (dt, J¼2.8,
15.0 Hz, 1H), 1.16e1.08 (dt, J¼2.6, 15.0 Hz, 1H), 0.0 (s, 9H). 13C NMR
4.3. General method for the preparation of enantioenriched
allenic alcohols
(75 MHz, CDCl3)
d 205.4, 141.0, 132.8, 129.1, 128.8, 127.6, 123.7,
104.16, 79.7, 73.7, 16.8, ꢂ1.1; IR (thin film) 3384, 2953, 1953 cmꢂ1
;
Inside a nitrogen atmosphere drybox, a mixture of CrCl2
(1.2 mg, 0.01 mmol), Mn powder (325 mesh, 22 mg, 0.4 mmol),
and carbazole ligand 1ab (5.5 mg, 0.01 mmol) were added to
a 2-dram vial. Then, the vial was capped with a Teflon lid and it
was removed from the drybox. Freshly distilled CH3CN (2 mL) was
added via syringe and a yellow suspension resulted. This was
HRMS (ESI) calcd for C14H19BrOSi (MꢂOH) 293.0356, found
293.0348; Enantiomeric excess determined by HPLC (250 nm) us-
ing a ChiralPAK AD-H column (hexanes/isopropanol¼98:2, flow
rate¼0.6 ml/min) retention time¼15.5 min (major), 13.9 (minor).
[a
]
23 ꢂ74.5 (c 1.0, CHCl3).
D
followed by addition of i-Pr2NEt (10
m
L, 0.06 mmol) and the mix-
4.3.5. (R)-1-(4-(Trifluoromethyl)phenyl)-2-((trimethylsilyl)methyl)-
buta-2,3-dien-1-ol (2ee). Obtainedasayellowoil (53 mg, 0.17 mmol,
ture was stirred for 5 min. After this time, (4-bromo-2-butyn-1-yl)
trimethylsilane (61 mg, 0.3 mmol) was added and the solution was
allowed to stir for 30 min. Next, the aldehyde (0.2 mmol) and
88%, 72% ee) 1H NMR (CDCl3, 300 MHz)
d
7.64e7.58 (d, J¼8.4 Hz, 2H),
7.52e7.46 (d, J¼8.4 Hz, 2H), 5.06 (m, 1H), 5.00 (q, J¼2.8, 2.9 Hz, 2H),
TMSCl (28 m
L, 0.22 mmol) were successively added at 0 ꢀC. The
2.31 (d, J¼4.75 Hz, 1H), 1.29e1.21 (dt, J¼2.9, 15.1 Hz, 1H), 1.06e0.98
mixture was stirred at rt for 48 h or until the reaction was com-
pleted as judged by TLC. HCl (1 M) was added and the obtained
green solution was stirred until the alcohol is completely depro-
tected as judged by TLC. The mixture was then extracted with
EtOAc. The mixed organic phases were washed with brine, dried
over MgSO4, and concentrated under reduced pressure to give
a dark orange oil. The residue was purified by flash chromato-
graphy using EtOAc/hexanes (1:50 to 1:9) as eluent.
(dt, J¼2.9,15.1 Hz,1H), 0.02 (s, 9H).13C NMR (75 MHz, CDCl3)
d 204.9,
146.06,127.28,125.22 (q, J¼3.72, 3.76 Hz),104.69, 79.94, 74.63,16.46,
ꢂ1.15; IR (thin film) 3307, 2956, 2895, 1951, 1326, 1249 cmꢂ1; HRMS
(ESI) calcd for C15H19F3OSi (MþLi) 307.1317, found 307.1320; Enan-
tiomeric excess determined by HPLC (250 nm) using a ChiralPAK AD-
H column (hexanes/isopropanol¼98:2, flow rate¼0.6 ml/min) re-
23
tention time¼13.55 min (major), 10.17 (minor). [
a
]
ꢂ101.9 (c 1.0,
D
CHCl3).
4.3.1. (R)-1-Phenyl-2-((trimethylsilyl)methyl)buta-2,3-dien-1-ol
4.3.6. (R)-1-(4-Bromophenyl)-2-((trimethylsilyl)methyl)buta-2,3-
dien-1-ol (2ff). Obtained as a clear oil (37 mg, 0.12 mmol, 60%, 74%
(2aa)10. Obtained as a clear oil (40 mg, 0.17 mmol, 88%, 78% ee) 1H
NMR (CDCl3, 300 MHz)
d
7.36e7.27(m, 5H), 4.98 (m, 3H), 2.23 (d,
ee) 1H NMR (CDCl3, 300 MHz)
d
7.48e7.44 (d, J¼8.559 Hz, 2H),
J¼4.5 Hz 1H), 1.30e1.23 (dt, J¼15.3, 2.4 Hz, 1H), 1.07e0.94 (dt,
7.25e7.21 (d, J¼8.37 Hz, 2H), 4.98 (q, J¼3.2 Hz, 2H), 4.94 (m,1H), 2.21
(d, J¼4.4 Hz 1H), 1.28e1.20 (dt, J¼2.7, 15.1 Hz, 1H), 1.04e0.96 (dt,
J¼2.8, 15.0 Hz, 1H), ꢂ0.03 (s, 9H). 13C NMR (75 MHz, CDCl3) 204.6,
J¼14.2, 2.6 Hz, 1H), 0.0 (s, 9H). 13C NMR (75 MHz, CDCl3)
d 204.7,
141.9, 128.3, 127.8, 127.0, 105.1, 79.7, 74.9, 16.8, ꢂ1.1; IR (thin film)
3387, 3029, 2954, 1952, 1247 cmꢂ1; HRMS (ESI) calcd for C14H20OSi
(MꢂOH) 215.1251, found 215.1252. Enantiomeric excess determined
by HPLC (250 nm) using a ChiralPAK AD-H column (hexanes/iso-
propanol¼98:2, flow rate¼0.6 ml/min) retention time¼14.3 min
141.0, 131.3, 128.8, 121.6, 104.9, 80.1, 74.4, 16.6, ꢂ0.9
d; IR (thin film)
3422, 2953, 1952, 1247 cmꢂ1; HRMS (ESI) calcd for C14H19BrOSi
(MꢂH) 309.0310, found 309.0314. Enantiomeric excess determined
by HPLC (250 nm) using a ChiralPAK AD-H column (hexanes/iso-
propanol¼98:2, flow rate¼0.6 ml/min) retention time¼18.4 min
(major), 13.0 (minor). [
a
]
D
23 ꢂ107.2 (c 1.0, CHCl3).
(major), 14.6 (minor). [
a
]
20 ꢂ69.8 (c 1.0, CHCl3).
D
4.3.2. (R)-1-p-Tolyl-2-((trimethylsilyl)methyl)buta-2,3-dien-1-ol
(2bb). Obtained as a clear oil (27 mg, 0.17 mmol, 75%, 70% ee) 1H
4.3.7. (R)-1-Cyclohexyl-2-((trimethylsilyl)methyl)buta-2,3-dien-1-ol
NMR (CDCl3, 300 MHz)
d
7.29e7.24 (d, J¼8.0 Hz, 2H), 7.19e7.14 (d,
(2gg). Obtained as a light yellow oil (32 mg, 0.14 mmol, 67%, 68%
J¼8.0 Hz, 2H), 5.01 (q, J¼2.8 Hz, 2H), 4.94 (m, 1H), 2.36 (s, 3H), 2.23
(d, J¼4.5 Hz 1H), 1.30e1.23 (dt, J¼2.7, 15.0 Hz, 1H), 1.05e0.97 (dt,
ee) 1H NMR (CDCl3, 300 MHz)
d
4.80 (q, J¼2.8 Hz, 2H), 3.67 (m, 1H),
1.79e0.81 (m, 13H). 13C NMR (75 MHz, CDCl3)
d
206.4, 104.5, 79.4,
J¼2.8, 15.0 Hz, 1H), 0.0 (s, 9H). 13C NMR (75 MHz, CDCl3)
d
204.6,
77.6, 42.3, 31.1, 28.1, 27.5, 27.4, 27.1, 17.7, 0.05; IR (thin film) 3415,
139.0, 137.5, 129.0, 126.9, 105.2, 79.7, 74.7, 21.2, 17.0, ꢂ1.0; IR (thin
2925, 2852, 1952, 1247 cmꢂ1; HRMS (ESI) calcd for C14H26OSi

7716
M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
(MꢂOH) 221.1720, found 221.1725. Enantiomeric excess de-
termined by HPLC (250 nm) using a ChiralPAK AD-H column
(hexanes/isopropanol¼98:2, flow rate¼0.6 ml/min) retention
113.4, 72.2, 20.1, 0.0; IR (thin film) 3374, 2956, 1620, 1486,
1248 cmꢂ1; HRMS (ESI) calcd for C15H22OSi (MþNa) 269.1338,
found 269.1334.
time¼8.14 min (major), 8.7 (minor). [
a]
20 ꢂ15.7 (c 1.0, CHCl3).
D
4.5. 1-Cyclohexyl-3-iodo-2-methylenebut-3-en-1-ol (11)
4.3.8. (R)-1-Phenyl-4-((trimethylsilyl)methyl)hexa-4,5-dien-3-ol
(2hh). Obtained as a yellow oil (30 mg, 0.11 mmol, 58%, 55% ee) 1H
Allenic alcohol 2g (20 mg, 0.08 mmol) was dissolved in dry
CH2Cl2 (1 mL). Then, at 0 ꢀC, a solution of NIS (40 mg, 0.17 mmol) in
CH2Cl2 (0.5 mL) was added via cannula. The pink solution was
stirred at rt for 1 h. After this time, 0.16 mL of a TBAF (1 M in THF,
0.16 mmol) was added via syringe and the mixture was stirred for
2 h. After this time, a saturated solution of NH4Cl was added and the
mixture was extracted with three portions of EtOAc. The combined
organic phases were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
flash chromatography using EtOAc/hexanes 1:6 as eluent. The title
compound was obtained as a yellow oil (35 mg, 0.12 mmol, 60%
NMR (CDCl3, 300 MHz)
d
7.28e7.13 (m, 5H), 4.83 (q, J¼2.7, 2.6 Hz,
2H), 3.89 (m, 1H), 2.8e2.57 (m, 2H), 2.00e1.87 (m, 1H), 1.84e1.7 (m,
1H), 1.57 (br s, 1H), 1.42e1.34 (dt, J¼2.8, 14.9 Hz, 1H), 1.24e1.15 (dt,
J¼2.9, 15.9 Hz, 1H), 0.0 (s, 9H). 13C NMR (75 MHz, CDCl3)
d 205.8,
142.36, 128.7, 128.62, 216.0, 104.8, 79.0, 72.2, 37.4, 32.1, 17.1, ꢂ0.8; IR
(thin film) 3362, 2951, 1951, 1247 cmꢂ1; HRMS (ESI) calcd for
C16H24OSi (MþLi) 267.1756, found 267.1759. Enantiomeric excess
determined by HPLC (250 nm) using a ChiralPAK AD-H column
(hexanes/isopropanol¼98:2, flow rate¼0.6 ml/min) retention time-
¼15.8 min (major), 14.38 (minor). [
a]
D
20 ꢂ5.6 (c 1.0, CHCl3).
yield). 1H NMR
1H), 4.28 (t, J¼4.8, 1H) 1.73e1.63 (m, 3H), 1.56 (m, 2H), 1.23e0.89
(m, 6H); 13C NMR (75 MHz, CDCl3)
150.8, 127.8, 118.9, 107.3, 76.3,
d
6.3 (d, J¼1.7H), 5.91 (d, J¼1.5H), 5.42 (s,1H), 5.30 (s,
4.4. General method for the preparation of 1,3-butadien-2-
ylcarbinols from allenic alcohols
d
41.5, 30.1, 27.7, 26.36, 26.33, 26.0; IR (thin film) 3437, 2926, 2852,
1723, 1260 cmꢂ1; HRMS (ESI) calcd for C11H17IO (MꢂI) 265.1274,
found 265.1274.
Allene (0.11 mmol) was dissolved in dry THF (1.5 mL). TBAF (1 M
in THF, 0.1 mL, 0.1 mmol) was added and the solution was stirred at
rt for 36 h. After this time, a saturated solution of NH4Cl (3 mL) was
added and the mixture was extracted with three portions of EtOAc.
The combined organic fractions were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by preparative TLC using (1:6) EtOAc/hexanes.
4.6. Preparation of (S)-2-methylene-1-phenylbut-3-en-1-ol (9a)
from (S)-1-(4-bromophenyl)-2-methylenebut-3-en-1-ol (9f)
Compound 9f (16 mg, 0.067 mmol) was dissolved in THF (2 mL)
and cooled to ꢂ78 ꢀC. Then n-BuLi (0.53 mL of 2.5 M solution,
0.13 mmol) was added dropwise and the mixture was stirred for
15 min. Water (0.5 mL) was added dropwise and stirred for 5 min.
The mixture was diluted with ethyl acetate, washed with brine,
dried over Mg2SO4, and concentrated under reduced pressure. The
residue was filtered through a short plug of silica. Compound 9a
was obtained as a yellow oil (11 mg, 0.06 mmol, 93% yield, 69% ee).
4.4.1. 1-(3,5-Dimethylphenyl)-2-methylenebut-3-en-1-ol
(9i). Allene 2i (25 mg, 0.09 mmol), 1 M TBAF in THF (0.09 mL,
0.09 mmol). Compound was obtained as yellow oil (19 mg,
0.07 mmol, 81%). 1H NMR (CDCl3, 300 MHz)
d 7.01 (s, 2H), 6.94 (s,
1H) 6.32 (dd, J¼11.4, 17.7 Hz, 1H), 5.45 (s, 1H), 5.41 (s, 1H), 5.35 (s,
1H), 5.24 (d, J¼18.09 Hz,1H), 5.05 (d, J¼11.3 Hz,1H), 2.32 (s,1H),1.94
(br s,1H). 13C NMR (75 MHz, CDCl3)
d
148.3,141.8, 138.0,135.9,129.5,
[a
]
19 ꢂ32.4 (c 1.0, CHCl3).
D
124.6, 115.3, 73.9, 21.3; IR (thin film) 3356, 3009, 2918, 1608 cmꢂ1
HRMS (ESI) calcd for C13H16O (MþLi) 195.1361, found 195.1348.
;
4.7. Representative procedure for the synthesis of carbazoles
4. 3,6-Di(naphthalen-2-yl)-9H-carbazole (4c)
4.4.2. 2-Methylene-1-(naphthalen-1-yl)but-3-en-1-ol (9j)6f. Allene
9j (25 mg, 0.09 mmol), 1 M TBAF in THF (0.16 mL, 0.16 mmol). The
title compound was obtained as yellow oil (28 mg, 0.13 mmol, 74%).
Prepared by modification of the procedure reported by Nakada
et al.9b 3,6-diiodocarbazole (2.00 g, 4.84 mmol), 2-naphthylboronic
acid (2.5 g, 14.5 mmol), and Ba(OH)2$8H2O (4.5 g, 14.5 mmol) were
dissolved in a 6:1 mixture of DME/H2O (60 mL). A solution of Pd
(OAc)2 (54.3 mg, 0.24 mmol) and P(o-tol)3 (148 mg, 0.48 mmol) in
DME (5 ml) was then added via cannula. The mixture was stirred at
80 ꢀC for 18 h and then cooled to rt. The precipitate was removed by
filtration and the filtrate was extracted with CH2Cl2. The organic
phase was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (30%
CH2Cl2 in hexanes as eluent) and then recrystallized from toluene.
The product was obtained in 23% yield as a white solid. 1H NMR
1H NMR (CDCl3, 300 MHz)
d
8.13 (d, J¼9.0, 1H), 7.89 (d, J¼7.3, 1H),
7.83 (d, J¼8.4, 1H), 7.63 (d, J¼8.4, 1H), 7.58e7.44 (m, 3H), 6.47 (dd,
J¼11.1, 18.2 Hz, 1H), 6.27 (s, 1H), 5.43 (s, 1H), 5.35 (s, 1H), 5.24 (d,
J¼19.0 Hz, 1H), 5.10 (d, J¼11.7 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d
147.3, 137.1, 136.4, 133.8, 131.0, 128.6, 126.3, 125.6, 125.5, 125.3,
124.4, 123.4, 117.3, 115.1, 69.6; HRMS (ESI) calcd for C15H14O (MþLi)
217.1205, found 217.1244.
4.4.3. 1-(4-Methoxyphenyl)-2-methylenebut-3-en-1-ol (9k)6f. Allene
9k (30 mg, 0.11 mmol), 1 M TBAF in THF (0.11 mL, 0.11 mmol). Title
compound was obtained as yellow oil (16 mg, 0.082 mmol, 75%). 1H
(CDCl3, 300 MHz)
d
8.53 (s, 2H), 8.19 (s, 3H), 8.01e7.83 (m, 10H),
139.7, 139.5, 134.1,
NMR (CDCl3, 300 MHz)
d
7.32 (d, J¼8.9 Hz, 2H), 6.89 (d, J¼8.9 Hz,
7.61e7.47 (m, 6H). 13C NMR (75 MHz, CDCl3)
d
2H), 6.32 (dd, J¼11.9, 18.4 Hz, 1H), 5.46 (s, 1H), 5.44 (s, 1H), 5.34 (s,
1H), 5.19 (d, J¼18.1 Hz, 1H), 5.04 (d, J¼11.5 Hz, 1H), 3.81 (s, 3H), 1.93
133.2, 132.5, 128.6, 128.3, 127.9, 126.4, 126.3, 126.1, 125.9, 125.8,
124.3, 119.5, 111.3; HRMS (MALDI) calcd for C32H22N (MþH)
420.1752, found 420.1708.
(d, J¼4.0, 1H). 13C NMR (75 MHz, CDCl3)
d 159.2, 147.6, 135.9, 134.2,
123.2, 115.4, 115.3, 113.9, 73.4, 55.3; IR (thin film) 3417, 3005, 2959,
1824, 1611, 1511, 1249, cmꢂ1; HRMS (ESI) calcd for C12H14O2 (MþLi)
197.1154, found 197.1154.
4.7.1. 3,6-di(2,6-Methylphenyl-1-yl)-9H-carbazole (4e). 3,6-Diiodo-
carbazole (0.10 g, 0.25 mmol), 2,6-dimethylbenzeneboronic acid
(0.112 g, 0.75 mmol), Ba(OH)2$8H2O (0.236 g, 0.75 mmol), Pd(OAc)2
(2.8 mg, 0.012 mmol), and P(o-tol)3 (7.6 mg, 0.025 mmol). After
flash chromatography purification (3:1 hexanes/CH2Cl2), the
product was obtained in 96% yield. The pure compound was char-
4.4.4. 1-o-Tolyl-2-((trimethylsilyl)methylene)but-3-en-1-ol (10). 1H
NMR (CDCl3, 300 MHz) d 7.31e7.27 (m, 1H), 7.09e7.00 (m, 3H), 5.56
(d, J¼2.9 Hz, 1H), 5.37 (s, 1H), 5.20 (d, J¼2.9 Hz, 1H), 4.93e5.15 (m,
2H), 2.37 (s, 3H), 1.76 (d, J¼3.8, 1H), ꢂ0.13 (s, 9H). 13C NMR (75 MHz,
acterized by 1H and 13C NMR. 1H NMR (CDCl3, 300 MHz)
1H), 7.84 (2, 2H), 7.53 (d, J¼8.4 Hz, 2H), 7.27e7.16 (m, 8H), 2.13, (s,
d 8.10 (s,
CDCl3)
d 152.7, 140.6, 136.6, 131.1, 128.4, 128.1, 128.0, 127.5, 126.8,

M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
7717
12H). 13C NMR (75 MHz, CDCl3)
127.2, 126.9, 123.5, 120.6, 110.5, 21.1.
d
142.5, 138.6, 136.8, 132.3, 127.3,
in 55% yield as a yellow oil. 1H NMR (300 MHz, CDCl3)
d
3.56 (dd,
J¼4.2, 10.8 Hz, 1H), 3.43 (dd, J¼6.3, 10.8 Hz, 1H), 3.28 (s, 3H), 3.19 (t,
J¼6.3 Hz,1H), 2.7 (br s, 1H), 1.08(d, J¼6.6 Hz, 3H). 13C NMR (75 MHz,
4.8. Procedure for the synthesis of carbazole 4d
CDCl3) d 63.2, 57.3, 56.4, 29.6, 15.2; IR 3362, 2929,1582,1462; HRMS
calcd for C5H14NO2: 120.1025 [MþH]þ, found 120.1022.
Prepared by slight modification of a procedure reported by
Routier et al.14a A solution of 3,6-diiodocarbazole (0.419 g,1.0 mmol)
and 9-anthracenylboronic acid 3d (2.5 equiv) in a mixture of tolu-
ene (21 mL), ethanol (13 mL), and saturated aq NaHCO3 solution
(8.4 ml) was degassed by bubbling Ar for 20 min. Pd(PPh3)4 (10 mol
%) was added and the mixture was immediately transferred to
a preheated oil bath and refluxed overnight. After hydrolysis (20 mL
H2O) the mixture was extracted with EtOAc (2ꢁ20 ml), washed with
brine (20 ml) and dried over MgSO4. The organic layer was then
concentrated under reduced pressure to yield the desired product.
4.12. General procedure for synthesis of bis(oxazoline)
carbazole ligand 1 from 1,8-dihalocarbazole (5) via Pd-
catalyzed carbonylative amidation followed by BF3$OEt2
induced cyclization
A modified procedure reported by Nakada and Inoue was
used.13 To a solution of 0.5 mmol of the 1,8-diiodocarbazole and Pd
(PPh3)4 (20 mol %) in 5 mL of dry, degassed DMF was added the
corresponding amino alcohol (2.6 equiv) and Et3N (4 equiv) via
a syringe. CO gas was then bubbled through the reaction mixture
and a balloon of CO placed over the reaction flask. The reaction
mixture was stirred at 60 ꢀC for 8 h. After the mixture was cooled
down it was diluted with CH2Cl2, washed with brine and 1 M
CuSO4 several times. The organic phase was dried over Na2SO4 and
concentrated under reduced pressure to give the desired bisamide.
The bisamide was partially purified by passing through a short
silica bed and eluting with DCM and methanol. The eluent was
concentrated under rotovap, dried under vacuum, and the bisa-
mide thus obtained was suspended in 15% w/v of BF3$Et2O. The
resulting suspension was stirred at 120 ꢀC for 6 h. The reaction
mixture was cooled to rt and poured into ice cold 2 M NaOH
(5 mL), extracted with CH2Cl2, washed with a saturated aq solution
of NaHCO3, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash chromatography to
afford the desired ligand.
4.9. 1,8-Diiodo-3,6-di(naphthalen-1-yl)-9H-carbazole (5b)
Prepared by a modification of previously reported proce-
dures.13,21 BnMe3NCl2I was added to a suspension of 4b in a mixture
of AcOH (33 mL) and H2SO4 (1 mL). The mixture was stirred at 60 ꢀC
until the reaction was completed as judged by TLC. The mixture was
cooled to rt and poured into 60 mL of water. The precipitate was
filtered and partitioned between EtOAc (33 mL) and a saturated
solution of NaHCO3 (10 mL). The organic layer was washed with
a saturated solution of Na2S2O3 (20 mL) and brine (40 mL), dried
over Na2SO4, and concentrated under reduced pressure. Flash
chromatography (ethyl acetate/hexanes, 1:50) afforded title com-
pound, more than 90% pure, in 40% yield. 1H NMR (CDCl3, 300 MHz)
d
8.32 (s, 1H), 8.11 (s, 2H), 7.99 (d, J¼1.4 Hz, 2H), 7.94e7.85 (m, 7H),
7.57e7.40 (m, 7H). 13C NMR (75 MHz, CDCl3)
d
140.3, 139.0, 136.9,
136.8, 134.7, 133.7,131.8, 128.3, 127.8, 127.4, 127.1,126.2, 125.8, 125.3,
124.0, 122.3; IR 3430, 3054, 2924, 1722, 1508; HRMS (MALDI) calcd
for C32H19I2N (MꢂI) 544.0557, found 544.0573.
4.12.1. (4R,40R)-2,20-(3,6-Diphenyl-9H-carbazole-1,8-diyl)bis(4-phe-
nyl-4,5-dihydrooxazole) (1ad). Purification by flash chromatogra-
phy (1:1 hexanes/CH2Cl2) afforded 27% of the product as a bright
4.10. 1,8-Dibromo-3,6-bis(4-methoxyphenyl)-9H-carbazole (5f)
yellow solid. 1H NMR (CDCl3, 300 MHz)
d 11.91 (br s, 1H), 8.51 (d,
J¼1.2 Hz, 2H), 8.29 (d, J¼1.7 Hz, 2H), 7.8 (d, J¼8.7 Hz, 4H), 7.53 (d,
J¼7.4 Hz, 4H), 7.45e7.28 (m, 12H), 5.55 (t, J¼9.4 Hz, 2H), 4.90 (t,
J¼9.2 Hz, 2H), 4.36 (t, J¼8.7 Hz, 2H). 13C NMR (75 MHz, CDCl3)
Prepared by slight modification of a procedure reported by
Routier et al.14a A solution of 1,3,6,8-tetrabromocarbazole 6 (0.240 g,
0.5 mmol) and 4-methoxyphenylboronic acid (2.2 equiv) in a mix-
ture of toluene (10.5 mL), ethanol (6.5 mL), and saturated aq NaHCO3
solution (4.2 ml) was degassed by bubbling Ar for 20 min. Pd(PPh3)4
(10 mol %) was added and the mixture was immediately transferred
to a preheated oil bath and refluxed for 5 h. After hydrolysis (20 mL
H2O) the mixture was extracted with EtOAc (2ꢁ20 ml), washed with
brine (20 ml) and dried over MgSO4. The organic layer was then
concentrated under reduced pressure to yield the desired product,
which was purified by column chromatography on silica gel (25:1
hexanes/EtOAc) to afford 40% of the product as a white solid. Mp
d
163.9, 142.6, 141.5, 139.1, 132.7, 129.1, 128.8, 127.5, 127.0, 126.9,
125.5, 124.5, 122.4, 110.7, 74.0, 70.1; IR (thin film) 3354, 3060, 2962,
1949, 1719, 1646, 1479; HRMS (MALDI) calcd for C42H32N3O2 (MþH)
18
610.2495, found 609.9933; [
a
]
ꢂ135.6 (c 1.0, CHCl3).
D
4.12.2. (4S,40S)-2,20-(3,6-Diphenyl-9H-carbazole-1,8-diyl)bis(4-ben-
zyl-4,5-dihydrooxazole) (1ae). Purification by flash chromatography
(1:1 hexanes/CH2Cl2) afforded 25% of the product as a bright yellow
solid.1H NMR (CDCl3, 300 MHz)
d
11.91 (br s,1H), 8.4 (d, J¼1.8 Hz, 2H),
8.12(d, J¼1. 7 Hz,2H), 7.68(d, J¼8.0 Hz,4H), 7.41(d, J¼7.1 Hz,4H), 7.25
(m, 12H), 4.7 (m, 2H), 4.4 (t, J¼8.8 Hz, 2H), 4.12 (t, J¼8.0 Hz, 2H), 3.22
(dd, J¼5.5, 5.2 Hz, 2H), 2.82 (dd, J¼8.3, 2H). 13C NMR (75 MHz, CDCl3)
195e197 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 10.50 (s, 1H), 8.42 (d,
J¼1.5 Hz, 2H), 7.65 (d, J¼4.3 Hz, 4H), 7.45 (d, J¼1.5 Hz, 2H), 7.06 (d,
J¼8.4 Hz, 4H), 3.80 (s, 6H). 13C NMR (75 MHz, CDCl3)
d
159.5, 137.4,
d 163.0,141.3,138.8,138.0,132.5,129.4,128.8,128.5,127.3,126.7,126.4,
129.9, 129.8, 128.7, 127.9, 125.2, 122.2, 114.8, 112.6, 55.6; HRMS calcd
125.3, 124.2, 122.0, 110.7, 71.3, 67.8, 42.0; IR (thin film) 3345, 2897,
1646, 1620, 1478, 1266; HRMS (MALDI) calcd for C44H36N3O2 (MþH)
for C26H20Br2NO2: 535.9855 [MþH]þ, found 535.9858.
638.2802, found 638.2807; [
a
]
18 þ51.34 (c 1.0, CHCl3).
D
4.11. (2R,3R)-2-Amino-3-methoxybutan-1-ol (7f)
4.12.3. (4S,40S)-2,20-(3,6-Di(naphthalen-1-yl)-9H-carbazole-1,8-diyl)-
bis(4-isopropyl-4,5-dihydrooxazole) (1bb). Purification by flash
chromatography (4:1 hexanes/CH2Cl2) afforded 35% of the product
A modification of the procedure reported by Hsiao and Hegedus
was used.17a Lithium aluminum hydride (480 mg, 12 mmol) was
suspended in THF (30 ml) at 0 ꢀC. Then
L-threonine methyl ether
as a yellow solid. Mp 139e141 ꢀC; 1H NMR (300 MHz, CDCl3)
d 12.20
(399 mg, 3 mmol) was added slowly in small portions. The reaction
mixture was heated at reflux overnight and then cooled to rt.
A saturated aq solution of K2CO3 was added slowly. Filtration and
evaporation of the solvent under reduced pressure afforded the
crude product. The residue was purified by flash chromatography
(1:10 MeOH/CH2Cl2 followed by MeOH) to give the pure compound
(s, 1H), 8.31 (d, J¼1.5 Hz, 2H), 8.10 (d, J¼1.5 Hz, 2H), 7.85e7.97 (m,
6H), 7.39e7.55 (m, 8H), 4.47e4.52 (m, 2H), 4.47e4.52 (m, 2H),
4.18e4.29 (m, 4H), 1.91e1.95 (m, 2H), 1.20 (d, J¼6.6 Hz, 6H), 1.06 (d,
J¼6.3 Hz, 6H). 13C NMR (75.4 MHz, CDCl3)
d 162.6, 140.4, 138.9,
134.0, 132.3, 131.7, 128.4, 128.1, 127.7, 127.6, 126.3, 126.2, 125.9,
125.5, 125.0, 123.7, 110.6, 73.1, 70.1, 33.7, 19.4, 18.9; IR (thin film)

7718
M. Durán-Galván et al. / Tetrahedron 66 (2010) 7707e7719
3430, 1719, 1508; HRMS calcd for C44H40N3O2 [MþH]þ 642.3114,
concentrated under reduced pressure to obtain desired product,
which was purified by column chromatography.
found 642.3123; [
a]
18 þ30.01 (c 1.0, CHCl3).
D
4.12.4. (4S,40S)-2,20-(3,6edi(Naphthalen-2-yl)-9H-carbazole-1,8-
diyl)bis(4-isopropyl-4,5-dihydrooxazole) (1cb). Prepared by a modi-
fication of previously reported procedures.13,21 Compound 4c
(470 mg,1.12 mmol) was suspended in a mixture of AcOH, H2O, and
H2SO4 (1:0.2:0.03). After addition of I2 (142 mg, 1.12 mmol) and
HIO4$2H2O (127 mg, 0.56 mmol), the pink suspension was stirred
at 80 ꢀC for 5 h. The mixture was then cooled down to rt and poured
into water. The solid was filtrated and dried under reduced pres-
sure (600 mg, 0.89 mmol, 80% crude yield). After recrystallization
from toluene pure 1,8-diiodo-3,6-di(naphthalen-2-yl)-9H-carba-
zole was obtained as a pink solid (130 mg, 0.2 mmol, 18% yield).
Next, the procedure described above for the synthesis of bis-oxa-
zoline carbazoles was followed. Purification by flash chromatog-
raphy (50e80% CH2Cl2 in hexanes) afforded the title compound as
a yellow solid, more than 90% pure (32 mg, 0.05 mmol, 25% yield).
4.13.1. (4S,40S)-2,20-(3,6-Diphenyl-9H-carbazole-1,8-diyl)bis(4-methyl-
4,5-dihydrooxazole) (1aa)9b. Purification by column chromatogra-
phy (1:1 hexanes/CH2Cl2) and recrystallization (from hexanes/
EtOAc) afforded 48% of the product as a yellow solid. 1H NMR
(300 MHz, CDCl3)
d
12.00 (s, 1H), 8.48 (d, J¼1.8 Hz, 2H), 8.22 (d,
J¼1.8 Hz, 2H), 7.77e7.80 (m, 4H), 7.49e7.54 (m, 4H), 7.36e7.41 (m,
2H), 4.61e4.70 (m, 4H), 4.05e4.09 (m, 2H), 1.55 (d, J¼6.3 Hz, 6H).
13C NMR (75.4 MHz, CDCl3)
d 162.6, 141.4, 138.8, 132.5, 128.8, 127.3,
126.7, 125.2, 124.2, 121.9, 110.7, 73.6, 62.3, 21.7.
4.13.2. (4R,40R)-2,20-(3,6-Diphenyl-9H-carbazole-1,8-diyl)bis(4-((R)-
1-methoxyethyl)-4,5-dihydrooxazole) (1af). Purification by column
chromatography (1e3% MeOH in CH2Cl2) afforded 61% of the product
asayellowsolid. Mp147e148 ꢀC;1HNMR(300 MHz, CDCl3)
d8.43(d,
J¼1.5 Hz, 2H), 8.18 (d, J¼1.8 Hz, 2H), 7.71e7.74 (m, 4H), 7.42e7.47 (m,
4H), 7.29e7.35 (m, 2H), 4.64e4.66 (m, 2H), 4.43e4.46 (m, 4H),
3.68e3.71 (m, 2H), 3.44 (s, 6H), 1.31 (d, J¼6.3 Hz, 6H). 13C NMR
1H NMR (CDCl3, 300 MHz)
d 8.65 (s, 2H), 8.35 (m, 2H), 8.22 (m, 2H),
7.99e7.88 (m, 8H), 7.58e7.46 (m, 4H), 4.54 (m, 2H), 4.28 (m, 4H),
1.95 (m, 2H), 1.22 (d, J¼6.2 Hz, 6H), 1.08 (d, J¼6.4 Hz, 6H). 13C NMR
(75.5 MHz, CDCl3) d 163.8,141.5,139.1,132.7,129.0,127.5,126.9,125.6,
(75 MHz, CDCl3)
d
162.4, 138.9, 138.7, 133.8, 132.37, 132.33, 128.4,
124.4, 122.2, 110.8, 77.8, 70.4, 68.1, 57.3, 14.7; HRMS calcd for
128.1,127.6, 126.2,125.9,125.7,125.6,125.5,124.3,122.1,110.9, 72.9,
70.0, 33.4, 19.2, 18.6; IR (thin film) 3053, 2959, 1649, 1601, 1486,
1436; LRMS (APCI) calcd for C44H40N3O2 (MþH) 642.31, found
C36H36N3O4 [MþH]þ 574.2706, found 574.2704; [
a]
23þ35.3 (c 1.0,
D
CHCl3).
642.54; [
a
]
18 þ55.6 (c 1.0, CHCl3).
4.13.3. (4S,40S)-2,20-(3,6-Bis(4-methoxyphenyl)-9H-carbazole-1,8-
diyl)bis(4-isopropyl-4,5-dihydrooxazole) (1fb). Purification by col-
umn chromatography (2% Et3N in CH2Cl2 then 1% MeOH in CH2Cl2)
and recrystallization (from hexanes/EtOAc; a few drops of petro-
leum ether induced crystallization) to afford 55% of the product as
D
4.12.5. (4S,40S)-2,20-(3,6-Di-tert-butyl-9H-carbazole-1,8-diyl)bis(4-iso-
propyl-4,5-dihydrooxazole) (1gb). Purification by flash chromatog-
raphy (3:1 hexanes/CH2Cl2) afforded 26% of the product as a yellow
solid. Mp 178e180 ꢀC; 1H NMR (300 MHz, CDCl3)
d
11.80 (s, 1H),
a white solid, mp 163e165 ꢀC; 1H NMR (300 MHz, CDCl3)
d 8.64 (d,
8.30 (d, J¼1.5 Hz, 2H), 8.03 (d, J¼1.8 Hz, 2H), 4.47e4.56 (m, 2H),
J¼1.5 Hz, 2H), 8.57 (s, 1H), 8.00 (d, J¼1.5 Hz, 2H), 7.49e7.53 (m, 4H),
6.96e7.00 (m, 4H), 4.40e4.41 (m, 2H), 4.10e4.14 (m, 4H), 3.81 (s,
6H), 1.83e1.85 (m, 2H), 1.01 (d, J¼6.9 Hz, 6H), 0.90 (d, J¼6.9 Hz, 6H).
4.19e4.30 (m, 4H), 1.90e1.97 (m, 2H), 1.54 (s, 18H), 1.20 (d, J¼6.6 Hz,
6H),1.07 (d, J¼6.6 Hz, 6H). 13C NMR (75.4 MHz, CDCl3)
d 162.7, 141.5,
137.6, 123.4, 123.2, 119.7, 109.7, 72.9, 69.8, 34.8, 33.4, 32.1, 19.2, 18.7;
13C NMR (75.5 MHz, CDCl3)
d 164.1, 159.5, 139.5, 130.4, 129.4, 126.4,
IR 3355, 2959, 1649, 1488, 1283; HRMS calcd for C32H44N3O2
125.0, 124.0, 120.7, 120.2, 114.9, 72.8, 70.3, 55.6, 33.1, 19.2, 18.3; IR
18
[MþH]þ 502.3434, found 502.3427; [
a
]
þ64.0 (c 1.0, CHCl3).
3474, 2959, 1770, 1647, 1515; HRMS calcd for C38H40N3O4 [MþH]þ
D
602.3013, found 602.3023; [
a]
2D3þ105.4 (c 1.0, CHCl3).
4.13. General procedure for synthesis of bis(oxazoline)
carbazole ligand 1 from 1,8-dihalocarbazole (6) via Pd-
catalyzed carbonylative amidation followed by CH3SO2Cl
induced cyclization
Acknowledgements
The Norman Hackerman Advanced Research Program and the
Robert A. Welch Foundation (A-1623) are acknowledged for sup-
port of this research.
Modified procedures from the literature were used.13,22 To
a solution of 0.5 mmol of the 1,8-diiodocarbazole and Pd(PPh3)4
(20 mol %) in 5 ml of dry, degassed DMF was added the corre-
sponding amino alcohol (2.6 equiv) and Et3N (4 equiv) via a syringe.
CO gas was then bubbled through the reaction mixture and a bal-
loon of CO placed over the reaction flask. The reaction mixture was
stirred at 60 ꢀC for 8 h. After the mixture was cooled down it was
diluted with CH2Cl2, washed with brine and 1 M aq CuSO4 several
times. The organic phase was dried over Na2SO4 and concentrated
under reduced pressure to give the desired bisamide. The bisamide
was partially purified by passing through a short silica bed and
eluting with CH2Cl2 and methanol. The eluent was concentrated
under rotovap, dried under vacuum, and the bisamide thus
obtained was dissolved in 3 mL CH2Cl2. NEt3 (2 equiv) was added
and the solution was cooled to 0 ꢀC. MeSO2Cl (2.5 equiv) was added
and the reaction mixture was allowed to warm to rt and stirred
overnight. It was then poured into saturated aq NH4Cl, the organic
layer was separated and the aqueous layer extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4 and con-
centrated under reduced pressure. The residue was treated with 5%
methanolic KOH soln (3 mL) and heated under reflux for 3 h. The
solvent was evaporated, residue poured into H2O, and extracted
with CH2Cl2. The organic phase was dried over Na2SO4 and
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.07.065.
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