Enantioselective Vanadium-Catalyzed Oxidative Coupling: Development and Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.8b02083

The evolution of a more reactive chiral vanadium catalyst for enantioselective oxidative coupling of phenols is reported, ultimately resulting in a simple monomeric vanadium species combined with a Br?nsted or Lewis acid additive. The resultant vanadium complex is found to effect the asymmetric oxidative ortho-ortho coupling of simple phenols and 2-hydroxycarbazoles with good to excellent levels of enantioselectivity. Experimental and quantum mechanical studies of the mechanism indicate that the additives aggregate the vanadium monomers. In addition, a singlet to triplet crossover is implicated prior to carbon-carbon bond formation. The two lowest energy diastereomeric transition states leading to the enantiomeric products differ substantially with the path to the minor enantiomer involving greater torsional strain between the two phenol moieties.

Full text of DOI:10.1021/acs.joc.8b02083

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Article
Enantioselective Vanadium Catalyzed Oxidative
Coupling: Development and Mechanistic Insights
Houng Kang, Madison R. Herling, Kyle A. Niederer, Young Eun Lee,
Peddiahgari Vasu Govardhana Reddy, Sangeeta Dey, Scott E. Allen, Paul
Sung, Kirsten Hewitt, Carilyn Torruellas, Gina J. Kim, and Marisa C Kozlowski
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02083 • Publication Date (Web): 30 Oct 2018
Downloaded from http://pubs.acs.org on October 31, 2018
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Enantioselective Vanadium Catalyzed Oxidative Coupling:
Development and Mechanistic Insights
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Houng Kang, Madison R. Herling, Kyle A. Niederer, Young Eun Lee, Peddiahgari Vasu Govardhana Reddy,
Sangeeta Dey, Scott E. Allen, Paul Sung, Kirsten Hewitt, Carilyn Torruellas, Gina J. Kim, and Marisa C.
Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United
States.
Supporting Information Placeholder
TS
R
V cat
O2
OH
OH
R
OH
R
O
Me
VVLn
ISC
O
H
Me
triplet
O
Me
Me
VIVLn
O
H
Me
Me
singlet
O
acetate
assembly
Me
H
O
Me
O
Me
singlet
VVLn
O
Me
ABSTRACT:
The evolution of a more reactive chiral vanadium catalyst for enantioselective oxidative coupling of phenols is reported
ultimately resulting in a simple monomeric vanadium species combined with a Brønsted or Lewis acid additive. The resultant vanadium
complex is found to effect the asymmetric oxidative ortho—ortho coupling of simple phenols and 2-hydroxycarbazoles with good to excellent
levels of enantioselectivity. Experimental and quantum mechanical studies of the mechanism indicate that the additives aggregate the vanadium
monomers. In addition, a singlet to triplet crossover is implicated prior to carbon-carbon bond formation. The two lowest energy
diastereomeric transition states leading to the enantiomeric products differ substantially with the path to the minor enantiomer involving
greater torsional strain between the two phenol moieties.
In 1999, Nakajima and coworkers reported that copper complexes
with proline derivatives as a ligand allowed access to BINOL
analogs.3 We discovered that the 1,5-diaza-cis-decalin ligand
afforded further improvement on both reactivity and
enantioselectivity.4 The unsymmetrical H8–BINAM ligand has
been utilized to construct a chiral axis by the Ha group in 2004.5
For these catalysts, however, it was necessary yo have an additional
coordinating group next to phenol to gain enantioselective control.
Introduction
Asymmetric oxidative catalysis offers a simple and atom-economic
method to generate an enantioenriched biaryl motif, which is widely
found in natural products1 and catalysts (
). Naturally
2
Scheme 1
occurring dimeric scaffolds, connected through a chiral axis, feature
intriguing structures as well as biological activities, such as agonism
of neuritic streaming1 or inhibition of cancer cell lines.2
Furthermore, these axially chiral backbones have been widely
utilized in asymmetric catalysts. BINOL has been proven to be
effective in reduction, oxidation, and diverse asymmetric C-C bond
forming reactions, which included the ene, Diels-Alder, aldol,
allylation, alkynylation, cycloaddition, and Friedel-Crafts reactions
etc.2a In addition, axially chiral bisphosphine ligands, which are
derived from the biphenols, have been used in numerous reactions,
including asymmetric hydrogenation and cycloaddition reaction.2b-d
Scheme 1. Examples of a Stereogonic Axis in Natural Products
and Catalysis
In the last three decades, a variety of transition metals have been
Scheme 2A
proven to effect enantioselective oxidative couplings (
).
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Scheme 2. Previous Approaches to Oxidative Coupling of Naphthols and Phenols
A. Naphthol coupling
Nakajima
B. Phenol coupling
Toste & Pappo
COOR
t-Bu
i) Uang: homo-coupling
R
R'
Ha
OH
OH
Et
NH
N
OH
VO(acac) 2
2-5 d
R
Ph
HO
O
O
OH
NHR R'
NH2
Kozlowski
P
Fe
O
3
O
COOR
H
N
R
R1
Waldvogel
ii)
: cross-coupling
N
H
t-Bu
BDD
anode
Cu
R1
R2
OH
X
R'
R'
OH
HO
OH
R'
R'
Fe, Ru
Fe
OH
OH
OH
OH
R'
BDD: boron doped diamond
R2
R1
OH
Kozlowski
Pappo
: cross-coupling
iii)
iv)
and
X
Bn
M
V
R1
OH
R2
R2
N
V
O
Kozlowski, M = Cr
Pappo, M = Fe
O
O
OH
and
t-Bu
OH
H
H
O
O
HO
N
N
N
O
OH
O
V
M
R'
R'
O
Liu Tan
Sun Kurti Xu
, & : asymmetric cross-coupling
&
O
Chen
O
O
OH
OH
R1
Ph
Ph
Uang
R1
phosphoric
acid
R2
O
t-Bu
OH
OH
N
O
N
V
O
O
O
X
O
OH
V
2
O
2
O
R2
O
O
2
X = O, NTs
O
OH
Katsuki
Sasai
Gong
Vanadium also has been widely used as an asymmetric catalyst
to couple BINOL derivatives. Monomeric vanadium complexes,
by the Uang6 and Chen groups,7 or dimeric vanadium complexes,
by the Gong8 and Sasai groups,9 afforded highly selective BINOL
analogs. Later, Katsuki and coworkers disclosed that a Schiff base-
iron complex was able to efficiently construct bisnaphthols, which
are connected through a chiral axis.10 Using an asymmetric
phosphoric acid coordinated to iron, Toste and Pappo introduced
the axial chiral bond in BINOL analogs in 2016.11
Compared to 2-naphthols, phenol couplings have been limited
and less explored (Scheme 2B). Furthermore, no highly
enantioselective oxidative phenol homocoupling was known prior
to our initial report.12 In 1999, Uang and coworkers reported
oxidative phenol dimerization by means of vanadium catalyst
(Scheme 2B, I).13 Recently, we (Cr14) Pappo (Fe-catalyzed15) and
Guo (Co16) disclosed metal catalysts for selective oxidative phenol
cross-coupling to bisphenols that are not atropisomerically stable
(Scheme 2B, III). Notably, the Liu and Kurti groups have
reported highly enantioselective phenol couplings by utilizing
preoxidized compounds, which imposes constraints on the
product types that can be formed (Scheme 2B, IV).17
Hydroxycarbazoles have been found to be effective in oxidative
coupling due to their electron-rich nature (Scheme 3). A variety of
different oxidants have enabled the formation of the central bond.
Benzoyl peroxide was utilized by Moody and coworkers to make
biscarbazole in 1989.18 Bringmann and other groups used tert-
butyl peroxide to oxidatively introduce the C-C bond from 1-
hydroxycarbazoles.19 Later, Knӧlker reported that tetrachloro-
para-benzoquinone produced an axial bond ortho to the hydroxyl
group.20 In 2015, the Kozlowski group revealed that the vanadium-
catalyzed oxidative coupling with N-protected 2-hydroxycarbazole
generated the ortho-ortho’ adduct as the major product.21
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Recently, we reported that vanadium-catalyzed asymmetric
placed under high vacuum. We attributed this reduced reactivity to
formation of a less potent, oxo-bridged species. Fortunately, using
VO(OEt)3 (eq 2) to generate the vanadium adduct as previously
described for asymmetric homoallylic oxidation, provided
1
2
3
4
5
6
7
8
oxidative coupling of phenols and hydroxycarbazoles afforded a
chiral axis in good to excellent yield and selectivity.12 Herein, we
describe further understanding of the transformation via
engineering of vanadium catalyst, expanded substrate scope, and
mechanistic studies, and calculations.
reproducible results.24 Using this procedure, product
was
catalyst can induce
enantioselectivity, but it is hampered by poor reactivity with only
1a
2a
V1
obtained in 37% ee. Clearly, the
Scheme 3. Oxidative Coupling of Hydroxycabazoles
49% conversion of starting material
after 3 days (Figure 1).
3a
Furthermore, the para-para isomer ( , 21%) formed to similar
2a
extent as (28%).
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To improve conversion and regioselectivity, it was necessary to
modify the reaction conditions. We speculated that the phenoxide
substrate accelerates the reaction rate. Using Et3N as an additive,
however, led to no product formation. Conversely, a protic acid
additive, which was capable of catalyst activation by means of
protonation, afforded both enhanced reactivity (91% conv, 75%
2a
isolated yield) and selectivity (60% ee) to produce ortho-ortho (
)
product (Figure 1).
To identify further means of activating the catalyst, an additive
screen was undertaken (see Supporting Information). In line with
the prior results, addition of water (2 equiv) resulted in a modest
improvement. Even greater improvement in terms of reactivity and
selectivity were seen with protic acids. Acetic acid proved optimal
relative to stronger acids (TFA) which result in a loss of selectivity
and weaker acids (alcohols and phenols) which maintain selectivity
but compromise reactivity. The optimal conditions were 0.5 M in
CH2Cl2 or 1,2-dichloroethane (DCE) with 6.25 equiv HOAc and
Results and Discussion
Catalyst Optimization.
Inspired by an effective oxidative
coupling with VO(acac)2,13 2,3,5-trimethylphenol
) was
1a
(
examined as the substrate in initial studies (eq 1). Its success in
asymmetric BINOL derivative syntheses indicates that vanadium
catalysts are highly efficient at introducing
V1
2a
which produced 75% of in 60% ee (Figure 1). To improve
a
chiral axis.
with dimeric
selectivity further, the framework of catalyst was modified. Altering
the amino acid substituent (see Supporting Information) resulted in
no improvement. The use of a scaffold with a greater dihedral angle
1a
Encouragingly, our initial attempts coupling
V0
2a
vanadium catalyst
provided only ortho-ortho and para-para
3a
products among the many potential outcomes (ortho-para
V2
between the upper and lower portions ( , Figure 1) improved
coupling, different C-O couplings).
yields to 83% and enantioselectivity to 77% ee. Such a scaffold would
disfavor the formation of strong µ-oxo-bridges between the two
vanadium centers, which may account for the greater reactivity.
OH
Me
t-Bu
Me
Me
N
V
Me
O
O
20 mol%
Me
O
Me
Me
Me
Me
Me
Me
OH
OH
V0 catalyst
O
+
V1
Similar improvements were seen with derivatives of
containing
HO
O
OH
(1)
toluene
O2, 3 d
O
Me
OH
V
electron-withdrawing groups (6,6’-dibromo 64% yield, 54% ee; 6,6’-
dinitro 49% yield, 78% ee). A more Lewis acidic and more oxidizing
vanadium center seems advantageous. Even so, avenues for
additional optimization of the biaryl scaffold were limited. The free
acid positions were not found to be crucial since similar results were
obtained with the methyl ester derived ligands. However, linking via
the carboxylic acids was not effective with the original
O
O
N
Me
Me
1a
Me
OH
t-Bu
V0
ortho-ortho
para-para
2a
3a
However, the outcome from trial to trial was found to vary
considerably. Part of the irreproducibility arose from exactly how the
catalyst was prepared as several protocols have been reported using
different vanadium sources including VO(SO4)8,22 and VO(Cl)3.23
A
V3
tetrahydronaphthol backbone using a variety of tether lengths ( ,
base is sometimes used for ligand deprotonation prior to
complexation and removal of inorganic salts is effected with an
aqueous phase. For the phenol couplings, we discovered that the
hydration state of the catalyst had a great influence on reactivity. For
example, an inactive catalyst was produced when the complex was
2a
34% , 0% ee). We hypothesized that a large group is needed where
the chiral axis had been to offer selective coupling. Thus, a tert-butyl
substituted phenol was employed. With a linker length of six carbons
V4
being optimal ( ), a larger improvement in selectivity was seen
(67% ee).
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additve screen revealed acids greatly H8-BINOL derivative ⇒
simpler synthesis, can adjust
monomer
is sufficient for
good selectivity
less electron rich ligands ⇒
enhanced ortho-ortho product ⇒
proton coupled electron tranfer
mechanism likely
larger dihedral angle ⇒
more strained OH bridge ⇒
faster ligand exchange
strain via tether length;
lower ee ⇒ group ortho to
phenol is important
larger group ortho to phenol
⇒ better selectivity
stabilize low oxidation state V ⇒
faster redox from VV to VIV
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
O
O
N
V
t-Bu
N
t-Bu
O
O
O
R1
O
O
O
O
V
N
V
N
O
O2N
O
N
O
O
N
O
O
O
O
O
V
OEt
OEt
t-Bu EtO OEt
O
EtO
O
O
H
H
EtO
V
(
)
(
)
V
4
4
O
O
O
EtO
OEt
EtO
t-Bu EtO
OEt
OEt
O
SAR on
Me
OMe
O
O
O
O
O
O
MeO
MeO
V
R2
V
V
V
Ar core
t-Bu
O
O
O
O
O
O
V5
N
N
N
N
V6 + HOAc
O
O
O
t-Bu
10
11
12
13
14
15
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60
V1
V2 + HOAc
t-Bu
V3
V4
t-Bu
t-Bu
t-Bu
R1 = R2 = t-Bu
V1 V1 + HOAc
SM : 2a : 3a 51:28:21 9:76:15
0:87:13
77
83
56:34:10
0
ND
63:31:6
67
ND
60:40:0
66
ND
0:100:0
83
80
ee 2a (%)
37
ND
60
75
yield 2a (%)
Figure 1.
Catalyst evolution in the asymmetric phenol coupling (eq 1).
aDetermined from 1H NMR; isolated yield in parentheses. bDetermined using
CSP HPLC.
To interrogate whether a dimeric catalyst was really necessary, a
V5
trial with monomer
was undertaken which revealed results
To tackle the low conversion issue, a more powerful oxidizing
catalyst was engineered by destabilizing the higher oxidation state of
the vanadium catalyst using electron withdrawing groups on the
ligand. To our delight, a nitro group (entry 15) facilitated the
reaction in accordance with this hypothesis (entry 13 vs 15). With
the modified monomeric catalyst ( ) in the presence of HOAc, the
ortho-ortho coupled product ( ) was obtained in 80% isolated
yield as the only product with 83% ee (Figure 1).
Phenol Scope.
optimized conditions (
phenol possessed an important role relative to the enantioselectivity.
Methyl was optimal, while smaller groups, such as a hydrogen,
showed drastically decreased selectivity (entries 2, 5). Further, the
larger tert-butyl group gave no selectivity (entry 3). 2,3,5-
Trisubstituted phenols generally provided better results.
Table
similar to those of the dimer. Bulky groups, such as tert-butyl (
, entry 1), SiR3 (entry 6–8), or adamantyl (entry 10), at the R
position tend to provide better selectivity. A sterically more
congested substituent, 1,1-dimethylbenzyl, gave higher selectivity
(entry 12, 76% ee). However, the reactivity declined as R2 became
larger than TMS (entry 6–8).
2
1
V6
2a
Table 1. SAR of Monomeric Vanadium Catalyst (eq 3)
t-Bu
R1
A variety of phenols were examined with the
N
O
O
Table 2
). The substituent ortho to the
V
Me
O
O
OMe
R2
Me
Me
40 mol% catalyst
Me
OH
Me
Me
OH
OH
MgSO4, O2
(3)
PhMe (0.5 M), rt
4 d
Me
Me
1a
Me
2a
Entry
1
R1
R2
Conversion (%)a ee (%)b
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
OMe
OAc
NO2
NO2
t-Bu
40
78
92
85
81
70
58
35
13
24
15
37
47
43
86
100
66
49
50
38
57
73
75
76
60
66
56
76
65
62
75
75
2
2-tolyl
3
2,6-xylyl
1-naphthyl
4
5
2-methoxy-1-naphthyl
6
SiMe3
7
SiEt3
SiiPr3
8
t
9
SiPh2 Bu
10
11
12
13
14
15
16
adamantyl
CPh3
CMe2Ph
t-Bu
t-Bu
t-Bu
SiEt3
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2
Table 2. Scope of Phenol Coupling (eq 4)a
20 mol% V6
additive
O2
3
4
R
R
OH
OH
R
(4)
5
6
toluene
16-48 h
OH
7
8
9
1
2
entry
1
substrate
additiveb
HOAc
T
rt
yield (%)c ee (%)d entry
substrate
additiveb
LiCl
T
yield (%)c ee (%)d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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46
47
48
49
50
51
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54
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56
57
58
59
60
89(72)e 85(95)e
9
66
56(99)g
80(98)g
44f
89
77
72
34
10
40
20
47
0 °C
2
3
4
5
6
7
8
HOAc
HOAc
HOAc
HOAc
rt
rt
rt
rt
100f
100f
ND
10
0
10
11
12
13
14
15
16
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
rt
rt
rt
rt
60
38f
38
50
100f
78
HOAc
LiCl
rt
0 °C
rt
100f
0 °C
rt
80(76)e 82(95)e
HOAc
LiCl
89
81
63
86
24f
0 °C
0 °C
HOAc
65
50
rt
12f
aReaction conditions: 20 mol% catalyst, x equiv additives, O2, 0.5 M PhCH3. b6.25 equiv HOAc, 0.4 equiv LiCl. cIsolated yield. ee determined by chiral
d
HPLC. eAfter trituration in parantheses. fConversion. gIsolated yield based on recovered substrate
compromised.
1g
Dioxygenated substrates such as
(eq 5) were examined next
with the expectation that the more electron-rich systems would
undergo oxidative coupling more readily. In line with this hypothesis,
reaction of occurred quickly at room temperature (Table 3, entry
1) and the selectivity could be increased by lowering the
temperature (entries 2-4). However, below 0 °C reaction rates were
1g
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the allyl or propyl group was no longer tolerated with either 3-
1
2
3
4
5
6
7
8
methoxy or 5-methoxy substrates (entry 12–14) in contrast to 3-
methoxy with 2-methyl substituent (entry 6). To examine the effects
of substituents at 5-position, experiments were conducted with a
phenyl (entry 8), alkynyl chain (entry 9), and electron-withdrawing
groups (entry 15, 16). Notably, oxidative coupling of the phenol an
bearing alkynyl chain afforded good selectivity (entry 9, 89% ee) in
the presence of LiCl. As we expected, 5-bromo analogs caused
Table 3. Oxidative Coupling of Dihydroxyarene 1g (eq 5)
OH
Me
20 mol%
OH
catalyst
AcOH
Me
OH
Me
Me
OH
OH
(5)
toluene
O2, 6 h
Me
1o
1p
slower oxidation with only 24% ( ) and 12% ( ) conversion after
48 h. Racemic biaryl products have much poorer solubility than
enantiopure biaryls. Exploiting this difference, one trituration with
hexanes was found to increase the enantiomeric excess of the filtrate
Me
1g
OH
9
2g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conversion (%)a
ee (%)
50
Temperature (oC)
Entry
1a
1f
and were enhanced to
substantially. For example, substrates
95% ee following trituration.
1
2
3
23
0
72
53
30
63
Hydroxycarbazoles.
hydroxycarbazoles allows access to dimeric compounds via oxidative
The electron rich nature of
75
–20
–40
4
15
85
4
coupling (Scheme 3). Accordingly, hydroxycarbazole
was
examined in our asymmetric oxidative coupling (eq 6).20 Our
previous report demonstrated that the N-protecing group was
essential for selective oxidation ortho to the hydroxyl group by
excluding reaction with amine.21
As a result, additional additive screening was undertaken with this
Table 4
class of substrates (
). Most additives resulted in lesser
reactivity although cationic lithium species resulted in significantly
higher reactivity (entries 10, 12, 17). LiCl (entry 5) afforded the
highest enantioselectivity (entry 5, 85% ee), which did not appear to
devolve solely from the chloride (c.f. entries 6-8). Using the LiCl
With the nitrogen position protected with a benzyl substituent,
promising levels of selectivity (70% ee) were observed (Table 5,
V7
entry 1). Examining related vanadium catalysts
and
(R = F, entry 2)
1f
Table
additive with substrate gave a similar boost in selectivity (
V8
(R = Oi-Pr, entry 3) revealed that a larger alkoxy group on
4
, entry 6, 82% ee). Unfortunately, LiCl did not provide equal levels
the vanadium center gave rise to higher selectivity (78% ee).
However, even larger substituents on vanadium (R = Ot-Bu, entry
4) did not afford further improvement. Finally, optimization of
solvent (CH2Cl2, DCE, CHCl3, toluene, dichlorobenzene) revealed
that chlorobenzene (entry 5) provided the best result (91% yield,
87% ee).
of improvement for all substrates.
Table 4. Additive Screening with Dihydroxyarene 1g (eq 5)a
Entry
1
Additives
-
Conversion (%)b ee (%)
70
33
43
48
46
52
59
28
46
100
12
94
43
53
-
52
43
67
69
85
47
45
78
46
63
57
73
18
27
68
70
60
2
Sn(OTf)2
Sc(OTf)3
Yb(OTf)3
LiCl
Table 5. Oxidative Coupling of 2-Hydroxycarbazole (eq 6) a
3
4
t-Bu
O2N
N
5
O
O
O
V
R
Me
HO
HO
Me
O
6
NaCl
t-Bu
20 mol %
N
N
Me
V-cat
7
KCl
R
R
(6)
HOAc, O2,
N
R
8
MgCl2
HO
0 oC, 2 d
9
LiF
4
10
11
12
13
14
15
16
17
LiBr
5
Entry
R
Catalyst
Solvent
PhMe
PhMe
PhMe
Yield (%)
ee (%)
70
LiI
1
2
3
4
5
6
7
8
9
Bn (4b
Bn (4b
Bn (4b
Bn (4b
Bn (4b
)
)
)
)
)
V6 (R = OMe)
V7 (R = F)
78
40
71
44
91
82
71
58
27
LiClO4
LiOAc
Li2CO3
4Å MS
MgSO4
LiCl + 12-crown-4
70
V8 (R = Oi-Pr)
78
V9 (R = Ot-Bu) PhMe
74
V8 (R = Oi-Pr)
V8 (R = Oi-Pr)
V8 (R = Oi-Pr)
V8 (R = Oi-Pr)
V8 (R = Oi-Pr)
PhCl
PhCl
PhCl
PhCl
PhCl
87
50
100
Me (4c
allyl (4d
i-Pr (4e
2,4,6-Me3Bn (4f
)
71
aReaction conditions: 20 mol % V6, 40 mol % additive, PhCH3, O2, 0 °C, 6 h.
bConversion was determined by 1H NMR.
)
76
)
42
)
37
aReaction Conditions: 20 mol% catalyst, 6.5 equiv HOAc, O2, 0.5 M solvent, 0 °C,
48 h.
Other substituents, such as allyl or propyl, ortho to the phenol,
resulted in comparable selectivity (Table 2, entry 10, 11). However,
6
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2
3
The Journal of Organic Chemistry
V8
With the optimal catalyst ( ), examination of the nitrogen
Scheme 6. 6-Methoxy-2-hydroxycarbazole synthesis
substituent showed that either smaller (Me, entry 6, 71% ee) or
larger groups (i-Pr; 2,4,6-trimethylbenzyl, entries 8-9) were
detrimental. Moderate sized groups such as allyl (entry 7, 76% ee)
and benzyl (entry 5, 87% ee) were superior.
1.BBr3, CH2Cl2
OMe
Pd(OAc)2
[HPt-Bu3][BF4]
Me
Cl
Me
Cl
-78οC to RT
2.NaH, BnBr
DMF/THF, rt
Br
NaOt-Bu
toluene, reflux
MeO
NH2
BnO
NH2
15
4
7
14
OMe
5
6
7
The synthetic routes to the 2-hydroxycarbazoles employed are
outlined in Schemes 4–6. Most of the substituted carbazoles were
prepared from commercially available aniline (Scheme 4). The
Pd(OAc)2
[HPt-Bu3][BF4]
Me
Cl
OMe
NaH, BnBr
Me
BnO
DMF/THF
rt
K2CO3, DMA
BnO
N
H
130 o
C
6
N
H
17
carboxylic acid was reduced exhaustively with BH3•SMe2, followed
by a Buchwald–Hartwig amination using a wide range of aryl
8
9
16
OMe
OMe
bromides, which allowed access to a variety of substituted precursors
Me
HO
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AlCl3, PhNMe2, CH2Cl2, rt
25
7
( ). Cyclization was achieved in the presence of Pd(OAc)2 and a
N
Bn
N
BnO
9 25
. To obtain
Bn
monodentate trialkyl ligand to generate carbazole
4o
18
nitrogen protected hydroxycarbazoles, BBr3 demethylation21
To investigate how introducing an electron donating group to the
carbazole affected enantioselectivity, a substrate with a methoxy
group at the C-6 position was synthesized. For substrates containing
two methoxy substituents, selective deprotection of the oxygen at
followed by selective N-benzylation (or vice versa) afforded 2-
hydroxy-3-methylcarbazoles ( ).
Scheme 4. 2-Hydroxy-3-methylcarbazoles syntheses
26
4
arylbromide
Pd(OAc)2
[HPt-Bu3][BF4]
O
1) BH3∙SMe2,
7
the C-2 position proved untenable. Thus, a demethylaton of was
Me
Cl
ClPh, 0 °C
Cl
HO
undertaken with BBr3 followed by a benzylation to yield the aniline
NaOt-Bu
toluene, reflux
2) 80 °C, 3 h
3)130 °C, 18 h
MeO
NH2
14
15
. Thereafter, a Buchwald Hartwig amination with aryl bromide
MeO
NH2
6
8
7
followed by cyclization in the presence of Pd(OAc)2 and a
monodentate trialkyl ligand generated carbazole . Finally, N-
R
Pd(OAc)2
[HPt-Bu3][BF4]
R
16
Me
Cl
Me
MeO
benzylation followed by selective O-debenzylation with AlCl3
K2CO3, DMA
N
H
MeO
N
H
130 o
C
4o
afforded
.
9
With these substrates in hand, the scope of the enantioselective
douplign was investigated (Table 6). Electron-withdrawing
substituents gave good to excellent selectivity (85–96% ee) along
with moderate to good conversions (46–87% yield). Highly
enantioenriched bishydroxycarbazoles were obtained with the
fluoride substituent regardless of distal position (entry 2–4, 91–92%
ee). More electron-deficient hydroxycarbazoles, 6-CF3 (entry 5)
and 7-CF3 (entry 6), offered excellent selectivities (93% and 94% ee)
with good yields. Use of an electron withdrawing carbonyl group
(entry 7), however, gave rise to solubility issues. A mixed solvent
system, which included hexafluoroisopropanol as a co-solvent, was
needed. Accordingly, compromised conversion was observed along
with slightly lower selectivity (85% ee). The ester substituted
compound provided the most selective coupling result (entry 8, 96%
ee). The diphenylamino group was an outlier with drastically lower
selectivity (entry 9, 37% ee). Faster oxidative coupling reactions
were observed with electron-donating substituents. For example, the
6-methoxyhydroxycarbazole coupling reaction was completed in 26
hours with moderate selectivity (entry 11, 74% ee). With a methyl
or allyl group adjacent to the phenol, good enantioselectivites were
observed (entry 1, 13). On the other hand, an electron-withdrawing
bromide (entry 14) or an aryl group (entry 15) at this site
compromised reactivity while retaining moderate levels of
selectivity.
R
R
BBr3, CH2Cl2
–78 °C to rt
Me
Me
N
H
N
H
HO
MeO
9
10
NaH, BnBr
NaH, BnBr
DMF/THF
rt
DMF/THF
rt
R
R
BBr3, CH2Cl2
–78 °C to rt
Me
HO
Me
N
Bn
N
Bn
MeO
11
4
Substrates containing a different group adjacent to the phenol
12
were prepared form the commercially available hydroxycarbazole
(Scheme 5). A one-pot benzylation of the oxygen and nitrogen was
13
followed by a bromination, using NBS, to obtain . Suzuki and
Negishi27 couplings introduced
phenyl and allyl groups,
respectively, to the C-3 position. Thereafter, deprotection of the
a
28
4q 4r
4s
.
phenol with AlCl3 afforded
Scheme 5. 3-Substituted-2-hydroxycarbazole syntheses
,
, and
AlCl3
PhNMe2
1.NaH, BnCl
DMF/THF, rt
Br
Br
CH2Cl2
rt
2.NBS, CH2Cl2
rt
N
Bn
N
H
N
Bn
BnO
HO
HO
4q
13
12
1.Zn(allyl)Br
1.Pd(dppf)2Cl2
Pd(OAc)2, CPhos
THF, rt
C6H5BF3K, Cs2CO3
THF/H2O, reflux
N
Bn
N
Bn
2.AlCl3, PhNMe2
CH2Cl2, rt
HO
HO
2.AlCl3, PhNMe2
CH2Cl2, rt
4r
4s
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Table 6. Scope of 2-Hydroxycarbazole Coupling (eq 7) a
Page 8 of 28
1
2
3
4
5
6
R2
20 mol % V8
R1
HOAc
chlorobenzene
O2
R2
R1
N
R3
HO
HO
(7)
R3
N
0 oC, 2 d
N
R3
HO
R1
4
5
R2
7
8
9
Entry
1
Substrate
Yield (%)b
ee (%)c Entry
Substrate
Yield (%)b
62
ee (%)c
37
NPh2
Me
HO
Me
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
91
87
92
92
91
9
N
Bn
N
Bn
4m
4a
F
Me
Me
HO
Me
HO
2
3
4
87
73
80
10
11g
12
90(45)f
82
60(76)f
74
N
Bn
N
Bn
4f
4n
OMe
F
Me
HO
Me
HO
N
Bn
N
Bn
4g
4o
Ph
Me
HO
Me
70
82
F
N
Bn
N
Bn
HO
4h
4p
CF3
Br
Me
HO
5
6
70
60
93
94
85
13
14
15
17(30)e
75
72
83
60
N
Bn
HO
N
Bn
4q
4i
CF3
Me
HO
N
Bn
N
Bn
HO
4j
4r
COPh
Me
7d
53(76)e
26(43)e
N
Bn
HO
N
Bn
HO
4s
4k
CO2Bu
Me
HO
8
46(67)e
96
N
Bn
4l
aReaction Conditions: 20 mol% catalyst, 6.5 equiv HOAc, O2, 0.5 M chlorobenzene, 48 h. bIsolated yield. cee determined by chiral
HPLC. dHFIP/PhCl as a solvent. eIsolatted yield based on recovered substrate. fReaction was conducted at -15 °C. gReaction time
was 26 h.
To determine whether the changes to the catalytic
2-naphthol using a valine analog of V6.22b Since the coupling
selectivities are very different with the dimeric vanadium
catalysts22c-g and the monomeric vanadium catalyst/Brønsted acid
system used herein, a study of the mechanism was undertaken.
Mechanism.
system, namely use of alkoxy derived monomeric vanadium catalysts
with HOAc, would also be beneficial with the parent naphthol
couplings, several substrates were screened (Scheme 7). However,
the selectivities were uniformly low in line with prior reports with
Scheme 7. Monomeric Vanadium Catalysts in Naphthol
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4
50 mol% V6
N2 atmosphere
26% (3 days)
Coupling
aReaction Conditions: 6.25 equiv HOAc, toluene, O2, rt, 2 d.
1
2
3
R
R
20 mol% V6, O2
6.25 equiv AcOH
OH
OH
R
toluene, rt, 18 h
OH
Based on these experiments, our initial proposed mechanism is
4
5
6
7
8
9
outlined in Figure 3a. To reconcile the acceleration by acid, we
speculated that additional catalyst activation would be achieved by
Me
OH
CO2Me
OH
A
protonation to produce , or an analog thereof. Hydrogen atom
OH
75 % yield
OH
abstraction was excluded by the absence of an isotope effect between
50 % conv.
28% ee
78 % yield
25% ee
NR
HOAc and acetic acid-D4 (Figure 4).29 Rather, ligand exchange with
44% ee(R)
1a
B
phenol would generate intermediate , which was observed by
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
LCMS analysis. Subsequent single electron transfer to oxidize the
V6
With 20 mol% of , the oxidative coupling of 2,3,5-trimethyl
phenol was completed within 2 days at ambient temperature under
oxygen (Table 7, entry 1). However, the addition of equimolar
radical inhibitor TEMPO relative to catalyst, led to low conversion
(35%, entry 2), which suggests a radical process. Under inert
atmosphere, 9% and 26% conversions were detected in the presence
C
phenol, would be followed by coupling ( ). The control experiment
in Table 7 (entry 2) supports such a radical coupling.
V6
of 20 and 50 mol% of
catalyst (entry 3–4). Accordingly,
vanadium(V) species were implicated as the active oxidant. Further,
the stoichiometry is consistent with each vanadium (V) abstracting
one electron [i.e. a V(V) to V(IV) redox couple].
Table 7. Control Experiments in Asymmetric Coupling (eq 8) a
Me
V6
20 mol%
Me
Me
6.25 equiv AcOH
O2
Me
OH
t (h)
Me
Me
OH
OH
(8)
toluene, rt, 2 d
Figure 2. Reaction rates with CH3COOH vs CD3COOD.
Me
Me
Me
entry
catalyst
conditiona
control
conversion
1
2
3
20 mol% V6
20 mol% V6
20 mol% V6
100%
35%
0.2 equiv TEMPO
N2 atmosphere
9% (3 days)
Me
Me
HO
(a)
(b)
100
MeOH
t-Bu
H
O
Me
t-Bu
H
O
O
90
80
70
60
50
40
O
O
N
O
O
V
Me
H
N
O
V
O
O2N
OMe
O2N
Me
Me
t-Bu
t-Bu
A
B
OAc
Me
1/2 O2, HOAc
Me
t-Bu
H
t-Bu H O
O
O
30
HO
HO
Me
Me
H
N
O
HOAc
O
O
O
N
O
Me
H
H
20
10
0
V
V
Me
O2N
O2N
O
O2N
O
t-Bu
O
Me
Me
t-Bu
t-Bu
Me
Me
Me
Me
t-Bu
t-Bu
Me
Me
Me
2a
O
V
O
N
O
Me
O
O
O
O2N
O
O
N
0
10
20
30
40
50
60
70
80
90
100
Me
OMe
O2N
V
V
H
H2O
Me
N
H
O
O
O
t-Bu
H
C
O
D
H
t-Bu
O
V6
H
t-Bu
Figure 3. a) Initial mechanism. B) Nonlinear effect vs theoretical linear plot.
To further test this theory, we performed the cross-coupling
statistical distribution is observed.8
1a 2e
1e
experiment with and (Scheme 8). The major product was ,
1e
which is derived from more readily oxidizable phenol . The overall
product distribution is consistent with radical-radical mechanism
where oxidizability dictates the rate of radical formation and a
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Page 10 of 28
Scheme 8. Cross-Coupling Experiment with 1a and 1e
Me
Me
OH
Me
Me
1
2
3
4
5
6
7
20 mol % V6
6.25 equiv AcOH
O2
Me
Me
Me
Me
Me
Me
OH
Me
Me
OH
OH
Me
Me
OH
OH
Me
Me
OH
OH
Me
Me
OH
OH
toluene, rt, 2 d
Me
Me
Me
OH
Me
Me
Me
Me
OH
2e
Me
2a
OH
2ae
Me
1 equiv
89% yield, 85% ee
(72% yield, 95% ee after trituraion)
1a
16
:
1
:
3.5
V6
20 mol%
8
9
Me
OH
6.25 equiv HOAc
toluene, O2, 0 °C
16 h
OH
Me
Me
Figure 4. Absolute axial stereochemistry of dimerized phenol.
Me
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
OH
Me
Me
OH
Me
To further understand the origin of regio- and enantioselectivity
and verify our proposed mechanism, a DFT study of the catalytic
cycle was initiated using a truncated catalyst structure. Calculations
were conducted with Gaussian09. Multiple pathways and
conformational isomers were explored using UB3LYP/(6-31G(d);
V, LANL2DZ. For anionic species, diffuse functions were explored,
but resulted in no change. In addition, both singlet and triplet states
were assessed. Additional single point calculations were done with
UM06/(6-311+G(d,p); V, LANL2DZ;SMD, toluene.
Me
HO
HO
OH
OH
1 equiv
Me
OH
Me
OH
1e
Me
Me
OH
Me
OH
Me
T1
T2
3
:
7.5
:
D
Bond formation via dimeric cluster was supported by positive
non-linear effect (Figure 3b). Subsequent tautomerization provides
product while oxygen acts as the terminal oxidant to regenerate
2a
the vanadium(V).
Initial assessment of the pathway illustrated in Figure 3 revealed
that protonated intermediate A was energetically unfavorable
regardless of the site of protonation, the inclusion of counterions, or
the use of solvation models. Thus, different roles for the acetic acid
were surveyed. Ultimately, a pathway with energetics in line with the
observed rates was found when acetate was used as a µ2-bridging
ligand (Figure 5). Notably, the same pathway without the bridging
acetate was substantially less favorable (∆H‡ = 29.0 kcal/mol, ∆G‡
= 42.2 kcal/mol; see Supporting Information).
The initial model depicted in Figure 3a engages the phenol after
1a
associative ligand exchange via the less hindered lone pair of
.
Subsequently, the ortho methyl group of the phenol points forward
B
B
C
as shown in . Dimerization of complex , via , by minimizing
steric interactions provides the P (aS) stereoconfiguration. The
stereochemistry was assessed experimentally by X-ray analysis of
2a
crystals of obtained from hexane and ethyl acetate (10:1). The
absolute axial stereochemistry was found to be the P (aS)
configuration (Figure 4) in accord with such a model.
O
Singlet state
TS A
‡
O
Triplet state
16.6
(–10.2)
Me
Me
N
O
O
O
V
Gibbs Free Energy (Enthalpy)
Me
O
O
O
O
Me
Me
O
N
O
O
O
H
H
VV
Me
O
Me
N
O
O
Me
O
VV
O
O
O
N
O
O
Me
O
MeO
Me
H
H
V
Me
N
O
O
Int B3
VIV
Me
Me
SM, Cat
O
Me
1.81
(–22.3)
O
O
N
0.0
(0.0)
Me
O
O
O
O
VV
O
Me
Me
OH
OH
O
+
Me
Me
O
Int A
O
O
Me
Me
N
O
O
O
MeOH
Me
O
Me
VIV
N
O
O
O
–5.57
(–2.26)
Int C
O
N
VIV
Me
–
Me
CH3CO2
VIV
O
Me
Me
Me
Prod
–7.18
O
O
O
O
(–32.7)
Me
Me
O
O
O
H
H
Me
N
O
H
H
O
O
O
Int B1
Me
VV
Me
Int D
Me
–13.1
(–40.6)
O
N
O
O
Me
O
N
O
VV
O
–16.1
(–26.6)
O
O
VIV
O
SM, Cat
–18.7
Me
O
H
Me
N
O
O
1/2 O2,
MeOH
VV
H2O,
CH3CO2
O
–
Me
(–24.9) MeO
O
UM06/6-311+G(d,p), V: LANL2DZ; SMD: toluene // UB3LYP/6-31G(d), V: LANL2DZ
Figure 5.
Reaction energy diagram representing alternative calculated pathway.
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In this revised model (Figure 5), ligand exchange to generate the
phenoxide adduct coordinated via the less hindered oxygen lone pair
IntA
the greatest spin density is located at the para position (0.437)
relative to the para position (0.231); on the other ring, the most
negative spin density is on the ortho position (-0.017). However,
when we modeled the ortho-para coupling, the transition state
(see Supporting Information) leading to ortho–para coupled
product was predicted to be 5.5 kcal/mol higher that that leading
to ortho-ortho coupling, which explains why the ortho–para
product is not observed and suggests that the coupling step is also
regiodetermining. Indeed, distortion of the bridge in the ortho–
para coupling transition state is readily apparent.
To model the enantioselectivity, we computed two
diastereomeric transition structures incorporating the complete
Schiff base ligand, which lead to formation of the S and R product
enantiomers, respectively (Figure 7). The higher energy TS A(R)
suffers from greater torsional strain along the forming C-C bond
with a dihedral angle of 168.5° vs a closer-to-ideal of 177.5° for the
lower energy TS A(S). This model predicts an enantiomeric
excess of 84% in favor of the S-enantiomer, which agrees with the
experimentally obtained value of 86% ee.
1
2
3
4
5
6
7
8
is again proposed to yield
. Assembly of two such adducts with
IntB1
2
an µ -acetate bridge to form
by 7.5 kcal/mol. Singlet to triplet transition to form the diradical
IntB3 IntB1 IntB3
is thermodynamically favorable
is uphill energetically. In going from
to
, one of
the V–OAr bond distances increases from 1.784 Å to 2.155 Å, which
is indicative of bond cleavage. Unsurprisingly, much of the spin
density is concentrated on the reduced vanadium center, with the
rest primarily delocalized around the phenol. This monoradical
intermediate stands in contrast to the mechanisms typically
proposed for these couplings involving two carbon-centered radicals
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IntB3
TS A
gives rise to a transition state
(c.f. Figure 3). Notably,
for C-C bond formation with a free energy of 16.6 kcal/mol which is
substantially lower in energy than that from the singlet. In this
transition state, the second vanadium center abstracts an electron
from the other phenol, which results in C-C bond formation.
Subsequent decoordination and tautomerization leads to the
product. The overall process is driven by the favorable oxidation of
the resultant V(IV) to V(V) by dioxygen.
To ascertain whether the singlet to triplet conversion was
energetically feasible and/or rate-determining, an estimate of the
Additional calculations (see Supporting Information) were
undertaken to estimate the conical intersection. The UB3LYP
IntB1
IntB1’
energy of
that of
from
was calculated as if it were a triplet (
), and
). Potential energy scans
IntB1’ IntB3
were performed.
IntB3
IntB3’
as if it were a singlet (
IntB1 IntB3’
to to
and from
The intersection of the two potential energy curves was marked as
MECP
the approximate conical intersection (
relative UB3LYP energy (–32.4 kcal/mol) was markedly less than
TS A
, Figure 6). Since the
that of
(-12.9 kcal/mol), we conclude that the singlet-triplet
transition was not rate-limiting. All told, the calculations support the
C-C bond forming step as overall rate-limiting.
TS A
(S)
Int B1'
–8.81
Distortion
Int B3' –12.9
Excitation
MECP
-32.4
Excitation
•
Int B3
–32.8
Distortion
TS A
(R)
Figure 7.
Diastereomeric transition states leading to enantiomeric
Int B1
–44.2
products (Dihedral angles are for bonds highlighted in red.
Hydrogen atoms not shown for clarity).
Figure 6. Estimate of singlet to triplet barrier (∆E, kcal/mol;
U3B3LYP/6-31G(D), V: LANL2DZ)
Of the two open sites on the dissociated phenol ring in IntB3,
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made using neutral atomic masses; the mass of the electron removed
Concluding Remarks
1
2
3
4
5
6
7
8
or added to create the charged species is not taken into account. Low
resolution LCMS data were obtained by use of a UPLC system with
a SQD mass analyzer equipped with electrospray ionization.
Circular dichroism and UV-vis spectroscopy measurements carried
out at ambient temperature (23 °C). Solution spectra in methanol
recorded in 10-mm quartz cuvettes and corrected by subtracting the
spectrum of the pure solvent at the same temperature. A scan rate of
100 nm/min with a response time of 1 s and a bandwidth of 1 nm
was used to measure the CD spectra, which were recorded in low
sensitivity mode with 4 accumulations. Melting points are corrected.
Enantiomeric excesses were determined using analytical HPLC with
UV detection at 254 nm. Analytical Chiralpak columns (4.6 mm x
250 mm, 5 µm) from Daicel were used. Optical rotations were
measured on a polarimeter with a sodium lamp.
Beginning from dimeric vanadium catalysts that had been
previously reported as highly effective in coupling of 2-naphthols, a
series of rational modifications were undertaken to identify a
selective catalyst for coupling 2-phenols. Ultimately, the use of
typically less reactive monomeric vanadium catalysts was found to
be effective when combined with a Brønsted or Lewis acid additive,
which provided considerable activation. The resultant vanadium
catalyst system effected the asymmetric oxidative ortho-ortho
coupling of a range of simple phenols and 2-hydroxycarbazoles with
good to excellent levels of enantioselectivity. Experimental and DFT
studies of the mechanism indicate that the additives serve to
aggregate the vanadium monomers. In addition, a relatively facile
singlet to triplet crossover is implicated prior to the carbon-carbon
bond forming event. The resultant triplet intermediate gives rise to
a transition state with character between an anion-radical coupling
and a radical-radical coupling. The differences in energies between
the transition states leading to the regiomeric (ortho-ortho vs ortho-
para) and enantiomeric products (R vs S) correlate well with the
observed selectivity. Overall, effective equivalents of dimeric
vanadium catalysts can be assembled in situ from simple, easily made
monomers, which may have implications for other vanadium
catalyzed transformations.
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60
(S,S)-Vanadium Catalyst V3.
Under an inert atmosphere, 1-
ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (174 mg, 0.91
mmol) was added to a solution of hexanediol (50 µL, 0.43 mmol),
Boc-protected tert-leucine30 (200 mg, 0.86 mmol), 4-
dimethylaminopyridine (11 mg, 0.09 mmol) in CH2Cl2 (0.75 mL)
at 0 oC and was stirred for 10 min. The reaction mixture was stirred
for a further 20 h at room temperature. The reaction mixture was
diluted with CH2Cl2, washed with a satd NH4Cl, and the aqueous
layer was back extracted with CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated. The residue was
chromatographed (10% EtOAc in hexane) to yield the N-Boc
protected tethered amino acid as clear oil (200 mg) in 85% yield: 1H
Experimental
General Considerations:
Unless otherwise noted, all non-
aqueous reactions were carried out under an atmosphere of dry N2
in dried glassware. When necessary, solvents and reagents were dried
prior to use. THF was distilled from sodium benzophenone ketyl.
CH2Cl2, ClCH2CH2Cl, and toluene were distilled from CaH2. High
throughput experiments were performed at the Penn/Merck High
Throughput Experimentation Laboratory at the University of
Pennsylvania. The screens were analyzed by HPLC by addition of an
internal standard.
NMR (300 MHz, CDCl3) d 5.10 (m, 2H), 4.15 (m, 4H), 4.09 (s,
2H), 1.66 (m, 4H), 1.44 (s, 18H), 1.39 (m, 4H), 0.97 (s, 18H).
To the the N-Boc protected tethered amino acid (200 mg) in 1,4-
dioxane (1.0 mL) was added 4 N HCl in 1,4-dioxane (4.0 mL)
followed by stirring for 3 h at room temperature. Removal of solvent
afforded
hexane-1,6-diyl
(2S,2'S)-bis(2-amino-3,3-
dimethylbutanoate)hydrochloric salt as a white solid (152 mg) in
99% yield.
Analytical thin layer chromatography (TLC) was performed on
EM Reagents 0.25 mm silica-gel 254-F plates. Visualization was
accomplished with UV light. Chromatography was performed using
a forced flow of the indicated solvent system on EM Reagents Silica
Gel 60 (230-400 mesh). When necessary, the column was pre-
Under an inert atmosphere, Et3N (43 µL, 0.31 mmol) was added
a solution of hexane-1,6-diyl (2S,2'S)-bis(2-amino-3,3-
to
dimethylbutanoate)hydrochloric salt (59 mg, 0.14 mmol) in
ethanol (3.0 mL) and the mixture was stirred for 10 min. 3-
Hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde31 (50 mg,
0.28 mmol) dissolved in benzene (5.0 mL) was added to the
reaction mixture. The mixture was then heated at reflux for 3 d.
After evaporating the solvent, the triethylamine salt was removed via
addition of diethyl ether and vacuum filtration. Removal of
remaining solvent afforded the bis-Schiff base product as a yellow
solid (72 mg) in 77% yield: 1H NMR (300 MHz, CDCl3) d 12.88 (s,
2H), 8.19 (s, 2H), 6.95 (s, 2H), 6.68 (s, 2H), 4.10 (m, 4H), 3.62 (s,
2H), 1.77 (m, 16H), 1.62 (m, 4H), 1.36 (m, 4H), 1.02 (s, 18H).
1
washed with 1% Et3N in the eluent system. H NMR spectra were
recorded on a 500 MHz spectrometer. Chemical shifts are reported
in ppm from tetramethylsilane (0 ppm) or from the solvent
resonance (CDCl3 7.26 ppm, DMSO-d6 3.58 ppm, acetone-d6 2.05
ppm, DMF-d7 2.50 ppm, CD3CN 1.94 ppm, CD2Cl2 5.32 ppm).
Data are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, br = broad, m = multiplet),
coupling constants, and number of protons. Decoupled 13C NMR
spectra were recorded at 125 MHz. IR spectra were taken on an FT-
IR spectrometer using a thin film on NaCl plate. Accurate mass
measurement analyses were conducted via time-of-flight mass
analyzer GCMS with electron ionization (EI) or via time-of-flight
mass analyzer LCMS with electrospray ionization (ESI). The signals
The bis-Schiff base (72 mg, 0.11 mmol) was redissolved in EtOH
(2.0 mL) and VO(OEt)3 (19 µL, 0.11 mmol) was added dropwise.
The resultant mixture was stirred for 3 h at room temperature.
V3
Removal of the solvent afforded
99% yield.
as a dark blue solid (105 mg) in
were
measured
against
an internal reference of
perfluorotributylamine for EI-GCMS and leucine enkephalin for
ESI-LCMS. The instrument was calibrated and measurements were
(S,S)-Vanadium Catalyst V4.
using 3,5-bis-tert-butyl-2-hydroxybenzaldehyde, was obtained as
Following the above procedure
V4
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The Journal of Organic Chemistry
1
Asymmetric coupling with catalyst V6: Method A.
a dark blue solid (111 mg) in 99% yield. Bis-Schiff Base: H NMR
To a
1
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3
4
5
6
7
8
microwave vial was added phenol (1.31 mmol), 20 mol%
(300 MHz, CDCl3) d 13.52 (s, 2H), 8.28 (s, 2H), 7.40 (s, 2H), 7.10
(s, 2H), 4.11 (m, 4H), 3.64 (s, 2H), 1.62 (m, 4H), 1.43 (s, 18H),
1.36 (m, 4H), 1.29 (s, 18H), 1.05 (s, 18H).
V6
oxovanadium catalyst (0.27 mmol), and acetic acid (8.26 mmol).
The vial was sealed and toluene (0.5 M) was added. Oxygen was
added via an active purge. The deep blue reaction solution was
stirred for 2 d at 25 °C and then, concentrated. The residue was
chromatographed to afford the coupled product.
3-(tert-Butyl)-2-hydroxy-5-nitrobenzaldehyde
.
Dry
formaldehyde (0.7 g, 23.3 mmol) was added in portions to a mixture
of 4-tert-butylphenol (1.0 g, 6.66 mmol), Et3N (2.6 mL, 18.8 mmol)
and anhydrous MgCl2 (2.0 g, 20.6 mmol) in THF (50 mL). The
mixture was heated at reflux for 8 h, cooled to room temperature,
acidified with 3 N HCl (70 mL), and extracted with Et2O (30 mL x
3). The ether layer was washed with water (50 mL) and brine (50
mL) and dried using MgSO4. Removal of solvent and
chromatography yielded 3-(tert-butyl)-2-hydroxy-benzaldehyde as
yellow oil (710 mg, 61% yield). Spectral data matched those
reported in the literature.32
In a 100 mL round-bottom flask was placed 3-(tert-butyl)-
2-hydroxy-benzaldehyde (710 mg, 4.0 mmol) in HOAc (12 mL).
Nitric acid (4.0 mL, 96 mmol) was added dropwise at 0 °C and the
mixture was stirred for 1 h at ambient temperature. The resulting
mixture was poured into iced water (100 mL) with vigorous stirring.
The orange precipitate formed was filtered through a sintered glass
funnel, and then washed with water (10 mL). The product was
recrystallized from ethanol to give 360 mg (65% yield) of the
Asymmetric coupling with catalyst V6: Method B.
To a
microwave vial was added phenol (1.30 mmol), 20 mol%
V6
oxovanadium catalyst
(0.27 mmol), and LiCl (0.52 mmol). The
9
vial was sealed and toluene (0.5 M) was added. Oxygen was added
via an active purge. The deep blue reaction solution was stirred for
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h at 0 °C, and then concentrated. The residue was
chromatographed to afford the coupled product.
(S)-3,3',4,4',6,6'-Hexamethyl-[1,1'-biphenyl]-2,2'-diol (2a)
.
Method A
Following
, the product was obtained as a pale yellow
solid (160 mg, 89%) in 83% ee. Crystallization from hexane and
ethyl acetate (10:1) afforded white crystals with 95% ee. The
absolute axial configuration was determined as S from the X-Ray
1
crystal structure: H NMR (500 MHz, CDCl3) d 6.74 (s, 2H), 4.74
(s, 2H), 2.29 (s, 6H), 2.17 (s, 6H), 1.92 (s, 6H); 13C NMR (125
MHz, CDCl3) d 151.7, 138.5, 135.0, 123.7, 120.3, 116.9, 19.9, 19.1,
11.8; IR (film) 3509, 3460, 2922, 2359, 1560, 1458, 1298, 1079 cm-
1; HRMS (ESI-TOF) m/z = 270.1620 calcd for C18H22O2 [M]+,
found 270.1623. Mp 144.5-145.5 °C. [α]D22 –52.39 (c 0.04, 86% ee,
CH2Cl2); Chiral HPLC: Chiralpak IA column (1% i-
PrOH/hexanes, 1 mL/min) tR(R) = 5.09 min, tR(S) = 6.11 min.
1
product as a yellow solid: H NMR (500 MHz, CDCl3) d 12.44 (s,
1H), 9.97 (s, 1H), 8.41 (s, 2H), 1.46 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 196.2, 165.8, 140.7, 140.1, 128.7, 127.0, 119.3, 35.4, 31.4;
Spectral data matched that reported in the literature.33
(S)-4,4',5,5',6,6'-Hexamethyl-[1,1'-biphenyl]-2,2'-diol (2b).
(S)-Vanadium Catalyst V6.
All glassware was flame dried. A
Method A
V6
, using 20 mol% catalyst , the product was
Following
mixture of L-tert-leucine (45 mg, 0.34 mmol) and 3-tert-butyl-5-
nitro-2-hydroxybenzaldehyde (76 mg, 0.34 mmol) in
MeOH:CH2Cl2 (2 mL, 1:1) was heated at reflux and monitored by
TLC. The reaction mixture was cooled to room temperature and
VO(OEt)3 (69 mg, 0.34 mmol) was added followed by stirring for 3
h under Ar. Removal of solvent afforded the catalyst (147 mg, 99%)
as a deep blue solid: HRMS (ESI-TOF) m/z = 433.1180 calcd for
C18H26N2O7V [M+H]+, found 433.1179.
obtained as a white solid (176 mg, 100% conv.) in 10% ee. 1H NMR
1
(300 MHz, CDCl3): H NMR (500 MHz, CDCl3) δ 1.92 (s, 6H),
2.16 (s, 6H), 2.31 (s, 6H), 4.46 (s, 2H), 6.75 (s, 2H). Spectral data
matched that reported in the literature.35 Chiral HPLC: Chiralpak
AS column (1% i-PrOH/hexanes, 1 mL/min) tR(R) = 15.5 min;
tR(S) = 19.0 min.
3,3'-Di-tert-butyl-5,5',6,6'-tetramethyl-[1,1'-biphenyl]-2,2'-
diol (2c).
Method A
V6
, using 20 mol% catalyst , the
Following
(S)-Vanadium
Catalyst
V8.
3-tert-Butyl-5-nitro-2-
1
product was obtained as a white solid (230 mg, 100% conv.). H
NMR (500 MHz, CDCl3) δ 1.40 (s, 18H), 1.82 (s, 6H), 2.26 (s, 6H),
4.80 (s, 2H), 7.13 (s, 2H). Spectral data matched that reported in
the literature.36
hydroxybenzaldehyde (300 mg, 1.34 mmol) and L-tert-leucine (176
mg, 1.34 mmol) in MeOH:CH2Cl2 (7.6 mL, 1:1) were added to an
oven-dried round-bottom flask. The resultant mixture was heated at
reflux for 3 h. After evaporation of organic solvents, the residual solid
was redissolved in CH2Cl2 (6.7 mL). VO(Oi-Pr)3 (0.32 mL, 1.34
mmol) was introduced to the mixture followed by stirring for 3 h
under Ar. Removal of solvent afforded the catalyst (590 mg, 99%) as
a deep blue solid: HRMS (ESI-TOF) m/z = 461.1493 calcd for
C20H30N2O7V [M+H]+, found 461.1476.
(S)-3,3',6,6'-Tetramethyl-[1,1'-biphenyl]-2,2'-diol
(2d).
, using 40 mol% catalyst , the product was
Method A V6
Following
obtained as a white solid in 60% ee: 1H NMR (500 MHz, CDCl3) d
1.96 (s, 6H), 2.26 (s, 6H), 4.72 (s, 2H), 6.83 (d, J = 7.6, 2H), 7.11
(d, J = 7.6, 2H). Spectral data match those reported in the
literature.37 Chiral HPLC: Chiralpak AD column (1% i-
PrOH/hexanes, 1 mL/min) tR(R) = 6.3 min; tR(S) = 7.0 min.
Racemic coupling with VO(acac) .
1a
Substrate (30 mg, 0.22
2
mmol) and VO(acac)2 (29 mg, 0.11 mmol) were dissolved in
toluene (1 mL) at room temperature. Oxygen was added via an
active purge. The resulting deep green solution was stirred for 3 d.
The solution was concentrated and chromatographed (5% ethyl
acetate in hexane) to yield racemic 3,3',4,4',6,6'-
(S)-4,4',6,6'-Tetramethyl-[1,1'-biphenyl]-2,2'-diol
(2e).
Method A
V6
, using 20 mol% catalyst , the product was
Following
obtained as a white solid in 38% ee. 1H NMR (500 MHz, CDCl3) δ
1.97 (s, 6H), 2.33 (s, 6H), 4.63 (s, 2H), 6.72 (s, 2H), 6.75 (s, 2H).
Spectral data matched that reported in the literature.38 Chiral
HPLC: Chiralpak AS column (25% i-PrOH/hexanes, 1 mL/min)
2a
hexamethylbiphenyl-2,2'-diol ( ) as a pale-yellow solid (19 mg,
63%). Spectral data matched those reported in the literature.34
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tR(R) = 9.9 min; tR(S) = 11.9 min.
(S)-4,4'-Dimethoxy-3,3',6,6'-tetramethyl-[1,1'-biphenyl]-
2,2'diol (2f) Method B
product was obtained as a yellow solid (194 mg) in 80% yield: H
NMR (500 MHz, CDCl3) d 6.46 (s, 2H), 4.80 (s, 2H), 3.86 (s, 6H),
DMF (13 mL) was transferred into the flask, followed by Et2NH
1
2
3
4
5
6
7
8
under Ar. The resultant mixture was stirred at 70˚C for 22 h. After
cooling to ambient temperature, the reaction mixture was treated
with satd NH4Cl (10 mL). The mixture was extracted with EtOAc
(15 mL X 3) and washed with brine. The organic layer was dried
over Na2SO4 and filtered. Removal of the solvent followed by
chromatography (15% EtOAc in hexane) gave the desired product
. Following
at 0 °C for 18 h, the ortho-ortho
1
2.12 (s, 6H), 1.97 (s, 6H); 13C NMR (125 MHz, CDCl3) d 158.7,
152.9, 136.3, 111.9, 109.9, 104.7, 55.5, 19.7, 8.4; IR (film) 3513,
2921, 1577, 1466, 1326, 1104, 819, 739 cm-1; HRMS (ESI-TOF)
m/z = 325.1416 calcd for C18H22O4Na [M+Na]+, found 325.1414.
[α]D22 –19.68 (c 0.05, 82% ee, CHCl3); Chiral HPLC: Chiralpak IA
column (1% i-PrOH/hexanes, 1 mL/min) tR(R) = 7.99 min, tR(S) =
15.1 min.
1
as a pale yellow solid (867 mg) in 93% yield: H NMR (500 MHz,
acetone-d6) d 8.20 (s, 2H), 6.44 (s, 2H), 2.86 (s, 3H), 2.35 (t, J = 7.0
Hz, 2H), 1.55 (m, 2H), 1.44 (m, 2H), 1.30 (m, 4H), 0.89 (t, J = 2.0
Hz, 3H); 13C NMR (125 MHz, acetone-d6) d 157.0, 122.4, 112.3,
110.5, 89.0, 81.7, 32.1, 28.6, 28.5, 22.5, 19.6, 14.3, 8.5; IR (film)
3435, 3053, 2931, 2857, 2232, 1772, 1735, 1618, 1583, 1322, 1080,
737 cm-1; HRMS (ESI-TOF) m/z = 232.1463 calcd for C15H20O2
[M]+, found 232.1457.
9
10
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
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35
36
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39
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59
60
(S)-3,3',6,6'-Tetramethyl-[1,1'-biphenyl]-2,2',4,4'-tetraol
(2g)
Method B
at 0 °C for 12 h, the product was obtained
. Following
as a white solid (144 mg) in 81% yield: 1H NMR (500 MHz, CDCl3)
d 6.41 (s, 2H), 4.85 (s, 2H), 4.71 (s, 2H), 2.15 (s, 6H), 1.91 (s, 6H);
13C NMR (125 MHz, CDCl3) d 155.2, 153.5, 137.0, 111.7, 109.4,
108.1, 19.5, 8.5; IR (film) 3459, 2925, 1592, 1326, 1078 cm-1;
HRMS (ESI-TOF) m/z = 273.1127 calcd for C16H17O4 [M–H]-,
(S)-3,3'-Dimethyl-6,6'-di(oct-1-yn-1-yl)-[1,1'-biphenyl]-
2,2',4,4'-tetraol (2i)
Method B
at 0 °C for 18 h, the
. Following
1
product was obtained as a yellow solid (19 mg) in 66% yield: H
NMR (500 MHz, CDCl3) d 6.57 (s, 2H), 5.01 (s, 2H), 4.84 (s, 2H),
2.16 (s, 6H), 2.16-2.15 (m, 4H), 1.34-1.20 (m, 10H), 1.18-1.12 (m,
6H), 0.87 (t, J = 8 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 154.6,
153.5, 123.1, 115.3, 111.2, 110.9, 93.1, 78.3, 31.4, 28.4, 28.1, 22.5,
19.3, 14.1, 8.5; IR (film) 3443, 3304, 3054, 2930, 2306, 1606, 1584,
1395, 1265, 1077, 739 cm-1; HRMS (ESI-TOF) m/z = 463.2848
calcd for C30H39O4 [M+H]+, found 463.2841; [α]D22 –50.96 (c 0.05,
89% ee, CHCl3); Chiral HPLC: Chiralpak IA column (20% i-
PrOH/hexanes, 1 mL/min) tR(S) = 6.76 min, tR(R) = 16.0 min.
22
found 273.1139. [α]D –52.39 (c 0.04, 86% ee, CH2Cl2); Chiral
HPLC: Chiralpak IA column (20% i-PrOH/hexanes, 1 mL/min)
tR(S) = 4.95 min, tR(R) = 6.88 min.
4-Methyl-[1,1'-biphenyl]-3,5-diol (1h)
.
Under an N2
atmosphere, a mixture of 5-bromo-2-methylbenzene-1,3-diol (203
mg, 1.0 mmol), potassium phenyltrifluoroborate (200 mg, 1.1
mmol), PdCl2(dppf)•CH2Cl2 (4.0 mg, 0.5 mol %), and Et3N (0.4
mL, 3.0 mmol) in EtOH (4.0 mL) was stirred at 80 °C for 12 h. After
completion as indicated by TLC, the reaction mixture was cooled to
room temperature. After removal of the solvent, the residue was
diluted with EtOAc (15 mL) and washed with water (15 mL).
Removal of the solvent followed by chromatography (20% ethyl
acetate in hexane) afforded the product as a yellow solid (110 mg)
2-Allyl-3,5-dimethylphenol (1j)
. Allyl bromide (0.2 mL, 2.2
mmol) was added to a solution of 3,5-dimethylphenol (244 mg, 2.0
mmol) and potassium carbonate (304 mg, 2.2 mmol) in DMF (4.0
mL). The reaction mixture was stirred 16 h at room temperature,
diluted with ether (15 mL), and quenched with water (10 mL). The
organic layer was separated and the aqueous layer was extracted with
ether (10 mL x 3). The combined organic layers were dried over
Na2SO4. The resultant product was used without further purification
for the next step.
To a solution of allyl aryl ether from above in CH2Cl2 (10 mL)
was added BBr3 (4.0 mL of 1.0 M solution in CH2Cl2, 4 mmol)
dropwise at –50 °C. After stirring for 2 h at –50 °C, the solution was
quenched with water (10 mL), extracted with dichloromethane (15
mL x 3), and dried over MgSO4. The product was chromatographed
1
in 55% yield: H NMR (500 MHz, CDCl3) d 7.52 (d, J = 8.0 Hz,
2H), 7.41 (t, J = 7.0 Hz, 2H), 7.33 (t, J = 7.0 Hz, 1H), 6.65 (s, 2H),
4.84 (s, 2H), 2.18 (s, 3H); 13C NMR (125 MHz, CDCl3) d 154.9,
140.4, 140.1, 128.7, 127.4, 126.8, 109.4, 106.6, 7.8; IR (film) 3331,
2919, 1590, 1572, 1410, 1076, 848, 762, 694 cm-1; HRMS (ESI-
TOF) m/z = 201.0916 calcd for C13H13O2 [M+H]+, found
201.0914.
(S)-4',5''-Dimethyl-[1,1':2',1'':2'',1'''-quaterphenyl]-
3',4'',5',6''-tetraol (2h)
product was obtained as a yellow solid (26 mg) in 65% yield: H
Method A
at 0 °C for 18 h, the
. Following
1
1c
(5% EtOAc/hexane) to give (292 mg) as a white solid in 90%
1
yield for 2 steps: H NMR (500 MHz, CDCl3) d 6.61 (s, 1H), 6.50
NMR (500 MHz, CDCl3) d 7.10 (t, J = 7.0 Hz, 2H), 7.02 (t, J = 8.0
Hz, 4H), 6.57 (d, J = 7.0 Hz, 4H), 6.31 (s, 2H), 5.32 (s, 2H), 4.87 (s,
2H), 2.23 (s, 6H); 13C NMR (125 MHz, CDCl3) d 155.0, 153.7,
141.9, 140.0, 128.5, 127.4, 126.5, 110.7, 109.6, 109.4, 8.5; IR (film)
3437, 2920, 1620, 1395, 1342, 1077, 790, 760, 738, 700 cm-1; HRMS
(ESI-TOF) m/z = 399.1596 calcd for C26H23O4 [M+H]+, found
399.1591; Chiral HPLC: Chiralpak IA column (50 % ee, 25% i-
PrOH/hexanes, 1 mL/min) tR(S) = 14.27 min, tR(R) = 16.97 min.
(s, 1H), 5.99- 5.91 (m, 1H), 5.05 (d, J = 10.5 Hz, 1H), 5.02 (d, J =
17 Hz, 1H), 4.73 (s, 1H), 3.39 (d, J = 4.5 Hz, 2H), 2.25 (s, 3H), 2.24
(s, 3H); 13C NMR (125 MHz, CDCl3) d 153.9, 137.8, 136.9, 135.8,
123.7, 120.6, 115.3, 114.1, 30.3, 20.9, 19.5; IR (film) 3466, 2921,
1623, 1584, 1458, 1308, 1207, 1138, 1110, 1039, 911, 837 cm-1;
HRMS (ESI-TOF) m/z = 161.0966 calcd for C11H13O [M–H]-,
found 161.0972.
3,5-Dimethyl-2-propylphenol (1k).
To a stirring solution of
2-Methyl-5-(oct-1-yn-1-yl)benzene-1,3-diol
(1i)
.
allylated phenol (400 mg, 2.4 mmol) in dry MeOH (4.0 mL) was
added Pd/C (10 wt%, 40 mg). The reaction flask was evacuated and
backfilled with H2 (3 times). The reaction was stirred under H2
Pd(PPh3)2Cl2 (561 mg, 0.80 mmol), CuI (152 mg, 0.80 mmol), and
1-octyne (1.2 mL, 8.0 mmol) were added to a flame-dried flask. A
solution of 5-iodo-2-methylbenzene-1,3-diol39 (1.0 g, 4.0 mmol) in
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atmosphere for 16 h. The reaction mixture was then filtered through extracted with CH2Cl2 (30 mL X 3), dried over Na2SO4, filtered, and
1
2
3
4
5
6
7
8
Celite and concentrated. The product was chromatographed (5%
EtOAc/hexane) to give the product (304 mg, 1.92 mmol) as a white
solid in 79% yield: 1H NMR (500 MHz, CDCl3) d 6.59 (s, 1H), 6.46
(s, 1H), 4.57 (s, 1H), 2.56 (t, J = 8.0 Hz, 2H), 2.26 (s, 3H), 2.23 (s,
3H), 1.54 (sextet, J = 8.0 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 153.4, 137.6, 136.0, 124.1, 123.6, 113.6, 28.1,
22.5, 20.8, 19.4, 14.4; IR (film) 3476, 2959, 1583, 1454, 1302, 1215,
1140, 1103, 1022, 949 cm-1; HRMS (ESI-TOF) m/z = 163.1123
calcd for C11H15O [M–H]–, found 163.1117.
the solvent was removed under reduced pressure. Chromatography
afforded the product.
General procedure D: palladium catalyzed cyclization (S-4).
Chlorobiphenylaniline (1.89 mmol), K2CO3 (783 mg, 5.67 mmol),
Pd(OAc)2 (21 mg, 0.09 mmol), and [HP(t-Bu)3][BF4] (55 mg, 0.19
mmol) were combined with DMA (7.6 mL) under an Ar
atmosphere. After stirring at 130 oC for 18 h, the mixture was cooled
and then quenched by addition of 2 M HCl (aq) (7 mL). The
mixture was poured into excess amount of water and extracted with
EtOAc (30 mL X 3). The combined organic layers were washed
thoroughly with H2O (2 mL X 5) and brine followed by drying over
Na2SO4. After filtration and removal of solvent, the compounds was
chromatographed.
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(S)-3,3'-Diallyl-4,4',6,6'-tetramethyl-[1,1'-biphenyl]-2,2'diol
(2j)
Method A
at room temperature for 3 d, the ortho-
. Following
ortho product was obtained as a white solid (36 mg) in 56% yield:
1H NMR (500 MHz, CDCl3) d 6.76 (s, 2H), 5.99-5.92 (m, 2H),
5.00-4.93 (m, 4H), 4.76 (s, 2H), 3.43 (d, J = 3.5 Hz, 4H), 2.30 (s,
6H), 1.93 (s, 6H); 13C NMR (125 MHz, CDCl3) d 151.8, 138.6,
136.0, 135.9, 124.2, 121.9, 117.2, 114.4, 30.6, 19.4, 19.2; IR (film)
3524, 3077, 2922, 1637, 1564, 1457, 1302, 1258, 1191, 1144, 1110,
1050, 995, 909, 851 cm–1; HRMS (ESI-TOF) m/z = 323.2011 calcd
for C22H27O2 [M+H]+, found 323.2020; [α]D22 –21.88 (c 0.2, 77% ee,
CHCl3); Chiral HPLC: Chiralpak IA column (1% i-PrOH/hexanes,
1 mL/min) tR(R) = 5.63 min, tR(S) = 7.19 min.
General procedure E: demethylation.
The 2-methoxycarbazole
(1.62 mmol) was dissolved in CH2Cl2 (23 mL). After cooling to –78
ºC, a solution of BBr3 (1 M in dichloromethane, 3.24 mmol) was
added dropwise. The resultant mixture was allowed to warm to room
temperature and stirred until completion as judged by TLC (30 min
– 18 h). The mixture was subsequently quenched with water (15
mL) under ice bath. The solution was then extracted with EtOAc
(30 mL X 3), washed with brine and the combined organic layers
were dried over Na2SO4. Removal of solvent was followed by
chromatography.
(S)-4,4',6,6'-Tetramethyl-3,3'-dipropyl-[1,1'-biphenyl]-
2,2'diol (2k)
Method A
at room temperature for 3 d, the
. Following
General procedure F: protection of carbazole nitrogen.
To a
ortho-ortho product was obtained as a white solid (52 mg) in 80%
1
stirring solution of DMF (1.4 mL) and NaH (85 mg, 3.55 mmol)
was added a solution of 2-hydroxycarbazole (1.42 mmol) in THF
(14 mL) at 0 °C. After stirring for 30 minutes at room temperature,
BnCl (1.6 mL, 1.56 mmol, 1.0 M in THF) was added to the solution.
After stirring for 18 h at 10 oC, the solution was quenched with ice-
water (15 mL), extracted with EtOAc (30 mL X 3). After washing
the combined organic layers with water (2 mL X 5) and brine, the
organic phase was dried with Na2SO4. Removal of solvent was
followed by chromatography.
yield: H NMR (500 MHz, CDCl3) d 6.73 (s, 2H), 4.72 (s, 2H),
2.64-2.61 (m, 4H), 2.32 (s, 6H), 1.92 (s, 6H), 1.58-1.53 (m, 4H),
0.99-0.96 (m, 6H); 13C NMR (125 MHz, CDCl3) d 151.8, 138.0,
135.2, 125.2, 124.0, 117.1, 28.5, 22.4, 19.4, 19.2, 14.3; IR (film)
3524, 2959, 2871, 1616, 1563, 1453, 1394, 1296, 1260, 1205, 1146,
1
1103, 1039, 954, 850 cm ; HRMS (ESI-TOF) m/z = 327.2324
calcd for C22H31O2 [M+H]+, found 327.2323; [α]D22 –26.12 (c 0.2,
72% ee, CHCl3); Chiral HPLC: Chiralpak IA column (1% i-
PrOH/hexanes, 1 mL/min) tR(R) = 4.79 min, tR(S) = 6.24 min.
General procedure G: asymmetric oxidative 2-
2-Chloro-5-methoxy-4-methylaniline (7)
4-Amino-5-chloro-2-
hydroxycarbazole coupling.
protected 2-hydroxycarbazole (0.42 mmol), catalyst
To a microwave vial was added N-
methoxybenzoic acid (5.00 g, 24.8 mmol) was suspended in
chlorobenzene (50 mL) and cooled to 0 °C. Neat BH3•SMe2 (7.1
mL, 74.4 mmol) was added with vigorous stirring. When
effervescence ceased, the mixture was heated for 3 h at 80 °C and
then for 18 h at 130 °C. The reaction was quenched by addition of
aqueous Na2CO3 (aq) (1 M, 82 mL). The mixture was extracted
with CH2Cl2 (50 mL X 3), dried (MgSO4), filtered, and the solvent
was removed under reduced pressure to give a yellow solid.
Chromatography (9:1 = hexane/EtOAc) afforded the product as a
white powder(2.76 g 65%): 1H NMR (360 MHz, CDCl3) d 6.90 (s,
1H), 6.40 (s, 1H), 5.05 (s, 2H), 3.68 (s, 3H), 1.96 (s, 3H). Spectra
are in accord with those previously reported.40
V8
(38 mg,
0.08 mmol) and HOAc (0.16 mL, 2.71 mmol). The vial was sealed
with a septum and the chlorobenzene (0.84 mL) was added. After
degassing and purging with O2 three times, the vial was sealed with a
microwave vial cap and was stirred at 0 oC for 48 h. Upon
completion, the reaction mixture was then directly
chromatographed using silica gel.
2-Chloro-5-methoxy-4-methyl-N-phenylaniline
(8a).
General Procedure C
Following
for 23 h, the product was obtained
as brown oil (1.26 g) in 87% yield. Rf = 0.6 (EtOAc/Hexanes =
1
1/4): H NMR (500 MHz, acetone-d6) d 7.30 (t, J = 6.3 Hz, 2H),
7.13-7.10 (m, 3H), 6.99 (s, 1H), 6.8 (s, 1H), 5.94 (s, 1H), 3.71 (s,
3H), 2.13 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 157.1, 143.3,
138.8, 130.7, 129.2, 120.9, 120.0, 118.2, 113.8, 101.3, 55.0, 14.5; IR
(neat) 3400, 2925, 2850, 1512, 1200, 605 cm-1; HRMS (ESI-TOF)
calcd for C14H15ClNO [M+H]+ 248.0842, found 248.0842.
General procedure C: Buchwald-Hartwig C-N coupling.
A
mixture of NaOt-Bu (2.8 g, 29.1 mmol), Pd(OAc)2 (52 mg, 0.23
mmol), and [HP(t-Bu)3][BF4] (85 mg, 0.29 mmol) was suspended
in toluene (0.17 M). 2-Chloro-5-methoxy-4-methylaniline (1.0 g,
5.83 mmol) and an aryl bromide (5.94 mmol) were added. The
reaction mixture was heated at reflux for 18 h. After the resultant
mixture was cooled to ambient temperature, the mixture was
quenched by addition of 2 M HCl (aq) (35 mL). The mixture was
2-Methoxy-3-methyl-9H-carbazole (9a).
General
Following
Procedure D
for 20 h, the product was obtained as a white solid
(342 mg) in 86% yield. Spectral data were in agreement with those
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reported.41
3-Methyl-9H-carbazol-2-ol (10a).
109.2, 95.7, 43.3, 21.1, 20.5, 16.2; IR (neat) 3241, 2954, 1604, 1460,
1300, 1188, 742 cm-1; HRMS (EI-TOF) calcd for C23H23NO [M]+
m/z = 329.1780; found 329.1798.
1
2
3
4
5
6
7
8
General
Following
Procedure E
for 23 h, the product was obtained as a white solid (342
2-Chloro-N-(4-fluorophenyl)-5-methoxy-4-methylaniline
mg) in 86% yield. Spectral data were in agreement with those
reported.41
(8f).
General Procedure C
, the product was obtained as
Following
brown oil (1.55 g) in 99% yield. Rf = 0.65 (EtOAc:Hexanes = 1:4):
1H NMR (500 MHz, acetone-d6) d 7.20-7.17 (m, 2H), 7.12 (s, 1H),
7.07-7.04 (m, 2H), 6.83 (s, 1H), 6.78 (s, 1H), 3.72 (s, 3H), 2.09 (s,
3H); 13C NMR (125 MHz, acetone-d6) d 158.0 (d, J = 238 Hz),
157.2, 139.54 (d, J = 2.1 Hz), 139.5, 130.9 (d, J = 1.8 Hz), 121.0 (d,
J = 8.2 Hz), 119.6, 115.7 (d, J = 22.0 Hz), 113.2, 100.5 (d J = 3.9 Hz),
55.1, 14.6; IR (neat) 3420, 2925, 1609, 1200, 602, cm-1; HRMS
(ESI-TOF) calcd for C14H14ClFNO [M+H]+ 266.0748, found
266.0743.
9-Benzyl-3-methyl-9H-carbazol-2-ol (4a).
Procedure F
General
Following
for 24 h, the product was obtained as an off-white
powder (72 mg) in 52% yield. Spectral data were in agreement with
those reported.41
9
3,9-Dimethyl-9H-carbazol-2-ol (4b).
Procedure F
General
Following
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using a 1.0 M solution of MeI in THF (0.067 mL) for
2 h, the product was obtained as a brown solid (10 mg) in 23% yield.
Rf = 0.4 (EtOAc:Hexanes = 1:4): 1H NMR (500 MHz, acetone-d6)
d 8.29 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.80 (s, 1H) 7.39 (d, J = 8.0
Hz, 1H), 7.30 (dt, J = 7.5, 1.0 Hz, 1H), 7.10 (dt, J = 8.0, 0.5 Hz, 1H),
6.89 (s, 1H), 3.76 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 155.9, 142.1, 141.8, 124.6, 124.0, 122.4, 119.7, 119.3,
117.6, 116.4, 109.1, 95.2, 29.2, 16.6; IR (neat) 3391, 2922, 2853,
1634, 1604, 815, 740, 719, 621 cm-1; HRMS (ESI-TOF) calcd for
C14H14NO [M+H]+ 212.1075, Found 212.1083.
6-Fluoro-2-methoxy-3-methyl-9H-carbazole (9f).
Following
General Procedure D
, the product was obtained as a yellow solid
(104 mg) in 72% yield. Rf = 0.20 (EtOAc:Hexanes = 1:4): 1H NMR
(500 MHz, acetone-d6) d 10.08 (s, 1H), 7.81 (s, 1H), 7.69 (dd, J =
9.3, 2.5 Hz, 1H), 7.40 (dd, J = 8.8, 4.4 Hz, 1H), 7.04 (td, J = 9.4, 2.4
Hz, 1H), 7.01 (s, 1H), 3.89 (s, 3H), 2.30 (3H); 13C NMR (125
MHz, acetone-d6) d 157.9, 157.3 (d, J = 233 Hz), 141.2, 136.3, 123.9
(d, J = 10.1 Hz), 121.4, 118.5, 115.7 (d, J = 3.8 Hz), 111.1, 111.0 (d,
J = 15.1 Hz), 104.4 (d, J = 23.9 Hz), 92.6, 54.9, 16.0; IR (neat) 3395,
2910, 1486, 847, 822, 803, 783, cm-1; HRMS (ESI-TOF) calcd for
C14H13FNO [M+H]+ 230.0981, Found 230.0986.
9-Allyl-3-methyl-9H-carbazol-2-ol (4c).
Procedure F
General
Following
, the product was obtained as a colorless solid (71 mg)
1
in 43% yield. Rf = 0.47 (EtOAc:Hexanes = 1:4): H NMR (500
MHz, CDCl3) d 7.98 (d, J = 7.7 Hz, 1H), 7.82 (s, 1H), 7.37 (td, J =
8.2, 1.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.20 (td, J = 7.8, 0.9 Hz,
1H), 6.79 (s, 1H), 6.00-5.93 (m, 1H), 5.16 (dd, J = 10.3, 1.3 Hz,
1H), 5.04 (dd, J = 17.1, 1.2 Hz, 1H), 4.85 (s, 1H), 4.81-4.80 (m,
2H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) d 153.3, 140.6,
132.4, 124.4, 123.2, 122.0, 119.5, 119.1, 117.0, 116.9, 115.9, 108.6,
95.1, 45.5, 16.2; IR (neat) 3350, 2918, 1633, 1604, 1495, 1461,
1326, 1251, 1183, 1141, 1120, 1022, 923, 808, 744, 721 cm-1; HRMS
(EI-TOF) calcd for C16H15NO [M]+ m/z = 237.1154; found
237.1152.
6-Fluoro-3-methyl-9H-carbazol-2-ol (10f).
General
Following
Procedure E
, the product was obtained as a brown solid (166 mg)
1
in 90% yield. Rf = 0.20 (EtOAc:Hexanes = 1:2): H NMR (500
MHz, acetone-d6) d 9.94 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.66
(dd, J = 9.5, 2.6 Hz, 1H), 7.35 (dd, J = 8.8, 4.5 Hz, 1H), 7.01 (td, J =
9.0, 2.5 Hz, 1H), 6.97 (s, 1H), 2.35 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 157.0 (d, J = 233 Hz), 155.3, 141.3, 136.3, 124.2 (d, J
= 10.1 Hz), 121.6, 117.2, 115.8 (d, J = 3.8 Hz), 110.9, 110.7 (d, J =
14.8 Hz), 104.4 (d, J = 23.9 Hz), 96.2, 15.8; IR (neat) 3406, 2919,
1485, 1406, 1257, 1146, 1013, 600 cm-1; HRMS (ESI-TOF) calcd
for C13H9NOF [M-H]+ 214.0668, Found 214.0672.
9-Isopropyl-3-methyl-9H-carbazol-2-ol (4d).
Following
General Procedure F
, the product was obtained as a white solid (65
mg) in 39% yield. Rf = 0.43 (EtOAc:Hexanes = 1:4): 1H NMR (500
MHz, CDCl3) d 7.97 (d, J = 7.7 Hz, 1H), 7.81 (s, 1H), 7.45 (d, J =
8.3 Hz, 1H), 7.35 (td, J = 8.2, 1.2 Hz, 1H), 7.17 (td, J = 7.8, 0.8 Hz,
1H), 6.95 (s, 1H), 4.91-4.84 (m, 1H), 4.82 (s, 1H), 2.42 (s, 3H),
9-Benzyl-6-fluoro-3-methyl-9H-carbazol-2-ol (4f).
Following
General Procedure F
, the product was obtained as a yellow solid
(193 mg) in 81% yield. Rf = 0.35 (EtOAc:Hexanes = 1:4): 1H NMR
(500 MHz, acetone-d6) d 8.40 (s, 1H), 7.85 (s, 1H), 7.73 (dd, J =
9.0, 5.0 Hz, 1H), 7.41 (dd, J = 10.0, 5.0 Hz, 1H), 7.28-7.19 (m, 3H),
7.15-7.13 (m, 2H), 7.05 (td, J = 10.0, 1.0 Hz, 1H), 6.89 (s, 1H), 5.50
1.67 (d, J = 7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 152.8,
139.7, 139.4, 124.0, 123.5, 121.9, 119.5, 118.6, 117.5, 115.4, 109.7,
96.4, 46.8, 20.8, 16.1; IR (neat) 3383, 2972, 2917, 2849, 1635, 1602,
1459, 1350, 1223, 1101, 996, 1879, 721 cm-1; HRMS (EI-TOF)
calcd for C16H17NO [M]+ m/z = 239.1310; found 239.1321.
(s, 2H), 2.34 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 157.4 (d,
J = 233 Hz), 155.6, 141.7, 137.9, 137.0, 128.6, 127.2, 126.5, 123.9,
(d, J = 10.6 Hz), 122.0, 117.5, 115.3, 110.9 (d, J = 25.6 Hz), 109.3
(d, J = 9.3 Hz), 104.6 (d, J = 24.3 Hz), 94.9, 46.1, 15.7; IR (neat)
3301, 2922, 2851, 1633, 862, 828, 791, 729, 696, 626 cm-1; HRMS
(ESI-TOF) calcd for C20H17FNO [M+H]+ 306.1494 Found:
306.1497.
3-Methyl-9-(2,4,6-trimethylbenzyl)-9H-carbazol-2-ol (4e).
Following
trimethylbenzylchloride (0.117 g, 0.70 mmol), the product was
obtained as a white solid (92 mg) in 40% yield. Rf = 0.4
General
Procedure
F
using
2,4,6-
1
(EtOAc:Hexanes = 1:4): H NMR (500 MHz, CDCl3) d 7.95 (d, J
2-Chloro-N-(3-fluorophenyl)-5-methoxy-4-methylaniline
= 7.7 Hz, 1H), 7.79 (s, 1H), 7.25 (td, J = 8.3, 1.2 Hz, 1H), 7.15 (td,
J = 7.9, 0.8 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.89 (s, 2H), 6.50 (s,
1H), 5.34 (s, 2H), 4.69 (s, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.18 (s,
6H); 13C NMR (125 MHz, CDCl3) d 153.0, 140.9, 140.8, 137.7,
137.6, 129.9, 129.6, 124.3, 123.3, 121.8, 119.3, 118.9, 117.1, 115.8,
(8g).
General Procedure C
, the product was obtained as
Following
brown oil (826 mg) in 65% yield. Rf = 0.78 (EtOAc:Hexanes = 1:4):
1H NMR (500 MHz, acetone-d6) d 7.24 (dd, J = 15.0, 8.0 Hz, 1H),
7.18 (s, 1H), 7.11 (br s, 1H), 6.95 (s, 1H), 6.90 (dd, J = 8.0, 2.0 Hz,
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1H), 6.80 (dt, J = 11.5, 2.5 Hz, 1H), 6.58 (td, J = 8.0, 2.5 Hz, 1H),
(500 MHz, acetone-d6) d 10.28 (br s, 1H), 8.43 (s, 1H), 7.80 (s,
3.79 (s, 3H), 2.13 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 163.8
(d, J = 243 Hz), 156.9, 144.6 (d, J = 10.0 Hz), 137.1, 131.0, 130.6 (d,
J = 10.0 Hz), 121.3, 114.2, 113.6 (d, J = 2.5 Hz), 108.0 (d, J = 21.3
Hz), 104.7 (d, J = 25.0 Hz), 101.3, 55.7, 15.4; IR (neat) 3405, 2920,
2851, 1604, 1582, 1518, 834, 815, 776, 767, 678, 615 cm-1; HRMS
(ESI-TOF) calcd for C14H14FClNO [M+H]+ 266.0748, found
266.0740.
1H), 7.75-7.74 (m, 1H), 7.06-7.03 (m, 3H), 2.37 (s, 3H); 13C NMR
(125 MHz, acetone-d6) d 156.3, 149.8 (d, J = 240.5 Hz), 141.2,
128.3 (d, J = 6.0 Hz), 128.1, 122.4 (d, J = 4.0 Hz), 119.6 (d, J = 5.9
Hz), 118.6, 116.8 (d, J = 2.6 Hz), 115.6, 109.6 (d, J = 16.6 Hz), 97.4,
16.7; IR (neat) 3540, 3404, 2911, 1623, 1576, 1475, 1450, 1429,
1299, 1290, 1262, 1237, 1219, 1200, 1174, 1157, 1137, 1057, 1050,
833 cm-1; HRMS (EI-TOF) calcd for C13H10FNO [M]+ m/z =
215.0746, found 215.0758.
1
2
3
4
5
6
7
8
7-Fluoro-2-methoxy-3-methyl-9H-carbazole (9g).
Following
9
General Procedure D
, the product was obtained as a yellow solid
9-Benzyl-8-fluoro-3-methyl-9H-carbazol-2-ol (4h).
Following
1
(60 mg) in 5% yield. Rf = 0.10 (EtOAc:Hexanes = 1:4): H NMR
(500 MHz, acetone-d6) d 10.18 (s, 1H), 7.92 (dd, J = 8.6, 5.5 Hz,
1H), 7.78 (s, 1H), 7.15 (dd, J = 10.0, 2.4 Hz, 1H), 7.03 (s, 1H), 6.90-
6.86 (m, 1H), 3.89 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 158.7 (d, J = 245 Hz), 158.5, 143.2 (d, J = 11.0 Hz),
140.6, 125.4 (d, J = 8.2 Hz), 124.0 (d, J = 2.9 Hz), 120.0, 114.0,
112.3, 107.6 (d, J = 3.5 Hz), 105.0 (d, J = 19.1 Hz), 93.5, 55.8, 16.8;
IR (neat) 3396, 2921, 1611, 841, 808, 742 cm-1; HRMS (ESI-TOF)
calcd for C14H11FNO [M-H]– 228.0825, Found 228.0822.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure F
, the product was obtained as a yellow solid
(55 mg) in 28% yield. Rf = 0.65 (EtOAc:Hexanes = 1:2): 1H NMR
(500 MHz, acetone-d6) d 8.49 (br s, 1H), 7.86 (s, 1H), 7.81 (d, J =
7.5 Hz, 1H), 7.27 (t, J = 7.0 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.15
(d, J = 7.2 Hz, 2H), 7.11-7.02 (m, 2H), 6.93 (s, 1H), 5.65 (s, 2H),
2.34 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 156.5, 150.2 (d, J
= 241.5 Hz), 142.1, 139.4, 129.5, 129.4, 128.3 (d, J = 5.0 Hz), 128.0,
127.1, 122.6, 120.1 (d, J = 6.3 Hz), 119.0, 116.6, 115.9 (d, J = 3.8
Hz), 110.8 (d, J = 18.9 Hz), 95.9, 49.0, 16.6; IR (neat) 3310, 2918,
1577, 1472, 1454, 1423, 1347, 1296, 1235, 1219, 1186, 1137, 1105,
1058, 1000, 819 cm-1; HRMS (ESI-TOF) calcd for C20H17FNO
[M+H]+ m/z = 306.1294, found 306.1314.
7-Fluoro-3-methyl-9H-carbazol-2-ol
(10g).
Following
General Procedure E
, the product was obtained as a brown solid
(69 mg) in 99% yield. Rf = 0.20 (EtOAc:Hexanes = 1:2): 1H NMR
2-Chloro-5-methoxy-4-methyl-N-(4-
(500 MHz, acetone-d6) d 10.06 (s, 1H), 8.26, (s, 1H), 7.89 (dd, J =
8.5, 5.5 Hz, 1H), 7.74 (s, 1H), 7.11 (dd, J = 10.5, 2.5 Hz, 1H), 6.96
(s, 1H), 6.88-6.84 (m, 1H) 2.33 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 161.0 (d, J = 235 Hz), 154.6, 140.6 (d, J = 14.8 Hz),
140.6, 121.2, 120.3, 119.7 (d, J = 10.5 Hz), 117.4, 115.7, 106.2 (d, J
= 24.1 Hz), 97.0 (d, J = 26.3 Hz), 96.5, 15.9; IR (neat) 3406, 2920,
1486, 1293, 834, 820, 810, 781, 600, cm-1; HRMS (ESI-TOF) calcd
(trifluoromethyl)phenyl)aniline (8i).
General
using Pd2(dba)3 as the catalyst at room temperature
Following
Procedure C
for 10 min, the product was obtained as a white solid (252 mg) in
45% yield. Rf = 0.57 (EtOAc:Hexanes = 1:4): 1H NMR (500 MHz,
CDCl3) d 7.54 (d, J = 8.5 Hz, 2H), 7.18 (s, 1H), 7.10 (d, J = 8.5 Hz,
2H), 6.89 (s, 1H), 6.08 (br s, 1H), 3.78 (s, 3H), 2.21 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 157.0, 146.3, 136.4, 131.2, 126.9, 124.6
(q, J = 271 Hz), 122.6 (q, J = 32.7 Hz), 122.5, 116.4, 115.5, 102.6,
55.7, 15.5; IR (neat) 3400, 2925, 1604, 1525, 1509, 1481, 1450,
1395, 1323, 1289, 1244, 1201, 1186, 1159, 1103, 1066, 990, 946, 873
cm-1; HRMS (ESI-TOF) calcd for C15H14ClF3NO [M+H]+ m/z =
316.0716, found 316.0742.
for C13H9FNO [M-H]– 214.0668, Found: 214.0669.
9-Benzyl-7-fluoro-3-methyl-9H-carbazol-2-ol (4g).
Following
General Procedure F
, the product was obtained as a yellow solid
(57 mg) in 83% yield. Rf = 0.17 (EtOAc:Hexanes = 1:4): 1H NMR
(500 MHz, acetone-d6) d 8.38 (s, 1H), 7.84 (s, 1H), 7.28-7.19 (m,
5H), 7.14 (d, J = 7.0 Hz, 2H), 6.91 (s, 1H), 6.84 (ddd, J = 8.5, 7.0,
1.5 Hz, 1H), 5.50 (s, 2H), 2.33 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 157.6 (d, J = 245 Hz), 155.0, 143.0, 140.3, 137.5,
128.5, 127.2, 126.4, 124.5 (d, J = 8.3 Hz), 123.7 (d, J = 3.0 Hz),
117.9, 112.8, 111.0, (d, J = 21.0 Hz), 104.9, 104.4 (d, J = 19.3 Hz),
94.3, 46.2, 15.5; IR (neat) 3456, 3370, 2918, 1470, 883, 776, 741,
715, 702, 693 cm-1; HRMS (ESI-TOF) calcd for C20H15FNO [M-
2-methoxy-3-methyl-6-(trifluoromethyl)-9H-carbazole (9i)
General Procedure D
Following
for 48 h, the product was obtained
as a light brown solid (94 mg) in 84% yield. Rf = 0.44
1
(EtOAc:Hexanes = 1:2): H NMR (500 MHz, CDCl3) d 8.21 (s,
1H), 7.87 (br s, 1H), 7.81 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.30 (d,
J = 8.5 Hz, 1H), 6.72 (s, 1H), 3.87 (s, 3H), 2.39 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 158.2, 140.7, 139.8, 125.5 (q, J = 271 Hz),
123.2, 121.8, 121.7 (q, J = 31.8 Hz), 121.0, 120.5, 116.8, 115.6,
110.3, 92.5, 55.6, 16.8; IR (neat) 3360, 2915, 1614, 1458, 1334,
1297, 1261, 1230, 1197, 1164, 1145, 1112, 1095, 1051, 1039, 1015,
978, 880, 819 cm-1; HRMS (EI-TOF) calcd for C15H12F3NO [M]+
m/z = 279.0871, found 279.0877.
H]– 304.0876 Found: 304.0875.
2-Chloro-N-(2-fluorophenyl)-5-methoxy-4-methylaniline
(8h).
General Procedure C
for 20 h, the product was
Following
obtained as brown oil (398 mg) in 64% yield. Spectral data were in
agreement with those reported.42
3-Methyl-6-(trifluoromethyl)-9H-carbazol-2-ol
(10i).
1-Fluoro-7-methoxy-6-methyl-9H-carbazole (9h).
Following
General Procedure E
Following
, the product was obtained as a light
General Procedure D
for 20 h, the product was obtained as a light
tan solid (98 mg) in 71% yield. Rf = 0.29 (EtOAc:Hexanes = 1:1):
brown solid (313 mg) in 91% yield. Spectral data were in agreement
with those reported.42
1H NMR (500 MHz, acetone-d6) d 10.36 (br s, 1H), 8.44 (s, 1H),
8.31 (s, 1H), 7.95 (s, 1H), 7.57-7.53 (m, 2H), 7.04 (s, 1H), 2.37 (s,
8-Fluoro-3-methyl-9H-carbazol-2-ol
General Procedure E
(10h).
, the product was obtained as a brown solid
(200 mg) in 69% yield. Rf = 0.38 (EtOAc:Hexanes = 1:2): 1H NMR
Following
3H); 13C NMR (125 MHz, acetone-d6) d 156.5, 142.5, 141.7, 126.7
(q, J = 270 Hz), 124.2, 122.7, 121.1 (q, J = 3.8 Hz), 121.0 (q, J = 31.4
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Hz), 119.0, 117.1 (q, J = 3.8 Hz), 116.3, 111.4, 97.3, 16.7; IR (neat) 7.30-7.24 (m, 3H), 7.16 (d, J = 7.1 Hz, 2H), 6.96 (s, 1H), 5.63 (s,
2H), 2.36 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 156.3, 142.0,
139.8, 137.5, 128.7, 127.3, 126.5, 126.2, 125.5 (q, J = 269 Hz), 125.1
(q, J = 31.0 Hz), 122.4, 119.4, 118.5, 115.3 (q, J = 4.0 Hz), 114.7,
105.8 (q, J = 4.0 Hz), 95.1, 46.1, 15.7; IR (neat) 3345(w), 2915,
1640, 1453, 1370, 1317, 1296, 1262, 1248, 1214, 1168, 1142, 1132,
1116, 1063, 1042, 1011, 887, 858, 821, 702, 665, 653 cm-1; HRMS
(ESI-TOF) m/z = 356.1262 calcd for C21H17F3NO [M+H]+, found
356.1247.
1
2
3
4
5
6
7
8
3412, 3270, 2925, 1641, 1616, 1414, 1330, 1298, 1255, 1225, 1210,
1194, 1169, 1156, 1137, 1108, 1052, 1015, 883 cm-1; HRMS (EI-
TOF) calcd for C14H10F3NO [M]+ m/z = 265.0714, found 265.0714.
9-Benzyl-3-methyl-6-(trifluoromethyl)-9H-carbazol-2-ol
(4i).
General Procedure F
, the product was obtained as
Following
a white powder (24 mg) in 29% yield. Rf = 0.50 (EtOAc:Hexanes =
1:2): 1H NMR (500 MHz, acetone-d6) d 8.52 (s, 1H), 8.37 (s, 1H),
8.01 (s, 1H), 7.64-7.58 (m, 2H), 7.30-7.24 (m, 3H), 7.17 (d, J = 7.0
Hz, 2H), 6.97 (s, 1H), 5.58 (s, 2H), 2.37 (s, 3H); 13C NMR (125
MHz, acetone-d6) d 156.7, 143.0, 142.4, 138.3, 129.5, 128.2, 127.4,
126.6 (q, J = 270 Hz), 124.0, 123.0, 121.4 (q, J = 3.6 Hz), 121.3 (q, J
= 31.7 Hz), 119.4, 117.2 (q, J = 4.3 Hz), 116.0, 109.8, 96.1, 47.0,
16.6; IR (neat) 3350, 2923, 1613, 1453, 1371, 1330, 1301, 1260,
1213, 1175, 1158, 1141, 1103, 1068, 1044, 1013, 963, 882 cm-1;
HRMS (EI-TOF) calcd for C21H16F3NO [M]+ m/z = 355.1184,
found 355.1175.
9
(4-((2-Chloro-5-methoxy-4-
methylphenyl)amino)phenyl)(phenyl)methanone
(8k).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure C
Following
using Pd2(dba)3 (4 mol %) as a
catalyst at room temperature for 20 min, the product was obtained
as a brown solid (497 mg) in 81% yield. Rf = 0.44 (EtOAc:Hexanes
= 1:4): 1H NMR (500 MHz, CDCl3) d 7.81 (d, J = 8.5 Hz, 2H), 7.77
(d, J = 7.0 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H),
7.16 (s, 1H), 7.05 (d, J = 6.5 Hz, 2H), 6.92 (s, 1H), 6.31 (s, 1H), 3.76
(s, 3H), 2.18 (s, 3H); 13C NMR (125 MHz, CDCl3) d 195.2, 156.8,
147.5, 138.5, 135.7, 132.6, 131.7, 131.1, 129.6, 129.3, 128.2, 122.9,
116.0, 115.1, 103.3, 55.7, 15.6; IR (neat) 3360, 3000, 2949, 1584,
1574, 1516, 1500, 1480, 1465, 1443, 1394, 1309, 1282, 1249, 1201,
1174, 1165, 1143, 837 cm-1; HRMS (ESI-TOF) calcd for
C21H19ClNO2 [M+H]+ m/z = 352.1104, found 352.1100.
2-Chloro-5-methoxy-4-methyl-N-(3-
(trifluoromethyl)phenyl)aniline (8j).
General
using Pd2(dba)3 as the catalyst at room temperature
Following
Procedure C
for 10 min, the product was obtained as a yellow oil (677 mg) in 92%
yield. Rf = 0.69 (EtOAc:Hexanes = 1:5): H NMR (500 MHz,
1
CDCl3) d 7.40-7.36 (m, 2H), 7.23-7.19 (m, 2 H), 7.15 (s, 1H), 6.81
(s, 1H), 6.03 (s, 1H), 3.74 (s, 3H), 2.16 (s, 3H); IR (neat) 3405,
2940, 1607, 1598, 1518, 1496, 1466, 1447, 1434, 1398, 1332, 1320,
1236, 1200, 1162, 1120, 1098, 1069, 1000, 875, 789, 697 cm-1;
HRMS (ESI-TOF) m/z = 315.0638 calcd for C15H13ClF3NO [M]+,
found 315.0627.
(7-Methoxy-6-methyl-9H-carbazol-3-yl)(phenyl)methanone
(9k).
General Procedure D
for 23 h, the product was
Following
obtained as a brown solid (288 mg) in 65% yield. Rf = 0.19
(EtOAc:Hexanes = 1:2): 1H NMR (500 MHz, DMF-d7) d 11.55 (br
s, 1H), 8.53 (s, 1H), 7.99 (s, 1H), 7.84 (d, J = 8.4 Hz, 3H), 7.70 (t,
J = 7.4 Hz, 1H), 7.63-7.60 (m, 3H), 7.15 (s, 1H), 3.96 (s, 3H), 2.33
(s, 3H); 13C NMR (125 MHz, DMF-d7) d 196.0, 158.2, 143.1, 141.2,
139.6, 131.9, 129.8, 128.6, 128.5, 126.6, 123.1, 122.7, 121.9, 119.4,
116.1, 110.6, 93.4, 55.5, 16.3; IR (neat) 3300, 2910, 1629, 1599,
1565, 1473, 1332, 1312, 1282, 1247, 1195, 1147, 1131, 1036, 1001,
876, 825 cm-1; HRMS (ESI-TOF) calcd for C21H18NO2 [M+H]+
m/z = 316.1338, found 316.1347.
2-Methoxy-3-methyl-7-(trifluoromethyl)-9H-carbazole (9j).
General Procedure D
as a light tan solid (295 mg) in 67% yield. Rf = 0.10 (EtOAc:Hexanes
Following
for 24 h, the product was obtained
= 1:6): 1H NMR (500 MHz, acetone-d6) d 10.43 (br s, 1H), 8.13 (d,
J = 8.2 Hz, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H),
7.10 (s, 1H), 3.93 (s, 3H), 2.33 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 159.6, 142.3, 139.9, 127.2, 126.5 (q, J = 269 Hz), 125.8
(q, J = 31.0 Hz), 122.7, 120.5, 120.4, 116.1 (q, J = 4.0 Hz), 116.0,
108.6, (q, J = 4.0 Hz), 93.7, 56.0, 17.0; IR (neat) 3395, 2935, 1630,
1478, 1448, 1332, 1323, 1293, 1217, 1197, 1163, 1146, 1114, 1070,
1057, 1035, 1002, 920, 874, 821, 791, 666 cm-1; HRMS (ESI-TOF)
m/z = 279.0871 calcd for C15H12F3NO [M]+, found 279.0866
(9-Benzyl-7-methoxy-6-methyl-9H-carbazol-3-
yl)(phenyl)methanone (11k).
General Procedure F
at
Following
room temperature for 22 h, the product was obtained as a pale yellow
solid (206 mg) in 80% yield. Rf = 0.80 (EtOAc:Hexanes = 1:1): 1H
NMR (500 MHz, acetone-d6) d 8.51 (s, 1H), 7.97 (s, 1H), 7.84 (dd,
J = 8.6, 1.6 Hz, 1H), 7.81 (dd, J = 8.1, 1.5 Hz, 2H), 7.64-7.54 (m,
3-Methyl-7-(trifluoromethyl)-9H-carbazol-2-ol
(10j).
4H), 7.31-7.24 (m, 6H), 5.72 (s, 2H), 3.91 (s, 3H), 2.32 (s, 3H); 13
C
General Procedure E
Following
, the product was obtained as a tan
solid (144 mg) in 68% yield. Rf = 0.15 (EtOAc:Hexanes = 1:5): 1H
NMR (500 MHz, acetone-d6) d 10.31 (br s, 1H), 8.52 (s, 1H), 8.11
(d, J = 8.1 Hz), 7.89 (s, 1H), 7.73 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H),
7.03, (s, 1H), 2.36 (s, 3H); IR (neat) 3505, 3380, 2920, 1635, 1620,
1473, 1451, 1433, 1351, 1322, 1302, 1285, 1217, 1161, 1115, 1056,
1010 917, 873, 843, 822, 727, 669 cm-1; HRMS (ESI-TOF) m/z =
265.0714 calcd for C14H10F3NO [M]+, found 265.0726.
NMR (125 MHz, acetone-d6) d 196.2, 159.1, 143.7, 142.4, 140.1,
138.4, 132.3, 130.4, 129.6, 129.5, 129.0, 128.2, 127.6, 127.3, 123.6,
123.1, 122.6, 120.6, 116.5, 109.6, 92.6, 56.0, 47.0, 16.8; IR (neat)
2925, 1649, 1630, 1600, 1452, 1356, 1310, 1283, 1254, 1194, 1174,
1161, 1140, 877 cm-1; HRMS (ESI-TOF) calcd for C28H24NO2
[M+H]+ m/z = 406.1807, found 406.1792.
(9-Benzyl-7-hydroxy-6-methyl-9H-carbazol-3-
yl)(phenyl)methanone (4k).
General Procedure E
at
Following
9-Benzyl-3-methyl-7-(trifluoromethyl)-9H-carbazol-2-ol
room temperature for 45 min, the product was obtained as an off-
(4j).
General Procedure F
, the product was obtained as
Following
white powder (97 mg) in quantitative yield. Rf
= 0.34
a white solid (77 mg) in 58% yield. Rf = 0.28 (EtOAc:Hexanes =
1
1
(EtOAc:Hexanes = 1:2): H NMR (500 MHz, acetone-d6) d 8.48
1:4): H NMR (500 MHz, acetone-d6) d 8.60 (s, 1H), 8.18 (d, J =
(d, J = 3.9 Hz, 2H), 7.94 (s, 1H), 7.84 (dd, J = 8.5, 1.6 Hz, 1H), 7.81
8.2 Hz, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H),
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The Journal of Organic Chemistry
(d, J = 7.0 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.61-7.55 (m, 3H), 7.32-
1H), 8.01 (s, 1H), 7.92 (dd, J = 8.5, 1.5 Hz, 1H), 7.56 (d, J = 9.0 Hz,
1H), 7.29-7.18 (m, 6H), 5.69 (s, 2H), 3.87 (s, 3H), 2.30 (s, 3H); 13
1
2
3
4
5
6
7
8
7.25 (m, 3H), 7.21 (d, J = 7.0 Hz, 2 H), 6.98 (s, 1H), 5.61 (s, 2H),
C
2.35 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 196.2, 156.5,
144.0, 142.3, 140.2, 138.3, 132.3, 130.4, 129.6, 129.5, 129.1, 128.3,
127.5, 127.4, 123.8, 122.98, 122.97, 119.3, 116.6, 109.2, 96.3, 47.1,
16.6; IR (neat) 3381, 2924, 2854, 1649, 1597, 1449, 1414, 1318,
1281, 1251, 1183, 1136, 1072, 1028, 1002, 948 cm-1; HRMS (ESI-
TOF) calcd for C27H22NO2 [M+H]+ m/z = 392.1651, found
392.1664.
NMR (125 MHz, DMSO-d6) d 168.0, 157.5, 142.3, 140.9, 137.4,
128.5, 127.2, 126.7, 125.4, 122.2, 121.6, 121.3, 121.2, 118.9, 114.8,
108.8, 92.1, 55.6, 45.7, 16.4; IR (neat) 3350, 2924, 1605, 1556, 1495,
1446, 1391, 1351, 1324, 1254, 1192, 1161, 1133, 1054, 1037, 884
cm-1; HRMS (ESI-TOF) calcd for C22H20NO3 [M+H]+ m/z =
346.1443, found 346.1460.
Butyl
carboxylate (4l).
9-benzyl-7-hydroxy-6-methyl-9H-carbazole-3-
19
9
4-((2-Chloro-5-methoxy-4-
methylphenyl)amino)benzonitrile (8l).
To a solution of
(267 mg, 0.77 mmol) in
General
Following
CH2Cl2 (11 mL) at –78 ºC, a solution of BBr3 (1 M in CH2Cl2, 1.5
mL, 1.54 mmol) was added dropwise. The resultant mixture was
allowed to warm to room temperature and stirred for 40 min. The
mixture was subsequently quenched with water (15 mL) with
cooling in an ice bath. The solution was extracted with EtOAc (30
mL X 3), washed with brine, and the combined organic layers were
dried over Na2SO4. Removal of solvent yielded the product (234
mg). No further purification was necessary.
10
11
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Procedure C
using Pd2(dba)3 as a catalyst at room temperature for
10 min, the product was obtained as a yellow powder (412 mg) in
86% yield. Rf = 0.41 (EtOAc:Hexanes = 1:4): 1H NMR (500 MHz,
CDCl3) d 7.51 (d, J = 8.5 Hz, 2H), 7.17 (s, 1H), 6.99 (d, J = 8.5 Hz,
2H), 6.83 (s, 1H), 6.11 (br s, 1H), 3.77 (s, 3H), 2.17 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 157.0, 147.5, 135.1, 133.9, 131.3, 124.0,
119.7, 116.9, 115.8, 104.1, 102.6, 55.8, 15.7; IR (neat) 3402, 2925,
2217, 1599, 1506, 1469, 1455, 1441, 1396, 1372, 1333, 1299, 1283,
1251, 1202, 1169, 985, 868, 815 cm-1; HRMS (ESI-TOF) calcd for
C15H13ClN2O [M]+ m/z = 272.0716, found 272.0706.
A microwave vial was charged with above product (103 mg, 0.31
mmol), n-BuOH (3.9 mL), and two drops of concentrated H2SO4.
After stirring at at 100 oC for 22 h, the solvent was removed and the
resultant residue was basified with satd NaHCO3 (aq) to a pH of 8.
The mixture was extracted with EtOAc (10 mL X 3) and the
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. Chromatography (hexane:ethyl
acetate = 10:1) afforded the product as a tan amorphous solid (59
mg) in 49% yield. Rf = 0.47 (EtOAc:Hexanes = 1:2): 1H NMR (500
MHz, acetone-d6) d 8.70 (d, J = 1.4 Hz, 1H), 8.44 (s, 1H), 8.01 (dd,
J = 8.6, 1.7 Hz, 1H), 7.96 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.29-7.23
(m, 3H), 7.17 (d, J = 7.1 Hz, 2H), 6.95 (s, 1H), 5.56 (s, 2H), 4.34 (t,
J = 6.5 Hz, 2H), 2.38 (s, 3H), 1.81-1.76 (m, 2H), 1.56-1.48 (m, 2H),
1.00 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, acetone-d6) d 167.5,
156.4, 144.1, 142.2, 138.3, 129.5, 128.2, 127.4, 126.3, 124.0, 122.8,
122.1, 121.8, 119.2, 116.5, 109.1, 96.2, 64.7, 47.0, 31.8, 20.0, 16.6,
14.1; IR (neat) 3351, 2955, 2930, 1674, 1633, 1602, 1450, 1388,
1353, 1297, 1281, 1241, 1178, 1134, 1100, 1020, 997, 972, 768 cm-
1; HRMS (ESI-TOF) calcd for C25H26NO3 [M+H]+ m/z =
388.1913, found 388.1911.
7-Methoxy-6-methyl-9H-carbazole-3-carbonitrile
(9l).
General Procedure D
Following
for 48 h, the product was obtained
as a light brown powder (249 mg) in 78% yield. Rf = 0.33
1
(EtOAc:Hexanes = 1:2): H NMR (500 MHz, acetone-d6) d 10.62
(br s, 1H), 8.38 (s, 1H), 7.93 (s, 1H), 7.57 (s, 2H), 7.09 (s, 1H),
3.92 (s, 3H), 2.32 (s, 3H); 13C NMR (125 MHz, acetone-d6) d
159.3, 142.5, 141.4, 127.8, 124.6, 124.4, 122.4, 121.2, 120.8, 115.7,
112.2, 102.2, 93.7, 55.8, 16.8; IR (neat) 3311, 2910, 2217, 1609,
1466, 1444, 1323, 1297, 1272, 1234, 1200, 1160, 1136, 1118, 1039,
1003, 862, 806 cm-1; HRMS (EI-TOF) calcd for C15H12N2O [M]+
m/z = 236.0950, found 236.0964.
9-Benzyl-7-methoxy-6-methyl-9H-carbazole-3-carbonitrile
(11l).
General Procedure F
at room temperature for 22
Following
h, the product was obtained as a yellow solid (249 mg) in 90% yield.
Rf = 0.63 (EtOAc:Hexanes = 1:2): H NMR (500 MHz, acetone-
1
d6) d 8.46 (s, 1H), 8.02 (s, 1H), 7.64-7.60 (m, 2H), 7.30-7.20 (m,
6H), 5.72 (s, 2H), 3.92 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 159.6, 142.9, 142.4, 138.1, 129.6, 128.3, 128.0, 127.6,
124.7, 124.3, 122.8, 121.1, 121.0, 115.5, 110.8, 102.5, 92.7, 56.1,
47.0, 16.8; IR (neat) 2923, 2852, 2211, 1632, 1602, 1487, 1469,
1455, 1352, 1326, 1255, 1198, 1171, 1141, 1051, 1039, 873 cm-1;
HRMS (EI-TOF) calcd for C22H18N2O [M]+ m/z = 326.1419, found
326.1436.
N1-(2-Chloro-5-methoxy-4-methylphenyl)-N4,N4-
diphenylbenzene-1,4-diamine (8m).
Procedure C
General
Following
for 18 h, the product was obtained as a pale brown
solid (720 mg) in 87% yield. Rf = 0.40 (EtOAc:Hexanes = 1:9): 1H
NMR (500 MHz, acetone-d6) d 7.26 (t, J = 7.4 Hz, 4H), 7.16 (d, J =
8.7 Hz, 2H), 7.13 (s, 1H), 7.03 (d, J = 7.7 Hz, 6H), 6.98 (t, J = 7.4
Hz, 2H), 6.90 (s, 1H), 6.83 (br s, 1H), 3.75 (s, 3H), 2.10 (s, 3H);
9-Benzyl-7-methoxy-6-methyl-9H-carbazole-3-carboxylic
13C NMR (125 MHz, acetone-d6) d 157.9, 149.0, 142.1, 140.1,
139.8, 131.6, 130.0, 127.4, 126.7, 124.1, 123.9, 123.3, 123.2, 123.0,
120.52, 120.49, 114.2, 101.8, 55.9, 15.4; IR (neat) 3401, 3036, 2926,
1586, 1506, 1463, 1395, 1313, 1246, 1200, 1186, 995, 876, 819 cm-
1; HRMS (EI-TOF) calcd for C26H23ClN2O [M]+ m/z = 414.1499;
found 414.1508.
acid (19).
11l
(90 mg, 0.28 mmol) in EtOH (1.0
To a solution of
mL) and H2O (0.5 mL) was added NaOH (276 mg, 6.89 mmol).
The reaction mixture was refluxed overnight and then cooled to
room temperature. EtOH was removed under reduced pressure, and
o
the resultant aqueous mixture was acidified at 0 C with 2 M HCl
(3.5 mL). The resultant insoluble solid was filtered, washed with
water (20 mL X 2), and dried to give the product as a white solid (95
7-Methoxy-6-methyl-N, N´-diphenyl-9H-carbazol-3-amine
1
(9m).
General Procedure D
for 24 h, the product was
Following
mg) in quantitative yield. Rf = 0.20 (EtOAc:Hexanes = 1:2): H
obtained as a colorless solid (529 mg) in 70% yield. Rf = 0.25
(EtOAc:Hexanes = 3:7): H NMR (500 MHz, acetone-d6) d 10.11
NMR (500 MHz, DMSO-d6) d 12.50 (br s, 1H), 8.64 (d, J = 1.0 Hz,
1
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1
(br s, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.73 (s,1H), 7.43 (d, J = 8.5 Hz,
1H), 7.23 (t, J = 8.0 Hz, 4H), 7.07 (dd, J = 8.5, 2.0 Hz, 1H), 7.04 (d,
J = 8.7 Hz, 5H), 6.93 (t, J = 7.3 Hz, 2H), 3.90 (s, 3H), 2.27 (s, 3H);
13C NMR (125 MHz, acetone-d6) d 158.5, 149.8, 141.6, 141.4,
140.1, 138.3, 138.1, 129.9, 125.4, 125.3, 124.7, 123.2, 122.2, 119.3,
118.7, 116.7, 112.4, 112.3, 93.50, 93.45, 55.8, 16.8; IR (neat) 3403,
3042, 2908, 1584, 1484, 1433, 1310, 1275, 1228, 1200, 1037 cm-1;
HRMS (EI-TOF) calcd for C26H22N2O [M]+ m/z = 378.1732;
found 378.1732.
in 94% yield. Rf = 0.24 (EtOAc:Hexanes = 1:2): H NMR (500
MHz, acetone-d6) d 9.75 (s, 1H), 8.15 (s, 1H), 7.74 (s, 1H), 7.72 (d,
J = 0.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 8.2, 1.3 Hz,
1H), 6.93 (s, 1H), 2.44 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 155.5, 141.3, 139.1, 128.2, 125.8, 124.6, 122.1, 119.7,
117.4, 116.9, 110.9, 97.1, 21.5, 16.8; IR (neat) 3398, 2921, 1603,
826, 744, 719, 640 cm-1; HRMS (ESI-TOF) calcd for C14H14NO
[M+H]+ 212.1075, Found 212.1080.
1
2
3
4
5
6
7
8
9-Benzyl-3,6-dimethyl-9H-carbazol-2-ol (4n).
Following
9
9-Benzyl-7-methoxy-6-methyl-N,N´-diphenyl-9H-carbazol-
General Procedure F
, the product was obtained as a yellow solid
(81 mg) in 53% yield. Rf = 0.40 (EtOAc:Hexanes = 1:4): 1H NMR
(500 MHz, acetone-d6) d 8.22 (s, 1H), 7.80 (s, 1H), 7.79 (s, 1H),
7.30 (d, J = 8.3 Hz, 1H), 7.27-7.21 (m, 3H), 7.14 (d, J = 7.0 Hz, 2H),
7.10 (dd, J = 8.3, 1.1 Hz, 1H), 6.86 (s, 1H), 5.46 (s, 2H), 2.46 (s,
3H), 2.35 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 154.8, 140.9,
138.9, 138.2, 128.5, 127.8, 127.1, 126.5, 125.1, 123.5, 121.5, 119.0,
116.8, 115.6, 108.3, 94.8, 45.9, 20.5, 15.7. IR (neat) 3421, 2919,
2852, 1494, 863, 796, 735, 697 cm-1; HRMS (ESI-TOF) calcd for
C21H20NO [M+H]+ 302.1545, Found: 302.1545.
3-amine (11m).
General Procedure F
at room
Following
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11
12
13
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15
16
17
18
19
20
21
22
23
24
25
26
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60
temperature for 2 h, the product was obtained as a colorless solid
(222 mg) in 95% yield. Rf = 0.46 (EtOAc:Hexanes = 1:4): 1H NMR
(500 MHz, acetone-d6) d 7.79 (dd, J = 7.8, 2.1 Hz, 2H), 7.44 (d, J =
8.6 Hz, 1H), 7.31-7.20 (m, 9H), 7.15 (s, 1H), 7.10 (dd, J = 8.6, 2.1
Hz, 1H), 7.03 (dd, J = 8.7, 1.0 Hz, 4H), 6.93 (t, J = 7.4 Hz, 2H), 5.62
(s, 2H), 3.89 (s, 3H), 2.28 (s, 3H); 13C NMR (125 MHz, acetone-
d6) d 158.8, 149.7, 142.3, 140.5, 138.9, 138.7, 129.9, 129.5, 128.2,
127.7, 125.1, 124.6, 123.3, 122.5, 122.3, 119.5, 118.7, 116.2, 110.8,
92.2, 56.0, 47.0, 16.7; IR (neat) 3021, 2912, 1632, 1585, 1490, 1470,
1423, 1354, 1317, 1254, 1193, 1037, 805, 736 cm-1; HRMS (EI-
TOF) calcd for C33H28N2O [M]+ m/z = 468.2202; found 468.2215.
5-Amino-4-chloro-2-methylphenol (S-2).
Procedure E
General
Following
, the product was obtained as a light tan solid (244 mg)
1
in 49% yield. Rf = 0.22 (EtOAc:Hexanes = 1:5): H NMR (500
9-Benzyl-6-(diphenylamino)-3-methyl-9H-carbazol-2-ol
MHz, CD3CN) d 6.97 (s, 1H), 6.25 (s, 1H), 4.50 (s, 1H), 3.82 (br s,
2H), 2.12 (s, 3H); 13C NMR (125 MHz, CD3CN) d 155.4, 143.5,
131.4, 115.8, 110.0, 103.3, 15.2; IR (neat) 3405, 3416, 3195 (w),
2923, 1618, 1515, 1413, 1378, 1311, 1274, 1197, 1164, 988, 847,
723, 630, 460 cm-1; HRMS (ESI-TOF) m/z = 158.0373 calcd for
C7H9ClNO [M+H]+, found 158.0380.
(4m).
General Procedure E
at room temperature for 1.5
Following
h, the product was obtained as a white solid (105 mg) in 93% yield.
1
Rf = 0.30 (EtOAc:Hexanes = 1:4): H NMR (500 MHz, CDCl3) d
7.77 (br s, 1H), 7.67 (s, 1H), 7.29-7.07 (m, 15H), 6.92 (s, 2H), 6.71
(s, 1H), 5.36 (s, 2H), 4.76 (s, 1H), 2.34 (s, 3H); 13C NMR (125
MHz, acetone-d6) d 155.2, 148.8, 141.2, 139.4, 137.93, 137.90,
128.9, 128.5, 127.1, 126.6, 124.3, 123.6, 122.3, 121.8, 121.3, 117.6,
117.3, 115.4, 109.5, 94.8, 46.1, 15.6; IR (neat) 3421, 2923, 1632,
1585, 1490, 1393, 1367, 1355, 1310, 648 cm-1; HRMS (EI-TOF)
calcd for C32H26N2O [M]+ m/z 454.2045; found 454.2072.
5-(Benzyloxy)-2-chloro-4-methylaniline (14).
Following
General Procedure F
DMF and 24 mL THF on a 2.41 mmol scale with
using 1 equiv NaH, 1 equiv BnBr, 2.4 mL
S-2
, the product
was obtained as a light tan solid (372 mg) in 62% yield. Rf = 0.40
(EtOAc:Hexanes = 1:5): 1H NMR (500 MHz, CDCl3) d 7.43-7.31
(m, 5H), 7.01 (s, 1H), 6.34 (s, 1H), 5.01 (s, 2H), 3.88 (s, 2H), 2.15
(s, 3H); 13C NMR (125 MHz, CDCl3) d 156.3, 141.2, 137.2, 130.6,
128.5, 127.8, 127.0, 118.3, 110.4, 100.4, 70.1, 15.3; IR (neat) 3465,
3390, 2945, 1619, 1506, 1454, 1413, 1380, 1282, 1265, 1215, 1201,
1169. 1079, 1045, 1028, 988, 875, 819, 801, 734, 695, 651 cm-1;
HRMS (ESI-TOF) m/z = 248.0842 calcd for C14H15ClNO
[M+H]+,found 248.0839.
2-Chloro-5-methoxy-4-methyl-N-(p-tolyl)aniline
(8n).
General Procedure C
Following
for 20 h, the product was obtained
as yellow oil (443 mg) in 73% yield. Rf = 0.75 (EtOAc:Hexanes =
1:4): 1H NMR (500 MHz, acetone-d6) d 7.12 (d, J = 8.0, 2H), 7.08
(s, 1H), 7.04 (d, J = 8.5, 2H), 6.72 (s, 1H), 6.72 (s, 1H), 5.88 (br s,
1H), 3.96 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 2 rotamers; IR (neat) 3420, 2921, 1589, 606 cm-1;
HRMS (ESI-TOF) calcd for C15H17ClNO [M+H]+ 262.0999, found
262.1003.
5-(Benzyloxy)-2-chloro-N-(4-methoxyphenyl)-4-
methylaniline (16).
General Procedure C
, the product
Following
2-Methoxy-3,6-dimethyl-9H-carbazole
General Procedure D
(9n).
, the product was obtained as a brown solid
Following
was obtained as red oil (316 mg) in 68% yield. Rf = 0.80
(EtOAc:Hexanes = 1:5): 1H NMR (500 MHz, CDCl3) d 7.38-7.31
(m, 5H), 7.09 (s, 1H), 6.97 (dd, J = 6.7, 2.2 Hz, 2H), 6.84 (dd, J =
5.7, 3.5 Hz, 2H), 6.55 (s, 1H), 5.79 (s, 1H), 4.92 (s, 2H), 3.82 (s,
3H), 2.18 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 157.3, 157.0,
141.8, 138.8, 136.5, 132.1, 129.8, 129.0, 128.5, 124.0, 119.6, 115.9,
112.9, 101.4, 71.0, 56.3, 16.1; IR (neat) 3400, 2940, 1611, 1578,
1508, 1489, 1454, 1416, 1399, 1375, 1287, 1242, 1164, 1032, 1002,
841, 820, 775, 735, 696, 655, 600 cm-1; HRMS (ESI-TOF) m/z =
354.1261 calcd for C21H21ClNO2 [M+H]+, found 354.1268.
1
(1.39 g) in 83% yield. Rf = 0.30 (EtOAc:Hexanes = 1:4): H NMR
(500 MHz, acetone-d6) d 7.79 (s, 1H), 7.74 (s, 2H), 7.25 (d, J = 8.0
Hz, 1H), 7.12 (d, J = 7.0 Hz, 1H), 6.84 (s, 1H), 3.91 (s, 3H), 2.56 (s,
3H), 2.35 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 157.3, 140.3,
138.2, 127.5, 125.0, 123.5, 121.0, 118.9, 117.9, 115.8, 110.1, 92.6,
54.8, 20.6, 15.0; IR (neat) 3390, 2920, 1634, 1615, 818, 746 cm-1;
HRMS (ESI-TOF) calcd for C15H16NO [M+H]+ 226.1232, found
226.1229.
3,6-Dimethyl-9H-carbazol-2-ol (10n).
General
Following
2-(Benzyloxy)-6-methoxy-3-methyl-9H-carbazole
(17).
Procedure E
, the product was obtained as a brown solid (510 mg)
General Procedure D
Following
, the product was obtained as a light
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tan solid (161 mg) in 80% yield. Rf = 0.23 (EtOAc:Hexanes = 1:4): 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H),
1H NMR (500 MHz, acetone-d6) d 9.86 (br s, 1H), 7.83 (s, 1H),
7.55-7.53 (m, 3H), 7.41 (td, J = 5.8, 1.6 Hz, 2H), 7.34-7.31 (m, 2H),
7.07 (s, 1H), 6.91 (dd, J = 8.7, 2.5 Hz, 1H), 5.19 (s, 2H), 3.86 (s,
3H), 2.38 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 157.3, 154.7,
141.5, 138.8, 135.7, 129.3, 128.5, 128.1, 124.7, 122.1, 119.0, 117.3,
113.8, 111.9, 103.2, 95.0, 70.6, 56.1, 17.1; IR (neat) 3385, 2910,
1648, 1486, 1472, 1450, 1429, 1298, 1276, 1217, 1203, 1179, 1170,
1135, 1113, 1026, 839, 837, 813, 743, 699, 468 cm-1; HRMS (ESI-
TOF) m/z = 317.1416 calcd for C21H19NO2 [M]+, found 317.1430.
3.84 (s, 3H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) d 157.7,
142.4, 139.9, 138.9, 132.9, 128.8, 127.4, 126.5, 124.1, 123.8, 121.6,
119.5, 117.9, 116.3, 110.6, 92.7, 55.5, 16.8; IR (neat) 3390, 2925,
1621, 1481, 1323, 1284, 1226, 1195, 1171, 1034, 881, 752 cm-1;
HRMS (ESI-TOF) calcd for C20H18NO [M+H]+ m/z = 288.1388,
found 288.1387.
1
2
3
4
5
6
7
8
3-Methyl-6-phenyl-9H-carbazol-2-ol
General Procedure E
(10p),
, the product was obtained as a dark brown
Following
solid (103 mg) in 76% yield. Rf = 0.21 (EtOAc:Hexanes = 1:2): 1H
NMR (500 MHz, CD3CN) d 8.74 (br s, 1H), 7.88 (d, J = 1.5 Hz,
1H), 7.52 (s, 1H), 7.39 (dd, J = 8.0, 1.0 Hz, 2H), 7.23 (dd, J = 8.0,
1.5 Hz, 1H), 7.15-7.12 (m, 3H), 6.99 (td, J = 8.0, 1.0 Hz, 1H), 6.67
(br s, 1H), 6.59 (s, 1H), 2.00 (s, 3H); 13C NMR (125 MHz,
CD3CN) d 155.5, 143.1, 141.2, 140.3, 132.9, 129.8, 127.9, 127.3,
124.9, 124.2, 122.6, 118.4, 118.1, 117.2, 111.7, 97.3, 16.7; IR (neat)
3409, 2923, 1635, 1480, 1398, 1264, 1175, 1122, 1009, 879, 764 cm-
1; HRMS (ESI-TOF) calcd for C19H16NO [M+H]+ m/z = 274.1232,
found 274.1245.
9
10
11
12
13
14
15
16
17
18
19
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22
23
24
25
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Benzyl-2-(benzyloxy)-6-methoxy-3-methyl-9H-carbazole
(18).
General Procedure F
using 1.1 equiv NaH, 1.1
Following
equiv BnBr, 0.51 mL DMF and 5.1 mL THF on a 0.51 mmol scale,
the product was obtained as a light tan solid (129 mg) in 62% yield.
1
Rf = 0.65 (EtOAc:Hexanes = 1:5): H NMR (500 MHz, acetone-
d6) d 7.88 (s, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 2H),
7.39 (t, J = 7.2 Hz, 2H), 7.33-7.31 (m, 2H), 7.24-7.20 (m, 4H), 7.16
(dd, J = 8.2 Hz, 1.5 Hz, 2H), 6.93 (dd, J = 8.8, 2.5 Hz, 1H), 5.86 (s,
2H), 5.21 (s, 2H), 3.86 (s, 3H), 2.39 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 157.5, 155.0, 142.0, 139.1, 138.7, 136.3, 129.4, 129.3,
128.5, 128.3, 128.0, 127.6, 124.5, 122.4, 119.2, 116.8, 113.7, 110.5,
103.5, 93.7, 70.7, 56.1, 46.9, 17.0; IR (neat) 2910, 1645, 1494, 1474,
1464, 1454, 1441, 1431, 1305, 1252, 1234, 1226, 1202, 1181, 1141,
1053, 1027, 807, 793, 778, 732, 698 cm-1; HRMS (ESI-TOF) m/z =
408.1964 calcd for C28H26NO2 [M+H]+, found 408.1960.
9-Benzyl-3-methyl-6-phenyl-9H-carbazol-2-ol
(4p).
General Procedure F
white powder (71 mg) in 52% yield. Rf = 0.45 (EtOAc:Hexanes =
1:2): H NMR (500 MHz, CDCl3) d 8.22 (d, J = 1.5 Hz, 1H), 7.89
Following
, the product was obtained as a
1
(s, 1H), 7.70 (dd, J = 8.5, 1.5 Hz, 2H), 7.59 (dd, J = 8.5, 1.5 Hz, 1H),
7.47 (t, J = 8.0 Hz, 2H), 7.36-7.32 (m, 2H), 7.30-7.24 (m, 3H), 7.16
(d, J = 8.0 Hz, 2H), 6.76 (s, 1H), 5.43 (s, 2H), 4.81 (s, 1H), 2.43 (s,
9-Benzyl-6-methoxy-3-methyl-9H-carbazol-2-ol (4o).
Mono
3H); 13C NMR (125 MHz, CDCl3) d 153.5, 142.3, 141.2, 140.3,
137.2, 132.8, 128.9, 128.8, 127.6, 127.4, 126.5, 126.4, 124.0, 123.8,
122.1, 118.1, 117.1, 116.4, 108.8, 95.3, 46.8, 16.2; IR (neat) 3305,
2920, 1634, 1607, 1482, 1466, 1454, 1368, 1348, 1300, 1249, 1219,
1174, 1139, 998, 871 cm-1; HRMS (ESI-TOF) calcd for C26H22NO
[M+H]+ m/z = 364.1701, found 364.1692.
18
4h
debenzylation of following the procedure for afforded a tan
solid (39 mg) in 58% yield. Rf = 0.17 (EtOAc:Hexanes = 1:5): 1H
NMR (500 MHz, acetone-d6) d 8.29 (s, 1H), 7.83 (s, 1H), 7.59
(dd, J = 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.25-7.20 (m, 3H),
7.13 (d, J = 7.1 Hz, 2H), 6.92 (dd, J = 8.8, 2.5 Hz, 1H), 6.86 (s,
1H), 5.44 (s, 2H), 3.86 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 156.0, 155.0, 142.3, 139.2, 136.5, 129.5, 128.1, 127.5,
124.8, 122.7, 117.7, 116.8, 113.4, 110.2, 103.6, 95.8, 56.2, 47.0,
16.7; IR (neat) 3375, 2910, 1633, 1474, 1453, 1433, 1298, 1275,
1253, 1233, 1219, 1202, 1182, 1170, 1140, 1046, 1014, 823, 803,
732, 700, 632 cm-1; HRMS (ESI-TOF) m/z = 318.1494 calcd for
C21H20NO2 [M+H]+, found 318.1492.
9-Benzyl-2-(benzyloxy)-9H-carbazole (S-3).
To a stirring
solution of DMF (20 mL) and NaH concentrated to a volume of 25
mL and EtOAc was added. The resultant precipitate was filtered and
(784 mg, 32.7 mmol) was added a solution of 2-hydroxycarbazole
(2.00 g, 10.9 mmol) in THF (75 mL). After stirring 30 min at room
temperature, BnBr (4.50 mL, 38.5 mmol) was added to the solution.
After stirring 3 h, the solution was quenched with H2O (100 mL),
extracted with CH2Cl2 (3 X 100 mL), washed with brine (100 mL),
and dried with MgSO4. EtOAc was then added to the filtrate and the
precipate was collected to afford a white powder (3.85 g) in 97%
yield. Rf = 0.5 (EtOAc:Hexanes = 1:4): 1H NMR (500 MHz,
CD2Cl2) d 8.02 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.45 (d,
J = 7.1 Hz, 2H), 7.38 (td, J = 8.6, 1.0 Hz, 2H), 7.36-7.31 (m, 3H),
7.24 (m, 4H), 7.13 (d, J = 6.7 Hz, 2H), 6.95-6.92 (m, 2H), 5.45 (s,
2H) 5.12 (s, 2H); 13C NMR (125 MHz, CD2Cl2) d 159.0 142.6,
141.4, 137.87, 137.85, 129.3, 129.0, 128.5, 128.2, 128.0, 127.1,
125.2, 123.7, 121.6, 120.0, 119.9, 117.6, 109.3, 108.9, 95.2, 71.0,
47.1; IR (neat) 3020, 1626, 1598, 1495, 1460, 1451, 1437, 1359,
1328, 1246, 1179, 1120, 1009, 993, 944, 820, 804, 735, 726, 719, 695
cm-1; HRMS (ESI-TOF) m/z = 363.1623 calcd for C26H21NO [M]+,
found 363.1612.
N-(2-Chloro-5-methoxy-4-methylphenyl)-[1,1'-biphenyl]-4-
amine (8p).
General Procedure C
, the product was
Following
obtained as a white solid (412 mg) in 73% yield. Rf = 0.75
1
(EtOAc:Hexanes = 1:4): H NMR (500 MHz, CDCl3) d 7.60 (d, J
= 8.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.33
(t, J = 7.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.15 (s, 1H), 6.89 (s,
1H), 6.03(br s, 1H), 3.76 (s, 3H), 2.17 (s, 3H); 13C NMR (125
MHz, CDCl3) d 157.0, 141.9, 140.8, 138.1, 134.8, 131.0, 128.9,
128.2, 126.9, 126.2, 120.2, 119.1, 113.4, 100.4, 55.7, 15.4; IR (neat)
3400, 2921, 1589, 1523, 1486, 1450, 1412, 1374, 1248, 1232, 992,
822 cm-1; HRMS (ESI-TOF) calcd for C20H19ClNO [M+H]+ m/z =
324.1155, found 324.1176.
2-Methoxy-3-methyl-6-phenyl-9H-carbazole (9p).
Following
General Procedure D
, the product was obtained as a brown solid
(143 mg) in 83% yield. Rf = 0.25 (EtOAc:Hexanes = 1:4): 1H NMR
(500 MHz, CDCl3) d 8.20 (s, 1H), 7.86 (s, 1H), 7.74 (d, J = 7.0 Hz,
2H), 7.64 (br s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.5 Hz,
9-Benzyl-2-(benzyloxy)-3-bromo-9H-carbazole (13).
stirring solution of 9-benzyl-2-(benzyloxy)-9H-carbazole (1.45 g,
21
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Page 22 of 28
3.99 mmol) and CH2Cl2 (40 mL) was added N-bromosuccinimide
719, 694 cm-1; HRMS (ESI-TOF) m/z = 403.1936 calcd for
C29H25NO [M]+, found 403.1939.
1
2
3
4
5
6
7
8
(729 mg, 4.11 mmol). After stirring 30 min at room temperature, the
mixture was quenched with ice-cold water, extracted with EtOAc,
washed (3 X 20 mL) with brine (30 mL), and dried with MgSO4.
After filtration and concentration, trituration with acetone (3 X 10
mL) afforded a white solid (1.46 g) in 83% yield. Rf = 0.43
3-Allyl-9-benzyl-9H-carbazol-2-ol (4r).
Mono debenzylation
S-9
4q
following the procedure for afforded a white solid (22 mg)
of
1
in 63% yield. Rf = 0.23 (EtOAc:Hexanes = 1:5): H NMR (500
MHz, acetone-d6) d 8.35 (s, 1H), 8.01 (dd, J = 7.6, 0.7 Hz, 1H), 7.85
(s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.31-7.21 (m, 4H), 7.18-7.12 (m,
3H), 6.91 (s, 1H), 6.15-6.07 (m, 1H), 5.51 (s, 2H), 5.11 (dd, J =
19.1, 2.1 Hz, 1H), 5.01 (dd, J = 10.1, 1.3 Hz, 1H), 3.53 (d, J = 6.6 Hz,
1
(EtOAc:Hexanes = 1:4): H NMR (500 MHz, CDCl3) d 8.26 (s,
1H), 7.98 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.35 (m, 5H),
7.24 (m, 4H), 7.08 (dd, J = 5.2, 1.7 Hz, 2H), 6.87 (s, 1H), 5.42 (s,
2H), 5.16 (s, 2H); 13C NMR (125 MHz, CD2Cl2) d 154.2, 141.31,
141.29, 137.4, 137.2, 129.4, 129.1, 128.5, 128.1, 127.9, 127.0, 125.8,
125.1, 122.7, 120.3, 120.2, 118.4, 109.5, 104.4, 95.2, 71.8, 47.1; IR
(neat) 3015, 1597, 1469, 1445, 1433, 1356, 1307, 1273, 1249, 1182,
1151, 1121, 1024, 996, 748, 736, 724, 715, 695, 673, 616 cm-1;
HRMS (ESI-TOF) m/z = 441.0278 calcd for C26H20BrNO [M]+,
found 441.0267.
2H); 13C NMR (125 MHz, acetone-d6) d 155.4, 141.8, 141.6,
138.98, 138.97, 129.5, 128.2, 127.5, 125.0, 124.3, 122.0, 120.6,
120.0, 119.9, 116.9, 115.2, 109.6, 96.0, 46.9, 35.4; IR (neat) 3300
(w), 2995, 1636, 1604, 1495, 1467, 1450, 1441, 1348, 1319, 1247,
1178, 1139, 1122, 959, 914, 823, 741, 729, 709, 697, 603 cm-1;
HRMS (ESI-TOF) m/z = 313.1467 calcd for C22H19NO [M]+,
found 313.1466.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Benzyl-3-bromo-9H-carbazol-2-ol (4q).
To
a stirring
9-Benzyl-2-(benzyloxy)-3-phenyl-9H-carbazole (S-5).
9-
solution of 9-benzyl-2-(benzyloxy)-3-bromo-9H-carbazole (1.20 g,
2.72 mmol) in CH2Cl2 (30.0 mL) was added N,N-dimethylaniline
(3.40 mL, 27.2 mmol) followed by the slow addition of AlCl3 (2.18
g, 16.32 mmol). After stirring 10 min at room temperature, the
solution was cooled to 0 0C and quenched with H2O (30 mL). The
solution was extracted with EtOAc (3 X 30 mL), washed with brine
(30 mL), and dried with MgSO4. Removal of solvent and
chromatography (5:1 Hex/EtOAc) afforded a white solid (382 mg)
Benzyl-2-(benzyloxy)-3-bromo-9H-carbazole (300 mg, 0.680
mmol), potassium phenyl trifluoroborate (188 mg, 1.02 mmol),
Pd(dppf)Cl2 (28 mg, 0.0340 mmol), and cesium carbonate (775
mg, 2.38 mmol) were treated with a 2:1 mixture of THF and H2O
(30 mL). After stirring 18 h at70 0C, the solution was cooled to room
temperature and diluted with H2O (20 mL). The solution was then
extracted with EtOAc (3 X 30 mL), washed with brine (30 mL), and
dried with MgSO4. Removal of solvent and chromatography (5:1 =
Hex/EtOAc) afforded a white solid (257 mg) in 88% yield. Rf = 0.52
1
in 40% yield. Rf = 0.27 (EtOAc:Hexanes = 1:4): H NMR (500
1
MHz, acetone-d6) d 8.72 (br s, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.5 Hz,
1H), 7.47 (d, J = 8.2 Hz, 1H), 7.36 (td, J = 8.3, 1.1 Hz, 1H), 7.28-
7.18 (m, 4H), 7.16(d, J = 7.1 Hz, 2H), 7.10 (s, 1H), 5.52 (s, 2H);
(EtOAc:Hexanes = 1:5): H NMR (500 MHz, CD2Cl2) d 8.12 (s,
1H), 8.10 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.50 (t, J =
7.5 Hz, 2H), 7.41-7.28 (m, 12H), 7.19 (d, J = 6.0 Hz, 2H), 7.04 (s,
1H), 5.49 (s, 2H), 5.15 (s, 2H); 13C NMR (125 MHz, CD2Cl2) d
155.8, 141.7, 141.3, 140.1, 137.8, 137.7, 130.6, 129.3, 129.0, 128.5,
128.3, 128.1, 127.7, 127.1, 127.0, 125.3, 124.8, 123.8, 123.0, 120.1,
120.0, 117.3, 109.4, 94.2, 71.3, 47.1; IR (neat) 2940, 1601, 1456,
1448, 1430, 1351, 1314, 1262, 1225, 1210, 1179, 1125, 1028, 1021,
809, 764, 737, 732, 701, 692, 662 cm-1; HRMS (ESI-TOF) m/z =
440.2014 calcd for C32H26NO [M+H]+, found 440.2003.
13C NMR (125 MHz, acetone-d6) d 153.4, 142.2, 142.0, 138.5,
129.6, 128.3, 127.5, 126.0, 125.1, 123.3, 120.53, 120.45, 118.5,
110.0, 102.9, 97.3, 47.0; IR (neat) 3410 (w), 2925, 1601, 1475,
1451, 1380, 1360, 1337, 1318, 1262, 1216, 1157, 1120, 1079, 1059,
1020, 946, 883, 824, 738, 717, 696 cm-1; HRMS (ESI-TOF) m/z =
351.0259 calcd for C19H14BrNO [M]+, found 351.0283.
3-Allyl-9-benzyl-2-(benzyloxy)-9H-carbazole (S-4).
To a flask
charged with 9-benzyl-2-(benzyloxy)-3-bromo-9H-carbazole (300
mg, 0.680 mmol), Pd(OAc)2 (7.60 mg, 0.034 mmol), and CPhos(24
mg, 0.068 mmol), was added THF (0.7 mL) followed by allyl zinc
bromide43 (1.85 mL, 1.02 mmol). After stirring 18 h under Ar
atmosphere, the solution was quenched with H2O (10 mL),
extracted with EtOAc (3 X 20 mL), washed with brine (20 mL), and
dried with MgSO4. Removal of solvent and chromatography (10:1
Hex/EtOAc) afforded a white solid (183 mg) in 67% yield. Rf = 0.6
9-Benzyl-3-phenyl-9H-carbazol-2-ol
S-10
white solid (25 mg) in 71% yield. Rf = 0.24 (EtOAc:Hexanes = 1:5):
(4s).
4q
Mono
afforded a
debenzylation of
following the procedure for
1H NMR (500 MHz, acetone-d6) d 8.39 (br s, 1H), 8.10 (d, J = 7.7
Hz, 1H), 8.06 (s, 1H), 7.66 (dd, J = 8.3, 1.3 Hz, 2H), 7.51 (d, J = 8.2
Hz, 1H), 7.42 (t, J = 5.8 Hz, 2H), 7.36-7.30 (m, 4H), 7.29 (dd, J =
6.0, 1.7 Hz, 1H), 7.22 (dd, J = 8.5, 1.4 Hz, 2H), 7.18 (td, J = 7.8, 0.8
Hz, 1H), 7.03 (s, 1H), 5.58, (s, 2H); 13C NMR (125 MHz, CDCl3)
d 152.0, 142.0, 141.2, 138.0, 137.2, 129.8, 129.6, 129.0, 127.8, 127.7,
126.7, 125.0, 123.5, 121.9, 121.6, 119.74, 119.65, 117.4, 109.0, 95.6,
46.9 cm-1; IR (neat) 3495 (w), 2910, 1633, 1603, 1490, 1477, 1453,
1431, 1353, 1324, 1291, 1263, 1218, 1167, 1122, 950, 822, 744, 723,
700, 660, 608 cm-1; HRMS (ESI-TOF) m/z = 350.1545 calcd for
C25H20NO [M+H]+, found 350.1556.
1
(EtOAc:Hexanes = 1:5): H NMR (500 MHz, acetone-d6) d 8.04
(dt, J = 7.9, 1.0 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.52 (dt, J = 7.5,
0.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.39 (td, J = 7.5, 1.5 Hz, 2H),
7.32-7.25 (m, 6H), 7.19 (dd, J = 8.3, 1.5 Hz, 2H), 7.14 (td, J = 7.0,
0.5 Hz, 1H), 6.14-6.09 (m, 1H), 5.62 (s, 2H), 5.23 (s, 2H), 5.10 (dd,
J = 17.1, 3.8 Hz, 1H), 5.01 (dd, J = 11.3, 2.4 Hz, 1H), 3.57 (d, J = 6.6
Hz, 2H); 13C NMR (125 MHz, acetone-d6) d 157.1, 141.7, 141.5,
139.0, 138.9, 138.6, 129.5, 129.4, 128.6, 128.4, 128.2, 127.7, 125.1,
124.1, 122.1, 121.9, 120.2, 120.0, 117.03, 115.4, 110.0, 94.1, 71.0,
46.9, 35.7; IR (neat) 3010, 1602, 1495, 1480, 1462, 1448, 1355,
1328, 1254, 1175, 1156, 1145, 1122, 1056, 1028, 910, 807, 740, 731,
9,9'-Dibenzyl-3,3'-dimethyl-9H,9'H-[1,1'-bicarbazole]-2,2'-
diol (5a).
General Procedure G
, the product was
Following
obtained as a yellow solid (109 mg) in 91% yield. Rf = 0.65
1
(EtOAc:Hexanes = 1:4): H NMR (500 MHz, acetone-d6) d 8.06
(d, J = 8.0 Hz, 2H), 7.94 (s, 2H), 7.23 (td, J = 8.2, 1.2 Hz, 2H), 7.17
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The Journal of Organic Chemistry
(t, J = 7.2 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.85-6.82 (m, 8H), 6.46-
product was obtained as yellow oil (4.0 mg) in 37% yield. Rf = 0.50
(EtOAc:Hexanes = 1:9): H NMR (500 MHz, CDCl3) d 7.96 (d, J
1
1
2
3
4
5
6
7
8
6.44 (m, 4H), 4.83 (d, J = 17.3 Hz, 2H), 4.61 (d, J = 17.3 Hz, 2H),
2.21 (s, 6H); 13C NMR (125 MHz, acetone-d6) d 153.6, 141.7,
139.0, 138.0, 127.5, 126.0, 125.4, 123.9, 123.1, 122.0, 119.0, 118.6,
117.5, 116.8, 109.0, 101.0, 46.5, 16.2; IR (neat) 3513, 2923, 1603,
736, 706 cm-1; HRMS (ESI-TOF) calcd for C40H31N2O2 [M-H]-
= 7.7 Hz, 2H), 7.94 (s, 2H), 7.12 (t, J = 7.8 Hz, 2H), 7.03 (td, J = 8.4,
1.2 Hz, 2H), 6.70 (s, 2H), 6.64 (s, 2H), 6.48 (d, J = 8.5 Hz, 2H),
5.30 (br s, 2H), 4.91 (d, J = 15.3 Hz, 2H), 4.75 (d, J = 15.3 Hz, 2H),
2.37 (s, 6H), 2.19 (s, 6H), 1.82 (s, 6H), 1.64 (s, 6H); 13C NMR (125
MHz, CDCl3) d 152.3, 141.4, 139.4, 137.2, 136.7, 130.0, 129.8,
129.22, 129. 124.6, 123.6, 123.4, 119.4, 119.0, 117.9, 117.5, 110.6,
100.2, 44.7, 20.9, 20.1, 19.6, 16.7; IR (neat) 3509, 2920, 1603, 1456,
1180, 1135, 1076, 1041, 851, 743m-1; HRMS (EI-TOF) calcd for
C46H43N2O2 [M-H]¯ m/z = 655.3325; found 655.3322; [α]D22 +182
(c 0.18, 37% ee, CH2Cl2); Chiral HPLC: Chiralpak IA column (5%
i-PrOH/hexanes, 1 mL/min) tR(1) = 5.09 min, tR(2) = 14.9 min.
22
571.2386, found 571.2380; [α]D +164 (c 0.35, 87% ee, CH2Cl2);
Chiral HPLC: Chiralpak IA column (10% i-PrOH/hexanes, 1
mL/min) tR(1) = 8.12 min, tR(2) = 11.8 min.
3,3',9,9'-Tetramethyl-9H,9'H-[1,1'-bicarbazole]-2,2'-diol
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5b).
General Procedure G
, the product was obtained as
Following
a yellow solid (9.0 mg) in 82% yield. Rf = 0.63 (EtOAc:Hexanes =
1
1:4): H NMR (500 MHz, acetone-d6) d 8.03 (dd, J = 7.8, 0.8 Hz,
9,9'-Dibenzyl-6,6'-difluoro-3,3'-dimethyl-9H,9'H-[1,1'-
2H), 8.00 (d, J = 1.0 Hz, 2H), 7.31-7.30 (m, 4H), 7.25 (s, 2H), 7.16
(ddd, J = 2.9, 5.2, 7.9 Hz, 2H), 3.45 (s, 6H), 2.45 (s, 6H); 13C NMR
Following
bicarbazole]-2,2'-diol (5f).
General Procedure G
, the
product was obtained as a yellow solid (26 mg) in 87% yield. Rf =
(125 MHz, acetone-d6) d 153.9, 141.7, 139.8, 123.9, 122.9, 122.1,
118.8, 118.6, 117.0, 116.3, 108.4, 101.7, 29.3, 16.3; IR (neat) 3509,
2924, 2854, 1626, 1603, 882, 768, 737 cm-1; HRMS (ESI-TOF)
1
0.58 (EtOAc:Hexanes = 1:4): H NMR (500 MHz, acetone-d6) d
7.94 (s, 2H), 7.78 (dd, J = 9.0, 2.5 Hz, 2H), 7.06 -6.98 (m, 6H), 6.86-
6.84 (m, 6H), 6.47-6.45 (m, 4H), 4.82 (d, J = 17.3 Hz, 2H), 4.60 (d,
J = 17.3 Hz, 2H), 2.21 (s, 6H); 13C NMR (125 MHz, acetone-d6) d
158.5 (d, J = 233 Hz), 155.3, 140.9, 139.0, 138.8, 128.5, 127.1, 126.2,
124.6 (d, J = 8.8 Hz), 123.4, 118.7, 117.4 (d, J = 3.8 Hz), 112.1 (d, J
= 26.4 Hz), 110.7 (d, J = 10.1 Hz), 105.2 (d, J = 23.9 Hz), 101.9,
47.7, 17.1; IR (neat) 3515, 2923, 1627, 856, 796, 781, 703 cm-1;
HRMS (ESI-TOF) calcd for C40H31F2N2O2 [M+H]+ 609.2354,
22
calcd for C28H25N2O2 [M+H]+ 421.1916, found: 421.1928. [α]D
+180 (c 0.43, 60% ee, CH2Cl2); CSP HPLC (Chiralpak AD, 1.0
mL/min, 90:10 hexanes:i-PrOH): tR(1) = 16.6 min, tR(2) = 20.9
min.
9,9'-Diallyl-3,3'-dimethyl-9H,9'H-[1,1'-bicarbazole]-2,2'-diol
(5c).
General Procedure G
, the product was obtained as
Following
pale yellow oil (5.7 mg) in 71% yield. Rf = 0.48 (EtOAc:Hexanes =
22
found 609.2368; [α]D +183 (c 0.40, 92% ee, CH2Cl2); Chiral
1
1:9): H NMR (500 MHz, CDCl3) d 8.05 (d, J = 7.7 Hz, 2H), 8.03
HPLC: Chiralpak IA column (10% i-PrOH/hexanes, 1 mL/min)
tR(1) = 9.52 min, tR(2) = 10.4 min.
(s, 2H), 7.36 (td, J = 8.2, 1.0 Hz, 2H), 7.25 (t, J = 7.6 Hz, 2H), 7.20
(d, J = 8.2 Hz, 2H), 5.40-5.33 (m, 2H), 5.17 (br s, 2H), 4.74 (dd, J
= 10.4, 1.2 Hz, 2H), 4.41 (dd, J = 17.2, 1.2 Hz, 2H), 4.25-4.15 (m,
4H), 2.46 (s, 6H); 13C NMR (125 MHz, CDCl3) d 152.4, 141.2,
138.2, 132.5, 124.8, 123.6, 122.9, 119.7, 119.2, 117.6, 117.4, 115.8,
109.3, 98.3, 46.0, 16.8; IR (neat) 3510, 2919, 1603, 1477, 1459,
1355, 1235, 1184, 1072, 737cm-1; HRMS (ESI-TOF) calcd for
9,9'-Dibenzyl-7,7'-difluoro-3,3'-dimethyl-9H,9'H-[1,1'-
bicarbazole]-2,2'-diol (5g).
General Procedure G
, the
Following
product was obtained as a yellow solid (17.8 mg) in 93% yield. Rf =
1
0.60 (EtOAc:Hexanes = 1:4): H NMR (500 MHz, acetone-d6) d
7.95 (s, 2H), 7.21 (td, J = 8.1, 5.5 Hz, 2H), 7.06 (s, 2H), 6.91 (d, J =
8.1 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 6.84-6.82 (m, 6H), 6.45-6.43
(m, 4H), 4.85 (d, J = 17.9 Hz, 2H), 4.60 (d, J = 17.4 Hz, 2H), 2.21
(s, 6H); 13C NMR (125 MHz, acetone-d6) d 157.7 (d, J = 243 Hz),
153.9, 144.1 (d, J = 10.6 Hz), 138.7, 137.5, 127.5, 126.1, 125.2, 124.6
(d, J = 20.1 Hz), 124.4 (d, J = 20.1 Hz), 118.4, 114.1, 110.8, 105.3,
104.7 (d, J = 18.7 Hz), 101.0, 47.0, 16.2; IR (neat) 3519, 2925, 1601,
965, 709 cm-1; HRMS (ESI-TOF) calcd for C40H29F2N2O2 [M-H]–
22
C32H29N2O2 [M+H]+ m/z = 473.2229; found 473.2236; [ α]D
+177 (c 0.28, 76% ee, CH2Cl2); Chiral HPLC: Chiralpak IA column
(10% i-PrOH/hexanes, 1 mL/min) tR(1) = 11.5 min, tR(2) = 21.1
min.
9,9'-Diisopropyl-3,3'-dimethyl-9H,9'H-[1,1'-bicarbazole]-
2,2'-diol (5d).
General Procedure G
, the product was
Following
22
607.2197, found 607.2191, [α]D +157 (c 0.35, 92% ee, CH2Cl2);
obtained as pale yellow oil (3.5 mg) in 58% yield. Rf = 0.60
1
Chiral HPLC: Chiralpak IA column (5% i-PrOH/hexanes, 1
mL/min) tR(1) = 6.80 min, tR(2) = 7.61 min.
(EtOAc:Hexanes = 1:9): H NMR (500 MHz, CDCl3) d 8.07 (d, J
= 7.7 Hz, 2H), 8.00 (s, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.33 (td, J =
8.3, 1.2 Hz, 2H), 7.23 (t, J = 7.7 Hz, 2H), 5.16 (s, 2H), 4.62-4.54
(m, 2H), 2.45 (s, 6H), 1.38 (d, J = 7.0 Hz, 6H), 1.18 (d, J = 7.0 Hz,
6H); 13C NMR (125 MHz, CDCl3) d 152.0, 139.1, 137.5, 124.2,
124.1, 123.2, 119.4, 119.2, 117.5, 117.2, 112.6, 99.2, 46.8, 20.9, 20.7,
16.7; IR (neat) 3510, 2918, 2832, 1601, 1459, 1395, 1183, 1133,
1066, 738 cm-1; HRMS (ESI-TOF) calcd for C32H33N2O2 [M+H]+
9,9'-Dibenzyl-8,8'-difluoro-3,3'-dimethyl-9H,9'H-[1,1'-
bicarbazole]-2,2'-diol (5h).
General Procedure G
, the
Following
product was obtained as yellow oil (12 mg) in 80% yield. Rf = 0.65
(EtOAc:Hexanes = 1:4): 1H NMR (500 MHz, acetone-d6) d 7.97 (s,
2H), 7.90 (d, J = 5.0 Hz, 2H), 7.16-7.12 (m, 2H), 7.00-6.96 (m, 4H),
6.87-6.83 (m, 6H), 6.38 (d, J = 5.0 Hz, 4H), 4.95 (d, J = 15.0 Hz,
2H), 4.81 (d, J = 15.0 Hz, 2H), 2.19 (s, 6H); 13C NMR (125 MHz,
acetone-d6) d 155.2, 150.2 (d, J = 243 Hz), 140.2, 139.9, 129.5 (d, J
= 7.5 Hz), 128.3, 128.1 (d, J = 5.0 Hz), 126.8, 125.6, 123.1, 120.4 (d,
J = 6.3 Hz), 119.5, 117.8, 115.6 (d, J = 2.5 Hz), 111.1 (d, J = 18.9
Hz), 102.0, 49.5, 17.1; IR (neat) 3516, 2920, 1630, 1613, 1579,
22
m/z = 477.2542; found 477.2522; [α]D +18 (c 0.15, 42% ee,
CH2Cl2); Chiral HPLC: Chiralpak IA column (10% i-
PrOH/hexanes, 1 mL/min) tR(1) = 7.46 min, tR(2) = 11.0 min.
3,3'-Dimethyl-9,9'-bis(2,4,6-trimethylbenzyl)-9H,9'H-[1,1'-
bicarbazole]-2,2'-diol (5e).
General Procedure G
, the
Following
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Page 24 of 28
1497, 1450, 1414, 1380, 1348, 1239, 1216, 1192, 1178, 1160, 1141,
mL/min) tR(1) = 29.8 min, tR(2) = 39.8 min.
Dibutyl 9,9'-dibenzyl-2,2'-dihydroxy-3,3'-dimethyl-9H,9'H-
[1,1'-bicarbazole]-6,6'-dicarboxylate (5l). General
1124, 1062, 987 cm-1; HRMS (ESI-TOF) calcd for C40H31F2N2O2
[M+H]+ m/z = 609.2354, found 609.2370; [α]D22 +211 (c 0.25, 91%
ee, CH2Cl2); Chiral HPLC: Chiralpak IA column (10% i-
PrOH/hexanes, 1 mL/min) tR(1) = 8.29 min, tR(2) = 9.39 min.
1
2
3
4
5
6
7
8
Following
, the product was obtained as light yellow oil (16 mg)
Procedure G
in 67% yield based on recovered starting material. Rf = 0.41
1
9,9'-Dibenzyl-3,3'-dimethyl-6,6'-bis(trifluoromethyl)-
(EtOAc:Hexanes = 1:4): H NMR (500 MHz, acetone-d6) d 8.75
9H,9'H-[1,1'-bicarbazole]-2,2'-diol (5i).
Procedure G
General
Following
(d, J = 1.5 Hz, 2H), 8.08 (s, 2H), 7.95 (dd, J = 8.6, 1.7 Hz, 2H), 7.15
(d, J = 8.9 Hz, 2H), 7.14 (s, 2H), 6.84-6.82 (m, 6H), 6.43-6.41 (m,
4H), 4.87 (d, J = 17.3 Hz, 2H), 4.65 (d, J = 17.3 Hz, 2H), 4.39-4.34
(m, 4H), 2.23 (s, 6H), 1.84-1.78 (m, 4H), 1.59-1.51 (m, 4H), 1.02
(t, J = 7.4 Hz, 6H); 13C NMR (125 MHz, acetone-d6) d 167.6, 155.3,
145.2, 140.6, 138.2, 128.5, 127.1, 126.4, 126.1, 123.8, 123.3, 122.4,
121.5, 119.7, 117.7, 109.6, 102.4, 64.8, 47.8, 31.8, 20.0, 17.1, 14.1;
IR (neat) 3395, 2958, 2926, 1697, 1603, 1577, 1495, 1451, 1412,
1382, 1364, 1348, 1287, 1240, 1182, 1132, 1102, 1071, 1004, 972
cm-1; HRMS (ESI-TOF) calcd for C50H49N2O6 [M+H]+ m/z =
, the product was obtained as light yellow oil (12 mg)
1
in 70% yield. Rf = 0.53 (EtOAc:Hexanes = 1:4): H NMR (500
MHz, acetone-d6) d 8.43 (s, 2H), 8.12 (s, 2H), 7.54 (d, J = 8.5 Hz,
2H), 7.25 (d, J = 8.5 Hz, 2H), 7.23 (s, 2H), 6.86-6.83 (m, 6H), 6.45-
6.43 (m, 4H), 4.89 (d, J = 17.4 Hz, 2H), 4.68 (d, J = 17.4 Hz, 2H),
2.23 (s, 6H); 13C NMR (125 MHz, acetone-d6) d 155.6, 144.0,
140.7, 138.2, 128.5, 127.1, 126.6 (q, J = 270 Hz), 126.0, 123.8, 123.5,
121.6 (q, J = 31.4 Hz), 121.5 (q, J = 2.5 Hz), 119.0, 117.2, 117.0 (q,
J = 3.8 Hz), 110.3, 102.2, 47.7, 17.1; IR (neat) 3525, 2925, 1609,
1451, 1411, 1365, 1346, 1325, 1300, 1262, 1186, 1163, 1148, 1113,
1080, 1069, 1051, 1034, 1005 cm-1; HRMS (ESI-TOF) calcd for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22
773.3591, found 773.3585; [α]D +100 (c 0.30, 96% ee, CH2Cl2);
Chiral HPLC: Chiralpak IA column (20% i-PrOH/hexanes, 1
mL/min) tR(1) = 9.80 min, tR(2) = 19.9 min.
22
C42H31F6N2O2 [M+H]+ m/z = 709.2292, found 709.2290; [α]D
+175 (c 0.6, 93% ee, CH2Cl2); Chiralpak IA column (10% i-
PrOH/hexanes, 1 mL/min) tR(1) = 8.61 min, tR(2) = 9.89 min.
9,9'-Dibenzyl-6,6'-bis(diphenylamino)-3,3'-dimethyl-
9H,9'H-[1,1'-bicarbazole]-2,2'-diol (5m).
General
Following
Procedure G
, the product was obtained as a colorless solid (8.0 mg)
9,9'-Dibenzyl-3,3'-dimethyl-7,7'-bis(trifluoromethyl)-
1
9H,9'H-[1,1'-bicarbazole]-2,2'-diol (5j).
General
Following
in 62% yield. Rf = 0.58 (EtOAc:Hexanes = 1:9): H NMR (500
MHz, acetone-d6) d 7.85 (s, 2H), 7.83 (d, J = 2.0 Hz, 2H), 7.27 (t,
J = 8.6 Hz, 8H), 7.09-7.03 (m, 12H), 7.00 (s, 2H), 6.96 (t, J = 7.4
Hz, 4H), 6.91-6.88 (m, 6H), 6.54 d, (J = 6.6 Hz, 4H), 4.87 (d, J =
17.2 Hz, 2H), 4.61 (d, J = 17.2 Hz, 2H), 2.19 (s, 6H); 13C NMR (125
MHz, acetone-d6) d 154.9, 149.7, 140.6, 140.5, 140.0, 138.9, 129.9,
128.5, 127.1, 126.3, 125.1, 124.7, 123.2, 122.3, 121.8, 118.6, 118.2,
117.5, 110.9, 101.8, 47.8, 17.1; IR (neat) 3526, 3032, 2919, 1635,
1585, 1490, 1454, 1326, 1285, 1257, 1217, 1164, 1132, 1028, 998,
804, 752 cm-1; HRMS (EI-TOF) calcd for C64H50N4O2Na [M+Na]+
Procedure G
, the product was obtained as yellow oil (15 mg) in 60%
1
yield. Rf = 0.55 (EtOAc:Hexanes = 1:4): H NMR (500 MHz,
acetone-d6) d 8.25 (d, J = 8.2 Hz, 2H), 8.07 (s, 2H), 7.48 (d, J = 8.3
Hz, 2H), 7.42 (s, 2H), 7.29 (s, 2H), 6.86-6.79 (m, 6H), 6.44 (d, J =
7.0 Hz, 4H), 4.93 (d, J = 17.5 Hz, 2H), 4.73 (d, J = 17.5 Hz, 2H),
2.24 (s, 6H); 13C NMR (125 MHz, acetone-d6) d 156.0, 141.6,
141.2, 138.3, 128.5, 127.1, 126.9, 126.3 (q, J = 271.1 Hz), 126.1 (q,
J = 31.2 Hz), 126.0, 123.7, 120.0, 119.8, 116.8, 116.5 (q, J = 3.6 Hz),
107.0 (q, J = 4.1 Hz), 102.0, 47.7, 17.1; IR (neat) 3519, 2925, 1629,
1574, 1451, 1351, 1321, 1294, 1280, 1264, 1232, 1164, 1135, 1118,
1061, 1005, 910 cm-1; HRMS (ESI-TOF) calcd for C42H31F6N2O2
[M+H]+ m/z = 709.2290, found 709.2270; [α]D22 +254 (c 0.42, 94%
ee, CH2Cl2); Chiral HPLC: Chiralpak IA column (5% i-
PrOH/hexanes, 1 mL/min) tR(1) = 6.42 min, tR(2) = 21.8 min.
22
m/z 929.3831; found 929.3810; [α]D +31 (c 0.35, 37% ee,
CH2Cl2); Chiral HPLC: Chiralpak IA column (5% i-
PrOH/hexanes, 1 mL/min) tR(1) = 6.95 min, tR(2) = 8.19 min.
9,9'-Dibenzyl-3,3',6,6'-tetramethyl-9H,9'H-[1,1'-
bicarbazole]-2,2'-diol (5n).
General Procedure G
, the
Following
(9,9'-Dibenzyl-2,2'-dihydroxy-3,3'-dimethyl-9H,9'H-[1,1'-
product was obtained as a yellow solid (13 mg) in 93% yield. Rf =
1
bicarbazole]-6,6'-diyl)bis(phenylmethanone) (5k).
Following
0.74 (EtOAc:Hexanes = 1:4): H NMR (500 MHz, acetone-d6) d
General Procedure G
with chlorobenzene/HFIP(1:1, 0.5 M) as a
7.89 (s, 2H), 7.84 (s, 2H), 7.06 (dd, J = 1.8, 7.5, 2H), 6.97 (d, J = 8.0,
2H), 6.86-6.82 (m, 6H), 6.71 (s, 2H), 6.45 (s, 2H), 6.46-6.42 (m,
2H), 4.77 (d, J = 17.1, 2H), 4.58 (d, J = 17.1, 2H), 2.49 (s, 6H), 2.19
(s, 6H); 13C NMR (125 MHz, acetone-d6) d 140.0, 139.2, 138.3,
128.1, 127.3, 126.1, 125.4, 125.2, 123.3, 121.9, 118.6, 117.2, 116.7,
108.9, 108.8, 100.9, 46.6, 20.5, 16.2; IR (neat) 3503, 2920, 1608,
793, 733, 701 cm-1; HRMS(ESI-TOF) calcd for C42H37N2O2
solvent, the product was obtained as an off-white solid (9.1 mg) in
76% yield based on recovered starting material. Rf = 0.50
1
(EtOAc:Hexanes = 1:2): H NMR (500 MHz, acetone-d6) d 8.56
(d, J = 1.0 Hz, 2H), 8.03 (s, 2H), 7.85 (d, J = 8.0 Hz, 4H), 7.79 (dd,
J = 8.5, 1.5 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.5 Hz, 4H),
7.25 (br s, 2H), 7.22 (d, J = 8.5 Hz, 2H), 6.89-6.86 (m, 6H), 6.50-
6.48 (m, 4H), 4.94 (d, J = 15.0 Hz, 2H), 4.70 (d, J = 15.0 Hz, 2H),
22
[M+H]+ 601.2855, found 601.2849 [α]D +180 (c 0.43, 60% ee,
2.23 (s, 6H); 13C NMR (125 MHz, acetone-d6) d 196.2, 155.4,
145.0, 140.7, 140.1, 138.2, 132.4, 130.4, 129.8, 129.1, 128.5, 127.4,
127.2, 126.1, 123.6, 123.4, 122.6, 119.7, 117.8, 109.6, 102.4, 47.8,
17.1; IR (neat) 3500, 2923, 2853, 1645, 1596, 1569, 1494, 1449,
1412, 1365, 1346, 1318, 1286, 1250, 1184, 1134, 1072, 1003, 948
cm-1; HRMS (ESI-TOF) calcd for C54H41N2O4 [M+H]+ m/z =
CH2Cl2); Chiral HPLC: Chiralpak IA column (10% i-
PrOH/hexanes, 1 mL/min): tR(1) = 8.97 min, tR(2) = 13.3 min.
9,9'-Dibenzyl-6,6'-dimethoxy-3,3'-dimethyl-9H,9'H-[1,1'-
bicarbazole]-2,2'-diol (5o).
26 h, the product was obtained as a light brown powder (10.6 mg)
in 82% yield. Rf = 0.33 (EtOAc:Hexanes = 1:4): H NMR (500
General Procedure G
for
Following
1
22
781.3066, found 781.3054; [α]D +55 (c 0.15, 85% ee, CH2Cl2);
MHz, acetone-d6) d 7.91 (s, 2H), 7.63 (d, J = 2.5 Hz, 2H), 6.98 (d, J
Chiral HPLC: Chiralpak IA column (20% i-PrOH/hexanes, 1
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1244, 1180, 1124, 919 cm-1; HRMS (ESI-TOF) calcd for
= 8.8 Hz, 2H), 6.88-6.83 (m, 8H), 6.81 (s, 2H), 6.46 (d, J = 7.8 Hz,
22
4H), 4.78 (d, J = 17.2 Hz, 2H), 4.56 (d, J = 17.2 Hz, 2H), 3.90 (s,
C44H36N2O2Na [M+Na]+ m/z = 647.2674, found 647.2659; [α]D
1
2
3
4
5
6
7
8
6H), 2.20 (s, 6H); 13C NMR (125 MHz, acetone-d6) d 155.1, 154.5,
140.4, 139.2, 137.4, 128.4, 126.9, 126.3, 124.4, 123.0, 117.9, 117.6,
113.5, 110.6, 102.9, 101,7, 56.1, 47.5, 17.1; IR (neat) 3500, 2925,
1627, 1482, 1450, 1433, 1409, 1349, 1298, 1229, 1191, 1181, 1159,
1145, 1073, 1055, 1027, 1004 cm-1; HRMS (ESI-TOF) calcd for
C42H37N2O4 [M+H]+ m/z = 633.2753, found 633.2766. [α]D22 +142
(c 0.45, 74% ee, CH2Cl2); Chiral HPLC: Chiralpak IA column (15%
i-PrOH/hexanes, 1 mL/min) tR(1) = 12.6 min, tR(2) = 14.1 min.
+268 (c 0.10, 83% ee, CH2Cl2); Chiral HPLC: Chiralpak IA column
(10% i-PrOH/hexanes, 1 mL/min) tR(1) = 9.72 min, tR(2) = 11.0
min.
9,9'-Dibenzyl-3,3'-diphenyl-9H,9'H-[1,1'-bicarbazole]-2,2'-
diol (5s).
General Procedure G
, the product was
Following
obtained as orange oil (12 mg) in 43% based on recovery of starting
1
material yield. Rf = 0.62 (EtOAc:Hexanes = 1:4): H NMR (500
9
MHz, acetone-d6) d 8.16 (d, J = 10.0 Hz, 2H), 8.14 (s, 2H), 7.40 (d,
J = 10.0 Hz, 4H), 7.35 (d, J = 10.0 Hz, 4H), 7.29-7.20 (m, 8H), 7.09
(d, J = 5.0 Hz, 2H), 6.88-6.86 (m, 6H), 6.63-6.61 (m, 4H), 5.10 (d,
J = 20.0 Hz, 2H), 4.74 (d, J = 20.0 Hz, 2H); 13C NMR (125 MHz,
acetone-d6) d 153.3, 142.7, 140.7, 140.3, 138.8, 130.6, 128.69,
128.65, 127.1, 127.0, 126.3, 125.3, 124.3, 123.4, 123.3, 120.3, 119.8,
118.5, 110.3, 102.8, 47.5; IR (neat) 3506, 2923, 1625, 1603, 1495,
1474, 1448, 1434, 1411, 1347, 1320, 1264, 1228, 1203, 1182, 1152,
1125, 958 cm-1; HRMS (ESI-TOF) calcd for C50H37N2O2 [M+H]+
9,9'-Dibenzyl-3,3'-dimethyl-6,6'-diphenyl-9H,9'H-[1,1'-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
bicarbazole]-2,2'-diol (5p).
product was obtained as a yellow solid (23 mg) in 70% yield. Rf =
0.64 (EtOAc:Hexanes = 1:4): H NMR (500 MHz, CDCl3) d 8.32
(d, J = 1.5 Hz, 2H), 8.04 (s, 2H), 7.77 (d, J = 7.0 Hz, 4H), 7.61 (dd,
J = 8.5, 2.0 Hz, 2H), 7.52 (t, J = 7.5 Hz, 4H), 7.34 (t, J = 7.0 Hz, 2H),
7.18 (d, J = 8.5 Hz, 2H), 6.94 (t, J = 7.0 Hz, 2H), 6.89 (t, J = 7.0 Hz,
4H), 6.31 (d, J = 7.0 Hz, 4H), 4.78 (s, 2H), 4.74 (d, J = 17.0 Hz, 2H),
4.69 (d, J = 17.0 Hz, 2H), 2.22 (s, 6H); 13C NMR (125 MHz,
General Procedure G
, the
Following
1
22
m/z = 697.2855, found 697.2839. [α]D +39 (c 0.25, 60% ee,
CH2Cl2); Chiral HPLC: Chiralpak IA column (10% i-
PrOH/hexanes, 1 mL/min) tR(1) = 10.4 min, tR(2) = 15.7 min.
Procedure Control Experiments
CDCl3) d 152.7, 142.2, 141.4, 138.7, 137.3, 133.3, 128.9, 128.0,
127.4, 126.8, 126.6, 125.1, 124.4, 123.4, 123.3, 118.0, 117.8, 117.7,
109.3, 99.2, 47.0, 16.6; IR (neat) 3502, 2921, 1603, 1468, 1450,
1406, 1361, 1347, 1290, 1251, 1178, 1135, 1076, 1003, 964, 878 cm-
1; HRMS (ESI-TOF) calcd for C52H41N2O2 [M+H]+ m/z =
1a
Radical Inhibitor: To a microwave vial was added 1.0 equiv of
,
V6
20 mol % of , 6.25 equiv of acetic acid, and 0.2 equiv of TEMPO.
The vials were sealed and toluene (0.5 M) was added. Oxygen was
added via an active purge. The deep blue reaction solution was
stirred at room temperature. The reaction conversion was
determined by 1H NMR.
22
725.3168, found 725.3168. [α]D +82 (c 0.25, 82% ee, CH2Cl2);
Chiral HPLC: Chiralpak IA column (10% i-PrOH/hexanes, 1
mL/min) tR(1) = 14.6 min, tR(2) = 27.1 min.
9,9'-Dibenzyl-3,3'-dibromo-9H,9'H-[1,1'-bicarbazole]-2,2'-
diol (5q).
General Procedure G
, the product was
Following
1a
Catalyst Stoichiometry: In microwave vials were added
equiv), acetic acid (6.25 equiv), and 20 mol % of
V6
(1.0
or 50 mol % of
in a separate vial. The vials were sealed and toluene (0.5 M) was
obtained as yellow oil (12.0 mg) in 30% yield based on recovered
starting material. Rf = 0.63 (EtOAc:Hexanes = 1:4): 1H NMR (500
MHz, acetone-d6) d 8.37 (s, 2H), 8.14 (d, J = 7.4 Hz, 2H), 7.56 (s,
2H), 7.31 (td, J = 8.3, 1.2 Hz, 2H), 7.23 (td, J = 7.8, 0.8 Hz, 2H), 7.13
(d, J = 8.2 Hz, 2H), 6.87-6.82 (m, 6H), 6.48 (dd, J = 8.1, 1.9 Hz, 4H),
4.90 (d, J = 17.3 Hz, 2H), 4.63 (d, J = 17.4 Hz, 2H); 13C NMR (125
MHz, acetone-d6) d 152.1, 143.0, 140.6, 138.4, 128.6, 127.3, 126.2,
126.1, 125.1, 123.1, 120.7, 120.1, 119.5, 110.3, 104.7, 103.6, 47.8; IR
(neat) 3503, 2924, 2853, 1591, 1473, 1446, 1412, 1340, 1319, 1259,
1205, 1184, 1123, 1027, 960, 777, 746, 730 cm-1; HRMS (ESI-TOF)
calcd for C38H27Br2N2O2 [M+H]+ m/z = 701.0439, found 701.0462;
V6
added. Argon was added via an active purge. The deep blue reaction
solution was stirred at an ambient temperature. The reaction
conversions were determined by 1H NMR.
Procedure for Deuterium Isotope Effects Experiment.
In
1a
V6
microwave vials were added (50 mg, 0.37 mmol), (32 mg, 0.07
mmol), 4,4’-di-tert-butylbiphenyl (24 mg, 0.09 mmol), and acetic
acid (0.13 mL, 2.23 mmol) or acetic acid-d4 (0.13 mL, 2.23 mmol)
in a separate vial. The vials were sealed and toluene (0.73 mL) was
added. Oxygen was added via an active purge. The deep blue
reaction solution was stirred at 0 °C. The reaction conversions and
yields were determined by 1H NMR.
22
[α]D +58 (c 0.25, 72% ee, CH2Cl2); Chiral HPLC: Chiralpak IA
column (20% i-PrOH/hexanes, 1 mL/min) tR(1) = 12.0 min, tR(2)
= 19.6 min.
Computational Studies.
Optimizations of intermediates and
3,3'-Diallyl-9,9'-dibenzyl-9H,9'H-[1,1'-bicarbazole]-2,2'-diol
transition states were performed using Gaussian 0944 software with
spin-unrestricted DFT at the UB3LYP45/(6-31G(d), V:
LANL2DZ46) level in the gas phase. For all species, vibrational
frequencies were also computed at the specified level of theory to
obtain thermal Gibbs Free Energy corrections (at 298 K) and to
characterize the stationary points as transition states (one and only
one imaginary frequency) or relative minima (zero imaginary
frequencies). Single point energy calculations were performed on
optimized geometries in toluene solvent using the SMD47-solvation
model with UM0648 functional and LANL2DZ basis set for
vanadium and 6-311+G(d,p) basis set for all other atoms. Obtained
single-point energies were converted to the enthalpies and Gibbs
(5r).
General Procedure G
, the product was obtained as
Following
a yellow powder (9.0 mg) in 75% yield. Rf = 0.72 (EtOAc:Hexanes
= 1:4): 1H NMR (500 MHz, acetone-d6) d 8.07 (d, J = 7.5 Hz, 2H),
7.94 (s, 2H), 7.23 (dt, J = 8.3, 1.3 Hz, 2H), 7.18 (dt, J = 7.8, 1.0 Hz,
2H), 7.06 (d, J = 8.0 Hz, 2H), 7.00 (br s, 2H), 6.83-6.81 (m, 6H),
6.48-6.46 (m, 4H), 6.00-5.93 (m, 2H), 5.11 (dq, J = 17.1, 1.6 Hz,
2H), 4.98 (dq, J = 10.0, 1.2 Hz, 2H), 4.88 (d, J = 17.2 Hz, 2H), 4.58
(d, J = 17.2 Hz, 2H), 3.42-3.33 (m, 4H); 13C NMR (125 MHz,
acetone-d6) d 154.1, 142.5, 140.0, 138.8, 138.6, 128.4, 126.9, 126.2,
125.0, 124.1, 122.3, 120.8, 120.0, 119.5, 118.0, 115.3, 110.1, 101.9,
47.4, 35.7; IR (neat) 3513, 2923, 1603, 1477, 1449, 1417, 1348,
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free energies using corrections from gas-phase frequency analysis.
Extensive conformational analysis of the transition states was
performed manually. Distortion-interaction analysis49 of the
coupling step was performed at UB3LYP/6-31g(d), V: LANL2DZ
using gas-phase geometries.
Page 26 of 28
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ASSOCIATED CONTENT
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Supporting Information. Mechanistic experimental results, NRM
spectra, and computational data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
marisa@sas.upenn.edu
ACKNOWLEDGMENT
We are grateful to the NIH (GM-112684, GM-08765) and the NSF
(CHE1764298) for financial support of this research. Computational
support was provided by XSEDE (TG-CHE120052). Partial
instrumentation support was provided by the NIH and NSF
(1S10RR023444, 1S10RR022442, CHE-0840438, CHE-0848460,
1S10OD011980). P.V.G.R. acknowledges the Raman Fellowship for
financial support [F.No.5.102/2016(1c)]. 3D structures for Figure 7
were generated using CYLview. Drs. Rakesh Kohli and Charles W. Ross
III are acknowledged for obtaining accurate mass data.
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