Directed Metalation-Suzuki-Miyaura Cross-Coupling Strategies: Regioselective Synthesis of Hydroxylated 1-Methyl-phenanthrenes

Article abstract of DOI:10.1021/acs.joc.5b01300

A general, efficient, and regioselective synthesis of a series of hydroxylated 1-methylphenanthrenes 9 by a combined directed ortho metalation (DoM)-Suzuki-Miyaura cross-coupling-directed remote metalation (DreM) sequence is reported. Diversity to this methodology was achieved by a regioselective DoM rather than DreM reaction, affording more highly substituted phenanthrols (Table 2). Application of the turbo-Grignard reagent (i-PrMgCl·LiCl) in the Ni-catalyzed Corriu-Kumada reaction gave efficient decarbamoylation (Tables 3and 4). Additional features are the TMS protecting group and halo-induced ipso-desilylation tactics applied to the regioselective synthesis of phenanthrenes (Scheme 2).

Full text of DOI:10.1021/acs.joc.5b01300

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Article
Directed Metalation – Suzuki-Miyaura Cross-coupling Strategies.
Regioselective Synthesis of Hydroxylated 1-Methyl-phenanthrenes
Kåre Bredeli Jørgensen, Toni Rantanen, Thilo Dorfler, and Victor Snieckus
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01300 • Publication Date (Web): 24 Aug 2015
Downloaded from http://pubs.acs.org on August 26, 2015
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Directed Metalation – Suzuki-Miyaura Cross-coupling Strategies.
Regioselective Synthesis of Hydroxylated 1-Methyl-phenanthrenes
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†
,*
‡
‡
‡,*
Kåre B. Jørgensen Toni Rantanen, Thilo Dörfler, and Victor Snieckus
†
‡
Faculty of Science and Technology, University of Stavanger, Nꢀ4036 Stavanger, Norway, Snieckus Innovations
and Department of Chemistry, Queen’s University, Kingston, ON, Canada K7L 3N6
*
corresponding authors, Eꢀmail: kare.b.jorgensen@uis.no; snieckus@chem.queensu.ca;
Graphics:
Abstract
A general, efficient, and regioselective synthesis of a series of hydroxylated 1ꢀ
methylphenanthrenes 9 by a combined directed ortho metalation (DoM) – SuzukiꢀMiyaura crossꢀ
coupling – directed remote metalation (DreM) sequence is reported. Diversity to this
methodology was achieved by a regioselective DoM rather than DreM reaction, affording more
highly substituted phenanthrols (Table 2). Application of the turboꢀGrignard reagent
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iPrMgCl•LiCl) in the Niꢀcatalyzed CorriuꢀKumada reaction gave efficient decarbamoylation
(Tables 3 and 4). Additional features are the TMS protecting group and haloꢀinduced ipsoꢀ
desilylation tactics applied to the regioselective synthesis of phenanthrenes (Scheme 2).
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Introduction
The phenanthrene nucleus represents one of the myriad of ring systems of polycyclic aromatic
1
2
hydrocarbons (PAHs), and is present in large classes of natural products, including a large
3
4
group of alkaloids. Substituted phenanthrenes have been exploited as antiꢀviral and antiꢀcancer
5
,6
7
8
agents, fluorescent probes for DNA as antioxidant resveratrol analogues, and in material
9
science areas. Unfortunately phenanthrenes, as most classes of PAHs, are also persistent
10,11
pollutants in the environment,
e.g., annelids on tidal flats concentrate phenanthrene in their
1
2
13
excrements, phenanthreneꢀbased synthetic musk fragrances have been found in shrimps, and
1
4
metabolites of phenanthrenes have been detected in goat’s milk. Among the many fractions of
1
1,15
PAHs in oil sources currently under study,
alkylated PAHs have been established to cause
1
0,16
17,18
general detrimental environmental effects
and in particular are toxic to marine life.
1
9
In the substantial body of literature on the construction of phenanthrenes, the dominant classical
2
0
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Pschorr and the more recent Mallory photoꢀ and oxidative cyclizations have been augmented
6,16,23
by an evolving number of transition metal catalyzed methods,
including the popular Suzukiꢀ
2
4
Miyaura crossꢀcoupling reaction. Furthermore, phenanthrenes have been prepared from
2
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26
functionalized biphenyls by [4+2] benzannulation reactions and by McMurryꢀlike reactions.
As part of our efforts to advance directed ortho metalation (DoM) reactions in aromatic and
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heteroaromatic synthesis,
we have devised combined metalationꢀcrossꢀcoupling strategies,
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0,31,32
which have had particular relevance to the construction of phenanthrene derivatives.
In
continuation of these efforts, we report herein a general route for the regioselective construction
of 1ꢀmethylꢀphenanthrenes bearing various positional hydroxyꢀsubstitutents by taking advantage
of sequential DoM – SuzukiꢀMiyaura crossꢀcoupling – directed remote metalation (DreM)
reactions. Its retrosynthetic analysis is depicted in Scheme 1. In the penultimate step, the selective
removal of the incipient 9ꢀOH of the phenanthrol is carried out by transfer hydrogenation of the
corresponding triflate or βꢀhydride induced excision of the corresponding Oꢀcarbamate under Niꢀ
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3
3 34
,
catalyzed conditions, a procedure of considerable as yet unfulfilled promise.
In this work, we
3
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also advantageously adapted the silicon protection tactic for most reactive DoM sites
(A,
Scheme 1) and the regioselective ipsoꢀhalodesilylation. Finally, we report on an apparent kinetic ꢀ
thermodynamic ortho ꢀ remote metalation selectivity (B) which allows the additional
regioselective electrophile introduction into biaryl systems and thence leads to more highly
substituted phenanthrenes.
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Scheme 1: The regioselective synthesis of substituted phenanthrenes by the DoM – crossꢀ
coupling – DreM strategy: Retrosynthetic analysis
DreM
HO
Me
Me
Et N
O
2
1
0
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Me
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Me
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MeO
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RO
6
MeO
R = H, Me
TMS Cl
Et2N
O
Et N
O
-
2
+
E
Et N
O
2
-
-
Kinetic
1
X
2
X-coupling
+
Y
Me
Me
OMe
Me
-
DoM
Step 1: more reactive DoM site
A )
Thermodynamic
MeO
(
( B )
X, Y = B(OH) and Halogen
2
Results and discussion
The results of SuzukiꢀMiyaura crossꢀcoupling reactions of benzamides 1 with tolyl and xylyl
derivatives 2 to give substituted biaryls 3 are summarized in Table 1. In many cases, both the
crossꢀcoupling of benzamideꢀderived boronic acid with halotoluene and the inverted reaction of
halo benzamide with tolueneꢀderived boronic acid were carried out to compare efficiency of the
respective routes. In addition, three different conditions were applied to establish generality. The
boronic acid benzamides 1, X = B(OH) and bromobenzamides 1, X = Br were prepared by DoM
2
reactions using standard procedures while the boronic acids 2, Y = B(OH) were obtained by
2
metalꢀhalogen exchange from the corresponding commercially available bromotoluenes followed
by quench with a boron electrophile. Boronic acids 1a, c, g were prepared by using triꢀisopropyl
boronate, [B(iꢀOPr) ] as the electrophile which has the advantage of being more benchꢀstable
3
than B(OMe) . However, the sterically hindered 1d gave poor yields of product with B(iꢀOPr)3
3
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and therefore required the use of B(OMe) . This reaction was difficult to reproduce, requiring a
3
careful quench at –40 °C to avoid decomposition of the product during workup.
The commercial bromotoluenes 2a and 2b conveniently served a double purpose since they were
also used as crossꢀcoupling partners. Two cases of iodotoluene coupling reaction were tested
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(
entries 7, 9). To comment briefly, crossꢀcoupling of unsubstituted boronic acid benzamides with
bromoarenes (entries 1, 2) or vice versa (entries 3, 4) under two different sets of conditions
proceeded in high yields to give both mono methyl and dimethyl biaryls. A slightly buttressing
influence of the 6ꢀOMe group may be responsible for the lower yield (74%) of the biaryl product
(entry 5). Interestingly, in moving from the 2,2′ꢀsubstituted biaryl 3a-c to the considerably more
hindered 2,2′,6ꢀsubstituted series 3d, 3e, the yields of products remained very good in both
3
7
1
coupling partner combinations (entries 6ꢀ10). The H NMRꢀspectra of all biphenyls indicated
38
the presence of rotamers, more pronounced in the more crowded biphenyls.
The crossꢀcoupling reactions of the 4ꢀOMe boronic acid benzamide and bromobenzamides series
proved to be unexceptional providing modest to good yields of biaryl products 3f and 3g (entries
1
1ꢀ16). While the 3ꢀOMe benzamide 2ꢀboronic acid 1d was prepared by DoM chemistry using
the less hindered B(OMe) reagent, the corresponding halogenated products 1e, 1f and 1h were
3
obtained via metalation and quench with Br or I . Interestingly, using Br as the electrophile
2
2
2
seemed to consistently lead to poor yields in this approach (see also Scheme 2). Therefore, an
alternative tactic was adopted and both 1e and 1f were conveniently synthesized by the selective
3
9
ipsoꢀbromo and ꢀiodo desilylation method of the corresponding silylated derivative 1k (Scheme
2) which was readily available on multigram scale. The requisite boronic acid and bromo
derivatives 1i and 1j were obtained by DoM chemistry using the siliconꢀprotection of most
3
5, 36
reactive metalation site method
followed by a second metalation and boronation or
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bromination. Crossꢀcoupled products 3h and 3i were subsequently desilylated with TBAF into 3k
(Table 3) and 3l (Table 2) in high yields for further use. The SuzukiꢀMiyaura coupling reaction of
1d with iodo toluene 2e proceeded in modest yields with Pd(PPh ) both under aqueous
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conditions, and even less efficiently under anhydrous conditions (K PO /DMF) previously
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developed in our laboratories, but was considerably improved even in reactions with the
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bromotoluene 2b using the Buchwald reaction under anhydrous conditions (entries 7 and 6).
Finally (entry 21), the fluorinated compound 2f was coupled with 1f to obtain biphenyl 3j in good
yields in order to extend the range of substituents.
Table 1. The SuzukiꢀMiyaura crossꢀcoupling route to biaryl amides 3a-i
1
2
1
2
a
b
Entry
Compd.
X
R
Compd.
Y
R
Compd
.
R
R
Cond.
Yield
(%)
89
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1d
1d
1e
B(OH)2
B(OH)2
Br
H
2a
2b
2c
2d
2b
2b
2e
2c
Br
H
3a
H
H
A
A
C
C
A
B
A
B
H
Br
Me
H
3b
3a
H
Me
H
95
H
B(OH)2
B(OH)2
Br
H
70ꢀ86
quant.
74
Br
H
Me
Me
Me
Me
H
3b
3c
H
Me
Me
Me
Me
H
B(OH)2
B(OH)2
B(OH)2
Br
6ꢀOMe
3ꢀOMe
3ꢀOMe
3ꢀOMe
3ꢀOMe
6ꢀOMe
6ꢀOMe
6ꢀOMe
Br
3d
3d
3e
71
I
47
B(OH)2
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4ꢀOMe
4ꢀOMe
5ꢀOMe,
6ꢀTMS
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5ꢀOMe,
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2b
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Br
H
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5ꢀOMe
5ꢀOMe
5ꢀOMe
5ꢀOMe
3ꢀTMS,
4ꢀOMe
3ꢀTMS,
4ꢀOMe
3ꢀTMS,
4ꢀOMe
3ꢀTMS,
4ꢀOMe
6ꢀOMe
H
B
B
A
A
B
C
B
C
A
82ꢀ97
61ꢀ73
40
0
1
1e
1g
1g
1h
1h
1h
1h
1i
Br
Me
H
Me
H
B(OH)2
B(OH)2
Br
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13
14
15
16
17
Br
Me
H
3g
3f
Me
H
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0
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0
B(OH)2
B(OH)2
B(OH)2
B(OH)2
Br
44
Br
H
3f
H
76ꢀ89
67
Br
Me
Me
Me
3g
3g
3h
Me
Me
Me
Br
71
B(OH)2
83
18
1j
1j
1l
1f
Br
Br
I
2c
2c
2c
2f
B(OH)2
B(OH)2
B(OH)2
B(OH)2
H
H
H
H,
3i
3i
3i
3j
H
H
H
B
C
C
B
64
81
95
75
1
2
3
9
0
0
6
ꢀTMS
5ꢀOMe,
ꢀTMS
3ꢀOMe
6
I
H,
5
ꢀF
5´ꢀF
a
Conditions: A: 3 mol% Pd(PPh ) , DME/2 M Na CO , 100 °C, 18ꢀ20h. B: 5 mol% Pd dba , Sꢀ
3
4
2
3
2
3
Phos, PhMe/K PO , 100 °C, 20ꢀ28 h. C: 4 mol% Pd(dppf)Cl *DCM, dioxane/2M K CO (3/1),
3
4
2
2
3
b
9
0ꢀ100 °C, 16 h. Yields of isolated products.
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Scheme 2. Siꢀprotection and ipsoꢀdesilylation routes to benzamides 1e, 1f, 1j and 1l
X=Br:
Et N
O
Et N
O
Et N
O
2
2
2
1
. s-BuLi/TMEDA
Br , DCM, 50 °C
2
X
TMS
OMe
2. X (1.1 equiv.)
TMS
OMe
X
2
X=I:
AgBF , I 0 °C
4
2,
OMe
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0
X= Br:
X= I:
1j
1l
29%
80%
1k
X= Br:
X= I:
1e 98%
1f 59%
In the course of the studies involving the conversion of the biaryl amides 3 into the corresponding
phenanthrenes (Table 3), we observed the formation of products 4e and 4g under sꢀ
BuLi/TMEDA metalation and MeI quench conditions (Scheme 3). Formation of compound 4e is
expected by the kinetic Cꢀ3 deprotonation under the standard and widely used DoM sꢀ
2
8
BuLi/TMEDA conditions for tertiary amides while the formation of Cꢀ3 ethyl derivative 4g is
likely the result of an intermolecular Cꢀ3 anion (3f) ꢀ Cꢀ3 methyl (4e) proton exchange followed
4
1
by methylation of the resulting tolyl anion. The formation of 4g is a function of the rate of
addition of the MeI reagent as expected since the incipient Cꢀ3 methyl anion is formed
competitively with the original Cꢀ3 methylation.
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Scheme 3. DoM reaction of 3f and slow stepwise quench with MeI
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Table 2. DoM reactions on biaryl amides 3. Synthesis of compounds 4a-f
Et N
O
Et N
O
2
2
2
2
E
3
3
1) s-BuLi, TMEDA, THF, -78 °C, 1 h
Me
+
Me
4
R1
2) E , fast addition( -78 °C to -50 °C)
4
R1
6
6
5
5
3
4
1
+
a
Entry
Compound
R
E
Product
4a
E
Yield (%)
85ꢀ95
70
1
2
3
4
5
6
3a
3a
3a
3e
3f
H
H
MeI
Me
Cl
C Cl
4b
2
6
H
TMSCl
4c
TMS
Me
Me
Me
92
6ꢀOMe
5ꢀOMe
4ꢀOMe
MeI
MeI
MeI
4d
78ꢀ82
77ꢀ94
72ꢀ89
4e
b
3l
4f
a
b
Yields of isolated products. Desilylation of 3i (Table 1) with TBAF gave 3l in 83% yield.
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The Cꢀ3 anion of 3f was efficiently trapped to give 4e in high yield by a procedure involving fast
quench with neat MeI. In consideration of the potential value of this result for general substituted
phenanthrene synthesis, it was generalized using two other electrophiles and for four biaryl
substrates (Table 2) which does not require further comment.
0
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0
With a series of biaryl amides in hand, the transformation to phenanthrols and eventually to the
oxygenated 1ꢀmethyl phenanthrenes was undertaken and the results are summarized in Table 3.
3
0,31
Application of the standard LDA conditions of the DreM procedure
to the 2′,3′ꢀdimethyl
biaryl amide 3b afforded the 1ꢀmethylphenanthrenꢀ9ꢀol 5a in 68% yield of recrystallized
material. The isomeric 3,2′ꢀdimethyl biaryl amide 4a, by treatment under the same LDA
conditions, furnished the 8ꢀmethylphenanthrenꢀ9ꢀol 5b in 89% yield of crude material. However
5b was significantly less stable than 5a and partly decomposed during flash chromatography, and
even Kugelrohr distillation, giving rapidly decreased yields upon purification. Therefore, rapid
carbamoylation of the crude phenanthrols from the methoxy dimethyl biaryl benzamides 4e, 4d
and 3d,g,k,c was undertaken and directly furnished the corresponding phenanthrol Oꢀcarbamates
6c-e, g-i respectively, without isolation of the respective phenanthrols, in modest to good yields.
In two cases, the corresponding triflates (6b and 6f) were also prepared. A study of the rotational
3
8
barriers of the starting biaryls may shed light upon the observed variations in yields. In this
context, it is noted that the oꢀsilylated amide 3h required desilylation to 3k before corresponding
DreM reaction to 5i could be achieved. The silylated derivative 3h is expected to give desilylated
42
phenanthrylamine product. Furthermore, in some cases 2 equivalents of LDA were required to
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effect the DreM transformation (e.g. 4d, 4e and 4f) as expected from the acidic CꢀH sites present
in these molecules.
Finally, one unexpected DreM transformation not related to the major aim of this work, 3j ꢀ 8
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(
entry 12), was observed. Although biphenyl 2ꢀamides lacking a 2′ꢀMe group are known to form
4
3
fluorenones, this represents, to our knowledge, the first example of a 2ꢀamidoꢀ2′ꢀMe biphenyl
forming a fluorenone derivative under DreM conditions and suggests higher equilibrating acidity
of Cꢀ6′ H over Cꢀ2′ methyl hydrogens under the LDA conditions. This result suggests an
4
4
overriding DMG = F effect as already established for DMG = OMe.
Table 3. Transformation of biaryls 3-4 to phenanthrenes 7
a
a
Entry
Biaryl
Cond.
Phenanthrene
Yield Cond.
(%)
Phenanthrene
Yield
b
(%)
1
2
3b
A
5a R = H
6a R = CONEt2
68
A, B
82
C
7a
97
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c
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5b R = H
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RO
Me
MeO
4
4f
A,D
6b R = Tf
55
E
7b
73
e
5
6
4e
A,B
A,B
6c R = CONEt2
40ꢀ44
40ꢀ52
C
C
7c
75
e
4d
6d R = CONEt2
7d
88
7
8
3d
A,B
A,D
6e R = CONEt2
6f R = Tf
77
92
E
7e
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e
9
3g
A,B
6g R = CONEt2
74ꢀ77
C
7f
83
d
1
0
3k
A,B
6h R = CONEt2
92
C
7g
79
1
1
3c
A,B
6i R = CONEt2
81
C
7h
67
1
2
3j
A
8
79ꢀ97
65
a
A: 2.5 equiv LDA, THF, 0 °Cꢀ r.t.; B: 1) NaH, THF, 0 °Cꢀr.t. 2) Et NC(O)Cl; C: 10% Ni(acac) ,
2
2
Et O, 2 equiv iPrMgCl•LiCl in THF, r.t.; D: CH Cl , pyridine (1.2 equiv), Tf O (1.2 equiv), r.t.,
2
2
2
2
8
ꢀ12 h.; E: Pd(OAc) (2 mol%), PPh (4 mol%), Et N (3 equiv), DMF (10 mL/mmol), HCO H (2
2 3 3 2
b
c
equiv), 80 °C, 1 h. Yields after flash chromatography. Yield of crude product after extraction.
The compound underwent rapid decomposition upon attempted purification by flash
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d
chromatography. Desilylation of 3h with TBAF gave 3k in 94% yield (see Experimental
e
Section). The compound is contaminated with crossꢀcoupled propyl and isopropyl group
products. See Experimental section for details.
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For the generalizion of the final reductive scission of the Oꢀaryl carbamates 6 to the oxygenated
1
ꢀmethylphenanthrenes 7, an optimization study was carried out (Table 4). In the original work
on the development of the Niꢀcatalyzed KumadaꢀCorriu crossꢀcoupling reaction, Kumada had
observed that Grignard reagents bearing βꢀhydrogens effect βꢀhydride transfer reactions and
4
5,46
thereby reductive cleavage of aryl halides.
In our laboratories, we discovered this reaction for
3
3
the Oꢀcarbamates. In spite of the knowledge that the Oꢀcarbamate is the most powerful DMG
33,47
48
and its promise in indole and scaleꢀup chemistry,
this reaction remains broadly unexploited.
Initial optimization studies on model compound 6a (Table 4) using commercially available
4
9,50
iPrMgCl or iPrMgCl•LiCl (turboꢀGrignard)
failed in THF solution at 10 mol % Ni(acac)2
loading (entry 1). However, in spite of using both reagents as THF solutions, reductive cleavage
was observed in Et O as reaction solvent at room temperature. While iPrMgCl produced mixtures
2
of the desired decarbamoylated 7a, together with the normal (7i) and isomeric (7j) Kumadaꢀ
4
6
Corriu crossꢀcoupled products in varying amounts (entries 2 and 3), rapid injection of
iPrMgCl•LiCl afforded high ratios of 7a to the two coupled products (entries 4 and 5). The
5
0
iPrMgCl•LiCl complex is considered to be more nucleophilic compared to iPrMgCl, and its use
5
1
in a Grignard reaction has shown increased amounts of reduction products but to our
knowledge, this result constitutes the first intentional use of the turboꢀGringard reagent as a
hydride source. For smallꢀscale experiments, the higher 10 mol% catalyst loading is
recommended to achieve fast completion of the reaction although, as gleaned from the
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experiments, large scale reactions should be feasible with low catalyst loading and thereby
avoidance of environmental problems with excessive Ni residues. Although the crossꢀcoupled
products (7i, 7j) were not isolated, they were readily identified on GCꢀMS by their main fragment
from EI ionization arose from alkyl chain cleavages.
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Table 4. Optimization of the reductive Oꢀdecarbamoylation of compound 6a to 7a
a
b
Entry
1
Ni(acac)2
Grignard
equiv
2
time
Product ratios (%)
(mol%)
7a
7i
7j
c
10
iPrMgCl•LiCl
1.5 h
No reaction
d
2
3
4
3
2
iPrMgCl
2
4
2
1 h
4 h
48
77
98
33
14
2
18
8
iPrMgCl
10
iPrMgCl•LiCl
iPrMgCl•LiCl
15 min
0
5
1
2
22 h
97
2
1
a
All Grignard reagents were commercial solutions in THF: iPrMgCl (1 M) and iPrMgCl•LiCl (14
b
c
d
w%). Ratios of products by GC/MS analysis. Reaction were carried out in THF. Grignard
reagent was added slowly (see Experimental Section).
The optimized conditions were then applied to the phenanthrene Oꢀcarbamates 6a, c-e, g-i (Table
3, conditions C) to give good to quantitative yields of 1ꢀmethylphenanthrenes 7a, c, g-h.
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6
Unfortunately, the reaction revealed its sensitivity as compounds 7c-d and 7f contained
significant amounts of crossꢀcoupled products. Presumably, due to steric hindrance by a periꢀtype
effect, 7h was obtained in lower yield. In the case of triflates 6b and 6f, reductive cleavage by
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30
hydride transfer from formic acid (condition E) gave products 7b and 7e respectively.
Although proceeding in very good yield, this method is less desirable due to its greater expense in
the synthesis of the triflate 6f compared to the Oꢀcarbamate derivative 6e. In contrast, the
byproducts formed in the reductive decarbamoylation route (cases 7i and 7j) were very difficult
to separate from the desired phenanthrenes, and therefore the triflate procedure has merit when
absolute purity is more important than cost.
To summarize, the reductive decarbamoylation completed the efficient regioselective synthesis of
the series of ring A 2ꢀ, 3ꢀ, and 4ꢀOMe 1ꢀmethylphenanthrenes as single isomers 7b-d.
Furthermore, the synthetic “walking tour” of OMe groups provided the isomeric Cꢀring OMe
substituted 1ꢀmethylphenanthrenes 7e-h by the regioselective DoM – crossꢀcoupling – DreM
strategy. It is of interest to note that, although the further transformation of 5b into the
corresponding phenanthrene 7a was not pursued, reductive excision of the OCONEt group from
2
the isomeric derivatives of 5a (6a) and 5b gives the same molecule. This observation is perhaps a
conceptual element of broader utility in PAH synthesis and certainly of step economy value since
3b is simpler to prepare than the isomeric 4a.
Scheme 4. Demethylation of 1ꢀmethylphenanthrenes 7 to phenanthrols 9
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As previously noted, phenanthrols are unstable to aerial oxidation to varying degrees. To
5
2
53
conclude our study, reliable BBr deprotection on three methoxy derivatives 7f, 7g, and 7h
3
was carried out to afford the corresponding phenols 9c, 9b and 9a respectively (Scheme 4) in
order to demonstrate the relative higher stability of non 9ꢀhydroxy phenanthrenes and the ability
17
to make such products available as standards for PAH environmental and metabolism studies.
In summary, we have provided a systematic study of a general, efficient, and regioselective
synthesis of phenanthrenes which allows the preparation of this class of PAHs with minimal
handling of potentially carcinogenic materials, and without using Lewisꢀacid and other powerful
reagents and harsh conditions. The route involves application of the combined DoM – Suzukiꢀ
Miyaura crossꢀcoupling – DreM strategy to give a significant number of phenanthrenes (Tables 1
and 3) via the intermediate phenanthrols which are subjected to conversion to the corresponding
triflates and Oꢀcarbamates followed by Niꢀcatalyzed scission. In addition, previously developed
silicon protecting group and ipsoꢀdesilylation reactions have been applied (Scheme 2) and a new
DoM over DreM reaction of 2ꢀamidoꢀ2’ꢀmethyl biphenyls has been uncoverd (Table 2) which
invite further application in aromatic synthesis.
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Experimental Section
General
1
13
Melting points were measured in capillary tubes and are uncorrected. H and C NMR spectra
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
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1
13
were recorded on 400 or 500 MHz spectrometers. The chemical shifts of H and C NMR signals
are quoted relative to internal CHCl (δ = 7.26) and CDCl (δ =77.0), DMSOꢀd (δ = 2.50 and
3
3
6
1
4
5.0), acetoneꢀd (δ = 2.05 and 29.8 / 206.3) or tetramethylsilane (δ = 0.0). H NMR data are
6
reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet, brs = broad singlet, etc.), coupling constant (Hz) and relative intensity.
1
3
C NMR data are reported as follows: chemical shift in ppm (δ). The GCꢀMS analyses were
performed under EI conditions. High resolution mass spectra were obtained on a EI or ESI Time
of Flight Mass Spectrometer. All reactions involving alkyllithiums were carried out under argon
in flameꢀdried glassware, using syringeꢀseptum cap techniques. Anhydrous THF and Et O were
2
obtained by treatment using solvent purification system with final drying through molecular
sieves under argon. All purchased chemicals were used without further purification.
54
Alkyllithiums were titrated before use. Flash column chromatography was carried out using
silica gel (particle size: 40ꢀ60 µm, 60A).
General Synthetic Procedures
The
starting
benzamides
(N,Nꢀdiethylꢀ2ꢀmethoxybenzamide,
N,Nꢀdiethylꢀ3ꢀ
methoxybenzamide, N,Nꢀdiethylꢀ4ꢀmethoxybenzamide and 1b) were synthesized from the
5
5
corresponding benzoic acids using SOCl and HNEt2 and the spectral and analytical data of the
2
5
6
products matched those that have been reported.
The benzamide boronic acids 1a, 1c, 1d, 1g and 1i were synthesized according to general
procedure A and were used directly without further purification. The synthesis and subsequent
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crossꢀcoupling of compound 1d was difficult to reproduce, despite the care taken to avoid
decomposition.
Orthoꢀtolyl (2c) and –xylyl (2d) boronic acids as well as 5ꢀfluoroꢀ2ꢀmethylbenzene boronic
acid (2f) were purchased from Sigma Aldrich, as were the corresponding bromides and iodides
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(
2a, 2b, 2e).
3
0
31
Compounds 3a, 3f, 3e were synthesized as reported, as were compounds 3b, 5a and 7a.
1
The more highly substituted biaryls exhibited rotamers, resulting in not well defined H NMR
spectra. For some biaryls VT NMR studies in DMSO solution indicated coalescence of certain
1
3
peaks and for some biaryls not all of the carbon peaks were observed in the C NMR.
For the synthesis of some final phenanthrenes, the Niꢀcatalyzed decarbamoylation reaction
leads to linear and rearranged iꢀPrMgCl coupling rather than decarbamoylation. In some cases, it
was not possible to fully eradicate this impurity from the desired product and these are indicated
where relevant.
General Procedure – Directed ortho Metalation (A): To a solution of TMEDA (1.0ꢀ2.2
o
equiv) in THF (5ꢀ10 mL / mmol) cooled to 0 C was added a solution of sꢀBuLi (1.0ꢀ2.2 equiv)
and the mixture was cooled to ꢀ78 °C. The starting material (1.0 equiv) in THF (5ꢀ10 mL / mmol)
was added dropwise while keeping the internal temperature below ꢀ70 °C. The reaction mixture
was stirred for 1 hour, or the time indicated in the specific procedure, and then the electrophile
was added, either neat or as a solution in THF. The cooling bath was removed and the reaction
mixture was warmed to room temperature. Saturated solution of NH Cl was added (10 mL /
4
mmol) and the mixture was extracted with CH Cl (3 x 20 mL). The organic layers were
2
2
combined, dried (MgSO ) and evaporated to dryness. The residue was purified via column
4
chromatography.
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General Procedure – Directed remote Metalation (B): Under argon LDA in THF (1.1ꢀ2.5
o
equiv) was either prepared at 0 C using nꢀBuLi (1.1ꢀ2.5 equiv) and diisopropylamine [DIPA]
0
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0
(
1.1ꢀ2.5 equiv) in THF (10ꢀ30 mL / mmol) or commercial LDA solution (2.0 M in
ethylbenzene/THF/heptane, 1.1ꢀ2.5 equiv) was utilized. The starting material (1.0 equiv) was
o
dissolved in dry THF (5ꢀ10 mL / mmol) and added to the LDA solution dropwise at ꢀ20ꢀ0 C.
The solution was stirred for 4ꢀ24 h and quenched with saturated NH Cl solution (20 mL / mmol).
4
The mixture was extracted with CH Cl (3 x 20 mL), dried (MgSO ) and evaporated to dryness in
2
2
4
vacuo. The residue was purified via column chromatography or taken directly onto the next step.
General Procedure – Cross-coupling I (C): The starting halide (1.0 equiv) and the boronic
acid (1.2ꢀ2.0 equiv) were dissolved in degassed dioxane / 2M aqueous K CO mixture (10 mL
2
3
dioxane / mmol substrate; 4ꢀ6 equiv K CO ). To this solution was added Pd(dppf)Cl *CH Cl
2
2
3
2
2
complex (4ꢀ5 mol%) and the mixture was immersed into a preheated oil bath at 90ꢀ100 °C and
maintained at this temperature for 16 h. Water (10 mL) was added and the mixture was extracted
with CH Cl (3 x 30 mL). The organic layers were dried (MgSO ) and evaporated to dryness. The
2
2
4
residue was purified by column chromatography.
General Procedure – Cross-coupling II (D): The starting halide (1.0 equiv) and boronic acid
(
1.1ꢀ1.5 equiv) were dissolved in toluene (7ꢀ10 mL / mmol) and degassed for 5ꢀ10 mins by
bubbling argon through the solution. K PO (4.0ꢀ5.0 equiv) was added, followed by Pd dba (2ꢀ3
3
4
2
3
mol%) and SPhos (5ꢀ10 mol%). The reaction mixture was immersed in a preheated oilbath at 110
o
C and the temperature maintained overnight. The reaction mixture was filtered, washed with
EtOAc and after evaporation the residue was purified via column chromatography.
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General Procedure – Cross-coupling III (E): The starting halide (1.0 equiv) and the boronic
acid (1.2ꢀ2.5 equiv) were dissolved in degassed dimethoxyethane and 2M aqueous Na CO
2
3
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11
12
13
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mixture (7ꢀ10 mL dimethoxyethane /mmol substrate; 4ꢀ6 equiv Na CO ). To this solution was
2
3
added Pd(PPh ) (3ꢀ5 mol%) and the solution was maintained at reflux temperature overnight (16
3 4
h). The mixture was extracted with diethylether (3 x 10 mL/mmol substrate). Organic layers were
dried (MgSO ) and evaporated. The residue was purified by column chromatography.
4
General Procedure – Desilylation (F): The starting biaryl (1.0 equiv) was dissolved in dry
THF (5ꢀ10 mL / mmol) and TBAF was added (1 M in THF, 2ꢀ3 equiv). After the reaction was
complete according to TLC (2ꢀ16 h) the solvent was evaporated. The residue was purified via
column chromatography.
General Procedure – Detriflation (G): The starting triflate (1.0 equiv) is dissolved in DMF
(10 mL / mmol) and the mixture is degassed by bubbling argon through with a needle for 5ꢀ10
mins. Then were added Et N (3.0 equiv), HCO H (2.0 equiv), PdOAc (2 mol%) and PPh (4
3
2
2
3
o
mol%). The mixture was placed in a preheated oilbath at 80 C for 1 h. The mixture was cooled
to r.t. and H O (15 mL / mmol) was added and the mixture was extracted with CH Cl (2 x 20
2
2
2
mL). After evaporating to dryness, the residue was purified via column chromatography.
General Procedure – Decarbamoylation (H): The starting material (1 equiv) was dissolved in
o
dry Et O (20 mL/mmol) and Ni(acac) (10 mol%) was added. The suspension was cooled to 0 C
2
2
and iꢀPrMgCl*LiCl (2.5 equiv, solution in THF) was added. The mixture was allowed to warm to
room temperature overnight. Then, H O (20 mL / mmol) was added, the layers separated and the
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aqueous layer extracted with CH Cl (2 x 20 mL). The combined organics were dried (MgSO )
2
2
4
and evaporated. The residue was purified via column chromatography.
0
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General Procedure – BBr Demethylation (I): The phenanthrene was dissolved in dry
3
CH Cl (50 mL / mmol). The solution was cooled to 0 °C, and BBr (2.0 equiv) was added
2
2
3
dropwise. The icebath was removed and the mixture stirred at room temperature overnight. Water
20 mL) was added and the organic layer separated. The aqueous layer was additionally extracted
with CH Cl (2 x 20 mL). The organic layers were combined, dried (MgSO ) and after
(
2
2
4
evaporation the residue was purified via column chromatography.
N,N-Diethyl-2-bromo-3-methoxy-benzamide (1e):
The title compound was synthesized by dissolving 1k (2.50 g, 8.95 mmol, 1.0 equiv) in CCl (50
4
o
mL). At 0 C Br (483 µL, 9.39 mmol, 1.05 equiv) was added and the mixture was warmed to 50
2
o
C for 2 h. After cooling to room temperature the solution was evaporated and the residue
subjected to column chromatography using pentane / Et O (1:1 to 0:1 gradient). The title
2
compound was isolated as a colorless oil (2.5 g, 98%). Physical and spectral data are in
5
7
agreement with those reported.
N,N-Diethyl-2-iodo-3-methoxy-benzamide (1f):
The title compound was synthesized by dissolving 1k (280 mg, 1.0 mmol, 1.0 equiv) in MeOH
o
(
10 mL) and adding AgBF (202 mg, 1.1 mmol, 1.1 equiv). At 0 C I (305 mg, 1.2 mmol, 1.2
4
2
equiv) was added and the mixture was warmed to room temperature and stirred at this
temperature overnight. The next day, EtOAc was added (20 mL) and the suspension was filtered
and evaporated to dryness. EtOAc (50 mL) was added and washed with 2M HCl (10 mL) and
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H O (20 mL). The organic layer was dried (MgSO ), evaporated and the residue subjected to
2
4
column chromatography using hexanes / EtOAc (2:1 to 1:1 gradient). The title compound was
1
isolated as a colorless oil (197 mg, 59%). H NMR data are similar to those reported but obtained
10
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58 1
in C D . H NMR (400 MHz, CDCl )  7.31 (t, J = 7.9 Hz, 1H), 6.80 (dd, J = 1.0, 7.5 Hz, 1H),
6
6
3
6
2
3
.77 (dd, J = 1.0, 8.2 Hz, 1H), 3.88 (s, 3H), 3.80ꢀ3.90 (m, 1H), 3.22ꢀ3.34 (m, 1H), 3.02ꢀ3.19 (m,
1
3
H), 1.28 (t, J = 7.2 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl )  12.4, 13.8,
3
+
8.8, 42.6, 56.5, 85.1, 110.3, 119.1, 129.8, 144.7, 158.2, 169.9; MS (EI, DIP) m/z 333 (M , 61),
ꢀ1
332 (56), 261 (100), 218 (15), 206 (34), 195 (30), 165 (19), 135 (19); FTIR (neat, cm ) 2972,
+
2
934, 1628, 1562, 1424, 1296, 1262, 1053, 786; HRMS (EIꢀTOF) m/z: [M] for C H INO
12
16
2
calcd 333.0226, found 333.0215.
N,N-Diethyl-2-bromo-4-methoxy-benzamide (1h):
The title compound was synthesized according to general procedure A using TMEDA (1.52 mL,
10.13 mmol, 1.05 equiv), sꢀBuLi (1.33M in cyclohexane, 7.62 mL, 10.13 mmol, 1.05 equiv) in
THF (25 mL), N,Nꢀdiethylꢀ4ꢀmethoxybenzamide (2.00 g, 9.65 mmol, 1.0 equiv) in THF (5 mL),
and Br (522 µL, 10.13 mmol, 1.05 equiv). After standard workup, with an additional wash with
2
sodium thiosulfate (sat., 20 mL), the residue was purified via column chromatography using
CH Cl /Et O (10/0 to 10/1 gradient). The title compound was isolated as a colorless oil (1.19 g,
2
2
2
1
43%): H NMR (400 MHz, CDCl )  7.15 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.86 (dd,
3
J = 2.4, 8.5 Hz, 1H), 3.79 (s, 4H [ꢀOCH + ꢀNCH]), 3.32 (br s, 1H), 3.14 (q, J = 7.1 Hz, 2H), 1.25
3
1
3
(
t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl )  12.5, 13.9, 39.0,
3
+
42.7, 55.5, 113.6, 117.9, 119.8, 128.2, 131.1, 160.0, 168.5; MS (EI, DIP) m/z 286/284 (M , 20),
ꢀ1
2
15/213 (100), 172/170 (15), 135 (26); FTIR (KBr, cm ) 2973, 2935, 1633, 1601, 1564, 1469,
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4
4
4
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5
5
5
5
5
6
+
1
427, 1288, 1195, 1032, 884; HRMS (ESIꢀTOF) m/z: [M+H] for C H BrNO calcd 286.0443,
12
17
2
found 286.0442.
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N,N-Diethyl-6-bromo-3-methoxy-2-trimethylsilyl-benzamide (1j):
The title compound was synthesized according to general procedure A using TMEDA (650 µL,
.31 mmol, 1.2 equiv), sꢀBuLi (1.35M in cyclohexane, 3.18 mL, 4.31 mmol, 1.2 equiv) in THF
20 mL), 1k (1.0 g, 3.58 mmol, 1.0 equiv) in THF (5 mL), and Br (202 µL, 3.93 mmol, 1.1
4
(
2
equiv) in THF (5 mL). After standard workup, with an additional wash with sodium thiosulfate
sat., 20 mL), the residue was purified via column chromatography using pentane/Et O (5/1 to 3/1
(
2
gradient). The title compound was isolated as a colorless oil that solidifies on standing (375 mg,
1
29%): Mp 99ꢀ100 °C (hexanes / Et O); H NMR (400 MHz, CDCl )  7.46 (d, J = 8.8 Hz, 1H),
2
3
6
.67 (d, J = 8.8 Hz, 1H), 3.91 (sex, J = 6.6 Hz, 1H), 3.77 (s, 3H), 3.01ꢀ3.27 (m, 3H), 1.26 (t, J =
1
3
7
.2 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H), 0.23 (s, 9H); C NMR (100 MHz, CDCl )  0.3, 12.0,
3
13.1, 38.7, 42.8, 55.3, 111.3, 111.4, 127.3, 134.5, 143.7, 163.9, 168.5; MS (EI, DIP) m/z 359/357
+
ꢀ1
(
M , 7), 344/342 (100), 287/285 (9), 219 (29); FTIR (KBr, cm ) 2975, 1639, 1461, 1413, 1380,
+
1
286, 1244, 1057, 846; HRMS (EIꢀTOF) m/z: [M] for C H BrNO Si calcd 357.0760, found
15 24
2
3
57.0759.
N,N-Diethyl-3-methoxy-2-trimethylsilylbenzamide (1k):
The title compound was synthesized according to general procedure A using TMEDA (1.65 mL,
1.0 mmol, 1.1 equiv), sꢀBuLi (1.4M in cyclohexane, 7.5 mL, 10.5 mmol, 1.05 equiv) in THF (25
1
mL), N,Nꢀdiethylꢀ3ꢀmethoxybenzamide (2.07 g, 10.0 mmol, 1.0 equiv) in THF (10 mL), and
TMSCl (4.0 mL, 31.5 mmol, 3.15 equiv). After standard workup, the residue was purified via
column chromatography using pentane/Et O (5/1 to 3/1 to 1/1 gradient). The title compound was
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isolated as a pale yellow solid (2.12 g, 76%). Mp 51ꢀ52 °C (hexanes, lit. 54ꢀ55 °C [hexanes]);
1
H NMR (400 MHz, CDCl )  7.30 (t, J = 8.1 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 7.5
3
Hz, 1H), 3.79 (s, 3H), 3.61 (br s, 1H), 3.40 (br s, 1H), 3.21 (br s, 1H), 3.13 (br s, 1H), 1.24 (t, J =
10
11
12
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14
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50
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53
54
55
56
57
58
59
60
13
7
.2 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H), 0.24 (s, 9H); C NMR (100 MHz, CDCl )  0.4, 12.7,
3
1
3.6, 38.9, 43.3, 55.1, 109.7, 118.8, 124.3, 130.4, 144.5, 164.8, 171.7.
N,N-Diethyl-6-iodo-3-methoxy-2-trimethylsilyl-benzamide (1l):
The title compound was synthesized according to general procedure A using TMEDA (335 µL,
2
.23 mmol, 1.3 equiv), sꢀBuLi (1.4M in cyclohexane, 1.5 mL, 2.1 mmol, 1.2 equiv) in THF (10
mL), 1k (480 mg, 1.72 mmol, 1.0 equiv) in THF (10 mL), and I (570 mg, 2.25 mmol, 1.3 equiv)
2
in THF (2 mL). After standard workup, with an additional wash with sodium thiosulfate (sat., 20
mL), the residue was purified via column chromatography using pentane/Et O (5/1 to 3/1
2
gradient). The title compound was isolated as a colorless solid (556 mg, 80%): Mp 108ꢀ109 °C
36 1
(Et O, lit. 100ꢀ101 °C [hexanes]); H NMR (400 MHz, CDCl )  7.73 (d, J = 8.7 Hz, 1H), 6.55
2
3
(
d, J = 8.7 Hz, 1H), 3.93 (sex, J = 6.7 Hz, 1H), 3.78 (s, 3H), 3.01ꢀ3.27 (m, 3H), 1.30 (t, J = 7.2
1
3
Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H), 0.24 (s, 9H); C NMR (100 MHz, CDCl )  0.4, 12.0, 13.1,
3
3
8.9, 43.0, 55.3, 84.3, 111.8, 127.5, 141.2, 147.5, 164.8, 170.1.
N,N-Diethyl-2'-methylbiphenyl-2-carboxamide (3a):
The title compound was synthesized according to general procedure E using 1a (2.42 g, 10.9
mmol, 1.4 equiv), 2a (1.21 g, 7.1 mmol, 1.0 equiv), 2M aqueous K CO (20 mL, 40.00 mmol, 5.6
2
3
equiv), Pd(PPh ) (246 mg, 0.213 mmol, 3.0 mol%) in 35 mL of dimethoxyethane and 5 ml
3
4
ethanol. After standard workup, the residue was purified via column chromatography using
heptane/Ethyl acetate (2/1) to afford the title product as a colorless oil that solidifies (1.74 g, 89%
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
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4
4
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5
5
5
5
5
5
6
30
1
yield): Mp 65ꢀ66.5 °C (cyclohexane, lit. 67ꢀ68 °C [hexanes] ); H NMR (400 MHz, DMSOꢀd ,
6
7
0 °C)  7.36ꢀ7.48 (m, 2H), 7.28ꢀ7.35 (m, 1H), 7.18ꢀ7.28 (m, 3H), 7.05ꢀ7.17 (m, 2H), 3.18 (br s,
1
3
2H), 2.93 (br s, 2H), 2.13 (s, 3H), 0.88 (br s, 3H), 0.67 (br s, 3 H); CꢀNMR (100 MHz, DMSOꢀ
d6)  12.2, 14.0, 20.4, 37.9, 42.5, 125.4, 126.6, 127.7, 128.0, 128.6, 129.9, 130.3, 130.5, 136.2,
0
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9
0
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2
3
4
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8
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0
+
+
1
37.8, 138.3, 139.7, 169.4; MS (EI, DIP) m/z 267 (M , 22), 266 (22), 195 (M , 100), 167 (40),
ꢀ1
+
1
65 (69), 152 (45); FTIR (KBr, cm ) 2965, 1631, 1428, 755; HRMS (EIꢀTOF) m/z: [M] for
C H NO calcd 267.1623, found 267.1635.
18
21
N,N-Diethyl-3-methoxy-2',3'-dimethylbiphenyl-2-carboxamide (3c):
Compound 1c was synthesized according to general procedure A using TMEDA (2.7 mL, 18.0
mmol, 1.20 equiv), sꢀBuLi (1.23 M in cyclohexane, 14.6 mL, 18.0 mmol, 1.20 equiv) in THF (30
mL), N,Nꢀdiethylꢀ2ꢀmethoxybenzamide (3.1 g, 15.0 mmol, 1.0 equiv) in THF (30 mL), and
triisopropylborate (8.3 mL, 36 mmol, 2.4 equiv). After standard workup (quench with sat. aq.
NH Cl and ether extraction) the crude 1c (3.94 g, 104%) was isolated and used in the next step
4
without further purification.
The title compound 3c was synthesized according to general procedure E using 1c (3.94 g, 15
mmol, 1.5 equiv), 2b (1.83 g, 9.89 mmol, 1.00 equiv), 2M aqueous Na CO (40 mL), Pd(PPh )
3 4
2
3
(
347 mg, 0.3 mmol, 3.0 mol%) in 40 mL of dimethoxyethane. After standard workup, the residue
was purified via column chromatography using heptane/ethyl acetate (2/1) to afford the title
1
product as a colorless oil that solidifies (2.28 g, 74% yield): Mp 123ꢀ124 °C (cyclohexane); H
NMR (400 MHz, CDCl a mixture of two rotamers major (A) and minor (B))  7.26ꢀ7.38 (A +
3
,
B, m, 3H), 7.03ꢀ7.14 (A + B, m, 3H), 7.00 (B, t, J = 7.5 Hz, 1H), 6.88ꢀ6.94 (A + B, m, 2H), 6.85
A, d, J = 4.2 Hz, 1H), 6.84 (B, d, J = 4.4 Hz, 1H), 6.79 (B, d, J = 7.6 Hz, 1H), 3.86 (B, s, 3H),
(
3
.85 (A, s, 3H), 3.78 (A + B, sex, J = 6.8 Hz, 2H), 3.26 (A, sex, J = 7.1 Hz, 1H), 3.10 (B, sex, J =
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7.0 Hz, 1H), 2.65ꢀ2.97 (A + B, m, 4H), 2.28 (B, s, 3H), 2.27 (A, s, 3H), 2.08 (B, s, 3H), 2.06 (A,
4
5
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1
1
1
1
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1
1
1
2
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2
2
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2
2
2
2
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4
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3
s, 3H), 1.03 (A, t, J = 7.1 Hz, 3H), 0.88 (B, t, J = 7.1 Hz, 3H), 0.52ꢀ0.67 (A + B, m, 3H);
NMR (100 MHz, CDCl )  11.5, 11.6, 13.5, 13.5, 17.0, 17.3, 20.4, 20.5, 37.3, 37.5, 42.1, 42.4,
C
3
0
1
2
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4
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8
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2
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4
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8
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2
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7
8
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9
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2
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4
5
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7
8
9
0
5
5.3, 55.6, 109.2, 109.3, 122.0, 123.2, 124.0, 124.9, 125.8, 126.0, 126.4, 128.3, 128.8, 128.9,
1
28.9, 129.0, 133.2, 136.0, 136.4, 136.8, 138.3, 139.4, 139.7, 141.1, 155.2, 155.9, 167.2, 167.4;
+
MS (EI, DIP) m/z 311 (M , 2), 280 (2), 239 (100), 224 (7), 196 (10), 181 (7), 165 (12), 152 (8);
+
FTIR (KBr, cmꢀ1) 2980, 2930, 1627, 1461, 1285, 1256, 1067; HRMS (EIꢀTOF) m/z: [M] for
C H NO calcd 311.1885, found 311.1879.
20
25
2
N,N-Diethyl-6-methoxy-2',3'-dimethylbiphenyl-2-carboxamide (3d):
The title compound was synthesized according to general procedure D using 1e (400 mg, 1.40
mmol, 1.0 equiv), 2d (300 mg, 2.00 mmol, 1.4 equiv), K PO (1.40 g, 6.60 mmol, 4.7 equiv),
3
4
Pd dba (32 mg, 0.035 mmol, 2.5 mol%) and SPhos (32 mg, 0.080 mmol, 5.7 mol%) in 10 mL
2
3
toluene. After standard workup, the residue was purified via column chromatography using
hexanes /EtOAc (3/1 to 1/1 gradient) to afford the title product as a colorless oil (310 mg, 71%
1
yield): H NMR (400 MHz, 70 °C, d ꢀDMSO)  7.40 (t, J = 7.9 Hz, 1H), 7.09 (t, J = 8.4 Hz,
6
2
H), 6.99 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.4 Hz, 2H), 3.70 (s, 3H), 2.75ꢀ3.30 (m, 4H), 2.25 (s,
1
3
3H), 1.93 (s, 3H), 0.91 (br s, 3H), 0.61 (br s, 3H); C NMR (100 MHz, 70 °C, d ꢀDMSO) 
6
1
1.0, 13.0, 15.8, 19.4, 36.6, 41.4, 55.1, 110.7, 117.3, 123.7, 126.8, 128.1 (2C), 134.9, 138.4,
+
1
56.1, 167.9; MS (EI, DIP) m/z 311 (M , 29), 239 (83), 238 (100), 224 (24), 209 (6), 195 (11),
ꢀ1
181 (13), 165 (16), 152 (13); FTIR (KBr, cm ) 2970, 2931, 1634, 1457, 1427, 1314, 1296, 1059;
+
HRMS (EIꢀTOF) m/z: [MꢀH] for C H NO calcd 310.1807, found 310.1795.
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N,N-Diethyl-6-methoxy-2'-methylbiphenyl-2-carboxamide (3e):
The title compound was synthesized according to general procedure D using 1f (1.44 g, 4.08
mmol, 1.0 equiv), 2c (832 mg, 6.11 mmol, 1.5 equiv), K PO (3.46 g, 16.30 mmol, 4.0 equiv),
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Pd dba (85 mg, 0.093 mmol, 2.3 mol%) and SPhos (135 mg, 0.33 mmol, 8.0 mol%) in 35 mL
2
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of toluene. After standard workup, the residue was purified via column chromatography using
pentane /Et O (1/1) to afford the title product as a colorless oil that solidifies (1.01 g, 82% yield).
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Physical and spectral data are in agreement with those reported: Mp 110.5ꢀ112.5 °C (hexanes /
3
0
1
Et O, lit. 105ꢀ107 °C [hexane] ); H NMR (400 MHz, DMSOꢀd , 70 °C)  7.41 (t, J = 8.0 Hz,
2
6
1H), 7.15ꢀ7.22 (m, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.98ꢀ7.06 (m, 1H), 6.88 (d, J = 7.5 Hz, 1H),
1
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3.71 (s, 3H), 2.70ꢀ3.35 (m, 4H), 2.04 (s, 3H), 0.93 (br s, 3H), 0.61 (t, J = 6.0 Hz, 3 H); CꢀNMR
(100 MHz, DMSOꢀd , 70 °C)  12.1, 14.0, 20.0, 37.6, 42.4, 56.2, 111.8, 118.3, 125.2, 127.7,
6
ꢀ1
1
29.3, 129.6, 135.9, 137.6, 139.4, 157.1, 168.9; FTIR (KBr, cm ) 2971, 2932, 1632, 1460, 1427,
+
1
296, 1256, 1059; MS (EI, DIP) m/z 297 (M , 48), 225 (100), 224 (90), 210 (45), 181 (27), 166
+
(42), 152 (29), 84 (55); HRMS (EIꢀTOF) m/z: [M] for C H NO calcd 297.1729, found
1
9
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297.1718.
N,N-Diethyl-5-methoxy-2',3'-dimethylbiphenyl-2-carboxamide (3g):
The title compound was synthesized according to general procedure C using 1h (143 mg, 0.50
mmol, 1.0 equiv), 2d (225 mg, 1.50 mmol, 3.0 equiv), 2M aqueous K CO (1.5 mL, 3.00 mmol,
2
3
6
.0 equiv), Pd(dppf)Cl *CH Cl (20 mg, 0.024 mmol, 4.9 mol%) in 5 mL of dioxane. After
2 2 2
standard workup, the residue was purified via column chromatography using hexanes/EtOAc (9/1
1
to 5/1 gradient) to afford the title product as a colorless oil (110 mg, 71% yield); H NMR (400
MHz, CDCl , one aromatic proton exhibits a very broad peak and is only visible when the
3
spectrum intensity is increased)  7.29 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.04 (t, J =
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7.5 Hz, 1H), 6.92 (dd, J = 2.5, 8.4 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 3.82 (s, 3H), 2.40ꢀ3.75 (m,
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H), 2.29 (s, 3H), 2.11 (s, 3H), 0.89 (br s, 3H), 0.67 (br s, 3H); C NMR (100 MHz, CDCl ) 
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11.7, 13.7, 17.1, 20.5, 37.9, 42.5, 55.3, 112.7, 115.5, 124.6, 127.5, 129.1, 129.7, 136.9, 159.1,
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70.2 MS (EI, DIP) m/z 311 (M , 11), 240 (100), 211 (24), 196 (42), 165 (24), 153 (25); FTIR
ꢀ1
+
(
KBr, cm ) 2934, 1633, 1455, 1379, 1288, 1223, 1109, 1035; HRMS (EIꢀTOF) m/z: [MꢀH] for
C H NO calcd 310.1807, found 310.1792.
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N,N-Diethyl-4-methoxy-3-trimethylsilyl-2',3'-dimethylbiphenyl-2-carboxamide (3h):
Compound 1i was synthesized according to general procedure A using TMEDA (3.1 mL, 20.7
mmol, 1.30 equiv), sꢀBuLi (1.23 M in cyclohexane, 16.8 mL, 20.7 mmol, 1.30 equiv) in THF (40
mL), 1k (4.45 g, 15.9 mmol, 1.0 equiv) in THF (30 mL), and triisopropylborate (11.0 mL, 47.8
mmol, 3.0 equiv). After standard workup (quench with sat. aq. NH Cl and ether extraction) the
4
crude 1i (5.32 g, 103%) was isolated and used in the next step without further purification.
The title compound 3h was synthesized according to general procedure E using 1i (5.32 g, 15.9
mmol, 1.4 equiv), 2b (2.09 g, 11.3 mmol, 1.00 equiv), 2M aqueous Na CO (40 mL), Pd(PPh )
3 4
2
3
(
394 mg, 0.34 mmol, 3.0 mol%) in 80 mL of dimethoxyethane. After standard workup, the
residue was purified via column chromatography using heptane/ethyl acetate (6/1) to afford the
1
title product as a colorless oil that solidifies (3.59 g, 83% yield); Mp 95ꢀ96 °C (cyclohexane); H
NMR (400 MHz, CDCl a mixture of two rotamers major (A) and minor (B))  7.08ꢀ7.15 (B, m,
3
,
1
H), 7.03 (A, d, J = 8.5 Hz, 1H), 6.98 (B, d, J = 8.3 Hz, 1H), 6.93 (A + B, d, J = 7.2 Hz, 2H),
.89 (B, d, J = 7.5 Hz, 1H), 6.84 (A, t, J = 7.8 Hz, 1H), 6.75 (A, d, J = 7.5 Hz, 1H), 6.72 (A, d, J
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= 4.2 Hz, 1H), 6.70 (B, d, J = 4.3 Hz, 1H), 3.71 (A, s, 3H), 3.70 (B, s, 3H), 3.50ꢀ3.65 (A + B, m,
2
H), 3.02 (B, sex, J = 7.0 Hz, 1H), 2.91 (A, sex, J = 7.0 Hz, 1H), 2.65 (B, sex, J = 7.1 Hz, 1H),
.54 (A, sex, J = 7.0 Hz, 1H), 2.46 (A, sex, J = 6.5 Hz, 1H), 2.35 (B, sex, J = 6.5 Hz, 1H), 2.15
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