The Directed ortho Metalation (D o M)-Cross-Coupling Connection: Synthesis of Polyfunctional Biaryls

Article abstract of DOI:10.1055/s-0037-1610273

A comparative evaluation of the combined directed ortho metalation (D o M)-Suzuki-Miyaura and D o M-Negishi cross-coupling reactions with aryl triflates for the synthesis of substituted biaryls is described. Both ortho -zinc and ortho -boron aryl directed

Full text of DOI:10.1055/s-0037-1610273

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–P
paper
A
en
C. A. Quesnelle, V. Snieckus
Paper
Synthesis
The Directed ortho Metalation (DoM)–Cross-Coupling Connection:
Synthesis of Polyfunctional Biaryls
Claude A. Quesnelle1
DMG1
DMG1
M
G1
G1
Victor Snieckus*
Ni or Pd
catalyst
+
TfO
G2
G2
Queen’s University, Department of Chemistry, Kingston, ON,
K7L 3N6, Canada
snieckus@chem.queensu.ca
DMG2
DMG2
M = B(OH)2, MgX, ZnX
DMG1, DMG2 = CONR2, OCONR2, OMOM, NHBoc
Dedicated to Scott Denmark, a man for all seasons in organic
chemistry.
Published as part of the Special Section dedicated to Scott E. Den-
mark on the occasion of his 65th birthday.
Received: 09.07.2018
Accepted after revision: 21.08.2018
Published online: 05.10.2018
DMG1
M
DMG1
G1
G1
Ni or Pd
catalyst
+
LG
DOI: 10.1055/s-0037-1610273; Art ID: ss-2018-c0465-op
G2
G2
DMG2
DMG2
Abstract A comparative evaluation of the combined directed ortho
metalation (DoM)–Suzuki–Miyaura and DoM–Negishi cross-coupling
reactions with aryl triflates for the synthesis of substituted biaryls is de-
scribed. Both ortho-zinc and ortho-boron aryl directed metalation group
(DMG = CON(i-Pr)2, OCONEt2, OMOM, NHBoc) substrates were evaluat-
ed. The superiority of the DoM–Negishi over the DoM–Suzuki–Miyaura
reaction in operational convenience and mild reaction conditions is not-
ed. Orthogonal Negishi and Suzuki–Miyaura with Corriu–Kumada reac-
tions for the synthesis of a teraryl derivative is also reported.
1
2
3
M = B, Mg, Zn, Sn, Si
DMG1, DMG2 = CONR2, OCONR2, OMOM, OP(O)(NR2)2
LG = I, Br, OTf
NHBoc (Piv), SO2NR2, P(O)R2, F (among others)
Nu–
+
E1
b
E1
a
–
DMG
Nu
E2
+
–
–
+
G
G
G
E2
a
4
5
6
Key words Suzuki–Miyaura coupling, Negishi coupling, cross-cou-
pling, directed ortho metalation
a: via DoM
b: via cross-coupling
aryl 1,2-dipole
synthon
Scheme 1 The DoM–cross-coupling nexus
The vast power of the transition-metal-catalyzed cross-
coupling reactions2 inherent in the Suzuki–Miyaura, Negi-
shi, Corriu–Kumada, Stille, and, most recently, Hiyama reac-
tions for the formation of aryl–aryl bonds stimulated our
research to establish synthetic links between these name
reactions and the directed ortho metalation (DoM) strate-
gy.3,4 In conceptual form, this involves an ortho-M directed
metalation group (DMG)1 substrate 1 undergoing a cross-
coupling reaction with an ortho-leaving group (LG) DMG2
derivative 2 leading to the formation of the biaryl product 3
(Scheme 1). A plethora of DMG1–DMG2 combinations are
available,3 a major selection of which is depicted in Table 1.
Advantageous for synthesis is the fact that the combina-
tions may be increased by inversion of the M and LGs in
partners 1 and 2. Further synthetic utility is derived from
the recent establishment by Knochel’s group of esters and
nitriles, groups sensitive to strong base conditions, as DMGs
for ortho-zincation either directly or indirectly via magnesi-
ates formed using the Grignard–LiCl (turbo Grignard) re-
agent.5 These species act as Corriu–Kumada and Negishi
coupling partners to form biaryls.
The value of these combined DoM–cross-coupling pro-
tocols is considerably enhanced by the discovery that cer-
tain DMGs also serve as surrogate leaving groups (4, DMG =
O-carbamate,6 O-sulfamate,7 sulfonamide8) in Ni- or Pd-cat-
alyzed Suzuki–Miyaura and Corriu–Kumada reactions, ef-
fectively creating opportunity for the construction of 1,2,3-
trisubstituted aromatics 5 and representing a conceptual
aryl 1,2-dipole (benzyne) equivalent 6. Furthermore, these
coupling reactions of DMG-bearing substrates may be ex-
plored in orthogonal Suzuki–Miyaura reactions and some
other coupling modes.7,8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

B
C. A. Quesnelle, V. Snieckus
Paper
Synthesis
Table 1 Combined DoM–Cross-Coupling Reactionsa
widely applied aryl ester coupling D14b and it, together with
the Corriu–Kumada (C-K) method, is demonstrated in or-
thogonal fashion in a teraryl synthesis E.8 A still rare exam-
ple of use of bis-DMG-facilitated S-M coupling reactions is
shown in a more complex teraryl F49 synthesis. Selected ex-
amples of use of the DoM–cross-coupling procedure2 in
bioactive molecule synthesis may be illustrated by the syn-
thesis of a serine protease inhibitor G50 which involves both
N or S-M methods, a CRF receptor antagonist H51 and Losar-
tan (I),52 the latter representing the largest scale S-M com-
mercial production process. An instructive example of the
use of DoM, S-M coupling, and DreM reactions is the kg-
scale production of MK-7285 (J).53 Moreover, the natural
products synthesis field has witnessed significant use of
this combined strategy, inter alia, the synthesis of a mixed
biogenesis origin molecule K54 and the alkaloid L55 (also in-
volving a DreM step). Similarly, the materials science area
has seen numerous applications, with an early example be-
ing the large-scale synthesis of liquid crystal substance M
by the S-M protocol.56 The polycyclic aromatic hydrocarbon
(PAH) class, especially as it relates to environmentally toxic
materials, has received attention,42a as demonstrated in the
DoM–C-K synthesis of a PAH precursor N.57
DMG1
DMG1
G1
G1
Ni or Pd
catalyst
+
M
LG
G2
G2
DMG2
DMG2
1
2
3
DMG1
DMG2
Mb
B(OR)2 MgX ZnX
SnR3 SiR3
9
c, 10
11
12
CONR2
H, OMe,
OMOM
☑
?
☑
☑
☑
13
17
14
10
18
CO2R
Oxd
H, F
H
?
☑
?
☑
☑
☑
?
?
15
16
☑
☑
?
?
19
12
OMe
H, CONR2,
OMe
☑
☑
☑
c, 20
c,
c, 10
c, 22
12
12
OMOM
H, OMOM
☑
☑
?
?
☑
☑
?
?
☑
☑
OCONR2
H, SO2NR2,
CONR2, F, Cl
6b,21
6c,7
7
OSO2NR2
H
☑
☑
☑
☑
☑
☑
☑
☑
?
?
?
X
?
23
c, 26
28
24,25
OP(O)(NR2)2
NHBoc (NHPiv)
SO2NR2
H
☑
☑
?
?
c
27
31
37
12
H
?
☑
?
☑
?
8
H
☑
☑
?
In the prequel,58 we presented a comparative study of
the C-K, N, and S-M cross-coupling reactions and evaluated
them on the basis of efficacy and operational ease. We
showed that the N and S-M tactics have considerable ad-
vantage over the C-K process in terms of yields, tolerance of
functional groups, and smooth reactivity. Aside from fur-
nishing biaryl products with enriched functional group
substitution patterns, the 2,2′-positioned DMGs allow im-
mediate consideration of potential further DoM and DreM
reactivity.
29
30
SO2R
H, OMe
?
☑
?
?
32
33
P(O)R2/P(O)(OR)2
F
H
H
☑
☑
?
34
35
18a,36
☑
☑
?
a In addition to aryl and heteroaryl coupling partners, included are perti-
nent indole N-DMG derivatives.
b Check mark = reaction successful; X = reaction failed or unknown; ? = re-
action not reported.
c This work.
d Ox = 2-oxazolidinyl.
Our original observations, involving the DoM–Suzuki–
Miyaura cross-coupling process for the synthesis of biar-
yls,38 subsequently encompassed the preparation of polyar-
yls,39 heteroaromatics,26a and phenanthridines40 and was
extended, as a consequence of the directed remote metala-
tion (DreM) variation,41 to include 9-phenanthrols,42 fluo-
renones,43 and dibenzopyranones.44,45 The categories of
combinations of DMGs–metal substrates for cross-coupling
with various LG partners (Table 1) show the paucity of sys-
tematic studies for the 1 (DMG1) with 2 (DMG2) partner
combinations.46
Over the years, the DoM–cross-coupling two-step se-
quence has become a dominant synthetic strategy for the
construction of biaryl and heterobiaryl molecules,47 and
found application in the commercial production of medici-
nal and agrochemical agents, and materials science mole-
cules. Figure 1 depicts representative small- and large-scale
synthesis examples of molecules prepared by the DoM– and
DreM–cross-coupling protocols. Thus, application of a
DoM–Suzuki–Miyaura (S-M) sequence may be seen in sim-
ple azabiaryl A,9b saccharin B,48 and bisazabiaryl C22 prepa-
ration. The Negishi (N) link is demonstrated in yet not
Herein, we build on preliminary observations previous-
ly reported59 and report extensive evaluation of the conver-
gent DoM–N and DoM–S-M protocols for the construction
of carbon- and heteroatom-based DMG biaryls. The meth-
odology offers ready access to biaryls with potential for en-
suing aromatic ring reactivity in the construction of highly
substituted biaryls and condensed polycyclic aromatic com-
pounds.
To initiate the study, we compared the N and S-M cross-
coupling reactions of several widely used DMG substrates3
with selected vinyl, aryl, and heteroaryl triflates60 (Table 2).
The ortho-ZnCl intermediates were prepared by transmeta-
lation of corresponding ortho-lithiated species obtained by
DoM reactions and used in situ; the ortho-boronic acids
were likewise obtained by borylation with B(OEt)3 of the
ortho-lithiated species and used in crude form in the cross-
coupling experiments. Comparative coupling reactions of
ortho-metalated aryl DMG = CON(i-Pr)2 substrate 8 with vi-
nyl triflate 7 (entry 1) show similar yields of product 9 from
the N and S-M reactions if refluxing conditions are used in
the former reaction (compare conditions A and B). The
comparison of the two methods for the coupling of 8 with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

C
C. A. Quesnelle, V. Snieckus
Paper
Synthesis
OMe
Cl
O
OMe
DoM-
N
NH
CO2Et
DoM
SO2
DoM-
S-M
DoM-
N
N
Et2NOCO
Ar
DoM-
N
D
DoM-
S-M
N
F
A
N
CN
B
C
TBS
C-K
E
(90%)
O
NEt2
DoM-
DoM-
Halogen Dance
S-M or N
O
O
S-M
Me
N
O
N
OMe
O
DoM-
S-M
Ph
O
SO2NHtBu
O
G
Cl
O
OBn
OMe NEt2
DoM-
S-M
Teraryl
Serine Protease
Factor Xa Inhibitor
(S-M: 58%, N: 83%)
NEt2
H
F
CRF Receptor Antagonist
MOMO
DoM-
N
K+
N
N
NC
n-Bu
OMOM
OH
N
N
N
N
F
N
N
H
O
NC
Cl
K
OH
O
O
J
DoM-
S-M
I
DreM
Antiinflammatory
DoM-
S
37%
(Monoterpenylmagnolol)
Losartan®
C5H11
DoM
TMS
DoM
OMe
OMe
O
MeO
MeO
F
F
OMOM
DoM
C-K
NH
DreM
S-M
DoM-
S-M
OMe
OMe
L
Liquid Crystal
(63%)
N
Merck Darmstadt
Piperolactam
(Piper species)
PAH
(88%)
C3H7
M
DoM = Directed ortho Metalation; C-K = Corriu-Kumada; S-M = Suzuki-Miyaura; N = Negishi
Figure 1 Combined DoM–cross-coupling reactions for biological and materials science molecules
5-indolyl triflate 10 (entry 2) favoured the N process for the
synthesis of heterobiaryl 11 although the yield of the S-M
reaction is augmented if one considers the considerable
amount of the isolated N-desilylated product 28 (Figure 2).
Coupling of the metalated benzamides 8 with the readily
available dimethyluracilyl triflate 12 (entry 3) failed for the
Ni-catalyzed N reaction (conditions A) but provided a very
good yield of product 13 under Pd-catalyzed conditions
(conditions D) while the S-M process proceeded in modest
yield. Turning attention to the ortho-metalated O-aryl car-
bamate species 21 (entry 7), representing the highest-pow-
er DMG substrates,3,61 the two coupling methods fared
equally well to give high yields of product 22. Investigation
of the ortho-metalated N-Boc-anilines 24 (entry 8) showed
clear superiority of the S-M procedure for the formation of
product 25 (compare conditions A and C). Compound 24,
M = B(OH)2 was one of the first ortho-DMG arylboronic ac-
ids investigated26a,40 and has been widely applied in syn-
thetic work.3,4,26
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D
C. A. Quesnelle, V. Snieckus
Paper
Synthesis
Table 2 Comparison of Cross-Coupling Reactions Connected to DoM
Entry
Triflate
Ar-M
Product
Yield (%)a, conditionsb
M = B(OH)2
M = ZnCl
CON(i-Pr)2
TfO
CON(i-Pr)2
20, A
50, B
1
62, C
M
8
7
9
CON(i-Pr)2
TfO
CON(i-Pr)2
2
75, A
18,c C
N
10
M
8
TBS
11
N
TBS
CON(i-Pr)2
O
O
CON(i-Pr)2
TfO
0, A
83, D
NMe
3
4
5
6
44, C
94, C
81, C
–
NMe
O
M
8
N
O
13
N
12
Me
Me
CON(i-Pr)2
CON(i-Pr)2
TfO
81, A
67, A
51, A
14
M
8
15
CON(i-Pr)2
TfO
TfO
CON(i-Pr)2
M
8
16
H3C
17
CON(i-Pr)2
CON(i-Pr)2
M
8
19
18
OMe
OMe
OCONEt2
TfO
O
OCONEt2
7
O
92, A
91, C
20
M
21
22
NHBoc
TfO
OMe
OMe
NHBoc
OMe
8
9
8, A
66, C
81, C
24
M
23
25
OCONEt2
OCONEt2
CONEt2
TfO
CONEt2
–
OMe
23
M
26
27
a Yield of chromatographically pure material.
b Reaction conditions: A: Ni(acac)2, PPh3, MeMgBr, THF, rt; B: Ni(acac)2, PPh3, MeMgBr, THF, reflux; C: Pd(PPh3)4, DME, EtOH, 2 M Na2CO3, reflux; D:
Pd(PPh3)4, THF, rt, reflux.
c Compound 28 (Figure 2) was also obtained, in 36% yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

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C. A. Quesnelle, V. Snieckus
Paper
Synthesis
idyl partners 29, 32, and 34 proceeded cleanly and afforded
consistently high yields of the corresponding biaryl and
heterobiaryl products 31, 33, and 36, respectively (entries
1–3). Comparison of aryl triflate vs aryl bromide (entries 3
and 4) showed no difference in efficiency of the reaction.
The coupling of ortho-ZnX O-aryl carbamates 37 and 40
with amide and O-carbamate triflates 29 and 39 also pro-
ceeded well to afford biaryls 38 and 41 (entries 5 and 6),
molecules clearly poised for additional DoM and DreM reac-
tions.3,41 ortho-ZnX aryl OMOM species 43, bearing this
popular DMG,61a underwent coupling with naphthyl, ben-
zoate, benzamide, and O-aryl carbamate substituted tri-
flates, 42, 45, 29, and 39, respectively, to furnish products
44, 46, 47, and 48, respectively, in satisfactory to high yields
(entries 7–10).62
CON(i-Pr)2
N
H
28
Figure 2 Side product from the reaction of Entry 2
As gleaned from Table 2, although the N and S-M proto-
cols are at times equally efficacious, the mildness of the N
reaction conditions and our wish to enhance its utility
prompted further investigation of a variety of aryl triflate–
ortho-ZnX DMG-bearing aromatic substrate coupling reac-
tions, some of which present both coupling partners with
DMGs and some with sensitive functional groups (Table 3).
As in the above study, starting with substrate 30 bearing
DMG = CON(i-Pr)2, N coupling with amide, fluoro, and pyr-
Table 3 Cross-Coupling of Organozinc Reagents with Triflates under Nickel Catalysis
Entry
1
Triflate
TfO
R-ZnX
Product
Yield (%)a
92
CON(i-Pr)2
CONEt2
31
CON(i-Pr)2
CONEt2
ZnCl
29
30
CON(i-Pr)2
TfO
F
CON(i-Pr)2
F
2
90
ZnCl
30
32
33
X
CON(i-Pr)2
CON(i-Pr)2
3
4
X = OTf 89
X = Br 94
N
ZnCl
30
X = OTf 34
= Br 35
36
N
OCONEt2
OCONEt2
ZnCl
TfO
CONEt2
CONEt2
5
6
74
92
29
37
38
OMe
OMe
OCONEt2
OMOM
TfO
OCONEt2
OCONEt2
ZnCl
OCONEt2
39
40
41
TfO
OMOM
ZnCl
7
8
68
73
43
43
42
44
OMOM
TfO
OMOM
ZnCl
CO2Et
45
46
CO2Et
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

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C. A. Quesnelle, V. Snieckus
Paper
Synthesis
Entry
9
Triflate
R-ZnX
Product
Yield (%)a
92
OMOM
OMOM
TfO
CONEt2
OMOM
ZnCl
CONEt2
43
43
29
47
TfO
OCONEt2
OMOM
ZnCl
OCONEt2
10
69
39
48
a Yield of chromatographically pure material.
The susceptibility of cross-coupling reactions to steric
factors has been well documented.63,64 Typically, the greater
the steric encumbrance around the C–LG bond undergoing
oxidative addition, the harsher the reaction conditions re-
quired, with the possibility of concomitant reduced yields
of the coupled products. Thus, whereas both N and S-M
coupling of ortho-metalated benzamides 8 (Table 2, entry 4)
proceeded smoothly with phenyl triflate (14) to give prod-
uct 15 with excellent yields, 2-tolyl triflate (16, entry 5) and
2,6-dimethylphenyl triflate (18, entry 6) show the trend of
decreasing yields as a function of increasing substitution.65
Curiously, N,N-diethylbenzamide, upon DoM reaction
using our standard s-BuLi/TMEDA conditions followed by
transmetalation with ZnCl2 and N coupling with 51 failed to
afford the cross-coupled product 52 (Scheme 2). With the
expectation that TMEDA acts as a ligand in the Pd- and Ni-
catalyzed cross-coupling step, the ortho-zinc species 50 was
generated under sequential t-BuLi/ZnCl2 conditions from 49
and subjected to Ni-catalyzed coupling reaction with tri-
flate 51 (Scheme 2). In contrast to the same reaction on the
corresponding diisopropylamide 30, the reaction failed to
give product 52 and resulted in the formation of complex
intractable mixtures of products for reasons currently un-
known. Clearly, this problem is not faced in the S-M cou-
pling reaction in view of the isolation of the metalation–bo-
ronation intermediate prior to the subjection to the cross-
coupling conditions, as demonstrated in many of the tabu-
lated S-M reactions (Table 2, entries 1–5, 7, and 8) and the
cross-coupling of 26 with triflate 23 to afford polyfunction-
alized biaryl 27 in high yield (entry 9).
Recent studies have shown that orthogonal cross-cou-
pling reactions for the construction of biaryl and polyaryl
derivatives are feasible, synthetically useful strate-
gies.6c,8,49,66 In the present study, teraryl derivative 57 was
synthesized by initial generation of the zinc and boronic
acid precursors 30 and 53, respectively, which, upon cou-
pling with aryl triflate 54, led to biaryl 55 in similar yields
(Scheme 3). Taking advantage of the C-K reaction on O-aryl
carbamates,6a treatment of 55 with commercially available
o-tolyl Grignard reagent 56 under Ni-catalyzed conditions
furnished compound 57 in modest yield.
TfO
CON(i-Pr)2
CON(i-Pr)2
54
OCONEt2
Pd(PPh3)4
M
M = ZnCl 30
= B(OH)2 53
M = ZnCl 51%
= B(OH)2 48%
OCONEt2
55
CH3
CON(i-Pr)2
MgBr
CH3
56
Ni(acac)2, Et2O
(38%)
57
Scheme 3 Synthesis of a teraryl via DoM and cross-coupling reactions
In conclusion, the present work illustrates the power of
the DoM–cross-coupling combination of reactions for the
regioselective construction of diversely substituted biaryls.
Our study has compared the metalation-derived ortho-zinc
and ortho-boron DMG-bearing aromatics in the N and S-M
coupling reactions, respectively, with a variety of aryl tri-
flates under Ni-catalyzed conditions (Table 2). In view of
their considerable utility in synthesis,3,4 we have focused on
the CON(i-Pr)2, OCONEt2, OMOM, and NHBoc DMG sub-
strates, and only the last DMG-comporting compound
failed to give a satisfactory cross-coupling result in the S-N
process (Table 2, entry 8). A complementary DoM–acylative
Negishi cross-coupling sequence has been reported by Ev-
ans and co-workers10 involving Pd-catalyzed couplings of
ortho-zinc oxazolino, CON(i-Pr)2, OMOM, and CH2NEt2
CONEt2
CONEt2
Br
CONEt2
ZnCl
a
b
OMe
49
50
52
TfO
OMe
51
Scheme 2 Reagents and conditions: (a) 1. t-BuLi, THF, –78 °C; 2. ZnCl2,
–78 °C → rt; (b) 51, Ni(acac)2, PPh3, EtMgBr.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

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C. A. Quesnelle, V. Snieckus
Paper
Synthesis
DMG-bearing aromatic substrates and this report notes the
failures of several other DMGs and the inferiority of the last
DMG compared to the other three DMGs as expected from
the hierarchical power of the DMGs.3,67 Koch and co-work-
ers only showed functionalized aromatics bearing oxazoli-
no and CON(i-Pr)2 DMGs in Negishi biaryl synthesis but,
significantly, demonstrated the tolerance of NO2 and CO2R
functional groups in the aryl triflate coupling partner. Our
work indicates the equality of DMG = CON(i-Pr)2, OCONEt2,
OMOM substrates and, to a lesser degree, NHBoc in serving
for cross-coupling reactions and the eminence of all four
DMGs over DMG = oxazolino based on the evaluation with
the reported data.67
In the comparison of the DoM–N and DoM–S-M con-
junctions, our study reveals the general superiority of the
former in yields of products (e.g., Table 2, entries 2 and 3;
however, there are exceptions in which the S-M is superior:
e.g., Table 2, entries 8 and 9), in its recognized functional
group tolerance towards CHO, COR, CN, CO2R, CONR2, and
halide groups68 (e.g., Table 3, entries 2 and 8), and in the
mild reaction conditions and convenience of operation. To
reiterate,59 mildness of conditions and functional group
compatibility provide some advantages of the N over the S-
M coupling methods. However, as pertains to synthetic
method studies in general, parallel scrutiny of the N and S-
M coupling methods is recommended for achievement of
optimum results.
NMR and 13C NMR spectra were recorded on AC-200 or AM-250 spec-
trometers, in CDCl3 solution using TMS as internal standard unless
otherwise specified. 1H NMR data are listed in the order: chemical
shift, multiplicity, coupling constant(s) in hertz, number of protons,
and assignment of protons. 13C NMR data are listed in the order:
chemical shift, type of carbon [‘o’ designates an odd number of at-
tached protons (i.e., CH3, CH), ‘e’ designates an even number (i.e., CH2,
C), as determined by the JMOD pulse sequence], multiplicity and cou-
pling constant(s) in hertz where applicable, and assignment of car-
bons. Mass spectra and HRMS were determined by Dr. R. Smith, Mc-
Master University, Canada using VG 7070F or Varian spectrometers,
by Dr. H. S. McKinnon, Guelph Centre for Mass Spectrometry, Univer-
sity of Guelph, Canada using KRATOS MS 890 spectrometers, or by Dr.
F. Hileman, Monsanto Co., St. Louis, MO, USA. Elemental analyses
were performed by Galbraith Laboratories, Knoxville, TN or MHW
Laboratories, Phoenix, AZ, USA.
All dry solvents used were purified according to Perrin.70 Tetrahydro-
furan, dimethoxyethane and diethyl ether were distilled from benzo-
phenone ketyl under nitrogen immediately prior to use. s-BuLi and
t-BuLi were purchased from Aldrich Chemical Co. as solutions in Et2O,
cyclohexane and pentane, respectively. n-BuLi was kindly supplied
by FMC, Lithco Division, as a solution in hexane. The alkyllithium re-
agents were stored in resealable containers and titrated periodically
against 1,10-phenanthroline/n-BuOH.71 N,N,N’N’-Tetramethylethylene-
diamine (TMEDA) was dried and distilled over CaH2 before use. ZnCl2
was purchased from Aldrich Chemical Co. as a 1.0 M solution in Et2O.
Solutions of MeMgBr, EtMgBr, i-PrMgCl, i-PrMgBr and o-tolyl magne-
sium bromide were purchased from Aldrich Chemical Co. as solutions
in Et2O. All the commercial materials were purchased from Aldrich
Chemical Co. or Lancaster Synthesis Ltd. Pd(PPh3)4 was prepared by
following the literature method.72
The synthetic consequences of the DMG-bearing biaryls
available from this work may be gleaned from selective ex-
amination of the products. Thus, the 5-indolylbenzamide
(Table 2, entry 2) is poised for DreM reaction into the C-4 or
C-6 position, the biaryldiamide and fluoroamide deriva-
tives (Table 3, entries 1 and 2) are set for regioselective
DreM reactions to fluorenones, the azabiaryls have been
shown to provide azafluorenones (entries 3 and 4), and the
biarylamide may participate in the remote anionic Fries re-
arrangements (entries 5 and 6). These, in addition to many
other substrates, similarly invite further DoM chemistry for
the preparation of more highly substituted and functional-
ized biaryls. As detailed in Table 1, there are relatively few
reported mono-DMG-bearing biaryls, there is a scarcity of
di-DMG-containing biaryls, and both types of derivatives
are untested in further DoM chemistry. Hence, systematic
exploration of both aspects based on the hierarchical power
of DMG1 and DMG2 in substrate 3 has potential to uncover
useful aromatic and heteroaromatic chemistry.
All the reactions were carried out under inert atmosphere (argon, N2)
unless otherwise specified. The transfer via cannula employed addi-
tional solvent for quantitative transfer, designated by: (amount of sol-
vent + additional amount of solvent). The –78 °C temperature desig-
nated is approximate, as achieved by a dry ice–acetone bath. Allowing
a reaction to proceed overnight implies a period of 10–12 h. The
phrase ‘normal workup’ means the addition of aq satd NH4Cl solution
to the reaction mixture followed by CH2Cl2 or Et2O extraction, drying
over Na2SO4, filtration, and concentration of the filtrate in vacuo to af-
ford the crude product.
Aryl Trifluoromethanesulfonates; General Procedure A
Prepared following an adaptation of the published procedure.73 To a
cooled (0 °C), stirred solution of the phenol (10 mmol) and pyridine
(20 mmol) in CH2Cl2 (50 mL) under argon or N2 was added via syringe
Tf2O (13 mmol). After stirring for 1–4 h, the reaction mixture was
treated with aq sat. NH4Cl. The CH2Cl2 phase was separated and
washed sequentially with aq copper sulfate (2 ×) and H2O, and dried
(MgSO4). Filtration, concentration of the filtrate in vacuo, and purifi-
cation afforded the product.
Arylzinc Reagents; General Procedure B
To a cold (–78 °C), stirred solution of the aryl DMG compound
(2 mmol) in THF (10 mL) under argon or N2 was added a solution of t-
BuLi (2.4 mmol). After 1 h, a solution of ZnCl2 (3 mmol) was added
and the solution allowed to warm to rt. This solution was then subse-
quently used.
Flash chromatography69 was carried out using ‘fine’ Merck silica gel
60 (0.04–0.06 mm) purchased from VWR Scientific of Canada Ltd.,
with hexane/EtOAc as eluent unless otherwise specified. Melting
points were determined using a Büchi model SMP-20 instrument and
are uncorrected. IR spectra were recorded on either a Perkin-Elmer
983 or Bomem FTIR spectrophotometer in neat or KBr plate form. 1H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

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C. A. Quesnelle, V. Snieckus
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Synthesis
Nickel-Catalyzed Coupling of Organozinc Reagents with Organo-
triflates; General Procedure C
13C NMR (50 MHz, CDCl3):  = –4.1 (o, Si(CH3)2C(CH3)3), 19.4 (e,
Si(CH3)2C(CH3)3), 26.2 (o, Si(CH3)2C(CH3)3), 70.6 (e, PhCH2), 103.8 (o),
104.6 (o), 112.0 (o), 114.3 (o), 127.4 (o), 127.6 (o), 128.4 (o), 131.7 (o),
131.8 (e), 136.1 (e), 137.8 (e), 153.3 (e).
To a stirred solution at rt of nickel catalyst (0.05 mmol) in THF (3 mL)
under argon or N2 was added sequentially MeMgBr (0.1 mmol), a
freshly prepared organozinc solution (2 mmol) via cannula, and an
organotriflate (1 mmol) in THF (2 mL) with an additional amount of
THF (1 mL) for quantitative transfer. Once all additions were com-
plete, the reaction mixture was stirred at rt until TLC indicated disap-
pearance of the starting material, typically 12–18 h. At this time, the
reaction mixture was treated with aq sat. NH4Cl and extracted with
Et2O. The combined extracts were dried (MgSO4), subjected to filtra-
tion, and the filtrate concentrated in vacuo to give a residue which
was subjected to flash chromatography on silica gel to afford the bi-
aryl product.
1-(tert-Butyldimethylsilyl)-5-hydroxyindole (10b)
A flask was charged with a solution of 5-(benzyloxy)-1-(tert-butyldi-
methylsilyl)indole (10a; 3.00 g, 8.89 mmol) and Pd/C (307 mg) in
EtOH (100 mL) and equipped with a hydrogen-filled balloon, and the
solution was stirred for 8–12 h. Upon completion of the reaction, the
contents were filtered through Celite with EtOH. The combined EtOH
washings were concentrated to afford a brown solid that was recrys-
tallized from cold hexane to give 10b (1.94 g, 88%) as a beige powder;
mp 96–97 °C (hexane) (Lit.22 98–99 °C).
Palladium-Catalyzed Coupling of Arylboronic Acids with Aryl Ha-
lides or Aryl Triflates; General Procedure D
1-(tert-Butyldimethylsilyl)-5-(trifluoromethylsulfonyloxy)indole
(10)
A mixture of Pd(PPh3)4 (0.04 mmol) and an aryl halide or aryl triflate
(1 mmol) in DME (3 mL) was stirred at rt for 10 min. A 2 M aq Na2CO3
solution (3 mL) was added, followed by a solution of an arylboronic
acid (1.4 mmol) in DME (3 mL), and EtOH (3 mL) if required for solu-
bility. The resulting mixture was heated at reflux overnight, then
cooled to rt to end always with a black solution. The crude mixture
was treated with aq sat. NH4Cl, extracted with Et2O, the extract was
dried (MgSO4) and subjected to filtration, and the filtrate was concen-
trated in vacuo and purified by flash chromatography to afford the bi-
aryl product.
According to General Procedure A, a solution of 1-(tert-butyldimeth-
ylsilyl)-5-hydroxyindole (10b; 1.50 g, 6.06 mmol) and pyridine
(1.0 mL, 12.4 mmol) in CH2Cl2 (50 mL) was treated with Tf2O (1.3 mL,
7.73 mmol). After 2 h, normal workup followed by flash chromatogra-
phy (hexane/Et2O, 9:1) gave 10 (762 mg, 33%) as a colourless solid;
mp 58–59 °C (hexane) (Lit.10 55–57 °C).
N,N′-Dimethyl-5-(trifluoromethylsulfonyloxy)uracil (12)
According to General Procedure A, a solution of N,N′-dimethyl-5-hy-
droxyuracil76 (1.64 g, 10.5 mmol) and pyridine (1.7 mL, 20.0 mmol) in
CH2Cl2 (40 mL) was treated with Tf2O (2.3 mL, 13.7 mmol). After 3 h,
normal workup gave a solid residue that was recrystallized from CH2-
Cl2/hexane to afford 12 (2.61 g, 86%) as colourless needles;77 mp 126–
127 °C (CH2Cl2/hexane).
Aryl Triflates
The preparation of aryl triflates 29, 32, 34, 39, 45, and 54 is described
elsewhere.58
4-tert-Butylcyclohex-1-enyl Trifluoromethanesulfonate (7)
Phenyl Trifluoromethanesulfonate (14)
Following the published procedure,74 a cold (0 °C), stirred solution of
4-tert-butylcyclohexanone (1.50 g, 9.72 mmol) and 2,6-di-tert-butyl-
4-methylpyridine (2.26 g, 13.3 mmol) in CH2Cl2 (75 mL) was treated
with Tf2O (1.8 mL, 10.7 mmol) via syringe. The reaction mixture was
allowed to warm to rt over 8–12 h at which time the reaction solvent
was removed and pentane (75 mL) was added. The reaction mixture
was refluxed for 30 min, cooled, and the resulting precipitate re-
moved by filtration and washed with pentane (5 × 20 mL). The filtrate
was washed with 10% HCl (2 × 50 mL), 10% NaOH (50 mL), and brine,
and dried (MgSO4). Filtration, concentration of the filtrate in vacuo,
and bulb-to-bulb distillation gave 7 (2.14 g, 77%) as a colourless oil;
bp 50–55 °C/0.05 mmHg (Lit.74 75–80 °C/0.5 mmHg).
According to General Procedure A, a solution of phenol (3.07 g,
32.7 mmol) and pyridine (5.0 mL, 61.8 mmol) in CH2Cl2 (50 mL) was
treated with Tf2O (6.6 mL, 39.2 mmol). After 4 h, normal workup fol-
lowed by flash chromatography (hexane/EtOAc, 4:1) afforded 14
(5.49 g, 74%) as a colourless oil; bp 105–107 °C/25 mmHg (Lit.78 87–
88 °C/13 mmHg).
2-Tolyl Trifluoromethanesulfonate (16)
According to General Procedure A, a solution of 2-methylphenol
(2.41 g, 22.3 mmol) and pyridine (3.6 mL, 44.5 mmol) in CH2Cl2
(50 mL) was treated with Tf2O (5.6 mL, 33.3 mmol). After 1 h, normal
workup followed by bulb-to-bulb distillation afforded 16 (4.56 g, 85%)
as a colourless oil; bp 42–45 °C/0.2 mmHg (Lit.82 80–82 °C/1.5
mmHg).
5-(Benzyloxy)-1-(tert-butyldimethylsilyl)indole (10a)
To a cold (0 °C), stirred solution of 5-(benzyloxy)indole75 (5.80 g,
25.9 mmol) in THF (150 mL) under argon was added NaH (1.20 g, 60%
in oil, 30.0 mmol) and the reaction mixture was allowed to warm to
rt. After 1 h, solid TBSCl (4.89 g, 32.4 mmol) was added and the reac-
tion mixture was stirred overnight. Normal workup afforded a solid
residue that was recrystallized from hexane to give 10a (7.04 g, 80%)
as beige needles; mp 108–108.5 °C (hexane).
1H NMR (200 MHz, CDCl3):  = 0.53 (s, 6 H, Si(CH3)2C(CH3)3), 0.89 (s, 9
H, Si(CH3)2C(CH3)3), 5.06 (s, 2 H, PhCH2), 6.51 (d, J = 2.9 Hz, 1 H), 6.89
(dd, J = 8.9, 2.3 Hz, 1 H), 7.11–7.16 (m, 2 H), 7.25–7.46 (m, 6 H).
2,6-Dimethylphenyl Trifluoromethanesulfonate (18)
To a cooled (0 °C), stirred solution of 2,6-dimethylphenol (2.66 g,
21.8 mmol) in Et2O (60 mL) was added a solution of n-BuLi (17.0 mL,
1.51 M, 25.7 mmol), and the whole was stirred for 30 min, then Tf2O
(4.4 mL, 26.2 mmol) was added. After 2 h, aq satd NH4Cl was added,
the phases were separated, and the Et2O layer was dried (MgSO4). Fil-
tration, concentration of the filtrate in vacuo, and bulb-to-bulb distil-
lation afforded 18 (4.56 g, 82%) as a colourless oil; bp 43–45 °C/0.2
mmHg.
IR (neat): 1406, 1222, 1134 cm–1
1H NMR (250 MHz, CDCl3):  = 2.35 (s, 6 H), 7.07 (m, 3 H).
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

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C. A. Quesnelle, V. Snieckus
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Synthesis
13C NMR (62.9 MHz, CDCl3):  = 16.9 (o), 118.8 (e, q, J = 319.3 Hz, CF3),
128.0 (o), 130.0 (o), 131.5 (e), 147.0 (e).
MS (CI; CH4): m/z (%) = 255 (100) [M + H]+.
13C NMR (62.9 MHz, CDCl3):  = 20.1 (o), 20.4 (o), 20.6 (o), 20.7 (o),
24.3 (e), 27.1 (o), 30.6 (e), 31.0 (e), 32.1 (e), 43.5 (o), 45.4 (o), 50.5 (o),
125.6 (o), 126.4 (o), 127.3 (o), 127.8 (o), 128.0 (o), 136.3 (e), 137.0 (e),
140.2 (e), 170.6 (e).
MS (EI; 70 eV): m/z (%) = 341 (25) [M+], 284 (18), 261 (26), 218 (33),
161 (100).
5,5-Dimethyl-3-oxocyclohex-1-enyl Trifluoromethanesulfonate
(20)
Procedure 2: According to General Procedure B, a solution of N,N-di-
isopropylbenzamide (409 mg, 1.99 mmol) in THF (10 mL) was se-
quentially treated with solutions of t-BuLi (1.50 mL, 1.64 M, 2.46
mmol) and ZnCl2 (3.0 mL, 1 M, 3.00 mmol). A second flask containing
Ni(acac)2 (14 mg, 0.055 mmol) and PPh3 (57 mg, 0.22 mmol) in THF (3
mL) was sequentially treated with MeMgBr (0.10 mL, 3 M, 0.30
mmol), the freshly prepared organozinc reagent solution via cannula,
and a solution of 4-tert-butylcyclohex-1-enyl trifluoromethanesul-
fonate (7; 292 mg, 1.02 mmol) in THF (3 mL). The reaction mixture
was heated at reflux for 24 h. Normal workup followed by flash chro-
matography (hexane/EtOAc, 6:1) gave 9 (174 mg, 50%), shown to be
identical to that prepared by Procedure 1 above.
According to General Procedure A, a solution of dimedone (3.05 g,
21.7 mmol) and pyridine (3.5 mL, 43.3 mmol) in CH2Cl2 (50 mL) was
treated with Tf2O (4.8 mL, 28.5 mmol). After 2 h, normal workup fol-
lowed by bulb-to-bulb distillation gave 20 (3.32 g, 56%) as a colour-
less oil; bp 85–90 °C/0.1 mmHg (Lit.79 47–49 °C/0.07 mmHg).
3-Methoxyphenyl Trifluoromethanesulfonate (23)
According to General Procedure A, a solution of 3-methoxyphenol
(4.68 g, 37.7 mmol) and pyridine (6.0 mL, 74.2 mmol) in CH2Cl2
(50 mL) was treated with Tf2O (8.5 mL, 50.5 mmol). After 2 h, normal
workup followed by bulb-to-bulb distillation afforded 23 (8.92 g,
92%) as
a
colourless oil; bp 55–57 °C/0.05 mmHg (Lit.80 135–
Procedure 3: According to General Procedure D, a solution of 4-tert-
137 °C/2.0 mmHg).
butylcyclohex-1-enyl
trifluoromethanesulfonate
(7;
297 mg,
1.04 mmol) in DME (3 mL) was treated with a solution of 2-(diisopro-
pylaminocarbonyl)phenylboronic acid (331 mg, 1.33 mmol) in DME
(3 mL) in the presence of Pd(PPh3)4 (46 mg, 0.040 mmol). After 21 h,
the reaction mixture was cooled to rt. Normal workup followed by
flash chromatography (hexane/EtOAc, 4:1) afforded 9 (220 mg, 62%),
shown to be identical to that prepared by Procedure 1 above.
2-Naphthyl Trifluoromethanesulfonate (42)
According to General Procedure A, a solution of 2-naphthol (3.06 g,
21.3 mmol) and pyridine (3.4 mL, 42.0 mmol) in CH2Cl2 (50 mL) was
treated with Tf2O (4.6 mL, 27.3 mmol). After 2 h, normal workup fol-
lowed by flash chromatography on silica gel (hexane/Et2O, 9:1) af-
forded 42 (5.69 g, 97%) as an oil that solidified; mp 27–28 °C (hexane)
(Lit.81 30–32 °C).
2-(1-(tert-Butyldimethylsilyl)-5-indolyl)-N,N-diisopropylben-
zamide (11)
4-Methoxyphenyl Trifluoromethanesulfonate (51)
Procedure 1: According to General Procedure D, a solution of 1-(tert-
butyldimethylsilyl)-5-(trifluoromethylsulfonyloxy)indole (10; 384 mg,
1.01 mmol) in DME (3 mL) was treated with a solution of 2-(diisopro-
pylaminocarbonyl)phenylboronic acid (387 mg, 1.55 mmol) in DME
(3 mL) in the presence of Pd(PPh3)4 (49 mg, 0.042 mmol). After 20 h,
the reaction mixture was cooled to rt. Normal workup followed by
flash chromatography (hexane/EtOAc, 4:1 → 1:1) afforded compound
11 (28 mg, ca. 6%) as a colourless solid and desilylated compound 28
(116 mg, 36%) as a colourless oil.
According to General Procedure A, a solution of 4-methoxyphenol
(4.70 g, 37.9 mmol) and pyridine (6.0 mL, 74.2 mmol) in CH2Cl2
(50 mL) was treated with Tf2O (8.5 mL, 50.5 mmol). After 2 h, normal
workup followed by bulb-to-bulb distillation afforded 51 (9.09 g, 94%)
as a colourless oil; bp 64–66 °C/0.05 mmHg (Lit.82 90–92 °C/3.5
mmHg).
Cross-Coupling Products
2-(4-tert-Butylcyclohex-1-enyl)-N,N-diisopropylbenzamide (9)
Compound 11
Procedure 1: According to General Procedure B, a solution of N,N-di-
isopropylbenzamide (408 mg, 1.99 mmol) in THF (10 mL) was se-
quentially treated with solutions of t-BuLi (1.4 mL, 1.72 M,
2.41 mmol) and ZnCl2 (3.0 mL, 1.0 M, 3.00 mmol). According to Gen-
eral Procedure C, to a second flask containing a solution of Ni(acac)2
(16 mg, 0.063 mmol) and PPh3 (57 mg, 0.22 mmol) in THF (3 mL) was
added sequentially solutions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol),
the freshly prepared organozinc reagent via cannula, and 4-tert-bu-
Mp 133–134 °C (hexane).
1H NMR (250 MHz, CDCl3):  = 0.12 (d, J = 6.6 Hz, 3 H), 0.61 (s, 6 H),
0.87 (d, J = 6.7 Hz, 3 H), 0.89 (s, 9 H), 1.23 (d, J = 6.8 Hz, 3 H), 1.51 (d,
J = 6.8 Hz, 3 H), 3.14 (sept, J = 6.7 Hz, 1 H), 3.46 (sept, J = 6.7 Hz, 1 H),
6.60 (d, J = 3.0 Hz, 1 H), 7.18 (d, J = 3.2 Hz, 1 H), 7.30–7.54 (m, 6 H),
7.79 (d, J = 1.6 Hz, 1 H).
MS (EI; 70 eV): m/z (%) = 434 (30) [M+], 334 (45), 278 (55), 238 (33),
181 (100).
tylcyclohex-1-enyl
trifluoromethanesulfonate
(7;
280 mg,
0.98 mmol) in THF (2 + 1 mL) via cannula. After 27 h, normal workup
followed by flash chromatography (hexane/EtOAc, 9:1) gave recov-
ered starting material (215 mg, 77%) and compound 9 (66 mg, 20%) as
a colourless solid; mp 94–95 °C (hexane).
Anal. Calcd for C27H38N2OSi: C, 74.60; H, 8.81; N, 6.44. Found: C,
74.58; H, 8.49; N, 6.45.
Compound 28
1H NMR (250 MHz, CDCl3):  = 0.89 (s, 9 H, C(CH3)3), 1.01 (d, J = 6.6 Hz,
3 H, NCH(CH3)2), 1.06–1.12 (m, 3 H), 1.21–1.39 (m, 2 H), 1.46–1.50 (m,
3 H), 1.56 (d, J = 6.8 Hz, 3 H, NCH(CH3)2), 1.85–1.95 (m, 2 H), 2.10–
2.30 (m, 2 H), 2.57 (m, 1 H), 3.44 (sept, J = 6.7 Hz, 1 H, NCH(CH3)2),
3.62 (m, 1 H, NCH(CH3)2), 5.87 (m, 1 H), 7.11–7.29 (m, 4 H).
1H NMR (250 MHz, CDCl3):  = 0.79 (d, J = 6.5 Hz, 3 H), 0.95 (d, J = 6.6
Hz, 3 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.50 (d, J = 6.8 Hz, 3 H), 3.39 (sept,
J = 6.8 Hz, 1 H), 3.96 (sept, J = 6.6 Hz, 1 H), 6.54 (m, 1 H), 7.03 (dd,
J = 8.9, 2.4 Hz, 1 H), 7.18–7.56 (m, 7 H), 9.09 (bs, 1 H, NH).
MS (EI; 70 eV): m/z (%) = 265 (54), 132 (100), 104 (70).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

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C. A. Quesnelle, V. Snieckus
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Synthesis
Procedure 2: According to General Procedure B, a solution of N,N-di-
isopropylbenzamide (414 mg, 2.02 mmol) in THF (10 mL) was se-
quentially treated with solutions of t-BuLi (1.5 mL, 1.66 M, 2.49
mmol) and ZnCl2 (3.0 mL, 1.0 M, 3.00 mmol). According to General
Procedure C, to a second flask containing Ni(acac)2 (19 mg, 0.076
mmol) and PPh3 (73 mg, 0.28 mmol) in THF (3 mL) was added sequen-
tially solutions of MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), the freshly
prepared organozinc reagent solution via cannula, and a solution of 1-
(tert-butyldimethylsilyl)-5-(trifluoromethylsulfonyloxy)indole (10;
386 mg, 1.02 mmol) in THF (3 mL) via cannula. After stirring over-
night, normal workup followed by flash chromatography (hex-
ane/EtOAc, 4:1 → 1:1) gave 11 (330 mg, 75%), shown to be identical to
that prepared by Procedure 1 above.
N,N-Diisopropyl-2-(2-tolyl)benzamide (17)
According to General Procedure B, a solution of N,N-diisopropylben-
zamide (403 mg, 1.96 mmol) in THF (10 mL) was sequentially treated
with solutions of t-BuLi (1.4 mL, 1.66 M, 2.32 mmol) and ZnCl2
(3.0 mL, 1.0 M, 3.00 mmol). According to General Procedure C, to a
second flask containing Ni(acac)2 (15 mg, 0.056 mmol) and PPh3
(72 mg, 0.27 mmol) in THF (3 mL) was added sequentially solutions
of MeMgBr (0.07 mL, 3.0 M, 0.21 mmol), the freshly prepared or-
ganozinc reagent solution via cannula, and a solution of 2-tolyl triflu-
oromethanesulfonate (16; 253 mg, 1.05 mmol) in THF (2 + 1 mL). Af-
ter 17 h, normal workup followed by flash chromatography (hex-
ane/EtOAc, 4:1) gave 17 (207 mg, 67%) as a colourless solid; mp 92–
93 °C (hexane) (Lit.83 93–94 °C).
5-(2-(Diisopropylaminocarbonyl)phenyl)-N,N′-dimethyluracil (13)
2-(2,6-Dimethylphenyl)-N,N-diisopropylbenzamide (19)
Procedure 1: According to General Procedure B, a solution of N,N-di-
isopropylbenzamide (408 mg, 1.99 mmol) in THF (10 mL) was se-
quentially treated with solutions of t-BuLi (1.4 mL, 1.72 M,
2.41 mmol) and ZnCl2 (3.0 mL, 1.0 M, 3.00 mmol). A second flask con-
According to General Procedure B, a solution of N,N-diisopropylben-
zamide (412 mg, 2.01 mmol) in THF (10 mL) was sequentially treated
with solutions of t-BuLi (1.6 mL, 1.58 M, 2.53 mmol) and ZnCl2
(3.0 mL, 1.0 M, 3.00 mmol). According to General Procedure C, to a
second flask containing Ni(acac)2 (16 mg, 0.063 mmol) and PPh3
(68 mg, 0.26 mmol) in THF (3 mL) was added sequentially solutions of
MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), the freshly prepared organoz-
inc reagent solution via cannula, and a solution of 2,6-dimethylphenyl
trifluoromethanesulfonate (18; 255 mg, 1.00 mmol) in THF
(2 + 1 mL). After 16 h, normal workup followed by flash chromatogra-
phy (hexane/EtOAc, 4:1) gave 19 (157 mg, 51%) as a colourless solid;
mp 122–124 °C (CH2Cl2/hexane).
taining
a
solution of N,N′-dimethyl-5-(trifluoromethylsulfony-
loxy)uracil (12; 301 mg, 1.04 mmol) and Pd(PPh3)4 (44 mg,
0.038 mmol) in THF (5 mL) was treated with the freshly prepared or-
ganozinc reagent solution via cannula, the flask was equipped with a
reflux condenser, and the reaction content was heated to reflux. After
22 h, the reaction mixture was cooled. Normal workup followed by
flash chromatography (hexane/EtOAc, 1:4) gave 13 (298 mg, 83%) as a
colourless solid; mp 158.5–159.5 °C (CH2Cl2/hexane).
1H NMR (250 MHz, CDCl3):  = 0.88 (d, J = 6.6 Hz, 3 H, NCH(CH3)2),
1.01 (d, J = 6.6 Hz, 3 H, NCH(CH3)2), 1.36 (d, J = 6.8 Hz, 3 H,
NCH(CH3)2), 1.53 (d, J = 6.8 Hz, 3 H, NCH(CH3)2), 3.39 (sept, J = 6.8 Hz,
1 H, NCH(CH3)2), 3.40 (s, 3 H, NCH3), 3.41 (s, 3 H, NCH3), 3.61 (sept,
J = 6.6 Hz, 1 H, NCH(CH3)2), 7.22–7.47 (m, 4 H), 7.59 (s, 1 H).
13C NMR (62.9 MHz, CDCl3):  = 19.9, 20.1, 20.6, 28.0, 36.9, 45.5, 50.8,
111.4, 125.4, 128.0, 128.5, 131.0, 138.2, 142.8, 151.4, 162.3, 169.9.
IR (KBr): 1609 cm–1
.
1H NMR (250 MHz, CDCl3):  = 0.80 (d, J = 6.5 Hz, 3 H), 1.07 (d, J = 6.5
Hz, 3 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.35 (m, 6 H), 1.49 (d, J = 6.8 Hz, 3 H),
3.38 (sept, J = 6.8 Hz, 1 H), 3.97 (sept, J = 6.5 Hz, 1 H), 7.26–7.34 (m, 6
H), 7.52 (m, 1 H).
13C NMR (50 MHz, CDCl3):  = 19.6 (o), 20.2 (o), 20.5 (o), 20.6 (o), 20.9
(o), 45.5 (o), 50.3 (o), 125.4 (o), 126.3 (o), 127.2 (o), 127.6 (o), 128.3
(o), 130.2 (o), 136.2 (e), 138.3 (e), 169.7 (e).
MS (EI; 70 eV): m/z (%) = 343 (3) [M+], 243 (100), 100 (15).
MS (EI; 70 eV): m/z (%) = 309 (26) [M+], 308 (100), 206 (42), 181 (47).
Anal. Calcd for C19H25N3O3: C, 66.45; H, 7.34; N, 12.24. Found: C,
66.50; H, 7.16; N, 12.49.
Procedure 2: According to General Procedure D, a solution of N,N′-di-
2-(5,5-Dimethyl-3-oxocyclohex-1-enyl)-6-methoxyphenyl Dieth-
ylcarbamate (22)
methyl-5-(trifluoromethylsulfonyloxy)uracil
(12;
289 mg,
1.00 mmol) in DME (3 mL) was treated with a solution of 2-(diisopro-
pylaminocarbonyl)phenylboronic acid (323 mg, 1.30 mmol) in DME
(3 mL) in the presence of Pd(PPh3)4 (49 mg, 0.042 mmol). After 15 h,
the reaction mixture was cooled to rt. Normal workup followed by
flash chromatography (hexane/EtOAc, 1:4) afforded 13 (150 mg, 44%),
shown to be identical to that prepared by Procedure 1 above.
Procedure 1: According to General Procedure B, a solution of 2-me-
thoxyphenyl diethylcarbamate (443 mg, 1.99 mmol) in THF (10 mL)
was sequentially treated with solutions of t-BuLi (1.4 mL, 1.73 M,
2.42 mmol) and ZnCl2 (3.0 mL, 1.0 M, 3.00 mmol). According to Gen-
eral Procedure C, to a second flask containing Ni(acac)2 (14 mg,
0.053 mmol) and PPh3 (50 mg, 0.19 mmol) in THF (3 mL) was added
sequentially solutions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the
freshly prepared organozinc reagent solution via cannula, and a solu-
tion of 5,5-dimethyl-3-oxocyclohex-1-enyl trifluoromethanesulfon-
ate (20; 293 mg, 1.08 mmol) in THF (2 + 1 mL) via cannula. After 13 h,
normal workup followed by flash chromatography (hexane/EtOAc,
3:2) gave 22 (341 mg, 92%) as a colourless oil.
N,N-Diisopropyl-2-phenylbenzamide (15)
According to General Procedure B, a solution of N,N-diisopropylben-
zamide (411 mg, 2.00 mmol) in THF (10 mL) was sequentially treated
with solutions of t-BuLi (1.4 mL, 1.74 M, 2.44 mmol) and ZnCl2
(3.0 mL, 1.0 M, 3.00 mmol). According to General Procedure C, to a
second flask containing a solution of Ni(acac)2 (17 mg, 0.064 mmol)
and PPh3 (77 mg, 0.30 mmol) in THF (3 mL) was added sequentially
solutions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the freshly pre-
pared organozinc reagent solution via cannula, and a solution of phe-
nyl trifluoromethanesulfonate (14; 294 mg, 1.10 mmol) in THF
(2 + 1 mL). After 22 h, normal workup followed by flash chromatogra-
phy (hexane/EtOAc, 5:1) gave 15 (253 mg, 81%) as a colourless solid;
mp 106–107 °C (Et2O/hexane) (Lit.84 106–108 °C).
IR (neat): 1719, 1667 cm–1
.
1H NMR (250 MHz, CDCl3):  = 1.09 (s, 6 H, CH3), 1.15 (t, J = 7.1 Hz, 3
H, NCH2CH3), 1.24 (t, J = 6.9 Hz, 3 H, NCH2CH3), 2.30 (s, 2 H, CH2), 2.56
(s, 2 H, CH2), 3.37–3.43 (m, 4 H, NCH2CH3), 3.82 (s, 3 H, OCH3), 6.14 (s,
1 H), 6.83 (d, J = 7.8 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 7.17 (t, J = 7.8 Hz,
1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

K
C. A. Quesnelle, V. Snieckus
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Synthesis
13C NMR (62.9 MHz, CDCl3):  = 13.1 (NCH2CH3), 13.8 (NCH2CH3), 27.9
(CH3), 33.8 (CH3), 41.8 (NCH2CH3), 42.0 (NCH2CH3), 43.9 (CH2), 50.9
(CH2), 55.9 (OCH3), 112.4, 119.4, 125.7, 127.5, 135.2, 137.3, 152.1,
153.2, 156.8, 199.3.
MS (EI; 70 eV): m/z (%) = 345 (19) [M+], 223 (8), 168 (6), 100 (100), 72
(66).
2-(Diethylaminocarbonyl)-3-(3-methoxyphenyl)-1-naphthyl Di-
ethylcarbamate (27)
According to General Procedure D, a solution of 3-methoxyphenyl tri-
fluoromethanesulfonate (23; 763 mg, 2.98 mmol) in DME (9 mL) was
treated with a solution of 3-(diethylaminocarbonyl)-4-(diethylcarba-
moyloxy)-2-naphthylboronic acid (26; 1.36 g, 3.53 mmol) in DME
(9 mL) in the presence of Pd(PPh3)4 (91 mg, 0.079 mmol). After 18 h,
the reaction mixture was cooled to rt. Normal workup followed by
flash chromatography (hexane/EtOAc, 2:1) gave 27 (1.06 g, 81%) as a
colourless solid; mp 115–116 °C (Et2O/hexane).
HRMS: m/z calcd for C20H27NO4: 345.1940; found: 345.1943.
Procedure 2: According to General Procedure D, a solution of 5,5-di-
methyl-3-oxocyclohex-1-enyl
trifluoromethanesulfonate
(20;
287 mg, 1.05 mmol) in DME (3 mL) was treated with 2-(diethylcarba-
moyloxy)-3-methoxyphenylboronic acid (383 mg, 1.43 mmol) in
DME (3 mL) and EtOH (2 mL) in the presence of Pd(PPh3)4 (44 mg,
0.038 mmol). After 18 h, the reaction mixture was cooled to rt. Nor-
mal workup followed by flash chromatography (hexane/EtOAc, 1:1)
afforded 22 (331 mg, 91%), shown to be identical to that prepared by
Procedure 1 above.
1H NMR (200 MHz, CDCl3):  = 0.64 (t, J = 7.1 Hz, 3 H, NCH2CH3), 0.95
(t, J = 7.1 Hz, 3 H, NCH2CH3), 1.20 (t, J = 7.1 Hz, 3 H, NCH2CH3), 1.36 (t,
J = 7.0 Hz, 3 H, NCH2CH3), 2.81 (m, 1 H, NCH2CH3), 2.97 (m, 1 H,
NCH2CH3), 3.23–3.63 (m, 6 H, NCH2CH3), 3.81 (s, 3 H, OCH3), 6.90 (m, 1
H), 7.17–7.34 (m, 3 H), 7.45–7.55 (m, 2 H), 7.77 (s, 1 H), 7.82–7.87 (m,
2 H).
13C NMR (50 MHz, CDCl3):  = 11.9 (o, NCH2CH3), 12.7 (o, NCH2CH3),
13.3 (o, NCH2CH3), 14.2 (o, NCH2CH3), 37.7 (e, NCH2CH3), 42.2 (e,
NCH2CH3), 42.4 (e, NCH2CH3), 55.1 (o, OCH3), 113.9 (o), 114.0 (o),
121.4 (o), 121.8 (o), 125.9 (o), 126.7 (o), 126.9 (o), 127.2 (e), 127.3 (e),
127.8 (o), 129.1 (o), 133.8 (e), 136.3 (e), 140.7 (e), 144.1 (e), 153.4 (e),
159.2 (e), 166.5 (e).
N-(tert-Butoxycarbonyl)-2-(3-methoxyphenyl)aniline (25)
Procedure 1: According to a literature procedure,20 a solution of N-
(tert-butoxycarbonyl)aniline (388 mg, 2.01 mmol) in Et2O (5 mL) at –
10 °C was treated with a solution of t-BuLi (3.1 mL, 1.43 M, 4.43
mmol). After 2 h at –5 °C, a solution of ZnCl2 (5.0 mL, 1.0 M, 5.00
mmol) and THF (10 mL) were added. According to General Procedure
C, to a second flask containing Ni(acac)2 (19 mg, 0.074 mmol) and
PPh3 (73 mg, 0.28 mmol) in THF (3 mL) was added sequentially solu-
tions of MeMgBr (0.10 mL, 3 M, 0.30 mmol), the freshly prepared or-
ganozinc reagent solution, and a solution of 3-methoxyphenyl triflu-
oromethanesulfonate (23; 267 mg, 1.04 mmol) in THF (3 mL) via can-
nula. After 23 h, normal workup followed by flash chromatography
(hexane/CH2Cl2, 1:1) gave 25 (25 mg, 8%) as a colourless solid; mp 58–
59 °C (hexane).
1H NMR (250 MHz, CDCl3):  = 1.46 (s, 9 H, OC(CH3)3), 3.83 (s, 3 H,
OCH3), 6.58 ( , 1 H, NH), 6.89–6.96 (m, 3 H), 7.08 (t, J = 7.6 Hz, 1 H),
7.20 (d, J = 7.6 Hz, 1 H), 7.24–7.41 (m, 2 H), 8.12 (d, J = 8.2 Hz, 1 H).
13C NMR (62.9 MHz, CDCl3):  = 28.2 (OC(CH3)3), 55.2 (OCH3), 80.3
(OC(CH3)3), 113.6, 114.6, 119.7, 121.4, 122.9, 128.3, 129.9, 130.0,
131.1, 135.2, 139.7, 152.8, 160.0.
MS (EI; 70 eV): m/z (%) = 448 (16) [M+], 377 (4), 276 (21), 265 (17),
181 (10), 132 (36), 100 (100), 72 (36).
Anal. Calcd for C27H32N2O4: C, 72.30; H, 7.19; N, 6.25. Found: C, 72.47;
H, 7.27; N, 6.39.
N,N-Diisopropyl-2-(3-(diethylaminocarbonyl)phenyl)benzamide
(31)
According to General Procedure B, a solution of N,N-diisopropylben-
zamide (411 mg, 2.00 mmol) in THF (10 mL) was sequentially treated
with solutions of t-BuLi (1.4 mL, 1.71 M, 2.39 mmol) and ZnCl2
(3.0 mL, 1.0 M, 3.00 mmol). According to General Procedure C, to a
second flask containing a solution of Ni(acac)2 (16 mg, 0.063 mmol)
and PPh3 (63 mg, 0.24 mmol) in THF (3 mL) was added sequentially
solutions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the freshly pre-
pared organozinc reagent solution via cannula, and N,N-diethyl-3-
(trifluoromethylsulfonyloxy)benzamide (29; 325 mg, 1.00 mmol) in
THF (2 + 1 mL) via cannula. After 19 h, normal workup followed by
flash chromatography (hexane/EtOAc, 1:1) gave 31 (349 mg, 92%) as a
colourless solid; mp 134–135 °C (Et2O/hexane).
1H NMR (250 MHz, CDCl3):  = 0.46 (d, J = 6.7 Hz, 3 H, NCH(CH3)2),
0.92 (d, J = 6.7 Hz, 3 H, NCH(CH3)2), 1.19 (bs, 6 H, NCH2CH3), 1.31 (d,
J = 6.8 Hz, 3 H, NCH(CH3)2), 1.52 (d, J = 6.8 Hz, 3 H, NCH(CH3)2), 3.20–
3.52 (m, 6 H), 7.27–7.44 (m, 6 H), 7.54 (s, 1 H), 7.66 (d, J = 7.1 Hz, 1 H).
13C NMR (62.9 MHz, CDCl3):  = 12.7 (o, NCH2CH3), 14.1 (o, NCH2CH3),
19.4 (o, NCH(CH3)2), 19.5 (o, NCH(CH3)2), 20.5 (o, NCH(CH3)2), 39.1 (e,
NCH2CH3), 43.2 (e, NCH2CH3), 45.4 (o, NCH(CH3)2), 50.4 (o,
NCH(CH3)2), 125.5 (o), 126.4 (o), 126.8 (o), 127.7 (o), 128.2 (o), 128.4
(o), 129.2 (o), 130.0 (o), 136.7 (e), 137.3 (e), 137.7 (e), 139.8 (e), 169.8
(e), 170.5 (e).
MS (EI; 70 eV): m/z (%) = 299 (6) [M+], 243 (21), 199 (32), 137 (37), 93
(51), 57 (100).
Procedure 2: According to General Procedure D, a solution of 3-me-
thoxyphenyl trifluoromethanesulfonate (23; 269 mg, 1.05 mmol) in
DME (3 mL) was treated with a solution of 2-(tert-butoxycarbonyl-
amino)phenylboronic acid (343 mg, 1.45 mmol) in DME (3 mL) in the
presence of Pd(PPh3)4 (49 mg, 0.042 mmol). After 24 h, the reaction
mixture was cooled to rt. Normal workup followed by flash chroma-
tography (hexane/CH2Cl2, 1:1) afforded 25 (208 mg, 66%), shown to be
identical to that prepared by Procedure 1 above.
3-(Diethylaminocarbonyl)-4-(diethylcarbamoyloxy)-2-naphthyl-
boronic Acid (26)
To a cooled (–78 °C), stirred solution of 2-(diethylaminocarbonyl)-1-
naphthyl diethylcarbamate (1.53 g, 4.47 mmol) and TMEDA (0.88 mL,
5.83 mmol) in THF (80 mL) was added a solution of s-BuLi (4.8 mL,
1.20 M, 5.76 mmol). After stirring for 1 h, neat B(OMe)3 (1.1 mL,
9.69 mmol) was added and the reaction mixture was warmed to rt
overnight. The reaction mixture was quenched with H2O and acidi-
fied to pH ~2 with 10% HCl. Extraction with Et2O gave, after drying
(MgSO4), filtration, and concentration of the filtrate in vacuo, the
product (1.52 g, 88%) as a pale yellow powder which was used with-
out further purification.
Anal. Calcd for C24H32N2O2: C, 75.75; H, 8.48; N, 7.36. Found: C, 75.90;
H, 8.26; N, 7.60.
N,N-Diisopropyl-2-(3-fluorophenyl)benzamide (33)
According to General Procedure B, a solution of N,N-diisopropylben-
zamide (400 mg, 1.95 mmol) in THF (10 mL) was sequentially treated
with solutions of t-BuLi (1.5 mL, 1.52 M, 2.28 mmol) and ZnCl2
(3.0 mL, 1.0 M, 3.00 mmol). According to General Procedure C, to a
second flask containing a solution of Ni(acac)2 (23 mg, 0.089 mmol)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

L
C. A. Quesnelle, V. Snieckus
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Synthesis
and PPh3 (95 mg, 0.36 mmol) in THF (3 mL) was added sequentially
solutions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the freshly pre-
pared organozinc reagent solution via cannula, and 3-fluorophenyl
trifluoromethanesulfonate (32; 198 mg, 0.81 mmol) in THF (2 + 1 mL)
via cannula. After 24 h, normal workup followed by flash chromatog-
raphy (hexane/EtOAc, 4:1) gave 33 (219 mg, 90%) as a colourless solid;
mp 84.5–85 °C (Et2O/hexane).
pared organozinc reagent via cannula, and N,N-diethyl-3-(trifluoro-
methylsulfonyloxy)benzamide (29; 328 mg, 1.01 mmol) in THF
(2 + 1 mL) via cannula. After 18 h, normal workup followed by flash
chromatography (hexane/EtOAc, 1:1) gave 38 (277 mg, 74%) as a co-
lourless oil.
IR (neat): 1717, 1628 cm–1
.
1H NMR (200 MHz, CDCl3):  = 1.00–1.25 (m, 12 H), 3.25 (q, J = 7.1 Hz,
6 H), 3.50 (bs, 2 H), 7.18–7.44 (m, 8 H).
IR (KBr): 1618 cm–1
.
1H NMR (200 MHz, CDCl3):  = 0.42 (d, J = 6.7 Hz, 3 H, NCH(CH3)2),
0.91 (d, J = 6.7 Hz, 3 H, NCH(CH3)2), 1.31 (d, J = 6.8 Hz, 3 H,
NCH(CH3)2), 1.53 (d, J = 6.8 Hz, 3 H, NCH(CH3)2), 3.25 (sept, J = 6.8 Hz,
1 H, NCH(CH3)2), 3.43 (sept, J = 6.7 Hz, 1 H, NCH(CH3)2), 7.02 (m, 1 H),
7.28–7.40 (m, 7 H).
13C NMR (50 MHz, CDCl3):  = 19.3 (o, NCH(CH3)2), 19.4 (o,
NCH(CH3)2), 20.5 (o, NCH(CH3)2), 20.6 (o, NCH(CH3)2), 45.5 (o,
NCH(CH3)2), 50.5 (o, NCH(CH3)2), 114.2 (o, d, J = 21.0 Hz), 116.1 (o, d,
J = 21.7 Hz), 124.9 (o, d, J = 2.7 Hz), 126.4 (o), 128.0 (o), 128.5 (o),
129.0 (o), 129.7 (o, d, J = 8.1 Hz), 136.2 (e), 137.8 (e), 141.9 (e, d, J = 7.7
Hz), 162.5 (e, d, J = 245.8 Hz, ArC-F), 169.8 (o).
13C NMR (50 MHz, CDCl3):  = 13.0 (o, NCH2CH3), 13.8 (o, NCH2CH3),
41.6 (e, NCH2CH3), 41.9 (e, NCH2CH3), 123.2 (o), 125.0 (o), 125.4 (o),
126.6 (o), 128.0 (o), 128.5 (o), 129.7 (o), 130.4 (o), 134.2 (e), 137.1 (e),
138.1 (e), 148.4 (e), 153.8 (e), 170.8 (e).
MS (EI; 70 eV): m/z (%) = 368 (0.3) [M+], 281 (58), 100 (100), 72 (52).
HRMS: m/z calcd for C22H28N2O3: 368.2099; found: 368.2019.
2-[3-(Diethylcarbamoyloxy)phenyl]-6-methoxyphenyl Diethyl-
carbamate (41)
According to General Procedure B, a solution of 2-methoxyphenyl di-
ethylcarbamate (445 mg, 1.99 mmol) in THF (10 mL) was sequentially
treated with solutions of t-BuLi (1.4 mL, 1.71 M, 2.39 mmol) and Zn-
Cl2 (3.0 mL, 1.0 M, 3.00 mmol). According to General Procedure C, to a
second flask containing a solution of Ni(acac)2 (15 mg, 0.058 mmol)
and PPh3 (61 mg, 0.23 mmol) in THF (3 mL) was added sequentially
solutions of MeMgBr (0.07 mL, 3.0 M, 0.21 mmol), the freshly pre-
pared organozinc reagent via cannula, and 3-(trifluoromethylsulfony-
loxy)phenyl diethylcarbamate (39; 353 mg, 1.03 mmol) in THF
(2 + 1 mL) via cannula. After 18 h, normal workup followed by flash
chromatography (hexane/EtOAc, 3:2) gave 41 (394 mg, 92%) as a co-
lourless oil.
MS (EI; 70 eV): m/z (%) = 299 (22) [M+], 256 (23), 199 (100), 170 (24).
Anal. Calcd for C19H22NOF: C, 76.23; H, 7.41; N, 4.68. Found: C, 76.25;
H, 7.17; N, 4.76.
N,N-Diisopropyl-2-(3-pyridyl)benzamide (36)
Procedure 1: According to General Procedure B, a solution of N,N-di-
isopropylbenzamide (400 mg, 1.95 mmol) in THF (10 mL) was se-
quentially treated with solutions of t-BuLi (1.4 mL, 1.71 M,
2.39 mmol) and ZnCl2 (3.0 mL, 1.0 M, 3.00 mmol). According to Gen-
eral Procedure C, to a second flask containing a solution of Ni(acac)2
(18 mg, 0.069 mmol) and PPh3 (76 mg, 0.29 mmol) in THF (3 mL) was
added sequentially solutions of i-PrMgBr (0.10 mL, 2.0 M,
0.20 mmol), the freshly prepared organozinc reagent solution via can-
nula, and 3-pyridyl trifluoromethanesulfonate (34; 244 mg,
1.07 mmol) in THF (2 + 1 mL) via cannula. After 15 h, normal workup
followed by flash chromatography (hexane/EtOAc, 1:2) gave 36
(270 mg, 89%) as a colourless solid; mp 86–87 °C (Et2O/hexane) (Lit.84
86–87 °C).
IR (neat): 1718 cm–1
.
1H NMR (250 MHz, CDCl3):  = 1.06–1.22 (m, 12 H), 3.25–3.39 (m, 8
H), 3.83 (s, 3 H), 6.91–6.99 (m, 2 H), 7.10–7.38 (m, 5 H).
13C NMR (62.9 MHz, CDCl3):  = 13.1 (o), 13.7 (o), 14.0 (o), 41.7 (e),
41.9 (e), 56.0 (o), 111.5 (o), 120.5 (o), 122.0 (o), 122.1 (o), 125.6 (o),
128.5 (o), 135.4 (e), 137.8 (e), 138.8 (e), 151.1 (e), 152.2 (e), 153.6 (e),
153.8 (e).
MS (EI; 70 eV): m/z (%) = 414 (0.2) [M+], 355 (63), 149 (15), 100 (100),
72 (66).
Procedure 2: According to General Procedure B, a solution of N,N-di-
isopropylbenzamide (413 mg, 2.01 mmol) in THF (10 mL) was se-
quentially treated with solutions of t-BuLi (1.4 mL, 1.74 M,
2.44 mmol) and ZnCl2 (3.0 mL, 1.0 M, 3.00 mmol). According to Gen-
eral Procedure C, to a second flask containing a solution of Ni(acac)2
(22 mg, 0.086 mmol) and PPh3 (99 mg, 0.38 mmol) in THF (3 mL) was
added sequentially solutions of MeMgBr (0.10 mL, 3.0 M, 0.30 mmol),
the freshly prepared organozinc reagent via cannula, and 3-bromopy-
ridine (35; 167 mg, 1.06 mmol) in THF (2 + 1 mL) via cannula. After
20 h, normal workup followed by flash chromatography (hexane/EtO-
Ac, 1:2) gave 36 (282 mg, 94%), shown to be identical to that prepared
by Procedure 1 above.
Methoxymethyl 2-(2-Naphthyl)phenyl Ether (44)
To a cooled (0 °C), stirred solution of methoxymethyl phenyl ether
(294 mg, 2.12 mmol) in Et2O (5 mL) under argon was added a solution
of t-BuLi (1.4 mL, 1.79 M, 2.51 mmol) and the reaction contents were
warmed slowly to rt over 2 h. The reaction mixture was then treated
with a solution of ZnCl2 (2.2 mL, 1.0 M, 2.20 mmol). A second flask
containing a solution of 2-naphthyl trifluoromethanesulfonate (42;
260 mg, 0.94 mmol) and Ni(acac)2 (14 mg, 0.054 mmol) in THF (3 mL)
was sequentially treated with solutions of i-PrMgCl (0.10 mL, 2.0 M,
0.20 mmol) and the freshly prepared organozinc reagent. After 2 h,
normal workup followed by flash chromatography (hexane/Et2O,
19:1) gave 44 (169 mg, 68%) as a colourless oil.
2-[3-(Diethylaminocarbonyl)phenyl]phenyl Diethylcarbamate
(38)
IR (neat): 3055, 2946, 1492, 1232, 1195, 1155, 1079, 992 cm–1
.
According to General Procedure B, a solution of phenyl diethylcarba-
mate (394 mg, 2.04 mmol) in THF (10 mL) was sequentially treated
with solutions of t-BuLi (1.6 mL, 1.54 M, 2.46 mmol) and ZnCl2
(3.0 mL, 1.0 M, 3.00 mmol). According to General Procedure C, to a
second flask containing a solution of Ni(acac)2 (15 mg, 0.057 mmol)
and PPh3 (55 mg, 0.21 mmol) in THF (3 mL) was added sequentially
solutions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the freshly pre-
1H NMR (250 MHz, CDCl3):  = 3.33 (s, 3 H, OCH2OCH3), 5.08 (s, 2 H,
OCH2OCH3), 7.09 (td, J = 7.3, 1.4 Hz, 1 H), 7.19–7.30 (m, 2 H), 7.39–
7.45 (m, 3 H), 7.67 (dd, J = 8.5, 1.6 Hz, 1 H), 7.80–7.85 (m, 3 H), 7.93 (s,
1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

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C. A. Quesnelle, V. Snieckus
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Synthesis
13C NMR (62.9 MHz, CDCl3):  = 55.9 (o, OCH2OCH3), 94.9 (e,
OCH2OCH3), 115.6 (o), 122.2 (o), 125.7 (o), 125.8 (o), 127.1 (o), 127.5
(o), 128.0 (o), 128.6 (o), 131.1 (o), 131.7 (e), 132.3 (e), 133.3 (e), 136.2
(e), 154.3 (e).
PPh3 (56 mg, 0.21 mmol) in THF (3 mL) was added sequentially solu-
tions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the freshly prepared
organozinc reagent via cannula, and 3-(trifluoromethylsulfony-
loxy)phenyl diethylcarbamate (39; 348 mg, 1.02 mmol) in THF
(2 + 1 mL) via cannula. After 42 h, normal workup followed by flash
chromatography (hexane/EtOAc, 4:1) gave 48 (231 mg, 69%) as a co-
lourless oil.
Ethyl 4-[2-(Methoxymethoxy)phenyl]benzoate (46)
To a cooled (0 °C), stirred solution of methoxymethyl phenyl ether
(286 mg, 2.07 mmol) in Et2O (5 mL) under argon was added a solution
of t-BuLi (1.6 mL, 1.55 M, 2.48 mmol). After 2 h at 0 °C, a solution of
ZnCl2 (3.0 mL, 1.0 M, 3.0 mmol) and THF (10 mL) were added, and the
whole was warmed to rt. According to General Procedure C, to a sec-
ond flask containing a solution of Ni(acac)2 (19 mg, 0.072 mmol) and
PPh3 (72 mg, 0.27 mmol) in THF (3 mL) was added sequentially solu-
tions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the freshly prepared
organozinc reagent via cannula, and ethyl 4-(trifluoromethylsulfony-
loxy)benzoate (45; 301 mg, 1.01 mmol) in THF (2 + 1 mL) via cannula.
After 15 h, normal workup followed by flash chromatography (hex-
ane/EtOAc, 19:1) gave 46 (212 mg, 73%) as a colourless oil.
IR (neat): 1715 cm–1
.
1H NMR (200 MHz, CDCl3):  = 1.23 (m, 6 H, NCH2CH3), 3.39 (s, 3 H,
OCH2OCH3), 3.40 (m, 4 H, NCH2CH3), 5.11 (s, 2 H, OCH2OCH3), 7.02–
7.42 (m, 8 H).
13C NMR (62.9 MHz, CDCl3):  = 13.2 (o, NCH2CH3), 14.0 (o, NCH2CH3),
41.7 (e, NCH2CH3), 42.0 (e, NCH2CH3), 55.8 (o, OCH2OCH3), 94.9 (e,
OCH2OCH3), 115.5 (o), 120.0 (o), 122.0 (o), 122.6 (o), 126.0 (o), 128.3
(o), 128.6 (o), 130.7 (o), 130.9 (e), 139.5 (e), 151.0 (e), 153.9 (e).
MS (EI; 70 eV): m/z (%) = 329 (5) [M+], 297 (14), 181 (18), 100 (100).
HRMS: m/z calcd for C19H23NO4: 329.1628; found: 329.1653.
IR (neat): 1713 cm–1
.
N,N-Diisopropyl-2-[4-(diethylcarbamoyloxy)phenyl]benzamide (55)
1H NMR (200 MHz, CDCl3):  = 1.39 (d, J = 7.1 Hz, 3 H, OCH2CH3), 3.35
(s, 3 H, CH2OCH3), 4.38 (q, J = 7.1 Hz, 2 H, OCH2CH3), 5.09 (s, 2 H,
CH2OCH3), 7.07 (m, 1 H), 7.18–7.34 (m, 3 H), 7.59 (d, J = 8.5 Hz, 2 H),
8.09 (d, J = 8.5 Hz, 2 H).
13C NMR (50 MHz, CDCl3):  = 14.2 (o, OCH2CH3), 55.9 (o, OCH2OCH3),
60.7 (e, OCH2CH3), 94.8 (e, OCH2OCH3), 115.4 (o), 122.2 (o), 128.7 (e),
129.1 (o), 129.2 (o), 129.4 (o), 130.6 (o), 143.1 (e), 154.0 (e), 166.4 (e).
MS (CI; CH4): m/z (%) = 287 (100) [M + 1]+, 255 (87), 211 (65), 183
(11).
HRMS: m/z [M + H]+ calcd for C17H19O4: 287.1283; found: 287.1283.
Procedure 1: According to General Procedure D, a solution of 4-(tri-
fluoromethylsulfonyloxy)phenyl diethylcarbamate (54; 355 mg,
1.05 mmol) in DME (3 mL) was treated with 2-(diisopropylaminocar-
bonyl)phenylboronic acid (53; 361 mg, 1.45 mmol) in DME (3 mL) in
the presence of Pd(PPh3)4 (48 mg, 0.041 mmol). After 24 h, the reac-
tion mixture was cooled to rt. Normal workup followed by flash chro-
matography (hexane/EtOAc, 2:1) gave 55 (200 mg, 48%) as a thick,
viscous oil.
1H NMR (200 MHz, CDCl3):  = 0.43 (d, J = 6.63 Hz, 3 H, NCH(CH3)2),
0.89 (d, J = 6.6 Hz, 3 H, NCH(CH3)2), 1.23 (m, 6 H, NCH2CH3), 1.32 (d,
J = 6.8 Hz, 3 H, NCH(CH3)2), 1.52 (d, J = 6.8 Hz, 3 H, NCH(CH3)2), 3.22–
3.47 (m, 4 H, NCH2CH3), 3.89–3.95 (m, 2 H, NCH(CH3)2), 7.14 (d, J = 8.4
Hz, 2 H), 7.29–7.39 (m, 4 H), 7.54 (d, J = 8.4 Hz, 2 H).
13C NMR (50 MHz, CDCl3):  = 13.3 (o, NCH2CH3), 14.1 (o, NCH2CH3),
19.5 (o, NCH(CH3)2), 20.7 (o, NCH(CH3)2), 41.8 (e, NCH2CH3), 42.0 (e,
NCH2CH3), 45.6 (o, NCH(CH3)2), 50.6 (o, NCH(CH3)2), 121.5 (o), 126.5
(o), 127.5 (o), 128.5 (o), 129.2 (o), 130.0 (o), 136.5 (e), 136.9 (e), 137.6
(e), 151.2 (e), 154.0 (e), 170.4 (e).
MS (EI; 70 eV): m/z (%) = 396 (30) [M+], 353 (4), 296 (40), 100 (100),
72 (44).
N,N-Diethyl-3-[2-(methoxymethoxy)phenyl]benzamide (47)
To a cooled (0 °C), stirred solution of methoxymethyl phenyl ether
(290 mg, 2.10 mmol) in Et2O (5 mL) under argon was added a solution
of t-BuLi (1.6 mL, 1.55 M, 2.48 mmol). After 2 h at 0 °C, a solution of
ZnCl2 (3.0 mL, 1.0 M, 3.0 mmol) and THF (10 mL) were added, and the
whole was warmed to rt. According to General Procedure C, to a sec-
ond flask containing a solution of Ni(acac)2 (19 mg, 0.075 mmol) and
PPh3 (67 mg, 0.25 mmol) in THF (3 mL) was added sequentially solu-
tions of MeMgBr (0.08 mL, 3.0 M, 0.24 mmol), the freshly prepared
organozinc reagent via cannula, and N,N-diethyl-3-(trifluoromethyl-
sulfonyloxy)benzamide (29; 333 mg, 1.02 mmol) in THF (2 + 1 mL)
via cannula. After 25 h, normal workup followed by flash chromatog-
raphy (hexane/EtOAc, 1:1) gave 47 (294 mg, 92%) as a colourless oil.
HRMS: m/z calcd for C24H32N2O3: 396.2413; found: 396.2422.
Procedure 2: According to General Procedure B, a solution of N,N-di-
isopropylbenzamide (1.50 g, 7.28 mmol) in THF (25 mL) was sequen-
tially treated with solutions of t-BuLi (4.8 mL, 1.84 M, 8.83 mmol) and
ZnCl2 (10.0 mL, 1.0 M, 10.00 mmol). To a second flask containing a
solution of 4-bromophenyl diethylcarbamate (1.00 g, 3.67 mmol) and
Pd(PPh3)4 (79 mg, 0.065 mmol) in THF (10 mL) was added the freshly
prepared solution of the organozinc reagent via cannula, and the re-
action mixture was subsequently heated to reflux. After 17 h, the re-
action mixture was cooled to rt. Normal workup followed by flash
chromatography (hexane/EtOAc, 2:1) gave 55 (745 mg, 51%), shown
to be identical to that prepared by Procedure 1 above.
IR (neat): 1628 cm–1
.
1H NMR (200 MHz, CDCl3):  = 1.16 (bs, 6 H, NCH2CH3), 3.35 (s, 3 H,
OCH2OCH3), 3.52 (bs, 4 H, NCH2CH3), 5.09 (s, 2 H, OCH2OCH3), 7.06 (td,
J = 7.2, 1.4 Hz, 1 H), 7.18–7.57 (m, 7 H).
13C NMR (50 MHz, CDCl3):  = 12.6 (o, NCH2CH3), 14.0 (o, NCH2CH3),
39.1 (e, NCH2CH3), 43.0 (e, NCH2CH3), 55.7 (o, OCH2OCH3), 94.7 (e,
OCH2OCH3), 115.3 (o), 122.0 (o), 124.6 (o), 127.8 (o), 128.7 (o), 129.9
(o), 130.7 (o), 136.6 (e), 138.4 (e), 153.9 (e), 171.0 (e).
3-[2-(Methoxymethoxy)phenyl]phenyl Diethylcarbamate (48)
N,N-Diisopropyl-2-[4-(2-tolyl)phenyl]benzamide (57)
To a cooled (0 °C), stirred solution of methoxymethyl phenyl ether
(287 mg, 2.07 mmol) in Et2O (5 mL) under argon was added a solution
of t-BuLi (1.6 mL, 1.55 M, 2.48 mmol). After 2 h at 0 °C, a solution of
ZnCl2 (3.0 mL, 1.0 M, 3.0 mmol) and THF (10 mL) were added, and the
whole was warmed to rt. According to General Procedure C, to a sec-
ond flask containing a solution of Ni(acac)2 (15 mg, 0.058 mmol) and
A flask charges with N,N-diisopropyl 2-(4-N,N-diethylcarbamoylphe-
nyl) benzamide (203 mg, 0.51 mmol) and Ni(acac)2 (17 mg, 0.065
mmol) in Et2O (4ml) under N2 was added a solution of o-tolylmagne-
sium chloride (2.0 mL, 1.0 M, 2.00 mmol). After 30 h, normal workup
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–P

N
C. A. Quesnelle, V. Snieckus
Paper
Synthesis
followed by flash chromatography (4:1 hexane–EtOAc) gave com-
pound 53 (74 mg, 39%) as colourless needles: mp 188–189 °C (hex-
ane).
1H NMR (200 MHz, CDCl3):  = 0.40 (d, J = 6.6 Hz, 3 H), 0.91 (d, J = 6.6
Hz, 3 H), 1.32 (d, J = 6.8 Hz, 3 H), 1.54 (d, J = 6.8 Hz, 3 H), 2.28 (s, 3 H),
3.25 (sept, J = 6.8 Hz, 1 H), 3.47 (sept, J = 6.6 Hz, 1 H), 7.23–7.47 (m, 11
H), 7.62 (d, J = 8.2 Hz, 1 H).
(11) (a) Brimble, M. A.; Chan, S. H. Aust. J. Chem. 1998, 51, 235.
(b) Chamoin, S.; Houldsworth, S.; Snieckus, V. Tetrahedron Lett.
1998, 39, 4175. (c) Echavarren, A. M.; Tamayo, N.; Cardenas, D. J.
J. Org. Chem. 1994, 59, 6075. (d) Fu, J. M.; Sharp, M. J.; Snieckus,
V. Tetrahedron Lett. 1988, 29, 5459.
(12) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 6790.
(13) Monzon, G.; Knochel, P. Synlett 2010, 304.
(14) (a) Rohbogner, C. J.; Wunderlich, S. H.; Clososki, G. C.; Knochel,
P. Eur. J. Org. Chem. 2009, 1781. (b) Wunderlich, S. H.;
Rohbogner, C. J.; Unsinn, A.; Knochel, P. Org. Process Res. Dev.
2010, 14, 339. (c) Clososki, G. C.; Rohbogner, C. J.; Knochel, P.
Angew. Chem. Int. Ed. 2007, 46, 7681. (d) See also ref. 13
(15) (a) Ghosh, S.; Kumar, A. S.; Mehta, G. N.; Soundararajan, R.; Sen,
S. J. Chem. Res. 2009, 205. (b) Bologna, A.; Barreca, G.; Allegrini,
P. Eur. Pat. Appl. EP 1878735, 2008; Chem. Abstr. 2008, 148,
144870
13C NMR (50 MHz, CDCl3):  = 19.4 (o), 19.5 (o), 20.7 (o), 20.8 (o), 21.4
(o), 45.6 (o), 50.5 (o), 125.8 (o), 126.6 (o), 127.3 (o), 127.6 (o), 128.5
(o), 129.1 (o), 129.7 (o), 130.3 (o), 135.2 (e), 137.3 (e), 138.0 (e), 138.3
(e), 141.2 (e), 170.3 (e).
MS (EI; 70 eV): m/z (%) = 371 (27) [M+], 328 (36), 271 (100), 228 (24).
Anal. Calcd for C26H29NO: C, 84.06; H, 7.87; N, 3.77. Found: C, 84.49;
H, 7.72; N, 3.74.
(16) (a) Fu, Y.; Laurent, S.; Muller, R. N. Eur. J. Org. Chem. 2002, 3966.
(b) Akine, S.; Nagumo, H.; Nabeshima, T. Dalton Trans. 2013, 42,
15974.
Funding Information
(17) (a) Hatakeyama, T. PCT Int. Appl. WO 2016143819, 2016; Chem.
Abstr. 2016, 165, 406046 (b) Numano, M.; Nagami, N.;
Nakatsuka, S.; Katayama, T.; Nakajima, K.; Tatsumi, S.; Yasuda,
N.; Hatakeyama, T. Chem. Eur. J. 2016, 22, 11574. (c) Bryan, Z. J.;
McNeil, A. J. Chem. Sci. 2013, 4, 1620. (d) Handa, S.; Arachchige,
Y. L. N. M.; Slaughter, L. M. J. Org. Chem. 2013, 78, 5694.
(18) (a) Jaric, M.; Haag, B. A.; Unsinn, A.; Karaghiosoff, K.; Knochel, P.
Angew. Chem. Int. Ed. 2010, 49, 5451. (b) McCann, L. C.; Organ,
M. G. Angew. Chem. Int. Ed. 2014, 53, 4386.
We are grateful to NSERC Canada, Discovery Grant (DG 05698) for
support of our synthetic programs. C.A.Q. thanks NSERC for a gradu-
ate fellowship.
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References
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Paper
Synthesis
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