Copper-Mediated Functionalization of Aryl Trifluoroborates

Article abstract of DOI:10.1055/s-0035-1562529

This paper describes the Cu(OTf)₂-mediated coupling of aryl and heteroaryl trifluoroborates with tetrabutylammonium or alkali metal salts to form C-O, C-N, and C-halogen bonds. The reactions proceed under mild conditions (often room temperature over 16 hours) with carboxylate, halide, and azide salts, all nucleophiles that have been underrepresented in the copper cross-coupling literature. Preliminary results show that copper salts bearing weakly coordinating X-type ligands are essential for enabling these transformations to proceed under mild conditions.

Full text of DOI:10.1055/s-0035-1562529

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
S. D. Schimler, M. S. Sanford
Letter
Synlett
Copper-Mediated Functionalization of Aryl Trifluoroborates
Sydonie D. Schimler
Melanie S. Sanford*
Br
Cl
I
R
R
R
Cu(OTf)2
MX
BF3K
Department of Chemistry, University of Michigan, 930 North
University Avenue, Ann Arbor, MI, 48109, USA
mssanfor@umich.edu
R
O
R'
N3
25–60 °C
bench top
R
R
O
38 examples
Received: 14.06.2016
Accepted after revision: 08.07.2016
Published online: 11.08.2016
heteroaryl systems,6b,d,e,7b–d,8a–c,9b in general heteroaryl-
boron coupling partners are underrepresented in many
state-of-the-art methods.
DOI: 10.1055/s-0035-1562529; Art ID: st-2016-r0388-l
We sought to begin to address these limitations through
the development of a new copper-mediated coupling of aryl-
boron compounds with heteroatom nucleophiles. We
sought a process that works for nucleophiles that are less
common in the literature (e.g., carboxylates, halides, sulfon-
ates, and azides) and that proceeds under mild conditions
with diverse aryl/heteroarylboron partners. Such a method
could be particularly valuable for assembling a series of an-
alogues in a medicinal chemistry and/or combinatorial
chemistry context.10 We report here that Cu(OTf)2 mediates
the coupling of aromatic and heteroaromatic trifluorobo-
rate salts with carboxylate, halide, tosylate, and azide nucle-
ophiles. Under the optimal conditions, the reactions pro-
ceed at temperatures ranging from room temperature to
60 °C and provide modest to excellent yields of the coupled
products.
Our initial efforts focused on the coupling of potassium
4-fluorophenyl trifluoroborate (1) with potassium trifluo-
roacetate (KOTFA) to form ester 2. This transformation was
selected as a test reaction based on the limited number of
copper-mediated couplings of arylboron compounds with
carboxylate salts,5,11 particularly using weakly nucleophilic
derivatives such as trifluoroacetate. Based on our recent
studies of the Cu(OTf)2-mediated fluorination of aryltriflu-
oroborate salts with KF,12 we selected analogous conditions
as a starting point for reaction development.13 The combi-
nation of 1, Cu(OTf)2 (4 equiv) and KOTFA (4 equiv) in MeCN
under N2 at 60 °C afforded the ester product 2 in 43% yield
(Table 1, entry 1).14 The reaction affords a comparable yield
when set up on the benchtop rather than under inert atmo-
sphere (46%, Table 1, entry 2). Reducing the reaction tem-
perature to room temperature resulted in a significantly
lower yield with KOTFA as the coupling partner (18%). How-
Abstract This paper describes the Cu(OTf)2-mediated coupling of aryl
and heteroaryl trifluoroborates with tetrabutylammonium or alkali
metal salts to form C–O, C–N, and C–halogen bonds. The reactions pro-
ceed under mild conditions (often room temperature over 16 hours)
with carboxylate, halide, and azide salts, all nucleophiles that have been
underrepresented in the copper cross-coupling literature. Preliminary
results show that copper salts bearing weakly coordinating X-type li-
gands are essential for enabling these transformations to proceed un-
der mild conditions.
Key words azides, copper, coupling, carboxylation, halogenation
Over the past two decades, copper-mediated carbon–
heteroatom bond-forming reactions have emerged as inex-
pensive and often complementary alternatives to palladi-
um-catalyzed cross-couplings.1,2 A particularly important
advance in this area was the development of the copper-
mediated Chan–Evans–Lam coupling of arylboron reagents
with nitrogen and oxygen nucleophiles.1–3 The arylboron
coupling partners for these reactions are readily available
and inexpensive, and their copper-mediated C–N and C–O
bond-forming reactions often proceed under mild condi-
tions. However, despite tremendous progress in this field,
there are still some limitations to state-of-the-art existing
methods.4 For example, the majority of these transforma-
tions involve strongly nucleophilic coupling partners (e.g.,
phenoxides or amines/amides). In contrast, weaker nucleo-
philes (e.g., carboxylates,5 sulfonates, azides,4,6 or halides4,7–9
)
are less commonly employed in these reactions. Additional-
ly, many literature methods are optimized for a specific he-
teroatom nucleophile, and thus are not readily generaliz-
able to a wider range of nucleophilic coupling partners. Fi-
nally, although some previous studies have addressed
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
S. D. Schimler, M. S. Sanford
Letter
Synlett
ever, the use of NaOTFA under otherwise analogous condi-
tions resulted in 51% yield of product 2 (Table 1, entry 4). A
slight improvement in yield was observed upon heating the
reaction of 1 with NaOTFA to 60 °C (Table 1, entry 5).15 Oth-
er organoboron reagents were also examined, and the cor-
responding boronic acid afforded a similar yield as 1
(50%).16 For the rest of these studies, we focused on organo-
trifluoroborate substrates due to the slightly higher yields
and enhanced stability of these organoboron reagents.
4 equiv Cu(OTf)2
4 equiv nucleophile (X–)
BF3K
X
R
R
MeCN, 16 h
OH
O
O
CF3
O
O
F
F
Ph
2 51% (NaOTFA)a
4 65% (NBu4OAc)
3 46% (NaOTFA)b
O
Ph
O
O
O
O
O
Table 1 Trifluoroacetoxylation of 1 To Form 2
F
F
F
6 67% (NaOPiv)
5 61% (NaO2C2H5)
7 70% (NBu4OBz)
4 equiv Cu(OTf)2
4 equiv MOTFA
BF3K
O
CF3
OPiv
OPiv
OPiv
O
MeCN, 16 h
O
F
F
2
NC
1
MeO
9 60%
8 62%
10 74%
Entrya
M
Temp (°C)
Yield 2 (%)b
O
S
OPiv
1c
2d
3d
4d
5d
K
60
60
25
25
60
43
46
18
51
55
OPiv
OPiv
O
K
K
11 68%
12 80%
13 31%
OPiv
Na
Na
OPiv
OPiv
N
OMe
N
OEt
S
a Conditions: substrate 1 (0.025 mmol), Cu(OTf)2 (0.1 mmol, 4 equiv),
MOTFA (0.1 mmol, 4 equiv) in MeCN (0.083 M) for 16 h.
b Yield determined by 19F NMR spectroscopy using 1,3,5-trifluorobenzene
as an internal standard.
14 47%
15 17%c
16 16%c
OMe
OPiv
c Reaction set up in N2-filled glovebox.
Cl
OPiv
OPiv
d Reaction set up on benchtop.
N
N
F3C
N
MeO
N
17 65%c
18 49%c
19 4%c
We next explored the scope of carboxylate nucleophiles
for this reaction, using potassium 4-fluorophenyl trifluo-
roborate (1) and potassium 4-biphenyl trifluoroborate as
the arylboron substrates (Scheme 1).17 A variety of alkyl
and aryl carboxylates participate in this transformation, in-
cluding acetate, propionate, pivalate, and benzoate salts, af-
fording products 4, 5, 6, and 7, respectively.5 4-Phenyl-
phenol (3) was isolated in 46% yield from the hydrolysis of
4-trifluoroacetoxybiphenyl.18 Overall, the mild reaction
conditions (room temperature, no additives) compare fa-
vorably to those employed in previous reports of copper-
mediated coupling between aryl/alkenylboron reagents and
carboxylate salts. Other methods typically utilize tempera-
tures of ≥60 °C along with additives such as urea,5a
Ag2CO3,5b or DMAP.5c
This reaction also exhibits good generality with respect
to the potassium trifluoroborate coupling partner, using
NaOPiv as a representative carboxylate (Scheme 1).19 Sub-
strates bearing both electron-withdrawing and electron-
donating substituents react to afford the corresponding es-
ters in reasonable yields (8–13). A variety of heteroaryltri-
fluoroborates are also compatible, although these generally
require a higher temperature (60 °C), and the yields are
modest in some cases (14–19).20 Pyridine derivatives bear-
ing electron-donating substituents afford particularly low
yields among these substrates (for example, see 15, 16, and
Scheme 1 Scope of Cu(OTf)2-mediated coupling of aryl/heteroaryl tri-
fluoroborates with carboxylate nucleophiles. Reagents and conditions:
potassium aryl trifluoroborate (0.5 mmol, 1 equiv), Cu(OTf)2 (4 equiv),
nucleophile (4 equiv), MeCN (0.083 M), 25 °C, 16 h. All yields are of iso-
lated products unless otherwise noted. a Yield determined by 19F NMR
spectroscopic analysis. b Product was obtained via hydrolysis of the tri-
fluoroacetate ester. c Reaction was performed at 60 °C.
19), and show significant quantities of unreacted trifluo-
roborate starting material remaining at the end of the reac-
tion. This may be due to competing coordination of the pyr-
idine to the copper center, which could impede the produc-
tive reaction.
We next explored the use of halide and pseudohalide
nucleophiles for this transformation with either potassium
4-fluorophenyl trifluoroborate (1) and/or potassium 4-bi-
phenyl trifluoroborate. As shown in Scheme 2, these sub-
strates react with tetraalkylammonium halide salts under
our standard conditions (4 equiv of Cu(OTf)2 and 4 equiv of
nucleophile in MeCN at room temperature for 16 h) to af-
ford the corresponding bromo-,7 iodo-,4,8 and chloroarenes9
in modest to excellent yields (20–22). The reaction of potas-
sium 4-biphenyl trifluoroborate with NBu4Br was also con-
ducted on a gram (3.9 mmol) scale, affording the brominat-
ed product 20 in 71% yield. Fluorination with KF also pro-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
S. D. Schimler, M. S. Sanford
Letter
Synlett
ceeds to form 23 at 60 °C.12 Overall, these reaction
conditions are milder1b than most previous examples of the
copper-mediated halogenation of arylboron compounds
(which often require temperatures of ≥80 °C to achieve high
yields).7b,7g,h,8c,9a Remarkably, even weakly nucleophilic
NaOTs undergoes Cu(OTf)2-mediated coupling with potas-
sium 4-fluorophenyl trifluoroborate to afford 4-fluorophe-
nyl tosylate at 60 °C (24), albeit in low (13%) yield. This is a
rare example of the use of TsO– as a nucleophile in a metal-
mediated coupling.21,22
substrates.6 The azidation proceeded efficiently under our
standard reaction conditions (4 equiv Cu(OTf)2, 4 equiv KN3,
MeCN, 25–60 °C, 16 h) to afford a diverse set of aryl (25–29)
and heteroaryl (30–37) azide products (Scheme 2).25 Unlike
the reaction with NaOPiv as the nucleophile (Scheme 1),
the reaction of potassium thiophene-3-trifluoroborate with
KN3 provided no detectable product (32). Modest to good
yields were obtained with pyridine and pyrimidine sub-
strates bearing both electron-withdrawing and electron-
donating groups (33–37). This is in notable contrast to the
corresponding carboxylation reaction (Scheme 1). We ten-
tatively hypothesize that the better coordinating ability of
N3– versus RCO2– to copper may impede unproductive pyri-
dine binding in this transformation.
4 equiv Cu(OTf)2
4 equiv nucleophile (X–)
BF3K
X
R
R
MeCN, rt, 16 h
To gain insights into the nature of the reactive copper
species in these transformations, we evaluated a series of
different copper(II) mediators. These were explored for the
reactions of both KN3 and NaOPiv with aryltrifluoroborate
1 (Table 2). Cu(OTf)2 provided the highest yield in both the
carboxylation and the azidation reactions (80% and 82%, re-
spectively). Significantly lower yields were obtained with
Cu(OMs)2 (Table 2, entry 2), while Cu(OTs)2 afforded none
of the desired product with either nucleophile. Notably, no
incorporation of TsO– was observed with this salt, and the
mass balance was unreacted starting material along with
traces of the proteodeborylation product fluorobenzene.
Copper(II) salts bearing weakly coordinating counterions
(e.g., BF4 and NO3 ) provided modest yields of both prod-
ucts (Table 2, entries 4 and 5). However, no functionalized
products were detected with the more coordinating sulfate
or acetate copper(II) salts (Table 2, entries 6 and 7). With
Cu(OAc)2, the mass balance was unreacted starting materi-
al, and the corresponding acetoxylated product was not de-
tected in either reaction.
Br
I
Cl
Ph
Ph
Ph
22 46% (NMe4Cl)a
20 86% (NBu4Br)
71% on 1 g scale
21 70% (NBu4I)
F
OTs
N3
Ph
F
Ph
25 51% (KN3)
N3
23 48% (KF)a
24 13% (NaOTs)a
N3
N3
O
MeO
NC
26 42%
26 16%
28 33%
–
–
O
S
N3
N3
N3
O
29 10%
30 80%
31 32%
N3
N3
N3
N
OMe
33 65%
N3
N
OEt
S
32 nd
34 71%
Table 2 Copper(II) Screen for Azidation and Pivalationa
OMe
N3
Cl
N3
4 equiv [Cu]
4 equiv KN3 or NaOPiv
N
BF3K
X
N
F3C
N
MeO
N
MeCN, rt, 16 h
F
F
35 55%
36 56%a
37 80%
38 X = N3
1
6 X = OPiv
Scheme 2 Scope of Cu(OTf)2-mediated coupling of aryl/heteroaryl
trifluoroborates with halide, pseudohalide, and azide nucleophiles. Re-
agents and conditions: potassium aryl trifluoroborate (0.5 mmol, 1 equiv),
Cu(OTf)2 (4 equiv), nucleophile (4 equiv), MeCN (0.083 M), 25 °C, 16 h.
Isolated yields are reported. a Reaction was performed at 60 °C; nd = not
detected.
Entry
[Cu]
Cu(OTf)2
Yield of 38 (%)b
Yield of 6 (%)b
1
2
3
4
5
6
7
82
11
<1
52
40
<1
<1
80
28
<1
35
61
<1
<1
Cu(OMs)2
Cu(OTs)2
Cu(NO3)2
Cu(BF4)2
CuSO4
We next employed potassium azide as a nucleophile in
these transformations.23 The aryl azide products are valu-
able as photoaffinity labels, substrates for copper-catalyzed
azide/alkyne cycloaddition, and as synthetic building
blocks for other important transformations.24 Furthermore,
many existing methods for coupling arylboron compounds
and N3– suffer from the requirement for high reaction tem-
peratures (>60 °C) and/or limited applicability to heteroaryl
Cu(OAc)2
a Conditions: 1 (0.025 mmol, 1 equiv), [Cu] (0.1 mmol, 4 equiv), KN3 or
NaOPiv (0.1 mmol, 4 equiv), MeCN (0.083 M), 25 °C, 16 h.
b Yields were determined by 19F NMR spectroscopic analysis of the crude
reaction mixture.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
S. D. Schimler, M. S. Sanford
Letter
Synlett
We next explored the effect of varying the amount of
the azide nucleophile on the reaction between 1 and KN3.
As shown in Scheme 3, the highest yield of the desired
product 38 was obtained with 4 equivalents of KN3, which
ator for the C–heteroatom coupling step. The efficient and
rapid derivatization of aromatic molecules into a variety of
related analogues is common practice in medicinal chemis-
try; as such, we anticipate that this method will find valu-
able applications in this context.
–
represents a 1:1 ratio between Cu and N3 . Increasing the
amount of KN3 beyond 4 equivalents had a detrimental im-
pact on the reaction yield; for example, with 8 equivalents
of KN3 the yield of 38 was <10%, and unreacted starting ma-
terial remained at the end of the reaction. An analogous
trend was observed when varying the stoichiometry of
NaOPiv in the reaction (Scheme 3). Again, the maximum
yield of product 6 was obtained with 4 equivalents of
NaOPiv, while <5% yield was observed with 8 equivalents of
NaOPiv.26 Overall, we hypothesize that the decrease in yield
at higher equivalents of nucleophile is due to the coordina-
tion of two azide or carboxylate ligands to the copper cen-
ter, which results in a significantly less reactive copper spe-
cies.
Acknowledgment
We thank Dow Chemical for support of this research. S.D.S. thanks
Rackham Graduate School for a graduate fellowship.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562529.
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References and Notes
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Scheme 3 Equivalents of KN3 and NaOPiv versus yield of 38 and 627
Given the above results, we propose that copper(II) like-
ly plays a dual role in this reaction: (1) it acts as an oxidant
to access a reactive copper(III) species and (2) it serves as a
promoter of the key C–Nuc coupling event.12,28 We hypoth-
esize that the strongly electrophilic CuII(OTf)2 is particularly
critical for the oxidation event. The addition of excess nuc-
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stitution), thereby reducing reactivity. This is consistent
with the observation of low yields with more than 8 equiv-
alents of nucleophile, since this stoichiometry should lead
to essentially complete conversion of Cu(OTf)2 into
Cu(Nuc)2.
In summary, this paper demonstrates the Cu(OTf)2-me-
diated functionalization of aryl/heteroaryltrifluoroborates
with various nucleophiles. This transformation enables the
formation of diverse carbon–heteroatom bonds under an
analogous set of mild reaction conditions (often at room
temperature and without additives). The use of superstoi-
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pothesize that it plays a dual role as an oxidant and a medi-
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Letter
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(176 MHz, CDCl3): δ = 177.11, 161.07 (J = 501 Hz), 146.91 (J =
5.2 Hz), 122.89 (J = 18.2 Hz), 116.05 (J = 49.4 Hz), 39.04, 27.09.
IR (cm–1): 1749, 1503, 1481, 1276, 1182, 1107, 1028, 891, 831,
796, 755. HRMS (ES): m/z [M]+ calcd for C11H13FO2: 196.0899;
found: 196.0899. The isolated yield reported in Scheme 1 (67%)
represents an average of two runs (68% and 65%).
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(11) Notably, many Chan–Evans–Lam coupling reactions employ
Cu(II) carboxylate salts as catalysts; however, aryl–OC(O)R side
products are rarely reported.
(12) Ye, Y.; Schimler, S. D.; Hanley, P. S.; Sanford, M. S. J. Am. Chem.
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(13) Experimental Optimization of Trifluoroacetoxylation of
Potassium (4-Fluorophenyl)Trifluoroborate Reported in
Table 1
(18) The product was intentionally hydrolyzed to the phenol. See
Supporting Information for details.
(19) General Procedure for Cu-Mediated Substrate Scope of Piva-
lation Reactions in Scheme 1
The aryl trifluoroborate substrate (0.5 mmol, 1 equiv), Cu(OTf)2
(723 mg, 2 mmol, 4 equiv), and sodium pivalate (248 mg, 2
mmol, 4 equiv) were weighed into a 20 mL vial equipped with a
magnetic stir bar. MeCN (6 mL) was added, and the vial was
sealed with a Teflon-lined cap. The reaction mixture was
allowed to stir at room temperature for 16 h. For pyridine sub-
strates, after 16 h, poly(4-vinylpyridine) (1 g) was added to the
solution, and the resulting mixture was stirred for an additional
12 h at room temperature. The resulting solution was diluted
with Et2O (10 mL), and then the organic layers were washed
with water (3 × 10 mL) and with a 1 M aq NH4OH solution, satu-
rated with EDTA (10 mL). The organic layer was dried over
MgSO4, filtered, and concentrated under pressure. The products
were purified by column chromatography on silica. For further
experimental and spectroscopic details, see Supporting Infor-
mation.
In a nitrogen-filled glovebox or on the benchtop, potassium (4-
fluorophenyl)trifluoroborate (5.1 mg, 0.025 mmol, 1 equiv),
Cu(OTf)2 (36.1 mg, 0.1 mmol, 4 equiv), and MOTFA (0.1 mmol, 4
equiv) were weighed into a 4 mL vial equipped with a magnetic
stir bar. MeCN (0.3 mL) was added, and the vial was sealed with
a Teflon-lined cap. The reaction mixture was allowed to stir at
60 °C or at room temperature for 16 h. The solution was then
cooled to room temperature and diluted with MeCN. 1,3,5-Tri-
fluorobenzene was added as an internal standard, and the reac-
tion was analyzed by 19F NMR spectroscopy.
2-Methoxypyridin-3-yl pivalate (15)
This reaction was performed using potassium (2-methoxypyri-
din-3-yl)trifluoroborate (108 mg, 0.5 mmol, 1 equiv) according
to the general procedure except with heating at 60 °C for 16 h.
Product 15 was obtained as a white solid (18 mg, 17% yield, mp
54–56 °C, Rf = 0.39 in 9:1 pentane–Et2O). 1H NMR (500 MHz,
CDCl3): δ = 8.01 (d, J = 5.0 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 1 H), 6.88
(dd, J = 7.5, 5.0 Hz, 1 H), 3.95 (s, 3 H), 1.37 (s, 9 H). 13C NMR (125
MHz, CDCl3): δ = 176.32, 156.53, 143.47, 135.28, 130.46, 116.74,
53.65, 39.07, 27.09. IR (cm–1): 1754, 1602, 1559, 1474, 1455,
1413, 1318, 1262, 1173, 1099, 1016, 885, 861, 780, 751. HRMS
(ES): m/z [M + H]+ calcd for C11H15NO3: 210.1125; found:
210.1123. The isolated yield reported in Scheme 1 (17%) rep-
resents an average of two runs (17% and 16%).
(14) Under the standard conditions, the reaction is homogenous. For
reactions in other solvents, see Supporting Information.
(15) For further optimization, see Supporting Information.
(16) For reactions with other organoboron reagents, see Supporting
Information.
(17) Cu-Mediated Nucleophile Scope of Potassium (4-Fluorophe-
nyl) Trifluoroborate (1) or Potassium (4-Biphenyl)Trifluo-
roborate with Tetraalkylammonium and Alkali Salts
Reported in Scheme 1 and Scheme 2
Potassium (4-fluorophenyl)trifluoroborate (1, 101 mg, 0.5
mmol, 1 equiv) or potassium (4-biphenyl)trifluoroborate (130
mg, 0.5 mmol, 1 equiv), Cu(OTf)2 (722 mg, 2 mmol, 4 equiv),
and tetraalkylammonium or alkali salt (2 mmol, 4 equiv) were
weighed into a 20 mL vial equipped with a magnetic stir bar.
MeCN (6 mL) was added, and the vial was sealed with a Teflon-
lined cap. The reaction mixture was allowed to stir at room
temperature for 16 h. For products that were isolated, the reac-
tions were diluted with Et2O or pentane (10 mL), and this solu-
tion was washed with water (3 × 10 mL). The organic layer was
dried over MgSO4, filtered, and concentrated under vacuum.
The products were purified by column chromatography on
silica gel. For product yields determined by 19F NMR spectros-
copy, the crude reaction mixture was diluted with MeCN, 1,3,5-
trifluorobenzene was added as an internal standard, and the
reaction was analyzed by 19F NMR spectroscopy. For experi-
mental and spectroscopic details, see Supporting Information.
4-Fluorophenyl Pivalate (6)
(20) Indole substrates were not compatible with these reaction con-
ditions.
(21) For an example of C(sp3)–OTs reductive elimination from
Pd(IV), see: Camasso, N. M.; Pérez-Temprano, M. H.; Sanford, M.
S. J. Am. Chem. Soc. 2014, 136, 12771.
(22) Xu, Y.; Yan, G.; Ren, Z.; Dong, G. Nat. Chem. 2015, 7, 829.
(23) More common Chan-Evans-Lam nitrogen nucleophiles includ-
ing potassium phthalimide, sodium saccharin, and potassium
pyridone also react with aryl trifluoroborates under our stan-
dard conditions to afford modest yields of C–N coupled prod-
ucts. See the Supporting Information for full details.
(24) (a) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.
Int. Ed. 2005, 44, 5188. (b) Scriven, E. F. V.; Turnbull, K. Chem.
Rev. 1988, 88, 297. (c) Applications of Photochemistry in Probing
Biological Targets, In Annals of the New York Academy of Sciences;
Vol. 346; Tometsko, A. M.; Richards, F. W., Eds.; The New York
Academy of Sciences: New York, 1980.
(25) General Procedure for Cu-Mediated Azidation Reactions in
Scheme 2
This reaction was performed with substrate 1 according to the
general procedure. Product 6 was obtained as as a clear liquid
(66 mg, 68% yield, Rf = 0.58 in 98:2 pentane–Et2O). 1H NMR
(500 MHz, CDCl3): δ = 7.07–6.99 (multiple peaks, 4 H), 1.35 (s,
9 H). 19F NMR (376 MHz, CDCl3): δ = –117.51 (m, 1 F). 13C NMR
The aryl trifluoroborate substrate (0.5 mmol, 1 equiv), Cu(OTf)2
(723 mg, 2 mmol, 4 equiv), and KN3 (162 mg, 2 mmol, 4 equiv)
were weighed into a 20 mL vial equipped with a magnetic stir
bar. MeCN (6 mL) was added, and the vial was sealed with a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
S. D. Schimler, M. S. Sanford
Letter
Synlett
Teflon-lined cap. The reaction mixture was allowed to stir at
room temperature for 12 h. For pyridine substrates, after 12 h,
poly(4-vinylpyridine) (1 g) was added to the solution, and the
resulting mixture was stirred for 12 h at room temperature. The
resulting solution was diluted with Et2O (10 mL), and the
organic layer was extracted with H2O (3 × 10 mL). The organic
layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The products were purified by column chro-
matography on silica. For further experimental and spectro-
scopic details, see Supporting Information.
NMR (125 MHz, CDCl3): δ = 156.13, 147.45, 127.71, 126.14,
124.78, 123.69, 123.56, 123.15, 120.87, 117.05, 116.87, 112.00.
IR: 2104, 1636, 1584, 1494, 1448, 1424, 1352, 1312, 1293, 1190,
1071, 915, 898, 845, 827, 787, 738 cm–1. HRMS (ES): m/z [M]+
calcd for C12H7N3O: 209.0589; found: 209.0582. The isolated
yield reported in Scheme 2 (80%) represents an average of two
runs (81% and 79%).
(26) When the reaction was performed using Cu(OPiv)2 with or
without exogenous NaOPiv, <14% of product 6 was detected.
When the reaction was performed using Cu(OPiv)2 (4 equiv)
and Cu(OTf)2 (4 equiv), 76% of product 6 was detected. Lowering
the amount of either Cu(II) species (2 equiv of each) lead to
lower yields.
4-Azidodibenzo[b,d]furan (30)
This reaction was performed using potassium dibenzofuran-4-
trifluoroborate (138 mg, 0.5 mmol, 1 equiv) according to the
general procedure. Product 30 was obtained as a yellow oil (84
mg, 81% yield, Rf = 0.32 in hexanes). 1H NMR (500 MHz, CDCl3):
δ = 7.90 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.0 Hz, 1 H), 7.60 (d, J =
8.0 Hz, 1 H), 7.48 (td, J = 8.0, 1.0 Hz, 1 H), 6.36 (td, J = 8.0, 1.0 Hz,
1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.10 (dd, J = 8.0, 1.0 Hz, 1 H). 13C
(27) Yields determined by 19F NMR spectroscopic analysis of the
crude reaction mixtures.
(28) (a) Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301. (b) Hickman, A.
J.; Sanford, M. S. Nature (London, U.K.) 2012, 484, 177.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F