Synthesis and Minisci reactions of organotrifluoroborato building blocks

Article abstract of DOI:10.1021/jo4005519

Copper-catalyzed borylation of a variety of organic halides with bis(pinacolato)diboron allows the preparation of diverse potassium organotrifluoroborates. The reactions are mild and general, providing access to a variety of interesting, boron-containing

Full text of DOI:10.1021/jo4005519

Note
pubs.acs.org/joc
Synthesis and Minisci Reactions of Organotrifluoroborato Building
Blocks
Marc Presset,†,‡ Nicolas Fleury-Breg
eot, Daniel Oehlrich, Frederik Rombouts,*
†
‡
,‡
́
,
†
and Gary A. Molander*
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
‡
Neuroscience Medicinal Chemistry, Research & Development, Janssen Pharmaceutica, Turnhoutseweg 30, 2340 Beerse, Belgium
*
S Supporting Information
ABSTRACT: Copper-catalyzed borylation of a variety of
organic halides with bis(pinacolato)diboron allows the
preparation of diverse potassium organotrifluoroborates. The
reactions are mild and general, providing access to a variety of
interesting, boron-containing building blocks, including those
containing piperidine, pyrrole, azetidine, tetrahydropyran, and oxetane substructures. Representative Minisci reactions are
reported for select examples.
s a consequence of their successful and, thus, increasing
We recently reported the preparation of potassium β-
alkoxyethyltrifluoroborates, using an adaptation of Marder
and Liu’s conditions, wherein a copper(I)-catalyzed bor-
A
use in a variety of reactions, the demand for new boron-
1
20
containing building blocks is constantly growing. Among
them, organotrifluoroborates have been shown to be a valuable
alternative to boronic acids owing to the increased stability
ylation of the corresponding primary bromides was followed by
treatment with KHF
resulting organotrifluoroborates were subsequently used in
to afford the target structures. The
2
2
,3
conferred by the tetracoordinated boron atom. In particular,
the efficiency of the organotrifluoroborates in a broad range of
reactions has been demonstrated, taking advantage of the
reactivity of the boron−carbon bond, as well as reactions where
27
Suzuki−Miyaura cross-coupling reactions (eq 1).
4
,5
the boron is retained.
Aliphatic potassium organotrifluoroborates can be easily
obtained by simply treating appropriate organoboron pre-
Based on the success of this approach, we explored other
alkyl halides as substrates for the copper-promoted borylation,
and we were particularly interested in saturated heterocycles
bearing a secondary halogen, which would provide access to
heterocyclic trifluoroborates that are challenging to access by
other means. To this end, N-Boc-4-bromopiperidine was used
as a test substrate under the same conditions used for the β-
alkoxyethyl system. The desired transformation proceeded
smoothly and afforded, after treatment with potassium
bifluoride, the corresponding potassium organotrifluoroborate
cursors with potassium bifluoride (KHF ) or KF in the
2
6
presence of tartaric acid. In general, the requisite organo-
borons can be accessed by different methods: (1) reaction of an
organometallic (organomagnesium or organolithium) reagent
7
,8
with an electrophilic boron species BX (X = Cl, F, OR); (2)
3
9
,10
hydroboration of alkenes;
or (3) borylation of alkanes by
Recently, much attention has been
placed on the use of nucleophilic boron species, and in
preference to the highly reactive boryllithiums or NHC-
1
1,12
C−H bond activation.
1
3,14
boranes,
activation of dibora compounds by a nucleophile
1
a in 72% yield (Table 1, entry 1). As was reported previously,
was found to be a more efficient and useful synthetic
the use of polystyrene-supported triphenylphosphine (PS-
1
5,16
protocol.
More precisely, copper(I)-catalyzed reactions
PPh ) was found to be crucial to obtain a pure product,
3
were particularly successful in the case of 1,4-additions to
avoiding contamination with triphenylphosphine oxide. More-
over, these conditions proved to be general and have been
successfully applied to various substrates. Indeed, different
protecting groups on the nitrogen atom are tolerated (Table 1,
entries 1 and 2) and six-, five-, and even four-membered
nitrogen heterocycles provided the desired products in
acceptable yields (Table 1, entries 1, 3, and 4, respectively).
1
7,18
unsaturated carbonyl compounds,
and after the pioneering
19
work on activated electrophiles by Miyaura, the past year has
witnessed the emergence of aliphatic borylation of halogenated
substrates. Therefore, primary, secondary, and even tertiary
2
0,21
22,23
alkylboronates have been prepared by Cu-,
Ni-,
or Pd-
2
4
25
catalysis, providing access to previously problematic targets.
Herein, we report the use of this method for the preparation of
a variety of organotrifluoroborate building blocks of potential
Received: March 15, 2013
26
use as synthons in the development of drug-like compounds.
©
XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
a
Table 1. Borylation of Various Heterocyclic Halides
trifluoroborates synthesized were found to be perfectly stable
to air and moisture upon storage.
Owing to the importance of the piperidine moiety in drug
discovery, we explored whether this strategy would allow the
preparation of other functionalized scaffolds. More precisely,
we were particularly interested in the 2-pyridinyl protecting
group as it has proven to be efficient in the functionalization of
29
piperidines. Consequently, the desired precursor 9 was
obtained in four steps from commercially available reagent 8:
a PEPPSI ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-
(
3-chloropyridyl)palladium(II) dichloride)-catalyzed Buch-
wald−Hartwig amination of 2-chloropyridine 7 provided
30
quantitatively the N-arylated intermediate, which, after two
steps of deprotection and reduction, was successfully converted
to the corresponding brominated compound 9 by heating at
31
reflux in aqueous HBr (43% over four steps). As in the case of
other piperidines 1a and 1b, the borylation of 9 was easily
achieved, providing 1c in a yield of 60% (Scheme 1).
Having synthesized an array of new heterocyclic trifluor-
oborates, we investigated their behavior in the Minisci reaction
with various heteroaromatic compounds. Although conditions
previously reported by our laboratory with stoichiometric
manganese(III) acetate were only successful in the case of the
32
tetrahydropyran derivative 4a, slight modifications of the
conditions recently developed by Baran proved to be effective
3
3,34
for this transformation.
Indeed, using an increased amount
of potassium persulfate and trifluoroacetic acid allowed us to
add building blocks 1a, 3, and 4a to lepidine in modest yields
(
Table 2, compounds 13a−c). Moreover, pyridazine and
quinoxaline (Table 2, compounds 13d and 13e−f) were also
valuable substrates, opening an alternative route for the
preparation of heteroarylazetidines by means of a Minisci
35
reaction.
In conclusion, we have prepared various potassium organo-
trifluoroborate building blocks by copper-catalyzed borylation
of the corresponding halides. This method is general and allows
the preparation of useful boron-containing synthons of
36
particular interest to medicinal chemistry in useful yields.
Some of these new trifluoroborates have been successfully
tested in the Minisci reaction, affording interesting compounds
in a straightforward manner with modest yields.
a
Reaction conditions: Halide (1.0 equiv), B pin (1.5 equiv), CuI (10
2
2
mol %), PS-PPh (13 mol %), MeOLi (2.0 equiv), DMF ([halide] =
3
0
.2 M), rt, 20 h then sat. aq KHF (4.0 equiv), THF, rt, 2 h.
2
EXPERIMENTAL SECTION
General Considerations. All commercially available reagents
including anhydrous solvents were used without purification. CuI
■
(
99.999%), PEPPSI-IPr, N-Boc-3-bromopyrrolidine, N-Boc-3-iodoaze-
Additionally, the analogous oxa-heterocyclic trifluoroborates 4,
tidine, 3-bromotetrahydropyran, and 3-bromotetrahydrofuran were all
contained from commercial sources and used as received. N-Tosyl-4-
bromopiperidine was prepared by the procedure of Gong et al.
Reactions under microwave irradiation were performed in a Biotage
Initiator system. Analytical thin-layer chromatography (TLC) was
performed on TLC silica gel plates (0.25 mm) precoated with a
fluorescent indicator. Flash chromatography (FC) was performed on a
5
, and 6 (Table 1, entries 5−8) were obtained under the same
conditions in decent yields, thus affording an alternative route
37
to the iridium-catalyzed borylation of cyclic ethers recently
28
reported by Hartwig. It should be noted that these new
building blocks were obtained in yields that appear to be
reflective of the efficiency of the borylation step. The
a
Scheme 1. Preparation of Potassium N-(2-Pyridinyl)-4-trifluoroboratopiperidine 1c
a
Reaction conditions: (a) 7 (1.0 equiv), 8 (1.2 equiv), PEPPSI-IPr (2 mol %), t-BuOK (1.5 equiv), DME, rt, 24 h, quant.; (b) TsOH (20 mol %),
H O/acetone:1/3, 150 °C (MW), 1 h, 83%; (c) NaBH (1.1 equiv), MeOH, rt, 1 h, 90%; (d) HBr (48% in H O, 17 equiv), 100 °C, 14 h, 58% (81%
2
4
2
brsm); (e) B pin (1.5 equiv); CuI (10 mol %), PS-PPh (13 mol %), MeOLi (2.0 equiv), DMF, rt, 20 h then sat. aq KHF (4.0 equiv), THF, rt, 2 h,
2
2
3
2
60%.
B
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The Journal of Organic Chemistry
Note
mL). The combined organic layers were washed successively with H O
Table 2. Minisci Reaction of Various Heterocyclic
Trifluoroborates
2
a
(
50 mL) and brine (50 mL), dried (MgSO ), and concentrated. The
residue was solubilized in THF (5 mL) in a round-bottomed flask
4
equipped with a stir bar, and sat. aq KHF (4.5 M, 0.9 mL, 4.0 equiv)
2
was added. The flask was closed with a septum, and the resulting
mixture was stirred at rt for 2 h. The reaction mixture was evaporated
to dryness, and the resulting salt was extracted several times with hot
acetone. The filtrate was concentrated to ∼5 mL, and precipitation was
achieved by dropwise addition of the filtrate to Et O (100 mL) at 0
2
°
C. The resulting product was collected by gravity filtration on a fritted
funnel and dried to afford the corresponding potassium heterocyclic
trifluoroborate as a white solid.
Potassium N-Boc-4-(Trifluoroborato)piperidine 1a. Following
general procedure A, the reaction performed with N-Boc-4-
bromopiperidine (0.94 g, 3.55 mmol) afforded 741 mg (72%) of the
1
title compound as a white solid. Mp 213−215 °C. H NMR (acetone-
6
d , 400 MHz): δ 3.97 (br, 2H), 2.52 (br, 2H), 1.49 (dd, J = 13, 3 Hz,
1
3
2
(
H), 1.41 (s, 9H), 1.26 - 1.10 (m, 2H), 0.28 (m, 1H). C NMR
6
acetone-d , 100 MHz): δ 155.3 (C), 78.4 (C), 46.6 (2 CH ), 29.1 (2
2
11
6
CH ), 28.8 (3 CH ). B NMR (acetone-d , 128 MHz): δ 4.84 (br).
F NMR (acetone-d , 377 MHz): δ −148.4. HRMS (ESI) m/z: (M −
2
3
19
6
−
K) Calcd for C H BF NO 252.1388; Found 252.1380.
10
18
3
2
Potassium N-Tosyl-4-(trifluoroborato)piperidine 1b. Following
general procedure A, the reaction performed with N-tosyl-4-
bromopiperidine (596 mg, 1.87 mmol) afforded 330 mg (51%) of
1
the title compound as a white solid. Mp 217−220 °C. H NMR
6
(
DMSO-d , 400 MHz): δ 7.56 (d, J = 8 Hz, 2H), 7.41 (d, J = 8 Hz,
2
H), 3.51−3.49 (m, 2H), 2.40 (s, 3H), 1.99−1.93 (m, 2H), 1.46 (dd, J
13
=
13, 2 Hz, 2H), 1.27−1.10 (m, 2H), −0.16 (br, 1H). C NMR
6
(DMSO-d , 100 MHz): δ 142.9 (C), 132.9 (C), 129.5 (2 CH), 127.3
11
(
2 CH), 47.9 (2 CH ), 27.4 (2 CH ), 20.9 (CH ). B NMR (DMSO-
2
2
3
6
19
6
d , 128 MHz): δ 4.71 (br). F NMR (DMSO-d , 377 MHz): δ
−
−
3
144.6. HRMS (ESI) m/z: (M − K) Calcd for C H BF NO S
1
2
16
3
2
06.0952; Found 306.0950.
Potassium N-Boc-3-(Trifluoroborato)pyrrolidine 2. Following
general procedure A, the reaction performed with N-Boc-3-
bromopyrrolidine (625 mg, 2.50 mmol) afforded 408 mg (59%) of
1
the title compound as a white solid. Mp 195−199 °C. H NMR
6
(
1
acetone-d , 400 MHz): δ 3.35−3.22 (m, 2H), 3.05−2.91 (m, 2H),
a
Reaction conditions: Heteroarene (1.0 equiv), potassium organo-
.69 (dt, J = 12, 6 Hz, 1H), 1.63−1.50 (m, 1H), 1.41 (s, 9H), 0.94 (br,
13 6
trifluoroborate (1.1 equiv), AgNO (20 mol %), K S O (5.0 equiv),
3
2
2
8
1H). C NMR (acetone-d , 100 MHz): δ 155.2 (C), 77.8 (C), 50.9
11
6
TFA (2.0 equiv), ClCH CH Cl/H O, 1:1 ([heteroarene] = 0.1 M), rt,
2
2
2
(CH ), 50.5 (CH ), 48.3 (CH ), 28.9 (3 CH ). B NMR (acetone-d ,
2 2 2 3
19
6
24 h.
1
28 MHz): δ 4.55 (br). F NMR (acetone-d , 377 MHz): δ −146.2.
−
HRMS (ESI) m/z: (M − K) Calcd for C H BF NO 238.1232;
9
16
3
2
Found 238.1223.
Biotage SP4 base system using GRACE Reveleris columns (silica size
0 μm) of various sizes. Visualization was effected with ultraviolet light
Potassium N-Boc-3-(Trifluoroborato)azetidine 3. Following gen-
eral procedure A, the reaction performed with N-Boc-3-iodoazetidine
(1.63 g, 5.75 mmol) afforded 826 mg (54%) of the title compound as a
4
and ethanolic KMnO . NMR spectra were recorded on a 400 MHz or
4
1
a 360 MHz spectrometer. Chemical shifts are given in ppm. H NMR
1
6
chemical shifts were referenced to the residual solvent signal; 13
white solid. Mp 182−185 °C. H NMR (DMSO-d , 400 MHz): δ 3.57
C
6
(
br, 4H), 1.34 (s, 9H), 1.31 (br, 1H). 13C NMR (DMSO-d , 100
MHz): δ 155.6 (C), 77.1 (C), 51.9 (CH ), 50.7 (CH ), 28.2 (3 CH ).
NMR chemical shifts were referenced to the deuterated solvent signal.
Multiplicity was defined by DEPT 135 analysis. The resonance of the
2
2
3
11
6
19
6
19
B NMR (DMSO-d , 128 MHz): δ 4.11 (br). F NMR (DMSO-d ,
carbon center linked to the boron atom was not observed. F NMR
11
−
chemical shifts were referenced to external CFCl (0.0 ppm).
B
377 MHz): δ −145.2. HRMS (ESI) m/z: (M − K) Calcd for
NO 224.1075; Found 224.1067.
Potassium 4-(Trifluoroborato)tetrahydropyran 4a. Following
3
NMR chemical shifts were referenced to external BF ·OEt (0.0 ppm)
C
8
H14BF
3
2
3
2
with a negative sign indicating an upfield shift. Data are presented as
follows: chemical shift δ (ppm), multiplicity (s = singlet, d = doublet, t
general procedure A, the reaction performed with 4-bromotetrahy-
=
triplet, m = multiplet, br = broad), coupling constant J (Hz),
dropyran (0.5 g, 3.0 mmol) afforded 155 mg (27%) of the title
1
6
integration. High-resolution mass spectra were obtained by electro-
spray ionization on a TOF instrument.
compound as a white solid. Mp >250 °C. H NMR (DMSO-d , 400
MHz): δ 3.74 (d, J = 10 Hz, 2H), 3.12 (td, J = 10, 3 Hz, 2H), 1.32−
1
3
6
General Procedure A for the Preparation of Compounds 1−
1.13 (m, 4H), 0.21−0.19 (m, 1H). C NMR (DMSO-d , 100 MHz):
11 6
6
. In air, B pin (1.5 equiv), LiOMe (2.0 equiv), PS-PPh (13 mol %),
δ 69.3 (2 CH ), 28.9 (2 CH ). B NMR (DMSO-d , 128 MHz): δ
2 2
2
2
3
19
6
and CuI (10 mol %) were weighed in a round-bottomed flask
equipped with a stir bar. The flask was closed with a septum,
4.39 (q, J = 58 Hz). F NMR (DMSO-d , 377 MHz): δ −145.0.
−
HRMS (ESI) m/z: (M − K) Calcd for C H BF O 153.0704; Found
5
9
3
evacuated, and backfilled with N . DMF (5 mL) and the halide (1.0
153.0697. Analytical data are consistent with those previously
2
32
mmol, 1.0 equiv) were successively added by syringes (or, if the halide
was solid, it was added as a solution in DMF), and the reaction was
vigorously stirred at rt for 20 h. Then, the reaction was diluted with
CH Cl (10 mL), filtered through a pad of Celite, and rinsed with
reported.
Potassium 3-(Trifluoroborato)tetrahydropyran 4b. Following
general procedure A, the reaction performed with 3-bromotetrahy-
dropyran (0.5 g, 3.0 mmol) afforded 304 mg (52%) of the title
2
2
1
6
CH Cl (20 mL). The resulting solution was concentrated, poured
compound as a white solid. Mp 204−207 °C. H NMR (DMSO-d ,
2
2
into sat. aq NH Cl (20 mL), and extracted three times with Et O (20
400 MHz): δ 3.73−3.64 (m, 2H), 3.03−3.17 (m, 2H), 1.57−1.53 (m,
4
2
C
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Note
1
H), 1.37−1.31 (m, 2H), 1.20−1.07 (m, 1H), 0.40 (br, 1H). 13C
afford the crude product. Purification by flash chromatography (SiO2,
CH Cl to CH Cl /MeOH, 95:5) afforded 5.7 g (90%) of the title
6
NMR (DMSO-d , 100 MHz): δ 72.3 (CH ), 67.7 (CH ), 28.0 (CH ),
2
2
2
2
2
2
2
11
6
19
1
2
5.7 (CH ). B NMR (DMSO-d , 128 MHz): δ 3.80 (br). F NMR
compound as a pale yellow oil. H NMR (CDCl , 360 MHz): δ 8.16
2
3
6
−
(
DMSO-d , 377 MHz): δ −143.2. HRMS (ESI) m/z: (M − K) Calcd
(dd, J = 5, 1 Hz, 1H), 7.51−7.40 (m, 1H), 6.73−6.62 (m, 1H), 6.58
(dd, J = 7, 5 Hz, 1H), 4.05 (ddd, J = 9, 8, 4 Hz, 2H), 3.90 (tt, J = 9, 4
Hz, 1H), 3.20−3.04 (m, 2H), 2.13 (br, 1H), 2.03−1.87 (m, 2H), 1.57
for C H BF O 153.0704; Found 153.0697.
5
9
3
Potassium 3-(Trifluoroborato)tetrahydrofuran 5. Following gen-
eral procedure A, the reaction performed with 3-bromotetrahydrofuran
(dtd, J = 13, 9, 4 Hz, 2H). 13C NMR (CDCl , 90 MHz): δ 159.2 (C),
3
(
0.5 g, 3.3 mmol) afforded 307 mg (52%) of the title compound as a
147.9 (CH), 137.5 (CH), 112.8 (CH), 107.2 (CH), 68.1 (CH), 43.1
1
6
+
white solid. Mp 169−171 °C. H NMR (DMSO-d , 400 MHz): δ 3.63
(2 CH ), 33.8 (2 CH ). HRMS (ESI) m/z: (M + H) Calcd for
2
2
(
(
0
t, J = 8 Hz, 1H), 3.53 (td, J = 8, 3 Hz, 1H), 3.41−3.35 (m, 1H), 3.23
C H N O 179.1184; Found 179.1155.
10 15 2
dd, J = 10, 8 Hz, 1H), 1.68−1.57 (m, 1H), 1.46 (t, J = 10 Hz, 1H),
N-(2-Pyridinyl)-4-bromopiperidine 9. In air, N-(2-pyridinyl)-4-
hydroxypiperidine (4.5 g, 25.5 mmol, 1.0 equiv) was solubilized in
.78 (br, 1H). 13C NMR (DMSO-d , 100 MHz): δ 71.8 (CH ), 67.6
6
2
11
6
(
5
CH ), 29.5 (CH ). B NMR (DMSO-d , 128 MHz): δ 4.32 (q, J =
9 Hz). F NMR (DMSO-d , 377 MHz): δ −141.0. HRMS (ESI) m/
HBr, 48% in H O (50 mL, 17 equiv) in a 250 mL round-bottom flask
2
2
2
19
6
equipped with a stir bar, and the flask was equipped with a condenser.
The reaction was heated at 120 °C (oil bath temperature) for 14 h.
Then, the reaction mixture was cooled to rt, and 1 M aq NaOH was
added until pH > 12. The resulting solution was extracted with
CH Cl (3 × 100 mL), and the combined organic layers were dried
−
z: (M − K) Calcd for C H BF O 139.0548; Found 139.0538.
Analytical data are consistent with those previously reported.
4
7
3
2
8
Potassium 3-(Trifluoroborato)oxetane 6. Following general
procedure A, the reaction performed with 3-iodooxetane (2.14 g,
1
solid. Mp 211−213 °C. H NMR (DMSO-d , 400 MHz): δ 4.44−4.42
(
CH2). B NMR (DMSO-d , 128 MHz): δ 3.97 (q, J = 59 Hz).
NMR (DMSO-d , 377 MHz): δ −144.2. HRMS (ESI) m/z: (M − K)
Calcd for C H BF O 125.0391; Found 125.0381.
Potassium N-(2-Pyridinyl)-4-trifluoroboratopiperidine 1c. N-(2-
Pyridinyl)-4-piperidinone Ethylene Ketal. In air, KOt-Bu (9.0 g, 79.86
mmol, 1.5 equiv) and PEPPSI-IPr (702 mg, 1.06 mmol, 2 mol %) were
weighed in a 250 mL round-bottom flask equipped with a stir bar. The
flask was closed with a septum, evacuated, and backfilled with N2.
DME (50 mL), 2-chloropyridine (6.04 g, 53.24 mmol, 1.0 equiv), and
2
2
1.63 mmol) afforded 580 mg (30%) of the title compound as a white
(MgSO ) and evaporated to afford the crude product. Purification by
4
1
6
flash chromatography (SiO , CH Cl to CH Cl /MeOH, 95:5)
2
2
2
2
2
13
6
br, 4H), 1.93 (br, 1H). C NMR (DMSO-d , 100 MHz): δ 74.7 (2
afforded 3.6 g (58%) of the title compound as a yellow oil (and
11
6
19
1
F
1.24 g of recovered starting material). H NMR (CDCl , 360 MHz): δ
3
6
−
8.24−8.12 (m, 1H), 7.55−7.42 (m, 1H), 6.74−6.53 (m, 2H), 4.42 (dt,
J = 8, 4 Hz, 1H), 4.02−3.84 (m, 2H), 3.52−3.33 (m, 2H), 2.26−2.17
3
5
3
13
(m, 2H), 2.14−1.95 (m, 2H). C NMR (CDCl , 90 MHz): δ 159.0
3
(C), 148.0 (CH), 137.5 (CH), 113.1 (CH), 107.1 (CH), 50.2 (CH),
+
44.1 (2 CH ), 35.4 (2 CH ). HRMS (ESI) m/z: (M + H) Calcd for
2
2
C H BrN 241.0340; Found 241.0369.
10
14
2
Potassium N-(2-Pyridinyl)-4-(trifluoroborato)piperidine 1c. Fol-
lowing general procedure A, the reaction performed with N-(2-
pyridinyl)-4-bromopiperidine 9 (3.4 g, 14.1 mmol) afforded 2.27 g
4
-piperidinone ethylene ketal (9.16 g, 63.89 mmol, 1.2 equiv) were
1
successively added by syringes. The reaction was stirred for 24 h.
Then, the reaction mixture was filtered through a pad of Celite (rinsed
with 100 mL of EtOAc), and the filtrate was evaporated to afford the
crude product. Purification by flash chromatography (SiO , CH Cl to
(60%) of the title compound as a white solid. Mp 215−217 °C. H
6
NMR (DMSO-d , 400 MHz): δ 8.06−7.98 (m, 1H), 7.41 (ddd, J = 9,
7, 2 Hz, 1H), 6.67 (d, J = 9 Hz, 1H), 6.51−6.42 (m, 1H), 4.19−4.16
(m, 2H), 2.61−2.56 (m, 2H), 1.49−1.45 (m, 2H), 1.20−1.09 (m, 2H),
2
2
2
1
3
6
CH Cl /EtOAc, 1:1) afforded 11.8 g (quant) of the title compound as
0.23−0.18 (m, 1H). C NMR (DMSO-d , 100 MHz): δ 159.3 (C),
2
2
1
a pale yellow oil. H NMR (CDCl , 360 MHz): δ 8.22−8.12 (m, 1H),
7
4
147.4 (CH), 137.1 (CH), 111.2 (CH), 106.6 (CH), 47.2 (2 CH ),
27.6 (2 CH ). B NMR (DMSO-d , 128 MHz): δ 4.47 (br). F NMR
(DMSO-d , 377 MHz): δ −144.5. HRMS (ESI) m/z: (M − K) Calcd
for C H BF N 229.1129; Found 229.1122.
3
2
11
6
19
.52−7.38 (m, 1H), 6.75−6.63 (m, 1H), 6.63−6.50 (m, 1H), 3.99 (s,
2
13
6
−
H), 3.74−3.63 (m, 4H), 1.81−1.72 (m, 4H). C NMR (CDCl , 90
3
MHz): δ 158.8 (C), 147.9 (CH), 137.4 (CH), 112.7 (CH), 107.5 (C),
07.0 (CH), 64.3 (2 CH ), 43.4 (2 CH ), 34.3 (2 CH ). HRMS (ESI)
10
13
3
2
1
General Procedure B for the Minisci Reactions. In air,
2
2
2
+
m/z: (M + H) Calcd for C H N O 221.1290; Found 221.1279.
potassium organotrifluoroborate (1.1 equiv), AgNO (0.2 equiv) and
12
17
2
2
3
2
9
Analytical data are consistent with those previously reported.
K S O (5.0 equiv) were weighed in a reaction tube equipped with a
2
2
8
N-(2-Pyridinyl)-4-piperidinone. In air, a solution of N-(2-
pyridinyl)-4-piperidinone ethylene ketal (9.8 g, 44.4 mmol, 1.0
equiv) and p-TsOH monohydrate (846 mg, 4.45 mmol, 10 mol %)
stir bar. ClCH CH Cl (2.5 mL), H O (2.5 mL), heteroarene (0.5
2 2 2
mmol, 1.0 equiv), and TFA (2.0 equiv) were successively added, and
the tube was sealed. The reaction was vigorously stirred at rt for 24 h.
Then, the reaction mixture was poured into 20 mL of a 1/1 v/v
mixture of sat. aq NaHCO and 5% aq NaS O , and the resulting
in acetone (36 mL) and H O (12 mL) was split equally in four 10−20
2
mL microwave vials equipped with a stir bar. The tubes were sealed,
and each of them was irradiated at 150 °C for 30 min. The tops were
removed, and another portion of p-TsOH (10 mol %) was added. The
tubes were sealed, and each of them was irradiated at 150 °C for 30
min. The tops were removed, and the reaction mixtures were
combined and concentrated to afford the crude product. Purification
by flash chromatography (SiO , CH Cl to CH Cl /MeOH, 98:2)
3
2
3
solution was extracted three times with CH Cl2 (30 mL). The
2
combined organic layers were dried (MgSO ) and evaporated to afford
4
the crude product. Purification by flash chromatography (SiO2,
CH Cl to CH Cl /MeOH, 95:5) afforded the desired product.
2
2
2
2
2-(N-Boc-4-Piperidinyl)lepidine 13a. Following general procedure
B, the reaction performed with 1a (160 mg, 0.55 mmol) and 10 (72
2
2
2
2
2
1
afforded 6.5 g (83%) of the title compound as a yellow oil. H NMR
mg, 0.50 mmol) afforded 88 mg (54%) of the title compound as a pale
1
(
CDCl , 360 MHz): δ 8.22−8.15 (m, 1H), 7.56−7.46 (m, 1H), 6.73
yellow oil. H NMR (CDCl , 360 MHz): δ 8.04 (d, J = 8 Hz, 1H),
3
3
(
d, J = 8 Hz, 1H), 6.65 (dd, J = 7, 5 Hz, 1H), 3.89 (d, J = 12 Hz, 4H),
7.96 (d, J = 8 Hz, 1H), 7.73−7.64 (m, 1H), 7.57−7.47 (m, 1H), 7.15
2
.48 (d, J = 12 Hz, 4H). 13C NMR (CDCl , 90 MHz): δ 208.4 (C),
(s, 1H), 4.29 (br, 2H), 3.09−2.96 (m, 1 H), 2.89 (br, 2H), 2.69 (s,
3
1
3
1
57.7 (C), 148.1 (CH), 137.7 (CH), 113.5 (CH), 106.8 (CH), 44.6 (2
3H), 2.04−1.92 (m, 2H), 1.92−1.75 (m, 2H), 1.50 (s, 9H). C NMR
+
CH ), 40.5 (2 CH ). HRMS (ESI) m/z: (M + H) Calcd for
(CDCl , 90 MHz): δ 164.3 (C), 154.8 (C), 147.6 (C), 144.6 (C),
2
2
3
C H N O 177.1028; Found 177.1008.
129.5 (CH), 129.1 (CH), 127.1 (C), 125.6 (CH), 123.6 (CH), 120.0
10
13
2
N-(2-Pyridinyl)-4-hydroxypiperidine. In air, N-(2-pyridinyl)-4-
(CH), 79.4 (C), 45.5 (CH), 43.6 (2 CH ), 31.6 (2 CH ), 28.5 (3
2
2
+
piperidinone (6.2 g, 35.3 mmol, 1.0 equiv) was solubilized in
MeOH (150 mL) in a 250 mL round-bottom flask equipped with a
stir bar. The flask was closed with a septum and cooled to 0 °C.
CH ), 18.8 (CH ). HRMS (ESI) m/z: (M + H) Calcd for
3 3
C H N O 327.2072; Found 327.2059.
20
27
2
2
2-(N-Boc-3-Azetidinyl)lepidine 13b. Following general procedure
B, the reaction performed with 3 (145 mg, 0.55 mmol) and 10 (72 mg,
NaBH (1.5 g, 38.8 mmol, 1.1 equiv) was added portionwise. The
4
reaction was stirred at rt for 1 h. Then, the reaction mixture was
0.50 mmol) afforded 47 mg (31%) of the title compound as a brown
1
poured into saturated aq NH Cl (200 mL), and the resulting solution
oil. H NMR (CDCl , 400 MHz): δ 8.05 (dd, J = 9, 1 Hz, 1H), 7.96
4
3
was extracted with EtOAc (2 × 100 mL). The combined organic layers
(dd, J = 8, 1.0 Hz, 1H), 7.69 (ddd, J = 8, 7, 1 Hz, 1H), 7.53 (ddd, J = 8,
7, 1 Hz, 1H), 7.25 (s, 1H), 4.43−4.34 (m, 2H), 4.32−4.24 (m, 2H),
were washed with brine (100 mL), dried (MgSO ), and evaporated to
4
D
dx.doi.org/10.1021/jo4005519 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4
(
.07−3.95 (m, 1H), 2.70 (d, J = 1 Hz, 3H), 1.48 (s, 9H). 13C NMR
CDCl , 100 MHz): δ 160.8 (C), 156.5 (C), 147.4 (C), 145.1 (C),
(3) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
(4) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
3
1
29.6 (CH), 129.3 (CH), 127.1 (C), 126.0 (CH), 123.6 (CH), 119.9
(5) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,
9240.
(6) Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2012,
51, 9385.
(7) Pintaric, C.; Olivero, S.; Gimbert, Y.; Chavant, P. Y.; Dunach, E. J.
Am. Chem. Soc. 2010, 132, 11825.
(8) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.
(9) Brown, H. C.; Subba Rao, B. C. J. Am. Chem. Soc. 1956, 78, 2582.
(10) Burgess, K.; Ohlmeyer, M. J. Chem. Rev. 1991, 91, 1179.
(11) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. Chem. Rev. 2010, 110, 890.
(12) Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2003, 680, 3.
(13) Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314, 113.
(14) Curran, D. P.; Solovyev, A.; Makhlouf Brahmi, M.; Fensterbank,
(
CH), 79.4 (C), 54.5 (2 CH ), 35.7 (CH), 28.4 (3 CH ), 18.7 (CH ).
2
3
3
+
HRMS (ESI) m/z: (M + H) Calcd for C H N O 299.1759; Found
18
23
2
2
2
99.1789. Analytical data are consistent with those previously
35
reported.
2
-(4-Tetrahydropyranyl)lepidine 13c. Following general procedure
B, the reaction performed with 4a (106 mg, 0.55 mmol) and 10 (72
mg, 0.50 mmol) afforded 44 mg (38%) of the title compound as a
white solid. Mp 108 °C. H NMR (CDCl , 400 MHz): δ 8.04 (dd, J =
1
3
8
, 1 Hz, 1H), 7.93 (dd, J = 8, 1 Hz, 1H), 7.66 (ddd, J = 8, 7, 1 Hz, 1H),
.49 (ddd, J = 8, 7, 1 Hz, 1H), 7.16 (s, 1H), 4.16−4.07 (m, 2 H), 3.58
7
(
td, J = 12, 2 Hz, 2H), 3.11 (tt, J = 11.9, 4.0 Hz, 1H), 2.65−2.70 (m,
H), 2.09−1.95 (m, 2H), 1.95−1.86 (m, 2H). C NMR (CDCl , 100
13
3
3
MHz): δ 164.1 (C), 147.5 (C), 144.8 (C), 129.4 (CH), 129.0 (CH),
1
27.0 (C), 125.5 (CH), 123.5 (CH), 119.8 (CH), 68.0 (2 CH ), 44.2
2
̂
L.; Malacria, M.; Lacote, E. Angew. Chem., Int. Ed. 2011, 50, 10294.
(15) Lee, K.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253.
+
(
CH), 32.2 (2 CH ), 18.7 (CH ). HRMS (ESI) m/z: (M + H) Calcd
2 3
for C H NO 228.1388; Found 228.1386. Analytical data are
consistent with those previously reported.
-Chloro-3-(N-Boc-3-azetidinyl)quinoxaline 13d. Following gen-
eral procedure B, the reaction performed with 3 (66 mg, 0.25 mmol)
and 11 (41 mg, 0.25 mmol) afforded 12 mg (15%) of the title
1
5
18
32
(
16) Bonet, A.; Gulyas, H.; Fernandez, E. Angew. Chem., Int. Ed.
010, 49, 5130.
17) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett.
000, 41, 6821.
(18) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982.
19) Ishiyama, T.; Oohashi, Z.; Ahiko, T.; Miyaura, N. Chem. Lett.
002, 780.
2
2
(
2
1
compound as a colorless oil. H NMR (CDCl , 500 MHz): δ 8.14−
3
8
4
.12 (m, 1H), 8.03−8.01 (m, 1H), 7.82−7.78 (m, 2H), 4.46 (br, 2H),
(
2
13
,41 (t, J = 8.0 Hz, 2H), 4.36−4.33 (m, 1H), 1.47 (s, 9H). C NMR
(
CDCl , 125.8 MHz): δ 156.3 (C), 153.1 (C), 146.8 (C), 141.0 (C),
3
(20) Yang, C.-T.; Zhang, Z.-Q.; Tajuddin, H.; Wu, C.-C.; Liang, J.;
Liu, J.-H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L.
Angew. Chem., Int. Ed. 2012, 51, 528.
1
(
40.5 (C), 130.6 (CH), 130.3 (CH), 128.9 (CH), 128.0 (CH), 79.6
C), 38.8 (2 CH ), 32.9 (CH), 28.3 (3 CH ). HRMS (ESI) m/z: (M
2
2
3
+
+
H) Calcd for C H N O Cl 639.2253; Found 639.2231.
32 37 6 4 2
(21) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890.
3
-Methyl-4-(4-tetrahydropyranyl)pyridazine 13e and 3-Methyl-
(22) Yi, J.; Liu, J.-H.; Liang, J.; Dai, J.-J.; Yang, C.-T.; Fu, Y.; Liu, L.
5
-(4-tetrahydropyranyl)pyridazine 13f. Following general procedure
Adv. Synth. Catal. 2012, 354, 1685.
B, the reaction performed with 4a (106 mg, 0.55 mmol) and 12 (47
(
(
23) Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693.
24) Joshi-Pangu, A.; Ma, X.; Diane, M.; Iqbal, S.; Kribs, R. J.; Huang,
4
5
mg, 0.50 mmol) afforded 33 mg (37%) of 13e and 13f (C and C
regioisomers, respectively) as a 40:60 mixture as a brown oil. H NMR
1
R.; Wang, C.-Y.; Biscoe, M. R. J. Org. Chem. 2012, 77, 6629.
(
CDCl , 400 MHz): δ 8.95 (d, J = 5 Hz, 1H), 8.89 (d, J = 2 Hz, 1H),
3
(
(
25) Georgiou, I.; Whiting, A. Eur. J. Org. Chem. 2012, 4110.
26) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
7
3
1
.21 (d, J = 5 Hz, 1H), 7.11 (d, J = 2 Hz, 1H), 4.12−4.01 (m, 4H),
.58−3.44 (m, 4H), 2.73−2.92 (m, 2H), 2.72 (s, 3H), 2.66 (s, 3H),
.68−1.79 (m, 8H). C NMR (CDCl , 100 MHz): δ 159.7 (C), 158.8
6
752.
27) Fleury-Breg
Oehlrich, D.; Rombouts, F.; Molander, G. A. J. Org. Chem. 2012, 77,
13
3
(
́
eot, N.; Presset, M.; Beaumard, F.; Colombel, V.;
(
1
C), 150.0 (CH), 149.2 (CH), 144.1 (C), 143.0 (C), 124.3 (CH),
22.9 (CH), 67.8 (2 CH ), 67.6 (2 CH ), 38.3 (CH), 36.4 (CH), 32.2
2
2
1
0399−10408.
(
2 CH ), 31.7 (2 CH ), 22.2 (CH ), 19.8 (CH ). HRMS (ESI) m/z:
2 2 3 3
+
(28) Liskey, C. W.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 12422.
(
M + H) Calcd for C H N O 179.1184; Found 179.1202.
10
15
2
(
́
29) Prokopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.;
Herrebout, W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W.
ASSOCIATED CONTENT
Supporting Information
■
Chem.Eur. J. 2010, 16, 13063.
*
S
(30) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Dubovyk, I.; Hadei,
N.; Kantchev, E. A. B.; O’Brien, C. J.; Sayah, M.; Valente, C. Chem.
Eur. J. 2008, 14, 2443.
Copies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
31) Bailey, J. M.; Booth, H.; Al-Shirayda, A. R. Y.; Trimble, M. L. J.
Chem. Soc., Perkin Trans. 1984, 2, 737.
32) Molander, G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13,
852.
33) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara,
AUTHOR INFORMATION
■
(
1
(
Corresponding Author
*
E-mail: frombout@its.jnj.com; gmolandr@sas.upenn.edu.
Notes
Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194.
(34) Lockner, J. W.; Dixon, D. D.; Risgaard, R.; Baran, P. S. Org. Lett.
The authors declare no competing financial interest.
2
(
011, 13, 5628.
35) Duncton, M. A.; Estiarte, M. A.; Johnson, R. J.; Cox, M.;
O’Mahony, D. J. R.; Edwards, W. T.; Kelly, M. G. J. Org. Chem. 2009,
4, 6354.
36) Burkhard, J. A.; Guer
ACKNOWLEDGMENTS
■
This research was supported by the NIH (NIGMS R01
GM35249) and the Neuroscience Medicinal Chemistry
Department of Janssen. Michel Carpentier (Janssen) and Dr.
Rakesh Kohli (University of Pennsylvania) are acknowledged
for obtaining HRMS data, and we thank DaWeon Ryu
7
(
́
ot, C.; Knust, H.; Rogers-Evans, M.;
Carreira, E. M. Org. Lett. 2010, 12, 1944.
(37) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett. 2011, 13,
2138.
(University of Pennsylvania) for providing some character-
ization data.
REFERENCES
1) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011.
2) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49.
■
(
(
E
dx.doi.org/10.1021/jo4005519 | J. Org. Chem. XXXX, XXX, XXX−XXX