Reinvestigation of aminomethyltrifluoroborates and their application in suzuki-miyaura cross-coupling reactions

Article abstract of DOI:10.1021/jo2001066

A reinvestigation into the chemical composition of potassium aminomethyltrifluoroborates is reported. These trifluoroborato salts have been reassigned as zwitterionic ammoniomethyltrifluoroborates. Minor adjustments to the previously disclosed reaction conditions are reported that permit a similar level of activity as nucleophiles in Suzuki-Miyaura cross-coupling reactions.

Full text of DOI:10.1021/jo2001066

ARTICLE
pubs.acs.org/joc
Reinvestigation of Aminomethyltrifluoroborates and Their
Application in Suzuki-Miyaura Cross-Coupling Reactions
Jessica Raushel,† Deidre L. Sandrock,† Kanth V. Josyula,‡ Deborah Pakyz,‡ and Gary A. Molander*,†
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
‡Sigma-Aldrich New Products, Milwaukee, Wisconsin 53209, United States
S Supporting Information
b
ABSTRACT: A reinvestigation into the chemical composition
of potassium aminomethyltrifluoroborates is reported. These
trifluoroborato salts have been reassigned as zwitterionic am-
moniomethyltrifluoroborates. Minor adjustments to the pre-
viously disclosed reaction conditions are reported that permit a similar level of activity as nucleophiles in Suzuki-Miyaura cross-
coupling reactions.
’ INTRODUCTION
Scheme 1. Previously Reported Synthesis of Potassium
Aminomethyltrifluoroborates
Recently, we disclosed a series of reports outlining the synthesis1
of potassium aminomethyltrifluoroborates and their use as nucleo-
philes with aryl and heteroaryl bromides2 and chlorides3 in Suzuki-
Miyaura cross-coupling reactions. Decreased toxicity and simpler
purification as compared to those of an analogous, specialized
aminomethylstannane4 provided an impetus for exploiting the
dissonant bond-forming connectivity conveyed through the agency
of the aminomethyltrifluoroborates. Thus, performing an amino-
methylation reaction via a Suzuki-Miyaura cross-coupling reaction
between an aminomethyltrifluoroborate and an aryl electrophile
is complementary to other commonly utilized routes to these mat-
erials, including alkylation of amines with benzylic halides, reductive
amination of aromatic aldehydes, and processes initiated from aro-
matic nitriles. Aminomethylation of aromatic and heteroaromatic
halides obviates the need to use lachrymal benzyl halides employed in
the amine alkylation approach. Furthermore, the greater commercial
availability5 of aryl and heteroaryl chlorides as compared to the
corresponding benzyl halides and aromatic nitriles and aldehydes
employed6 in traditional routes allows inherently less expensive and
more rapid access to starting materials and also provides greater
structural diversity in targeted aminomethyl compounds.
coalescence of peaks, indicating an increase in fluxionality as well as a
symmetrization of the axial and equatorial protons, as one might
observe concomitant with deprotonation.
Although their precise chemical identity and composition was now
in question, aminomethyltrifluoroborates prepared in this manner
had already proven to be versatile reagents with broad substrate scope
and functional group compatibility. Herein, we disclose a reinvestiga-
tion of this chemistry and report the synthesis and isolation of
ammoniomethyltrifluoroborates in addition to their use as nucleo-
philic partners in Suzuki-Miyaura cross-coupling reactions.
’ RESULTS AND DISCUSSION
Because of their utility, we have continued to investigate the
reported potassium aminomethyltrifluoroborates and their deriva-
tives.7 During the course of these investigations and in particular
The first goal was to address whether the observations concerning
the nature of the aminomethyltrifluoroborates were the result of a
systemic misassignment or represented a case-by-case event. Almost
immediately difficulties were encountered in reproducing the pre-
vious procedures for the synthesis of the trifluoroborates;1,2 stirring
2a with either KHCO3 (20 min) or K2CO3 (30 min) in acetone
did not lead to a replication of the reported spectra. Finally, after
the preliminary product was stirred with K3PO4 in acetone over-
night, duplication of the observed changes in the 1H NMR spectra
considered indicative of a deprotonation to the potassium
1
through characterization by H NMR and elemental analysis, we
discovered that many of the samples assigned as potassium amino-
methyltrifluoroborates 3 were instead composed principally of the
internal salts 2 and varying amounts of KBr (Scheme 1). Previously,
we believed that treatment with either KHCO3 or K2CO3 in acetone
was sufficient to effect deprotonation, leading to the desired
potassium salts, and this belief was supported by several observed
changes in the 1H NMR spectra (Figure 1). In addition to the loss of
the broad, exchangeable proton assigned to the protonated amine
from the piperidine-derived preliminary internal salt, there was a
Received: January 22, 2011
Published: March 15, 2011
r
2011 American Chemical Society
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Figure 1. Observed changes in the 1H NMR spectra of 2a after exposure to base.
Figure 2. Observed changes in the 1H NMR spectra of 2e after exposure to base.
aminomethyltrifluoroborate 3a (Figure 1) was observed, but these
results were capricious and not reproducible. It was expected that
with compounds presenting the same 1H NMR spectra as previously
reported, an X-ray crystal structure of the potassium aminomethyl-
trifluoroborate could be acquired to confirm the structure, and the
purity could be determined by elemental analysis. Although the
composition of the internal salt 2a was confirmed by X-ray analysis
(see Figure S1 in the Supporting Information), the structure of the
presumed deprotonated potassium aminomethyltrifluoroborate salt
3a could not be. In agreement with the preliminary elemental
analysis results, no potassium ions were detected8 in crystals formed
salt because it contained only 3.89% K instead of the expected
12.77% K. Although both analytical techniques convinced us that the
deprotonation procedures were inconsistent at best and ineffective at
worst, neither addressed the additional possibility of KBr or KI
contamination in the final product.
Previously, the aminomethyltrifluoroborates were prepared by
alkylation of the desired amine with potassium iodomethyltri-
flu;oroborate1 (1a) or potassium bromomethyltrifluoroborate2,3
(1b) under neat conditions for inexpensive amines or stoichiometric
conditions in THF for the more valuable amines. The resulting crude
ammoniomethyltrifluoroborates (2) were subjected to treatment
with either KHCO3 or K2CO3, followed by filtration in hot acetone.
To address the probable contamination with KI or KBr in addition to
the precise composition of the aminomethyltrifluoroborates, a meth-
od was developed to synthesize many of the aminomethyltrifluor-
oborates from chloromethyltrifluoroborate 1c. Unexpectedly, in
simply replacing bromochloromethane for dibromomethane in our
1
from compounds having H NMR spectra matching those in
Figure 1B. Further support of a systemic misassignment came from
investigations with internal salt 2e. Although the same characteristics
were exhibited in the 1H NMR of 2e when it was treated with base,
elemental analysis of the resultant product thought to be 3e
(Figure 2B) revealed that this sample could not be the potassium
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Table 1. Synthesis of Ammoniomethyltrifluoroboratesa
Table 2. Cross-Coupling of Trifluoro(piperidin-1-ium-1-yl-
methyl)borate with Aryl Bromidesa
a All reactions were carried out using 1.0 mmol of the aryl bromide and 1.3
mmol of the trifluoro(piperidin-1-ium-1-ylmethyl)borate. b Isolated yield.
was removed in vacuo. The reaction mixture was subsequently
suspended in hot acetone and filtered to remove the KCl byproduct.
The internal salts were isolated substantially free from inorganic salt
contamination, as KCl is less soluble in acetone than KBr. The
procedure used to purify the isolated products (precipitation from
hot acetone with diethyl ether) was similar to that commonly used
for most potassium organotrifluoroborates. Most importantly, the
majority of the ammoniomethyltrifluoroborates retained many of
the favorable properties of potassium trifluoroborate salts as easy to
manipulate air- and moisture-stable crystalline solids that have
proved to be indefinitely bench-stable.
The behavior of the isolated internal salts in Suzuki-Miyaura
cross-coupling reactions was next examined, particularly as to how
they compared to the previously reported reaction conditions.2,3
Most of the original research samples were determined11 to be >90%
pure by elemental analysis when reassigned as the internal salt with
KBr contamination. Their previous structural misassignment, how-
ever, meant that the nucleophilic partner was used in slightly larger
excess (<25%) than originally reported.2 Aryl bromides could be
cross-coupled with the ammoniomethyltrifluoroborate under almost
identical reaction conditions, after adjusting for the effective molar
excess of the trifluoroborate (i.e., 1.3 equiv of trifluoroborate vs the
reported 1.1 equiv; Table 2). Under these reaction conditions, we
often observed <10% electrophile homocoupling. Isolated yields were
decreased in the presence of 1.3 equiv of KBr (54%), were not
affected by 1.3 equiv of KCl (80%), and were not improved by the use
of 4.0 equiv of Cs2CO3 (70%; see Table S1 in the Supporting
Information).
a A 5.00 mmol scale was used unless otherwise noted. Conditions: (A)
alkylamine (1.01-2.0 equiv), 3:1 THF:t-BuOH (1.0 M), 80 °C, 2-24
h; (B) alkylamine (1.2-2.0 equiv), acetone (0.5 M), 80 °C, 16 h; (C)
alkylamine (1.01 equiv), 3:1 CPME:tert-amyl alcohol, 110 °C, 6.5 h.
b Isolated yield. c 10.0 mmol scale.
optimized bromomethyltrifluoroborate synthesis (eq 1)9 the iso-
lated yield of 1c reached a ceiling of ∼50%. We considered this
insufficient as a replacement for such a robust starting material.
Adapting Whiting’s10 procedure for the synthesis of pinacol
(chloromethyl)boronate by quenching with aqueous KHF2 instead
of ethereal pinacol resulted in a procedure that reliably delivered
70-77% yields of 1c on scales up to 5 g (eq 2).
Aryl and heteroaryl chlorides also behaved similarly under the
previously reported cross-coupling reaction conditions3 when a
few minor modifications were implemented. After adjusting for
the effective molar excess of the trifluoroborate (i.e., 1.2 equiv of
trifluoroborate vs the reported 1.01 equiv), changing the solvent
ratio to 4:1 THF:H2O, and increasing the reaction time to 45 h,
aryl and heteroaryl chlorides remained competent cross-coupling
partners for the ammoniomethyltrifluoroborates (Table 3).
The reaction conditions remained general across electron-
deficient (Table 3, entry 1) and hindered (Table 3, entries 2 and 3)
aryl chlorides, providing moderate to good yields of the desired
products. Heteroaryl chlorides were tolerated, including those
The synthesis of the ammoniomethyltrifluoroborates was readily
accomplished by reacting a variety of amines with 1c in a cosolvent
mixture of THF and tert-butyl alcohol. In comparison to the
conditions utilized for bromomethyltrifluoroborate (1b), increased
reaction times were required (Table 1). A few examples (2b,h)
resulted in increased yields by heating in acetone in a sealed tube.
After the reactions were judged complete by 19F NMR, the solvent
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Table 3. Cross-Coupling of Trifluoro(piperidin-1-ium-1-yl-
Table 4. Cross-Coupling of Various N,N-Dialkylammonio-
methyltrifluoroborates with 4-Chloroanisolea
methyl)borate with Aryl Chloridesa
a All reactions were carried out using 1.0 mmol of the aryl chloride and 1.2
mmol of the trifluoro(piperidin-1-ium-1-ylmethyl)borate. b Isolated yield.
c 10:1 CPME:H2O (0.25 M) was used as the solvent, 95 °C.
a All reactions were carried out using 1.0 mmol of 4-chloroanisole and
1.2 mmol of the ammoniomethyltrifluoroborate. b Isolated yield. c Aver-
age of three trials.
with complementary functional groups, such as aldehydes and
ketones (Table 3, entries 4 and 5). 3-Chloropyridines partici-
pated in good to excellent yields (Table 3, entries 6 and 7),
whereas coupling with heterocycles chlorinated adjacent to
nitrogen, such as 2-chloropyridine and 2-chloropyrimidine,
remained elusive. Ethanol12 or cosolvent mixtures, including
CH3CN, tert-butyl alcohol, tert-amyl alcohol, and n-butyl alcohol
failed to resolve the challenges of these cross-coupling partners.
To illustrate the scope of the ammoniomethyltrifluoroborate
cross-coupling partner, the breadth of available ammoniomethyl-
trifluoroborates (Table 1) was cross-coupled with both electron-
rich 4-chloroanisole (Table 4) and 3-chloropyridine (Table 5).
Most of the ammoniomethyl derivatives participated in the cross-
coupling with 4-chloroanisole in good yields, whereas 3-chlor-
opyridine resulted in more moderate yields.
corresponding potassium aminomethyltrifluoroborates. The de-
scribed ammoniomethyltrifluoroborates retained many of the favor-
able characteristics associated with materials previously assigned as
potassium trifluoroborate salts. Furthermore, it has been established
that minor changes to the previously reported conditions are all that
are necessary to achieve a cross-coupling of the isolated and pure
ammoniomethyltrifluoroborates with both aryl and heteroaryl bro-
mides and chlorides. Finally, it should be emphasized that the
previously reported1-3 deprotonation procedure with potassium
carbonate is required and is sufficient to provide full conversion to
the potassium trifluoroborates when a less basic nitrogen has been
incorporated within the organoboron substructure (e.g., with pyridyl-
and quinolinyltrifluoroborates).
’ EXPERIMENTAL SECTION
’ CONCLUSION
In summary, the products generated after alkylation of amine
nucleophiles with chloromethyltrifluoroborate (1c) have been iden-
tified as ammoniomethyltrifluoroborates, and it has been confirmed
that treatment with base is insufficient to transform them to the
General Considerations. Tetrahydrofuran (THF) was distilled
from sodium/benzophenone prior to use. Acetone, diethyl ether (Et2O),
tert-butyl alcohol (t-BuOH), Pd(OAc)2, XPhos (2-dicyclohexylphosphino-
20,40,60-triisopropylbiphenyl), and Cs2CO3 were used as received. H2O was
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Table 5. Cross-Coupling of Various N,N-Dialkylammonio-
methyltrifluoroborates with 3-Chloropyridinea
chromatography (TLC) was performed on TLC silica gel plates (0.25 mm)
precoated with a fluorescent indicator. Standard flash chromatography
procedures were followed using 32-63 μm silica gel. Visualization was
effected with ultraviolet light and KMnO4. Reactions conducted in micro-
wave vials were heated conventionally.
Preparation of Potassium Chloromethyltrifluoroborate (1c). BrCH2Cl
(3.0 mL, 1.991 g/mL, 44.0 mmol) and B(O-i-Pr)3 (8.25 mL, 0.912 g/mL,
40.0 mmol) were placed in an oven-dried 250 mL three-neck flask equipped
with a stirrer bar and internal thermometer under N2. Anhydrous THF
(39 mL) was added from a syringe. The reaction mixture was cooled to an
internal temperature of -50 °C. n-BuLi (17.6 mL, 2.5 M in hexanes, 44.0
mmol) was added to an oven-dried 50 mL pear-shaped flask and cooled in a
dry ice/acetone bath. The precooled n-BuLi was added dropwise at a rate of 1
drop/s, maintaining an internal temperature below -50 °C. After the
addition of n-BuLi was complete, the reaction mixture was stirred at -50 °C
for 30 min before TMSCl (6.1 mL, 0.856 g/mL, 48 mmol) was added
dropwise via syringe. After the reaction mixture was stirred for 10 min, the
cooling bath was removed and the reaction mixture was stirred at room
temperature for 24 h. Then, the flask was cooled in an ice-water bath and
saturated aqueous KHF2 (36 mL, ∼4.5 M, 160 mmol) was added dropwise.
The reaction mixture was stirred for 30 min (and judged complete by 11
B
NMR) before being concentrated in vacuo. Residual water was removed by
azeotroping with toluene before drying in vacuo overnight. The dry, crude
mixture was purified by Soxhlet extraction with 250 mL HPLC grade acetone
for 10 h. The acetone extracts were concentrated in vacuo to a volume of
50 mL, and Et2O (5 mL) was added to precipitate the trifluoroborate
product. Additional Et2O (200 mL) was added to assist filtration. Filtration
gave a 77% yield of 1c (4.80 g, 30.7 mmol) as a white powder. Mp: 180-
184 °C. IR: νmax(HATR)/cm-1 1418, 1246, 1140, 1112, 1068, 994, 966,
774, 737, 684. 1H NMR (500 MHz): acetone-d6, δ 2.43 (bs, 2H); DMSO-
d6, δ 2.31 (bs, 2H); CD3CN, δ 2.44 (bs, 2H). 13C NMR (125 MHz):
acetone-d6, no peaks observed. 19F NMR (470 MHz): acetone-d6, δ-146.8
(q, J = 51.0 Hz); DMSO-d6, δ -143.3 (q, J = 50.4 Hz); CD3CN, δ -146.4
(q, J = 51.0 Hz). 11B NMR (128 MHz): acetone-d6, δ 1.9 (q, J = 51.4 Hz);
DMSO-d6, δ 2.0-0.2 (m); CD3CN, δ 1.5 (q, J = 51.2 Hz). Anal. Calcd for
CH2BClF3K: C, 7.68; H, 1.29; N: 0.0. Found: C, 7.93; H, 1.02; N, <0.02.
General Experimental Procedure for the Preparation
of Ammoniomethyltrifluoroborates. Reaction Conditions A. Pre-
paration of Trifluoro(piperidin-1-ium-1-ylmethyl)borate (2a). An
oven-dried 10-20 mL microwave vial equipped with a stirrer bar was
charged with 1c (1.56 g, 10.0 mmol) and sealed with a cap lined with a
disposable PTFE septum. The vial was then evacuated under vacuum and
purged with N2 (3ꢀ). Anhydrous THF (5.5 mL), t-BuOH (2.5 mL), and
piperidine (2.0 mL, 8.62 g/mL, 20.0 mmol) were added via syringes (solid
amines were added with 1c). The reaction mixture was stirred and heated to
80 °C for 2 h and judged complete by 19F NMR. At this point the reaction
mixture was transferred to a 100 mL round-bottom flask, and the volatiles
were removed in vacuo. The crude solid was dried under high vacuum
overnight before being dissolved in a solution of hot HPLC acetone and the
solution filtered to remove KCl. The filtrate was concentrated in vacuo,
dissolved in a minimal amount of hot acetone (20 mL), and precipitated by
the dropwise addition of Et2O (5 mL). Additional Et2O(150mL) wasadded
to facilitate filtering. Filtration and drying overnight in vacuo over P2O5
afforded 2a (1.51 g, 90%, 9.04 mmol) as a white powder: mp 147-150 °C;
IR ν(HATR)/cm-1 3405 (bs, R3NHþ), 3176, 2950, 1458, 1307, 1058, 980,
956; 1H NMR (500 MHz, CD3CN) δ 6.04 (s, 1H), 3.47 (d, J = 12.4 Hz,
2H), 2.80 (t, J = 12.1 Hz, 2H), 2.07 (s, 2H), 1.81 (s, 2H), 1.71 (s, 3H), 1.41
(d, J = 10.9 Hz, 1H); 13C NMR (126 MHz, CD3CN) δ 56.5, 23.9, 22.3;
19F NMR (471 MHz, CD3CN) δ -141.9 (q, J = 49.7 Hz); 11B NMR (128
MHz, CD3CN) δ2.3 (q, J= 51.4 Hz). Anal. Calcd for C6H13BF3N: C, 43.16;
H, 7.85; N, 8.39. Found: C, 42.95; H, 7.84; N, 8.39.
a All reactions were carried out using 1.0 mmol of 3-chloropyridine and
c
1.2 mmol of the ammoniomethyltrifluoroborate. b Isolated yield. Un-
able to isolate any desired product.
sparged with nitrogen for at least 20 min prior to use. Standard benchtop
techniques were employed for handling air-sensitive reagents.
Amines were fractionally distilled under nitrogen from potassium
hydroxide onto activated molecular sieves. All aryl bromides and
chlorides were used as received.
Melting points (°C) are uncorrected. NMR spectra were recorded on a
1
500 or 400 MHz spectrometer. H NMR spectra were referenced using
residual undeuterated solvent as an internal reference (δ 7.26 for CDCl3; δ
2.50 for DMSO-d6; δ 2.05 for acetone-d6; δ 1.94 for CD3CN). 13C NMR
spectra were referenced to either the δ 77.0 resonance of CDCl3, the δ 39.5
resonance of DMSO-d6, the δ 29.84 resonance of acetone-d6, or the δ 1.32
resonance of CD3CN. 19F NMR chemical shifts were referenced to external
CFCl3 (0.0 ppm). 11B NMR spectra were obtained on a spectrometer
equipped with the appropriate decoupling accessories. All 11B NMR
chemical shifts were referenced to external BF3 OEt2 (0.0 ppm), with a
3
negative sign indicating an upfield shift. Data are presented as follows:
chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, sept = septet, m = multiplet, b = broad), coupling constant J (Hz),
and integration. Infrared spectra were recorded on a FT-IR instrument with a
horizontal attenuated total reflectance (HATR) device. Analytical thin-layer
Reaction Conditions B. Preparation of [(Diethylammonio)methy-
l]trifluoroborate (2b). An oven-dried 10-20 mL microwave vial equipped
with a stirrer bar was charged with 1c (1.56 g, 10.0 mmol) and sealed with a
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cap lined with a disposable PTFE septum. The vial was then evacuated under
vacuum and then purged with N2 (3ꢀ). Acetone (20 mL) and Et2NH
(2.0 mL, 0.707 g/mL, 20.0 mmol) were added via syringe. The reaction
mixture was heated to 80 °C for 24 h and judged complete by 19F NMR. At
this point the reaction mixture was transferred to a 100 mL round-bottom
flask, and the volatiles were removed in vacuo. The crude solid was dried
under high vacuum overnight before being dissolved in a solution of hot
HPLC acetone and the solution filtered to remove KCl. The filtrate was
concentrated in vacuo, dissolved in a minimal amount of hot acetone
(20 mL), and precipitated by the dropwise addition of Et2O (100 mL).
Filtration and drying overnight in vacuo over P2O5 afforded 2b (0.895g, 57%,
5.77 mmol) as an off-white powder: mp 108-111 °C; IR ν(HATR)/cm-1
3592 (bs, R3NHþ), 3188, 1470, 1019, 988; 1H NMR (500 MHz, CD3CN) δ
6.25-5.87 (m, 1H), 3.23-3.02 (m, 4H), 2.08 (s, 2H), 1.23 (q, J = 7.5 Hz,
6H); 13C NMR (126 MHz, CD3CN) δ 50.4, 9.3; 19F NMR (471 MHz,
CD3CN) δ -142.4 (q, J = 49.9 Hz); 11B NMR (128 MHz, CD3CN) δ 2.0
(q, J = 51.3 Hz); Anal. Calcd for C5H13BF3N: C, 38.75; H, 8.46; N, 9.04.
Found: C, 38.14 (low); H, 8.34 (low); N, 8.79 (low). HRMS (ESI-TOF):
calcd for C5H12BF3N- [M - H]- 154.1015, found 154.1016.
NMR (471 MHz, CD3CN) δ -141.9 (q, J = 47.7 Hz); 11B NMR
(128 MHz, CD3CN) δ 2.0 (q, J = 50.7 Hz). Anal. Calcd for C6H14BF3N2:
C, 39.60; H, 7.75; N, 15.39. Found: C, 38.05 (low); H, 7.66 (low); N, 14.44
(low). HRMS (ESI-TOF): calcd for C6H13BF3N2- [M - H]- 181.1124,
found 181.1120.
{[Cyclohexyl(methyl)ammonio]methyl}trifluoroborate (2g). Using
general reaction conditions A with N-methylcyclohexylamine (0.72 mL,
0.868 g/mL, 5.50 mmol) and 1c (0.782 g, 5.0 mmol) for 24 h, 2g was
obtained (0.671 g, 69%, 3.44) as a white powder: mp 105-108 °C; IR
1
ν(HATR)/cm-1 3182, 2942, 2863 1293, 1061, 1024, 985, 944; H
NMR (500 MHz, DMSO-d6) δ 8.38-7.84 (m, 1H), 2.95 (s, 1H),
2.57 (s, 3H), 2.07-1.50 (m, 7H), 1.37-0.99 (m, 5H); 13C NMR
(126 MHz, DMSO-d6) δ 64.5, 38.8, 25.9, 25.7, 24.8, 24.5; 19F NMR
(471 MHz, DMSO-d6) δ -138.2; 11B NMR (128 MHz, DMSO-d6) δ
1.9. Anal. Calcd for C8H17BF3N: C, 49.27; H, 8.79; N, 7.18. Found: C,
48.04 (low); H, 8.04 (low); N, 6.84. HRMS (ESI-TOF): calcd for
C8H16BF3N- [M - H]-: 194.1330, found 194.1328.
Trifluoro(thiomorpholino-4-iummethyl)borate (2h). Using general
reaction conditions B and reaction with thiomorpholine (0.57 mL, 1.026
g/mL, 6.0 mmol) and 1c (0.782 g, 5.0 mmol) for 16 h, 2h was obtained
(0.693 g, 75%, 3.74 mmol) as an off-white powder after trituration with
cold acetone: mp 188-189 °C; IR ν(HATR)/cm-1 3178, 1736, 1408,
Trifluoro(morpholin-4-iummethyl)borate (2c). Using general reaction
conditions A with morpholine (0.87 mL, 0.996 g/mL, 10.0 mmol) and 1c
(0.782 g, 5.0 mmol) for 1.5 h, 2c was obtained (0.739 g, 87%, 4.37 mmol) as
a pale yellow powder: mp 170-172 °C; IR ν(HATR)/cm-1 3537, 3112,
1
1075, 1028, 967, 952, 925; H NMR (500 MHz, CD3CN) δ 6.26 (s,
1
1638, 1442, 1262, 1122, 1079, 1054, 1028, 960; H NMR (500 MHz,
1H), 3.72 (d, J = 12.0, 2H), 3.2-2.92 (m, 4H), 2.77 (d, J = 14.0, 2H),
2.14 (s, 2H);13C NMR (126 MHz, CD3CN) δ 57.0, 25.4; 19F NMR
(471 MHz, CD3CN) δ -141.6 (q, J = 49.3 Hz); 11B NMR (128 MHz,
CD3CN) δ 1.6 (q, J = 51.1 Hz). Anal. Calcd for C5H11BF3NS: C, 32.46;
H, 5.99; N, 7.57; S, 17.33. Found: C, 32.39; H, 5.86; N, 7.36; S, 17.14.
General Experimental Procedure for the Suzuki-Miyaura Cross-
Coupling Reactions of Aryl Bromides. Preparation of 4-(Piperidin-1-
ylmethyl)benzonitrile (5a). A 2-5 mL microwave vial equipped with a
stirrer bar was charged with 2a (0.217 g, 1.3 mmol), Cs2CO3 (0.977 g,
3.0 mmol), 4a (0.182 g, 1.0 mmol), Pd(OAc)2 (0.067 g, 0.03 mmol), and
XPhos13 (0.029 g, 0.06 mmol) and then sealed with a cap lined with a
disposable PTFE septum. The vial was then evacuated under vacuum
and purged with N2 (3ꢀ). Anhydrous THF (3.63 mL) and H2O
(0.36 mL) were added by syringe (aryl bromides that were liquids at
room temperature were added by syringe), and the reaction mixture was
stirred and heated at 80 °C for 24 h and then cooled to room
temperature and diluted with H2O (1 mL). The reaction mixture was
extracted with EtOAc (3 ꢀ 3 mL). The combined organics were dried
(MgSO4), filtered through Celite, and concentrated in vacuo. Purifica-
tion by flash column chromatography, with 7/1 hexanes/EtOAc with
0.2% Et3N to 1/1 hexanes/EtOAc with 0.2% Et3N as eluent, afforded 5a
(0.156 g, 78%, 0.78 mmol) as a yellow oil: Rf = 0.08 (silica gel, hexanes/
EtOAc 7/1 with 0.2% Et3N). 1H and 13C NMR spectra are comparable
to those reported in the literature.3
1-(4-Methoxybenzyl)piperidine (5b). Using the general procedure
with 4b (0.187 g, 1.0 mmol) for 44 h, 5b was obtained in 68% yield
(0.140 g, 0.68 mmol) as a yellow oil after silica gel column chromatography
(with 7/1 hexanes/EtOAc with 0.2% Et3N to 1/1 hexanes/EtOAc with
0.2% Et3N as eluent): Rf = 0.05 (7/1 hexanes/EtOAc with 0.2% Et3N). 1H
and 13C NMR spectra are comparable to those reported in the literature.2
General Experimental Procedure for the Suzuki-Miyaura Cross-
Coupling Reactions of Aryl and Heteroaryl Chlorides. Preparation of
4-(Piperidin-1-ylmethyl)benzonitrile (5a). A 2-5 mL microwave vial
equipped with a stirrer bar was charged with 2a (0.200 g, 1.2 mmol),
Cs2CO3 (0.977 g, 3.0 mmol), 6a (0.138 g, 1.0 mmol), Pd(OAc)2 (0.067
g, 0.03 mmol), and XPhos (0.029 g, 0.06 mmol) and then sealed with a
cap lined with a disposable PTFE septum. The vial was then evacuated
under vacuum and purged with N2 (3ꢀ). Anhydrous THF (3.2 mL) and
H2O (0.80 mL) were added by syringe (aryl and heteroaryl chlorides
that were liquids at room temperature were added by syringe), and the
reaction mixture was stirred and heated at 80 °C for 45 h and then cooled
CD3CN) δ 6.57 (s, 1H), 3.93 (d, J = 13.0 Hz, 2H), 3.73 (dd, J = 18.1, 6.7
Hz, 2H), 3.43 (d, J = 13.5 Hz, 2H), 3.06-2.92 (m, 2H), 2.15 (s, 2H); 13C
NMR (126 MHz, CD3CN) δ 64.7, 55.3; 19F NMR (471 MHz, CD3CN) δ
-141.8 (q, J = 50.2 Hz); 11B NMR (128 MHz, CD3CN) δ 2.9-1.0 (m).
Anal. Calcd. for C5H11BF3NO: C, 35.54; H, 6.56; N, 8.29. Found: C, 34.44
(low); H, 6.74 (high); N, 7.92 (low). HRMS (ESI-TOF): calcd for
C5H10BF3NO- [M - H]- 168.0808, found 168.0809.
{[Benzyl(methyl)ammonio]methyl}trifluoroborate (2d). Using gen-
eral reaction conditions A with N-benzylmethylamine (0.65 mL, 0.939
g/mL, 5.05 mmol) and 1c (0.782 g, 5.0 mmol) for 16 h, 2d was obtained
(0.895 g, 88%, 4.40 mmol) as an off-white powder: mp 109-112 °C; IR
ν(HATR)/cm-1 3188, 1458, 1318, 1045, 1003, 934, 780, 748, 700;
1H NMR (500 MHz, CD3CN) δ 7.47 (s, 5H), 6.56 (bs, 1H), 4.30
(d, J = 13.0 Hz, 1H), 4.08 (d, J = 13.0 Hz, 1H), 2.71 (s, 3H), 2.17 (bs,
1H), 2.03 (bs, 1H); 13C NMR (126 MHz, CD3CN) δ 132.0, 131.5,
130.7, 130.0, 62.3, 43.3; 19F NMR (471 MHz, CD3CN) δ -141.94 (q,
J = 47.4 Hz); 11B NMR (128 MHz, CD3CN) δ 2.0 (q, J = 50.7 Hz). Anal.
Calcd for C9H13BF3N: C, 53.25; H, 6.45; N, 6.90. Found: C, 52.05
(low); H, 5.98 (low); N, 6.68. HRMS (ESI-TOF): calcd for C9H13
BF3N- [M - H]- 202.1015, found 202.1018.
{[4-(tert-Butoxycarbonyl)piperazin-1-ium-1-yl]methyl}trifluoroborate
(2e). Using general reaction conditions A with tert-butyl piperazine-1-
carboxylate (0.940 g, 5.05 mmol) and 1c (0.782 g, 5.0 mmol) for 6.5 h in
3/1 CPME/tert-amyl alcohol, 2e was obtained (1.07 g, 80%, 3.99 mmol) as
an off-white powder: mp 185 °Cdec;IRν(HATR)/cm-1 3177, 1697, 1646
(CdO), 1421, 1284, 1170, 1143, 1034, 959; 1H NMR (360 MHz, acetone-
d6) δ 7.43 (s, 1H), 4.17 (d, J = 14.6 Hz, 2H), 3.65 (d, J = 13.1 Hz, 2H),
3.47-3.27 (m, 2H), 3.05 (td, J = 12.6, 3.5 Hz, 2H), 2.20 (s, 2H), 1.46
(s, 9H); 13C NMR (126 MHz, acetone-d6) δ 154.6, 80.8, 55.0, 41.4, 28.4;
19F NMR (339 MHz, acetone-d6) δ -142.1 (q, J = 43.7 Hz); 11B NMR
(128 MHz, acetone-d6) δ 2.2 (q, J = 49.5 Hz). Anal. Calcd for C10H20
BF3N2O2: C, 44.80; H, 7.52; N, 10.45. Found: C, 44.52; H, 7.52; N, 10.40.
Trifluoro[(4-methylpiperazin-1-ium-1-yl)methyl]borate (2f). Using
general reaction conditions A with 1-methylpiperazine (0.61 mL, 0.903 g/mL,
5.50 mmol) and 1c (0.782 g, 5.0 mmol) for 4 h, 2f was obtained (0.722 g,
79%, 3.96 mmol) as a white powder: mp 73-78 °C; IR ν(HATR)/cm-1
3601, 3168, 2808, 1455, 1068, 1040, 966; 1H NMR (500 MHz, CD3CN)
δ 6.16 (s, 1H), 3.44 (d, J = 12.3 Hz, 2H), 2.96 (t, J = 11.0 Hz, 2H), 2.82
(d, J = 12.5 Hz, 2H), 2.31 (t, J = 11.4 Hz, 2H), 2.25 (d, J = 4.0 Hz, 3H),
2.11 (s, 2H); 13C NMR (126 MHz, CD3CN) δ 55.4, 52.6, 45.6; 19F
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The Journal of Organic Chemistry
ARTICLE
to room temperature and diluted with H2O (1 mL). The reaction
mixture was extracted with EtOAc (3 ꢀ 3 mL). The combined organics
were dried (MgSO4), filtered through Celite, and concentrated in vacuo.
Purification by flash column chromatography, with 7/1 hexanes/EtOAc
with 0.2% Et3N to 4/1 hexanes/EtOAc with 0.2% Et3N as eluent,
afforded 5a (0.163 g, 81%) as a yellow oil: Rf = 0.06 (silica gel, hexanes/
EtOAc 7/1 with 0.2% Et3N). 1H and 13C NMR spectra are comparable
to those reported in the literature.3
1-(2-Methylbenzyl)piperidine (5c). Using the general procedure with
6c (0.126 g, 1.0 mmol), 5c was obtained in 73% yield (0.138 g, 0.73 mmol)
as a pale yellow oil after silica gel column chromatography (with 9/1
hexanes/EtOAc with 0.2% Et3N to 7/1 hexanes/EtOAc with 0.2% Et3N as
eluent): Rf = 0.2 (silica gel, 7/1 hexanes/EtOAc with 0.2% Et3N). 1H and
13C NMR spectra are comparable to those reported in the literature.3
1-(2,6-Dimethylbenzyl)piperidine (5d). Using the general procedure
with 6d (0.145 g, 1.0 mmol), 5d was obtained in 53% yield (0.107 g, 0.53
mmol) as a yellow solid after silica gel column chromatography (with
99/1 hexanes/EtOAc to 9/1 hexanes/EtOAc as eluent): Rf = 0.5 (silica
gel, 9/1 hexanes/EtOAc); mp 25-26 °C. 1H and 13C NMR spectra are
comparable to those reported in the literature.3
4-(4-Methoxybenzyl)morpholine (7b). Using the general procedure
with 2c (0.203 g, 1.2 mmol) and 6b (0.142 g, 1.0 mmol), 7b was
obtained in 85% yield (0.176 g, 0.85 mmol) as a yellow oil after silica gel
column chromatography (with 7/1 hexanes/EtOAc with 0.2% Et3N to
1/1 hexanes/EtOAc with 0.2% Et3N as eluent): Rf = 0.05 (silica gel, 7/1
hexanes/EtOAc with 0.2% Et3N). 1H and 13C NMR spectra are
comparable to those reported in the literature.2
N-Benzyl-1-(4-methoxyphenyl)-N-methylmethanamine (7c). Using
the general procedure with 2d (0.244 g, 1.2 mmol) and 6b (0.142 g, 1.0
mmol), 7c was obtained in 87% yield (0.211 g, 0.87 mmol) as a clear,
colorless oil after silica gel column chromatography (with 9/1 hexanes/
EtOAc with 0.2% Et3N to 1/1 hexanes/EtOAc with 0.2% Et3N as eluent):
Rf = 0.4 (silica gel, 7/1 hexanes/EtOAc with 0.2% Et3N). 1H and 13C NMR
spectra are comparable to those reported in the literature.2
tert-Butyl-4-(4-methoxybenzyl)piperazine-1-carboxylate
(7d).
Using the general procedure and reaction with 2e (0.322 g, 1.2 mmol)
and 6b (0.142 g, 1.0 mmol), 7d was obtained in 98% yield (0.302 g, 0.98
mmol) as a white solid after silica gel column chromatography (with 7/1
hexanes/EtOAc with 0.2% Et3N to 1/1 hexanes/EtOAc with 0.2% Et3N
as eluent): Rf = 0.09 (silica gel, 7/1 hexanes/EtOAc with 0.2% Et3N);
1
mp 55-57 °C. H and 13C NMR spectra are comparable to those
1-[5-(Piperidin-1-ylmethyl)thiophen-2-yl]ethanone (5e). Using the
general procedure with 6e (0.161 g, 1.0 mmol), 5e was obtained in 83%
yield (0.184 g, 0.82 mmol) as a yellow solid after silica gel column
chromatography (with 9/1 CHCl3/EtOAc to 100% EtOAc as eluent):
Rf = 0.08 (silica gel, 8/2 CHCl3/EtOAc); mp 50-52 °C. NMR spectra
are comparable to those reported in the literature.3
reported in the literature.2
1-(4-Methoxybenzyl)-4-methylpiperazine (7e). Using the general
procedure and reaction with 2f (0.218 g, 1.2 mmol) and 6b (0.142 g, 1.0
mmol), 7e was obtained in 76% yield (0.168 g, 0.76 mmol) as a dark yellow
oil after silica gel column chromatography (with 8/2 CHCl3/EtOAc to 98/
2 EtOAc/Et3N as eluent): Rf = 0.4 (silica gel, EtOAc/Et3N 99/1). 1H and
13C NMR spectra are comparable to those reported in the literature.3
N-(4-Methoxybenzyl)-N-methylcyclohexanamine (7f). Using the
general procedure with 2g (0.234 g, 1.2 mmol) and 6b (0.142 g, 1.0
mmol), 7f was obtained in 81% yield (0.189 g, 0.81 mmol) as a clear orange
oil after silica gel column chromatography (with 7/1 hexanes/EtOAc with
0.2% Et3N to 1/1 hexanes/EtOAc with 0.2% Et3N as eluent): Rf = 0.08
(silica gel, 7/1 hexanes/EtOAc with 0.2% Et3N). 1H and 13C NMR spectra
are comparable to those reported in the literature.3
5-(Piperidin-1-ylmethyl)thiophene-2-carbaldehyde (5f). Using the
general procedure with 6f (0.147 g, 1.0 mmol), 5f was obtained in 70%
yield (0.147 g, 0.70 mmol) as an orange oil after silica gel column
chromatography (with 9/1 hexanes/EtOAc with 0.2% Et3N to 1/1
hexanes/EtOAc with 1% Et3N as eluent): Rf = 0.2 (silica gel, 8/2
1
CHCl3/EtOAc). H and 13C NMR spectra are comparable to those
reported in the literature.3
2-Methoxy-5-(piperidin-1-ylmethyl)pyridine (5g). Using the general
procedure with 6g (0.144 g, 1.0 mmol), 5g was obtained in 96% yield
(0.197 g, 0.96 mmol) as a yellow oil after silica gel column chromato-
graphy(with8/2 CHCl3/EtOActo98/2EtOAc/Et3Naseluent):Rf =0.1
(silica gel, 8/2 CHCl3/EtOAc). 1H and 13C NMR spectra are comparable
to those reported in the literature.3
2-Fluoro-5-(piperidin-1-ylmethyl)pyridine (5h). Using the general
procedure with 6h (0.132 g, 1.0 mmol), 5h was obtained in 68% yield
(0.132 g, 0.68 mmol) as a yellow oil after silica gel column chromatography
(with 8/2 CHCl3/EtOAc to 99/1 EtOAc/Et3N as eluent): Rf = 0.04 (silica
gel, 8/2 CHCl3/EtOAc); IR ν(HATR)/cm-1 2937, 1598, 1483, 1245,
1114, 908, 858, 832, 755, 733; 1H NMR (500 MHz, CDCl3) δ8.10 (s, 1H),
7.78 (t, J= 8.1 Hz, 1H), 6.88 (d, J= 8.3 Hz, 1H), 3.44 (s, 2H), 2.36 (bs, 4H),
1.61-1.49 (m, 4H), 1.48-1.38 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
163.1 (d, J = 237.9 Hz), 147.8 (d, J = 14.5 Hz), 142.1 (d, J = 7.9 Hz),
132.0 (d, J = 4.4 Hz), 109.2 (d, J = 37.4 Hz) 60.1, 54.5, 26.0, 24.4; 19F NMR
(471 MHz, CDCl3) δ -70.8; HRMS (ESI-TOF) m/z calcd for C11H16
FN2þ [M þ H]þ 195.1298, found 195.1293.
4-(4-Methoxybenzyl)thiomorpholine (7g). Using the general proce-
dure with 2h (0.222 g, 1.2 mmol) and 6b (0.142 g, 1.0 mmol), 7g was
obtained in 72% yield (0.160 g, 0.72 mmol) as a yellow oil after silica gel
column chromatography (with 7/1 hexanes/EtOAc with 0.2% Et3N to
1/1 hexanes/EtOAc with 0.2% Et3N as eluent): Rf = 0.4 (silica gel, 7/1
hexanes/EtOAc with 0.2% Et3N); IR ν(HATR)/cm-1 2908, 2803,
1611, 1511, 1242, 1035, 957, 823; 1H NMR (500 MHz, CDCl3) δ 7.21
(d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.45 (s, 2H),
2.74-2.61 (m, 8H); 13C NMR (126 MHz, CDCl3) δ 158.8, 130.3,
130.1, 113.7, 63.2, 55.3, 54.9, 28.1; HRMS (ESI-TOF) m/z calcd for
C12H18NOSþ [M þ H]þ 224.1109, found 224.1103.
3-(Piperidin-1-ylmethyl)pyridine (5i). Using the general procedure
with 6i (0.114 g, 1.0 mmol), 5i was obtained in 61% yield (0.107 g, 0.61
mmol) as an orange oil after silica gel column chromatography (with 9/1
CHCl3/EtOAc to 98/2 EtOAc/Et3N as eluent): Rf = 0.4 (silica gel, 99/1
EtOAc/Et3N). 1H and 13C NMR spectra are comparable to those reported
in the literature.2
1-(4-Methoxybenzyl)piperidine (5b). Using the general procedure
with 6b (0.142 g, 1.0 mmol), 5b was obtained in 90% yield (0.185 g,
0.90 mmol) as a yellow oil after silica gel column chromatography (with 7/1
hexanes/EtOAc with 0.2% Et3N to 1/1 hexanes/EtOAc with 0.2% Et3N as
eluent): Rf = 0.05 (silica gel, 7/1 hexanes/EtOAc with 0.2% Et3N). 1H and
13C NMR spectra are comparable to those reported in the literature.2
N-Ethyl-N-(4-methoxybenzyl)ethanamine (7a). Using the general
procedure with 2b (0.186 g, 1.2 mmol) and 6b (0.142 g, 1.0 mmol), 7a
was obtained in 63% yield (0.122 g, 0.63 mmol) as a yellow oil after silica
gel column chromatography (with 7/1 hexanes/EtOAc with 0.2% Et3N
to 1/1 hexanes/EtOAc with 0.2% Et3N as eluent): Rf = 0.08 (silica gel,
N-Ethyl-N-(pyridin-3-ylmethyl)ethanamine (8a). Using the general
procedure with 2b (0.186 g, 1.2 mmol) and 6i (0.114 g, 1.0 mmol), 8a
was obtained in 30% yield (0.050 g, 0.30 mmol) as an orange oil after
silica gel column chromatography (with 9/1 CHCl3/EtOAc to 98/2
EtOAc/Et3N as eluent): Rf = 0.4 (silica gel, 99/1 EtOAc/Et3N); IR
1
ν(HATR)/cm-1 3029, 2966, 2935, 2806, 1576, 1424, 1201, 714; H
NMR (500 MHz, CDCl3) δ 8.54 (d, J = 1.5 Hz, 1H), 8.48 (dd, J = 4.7,
1.3 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.7, 4.8 Hz, 1H), 3.57
(s, 2H), 2.52 (q, J = 7.1 Hz, 4H), 1.04 (t, J = 7.1 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 150.4, 148.4, 136.6, 135.5,þ123.4, 55.0, 46.9, 11.9;
HRMS (ESI-TOF) m/z calcd for C10H17N2 [M þ H]þ 165.1392,
found 165.1389.
1
hexanes/EtOAc 7/1 with 0.2% Et3N). H and 13C NMR spectra are
comparable to those reported in the literature.3
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The Journal of Organic Chemistry
ARTICLE
4-(Pyridin-3-ylmethyl)morpholine (8b). Using the general procedure
with 2c (0.203 g, 1.2 mmol) and 6i (0.114 g, 1.0 mmol), 8b was obtained in
64% yield (0.113 g, 0.63 mmol) as an orange oil after silica gel column
chromatography (with 9/1 CHCl3/EtOAc to 98/2 EtOAc/Et3N as
eluent): Rf = 0.06 (silica gel, 8/2 CHCl3/EtOAc); IR ν(HATR)/cm-1
3416, 2809, 1115, 1007, 865, 715; 1H NMR (500 MHz, CD3CN) δ 8.54-
8.39 (m, 2H), 7.69 (s, 1H), 7.30 (s, 1H), 3.61 (s, 4H), 3.49 (s, 2H), 2.39
(s, 4H); 13C NMR (126 MHz, CDCl3) δ 150.7, 148.9, 136.9, 133.4, 123.5,
67.1, 60.7, 53.7; HRMS (ESI-TOF) calcd for C10H15N2Oþ [M þ H]þ
179.1184, found 179.1183.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
’ ACKNOWLEDGMENT
This research was supported by the NIH (R01 GM-081376)
and Sigma-Aldrich. Dr. Rakesh Kohli (University of Pennsylvania)
is acknowledged for obtaining HRMS data, and Dr. Patrick
Carroll (University of Pennsylvania) is acknowledged for obtain-
ing X-ray data.
N-Benzyl-N-methyl-1-(pyridin-3-yl)methanamine (8c). Using the
general procedure with 2d (0.244 g, 1.2 mmol) and 6i (0.114 g, 1.0
mmol), 8c was obtained in 83% yield (0.178 g, 0.83 mmol) as a pale
yellow oil after silica gel column chromatography (with 9/1 CHCl3/
EtOAc to 100% EtOAc as eluent): Rf = 0.2 (silica gel, 8/2 CHCl3/
EtOAc); IR ν(HATR)/cm-1 3028, 2788, 1576, 1453, 1425, 1367, 1023,
788, 740, 714, 699; 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.49
(dd, J = 4.7, 1.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.40-7.28 (m, 4H),
7.28-7.20 (m, 2H), 3.53 (s, 2H), 3.50 (s, 2H), 2.18 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 150.4, 148.6, 139.0, 136.5, 134.8, 128.9, 128.4,
127.2, 123.4, 62.0, 58.9, 42.2; HRMS (ESI-TOF) m/z calcd for
C14H17N2þ [M þ H]þ 213.1392, found 213.1386.
’ REFERENCES
(1) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031–2034.
(2) Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597–1600.
(3) Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem.
2008, 73, 2052–2057.
(4) Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.; Wells, K. M.;
Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2000,
2, 1081–1084.
tert-Butyl-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate
(8d).
Using the general procedure with 2e (0.322 g, 1.2 mmol) and 6i
(0.114 g, 1.0 mmol), 8d was obtained in 99% yield (0.274 g, 0.99 mmol)
as a yellow solid after silica gel column chromatography (with 8/2
CHCl3/EtOAc to 98/2 EtOAc/Et3N as eluent): Rf = 0.1 (silica gel, 8/2
CHCl3/EtOAc); mp 93 °C dec; IR ν(HATR)/cm-1 2975, 2950, 2809,
1679 (CdO), 1426, 1240, 1163, 1129, 998; 1H NMR (500 MHz,
CDCl3) δ 8.53 (s, 1H), 8.52-8.48 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H),
7.27-7.23 (m, 1H), 3.51 (s, 2H), 3.45-3.38 (m, 4H), 2.42-2.34 (m,
4H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 154.8, 150.6, 148.9,
136.7, 133.5, 123.4, 79.7, 60.3, 52.9, 44.2, 43.3, 28.5; HRMS (ESI-TOF)
m/z calcd for C15H24N3O2þ [M þ H]þ 278.1869, found 278.1860.
N-Methyl-N-(pyridin-3-ylmethyl)cyclohexanamine (8f). Using the
general procedure with 2g (0.234 g, 1.2 mmol) and 6i (0.114 g, 1.0 mmol),
8f was obtained in 75% yield (0.154 g, 0.75 mmol) as a clear, yellow oil after
silica gel column chromatography (with 9/1 CHCl3/EtOAc to 98/2
EtOAc/Et3N as eluent): Rf = 0.2 (silica gel, 8/2 CHCl3/EtOAc); IR
ν(HATR)/cm-1 3030, 2928, 2853, 1450, 1426, 1026, 793, 714; 1H NMR
(500 MHz, CDCl3) δ 8.52 (s, 1H), 8.48 (d, J = 4.7 Hz, 1H), 7.67 (d, J = 7.7
Hz, 1H), 7.23 (dd, J = 7.7, 4.9 Hz, 1H), 3.57 (s, 2H), 2.48-2.37 (m, 1H),
2.18 (s, 3H), 1.91-1.76 (m, 4H), 1.68-1.58 (m, 1H), 1.37-1.16 (m, 4H),
1.17-1.05 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 150.4, 148.4, 136.5,
136.0, 123.4, 62.8, 55.3, 37.7, 28.8, 26.5, 26.1; HRMS (ESI-TOF) m/z calcd
for C13H21N2þ [M þ H]þ 205.1705, found 205.1706.
(5) Compare 2 779 133 commercially available aryl and heteroaryl
chlorides versus 397 551 commercially available aryl and heteroaryl
nitriles and aldehydes: SciFinder, version 2010; Chemical Abstracts
Service, Columbus, OH, 2010 (as of December 28, 2010).
(6) Schaumann, E. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations; Enders, D., Ed.; Thieme: New York, 2008;
Vol. 40, pp 7-411.
(7) Molander, G. A.; Hiebel, M.-A. Org. Lett. 2010, 12, 4876–4879.
(8) After this observation was made, the collected data were not
refined to a final structure.
(9) Molander, G. A.; Canturk, B. Org. Lett. 2008, 10, 2135–2138.
(10) Whiting, A. Tetrahedron Lett. 1991, 32, 1503–1506.
(11) Sandrock, D. L. Suzuki-Miyaura Cross-Coupling Reactions
and Method Development of Potassium Organotrifluoroborates. Ph.D.
Dissertation, University of Pennsylvania, Philadelphia, PA, 2010.
(12) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem.
2009, 74, 973–980.
(13) XPhos= 2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
4-(Pyridin-3-ylmethyl)thiomorpholine (8g). Using the general proce-
dure with 2h (0.222 g, 1.2 mmol) and 6i (0.114 g, 1.0 mmol), 8g was
obtained in 39% yield (0.075 g, 0.39 mmol) as a dark orange oil after silica gel
column chromatography (with 8/2 CHCl3/EtOAc to 98/2 EtOAc/Et3N as
eluent): Rf =0.10(silicagel, 8/2CHCl3/EtOAc); IR ν(HATR)/cm-1 3025,
2925, 2806, 1457, 1424, 1286, 1101, 1006, 955, 801, 708; 1H NMR (500
MHz, CDCl3) δ 8.50 (s, 1H), 8.47 (d, J = 3.7 Hz, 1H), 7.61 (d, J = 7.7 Hz,
1H), 7.22 (dd, J = 7.6 Hz, 4.9, 1H), 3.49 (s, 2H), 2.72-2.59 (m, 8H); 13C
NMR (126 MHz, CDCl3) δ 150.5, 148.8, 136.7, 133.7, 123.5, 61.0, 55.0,
28.1; HRMS (ESI-TOF) calcd for C10H15N2Sþ [Mþ H]þ 195.0956, found
195.0959.
’ ASSOCIATED CONTENT
S
Supporting Information. Text, tables, figures, and a CIF
b
file giving full experimental details and NMR spectra for all
compounds and X-ray crystal structure data for compound 2a.
2769
dx.doi.org/10.1021/jo2001066 |J. Org. Chem. 2011, 76, 2762–2769