General Procedures for the Lithiation/Trapping of N-Boc Piperazines

Article abstract of DOI:10.1021/acs.joc.7b00913

To provide α-substituted piperazines for early stage medicinal chemistry studies, a simple, general synthetic approach is required. Here, we report the development of two general and simple procedures for the racemic lithiation/trapping of N-Boc piperazin

Full text of DOI:10.1021/acs.joc.7b00913

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General Procedures for the Lithiation/Trapping of N-Boc Piperazines
James D. Firth, Peter O'Brien, and Leigh Ferris
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General Procedures for the Lithiation/Trapping of N-Boc Piperazines
James D. Firth†, Peter O’Brien*,† and Leigh Ferris‡
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†Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
‡AstraZeneca UK, Macclesfield, Cheshire, SK10 2NA, UK
ABSTRACT: In order to provide α-substituted piperazines for early-stage medicinal chemistry studies, a simple, general
synthetic approach is required. Here, we report the development of two general and simple procedures for the racemic
lithiation/trapping of N-Boc piperazines. Optimum lithiation times have been determined using in situ IR spectroscopy
and the previous complicated and diverse literature procedures have been simplified. Subsequent trapping with electro-
philes delivered a wide range of α-functionalised N-Boc piperazines. The scope and limitations of the distal N-group has
been investigated. The selective α- and β- arylation of N-Boc piperazines via lithiation/Negishi coupling is reported.
Piperazines are privileged groups within small molecule
drugs. Of the 1175 drugs approved by the FDA between
1983 and 2012, 51 drugs contain the motif, making pipera-
zine the 4th most common ring in drugs1 and the 3rd most
common nitrogen heterocycle.2 Nevertheless, piperazines
substituted at carbon are rare within small molecule ther-
apeutics, with Indinavir3 (an antiretroviral) and Vestipi-
tant (a NK-1 antagonist currently in clinical trials) being
notable examples (Figure 1).4
reaction, there remains a need to explore conditions for
racemic lithiation/trapping for the following reasons.
First, early-stage medicinal chemistry studies require
rapid access to racemic products. Second, the racemic and
asymmetric reactions do not always behave analogously.
Third, the racemic lithiation/trapping of N-Boc
piperazines is relatively under investigated and the few
reports15 have significant variation in the conditions used,
involving very different reaction times and temperatures
(Scheme 1). For example, van Maarseveen’s conditions
involved multiple warm/cool cycles.15a Subsequent reports
by Coldham15b and ourselves15c employed either lengthy
reaction times at –78 °C or short reaction times at
elevated temperatures. Additional reports, focused on
target synthesis, have used further modifications of these
procedures.15d-i
Figure 1. Structures of bio-active piperazines Indi-
navir and Vestipitant
Scheme 1. Direct Functionalization of N-Boc Pipera-
zines via Lithiation/Trapping
The use of α-substituted piperazines in medicinal
chemistry is somewhat limited by their poor commercial
availability and the lack of simple methods for their syn-
thesis. Available approaches include the formation of the
piperazine ring, traditionally from amino acids (via keto-
piperazines),5 or more recently via Mitsunobu chemistry,6
Pd-7 or Au-catalysis,8 photoredox catalysis,9 or Bode’s
SnAP10 and SLAP11 reagents. The direct functionalization
of the intact piperazine ring is an alternative strategy,
allowing late stage introduction of the α-substituent. As
an example, photoredox catalysis has been used for direct
α-arylation and vinylation of N-aryl substituted
piperazines but is limited to N-aryl substituents.12 In 2016,
we reported a route to a wide range of α-substituted
piperazines via the enantioselective α-lithiation/trapping
of N-Boc piperazines.13,14 Although this previous study
focused on the arguably more challenging asymmetric
Due to the wide range of experimental conditions that
have been reported to date and the need to have simple
access to racemic products for medicinal chemistry
studies, we set out to develop a general, unified and
experimentally simple procedure for the direct
functionalization of N-Boc piperazines via racemic
lithiation/trapping (Scheme 1). Herein, we report our
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results and present two complementary, general 74%) were obtained with Me3SiCl, Bu3SnCl, MeI, methyl
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procedures which were informed by in situ IR
spectroscopic studies.
chloroformate and paraformaldehyde. The use of cyclo-
hexanone and benzophenone gave oxazolidinones 3f and
3g in 44% and 90% respectively, after cyclisation of the
intermediate alkoxide on to the Boc group. The low yield
of 3f is probably due to the electrophile undergoing facile
enolisation.
The simplest piperazine lithiation protocol involves the
use of commercially available, orthogonally protected N-
Boc-N’-benzyl piperazine 1 and diamine-free lithiation
conditions, carried out at easily manageable (on a re-
search scale) cryogenic conditions (–78 °C). Additionally,
in our hands, we found that performing the reactions at –
78 °C gave more reproducible yields than when using our
previously published high-temperature (–30 °C) lithiation
conditions.15c To assess the feasibility of such a system, we
employed the use of in situ IR spectroscopy to identify the
time taken for lithiation (by monitoring the change in
νC=O).16 A solution of 1 in THF at –78 °C showed a νC=O
peak at 1696 cm-1. Upon addition of s-BuLi, lithiation of 1
proceeded to give lithiated intermediate 2 (νC=O peak at
1645 cm-1) in 1 h (Scheme 2). In contrast to our previous in
situ IR spectroscopic studies with s-BuLi/diamines in
Et2O, the pre-lithiation species was not detected.16b
With an operationally simple lithiation/trapping proce-
dure established, we chose to investigate the substrate
scope and varied the expectedly innocuous distal N-
substituent. Interestingly, our optimized diamine-free
lithiation protocol gave varied results when applied to N-
Boc-N’-methyl piperazine 4. Lithiation under our stand-
ard conditions (s-BuLi, THF, –78 °C, 1 h) proceeded in the
usual way, as shown by in situ IR monitoring (see Sup-
porting Information) However, trapping with Me3SiCl
gave no α-silylated piperazine 6 (Scheme 4). The only
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1
product observed by H NMR spectroscopy was the ring
fragmented side-product 5, which was isolated in 30%
yield. As reported in our study into the asymmetric lithia-
tion/trapping of N-Boc piperazines,13 this side-product is
formed by attack of the distal nitrogen on the electro-
phile, followed by ring fragmentation and N-Si bond
cleavage upon work-up. Likewise, trapping with methyl
chloroformate gave ring fragmented side-products 7 and
8 in 34% and 11% yields respectively. The latter formed
from a subsequent Boc-directed vinylic lithiation (and
trapping) event. In contrast, trapping with benzophenone
gave α-substituted products 9 and 10 in 83% and 12%
yields with no evidence of ring fragmented side-products.
We suggest that ketones are less likely to interact with
the distal nitrogen lone pair than Me3SiCl and methyl
chloroformate and so ring fragmentation did not occur.
Scheme 2. In situ IR Spectroscopic Monitoring of the
s-BuLi/THF-mediated Lithiation of N-Boc Piperazine
1
Scheme 3. Lithiation/Trapping of N-Boc-N-benzyl
Piperazine 1
Scheme 4. Lithiation/Trapping of N-Boc-N-methyl
Piperazine 4
Our unsuccessful trapping of lithiated N-Boc-N’-methyl
piperazine 4 with Me3SiCl was reminiscent of van Maar-
seveen et al.’s result. When lithiating 4 under different
conditions they isolated only 5% of the desired α-silylated
piperazine 6 when trapping with Me3SiCl.15a To verify
whether their low yield was in fact due to ring fragmenta-
Having determined the time required for the diamine-
free lithiation of 1, the full lithiation/trapping process was
investigated. Treatment of N-Boc-N’-benzyl piperazine 1
with 1.3 eq. of s-BuLi in THF at –78 °C for 1 h followed by
addition of the electrophile gave α-substituted pipera-
zines 3a-g in 44–90% yields (Scheme 3). Good yields (60-
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and 95% yield respectively. Transmetallation to copper
tion, we repeated van Maarseveen’s experiment. In our
followed by trapping with allyl bromide15a,17 gave α-allyl
piperazine 18d in 80% yield. Lithiation/trapping of 16 and
12 with methyl chloroformate resulted in methyl esters
18e and 17a in 66% and 45% yields. Trapping 16 with
paraformaldehyde gave a mixture of oxazolidinone 18f
and alcohol 18g in 26% and 57% yield. Use of cyclohexa-
none gave solely oxazolidinone 18h in 58% yield. Trap-
ping of 16 with benzophenone gave 18i and 18j in a total
yield of 97%, whereas trapping of 12 gave only oxazoli-
dinone 17b in 57% yield. Importantly, no ring fragmented
side-products were observed in any case (due to the steri-
cally demanding N-substituent), and the cumyl protecting
group can be easily removed by hydrogenolysis.13 Interest-
ingly, for the same electrophile, the yields with N-Boc-N’-
cumyl piperazine 16 (Scheme 7) were higher than when
using N-Boc-N’-benzyl piperazine 1 (Scheme 3). It is pos-
sible that the larger protecting group prevents unwanted
coordination of the distal nitrogen to the electrophiles.
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5
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7
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hands, none of the desired product 6 was formed and the
only fragmentation side-products 5 (isolated in 37% yield)
and vinyl silane 11 (isolated in 32%) were observed
(Scheme 5).
Scheme 5. Explanation of the Failure of the Lithia-
tion/Trapping of 4 with Me3SiCl
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Thus, the use of a small distal N-substituent led to limi-
tations with some electrophiles (Me3SiCl and methyl
chloroformate) due to ring fragmentation. In contrast
increasing the size of the group led to a pronounced re-
duction in the rate of lithiation. Initial in situ IR studies
with the previously reported14,15b N-Boc-N’-tert-butyl pi-
perazine 12 showed that diamine-free lithiation was much
slower than with N-Boc-N’-benzyl piperazine 1.13 Upon
addition of s-BuLi to 12 in THF at –78 °C (νC=O 1694 cm-1),
lithiation proceeded to give lithiated intermediate 13 (νC=O
1645 cm-1). However, after 2 h the reaction was incomplete
(Scheme 6). Conversely, lithiation using s-BuLi/TMEDA
in Et2O at –78 °C was much faster: 12 (νC=O 1700 cm-1) was
converted in to lithiated intermediate 15 (νC=O 1644 cm-1)
via pre-lithiation complex 14 (νC=O 1681 cm-1)17 within 15
min (Scheme 6).
Scheme 7. Lithiation/Trapping of N-Boc Piperazines
12 and 16
R
R
1. sBuLi, TMEDA
Et2O, –78 °C, 1 h
N
N
N
N
2. E+
E
Boc
Boc
12 R = Me
16 R = Ph
17 R = Me
18 R = Ph
Scheme 6. In situ IR Spectroscopic Monitoring of the
Lithiation of N-Boc Piperazine 12
Ph
Ph
Ph
Ph
N
N
N
N
N
N
SiMe3
N
SnBu3
N
Boc
Boc
Boc
Boc
18d 80%
(allyl-Br via Li/Cu
transmetallation)
18a 98%
(Me3SICl)
18b 80%
(Bu3SnCl)
18c 95%
(MeI)
Ph
Ph
N
Ph
N
tBu
N
N
OMe
OMe
N
N
N
N
Boc
O
Boc
O
Boc OH
O
O
18e 66%
(MeOCOCl)
17a 45%
(MeOCOCl)
18f 26%
((CHO)n)
18g 57%
((CHO)n)
Ph
N
Ph
N
Ph
tBu
N
N
Ph
Ph
Ph
Ph
N
O
O
N
N
N
Due to the shorter lithiation time and associated opera-
tional ease, we opted to perform lithiation/trapping reac-
tions of the sterically hindered N-Boc-N’-tert-butyl piper-
azine 12 and N-Boc-N’-cumyl piperazine 16 using s-
BuLi/TMEDA in Et2O at –78 °C for 1 h. Exposure of either
12 or 16 to these conditions followed by trapping led to α-
substituted piperazines 17 and 18 in 45-98% yields
(Scheme 7). Since we were unsuccessful in our attempts
to cleave the N-tert-butyl group we focused mostly on
cumyl protected piperazine 16 as it can be removed by
hydrogenolysis.13 Silylated, stannylated and methylated
piperazines 18a, 18b and 18c were isolated in 98%, 80%
Ph
Ph
Boc OH
O
O
O
O
18h 58%
(cyclohexanone)
18i 74%
(Ph2CO)
18j 23%
(Ph2CO)
17b 57%
(Ph2CO)
One of the most useful extensions to the lithia-
tion/trapping of N-Boc heterocycles for synthetic applica-
tions is the α-arylation methodology developed by Cam-
pos and co-workers.18 This process proceeds via Li/Zn
transmetallation and subsequent Negishi cross-coupling
and has been well studied using N-Boc pyrrolidine19 and
piperidine.16b,20 In 2010, our group reported the only ex-
ample with an N-Boc piperazine.15c Therefore we decided
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to explore the arylation reaction using our diamine free stage medicinal chemistry programmes. Additionally, the
1
2
conditions, since TMEDA was known to hinder the
Negishi coupling.
selective formation of both α- and β-arylated piperazines
has been discovered.
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After lithiation, N-Boc-N’-benzyl piperazine 1 under-
went Li/Zn transmetallation with ZnCl2, prior to Negishi
coupling with bromobenzene, catalysed by Pd(OAc)2 and
Experimental Section
All-non aqueous reactions were carried out under oxy-
gen free Ar or N2 using flame-dried glassware. Et2O and
THF were freshly distilled from sodium and benzophe-
-
tBu3PH+BF4 . Surprisingly, a 33:67 mixture of inseparable
regioisomers 19 and 20 was obtained in a combined 42%
yield (Scheme 8). Formation of the unexpected regioiso-
mer 20 presumably occurs through a β-hydride elimina-
tion/insertion sequence of the intermediate organopalla-
dium species.20c,21 This result corrects our previous incor-
rect report that only 19 was formed.15c A catalyst/ligand
screen was performed in an attempt to selectively form
either α- or β-arylated N-Boc piperazines (see Supporting
Information for full details). Use of PEPPSI-iPr22 resulted
in near complete selectivity for β-arylation with a 5:95
mixture of 19 and 20 being isolated in a moderate 38%
yield (Scheme 8).
none. Alkyllithiums were titrated against
N-
benzylbenzamide before use. TMEDA was distilled over
CaH2 before use. Petrol refers to the fraction of petroleum
ether boiling in the range 40-60 °C and was purchased in
Winchester quantities. Water is distilled water.
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Flash column chromatography was carried out using
Fluka Chemie GmbH silica (220-440 mesh). Thin layer
chromatography was carried out using commercially
available Merck F254 aluminium backed silica plates. Pro-
ton (400 MHz) and carbon (100.6 MHz) NMR spectra
were recorded on a Jeol ECX-400 instrument using an
internal deuterium lock. For samples recorded in CDCl3,
chemical shifts are quoted in parts per million relative to
CHCl3 (δH 7.26) and CDCl3 (δC 77.0, central line of triplet).
Carbon NMR spectra were recorded with broad band pro-
ton decoupling and assigned using DEPT experiments.
Coupling constants (J) are quoted in Hertz. Melting
points were carried out on a Gallenkamp melting point
apparatus. Boiling points give for compounds purified by
Kügelrohr distillation correspond to the oven tempera-
ture during distillation. Infrared spectra were recorded on
an ATI Mattson Genesis FT-IR spectrometer or a Perkin
Elmer UATR Two FT-IR spectrometer. Electrospray high
and low resonance mass spectra were recorded at room
temperature on a Bruker Daltronics microOTOF spec-
trometer. In situ ReactIR™ infra-red spectroscopic moni-
toring was performed on a Mettler-Toledo ReactIR iC10
spectrometer with a silicon-tipped (SiComp) probe.
Scheme 8. Arylation of N-Boc piperazines 1 and 16
Diamine Free Lithiation/Trapping of N-Boc-N’-
Benzyl Piperazine 1. s-BuLi (1.3 M solution in hexanes,
1.3 eq.) was added dropwise to a stirred solution of N-Boc-
N’-Benzyl Piperazine 1 (1.0-3.0 mmol, 1.0 eq.) in THF (0.14
M) at –78 °C under Ar. The resulting solution was stirred
at –78 °C for 1 h. Then the electrophile (2.0 eq.) was added
dropwise, as a solution in THF (1 mL) if necessary. The
reaction mixture was stirred at –78 °C for 15 min and then
allowed to warm to rt over 30 min. Then, saturated
NH4Cl(aq) (10 mL), 20% NaOH(aq) (10 mL) and Et2O (10 mL)
were added and the two layers were separated. The aque-
ous layer was extracted with Et2O (3 × 10 mL). The com-
bined organic layers were dried (MgSO4), filtered and
evaporated under reduced pressure to give the crude
product which was purified by flash column chromatog-
raphy on silica gel.
Submitting N-Boc-N’-cumyl piperazine 16 to arylation
catalyzed by Pd(dba)2 and RuPhos resulted in formation
of only the α-arylated piperazine 21 in 15% yield, along
with ring-fragmentation side-product 22 which was
isolated in 30% yield (Scheme 8). Thus, selective synthesis
of both the α- and β-arylated piperazines can be achieved
through substrate control by varying the distal nitrogen
protecting group and catalyst system. These initial
preliminary results are encouraging and could warrant
further investigation.
In conclusion, we have developed unifying, simple and
general procedures for the racemic lithiation/trapping of
N-Boc piperazines. In situ IR spectroscopic methods were
used to determine the optimum conditions for lithiation
of substrates with both sterically small (benzyl) and large
(cumyl) substituents. The previous complicated and di-
verse literature procedures have been simplified, resulting
an easy diamine-free lithiation/trapping of N-Boc-N-
benzyl piperazine 1 and a slightly more complicated but
higher yielding lithiation/trapping of N-Boc-N-cumyl pi-
perazine 16. These methods represent much needed sim-
ple and general approaches for the direct racemic func-
tionalization of piperazines, and will find use in early-
tert-Butyl
4-benzyl-2-(trimethylsilyl)piperazine-1-
carboxylate (3a). N-Boc-N’-benzyl piperazine 1 (276 mg,
1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0 mL, 1.3
mmol) and Me3SiCl (254 µL, 2.0 mmol) gave, after purifi-
cation (SiO2, 9:1 petrol-EtOAc), substituted piperazine 3a
(236 mg, 68%) as a colourless oil; RF (9:1 petrol-EtOAc)
1
0.4; H NMR (400 MHz, CDCl3) (60:40 mixture of rota-
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0.45H), 3.73 (s, 1.35H), 3.71 (s, 1.65H), 3.58 (d, J = 13.0 Hz,
mers) δ 7.32-7.30 (m, 4H), 7.27-7.22 (m, 1H) 4.20 (br s,
1
2
3
4
5
6
7
8
0.6H), 3.80 (br s, 0.4H), 3.61-3.55 (m, 1H), 3.44 (d, J = 13.0
Hz, 1H), 3.40 (d, J = 13.0 Hz, 1H), 3.05 (br s, 0.4H), 2.92 (br
s, 0.6H), 2.80 (d, J = 12.0 Hz, 1H), 2.72 (m, 0.6H), 2.64 (br
s, 0.4H), 2.24 (br s, 1H), 1.93 (td, J = 12.0, 3.0 Hz, 1H), 1.46
0.45H), 3.58 (d, J = 13.0 Hz, 0.55H), 3.45 (d, J = 13.0 Hz,
0.55H), 3.41 (d, J = 13.0 Hz, 0.45H), 3.34-3.27 (m, 1.55H),
3.18 (td, J = 13.0, 3.0 Hz, 0.45H), 2.79 (br d, J = 11.0 Hz,
0.45H), 2.74 (d, J = 11.0 Hz, 0.55H), 2.18 (td, J = 11.0, 4.0 Hz,
1H), 2.11 (br d, J = 11.0 Hz, 0.55H), 2.11 (br d, J = 11.0 Hz,
13
(s, 9H), 0.12 (s, 9H); C NMR (100.6 MHz, CDCl3) δ 154.7,
13
138.3, 129.1, 128.1, 127.0, 79.1, 63.4, 54.3, 53.2, 45.3, 41.4, 28.4,
–0.8; IR (CHCl3) 2977, 2804, 1673 (C=O), 1454, 1420, 1366,
1296, 1168, 1111, 1027, 840 cm–1; HRMS (ESI) m/z calcd for
C19H33N2O2Si (M+H)+ 349.2306, found 349.2297 (+1.7 ppm
error). Spectroscopic data consistent with those reported
in the literature.13
0.45H), 1.47 (s, 4.9H), 1.42 (s, 4.1H); C NMR (100.6 MHz,
CDCl3) (mixture of rotamers) δ 171.3, 171.1, 155.8, 155.3,
137.6, 128.7, 128.1, 127.2, 80.2, 62.3, 55.5, 54.3, 53.5, 52.4,
52.3, 51.9, 42.0, 41.0, 28.3; IR (CHCl3) 2979, 1744 (C=O,
CO2Me), 1691 (C=O, Boc), 1408, 1366, 1301, 1169, 1119, 1046,
976, 867 cm–1; HRMS (ESI) m/z calcd for C18H27N2O4
(M+H)+ 335.1965, found 335.1974 (–2.7 ppm error). Spec-
troscopic data consistent with those reported in the liter-
ature.13
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tert-Butyl
4-benzyl-2-(tributylstannyl)piperazine-1-
carboxylate (3b). N-Boc-N’-benzyl piperazine 1 (276 mg,
1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0 mL, 1.3
mmol) and Bu3SnCl (542 µL, 2.0 mmol) gave, after purifi-
cation (SiO2, 19:1 petrol-EtOAc), substituted piperazine 3b
(387 mg, 68%) as a colourless oil; RF (9:1 petrol-EtOAc)
tert-Butyl
4-benzyl-2-(hydroxymethyl)piperazine-1-
carboxylate (3e). N-Boc-N’-benzyl piperazine 1 (276 mg,
1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0 mL, 1.3
mmol) and paraformaldehyde (60 mg, 2.0 mmol) gave,
after purification (SiO2, 7:3 to 1:1 petrol-EtOAc), substitut-
ed piperazine 3e (197 mg, 64%) as a colourless oil; RF (1:1
1
0.2; H NMR (400 MHz, CDCl3) (50:50 mixture of rota-
mers) δ 7.38-7.21 (m, 5H), 4.13 (s, 0.5H), 4.03 (br d, J = 13.0
Hz, 0.5H), 3.80-3.16 (m, 4H), 2.82-2.37 (m, 3H), 2.21 (br s,
0.5H), 1.96-1.80 (m, 0.5H), 1.55-1.35 (m, 15H), 1.35-1.23 (m,
6H), 0.99-0.78 (m, 15H); 13C NMR (100.6 MHz, CDCl3)
(mixture of rotamers) δ 154.6, 154.2, 138.2, 129.4, 128.3,
127.2, 79.5, 79.4, 63.3, 58.1, 53.2, 53.0, 46.5, 45.5, 44.8, 42.6,
29.3, 29.3, 28.5, 27.9, 27.7, 13.8, 11.1, 10.4; IR (CHCl3) 2961,
2911, 2881, 2827, 1647 (C=O), 1433, 1395, 1395, 1344, 1278,
1231, 1151, 1088, 1055, 1007, 850, 688 cm–1; HRMS (ESI) m/z
calcd for C28H51N2O2Sn (M+H)+ 567.2972, found 567.2945
(+3.9 ppm error). Spectroscopic data consistent with
those reported in the literature.13
1
petrol-EtOAc) 0.2; H NMR (400 MHz, CDCl3) δ 7.36-7.24
(m, 5H), 4.07 (br s, 1H), 3.96-3.81 (m, 3H), 3.51 (d, J = 13.0
Hz, 1H), 3.47 (d, J = 13.0 Hz, 1H), 3.40 (br s, 1H), 2.98 (dt, J
= 11.5, 2.0 Hz, 1H), 2.83 (br d, J = 10.0 Hz, 1H), 2.31 (ddd, J =
11.5, 4.0, 1.0 Hz, 1H), 2.09 (ddd, J = 12.5, 11.5, 4.0 Hz, 1H),
1.45 (s, 3H), OH not resolved; 13C NMR (100.6 MHz,
CDCl3) δ 155.1, 137.0, 129.0, 128.5, 127.5, 80.0, 66.7, 63.0,
55.1, 52.5, 51.1, 41.4, 28.4; IR (CHCl3) 3280 (OH), 2971, 2913,
2781 1658 (C=O), 1433, 1390, 1345, 1302, 1197, 1152, 1103, 1060,
1035, 997, 743 cm–1; HRMS (ESI) m/z calcd for C17H27N2O3
(M+H)+ 307.2016, found 307.2023 (–2.2 ppm error). Spec-
troscopic data consistent with those reported in the liter-
ature.23
tert-Butyl
4-benzyl-2-methylpiperazine-1-carboxylate
(3c). N-Boc-N’-benzyl piperazine 1 (829 mg, 3.0 mmol), s-
BuLi (1.3 M solution in hexanes, 3.0 mL, 3.9 mmol) and
MeI (374 µL, 6.0 mmol) gave, after purification (SiO2, 9:1
petrol-EtOAc), substituted piperazine 3c (645 mg, 74%)
as a colourless oil; RF (7:3 petrol-EtOAc) 0.6; 1H NMR (400
MHz, CDCl3) δ 7.36-7.29 (m, 4H), 7.26-7.22 (m, 1H), 4.18
(br s, 1H), 3.80 (br d, J = 12.5 Hz, 1H), 3.53 (d, J = 13.0 Hz,
1H), 3.40 (d, J = 13.0 Hz, 1H), 3.11 (td, J = 12.5, 3.5 Hz, 1H),
2.77-2.73 (m, 1H), 2.59 (dt, J = 11.0, 1.5 Hz, 1H), 2.12 (dd, J =
11.0, 4.0 Hz, 1H), 2.00 (ddd, J = 12.5, 11.5, 3.5 Hz, 1H), 1.45 (s,
9H), 1.24 (d, J = 6.5 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 154.8, 138.4, 128.7, 128.2, 127.0, 79.3, 62.8, 57.3, 53.2, 47.0,
39.1, 28.4, 15.9; IR (ATR) 2973, 1688 (C=O), 1452, 1407,
1392, 1364, 1341, 1322, 1305, 1279, 1247, 1223, 1158, 1107, 1059,
1039, 1028, 740, 700 cm-1; HRMS (ESI) m/z calcd for
C17H27N2O2 (M+H)+ 291.2067, found 291.2072 (–1.0 ppm
error). Spectroscopic data consistent with those reported
in the literature.13
7-Benzyl-hexahydrospiro[[1,3]oxazolo[3,4-a]piperazine-
1,1'-cyclohexane]-3-one (3f). N-Boc-N’-benzyl piperazine 1
(276 mg, 1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0
mL, 1.3 mmol) and cyclohexanone (207 µL, 2.0 mmol)
gave, after purification (SiO2, 1:1 petrol-EtOAc), oxazoli-
dinone 3f (131 mg, 44%) as a white solid; RF (1:1 petrol-
1
EtOAc) 0.1; mp 64-66 °C; H NMR (400 MHz, CDCl3) δ
7.35-7.25 (m, 5H), 3.76 (dd, J = 13.0, 3.5 Hz, 1H), 3.61-3.49
(m, 2H), 3.39 (dd, J = 11.0, 3.5 Hz, 1H), 3.05 (td, J = 12.5, 3.5
Hz, 1H), 2.77-2.73 (m, 2H), 2.05-1.97 (m, 2H), 1.89-1.20 (m,
10H); 13C NMR (100.6 MHz, CDCl3) δ 156.4, 137.3, 128.8,
128.3, 127.3, 80.7, 63.0, 61.7, 52.8, 51.7, 41.0, 36.7, 30.7, 28.3,
25.0, 21.9; IR (CHCl3) 2896, 1710 (C=O), 1428, 1331, 1286,
1074, 1025, 961, 890, 745 cm–1; HRMS (ESI) m/z calcd for
C18H25N2O2 (M+H)+ 301.1905, found 301.1911 (+1.6 ppm er-
ror).
1-tert-Butyl
2-methyl
4-benzylpiperazine-1,2-
7-Benzyl-1,1-diphenyl-hexahydro-1H-[1,3]oxazolo[3,4-
a]piperazin-3-one (3g). N-Boc-N’-benzyl piperazine 1 (415
mg, 1.5 mmol), s-BuLi (1.3 M solution in hexanes, 1.5 mL,
1.95 mmol) and benzophenone (547 mg, 3.0 mmol) in
THF (1 mL) gave, after purification (SiO2, 4:1 to 7:3 petrol-
EtOAc), substituted piperazine 3g (520 mg, 90%) as a
dicarboxylate (3d). N-Boc-N’-benzyl piperazine 1 (276 mg,
1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0 mL, 1.3
mmol) and MeOCOCl (155 µL, 2.0 mmol) gave, after puri-
fication (SiO2, 9:1 to 7:3 petrol-EtOAc), substituted piper-
azine 3d (200 mg, 60%) as a colourless oil; RF (7:3 petrol-
1
1
EtOAc) 0.7; H NMR (400 MHz, CDCl3) (55:45 mixture of
white solid, RF (7:3 petrol-EtOAc) 0.2; mp 146-149 °C; H
rotamers) δ 7.32-7.24 (m, 5H), 4.71 (br s, 0.55H), 4.54 (br s,
0.45H), 3.85 (br d, J = 13.0 Hz, 0.55H), 3.77-3.75 (m,
NMR (400 MHz, CDCl3) δ 7.53-7.50 (m, 2H), 7.40-7.21 (m,
13H), 4.54 (dd, J = 11.0, 3.5 Hz, 1H), 3.80 (ddd, J = 13.0, 3.5,
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The Journal of Organic Chemistry
1.5 Hz, 1H), 3.50 (d, J = 13.0 Hz, 1H), 3.31 (d, J = 13.0 Hz,
Page 6 of 11
1368, 1233, 1216, 1155, 575 cm–1; HRMS (ESI) m/z calcd for
C12H22N2NaO4 (M+Na)+ 281.1476, found 281.1472 (–1.0 ppm
1
2
3
4
5
6
7
8
1H), 3.09 (ddd, J = 13.0, 12.0, 3.5 Hz, 1H), 2.70-2.66 (m, 1H),
2.55 (ddd, J = 11.0, 3.5, 1.5 Hz, 1H), 1.93 (td, J = 12.0, 3.5 Hz,
1H), 1.57 (t, J = 11.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ
156.5, 142.7, 139.1, 137.6, 129.1, 128.8, 128.7, 128.6, 128.5, 128.1,
127.6, 126.2, 126.0, 85.3, 62.9, 61.1, 55.7, 50.7, 41.5; IR
(CHCl3) 3020, 2400, 1751 (C=O), 1422, 1215, 929, 759, 669
cm–1; HRMS (ESI) m/z calcd for C25H25N2O2 (M+H)+
385.1911, found 385.1899 (+3.6 ppm error). Spectroscopic
data consistent with those reported in the literature.13
error); and vinyl carbamate 8 (35 mg, 11%) as a colourless
oil, RF (7:3 petrol-EtOAc) 0.2; H NMR (400 MHz, CDCl3)
1
(50:50 mixture of rotamers) δ 5.92 (br s, 1H), 5.56 (br s,
0.5H), 5.40 (br s, 0.5H), 3.78 (s, 1.5H), 3.77 (s, 1.5H), 3.67
(s, 3H), 3.62-3.55 (m, 2H), 3.48-3.45 (m, 2H), 3.95 (s, 1.5H),
3.94 (s, 1.5H), 1.41 (br s, 9H); 13C NMR (100.6 MHz, CDCl3)
(mixture of rotamers) δ 166.2, 157.0, 156.7, 153.7, 153.6,
140.5, 140.0, 117.7, 81.4, 81.2, 52.6, 52.5, 52.3, 52.2, 47.9, 47.1,
35.2, 34.8, 28.0; IR (CHCl3) 3023, 1734 (C=O, CO2Me), 1699
(C=O, Boc), 1486, 1439, 1395, 1369, 1236, 1161, 765; HRMS
(ESI) m/z calcd for C14H24N2NaO6 (M+Na)+ 339.1527,
found 339.1526 (+0.2 ppm error).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tert-Butyl 4-methylpiperazine-1-carboxylate (4). A solu-
tion of di-tert-butyl dicarbonate (21.6 g, 99.2 mmol, 1.1
eq.) in CH2Cl2 (50 mL) was added dropwise to a stirred
solution of N-methyl piperazine (10 mL, 90.2 mmol, 1.0
eq.) in CH2Cl2 (150 mL) at 0 °C under Ar. The resulting
solution was allowed to warm to rt and stirred for at rt for
16 h. Water (100 mL) and 20% NaOH(aq) (100 mL) were
added and the layers separated. The aqueous layer was
extracted with CH2Cl2 (3 × 100 mL). The combined organ-
ic layers were dried (MgSO4), filtered and evaporated un-
der reduced pressure to give the crude product. Purifica-
tion by Kugelrohr distillation gave N-Boc-N′-methyl pi-
perazine 4 (16.5 g, 92%) as a colourless oil, RF (9:1 CH2Cl2-
7-Methyl-1,1-diphenyl-hexahydro-1H-[1,3]oxazolo[3,4-
a]pyrazin-3-one
(hydroxydiphenylmethyl)-4-methylpiperazine-1-
carboxylate (10). N-Boc-N’-methyl piperazine 4 (200 mg,
1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0 mL, 1.3
mmol) and benzophenone (364 mg, 2.0 mmol) in THF (1
mL) gave, after purification (SiO2, 98:2 to 95:5 CH2Cl2-
MeOH), oxazolidinone 9 (263 mg, 83%) as a white solid,
(9)
and
tert-butyl
2-
1
RF (19:1 CH2Cl2-MeOH) 0.4; mp 96-98 °C; H NMR (400
1
MeOH) 0.2; bp 105-110 °C / 0.9 mmHg; H NMR (400
MHz, CDCl3) δ 7.52-7.47 (m, 2H), 7.37-7.23 (m, 8H), 4.50
(dd, J = 11.0, 3.5 Hz, 1H), 3.83 (ddd, J = 13.0, 3.5, 1.0 Hz, 1H),
3.12 (ddd, J = 13.0, 12.0, 3.5 Hz, 1H), 2.68-2.64 (m, 1H), 2.43
(ddd, J = 12.0, 3.5, 1.0 Hz, 1H), 2.18 (s, 3H), 1.93 (td, J = 12.0,
3.5 Hz, 1H), 1.43 (t, J = 11.0 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3) δ 158.8, 142.2, 138.6, 128.5, 128.3, 128.2, 127.8, 125.8,
125.6, 85.1, 60.9, 56.9, 53.2, 46.3, 41.5; IR (CHCl3) 2948,
2804, 1751 (C=O), 1450, 1409, 1360, 1301, 1255, 1138, 1032,
988, 757 cm–1; HRMS (ESI) m/z calcd for C19H21N2O2
(M+H)+ 309.1598, found 309.1599 (+0.1 ppm error) and
alcohol 10 (45 mg, 12%) as a pale yellow oil, RF (9:1 CH2Cl2-
MHz, CDCl3) δ 3.39 (t, J = 5.0 Hz, 4H), 2.29 (t, J = 5.0 Hz,
4H), 2.24 (s, 3H), 1.41 (s, 9H). 13C NMR (100.6 MHz, CDCl3)
δ 154.6, 79.5, 54.7, 46.1, 43.5, 28.3. Spectroscopic data con-
sistent with those reported in the literature.24
tert-Butyl
N-ethenyl-N-[2-
(methylamino)ethyl]carbamate (5). N-Boc-N’-methyl pi-
perazine 4 (200 mg, 1.0 mmol), s-BuLi (1.3 M solution in
hexanes, 1.0 mL, 1.3 mmol) and Me3SiCl (254 µL, 2.0
mmol) gave, after purification (SiO2, 9:1 CH2Cl2-MeOH),
vinyl carbamate 5 (60 mg, 30%) as a pale yellow oil, RF (9:1
1
1
MeOH) 0.5; H NMR (400 MHz, CDCl3) (50:50 mixture of
CH2Cl2-MeOH) 0.1; H NMR (400 MHz, CDCl3) δ 7.01 (br
rotamers) δ 7.70-7.07 (m, 10H), 5.23 (br d, J = 4.0 Hz,
0.5H), 4.90 (br d, J = 4.0 Hz, 0.5H), 4.17-4.11 (m, 0.5H),
3.86-3.72 (m, 1.5H), 2.97-2.92 (m, 1H), 2.87-2.84 (m, 0.5H),
2.78-2.76 (m, 0.5H), 2.28 (dd, J = 12.0, 4.0 Hz, 0.5H), 2.24
(dd, J = 12.0, 4.0 Hz, 0.5H), 2.17 (s, 1.5H), 2.14 (s, 1.5H),
2.10-1.98 (m, 1H), 1.25 (s, 4.5H), 1.21 (s, 4.5H); 13C NMR
(100.6 MHz, CDCl3) (mixture of rotamers) δ 154.6, 154.2,
147.7, 147.2, 145.0, 144.7, 128.3, 128.1, 127.5, 127.3, 126.7,
126.6, 126.5 126.3, 126.1, 126.0, 83.5, 83.4, 79.8, 79.7, 56.6,
55.8, 55.2, 54.4, 54.3, 53.5, 45.8, 45.7, 41.4, 40.3, 28.2, 28.0;
IR (CHCl3) 3680 (OH), 3019, 2980, 2855, 2807, 1681 (C=O),
1461, 1417, 1367, 1350, 1304, 1287, 1215, 1169, 1146, 1027, 765
cm–1; HRMS (ESI) m/z calcd for C23H31N2O3 (M+H)+
383.2329, found 383.2317 (+3.6 ppm error).
s, 1H), 4.35 (d, J = 16.0 Hz, 1H), 4.21 (br s, 1H), 3.65 (br s,
2H), 2.79 (t, J = 7.0 Hz, 2H), 2.47 (s, 3H), 2.11 (br s, 1H),
1.49 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 152.9, 132.9,
90.8, 81.3, 48.2, 41.9, 36.0, 28.2; IR (CHCl3) 3513 (NH),
2978, 1698 (C=O), 1629, 1456, 1368, 1152, 862, 759 cm–1;
HRMS (ESI) m/z calcd for C10H21N2O2 (M+H)+ 201.1598,
found 201.1595 (+2.0 ppm error).
tert-Butyl
[(methoxycarbonyl)(methyl)amino]ethyl}carbamate (7)
and methyl 2-{[(tert-butoxy)carbonyl]({2-
N-ethenyl-N-{2-
[(methoxycarbonyl)(methyl)amino]ethyl})amino}prop-2-
enoate (8). N-Boc-N’-methyl piperazine 4 (200 mg, 1.0
mmol), s-BuLi (1.3 M solution in hexanes, 1.0 mL, 1.3
mmol) and MeOCOCl (155 µL, 2.0 mmol) gave, after puri-
fication (SiO2, 9:1 CH2Cl2-MeOH), vinyl carbamate 7 (88
tert-Butyl
N-ethenyl-N-[2-
1
(methylamino)ethyl]carbamate (5) and tert-butyl N-[2-
(methylamino)ethyl]-N-[1-
mg, 34%) as a colourless oil, RF (7:3 petrol-EtOAc) 0.4; H
NMR (400 MHz, CDCl3) (50:50 mixture of rotamers) δ 7.11
(dd, J =15.0, 10.0 Hz, 0.5H), 6.95 (dd, J = 15.0, 10.0 Hz,
0.5H), 4.48 (m, 0.5H), 4.46-4.18 (m, 1.5H), 3.69 (s, 3H),
3.69-3.57 (m, 2H), 3.39-3.35 (m, 2H), 2.93 (s, 1.5H), 2.91 (s,
(trimethylsilyl)ethenyl]carbamate (11). s-BuLi (1.85 mL of
a 1.3 M solution in hexanes, 2.4 mmol) was added drop-
wise to a stirred solution of N-Boc-N′-methyl piperazine 4
(200 mg, 1.0 mmol) and TMEDA (360 µL, 2.4 mmol) in
Et2O (7 mL) at –78 °C under Ar. The resulting solution
was warmed to –10 °C and stirred for 1 h. The solution was
cooled to –78 °C then Me3SiCl (305 µL, 2.4 mmol) was
13
1.5H), 1.50 (s, 9H); C NMR (100.6 MHz, CDCl3) (mixture
of rotamers) δ 156.6, 152.9, 152.5, 132.9, 132.6, 91.1, 90.6,
81.4, 81.2, 52.6, 52.5, 45.9, 45.6, 41.2, 40.4, 35.5, 28.1; IR
(CHCl3) 2983, 1697 (C=O), 1630 (C=O), 1486, 1423, 1393,
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The Journal of Organic Chemistry
purification (SiO2, 19:1 petrol-Et2O), substituted pipera-
added dropwise. The reaction mixture was warmed to –60
1
2
3
4
5
6
7
8
°C, stirred for 1 h then allowed to warm to rt over 16 h.
Then, saturated NH4Cl(aq) (10 mL) and 20% NaOH(aq) (10
mL) were added and the two layers were separated. The
aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic layers were dried (MgSO4), filtered and
evaporated under reduced pressure to give the crude
products. Purification by flash column chromatography
(SiO2, 9:1 CH2Cl2-MeOH) gave vinyl carbamate 5 (75 mg,
37%) as a pale yellow oil and silane 11 (86 mg, 32%) as a
zine 18b (260 mg, 81%) as a colourless oil; RF (19:1 petrol-
EtOAc) 0.3; H NMR (400 MHz, CDCl3) (50:50 mixture of
1
rotamers) δ 7.49 (d, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz,
2H), 7.23-7.16 (m, 1H), 4.21-4.12 (m, 0.5H), 3.97 (br d, J =
12.0 Hz, 0.5H), 3.60-3.25 (m, 1.5H), 2.86-2.52 (m, 2.5H),
2.31 (br s, 1H), 2.06-1.84 (m, 1H), 1.55-1.37 (m, 15H), 1.33-1.22
(m, 12H), 0.95-0.83 (m, 15H); 13C NMR (100.6 MHz, CDCl3)
(mixture of rotamers) δ 154.6, 153.9, 148.3, 148.2, 128.0,
126.3, 79.3, 79.0, 60.0, 50.2, 46.9, 45.9, 45.6, 43.0, 29.2,
28.4, 27.9, 27.8, 27.6, 27.3, 26.8, 25.7, 22.1, 20.7, 13.7, 11.1,
10.4; IR (CHCl3) 2971, 2913, 2881, 2827, 1645 (C=O), 1432,
1397, 1344, 1280, 1197, 1152, 1090, 1002, 947, 908, 849, 743,
691, 658 cm–1; HRMS (ESI) m/z calcd for C30H55N2O2Sn
(M+H)+ 595.3285, found 595.3261 (+3.6 ppm error). Spec-
troscopic data consistent with those reported in the liter-
ature.13
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pale yellow oil, RF (9:1 CH2Cl2-MeOH) 0.2; H NMR (400
MHz, CDCl3) δ 5.38 (br s, 1H), 5.13 (br s, 1H), 3.59 (t, J = 7.0
Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 2.53 (br s, 1H), 2.49 (s,
3H), 1.47 (s, 9H), 0.15 (s, 9H); 13C NMR (100.6 MHz, CDCl3)
δ 154.4, 153.3, 112.7 (br), 80.6, 49.5, 46.7, 35.6, 28.5, 0.5; IR
(CHCl3) 2972, 1656 (C=O), 1432, 1372, 1346, 1228, 1197, 1136,
831, 742 cm–1; HRMS (ESI) m/z calcd for C13H29N2O2Si
(M+H)+ 273.1993, found 273.2000 (–1.9 ppm error).
tert-Butyl 2-methyl-4-(2-phenylpropan-2-yl)piperazine-
1-carboxylate (18c). N-Boc-N’-cumyl piperazine 16 (152
mg, 0.5 mmol), s-BuLi (1.3 M solution in hexanes, 0.5 mL,
0.65 mmol), TMEDA (97 µL, 0.65 mmol) and MeI (62 µL,
1.0 mmol) gave, after purification (SiO2, 8:2 petrol-Et2O),
substituted piperazine 18c (152 mg, 95%) as a colourless
TMEDA mediated lithiation/trapping of N-Boc-N’-
tert-butyl piperazine 12 and N-Boc-N’-cumyl pipera-
zine 16. s-BuLi (1.3 M solution in hexanes, 1.3 eq.) was
added dropwise to a stirred solution of N-Boc piperazine
(0.5-1.0 mmol, 1.0 eq.) and TMEDA (1.3 eq.) in Et2O (0.14
M) at –78 °C under Ar. The resulting solution was stirred
at –78 °C for 1 h. Then the electrophile (2.0 eq.) was added
dropwise, as a solution in THF (1 mL) if necessary. The
reaction mixture was stirred at –78 °C for 15 min and then
allowed to warm to rt over 30 min. Then, saturated
NH4Cl(aq) (10 mL), 20% NaOH(aq) (10 mL) and Et2O (10 mL)
were added and the two layers were separated. The aque-
ous layer was extracted with Et2O (3 × 10 mL). The com-
bined organic layers were dried (MgSO4), filtered and
evaporated under reduced pressure to give the crude
product which was purified by flash column chromatog-
raphy on silica gel.
1
oil; RF (8:2 petrol-Et2O) 0.3; H NMR (400 MHz, CDCl3) δ
7.54-7.51 (m, 2H), 7.33-7.27 (m, 2H), 7.23-7.18 (m, 1H), 4.12
(br s, 1H), 3.75 (br d, J = 13.0 Hz, 1H), 3.04 (td, J = 12.5, 3.5
Hz, 1H), 2.76-2.67 (m, 1H), 2.52 (dt, J = 11.0, 2.0 Hz, 1H),
2.31 (dd, J = 11.0, 3.5 Hz, 1H), 2.14 (td, J = 12.5, 3.5 Hz, 1H),
1.44 (s, 9H), 1.33 (s, 3H), 1.30 (s, 3H), 1.22 (d, J = 7.0 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 154.9, 149.2, 128.0,
126.3, 126.2, 79.3, 59.4, 50.8, 47.6, 46.5, 39.9, 28.5, 24.3,
23.6, 15.8; IR (CHCl3) 2931, 1652 (C=O), 1427, 1393, 1345,
1300, 1263, 1214, 1152, 1093, 1005, 691 cm–1; HRMS (ESI) m/z
calcd for C19H31N2O2 (M+H)+ 319.2380, found 319.2369
(+3.5 ppm error).
tert-Butyl
4-(2-phenylpropan-2-yl)-2-
tert-Butyl
4-(2-phenylpropan-2-yl)-2-(prop-2-en-1-
(trimethylsilyl)piperazine-1-carboxylate (18a). N-Boc-N’-
cumyl piperazine 16 (152 mg, 0.5 mmol), s-BuLi (1.3 M
solution in hexanes, 0.5 mL, 0.65 mmol), TMEDA (97 µL,
0.65 mmol) and Me3SiCl (127 µL, 1.0 mmol) gave, after
purification (SiO2, 9:1 petrol-Et2O), substituted piperazine
18a (184 mg, 98%) as a colourless oil; RF (9:1 petrol-Et2O)
yl)piperazine-1-carboxylate (18d). s-BuLi (1.3 M solution in
hexanes, 0.5 mL, 0.65 mmol) was added dropwise to a
stirred solution of N-Boc-N’-cumyl piperazine 16 (152 mg,
0.5 mmol) and (97 µL, 0.65 mmol) in Et2O (4 mL) at –78
°C under Ar. The resulting solution was stirred at –78 °C
for 1 h. Then, a solution of CuCN.2LiCl (0.25 mmol, 0.5
eq.) in THF (0.5 mL) was added dropwise. The resulting
solution was stirred at –78 °C for 1 h. Then, allyl bromide
(87 µL, 1.0 mmol) was added dropwise. The reaction mix-
ture was stirred at –78 °C for 15 min and then allowed to
warm to rt over 30 min. Then, saturated NaHCO3(aq) was
added and the two layers were separated. The aqueous
layer was extracted with Et2O (3 × 10 mL). The combined
organic layers were dried (MgSO4) and evaporated under
reduced pressure to give the crude product. Purification
by flash column chromatography (SiO2, 8:2 petrol-Et2O)
gave substituted piperazine 18d (138 mg, 80%) as a col-
1
0.3; H NMR (400 MHz, CDCl3) (60:40 mixture of rota-
mers) δ 7.52-7.47 (m, 2H), 7.34-7.28 (m, 2H), 7.24-7.18 (m,
1H), 3.95 (br s, 0.6H), 3.72 (br s, 0.4H), 3.63-3.56 (br m,
1H), 2.95 (dt, J = 11.5, 2.0 Hz, 1H), 2.93 (br s, 0.4H), 2.84 (br
s, 0.6H), 2.45 (br s, 2H), 2.03 (td, J = 11.5, 3.0 Hz, 1H), 1.43
(s, 9H), 1.35 (s, 6H), 0.13 (s, 9H); 13C NMR (100.6 MHz,
CDCl3) (mixture of rotamers) δ 154.5, 154.4, 148.4, 127.9,
126.3, 126.3, 79.1, 59.9, 47.1, 46.9, 46.5, 45.7, 44.7, 43.7, 42.0,
28.4, 26.7, 20.4, –0.6; IR (CHCl3) 2965, 2931, 1645 (C=O),
1428, 1399, 1344, 1277, 1261, 1228, 1197, 1154, 1094, 916, 825,
749, 691 cm–1; HRMS (ESI) m/z calcd for C21H37N2O2Si
(M+H)+ 377.2619, found 377.2601 (+4.3 ppm error).
1
ourless oil, RF (8:2 petrol-Et2O) 0.3; H NMR (400 MHz,
CDCl3) δ 7.55-7.48 (m, 2H), 7.34-7.28 (m, 2H), 7.24-7.18
(m, 1H), 5.73-5.63 (m, 1H), 5.09-5.02 (m, 1H), 4.99-4.94 (m,
1H), 4.01 (br s, 1H), 3.80 (br s, 1H), 2.98 (t, J = 11.5 Hz, 1H),
2.67 (br s, 2H), 2.57- 2.37 (m, 2H), 2.26 (dd, J = 11.5, 3.5 Hz,
1H), 2.21-2.08 (m, 1H), 1.43 (s, 9H), 1.33 (s, 3H), 1.30 (s, 3H);
tert-Butyl
4-(2-phenylpropan-2-yl)-2-
(tributylstannyl)piperazine-1-carboxylate (18b). N-Boc-N’-
cumyl piperazine 16 (152 mg, 0.5 mmol), s-BuLi (1.3 M
solution in hexanes, 0.5 mL, 0.65 mmol), TMEDA (97 µL,
0.65 mmol) and Bu3SnCl (271 µL, 1.0 mmol) gave, after
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1
13C NMR (100.6 MHz, CDCl3) δ 154.8, 148.9, 125.7, 128.0,
126.3, 126.0, 116.8, 79.3, 59.4, 52.0 (br), 48.0, 46.4, 39.6 (br),
34.5, 28.4, 24.5, 23.2; IR (CHCl3) 2972, 2930, 2776, 1658
(C=O), 1397, 1344, 1305, 1197, 1153, 1092, 972, 950, 907, 761,
732, 691, 658 cm–1; HRMS (ESI) m/z calcd for C21H33N2O2
(M+H)+ 345.2537, found 345.2526 (+3.1 ppm error).
yellow oil, RF (7:3 petrol-EtOAc) 0.1; H NMR (400 MHz,
CDCl3) δ 7.53-7.47 (m, 2H), 7.35-7.29 (m, 2H), 7.26-7.20
(m, 1H), 4.32 (t, J = 8.0 Hz, 1H), 3.88-3.72 (m, 3H), 3.05 (td,
J = 12.0, 3.5 Hz, 1H), 2.85-2.74 (m, 2H), 2.21 (td, J = 12.0, 3.5
Hz, 1H), 2.04 (t, J = 11.0 Hz, 1H), 1.34 (s, 6H); 13C NMR
(100.6 MHz, CDCl3) δ 157.0, 148.3, 128.2, 126.5, 125.9, 65.5,
60.2, 54.0, 51.3, 45.4, 42.0, 25.2, 23.1; IR (CHCl3) 2973, 1720
(C=O), 1496, 1545, 1404, 1194, 1045, 914, 771, 725, 659, 617
cm–1; HRMS (ESI) m/z calcd for C15H21N2O2 (M+H)+
261.1598, found 261.1587 (+3.9 ppm error) and substituted
piperazine 18g (96 mg, 57%) as a pale yellow oil, RF (7:3
1
2
3
4
5
6
7
8
1-tert-Butyl
2-methyl
4-(2-phenylpropan-2-
yl)piperazine-1,2-dicarboxylate (18e). N-Boc-N’-cumyl
piperazine 16 (152 mg, 0.5 mmol), s-BuLi (1.3 M solution in
hexanes, 0.5 mL, 0.65 mmol), TMEDA (97 µL, 0.65 mmol)
and MeOCOCl (77 µL, 1.0 mmol) gave, after purification
(SiO2, 97:3-8:2 CH2Cl2-Et2O), substituted piperazine 18e
(119 mg, 66%) as a pale yellow oil; RF (19:1 CH2Cl2-Et2O)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
petrol-EtOAc) 0.2; H NMR (400 MHz, CDCl3) δ 7.43 (d, J
= 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.25-7.20 (m, 1H),
4.19-3.57 (m, 5H), 3.26 (br s, 1H), 2.94 (d, J = 11.0 Hz, 1H),
2.72 (br s, 1H), 2.41 (dd, J = 11.5, 4.0 Hz, 1H), 2.19 (td, J =
1
0.2; H NMR (400 MHz, CDCl3) (55:45 mixture of rota-
mers) δ 7.42–7.37 (m, 2H), 7.31–7.25 (m, 2H), 7.23–7.17 (m,
1H), 4.66 (br s, 0.55H), 4.50 (br s, 0.45H), 3.80 (d, J = 11.0
Hz, 0.55H), 3.72 (s, 1.35H), 3.70 (s, 1.65H), 3.72-3.69 (m,
0.45H), 3.35–3.19 (m, 1.55H), 3.13 (td, J = 12.0, 3.0 Hz,
0.45H), 2.74 (d, J = 10.5 Hz, 0.45H), 2.67 (d, J = 10.5 Hz,
0.55H), 2.37 (dd, J = 11.5, 3.5 Hz, 1HH), 2.18 (td, J = 11.5, 3.5
Hz, 1H), 1.46 (s, 5H), 1.41 (s, 4H), 1.31 (s, 6H); 13C NMR
(100.6 MHz, CDCl3) (mixture of rotamers) δ 171.6, 171.4,
156.0, 155.4, 148.4, 148.3, 127.9, 126.3, 125.9, 80.1, 59.2, 56.0,
54.9, 51.8, 47.8, 45.7, 42.7, 41.7, 28.3, 28.2, 24.0, 23.9, 23.7;
IR (CHCl3) 2972, 2933, 1718 (C=O, CO2Me), 1662 (C=O,
Boc), 1469, 1452, 1391, 1369, 1346, 1331, 1310, 1284, 1195, 1155,
1101, 1016, 951, 736, 692 cm–1; HRMS (ESI) m/z calcd for
C20H31N2O4 (M+H)+ 363.2278, found 363.2277 (0.0 ppm
error). Spectroscopic data consistent with those reported
in the literature.13
13
11.5, 3.0 Hz, 1H), 1.44 (s, 9H), 1.38 (s, 6H); C NMR (100.6
MHz, CDCl3) δ 155.0, 147.4, 128.3, 126.7, 125.9, 79.8, 65.4,
59.9, 52.0, 48.1, 46.2, 42.1, 28.5, 24.2, 22.7; IR (CHCl3) 2972,
2933, 1655 (C=O), 1392, 1370, 1345, 1290, 1196, 1152, 1100,
995, 895, 767, 747, 728, 692, 658 cm–1; HRMS (ESI) m/z
calcd for C19H31N2O3 (M+H)+ 335.2329, found 335.2325 (+1.2
ppm error).
7-(2-Phenylpropan-2-yl)-
hexahydrospiro[[1,3]oxazolo[3,4-a]pyrazine-1,1'-
cyclohexane]-3-one (18h). N-Boc-N’-cumyl piperazine 16
(152 mg, 0.5 mmol), s-BuLi (1.3 M solution in hexanes, 0.5
mL, 0.65 mmol), TMEDA (97 µL, 0.65 mmol) and cyclo-
hexanone (104 mg, 1.0 mmol) gave, after purification
(SiO2, 9:1-7:3 petrol-EtOAc), oxazolidinone 18h (95 mg,
1
58%) as a pale yellow oil, RF (8:2 petrol-EtOAc) 0.2; H
NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 2H), 7.31 (t, J
= 7.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 3.73 (dd, J = 13.0, 2.0
Hz, 1H), 3.31 (dd, J = 11.0, 3.5 Hz, 1H), 2.97 (td, J = 12.0, 3.5
Hz, 1H), 2.76-2.67 (m, 2H), 2.19-2.06 (m, 2H), 1.91-1.40 (m,
10H), 1.33 (s, 6H); 13C NMR (100.6 MHz, CDCl3) δ 156.5,
148.5, 128.2, 126.4, 125.8, 80.8, 62.7, 60.3, 46.7, 45.4, 41.9,
36.8, 30.7, 25.0, 24.4, 24.1, 22.0, 21.9; IR (CHCl3) 2972, 2930,
2895, 1708 (C=O), 1497, 1425, 1404, 1342, 1263, 1199, 1162,
913, 771, 726, 691, 658 cm–1; HRMS (ESI) m/z calcd for
C20H29N2O2 (M+H)+ 329.2224, found 329.2207 (+4.6 ppm
error).
1-tert-Butyl
2-methyl
4-tert-butylpiperazine-1,2-
dicarboxylate (17a). N-Boc-N’-tert-butyl piperazine 12 (242
mg, 1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0 mL,
1.3 mmol), TMEDA (195 µL, 1.3 mmol) and MeOCOCl (155
µL, 2.0 mmol) gave, after purification (SiO2, 7:3 petrol-
EtOAc), substituted piperazine 17a (135 mg, 45%) as a pale
1
yellow oil; RF (7:3 petrol-EtOAc) 0.4; H NMR (400 MHz,
CDCl3) (50:50 mixture of rotamers) δ 4.70 (br s, 0.5H),
4.53 (br s, 0.5H), 3.83 (br d, J = 12.5 Hz, 0.5H), 3.75-3.73
(m, 0.5H), 3.73 (s, 1.5H), 3.72 (s, 1.5H), 3.52-3.45 (m, 1H),
3.13 (td, J = 12.5, 3.5 Hz, 0.5H), 3.03 (td, J = 12.5, 3.5 Hz,
0.5H), 2.92 (br d, J = 11.0 Hz, 0.5H), 2.84 (br d, J = 11.0 Hz,
0.5H), 2.28-2.23 (m, 1H), 2.11 (td, J = 11.0, 3.5 Hz, 1H), 1.46
(s, 4.5H), 1.42 (s, 4.5H), 0.96 (s, 9H); 13C NMR (100.6 MHz,
CDCl3) (mixture of rotamers) δ 171.6, 171.3, 155.8, 155.4,
80.0, 56.3, 55.0, 53.3, 51.9, 47.6, 45.2, 42.9, 42.0, 28.3, 25.8;
IR (CHCl3) 2976, 1745 (C=O, CO2Me), 1689 (C=O, Boc),
1455, 1393, 1367, 1304, 1253, 1170, 1119, 1041, 965, 865, 761 cm–
1; HRMS (ESI) m/z calcd for C15H29N2O4 (M+H)+ 301.2122,
found 301.2122 (0.0 ppm error). Spectroscopic data con-
sistent with those reported in the literature.13
1,1-Diphenyl-7-(2-phenylpropan-2-yl)-hexahydro-1H-
[1,3]oxazolo[3,4-a]pyrazin-3-one (18i) and tert-butyl 2-
(hydroxydiphenylmethyl)-4-(2-phenylpropan-2-
yl)piperazine-1-carboxylate (18j). N-Boc-N’-cumyl pipera-
zine 16 (152 mg, 0.5 mmol), s-BuLi (1.3 M solution in hex-
anes, 0.5 mL, 0.65 mmol), TMEDA (97 µL, 0.65 mmol)
and benzophenone (182 mg, 1.0 mmol) gave, after purifi-
cation (SiO2, 9:1-8:2 petrol-EtOAc), oxazolidinone 18i (152
mg, 74%) as a white solid, RF (7:3 petrol-EtOAc) 0.1; mp
1
122-124 °C; H NMR (400 MHz, CDCl3) δ 7.49–7.43 (m,
4H), 7.39–7.19 (m, 11H), 4.42 (dd, J = 11.0, 3.5 Hz, 1H), 3.83–
3.72 (m, 1H), 3.04 (td, J = 12.0, 4.0 Hz, 1H), 2.69–2.63 (m,
1H), 2.56 (ddd, J = 11.5, 3.5, 2.0 Hz, 1H), 2.09 (td, J = 11.5, 3.5
Hz, 1H), 1.55 (t, J = 11.0 Hz, 1H), 1.24 (s, 3H), 1.18 (s, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 156.2, 148.3, 142.5, 138.9, 128.5,
128.3, 128.2, 128.1, 127.8, 126.5, 125.9, 125.8, 125.7, 88.3, 62.4,
60.2, 49.3, 45.3, 42.5, 25.0, 23.3; IR (CHCl3) 2963, 2931, 1723
(C=O), 1470, 1426, 1390, 1342, 1282, 1241, 1159, 1100, 1059,
7-(2-Phenylpropan-2-yl)-hexahydro-1H-[1,3]oxazolo[3,4-
a]pyrazin-3-one (18f) and tert-butyl 2-(hydroxymethyl)-4-
(2-phenylpropan-2-yl)piperazine-1-carboxylate (18g). N-
Boc-N’-cumyl piperazine 16 (152 mg, 0.5 mmol), s-BuLi
(1.3 M solution in hexanes, 0.5 mL, 0.65 mmol), TMEDA
(97 µL, 0.65 mmol) and paraformaldehyde (30 mg, 1.0
mmol) in Et2O (1 mL) gave, after purification (SiO2, 7:3-1:1
petrol-EtOAc), oxazolidinone 18f (34 mg, 26%) as a pale
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The Journal of Organic Chemistry
(20 mL). The filtrate was washed with H2O (20 mL), dried
1016, 971, 895, 690 cm–1; HRMS (ESI) m/z calcd for
C27H29N2O2 (M+H)+ 413.2224, found 413.2216 (+2.6 ppm
(MgSO4), filtered and evaporated under reduced pressure
to give the crude product. Purification by flash column
chromatography (SiO2, 19:1 petrol-EtOAc) gave a 33:67
1
2
error) and substituted piperazine 18j, (55 mg, 23%) as a
1
3
white solid, RF (7:3 petrol-EtOAc) 0.2; mp 54-56 °C; H
1
4
5
6
7
8
9
NMR (400 MHz, CDCl3) (50:50 mixture of rotamers) δ
8.25 (s, 0.5H), 8.10 (s, 0.5H), 7.70 (d, J = 7.5 Hz, 2H), 7.62
(t, J = 7.5 Hz, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.42-7.07 (m,
10H), 5.16 (d, J = 3.0 Hz, 0.5H), 4.84 (d, J = 3.0 Hz, 0.5H),
4.09 (dd, J = 13.5, 3.0 Hz, 0.5H), 3.82-3.62 (m, 1.5H), 3.27-
3.16 (m, 1H), 2.69 (d, J = 11.0 Hz, 0.5H), 2.61 (d, J = 11.0 Hz,
0.5H), 2.46 (dd, J = 11.5, 4.0 Hz, 0.5H), 2.41 (dd, J = 11.5, 4.0
Hz, 0.5H), 2.25-2.09 (m, 1H), 1.32 (s, 1.5H), 1.29 (s, 1.5H),
mixture of substituted piperazines 19 and 20 (by H NMR
spectroscopy) (147 mg, 42%) as a colourless oil, RF (9:1
1
petrol-EtOAc) 0.3; H NMR (400 MHz, CDCl3) δ 7.51-7.47
(m, 1.34H), 7.31-7.19 (m, 8.66H), 5.23 (br s, 0.33H), 4.10-
3.89 (m, 1.67), 3.79 (d, J = 13.5 Hz, 0.67H), 3.57 (d, J = 13.0
Hz, 0.33H), 3.45 (d, J = 13.0 Hz, 0.33H), 3.30-3.27 (m, 1H),
3.03 (td, J = 12.5, 3.5 Hz, 0.33H), 3.02-2.76 (m, 3H), 2.41
(dd, J = 12.0, 4.0 Hz, 0.33H), 2.16 (td, J = 12.0, 3.5 Hz,
0.33H), 2.07 (td, J = 12.0, 3.0 Hz, 0.67H), 1.47 (s, 3H), 1.45
(s, 6H); HRMS (ESI) m/z calcd for C22H29N2O2 (M+H)+
353.2224, found 353.2224 (0.0 ppm error). Spectroscopic
data of 20 consistent with those reported in the litera-
ture.25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1.24 (s, 1.5H), 1.22 (s, 4.5H), 1.16 (s, 1.5H), 1.15 (s, 4.5H); C
NMR (100.6 MHz, CDCl3) (mixture of rotamers) δ 154.5,
154.2, 147.1, 146.5, 145.7, 145.5, 145.0, 144.7, 128.4, 128.1,
128.0, 127.6, 127.5, 127.3, 126.9, 126.9, 126.8, 126.7, 126.5,
126.4, 126.4, 126.2, 126.2, 126.0, 126.0, 83.9, 83.8, 79.6, 60.3,
60.3, 55.6, 54.0, 48.5, 47.5, 46.8, 46.7, 42.2, 41.2, 28.1, 27.9,
26.4, 26.3, 19.7, 19.6; IR (CHCl3) 2961, 2934, 1655 (C=O),
1427, 1395, 1345, 1326, 1284, 1232, 1151, 1096, 1001, 957, 690,
628 cm–1; HRMS (ESI) m/z calcd for C30H39N2O3 (M+H)+
487.2955, found 487.2944 (+2.4 ppm error). Spectroscopic
data of 18i consistent with those reported in the litera-
ture.13
s-BuLi (1.3 M solution in hexanes, 1.0 mL, 1.3 mmol) was
added dropwise to a stirred solution of N-Boc-N′-benzyl
piperazine 1 (276 mg, 1.0 mmol) in THF (7 mL) at –78 °C
under Ar. The resulting solution was stirred at –78 °C for 1
h. Then, ZnCl2 (1.0 M solution in Et2O, 0.6 mL, 0.6 mmol)
was added and the resulting solution was stirred at –78 °C
for 30 min. The solution was allowed to warm to rt and
stirred at rt for 30 min. Then, bromobenzene (140 μL, 1.3
mmol) was added, followed by the addition of PEPPSI-iPr
(34 mg, 0.05 mmol). The mixture was stirred at rt for 16 h.
Then, 35% NH4OH(aq) (0.2 mL) was added and the solu-
tion stirred at rt for 30 min. The solids were removed by
filtration through Celite® and washed with Et2O (20 mL).
The filtrate was washed with H2O (20 mL), dried
(MgSO4), filtered and evaporated under reduced pressure
to give the crude product. Purification by flash column
chromatography (SiO2, 19:1 petrol-EtOAc) gave a 5:95
7-tert-Butyl-1,1-diphenyl-hexahydro-1H-[1,3]oxazolo[3,4-
a]pyrazin-3-one (17b). N-Boc-N’-tert-butyl piperazine 12
(242 mg, 1.0 mmol), s-BuLi (1.3 M solution in hexanes, 1.0
mL, 1.3 mmol), TMEDA (195 µL, 1.3 mmol) and benzophe-
none (364 mg, 2.0 mmol) in Et2O (1 mL) gave, after purifi-
cation (SiO2, 99:1-98:2 CH2Cl2-MeOH), oxazolidinone 17b
(200 mg, 57%), as a white solid, RF (99:1 CH2Cl2-MeOH)
1
0.2; mp 193-195 °C; H NMR (400 MHz, CDCl3) δ 7.53-7.50
(m, 2H), 7.39-7.24 (m, 8H), 4.43 (dd, J = 11.0, 3.5 Hz, 1H),
3.85 (ddd, J = 13.0, 3.5, 1.0 Hz, 1H), 3.08 (ddd, J = 13.0, 12.0,
3.5 Hz, 1H), 2.92-2.88 (m, 1H), 2.62 (ddd, J = 12.0, 3.5, 1.0
Hz, 1H), 2.06 (td, J = 12.0, 3.5 Hz, 1H), 1.51 (t, J = 11.0 Hz,
1H), 0.93 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 156.1,
142.4, 138.8, 128.5, 128.4, 128.2, 127.8, 126.0, 125.7, 85.4, 61.9,
54.3, 48.8, 44.8, 42.6, 26.0; IR (CHCl3) 2975, 1750 (C=O),
1449, 1363, 1302, 1255, 1203, 1036, 984 cm–1; HRMS (ESI)
m/z calcd for C22H26N2O2 (M+H)+ 351.2067, found 351.2062
(+0.7 ppm error). Spectroscopic data consistent with
those reported in the literature.17
1
mixture of substituted piperazines 19 and 20 (by H NMR
spectroscopy) (54 mg, 38%) as a colourless oil.
tert-Butyl 2-phenyl-4-(2-phenylpropan-2-yl)piperazine-
1-carboxylate (21) and tert-butyl N-ethenyl-N-{2-[(2-
phenylpropan-2-yl)amino]ethyl}carbamate (22). s-BuLi
(1.3 M solution in hexanes, 0.5 mL, 0.65 mmol) was added
dropwise to a stirred solution of N-Boc-N′-cumyl pipera-
zine 16 (152 mg, 0.5 mmol) in THF (4 mL) at –78 °C under
Ar. The resulting solution was stirred at –78 °C for 2 h.
Then, ZnCl2 (1.0 M solution in Et2O, 0.3 mL, 0.3 mmol)
was added and the resulting solution was stirred at –78 °C
for 30 min. The solution was allowed to warm to rt and
stirred at rt for 30 min. Then, bromobenzene (70 μL, 0.65
mmol) was added, followed by the addition of of Pd(dba)2
(14 mg, 0.025 mmol) and RuPhos (12 mg, 0.025 mmol).
The mixture was stirred at rt for 16 h. Then, 35%
NH4OH(aq) (0.2 mL) was added and the solution stirred at
rt for 30 min. The solids were removed by filtration
through Celite® and washed with Et2O (20 mL). The fil-
trate was washed with H2O (20 mL), dried (MgSO4), fil-
tered and evaporated under reduced pressure to give the
crude product. Purification by flash column chromatog-
raphy (SiO2, 85:15 petrol-Et2O then 4:1 petrol:EtOAc) gave
substituted piperazine 21 (29 mg, 15%) as a colourless oil,
RF (4:1 petrol-Et2O) 0.3; 1H NMR (400 MHz, CDCl3) δ 7.36-
tert-Butyl
4-benzyl-2-phenylpiperazine-1-carboxylate
(19) and tert-butyl 4-benzyl-3-phenylpiperazine-1-
carboxylate (20). s-BuLi (1.3 M solution in hexanes, 1.0
mL, 1.3 mmol) was added dropwise to a stirred solution of
N-Boc-N′-benzyl piperazine 1 (276 mg, 1.0 mmol) in THF
(7 mL) at –78 °C under Ar. The resulting solution was
stirred at –78 °C for 1 h. Then, ZnCl2 (1.0 M solution in
Et2O, 0.6 mL, 0.6 mmol) was added and the resulting so-
lution was stirred at –78 °C for 30 min. The solution was
allowed to warm to rt and stirred at rt for 30 min. Then,
bromobenzene (140 μL, 1.3 mmol) was added, followed by
the addition of Pd(OAc)2 (11 mg, 0.05 mmol) and
tBu3PHBF4 (18 mg, 0.06 mmol). The mixture was stirred at
rt for 16 h. Then, 35% NH4OH(aq) (0.2 mL) was added and
the solution stirred at rt for 30 min. The solids were re-
moved by filtration through Celite® and washed with Et2O
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The Journal of Organic Chemistry
Page 10 of 11
(b) Mickelson, J. W.; Belonga, K. L.; Jacobsen, E. J. J.
7.17 (m, 10H), 5.17 (br s, 1H), 3.90 (d, J = 13.0 Hz, 1H), 3.26
(d, J = 12.0 Hz, 1H), 3.07 (td, J = 12.5, 3.5 Hz, 1H), 2.71 (d, J =
8.5 Hz, 1H), 2.63 (dd, J = 12.0, 4.0 Hz, 1H), 2.29 (td, J = 12.0,
3.5 Hz, 1H), 1.43 (s, 9H), 1.35 (s, 3H), 1.33 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 155.2, 148.4, 140.9, 128.0, 127.9, 127.2,
126.4, 126.2, 79.7, 59.8, 54.2, 49.2, 46.4, 41.0, 28.4, 24.0, 23.3
(one Ph not resolved); IR (ATR) 2974, 1689 (C=O), 1494,
1448, 1412, 1390, 1364, 1295, 10251, 1230, 1164, 1113, 1029, 1012,
975, 956, 762, 697 cm-1; HRMS (ESI) m/z calcd for
C24H33N2O2 (M+H)+ 381.2537, found 381.2533 (+0.8 ppm
error), and vinyl carbamate 22 (46 mg, 30%) as a pale yel-
low oil, RF (4:1 petrol-Et2O) 0.1; 1H NMR (400 MHz, CDCl3)
δ 7.42 (d, J = 7.5 Hz, 2H), 7.34-7.28 (m, 2H), 7.23-7.17 (m,
1H), 7.14-6.80 (br m, 1H), 4.16 (br s, 2H), 3.53 (br s, 2H),
2.51 (t, J = 7.0 Hz, 2H), 1.47-1.42 (br m, 15H) (NH not re-
solved); 13C NMR (100.6 MHz, CDCl3) δ 153.1, 147.8, 133.0,
128.3, 126.3, 125.8, 90.8, 81.2, 55.9, 43.6, 40.5, 29.7, 28.3; MS
(ESI) m/z 305 (M + H)+; IR (ATR) 2974, 2930, 1703 (C=O),
1625 (CH=CH2), 1454, 1421, 1358, 1327, 1249, 1215, 1155, 1129,
1029, 835, 763, 699 cm-1; HRMS (ESI) m/z calcd for
C18H28N2O2 (M + H)+ 305.2224, found 305.2213 (+3.9 ppm
error) and N-Boc piperazine 16 (80 mg, 53%).
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ASSOCIATED CONTENT
Supporting Information. NMR spectra, in situ IR spectro-
scopic data, and arylation catalyst/ligand screen. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(15) (a) Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer,
D. J.; Terpstra, J. W.; Hiemstra, H.; Iwema Bakker, W.
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(e) Trapella, C.; Pela, M.; Del Zoppo, L.; Calo, G.;
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lasi, V.; Reinscheid, R. K.; Salvadori, S.; Guerrini, R. J.
Med. Chem. 2011, 54, 2738. (f) Fukatsu, K.; Nakayama,
Y.; Tarui, N.; Mori, M.; Matsumoto, H.; Kurasawa, O.;
Banno, H. (Takeda Pharmaceutical Company Limited).
Eur. Patent Appl. EP 1661898A1, 2006. (g) Okamura,
N.; Habay, S. A.; Zeng, J.; Chamberlin, A. R.; Rein-
scheid, R. K. J. Pharmacol. Exp. Ther. 2008, 325, 893.
(h) Garvey, D. S.; Larosa, G. J.; Greenwood, J., Robert;
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burger, G. A.; Faibish, N. C.; Beak, P. J. Am. Chem. Soc.
2001, 123, 4919. (b) Stead, D.; Carbone, G.; O’Brien, P.;
Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem.
Soc. 2010, 132, 7260. (c) Sheikh, N. S.; Leonori, D.;
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J.; Leonori, D.; Hassall, L. A.; Coldham, I. Chem. Com-
* peter.obrien@york.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by EPSRC (DTA) and AstraZeneca.
The University of York funded the Mettler Toledo ReactIR
ic10 spectrometer and Si-probe and the equipment has been
supported in-part by the EPSRC 'ENERGY' grant
EP/K031589/1. We thank Mettler Toledo for permission to
use the image of a ReactIR 45m.26
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