An orthogonal protection strategy for the synthesis of 2-substituted piperazines

Article abstract of DOI:10.1016/j.tet.2007.01.044

Tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones are readily prepared from the bis-carbamate protected piperazine-2-carboxylic acids and serve as orthogonally protected piperazines from which a variety of 2-substituted piperazines can be prepared. Sodium benzylate and sodium phenoxides react at the C-5 carbon of the oxazolidinone to yield 2-(benzyloxymethyl)piperazines and 2-(phenoxymethyl)piperazines, respectively. The tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones also provide convenient scaffolds from which 2-benzyl- and 2-phenethylpiperazines are prepared.

Full text of DOI:10.1016/j.tet.2007.01.044

Tetrahedron 63 (2007) 3057–3065
An orthogonal protection strategy for the synthesis
of 2-substituted piperazines
*
Roger B. Clark and Daniel Elbaum
Critical Therapeutics, Inc., 60 Westview Street, Lexington, MA 02421, USA
Received 13 November 2006; revised 8 January 2007; accepted 22 January 2007
Available online 25 January 2007
Abstract—Tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones are readily prepared from the bis-carbamate protected piperazine-2-carboxylic
acids and serve as orthogonally protected piperazines from which a variety of 2-substituted piperazines can be prepared. Sodium benzylate
and sodium phenoxides react at the C-5 carbon of the oxazolidinone to yield 2-(benzyloxymethyl)piperazines and 2-(phenoxymethyl)piper-
azines, respectively. The tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones also provide convenient scaffolds from which 2-benzyl- and
2-phenethylpiperazines are prepared.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
orthogonally protected 2-(hydroxymethyl)piperazine 3 was
initially chosen as a common intermediate from which
compounds 4 would be prepared (Scheme 1). Compound 3
is prepared by reduction of the orthogonally protected piper-
azine-2-carboxylic acid 2. This, in turn, is readily prepared
from piperazine-2-carboxylic acid, which can be selectively
Boc-protected at the 4-position, followed by Cbz-protection
at the 1-position.9,1b The 4-Cbz-1-Boc-protected piperazine-
2-carboxylic acid can be prepared in a similar fashion al-
though in somewhat lower yield due to the reduced steric
bulk of the Cbz protecting group and resulting formation
of the bis-Cbz compound.10,11
The piperazine ring is found in a number of biologically
active compounds, including several marketed drugs,1 and
is considered to be a privileged structure in drug discovery.2
For an exploratory medicinal chemistry program, we were
interested in preparing a diverse set of trisubstituted piper-
azines, 4, and required a suitably flexible synthetic route to
allow for the introduction of a variety of linkers, X, and
aryl groups. An orthogonal protection strategy for the two
piperazine nitrogens would also be necessary to facilitate
the selective introduction of the R1 and R2 groups.
2-Substituted piperazines are commonly prepared by
ring construction and reduction of diketopiperazines3,4 or
2-ketopiperazines,5 via alkylation and reduction of 2-
methylpyrazines,6 or by a-lithiation and alkylation of N-
Boc piperazines.7 In many of these cases, the piperazine
derivatives must then be selectively protected prior to further
modification. Whereas most of these methods lock in the
2-substituent at an early stage in the synthesis, we were in-
terested in introducing the substituent at a later stage in order
to maximize synthetic efficiency. A second strategy involves
the elaboration of 2-substituted piperazine derivatives such
as piperazin-2-ylmethanol.8 As this route offered the
greatest flexibility for introducing a wide array of linkers
and aryl substituents at a later stage in the synthesis, the
In our initial attempt at preparing 2-(aryloxymethyl)piper-
azines via a Mitsunobu reaction between compound 3 and
an aryl alcohol, the tetrahydro-1H-oxazolo[3,4-a]pyrazin-
3(5H)-one 5a was isolated as a major side product. We
have since demonstrated that compounds 5 can themselves
serve as orthogonally protected piperazine intermediates
for the synthesis of a variety of 2-substituted piperazines.
As described below, this strategy has the advantage of not
requiring selective protection of the piperazine starting
material since compounds 5 are prepared from the di-Boc
or di-Cbz-protected piperazine-2-carboxylic acids.
2. Results and discussion
Tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones 5a and
5b were prepared in three steps as outlined in Scheme 2.
Compounds 612 and 713 were readily prepared in identical
96% yields from piperazine-2-carboxylic acid using 2 equiv
of di-tert-butyldicarbonate and benzyl chloroformate,
respectively. The carboxylic acids were reduced to the
Keywords: Piperazine; Orthogonal protection; 2-(Phenoxymethyl)piper-
azines; Oxazolidinone.
* Corresponding author at present address: TetraPhase Pharmaceuticals,
Inc., 480 Arsenal St., Suite 110, Watertown, MA 02472-2805, USA.
Tel.: +1 617 715 3558; fax: +1 617 715 3557; e-mail: rclark@
tetraphasepharma.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.044

3058
R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
PG
N
R1
N
Boc
N
Boc
N
H
N
1) (Boc)2O
2) CbzCl
[H-]
X
OH
R3
N
N
R2
Ar
N
H
CO2H
N
Cbz
CO2H
N
Cbz
O
O
1
2
3
4
5a: PG = Boc, R3 = H
5b: PG = Cbz, R3 = H
5c: PG = Boc, R3 = Ph
Scheme 1.
alcohols with borane–THF complex, and the compounds
were cyclized to give 5a and 5b under basic conditions.
The Cbz-protected compound cyclized more easily, requir-
ing only potassium carbonate in refluxing ethanol.14 The
Boc-protected compound was more efficiently prepared by
alkoxide formation with catalytic sodium hydride in reflux-
ing THF. Compound 5a was purified by recrystallization in
80% yield. While compound 5b was also a crystalline solid,
the presence of benzyl alcohol in the crude reaction mixture
complicated recrystallization, and the compound was iso-
lated in 81% yield following column chromatography.
Both enantiomers of piperazine-2-carboxylic acid are com-
mercially available, and we have applied these routes to
the synthesis of both enantiomers of 5a and 5b.
irreversible process, driving the reaction toward 13 upon
decarboxylation. The ratio of 11 and 13 formed would likely
depend on the reaction conditions. In the case of an aryl-
oxide, however, pathway Awould not be favorable since the
aryloxide is a much better leaving group than the alkoxide of
compound 9. This would leave pathway B as the only
productive reaction pathway.
X
X
X
O-
N
A
N
B
O
N
R
B
O
O
O
O
R
-OR
O
O-
10
A
9
8
KOH
H2O
Boc
N
1) BH3-THF
H2O
H2O
Boc
N
(Boc)2O
Et3N
H
N
50 °C
2) NaH
(0.1 eq.)
THF, reflux
(80%)
MeOH
50 °C
(96%)
X
N
N
H
CO2H
N
Boc
CO2H
X
X
O
OH
N
O
OH
O
N
H
N
H
R
1
6
5a
O
O
R
Cbz
N
1) BH3-THF
50 °C
2) K2CO3
EtOH, reflux
(81%)
Cbz
N
CbzCl
NaOH
H
N
11
12
13
Scheme 3.
H2O
(96%)
N
N
H
CO2H
N
Cbz
CO2H
O
In order to explore the differences in reactivity between
alkoxides and aryloxides, compound 5a was reacted with
benzyl alcohol or phenol under several conditions (Table 1).
Haddad et al reported the reaction of lithium benzylate with
a tetrahydropyrrolo[1,2-c]oxazol-3(1H)-one derivative to
proceed via pathway A to provide the corresponding Cbz-
protected 2-(hydroxymethyl)pyrrolidine.15b Under these
conditions, only a trace of compound 3 was observed with
lithium benzylate and none of the 2-(benzyloxymethyl)-
piperazine 14a (entry 1) was observed. By increasing to
3 equiv of the alkoxide, compound 3 was isolated in 9%
yield while compound 14a was formed in 8% yield. In
both examples, the remainder of the material was the un-
reacted 5a. With sodium benzylate, however, only reaction
products formed via pathway B were observed, with 14a
isolated in 10% yield and 15a isolated in 27% yield, arising
from reaction of excess sodium benzylate with the Boc
group (entry 3). With DMF as solvent, somewhat better
yields of 22% and 52% were observed for 14a and 15a,
respectively. This counterion dependent difference in reac-
tivity may allow for tuning of reactivity between pathways
A and B. The less nucleophilic sodium phenoxide gave
only an 8% yield of the 2-(phenoxymethyl)piperazine 14b
at 70 ꢀC in THF (entry 5). As expected, neither the com-
pound arising from pathway A nor the exchange of the
O
1
Scheme 2.
7
5b
2.1. 2-(Benzyloxymethyl)piperazines and 2-(phenoxy-
methyl)piperazines
Bicyclic oxazolidinones have been shown to react with
alkoxides15 at the carbonyl carbon (Scheme 3, pathway A)
to provide the corresponding N-carbamoyl-2-(hydroxyme-
thyl)pyrrolidines 11 (X¼bond) or with aqueous hydroxide16
to yield the corresponding 2-(hydroxymethyl)heterocycles
12 (X¼bond, CH2, NR). There have also been reports of
alkoxide ring opening of monocyclic oxazolidinones on
the C-5 carbon to form 2-alkoxy-1-aminoethane derivatives
(pathway B).17 While there have been no reports of this
type of reaction with aryloxides,18,19 and no examples with
tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones, we were
intrigued by the possibility of preparing 2-(aryloxymethyl)-
piperazines from 5 by oxazolidinone ring opening via path-
way B. Alkoxides were expected to react preferentially via
pathway A, establishing an equilibrium between the carba-
mate 9 and the oxazolidinone 8. If the alkoxide did react
via pathway B, compound 10 would be formed in an

R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
Table 1. Reaction of 5a with oxygen nucleophiles
3059
Boc
N
Boc
N
PG
N
ROH,
Base
OH
+
N
N
O
70 °C
N
H
R
O
O
O
O
R
5a
3
14: PG = Boc
15: PG = Cbz
Entry
ROH (equiv)
Base
Solvent
Yield 3
Yield 14/15
1
2
3
4
5
6
BnOH (1.5)
BnOH (3.0)
BnOH (3.0)
BnOH (3.0)
PhOH (3.0)
PhOH (3.0)
n-BuLi
n-BuLi
NaH
NaH
NaH
THF
THF
THF
DMF
THF
Tracea
9%
Noneb
14a: 8%
14a: 10%, 15a: 27%
14a: 22%, 15a: 52%
14b: 8%
Noneb
Noneb
—
NaH
DMF (120 ꢀC)
—
14b: 66%
a
Compound was not isolated, but a small amount was observed by LC–MS during reaction.
Compound was not observed by LC–MS during course of reaction.
b
Boc group was observed. By heating to 120 ꢀC in DMF,
however, compound 14b was isolated in 66% yield, indicat-
ing that this reaction could be a synthetically useful method
for the synthesis of 2-(aryloxymethyl)piperazines.
aromatic groups while simultaneously unmasking the
nitrogen at the 1-position of the piperazines for further
elaboration.
2.2. 2-Benzylpiperazines
Table 2 illustrates the reaction of several substituted phenox-
ides with 5a. Overall, the desired 2-(phenoxymethyl)piper-
azines 14b and 16–21 were isolated in good yields, ranging
from 48 to 76%. The phenoxides were preformed from
3 equiv of the phenol and sodium hydride in DMF, followed
by addition of 5a and heating at 120 ꢀC overnight. Preform-
ing the phenoxide with sodium hydroxide was not ideal as a
significant amount of the hydrolysis product 12 (X¼N–Boc)
was formed, even when using excess phenol. We are cur-
rently exploring the use of other bases and solvent systems.
Neither electron rich nor electron deficient substituents had
a significant impact on yields (examples 16, 19, and 21).
While phenoxides with a methoxy substituent at the 3- or
4-position reacted similarly, a methoxy substituent at the
2-position gave a reduced yield (example 16–18). Although
the full scope of this reaction has yet to be elucidated, this
appears to be a convenient and general method for the
synthesis of 2-(phenoxymethyl)piperazines. The method is
also ideal for the synthesis of our target compounds, 4, as
it allows for the introduction of a variety of substituted
Orthogonally protected 2-benzylpiperazines were also pre-
pared in a similar fashion to 5a and 5b (Scheme 4). The di-
Boc-protected piperazine-2-carboxylic acid was converted
to aldehyde 22 by borane reduction followed by Swern oxi-
dation in 74% yield for the two steps. Reaction with phenyl-
magnesium bromide at ꢁ78 ꢀC followed by cyclization with
sodium hydride in THF at 70 ꢀC gave 5c in 70% yield as a 2:1
mixture of diastereomers. Under the Grignard conditions,
a small amount of cyclized product was observed, but heating
was necessary for complete cyclization. Because excess
Grignard reagent was found to react with the carbonyl of
the oxazolidinone, the two step sequence was preferred. As
demonstrated, compound 5c serves as an orthogonally pro-
tected 2-benzylpiperazine derivative. The nitrogen at the
1-position was deprotected under transfer hydrogenation
1) BH3-THF
Boc
N
Boc
N
1) PhMgBr
THF, 50 °C
(85%)
THF, -78 °C
2) (COCl)2
DMSO, Et3N
CH2Cl2, -60 °C
(87%)
2) NaH
THF, 70 °C
(70%)
OH
O
N
Boc
N
Boc
H
O
Table 2. Synthesis of 2-(aryloxymethyl)piperazines from 5a
6
22
Boc
N
Boc
N
HO
R1
Boc
N
Boc
N
NH4HCO2
Pd(OH)2/C
O
N
N
H
NaH, DMF
120 °C
R1
O
EtOH, 70 °C
(88%)
N
O
N
H
O
14b, 16-21
5a
O
5c
23
Example
R1
Yield (%)
H
N
14b
16
17
18
19
20
21
H
66
63
76
48
75
62
58
HCl, EtOH
4-OMe
3-OMe
2-OMe
4-Cl
3-F
4-OCF3
5c
1,4-Dioxane
(89%)
N
O
O
24
Scheme 4.

3060
R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
conditions to give compound 23 in 88% yield. For further
reaction of the nitrogen at the 4-position, the Boc group
was removed with HCl in 89% yield to give compound 24.
The 1-position could later be deprotected by transfer hydro-
genation. With the use of readily available aryl Grignard re-
agents this route should provide an efficient method for the
preparation of orthogonally protected 2-benzylpiperazines.
Finally, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones 5
provide a scaffold from which orthogonally protected
piperazin-2-ylmethanol derivatives can be prepared. These
compounds can then be converted to orthogonally protected
2-arylethylpiperazines.
4. Experimental
2.3. 2-Phenethylpiperazines
4.1. General experimental
The tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones also
provide a convenient scaffold from which orthogonally pro-
tected piperazin-2-ylmethanol derivatives can be prepared.
This is demonstrated by the introduction of a Cbz group as
found in Scheme 5. Compound 5a was treated with potas-
sium hydroxide in refluxing ethanol, followed by benzyl
chloroformate to give compound 3 in 87% yield. In princi-
ple, other nitrogen protecting groups could be introduced
as long as they react selectively with the amine over the pri-
mary alcohol. We have used compound 3 as the starting
point for the synthesis of 2-arylethylpiperazines such as
compound 26. Compound 3 was oxidized by Swern oxida-
tion and converted to the alkene 25 via Witting olefination
in 74% yield for the two steps. This was then converted
to compound 26 in a hydroboration/Suzuki20 coupling se-
quence with 4-iodoanisole in 68% yield.21 With the use of
substituted halobenzenes, this procedure allows for the intro-
duction of a wide range of substitution on the phenyl ring.
Air and moisture sensitive liquids and reagents were trans-
ferred via syringe or cannula and were introduced into
oven-dried glassware under a positive pressure of dry nitro-
gen through rubber septa. All reactions were stirred magnet-
ically. Commercial reagents were used without further
purification. Analytical thin-layer chromatography was per-
formed on EM Science pre-coated glass-backed silica gel
˚
60 A F254 250 mm plates. Visualization of the plates was
effected by one or more of the following techniques: (a)
ultraviolet illumination, (b) exposure to iodine vapor, and/or
(c) immersion of the plate in a 10% solution of phosphomo-
lybdic acid in ethanol followed by heating. Column chroma-
tography was performed on a FlashMasterÔ Personal or
FlashMaster Personal PlusÔ system using ISOLUTEÒ Flash
Si II silica gel pre-packed cartridges (available from Biot-
age). Preparative reversed-phase HPLC chromatography
(HPLC) was accomplished using an Agilent 1100 Series
system and an Agilent Prep-C18 (21.2 mm I.D.ꢂ150 mm)
column equipped with an Agilent Prep-C18 (21.2 mm
I.D.) guard column. The mobile phase used was a mixture
of H2O (A) and MeCN (B) containing 0.1% TFA.
Boc
N
1) KOH
H2O, EtOH
reflux
Boc
N
1) Swern Ox.
2) CH3PPh3Br
n-BuLi, THF
-78 °C to rt
(74%)
1H NMR spectra were recorded on a Varian Gemini 2400
(400 MHz) spectrometer and are reported in parts per mil-
lion using residual solvent as the internal standard (CDCl3
at 7.24 ppm or DMSO-d6 at 2.50 ppm). Data are reported
as: br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet; coupling constant(s) in hertz, integration.
13C NMR spectra were recorded on a Varian Gemini 2400
(100 MHz) spectrometer and are reported in parts per mil-
lion using residual solvent as the internal standard (CDCl3
at 77.2 ppm or DMSO-d6 at 39.5 ppm).
2) Cbz-Cl
Et3N, THF
(87%)
OH
N
N
Cbz
O
O
5a
3
a) 9-BBN
THF
Boc
N
Boc
N
b) 4-iodoanisole
PdCl2(dppf)2-CH2Cl2
NaOH, H2O
reflux
N
Cbz
N
Cbz
OMe
(68%)
25
Scheme 5.
26
High-performance liquid chromatography–electrospray
mass spectra (LC–MS) were obtained using an Agilent
1100 Series HPLC equipped with a binary pump, a diode
array detector monitored at 254 and 214 nm, an Agilent
Zorbax Eclipse XDB-C8 (4.6 mm I.D.ꢂ150 mm, 5 micron)
column, and an Agilent 1100 Series LC/MSD mass spec-
trometer with electrospray ionization. Spectra were scanned
from 100 to 1000 amu. The eluant was a mixture of H2O (A)
and MeCN (B) containing 0.1% AcOH at a flow rate of
1 mL/min. A typical gradient was: (a) time¼0 min, 90%
A, 10% B; (b) time¼9 min, 10% A, 90% B; (c) time¼
9.5 min, 90% A, 10% B; (d) time¼12 min, 90% A, 10% B.
3. Conclusions
In conclusion, we have demonstrated that tetrahydro-1H-ox-
azolo[3,4-a]pyrazin-3(5H)-ones 5 can serve as orthogonally
protected piperazines from which a variety of 2-substituted
piperazines can be conveniently prepared. These compounds
are readily prepared from piperazine-2-carboxylic acid with-
out the need for selective protection of the two nitrogens. So-
dium benzylate and sodium phenoxides react with 5 to yield
2-(benzyloxymethyl)piperazine and 2-(phenoxymethyl)-
piperazines, respectively. In the process, the 1-position of
the piperazine is unmasked while the 4-position remains
protected, providing a convenient scaffold for further
derivatization. The 1-phenyltetrahydro-1H-oxazolo[3,4-a]-
pyrazin-3(5H)-one 5c is also readily prepared from
di-Boc-protected piperazine-2-carboxylic acid and serves
as an orthogonally protected 2-benzylpiperazine derivative.
Elemental analysis (C, H, N) was performed by Atlantic
Microlab, Inc. (Norcross, Georgia).
4.2. Experimental details
4.2.1. 1,4-Bis(tert-butoxycarbonyl)piperazine-2-carb-
oxylic acid (6). According to the literature procedure,12a

R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
3061
a solution of di-tert-butyldicarbonate (63 g, 290 mmol) in
MeOH (100 mL) was added portionwise to a solution of
piperazine-2-carboxylic acid dihydrochloride (25.0 g,
123 mmol) and triethylamine (48 mL, 340 mmol) in MeOH
(150 mL) over 30 min. Upon complete addition, the reaction
mixture was heated to 50 ꢀC for 2 h. Upon cooling to rt, the
reaction mixture was concentrated under reduced pressure.
The material was dissolved in water (300 mL) and the solu-
tion was brought to pH 2 with 1 M aqueous HCl. This was
extracted with EtOAc (4ꢂ200 mL), and the combined ex-
tracts were dried over Na2SO4, filtered, and concentrated un-
der reduced pressure until w100 mL EtOAc remained. The
solution was diluted with hexanes (150 mL) and cooled to
0 ꢀC. The resulting solid was collected by filtration, washed
with hexanes (2ꢂ), and air-dried. This gave 38.9 g (96%) of
the title compound as a white solid. Analytical data for 6: 1H
NMR (400 MHz, DMSO-d6) d 13.02–12.80 (br, 1H), 4.50–
4.24 (m, 2H), 3.94–3.72 (br, 1H), 3.66 (d, J¼12.8 Hz, 1H),
3.22–2.92 (m, 2H), 2.90–2.68 (br, 1H), 1.42–1.34 (m, 18H).
with EtOAc (3ꢂ200 mL). The combined EtOAc extracts
were dried over Na2SO4, filtered, and concentrated under
reduced pressure to give 18.9 g (96%) of the desired product
as a thick oil. The material was used without further purifi-
cation. Analytical data for 7: LC–MS: tR¼9.250 min;
[M+H]+¼421.1.
4.2.4. Benzyl 3-oxotetrahydro-1H-oxazolo[3,4-a]pyr-
azine-7(3H)-carboxylate (5b). Borane–THF complex
(1.0 M solution in THF, 100 mL, 100 mmol) was added
slowly to a solution of 7 (18.9 g, 47.4 mmol) in THF
(200 mL). Upon complete addition, the reaction mixture
was heated to 50 ꢀC for 3 h. Upon cooling to rt, the reaction
mixture was carefully quenched by the dropwise addition of
MeOH. After gas evolution ceased, the reaction mixture was
heated to 50 ꢀC for 1 h. Upon cooling to rt, the reaction
mixture was concentrated under reduced pressure. The ma-
terial was dissolved in EtOH (200 mL) and K2CO3 (6.9 g,
49.9 mmol) was added. The reaction mixture was heated
to 70 ꢀC overnight. Upon cooling to rt, the reaction mixture
was concentrated under reduced pressure, diluted with water
(200 mL), and extracted with EtOAc (3ꢂ200 mL). The
combined organics were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The material was puri-
fied by column chromatography (10–40% EtOAc in hexanes
gradient) to give 10.7 g (81%) of the title compound as
a white solid. Analytical data for 5b: Rf¼0.53 in 80%
4.2.2. tert-Butyl 3-oxotetrahydro-1H-oxazolo[3,4-a]pyr-
azine-7(3H)-carboxylate(5a). Borane–THF complex (1.0 M
solution in THF, 200 mL, 200 mmol) was added slowly to
a
solution of 1,4-bis(tert-butoxycarbonyl)piperazine-2-
carboxylic acid (35.2 g, 106 mmol) in THF (200 mL). Upon
complete addition, the reaction mixture was heated to 50 ꢀC
for 3 h. Upon cooling to rt, the reaction mixture was carefully
quenched by the dropwise addition of MeOH (25 mL).
After gas evolution ceased, the reaction mixture was heated
to reflux for 1 h. Upon cooling to rt, the reaction mixture
was concentrated under reduced pressure. The material was
dissolved twice in THF (50 mL) and concentrated under
reduced pressure. The material was dissolved in THF
(200 mL) and NaH (60% dispersion in mineral oil, 4.24 g,
106 mmol) was added portionwise. The reaction mixture
was heated to reflux overnight. Upon cooling to rt, the reac-
tion mixture was quenched with NH4Cl (saturated, aqueous,
100 mL) and diluted with water (100 mL). The solution was
extracted with EtOAc (3ꢂ300 mL), and the combined ex-
tracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The material was recrystallized from
EtOAc/hexanes (1:4) to give 17.6 g (68%) of the title com-
pound as a white solid. Analytical data for 5a: Rf ¼0.43 in
1
EtOAc/hexanes; H NMR (400 MHz, CDCl3) d 7.39–7.28
(m, 5H), 5.12 (s, 2H), 4.44–4.04 (br m, 3H), 3.96–3.85 (br,
1H), 3.84–3.70 (br, 2H), 3.08–2.93 (br m, 1H), 2.93–2.62
(br m, 2H); 13C NMR (100 MHz, CDCl3) d 156.5, 154.9,
136.1, 128.7, 128.4, 128.2, 68.0, 65.4, 52.8, 47.9, 43.4,
41.0. LC–MS: tR¼7.85 min; [M+Na]+¼299.1. Anal. Calcd
for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C,
60.85; H, 5.83; N, 10.09.
4.2.5. 1-Benzyl 4-tert-butyl 2-(hydroxymethyl)piper-
azine-1,4-dicarboxylate (3) and tert-butyl 3-(benzyloxy-
methyl)piperazine-1-carboxylate (14a).
4.2.5.1. Reaction of 5a with 3 equiv of benzyl alcohol
and n-BuLi in THF. n-BuLi (2.5 M solution in hexanes,
1.25 mL, 3.13 mmol) was added to a solution of benzyl alco-
hol (0.32 mL, 3.1 mmol) at 0 ꢀC. The reaction mixture was
allowed to warm to rt for 30 min. Compound 5a (0.250 g,
1.03 mmol) was added, and the reaction mixture was heated
to reflux overnight. Upon cooling to rt, the reaction mixture
was diluted with water (1 mL) and concentrated under
reduced pressure. The material was purified by HPLC (5–
50% CH3CN in H2O, 0.1% TFA gradient), yielding two
major fractions. The fraction containing 3 was concentrated
under reduced pressure, yielding 0.033 g (9%) of 3 as a thick,
colorless oil. Analytical data for compound 3 are given in
Section 4.3.13. The fraction containing 14a was brought to
pH w12 with 1 N NaOH and extracted with EtOAc (3ꢂ).
The extracts were dried over Na2SO4, filtered, and concen-
trated under reduced pressure, yielding 0.025 g (8%) of 14a
1
80% EtOAc/hexanes; H NMR (400 MHz, CDCl3) d 4.41
(t, J¼8.4 Hz, 1H), 4.35–3.98 (br, 2H), 3.92 (dd, J¼5.6 and
8.8 Hz, 1H), 3.80–3.72 (m, 2H), 2.98 (dt, J¼3.6 and 12.4 Hz,
1H), 2.86–2.70 (br, 1H), 2.70–2.55 (br, 1H), 1.45 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 156.7, 154.2, 81.1, 65.5, 52.9,
47.7 (br), 43.4 (br), 41.1, 28.7. LC–MS: tR¼6.46 min;
[M+Na]+¼264.9. Anal. Calcd for C11H18N2O4: C, 54.53;
H, 7.49; N, 11.56. Found: C, 54.38; H, 7.44; N, 11.35.
4.2.3. 1,4-Bis(benzyloxycarbonyl)piperazine-2-carb-
oxylic acid (7). According to the literature procedure,13a
piperazine-2-carboxylic acid dihydrochloride (10.0 g,
49.2 mmol) was dissolved in H2O (125 mL) and 1,4-dioxane
(200 mL), and the solution was brought to pH 11 with 50%
NaOH in H2O. Benzyl chloroformate (14 mL, 98 mmol) was
added while maintaining the pH at 11 with 50% NaOH in
H2O. After 1 h, an additional portion of benzyl chlorofor-
mate (2 mL, 14 mmol) was added. After 30 min, the solution
was extracted with Et2O (3ꢂ100 mL). The aqueous layer
was brought to pH 2 with concentrated HCl and extracted
1
as a thick, colorless oil. Analytical data for 14a: H NMR
(400 MHz, CDCl3) d 7.36–7.24 (m, 5H), 4.49 (s, 2H),
4.01–3.75 (br, 2H), 3.46 (dd, J¼3.8 and 9.0 Hz, 1H), 3.32
(dd, J¼7.8 and 9.0 Hz, 1H), 3.00–2.76 (m, 3H), 2.76–2.65
(m, 1H), 2.65–2.45 (br, 1H), 2.15 (s, 1H), 1.43 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 154.8, 138.0, 128.5, 127.8,
79.9, 73.7, 72.1, 54.7, 48.0–45.8 (br), 45.3, 45.3–44.0 (br),

3062
R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
28.7. LC–MS: tR¼5.45 min; [M+H]+¼307.2. Anal. Calcd
for C17H26N2O3: C, 66.64; H, 8.55; N, 9.14. Found: C,
66.63; H, 8.64; N, 9.10.
concentrated under reduced pressure. The material was puri-
fied by column chromatography (0–3% MeOH in CH2Cl2
gradient) to give 0.025 g (8%) of the title compound as a tan
solid. Analytical data for 14b: Rf¼0.51 in 10% MeOH/
CH2Cl2; 1H NMR (400 MHz, CDCl3) d 7.29–7.24 (m, 2H),
6.96–6.91 (m, 1H), 6.90–6.85 (m, 2H), 4.12–3.80 (m, 4H),
3.12–3.03 (m, 1H), 3.03–2.86 (m, 3H), 2.84–2.60 (m, 1H),
2.40–2.20 (br, 1H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 158.6, 154.8, 129.6, 121.2, 114.7, 80.1, 69.5, 54.3,
48.0–45.3 (br), 45.2, 45.2–43.8 (br), 28.8. LC–MS: tR¼
5.15 min; [M+H]+¼293.1. Anal. Calcd for C16H24N2O3:
C, 65.73; H, 8.27; N, 9.58. Found: C, 65.56; H, 8.27; N, 9.49.
4.2.6. tert-Butyl 3-(benzyloxymethyl)piperazine-1-car-
boxylate (14a) and benzyl 3-(benzyloxymethyl)piper-
azine-1-carboxylate (15a).
4.2.6.1. Reaction of 5a with 3 equiv of benzyl alcohol
and NaH in THF. Benzyl alcohol (0.32 mL, 3.1 mmol)
was added to a suspension of sodium hydride (60% disper-
sion in mineral oil, 0.124 g, 3.09 mmol) in THF (5 mL) at
0 ꢀC. The reaction mixture was allowed to warm to rt for
30 min. Compound 5a (0.250 g, 1.03 mmol) was added, and
the reaction mixture was heated to reflux overnight. Upon
cooling to rt, the reaction mixture was diluted with water
(1 mL) and concentrated under reduced pressure. The mate-
rial was purified by HPLC (5–50% CH3CN in H2O, 0.1%
TFA gradient), yielding two major fractions corresponding
to 14a and 15a. The fractions were independently brought
to pHw12 with 1 N NaOH and extracted with EtOAc (3ꢂ).
The extracts were dried over Na2SO4, filtered, and concen-
trated under reduced pressure. This gave 0.030 g (10%) of
14a as a thick, colorless oil and 0.095 g (27%) of 15a as
4.3. General procedure for the reaction of 5a with
phenols
Phenol (6.18 mmol) was added portionwise to a suspension
of sodium hydride (60% dispersion in mineral oil, 0.247 g,
6.18 mmol) in DMF (5 mL). Compound 5a (0.500 g,
2.06 mmol) was added, and the reaction mixture was heated
to 120 ꢀC overnight. Upon cooling to rt, the reaction mixture
was diluted with water (25 mL) and extracted with EtOAc
(3ꢂ25 mL). The combined extracts were washed with 1 N
NaOH (2ꢂ40 mL) and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The material
was purified by column chromatography (0–3% MeOH in
CH2Cl2 gradient) to give 14b and 16–21.
1
a thick, colorless oil. Analytical data for 15a: H NMR
(400 MHz, CDCl3) d 7.37–7.22 (m, 10H), 5.18–5.06 (br m,
2H), 4.49 (s, 2H), 4.09–3.88 (br, 2H), 3.52–3.40 (br, 1H),
3.38–3.29 (br, 1H), 3.03–2.82 (br m, 3H), 2.81–2.59 (br m,
2H), 2.27–2.12 (br, 1H); 13C NMR (100 MHz, CDCl3) d
155.3, 137.9, 136.8, 128.6, 128.1, 128.0, 127.9, 127.8, 73.8,
71.9, 67.4, 54.7, 46.6 (br), 45.3, 44.8. LC–MS: tR¼5.48 min;
[M+H]+¼341.1. Anal. Calcd for C20H24N2O3: C, 70.56; H,
7.11; N, 8.23. Found: C, 70.26; H, 7.16; N, 8.21.
4.3.1. tert-Butyl 3-(phenoxymethyl)piperazine-1-carb-
oxylate (14b). Compound 14b (0.398 g, 66%) was prepared
from phenol (0.581 g, 6.18 mmol) and isolated as a tan solid.
For analytical data of compound 14b, see Section 4.2.7.1.
4.2.6.2. Reaction of 5a with 3 equiv of benzyl alcohol
and NaH in DMF. Benzyl alcohol (0.64 mL, 6.18 mmol)
was added portionwise to a suspension of sodium hydride
(60% dispersion in mineral oil, 0.247 g, 6.18 mmol) in
DMF (5 mL). Compound 5a (0.500 g, 2.06 mmol) was
added, and the reaction mixture was heated to 70 ꢀC over-
night. Upon cooling to rt, the reaction mixture was diluted
with water (30 mL) and extracted with EtOAc (3ꢂ). The
combined extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The material was puri-
fied by HPLC (5–50% CH3CN in H2O, 0.1% TFA gradient),
yielding two major fractions corresponding to 14a and 15a.
The fractions were independently brought to pH w12 with
1 N NaOH and extracted with EtOAc (3ꢂ). The extracts
were dried over Na2SO4, filtered, and concentrated under
reduced pressure. This gave 0.139 g (22%) of 14a and
0.365 g (52%) of 15a.
4.3.2. tert-Butyl 3-((4-methoxyphenoxy)methyl)piper-
azine-1-carboxylate (16). Compound 16 (0.421 g, 63%)
was prepared from 4-methoxyphenol (0.767 g, 6.18 mmol)
and isolated as a thick oil. Analytical data for 16: Rf ¼0.49
in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) d
6.84–6.77 (m, 4H), 4.12–3.84 (m, 3H), 3.82–3.72 (m, 4H),
3.09–2.96 (m, 2H), 2.96–2.84 (m, 1H), 2.84–2.60 (m, 2H),
2.16–1.96 (br, 1H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 154.9, 154.2, 152.8, 115.7, 114.8, 80.0, 70.5,
56.0, 54.4, 48.0–45.3 (br), 45.3, 45.3–43.8 (br), 28.8. LC–
MS: tR¼4.98 min; [M+H]+¼323.5. Anal. Calcd for
C17H26N2O4: C, 63.33; H, 8.13; N, 8.69. Found: C, 63.60;
H, 8.14; N, 8.66.
4.3.3. tert-Butyl 3-((3-methoxyphenoxy)methyl)piper-
azine-1-carboxylate (17). Compound 17 (0.505 g, 76%)
was prepared from 3-methoxyphenol (0.767 g, 6.18 mmol)
and isolated as a thick oil. Analytical data for 17: Rf ¼0.52
in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) d 7.14
(t, J¼8.0 Hz, 1H), 6.52–6.41 (m, 3H), 4.12–3.85 (m, 3H),
3.81 (dd, J¼7.2 and 8.8 Hz, 1H), 3.75 (s, 3H), 3.10–2.95 (m,
2H), 2.95–2.82 (m, 1H), 2.82–2.58 (m, 2H), 2.15–2.05 (br,
1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) d 160.8,
159.9, 154.8, 130.0, 106.84, 106.76, 101.2, 80.0, 69.6, 55.5,
54.2, 48.0–45.3 (br), 45.2, 45.2–43.8 (br), 28.7. LC–MS:
tR¼5.31 min; [M+H]+¼323.5. Anal. Calcd for C17H26N2O4:
C, 63.33; H, 8.13; N, 8.69. Found: C, 63.01; H, 8.27; N, 8.64.
4.2.7. tert-Butyl 3-(phenoxymethyl)piperazine-1-carb-
oxylate (14b).
4.2.7.1. Reaction of 5a with phenol and NaH in THF at
70 ꢀC. Phenol (0.291 g, 3.09 mmol) was added to a suspen-
sion of sodium hydride (60% dispersion in mineral oil,
0.124 g, 3.09 mmol) in THF (5 mL) at 0 ꢀC. After warming
to rt for 30 min, 5a (0.250 g, 1.03 mmol) was added and the
reaction mixture was heated to reflux overnight. Upon cool-
ing to rt, the reaction mixture was diluted with water
(25 mL) and extracted with EtOAc (3ꢂ25 mL). The com-
bined extracts were washed with 1 N NaOH (2ꢂ30 mL)
and brine (30 mL), dried over Na2SO4, filtered, and
4.3.4. tert-Butyl 3-((2-methoxyphenoxy)methyl)piper-
azine-1-carboxylate (18). Compound 18 (0.320 g, 48%)

R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
3063
was prepared from 2-methoxyphenol (0.767 g, 6.18 mmol)
and isolated as a thick oil. Analytical data for 18: Rf ¼0.47
in 10% MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) d
6.96–6.84 (m, 4H), 4.06–3.80 (m, 7H), 3.16–3.06 (m, 1H),
3.04–2.84 (m, 2H), 2.84–2.60 (m, 2H), 2.44–2.28 (br, 1H),
1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) d 154.9, 150.0,
148.3, 122.1, 121.1, 115.0, 112.3, 80.0, 71.5, 56.1, 54.3,
48.0–45.2 (br), 45.2, 45.2–43.8 (br), 28.8. LC–MS: tR¼
5.20 min; [M+H]+¼323.5. Anal. Calcd for C17H26N2O4:
C, 63.33; H, 8.13; N, 8.69. Found: C, 63.17; H, 8.04; N, 8.65.
reflux for 1 h. Upon cooling to rt, the reaction mixture was
concentrated under reduced pressure. The material was puri-
fied by column chromatography (0–40% EtOAc in hexanes
gradient) to give 0.819 g (85%) of the title compound as
a white solid. Analytical data:22 Rf ¼0.22 in 30% EtOAc/
hexanes; 1H NMR (400 MHz, DMSO-d6) d 4.76 (t,
J¼5.0 Hz, 1H), 4.04–3.85 (m, 2H), 3.85–3.64 (m, 2H),
3.42–3.26 (m, 2H), 3.00–2.64 (m, 3H), 1.39 (s, 18H). LC–
MS: tR¼8.27 min; [M+Na]+¼339.6.
4.3.9. Di-tert-butyl 2-formylpiperazine-1,4-dicarboxylate
(22). A solution of DMSO (0.20 mL, 2.9 mmol) in CH2Cl2
(2 mL) was added to a solution of oxalyl chloride
(0.124 mL, 1.43 mmol) in CH2Cl2 (10 mL) at ꢁ60 ꢀC. After
5 min, a solution of di-tert-butyl 2-(hydroxymethyl)piper-
azine-1,4-dicarboxylate (0.410 g, 1.30 mmol) in CH2Cl2
(2 mL) was added. After 15 min, triethylamine (0.91 mL,
6.5 mmol) was added and the reaction mixture was allowed
to warm to rt. After 1 h, water (25 mL) was added, the or-
ganics were separated, and the aqueous layer was extracted
with CH2Cl2 (3ꢂ25 mL). The combined organics were
washed with brine (3ꢂ50 mL), 1% HCl (3ꢂ50 mL), water
(50 mL), and 5% NaHCO3 (3ꢂ50 mL). The organics were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The material was purified by column chromato-
graphy (10–20% EtOAc in hexanes gradient) to give
0.354 g (87%) of the title compound as a white solid. Ana-
4.3.5. tert-Butyl 3-((4-chlorophenoxy)methyl)piperazine-
1-carboxylate (19). Compound 19 (0.505 g, 75%) was
prepared from 4-chlorophenol (0.795 g, 6.18 mmol) and iso-
lated as a thick oil. Analytical data for 19: Rf ¼0.57 in 10%
MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) d 7.19 (d, J¼
9.0 Hz, 2H), 6.79 (d, J¼9.0 Hz, 2H), 4.10–3.84 (m, 3H),
3.79 (dd, J¼7.6 and 8.8 Hz, 1H), 3.08–2.83 (m, 3H), 2.83–
2.58 (m, 2H), 2.18–2.04 (br, 1H), 1.44 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 157.2, 154.8, 129.4, 126.1, 115.9,
80.0, 70.0, 54.1, 48.0–45.2 (br), 45.2, 45.2–43.8 (br), 28.7.
LC–MS: tR¼5.52 min; [M+H]+¼327.5. Anal. Calcd for
C16H23ClN2O3: C, 58.80; H, 7.09; N, 8.57. Found: C,
59.06; H, 7.22; N, 8.61.
4.3.6. tert-Butyl 3-((3-fluorophenoxy)methyl)piperazine-
1-carboxylate (20). Compound 20 (0.397 g, 62%) was
prepared from 3-fluorophenol (0.693 g, 6.18 mmol) and iso-
lated as a thick oil. Analytical data for 20: Rf ¼0.51 in 10%
MeOH/CH2Cl2; 1H NMR (400 MHz, CDCl3) d 7.18 (q, J¼
7.9 Hz, 1H), 6.67–6.55 (m, 3H), 4.10–3.85 (m, 3H), 3.80
(dd, J¼7.6 and 8.8 Hz, 1H), 3.10–2.83 (m, 3H), 2.83–2.58
(m, 2H), 2.18–2.04 (br, 1H), 1.44 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 163.6 (d, J¼244 Hz), 159.9 (d, J¼
10.6 Hz), 154.8, 130.3 (d, J¼9.9 Hz), 110.3 (d, J¼2.2 Hz),
108.1 (d, J¼21.2 Hz), 102.5 (d, J¼25.0 Hz), 80.1, 69.9, 54.1,
48.0–45.2 (br), 45.2, 45.2–43.8 (br), 28.7. LC–MS: tR¼
5.30 min; [M+H]+¼311.5. Anal. Calcd for C16H23FN2O3:
C, 61.92; H, 7.47; N, 9.03. Found: C, 62.17; H, 7.53; N, 9.03.
1
lytical data for 22:23 Rf ¼0.53 in 40% EtOAc/hexanes; H
NMR (400 MHz, DMSO-d6) d 9.53 (br, 1H), 4.64–4.37
(m, 1H), 4.42 (d, J¼14 Hz, 1H), 3.80–3.62 (m, 2H), 3.24–
3.08 (m, 1H), 3.02–2.74 (m, 2H), 1.44–1.34 (m, 18H).
4.3.10. tert-Butyl 3-oxo-1-phenyltetrahydro-1H-
oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (5c). Phenyl-
magnesium bromide (1.0 M solution in THF, 0.66 mL,
0.66 mmol) was added dropwise to a solution of 22 (0.208 g,
0.662 mmol) in THF (5 mL) at ꢁ78 ꢀC overw2 min. After
2 h, the reaction mixture was quenched with saturated aque-
ous ammonium chloride and allowed to warm to rt. The
reaction mixture was diluted with water (20 mL) and ex-
tracted with EtOAc (3ꢂ20 mL). The combined extracts
were dried over Na2SO4, filtered, and concentrated under re-
duced pressure. The material was dissolved in THF (5 mL)
and sodium hydride (60% dispersion in mineral oil,
0.026 g, 0.66 mmol) was added in one portion. The reaction
mixture was heated to reflux for 1 h. Upon cooling to rt,
the reaction mixture was diluted with water (20 mL) and
extracted with EtOAc (3ꢂ20 mL). The combined extracts
were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The material was purified by HPLC (10–
90% CH3CN in H2O, 0.1% TFA gradient) to give 0.147 g
(70%) of the title compound as a white solid. The material
was isolated as a 2:1 ratio of diastereomers. Analytical
data for 5c:24 1H NMR (400 MHz, CDCl3) d 7.46–7.24
(m, 5H), 5.67 (d, J¼8.4 Hz, 0.33H), 5.03 (d, J¼6.8 Hz,
0.67H), 4.54–4.3 (br, 0.67H), 4.20–3.88 (m, 1.33H), 3.86–
3.76 (m, 1H), 3.60–3.52 (m, 0.67H), 3.06–2.92 (m, 1H),
2.90–2.64 (br, 2H), 2.18–2.06 (m, 0.33H), 1.43 (s, 6H),
1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.7, 156.1,
154.4, 154.2, 137.3, 134.0, 129.2, 129.1, 128.9, 128.8,
125.6, 125.4, 81.2, 80.9, 79.1, 76.7, 60.3, 56.6, 48.0–47.0
(br), 45.5–44.4 (br), 44.2–42.8 (br), 41.6, 41.1, 28.6, 28.6.
LC–MS: tR¼8.72 min; [M+Na]+¼341.1.
4.3.7. tert-Butyl 3-((4-(trifluoromethoxy)phenoxy)-
methyl)piperazine-1-carboxylate (21). Compound 21
(0.454 g, 58%) was prepared from 4-(trifluoromethoxy)phe-
nol (1.10 g, 6.18 mmol) and isolated as a thick oil. Analyti-
1
cal data for 21: Rf ¼0.56 in 10% MeOH/CH2Cl2; H NMR
(400 MHz, CDCl3) d 7.11 (d, J¼9.0 Hz, 2H), 6.86 (d,
J¼9.0 Hz, 2H), 4.13-3.86 (m, 3H), 3.82 (dd, J¼7.2 and
8.8 Hz, 1H), 3.12–2.85 (m, 3H), 2.85–2.60 (m, 2H), 2.25–
1.95 (br, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 157.1, 154.8, 143.1, 122.6, 120.7 (q, J¼254 Hz), 115.4,
80.1, 70.1, 54.2, 48.0–45.2 (br), 45.2, 45.2–43.8 (br), 28.8.
LC–MS: tR¼6.07 min; [M+H]+¼377.6. Anal. Calcd for
C17H23F3N2O4: C, 54.25; H, 6.16; N, 7.44. Found: C,
54.24; H, 6.15; N, 7.43.
4.3.8. Di-tert-butyl 2-(hydroxymethyl)piperazine-1,4-
dicarboxylate. Borane–THF complex (1.0 M solution in
THF, 6.0 mL, 6.0 mmol) was added slowly to a solution of
6 (1.00 g, 3.03 mmol) in THF (10 mL). Upon complete
addition, the reaction mixture was heated to 50 ꢀC for 2 h.
Upon cooling to rt, the reaction mixture was carefully
quenched by the dropwise addition of MeOH (10 mL). After
gas evolution ceased, the reaction mixture was heated to

3064
R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
4.3.11. tert-Butyl 3-benzylpiperazine-1-carboxylate (23).
Palladium hydroxide on carbon (w20% Pd, 7 mg,
0.01 mmol) was added to a solution of 5c (35 mg,
0.11 mmol) and ammonium formate (14 mg, 0.22 mmol)
in EtOH (1 mL). The reaction mixture was heated to 70 ꢀC
for 2 h. Upon cooling to rt, the reaction mixture was filtered
through CeliteÒ, and the filtrate was concentrated under
reduced pressure. The material was purified by column chro-
matography (0–4% MeOH in CH2Cl2 gradient), yielding
26.8 mg (88%) of the title compound. Analytical data
for 23:25 Rf¼0.44 in 10% MeOH/CH2Cl2; 1H NMR
(400 MHz, DMSO-d6) d 7.32–7.16 (m, 5H), 4.15–3.80 (br,
2H), 3.00–2.50 (m, 8H), 1.42 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 154.7, 137.7, 129.3, 128.7, 126.7,
80.0, 56.4, 50.0–48.6 (br), 45.7, 45.7–43.8 (br), 40.2, 28.7.
LC–MS: tR¼5.34 min; [M+H]+¼277.1.
4.3.14. 1-Benzyl 4-tert-butyl 2-vinylpiperazine-1,4-dicarb-
oxylate (25). A solution of DMSO (0.286 mL, 4.03 mmol) in
CH2Cl2 (2 mL) was added to a solution of oxalyl chloride
(0.176 mL, 2.01 mmol) in CH2Cl2 (15 mL) at ꢁ60 ꢀC. After
5 min, a solution of 3 (0.640 g, 1.83 mmol) in CH2Cl2
(2 mL) was added. After 15 min, triethylamine (1.27 mL,
9.15 mmol) was added and the reaction mixture was allowed
to warm to rt. After 1 h, water (20 mL) was added, the or-
ganics were separated, and the aqueous layer was extracted
with CH2Cl2 (3ꢂ20 mL). The combined organics were
washed with brine (3ꢂ50 mL), 1% HCl (3ꢂ50 mL), water
(50 mL), and 5% NaHCO3 (3ꢂ50 mL). The organics were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. This gave 0.626 g of 1-benzyl 4-tert-butyl 2-
formylpiperazine-1,4-dicarboxylate as a thick oil, which
was w90% pure and used without further purification.
Rf¼0.10 in 30% EtOAc/hexane; 1H NMR (400 MHz,
CDCl3) d 9.57 (br d, J¼7.6 Hz, 1H), 7.40–7.24 (m, 5H),
5.14 (br d, J¼17 Hz, 2H), 4.75–4.50 (br, 2H), 4.08–3.80
(br, 2H), 3.22–3.05 (br m, 2H), 2.94–2.78 (br, 1H), 1.42 (s,
9H). n-Butyl lithium (2.5 M solution in hexane, 0.80 mL,
2.0 mmol) was added to a suspension of methyltriphenyl-
phosphonium bromide (0.832 g, 2.33 mmol) in THF
(15 mL) at ꢁ78 ꢀC. After 10 min, the reaction mixture was
allowed to warm to rt. After 1 h, the reaction mixture was
cooled to ꢁ78 ꢀC and a solution of 1-benzyl 4-tert-butyl
2-formylpiperazine-1,4-dicarboxylate (0.626 g, 1.80 mmol)
in THF (5 mL) was added dropwise. After 1 h, the reaction
mixture was allowed to warm to rt and quenched with
NH4Cl (saturated, aqueous solution). The reaction mixture
was diluted with water (50 mL) and extracted with EtOAc
(3ꢂ50 mL). The combined organics were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography (0–20% EtOAc in
hexane gradient) gave 0.471 g (74%, 2 steps) of the title
compound as a thick oil. Analytical data for 25: Rf ¼0.48
in 30% EtOAc/hexane; 1H NMR (400 MHz, CDCl3)
d 7.37–7.27 (m, 5H), 5.74 (ddd, J¼4.8, 10.8, and 17.2 Hz,
1H), 5.26–5.10 (m, 4H), 4.77–4.66 (br, 1H), 4.40–3.82 (br
m, 3H), 3.16–2.74 (br m, 3H), 1.43 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 155.5, 154.7, 136.5, 134.4, 128.6,
128.2, 128.0, 117.6, 80.5, 67.7, 53.4, 46.9–45.0 (br), 44.3–
42.2 (br), 39.8, 28.7. LC–MS: tR¼10.3 min, [M+H]+¼
369.1. Anal. Calcd for C19H26N2O4: C, 65.86; H, 7.56; N,
8.09. Found: C, 65.47; H, 7.49; N, 8.04.
4.3.12. 1-Phenyltetrahydro-1H-oxazolo[3,4-a]pyrazin-
3(5H)-one (24). HCl (4.0 M solution in 1,4-dioxane,
2 mL, 8 mmol) was added to a solution of 23 (0.035 g,
0.11 mmol) in EtOH (1 mL). After 1 h, the reaction mixture
was concentrated under reduced pressure, dissolved in
EtOAc (20 mL), and washed with 1 N NaOH (2ꢂ10 mL)
and brine (10 mL). The EtOAc layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
This gave 21.3 mg (89%) of the title compound as a 2:1 ratio
of diastereomers. Analytical data for 24: 1H NMR
(400 MHz, CDCl3) d 7.42–7.24 (m, 5H), 5.63 (d,
J¼8.8 Hz, 0.3H), 5.00 (d, J¼7.2 Hz, 0.7H), 4.04 (ddd,
J¼4.0, 8.6, and 11.8 Hz, 0.3H), 3.86–3.76 (m, 1H), 3.59
(ddd, J¼4.0, 7.0, and 10.6 Hz, 0.7H), 3.24 (dd, J¼4.0 and
11.4 Hz, 0.7H), 3.13 (ddd, J¼3.8, 12.4, and 13.4 Hz,
0.3H), 3.04–2.96 (m, 1.4H), 2.92 (dd, J¼4.0 and 12.4 Hz,
0.3H), 2.76–2.66 (m, 1.4H), 2.64–2.54 (m, 1.3H), 2.42
(dd, J¼3.6 and 12.0 Hz, 0.3H), 2.09 (t, J¼11.6 Hz, 0.3H);
13C NMR (100 MHz, CDCl3) d 156.8, 156.3, 137.7, 134.3,
129.0, 128.9, 128.7, 128.1, 125.6, 125.5, 79.6 (br), 76.8
(br), 61.3, 57.5, 50.1, 47.0, 44.8, 44.6, 42.2, 42.1. LC–MS:
tR¼3.17 min, [M+H]+¼339.6 and tR¼3.45 min, [M+H]+¼
219.1. Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N,
12.84. Found: C, 66.13; H, 6.76; N, 12.82.
4.3.13. 1-Benzyl 4-tert-butyl 2-(hydroxymethyl)piper-
azine-1,4-dicarboxylate (3). Sodium hydroxide (1 N aque-
ous solution, 8.6 mL, 8.6 mmol) was added to a solution of
5a (1.05 g, 4.32 mmol) in EtOH (10 mL), and the reaction
mixture was heated to 70 ꢀC for 1 h. Upon cooling to rt,
EtOH was removed under reduced pressure. The aqueous
solution was diluted with THF (10 mL) and benzyl chloro-
formate (0.640 mL, 4.32 mmol) was added. After 2 h, the
reaction mixture was diluted with water (25 mL) and ex-
tracted with EtOAc (3ꢂ25 mL). The combined extracts
were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The material was purified by column chro-
matography (20–40% EtOAc in hexane gradient) to give
1.32 g (87%) of the title compound as a thick, colorless
oil. Analytical data for 3:26 Rf¼0.32 in 50% EtOAc/hexanes;
1H NMR (400 MHz, CDCl3) d 7.38–7.28 (m, 5H), 5.13
(ABq, JAB¼12.4 Hz, 2H), 4.34–3.80 (br m, 4H), 3.74–3.48
(br, 2H), 3.18–2.80 (br m, 3H), 1.45 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 155.8 (br), 136.4, 128.6, 128.2, 128.0,
80.8, 67.8, 60.8–58.2 (br), 52.9, 44.5 (br), 42.9 (br), 39.9,
28.6. LC–MS: tR¼8.63 min; [M+Na]+¼373.1.
4.3.15. 1-Benzyl 4-tert-butyl 2-(4-methoxyphenethyl)-
piperazine-1,4-dicarboxylate (26). 9-Borabicyclo[3.3.1]-
nonane (0.5 M solution in THF, 2.4 mL, 1.2 mmol) was
added to 25 (102 mg, 0.294 mmol). After 2 h, 4-iodoanisole
(103 mg, 0.441 mmol) and [1,10-bis(diphenylphosphino)-
ferrocene] dichloropalladium(II) complex with dichloro-
methane (1:1) (12 mg, 0.015 mmol) were added. Sodium
hydroxide (1 N aqueous solution, 0.74 mL, 0.74 mmol)
was added dropwise, and the reaction mixture was heated
to reflux overnight. Upon cooling to rt, the reaction mixture
was diluted with water (20 mL) and extracted with EtOAc
(3ꢂ20 mL). The combined organics were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography (0–20% EtOAc in
hexane gradient) gave 90.6 mg (68%) of the desired product
as a thick oil. Analytical data for 26: Rf ¼0.13 in 20%
1
EtOAc/hexane; H NMR (400 MHz, CDCl3) d 7.38–7.26

R. B. Clark, D. Elbaum / Tetrahedron 63 (2007) 3057–3065
3065
12. (a) Brieden, W.; Roduit, J.-P. U.S. Patent 5,856,485, 1999; (b)
Watkins, W. J.; Landaverry, Y.; Leger, R.; Litman, R.; Renau,
T. E.; Williams, N.; Yen, R.; Zhang, J. Z.; Chamberland, S.;
Madsen, D.; Griffith, D.; Tembe, V.; Huie, K.; Dudley, M. N.
Bioorg. Med. Chem. Lett. 2003, 13, 4241.
13. (a) Orme, M. W.; Sawyer, J. S. U.S. Patent 6,825,197, 2004;
(b) Balan, C.; Bo, Y.; Dominguez, C.; Fotsch, C. H.; Gore, V.
K.; Ma, V. V.; Norman, M. H.; Ognyanov, V. I.; Qian, Y.-X.;
Wang, X.; Xi, N.; Xu, S. PCT Int. Appl. WO 04035549,
2004.
(m, 10H), 7.12–6.96 (br, 2H), 6.82–6.72 (br, 2H), 5.12 (ABq,
JAB¼12.4 Hz, 2H), 4.30–3.82 (br m, 4H), 3.75 (s, 3H), 3.10–
2.40 (br m, 5H), 1.87–1.76 (m, 2H), 1.44 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 157.9, 155.3, 154.9, 136.6, 133.4,
129.2, 128.6, 128.2, 128.0, 113.9, 80.3, 67.5, 55.5, 51.4,
47.0–45.0 (br), 45.0–42.8 (br), 39.2, 31.6, 31.0, 28.7. LC–
MS: tR¼11.0 min, [M+Na]+¼477.2. Anal. Calcd for
C25H32N2O4: C, 68.70; H, 7.54; N, 6.16. Found: C, 69.00;
H, 7.62; N, 6.13.
14. The methyl ester of compound 7 will cyclize spontaneously at
rt upon reduction with lithium borohydride. See: Ref. 16b.
15. For selected examples, see: (a) Hirai, Y.; Chintani, M.;
Yamazaki, T.; Momose, T. Chem. Lett. 1989, 1449; (b)
Haddad, M.; Imogai, H.; Larcheveque, M. J. Org. Chem.
1998, 63, 5680; (c) Chevliakov, M. V.; Montgomery, J.
J. Am. Chem. Soc. 1999, 121, 11139.
16. For closely related examples, see: (a) Kano, S.; Yokomatsu, T.;
Yuasa, Y.; Shibuya, S. Heterocycles 1986, 24, 621; (b) Thomas,
R. C.; Cleek, G. J.; Hutchinson, D. K.; Yamada, H. U.S. Patent
5,922,707, 1999.
17. For N-alkyloxazolidinones, see: (a) Tamura, Y.; Kato, T.
Japanese Patent 030049, 2002; For N-phenyloxazolidinones,
see: (b) Fancher, L. W.; Gless, R. D., Jr.; Wong, R. Y.
Tetrahedron Lett. 1988, 29, 5095.
18. For reactions with thiols, see: (a) Kunde, K.; Herd, K.-J. U.S.
Patent 5,410,081, 1995; (b) Ishibashi, H.; Uegaki, M.; Sakai,
M. Synlett 1997, 915; (c) Ishibashi, H.; Uegaki, M.; Sakai,
M.; Takeda, Y. Tetrahedron 2001, 57, 2115.
19. For amines, see: (a) Rooney, P. C.; Nutt, M. O. U.S. Patent
5,491,263, 1996; For an intramolecular example with anilines,
see: (b) Poindexter, G. S.; Bruce, M. A.; LeBoulluec, K. L.;
Monkovic, I. Tetrahedron Lett. 1994, 35, 7331.
20. Aicher, T. D. l; Chen, Z.; Chen, Y.; Faul, M. M.; Krushinski, J.
H., Jr.; Le H. Y.; Pineiro-Nunez, M. M.; Rocco, V. P.; Ruley, K.
M.; Schaus, J. M.; Thompson, D. C.; Tupper, D. E. PCT Int.
Appl. WO 03082877, 2003.
21. For synthesis of orthogonally protected 2-styrylpiperazines
using Witting reactions with benzyltriphenylphosphonium
halides, see: Hauske, J. R.; Aquila, B. M. PCT Int. Appl. WO
03016274, 2003.
22. For comparison to published data, see: Yoshikawa, S.; Emori,
E.; Matsuura, F.; Clark, R.; Ikuta, H.; Yasuda, N.; Nagakura,
T.; Yamazaki, K.; Aoki, M. European Patent Application
1338595, 2003.
References and notes
1. For several examples, see: (a) For Ciprofloxacin, see: Grohe,
K.; Heitzer, H. Liebigs Ann. Chem. 1987, 29; (b) For
Indinavir, see: Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.;
Vacca, J. P.; Guare, J. P.; Darke, P. L.; Zugay, J. A.; Emini,
E. A.; Schleif, W. A.; Quintero, J. C.; Lin, J. H.; Chen, I.-W.;
Holloway, M. K.; Fitzgerald, P. M. D.; Axel, M. G.; Ostovic,
D.; Anderson, P. S.; Huff, J. R. J. Med. Chem. 1994, 37,
3443; (c) For Glivec, see: Capdeville, R.; Buchdunger, E.;
Zimmermann, J.; Matter, A. Nat. Rev. 2002, 1, 493.
2. For a recent review, see: Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. Rev. 2003, 103, 893.
3. For a review, see: (a) Dinsmore, C. J.; Beshore, D. C.
Tetrahedron 2002, 58, 3297; For leading references, see: (b)
Kopple, K.; Ghazarian, H. J. J. Org. Chem. 1968, 33, 862; (c)
Nitecki, D. E.; Halpern, B.; Westley, J. W. J. Org. Chem.
1968, 33, 864; (d) Grahl-Nielsen, O. Tetrahedron Lett. 1969,
2827; (e) Suzuki, K.; Sasaki, Y.; Endo, N.; Mihara, Y. Chem.
Pharm. Bull. 1981, 29, 233; (f) Ueda, T.; Saito, M.; Kato, T.;
Izumiya, N. Bull. Chem. Soc. Jpn. 1983, 56, 568.
4. Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids;
Wiley: New York, NY, 1961; Vol. 2, p 793.
5. For a review, see: Dinsmore, C. J.; Beshore, D. C. Org. Prep.
Proced. Int. 2002, 34, 367.
6. For recent examples, see: (a) Binisti, C.; Assogba, L.; Touboul,
E.; Mounier, C.; Huet, J.; Ombetta, J.-E.; Dong, C. Z.;
Redeuilh, C.; Heymans, F.; Godfroid, J.-J. Eur. J. Med.
Chem. 2001, 36, 809; (b) Scapecchi, S.; Martini, E.; Manetti,
D.; Ghelardini, C.; Martelli, C.; Dei, S.; Galeotti, N.;
Guandalini, L.; Novella, R. M.; Teodori, E. Bioorg. Med.
Chem. 2004, 12, 71.
7. Berkheij, M.; van der Sluis, L.; Sewing, C.; den Boer, D. J.;
Terpstra, J. W.; Hiemstra, H.; Iwema Bakker, W. I.; van den
Hoogenband, A.; van Maarseveen, J. H. Tetrahedron Lett.
2005, 46, 2369.
8. For several examples, see: (a) Mueller, W.; Stauss, U. Helv.
Chim. Acta 1982, 65, 2118; (b) Phillips, G. B.; Morgan,
T. K., Jr.; Lumma, W. C., Jr.; Gomez, R. P.; Lind, J. M.; Lis,
R.; Argentieri, T.; Sullivan, M. E. J. Med. Chem. 1992, 35, 743.
9. Bigge, C. F.; Hays, S. J.; Novak, P. M.; Drummond, J. T.;
Johnson, G.; Bobovski, T. P. Tetrahedron Lett. 1989, 30, 5193.
10. Kempf, D. J.; Norbeck, D. W.; Sham, H. L. U.S. Patent
5,455,351, 1995.
23. For comparison to published data, see: Kobayashi, S.;
Komoriya, S.; Haginoya, N.; Suzuki, M.; Yoshino, T.;
Nagahara, T.; Nagata, T.; Horino, H.; Ito, M.; Mochizuki, A.
U.S. Patent 6,747,023, 2004.
24. For comparison to published data, see: Fukatsu, K.; Nakayama,
Y.; Tarui, N.; Mori, M.; Matsumoto, H.; Kurasawa, O.; Banno,
H. European Patent 1661898, 2006.
25. For comparison to published data, see: Hamilton, A. D.; Ernst,
J.; Orner, B. U.S. Patent 6,858,600, 2005.
26. For comparison to published data, see: Arkin, M. R.;
McDowell, R. S.; Oslob, J. D.; Raimundo, B. C.; Waal, N.
D.; Yu, C. H. U.S. Patent 6,806,279, 2004.
11. For an asymmetric synthesis, see: Warshawsky, A. M.; Patel,
M. V.; Chen, T.-M. J. Org. Chem. 1997, 62, 6439.