A convenient preparation of di-p-chlorobenzyl azodicarboxylate (DCAD) for mitsunobu couplings

Article abstract of DOI:10.1055/s-0028-1083274

Gram-scale synthesis of pure, bench-stable solid di-p-chlorobenzyl azodicarboxylate (DCAD) is performed in two steps without resorting to chromatography. This novel reagent effects Mitsunobu couplings with yields comparable to DEAD or DIAD, while addressi

Full text of DOI:10.1055/s-0028-1083274

3
32
PRACTICAL SYNTHETIC PROCEDURES
A Convenient Preparation of Di-p-chlorobenzyl Azodicarboxylate (DCAD) for
Mitsunobu Couplings
A
B
C
onvenient
P
re
e
paration of
n
D
i-
p
-chlor
o
j
benzyl
a
A
zodicarb
m
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
Santa Barbara, CA 93106, USA
Fax +1(805)8938265; E-mail: Lipshutz@chem.ucsb.edu
PSP
Received 27 August 2008
No143
Abstract: Gram-scale synthesis of pure, bench-stable solid di-p-chlorobenzyl azodicarboxylate (DCAD) is performed in two steps without
resorting to chromatography. This novel reagent effects Mitsunobu couplings with yields comparable to DEAD or DIAD, while addressing
several of the drawbacks frequently associated with these common reagents.
Keywords: Mitsunobu reaction, azo compounds, alcohols, esters, DCAD
O
O
OH
THF
H2N
NH2
+
O
N
N
N
0 °C to r.t.
N
Et3N, heat
overnight
N
N
Cl
1–2 h
Cl
8
5–92% (~16 g)
2
CDI
3
O
O
O
O
NBS, pyridine
toluene, 1–2 h
N
N
O
N
N
O
O
O
H
H
9
8% (~23 g)
Cl
Cl
Cl
Cl
4
1 (DCAD)
Scheme 1 Two-pot procedure for the synthesis of DCAD (1)
Introduction
Scope and Limitations
Since its discovery in 1967, the Mitsunobu reaction has DCAD (1) is readily prepared by initial treatment of a
found many synthetic applications due to its versatility slurry of 1,1¢-carbonyldiimidazole (CDI) in anhydrous
1
and effectiveness. Despite widespread use, traditional THF with one equivalent of p-chlorobenzyl alcohol
azo-reagents can be problematic: they (a) are unstable in (CBA, 2) at 0 °C followed by 1–2 hours of mixing
the absence of solvent, (b) oftentimes lead to difficult-to- (Scheme 1). The CDI slurry should be off-white in color;
separate hydrazine by-products, and (c) are not usually when in solution it becomes transparent and slightly yel-
4
amenable to recycle. Research aimed at solving some of low following the addition of CBA. The resulting in situ-
2
these drawbacks continues. Diethyl azodicarboxylate derived carbamate 3 is then exposed to hydrazine and
(
DEAD) or diisopropyl azodicarboxylate (DIAD) are typ- heated to reflux for several hours to afford the correspond-
ically the reagents of choice, although others have also ing dicarboxylate derivative 4. Purification is achieved
2
been developed. One alternative recently introduced simply by removing the solvent (in vacuo) and washing
from our laboratory is di-p-chlorobenzyl azodicarboxy- the crude solid in a fritted funnel with cold water. The wa-
3
late (DCAD, 1), which has similar reactivity to DEAD ter washing step ensures removal of the imidazole by-
and DIAD in numerous Mitsunobu reactions. Reagent 1 product, along with any remaining CDI. Following a
has several advantages, including easy handling as a pure, rapid wash with 4:1 hexanes–Et O to remove final traces
2
bench-stable solid, facile separation of its reduced form of CBA, the hydrazine dicarboxylate 4 is isolated as a
generated from use, and recycling capability. Herein we pure, white, amorphous powder in high yield (91–92%),
5
present a detailed report on the synthesis of DCAD (1) in- mp 178–179 °C. Purified product 4 shows a single spot
3
volving a two-step process that has been scaled to >15 by TLC, R = 0.45, (1:1 EtOAc–hexanes). With proper
f
gram batches.
washings (500–750 mL of cold H O per 50 mmol prod-
2
uct), the imidazole impurity can be thoroughly removed.
Oxidation is performed by addition of NBS and pyridine
to a toluene slurry of hydrazine dicarboxylate 4 at room
temperature, which transforms the white mixture to or-
ange in color (Scheme 1). This event is nearly quantita-
SYNTHESIS 2009, No. 2, pp 0332–0334
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083274; Art ID: Z19908SS
x
x
.
x
x
.2
0
0
8
©
Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Convenient Preparation of Di-p-chlorobenzyl Azodicarboxylate
333
a
Table 1 Mitsunobu Couplings Mediated by DEAD/Ph P and DCAD/Ph P
3
3
Entry
1
Acid
Alcohol
Product
Time (h)
18
DEAD
Yield (%)
DCAD
Yield (%)
b
b
O
O
OH
O
OMe
98c
97
88c
OMe
p-NO2C6H4CO2H
O
O
O
O2N
O2N
2
3
HO
O
0.75
98
p-NO2C6H4CO2H
O
O
O
OH
1
76d
80d
NH
N
n-Hex
n-Hex
O
O
Ph
Ph
4
N
N
HO
N
N
1.5
quant
quant
SH
S
N
N
N
N
a
All reactions were conducted with 0.3 M alcohol (1.0 equiv), 1.1 equiv of acid, 1.1 equiv of Ph P, and 1.1–1.2 equiv of azodicarboxylate.
3
b
c
d
Isolated, chromatographically pure material.
20
20
Optical rotations measured in CHCl for reaction with DEAD: [a] –19.4 (c = 10.7 mg/mL) and DCAD: [a]D –19.4 (c = 10.0 mg/mL).
3
D
20
20
Optical rotations measured in CHCl for reaction with DEAD: [a] –15.9 (c = 9.0 mg/mL) and DCAD: [a]D –15.9 (c = 16.2 mg/mL).
3
D
tive, reaching completion within 1–2 hours. Impurities are occurs as expected. Phthalimide can be used to arrive at an
removed via standard aqueous workup and careful extrac- optically active protected amine, and lastly, a thiol can be
tions with aqueous Na S O , HCl (1%), and aqueous converted to its propargylic derivative in quantitative
2
2
3
NaHCO . Of note is that Na SO cannot be substituted for yield (Table 1, entries 3, 4). Reactions performed in
3
2
3
Na S O during washing; that is, an aqueous solution of CH Cl precipitate the DCAD hydrazine precursor 4,
2
2
3
2
2
Na SO can reduce DCAD (1) back to its precursor hydra- which can be easily separated from the product and recov-
2
3
zine dicarboxylate 4. No chromatographic purification is ered via filtration. This material can then be recycled by
needed in either step of this procedure; the washings re- re-exposure to NBS.
ported herein are sufficient to yield clean material. The
slightly light sensitive title compound 1 is isolated as
bright-orange crystalline flakes that, unlike DEAD and
In conclusion, bench-stable reagent DCAD (1) can be
conveniently prepared on a multi-gram scale in purified
form without resorting to chromatography. This bright
DIAD, can be stored indefinitely at room temperature on
orange solid can be used for various Mitsunobu couplings
the shelf (Figure 1).
with a variety of reaction partners, with yields comparable
to those typically seen using DEAD or DIAD. Further-
more, the simplicity of handling this bench-stable solid,
along with the facile separation of spent material and the
capability of recycling, makes DCAD a very attractive al-
ternative to azo-reagents traditionally used in Mitsunobu
reactions.
Procedures
All reactions were conducted in oven-dried, argon purged glassware
using Teflon coated magnetic stir bars and rubber septum stoppers.
THF and pyridine were freshly distilled from Na/benzophenone
®
Figure 1 DCAD (1), an orange, bench-stable solid
ketyl and CaH , respectively, prior to use. CBA and CDI were pur-
2
DCAD (1) can be used in the same fashion as DEAD or
DIAD for all reactions screened to date. Ester formation is
chased from Alfa Aesar and used as received. Hydrazine (anhyd)
was purchased from Aldrich and used as received. NBS was pur-
chased from ACROS and used as received. TLC analyses were per-
smoothly effected in CH Cl at room temperature and
2
2
yields are comparable to those using DEAD (Table 1, en- formed on commercial Kieselgel 60 F254 silica gel plates. NMR
tries 1, 2). Inversion of absolute stereochemistry of the spectra were obtained on a Varian Inova system using DMSO-d
secondary alcohol in optically pure (S)-(+)-methyl lactate
or
6
CDCl as solvent, with proton and carbon resonances at 400 and 100
3
Synthesis 2009, No. 2, 332–334 © Thieme Stuttgart · New York

3
34
B. R. Taft et al.
PRACTICAL SYNTHETIC PROCEDURES
MHz, respectively. Mass spectral data were acquired on a VF
Autospec or an analytical VG-70-250-HF instrument.
(300 mL), 1% aq HCl (225 mL), sat. aq NaHCO (300 mL), H O
3
2
(3 × 225 mL), and brine (300 mL). The organics were then dried
over anhydrous Na SO and concentrated in vacuo to afford the title
2
4
Bis(4-chlorobenzyl) Hydrazine-1,2-dicarboxylate (4)
A clear solution of 4-chlorobenzyl alcohol (2; 14.258 g, 100.0
mmol) in anhyd THF (40 mL) was added dropwise via cannula at 0
compound as orange crystalline flakes; yield: 23.020 g (99%);
mp 107–108 °C.
1
H NMR (400 MHz, CDCl ): d = 7.38 (s, 8 H), 5.40 (s, 4 H).
3
°
1
C to an off-white slurry of 1,1¢-carbonyldiimidazole (16.215 g,
00.0 mmol) in anhyd THF (50 mL). The resulting clear, pale yel-
low solution was stirred and warmed to r.t. over 2 h. Hydrazine
1.55 mL, 49.5 mmol) and freshly distilled Et N (14.02 mL, 101.0
1
3
C NMR (100 MHz, CDCl ): d = 160.1, 135.4, 132.1, 130.4, 129.2,
3
7
0.1.
(
HRMS-ESI: m/z calcd for C H Cl N O + Na [M + Na]+:
3
16 12 2 2 4
mmol) were sequentially added and the solution was refluxed in an
0 °C oil bath for 12 h. After cooling, the solution was concentrated
in vacuo leading to an amorphous white solid that was transferred
3
89.0066, found: 389.0083.
8
to a fritted Büchner funnel and washed (vacuum filtration) with cold Acknowledgment
H O (5 × 150 mL) and 1:4 Et O–hexanes (2 × 100 mL). The color-
2
2
Financial support provided by the NSF is warmly acknowledged.
less solid was then collected and dried in vacuo to afford the title
compound; yield: 16.598 g (91%); R = 0.45 (1:1 EtOAc–hexanes,
f
KMnO stain); mp 177–179 °C.
4
References
1
H NMR (400 MHz, DMSO-d ): d = 9.35, 8.98 (NH rotamers, 2 H),
6
(
(
1) Toy, P. H.; But, T. Y. S. Chem. Asian J. 2007, 2, 1340.
2) Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
7
.45–7.28 (m, 8 H), 5.08 (s, 4 H).
1
3
C NMR (100 MHz, DMSO-d ): d = 156.5, 135.7, 132.8, 129.8,
6
(3) (a) Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org.
1
28.9, 65.3.
Lett. 2006, 8, 5069. (b) Our originally reported R for the
hydrazine dicarboxylate 4 is misleading, as the material was
impure due to the presence of residual imidazole.
f
HRMS-ESI: m/z calcd for C H Cl N O + Na [M + Na]+:
1
6
14
2
2
4
3
91.0222; found: 391.0227.
(4) Optimum results were achieved using CDI and CBA
Di-p-chlorobenzyl Azodicarboxylate (DCAD, 1)
obtained from Alfa Aesar.
Freshly distilled pyridine (5.21 mL, 64.67 mmol) and NBS (11.51
g, 64.67 mmol) were sequentially added to a slurry of 4 in toluene
(5) Imidazole is water soluble while 4 is not. Use of 1:1
hexanes–Et O leads to substantial loss of product 4.
2
(250 mL). After stirring the resulting orange cloudy mixture for 2 h,
Exposure time of the product to solvent can be minimized by
using vacuum filtration.
the mixture was diluted with toluene (375 mL, to completely dis-
solve all solids) and washed with H O (300 mL), sat. aq Na S O
2
2
2
3
Synthesis 2009, No. 2, 332–334 © Thieme Stuttgart · New York