Simplification of the Mitsunobu reaction. Di-p-chlorobenzyl azodicarboxylate: A new azodicarboxylate

Article abstract of DOI:10.1021/ol0618757

(Chemical Equation Presented) Di-p-chlorobenzyl azodicarboxylate (DCAD) is introduced as a novel, stable, solid alternative to DEAD and DIAD for a variety of Mitsunobu couplings. DCAD/Ph₃P-mediated reactions in CH ₂Cl₂ gen

Full text of DOI:10.1021/ol0618757

ORGANIC
LETTERS
2
006
Vol. 8, No. 22
069-5072
Simplification of the Mitsunobu
Reaction. Di-p-chlorobenzyl
Azodicarboxylate: A New
Azodicarboxylate
5
Bruce H. Lipshutz,* David W. Chung, Brian Rich, and Ricardo Corral
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received July 28, 2006
ABSTRACT
Di-p-chlorobenzyl azodicarboxylate (DCAD) is introduced as a novel, stable, solid alternative to DEAD and DIAD for a variety of Mitsunobu
couplings. DCAD/Ph P-mediated reactions in CH Cl generate a readily separable hydrazine byproduct.
3
2
2
The Mitsunobu coupling is among an elite group within a
1
vast array of name reactions. It is used so frequently that
2
3
oftentimes literature reviews, as well as its origins, are
excluded from among the citations. These reactions rely on
3
an initial adduct 1 formed between Ph P and an azodicar-
boxylate, with the diethyl derivative (i.e., DEAD; Figure 1)
2
credited with the majority of reported examples. The
2
diisopropyl ester (DIAD) is also very commonly utilized.
Notwithstanding its popularity, research continues to address
various aspects of Mitsunobu chemistry as usage evolves
with time. Perhaps chief among these lies the issue of product
3
separation from triphenylphosphine oxide (Ph PdO) and the
attendant hydrazines 2, with new technologies having been
4,5
recently reviewed. Additional alternatives, such as Charette’s
(1) (a) Name Reactions, 2nd ed.; Li, J., Ed.; Springer-Verlag: Berlin,
Germany, 2003; p 265. (b) Strategic Applications of Named Reactions in
Organic Synthesis; Kurti, L., Czako, B., Eds.; Elsevier: Burlington, MA,
2
005; pp 294-295.
2) (a) Mitsunobu, O. Synthesis 1981, 1, 1-28. (b) Hughes, D. L. Organic
Reactions; Wiley: New York, 1992; Vol. 42, pp 335-656.
3) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
(
Figure 1. Reaction intermediates and azodicarboxylate reagents
used in Mitsunobu couplings.
(
2
4
1
380-2382. (b) Mitsunobu, O.; Eguchi, M. Bull. Chem. Soc. Jpn. 1971,
4, 3427-3430. (c) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc.
972, 94, 679-680.
recent report on a phosphonium salt analogue of DEAD,
continue to appear. Our goal was to develop a new solution-
based reagent that offers the important feature of straight-
6
(
4) (a) Dembinski, R. Eur. J. Org. Chem. 2004, 13, 2763-2772. (b)
Dandapani, S.; Curran, D. P. Chem.-Eur. J. 2004, 10, 3130-3138.
1
0.1021/ol0618757 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/29/2006

forward separation and recovery of the hydrazine byproduct.
Such a reagent not only would facilitate purification of the
desired product but also might encourage recycling of what
would otherwise be regarded as chemical waste. In this Letter
we describe, along with full experimental details, the
preparation of di-p-chlorobenzyl azodicarboxylate (DCAD)
by DCAD/Ph
results for the analogous reactions using DEAD/Ph
3
P are highlighted in Table 1, together with
P. Two
3
related cases of ester formations include coupling of p-
nitrobenzoic acid with (S)-(+)-methyl lactate to afford the
(R)-diester product of inversion 6 (entry 1) and with glycidol
to give epoxide 7 (entry 2). Etherifications, of both an
intermolecular (entry 3) and intramolecular (entry 4) nature
were carried out. The former involved nonracemic 2-octanol
and led to product 8, indicative of the expected inversion.
Nucleophilic components based on nitrogen, also well-known
3, a typical procedure for its selected use in Mitsunobu
reactions, direct comparison data for reactions also run with
DEAD, and the successful reisolation of the byproduct
hydrazine dicarboxylate.
DCAD is readily prepared in two steps by the initial
treatment of p-chlorobenzyl alcohol with an equivalent of
2
partners in Mitsunobu reactions, showed similar behavior
in the presence of either DCAD or DEAD. Phthalimide could
be smoothly converted to the optically active protected amine
derivative 9 (entry 5), and very sensitive retinol led to low
yields of isolated polyene 10 as a mixture of two regioiso-
1,1′-carbonyldiimidazole (CDI) in THF (Scheme 1). The in
N N
mers (entry 6; S 2 and presumably the product of S 2′
displacement). Much better results were forthcoming using
succinimide together with geraniol (entry 7). Intramolecular
Scheme 1. Synthesis of DCAD, 3
(5) (a) DBAD: Kiankarimi, M.; Lowe, R.; McCarthy, J. R.; Whitten, J.
P. Tetrahedron Lett. 1999, 40, 4497-4500. (b) PS-DEAD: Arnold, L. D.;
Assil, H. I.; Vederas, J. C. J. Am. Chem. Soc. 1989, 111, 3973-3976. (c)
Chromatography-free Mitsunobu: Proctor, A. J.; Beautement, K.; Clough,
J. M.; Knight, D. W.; Li, Y. Tetrahedron Lett. 2006, 47, 5151-5154. (d)
Phosphine oxide complex: Anderson, N. G.; Lust, D. A.; Colapret, K. A.;
Simpson, J. H.; Malley, M. F.; Gougoutas, J. Z. J. Org. Chem. 1996, 61,
7
955-7958.
6) Poupon, J.-C.; Boezio, A. A.; Charette, A. B. Angew. Chem., Int.
Ed. 2006, 45, 1415-1420.
7) The unsubstituted dibenzyl azodicarboxylate is also commercially
(
(
available and gave a roughly comparable yield in this reaction. However,
the hydrazine byproduct does not show the same solubility profile in CH2-
Cl2 as DCAD and, therefore, was not pursued further.
situ-derived carbamate is subsequently exposed to hydrazine,
(8) (a) Di-(p-chlorobenzyl) azodicarboxylate (DCAD) [3]. Pyridine
leading to the corresponding dicarboxylate derivative 4
(0.610 mL, 7.54 mmol) and NBS (1.34 g, 7.54 mmol) were sequentially
added to a suspension of 4 (2.73 g, 7.39 mmol) in toluene (28.0 mL). After
stirring the resulting orange cloudy mixture at rt for 17 min, the mixture
was diluted with 25-30 mL of toluene and washed with water (15 mL),
saturated aqueous Na2S2O3 (15 mL), 1 wt % aqueous HCl (15 mL), saturated
aqueous NaHCO3 (15 mL), water (3 × 15 mL), and brine (15 mL). The
organics were then dried over anhydrous Na2SO4 and concentrated in vacuo
to afford the title compound as orange crystalline flakes (2.66 g, 98%):
(84%). Oxidation with NBS affords the solid reagent 3
(98%), which, unlike liquids DEAD or DIAD, can be stored
at room temperature.
To evaluate DCAD, initially, esterification of 2,6-
dimethoxybenzoic acid with benzyl alcohol was selected for
comparison with both DEAD and DIAD (Scheme 2). Under
-1 1
mp 108-110 °C; IR (NaCl, neat) 2360, 2342, 1764 cm ; H NMR (CDC13)
13
δ 7.38 (s, 8H), 5.40 (s, 4H); C NMR (CDCl3) δ 160.10, 135.54, 132.10,
1
3
30.46, 129.28, 70.14; HRMS(ESI+) m/z calcd for C16H12N2O4Cl2Na
+
89.0066 (M + Na) , found 389.0083. (b) Di-(p-chlorobenzyl) hydra-
zodicarboxylate [4]. A solution of 4-chlorobenzyl alcohol (2.75 g, 19.30
mmol) in THF (11.0 mL) was slowly added at 0 °C to a solution of 1,1′-
carbonyldiimidazole (3.13 g, 19.30 mmol) in THF (9.0 mL), and the
resulting solution was stirred at 0 °C to rt for 1 h. Hydrazine (0.300 mL,
Scheme 2. Comparison of Azodicarboxylate Reagents in a
Mitsunobu Couplinga
9
.56 mmol) and triethylamine (2.70 mL, 19.37 mmol) were sequentially
added, and the solution was refluxed for 7.5 h after taking 30 min to achieve
reflux temperature. The solution was concentrated in vacuo to a peach-
colored slurry that was transferred into a fritted buchner funnel and washed
with water (5×) and 1:1 Et2O/hexanes (3×) to afford the title compound
as a light-pink powder (2.96 g, 84%): Rf ) 0.05 major rotamer, 0.43 minor
rotamer (KMnO4 stain), 1:1 EtOAc/hexanes; mp 171-173 °C; IR (NaCl,
-
1 1
neat) 3239, 2360, 1750, 1695 cm
; H NMR (DMSO-d6) δ 9.34, 8.97
(
mix of rotamers, 2H total), 8.94 (d, 1H), 7.46-7.30 (m, 8H), 5.08 (s, 4H);
1
3
C NMR (DMSO-d6) δ 156.38, 135.64, 132.65, 129.77, 128.46, 65.16;
+
HRMS(ESI+) m/z calcd for C16H14N2O4Cl2 391.0222 (M + Na) , found
3
91.0227.
(
9) General procedure for Mitsunobu couplings. Benzyl 2,6-dimethox-
a
Reactions were carried out with 1.0 equiv of benzyl alcohol
ybenzoate [5]. A solution of 3 (820 mg, 2.23 mmol) in CH2Cl2 (6.0 mL)
was slowly added at rt via cannula to a solution of triphenylphosphine (586
mg, 2.23 mmol), 2,6-dimethoxybenzoic acid (409 mg, 2.24 mmol), and
benzyl alcohol (210 µL, 2.03 mmol) in CH2Cl2 (2.0 mL), and the resulting
cloudy mixture was stirred at rt for 33 min. Filtration of the mixture afforded
the reduced azodicarboxylate 4 as a white powder (675 mg, 82 mol %
recovery). The filtrate was concentrated in vacuo. Flash chromatography
of the crude product (hexanes to 1:9 EtOAc/hexanes) afforded the title
compound as a colorless oil that gradually crystallized upon standing at rt
and 1.1 equiv of all other reagents.
identical conditions, benzyl ester 5 was formed in each case
in essentially the same isolated yields, suggesting that the
rates and efficiency of DCAD are comparable to the industry
standards.7
10
(
508 mg, 92%). The spectral data matched those provided in the literature.
10) Kodpinid, M.; Sadavongvivad, C.; Thebtaranonth, C.; Thebtaranonth,
Y. Phytochemistry 1984, 23, 199-200.
(
Several types of additional Mitsunobu couplings mediated
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Org. Lett., Vol. 8, No. 22, 2006

3 3
Table 1. Comparison of Mitsunobu Couplings Mediated by DEAD/Ph P and DCAD/Ph
Pa
a
All reactions were conducted with 0.3 M alcohol (1.0 equiv), 1.1 equiv of acid, 1.1 equiv of Ph3P, and 1.1-1.2 equiv of azodicarboxylate reagent,
b
except for entry 4, which was run at 0 °C, and entry 6, which was run with 1.05 equiv of phthalimide and 1.05 equiv of Ph3P at -78 °C. Isolated,
c
20
20
chromatographically pure material. Optical rotations measured in CHCl3 for reaction with DEAD: [R]D ) -19.4° (c ) 10.7 mg/mL). DCAD: [R]D
)
d
20
20
-
(
19.4° (c ) 10.0 mg/mL). Optical rotations measured in CHCl3 for reaction with DEAD: [R]D ) -8.4° (c ) 10.1 mg/mL). DCAD: [R]D ) -8.2°
e 20
c ) 10.7 mg/mL). Optical rotations measured in CHCl3 for reaction with DEAD: [R]D20 ) -15.9° (c ) 9.0 mg/mL). DCAD: [R]D ) -15.9° (c ) 16.2
f
mg/mL). Mixture of two regioisomers.
attack by nitrogen in Boc-protected benzyl serine cleanly
led to aziridination (entry 8). Last, thiol 11 was quantitatively
converted to the corresponding propargylic derivative 12 by
both azodicarboxylates. All reactions studied with DCAD
has very different polarities by TLC (e.g., R
hexanes ) 0.05, major rotamer) relative to reduced DEAD
(R ) 0.37) and DIAD (R ) 0.39) and has some (albeit far
f
in 1:1 EtOAc/
f
f
less than expected) UV activity on silica gel plates.
2 2
were performed in CH Cl , which was chosen to reflect the
very limited solubility of hydrazine byproduct 4 in this
solvent.
In summary, an alternative reagent to DEAD and DIAD,
8
the p-Cl-benzylic analogue (DCAD, 3), useful in Mitsunobu
9
reactions, has been developed. It is easily prepared in only
To quantify the level at which 4 could be recovered,
Mitsunobu reactions for all but product 10 were carefully
processed upon completion. Dilution of each reaction mixture
with additional CH Cl followed by filtration led to isolated
2 2
hydrazine in 66-82% yield. Moreover, the residual material
two pots and leads to yields of desired coupling products
and reaction rates that are comparable to those of the
commonly used reagents. By contrast, DCAD offers the
following advantages: (1) it is a stable solid at ambient
temperatures; (2) the polarity of its reduced byproduct on
Org. Lett., Vol. 8, No. 22, 2006
5071

silica gel is distinctly different from those of DEAD/DIAD;
and (3) in particular, its hydrazine byproduct is removed, in
large measure, by precipitation with CH Cl directly from
2 2
the reaction mixture, simplifying and potentially expanding
the use of the Mitsunobu reaction.
Creative Studies at UCSB). Technical assistance by Mr.
Shawn Jia (UCSB) is greatly appreciated. Vitamin A (acetate)
was generously supplied by Dr. Keith Drouet (Cambridge
Major Labs).
Supporting Information Available: Procedures and
spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are pleased to warmly acknowl-
edge financial support of this work by the NSF (CHE 05-
50232) and fellowships to R.C. (NIH) and B.R. (College of
OL0618757
5072
Org. Lett., Vol. 8, No. 22, 2006