Dandapani and Curran
TABLE 4. Pronucleophiles, Alcohols, Products, Product
Yields, and Purities of Mitsunobu Reactions Promoted
by Fluorous and Organic Reagents
Conclusions
We have demonstrated that the retention behavior of
fluorous hydrazides on fluorous silica gel can be altered
by varying the fluorine content as well as the organic
content. Likewise, the reactivity can be tuned by varying
the spacer. F-DEAD-1 with an ethylene spacer under-
performs in several classes of Mitsunobu reactions with
stiff resistance to promote alkylation of less acidic phe-
nols. Both F-DEAD-2 and F-DEAD-3 with propylene
spacers promote Mitsunobu reactions of not only phenols
but also acids and sulfonamides. Although the yields for
less acidic phenol coupling reactions with F-DEAD-2 and
F-DEAD-3 are about 15% lower than with TPP and
DIAD, pure products can be readily isolated by simple
fluorous procedures, whereas the standard reagents must
be separated by traditional silica chromatography. With
acids and sulfonamides, pure products can be easily
isolated in yields comparable to those of the organic
reagents TPP and DIAD.
On the basis of these results, we recommend that the
use of F-DEAD-1 for Mitsunobu reactions be discontin-
ued. We recommend the light fluorous reagent F-DEAD-2
for applications in parallel or sequential separations with
automated fluorous chromatography in a suitable medium-
pressure LC instrument. For rapid FSPE isolation of
products from all classes of Mitsunobu reactions, we
recommend the fluorous reagent F-DEAD-3 in conjunc-
tion with F-TPP. These separation-friendly fluorous
Mitsunobu reagents will widen the application of Mit-
sunobu reactions in medicinal chemistry since the major
deterrence for conducting parallel Mitsunobu reactions
is often the inefficient product isolation encountered with
traditional reagents.
GC
pronu-
yield purity
entry cleophile alcohol product
reagents
(%)
(%)
1
4a
4a
4a
4b
4b
4b
4a
4a
4a
4d
4d
4d
4d
4c
4e
4e
4b
4b
4f
5a
5a
5a
5b
5b
5b
5b
5c
5e
5a
5b
5c
5e
5b
5f
6aa
6aa
6aa
6bb
6bb
6bb
6ab
6ac
6ae
6da
6db
6dc
6de
6cb
6ef
F-TPP + 2
F-TPP + 3
99a
97
99
nd
98
97
nd
98
92
92
98
na
na
94
100
97
nd
99
95
95e
96e
nd
2
92b
3
TPP + DIAD 95c
4
F-TPP + 2
F-TPP + 3
61d
60b
5
6
TPP + DIAD 75c
7
F-TPP + 2
F-TPP + 2
F-TPP + 2
F-TPP + 2
F-TPP + 2
F-TPP + 2
F-TPP + 2
F-TPP + 2
F-TPP + 3
84a
88a
96a
95a
na
8
9
10
11
12
13
14
15
16
17
18
19
20
21
na
98a
98d
55b
5f
6ef
TPP + DIAD 74c
5d
5f
5d
5f
5f
6bd
6bf
6fd
6ff
F-TPP + 3
F-TPP + 3
F-TPP + 3
F-TPP + 3
54b
55b
100b
94b
4f
4f
6ff
TPP + DIAD 94c
a Purified by automated fluorous chromatography over 12+M
Biotage cartridge. b Purified by FSPE over 5 g FluoroFlash
cartridge. c Purified by flash column chromatography over normal
silica gel. d Purified by manual fluorous chromatography over 20
g FluoroFlash cartridge. e Determined by LC-MS over C18 column.
FSPE over a 5 g fluorous cartridge.15 This removed all
fluorous products derived from both the Mitsunobu
reagents and provided the crude target product 6. That
the retention of hydrazide 35 resulting from 2 was not
long enough for removal by FSPE when using 80% MeOH
was revealed by substantial (>5%) leaching during the
fluorophobic pass of a control FSPE experiment using
pure 35. However, the crude Mitsunobu reaction mix-
tures (approximately 600 mg or 1.2 g) resulting from 2
were purified by fluorous flash chromatography using
commercially available FluoroFlash cartridges (contain-
ing 20 g of fluorous silica gel) or using fluorous columns
(Biotage; 12+M size, containing approximately 12 g of
fluorous silica gel) for automated medium-pressure liquid
chromatography.
Mechanistic studies of the Mitsunobu reactions with
the different fluorous DEAD reagents 1-3 were not
undertaken. However, on the basis of the observations
reported in this paper, we hypothesize that the rate
of proton transfer from the pronucleophile to the be-
taine formed by the addition of phosphine to the azo-
dicarboxylate is an important factor determining the
extent of success of the Mitsunobu reactions.16 The
betaine formed from F-DEAD-1 is less basic because of
the ethylene spacer, and hence difficult Mitsunobu reac-
tions such as the ones involving less acidic phenols do
not succeed. However, F-DEAD-2 and F-DEAD-3 have
propylene spacers, and hence the betaines formed from
these reagents are sufficiently basic to allow ready
protonation by even less acidic pronucleophiles such as
phenols.
Experimental Section
The experimental details of synthesis and full characteriza-
tion data for fluorous carbazate 13, all new fluorous hy-
drazides, and fluorous DEAD reagents are given in Supporting
Information. In this section, typical procedures for Mitsunobu
reactions and separations with fluorous and organic reagents
are exemplified with the coupling of acid 4a with alcohol 5a
to give the ester 6aa. The experimental details of synthesis,
separation, and full characterization (of new compounds) of
other Mitsunobu products are reported in Supporting Informa-
tion.
4-(4-Nitrophenyl)butyric Acid 3,3-Dimethylbutyl Ester
6aa. (a) With F-TPP and F-DEAD-2. A solution of F-DEAD-2
2 (450 mg, 0.71 mmol) in THF (5 mL) was slowly added to a
solution of 4-(4-nitrophenyl)butyric acid 4a (98 mg, 0.47 mmol),
3,3-dimethylbutanol 5a (86 µL, 0.71 mmol), and F-TPP (500
mg, 0.71 mmol) in THF (5 mL) at room temperature. This
mode of mixing the Mitsunobu substrates and reagents is also
referred to as Procedure B in the earlier paper.4 All Mitsunobu
reactions in this paper were conducted by Procedure B. After
stirring at room temperature for 3 h, the reaction mixture was
concentrated.
Automated fluorous chromatography was carried out as
follows. After loading the crude reaction mixture using THF
(1 mL), the fluorous column (12+M size) was placed inside
the steel casing of the Biotage Horizon system. The column
was flushed with 80:20 MeOH/water (60 mL, 5 column
volumes) to elute the organic product. The solvent system was
(15) (a) FluoroFlash fluorous silica gel products were purchased from
equity interest in this company.
(16) Review on spacer effects: Gladysz, J. A. In Handbook of
Fluorous Chemistry; Gladysz, J. A., Curran, D. P., Horvath, I., Eds.;
Wiley-VCH: Weinheim, 2004; pp 41-55.
8756 J. Org. Chem., Vol. 69, No. 25, 2004