[Bis(2-methoxyethyl)amino]sulfur Trifluoride, the Deoxo-Fluor Reagent: Application toward One-Flask Transformations of Carboxylic Acids to Amides

Article abstract of DOI:10.1021/jo035658k

The use of the Deoxo-Fluor reagent is a versatile method for acyl fluoride generation and subsequent one-flask amide coupling. It provides mild conditions and facile purification of the desired products in good to excellent yields. We have explored the utility of this reagent for the one-flask conversion of acids to amides and Weinreb amides and as a peptide-coupling reagent.

Full text of DOI:10.1021/jo035658k

[Bis(2-m eth oxyeth yl)a m in o]su lfu r
Tr iflu or id e, th e Deoxo-F lu or Rea gen t:
Ap p lica tion tow a r d On e-F la sk Tr a n s-
for m a tion s of Ca r boxylic Acid s to Am id es
F IGURE 1. Structures of Deoxo-Fluro (1) and DAST (2).
J onathan M. White, Ashok Rao Tunoori,
Brandon J . Turunen, and Gunda I. Georg*
ditional transformations were explored as well, including
the conversion of carboxylic acids to acyl fluorides.7 Based
on these observations, we sought to take advantage of
the properties of acyl fluorides combined with this new
and facile protocol for their preparation. Our efforts have
led to a one-flask protocol for the conversion of carboxylic
acids to a variety of amides obtained through an inter-
mediate acyl fluoride. A full account of this work is
presented herein.9
Department of Medicinal Chemistry, University of Kansas,
1251 Wescoe Hall Drive, Lawrence, Kansas 60045-7582
georg@ku.edu
Received November 10, 2003
Abstr a ct: The use of the Deoxo-Fluor reagent is a versatile
method for acyl fluoride generation and subsequent one-flask
amide coupling. It provides mild conditions and facile
purification of the desired products in good to excellent
yields. We have explored the utility of this reagent for the
one-flask conversion of acids to amides and Weinreb amides
and as a peptide-coupling reagent.
Con ver sion of Ca r boxylic Acid s to Am id es. The
importance of amides cannot be overstated as they are
crucial in the architecture of biological systems and
prevalent in natural products and commercial medicines,
and their formation is widely utilized in the construction
of many molecules/materials. A special group of amides
which shows additional versatility are the N,O-dimeth-
ylhydroxylamides (Weinreb amides).10 These compounds
have become important and widely used building blocks
in organic synthesis.11-14 Accordingly, several methods
are available for their formation including the direct
conversion of carboxylic acids to amides. Some of these
procedures utilize peptide coupling reagents such as
BOP,15,16 DCC,17 or propylphosphonic anhydride/N-eth-
ylmorpholine.18,19 Einhorn et al. have developed a method
for the synthesis of Weinreb amides from carboxylic acids
using carbon tetrabromide and triphenylphosphine.20 Sibi
et al. have reported the synthesis of Weinreb amides from
carboxylic acids using 2-chloro-1-methylpyridinium iodide
(CMPI) or BMPI as the coupling agent.21 Drawbacks of
these methods include expensive coupling reagents and
difficult removal of excess reagent and reagent byprod-
ucts. Therefore, a continued interest exists in the devel-
opment of alternative methods for amide formation from
carboxylic acids that are operationally simple and allow
for easy removal of reagents and reagent byproducts.
In the course of our study, we found that carboxylic
acids could be readily converted to the corresponding
Acyl fluorides are versatile functional groups in organic
chemistry due to the unique nature of the carbonyl-
fluorine bond.1 Many useful chemical transformations are
elicited via this functionality since it possesses greater
stability than the corresponding acid chloride toward
neutral oxygen nucleophiles, yet is of high reactivity
toward anionic nucleophiles and amines.2 It has been
observed that acid fluorides react more like activated
esters than acid halides (Cl, Br, I).2 For example, Fmoc,3,4
Boc, and Cbz amino acid fluorides5 were found to be
stable, rapid-acting, acylating reagents for peptide bond
formation. It is also of note that no significant loss of
optical purity is observed during the conversion of acid
fluorides to amides.5,6 These properties make shelf-stable
acid fluorides possible and allow for their isolation
through organic extraction. It is these characteristics
which make them important for further synthetic study.1
A variety of techniques are available for the generation
of acyl fluorides.1,2 There are, however, disadvantages
associated with these methods, including poor yields,
dangerous or toxic chemicals, forcing reaction conditions,
and costly reagents. A recently developed alternative,
[bis(2-methoxyethyl)amino]sulfur trifluoride,the Deoxo-
Fluor reagent (1), which was first described by Lal et al.
as a thermally stable alternative to the DAST reagent
(2), overcomes several of these problems (Figure 1).7,8 The
initial investigation of this reagent showcased its utility
for the conversion of hydroxy alkanes to the correspond-
ing alkyl fluorides (deoxygenation-fluorination).8 Ad-
(9) Tunoori, A. R.; White, J . M.; Georg, G. I. Org. Lett. 2000, 2, 4091-
4093.
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(11) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15-40.
(12) Overhand, M.; Hecht, S. M. J . Org. Chem. 1994, 59, 4721-
4722.
* Corresponding author.
(1) Patai, S. The Chemistry of Acyl Halides; Interscience Publish-
ers: New York, 1972.
(2) Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M. Acc.
Chem. Res. 1996, 29, 268-274.
(3) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J .
Am. Chem. Soc. 1990, 112, 9651-9652.
(13) Lucet, D.; Le Gall, T.; Mioskowski, C.; Ploux, O.; Marquet, A.
Tetrahedron: Asymmetry 1996, 7, 985-988.
(14) Angelastro, M. R.; Mehdi, S.; Burkhart, J . P.; Peet, N. P.; Bey,
P. J . Med. Chem. 1990, 33, 11-13.
(15) Maugras, I.; Poncet, J .; J ouin, P. Tetrahedron 1990, 46, 2807-
2816.
(16) Shreder, K.; Zhang, L.; Goodman, M. Tetrahedron Lett. 1998,
39, 221-224.
(4) Kaduk, C.; Wenschuh, H.; Beyermann, M.; Forner, K.; Carpino,
L. A.; Bienert, M. Lett. Pept. Sci. 1996, 2, 285-288.
(5) Carpino, L. A.; Mansour, M. E.; Sadat-Aalaee, D. J . Org. Chem.
1991, 56, 2611-2614.
(17) Braun, M.; Waldmueller, D. Synthesis 1989, 856-858.
(18) Oppolzer, W.; Cunningham, A. F. Tetrahedron Lett. 1986, 27,
5467-5470.
(6) Bertho, J . N.; Loffet, A.; Pinel, C.; Reuther, F.; Sennyey, G.
Tetrahedron Lett. 1991, 32, 1303-1306.
(19) Dechantsreiter, M. A.; Burkhart, F.; Kessler, H. Tetrahedron
Lett. 1998, 39, 253-254.
(7) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M.; Cheng, H.
J . Org. Chem. 1999, 64, 7048-7054.
(20) Einhorn, J .; Einhorn, C.; Luche, J . L. Synth. Commun. 1990,
20, 1105-1112.
(8) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M. Chem.
Commun. 1999, 215-216.
(21) Sibi, M. P.; Stessman, C. C.; Schultz, J . A.; Christensen, J . W.;
Lu, J .; Marvin, M. Synth. Commun. 1995, 25, 1255-1264.
10.1021/jo035658k CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/04/2004
J . Org. Chem. 2004, 69, 2573-2576
2573

TABLE 1. P r ep a r a tion of Am id esa
a
b
All compounds in Table 1 were prepared via method A (see the Experimental Section, general procedures). Isolated yield.
amides and peptides (Table 1) or Weinreb amides (Table
2) in a one-flask protocol by using the Deoxo-Fluor
reagent. This procedure met our goals by providing a
straightforward method where the resulting byproducts
of the reaction22 can be easily removed. As shown in
Tables 1 and 2, a variety of amides can be prepared from
commercially available carboxylic acids. Saturated ali-
phatic and cyclic acids were cleanly converted to the
corresponding amides (entries 1 and 2, Table 1; entries
1 and 3, Table 2). We also prepared the Weinreb amide
from trans-crotonic acid in good yield (entry 2, Table 2).
Benzoic acids with electron-withdrawing and electron-
releasing groups (entries 3 and 4, Table 1; entry 5, Table
2) and 2-thiophenecarboxylic acid (entry 5, Table 1; entry
6, Table 2) provided good yields of the amides. This
methodology is also applicable to the synthesis of Wein-
reb amides from amino acids (entries 7-10, Table 2).
Carpino has extensively studied and shown many of the
advantages of utilizing amino acid fluorides in peptide
bond formation.3-5,23,24 As seen in Table 1 (entries 7-9),
dipeptides can similarly be generated utilizing this
reagent. The generation of these chiral Weinreb amides
and peptides illustrates the amenability of this procedure
for a racemization free protocol as determined by optical
rotation and chiral HPLC.
Ad d ition a l Obser va tion s. In our experimentation,
an observation was made related to substrate compat-
(23) Carpino, L. A.; Mansour, E. S. M. E.; El-Faham, A. J . Org.
Chem. 1993, 58, 4162-4164.
(24) Carpino, L. A.; El-Faham, A. J . Am. Chem. Soc. 1995, 117,
5401-5402.
(22) Reagent byproducts SO2 (gas) and HN(CH2CH2OMe)2 (liquid
bp 170-176 °C) are easily removed under reduced pressure: Chem.
Ber. 1959, 92, 1789-1797.
2574 J . Org. Chem., Vol. 69, No. 7, 2004

TABLE 2. P r ep a r a tion of Wein r eb Am id es
a
b
All compounds in Table 2 were prepared via method A or B as indicated (see the Experimental Section, general procedures). Isolated
yield.
ibility in regards to this method. When we attempted to
side product is able to participate in the acylation
reaction. This hypothesis was confirmed by treating
benzoic acid with the Deoxo-Fluor reagent under our
typical conditions for acid fluoride formation (Scheme 1).
The reaction mixture was allowed to stir for a period of
8 h without the addition of an external, secondary amine.
Upon completion, 67% of the corresponding bis(methoxy-
ethyl)amide (Scheme 1, 24) was generated. It has been
demonstrated with this reagent7 and DAST4 that the
intermediate acyl fluoride can be readily isolated. Typical
add N,N-diisopropylamine to the corresponding acyl
fluoride of 2-thiophenecarboxylic acid, none of the desired
diisopropylamide product was formed. Instead, we ob-
tained the bis(methoxyethyl)amide exclusively (Scheme
1, 23). In a proposed mechanism for acyl fluoride forma-
tion utilizing 1 (Scheme 2) the corresponding bis-
(methoxyethyl)amine is generated along with SO2.33 We
propose that in the case of sterically encumbered amines,
or a lack of external amine, the bis(methoxyethyl)amine
J . Org. Chem, Vol. 69, No. 7, 2004 2575

SCHEME 1
SCHEME 2
the reaction was diluted with additional CH2Cl2 and sequentially
extracted with aqueous saturated sodium bicarbonate, water,
and brine. The organic layer was then dried over magnesium
sulfate, filtered, and concentrated under reduced pressure.
Purification via silica gel column chromatography then provided
the final product.
Meth od B. In cases where the substrate was not soluble in
CH2Cl2, N,N-dimethylformamide could be used. The same molar
ratios were used; however, the workup protocol required dilution
of the crude reaction mixture in ether, with sequential extraction
using aqueous saturated sodium bicarbonate, water, and brine
as before.
En a n tiop u r ity Deter m in a tion . The dipeptides, compounds
9-11, were evaluated on the basis of reported optical rotations
(see the Supporting Information for references). The enantiopu-
rity of compounds 18-20 and 22 was determined by HPLC
analysis. HPLC analysis was conducted using the Chiralcel AD-
RH column: solvent, hexanes/2-propanol (95/5); flow rate, 1.00
mL/min; detection 225 nm. Retention times (in minutes) was
found as follows: 18 (R) 8.2, 18 (S) 6.6; 19 (R) 7.9, 19 (S) 8.7; 20
(R) 7.0, 20 (S) 6.0; 22 (R) 5.6, 22 (S) 6.4. Compound 21 could
not be resolved under these conditions. The optical purity was
>97% for all compounds.
reaction times in these cases are 10-30 min. The result-
ant product can then be treated with the desired nucleo-
phile in a second step.3-6 This two step protocol would
remedy the side product formation, however, the advan-
tage of the one-flask reaction sequence would be lost.
The use of the Deoxo-Fluor reagent was shown to be a
versatile method for acyl fluoride generation and subse-
quent one-flask amide coupling. It provides mild condi-
tions and facile purification of the desired products and
proceeds in good to excellent yields. We have explored
the utility of this reagent for the one-flask conversion of
acids to amides, Weinreb amides, and as a peptide-
coupling reagent. Overall, this method appears to be a
robust and easily utilized technique for the aforemen-
tioned processes.
Exp er im en ta l Section
Gen er a l P r oced u r e. Meth od A. The carboxylic acid (1
equiv) was dissolved in CH2Cl2 under an argon atmosphere,
cooled to 0 °C, and then N,N-diisopropylethylamine (1.5 equiv)
and [bis(2-methoxyethyl)amino]sulfur trifluoride (1.2 equiv) were
added dropwise. After being stirred for 15-30 min (acyl fluoride
formation), a solution of the amine (1.5 equiv) in CH2Cl2 was
added. This mixture was stirred at 0 °C for an additional 15
min and then allowed to warm to room temperature. Stirring
was continued for 3-8 h (monitored by TLC). After completion,
Ack n ow led gm en t. We thank Professor Apurba
Datta for helpful discussions. Support for this work was
provided by the National Institutes of Health (CA-
084173). J .M.W. is a recipient of the NIH pre-doctoral
training grant in dynamic aspects of chemical biology
(GM-08454). B.J .T. is a recipient of the Department of
Defense Breast Cancer pre-doctoral training grant
(DAMD17-02-1-0435).
Su p p or tin g In for m a tion Ava ila ble: A description of
general methods and characterization data for all new com-
pounds (3, 4, 8, 14, 16, 17, 23, and 24). Compounds 5,25 6,26
7,27 9,5 11,28 12,29 13,20 15,30 and 18-2211,20,31,32 have been
previously reported. Our spectroscopic data were in agreement
with the reported values. Compound 10 is commercially
available. This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) Yuste, F.; Origel, A. E.; Brena, L. J . Synthesis 1983, 109-110.
(26) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetrahedron
1981, 37, 31-36.
(27) J ones, E.; Moodie, I. M. J . Chem. Soc. C 1968, 1195-1196.
(28) Mazurov, A. A.; Kabanov, V. M.; Andronati, S. A. Dokl. Akad.
Nauk SSSR 1989, 306, 364-366.
(29) Trost, B. M.; Lee, C. B. J . Am. Chem. Soc. 1998, 120, 6818-
6819.
(30) Satyamurthi, N.; Singh, J .; Aidhen, I. S. Synthesis 2000, 375-
382.
(31) Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. Org. Synth. 1989,
67, 69-75.
(32) Angelastro, M. R.; Burkhart, J . P.; Bey, P.; Peet, N. P.
Tetrahedron Lett. 1992, 33, 3265-3268.
(33) Hudlicky, M. Org. React. 1988, 25, 513.
J O035658K
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