2,2,2-trifluoroethyl formate: a versatile and selective reagent for the formylation of alcohols, amines, and N-hydroxylamines.

Article abstract of DOI:10.1021/ol016976d

[reaction: see text] Treatment of a variety of alcohols, amines, and N-hydroxylamines with 2,2,2-trifluoroethyl formate gave the corresponding formylated adducts in high yields.

Full text of DOI:10.1021/ol016976d

ORGANIC
LETTERS
2002
Vol. 4, No. 1
111-113
2,2,2-Trifluoroethyl Formate: A Versatile
and Selective Reagent for the
Formylation of Alcohols, Amines, and
N-Hydroxylamines
David R. Hill,* Chi-Nung Hsiao, Ravi Kurukulasuriya, and Steven J. Wittenberger
Abbott Laboratories, Global Pharmaceutical R&D, 1401 Sheridan Road, D-R450,
Bldg. R8, North Chicago, Illinois 60064-4000
daVid.hill@abbott.com
Received October 30, 2001
ABSTRACT
Treatment of a variety of alcohols, amines, and N-hydroxylamines with 2,2,2-trifluoroethyl formate gave the corresponding formylated adducts
in high yields.
As part of an ongoing program directed at the synthesis of
matrix metalloproteinase inhibitors, we required an efficient
method for the formylation of the N-hydroxylamine 1 to give
N-hydroxyformamide 2 (Scheme 1). The N-hydroxyforma-
formate6 gave selective O-formylation. Pentafluorophenyl,7
4-nitrophenyl,8 phenyl,9 and N-formyl imidazole10 reacted
similarly. Heating with ethyl formate11 (or other simple alkyl
formates) was more promising, but the reactions took several
days at elevated temperatures to reach completion. These
extended reaction times led to significant disproportionation12
of the N-hydroxylamine to produce mixtures of E- and
Z-oximes (4) and formamide (5), i.e., formylated primary
amine (Scheme 2).
Scheme 1
It was evident that a more reactive formylating reagent
that would result in reduced reaction times was required.
However, such a reagent (or reagents) should include a
nucleophile to recycle any O-formylated adduct produced.
2,2,2-Trifluoroethyl formate (TFEF) was envisioned to be
such a reagent. Surprisingly, a survey of the literature
revealed that this compound has not been reported for the
mide function is essential for the MMP inhibitory activity
exhibited by this class of compounds.1
(3) Waki, M.; Meienhofer, J. J. Org. Chem. 1977, 42, 2019.
(4) Strazzolini, P.; Giumanini, A. G.; Cauci, S. Tetrahedron 1990, 46,
1081.
A variety of literature methods were examined but were
found to give unsatisfactory results. In general, mixed
anhydride methodologies (formic acid/EDAC,2 formic acid/
DCC,3 acetic formic anhydride,4 formyl-pivaloyl anhydride,5
etc.) produced unacceptable amounts of N,O-bisformyl,
O-formyl, and the associated acylated adducts. Cyanomethyl
(5) Vlietstra, E. J.; Zwikker, J. W.; Nolte, R. J. M.; Drenth, W. J. R.
Neth. Chem. Soc. 1982, 101, 460
(6) Deutsch, J.; Niclas, H.-J. Synth. Commun. 1993, 23(11), 1561-1568.
Duczek, W.; Deutsch, J.; Vieth, S.; Niclas, H.-J. Synthesis 1996, 37-38.
(7) Kisfaludy, L.; Otvos, L., Jr. Synthesis 1987, 510.
(8) Yamamoto, K. Bull. Chem. Soc. Jpn. 1972, 45, 1253; Martinez, J.;
Laur, J. Synthesis 1982, 979.
(9) Yale, H. L. J. Org. Chem. 1971, 36, 3238.
(10) Kitagawa, T.; Ito, J.; Tsutsui, C. Chem. Pharm. Bull. 1994, 42, 1931.
(11) Schmidhammer, H.; Brossi, A. Can. J. Chem. 1982, 60, 3055.
(12) Yang, C. H.; Lin, Y. C. J. Chin. Chem. Soc. 1987, 34, 19.
(1) Michaelides, M. et al. Curr. Pharm. Design 1999, 5, 787-819.
(2) Chen, F. M. F.; Benoiton, N. L. Synthesis 1979, 709.
10.1021/ol016976d CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

Scheme 2
Table 1. N-Formylation of N-Hydroxylamines with
2,2,2-Trifluoroethyl Formate (TFEF)
selective N-formylation of N-hydroxylamines, nor has the
formylation of alcohols, amines and N-hydroxylamines been
described. A report of the formylation of enolates has recently
appeared.13 We describe here our findings on the utility of
TFEF as a versatile and selective reagent for the formylation
of alcohols, amines, and hydroxylamines.
In contrast to many of the formylating reagents mentioned
earlier, TFEF was simple to prepare from formic acid and
2,2,2-trifluoroethanol using a straightforward literature pro-
cedure.14 TFEF was distilled from the reaction.15 This
procedure has been scaled up to prepare multi-kilogram
quantities of the reagent. TFEF is stable at ambient temper-
ature and can be stored on the bench for more than 2 years
with no significant degradation.
a Yields determined after purification.
isomer and by the end of the reaction dominates the mixture
(Scheme 2).
As illustrated in (Table 1) various N-hydroxylamines gave
high yields of the corresponding N-formyl derivatives upon
treatment with the TFEF reagent. It was typically necessary
to heat these reactions in order to rapidly obtain the
Trifluoroethyl formate can be used in a variety of reaction
manifolds depending on the presence of other additives.
Initially we thought that the 2,2,2-trifluoroethanol produced
in the reaction might act as a nucleophile and recycle the
O-formyl adduct. However, it was quickly apparent that
2,2,2-trifluorethanol was too poor a nucleophile to deformy-
late this side product. For N-hydroxylamines (e.g., 1), formic
acid was typically employed. The presence of some formic
acid in the reaction mixture appears to facilitate the conver-
sion of the O-formyl isomer to the N-formyl product, either
by O-to-N formyl transfer or by nucleophilic O-deformylation
to regenerate starting material. A systematic study of formic
acid concentration revealed that up to 20 wt % formic acid
was tolerated in the reaction without significant degradation
of the N-hydroxyformamide product. The optimum rate
enhancement was seen when 10 wt % formic acid was used.
Thus, for the formylation of N-hydroxylamine 1, 10 equiv
of TFEF reagent containing 10 wt % formic acid was
employed. The resulting mixture was then heated at reflux
until the substrate was consumed.16 Early in the formylation
reaction, the amount of O-formyl-N-hydroxylamine 3 relative
to N-hydroxyformamide 2 was much greater than later on
in the reaction, indicating that O-formylation was kinetically
competitive with N-formylation. However, the N-formyl
isomer is thermodynamically more stable than the O-formyl
(16) Typical Experiment. The tosylate salt of N-hydroxylamine 1 (1.95
kg), was free based in tetrahydrofuran (5.07 kg) and methyl tert-butyl ether
(4.12 kg) using 15% aqueous potassium bicarbonate solution (4.29 kg, 2.06
equiv vs tosylate salt of 1). The mixture was stirred until all of the solids
had dissolved. The separated organic portion assayed by HPLC for 1.346
kg (2.97 mol) N-hydroxylamine free base 1. HPLC conditions: Zorbax SB-
C8 (4.6 mm × 25 cm) column, gradient 40/60 to 43/57 0.1% phosphoric
acid/acetonitrile over 5 min, then 43/57 isocratic to 15 min, then gradient
43/57 to 90/10 over 5 min, hold at 90/10 5 min; flow rate at 1.5 mL/min,
UV detection at 260 nm. Peak identification: N-hydroxylamine 1 (7.1 min).
The N-hydroxylamine free base solution was charged to a 100-L round-
bottom flask. The solution was concentrated in vacuo to 20-30 wt %
solution of N-hydroxylamine free base. The 2,2,2-trifluoroethyl formate
reagent (5.27 kg at 71.9 wt % ) 3.79 kg [29.6 mol, 10 equiv] containing
10 wt % formic acid) was charged to the N-hydroxylamine free base
solution. The mixture was warmed to gentle reflux (internal temperature
ca. 65 °C), and the reaction was monitored by HPLC for the disappearance
of starting material. The reaction was continued until the peak area of the
N-hydroxylamine 1 was less than 0.5% area (typically in ca. 4 h). The
reaction mixture was cooled to less than 30 °C, water (5.33 kg) was added
and mixed, and then the layers were separated. The organic portion was
washed twice with 15 wt % aqueous potassium bicarbonate solution (ca.
5.3 kg portions). The organic portion was washed with water (4.76 kg).
The organic layer was then solvent switched to ethyl acetate in vacuo. The
concentration was measured by HPLC assay and adjusted by either solvent
removal in vacuo or addition to within the range of 10-35% weight solution
of product. To the stirred product solution was added heptanes (10.71 kg,
1.5 × wt of EtOAc in the solution) over 25 min. The suspension was stirred
at ambient temperature for 2-4 h. The product was collected by filtration.
The cake was rinsed with a solution of 1:2 (v/v) EtOAc/heptanes (5.63
kg). After the solvent was removed by suction, the solid was dried in vacuo
(ca. 100 mmHg with a nitrogen sweep at 100 °C). The dried product, 2.685
kg (92% yield), had a potency of 100% and a chiral purity of g99% ee.
Spectral data: 1H NMR (300 MHz, d6-DMSO) δ 9.95 (br s, 0.5H), 9.80
(br s, 0.5H), 8.41 (br s, 0.5H), 8.37 (br s, 0.5H), 8.35 (s, 0.5H), 7.95 (s,
0.5H), 7.76 (d, 2H, J ) 8.9 Hz), 7.65 (d, 2H, J ) 8.5 Hz), 7.43 (d, 2H, J
) 8.5 Hz), 7.04 (d, 2H, J ) 8.9 Hz), 4.92-4.80 (m, 0.5H), 4.50-4.38 (m,
0.5H), 4.28-4.06 (m, 2H), 3.82-3.68 (m, 1H), 3.66-3.54 (m, 1H), 3.88 (s,
3H), 3.84 (s, 3H).
(13) Zayia, G. H. Org. Lett. 1999, 1, 989.
(14) Blackburn, G. M.; Dodds, H. L. H. J. Chem. Soc. B 1971, 826.
(15) Preparation of Trifluoroethyl Formate (TFEF). In a 3-L jacketed
flask fitted with reflux condenser and temperature probe, 2,2,2-trifluoro-
ethanol (500 g, 5.0 mol, 1.0 equiv) was combined with 95% formic acid
(1000 g, 21.7 mol, 4.3 equiv). The mixture was then heated at an internal
temperature of 80 °C for 18 h. NMR analysis of a sample taken after 18 h
showed a 1.4:1 ratio of trifluoroethanol to trifluoroethyl formate. The mixture
was then subjected to fractional distillation though a 10-in. vacuum jacketed
fractionating column packed with Aldrich “Pro-pak” packing. The fraction
boiling at <70 °C was collected; 448 g of distillate was obtained (70%
yield adjusted for purity). The purity was assessed by NMR. Typically some
2,2,2-trifluoroethanol and formic acid codistill with the product if the
distillation temperature is allowed to rise above 70 °C.
112
Org. Lett., Vol. 4, No. 1, 2002

N-hydroxyformamide as the exclusive product. Formic acid
was again used as a catalyst in entry 2. In this case, it was
beneficial to add 1 equiv of sodium formate to prevent the
1-2% acetonide cleavage that otherwise occurred.
Table 3. N-Formylation of Alcohols and Amino Alcohols with
2,2,2-Trifluoroethyl Formate (TFEF)
To further explore the utility of the TFEF reagent, a variety
of amine and alcohol substrates were formylated with the
reagent. The results of this study are described below.
Table 2 illustrates that primary and secondary amines were
rapidly converted into the corresponding formamides in near
Table 2. N-Formylation of Amines with 2,2,2-Trifluoroethyl
Formate (TFEF)
a Isolated yield after purification.
yield within 18 h. The reaction was initiated at 0 °C and
subsequently warmed to ambient temperature. In the case
Table 4. N-Formylation of Amino Acid Derivatives with
2,2,2-Trifluoroethyl Formate (TFEF)
a Isolated yield after purification.
quantitative yield using 1.1 equiv of TFEF reagent. These
reactions were mildly exothermic, requiring initial cooling
(ice bath) while the TFEF reagent was added.
TFEF was also found to be effective in formylating both
electron-rich and electron-poor anilines in high yields. The
reaction of 2-nitroaniline is particularly noteworthy, requiring
24 h at 65 °C to produce the expected formamide in 83%.
This compares favorably with the corresponding reaction
using N-formylbenzotriazole,17 which required 48 h at 138
°C to achieve a similar yield of 2-nitroformanilide
Secondary and tertiary alcohols were also efficiently
transformed into the corresponding formates using TFEF.
Thus, (1R,2S,5R)-(-)-menthol afforded the corresponding
formate in 93% isolated yield after 18 h. As an example of
a tertiary alcohol, 1-adamantanol yielded 53% of the corre-
sponding formate after 72 h. In both cases, TFEF was used
as the solvent. These results compare very favorably with
corresponding formylations using other reagents. Moreover,
this difference in reactivity between amines and alcohols
toward the TFEF reagent is sufficient that a chemospecific
formylation of a primary amine could be readily achieved
in the presence of an unprotected primary alcohol.
a Isolated yield after purification.
of serine benzyl ester, formylation of the amine function
occurred exclusively and no O-formylated product was
observed. Phenylalanine ethyl ester and proline benzyl ester
were somewhat more sluggish to react, requiring 18 h at
reflux in THF for complete reaction. The hydrochloride salts
could be neutralized either in situ with sodium formate or
as a separate step using potassium carbonate for example.
In conclusion, 2,2,2-trifluoroethyl formate is easily pre-
pared from inexpensive starting materials and can clearly
be a powerful and versatile reagent for a variety of formy-
lation reactions.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The formylation of amino acid derivatives (Table 4) was
readily achieved with TFEF. For example, serine benzyl ester
was formylated starting with the hydrochloride salt in high
(17) Katritzky, A. R.; Chang, H.-X.; Yang, B. Synthesis 1995, 503.
Org. Lett., Vol. 4, No. 1, 2002
OL016976D
113