Direct transacylation of 2,2,2-trihaloethyl esters with amines and alcohols using phosphorus(III) reagents for reductive fragmentation and in situ activation

Article abstract of DOI:10.1021/jo991711m

Amides and esters have been synthesized from 2,2,2-trihaloethyl esters in one pot using phosphorus(III) reagents as reductants, with resultant carboxylate activation as an acyloxyphosphonium intermediate, and in situ trapping by amine or alcohol nucleophiles. Secondary and tertiary amides were synthesized, including a dipeptide, in good yields using hexamethylphosphorous triamide, (Me₂N)₃P, as reducing agent. Optimal yields of esters derived from primary and secondary alcohols were obtained using tributylphosphine and DMAP. Tribromoethyl esters provided yields superior to those obtained with trichloroethyl esters.

Full text of DOI:10.1021/jo991711m

2114
J . Org. Chem. 2000, 65, 2114-2121
Dir ect Tr a n sa cyla tion of 2,2,2-Tr ih a loeth yl Ester s w ith Am in es
a n d Alcoh ols Usin g P h osp h or u s(III) Rea gen ts for Red u ctive
F r a gm en ta tion a n d in Situ Activa tion
J eremy J . Hans, Russell W. Driver, and Steven D. Burke*
Department of Chemistry, University of WisconsinsMadison, 1101 University Avenue,
Madison, Wisconsin 53706-1369
Received November 2, 1999
Amides and esters have been synthesized from 2,2,2-trihaloethyl esters in one pot using phosphorus-
(III) reagents as reductants, with resultant carboxylate activation as an acyloxyphosphonium
intermediate, and in situ trapping by amine or alcohol nucleophiles. Secondary and tertiary amides
were synthesized, including a dipeptide, in good yields using hexamethylphosphorous triamide,
(Me2N)3P, as reducing agent. Optimal yields of esters derived from primary and secondary alcohols
were obtained using tributylphosphine and DMAP. Tribromoethyl esters provided yields superior
to those obtained with trichloroethyl esters.
In tr od u ction
in trihaloethyl ester cleavage. Letsinger and co-workers
have used tributylphosphine and (Me2N)3P [hexameth-
ylphosphorous triamide, tris(dimethylamino)phosphine]
to cleave 2,2,2-trichloroethyl and 1,1-dimethyl-2,2,2-tri-
chloroethyl esters of phosphoric acids in their syntheses
of oligonucleotides,13 demonstrating the ability of phos-
phorus(III) reagents to reduce trihaloethyl esters.
2,2,2-Trihaloethyl esters are useful groups for the
protection of carboxylic acids and other functional groups
as a result of the mild, nonhydrolytic conditions used for
their cleavage.1,2 Although the trichloroethyl ester has
been the most widely used haloethyl protecting group,1,3
other â-haloethyl esters have been used for this purpose,
including tribromoethyl4 and 1,1-dimethyl-2,2,2-trichlo-
roethyl groups.5 Trihaloethyl groups can be used to
protect both carbon1-4b and phosphorus oxy acids,4c,5 and
the related trichloroethoxycarbonyl (TROC) protecting
group has been used to protect alcohols and amines as
carbonates or carbamates, respectively.1
Deprotection of trihaloethyl esters is achieved using
reducing conditions to effect â-elimination, as shown in
eq 1.2 A variety of methods have been developed for the
cleavage of these esters, with zinc being the most
commonly used reductant.3,6 Other transition-metal re-
agents have been employed for cleavage including zinc-
copper7 and zinc-lead couples,8 as well as cobalt-
phthalocyanine complex.9 Selenium10 and tellurium
reagents,11 as well as electrolysis,4b,12 have also been used
Phosphorus(III) reagents are also used in the genera-
tion of phosphonium salts, which are mild and efficient
reagents for condensation reactions.14-19 These reactions
can be described as “oxidation-reduction condensa-
tions”19 in which attack at a heteroatom by a phosphorus
nucleophile results in oxidation of the latter to an
electrophilic phosphonium salt. These salts then activate
alcohol or carboxylic acid groups for condensation with
various nucleophiles. Examples of the use of phosphorus-
(III) reagents in coupling reactions include their combi-
nation with azodicarboxylates in the Mitsunobu reac-
tion,14,16,17 the reaction of phosphines with disulfides in
the Mukaiyama coupling method,19 and the reaction of
phosphorus(III) reagents with halogenated alkanes such
as carbon tetrachloride to effect condensations.15,18
Preparation of amide and ester condensation products
from protected carboxylic acids is usually achieved by
* To whom all correspondence should be sent. Phone: (608) 262-
4941. Fax: (608) 265-4534. E-mail: burke@chem.wisc.edu.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed; Wiley-Interscience: New York, 1991.
(2) Haslam, E. Tetrahedron 1980, 36, 2409-2433.
(3) Woodward, R. B.; Heusler, K.; Gosteli, J .; Naegeli, P.; Oppolzer,
W.; Ramage, R.; Ranganathan, S.; Vorbru¨ggen, H. J . Am. Chem. Soc.
1966, 88, 852-853.
(4) (a) Stark, W. M.; Hawker, C. J .; Hart, G. J .; Philippides, A.;
Petersen, P. M.; Lewis, J . D.; Leeper, F. J .; Battersby, A. R. J . Chem.
Soc., Perkin Trans. 1 1993, 2875-2892. (b) Weiguny, J .; Scha¨fer, H.
J . Liebigs Ann. Chem. 1994, 225-233. (c) van Boom, J . H.; Crea, R.;
Luyten, W. C.; Vink, A. B. Tetrahedron Lett. 1975, 32, 2779-2782.
(5) (a) Lemmen, P.; Buchweitz, K. M.; Stumpf, R. Chem. Phys. Lipids
1990, 53, 65-75. (b) Strasser, M.; Ugi, I. Acta Chem. Scand. 1993, 47,
125-130. (c) Hohgardt, H.; Dietrich, W.; Ku¨hne, H.; Mu¨ller, D.;
Grzelak, D.; Welzel, P. Tetrahedron 1988, 44, 5771-5790.
(6) J ust, G.; Grozinger, K. Synthesis 1976, 457-458.
(12) Semmelhack, M. F.; Heinsohn, G. E. J . Am. Chem. Soc. 1972,
94, 5139-5140.
(13) (a) Letsinger, R. L.; Groody, E. P.; Tanaka, T. J . Am. Chem.
Soc. 1982, 104, 6805-6806. (b) Letsinger, R. L.; Groody, E. P.; Lander,
N.; Tanaka, T. Tetrahedron 1984, 40, 137-143.
(14) Castro, B. R. Org. React. 1983, 29, 1-162.
(15) (a) Appel, R.; Halstenberg, M. In Organophosphorus Reagents
in Organic Synthesis; Cadogan, J . I. G., Ed.; Academic: London, 1979;
pp 387-432. (b) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801-
811 and references therein.
(7) Cook, A. F. J . Org. Chem. 1968, 33, 3589-3593.
(8) Overman, L. E.; Freerks, R. L. J . Org. Chem. 1981, 46, 2833-
2835.
(16) Mitsunobu, O. Synthesis 1981, 1-28.
(17) Hughes, D. L. Org. React. 1992, 42, 335-656.
(18) Ramage, R. In Organophosphorus Reagents in Organic Syn-
thesis; Cadogan, J . I. G., Ed.; Academic: London, 1979; pp 511-536.
(19) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1976, 15, 94-
103 and references therein.
(9) Eckert, H.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1976, 15, 681.
(10) (a) Ho, T.-L. Synth. Commun. 1978, 8, 301-304. (b) Huang,
Z.-Z.; Zhou, X.-J . Synthesis 1989, 693-694.
(11) Chen, J .; Zhou, X.-J . Synth. Commun. 1987, 17, 161-164.
10.1021/jo991711m CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/16/2000

Transacylation of 2,2,2-Trihaloethyl Esters
J . Org. Chem., Vol. 65, No. 7, 2000 2115
Sch em e 1
stepwise carboxylic acid deprotection followed by forma-
tion of an activated acyl species and treatment with an
amine or alcohol nucleophile. Such a deprotection-con-
densation protocol requires two or more steps and can
be attended by difficulties in working with the free
carboxylic acid intermediate. In light of the ability of
phosphorus(III) reagents to cleave trihaloethyl esters and
to act as efficient redox agents for condensation reactions,
we believed the combination of these functions would
produce a simple, one-pot procedure for the deprotection
and condensation of trihaloethyl-protected acids. Al-
though phosphonium salts have long been used to
activate carboxylate functional groups in condensation
reactions,14-27 in situ formation of these species by
reduction of trihaloethyl esters to effect condensation
reactions has not been exploited. Toward this end, the
amidation or transesterification of trihaloethyl esters
using phosphorus(III) compounds, as generalized in eq
2, has been investigated.28 This in situ deprotection,
activation, and acyl-transfer sequence provides an op-
erationally simple method for the title transformations.
Ta ble 1. In itia l Stu d ies of Am id e F or m a tion
entry
solvent
T (°C)
% yield of 7a a
1
2
3
4
5
THF
0
0
0
36
35
70
75
83
benzene
CH3CN
DMF
0
DMF
-55
a
Isolated yields.
triamide [(Me2N)3P] was selected to determine the opti-
mal reaction conditions for this transformation (Table 1).
The tribromoethyl ester provides a softer, more reactive
halogen electrophile than its trichloroethyl analogue, and
(Me2N)3P was chosen for its high nucleophilicity.14 Treat-
ment of 2a with 1.2 equiv of (Me2N)3P, 1 equiv of
butylamine, and 2.5 equiv of triethylamine in THF at 0
°C provided 7a in 36% yield (Table 1, entry 1). Use of
benzene as a nonpolar solvent gave a similar yield (Table
1, entry 2), while more polar solvents such as acetonitrile
(Table 1, entry 3) or dimethylformamide (DMF, Table 1,
entry 4) facilitated the reaction, with DMF providing the
best yield. Lowering the reaction temperature improved
the yield of 7a to 83% (Table 1, entry 5). Small amounts
of 2,2-dibromoethyl benzoate, and N,N-dimethylbenz-
amide were isolated as byproducts in these reactions.
Investigation of the choice of reductant and electrophile
revealed the combination of (Me2N)3P and tribromoethyl
protecting group to be the most effective for amide
synthesis (Table 2). The reaction of (Me2N)3P with 2a
proceeded rapidly at -55 °C to give 7a (Table 2, entry
1). Use of tributylphosphine as the phosphorus reagent
resulted in a slower reaction and provided 7a in reduced
yield (Table 2, entry 2). Decreasing the nucleophilicity
of the phosphorus reagent by using triphenylphosphine
resulted in a markedly slower reaction at room temper-
ature (Table 2, entry 3) and provided 7a in only 24% yield
after 48 h. This yield is similar to that of the correspond-
ing control experiment conducted in the absence of
phosphine (Table 2, entry 4). Heating the triphenylphos-
phine reactions produced yields only marginally higher
than controls. Use of the trichloroethyl ester necessitated
higher temperatures for complete consumption of starting
material, and lower yields were obtained (Table 2, entries
5 and 6). Using the optimized conditions, secondary and
tertiary amides of aromatic (7b,c) and aliphatic (8a ,b)
acids, as well as a Boc-Ala-Ala-OEt dipeptide (9), have
Resu lts a n d Discu ssion
The 2,2,2-tribromoethyl and 2,2,2-trichloroethyl ben-
zoate esters34 employed in these studies were synthesized
from benzoyl chloride and the corresponding 2,2,2-
trihaloethanol. Tribromoethyl esters of cyclohexanecar-
boxylic acid and N-Boc-alanine were synthesized using
carbodiimide coupling conditions with diisopropylcarbo-
diimide (DIC) as the coupling reagent (Scheme 1).29
The conversion of 2,2,2-tribromoethyl benzoate (2a ) to
N-butylbenzamide (7a ) using hexamethylphosphorous
(20) Lee, J . B. J . Am. Chem. Soc. 1966, 88, 3440-3441.
(21) Castro, B.; Dormoy, J . R. Bull. Chim. Soc. Fr. 1971, 3034-3056.
(22) (a) Barstow, L. E.; Hruby, V. J . J . Org. Chem. 1971, 36, 1305-
1306. (b) Yamada, S.; Takeuchi, Y. Tetrahedron Lett. 1971, 3595-3598.
(c) Wieland, T.; Seeliger, A. Chem. Ber. 1971, 104, 3992-3994. (d)
Appel, R.; Ba¨umer, G.; Stru¨ver, W. Chem. Ber. 1975, 108, 2680-2692.
(e) Appel, R.; Ba¨umer, G.; Stru¨ver, W. Chem. Ber. 1976, 109, 801-
804. (f) Manhas, M. S.; Amin, S. G.; Ram, B.; Bose, A. K. Synthesis
1976, 689-690.
(23) Gawne, G.; Kenner, G. W.; Sheppard, R. C. J . Am. Chem. Soc.
1969, 91, 5669-5671.
(24) Castro, B.; Dormoy, J .-R. Tetrahedron Lett. 1972, 4747-4750.
(25) (a) Castro, B.; Dormoy, J .-R.; Evin, G.; Selve, C. Tetrahedron
Lett. 1975, 1219-1222. (b) Castro, B.; Dormoy, J .-R.; Dourtoglou, B.;
Evin, G.; Selve, C. Ziegler, J .-C. Synthesis 1976, 751-752.
(26) Coste, J .; Fre´rot, E.; J ouin, P. J . Org. Chem. 1994, 59, 2437-
2446.
(27) (a) Mulzer, J .; Bru¨ntrup, G. Angew. Chem., Int. Ed. Engl. 1977,
16, 255-256. (b) Mulzer, J .; Pointner, A.; Chucholowski, A.; Bru¨ntrup,
G. J . Chem. Soc., Chem. Commun. 1979, 52-54. (c) Mulzer, J .;
Bru¨ntrup, G.; Chucholowski, A. Angew. Chem., Int. Ed. Engl. 1979,
18, 622-623. (d) Grynkiewicz, G.; Schmidt, P. Rocz. Chem. 1976, 50,
1449-1451. (e) Kunz, H.; Schmidt, O. Z. Naturforsch., B 1978, 33,
1009-1011.
(28) For our preliminary communication of this work, see: Hans,
J . J .; Driver, R. W.; Burke, S. D. J . Org. Chem. 1999, 64, 1430-1431.
(29) (a) Boden, E. P.; Keck, G. E. J . Org. Chem. 1985, 50, 2394-
2395. (b) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475-
4478. (c) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978,
17, 522-524.

2116 J . Org. Chem., Vol. 65, No. 7, 2000
Hans et al.
Ta ble 2. Effect of P h osp h or u s Nu cleop h ile a n d Ha logen
on th e Syn th esis of 7a
Ta ble 4. Effect of P h osp h or u s Nu cleop h ile a n d Ad d itive
on Tr a n sester ifica tion
entry
X
phosphorus rgt
T (°C)
time (h) % yield of 7a a
1
2
3
4
5
6
Br
Br
Br
Br
Cl
Cl
(Me2N)3P
PBu3
PPh3
none
(Me2N)3P
PBu3
-55
0.5
1.2
48
48
4.5
3.5
83
-55 f 0
25
rt
rt
rt
90
24b
17c
18
39
a
Isolated yields. b42% of 2a was recovered. c66% of 2a was
trihaloethyl phosphorus
ester
entry
ester
reagent
additive product % yielda
recovered.
1
2
3
2a
2a
2a
PBu3
PBu3
(Me2N)3P
none
DMAP
DMAP
10a
10a
10a
21
69
50
Ta ble 3. Con ver sion of Tr ibr om oeth yl Ester s to Am id es
(18 of 12)
4
5
5
5
PBu3
(Me2N)3P
DMAP
DMAP
11a
11a
74
44
(28 of 13)
63
6
2a
(Me2N)3P
HOBt
10a
a
Isolated yields.
In contrast to the amidation reactions, tributylphos-
phine provided yields of ester products superior to those
obtained with (Me2N)3P (Table 4). Substantial amounts
of N,N-dimethylamide products were observed when
(Me2N)3P was used as reductant (Table 4, entries 3 and
5).41,42 This presumably results from attack of activated
acyl intermediates by dimethylamine liberated in the
alcoholysis of (Me2N)3P.32 To substantiate this theory, the
behavior of (Me2N)3P under similar reaction conditions
in the absence of tribromoethyl ester was monitored by
phosphorus NMR. After a solution of (Me2N)3P in DMF
was stirred for 1.5 h, 31P NMR analysis of an aliquot of
this solution in CD2Cl2 revealed a peak corresponding to
(Me2N)3P (122.7 ppm, Figure 1) and a small amount of
HMPA impurity (24.1 ppm, not shown). The (Me2N)3P
solution was then treated with methanol (1.4 equiv),
DMAP (1 equiv), and 4-(N,N-dimethylamino)pyridinium
trifluoroacetate (DMAP‚TFA, 0.4 equiv) as a surrogate
entry trihaloethyl ester
amine
HNEt2
HCl‚GlyOEt
BuNH2
HNEt2
HCl‚AlaOEt
product
% yielda
1
2
3
4
5
2a
2a
5
5
6
7b
7c
8a
8b
9
76
77
88
57
70
a
Isolated yields.
been synthesized in good yields from the corresponding
tribromoethyl esters (Table 3).
Modification of the amide synthesis conditions allowed
for the synthesis of esters using this deprotection-
condensation strategy. Initial attempts to effect the
transesterification of trihaloethyl esters by addition of
(Me2N)3P to tribromoethyl esters failed to produce the
desired products. The use of PBu3 as phosphine reagent
gave the ester products, albeit in low yield (Table 4, entry
1). Addition of 2 equiv of the acylation catalyst 4-(N,N-
dimethylamino)pyridine (DMAP)30 markedly improved
yields in both (Me2N)3P- and tributylphosphine-induced
reactions (Table 4, entries 2-5). Esterification protocols
using benzotriazol-1-yloxytris(dimethylamino)phospho-
nium hexafluorophosphate (BOP) reagent25 have ap-
peared relatively recently.31 In these studies, esterifica-
tion of N-protected amino acids and phenylacetic acid
proceeded in high yield, possibly via acylated hydroxy-
benzotriazole intermediates.25,26,31b This suggested the
addition of 1-hydroxybenzotriazole (HOBt) as a trans-
acylating agent in the (Me2N)3P-mediated reactions. In
practice, HOBt-promoted esterification (Table 4, entry 6)
but did not provide yields superior to the PBu3-DMAP
reagent combination.
(32) (a) Schliebs, R. West German Patent 1,079,022, 1960. (b) Petrov,
K. A.; Nifant’ev, EÄ . E.; Lysenko, T. P.; Evdakov, V. P. Zh. Obshch.
Khim. 1961, 31, 2377-2380. (c) Nifant’ev, EÄ . E.; Ivanova, N. L.;
Fursenko, I. V. Zh. Obshch. Khim. 1969, 39, 854-856. (d) Kibardin,
A. M.; Gryaznov, P. I.; Gazizov, T. K.; Pudovik, A. N. Izv. Akad. Nauk.
SSSR, Ser. Khim., 1987, 1826-1828. (e) Houalla, D.; Sanchez, M.;
Wolf, R. Bull. Soc. Chim. Fr. 1965, 2368-2373.
(33) (a) Tobey, S. W. J . Org. Chem. 1969, 34, 1281-1298. (b)
Barchiesi, E.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A. J . Chem.
Soc., Perkin Trans. 2 1990, 375-383.
(34) Blay, G.; Cardona, L.; Garcia, B.; Garcia, C. L.; Pedro, J . R.
Synth. Commun. 1998, 28, 1405-1414.
(35) Fache, F.; J acquot, L.; Lemaire, M. Tetrahedron Lett. 1994, 35,
3313-3314.
(36) (a) Lluch, A.-M.; Gibert, M.; Sanchez-Baeza, F.; Messegeur, A.
Tetrahedron 1996, 52, 3973-3982. (b) Gajda, T.; Zwierzak, A. Synthesis
1981, 1005-1008.
(37) Andersen, T. P.; Ghattas, A.-B. A. G.; Lawesson, S.-O. Tetra-
hedron 1983, 39, 3419-3427.
(38) (a) Marko, I. E.; Mekhalfia, A. Tetrahedron Lett. 1990, 31,
7237-7240. (b) Barton, D. H. R.; Ferreira, J . A. Tetrahedron 1996,
52, 9347-9366.
(30) (a) Ho¨fle, G.; Steglich, W.; Vorbru¨ggen, H. Angew. Chem., Int.
Ed. Engl. 1978, 17, 569-583. (b) Scriven, E. F. V. Chem. Soc. Rev.
1983, 12, 129-161. (c) Hassner, A. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol.
3, pp 2022-2024.
(31) (a) Kim, M. H.; Patel, D. V. Tetrahedron Lett. 1994, 35, 5603-
5606. (b) Coste, J .; Campagne, J .-M. Tetrahedron Lett. 1995, 36, 4253-
4256.
(39) Bizzozero, S. A.; Dutler, H.; Franzstack, R.; Rovagnati, B. A.
Helv. Chim. Acta 1985, 68, 981-987.
(40) Li, P.; Alper, H. Can. J . Chem. 1993, 71, 84-89.
(41) Suezawa, H.; Tsuchiya, K.; Tahara, E.; Hirota, M. Bull. Chem.
Soc. J pn. 1988, 61, 4057-4066.
(42) Ghosez, L.; George-Koch, I.; Patiny, L.; Houtekie, M.; Bovy, P.;
Nshimyumukiza, P.; Phan, T. Tetrahedron 1998, 54, 9207-9222.

Transacylation of 2,2,2-Trihaloethyl Esters
J . Org. Chem., Vol. 65, No. 7, 2000 2117
F igu r e 1. (a) 31P NMR spectrum (121 MHz, CD2Cl2) of (Me2N)3P. (b) 31P spectrum of aliquot 10 min after addition of MeOH,
DMAP, and DMAP‚TFA.
Ta ble 5. Tr a n sester ifica tion of Tr ih a loeth yl Ester s
for the DMAP‚HBr formed in these reactions. Analysis
of an aliquot of this reaction mixture after 10 min showed
no (Me2N)3P resonance and two downfield resonances
that correspond to MeOP(NMe2)2 (137.9 ppm) and
(MeO)2PNMe2 (147.6 ppm), indicating the rapid metha-
nolysis of (Me2N)3P. A similar 31P NMR spectrum was
observed in the ethanolysis of (Me2N)3P by Houalla and
co-workers.32e The reduced nucleophilicity of alcohols
relative to amines allows attack by dimethylamine to
become a competitive reaction pathway in the (Me2N)3P-
mediated transesterifications.
entry trihaloethyl ester
alcohol (R′OH) product % yielda
1
2
3
4
5
6
2a
2a
2a
2a
2a
2a
CH3O(CH2)2OH
BuOH
BnOH
2-pentanol
(-)-menthol
trans-2-phenyl-
cyclohexanol
CH3O(CH2)2OH
BuOH
10a
10b
10c
10d
10e
10f
69
81
77
62
61
68
Esters of both primary and secondary alcohols were
produced in good yields using the tributylphosphine-
DMAP procedure (Table 5, entries 1-11). Acylation of
primary alcohols (Table 5, entries 1-3, 7-9) proceeded
in yields superior to that of sterically more hindered
secondary alcohols (Table 5, entries 4-6, 10, and 11).
Acylation of tert-butyl alcohol proved difficult, giving only
11% of the tert-butyl benzoate ester when tert-butyl
alcohol was used as cosolvent (Table 5, entry 12). As a
control, treatment of 2a with 2-methoxyethanol and
DMAP in the absence of phosphine for 24 h at room
temperature produced no product by TLC analysis. As
with the amidation reactions, the use of the trichloroethyl
ester derivatives required higher temperatures for start-
ing material consumption and provided lower yields
(Table 5, entry 13).
7
8
5
5
11a
11b
11c
11d
11e
10g
10a
74
65
70
63
65
11
44c
9
5
BnOH
10
11
12
13
5
5
2a
2b
2-pentanol
(-)-menthol
t-BuOHb
CH3O(CH2)2OH
Isolated yields. b1:1 DMF/t-BuOH was used as solvent. cRe-
action temperature ) 100 °C.
a
convert 17 to macrolactam 19 using similarly modified
amidation conditions failed to produce an observable
amount of cyclized product. Other products isolated in
these reactions include 2,2-dibromoethyl ester derivatives
of the ester substrates and the free carboxylic acids.
Further optimization of these conditions will be required
to establish the applicability of this procedure for mac-
rocyclic lactone and lactam synthesis.
The proposed mechanism for this deprotection-con-
densation reaction, as implied in eq 2, involves initial
attack upon a halogen of the trihaloethyl ester protecting
group by the phosphorus(III) reagent, resulting in release
of a 1,1-dihaloethylene and the carboxylate nucleofuge.
Preliminary investigations of the application of this
method toward macrocyclization of ω-hydroxy and ω-ami-
no carboxylic acids have been conducted. Tribromoethyl
esters of 12-hydroxystearic acid (15) and N-Boc-protected
12-aminododecanoic acid (17) were synthesized as shown
in Scheme 2. Subjecting ester 15 to the optimized
esterification conditions modified slightly to allow for
high dilution and temperature afforded only small
amounts of macrolactone 18 (Scheme 3). Attempts to

2118 J . Org. Chem., Vol. 65, No. 7, 2000
Hans et al.
Sch em e 2
F igu r e 2.
hydroxyl group acylation. Ester formation therefore does
not proceed by a Mitsunobu-type inversion in which the
alcohol is activated by a phosphonium species and then
displaced by a carboxylate anion.14,16,17
Con clu sion
Sch em e 3
In summary, tribromoethyl esters can be converted
directly to secondary and tertiary amides in moderate
to good yields by treatment with (Me2N)3P and an amine.
Similarly, esters of primary and secondary alcohols have
been prepared from tribromoethyl esters by treatment
with tributylphosphine in the presence of DMAP. Trichlo-
roethyl carboxylates gave lower yields of ester and amide
products when subjected to these reaction conditions. The
mechanism of this transformation involves reductive
fragmentation, releasing a 1,1-dihaloethylene and forma-
tion of an acyloxyphosphonium activated ester interme-
diate, which is trapped by an amine or alcohol nucleo-
phile. This method conveniently bypasses the carboxylic
acid form of the substrate and provides an efficient, one-
step conversion of tribromoethyl esters to amides or other
esters.
Attack at the new electrophilic phosphorus(V) center by
the carboxylate generates an acyloxyphosphonium inter-
mediate. Acyloxyphosphonium species are believed to be
common intermediates in condensation reactions that
employ phosphonium salts as coupling reagents.14,15,19-27
The activated ester shown in eq 2 then proceeds to the
amide or ester product in the presence of an amine or
alcohol nucleophile, respectively. The beneficial effect of
catalytic DMAP observed in the transesterification reac-
tions reflects the lower nucleophilicity of alcohols, relative
to amines.30
Exp er im en ta l Section
Gen er a l P r oced u r es. Infrared spectra (IR) are reported
in wavenumbers (cm-1) with broad signals denoted by “br”.
Mass spectra (MS) were obtained using electron impact (EI,
70 eV) or fast-atom bombardment (FAB, 8 kV, Xe carrier gas)
techniques. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded at 300 MHz. Carbon-13 nuclear mag-
netic resonance (13C NMR) spectra were recorded at 75 MHz.
Carbon resonance assignments were made by DEPT 135
spectral analysis.
Tetrahydrofuran (THF) and benzene (PhH) were distilled
from sodium/benzophenone ketyl immediately prior to use.
Triethylamine (Et3N), dichloromethane (CH2Cl2), butylamine,
and diethylamine were distilled from calcium hydride prior
to use. Acetonitrile (CH3CN) was distilled from calcium
hydride and stored over 4 Å molecular sieves. N,N-Dimethyl-
formamide (DMF) was distilled under reduced pressure from
magnesium sulfate, twice dried over 4 Å molecular sieves, and
stored over 4 Å molecular sieves. N,N-(Dimethylamino)-
pyridine (DMAP) was recrystallized from toluene. Tribu-
tylphosphine (PBu3) was distilled under reduced pressure from
calcium hydride or used as received from the Aldrich Chemical
Co. Butanol, 2-pentanol, and tert-butyl alcohol were distilled
from sodium metal. Menthol was dried by azeotropic removal
of water with benzene and further dried in vacuo. 2-Methoxy-
ethanol (anhydrous, 99.8%) was used as received from Aldrich
Chemical Co. Deuteriochloroform (chloroform-d; CDCl3) was
stored over 4 Å molecular sieves. All other commercially
obtained reagents and solvents were used as received without
further purification unless otherwise indicated.
Condensation by way of the proposed mechanism
would produce a dihaloethylene byproduct. Formation of
haloethylenes has been observed in the deprotection of
trichloroethyl esters using NaHSe10b as well as in the
reaction of triphenylphosphine with hexachloroethane (eq
3).15 The release of 1,1-dibromoethylene has been verified
in the current procedure by NMR analysis. Crude distil-
lates of the reaction mixtures from the conversion of 2a
1
to 7a and 2a to 10a showed H (δ ) 6.26 ppm) and 13C
(δ ) 125.6, 94.6 ppm) resonances characteristic of 1,1-
dibromoethylene.33
Proton NMR analyses of esters derived from chiral
secondary alcohols also support the proposed mechanism.
Menthol-derived esters 10e and 11e, as well as trans-
2-phenylcyclohexanol-derived ester 10f, display large
coupling constants (10.5-10.9 Hz) for the acyloxy-bearing
methine proton signals. This indicates the axial position
of these protons (Figure 2) and the retention of configu-
ration at the carbinol carbons that is consistent with
All moisture-sensitive reactions were performed in flame-
dried or oven-dried glassware under a positive pressure of
nitrogen. Bath temperatures were used to record the reaction
temperature in all cases. All reactions were stirred magneti-
cally unless otherwise indicated. Volatile solvents from reac-

Transacylation of 2,2,2-Trihaloethyl Esters
J . Org. Chem., Vol. 65, No. 7, 2000 2119
tion workups and chromatography solutions were concentrated
using a Bu¨chi rotary evaporator at reduced pressure. Residual
solvents were removed by evacuation under high vacuum at
approximately 1 mmHg. Analytical thin-layer chromatography
(TLC) was carried out on E. Merck (Darmstadt) TLC plates
precoated with silica gel 60 F254 (250 µm layer thickness).
TLC visualization was accomplished using either a UV lamp,
iodine adsorbed on silica gel, or charring solution [p-anisal-
dehyde (PAA)]. Flash chromatography was performed on EM
Science silica gel 60 (230-400 mesh). Solvent mixtures used
18.4 (CH3); MS (FAB + NaI) m/e (relative intensity, assign-
ment) 477.8 (51.2, M + Na+), 399.8 (35.2), 176.0 (100).
N-Bu tylben za m id e (7a )35 fr om 2a u sin g (Me2N)3P . To
a solution of 2a (141 mg, 0.364 mmol), butylamine (37 µL, 0.37
mmol), and NEt3 (0.13 mL, 0.93 mmol) in 3.6 mL of DMF at
-55 °C was added (Me2N)3P (73 µL, 0.40 mmol) dropwise. The
reaction mixture was stirred at -55 °C for 30 min. The reaction
mixture was diluted with Et2O (20 mL) and washed with 2 M
HCl. The aqueous phase was extracted with Et2O, and the
combined organics were washed with saturated aqueous NaCl
and H2O, dried (MgSO4), filtered, and concentrated. Purifica-
tion by flash chromatography (30% EtOAc in hexanes) pro-
vided 53.9 mg of 7a (0.304 mmol, 83%) as a colorless oil. Data
for 7a : Rf 0.43 (50% EtOAc in hexanes, PAA); IR (thin film)
3313, 2958, 2871, 1638, 1543, 1308, 695 cm-1; 1H NMR (CDCl3,
300 MHz) δ 7.77 (m, 2H), 7.46 (m, 3H), 7.38 (m, 2H), 6.57 (br
s, 1H), 3.42 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.93 (t, J )
7.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 167.5 (C), 134.8 (C), 131.1
(CH), 128.3 (CH × 2), 126.8 (CH × 2), 39.7 (CH2), 31.6 (CH2),
20.0 (CH2), 13.7 (CH3); MS (EI) m/e (relative intensity, assign-
ment) 177.1 (17.6, M+), 105.0 (100, M+ - NHC4H9).
for TLC and flash chromatography are reported in V/Vtotal
×
100.
2,2,2-Tr ibr om oeth yl Ben zoa te (2a ). To a solution of 2,2,2-
tribromoethanol (3.50 g, 12.4 mmol) and NEt3 (3.80 mL, 27.3
mmol) in 75 mL of THF at 0 °C was added benzoyl chloride
(1.60 mL, 13.8 mmol) dropwise over 10 min. The cold bath was
removed, and the reaction mixture stirred at ambient tem-
perature for 6 h. The reaction mixture was filtered and diluted
with diethyl ether (150 mL). This solution was washed with 2
M HCl and saturated NaHCO3, dried (MgSO4), filtered, and
concentrated. Purification by flash chromatography (gradient
elution, 1% to 2% EtOAc in hexanes) provided 4.1 g of 2a (10.6
mmol, 86%) as a colorless oil. Data for 2a : Rf 0.43 (10% EtOAc
in hexanes); IR (thin film) 3066, 2941, 1732, 1263, 1111, 731
cm-1; 1H NMR (CDCl3, 300 MHz) δ 8.17 (m, 2H), 7.62 (tt, 1H,
J ) 7.4, 1.3 Hz), 7.50 (m, 2H), 5.16 (s, 2H); 13C NMR (CDCl3,
75 MHz) δ 164.4 (C), 133.5 (CH), 129.8 (CH × 2), 128.6 (C),
128.4 (CH × 2), 76.3 (CH2), 35.5 (C); MS (EI) m/e (relative
intensity, assignment) 385.8 (7.7, M+), 306.9 (23.8, M+ - Br),
105.0 (100, M+ - OCH2CBr3); isotope pattern calculated for
C9H7Br3O2 matches that observed.
2,2,2-Tr ibr om oeth yl Cycloh exa n eca r boxyla te (5). To a
slurry of DMAP (0.93 g, 7.6 mmol), DMAP‚TFA (4-(N,N-
dimethylamino)pyridinium trifluoroacetate, 1.8 g, 7.6 mmol),
and diisopropylcarbodiimide (DIC, 1.3 mL, 8.30 mmol) in 20
mL of CH2Cl2 was added a solution of cyclohexanecarboxylic
acid (1.1 g, 8.6 mmol) and 2,2,2-tribromoethanol (2.23 g 7.9
mmol) in 15 mL of CH2Cl2 plus two 5 mL rinses via cannula.
The reaction mixture was stirred at ambient temperature for
6 h. The reaction mixture was then washed with 2 M HCl.
The aqueous phase was extracted with CH2Cl2, and the
combined organics were dried (MgSO4), filtered, and concen-
trated. Purification by flash chromatography (5% EtOAc in
hexanes) provided 2.57 g of 5 (6.54 mmol, 83%) as a colorless
oil. Data for 5: Rf 0.36 (5% EtOAc in hexanes); IR (thin film)
2931, 2854, 1747, 1153, 1124, 631 cm-1; 1H NMR (CDCl3, 300
MHz) δ 4.92 (s, 2H), 2.48 (tt, 1H, J ) 11.0, 3.8 Hz), 2.02 (br d,
2H), 1.78 (m, 2H), 1.67 (m, 1H), 1.51-1.45 (m, 2H), 1.40-1.20
(m, 3H); 13C NMR (CDCl3, 75 MHz) δ 173.9 (C), 76.4 (CH2),
Gen er a l P r oced u r e for th e Syn th esis of Am id es u sin g
(Me2N)3P . To a 0.1 M solution of tribromoethyl ester (1 equiv),
amine or amine hydrochloride (1 equiv), and NEt3 (2.5-3
equiv) in DMF at -55 °C was added (Me2N)3P (1.2 equiv)
dropwise. The reaction mixture was stirred at -55 °C for 30
min. The reaction mixture was diluted with Et2O (20 mL) and
washed with 2 M HCl. The aqueous phase was extracted with
Et2O, and the combined organics were washed with saturated
NaCl and H2O, dried (MgSO4), filtered, and concentrated.
Purification by flash chromatography (EtOAc-hexanes) af-
forded the amide product.
N,N-Dieth ylben za m id e (7b).36 Amide 7b was obtained in
76% yield (38.5 mg) from 2a and diethylamine as a colorless
oil (flash chromatography 40% EtOAc in hexanes). Data for
7b: Rf 0.32 (50% EtOAc in hexanes); IR (thin film) 2986, 2942,
1655, 1427, 1287, 1096 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.39-7.31 (m, 5H), 3.53 (br s, 2H), 3.23 (br s, 2H), 1.23 (br s,
3H), 1.09 (br s, 3H); 13C NMR (CDCl3, 75 MHz) δ 171.1 (C),
137.1 (C), 128.9 (CH), 128.2 (CH × 2), 126.1 (CH × 2), 43.1
(CH2), 39.0 (CH2), 14.0 (CH3), 12.8 (CH3); MS (EI) m/e (relative
intensity, assignment) 177.1 (31.5, M+), 105.0 (100, C6H5CO+).
N-Ben zoylglycin e Eth yl Ester (7c).37 Amide 7c was
obtained in 77% yield (25.2 mg) from 2a and glycine ethyl ester
hydrochloride as a colorless oil (flash chromatography 40%
EtOAc in hexanes). Data for 7c: Rf 0.36 (60% EtOAc in
hexanes); IR (thin film) 3336, 3063, 2981, 2937, 1751, 1642,
1
1533, 1200 cm-1; H NMR (CDCl3, 300 MHz) δ 7.82 (m, 2H),
7.48 (tt, 1H, J ) 7.4, 1.3 Hz), 7.41 (m, 2H), 6.76 (br s, 1H),
4.26 (q, 2H, J ) 7.2 Hz), 4.23 (d, 2H, J ) 5.0 Hz), 1.31 (t, 3H,
J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 170.1 (C), 167.4 (C),
133.7 (C), 131.7 (CH), 128.6 (CH × 2), 127.0 (CH × 2), 61.6
(CH2), 41.9 (CH2), 14.1 (CH3); MS (EI) m/e (relative intensity,
assignment) 207.1 (14.8, M+), 134.1 (25.2, M+ - CO2C2H5)
105.0 (100, C6H5CO+).
42.8 (CH), 36.2 (C), 28.8 (CH2 × 2), 25.6 (CH2), 25.2 (CH2
×
2); MS (EI) m/e (relative intensity, assignment) 392.8 (13.2),
306.9 (23.8), 264.8 (11.8, CH2CBr3+) 127.0 (58.2, M+
-
CH2CBr3), 111.1 (100, M+ -OCH2CBr3) 83.1 (60.7, C6H11+);
isotope pattern calculated for C9H13Br3O2 matches that ob-
served.
N-(ter t-Bu toxyca r bon yl)-L-a la n in e
2,2,2-Tr ibr om o-
N-Bu tylcycloh exa n eca r boxa m id e (8a ).38 Amide 8a was
obtained in 88% yield (41.9 mg) from 5 and butylamine as a
white solid (flash chromatography gradient elution 30% to 40%
EtOAc in hexanes). Data for 8a : Rf 0.33 (40% EtOAc in
hexanes); IR (thin film) 3295, 3083, 2930, 2854, 1642, 1551,
1447 cm-1; 1H NMR (CDCl3, 300 MHz) δ 5.85 (br s, 1H), 3.27-
3.20 (br q, 2H, J ) 7.2 Hz), 2.08 (tt, 1H, J ) 11.8, 3.5 Hz),
1.90-1.16 (m, 14H), 0.92 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3,
75 MHz) δ 176.0 (C), 45.5 (CH), 38.9 (CH2), 31.7 (CH2), 29.6
(CH2 × 2), 25.7 (CH2 × 3), 19.9 (CH2), 13.6 (CH3); MS (EI) m/e
(relative intensity, assignment) 183.2 (46.4, M+), 168.1 (16.5,
eth yl Ester (6). To a slurry of DMAP (66 mg, 0.54 mmol),
DMAP‚TFA (125 mg, 0.529 mmol), and diisopropylcarbodiim-
ide (90 µL, 0.57 mmol) in 2.4 mL of CH2Cl2 was added a
solution of N-(tert-butoxycarbonyl)-L-alanine (101 mg, 0.534
mmol) and 2,2,2-tribromoethanol (178 mg, 0.629 mmol) in 1.0
mL of CH2Cl2 plus two 0.5 mL rinses via cannula. The reaction
mixture was stirred at ambient temperature for 17.5 h. The
reaction mixture was diluted with CH2Cl2 (15 mL) and washed
with 2 M HCl. The aqueous phase was extracted with
CH2Cl2, and the combined organics were dried (MgSO4),
filtered, and concentrated. Purification by flash chromatogra-
phy (20% EtOAc in hexanes) provided 209 mg of 6 (6.54 mmol,
86%) as a yellow oil. Data for 6: Rf 0.47 (20% EtOAc in
M+ - CH3), 154.1 (17.8, M+ - CH2CH3) 128.1 (82.4, C7H14
NO+), 111.1 (42.5, M+ - NH(CH2)3CH3), 83.1 (100, C6H11+).
-
N,N-Dieth ylcycloh exa n eca r boxa m id e (8b).38b Amide 8b
was obtained in 57% yield (29.6 mg) from 5 and diethylamine
as a colorless oil (flash chromatography 40% EtOAc in hex-
anes). Data for 8b: Rf 0.22 (30% EtOAc in hexanes); IR (thin
film) 2970, 2929, 2854, 1638, 1449, 1429 cm-1; 1H NMR (CDCl3,
300 MHz) δ 3.36 (q, 2H, J ) 7.2 Hz), 3.32 (q, 2H, J ) 7.2 Hz),
2.40 (tt, 1H, J ) 11.4, 3.5 Hz), 1.85-1.45 (m, 7H), 1.35-1.20
hexanes); [R]22 -30.8 (c ) 1.86, EtOH); IR (thin film) 3364,
D
2978, 1760, 1708, 1507, 1158 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 5.07 (br s, 1H,), 4.98 (ABq, 2H, J AB ) 12.2 Hz, ∆νAB ) 91.5
Hz), 4.48 (br quin, 1H, J ) 7.2 Hz), 1.52 (d, 3H, J ) 7.2 Hz),
1.46 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 171.6, (C), 155.0,
(C), 80.1 (C), 77.0 (CH2), 49.3 (CH) 35.0 (C), 28.3 (CH3 × 3),

2120 J . Org. Chem., Vol. 65, No. 7, 2000
Hans et al.
(m, 3H), 1.18 (t, 3H, J ) 7.0 Hz), 1.09 (t, 3H, J ) 7.2 Hz); 13
NMR (CDCl3, 75 MHz) δ 175.3 (C) 41.6 (CH2), 40.7 (CH), 39.9
(CH2), 29.5 (CH2 × 2), 25.8 (CH2 × 2), 25.7 (CH2), 14.9 (CH3),
13.0 (CH3).
C
(C), 133.0 (CH), 130.1 (C), 129.7 (CH × 2), 128.5 (CH × 2),
128.3 (CH × 2), 128.2 (CH), 128.1 (CH × 2), 66.6 (CH2); MS
(EI) m/e (relative intensity, assignment) 212.1 (39.6, M+), 105.0
(100, C6H5CO+), 91.0 (55.4, C6H5CH2+), 77.0 (34.6, C6H5+).
2-P en tyl Ben zoa te (10d ). Ester 10d was obtained in 62%
yield (31.4 mg) from 2a and 2-pentanol as a colorless oil (flash
chromatography 1.5% EtOAc in hexanes). Data for 10d : Rf
0.51 (10% EtOAc in hexanes); IR (thin film) 2960, 2925, 2854,
1718, 1278, 1118 cm-1; 1H NMR (CDCl3, 300 MHz) δ 8.05 (m,
2H), 7.55 (tt, 1H, J ) 7.4, 1.3 Hz), 7.43 (m, 2H), 5.18 (m, 1H),
1.81-1.30 (m, 4H), 1.34 (d, 3H, J ) 6.2 Hz), 0.94 (t, 3H, J )
7.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 166.2 (C), 132.7 (CH),
130.9 (C), 129.5 (CH × 2), 128.3 (CH × 2), 71.5 (CH), 38.2
(CH2), 20.1 (CH3), 18.7 (CH2), 14.0 (CH3); MS (EI) m/e (relative
intensity, assignment) 192.1 (0.9, M+), 123.0 (41.9, C6H5-
CO2H2+), 105.0 (100, C6H5CO+).
N-ter t-Bu toxyca r bon yl-L-a la n yl-L-a la n in e Eth yl Ester
(9).39 Amide 9 was obtained in 70% yield (39.1 mg) from 6 and
L-alanine ethyl ester hydrochloride as a white solid (flash
chromatography 50% EtOAc in hexanes). Data for 9: Rf 0.38
(60% EtOAc in hexanes); [R]22D -48.1 (c ) 1.0, EtOH); IR (thin
film) 3332, 3261, 3075, 2948, 1752, 1688, 1656, 1540, 1521,
1269, 1167 cm-1; 1H NMR (CDCl3, 300 MHz) δ 6.73 (br s, 1H),
5.12 (br s, 1H), 4.55 (quin, 1H, J ) 7.4 Hz), 4.23-4.16 (m, 3H),
1.45 (s, 9H), 1.40 (d, 3H, J ) 7.2 Hz), 1.37 (d, 3H, J ) 7.2 Hz),
1.28, (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 172.7
(C), 172.2 (C), 155.4 (C), 79.5 (C). 61.4 (CH2), 49.9 (CH), 48.0
(CH), 28.3 (CH3 × 3), 18.5 (CH3), 18.3 (CH3), 14.1 (CH3); MS
(EI) m/e (relative intensity, assignment) 288.2 (2.4, M+), 144.1
(100, C4H9O2CNHCHCH3+) 116.1 (43.4, C4H9O2CNH+).
Gen er a l P r oced u r e for th e Syn th esis of Ester s. To a
0.1 M solution of tribromoethyl or trichloroethyl ester (1 equiv),
alcohol (1 equiv), and DMAP (2 equiv) in DMF was added
tributylphosphine (1.5 equiv) dropwise. The reaction mixture
was stirred at ambient temperature for 1-5 h. The reaction
mixture was diluted with Et2O (20 mL) and washed with 2 M
HCl. The aqueous phase was extracted with Et2O, and the
combined organics were washed with saturated NaCl and H2O,
dried (MgSO4), filtered, and concentrated. Purification by flash
chromatography (EtOAc-hexanes) and/or Kugelrohr distilla-
tion afforded the ester product.
Men th yl Ben zoa te (10e).45 Ester 10e was obtained in 61%
yield (39.6 mg) from 2a and (-)-menthol as a colorless oil (flash
chromatography 1.5% EtOAc in hexanes). Data for 10e: Rf
0.63 (10% EtOAc in hexanes); IR (thin film) 2954, 1714, 1274,
710 cm-1; 1H NMR (CDCl3, 300 MHz) δ 8.05 (m, 2H), 7.55 (tt,
1H, J ) 7.3, 1.5 Hz), 7.44 (m, 2H), 4.94 (td, 1H, J ) 10.9, 4.2
Hz), 2.13 (m, 1H), 1.97 (sep d, 1H, J ) 8.8, 2.6 Hz), 1.78-1.68
(m, 2H), 1.63-1.47 (m, 2H), 1.2-0.9 (m, 3H), 0.93 (d, 3H, J )
7.0 Hz), 0.92 (d, 3H, J ) 7.0 Hz), 0.79 (d, 3H, J ) 6.8 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 166.1 (C), 132.6 (CH), 130.8 (C), 129.5
(CH × 2), 128.2 (CH × 2), 74.8 (CH), 47.3 (CH), 41.0 (CH2),
34.3 (CH2), 31.4 (CH), 28.2 (CH), 26.6 (CH2), 23.6 (CH3), 22.0
(CH3), 16.5 (CH3).
2-Meth oxyeth yl Ben zoa te (10a ) fr om 2,2,2-Tr ibr om o-
eth yl Ben zoa te (2a ). Ester 10a 40 was obtained in 69% yield
(51.7 mg) from 2a and 2-methoxyethanol as a colorless oil
(flash chromatography 10% EtOAc in hexanes). Data for 10a :
Rf 0.48 (40% EtOAc in hexanes); IR (thin film) 2986, 1736,
Ben zoic Acid tr a n s-2-P h en ylcycloh exyl Ester (10f).
Ester 10f was obtained in 68% yield (43.0 mg) from 2a and
trans-2-phenylcyclohexanol as a white solid (flash chromatog-
raphy 3% EtOAc in hexanes). Data for 10f: Rf 0.32 (5% EtOAc
in hexanes); IR (thin film) 3061, 3029, 2934, 2858, 1714, 1272,
1704, 1515, 1246, 1167 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1
1110, 711 cm-1; H NMR (CDCl3, 300 MHz) δ 7.82-7.77 (m,
8.08 (m, 2H), 7.55 (tt, 1H, J ) 7.4, 1.3 Hz), 7.43 (m, 2H), 4.48
(m, 2H), 3.73 (m, 2H), 3.43 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 166.4 (C), 132.8 (CH), 129.9 (C), 129.4 (CH × 2), 128.2 (CH
× 2), 70.4 (CH2), 63.9 (CH2), 58.9 (CH3).
2H), 7.48-7.41 (m, 1H), 7.35-7.18 (m, 6H), 7.14-7.07 (m, 1H),
5.18 (td, 1H, J ) 10.5, 4.5 Hz), 2.85 (ddd, 1H, J ) 11.0, 10.8,
3.6 Hz), 2.29 (m, 1H), 2.04-1.77 (m, 3H), 1.72-1.32 (m, 4H);
13C NMR (CDCl3, 75 MHz) δ 165.8 (C), 143.1 (C), 132.5 (CH),
130.6 (C), 129.3 (CH × 2), 128.3 (CH × 2), 128.1 (CH × 2),
127.4 (CH × 2), 126.4 (CH), 76.8 (CH), 49.8 (CH), 33.9 (CH2),
32.4 (CH2), 25.9 (CH2), 24.8 (CH2).
2-Meth oxyeth yl Cycloh exa n eca r boxyla te (11a ). Ester
11a was obtained in 74% yield (33.8 mg) from 5 and 2-meth-
oxyethanol as a colorless oil (flash chromatography 10% EtOAc
in hexanes). Data for 11a : Rf 0.50 (20% EtOAc in hexanes);
Bu tyl Cycloh exa n eca r boxyla te (11b). Ester 11b was
obtained in 65% yield (40.4 mg) from 5 and 1-butanol as a
colorless oil (flash chromatography 1.5% EtOAc in hexanes).
Data for 11b: Rf 0.55 (10% EtOAc in hexanes); IR (thin film)
2858, 2932, 2856, 1733, 1171 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 4.06 (t, 2H, J ) 6.6 Hz), 2.28 (tt, 1H, J ) 11.0, 3.5 Hz), 1.95-
1.84 (m, 2H), 1.79-1.69 (m, 2H), 1.68-1.54 (m, 3H), 1.50-
1.13 (m, 7H), 0.93 (t, 3H, J ) 7.4 Hz); 13C NMR (CDCl3, 75
MHz) δ 176.2 (C), 63.9 (CH2), 43.3 (CH), 30.7 (CH2), 29.0 (CH2
× 2), 25.8 (CH2), 25.5 (CH2 × 2), 19.1 (CH2), 13.7 (CH3); MS
(EI) m/e (relative intensity, assignment) 184.1 (1.5, M+), 129.1
(100, C6H11CO2H2+), 111.1 (73.1, C6H11CO+), 83.1 (98.2, C6H11+).
Ben zyl Cycloh exa n eca r boxyla te (11c). Ester 11c was
obtained in 70% yield (43 mg) from 5 and benzyl alcohol as a
colorless oil (flash chromatography 1.5% EtOAc in hexanes).
Data for 11c: Rf 0.22 (5% EtOAc in hexanes); IR (thin film)
IR (thin film) 2932, 2855, 1734, 1171, 1129 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 4.22 (m, 2H), 3.59 (m, 2H), 3.39 (s, 3H),
2.35 (tt, 1H, J ) 11.2, 3.6 Hz), 1.94-1.89 (m, 2H), 1.80-1.71
(m, 2H), 1.65 (m, 1H), 1.52-1.37 (m, 2H), 1.36-1.13 (m, 3H);
13C NMR (CDCl3, 75 MHz) δ 176.0 (C), 70.5 (CH2), 63.1 (CH2),
58.9 (CH3), 42.9 (CH), 28.9 (CH2), 25.6 (CH2), 25.3 (CH2); MS
(EI) m/e (relative intensity, assignment) 186.1 (1.5, M+), 111.1
(64.0, C6H11CO+), 83.1 (87.8, C6H11+) 58.0 (100 C3H6O+).
Bu tyl Ben zoa te (10b).43 Ester 10b was obtained in 81%
yield (51.8 mg) from 2a and 1-butanol as a colorless oil after
flash chromatography (1.5% EtOAc in hexanes) followed by
Kugelrohr distillation. Data for 10b: Rf 0.42 (10% EtOAc in
hexanes); IR (thin film) 2958, 1720, 1274, 709 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 8.05 (m, 2H), 7.55 (tt, 1H, J ) 7.4, 1.3
Hz), 7.43 (m, 2H), 4.33 (t, 2H, J ) 6.7 Hz), 1.81-1.70 (m, 2H),
1.55-1.41 (m, 2H), 0.98 (t, 3H, J ) 7.3 Hz); 13C NMR (CDCl3,
75 MHz) δ 166.7 (C), 132.7 (CH), 130.5 (C), 129.5 (CH × 2),
128.3 (CH × 2), 64.8 (CH2), 30.8 (CH2), 19.2 (CH2), 13.7 (CH3);
MS (EI) m/e (relative intensity, assignment) 178.1 (3.2, M+),
123.0 (85.4, C6H5CO2H2+), 105.0 (100, C6H5CO+).
2932, 2854, 1733, 1165 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.39-7.29 (m, 5H), 5.11 (s, 2H), 2.35 (tt, 1H, J ) 11.2, 3.5 Hz),
1.98-1.87 (m, 2H), 1.80-1.70 (m, 2H), 1.68-1.59 (m, 1H),
1.54-1.38 (m, 2H), 1.36-1.13 (m, 3H); 13C NMR (CDCl3, 75
MHz) δ 175.9 (C), 136.3 (C), 128.5 (CH × 2), 128.0 (CH), 127.9
(CH × 2), 65.8 (CH2), 43.2 (CH), 29.0 (CH2 × 2), 25.7 (CH2),
25.4 (CH2 × 2); MS (EI) m/e (relative intensity, assignment)
218.1 (40.6, M+), 111.1 (45.1, C6H11CO+), 91.0 (100, C6H5CH2+),
83.1 (98.2, C6H11+).
Ben zyl Ben zoa te (10c).44 Ester 10c was obtained in 77%
yield (40.3 mg) from 2a and benzyl alcohol as a colorless oil
(flash chromatography 1.5% EtOAc in hexanes). Data for
10c: Rf 0.58 (20% EtOAc in hexanes); IR (thin film) 3063,
3033, 1719, 1271, 1109, 711 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 8.08 (m, 2H), 7.54 (tt, 1H, J ) 7.3, 1.3 Hz), 7.47-7.30 (m,
7H), 5.36 (s, 2H); 13C NMR (CDCl3, 75 MHz) δ 166.4 (C), 136.0
2-P en tyl Cycloh exa n eca r boxyla te (11d ). Ester 11d was
obtained in 63% yield (34.9 mg) from 5 and 2-pentanol as a
colorless oil after flash chromatography (1.5% EtOAc in
hexanes) followed by Kugelrohr distillation. Data for 11d : Rf
(43) Paredes, R.; Bastos, H.; Montoya, R.; Chavez, A. L.; Dolbier,
W. R.; Burkholder, C. R. Tetrahedron 1988, 44, 6821-6830.
(44) Chen, P.-S.; Chou, C.-H. J . Chin. Chem. Soc. (Taipei) 1994, 41,
597-600.
(45) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J . Org.
Chem. 1996, 61, 4560-4567.

Transacylation of 2,2,2-Trihaloethyl Esters
J . Org. Chem., Vol. 65, No. 7, 2000 2121
0.28 (5% EtOAc in hexanes); IR (thin film) 2933, 2856, 1729,
(CH2), 22.6 (CH2), 14.1 (CH3); MS (FAB + NaI) m/e (relative
intensity, assignment) 587.0 (100, M + Na+).
1
1173 cm-1; H NMR (CDCl3, 300 MHz) δ 4.90 (m, 1H), 2.25
(tt, 1H, J ) 11.0, 3.5 Hz), 1.94-1.83 (m, 2H), 1.80-1.21 (m,
12H), 1.18 (d, 3H, J ) 6.2 Hz), 0.90 (t, 3H, J ) 7.2 Hz); 13C
NMR (CDCl3, 75 MHz) δ 175.8 (C), 71.1 (CH), 43.5 (CH), 38.1
(CH2), 29.1 (CH2), 29.0 (CH2), 25.8 (CH2), 25.5 (CH2), 25.4
(CH2), 20.0 (CH3), 18.6 (CH2), 13.9 (CH3); MS (EI) m/e (relative
intensity, assignment) 198.2 (0.35, M+), 155.1 (7.4, M+ - C3H7),
129.1 (88.3, C6H11CO2H2+), 111.1 (92.2, C6H11CO+), 83.1 (100,
C6H11+).
12-ter t-Bu toxyca r bon yla m in od od eca n oic Acid 2,2,2-
Tr ibr om oeth yl Ester (17). A slurry of 12-aminododecanoic
acid (364 mg, 1.69 mmol) and di-tert-butyl dicarbonate (790
mg, 3.62 mmol) in 2.5 mL of 10% v/v triethylamine in methanol
was refluxed until the reaction mixture became homogeneous
(10 min). The reaction mixture was then concentrated to afford
578 mg of the crude triethylammonium N-BOC-12-aminodode-
canoate salt as a white solid. This solid and 2,2,2-tribromo-
ethanol (586 mg, 2.07 mmol) were dissolved in 6.0 mL of CH2-
Cl2 and added dropwise via cannula to a slurry of DMAP (206
mg, 1.68 mmol), DMAP‚TFA (437 mg, 1.85 mmol), and DIC
(0.30 mL, 1.90 mmol) in 5 mL of CH2Cl2. The reaction mix-
ture was stirred at ambient temperature for 2.5 h. The reac-
tion mixture was then diluted with CH2Cl2 (20 mL) and
washed with 2 M HCl. The aqueous phase was extracted with
CH2Cl2, and the combined organics were dried (MgSO4),
filtered, and concentrated. Purification by flash chromatogra-
phy (gradient elution, 20-10% hexanes in CHCl3/5% methanol
in CHCl3) provided 720 mg of 17 (1.24 mmol, 73%) as a white
solid. Data for 17: Rf 0.53 (CHCl3); IR (thin film) 3356 (br),
Men th yl Cycloh exa n eca r boxyla te (11e). Ester 11e was
obtained in 65% yield (34.4 mg) from 5 and (-)-menthol as a
colorless oil (flash chromatography 1.5% EtOAc in hexanes).
Data for 11e: Rf 0.65 (30% EtOAc in hexanes); IR (thin film)
2931, 2856, 1728, 1172 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
4.65 (td, 1H, J ) 10.8, 4.2 Hz), 2.26 (tt, 1H, J ) 11.0, 3.7 Hz),
2.00-0.80 (m, 19H), 0.90, (d, 3H, J ) 6.4 Hz), 0.89 (d, 3H, J
) 7.0 Hz), 0.74 (d, 3H, J ) 7.0 Hz); 13C NMR (CDCl3, 75 MHz)
δ 175.7 (C), 73.5 (CH), 47.1 (CH), 43.5 (CH), 40.9 (CH2), 34.3
(CH2), 31.3 (CH), 29.1 (CH2), 29.0 (CH2), 26.1 (CH), 25.8 (CH2),
25.5 (CH2), 25.4 (CH2), 24.2 (CH2), 23.3 (CH3), 22.0 (CH3), 16.1
(CH3); MS (FAB + NaI) m/e (relative intensity, assignment)
289.3 (54.8, M + Na+), 139.2 (100.0, C10H19+).
1
3231 (br), 2924, 2854, 1752, 1703, 1518, 1249, 1172 cm-1; H
NMR (CDCl3, 300 MHz) δ 4.93 (s, 2H), 4.48 (m, 1H), 3.09 (br
q, 2H, J ) 6.9 Hz), 2.48 (t, 2H, J ) 7.8 Hz), 1.71 (quin, 2H J
) 7.5 Hz), 1.50-1.23 (m, 16 H), 1.44 (s, 9H); 13C NMR (CDCl3,
75 MHz) δ 172.0 (C), 156.0 (C), 79.0 (C), 76.7 (CH2), 40.6 (CH2),
36.0 (C), 34.1 (CH2), 30.0 (CH2), 29.5 (CH2 × 2), 29.4, (CH2)
29.3 (CH2), 29.2 (CH2), 29.0 (CH2), 28.4 (CH3 × 3), 26.8 (CH2),
24.8 (CH2); MS (FAB + NaI) m/e (relative intensity, assign-
ment) 602.0 (100, M + Na+).
ter t-Bu tyl Ben zoa te (10g).46 To a solution of 2a (101 mg,
0.261 mmol) and DMAP (60.5 mg, 0.52 mmol) in 2.6 mL of 1:1
v/v tert-butyl alcohol/DMF was added tributylphosphine (0.13
mL, 0.52 mmol) dropwise. The reaction mixture was stirred
at ambient temperature for 6.2 h. The reaction mixture was
diluted with Et2O (20 mL) and washed with 2 M HCl. The
aqueous phase was extracted with Et2O, and the combined
organics were washed with saturated NaCl and H2O, dried
(MgSO4), filtered, and concentrated. Purification by flash
chromatography (1.5% EtOAc in hexanes) followed by Kugel-
rohr distillation afforded 5.0 mg of 10g (0.028 mmol, 11%) as
a colorless oil. Data for 10g: Rf 0.59 (20% EtOAc in hexanes);
La cton e 18.47 To DMAP (118 mg, 0.966 mmol) and tribu-
tylphosphine (0.10 mL, 0.40 mmol) in 10 mL of DMF at 100
°C was added a solution of 15 in 40 mL of DMF via syringe
pump over 10 h. The reaction solution was stirred at 100 °C
for an additional 12 h and then allowed to cool. The reaction
mixture was diluted with Et2O (100 mL) and washed with 2
M HCl. The aqueous phase was extracted with Et2O, and the
combined organics were washed with saturated NaCl and H2O,
dried (MgSO4), filtered, and concentrated. Purification by flash
chromatography (gradient elution 3-20% EtOAc in hexanes)
afforded 2.5 mg of 18 (0.088 mmol, 9%) as a colorless film.
Data for 18: Rf 0.54 (10% EtOAc in hexanes); 1H NMR (CDCl3,
300 MHz) δ 4.88 (br quin, 1H, J ) 5.5 Hz), 2.28 (m, 2H), 1.74-
1.38 (m, 6H), 1.35-1.17 (m, 22H), 0.90-0.84 (m, 3H).
IR (thin film) 2964, 2928, 2871, 1729, 1275 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 8.00, (m, 2H), 7.52 (tt, 1H, J ) 7.4, 1.4
Hz), 7.41 (m, 2H), 1.60 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ
165.5 (C), 132.4 (CH), 132.0 (C), 129.4 (CH × 2), 128.2 (CH ×
2), 118 (C), 80.5 (C), 28.2 (CH3 × 3); MS (EI) m/e (relative
intensity, assignment) 178.1 (1.8, M+), 123.0 (96.7, C6H5-
CO2H2+), 105.0 (100, C6H5CO+).
2,2,2-Tr ibr om oeth yl 12-h ydr oxystear ate (15). To a slurry
of DMAP (202 mg, 1.65 mmol), DMAP‚TFA (402 mg, 1.70
mmol), 12-hydroxystearic acid (504 mg, 1.68 mmol), and 2,2,2-
tribromoethanol (2.35 g, 8.31 mmol) in 10 mL of CH2Cl2 was
added a solution of diisopropylcarbodiimide (DIC, 0.29 mL,
1.85 mmol) in 7 mL of CH2Cl2 via cannula over 1 h. The
reaction mixture was stirred at ambient temperature for an
additional 4 h. The reaction mixture was then washed with 2
M HCl. The aqueous phase was extracted with CH2Cl2, and
the combined organics were dried (MgSO4), filtered, and
concentrated. Purification by flash chromatography (15%
EtOAc in hexanes) provided 489 mg of 15 (0.865 mmol, 52%)
as a yellow oil. Data for 15: Rf 0.28 (10% EtOAc in hexanes);
Ack n ow led gm en t. This research was supported by
NIH Grants GM 28321 and CA74394. Additional sup-
port from Abbott, Wyeth-Ayerst, Merck, and Pfizer is
gratefully acknowledged. The University of Wisconsin
NMR facility receives financial support from NSF (CHE-
9208463) and NIH (1S10 RR0 8389-D1).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 2b, 7a (Table 2, entries 2 and 6), 10a (Table 4,
entry 3, and Table 5, entry 13), and 11a (Table 4, entry 5). 1H
and 13C NMR spectra for compounds 2a ,b, 5, 6, 7a -c, 8a ,b,
9, 10a -e, and 11a -e. This material is available free of charge
via the Internet at http://pubs.acs.org.
IR (thin film) 3324 (br), 3231 (br), 2922, 2851, 1750, 1152 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 4.92 (s, 2H), 3.57 (m, 1H), 2.47
(t, 2H, J ) 7.8 Hz), 1.80-1.65 (m, 2H), 1.49-1.25 (m, 27 H),
0.88 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 172.0 (C), 76.7
(CH2), 72.0 (CH), 37.5 (CH2), 37.5 (CH2), 36.0 (C), 34.0 (CH2),
31.8 (CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.4
(CH2), 29.2 (CH2), 29.0, (CH2) 25.6 (CH2), 25.6 (CH2), 24.8
J O991711M
(47) (a) Shono, T.; Ishige, O.; Uyama, H.; Kashimura, S. J . Org.
Chem. 1986, 51, 546-549. (b) Inanaga, J .; Hirata, K.; Saeki, H.;
Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. J pn. 1979, 52, 1989-
1993.
(46) Barluenga, J .; Alonso-Cires, L.; Campos, P. J .; Asensio, G.
Synthesis 1983, 649-651.