Amide-forming ligation of acyltrifluoroborates and hydroxylamines in water

Article abstract of DOI:10.1002/anie.201201077

Come together, right now: Acyltrifluoroborates and O-benzoyl hydroxylamines come together to form amides in water (see scheme). The ligations are complete within minutes at room temperature and do not require any reagents or catalysts. The reaction has a broad substrate scope and tolerates unprotected functional groups. Copyright

Full text of DOI:10.1002/anie.201201077

Angewandte
Chemie
DOI: 10.1002/anie.201201077
Amide Ligation
Amide-Forming Ligation of Acyltrifluoroborates and Hydroxylamines
in Water**
Aaron M. Dumas, Gary A. Molander, and Jeffrey W. Bode*
Amides are among the most prevalent organic functional
groups, especially as components of natural products and
pharmaceuticals and as the backbone of peptides.[1,2] The
most common means of preparing amides is the dehydrative
coupling of amines with carboxylic acids, but the need to fully
protect other functional groups and to employ excess amounts
of coupling reagents renders it increasingly unattractive in
comparison to a new generation of bond-forming reactions.
Carbon–carbon bonds, for example, are now routinely
prepared from prefunctionalized reagents, such as boronic
acids, using operationally simple and catalytic conditions,
which tolerate unprotected functional groups. Amide-forming
reactions that meet these strict criteria have the potential to
facilitate small-molecule drug discovery and enable chemo-
selective bioconjugation reactions. Our group and others have
therefore sought to identify mechanistically unique amide-
forming reactions from precursors other than amines and
carboxylic acids.[3–7]
Our discovery arose from the combination of our interest
in new amide-forming ligations and our previous synthesis of
acyltrifluoroborate 1a.[8] It was also reported that 1a reacts
with azides in an HBF4-promoted process to form amides.
This transformation is related to the elegant work of
Matteson and Kim on the preparation of secondary amines
from alkyldihaloboranes and azides.[9] This amide-forming
reaction had limitations in the form of a narrow substrate
scope and the need for a strong fluorophilic reagent. We
hypothesized that acyltrifluoroborates could instead serve as
surrogates for a-ketoacids in amide-forming ligations with
hydroxylamines.[10] We found that O-unsubstituted hydroxyl-
amines reacted with acyltrifluoroborates to give stable nitro-
nes rather than amides.[11] In contrast, and disclosed herein,
O-benzoyl hydroxylamines[12] underwent rapid amide forma-
tion in aqueous solvents without the need for reagents or
catalysts.
Our initial studies were performed using phenylacetyl
trifluoroborate (1a) and O-benzoyl hydroxylamine 2a. A
solvent screen, in which the reactions were performed in the
presence or in the absence of oxalic acid, revealed that
aqueous mixtures were particularly well suited for the
reaction (Table 1). In contrast to the reaction of a-ketoacids,
reactions performed in polar aprotic solvents such as DMSO
and DMF, in the absence of water or acid, were ineffective
As part of our continuing efforts towards this goal we now
disclose a rapid and remarkably simple amide-forming
ligation using acyltrifluoroborates and O-benzoyl hydroxyl-
amines [Eq. (1); Bz = benzoyl]. This chemoselective amida-
tion occurs in water at room temperature without the need for
reagents or catalysts. These reactions represent a new
approach to amide formation and establish acyltrifluorobo-
rates as robust, synthetically useful reagents that serve as
prefunctionalized monomers for predictable cross-coupling
reactions.
Table 1: Solvent screening for the ligation of acyltrifluoroborate 1a.[a]
Entry Conditions
T [8C] [1a]
Result
1[b]
2[b]
[D6]DMSO or DMF
DMF, (CO2H)2 (1 equiv) 40
40
0.1m No reaction
0.1m 90% conversion of
1a
[*] Dr. A. M. Dumas, Prof. Dr. J. W. Bode
Laboratorium fꢀr Organische Chemie
3
4
THF
7:3 THF/H2O
RT
RT
0.1m 1a not soluble
0.1m Full conversion of 1a
after 30 min
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology (ETH) Zꢀrich
Wolfgang Pauli Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: bode@org.chem.ethz.ch
5
6
MeOH
1:1 H2O/tBuOH
RT
RT
0.1m Methanolysis of 2a
0.1m Full conversion of 1a
after 15 min
Homepage: http://www.bode.ethz.ch/
7
1:1 H2O/tBuOH,
(CO2H)2 (1 equiv)
1:1 H2O/tBuOH
RT
RT
RT
0.1m Full conversion of 1a
after 15 min
0.01m Full conversion of 1a
after 30 min
0.1m Full conversion of 1a
after 15 min
Prof. Dr. G. A. Molander
Roy and Diana Vagelos Laboratories
University of Pennsylvania
8[c]
9
Philadelphia, PA 19106 (USA)
1:1 LB medium/tBuOH
(protein digests)
[**] This work was supported by ETH Research Grant ETH-12 11-1 and
the ETH-Zꢀrich. We are grateful to Noel Ellis (Univ. Penn.) for a gift
of 1a and to David Furrer, Lei Ju, and Shouyun Yu for preliminary
experiments.
[a] 1a (0.05 mmol), 2a (0.055 mmol), solvent (0.5 mL), 30 min.
[b] Reaction time of 6 h. [c] Reaction time of 1 h; 5 mL of solvent.
DMF=dimethylformamide, DMSO=dimethyl sulfoxide, LB=lysogeny
broth, THF=tetrahydrofuran.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201077.
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(Table 1, entry 1). In some cases, the insolubility of the
trifluoroborate prevented the reaction, as in THF for example
(Table 1, entry 3); however, in aqueous THF, in which the
acyltrifluoroborate was soluble, the ligation proceeded
cleanly (Table 1, entry 4). Our preferred solvent system was
1:1 H2O/tBuOH because the acyltrifluoroborate was soluble
and the reaction was rapid and clean, with full conversion
being achieved within 15 minutes at room temperature at
0.1m substrate concentration (Table 1, entries 6 and 7). Even
upon dilution of the reaction mixture by 10-fold, full
conversion of the acyltrifluoroborate was observed within
30 minutes at 238C (Table 1, entry 8). A ligation performed in
a solution of protein digests (LB medium, 10 mgmLÀ1 in
peptide fragments) occurred smoothly, thus indicating that
the ligation can be performed in the presence of unprotected
functional groups and is chemoselective (Table 1, entry 9).
The ligation was remarkably general with respect to the
acyl donor; all acyltrifluoroborates subjected to the reaction
thus far have given the expected amide product in good yield
(Scheme 1). Monitoring the reactions by LC/MS indicated
that complete conversion was often achieved in less than
5 minutes at 0.1m; the experiments were allowed to run for
30 minutes in the interests of convenience. Bulky 1-naph-
thoyltrifluoroborate (1k) was the only substrate that required
longer reaction times (1 hour). In the phenylacetyl series,
both a-unsubstituted (1a and 1b) and branched substrates
(1c) reacted to form amides within the same amount of time
(30 minutes at 238C). Alkyl-substituted acyltrifluoroborates,
even those with long hydrocarbon chains, such as 1e, were
also fully soluble in the aqueous solvent; this solubility is
attributable to the high polarity of the trifluoroborate moiety.
Benzoyltrifluoroborates 1g–l were also excellent reaction
partners; in contrast, the corresponding a-ketoacids reacted
sluggishly. The reaction was compatible with the presence of
unprotected alcohols (3m), aldehydes (3n), carbamates (3o
and 3p), and alkyl chlorides (3q).
A preliminary evaluation of a series of O-benzoyl
hydroxylamines showed that the reaction was also general
with respect to this substrate (Table 2). Ligation with cyclo-
hexenyl-containing hydroxylamine 2b, designed as a mecha-
nistic probe for nitrone intermediates,[13] gave amide 3r
cleanly (Table 2, entry 1). Compatibility of the reaction with
esters and carbamate-protected amines, which is important
for future extensions of this method, was demonstrated by the
reactions of 2c and 2d. Branched amine 2e was unreactive
Table 2: Ligation of 1a with O-benzoyl hydroxylamines and isoxazolidi-
nes.[a]
Entry
1
RO-NHR1
Product
Yield [%]
82
2b
3r
2
90
96
79
88
2c
2d
2e
4
3s
3t
3u
5
3
4[b]
5[b,c]
6[d]
99
Scheme 1. Ligation of acyltrifluoroborates with O-benzoyl hydroxyla-
mine 2a. Reaction conditions: acyltrifluoroborate (0.10 mmol), 2a
(0.11 mmol), 1:1 H2O/tBuOH (1 mL), RT, 30 min. [a] Yield in paren-
theses is for reaction performed in 1:1 LB medium/tBuOH. [b] Reac-
tion time of 1 h. [c] After 30 min at RT, reaction warmed to 608C for
30 min. Cbz=benzyloxycarbonyl.
6
7
[a] 1a (0.10 mmol), RONHR1 (0.11 mmol), 1:1 H2O/tBuOH (1 mL), RT,
30 min. [b] Solvent contained 0.1m oxalic acid [c] After 5 min at RT,
warmed to 408C for 4.5 h. [d] After 30 min at RT, warmed to 608C for
30 min. Bn=benzyl, Boc=tert-butoxy carbonyl.
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under the standard reaction conditions; however, the addition
of oxalic acid (1 equivalent) to the reaction mixture resulted
in clean conversion to amide 3u within 1 hour. In contrast,
a-ketoacids do not undergo ligation with 2e under any
conditions. As expected from previous investigations of
reactions involving a-ketoacids, isoxazolidines were excellent
substrates;[14] 4 reacted to give ketoester 5 in 88% yield. In
this case, LC/MS analysis of the reaction mixture indicated
that an iminium adduct was formed as an intermediate;
increasing the temperature of the reaction mixture to 408C
caused a gradual decrease in the concentration of this species
with simultaneous appearance of amide 5. Intriguingly, the
iminium adduct 7 was the only product formed from the
reaction of isoxazolidine 6; 7 did not transform into the
expected amide even after heating the reaction mixture at
608C for 2 hours.
Three general pathways for amide formation can be
envisioned (Scheme 3). In the first pathway, amide formation
proceeds via acyldifluoroborane 9 (Scheme 3, path A) fol-
The acyltrifluoroborates appear to be far more reactive
than a-ketoacids in amide-forming ligations with O-benzoyl
hydroxylamines: reactions of acyltrifluoroborates were com-
plete within minutes at 238C, whereas those of a-ketoacids
generally required longer reaction times at higher temper-
atures. The relative rates of reaction of the two substrate
classes was determined by conducting a competition reaction
involving the acyltrifluoroborates and a-ketoacids
(Scheme 2); these reactions were performed at 408C because
Scheme 3. Possible mechanisms for the ligation of acyltrifluoroborates
with O-benzoyl hydroxylamines.
lowed by 1,2-migration, a pathway, which parallels the known
reactivity of organoboranes and O-benzoyl hydroxylamines
to give amines.[15] Such reactions, however, generally require
À
a fluorophile to break the strong B F bond. In the other two
pathways, the hydroxylamine would attack the electrophilic
carbonyl group of the acyltrifluoroborate to form hemiaminal
10, which would proceed to the amide by concerted elimi-
nation (path B) or via nitrilium 12 generated from iminium 11
(path C). The involvement of an oxaziridine intermediate, 13,
a species involved in the ligation of a-ketoacids and hydroxyl-
amines, cannot be completely ruled out at this point.[16] It is
also possible that hydrolysis of the trifluoroborate to a boronic
acid occurs as part of the process, although such intermediates
have not been observed to date.
Some observations made in the course of our studies
suggest that path A is unlikely (Scheme 4). Firstly, the
formation of iminium 7 under the ligation conditions dem-
onstrates that interaction of the nucleophilic nitrogen atom
with the carbonyl group can occur (Table 2, entry 6). Sec-
ondly, during the ligation of acyltrifluoroborate 1m, two
intermediates with m/z [M+H]+ 204 were observed by
Scheme 2. Competition experiments between acyltrifluoroborates and
a-ketoacids; percent values are relative integrations of the correspond-
ing peaks in the LC/MS trace.
the ketoacids do not react at all at room temperature. In
a reaction with O-benzoyl hydroxylamine 2a, acyltrifluoro-
borate 1b was consumed 50 times faster than a-ketoacid 8a
(Scheme 2a). In the case of the benzoyl derivatives 1h and
8b, only the product derived from the acyltrifluoroborate was
observed in the crude reaction mixture (Scheme 2b). The
same result was observed in the competition reaction involv-
ing acyltrifluoroborate 1b and a-ketoacid 8a with branched
hydroxylamine 2e or isoxazolidine 4 (not shown). In the case
of isoxazolidine 4, rapid consumption of 4 by condensation to
an iminium ion involving 1b effectively prevented any
reaction with the a-ketoacid.
Scheme 4. Intermediates observed during ligation of 1m and 2a.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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LC/MS analysis of the reaction mixture shortly after the
reaction had begun; upon warming the reaction to 608C these
intermediates were consumed, with concomitant formation of
the expected amide 3m. The most likely identity of these
compounds is imine 14 and enamine 15,[17] both of which are
feasible products arising from intermediates involved in
path B or C, and unlikely to be formed by a direct acyl
migration as in path A. Although these observations cannot
distinguish path B from C, they strongly suggest that the key
interaction is between the hydroxylamine and the carbonyl
carbon, and not between the hydroxylamine and the boron
atom.
[1] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451 –
3479.
[2] The Amide Linkage: Selected Structural Aspects in Chemistry,
Biochemistry and Materials Science (Eds.: A. Greenburg, C. M.
Breneman, J. F. Liebman), Wiley, New York, 2000.
[3] V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471 – 479.
[4] a) E. Saxon, J. I. Armstrong, C. R. Bertozzi, Org. Lett. 2000, 2,
2141 – 2143; b) B. L. Nilsson, L. L. Kiessling, R. T. Raines, Org.
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[5] N. Shangguan, S. Katukojvala, R. Greenberg, L. J. Williams, J.
Am. Chem. Soc. 2003, 125, 7754 – 7755.
[6] B. Shen, D. M. Makley, J. N. Johnston, Nature 2010, 465, 1027 –
1032.
In summary, we have demonstrated that acyltrifluorobo-
rates are extremely reactive acyl donors for ketoacid/hydrox-
ylamine (KAHA) type ligations with O-benzoyl hydroxyl-
amines and isoxazolidines. The reactions occurred within
minutes at room temperature and are chemoselective, high
yielding, and operationally simple. The use of acyltrifluor-
oborates permitted an expansion of the scope to include
substrates that are poor partners in the ligation of a-ketoacids
and O-benzoyl hydroxylamines. Combined with our efforts to
develop more elaborately functionalized acyltrifluoroborates,
we believe that this mechanistically distinct and remarkably
facile variant of the KAHA ligation will find new applica-
tions.
[7] a) X. Wu, J. L. Stockdill, P. Wang, S. J. Danishefsky, J. Am.
Chem. Soc. 2010, 132, 4098 – 4100; b) Y. Yuan, J. Zhu, X. Li, X.
Wu, S. J. Danishefsky, Tetrahedron Lett. 2009, 50, 2329 – 2333.
[8] G. A. Molander, J. Raushel, N. M. Ellis, J. Org. Chem. 2010, 75,
4304 – 4306.
[9] D. S. Matteson, G. Y. Kim, Org. Lett. 2002, 4, 2153 – 2155.
[10] J. W. Bode, R. M. Fox, K. D. Baucom, Angew. Chem. 2006, 118,
1270 – 1274; Angew. Chem. Int. Ed. 2006, 45, 1248 – 1252.
[11] A. Dumas, J. W. Bode, Org. Lett. 2012, DOI: 10.1021/ol300668m.
[12] O-Benzoyl hydroxylamines are easily prepared from the corre-
sponding amines by reaction with benzoyl peroxide, see: a) Q. X.
Wang, J. King, O. Phanstiel, J. Org. Chem. 1997, 62, 8104 – 8108;
for their ligation with a-ketoacids, see: b) J. S. Arora, N. Kaur, O.
Phanstiel, J. Org. Chem. 2008, 73, 6182 – 6186; c) L. Ju, J. W.
Bode, Org. Synth. 2010, 87, 218 – 225.
[13] W. Oppolzer, S. Siles, R. L. Snowden, B. H. Bakker, M.
Petrzilka, Tetrahedron 1985, 41, 3497 – 3509.
[14] N. Carrillo, E. A. Davalos, J. A. Russak, J. W. Bode, J. Am.
Chem. Soc. 2006, 128, 1452 – 1453.
[15] Trialkylboranes are known to react with O-benzoyl hydroxyl-
amines to give secondary amines, see: O. Phanstiel, Q. X. Wang,
D. H. Powell, M. P. Ospina, B. A. Leeson, J. Org. Chem. 1999, 64,
803 – 806.
Experimental Section
Ligation of 1 f and 2a to form amide 3 f: Hydroxylamine 2a (26.1 mg,
0.11 mmol) was dissolved in 1:1 H2O/tBuOH (1 mL) at RT. Acyltri-
fluoroborate 1 f (25.4 mg, 0.10 mmol) was added and the reaction
mixture was shaken until the starting materials had dissolved. After
30 min, the reaction was diluted with EtOAc (20 mL), washed with
1:1 saturated aqueous NaHCO3 solution/H2O (2 ꢀ 5 mL), brine
(5 mL), dried over Na2SO4, filtered, and concentrated. The crude
material was triturated with hexane (2 mL), decanted, and dried to
give amide 3 f as a white solid (24 mg, 90% yield).
[16] I. Pusterla, J. W. Bode, Angew. Chem. 2012, 124, 528 – 531;
Angew. Chem. Int. Ed. 2012, 51, 513 – 516.
[17] Iminoethers similar to 14 have been hydrolyzed to the corre-
sponding lactone in aqueous AcOH solution at 408C, however,
the differences in structure and conditions preclude direct
comparison of the two reactions. See: M. Pfau, A. Felk, G.
Revial, Tetrahedron Lett. 1994, 35, 1549 – 1552.
Received: February 8, 2012
Published online: && &&, &&&&
Keywords: acyltrifluoroborates · amides · boron ·
.
cross-coupling · ligation
4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Amide Ligation
A. M. Dumas, G. A. Molander,
J. W. Bode*
&&&& — &&&&
Amide-Forming Ligation of
Acyltrifluoroborates and Hydroxylamines
in Water
Come together, right now: Acyltrifluoro-
borates and O-benzoyl hydroxylamines
come together to form amides in water
(see scheme). The ligations are complete
within minutes at room temperature and
do not require any reagents or catalysts.
The reaction has a broad substrate scope
and tolerates unprotected functional
groups.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!