Synthesis of an acyltrifluoroborate and its fusion with azides to form amides

Article abstract of DOI:10.1021/jo1004058

A uniquely stable acyl potassium trifluoroborate, potassium (2-phenylacetyl)trifluoroborate, has been synthesized and isolated. In the presence of an activating Lewis acid, this reagent reacts with azides to form amides in good yields.

Full text of DOI:10.1021/jo1004058

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We report herein the synthesis of a stable potassium
Synthesis of an Acyltrifluoroborate and Its Fusion
with Azides To Form Amides
acyltrifluoroborate and its reaction with azides to form amides.
Currently, there is only one reported example of a fully
characterized and isolated acyl boron species (Figure 1, 1);12
however, no subsequent reactivity for this acyl boron has been
described. Acyl boron species have been hypothesized to form
transiently, but are subject to rapid rearrangement and oxida-
tion to tertiary alcohols or ketones.13
Gary A. Molander,* Jessica Raushel, and Noel M. Ellis
Roy and Diana Vagelos Laboratories, Department of
Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323
gmolandr@sas.upenn.edu
Received March 4, 2010
FIGURE 1. Related acyl boron and acyl boron equivalents.
Our synthesis of an acyltrifluoroborate avoids destructive
rearrangement by conducting the carbonyl formation simul-
taneously with that of the trifluoroborate via direct deproto-
nation of (E)-(2-methoxyvinyl)benzene 5 with tert-butyl-
lithium (route A, Scheme 1), followed by quenching with
triisopropyl borate and aqueous KHF2, a method similar
to the one employed by Matteson14 in the synthesis of (S)-
pinanediol (1-methoxyvinyl)boronate 2 (Figure 1). Alter-
natively, we were able to access the same intermediate enol
ether “ate” complex 6 (route B, Scheme 1) via metalation of
dimethoxy acetal 8, an approach outlined by Venturello
et al.15 in the synthesis of styrylboronic ester 3 (Figure 1). In
contrast to the recently reported16 synthesis of 1-trifluoroborato
2,2-difluoro enol ether 4 (Figure 1), treatment of intermediate 6
with aqueous KHF2 led directly to acyltrifluoroborate salt 7, as
opposed to a trifluoroborato enol ether.
A uniquely stable acyl potassium trifluoroborate, potas-
sium (2-phenylacetyl)trifluoroborate, has been synthe-
sized and isolated. In the presence of an activating Lewis
acid, this reagent reacts with azides to form amides in good
yields.
As a functional class, boronic acids display wide utility in
organic synthesis,1 participating in a broad range of reac-
tions including Suzuki-Miyaura cross-coupling2,3 as well as
borono-Mannich4 and rhodium-catalyzed 1,4-addition5 re-
actions. Nevertheless, the empty p-orbital of tricoordinate
boronic acids leaves them susceptible to oxidation and
protodeboronation and thereby limits their functional group
compatibility when carried through multiple synthetic steps,
as well as their utility as bench-stable reagents.6 In recent
years, these laboratories have focused on the synthesis and
reactivity of potassium organotrifluoroborates as an alter-
native to boronic acids.7 Because of their tetracoordinate
nature, trifluoroborates are less susceptible to decomposi-
tion, enabling the synthesis of potassium vinyltrifluoro-
borate,8 as well as alkynyl-9,10 and 2-substituted heteroaryl-
trifluoroborates,11 the boronic acid derivatives of which are
quite often unstable.
SCHEME 1. Preparation of Acyltrifluoroborate 7
Disappointedly, acyltrifluoroborate 7 not only persisted
as the sole example accessible through this method, but also
failed to serve as a viable Suzuki-Miyaura cross-coupling
partner in our hands, even under anhydrous conditions with
aryl diazonium salt electrophiles. Nevertheless, we remained
intrigued by the possibility of a reactive, isolable acyl boron
species, and to study the fundamental reactivity of 7 we
(1) Hall, D. G. Boronic Acids: Preparation and Applications in Organic
Synthesis and Medicine: Wiley-VCH: New York, 2005.
(2) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., de Meijere, A., Eds.; Wiley-VCH: New York, 2004; Chapter 2.
(3) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(4) McReynolds, M. D.; Hanson, P. R. Chemtracts 2001, 14, 796–801.
(5) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844.
(6) Thomas, S. E. Organic Synthesis: The Roles of Boron and Silicon:
Oxford University Press: New York, 1991; pp 1-46.
(7) Molander, G. A.; Ellis, N. M. Acc. Chem. Res. 2007, 40, 275–286.
(8) Darses, S.; Michaud, G.; Genet, J.-P. Tetrahedron Lett. 1998, 39,
5045–5048.
(12) Yamashita, M.; Suzuki, Y.; Segawa, Y.; Nozaki, K. J. Am. Chem.
Soc. 2007, 129, 9570–9571.
(13) Kabalka, G. W.; Gotsic, J. T.; Pace, R. D.; Li, N.-S. Organometallics
1994, 13, 5163–5165.
(14) Matteson, D. S.; Beedle, E. C. Heteroat. Chem. 1990, 1, 135–140.
(15) Tivola, P. B.; Deagostino, A.; Prandi, C.; Venturello, P. Org. Lett.
2002, 4, 1275–1277.
(9) Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002,
67, 8416–8423.
(10) Darses, S.; Michaud, G.; Genet, J.-P. Eur. J. Org. Chem. 1999, 1875–
1883.
(11) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009,
74, 973–980.
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8866–8869.
4304 J. Org. Chem. 2010, 75, 4304–4306
Published on Web 05/18/2010
DOI: 10.1021/jo1004058
r
2010 American Chemical Society

Molander et al.
JOCNote
TABLE 1. Reaction of Acyltrifluoroborate 7 with Azides (9)
SCHEME 2. Plausible Reaction Mechanism
In summary, we have developed a bench-stable acyltri-
fluoroborate salt 7 that is capable of reacting as a stable acyl
anion equivalent. Alkyl azides were compatible with the
Lewis acid activated acyl boron species; however, aryl-,
sulfonyl-, and alkenyl-containing azides were not.
Experimental Section
Synthesis of Acyltrifluoroborate 7: Route A. To a stirred
solution of β-methoxystyrene (3 mL, 22.4 mmol, 3 equiv) in
THF (25 mL) at -78 °C was added tert-butyllithium (6.6 mL,
1.7 M in pentane, 11.2 mmol, 1.5 equiv) dropwise. The reaction
mixture was allowed to stir for 80 min at -78 °C, at which point
it was warmed to 0 °C and stirred for an additional 45 min. After
the reaction mixture had cooled to -78 °C, triisopropyl borate
(1.73 mL, 7.5 mmol) was added dropwise, and the reaction was
allowed to stir at -78 °C for 30 min before being warmed to
room temperature. Stirring was continued for 2 h, at which
point saturated aq KHF2 (17 mL, ∼4.5 M, 76 mmol) was slowly
added. The reaction mixture was stirred vigorously overnight,
and the solvents were removed in vacuo. The resulting mixture
of solids was dried under high vacuum overnight, then subjected
to extraction with acetone (3 ꢀ 20 mL). The acetone extracts
were concentrated in vacuo, and Et2O (50 mL) was added to
precipitate the trifluoroborate product. Filtration gave 7 (0.53 g,
31%) as white crystals: mp >250 °C; νmax(KBr)/cm-1 3400,
1661, 1319, 1001; 1H NMR (300 MHz, acetone-d6) δ 7.15-7.26
(m, 2H), 7.04-7.14 (m, 3H), 3.71 (s, 2H); 13C NMR (125 MHz,
acetone-d6) δ 138.0, 130.9, 128.4, 126.1, 51.6; 19F NMR (470 MHz,
acetone-d6) δ -151.32; 11B NMR (128 MHz, acetone-d6) δ -1.88;
aReaction conditions: 7(0.3mmol), 9(0.3mmol), HBF4 OEt2 (2 equiv),
CH3CN (1.5 mL), 0 °C to rt.
3
turned our attention to other known reactions of organotri-
fluoroborates.
Matteson and co-workers17 have demonstrated that Lewis
acid-activated trifluoroborates are viable precursors to inter-
mediate dihaloboranes, which react with azides to form
secondary amines. The same protocol applied to acyltrifluor-
oborates would be expected to provide a novel approach to
amides. To pursue this goal, we initiated an investigation to
realize this intriguing transformation. Initial studies began
with an exploration of various Lewis acids/fluorophiles that
were expected to promote the reaction. In our hands, SiCl4,
chlorotrimethylsilane, Sc(OTf)3, and BF3 OEt2 were effective
3
in promoting the desired reaction between acyltrifluoroborate
7 and azides, but in poor conversions. In contrast, the use of
tetrafluoroboric acid diethyl etherate resulted in reproducible,
moderate yields of the desired amides (Table 1).
-
HRMS (ESI-TOF) calcd for C8H7OBF3 [M - K]- 187.0542,
found 187.0540.
Representative Amide Synthesis: N-Benzyl-2-phenylacetamide
(10a). An oven-dried 2-5 mL microwave vial was charged with
trifluoroborate salt 7 (0.068 g, 0.30 mmol), capped with a rubber
septum, and evacuated. After backfilling with N2, this process
was repeated twice more. To the microwave vial was added
anhydrous CH3CN (1.5 mL) and benzyl azide (9a) (0.040 g,
0.3 mmol). The reaction mixture was cooled in an ice/water
bath before slowly adding tetrafluoroboric acid diethyl etherate
(0.082 mL, 1.19 g/mL, 0.6 mmol) via a PTFE needle. The reaction
mixture was allowed towarmto roomtemperature and stirred for
4 h. The reaction was quenched with H2O (1.5 mL) and the
aqueous layer was extracted with EtOAc (2 ꢀ 2 mL). The
combined organic layers were washed with brine (1 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by
flash column chromatography, eluting with 7:3 hexanes:EtOAc
with 0.1% Et3N, afforded 10a (0.051 g, 75%) as a white solid: mp
118-119 °C; (lit.19 mp 119 °C); Rf 0.2 (silica gel, hexanes:EtOAc
Although the reaction conditions were tolerant of simple
alkyl azides (entries 1-4), the method unfortunately lacks
broad substrate scope. A few functional groups, such as
esters (entry 5) and nitriles (entry 6), were tolerated, but aryl
azides (entry 7) and azides containing alkenes (entry 8) were
so badly decomposed that only trace amounts of the corre-
sponding amides could be isolated. Additionally, no acyl-
sulfonamide products could be isolated from the reaction of
trifluoroborate salt 7 and sulfonyl azides.
Similar to the reaction of alkyldichloroboranes and azides
reported by Brown et al.,18 the reaction may proceed through
reversible coordination of the azide 9 with the dihaloborane
11. Concurrent migration of the acyl group from boron to
nitrogen and loss of dinitrogen would afford intermediate
13, hydrolysis of which would produce amides of type 10
(Scheme 2).
1
7:3); H NMR (500 MHz, CDCl3) δ 7.31 (t, J=7.2 Hz, 2H),
7.28-7.18 (m, 6H), 7.14 (d, J = 7.0, 2H) 5.71 (br s, 1H), 4.37 (d,
(17) Matteson, D. S.; Kim, G. Y. Org. Lett. 2002, 4, 2153–2155.
(18) Brown, H. C.; Midland, M. M.; Levy, A. B. J. Am. Chem. Soc. 1973,
95, 2394–2396.
(19) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron
Lett. 2007, 48, 3863–3866.
J. Org. Chem. Vol. 75, No. 12, 2010 4305

Molander et al.
JOCNote
J = 5.8, 2H), 3.58 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
171.0, 138.3, 135.0, 129.6, 129.2, 128.8, 127.63, 127.55, 127.50,
43.9, 43.7; HRMS (ESI-TOF) calcd for C15H16NOþ [M þ H]þ
226.1232, found 226.1238.
the NIH (R01 GM-081376), and Merck Research Labora-
tories. Dr. Rakesh Kohli (University of Pennsylvania) is
acknowledged for obtaining HRMS data.
Supporting Information Available: Experimental proce-
dures, characterization data, and NMR spectra for all com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. This research was supported by a
National Priorities Research Program (NPRP) grant from
the Qatar National Research Fund (Grant no. 08-035-1-008),
4306 J. Org. Chem. Vol. 75, No. 12, 2010