Copper-catalyzed petasis-type reaction: A general route to α-substituted amides from imines, acid chlorides, and organoboron reagents

Article abstract of DOI:10.1021/jo202339v

A copper-catalyzed Petasis-type reaction of imines, acid chlorides, and organoboranes to form α-substituted amides is described. This reaction does not require the use of activated imines or the transfer of special units from the organoboranes and represent a useful generalization of the Petasis reaction.

Full text of DOI:10.1021/jo202339v

Note
pubs.acs.org/joc
Copper-Catalyzed Petasis-Type Reaction: A General Route to
α-Substituted Amides From Imines, Acid Chlorides, and
Organoboron Reagents
Marie S. T. Morin,† Yingdong Lu,† Daniel A. Black, and Bruce A. Arndtsen*
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A 2K6, Canada
S
* Supporting Information
ABSTRACT: A copper-catalyzed Petasis-type reaction of
imines, acid chlorides, and organoboranes to form α-
substituted amides is described. This reaction does not require
the use of activated imines or the transfer of special units from
the organoboranes and represent a useful generalization of the
Petasis reaction.
Because of their relevance in pharmaceuticals and other bio-
active compounds, there is significant interest in the synthesis
of α-substituted amines and amides.1 One straightforward
strategy is the nucleophilic addition of organometallic reagents
to imines.2 However, this approach can be limited by the poor
electrophilicity of the CN double bond and the instability of
some imines toward reactive organometallic reagents (e.g., organ-
olithium and organomagnesium compounds). Because of
their low toxicity, stability to air and water, and functional
group tolerance, organoboron reagents have become wildly
used in organic synthesis.3 This includes in carbon−carbon
bond-forming reactions with imines, via either transition-metal-
catalyzed4 or noncatalytic pathways.5 Transition-metal-medi-
ated variants of this reaction often employ rhodium or
palladium catalysts and can be very effective, though they do
generally require activated imines bearing electron-withdrawing
groups on the nitrogen, such as N-sulfonyl, N-diphenylphos-
phinoyl, and N-sulfinyl imines.4 Alternatively, the non-metal-
catalyzed couplings with organoboranes often involve the use of
in situ generated iminium ions, i.e., the Petasis reaction.5 These
typically require directing groups at the α- or β-position to the
iminium salt carbon (e.g., α-keto acids, α-hydroxy aldehydes,
and salicylaldehydes). While there are exceptions to the latter,6
particularly with less sterically hindered aldehydes (e.g., para-
formaldehyde) or reactive organoboranes (e.g., allylic boranes
or 2-fufurylboranes), this can limit the scope of α-substituted
amines available via this route.
Considering the availability and stability of organoboron
reagents, we became interested in the potential development of
a general approach to employ these reagents in imine addition.
We have recently demonstrated that palladium or copper com-
plexes can catalyze the cross-coupling like reaction between in
situ generated N-acyl iminium salts and organo-tin or -indium
reagents.7,8 Similarly, Doyle has reported that heterocyclic
ethoxy-substituted carbamates can undergo a nickel-catalyzed
Petasis-type coupling with aryl-boron reagents,9 while Li has
found that rhodium complexes can catalyze aryl-borane reac-
tions with α-amido sulfones.10 In addition, various research
groups have found that copper salts can catalyze the addition
of organometallic reagents to in situ generated iminium salts,
in reactions that presumably proceed via the formation of
organocopper intermediates from transmetalation.11 We show
herein how copper catalysis and the correct organoboron
reagent can provide a novel method to assemble α-substituted
amides from imines, acid chlorides, and borates. Notably, this
reaction does not require activated or specialized imines and
proceeds with a variety of organoboron reagents.
Our initial studies involved the CuCl-catalyzed reaction of
the unactivated imine 1 with various phenyl-substituted organo-
boranes. As can be seen in Table 1, no amide product is
observed either with or without acid chloride (entries 1, 2), nor
in the presence of known organoborane activators (K3PO4, F−,
entries 3, 4). Similar results were observed with other phenyl-
substituted organoboranes (entries 5, 6). Considering the
cationic charge on the in situ generated iminium salts (vide
infra), we postulated that negatively charged boron reagents
might be better suited for this reaction, through initial ion
pairing to the iminium unit. Indeed, the use of Na+BPh4− does
result in the formation of trace amounts of 2a (11%, entry 8),
along with significant decomposition. A similar decomposition
is observed without copper catalysts present (though without
2a formation) and presumably arises from the generation of an
unstable, uncoordinated N-acyl iminium cation with BPh4− as
the counterion.12
It has been postulated in copper-catalyzed cross-coupling
reactions that transmetalation of organic units from main group
elements to copper(I) salts is reversible and can be inhibited by
the buildup of the organometallic-halide byproduct as the
reaction proceeds.13 In our case, this byproduct is BPh3. This
product could in principle be trapped by Lewis bases. In
addition, Lewis bases could coordinate to the N-acyl iminium
salt, thereby lowering its background decomposition with BPh4−.
As shown in Table 2, the addition of a catalytic amount of
Received: November 25, 2011
Published: January 17, 2012
© 2012 American Chemical Society
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Note
Table 1. Copper-Catalyzed Reaction of Imines and
Organoboranes
Scheme 1. Proposed Mechanism of the Copper-Catalyzed
Coupling
a
Compound 3 appears to be a viable intermediate in the cataly-
tic reaction. Warming of the solution of 3 in the presence of the
copper catalyst and NaBPh4 leads to its slow disappearance
together with the formation of amide 2a. In addition to 2a, a
new organoboron product is observed in similar yield to 2a:
the pyridine-BPh3 adduct 4.
a
p-tolyl(H)NBn (41.8 mg, 0.20 mmol), p-toluoyl chloride (34 mg,
0.22 mmol), CuCl (2.0 mg, 0.02 mmol), organoborane (0.20 mmol),
b
additive (0.30 mmol), CH2Cl2, rt, 18 h. Without p-toluoyl chloride.
c
No CuCl.
A useful feature of this catalytic coupling is that it does not
require the use of specifically substituted imines or organo-
boranes. As such, it is easily diversified to assemble a range of
α-substituted amides. For example, a number of simple imines
can be used in this reaction. This includes N-benzyl, -aryl, and
-alkyl imines, as well as imines derived from aryl- or heteroaryl-
aldehydes (Table 3). Similarly, aryl-, alkyl-, and heteroaryl-acid
chlorides provide amides in good yield (2g−i). The borate unit
can also be easily tuned. In addition to simple phenyl-
substituted borates, functionalized aryl- (2b, 2c), heteroaryl-
(2d), and even alkyl groups can be transferred to imines with
good yields at room temperature (2f, 2 g). α,β-unsaturated
imines can also be employed in this reaction, leading to the 1,2-
addition product 2k.
a
Table 2. Reaction Optimization with Lewis Base Additives
The formation of the Lewis base coordinated intermediate 3
also allows the use of less stabilized imines in this chemistry.
For example, due to their sensitivity to base, enolizable imines
can be more challenging substrates for coupling with organo-
metallic reagents, and their corresponding N-acyl iminium salts
are very prone to enamide formation. The latter has precluded
their use in similar copper-catalyzed coupling reactions with
other organometallic reagents.16 However, because of the
low basicity of organoborates and the generation of a stabi-
lized pyridinium salts 3, these imines can also be employed
in this copper-catalyzed reaction, affording 2l in good yield
(Scheme 2).
In conclusion, we have developed a copper-catalyzed multi-
component synthesis of α-substituted amides from imines,
acid chlorides, and organoborane reagents. Considering the
simplicity of the catalyst, the generality of the reaction, and
the stability of these reagents, this provides a straightforward
route to construct α-substituted amides. This approach does
not require the use of activated imines or the transfer of special
units from the organoboranes. As such, it represents a useful
generalization of Petasis-type coupling reactions of in situ
generated iminium salts with organoboranes.
a
p-tolyl(H)NBn (41.8 mg, 0.20 mmol), p-toluoyl chloride (34 mg,
0.22 mmol), NaBPh4 (68.4 mg, 0.20 mmol), catalyst (0.02 mmol), and
Lewis base (0.20 mmol), 2 mL CH2Cl2, rt, 18 h, yields determined by
b
c
1H NMR. 30 min, rt. 60 °C.
pyridine base (10 mol %) increases the yield of 2a to 14%,
while the use of stoichiometric pyridine leads to near quan-
titative 2a formation (83%, entry 2). This coupling is extremely
rapid and proceeds to completion within 30 min at ambient
temperature (entry 5). DMAP is also effective as the Lewis
base additive (entry 8), while the more electron-rich phos-
phines either slow (PPh3, entry 7) or inhibit (PBu3, entry 9)
catalysis.
The role of Lewis bases in this transformation can be probed
by monitoring the copper-catalyzed reaction by 1H NMR
spectroscopy. This shows the immediate formation of a
pyridine-containing intermediate prior to the addition of the
copper catalyst.14 This intermediate can be independently
generated via the addition of pyridine to the N-acyl iminium
salt and has been characterized as the pyridinium salt 3
(Scheme 1; B = pyridine).15 The formation of 3 provides a
rationale for the slower coupling reaction with DMAP relative
to pyridine or inhibition with phosphines, since these more
Lewis basic units presumably undergo slower displacement by
the in situ formed organocopper complex to form the product.
EXPERIMENTAL SECTION
■
General Procedures. Unless otherwise noted, all manipulations
were performed under an inert atmosphere dry glovebox or by using
standard Schlenk or vacuum line techniques. Imines were prepared
using literature procedures.17 R4B−Na+ were synthesized from the
corresponding Grignard reagent and sodium tetrafluoroborate.18
Acetonitrile and CH2Cl2 were distilled from CaH2 under nitrogen.
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Note
Table 3. Diversity of Copper-Catalyzed Multicomponent
Coupling of Imines, Acid Chlorides, and Organoboron
Reagents
In Situ Formation of 3. p-Tolyl(H)NBn (41.8 mg, 0.20 mmol)
and benzoyl chloride (39.3 mg, 0.28 mmol) were mixed neat. After
15 min, pyridine (31.6 mg, 0.40 mmol) was added, and the neat
mixture was allowed to stand for 30 min. Pentane (3 mL) was added,
and the precipitate was collected in 50% yield. NMR data shows this
precipitate is 3 in rapid equilibrium with small amounts of free
pyridine, acid chloride, and N-acyl iminium salt. As such, its structure
1
was assigned by in situ by NMR spectroscopy. H NMR (500 MHz,
CDCl3, −10 °C): δ 9.77 (d, J = 6.0 Hz, 2H), 8.60 (s, 1H), 8.34 (t, J =
7.5 Hz, 1H), 7.88 (t, J = 7.0 Hz, 2H), 7.68 (d, J = 7.5 Hz, 2H), 7.38−
7.43 (m, 3H), 7.07 (d, J = 8.0 Hz, 2H), 6.91 (m, 7H), 5.42 (d, J =
15.5 Hz, 1H), 5.24 (d, J = 16.0 Hz, 1H), 2.19 (s, 3H). 13C NMR
(125 MHz, CDCl3, −10 °C): δ 174.1, 145.9, 144.6, 140.0, 136.2,
134.1, 131.5, 129.6, 129.0, 128.9, 128.5, 128.0, 127.98, 127.8, 127.7,
127.5, 84.7, 55.2, 21.3.
Generation of Pyridine:BPh3 (4). Pyridine (31.6 mg, 0.40 mmol)
and BPh3 (96.8 mg, 0.40 mmol) were dissolved in 2 mL of CHCl3.
After 1 h of stirring at 65 °C, an amorphous white solid was formed,
which was collected and washed with CH3CN. The complex 4 was
1
obtained in 30% yield. H NMR (500 MHz, CDCl3): δ 8.59 (d, J =
5.5 Hz, 2H), 8.03 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.0 Hz, 2H), 7.16−
7.26 (m, 15H). 13C NMR (125 MHz, CDCl3): δ 151.9, 148.1, 140.3,
134.7, 127.1, 125.3, 124.9. 11B (160 MHz, CDCl3): δ 4.4.
Spectroscopic Data for α-Substituted Amides. N-Benzyl-4-
methyl-N-(phenyl(p-tolyl)methyl)benzamide (2a). Isolated yield
1
83%. White amorphous solid. H NMR (400 MHz, CDCl3): δ 6.85−
8.00 (m, 18H), 6.68 (br, 1H), 4.76 (s, 2H), 2.38 (s, 3H), 2.36 (s, 3H).
13C NMR (125 MHz, CDCl3, 50 °C): δ 173.4, 144.3, 139.6, 139.4,
138.2, 137.3, 136.3, 134.1, 130.2, 129.0, 128.9, 128.3, 127.7, 127.5,
127.1, 126.5, 126.1, 65.9, 48.5, 21.3, 20.9. IR: νmax (KBr) 1639
(CO). HRMS: calcd for C29H27ONNa+ 428.1979, found 428.1981.
N-Ethyl-N-(thiophen-2-yl(p-tolyl)methyl)benzamide (2b). Isolated
1
yield 74%. Brown solid, mp 95−96 °C. H NMR (500 MHz, CDCl3,
a
Imine (0.20 mmol), acid chloride (0.22 mmol), organoborane (0.20
55 °C): δ 7.38−7.46 (m, 5H), 7.29 (dd, J = 1.5, 5.5 Hz, 1H), 7.15−
7.20 (m, 4H), 7.00 (dd, J = 3.5, 5 Hz, 1H), 6.89−6.90 (m, 1H), 6.57
(br, 1H) 3.53 (q, J = 6.5 Hz, 2H), 2.36 (s, 3H), 0.80 (br, 3H). 13C
NMR (125 MHz, CDCl3, 55 °C): δ 171.8, 143.7, 137.8, 137.2, 136.2,
129.3, 129.1, 128.4, 128.2, 127.0, 126.7, 126.3, 125.2, 61.0, 40.1, 20.9,
13.9. IR: νmax (KBr) 1618 (CO). HRMS: calcd for C21H21ONSNa+
358.1236, found 358.1238.
mmol), CuCl (2.0 mg, 0.020 mmol), pyridine (15.8 mg, 0.20 mmol), 2
mL CH2Cl2, rt, 18 h. With KB(2-thiophenyl)4.
b
Scheme 2. Coupling Reaction with Enolizable Imine
N-Benzyl-N-((4-fluorophenyl)(p-tolyl)methyl)benzamide (2c).
Product was purified by silica gel chromatograph using 5:95 ethyl
acetate/toluene mixture as eluent, isolated yield 90%. White solid, mp
1
88−90 °C. H NMR (300 MHz, CD3CN): δ 6.90−7.42 (m, 18H),
6.42 (br, 1H) 4.94 (d, J = 11.4 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H),
2.38 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 173.1, 162.1 (d, 1JC−F
=
245.6 Hz), 137.9, 137.6, 136.8, 135.9, 135.1 (d, 4JC−F = 2.7 Hz), 130.7
Deuterated solvents were dried as their protonated analogues but were
transferred under vacuum from the drying agent and stored over 3 Å
molecular sieves. 1H, 13C, and 11B NMR spectra were recorded on 300,
400, or 500 MHz spectrometers.
3
(d, JC−F = 6.8 Hz), 129.5, 129.3, 128.6, 128.5, 127.8, 127.0, 126.4,
126.3, 115.2 (d, 2JC−F = 21.3 Hz), 65.6, 47.4, 21.1. IR: νmax (KBr) 1638
(CO). HRMS: calcd for C28H24ONFNa+ 432.1732, found 432.1734.
N-Benzyl-N-(thiophen-2-yl(p-tolyl)methyl)thiophene-2-carboxa-
Typical Synthesis of α-Substituted Amides. p-Tolyl(H)NBn
(41.1 mg, 0.20 mmol) and p-toluoyl chloride (34 mg, 0.22 mmol)
were dissolved in CH2Cl2 (0.5 mL), after 30 min pyridine (15.8 mg,
0.20 mmol) was added with 0.5 mL of CH2Cl2, and the solution
was transferred to a vial with NaBPh4 (68.4 mg, 0.20 mmol). CuCl
(2.0 mg, 0.020 mmol) in 0.5 mL of CH2Cl2 was added, and the
reaction solution was stirred at room temperature for 18 h. The
solvent was removed in vacuo, and the resulting product was isolated
by chromatography on silica gel 60 using hexanes/ethyl acetate as
eluent, affording the 2a in 83% yield.
1
mide (2d). Isolated yield 80%. Light yellow oil. H NMR (400 MHz,
CDCl3): δ 6.98−7.44 (m, 16H), 4.90 (dd, 2H), 2.39 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 166.1, 143.1, 138.2, 138.1, 138.0, 136.0,
129.7, 129.5, 129.0, 128.7, 128.3, 128.1, 127.2, 127.1, 127.0, 126.8,
126.0, 61.8, 50.4, 21.8. IR: νmax (KBr) 1629 (CO). HRMS: calcd for
C24H21ONS2Na+ 426.0955, found 426.0957.
N-Methyl-N-(naphthalen-2-yl(p-tolyl)methyl)benzamide (2e).
Product was purified by silica gel chromatograph using 5:95 ethyl
1
acetate/toluene mixture as eluent, isolated yield 71%. Clear oil. H
Synthesis of 2l. Isopropyl(H)NBn (32.2 mg, 0.20 mmol) was
dissolved in 0.5 mL of CH2Cl2 in a Schlenk flask and cooled to
−40 °C. p-Toluoyl chloride (37.0 mg, 0.24 mmol) in 0.5 mL of CH2Cl2
was added via syringe over 5 min. After15 min of stirring at −40 °C,
pyridine (15.8 mg, 0.20 mmol), NaBPh4 (68.4 mg, 0.20 mmol), and
CuCl (2.0 mg, 0.020 mmol) in 1 mL of CH3CN was added over
5 min. The reaction warmed to ambient temperature overnight, the
solvent removed was in vacuo, and the resulting product was isolated
by chromatography on silica gel 60 using hexanes/ethyl acetate as
eluent, affording the amide 2l in 62% yield.
NMR (500 MHz, CD3CN, 70 °C): δ 7.86−7.94 (m, 3H), 7.75
(s, 1H), 7.52−7.56 (m, 2H), 7.42−7.48 (m, 5H), 7.33 (d, J = 8 Hz, 1H),
7.25 (d, J = 8 Hz, 2H), 7.17 (d, J = 7.5 Hz, 2H), 6.80 (br, 1H), 2.84
(s, 3H), 2.40 (s, 3H). 13C NMR (125 MHz, CD3CN, 70 °C): δ 171.8,
137.5, 137.3, 137.1, 136.2, 133.4, 132.8, 129.3, 129.2, 128.8, 128.4,
128.0, 127.9, 127.5, 127.1, 126.6, 126.5, 126.3, 126.2, 63.6, 32.2, 20.0.
IR: νmax (KBr) 1628 (CO). HRMS: calcd for C26H24ON+ 366.1852,
found 366.1866.
N-Benzyl-N-(2-phenyl-1-p-tolylethyl)benzamide (2f). Isolated
yield 71%. White solid, mp 68−70 °C. 1H NMR (400 MHz,
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Note
CD3CN, 80 °C): δ 6.88−7.49 (m, 19H), 5.52 (br, 1H), 4.62 (d, J =
ACKNOWLEDGMENTS
■
2
3
13.5 Hz, 1H), 4.53 (d, J = 13.5 Hz, 1H), 3.43 (dd, J = 13.5 Hz, J =
6.8 Hz, 1H), 3.36 (dd, 2J = 13.5 Hz, 3J = 6.8 Hz, 1H), 2.38 (s, 3H). 13
C
We thank NSERC, FQRNT, and CFI for their financial support
of this research.
NMR (125 MHz, CDCl3, 60 °C): δ 173.0, 138.5, 137.7, 136.5, 129.5,
129.4, 129.3, 129.1, 128.7, 128.5, 128.4, 127.9, 127.1, 126.9, 126.8,
126.7, 126.6, 62.3, 47.7, 38.5, 21.1. IR: νmax (KBr) 1635 (CO).
HRMS: calcd for C29H27NONa+ 428.1979, found 428.1985.
N-Benzyl-N-(1-p-tolylpropyl)benzamide (2g). Isolated yield 74%.
Clear oil. 1H NMR (500 MHz, CDCl3, 50 °C): δ 7.12−7.40 (m, 13H),
5.20 (br, 1H), 4.72 (br, 1H), 4.28 (d, J = 15.3 Hz, 1H), 2.39 (s, 3H),
2.37 (s, 3H), 1.96 (m, 2H), 0.86 (b, 3H). 13C NMR (125 MHz,
CDCl3, 50 °C): δ 173.2, 139.3, 139.2, 137.5, 136.5, 134.9, 129.4, 129.2,
128.3, 128.0, 127.8, 127.1, 126.9, 62.5, 47.0, 25.4, 21.2, 21.1, 11.6. IR:
νmax (KBr) 1634 (CO). HRMS: calcd for C25H27ONNa+ 380.1980,
found 380.1985.
REFERENCES
■
(1) (a) Chemistry and Biochemistry of the Amino Acids Barrett, G. C., Ed.;
Chapman and Hall: London, 1985. (b) Taggi, A. E.; Hafez, A. M.;
Lectka, T. Acc. Chem. Res. 2003, 36, 10 andreferences therein.
(2) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
(3) (a) Doucet, H. Eur. J. Org. Chem. 2008, 12, 2013. (b) Alonso, F.;
Beletskaya, I. P.; Yus, M. Tetrahedron 2008, 64, 3047. (c) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147.
(4) (a) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc.
2006, 128, 6304. (b) Dai, H.; Lu, X. Org. Lett. 2007, 9, 3077.
(c) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am.
Chem. Soc. 2004, 126, 8128. (d) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am.
Chem. Soc. 2005, 127, 1092. (e) Tokunaga, N.; Otomaru, Y.;
Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem.
Soc. 2004, 126, 13584. (f) Otomaru, Y.; Tokunaga, N.; Shintani, R.;
Hayashi, T. Org. Lett. 2005, 7, 307. (g) Bolshan, Y.; Batey, R. A. Org.
Lett. 2005, 7, 1481.
N-Benzyl-N-((4-fluorophenyl)(phenyl)methyl)furan-2-carboxa-
1
mide (2h). Isolated yield 70%. Yellow solid, mp 65−67 °C. H NMR
(300 MHz, CDCl3): δ 6.84−7.42 (m, 17H), 6.42 (s, 1H), 4.96 (d, J =
16.4 Hz, 1H), 4.80 (d, J = 16.4 Hz, 1H). 13C NMR (75 MHz, CDCl3):
δ 162.3 (d, 1JC−F = 245.3 Hz), 161.5, 148.0, 144.4, 139.0, 138.0, 135.0
4
3
(d, JC−F = 3.2 Hz), 131.2 (d, JC−F = 8.1 Hz), 129.0, 128.7, 128.1,
2
127.9, 127.1, 126.7, 117.3, 115.3 (d, JC−F = 21.4 Hz), 111.7, 63.8,
49.9. IR: νmax (KBr) 1628 (CO). HRMS: calcd for C25H20O2NFNa+
408.1369, found 408.1370.
(5) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
(b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
For representative examples, see: (c) Batey, R. A.; MacKay, C. B.;
Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075. (d) Lou, S.;
Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922. (e) Hong, Z.; Liu, L.;
Sugiyama., M.; Fu, Y.; Wong, C.-H. J. Am. Chem. Soc. 2009, 131, 8352.
(f) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
(g) Yadav, J. S.; Reddy, B. V. S.; Lakshmi, P. N. J. Mol. Catal. A Chem.
2007, 274, 101. (h) Kumagai, N.; Muncipinto, G.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2006, 45, 3635. (i) Southwood, T. J.; Curry,
M. C.; Hutton, C. A. Tetrahedron 2006, 62, 236. (j) Thompson, K. A.;
Hall, D. G. Chem. Commun. 2000, 23, 2379. (k) Batey, R. A.; Quach,
T. D.; Shen, M.; Thadani, A. N.; Smil, D. V.; Li, S.-W.; MacKay, D. B.
Pure Appl. Chem. 2002, 74, 43.
(6) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583. (b) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.; Luke, R. W. A.
Chem. Commun. 1996, 16, 1953. (c) Yamamoto, Y.; Asao, N. Chem.
Rev. 1993, 93, 2207. (d) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am.
Chem. Soc. 2007, 129, 6686.
(7) Palladium catalysis: (a) Davis, J. L.; Dhawan, R.; Arndtsen, B. A.
Angew. Chem., Int. Ed. 2004, 43, 590. (b) Siamaki, A. R.; Black, D. A.;
Arndtsen, B. A. J. Org. Chem. 2008, 73, 1135.
N-Benzyl-N-(phenyl(p-tolyl)methyl)isobutyramide (2i). Isolated
yield 57%. White solid, mp 65−67 °C. 1H NMR (300 MHz,
CDCl3): δ 6.64−7.26(m, 15H), 4.82 (s, 2H), 2.80 (br, 1H), 2.30
(s, 3H), 1.18 (b, 6H). 13C NMR (75 MHz, CDCl3): δ 178.8, 140.0,
138.8, 137.3, 136.7, 129.2, 128.7, 128.6, 128.4, 128.0, 127.5, 126.5, 115.6,
62.2, 48.7, 31.7, 21.0, 20.0. IR: νmax (KBr) 1635 (CO). HRMS: calcd
for C25H27ONNa+ 380.1990, found 380.1983.
N-(4-Methoxyphenyl)-4-nitro-N-(phenyl(p-tolyl)methyl)-
1
benzamide (2j). Isolated yield 83%. Yellow oil. H NMR (400 MHz,
CDCl3): δ 6.48−8.02 (m, 18H), 3.64 (s, 3H) 2.39 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 169.2, 158.9, 143.5, 139.0, 137.6, 135.6, 135.0,
131.5, 129.7, 129.7, 129.5, 129.2, 128.5, 127.8, 127.3, 123.2, 114.0,
65.0, 55.4, 21.3. IR: νmax (KBr) 1646 (CO). HRMS: calcd for
C28H24O4N2Na+ 475.1626, found 475.1628.
(E)-N-Allyl-N-(1,3-diphenylallyl)-4-methylbenzamide (2k). Iso-
lated yield 62%. Clear oil. 1H NMR (500 MHz, CDCl3, 50 °C):
δ 7.21−7.45 (m, 14H), 6.58 (br, 2H), 5.81 (br, 2H), 5.04 (d, J = 9.5 Hz,
2H), 4.22 (b, 1H), 3.84 (dd, 1H), 2.39 (s, 3H). 13C NMR (125 MHz,
CDCl3, 50 °C): δ 172.5, 139.8, 139.7, 136.8, 135.1, 134.2, 133.8, 129.3,
128.9, 128.8, 128.2, 127.9, 127.2, 126.9, 126.9, 126.8, 116.7, 63.6, 47.7,
21.5. IR: νmax (KBr) 1635 (CO). HRMS: calcd for C26H25ONNa+
390.1825, found 390.1828.
N-Benzyl-4-methyl-N-(2-methyl-1-phenylpropyl)benzamide (2l).
(8) Copper catalysis: (a) Black, D. A.; Arndtsen, B. A. J. Org. Chem.
2005, 70, 5133. (b) Black, D. A.; Arndtsen, B. A. Org. Lett. 2006, 8,
1991. (c) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107.
(d) Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem. 2008,
73, 1906.
(9) Graham, T. J. A.; Schields, J. D.; Doyle, A. G. Chem. Sci. 2011, 2,
980.
(10) Dou, X.-Y. ; Shuai, Q.; He, L.-N.; Li, C.-J. Inorg. Chim. Acta
1
Isolated yield 62%. White solid, mp 55−57 °C. H NMR (300 MHz,
CD3CN, 80 °C): δ 6.83−7.40 (m, 14H), 4.65−4.96 (b, 2H), 4.38
(d, J = 15.3, 1H), 2.71 (br, 1H), 3.39 (s, 3H), 1.16 (d, 3H), 0.78
(d, 3H). 13C NMR (68 MHz, CD3CN, 80 °C): δ 173.2, 139.5, 139.4,
139.2, 135.8, 129.8, 129.6, 128.7, 128.0, 127.8, 127.6, 127.1, 126.8,
69.6, 48.1, 29.6, 20.4, 20.3. IR: νmax (KBr) 1633 (CO). HRMS:
calcd for C25H27ONNa+ 380.1990, found 380.1983.
2011, 369, 284.
ASSOCIATED CONTENT
(11) (a) Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 9, 1472.
(b) Fernandez-Ibanez, M. A.; Macia, B.; Pizzuti, M. G.; Minnaard,
A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2009, 48, 9339. (c) Zhang,
L.; Lushington, G. H.; Neuenswander, B.; Hershberger, J. C.;
Malinakova, H. C. J. Comb. Chem. 2008, 10, 285. (d) Gommermann,
N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003,
42, 5763. (e) Luan, Y.; Schaus, S. E. Org. Lett. 2011, 13, 2510.
(f) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett.
2006, 8, 2437.
(12) The reaction of p-tolyl(H)CNBn, p-tolylCOCl, and NaBPh4
in CH2Cl2 leads to a complex mixture of decomposition products
within 3 h at ambient temperature, including p-tolylCON(Bn)H and
(p-tolyl)H2CN(Bn)CO(p-tolyl).
■
S
* Supporting Information
1H and 13C NMR spectra for compounds 2a−l, 3, and 4. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bruce.arndtsen@mgill.ca.
Author Contributions
†These authors contributed equally to this work.
Notes
(13) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
The authors declare no competing financial interest.
2748.
2016
dx.doi.org/10.1021/jo202339v | J. Org. Chem. 2012, 77, 2013−2017

The Journal of Organic Chemistry
Note
(14) The added pyridine presumably also coordinates to the copper
catalyst, which may also influence catalytic activity. However, only a
slight increase of yield is observed when a catalytic amount of pyridine
is added (Table 2, entry 1).
(15) The intermediate 3 is formed in equilibrium and cannot be
1
isolated in clean form. However, its in situ H and 13C NMR data are
consistent with its formation. See Supporting Information for spectral
data.
(16) These N-acyl iminium salts cannot be employed in the copper-
catalyzed couplings with organotin and organoindium reagents.8
(17) Layer, R. W. Chem. Rev. 1963, 63, 489.
(18) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi,
T. J. Am. Chem. Soc. 2009, 131, 13588.
2017
dx.doi.org/10.1021/jo202339v | J. Org. Chem. 2012, 77, 2013−2017