Ketene reactions with tertiary amines

Article abstract of DOI:10.1021/jo402438w

Tertiary amines react rapidly and reversibly with arylketenes in acetonitrile forming observable zwitterions, and these undergo amine catalyzed dealkylation forming N,N-disubstituted amides. Reactions of N- methyldialkylamines show a strong preference for methyl group loss by displacement, as predicted by computational studies. Loss of ethyl groups in reactions with triethylamine also occur by displacement, but preferential loss of isopropyl groups in the phenylketene reaction with diisopropylethylamine evidently involves elimination. Quinuclidine rapidly forms long-lived zwitterions with arylketenes, providing a model for catalysis by cinchona and related alkaloids in stereoselective additions to ketenes.

Full text of DOI:10.1021/jo402438w

Article
pubs.acs.org/joc
Ketene Reactions with Tertiary Amines
Annette D. Allen, John Andraos, Thomas T. Tidwell,* and Sinisa Vukovic
Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: Tertiary amines react rapidly and reversibly
with arylketenes in acetonitrile forming observable zwitterions,
and these undergo amine catalyzed dealkylation forming
N,N-disubstituted amides. Reactions of N-methyldialkylamines
show a strong preference for methyl group loss by displacement,
as predicted by computational studies. Loss of ethyl groups in
reactions with triethylamine also occur by displacement, but
preferential loss of isopropyl groups in the phenylketene
reaction with diisopropylethylamine evidently involves elimi-
nation. Quinuclidine rapidly forms long-lived zwitterions with
arylketenes, providing a model for catalysis by cinchona and
related alkaloids in stereoselective additions to ketenes.
1 generated by thermal rearrangement of a dienyl aldehyde and
proposed to cyclize to a zwitterionic intermediate which ring
opens to an amide product (eq 3).7 Allylic tertiary amines had
INTRODUCTION
■
Additions to ketenes catalyzed by chiral tertiary amines are
useful in asymmetric synthesis1 and continue to find new
applications,2 which have been recently reviewed.2e,f Early
examples include brucine catalyzed ketene esterification over
a range of temperatures (eq 1)1a and quinidine catalyzed
previously been found to react with ketenes to give similar
rearrangements of zwitterionic intermediates to amides.8a
Intramolecular [4 + 2] electrocyclization of vinylketene 2
generated by cyclobutenone ring opening occurs with attack of
the pyridyl nitrogen on the ketene to give a substituted
quinolizinone (eq 4).8b
Ketene 3 generated by diazo ketone flash photolysis in
acetonitrile was observed by IR and UV and reported to react
with triethylamine producing a transient zwitterion, which
formed the amide 4 with removal of an ethyl group (eq 5).5a−c
It was concluded that “In the case of tertiary amines product
formation involves alkene loss, for example, diethylamine and
triethylamine give the same product, but in the latter case
ethylene is lost.”5c Identification of ethylene as a product has
however not been described, and the mechanism by which the
β-lactone formation (eq 2),1b in which reactions of ketene/
tertiary amine complexes with methanol and chloral, respectively,
were proposed. Recent studies include asymmetric synthesis of
β-lactams2a,c and of α-fluoroacyl chlorides.2d
Dehydrochlorination of acyl chlorides with tertiary amines is
one of the first3 and most widely used methods for ketene
generation,2 but ketenes are also known to react with tertiary
amines, forming observable transients assigned as zwitterionic
intermediates.4,5 Aminations of ketenes by primary and
secondary amines have been the object of mechanistic study,6a−d
and a ketene−benzoylquinine complex has been identified using
IR spectroscopy.2c In a recent report asymmetric ketene
esterification with R-pantolactone in the preparation of a
glucokinase activator proceeded with catalysis by the
dimethylethylamine used in the generation of the ketene.6e
Examples of tertiary amine reactions with ketenes include
intramolecular reaction of the tertiary amine substituted vinylketene
Received: November 3, 2013
© XXXX American Chemical Society
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Table 1. Rate Constants for Reactions of Ketenes 6
(4-RC6H4CHCO) with Et3N and Quinuclidine (9) in
CH3CN, 25 °C
k (M−1 s−1) ketene
k (M−1 s−1) amide
a
c
ketene, amine
decay
formation
6a (R = MeO), Et3N
6b (R = H), Et3N
6c (R = NO2), Et3N
6a (R = MeO), 9
6b (R = H), 9
2.57 × 106
1.40 × 105
1.30 × 105
6.62 × 102
not formed
not formed
not formed
b
9.6 × 105
3.81 × 108
1.42 × 109
1.66 × 109
6c (R = NO2), 9
2.44 × 109
a
b
Measured by UV spectroscopy. Previously5a measured using IR
c
spectroscopy as 2.3 × 105 M−1 s−1 at 23 °C. Decay of transient,
product formation not monitored.
measurements show higher reactivity for the p-NO2 substituted
ketene 6c, consistent with stabilization of the intermediate
enolate 7c, and similarly a slower decay of this intermediate.
Reactions of quinuclidine (9) with arylketenes 6 were also
studied and gave high rate constants, near the diffusion
controlled limit (Table 1). The intermediates from these
reactions were long-lived but did not form observable products.
The measured rate constants show that 4-nitrophenylketene
is the most reactive with both amines, as expected for the
formation of zwitterionic intermediates 7 and 10, while the
4-methoxy and unsubstituted derivatives have similar but
lower reactivity. Correlation of the rate constants for the
ketene−quinuclidine reactions with σ− values gives a ρ value
of 0.15, showing a very small dependence on the substituents,
characteristic of reactions near diffusion control.
alkyl group is removed has apparently not been confirmed, or
even discussed further.
RESULTS AND DISCUSSION
The high reactivity of quinuclidine 9 in forming zwitterions
■
10 (eq 7) has been observed previously,5c and this and the slow
In view of the great utility of tertiary amines in ketene
generation and catalysis, and the seemingly unexplained
occurrence of degradation of tertiary amines in diarylketene
reactions (eq 5),5b,c we have now carried out systematic
experimental and computational studies of the reaction of
arylketenes with tertiary amines.
Photolysis of diazo ketones 59 was carried out as in previous
studies,6c,9 with 308 nm light in CH3CN containing Et3N, and
subsequent reactions were monitored using UV spectroscopy
(eq 6). Products from amine reactions with arylketenes formed
decay of these transients are as expected for the unencum-
bered facade of the amino nitrogen. Isolable products from
quinuclidine reactions with arylketenes incorporating quinucli-
dine have not been reported, but N-methylquinuclidinium
hydroxide upon heating is converted to 9, 4-vinyl-N-methyl-
piperidine, and 4-(2-hydroxylethyl) N-methylpiperidine (eq 8).10a
Also a sample of the hydroxide heated at 65 °C under high
by preparative photolysis in a Rayonet reactor were isolated and
identified and, in some cases, were confirmed to be the same
for ketene generation by diazo ketone photolysis followed by
amine addition, showing the products were not formed during
the photolysis step.
Rate constants for ketene reactions with triethylamine
forming transient zwitterions and subsequent amine catalyzed
dealkylation forming amides (eq 6) were measured by UV
spectroscopy (Table 1). Previously arylketene intermediates 6
formed similarly in acetonitrile5a or hexane9 had also been
identified by their characteristic IR spectra. The kinetic
vacuum to dehydrate the sample resulted in the formation of 9 and
CH3OH.10b Extreme conditions are required for alkene formation by
proton abstraction from the bridging groups because of the almost
orthogonal arrangement of the breaking C−H and C−N bonds.
Tertiary amines are present in considerable excess relative to
the diazo ketones in our reactions (eq 6), but the final absor-
bance of the zwitterion from 4-methoxyphenylketene and qui-
nuclidine increases with quinuclidine concentration, indicating
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that the reactions are reversible. Similar results are found for
the phenylketene reaction with triethylamine. Our calcula-
tions11 show the reaction of phenylketene with triethylamine in
acetonitrile forming the zwitterion is exothermic by 4.6 kcal/mol
(B3LYP/6-31+G(d)) or 13.0 kcal/mol (RI-MP2/6-31G(d)),
with free energy barriers of 2.6 or 0.5 kcal/mol, respectively.
Consistent with this interpretation the reaction of phenylketene
with pyridine in water has been reported to form an observable
zwitterion, which decays with formation of phenylacetic
acid, in a process interpreted as involving the reversible
dissociation of the zwitterion to the ketene and capture by
water (eq 9).4d
The high reactivity of quinuclidine with ketenes and the long
lifetime of the quinuclidine zwitterion explain the ability of the
structurally related alkaloids such as quinine (11) and brucine
(12) to form chiral zwitterions with long lifetimes that can be
converted stereoselectively to the final products. These
compete effectively in ketene capture with acyclic trialkylamines
used in ketene generation. Comparative nucleophilicity N
values have been reported as Et3N (17.1),12a N-methylpiper-
idine (18.72),12a and quinuclidine (20.54).12b
found that methyl and ethyl groups are displaced much more
readily than the attack on pyrrolidinyl or piperidinyl rings.15c,d
Product studies of the reactions of other tertiary amines with
ketenes were undertaken, and phenylketene generated in the
presence of diisopropylethylamine (DIPEA, Hunig’s base) gave
̈
the diisopropyl amide 17,13b the ethyl isopropyl amide 18, and
the ketone 19 (eq 13), in a ratio of 1:5:4. The loss of the ethyl
To test for alkene formation by elimination from inter-
mediate zwitterions, we examined the reaction of tri-n-octylamine
with phenylketene, since ethylene formed from the reaction
with triethylamine5c would be difficult to detect, but the less
volatile 1-octene is expected to be easily observable. However
an elimination reaction was not confirmed, as while N,N-di-n-
octyl phenylacetamide was isolated, no trace of 1-octene was
group is consistent with the loss of ethyl groups shown above
(eqs 5, 6) by a displacement reaction, and formation of 19 may
be explained by the reaction of phenylketene with the enamine
CH2CMeNEt-i-Pr, as in the formation of 15. However the
preferential formation of 18 with the loss of an isopropyl group
indicates that in this case an elimination reaction is involved, as
originally proposed for ethyl group loss.5c
Although tertiary amines are frequently used in ketene
preparations by dehydrohalogenation for in situ reactions with
other substrates, such dealkylations have not been observed
under these conditions. This is evidently due to rapid reactions
of the ketenes and zwitterions with the intended substrates such
as imines or alkenes, and also because the amine concentrations
are typically much lower than in the experiments reported here.
Diarylketenes react similarly,16 as photolysis of azibenzil in an
aqueous solution containing N-methylmorpholine gives
diphenylacetic acid by diphenylketene hydration, as well the
corresponding N-morpholinyl amide 20,16a in a ratio of 1:5 as
1
detected by H NMR in the reaction product.
Similarly no elimination product was detected upon
generation of phenylketene in the presence of N-methylpiper-
idine, but N-piperidinyl phenylacetamide (14)13 was isolated in
34% yield, with CH3 group loss from the expected intermediate
13 (eq 10). The enone 15 was also isolated and evidently
results from ketene addition14a,b to the enamine 15a14c derived14d,e
by oxidative hydrogen abstraction from N-methylpiperidine (eq 11).
The decays of the zwitterionic intermediates are amine
catalyzed, and in the absence of evidence for alkene formation a
displacement reaction by a further amine provides a plausible
explanation of these results (eq 12). Displacement of alkyl
groups from tertiary amines with nucleophiles occurs by the
von Braun reaction,15a,b and preparative reactions by alkyl
group displacement from quaternary ammonium ions by tertiary
amines were developed by Hunig and Baron.15c,d These studies
̈
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determined by HPLC, indicating competitive nucleophilic
addition of water and the amine to the ketene and
demethylation of an initial zwitterion by water, hydroxide, or
the amine (eq 14).16b
products remains a matter of conjecture that requires further
study.19
Computations at both the MP2 and B3LYP/6-31G+d levels
are in agreement with the conclusion from the experimental
results that triethylamine catalyzed dealkylation of the zwitterion
7b from phenylketene and triethylamine occurs preferentially
by displacement (Scheme 1).11 Thus the free energy of elimination
Scheme 1. Comparative Free Energies (MP2 and B3LYP/6-
31G+d) (kcal/mol) for Dealkylation of the Zwitterion 7b by
Et3N in CH3CN by Displacement and Elimination Routes11
N-Methylmorpholine also reacts with phenylketene in
CH3CN by demethylation, giving the analogous morpholinyl
phenylacetamide (21),13a in 27% isolated yield (eq 15).
Phenylketene with diethylmethylamine gave three products,
dialkylamides 8b17a and 2217b resulting from the loss of methyl
or ethyl groups, respectively, together with the methyl ester 23,
in the ratio 8b:22:23 = 3:1:2.5, again with preferential methyl
loss by zwitterion dealkylation (eq 16). Similarly the reaction of
phenylketene with PhCH2NMe2 gave the amide 2417 by
demethylation and 25 by the loss of benzyl, as well as the ester
26 (eq 17). The formation of esters 23 and 26, evidently by net
with alkene loss is found to be 8.3 (MP2) or 7.4 (B3LYP) kcal/mol
higher than for the displacement pathway.
CONCLUSION
■
The dealkylation of zwitterions obtained from tertiary amine
additions to ketenes occurs with preferential loss of methyl
groups, and displacement reactions by amines offer a plausible
mechanism for this process. Computational studies and the
failure to detect elimination products from dealkylation of tri-n-
octylamine adducts with phenylketene indicate displacement is
also the preferred route for the loss of n-alkyl groups. However
for the diisopropylethylamine reaction with phenylketene, loss
of an isopropyl group is favored, evidently by an elimination
route. Ketene reactions with tertiary amines are found to be
reversible, and the fast reaction of quinuclidine with ketenes
and the long lifetimes of the resulting zwitterions provide a
rationale for how the structurally related cinchona alkaloids can
effect addition to ketenes with zwitterion formation and pro-
mote subsequent stereoselective additions even in the presence
of triethylamine. The dealkylation reaction is remarkable due to
its occurrence with the stable diphenylketene as well as the
much more reactive phenylketene. We can envision many
extensions of this work to other ketenes and amines, as well as
investigations to elucidate the formation of the esters 23 and
26, but can no longer pursue such studies, and welcome others
to these tasks.
EXPERIMENTAL SECTION
■
General Procedure: N,N-Diethyl-2-phenylacetamide (8b)
[CAS 2431-96-1]17a from Phenylketene and Triethylamine.
To a glass tube (20 cm × 3.5 cm) equipped with a septum cap
was added acetonitrile (130 mL, HPLC grade, dried and kept
over molecular sieve 3A), 2-diazo-1-phenylethanone (5b, 6.5 mg,
0.044 mmol), and triethylamine (1.8 mL, 12.9 mmol). The solution
was purged with argon for 30 min and then irradiated 5 min in a
Rayonet reactor at 300 nm while purging with argon. The UV
spectrum of the irradiated solution showed that all starting diazo
ketone had been consumed. The solution was evaporated to give the
transfer of methyl or benzyl to oxygen with loss of the amino
group, is apparently unprecedented, and the origin of these
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1
crude product (7.2 mg, 85%), and the H NMR spectrum showed 8b
(s, 2H), 3.69 (s, 2H), 3.26 (q, J = 7.04 Hz, 2H), 3.23 (q, J = 7.04 Hz,
2H), 1.19 [(t, J = 7.04 Hz, 3H), 1.17 (t, J = 7.04 Hz, 3H), 1.16 (d, J =
6.6 Hz, 6H), 1.03 (d, J = 6.6 Hz) (6H)]. ESIMS (AIMS AccuTOF-
DART-MS) m/z ([M•H]+) 206. HRESIMS m/z calcd for
C13H20N1O1 206.15449, found 206.15485.
1-Phenyl-4-(ethylisopropylamino)-pent-2-one-3-ene (19).
Previously unreported (19), pale yellow oil. 1H NMR (400 MHz,
CDCl3) δ 7.28 (m, 5H), 5.02 (s, 1H), 4.11 (sept, J = 6.6 Hz, 1H), 3.58
(s, 2H), 3.11 (q, J = 7.0 Hz, 2H), 2.55 (s, 3H), 1.13 (d, J = 6.6 Hz, 2 ×
CH3), 1.05 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 194.3,
161.1, 138.2, 129.4, 128.3, 126.0, 94.6, 52.0, 48.4, 37.9, 20.6, 15.7. UV
λmax = 313 nm (CH3CN), IR (CDCl3) νmax 1600, 1525 cm−1. ESIMS
as the major product. Column chromatography (silica gel, CHCl3
followed by CHCl3/MeOH 9:1 v/v) gave 8b (3.1 mg, 36%). 1H NMR
(400 MHz, CDCl3) δ 7.31−7.25 (m, 5H), 3.70 (s, 2H), 3.39 (q, J =
7.24 Hz, 2H), 3.30 (q, J = 7.04 Hz, 2H), 1.18−1.08 (m, 6H).
N,N-Diethyl-2-(4-methoxyphenyl)acetamide (8a) CAS
[115348-15-7].18 By the general procedure, 2-diazo-1-(4-
methoxyphenyl)ethanone (5a, 9 mg, 0.051 mmol) and triethylamine
(1.9 mL, 13.6 mmol) in CH3CN gave a crude product (6.2 mg) found
1
by H NMR to contain 8a and 4-methoxyacetophenone in a ratio of
76:24. Column chromatography (silica gel CH2Cl2/EtOAc 8:2 v/v)
gave 8a (2.6 mg, 24%): H NMR (400 MHz, CDCl3) δ 7.17 (d, J =
1
8.80 Hz, 2H), 6.85 (d, J = 8.61 Hz, 2H), 3.79 (s, 3H), 3.63 (s, 2H),
3.38 (q, J = 7.04 Hz, 2H), 3.30 (q, J = 7.04 Hz, 2H), 1.18−1.08 (m,
6H) and 4-methoxyacetophenone 1H NMR (400 MHz, CDCl3) δ
7.94 (d, J = 9.00 Hz, 2H), 6.94 (d, J = 9.00 Hz, 2.6 H), 3.87 (s, 3 H),
2.56 (s, 3H). The latter product is evidently a byproduct from the
photo-Wolff rearrangement.
N,N-Diethyl-2-(4-nitrophenyl)acetamide (8c) CAS [50507-86-
3].18 By the general procedure, 2-diazo-1-(4-nitrophenyl)ethanone
(9.2 mg, 0.048 mmol) and triethylamine (1.8 mL, 12.9 mmol) in
CH3CN gave the crude product which after column chromatography
(AIMS Accu TOF-DART-MS) m/z ([M•H]+) 246; HRESIMS m/z
calcd for C16H24N1O1 246.18579, found 246.18748.
1
(silica gel EtOAc/hexanes 7:3 v/v) gave 8c (3 mg, 27%). H NMR
The UV spectrum may be compared to that reported for trans-
MeCOCHC(Me)NMe2: (MeOH) λmax 310 nm (28 700).20
Diphenylketene N-Methylmorpholine Reaction.16 Flash
photolysis of azibenzil in aqueous N-methylmorpholine afforded
N-morpholinyldiphenylacetamide (20)16a and diphenylacetic acid at a
buffer ratio of 0.993. The amide−acid product ratio at this buffer
concentration is 0.16, in good agreement with the value from kinetic
experiments.16c
Phenylketene N-Methylmorpholine Reaction. By the general
procedure, the product from 2-diazo-1-phenylethanone (7.8 mg,
0.053 mmol) and N-methylmorpholine (1.4 mL, 12.7 mmol) upon
column chromatography (silica gel, CH2Cl2/EtOAc 8:2 v/v) gave the
known13 amide 1-(4-morpholinyl)-2-phenyl ethanone (21). CAS:
17123-83-0 (3 mg, C12H15NO2, MW 205.25, 15 mmol, 27%). Further
chromatography gave the sample for 1H NMR measurement. 1H NMR
(400 MHz, CDCl3) 21 δ 7.33−7.23 (m, 5H), 3.74 (s, 2H), 3.65 (bd s,
4H), 3.5−3.4 (m, 4H).
(400 MHz, CDCl3) δ 8.18 (d, J = 8.80 Hz, 2H), 7.47 (d, J = 8.80 Hz,
2H), 3.79 (s, 3H), 3.41 (q, J = 7.24 Hz, 2H), 3.34 (q, J = 7.24 Hz, 2H),
1.18−1.08 (m, 6H).
Product Study for Phenylketene Reaction with Tri-n-
octylamine: N,N-Di-n-octyl-4-phenylacetamide (8d). To a
septum capped NMR tube was added 850 μL of CDCl3, 2-diazo-1-
phenylethanone (5.8 mg, 0.044 mmol), and tri-n-octylamine (28 μL,
0.064 mmol), and the solution was purged with argon for 5 min and
then irradiated in a Rayonet reactor for 5 min while being purged with
argon. The 1H NMR spectrum of the irradiated solution showed some
starting material remained which upon further irradiation for 21 min
1
disappeared. H NMR showed the presence of 8d, but no absorption
attributable to the vinyl H of 1-octene was observed (estimated
detection limit 5% relative to 8d). The solution was evaporated (0.029 g,
crude), and N,N-di-n-octyl phenylacetamide (8d, CAS [514808-21-0],
a previously unreported compound) was obtained after 3-fold column
chromatographic separation (CH2Cl2/hexanes 8:2 v/v), (CH2Cl2/
EtOAc 8:2 v/v) and (CH2Cl2/EtOAc 98:2 v/v); 1H NMR (400 MHz,
CDCl3) δ 7.3−7.2 (m, 5H), 3.69 (s, 2 H), 3.30 (t, J = 7.63 Hz, 2H),
3.19 (t, J = 7.82 Hz, 2H), 1.4−1.6 (m, 4H), 1.2−1.3 (m, 20 H),
0.9−0.8 (m, 6H).
Phenylketene Diethylmethylamine Reaction with in Situ
Ketene Generation and Amine Reaction. By the general
procedure, 2-diazo-1-phenylethanone (5b, 7.4 mg, 0.051 mmol) and
N,N-diethylmethylamine (1.4 mL, 11.6 mmol) in 130 mL of
acetonitrile were purged for 40 min with argon, and the solution
was then irradiated for 5 min in a Rayonet reactor with 300 nm lamps
Phenylketene N-Methylpiperidine Reaction. By the general
procedure, the product from 2-diazo-1-phenylethanone (7.8 mg,
0.053 mmol) and N-methylpiperidine (1.5 mL, 12.3 mmol) in
acetonitrile upon chromatography (silica gel, CH2Cl2/EtOAc 8:2 v/v)
gave amide 14 (3.7 mg, 34%) and a later fraction gave ketone 15,
evidently derived from the corresponding enamine, 1,2,3,4-tetrahydro-
1-methylpyridine CAS [57005-69-3].10 Another column chromato-
graphy (silica gel, EtOAc/CH2Cl2, 8:2 v/v) gave pure 15.
1
while purging with argon. The solvent was evaporated, and the H
NMR spectrum showed a mixture of products. Column chroma-
tography (silica gel, CH2Cl2/EtOAc 9:1 v/v) gave in fractions
1−5 PhCH2CO2Me (23)11 and fractions 11−17 PhCH2CONEt2
(8b). Further elution with EtOAc gave PhCH2CONMeEt (22).
Relative yields by 1H NMR intergration are PhCH2CONEt2 (8b)
(47%); PhCH2CONMeEt (22) (11%); PhCH2CO2Me (23) (42%).
N,N-Diethyl-2-phenylacetamide (8b). CAS: [2431-96-1].
1H NMR (400 MHz, CDCl3) δ 7.31−7.26 (m, 5H), 3.70 (s, 3H),
3.63 (s, 2H), 3.39 (q, J = 7.04 Hz, 2H), 3.30 (q, J = 7.04 Hz, 2H),
1.14−1.07 (m, 6H).
2-Phenyl-1-(1-piperidinyl)ethanone (14) [CAS: 3626-62-8].13
1H NMR (400 MHz, CDCl3) 14 δ 7.31−7.25 (m, 5H), 3.73 (s, 2H),
3
3
3.57 (t, JH,H = 5.7 Hz, 2H), 3.37 (t, JH,H = 5.7 Hz, 2H), 1.59−1.52
(m, 4H), 1.37−1.33 (m, 2H). EIMS m/z 203 (51, M+), 112 (100,
[M+ − CH2Ph]). HREIMS m/z calcd for C13H17NO 203.1315, found
203.1310.
Identification of PhCH2CONMeEt (22). N-Methyl-N-ethyl-2-
phenylacetamide [CAS: 105879-33-2]. 1H NMR (400 MHz,
CDCl3) 22 mixture of rotamers, 1:1.2 (average 2.8 to 3.8 ppm) (major
rotamer) δ 7.38−7.20 (m, 5H), 3.70 (s, 3H), 3.34 (q, J = 7.04 Hz,
2H), 2.94 (s, J = 7.04, 2H), 1.08−1.26 (rotamers overlapping t, 3H);
(minor rotamer) δ 7.38−7.20 (m, 5H), 3.72 (s, 3H), 3.44 (q, J = 7.43
Hz, 2H), 2.93 (s, J = 7.04, 2H), 1.08−1.26 (rotamers overlapp-
ing t, 3H).
Phenylketene Diisopropylethylamine Reaction. By the
general procedure, photolysis of 2-diazo-1-phenylethanone (5b,
7.1 mg, 0.049 mmol) and DIPEA (2.0 mL, 11.5 mmol) in CH3CN and
purification by 3-fold chromatography on silica gel {(CH2Cl2/EtOAc
8:2 v/v), (hexanes/EtOAc 6:4 v/v), (CH2Cl2/EtOAc 6:4 v/v)}
gave three isolated products identified as (N,N-diisopropyl-2-
phenylacetamide, 17, CAS: [34251-46-310 2])13b,15e 18, and 19,
Identification of PhCH2CO2Me (23).21 1H NMR (400 MHz,
CDCl3) 25 δ 7.31−7.26 (m, 5H), 3.70 (s, 3H), 3.63 (s, 2H).
Modified Phenylketene Diethylmethylamine Reaction. A
solution of 5b (3.8 mg, 0.026 mmol) in 35 mL of acetonitrile was
purged for 40 min with argon, and the solution was then irradiated in a
Rayonet reactor for 3 min with 16 lamps at 300 nm while purging with
1
which from the H NMR spectra of three separate preparations were
present in the crude product in a ratio of 11:51:38.
N-Ethyl-N-isopropyl-2-phenylacetamide (18) CAS: [125576-
07-0].13c Pale yellow oil: H NMR (400 MHz, CDCl3) δ 7.38−7.20
1
(m, 10H), 4.69 (sept, J = 6.6 Hz, 1H), 4.05 (sept, J = 6.6 Hz, 1H), 3.74
E
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Article
argon. Immediately after irradiation diethylmethylamine (0.7 mL,
5.8 mmol) was added, and the solution turned bright yellow. After 10 min,
the purging was stopped and the solvent evaporated under reduced
(4) (a) Pacansky, J.; Chang, J. S.; Brown, D. W.; Schwarz, W. J. Org.
Chem. 1982, 47, 2233−2234. (b) Qiao, G. G.; Andraos, J.; Wentrup,
C. J. Am. Chem. Soc. 1996, 118, 5634−5638. (c) Visser, P.; Zuhse, R.;
Wong, M. W.; Wentrup, C. J. Am. Chem. Soc. 1996, 118, 12598−
12602. (d) Chiang, Y.; Kresge, A. J.; Popik, V. V. J. Am. Chem. Soc.
1999, 121, 5930−5932. (e) Kirmse, W. Eur. J. Org. Chem. 2002,
2193−2256. (f) Gompper, R.; Wolf, U. Liebigs Ann. Chem. 1979,
1388−1405. (g) Kollenz, G.; Holzer, S.; Kappe, C. O.; Dalvi, T. S.;
Fabian, W. M. F.; Sterk, H.; Wong, M. W.; Wentrup, C. Eur. J. Org.
Chem. 2001, 1315−1322.
(5) (a) Wagner, B. D.; Arnold, B. R.; Brown, G. S.; Lusztyk, J. J. Am.
Chem. Soc. 1998, 120, 1827−1834. (b) de Lucas, N. C.; Netto-Ferreira,
J. C.; Andraos, J.; Lusztyk, J.; Wagner, B. D.; Scaiano, J. C. Tetrahedron
Lett. 1997, 38, 5147−5150. (c) De Lucas, N. C.; Netto-Ferreira, J. C.;
Andraos, J.; Scaiano, J. C. J. Org. Chem. 2001, 66, 5016−5021.
(d) Raspoet, G.; Nguyen, M. T.; Kelly, S.; Hegarty, A. F. J. Org. Chem.
1998, 63, 9669−9677.
(6) (a) Allen, A. D.; Tidwell, T. T. J. Org. Chem. 1999, 64, 266−271.
(b) Allen, A. D.; Moore, P. A.; Missiha, S.; Tidwell, T. T. J. Org. Chem.
1999, 64, 4690−4696. (c) Acton, A. W.; Allen, A. D.; Antunes, L. M.;
Fedorov, A. V.; Najafian, K.; Tidwell, T. T.; Wagner, B. D. J. Am.
Chem. Soc. 2002, 124, 13790−13794. (d) Sung, K.; Tidwell, T. T. J.
Am. Chem. Soc. 1998, 120, 3043−3048. (e) DeBaillie, A. C.; Magnus,
N. A.; Lauilla, M. E.; Wepsiec, J. P.; Ruble, J. C.; Petkus, J. J.; Vaid, R.
K.; Niemeier, J. K.; Mick, J. F.; Gunter, T. Z. Org. Process Res. Dev.
2012, 16, 1538−1543.
1
pressure giving a residue of 5.7 mg, which by H NMR showed the
presence of PhCH2CONEt2 (8b), PhCH2CO2NMeEt (22), and
PhCH2CO2Me (23), in a similar ratio to that observed previously.
Phenylketene Reaction with N,N-Dimethylbenzylamine. By
the general procedure, 5b (2-diazo-1-phenylethanone, 7.7 mg,
0.053 mmol) and N,N-dimethylbenzylamine (1.75 mL, 11.6 mmol)
in 130 mL of acetonitrile were purged with argon for 30 min. The
solution was then irradiated in a Rayonet reactor for 5 min at 300 nm
while purging with argon. The reaction was monitored by UV, which
showed the depletion of all starting material. The solvent was
evaporated, and the 1H NMR spectrum of the residue showed unreacted
amine and a mixture of products. Characteristic peaks for
PhCH2CO2CH2Ph (26) at 5.12 and 3.66 ppm were observed in the
crude 1NMR and in the early CH2Cl2 chromatography fraction. Gradient
column chromatography on silica gel from CH2Cl2 to CH2Cl2/EtOAc
9:1 to CH2Cl2/EtOAc 8:2 to EtOAC and MeOH was performed, and by
further column chromatography on silica gel hexanes/EtOAc 9:1, pure
PhCH2CO2CH2Ph (26) and PhCH2CONMeCH2Ph (24)17 were
isolated from CH2Cl2/EtOAc 8:2 fractions and PhCH2CONMe2 (25)
was isolated in the EtOAc fraction.
Identification of PhCH2CONMeCH2Ph (24).17 N-Benzyl-N-
methyl-2-phenylacetamide CAS: [105879-33-2]. 1H NMR
(400 MHz, CDCl3) 24 1:1.4 (average 2.8 to 4.8 ppm) mixture of
rotamers: (major rotamer) δ 7.38−7.21 (m, 9H), 7.11−7.09 (m, 1H),
4.61 (s, 2H), 3.79 (s, 2H), 2.90 (s, 3H); (minor rotamer) δ 7.38−7.21
(m, 9H), 7.11−7.09 (m, 1H), 4.53 (s, 2H), 3.76 (s, 2H), 2.96 (s, 3H).
Identification of PhCH2CONMe2 (25).22a N,N-Dimethyl-2-
phenylacetamide CAS: [135339-78-5]. 1H NMR (400 MHz,
CDCl3) δ 7.5−7.22 (m, 5H), 3.72 (s, 2H), 3.00 (s, 3H), 2.97 (s, 3H).
Identification of PhCH2CO2CH2Ph (C15H141O2) (26).22b Phenyl-
acetic acid benzyl ester CAS: [102-16-9]. H NMR (400 MHz,
CDCl3) δ 7.4−7.3 (m, 5H), 5.14 (s, 2H), 3.67 (s, 2H). HRESIMS
m/z calcd for M + H+ C15H15O2 227.10720, found 227.10765; calcd
(7) (a) Paton, R. S.; Steinhardt, S. E.; Vanderwal, C. D.; Houk, K. N. J.
Am. Chem. Soc. 2011, 133, 3895−3905. (b) Steinhardt, S. E.; Silverston,
J. S.; Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130, 7560−7561.
(8) (a) Edstrom, E. D. J. Am. Chem. Soc. 1991, 113, 6690−6692.
(b) Birchler, A. G.; Liu, F.; Liebeskind, L. S. J. Org. Chem. 1994, 59,
7737−7745.
(9) Allen, A. D.; Fedorov, A.; Henry-Riyad, H.; Tidwell, T. T. J. Phys.
Org. Chem. 2006, 19, 841−846.
(10) (a) Lukes, R. Collect. Czech. Chem. Commun. 1957, 22, 1173−1179.
(b) Harmon, K. M.; Southworth, B. A. J. Mol. Struct. 1993, 298, 23−36.
(11) (a) Details are given in the Supporting Information.
(b) Gaussian 98, revision B-1; Gaussian, Inc.: Pittsburgh, PA, 1998.
(12) (a) Ammer, J.; Baidya, M.; Kobayashi, S.; Mayr, H. J. Phys. Org.
Chem. 2010, 23, 1029−1035. (b) Baidya, M.; Kobayashi, S.; Brotzel,
F.; Schmidhammer, U.; Riedle, E.; Mayr, H. Angew. Chem., Int. Ed.
2007, 46, 6176−6179.
+
for M + NH4 C15H18NO2 244.13375, found 244.13390.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR, UV, and IR spectra, computational results. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) (a) Ghosh, S. C.; Hong, S. H. Eur. J. Org. Chem. 2010, 4266−
4270. (b) Song, B.; Wang, S.; Sun, C.; Deng, H.; Xu, B. Tetrahedron
Lett. 2007, 48, 8982−8986. (c) Antonovic, D. G.; Mijin, D. Z.;
Stojanovic, N. D.; Jeremic, L. A.; Petrovic, S. D. J. Serb. Chem. Soc.
1994, 59, 967−971.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ttidwell@chem.utoronto.ca.
Notes
(14) (a) Hunig, S.; Hoch, H. Tetrahedron Lett. 1966, 7, 5215−5220.
̈
(b) Abe, N.; Osaki, I.; Kojima, S.; Matsuda, H.; Sugihara, Y.; Kakehi, A.
J. Chem. Soc., Perkin Trans. 1 1996, 2351−2356. (c) Beeken, P.;
Fowler, F. W. J. Org. Chem. 1980, 45, 1336−1338. (d) Bunce, N. J.;
Cater, S. R.; Scaiano, J. C.; Johnston, L. J. J. Org. Chem. 1987, 52,
4214−4223. (e) Scaiano, J. C. J. Phys. Chem. 1981, 85, 2851−2855.
(15) (a) v. Braun, J. Chem. Ber. 1900, 33, 1438−1452. (b) Olofson,
R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J. Org. Chem.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Natural Sciences and Engineering
Research Council of Canada is gratefully acknowledged.
1984, 49, 2081−2082. (c) Hunig, S.; Baron, W. Chem. Ber. 1957, 90,
̈
REFERENCES
395−402. (d) Hunig, S.; Baron, W. Chem. Ber. 1957, 90, 403−413.
̈
■
(e) Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org. Lett. 2009, 11, 1667−1670.
(16) (a) Rossi, R. A.; Alonso, R. A. J. Org. Chem. 1980, 45, 1239−
1241. (b) Andraos, J. A. PhD Thesis, University of Toronto, 1990.
(c) Andraos, J.; Kresge, A. J. J. Am. Chem. Soc. 1992, 114, 5643−5646.
(d) The kinetics of the reaction of dimesitylketene in CHCl3 with N-
methylmorpholine and with N-ethylpiperidine have been reported,5d
but not the products of these reactions.
(17) (a) Petrovic, S.; Vajs, V. E.; Nikolic, A. D.; Stojanovic, N. D. J.
Mol. Struct. 1986, 142, 451−453. (b) Chen, C.; Zhang, Y.; Hong, S. H.
J. Org. Chem. 2011, 76, 10005−10010.
(18) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 4976−4985.
(1) (a) Pracejus, H. Liebigs Ann. Chem. 1960, 634, 9−22.
(b) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104,
166−168.
(2) (a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542−547. (b) Fu, G. C.
Acc. Chem. Res. 2000, 33, 412−420. (c) Taggi, A. E.; Hafez, A. M.;
Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002,
124, 6626−6635. (d) Erb, J.; Paull, D. H.; Dudding, T.; Belding, L.;
Lectka, T. J. Am. Chem. Soc. 2011, 133, 7536−7546. (e) Allen, A. D.;
Tidwell, T. T. Eur. J. Org. Chem. 2012, 1081−1096. (f) Allen, A. D.;
Tidwell, T. T. Chem. Rev. 2013, 113, 7287−7342.
(3) (a) Wedekind, E. Chem. Ber. 1901, 34, 2070−2077.
(b) Staudinger, H. Chem. Ber. 1911, 44, 1619−1623.
F
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(19) Computations reported in the Supporting Information indicate
that methyl migration from nitrogen to oxygen in the zwitterion from
the reaction of phenylketene with diethylmethylamine has an
appreciable barrier.
(20) Dabrowski, J.; Kamienska-Trela, K. J. Am. Chem. Soc. 1976, 98,
2826−2834.
(21) (a) Dhakshinamoorthy, M.; Sharmila, A.; Pitchumani, K.
Chem.Eur. J. 2010, 16, 1128−1132. (b) Geise, C. M.; Wang, Y.;
Mykhaylova, O.; Frink, B. T.; Toscano, J. P.; Hadad, C. M. J. Org.
Chem. 2002, 67, 3079−3088.
(22) (a) Chiba, S.; Zhang, L.; Sanjaya, S.; Ang, G. Y. Tetrahedron
2010, 66, 5692−5700. (b) Hoffman, M. K.; Wallace, J. C. J. Am. Chem.
Soc. 1973, 95, 5064−5065.
G
dx.doi.org/10.1021/jo402438w | J. Org. Chem. XXXX, XXX, XXX−XXX