On DABAL-Me3 promoted formation of amides

Article abstract of DOI:10.1016/j.tet.2013.08.062

The range and utility of DABAL-Me₃ couplings of methyl esters and free carboxylic acids with primary and secondary amines under a variety of conditions (reflux, sealed tube, microwave) has been compared for a significant range of coupling partners of relevance to the preparation of amides of interest in pharmaceutical chemistry. Commercial microwave reactors promote the fastest couplings and allow the use of significantly sterically hindered amines (primary and secondary) and carboxylic acids derivatives. The influence of microwave energy on the reaction system was shown to be typically related to thermal effects (over-pressuring and superheating).

Full text of DOI:10.1016/j.tet.2013.08.062

Tetrahedron 69 (2013) 9890e9897
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
On DABAL-Me3 promoted formation of amides
Nathalie Dubois a, Daniel Glynn a, Thomas McInally a, Barrie Rhodes b,
,
c
c
Simon Woodward a , Derek J. Irvine , Chris Dodds
*
a School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
b Aesica Pharmaceuticals Ltd, Quorum Business Park, Benton lane, Newcastle upon Tyne NE12 8BS, UK
c Department of Chemical and Environmental Engineering, University of Nottingham, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2013
Received in revised form 12 August 2013
Accepted 23 August 2013
Available online 2 September 2013
The range and utility of DABAL-Me3 couplings of methyl esters and free carboxylic acids with primary
and secondary amines under a variety of conditions (reflux, sealed tube, microwave) has been compared
for a significant range of coupling partners of relevance to the preparation of amides of interest in
pharmaceutical chemistry. Commercial microwave reactors promote the fastest couplings and allow the
use of significantly sterically hindered amines (primary and secondary) and carboxylic acids derivatives.
The influence of microwave energy on the reaction system was shown to be typically related to thermal
effects (over-pressuring and superheating).
Keywords:
Coupling agent
Trimethylaluminium
Amide
Ó 2013 Elsevier Ltd. All rights reserved.
Ester
Carboxylic acid
Microwave
1. Introduction
The formation of amide linkages from carboxylic acid de-
rivatives and amines constitutes a fundamental process in organic
chemistry that is of high utility in the preparation of pharmaceu-
tical and medicinal chemistry intermediates and is extensively used
in ubiquitous poly-peptide preparations.1 Typically, the combina-
tion of R1CO2H and HNR2R3 (1ꢀ or 2ꢀ amines) requires the presence
of an activating ‘coupling agent’ to facilitate removal of the ele-
ments of water from the two components. Over 300 such ‘coupling
agents’ are described in key reviews covering this area2 and some of
the more commonly used species are shown in Scheme 1. In 20063
and 20084 we provided preliminary details of the use of DAB-
CO(AlMe3)2 (which we call DABAL-Me3) in such rolesdbased on
the seminal direct coupling of RCO2Me and amines using AlMe3 by
Weinreb.5 Recently, related AlMe3 alone couplings of free carbox-
ylic acids and amines have also appeared.6 The study herein arose
out of a number of underlying questions that were frequently put to
us regarding our own chemistry: (i) How wide is the scope of the
DABAL-Me3 amide coupling? (ii) Are functional groups present in
typical active pharmaceutical ingredients (APIs) tolerated? (iii)
How adaptable and scalable are these reactions? (iv) Can free
Scheme 1. Commonly used RCO2H/amine ‘coupling agents’ and the structure of DA-
BAL-Me3.
carboxylic acids be used? (v) Finally, how does DABAL-Me3 com-
pare against the literature standard ‘coupling agents’ in Scheme
1ddoes it offer any competitive advantage for particular combi-
nations? In this regard it is insightful to initially compare the
* Corresponding author. Fax: þ44 (0)115 9513541; e-mail address:
simon.woodward@nottingham.ac.uk (S. Woodward).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.062

N. Dubois et al. / Tetrahedron 69 (2013) 9890e9897
9891
reagents of Scheme 1 in a hypothetical R1CO2H(Me)/HNR1R2 cou-
pling on a 5 mmol scale against several criteria (Table 1). It might be
suggested, based on Table 1 that AlMe3-based ‘coupling agents’3,4,6
are: mid-cost, rather too active for peptide coupling, uniquely able
to use both free carboxylic acids and their esters (see later), but of
significant utility for formation of tert-amides.
PhCO2Me) it was observed that with DABAL-Me3 loadings at or be-
low 0.8 equiv (with 0.25 M [substrate]) conversion efficiency could
become poor or erratic. This was attributed the presence of minor
variations in THF solvent quality (which result if it has not been
rigorously dried). Increasing the ester/amine concentrations to ca.
1 M was found to produce a much more robust MWH process,
Table 1
Comparison of ‘coupling agents’ in Scheme 1 for simple amide formation at a 5 mmol scale
Coupling agent (minimum Rel. Cost/£a Can use
Can use
RCO2Me
Efficient
for tertiary
rac?b By products formed and any complications
Mass waste
(in g) per
Waste
stream
viable amount)
RCO2H
directly? directly? amides?
5 mmol acidc
Thionyl chloride/NEt3
(1.0 equiv each)
DCC (1.0 equiv)
0.1
0.2
7
U
U
U
U
U
✗
✗
✗
✗
✗
U
U
SO2, 2ꢁ HNEt3Cl; SOCl2 often used in large excess;
0.34
Aq
racemization very common
✗
✗/U
✗/U
✗/U
✗
CyNHC(O)NHCy (often poor separation); HOBt can be 1.12
needed to avoid racemisation
EtNHC(O)NH(CH2)3NHMe2Cl; HOBt can be needed to
avoid racemisation
Org.
Aq
EDC-HCl (1.0 equiv)
T3P (1.0 equiv)
✗
1.05
8
✗/Ud
Uf
HOP(O)PrOPPr(O)OP(O)PrOH; 2 equiv T3P needed for 1.68
Aq
minimised recemisatione
€
HATU/Hunig’s base
28
Triazole, Me2NC(O)NMe2, [NHEtiPr2]PF6; excess
amine can be required to avoid formation of
tetramethyl guanidinium derivatives
2.64
Aq
PyBrOP (1.0 equiv)
29
14
U
U
✗
Ug
U
✗
P(O)(NC4H4)3, HBr, HPF6; N-Boc
a
-aminoacids not
2.42
2.09
Aq
Aq
viable partners.h
DABAL-Me3 (0.8 equiv),
present paper
U
✗/U
2ꢁ Al3þ, 6ꢁ MeH, DABCO (0.8 equiv of each)
a
Approximation based on costs (£) for 5e100 g quantities from SigmaeAldrich (2013). Self-prepared DABAL-Me3 (Ref. 7) is w£2.5 per 5 mmol coupling.
Tendency of the reagent to racemise stereochemically labile centres; ✗/U indicates mixed success in the primary literature.
Only that generated explicitly by the ‘coupling agent’ (excludes solvent and any external aqueous quench acids and other quench agents).
Only limited examples have been reported to date (Ref. 8).
b
c
d
e
f
See Ref. 9.
Higher quantities of HATU are often required and yields suffer as the steric profile of the amine increases. For instructive comparisons see Ref. 10.
For comparisons of PyBroP against HATU, EDC and T3P see Ref. 11.
See Ref. 12.
g
h
This present paper attempts to provide comprehensive answers
to the questions (i)e(v) posed above and thus more fully define the
scope and limitations of these DABAL-Me3 promoted couplings.
i.e., complete conversion to the target compound was attained in
>20 repeat reactions. However, it was noted that anhydrous THF is
still a requirement to achieve success.
A comparison between MWH and CH processing was conducted
using the same model system (i.e.,1) in various solvents. In this case
sealed tubes were used for MWH (130 ꢀC) and CH (85 or 120 ꢀC)
versus overnight CH refluxes in standard glassware at atmospheric
pressure. The results of these reactions are contained in Table 3.
Furthermore, to ensure a fair comparison between the MWH and
CH sealed tube experiments the oil baths used were pre-
equilibrated at 120 ꢀC (for toluene) and 85 ꢀC (for ethers) and run
for 35 min (to simulate the advantageous heating in the 20 min
‘cool down’ period that follows 8 min of heating at 130 ꢀC in our
CEM reactor). Reflux reactions were conducted overnight as these
were initially expected to be a lot slower. The solvents selected for
comparison against THF were toluene, MTBE, 2-MeTHF as these
provide a range of polarities and boiling points.
2. Results and discussion
2.1. Comparison of heating methods, solvents and scales
DABAL-Me3 amide formation has been reported to proceed
slowly in refluxing THF under conventional heating (CH), such as
isomantles or oil baths,3 but much more rapidly when microwave
heating (MWH) is used.4 In previous reports, we had recommended
the use of 0.8 equiv of DABAL-Me3 per equivalent of a 1:1 methyl
ester:amine mixture at 0.25 M in THF.4 However, when model cou-
plings of methyl benzoate and pyrrolidine were compared applying
the varying reaction conditions detailed in Table 2 (1 mmol scales in
These results showed, with the exception of MTBE that the
sealed tube reaction results (MWH vs CH) are very similar; both in
terms of yield attained and conversion. Again, with the exception of
Table 2
Optimization of the microwave-based reactiona
Table 3
Comparison of heating modes and solvents for reaction of PhCO2Me with pyrroli-
dine to produce (1)a
Solvent
(bp/ꢀC)
Yield microwave
(8 min at 130 ꢀC)/% (35 min)/%
Yield sealed tubeb Yield reflux
Run
DABAL-Me3 (equiv)
[PhCO2Me]/M
Yield (1)/%
(15 h at solvent bp)/%
1
2
3
4
5
0.8
1.0
0.8
0.8
1.0
0.25
0.25
1.0
Neat
1.0
78e92b
90
THF (66)
Toluene (110) 80%
2-MeTHF (80) 83%
90%
86%
79%
86%
56%
88% (5% ester)
84%
69% (20% ester)
90% (9% ester)
ꢂ90
0c
MTBE (55)
72%
84
a
Conducted on a 1 mmol scale (1:1 PhCO2Me: pyrrolidine, 1 M in solvent) with
0.8 equiv DABAL-Me3. Crude yields (1H NMR spectra indicate clean reactions con-
taining only tert-amide or unreacted PhCO2Me in all cases. Complete conversions
were attained in all non-reflux reactions.
a
Reactions carried out on 1.00 mmol PhCO2Me and pyrrolidine in THF (1e4 mL)
in a CEM Discover microwave reactor.
b
A range of yields were found.
Intractable tar formed.
c
b
THF, 2-MeTHF, MTBE heated at 85 ꢀC, toluene at 120 ꢀC.

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N. Dubois et al. / Tetrahedron 69 (2013) 9890e9897
MTBE, they were close to the yield observed from the 16 h reflux
reaction, but in the latter full conversion was not always attained.
Shorter reaction times and higher temperatures favoured the
model transformation. The increased reaction rate in the sealed
systems was attributed to over pressures resulting from heating the
system above its solvent bp leading to superheating in the system.
The reduced reaction time of the sealed tube experiments were
ascribed to higher than target internal reaction temperatures. This
may be exacerbated in the CEM reactor as its reaction temperature
monitoring is achieved by indirect IR measurement of the vessel
wall. This method has been extensively shown to underestimate
the true bulk temperature of the bulk reaction medium contrib-
uting to further overheating. Typically, a direct measurement of the
bulk temperature would be used to offset this issue. However, the
use of sealed tubes prevented us from screening this. The anoma-
lous high temperature behaviour of MTBE may be due to solvent
degradation at high temperatures.
The technical simplicity of the toluene reflux conditions (com-
bine all components and heat under argon) was appealing, so these
conditions were investigated further. It was found that on a 1 mmol
scale such reactions such were typically complete within 1 h.
Therefore a key conclusion was that all the effects observed here are
either thermal (i.e., superheating) or concentration (DABAL and
substrate) based.
complete conversions within only 8 min. Comparative 5 mmol
scale sealed tube CH reaction, was also found to produce 3 in
85e64% yields in 60e120 min (toluene, 1 M, 130 ꢀC on 1e5 mmol
scales). This again stressed the importance of the higher reaction
temperatures to the system and that microwave heating is likely to
produce a greater level of superheating due to a combination of the
IR temperature measure and potentially the dielectric properties of
the differing precursors and products.
We believe two factors are important in explaining these find-
ings. Firstly, it is known that DABAL-Me3 binds AlMe3 relatively
loosely (AleN ca. 30 kcal molꢃ1) and the latter is quite volatile (bp
125 ꢀC).13 A simple Raoult’s law analysis indicates that AlMe3 will
account of 36 mol % of the vapour above a reaction mixture in
refluxing toluene at 110 ꢀC. We believe that partial loss of AlMe3 to
the vapour head-space phase is facilitated in large apparatus and
this can stave the reaction of ‘coupling agent’ slowing the coupling.
The influence of this effect will be significantly reduced in the
overpressure experiments (regardless of the heating method),
which will retain a far more dissolved AlMe3. Further credence is
given to this idea by observation that larger scale couplings using
methyl-p-iodobenzoate (1.31 g, 10 mmol) in a lower ‘dead volume’
steel bomb at 130 ꢀC gave ca. 70% yields after 2 h. Finally, the
DABAL-Me3 coupling reaction also seems to be simply favoured by
rapid heating/superheating in a manner akin to the positive affects
observed in other rapid heating procedures, e.g., flash vacuum
pyrolysis.14 By comparison, the slower temperature increase/time
profiles associated with large reflux reactions result in less efficient
heat transfer with time and thus impaired reaction efficiency.
In a related study, using methyl-4-iodobenzoate and pyrrolidine,
at increased scales (5 mmol of ester and amine, 1 M) the rate of the
reflux reaction was found to slow significantly and extended reflux
wasrequiredtoattainevenmoderateyieldsofamide2(Fig.1). Further
extension of the reflux time did not significantly improve the yield.
However, conducting the formation of 2 at a 1 mmol scale, using
a toluene reflux was found to result in an 80% yield of 2 within 60 min
(approximately6ꢁ fasterthanthe5mmolscalereactionofFig.1)even
though the concentration of all the reagents was identical.
2.2. Amine coupling partner scope
For convenience of analysis we initially focused on variation of
the amine partner. The tolerance of the DABAL-Me3 induced re-
actions to changes in the steric and electronic properties of the
amine using the simple esters RCO2Me (R¼Ph, halophenyl and
Hex¼nC6H13). The two most useful conditions identified earlier:
microwave promotion in THF at 130 ꢀC and simple reflux in toluene
were used at 1 mmol scales. The outcomes of these studies are
reported in Scheme 2. Reactions containing products with proto-
natable functional groups were quenched with Rochelle salt, all
others with aqueous 2 M HCl.
Comparison of compounds 4e6 (tert-amides) versus 9e11 (sec-
amides) shows that while the reaction is more tolerant of steric
hindrance in primary amines, acceptable yields are attained in all
but the most challenging cases 29 (21%) for both sec and tert-amide
formation regardless of the heating methods used at a 1 mmol
scale. In the formation of sec-amides even highly demanding 2,6-
diisopropyl aniline was tolerated (10, 83%). Electronically and ste-
rically deactivated 2,6-dichloroaniline gave 11 (60%, 8 min), which
is comparable to Li’s AlMe3/RCO2H couplings to perfluoroaniline
(80e85% yield after 18 h).6a The convenience of DABAL-Me3 me-
diated couplings to provide sterically hindered amides should be
compared to other recent organometallic approaches where the
use of an isocyanate is required.15 Phenylethylamine (R >98% ee)
was coupled to ethylheptanoate in THF (giving 11, 96%) without any
detectable racemisation as measured by chiral HPLC. The following
functional groups were also tolerated in the amine coupling part-
ner: C(sp2)ehalides, OMe, alkenes, alkynes, C(sp)eH, tertiary
amines, sec-amides, nitriles and in some cases Boc groups and tert-
butyl esters. Free hydroxyl functions were additionally tolerated,
but more DABAL-Me3 was required to ensure higher yield (21e22),
presumably through in situ OH deprotonation. Unfortunately, this
could not be extended to allow use of hydroxylamine (H2NOH).
Strongly chelating functions dramatically downgrade the coupling
efficiency and product purity (24e25). Low yields were also
attained for some 1,2-diamines (31 and 32) and in this case the
Fig. 1. Course of 5 mmol coupling under reflux conditions compared to microwave
conditions. In toluene 1 M ester and amine; yields of 2 determined by 1H NMR
spectroscopy. A first order fit to the 5 mmol data produces an approximate rate con-
stant of ca. 0.3 hꢃ1. A 1 mmol preparation of 2 produced an 80% yield within 60 min
under reflux conditions.
In comparison, comparative MWH reactions (130 ꢀC, toluene,
1 M in substrates) for the preparation of N-benzylnicotinamide (3
in Fig. 1) at both 1 and 5 mmol scales intriguingly produced es-
sentially identical high yields of 3 (80 and 78%) and achieved

N. Dubois et al. / Tetrahedron 69 (2013) 9890e9897
9893
Scheme 3. Diamine effects and amines incompatible with DABAL-Me3 couplings.
Scheme 2. Amine structure effects in DABAL-Me3 couplings. Duplicate yields in reflux
reactions (1 h, 1 mmol) were typically within 5% of the microwave reactions (8 min) so
only representative examples are shown (but see also scale effects of Section 2.1).
Additional DABAL-Me3 (1.6 equiv vs 0.8 normally used).
reactions resulted in the formation of benzimidazoles (Scheme 3)
instead of the desired bis-amides. This is probably a proximity ef-
fect as 1,4-diamines were tolerated and gave the expected products.
Other problematic and intractable amine coupling functional
groups are also shown in Scheme 3.
Scheme 4. Ester structure effects in DABAL-Me3 couplings. Under either microwave
conditions (8 min, 130 ꢀC, THF) or toluene reflux (60 min); 1 mmol scale; Mes¼mesityl.
Use of substrates containing: nitro, isoxazole, and pyrazine
functions resulted in extensive byproduct formation. Coupling
partners containing highly hindered sec-amines, primary amide,
pyrimidine and aminoacideHCl salts led also to recovery of starting
materials. Free carboxylic acids were also not tolerated as these
proved substrates for amide coupling themselves (see Section 2.4).
Again the coupling was tolerant of a range of moderate steric
factors in the ester and could accommodate functional groups of
low reactivity, especially halogens, but was incompatible with
functions more electrophilic that tert-butyl esters (especially al-
dehydes). (ꢃ)-(
L)-Lactate coupled in THF (providing 40, 94%) with
retention of enantio purity (>95% ee). sec-Amines and alcohols
could be used provided extra DABAL-Me3 was employed; but for
reasons that were not initially clear, primary alcohols and phenols
caused issues leading to low yields, even in the presence of addi-
tional DABAL-Me3. To estimate the pKa of DABAL-Me3 in toluene at
110 ꢀC a series of known enolate forming carbonyl species
R1COCH2R2 were briefly refluxed with equimolar DABAL-Me3 in
2.3. Ester coupling partner scope
Further coupling reactions on various methyl esters of differing
steric profile and containing representative functional groups were
carried out and these are summarized in Scheme 4.

9894
N. Dubois et al. / Tetrahedron 69 (2013) 9890e9897
toluene, the reactions cooled and quenched with D2O. These
studies revealed that only species more acidic than deoxybenzoin
R1,R2¼Ph; pKa 17.7) were deprotonated. This result might indicate
that while sec-alcohols and amines survive deprotonation in the
reaction primary alcohols and phenols do not leading to potentially
less active aluminium alkoxides that fail to couple. Credence to this
idea is given by the fact that although (ꢄ)-BnNHCHMeCO2Me
couples in toluene to provide 43 in good yield use of the (R)
enantiomically pure starting material led to essentially racemic 43
production. In particular for Ranolazine and Imatinib (Gleevec)
(Scheme 6). However, we selected Asmadoline (49) as a target for
the precursor amine (48) as it is commercially available (if rather
expensive). Amine (48) is a stern test for any ‘coupling agent’ as the
acyclic hindered NMeH unit combined with potentially epimeris-
able centres and unprotected hydroxyl group are all challenging
motifs. In fact the commercial route couples 48 with the Ph2COCl
yielding 49 in just 70% yield only after vigorous heating.16 In a sin-
gle, unoptimised run microwave coupling of 48 and Ph2CO2Me
provided analytically pure 10 in 25% yield (45% crude with ca. 60%
conversion of 48).
based on its negligible
deprotonation.
[
a]
value, presumably through
D
2.4. Carboxylic acid coupling partner scope
During our scoping reactions we discovered that direct coupling
of free carboxylic acids under toluene reflux is possible using only
the standard 0.8 equiv of DABAL-Me3 despite the presence of the
additional acidic OH unit. Reactions under microwave promotion
proved too vigorous to be controlled. While the yields of these di-
rect coupling reflux reactions were somewhat suppressed com-
pared to the ester couplings of Sections 2.2 and 2.3 the technical
simplicity of the reactions led us to briefly investigate short scope
study, which is reported in Scheme 5.
Scheme 6. Relation of this work to commercial targets.
Finally, as direct coupling of R1CO2Me and H2NR2 represent only
one of a potentially greater set of combinations we attempted some
related DABAL-Me3 promoted couplings of TolSO2OMe, dime-
thylcarbonate and the urethane PhCHMeNHCO2Et under micro-
wave conditions. The sulfonate and the carbonate reactions
provided only highly polar mixtures. The urethane provided traces
of product but this was not isolable in a pure form with the present
reaction conditions.
Scheme 5. Carboxylic acid structure effects in DABAL-Me3 couplings; toluene reflux
(60 min); 1 mmol scale.
3. Conclusions
The range of yields in Scheme 5 (50e80%) is of use in medicinal
discovery chemistry but not as high as our processes based on
methyl esters. We have typically found both tert-butyl ester and Boc
groups reliable in our couplings and the formation of the unusual
bicycle (47) is probably a proximity effect. As far as we can de-
termine it is formed as a single diastereomer, but in moderate yield
(no other stereoisomer was present in the crude mixture as far as
determined by 1H NMR spectroscopy). In view of the extensive
racemization of 43 this behaviour is notable. Presumably its cyclic
structure accounts for its stereo-integrity. As in the amine com-
ponent, potentially deprotonatable functional groups were not
tolerated. Surprisingly, attempts to use 1,2 structurally related di-
acids led only to their recovery regardless of the reagent stoichi-
ometry used.
While DABAL-Me3 is a rather too aggressive reagent for peptide
synthesis it is quite useful in general amide preparation and is able
to accommodate a significant range of functional groups and steric
demands in both coupling partners. It seems of particular use for:
ꢅ Formation of tert-amides where routes via acid chlorides are
non-viable or non-desirable.
ꢅ When either the amine or carboxylic acid coupling partner is
‘precious’ (no excess of either is required).
ꢅ Direct coupling of esters containing free sec-amines or alcohols
without protection of the latter.
Reactions may be conducted quickly (8e60 min) at small scales
(ꢆ1 mmol). Larger scale reactions are best conducted by microwave
promotion or through use of sealed reactors but scales of at least
5 mmol could be realized easily. Stereogenic centres in the amine
2.5. Applications and other systems
A number of sub-structures accessible by DABAL-Me3 chemistry
are directly applicable to amide structures currently in commercial
partner were coupled without racemisation while
in aminoacids are extensively racemised unless special factors
a-stereocentres

N. Dubois et al. / Tetrahedron 69 (2013) 9890e9897
9895
operate (cyclic substrate or deprotonatable
mary of the utility of DABAL-Me3 based couplings is given in Table 1.
a
-OH groups). A sum-
22.5, 19.8, 14.0. HRMS (EIþ) m/z: [MþNa]þ Expected C17H31NNaOþ:
288.2298. Found: 288.2281.
4. Experimental
4.1. General
4.4. N-(3-Cyanophenyl)benzamide (14)
Yellow powder isolated by chromatography (161 mg, 73%). Mp
138e139 ꢀC. nmax (CHCl3)/cmꢃ1 3433, 3007, 2360, 2234, 1685, 1605,
1587, 1528. 1H NMR (400 MHz, CDCl3) dH¼8.08 (1H, m), 7.90e7.85
(3H, m), 7.61 (1H, m), 7.55e7.44 (4H, m), 1.56 (1H, br s). 13C NMR
(101 MHz, CDCl3) dC¼165.8 (CO), 138.8 (C), 134.1 (C), 132.4 (CH),
129.9 (CH),129.0 (CH),127.9 (CH), 127.0 (CH),124.2 (CH),123.2 (CH),
118.4 (C), 113.2 (C). HRMS (ESIþ) m/z: [MþNa]þ Expected
All reactions involving air sensitive materials were carried out
under argon atmosphere using standard Schlenk techniques.
Microwave reactions were conducted in a CEM Discover bench-
top reactor (1 mmol) or a Biotage Initiator with an 8-position
robot (5 mmol). Reagents and catalysts were purchased reagent
grade and used without further purification. Tetrahydrofuran was
distilled from sodium-benzophenone. Toluene and other solvents
were anhydrous reagent grade. Flash column chromatography:
C
14H10N2NaOþ: 245.0685. Found: 245.0685.
4.5. N-2-Methoxyphenyl-4-iodobenzamide (18)
silica gel 35e70 m
, 60 A. 1H and 13C NMR spectra were recorded
on Bruker (DPX400 or AV400) or Jeol (EX270) spectrometers; J
values are given in Hertz. Many of the amide products show
restricted COeNR1R2 rotation; in some cases improved spectra
were attained at 90 ꢀC. Infrared spectra were recorded using
Bruker Tensor 27 spectrometer. Mass spectra were obtained on
Bruker Daltonics micro TOF (ESI), Bruker Daltonics APEX 4 ECR
FTMS (EI) and VG Autospec (EI). Optical rotations were de-
termined on an ADP 440 polarimeter at ambient temperatures
(20e22 ꢀC). The general procedures and spectroscopic data for
new chemical entities are reported below. The equivalent in-
formation for literature compounds is restricted to the
Supplementary data.
Solid isolated by chromatography (144 mg, 51%). Mp
129e131 ꢀC. nmax (CHCl3)/cmꢃ1 3426, 3011, 2941, 2840, 1675, 1603,
1587, 1525. 1H NMR (400 MHz, CDCl3) dH¼8.54e8.51 (m, 2H, Aryl
CH), 7.89e7.86 (m, 2H, Aryl CH), 7.66e7.39 (m, 2H, 2ArCH), 7.13 (m,
1H, Aryl CH), 7.05 (m, 1H, Aryl CH), 6.95 (dd, 1H, J¼8.0, 1.3 Hz, Aryl
CH), 3.96 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) dC¼164.5, 148.1,
138.0, 134.8, 128.7, 124.1, 121.3, 119.9, 110.0, 98.7, 55.9. HRMS (EIþ)
m/z: [MþNa]þ Expected C14H12INNaOþ: 375.9805. Found:
375.9803.
4.6. (S)-(4-Bromophenyl)(2-(methoxymethyl)pyrrolidin-1-yl)
methanone (19)
21
4.2. General procedures
Colourless oil isolated by chromatography (178 mg, 60%). [
a
]
D
ꢃ115 (c 5.2, CHCl3); nmax (CHCl3)/cmꢃ1 2985, 2925, 2882, 2827,
1619, 1424, 1079, 1012. 1H NMR (270 MHz, DMSO-d6, 90 ꢀC)
dH¼7.61 (2H, d, J¼8.4 Hz, CHAr), 7.41 (2H, d, J¼8.4 Hz, CHAr), 7.20
(1H, m, NCH), 3.42e3.35 (7H, m, NCH2, CH2OCH3), 2.01e1.80 (4H,
m, (CH2)2). 13C NMR (68 MHz, DMSO-d6, 90 ꢀC) dC¼167.3 (CO),
136.2 (C), 130.7 (CH), 128.5 (CH), 122.3 (C), 72.1 (CH), 57.9
(CH2), 56.2 (CH2), 48.0 (CH3), 27.2 (CH2), 23.1 (CH2). HRMS
(ESIþ) m/z: [MþNa]þ Expected 79BrC13H16NNaOþ2 : 320.0262.
Found: 320.0264. Expected 81BrC13H16NNaO2þ: 322.0242. Found:
322.0246.
A. Microwave. Neat samples of amine (1.00 mmol) and carbox-
ylic derivative (methyl ester or acid, 1.00 mmol) and DABAL-Me3
(202 mg, 0.8 equiv) were placed in a 5 mL microwave vial and dry
THF added (1 mL) under a blanket of argon. For coupling partners
containing acidic hydrogens additional DABAL-Me3 (total of
410 mg, 1.6 equiv) was used. The vial was promptly capped and
placed in a CEM Discover microwave reactor. After irradiation
(290 W, 130 ꢀC, 8 min) and programmed cool down (ca. 20 min).
The reactions were quenched by cautious addition of HCl (2 M,
4 mL) or aqueous solutions of Rochelle salt (saturated potassium
sodium tartrate, 4 mL) (CARE: methane liberated). Extraction with
dichloromethane, drying (MgSO4) and evaporation frequently
provided the pure products directly. If purification was required
column chromatography 3:2 to 2:3 hexane:EtOAc was used for
amides lacking highly polar functional groups (CH2Cl2 with 2% v/v
MeOH was used for amides bearing pendant amines, alcohols and
other polar functional groups).
4.7. N-(3,4-Methelenedioxyphenyl)heptanamide (20)
Solid isolated by chromatography (177 mg, 89%). Mp 76e78 ꢀC.
nmax (CHCl3)/cmꢃ1 3437, 3008, 2958, 2930, 2860, 1682, 1504, 1489.
1H NMR (400 MHz, CDCl3) dH¼7.25 (d, 1H, J¼2.0 Hz, Aryl CH), 7.20
(br, s, 1H, NH), 6.79 (dd, 1H, J¼8.3, 2.0 Hz, Aryl CH), 6.74 (d, 1H,
J¼8.3 Hz, Aryl CH), 5.95 (s, 2H, CH2), 2.33 (t, 2H, J¼7.5 Hz, CH2),
1.76e1.68 (m, 2H, CH2), 1.42e1.28 (m, 6H, 3CH2), 0.90 (t, 3H,
J¼6.7 Hz, CH3). 13C NMR (101 MHz, CDCl3) dC¼171.3, 147.8, 144.2,
132.2, 113.0, 108.0, 102.9, 101.2, 37.7, 31.6, 29.0, 25.6, 22.5, 14.0.
HRMS (EIþ) m/z: [MþNa]þ Expected C14H19NNaOþ3 : 272.1257.
Found: 272.1256.
B. Sealed tube reactions. Thick walled (3 mm) Pyrex tubes (ca.
190 mm long, diameter 25 mm sealable with Young’s taps) were
charged as in A above and placed in pre-equilibrated heated baths
(CARE: ensure blast screen protection). Reactions were worked up
exactly as described in A above.
C. Reflux. Carried out under an inert atmosphere in the normal
way.
4.8. 4-(4-Bromobenzoyl)piperazin-2-one (23)
4.3. N-Myrtenylheptanamide (12)
Pale yellow powder isolated by chromatography (180 mg, 64%).
Mp 155e157 ꢀC. nmax (CHCl3)/cmꢃ1 3409, 3009, 1680, 1642, 1428,
1333. 1H NMR (400 MHz, CDCl3) dH¼7.59 (2H, d, J¼8.4 Hz, CHAr),
7.33 (2H, d, J¼8.4 Hz, CHAr), 6.55 (1H, s, NH), 4.22 (2H, br s), 3.86
(2H, br s), 3.46 (2H, br s). 13C NMR (101 MHz, CDCl3) dC¼169.4 (CO),
133.3 (C), 132.0 (CH), 128.9 (CH), 125.0 (C). Peaks from the piper-
azinone could not be distinguished due to exchange leading to
broad envelopes at 41.0 and 166.8 ppm. HRMS (ESIþ) m/z: [MþNa]þ
Expected 79BrC11H11N2NaOþ2 : 304.9902. Found: 304.9896. Expected
81BrC11H11N2NaO2þ: 306.9881. Found: 306.9871.
Colourless oil isolated by chromatography (140 mg, 66%). nmax
(CHCl3)/cmꢃ1 3449, 3000, 2928, 2870, 1660, 1518. 1H NMR
(400 MHz, CDCl3) dH¼5.50 (br, s, 1H, NH), 3.29e3.24 (m, 2H, CH2),
2.38e2.35 (m, 1H, CH), 2.18e2.14 (m, 3H, CH, CH2), 1.97e1.85 (m,
5H, CH, 2CH2), 1.65e1.61 (m, 2H, CH2), 1.52e1.47 (m, 1H, CH),
1.34e1.27 (m, 6H, 3CH2), 1.20 (s, 3H, CH3), 1.05 (s, 3H, CH3),
0.91e0.87 (m, 4H, CH, CH3); 13C NMR (101 MHz, CDCl3) dC¼173.1,
45.1, 43.8, 41.4, 41.3, 38.7, 36.9, 33.2, 31.6, 29.0, 28.0, 26.0, 25.8, 23.2,

9896
N. Dubois et al. / Tetrahedron 69 (2013) 9890e9897
4.9. N-(Pyridin-4-ylmethyl)benzamide (27)
HRMS (EIþ) m/z: [MþNa]þ Expected C11H13BrFNNaOþ: 296.0057.
Found: 296.0052.
Yellow powder isolated by chromatography (172 mg, ca. 81%)
traces of the starting amine (<5%) co-elute with (27). Mp
102e104 ꢀC. nmax (CHCl3)/cmꢃ1 3455, 3008, 1664, 1603, 1517,
1486, 1417, 1284. 1H NMR (400 MHz, CDCl3) dH¼8.52 (2H, d,
J¼5.6 Hz, CHPyr), 7.83 (2H, d, J¼7.1 Hz, CHPyr), 7.52 (1H, d,
J¼7.6 Hz, CHAr), 7.44 (2H, dd, J¼7.6, 7.1 Hz, CHAr), 7.23 (2H, d,
J¼5.6 Hz, CHAr), 6.98 (1H, br s, NH), 4.63 (2H, d, J¼6.1 Hz, CH2).
13C NMR (101 MHz, CDCl3) dC¼167.7 (CO), 149.9 (CH), 147.5 (C),
133.8 (C), 131.8 (CH), 128.7 (CH), 127.0 (CH), 122.3 (CH), 42.7
(CH2). HRMS (ESIþ) m/z: [MþH]þ Expected C13H13N2Oþ:
213.1022. Found: 213.1024.
4.14. N-Benzyl-N-methyl-2,2-diphenylacetamide (38)
Yellow oil isolated by chromatography (282 mg, 89%). nmax
(CHCl3)/cmꢃ1 3008, 1645, 1495, 1453, 1401. 1H NMR (270 MHz,
DMSO-d6, 90 ꢀC) dH¼7.30e7.17 (15H, m), 5.47 (1H, s), 4.60 (2H, s),
2.93 (3H, s). 13C NMR (68 MHz, DMSO-d6, 90 ꢀC) dC¼170.9 (CO),
139.6 (C), 137.0 (C), 128.4 (CH), 127.9 (CH), 127.6 (CH), 127.0 (CH),
126.5 (CH), 126.0 (CH), 52.8 (CH2), 50.2 (CH3), 34.6 (CH). HRMS
(ESIþ) m/z: [MþNa]þ Expected C22H21NNaOþ: 338.1515. Found:
338.1519.
4.10. (4-Iodophenyl)(4-methyl-2-phenylpiperazin-1-yl)meth-
anone (29)
4.15. N-Myrtenyl-(1-adamantyl)-3-oxoproprionamide (39)
Oil isolated by chromatography (240 mg, 84%). nmax (CHCl3)/
cmꢃ1 3690, 3300, 3005, 2910, 2854, 1731, 1692. 1H NMR (400 MHz,
CDCl3) dH¼7.17 (br, s, 1H, NH), 3.46 (s, 2H, CH2), 3.30e3.26 (m, 2H,
CH2), 2.39e2.35 (m, 1H, CH), 2.25e2.19 (m, 1H, CH), 2.09 (s, 3H,
CH3), 1.94e1.68 (m, 17H), 1.52e1.47 (m, 1H, CH), 1.21 (s, 3H, CH3),
1.05 (s, 3H, CH3), 0.92e0.90 (m, 2H, CH2). 13C NMR (101 MHz, CDCl3)
dC¼212.5, 165.8, 47.4, 45.2, 43.8, 42.8, 41.3, 41.1, 38.7, 37.6, 36.3, 33.2,
28.0, 27.8, 26.0, 23.2, 19.8. HRMS (EIþ) m/z: [MþNa]þ Expected
Yellow oil isolated by chromatography (89 mg, 21%), 45% of
the starting amine also recovered. 1H NMR (400 MHz, CDCl3)
dH¼7.77 (2H, d, J¼8.1 Hz), 7.50 (2H, br), 7.42e7.37 (2H, m),
7.33e7.27 (1H, m), 7.22e7.15 (2H, m), 5.91 (1H, br), 3.42 (1H, d),
5.33 (1H, s), 3.45 (1H, br d, J¼12.2 Hz), 3.45 (1H, br t, J¼12.2 Hz),
2.79 (1H, br d, J¼7.9 Hz), 2.47 (1H, dd, J¼12.2, 4.1 Hz), 2.34 (3H,
s), 2.12 3.45 (1H, br d, J¼12.2 Hz), 1.64 (1H, br). Partial 13C NMR
(101 MHz, CDCl3) dC¼137.7 (CH), 135.4 (CH), 128.7 (CH), 127.3
(CH), 95.8 (CH), 55.4 (CH2), 46.3 (CH3). Due to fluxional exchange
C
12H17NNaOþ2 : 364.1519. Found: 364.1527.
quaternary and
a-NCH/NCH2 signals were not observed. HRMS
(ESIþ) m/z: [MþH]þ Expected C18H20IN2Oþ: 407.0615. Found:
4.16. N-Benzyl-N-butylbenzamide (41)
407.0617.
Solid isolated by chromatography (171 mg, 91%). Mp 117e119 ꢀC.
nmax (CHCl3)/cmꢃ1 3453, 3010, 2962, 2932, 1645, 1609, 1502. 1H
NMR (400 MHz, CDCl3) dH¼7.68e7.65 (m, 2H, Aryl CH), 7.37e7.35
(m, 3H, Aryl CH), 7.31e7.28 (m, 2H, Aryl CH), 6.58e6.54 (m, 2H, Aryl
CH). 6.36 (br, s, 1H, NH), 4.63 (d, 2H, J¼5.7 Hz, CH2), 4.05 (br, s, 1H,
NH), 3.16 (t, 2H, J¼7.0 Hz, CH2), 1.66e1.59 (m, 2H, CH2), 1.48e1.42
(m, 2H, CH2), 0.98 (t, 3H, J¼7.3 Hz, CH3). 13C NMR (101 MHz, CDCl3)
dC¼167.3,151.2,138.8,128.7,127.9,127.4,122.1,111.6, 43.9, 43.2, 31.4,
20.2, 13.9. HRMS (ESIþ) m/z: [MþNa]þ Expected C18H22N2NaOþ:
305.1624. Found: 305.1621.
4.11. tert-Butyl 4-(4-iodobenzoyl)piperazine-1-carboxylate (30)
Colourless powder isolated by chromatography (319 mg, 77%).
Mp 125e127 ꢀC. nmax (CHCl3)/cmꢃ1 3008, 1690, 1629, 1458, 1422,
1367, 1249, 1157, 1004. 1H NMR (270 MHz, DMSO-d6, 90 ꢀC) dH¼7.81
(2H, d, J¼8.4 Hz), 7.21 (2H, d, J¼8.4 Hz), 3.46e3.36 (8H, m), 1.43 (9H,
s). 13C NMR (101 MHz, CDCl3) dC¼169.7 (CO), 154.5 (CO), 137.8 (CH),
134.8 (C), 128.8 (CH), 96.1 (C), 80.4 (C), 47.4 (CH2), 43.6 (CH2), 28.3
(CH3). HRMS (ESIþ) m/z: [MþNa]þ Expected C16H21IN2NaOþ3 :
439.0489. Found: 439.0491.
4.17. N-Propargyl-N-butylbenzamide (42)
4.12. N-Benzyl-3-bromo-N-methylbenzamide (35)
Solid isolated by chromatography (164 mg, 89%). Mp 93e95 ꢀC.
nmax (CHCl3)/cmꢃ1 3462, 3308, 3010, 2962, 2932, 2874, 1651, 1609,
1574, 1531, 1498. 1H NMR (400 MHz, CDCl3) dH¼7.67e7.63 (m, 2H,
Aryl CH), 6.59e6.55 (m, 2H, Aryl CH), 6.17 (br, s,1H, NH), 4.25 (q, 2H,
J¼2.6 Hz, CH2), 4.05 (br, s,1H, NH), 3.16 (t, 2H, J¼7.0 Hz, CH2), 2.27 (t,
1H, J¼5.1 Hz, ^CH), 1.66e1.59 (m, 2H, CH2), 1.49e1.41 (m, 2H, CH2),
0.98 (t, 3H, J¼7.3 Hz, CH3). 13C NMR (101 MHz, CDCl3) dC¼167.0,
151.3, 128.8, 121.4, 111.6, 80.1, 71.5, 43.2, 31.4, 29.6, 20.2, 13.9. HRMS
(ESIþ) m/z: [MþNa]þ Expected C14H18N2NaOþ: 253.1311. Found:
253.1313.
Colourless oil isolated by chromatography (228 mg, 75%). nmax
(CHCl3)/cmꢃ1 3008, 1628, 1402, 1255, 1077. 1H NMR (270 MHz,
DMSO-d6, 90 ꢀC) dH¼7.65e7.59 (2H, m, CHAr), 7.54e7.35 (4H, m,
CHAr), 7.32e7.26 (3H, m, CHAr), 4.59 (2H, s, CH2), 2.88 (3H, s, CH3).
13C NMR (68 MHz, DMSO-d6, 90 ꢀC) dC¼168.5 (CO), 138.4 (C), 136.6
(C), 131.7 (CH), 130.0 (CH), 128.9 (CH), 128.0 (CH), 126.8 (CH), 126.7
(CH), 125.1 (CH), 121.1 (C), 51.4 (CH2), 34.7 (CH3). HRMS (ESIþ) m/z:
[MþNa]þ Expected 79BrC15H14NNaOþ: 326.0156. Found: 326.0143.
Expected 81BrC15H14NNaOþ: 328.0136. Found: 328.0125.
4.13. N-2-Bromo-4-fluorophenyl -2-methylbutanamide (36)
4.18. 2-(Benzylamino)-N-mesitylpropanamide (43)
Solid isolated by chromatography (205 mg, 94%). Mp 96e98 ꢀC.
nmax (CHCl3)/cmꢃ1 3414, 3011, 2970, 2935, 1694, 1596, 1518. 1H NMR
(400 MHz, DMSO-d6) dH¼9.46 (br s, 1H, NH), 7.63 (dd, 1H, J¼8.5,
2.9 Hz, Aryl CH), 7.50 (dd, 1H, J¼8.9, 5.7 Hz, Aryl CH), 7,26 (td, 1H,
J¼8.5, 2.9 Hz, Aryl CH), 2.49e2.46 (m, 1H, CH), 1.67e1.58 (m, 1H,
CH), 1.46e1.37 (m, 1H, CH), 1.11 (d, 3H, J¼6.9 Hz, CH3), 0.92 (t, 3H,
J¼7.4 Hz, CH3). 13C NMR (101 MHz, DMSO-d6) dC¼175.3, 159.7 (d,
J(CeF)¼246 Hz, CeF), 133.6 (d, J(CeF)¼3.0 Hz, C), 129.8 (d, J(CeF)¼
8.3 Hz, CH), 120.1 (d, J(CeF)¼9.2 Hz, CeBr), 119.8 (d, J(CeF)¼
25.2 Hz, CH), 115.4 (d, J(CeF)¼22.1 Hz, CH), 41.8, 27.2, 17.9, 12.3.
Pale yellow paste isolated by chromatography (135 mg, 46%).
nmax (CHCl3)/cmꢃ1 3320, 2973, 2923, 2861, 1667, 1495, 1445. 1H
NMR (400 MHz, CDCl3) dH¼8.70 (1H, s, NH), 7.37e7.30 (5H, m,
CHAr), 6.91 (2H, s, CHAr), 3.98 (1H, d, J¼13.1 Hz, CHaHb), 3.87 (1H, d,
J¼13.1 Hz, CHaHb), 3.46 (1H, q, J¼6.9 Hz, CHCH3), 2.28 (3H, s, CH3),
2.21 (6H, s, CH3), 1.67 (1H, br s, NH), 1.48 (3H, d, J¼6.9 Hz, CHCH3).
13C NMR (101 MHz, CDCl3) dC¼173.3 (CO), 139.4 (C), 136.7 (C), 134.9
(C), 131.0 (C), 128.9 (CH), 128.7 (CH), 127.9 (CH), 127.5 (CH), 58.5
(CH), 53.1 (CH2), 20.9 (CH3), 20.3 (CH3), 18.4 (CH3). HRMS (ESIþ)
m/z: [MþH]þ Expected C19H25N2Oþ: 297.1961. Found: 297.1965.

N. Dubois et al. / Tetrahedron 69 (2013) 9890e9897
9897
4.19. N-Benzyl-2-(4-benzylpiperazin-1-yl)-N-methyl-
acetamide (44)
generous donations of amine and carboxylic acid libraries. We
thank Jennifer O’Leary for estimating the pKa of DABAL-Me3 and
Tim Evans for conducting preliminary investigations as part of
a Nuffield Undergraduate Bursary.
Yellow-orange oil isolated by chromatography (241 mg, 71%). nmax
(CHCl3)/cmꢃ1 3009, 2940, 2817, 1637, 1454, 1011. 1H NMR (270 MHz,
DMSO-d6, 90 ꢀC) dH¼7.34e7.21 (10H, m), 4.56 (2H, s), 3.47 (2H, s),
3.20 (2H, s), 2.92 (3H, s), 2.41e2.39 (8H, m). 13C NMR (68 MHz,
DMSO-d6, 90 ꢀC) dC¼168.7 (CO), 137.8 (C), 137.3 (C), 128.2 (CH), 127.8
(CH), 127.5 (CH), 126.7 (CH), 126.4 (CH), 126.2 (CH), 61.6 (CH2), 59.9
(CH2), 52.2 (CH2), 52.0 (CH2), 50.3 (CH2), 33.6 (CH3). HRMS (ESIþ) m/
z: [MþH]þ Expected C21H28N3Oþ: 338.2227. Found: 338.2231.
Supplementary data
Experimental data for literature compounds and copies of 1H
and 13C NMR spectra (all compounds). Supplementary data related
to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.08.062.
4.20. 2-(4-Benzylpiperazin-1-yl)-N-mesitylacetamide (45)
References and notes
Colourless powder isolated by chromatography (258 mg, 74%).
Mp 139e140 ꢀC. nmax (CHCl3)/cmꢃ1 3008, 2943, 2821, 1676, 1503. 1H
NMR (400 MHz, CDCl3) dH¼8.59 (1H, br s), 7.34e7.32 (4H, m), 7.28
(1H, m), 6.91 (2H, s), 3.55 (2H, s), 3.20 (2H, s), 2.73 (4H, br s), 2.55
(4H, br s), 2.28 (3H, s), 2.19 (6H, s). 13C NMR (101 MHz, CDCl3)
dC¼168.7 (CO), 137.9 (C), 136.8 (C), 134.7 (C), 130.9 (C), 129.1 (CH),
128.9 (CH), 128.3 (CH), 127.1 (CH), 62.9 (CH2), 61.7 (CH2), 53.8 (CH2),
53.2 (CH2), 20.8 (CH3), 18.5 (CH3). HRMS (ESIþ) m/z: [MþH]þ Ex-
pected C22H30N3Oþ: 352.2383. Found: 352.2386.
1. Overview texts on amide and peptides: (a) Patai’s Chemistry of Functional
Groups e Amides; Zabicky, J., Ed.; Wiley-VCH: Weinheim, Germany, 1970; (on-
line version 2010); (b) Amino Acids, Peptides and Proteins in Organic Chemistry;
Hughes, A. B., Ed.; Wiley-VCH: Weinheim, Germany, 2009; Vol. 6; (c) Benoiton,
N. L. Chemistry of Peptide Synthesis; CRC: London, UK 2006.
ꢀ
2. Comparisons of coupling agent efficiency: (a) Joullie, M. M.; Lassen, K. M. AR-
KIVOC 2010, 189e250; (b) Eric Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38,
606e631; (c) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61,
10827e10852; (d) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447e2467 Re-
cent developments in amide formation: (e) Pattabiraman, V. R.; Bode, J. W.
Nature 2011, 480, 471e479.
3. Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S. Tetrahedron Lett.
2006, 47, 5767e5769.
4.21. (R)-2-((S)-1-Phenylethyl)tetrahydroimidazo[1,5-a]pyri-
dine-1,3(2H,5H)-dione (47)
4. Glynn, D.; Bernier, D.; Woodward, S. Tetrahedron Lett. 2008, 49, 5687e5688.
5. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 48, 4171e4174.
6. (a) Li, J.; Subramaniam, K.; Smith, D.; Qiao, J. X.; Li, J. J.; Qian-Cutrone, J.; Kadow,
J. F.; Vite, G. D.; Chen, B.-C. Org. Lett. 2012, 14, 214e217; (b) Chung, W.; Uccello,
D. P.; Choi, H.; Montgomery, J. I.; Chen, J. Synlett 2011, 2072e2074.
7. Vinogradov, A.; Woodward, S. Org. Synth. 2010, 87, 104e114.
8. (a) Bisaha, J. J.; Kovacs, P. R.; Lett, R. M.; Long, J. K.; Pasteris, R. J.; Finkelstein, B.
L.; Smith, B. T.; Klyashchitsky, B. A., PCT Int. Appl. WO 2007014290 A2
20070201, 2007. (b) Klose, J.; Bienert, M.; Mollenkopf, C.; Wehle, D.; Zhang, C.;
Carpinoc, L. A.; Henklein, P. Chem. Commun. 1999, 1847e1848.
21
Colourless oil isolated by chromatography (140 mg, 54%). [
a
]
D
ꢃ36.0(c¼2.8, CHCl3). nmax (CHCl3)/cmꢃ13069, 2983, 2945, 2861,1763,
1702, 1445, 1431. 1H NMR (400 MHz, CDCl3) dH¼7.48e7.46 (2H, m,
CHAr), 7.36e7.31 (2H, m, CHAr), 7.28 (1H, m, CHAr), 5.34 (1H, q,
J¼7.3 Hz, CHCH3), 4.14 (1H, dt, J¼13.4, 4.1 Hz, NCHaHb), 3.68 (1H, td,
J¼11.9, 4.1Hz,NCHCO), 2.79(1H, m, NCHaHb),2.18(1H, m, NCHCHaHb),
1.97 (1H, m, N(CH2)2CHaHb),1.85 (3H, d, J¼7.3 Hz, CHCH3),1.71 (1H, m,
NCH2CHaHb), 1.49e1.20 (3H, m, NCH2CHaHbCHaHbCHaHb). 13C NMR
(101 MHz, CDCl3) dC¼172.9 (CO), 154.3 (C), 140.4 (C), 128.9 (C), 128.4
(CH),127.6(CH),127.5(CH),127.4(CH),127.3(CH), 57.0(CH), 50.2(CH),
39.2 (CH2), 27.7 (CH2), 24.9 (CH2), 22.7 (CH2),17.2 (CH3). HRMS (ESIþ)
m/z: [MþNa]þ Expected C15H18N2NaOþ2 : 281.1260. Found: 281.1261.
9. Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett. 2011, 13, 5048e5051.
10. Tran, T. P.; Mullins, P. B.; am Ende, C. W.; Pettersson, M. Org. Lett. 2013, 15,
642e645.
ꢀ
11. (a) Coste, J.; Frerot, E.; Jouin, P.; Castro, B. Tetrahedron Lett. 1991, 32, 1967e1979;
ꢀ
(b) Angell, Y. M.; Garcia-Echeverría, C.; Rich, D. H. Tetrahedron Lett. 1994, 35,
5981e5984; (c) García-Rubio, S.; Wilson, C. D.; Renner, D. A.; Rosser, J. O.; Patra,
D.; Reid, J. G.; Pines, S. H. Org. Process Res. Dev. 2004, 8, 360e362.
ꢀ
12. Frerot, E.; Coste, J.; Poncet, J.; Jouin, P. Tetrahedron Lett. 1992, 33, 2815e2816.
13. (a) The AleN bond energy data for Me3Al$NMe3 in Henrickson, C. H.; Duffy, D.;
Eyman, D. P. Inorg. Chem. 1968, 7, 1047e1051; (b) Vapour pressure and bp data
for AlMe3 from www.sigmaaldrich.com (product number J100013).
Acknowledgements
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Financial support by EPSRC (2013 Pathways to Impact Scheme)
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