Cyclodehydration of N -(aminoalkyl)benzamides under mild conditions with a hendrickson reagent analogue

Article abstract of DOI:10.1021/jo401082q

Methods for the cyclodehydration of N-(aminoalkyl)benzamides are few and employ harsh reaction conditions. We have found that the easily prepared phosphonium anhydrides 1 (Hendrickson reagent) or 2 can be used for cyclodehydration of N-(aminoalkyl)benzamides under very mild conditions (room temperature) to produce five-, six-, and seven-membered cyclic amidines. Good yields are obtained by employing a temporary trityl group protection strategy. Cyclic analogue 2 can be used when the product cyclic amidine is organic-soluble, thus producing water-soluble byproducts.

Full text of DOI:10.1021/jo401082q

Note
pubs.acs.org/joc
Cyclodehydration of N‑(Aminoalkyl)benzamides under Mild
Conditions with a Hendrickson Reagent Analogue
Wendy A. Loughlin,†,* Ian D. Jenkins,‡ and Maria J. Petersson‡
‡
†School of Biomolecular and Physical Sciences and Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD 4111,
Australia
S
* Supporting Information
ABSTRACT: Methods for the cyclodehydration of N-(aminoalkyl)benzamides are
few and employ harsh reaction conditions. We have found that the easily prepared
phosphonium anhydrides 1 (Hendrickson reagent) or 2 can be used for
cyclodehydration of N-(aminoalkyl)benzamides under very mild conditions
(room temperature) to produce five-, six-, and seven-membered cyclic amidines.
Good yields are obtained by employing a temporary trityl group protection
strategy. Cyclic analogue 2 can be used when the product cyclic amidine is organic-soluble, thus producing water-soluble
byproducts.
e were interested in the cyclodehydration of N-
(aminoalkyl)benzamides to give cyclic amidines. Cyclic
1)26−29 might overcome these difficulties. It is one of the
mildest reagents known for cyclization/cyclodehydration29,30
and being highly “oxophilic” was expected to react preferen-
tially with the carbonyl oxygen of the amide rather than the
amino group. In this paper we explore the use and generality of
the Hendrickson reagent (1), the cyclic analogue 1,1,3,3-
tetraphenyl-2-oxa-1,3-phospholanium bis(trifluoro methanesul-
fonate) 2,31 and polymer-supported triphenylphosphine
ditriflate 332,33 for the cyclodehydration of N-(aminoalkyl)-
benzamides to give cyclic amidines such as tetrahydropyr-
imidines and imidazolines.
W
amidines such as tetrahydropyrimidines and imidazolines have
been shown to be important pharmacophores in drug discovery
because they exhibit a broad spectrum of biological and
pharmacological activities including antihypertensive,1 anti-
inflammatory,2,3 and antituberculosis4 activity. Cyclic amidines
also occur in a number of natural products such as Clathramide
A5 and Manzacidin A,6,7 isolated from marine sponges. Cyclic
amidines are also useful in organic synthesis as synthetic
intermediates,8,9 chiral auxiliaries,10,11 chiral catalysts,12−14 and
ligands for asymmetric catalysis.15,16
Most of the commonly used methods for the synthesis of
cyclic amidines involve treating a diamine with a carboxylic
acid,17,18 an ester,19,20 or a nitrile,21 and many of the synthetic
protocols reported use quite forcing conditions. We were
surprized to find that the most obvious method of synthesis, the
cyclodehydration of N-(aminoalkyl)benzamides to produce
products such as 13 or 16, has only rarely been used. For
example, a simple SciFinder substructure reaction search from
amino amide to 13 as the product gave no hits. Of the four
references22−25 found in the seach from amino amide to 16 as
the product, one method22 employed xylene at 200 °C, while
another patent method23 employed POCl3 at 80−90 °C for 4−
8 h. The remaining two patents used silylating agents:24,25
hexamethyldisilazane/TMSCl at 100 °C for 16−48 h or TMSI/
dimethylaminomethyl polystyrene for 2−18 d. In contrast,
cyclodehydration of the corresponding hydroxy amides is much
more common (15 references for the oxazine analogue of 13
and 370 references for the oxazoline analogue of 16).
Initially, activated polymer-supported oxyphosphonium
intermediates 4 or 5 were generated by stirring a mixture of
reagent 3 (2 equiv) and benzoic or 4-nitrobenzoic acid (1
equiv), respectively, for 1 h in dry DCM, followed by addition
of propane-1,3-diamine (1 equiv) and DIPEA. The major
product formed in each case was the bis-amide 834 (66% yield
based on benzoic acid) or 934 (86% yield based on 4-
nitrobenzoic acid) rather than the corresponding tetrahydro-
pyrimidine (Scheme 1). These results confirmed that the first
intermolecular dehydration, via the oxyphosphonium inter-
mediate 4 or 5, had occurred to give amides 6 and 7,
respectively. However, instead of activation of amide 6 or 7
with the polymer-supported triphenylphosphine ditriflate 3 and
subsequent intramolecular dehydration, a second intermolecu-
lar reaction had occurred between the amine groups of 6 or 7
and a second equivalent of 4 or 5, respectively, to give the
corresponding bis-amides 8 or 9.
As noted by Chouiery et al.,24 most of the literature
procedures for the cyclodehydration of amino amides suffer
from disadvantages such as harsh reaction conditions,
potentially hazardous reagents, prolonged reaction times, low
yields, difficulty in preparation of starting materials, and tedious
workups. We considered that the Hendrickson reagent
(triphenylphosphonium anhydride trifluoromethane sulfonate,
Received: June 2, 2013
Published: June 27, 2013
© 2013 American Chemical Society
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Note
a
Scheme 1. Attempted Cyclodehydration of Amides 6 and 7 with Polymer-Supported Reagent 3
a
Reagents and conditions: (a) benzoic acid or nitrobenzoic acid, DCM; (b) 1,3-propanediamine, DIPEA, DCM; (c) 4 or 5.
a
Treatment of amide 6 with acetyl chloride (2.0 equiv) and
triethylamine (2.0 equiv) gave N-[3-(acetylamino)propyl]-
benzamide35 (52%). Addition of N-[3-(acetylamino)propyl]-
benzamide and DIPEA to a mixture of reagent 3 (1.0 equiv) in
dry DCM gave recovered N-[3-(acetylamino)propyl]-
benzamide. Direct treatment of amide 636,37 with reagent 3
in the presence of DIPEA in dry DCM also failed to give the
desired cyclic amidine. The only product isolated (apart from
starting material) was the sulfonamide 10 (25%), which was
characterized additionally as the stable acetyl derivative.
Scheme 3. Formation of Aminophosphonium Salt 17
a
Reagents and conditions: (a) reagent 1, DIPEA, DCM.
chromatography is hydrolyzed to give the starting amide 6 (n
= 3) or 14 (n = 2). Presumably, despite the oxophilicity of 1,
the primary amino group of 6 is so reactive that it can compete
with the amide carbonyl group for the phosphorus atom of 1. If
the reactivity of the amino group in amides 6 and 14 toward
reagent 1 could be reduced, so that activation of the amide
functionality became kinetically favored, this problem might be
avoided.
What was required was a “temporary” protecting group that
increased the steric hindrance of the amino group sufficiently to
prevent or slow its reaction with 1 but would ideally drop off
once activation of the amide (by 1) had occurred. Two
possibilities were considered, the trityl group and the Boc
group.
It is possible that the amino group of 6 reacts competitively
with reagent 3 to give the aminophosphonium salt 11. The
formation of 11 would block the cyclodehydration reaction, as
activation of the amide would be rendered most unlikely given
that the substrate is already bound to the polymer bead. Upon
aqueous workup, 11 would be hydrolyzed to give back the
amide 6.
Accordingly, amide 6 was converted to the trityl amide 12,
which was then treated with reagent 1 (1.5 equiv) in the
absence of base in dry DCM. The cyclic amidine 13 was
isolated in good yield (79%) after chromatography on basic
alumina (Scheme 2). Similar results were obtained with the
trityl amide 15, which upon treatment with 1 was converted to
the desired imidazoline 16 (Scheme 2) in high yield (89%).
The trityl group strategy was clearly successful. Interestingly,
when the reaction of 12 with 1 was carried out in the presence
of DIPEA (2.0 equiv), the cyclic amidine 13 was not formed.
Only the starting material 12 and triphenylphosphine oxide
were recovered. This suggests that the tritylamino group is too
sterically crowded to undergo the cyclization reaction and must
be detritylated prior to this step (triflic acid is formed during
activation of the amide functionality by 1).
Much more promising results were obtained with the
solution phase reagent 1. Thus, when the amide 6 was treated
with 1 equiv of reagent 1 and DIPEA in dry DCM (Scheme 2),
Scheme 2. Synthesis of Tetrahydropyrimidine 13 and
a
Imidazoline 16 with Reagent 1
It is also interesting to note in this regard that the
isopropylamino benzamide 1842 (formed in 94% yield from
N-isopropyl-1,3-propanediamine by treatment with benzoic
anhydride) undergoes cyclization to the corresponding cyclic
amidine 19 with reagent 1 in high yield (86%) without recourse
to trityl group protection (Scheme 4). Presumably the
isopropyl group provides sufficient steric hindrance to slow
down the (bimolecular) reaction of the amino group with the
phosphonium reagent but is small enough to allow the
(intramolecular) cyclization reaction. Extension of the trityl
group strategy to the synthesis of tetrahydropyrimidine 2243,44
and hexahydro-1H-benzimidazole 2545 is illustrated in Scheme
4.
a
Reagents and conditions: (a) TrCl, TEA, DCM; (b) reagent 1,
DIPEA, DCM; (c) reagent 1, DCM.
the desired cyclic amidine 1338,39 was isolated in 36% yield
following an aqueous workup (the triphenylphosphine oxide
byproduct remains in the organic layer) and chromatography
on basic alumina.
Similar results were obtained when the amide 1440 was
treated with 1 and DIPEA in dry DCM. The desired
imidazoline 1618,41 was again isolated but only in modest
yield (29%, Scheme 2). We considered that the low yields of
tetrahydropyrimidine 13 (36%) and imidazoline 16 (29%) and
the recovery of amides 6 and 14, respectively, could be the
result of competitive formation of an aminophosphonium salt
of the type 17 (Scheme 3), which upon workup and
A mechanism, involving a (favored) 5- or 6-endo-dig
cyclization, for the formation of the five- or six-membered
cyclic amidines is suggested in Scheme 5 (illustrated for the
conversion of 6 to 13).
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Note
a
Scheme 4. Synthesis of Tetrahydropyrimidines 19 and 22
and Hexahydro-1H-benzimidazole 25 with Reagent 1
Scheme 6. Cyclodehydration of Bis-amides with 1 or 2
a
a
Reagents and conditions: (a) reagent 2, DIPEA, DCM.
As the reagents 1 and 2 could be used to convert Boc-amide
26 into the cyclic amidine 27 without loss of the Boc group, we
examined the reaction of the (symmetrical) bis-amide 8 with
reagent 2 in the presence of DIPEA in dry DCM. Analysis by
1H NMR spectroscopy showed the clean formation of the cyclic
amidine 28 (ratio 28:8 = 92:8) (Scheme 6). After
chromatography on silica gel, cyclic amidine 28 was isolated
in good yield (85%).
The success of the temporary trityl protecting group strategy
prompted us to extend the cyclization reaction to the synthesis
of the seven-membered tetrahydrodiazepine 31. The amide
2948 was readily prepared by treatment of a dilute solution of
butane-1,4-diamine (5 equiv) with benzoic anhydride. After
conversion to the trityl derivative 30, treatment with reagent 1
(1.5 equiv) in the absence of base gave the tetrahydrodiazepine
3138 in modest yield (51%) (Scheme 7).
a
Reagents and conditions: (a) TrCl, TEA, DCM; (b) reagent 1,
DIPEA, DCM; (c) reagent 1, DCM.
Scheme 5. Proposed Mechanism for Formation of
Tetrahydropyrimidine 13
a
a
Scheme 7. Synthesis of Tetrahydrodiazepine 31
a
Reagents and conditions: (a) TrCl, TEA, DCM; (b) reagent 1, DCM.
a
Reagents and conditions: (a) reagent 1, DIPEA, DCM; (b) DIPEA.
In conclusion, a convenient synthesis of five-, six-, and seven-
membered cyclic amidines from N-(aminoalkyl)benzamides
under mild conditions is reported. Good yields are obtained by
employing a temporary trityl group protection strategy and the
easily prepared phosphonium anhydrides 1 or 2 as cyclo-
dehydrating agents. When the product cyclic amidine is water-
soluble, 1 is the preferred reagent; however, when the amidine
is organic-soluble, the preferred reagent is 2. Several examples
of tetrahydropyrimidines and imidazolines are reported as well
as a hexahydro-1H-benzimidazole and a tetrahydrodiazepine.
The method is much milder than the hexamethyldisilazane
procedure of Chouiery et al.24 and gives as good or better yields
(their yield for the seven-membered ring 31 was only 5%,
whereas our procedure gives 57%).
Use of the benzyl or Boc protecting group was also
investigated. Thus treatment of N-[3-(benzylamino)propyl]-
benzamide46 with 1 (1.0 equiv) and DIPEA (2.2 equiv) in dry
DCM for 2 h at room temperature resulted in the recovery of
N-[3-(benzylamino)propyl]benzamide, after silica chromatog-
1
raphy. H NMR spectroscopy of the crude product suggested
the presence of a cyclic amidine product; however, none was
isolated. Instead, treatment of Boc-amide 2647 with 1 (1 equiv)
and DIPEA (2.2 equiv) in dry DCM for 2 h at room
temperature resulted in the formation of the cyclic amidine 27.
Analysis of the crude mixture by 1H NMR spectroscopy
showed that Boc-amide 26 and cyclic amidine 27 were present
in a ratio of approximately 40:60. There was no change in this
ratio after 24 h. Use of >1.5 equiv of 1 led to a decrease in the
yield of cyclic amidine 27. Due to the difficulty of separating 27
from triphenylphosphine oxide, the reaction was repeated but
with reagent 2 instead of 1.
Reagent 2 has the advantage over reagent 1 in that the bis-
phosphine oxide byproduct, 1,2-bis(diphenylphosphinyl)ethane
is water-soluble and readily removed by a water wash.
Treatment of Boc-amide 26 with reagent 2 (1.0 or 1.5 equiv)
and DIPEA in dry DCM gave the cyclic amidine 27 in
moderate (51% or 64%, respectively) isolated yield (Scheme 6).
Surprisingly, when the reaction was repeated but in the absence
of DIPEA (i.e., trityl amide conditions), only traces of 27 were
observed. The major product formed was the amide 6. This
suggests that under these reaction conditions, Boc-deprotection
is faster than detritylation.
EXPERIMENTAL SECTION
■
General Methods. Air-sensitive reactions were carried out in
flame-dried or oven-dried glassware under an inert atmosphere.
CH2Cl2 and THF were freshly distilled. Triflic anhydride was distilled
from phosphorus pentoxide before use. 1,2-Bis(diphenylphosphinyl)-
ethane, triphenylphosphine oxide, benzoic acid, and all synthesized
amides were dried under high vacuum for 48 h prior to use. All other
reagents were purchased from commercial suppliers and used without
further purification. Column chromatography was performed using
silica gel 60 Å (0.040−0.063 mm). Analytical thin layer chromatog-
raphy (TLC) was performed using aluminum plates coated with silica
gel 69 F254 (0.2 mm) and visualized by means of ultraviolet light.
Melting points were measured on a variable temperature apparatus by
the capillary method and are uncorrected. Infrared (IR) spectra were
recorded on a FTIR apparatus. High resolution mass spectroscopy
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Note
(HRMS) was performed on a Fourier transform mass spectrometer
equipped with an electrospray source (ESI-FTMS). Mass spectra were
recorded using electrospray as the ionization technique. 1H NMR
spectra were obtained at 300 or 400 MHz and chemical shifts are
reported in parts per million, using the appropriate signal for solvent
protons as a reference. The following are abbreviations were used for
signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad, quin = quintet, sept = septet, dt = doublet of
triplets. Compound structures were assigned and confirmed using
gCOSY, gHMBC, and gHSQC NMR spectroscopy.
Typical Procedure for the Preparation of Trityl Amides.
Tritylchloride (626 mg, 2.24 mmol) was added to N-(3-aminopropyl)-
benzamide (8) (200 mg, 1.12 mmol) and TEA (390 μL, 2.81 mmol)
in dry CH2Cl2 (10 mL), and the mixture stirred at room temperature
under a nitrogen atmosphere for 16 h. The solvent was removed under
reduced pressure, and the residue purified by silica column
chromatography (ethyl acetate/hexane, gradient from 10:90 to
50:50). N-[3-(Tritylamino)propyl]benzamide (12) was obtained as
an amorphous white solid (678 mg, 94%); Rf 0.33 (ethyl acetate/
hexane, 1:3); mp 167−169 °C; IR (KBr disc) ν 3422, 3291, 3056,
3023, 2835, 1646, 1519, 1487, 1475 cm−1; 1H NMR (400 MHz;
CDCl3) δ 7.63−7.66 (2H, m), 7.29−7.41 (9H, m), 7.09−7.21 (9H,
m), 6.83 (1H, br s), 3.56 (2H, dt, J = 6.2, 6.2 Hz), 2.25 (2H, t, J = 6.2
Hz), 1.69 (2H, quin, J = 6.2 Hz), NH not observed; 13C NMR (100
MHz, CDCl3) δ 167.6, 145.7, 134.9, 131.3, 128.6, 128.5, 127.9, 126.9,
126.4, 71.2, 42.1, 39.0, 30.0; MS (ESI+) m/z 443.3 (M + Na+, 63%),
243.0 ([C(C6H5)3]+, 100%), 427.3 (M + Li+, 100%); HRMS (ESI-
FTMS, MNa+) m/z calcd for C29H28N2ONa 443.2094, found
443.2106. Anal. Calcd for C, 82.82; H, 6.71; N, 6.66. Found: C,
82.96; H, 6.64; N, 6.70.
N-[2-(Tritylamino)ethyl]benzamide (15). Amorphous white
solid (366 mg, 87%); Rf 0.47 (ethyl acetate/hexane, 1:3); mp 149−
151 °C; IR (KBr disc) ν 3263, 3052, 2917, 2840, 1639, 1545, 1488,
1311 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.79−7.81 (2H, m); 7.42−
7.53 (9H, m), 7.24−7.28 (6H, m), 7.17−7.21 (3H, m), 6.70 (1H, br
s), 3.54 (2H, dt, J = 6.0, 6.0 Hz), 2.43 (2H, t, J = 6.0 Hz), 1.81 (1H, s);
13C NMR (100 MHz, CDCl3) δ 167.6, 145.4, 134.5, 131.5, 128.61,
128.56, 128.0, 127.0, 126.7, 77.3, 43.8, 40.3; MS (ESI+) m/z 429.2 ([M
+ Na]+, 3%), 243.0 ([C(C6H5)3]+, 100%); HRMS (ESI-FTMS, MH+)
m/z calcd for C28H27N2O 407.2118, found 407.2114. Anal. Calcd for
C28H26N2O: C, 82.73; H, 6.45; N, 6.89. Found: C, 82.61; H, 6.43; N,
6.78.
Typical Procedure for the Preparation of Amides. Benzoic
anhydride (1.0 g, 4.42 mmol) in dry CH2Cl2 (100 mL) was added
dropwise (over 2 h) to a vigorously stirred solution of 2,2-
dimethylpropane-1,3-diamine (2.65 mL, 22.1 mmol) in dry CH2Cl2
(300 mL) at −78 °C under a nitrogen atmosphere. The reaction
mixture was warmed slowly (over 2 h) to room temperature and
stirred for 16 h. The mixture was extracted with hydrochloric acid (5%
in aqueous solution, 3 × 100 mL). The acidic water layer was
neutralized by addition of sodium hydroxide (2 M, aqueous solution),
then extracted with CH2Cl2 (4 × 100 mL), dried (anhydrous Na2SO4),
and filtered, and the solvent was removed under reduced pressure.
Purification of the residue by aluminum oxide (basic) chromatography
(methanol/CH2Cl2/hexane,1:3:6) gave N-(3-amino-2,2-
dimethylpropyl)benzamide (20) as a colorless oil (866 mg, 95%);
IR (neat) ν 3298, 3061, 2958, 1643, 1577, 1546, 1311 cm−1; 1H NMR
(400 MHz; acetone-d6) δ 8.75 (1H, br s), 7.84−7.87 (2H, m), 7.43−
7.52 (3H, m), 3.39 (2H, d, J = 4.8 Hz), 3.17 (2H, s), 0.99 (6H, s),
NH2 not observed); 13C NMR (100 MHz; acetone-d6) δ 166.3, 135.9,
131.0, 128.5, 127.1, 62.5, 50.5, 34.7, 24.1; MS (ESI+) m/z 206.9 (M +
+
Na+, 58%), 243.0 [C(C6H5)3 , 100%]; HRMS (ESI-FTMS, MH+) m/z
calcd for C12H20N2O requires 207.1492, found 207.1490.
N,N′-Propane-1,3-diylbis(4-nitrobenzamide) (9). Amorphous
white solid (79 mg, 86%); crystallized from CH2Cl2; mp 226−229 °C;
N-[3-(Tritylamino)-2,2-dimethylpropyl]benzamide (21).
Amorphous white solid (1.03 g, 86%); Rf 0.61 (ethyl acetate/hexane,
1:3); mp 143−145 °C; IR (KBr disc) ν 3322, 3052, 2958, 2917, 1644,
1
IR (KBr disc) ν 3448, 3333, 1640, 1598, 1518, 1353 cm−1; H NMR
(400 MHz, DMSO-d6) δ 8.83 (2H, br t, J = 5.7 Hz), 8.31 (4H, d, J =
9.0 Hz), 8.07 (4H, d, J = 9.0 Hz), 3.37 (4H, dt, J = 5.7, 6.9 Hz), 1.83
(2H, quin, J = 6.9 Hz); 13C NMR (100 MHz, DMSO-d6) δ 165.1,
149.4, 140.7, 129.1, 124.0, 37.9, 29.3; MS (ESI+) m/z 373.1 (M + H+,
53%), 395.2 (M + Na+, 46%); HRMS (ESI-FTMS, MH+) m/z calcd
for C17H17N4O6 373.1143, found 373.1147.
1
1538, 1487, 1448 cm−1; H NMR (400 MHz; CD3OD) δ 7.58−7.60
(2H, m), 7.44−7.52 (7H, m), 7.37−7.41 (2H, m), 7.15−7.19 (6H, m),
7.07−7.11 (3H, m), 3.34 (2H, s), 1.91 (2H, s), 1.01 (6H, s), NH and
C(O)NH not observed); 13C NMR (100 MHz; CD3OD) δ 170.6,
147.6, 135.9, 132.5, 130.0, 129.4, 128.6, 128.4, 127.1, 72.0, 52.5, 48.6,
N-[3-(Isopropylamino)propyl]benzamide (18).42 Colorless oil
(919 mg, 94%) using alumina (basic) chromatography (methanol/
+
37.7, 25.3; MS (ESI+) m/z 243.0 (C(C6H5)3 , 100%); HRMS (ESI-
FTMS, MH+) m/z calcd for C31H33N2O 449.2587, found 449.2607.
Anal. Calcd for C31H32N2O C, 83.00; H, 7.19; N, 6.24. Found: C,
83.12; H, 7.00; N, 6.40.
1
CH2Cl2, 0:100 to 3:97); H NMR (400 MHz; CD3OD) δ 7.80−7.82
(2H, m), 7.51−7.55 (1H, m), 7.44−7.47 (2H, m), 3.45 (2H, t, J = 7.0
Hz), 2.80 (1H, sept, J = 6.3 Hz), 2.65 (2H, t, J = 7.0 Hz), 1.81 (2H,
quin, J = 7.0 Hz), 1.08 (6H, d, J = 6.3 Hz), NH and C(O)NH not
observed); 13C NMR (100 MHz; CD3OD) δ 170.4, 135.9, 132.6,
129.8, 128.1, 49.8, 45.5, 38.8, 30.6, 22.3; MS (ESI+) m/z 221.0 ([M +
H]+, 71%); HRMS (ESI-FTMS, MH+) m/z calcd for C13H21N2O
221.1648, found 221.1647.
N-[2-(Tritylamino)cyclohexyl]benzamide (24). Amorphous
white solid (936 mg, 92%); Rf 0.5 (ethyl acetate/hexane, 1:3); mp
163−164 °C; IR (KBr disc) ν 3422, 3300, 3052, 2932, 1624, 1535,
1
1488 cm−1; H NMR (400 MHz; DMSO-d6) δ 7.91−7.95 (3H, m),
7.49−7.58 (9H, m), 7.23 (6H, t, J = 7.4 Hz), 7.15 (3H, t, J = 7.4 Hz),
4.13 (1H, br s), 2.58 (2H, br s, H2), 1.91−1.94 (1H, m), 1.18−1.41
(4H, m), 0.91−0.99 (1H, m), 0.75−0.81 (1H, m), 0.26 (1H, br d, J =
12.8 Hz); 13C NMR (100 MHz; DMSO-d6) δ 166.9, 147.1, 135.4,
130.9, 128.4, 128.1, 127.6, 127.5, 126.1, 70.7, 52.5, 51.6, 29.1, 27.9,
N-(2-Aminocyclohexyl)benzamide (23).45 Amorphous pale
yellow solid (752 mg, 97%) crystallized from CH2Cl2; mp 110−112
°C; IR (KBr disc) ν 3307, 3055, 2931, 2857, 1638, 1578, 1532, 1488
1
cm−1; H NMR (400 MHz; CD3OD) δ 7.83−7.86 (2H, m), 7.51−
+
23.7, 20.8; MS (ESI+) m/z 243.0 (C(C6H5)3 , 100%); HRMS (ESI-
FTMS, MH+) m/z calcd for C32H32N2ONa 483.2387, found 483.2387.
Anal. Calcd for C30H30N2O C, 83.44; H, 7.00; N, 6.08. Found: C,
83.27; H, 6.90; N, 5.88.
7.56 (1H, m), 7.44−7.48 (2H, m), 4.12−4.16 (1H, m), 3.16 (1H, m),
1.44−1.82 (8H, m), NH and C(O)NH not observed); 13C NMR (100
MHz; CD3OD) δ 170.3, 136.0, 132.6, 129.5, 128.5, 53.0, 51.0, 32.1,
28.0, 24.4, 21.7; MS (ESI+) m/z 219.0 (M + H+, 100%), 241.0 (M +
N-[4-(Tritylamino)butyl]benzamide (30). Amorphous white
solid (883 mg, 78%); Rf 0.29 (ethyl acetate/hexane, 1:3); mp 140−
143 °C; IR (KBr disc) ν 3299, 3056, 2950, 2860, 2815, 1630, 1534,
1489, 1449 cm−1; 1H NMR (400 MHz; CDCl3) δ 7.72−7.74 (2H, m),
7.40−7.50 (9H, m), 7.24−7.28 (6H, m), 7.15−7.19 (3H, m), 6.11
(1H, br s), 3.42 (2H, dt, J = 6.0, 6.8 Hz), 2.18 (2H, t, J = 6.8 Hz),
1.53−1.69 (5H, m); 13C NMR (100 MHz; CDCl3) δ 167.5, 146.1,
134.8, 131.3, 128.6, 128.5, 127.8, 126.8, 126.2, 70.9, 43.3, 40.1, 28.3,
27.6; MS (ESI+) m/z 435.3 (M + H+, 16%), 457.3 (M + Na+, 100%;
HRMS (ESI-FTMS, MH+) m/z calcd for C30H30N2ONa 457.2250,
found 457.2250. Anal. Calcd for C30H30N2O requires C, 82.91; H,
6.96; N, 6.45. Found: C, 83.06; H, 6.82; N, 6.32.
+
Na+, 28%), 225.0 (M + Li , 66%); HRMS (ESI-FTMS, MH+) m/z
calcd for C13H19N2O 219.1492, found 219.1498.
N-(4-Aminobutyl)benzamide (29).48 Colorless oil (802 mg,
94%) isolated from CH2Cl2; IR (neat) ν 3300, 3065, 2933, 2866, 1637,
1
1544, 1310 cm−1; H NMR (400 MHz; CD3OD) δ 7.80−7.83 (2H,
m), 7.50−7.54 (1H, m), 7.42−7.47 (2H, m), 3.39 (2H, t, J = 7.0 Hz),
2.68 (2H, t, J = 7.0 Hz), 2.64 (2H, br s), 1.47−1.69 (4H, m), NH not
observed); 13C NMR (100 MHz; CD3OD) δ 170.3, 135.8, 132.6,
129.6, 128.2, 41.6, 40.5, 29.5, 27.8; MS (ESI+) m/z 193.0 (M + H+,
95%); HRMS (ESI-FTMS, MH+) m/z calcd for C11H17N2O 193.1335,
found 193.1337.
7359
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The Journal of Organic Chemistry
Note
Reaction of N-(3-Aminopropyl)benzamide (6) with Polymer-
Supported Triphenylphosphine Ditriflate 3. Prior to use,
polymer-supported triphenylphosphine oxide32 beads (250 mg, 0.76
mmol, 3 mmol/g) were dried under high vacuum for 48 h. The
polymer was swollen in dry CH2Cl2 (8 mL) under an atmosphere of
nitrogen. Triflic anhydride (94 μL, 0.56 mmol) was added, and the
mixture stirred for 1 h. N-(3-Aminopropyl)benzamide (6) (100 mg,
0.56 mmol) and DIPEA (341 μL, 1.97 mmol) were added
consecutively, and the slurry was stirred at room temperature for 16
h. The polymer beads were removed by filtration and washed with
CH2Cl2 (35 mL), and the filtrate was washed with sodium hydrogen
carbonate (5% aqueous solution, 3 × 20 mL). The solvent was
removed under reduced pressure, and the residue was purified by silica
column chromatography (CH2Cl2/CH3OH, gradient from 100:0 to
90:10). N-(3-{[(Trifluoromethyl)sulfonyl]amino}propyl) benzamide
(10) was obtained as an amorphous white solid (43 mg, 25%)
recrystallized from ethyl acatate; mp 114−116 °C; IR (KBr disc) ν
3436, 3060, 2864, 1640, 1368, 1183 cm−1; 1H NMR (400 MHz;
CDCl3) δ 7.76−7.78 (2H, m), 7.54−7.58 (1H, m), 7.45−7.49 (2H,
m), 7.22 (1H, br t), 6.46 (1H, br s), 3.65 (2H, dt, J = 5.2, 6.6 Hz), 3.34
(2H, dt, J = 5.2, 6.6 Hz), 1.81−1.87 (2H, m); 13C NMR (100 MHz;
CDCl3) δ 169.4, 133.4, 132.1, 128.8, 126.9, 119.8 (1C, q, J = 320 Hz),
40.7, 36.1, 30.6; MS (ESI+) m/z 311.1 (M + H+, 95%), 333.0 (M +
Na+, 100%), 317.1 (M + Li+, 100%); HRMS (ESI-FTMS, MH+) m/z
calcd for C11H14F3N2O3S 311.0672, found 311.0679.
N-(3-{Acetyl[(trifluoromethyl)sulfonyl]amino}propyl)-
benzamide. Acetyl chloride (7.6 μL, 0.11 mmol) was added dropwise
to 10 (18 mg, 0.058 mmol) and TEA (15 μL, 0.11 mmol) in dry
CH2Cl2 (3 mL), and the mixture was stirred at room temperature
under a nitrogen atmosphere for 16 h. The mixture was washed with
sodium hydroxide (2 M aqueous solution, 5 mL) and brine (5 mL),
dried (anhydrous Na2SO4), and filtered. The solvent was removed
under reduced pressure, and the residue was purified by silica column
chromatography (ethyl acetate/hexane, gradient from 5:95 to 50:50).
N-(3-{Acetyl[(trifluoromethyl)sulfonyl]amino}propyl)benzamide was
obtained (in approximately 95% purity) as a pale yellow oil (20 mg,
98%); IR νmax 3444, 3321, 2929, 1732, 1638, 1405, 1209, 1194 cm−1;
1H NMR (400 MHz; CDCl3) δ 7.79−7.82 (2H, m), 7.41−7.53 (3H,
2-Phenyl-4,5-dihydro-1H-imidazole (16).18,41 Amorphous
white solid (65 mg, 89%) recrystallized from CH2Cl2; mp 147−150
°C (lit.18,49 mp 149−151 and 147−149 °C).
Triflic anhydride (41 μL, 0.24 mmol), triphenylphosphine oxide
(163 mg, 0.58 mmol), N-(2-aminoethyl)benzamide (14) (40 mg, 0.24
mmol), and DIPEA (91 μL, 0.53 mmol) were reacted in dry CH2Cl2
(3 mL) and worked up as above gave compound 16 (10 mg, 29%).
1-Isopropyl-2-phenyl-1,4,5,6-tetrahydropyrimidine (19).
Colorless oil (159 mg, 86%); IR (neat) ν 3425, 3245, 3121, 1621,
1280, 1251, 1154, 1030 cm−1; 1H NMR (400 MHz; CD3OD) δ 7.59−
7.69 (3H, m), 7.54−7.57 (2H, m), 3.89 (1H, sept, J = 6.7 Hz), 3.61
(2H, t, J = 5.6 Hz), 3.51 (2H, t, J = 5.6 Hz), 2.17 (2H, quin, J = 5.6
Hz), 1.23 (6H, d, J = 6.7 Hz); 13C NMR (100 MHz; CD3OD) δ 163.0,
133.0, 131.2, 130.6, 128.4, 54.4, 40.7, 40.0, 20.2, 19.5; MS (ESI+) m/z
203.1543 (M + H+, 100%); HRMS (ESI-FTMS, MH+) m/z calcd for
C13H19N2 203.1543, found 203.1549.
5,5-Dimethyl-2-phenyl-1,4,5,6-tetrahydropyrimidine
(22).43,44 Colorless oil that solidified upon standing (109 mg, 93%),
crystallized from CH2Cl2/methanol; mp 113−116 °C (lit.43 mp 116−
118 °C).
2-Phenyl-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole (25).45
From alumina oxide (basic) (methanol/CH2Cl2, gradient from 0:100
to 5:95) and characterized as the CF3SO2OH salt; mp 140−142 °C;
IR (KBr disc) ν 3223, 2946, 2868, 1616, 1587, 1557, 1237, 1167, 1032
1
cm−1; H NMR (400 MHz; CD3OD) δ 7.87−7.90 (2H, m), 7.78−
7.82 (1H, m), 7.64−7.68 (2H, m), 4.36−4.42 (2H, m), 1.96−2.02
(2H, m), 1.76−1.81 (2H, m), 1.51−1.68 (4H, m), NH not observed;
13C NMR (100 MHz; CD3OD) δ 167.4, 136.1, 130.8, 129.2, 123.9,
121.8 (1C, q, J = 316.7 Hz), 57.8, 26.8, 19.9; MS (ESI+) m/z 200.9 (M
+ H+, 100%); HRMS (ESI-FTMS, MH+) m/z calcd for C13H17N2
201.1386, found 201.1393.
2-Phenyl-4,5,6,7-tetrahydro-1H-1,3-diazepine (31).38 Amor-
phous white solid (52 mg, 51%), crystallized from CH2Cl2; mp 96−99
°C (lit.38 mp 99−102 °C).
Typical Procedure Using Reagent 2. Triflic anhydride (25 μL,
0.15 mmol) was added slowly to a solution of 1,2-bis-
(diphenylphosphinyl)ethane (78 mg, 0.18 mmol) in dry CH2Cl2 (3
mL) at 0 °C under a nitrogen atmosphere. A thick white precipitate
was formed, and the mixture was stirred at 0 °C for 30 min. tert-Butyl
[3-(benzoylamino)propyl]carbamate (26) (42 mg, 0.15 mmol) and
DIPEA (57 μL, 0.33 mmol) in dry CH2Cl2 (3 mL) were added
dropwise over 5 min to the reaction mixture. The pale yellow mixture
was warmed to room temperature. After 16 h, the reaction mixture was
quenched with sodium hydrogen carbonate (5% aqueous solution, 2 ×
8 mL), dried (anhydrous Na2SO4), and filtered. The solvent was
removed under reduced pressure, and the residue was purified by silica
column chromatography (ethyl acetate/hexane, gradient from 25:75 to
100:0), followed by aluminum oxide (basic) chromatography
(methanol/CH2Cl2/hexane, gradient from 0:50:50 to 1:99:0). tert-
Butyl 2-phenyl-5,6-dihydropyrimidine-1(4H)-carboxylate (27) was
obtained as a colorless oil (20 mg, 51%); IR (neat) ν 3395, 2969,
2931, 1711, 1624, 1366, 1336, 1158 cm−1; 1H NMR (400 MHz;
CD3OD) δ 7.83−7.85 (2H, m), 7.51−7.56 (1H, m), 7.43−7.49 (2H,
m), 3.92 (2H, t, J = 6.9 Hz), 3.49 (2H, t, J = 6.9 Hz), 1.99 (2H, quin, J
= 6.9 Hz), 1.14 (9H, s); 13C NMR (100 MHz; acetone-d6) δ 159.0,
154.5, 140.5, 130.6, 129.2, 128.0, 83.3, 46.7, 44.4, 27.8, 24.9; MS
m), 6.62 (1H, br s), 3.94 (2H, t, J = 7.0 Hz), 3.49 (2H, dt, J = 5.9, 7.0
Hz), 2.55 (3H, s), 2.01 (2H, quin, J = 5.9 Hz); 13C NMR (100 MHz;
CDCl3) δ 170.0, 167.8, 134.5, 131.8, 128.8, 127.1, 119.8 (1C, q, J =
321 Hz), 46.3, 36.7, 29.6, 25.3; MS (ESI+) m/z 353.1 (M + H+, 66%),
359.1 (M + Li+, 100%); HRMS (ESI-FTMS, MH+) m/z calcd for
C13H16F3N2O4S 353.0777, found 353.0767.
Typical Procedure Using Hendrickson Reagent 1. Triflic
anhydride (180 μL, 1.07 mmol) was added slowly to a solution of
triphenylphosphine oxide (715 mg, 2.57 mmol) in dry CH2Cl2 (15
mL) at 0 °C under a nitrogen atmosphere. A thick white precipitate
was formed, and the mixture was stirred at 0 °C for 30 min. N-[3-
(Tritylamino)propyl]benzamide (12) (300 mg, 0.71 mmol) in dry
CH2Cl2 (5 mL) was added dropwise (over 5 min), and the reaction
mixture was warmed to room temperature. After 16 h of stirring, water
(10 mL) was added, and the layers separated. The organic layer
(containing the triphenylphosphine oxide) was discarded. The
aqueous layer was concentrated and redissolved in a 1:1 CH2Cl2/
sodium hydroxide (2 M aqueous solution) mixture (20 mL), and the
two layers separated. The organic layer was concentrated, and the
residue was purified by aluminum oxide (basic) chromatography
(methanol/CH2Cl2/hexane, gradient from 0:4:6 to 1:3:6). 2-Phenyl-
1,4,5,6-tetrahydropyrimidine (13): compound 1338,39 was obtained as
+
(ESI+) m/z 261.1598 (M + H+, 4%), 204.9 (M-OC(CH3)3 , 64%);
+
MS (ESI+) m/z 261.1598 (M + H+, 4%), 204.9 (M-OC(CH3)3 ,
64%); HRMS (ESI-FTMS, MH+) m/z calcd for C15H21N2O2
261.1598, found 261.1588.
1-Benzoyl-2-phenyl-1,4,5,6-tetrahydropyrimidine (28). The
compound was unstable, and repeated aluminum oxide (basic)
chromatography (ethyl acetate/CH2Cl2/hexane, gradient from
0:75:25 to 80:20:0) continued to give a mixture of 28 (∼90%) and
8 (∼10%); 1H NMR (400 MHz; CDCl3) δ 7.29−7.32 (4H, m), 7.18−
7.22 (1H, m), 7.06−7.15 (5H, m), 3.92 (2H, t, J = 7.0 Hz), 3.76 (2H,
t, J = 6.4 Hz), 2.05 (2H, tt, J = 6.4, 7.0 Hz); 13C NMR (100 MHz;
CDCl3) δ 171.7, 157.9, 137.8, 136.3, 131.0, 129.5, 128.1, 127.90,
127.89, 127.3, 46.4, 43.2, 24.5; MS (ESI+) m/z 265.1 (M + H+, 100%).
1
a white solid (90 mg, 79%) recrystallized from ethyl acetate. The H
NMR was identical to that in the literature;39 mp 98−99 °C (lit.38 mp
88−91 °C).
Triflic anhydride ((94 μL, 0.56 mmol), triphenylphosphine oxide
(375 mg, 1.35 mmol), N-(3-aminopropyl)benzamide (6) (100 mg,
0.56 mmol), and DIPEA (214 μL, 1.23 mmol) were reacted in dry
CH2Cl2 (5 mL) and worked up as above gave compound 13 (32 mg,
36%).
7360
dx.doi.org/10.1021/jo401082q | J. Org. Chem. 2013, 78, 7356−7361

The Journal of Organic Chemistry
Note
H.; Siegmund, A. C.; Stec, M.; Xi, N.; Yang, K. Patent WO
2008103277, 2008.
ASSOCIATED CONTENT
* Supporting Information
Spectroscopic data for compounds 9, 10, 12, 13, 15, 16, 18−
25, and 27−31]. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
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Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 8, p 5404.
(30) Wu, M.; Wang, S. Synthesis 2010, 587.
(31) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Aust. J. Chem. 2004,
57, 371.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: w.loughlin@griffith.edu.au.
■
2004, 45, 2491.
Notes
(33) Fairfull-Smith, K. E.; Jenkins, I. D.; Loughlin, W. A. Org. Biomol.
Chem. 2004, 2, 1979.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support for this work was provided by Griffith
University and the Eskitis Institute for Drug Discovery, Griffith
University.
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