Tetrahydropyrimidine derivatives as efficient organic reductants for transfer hydrogenation

Article abstract of DOI:10.3987/COM-08-11603

Two six-membered heterocyclic organic reductants, 1-acetyl-2,3-dimethyltetrahydropyrimidine (ADMP) and 1-tosyl-2,3-dimethyltetrahydro-pyrimidine (TDMP), were designed and synthesized for transfer hydrogenation. It was shown that both the two reductants could directly reduce a variety of aldehydes and imines to the corresponding saturated products in good yields.

Full text of DOI:10.3987/COM-08-11603

HETEROCYCLES, Vol. 78, No. 6, 2009
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HETEROCYCLES, Vol. 78, No. 6, 2009, pp. 1541 - 1548. © The Japan Institute of Heterocyclic Chemistry
Received, 16th November, 2008, Accepted, 29th January, 2009, Published online, 2nd February, 2009
DOI: 10.3987/COM-08-11603
TETRAHYDROPYRIMIDINE DERIVATIVES AS EFFICIENT ORGANIC
REDUCTANTS FOR TRANSFER HYDROGENATION
Yongbin Zhang, Guofu Zhou, and Wei Guo*
School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan
030006, China; Email: guowsxu@yahoo.com.cn; Fax: 0086-351-7011600
Abstract – Two six-membered heterocyclic organic reductants, 1-acetyl-2,3-
dimethyltetrahydropyrimidine (ADMP) and 1-tosyl-2,3-dimethyltetrahydro-
pyrimidine (TDMP), were designed and synthesized for transfer hydrogenation.
It was shown that both the two reductants could directly reduce a variety of
aldehydes and imines to the corresponding saturated products in good yields.
The investigations on heterocycles having hydrogen-donating ability as practical reductants have attracted
attention in organic chemistry in recent years due to their good chemoselectivity, mild reaction condition,
easily asymmetric modification as well as transition metal-free property which is especially important in
medicinal area.1-23 Because 1,4-dihydropyridines are known to be the active part of the reduced form of
the nicotinamide adenine dinucleotide (NADH), which plays a vital role in many biological reductions,1
1-benzyl-1,4-dihydronicotinamide, Hantzsch 1,4-dihydropyridine, 10-methyl-9,10-dihydroacridine, and
many other 1,4-dihydropyridine derivatives have been extensively used as models to mimic the function
of NADH, and indeed showed to have excellent reducibility in some reducing reactions.2-14 In addition to
1,4-dihydropyridine derivatives, some attention has also been paid to five-membered heterocycles, such
as 2-phenylbenzimidazoline (PBI) and its derivative 1,3-dimethyl-2-phenylbenzimidazoline (DMBI).
Me
N
H
H
H
N
R
R
2
1
Ph
H
Ph
H
N
H
N
N
Me
R
3
NADH models
PBI
DMBI
Scheme 1
Twenty years ago, Chikashita and coworkers reported that DMBI and PBI could selectively reduce C-C
double bonds conjugated with strong electron-withdrawing groups (CN, NO2, COMe)15-17 to the

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HETEROCYCLES, Vol. 78, No. 6, 2009
corresponding saturated compounds. Thereafter, this group reported that DMBI could reduce a series of
α-halocarbonyl compounds to their corresponding aldehydes or ketones without affecting the carbonyl
group.18 Also, DMBI or its analog were used as reductant in photoinduced electron transfer (PET)
reaction systems for the reduction of α,β-epoxy ketone, aromatic ketones, etc.19-23 However, subsequent
activities have been carried out to focus on the mechanistic details of these systems,24-32 little attention has
been paid in organic synthesis.
Recently, we developed a mild, efficient, and selective five-membered heterocyclic organic reductant,
1-acetyl-2,3-dimethylimidazolidine (ADMI), for the reduction of aromatic, aliphatic and α,β-unsaturated
aldehydes as well as imines in good yields.33 In the present work, we wish to report two six-membered
heterocyclic organic reductants, 1-acetyl-2,3-dimethyltetrahydropyrimidine (ADMP) and 1-tosyl-
2,3-dimethyltetrahydropyrimidine (TDMP), and these successful applications in transfer hydrogenation
reaction.
H
Me
H
Ne
Me
H
N
Ac
N
N Me
Ts
N
N Me
Ac
N Me
ADMI
ADMP
TDMP
Scheme 2
Recently, we described ADMI as a five-membered heterocyclic compound showing excellent reactivity
for reducing a series of aldehydes and imines.33 The deuterated experiment demonstrated that the
reduction involving the transfer of a hydrogen atom to substrates from C-2 position of ADMI. A
plausible mechanism is that the 1,3-diaza-type structure in ADMI possibly allows a hyperconjugative
interaction between nonbonding tertiary amine lone pair and the σ* (C2-H) orbital (expressed by
resonance between the canonical structure A-A′, Scheme 3), thus, induces a weakening of the C2-H bond
and an increase of negative charge density at the hydrogen atom.32 In fact, similar structural feature is also
found in the structure of PBI, DMBI as well as a 1,3,2-diazaphospholene compound.34 Although the
detailed mechanism is unclear at present, the results have prompted us to exploit new 1,3-diaza-type
heterocycles, such as six-membered heterocycles ADMP and TDMP, for their application in organic
synthesis.
Ac
N
Ac
N
H
N
N
H
Me
Me
Me
Me
A
A
Scheme 3

HETEROCYCLES, Vol. 78, No. 6, 2009
1543
ADMP could be readily prepared in a three-step procedure (eq-1) involving (i) acetylation of the starting
material, 2-methyl tetrahydropyrimidine (1), with Ac2O to 2, and (ii) methylation of 2 with CH3I to 3 and
(iii) subsequent reduction with NaBH4 to the objective compound. TDMP was synthesized by the same
procedure except that TsCl was used in the first step (eq-2).
Me
Me
Me
N Me
H
Me
Ac O
2
MeI
MeI
NaBH
4
HN
HN
N
Ac
N
N
Ac
N
Ac
N
N Me
eq-1
eq-2
NEt
I
3
1
ADMP
2a
3a
Me
Me
Me
H
Me
N Me
TsCl
NaBH
4
N
Ts N
N
Ts N
N Me
I
Ts N
NEt
3
1
TDMP
2b
3b
Subsequently, the potential reduction ability of ADMP and TDMP was tried with 4-nitrobenzaldehyde as
substrate in our standard conditions (reductant: 1 mmol, substrate: 1 mmol, Mg(ClO4)2: 0.1 mmol,
MeCN-MeOH: 1:1, 4 mL).33 As expected, both the two reductants showed good reactivity at room
temperature. The reactions could be completed within 12 hr and 4-nitrobenzyl alcohol was obtained in
85% and 83% yields for ADMP and TDMP, respectively. It is interesting to note that when the
temperature was raised to 50 oC, the reactions could be completed after 0.5 hr with the improved yields of
90% and 92% for ADMP and TDMP, respectively. The results suggest that the reaction rate of this type
of reductive reaction is sensitive to temperature, and ADMP and TDMP have similar reactivity in the
condition.
Next, we examined the application scope with ADMP as reductant and various aldehydes as substrates, as
shown Table 1. It was found that all aldehydes tested in this study, including electron-deficient,
electron-rich, and aliphatic aldehydes could be efficiently reduced in good yields within 1 hr (Entry 1-6).
Noteworthy is that the α, β-unsaturated aldehydes examined can be reduced to the corresponding
unsaturated alcohols in high yields without any effect on the carbon-carbon double bonds (Entry 7-9), and
the desired unsaturated alcohols were obtained as the sole products. The scope of this new reduction was
further extended to a variety of imines. As shown in Table 2, for both N-tosyl imines and N-phenyl
imines, the reductions worked well in our conditions. The low yield for N-tosyl-4-nitrobenzaldimine
(Entry 1) and N-phenyl-4-nitrobenzaldimines (Entry 4) is mainly due to their quick decomposition in
reaction conditions. In addition, similar case could also be found when TDMP as reductant. However, no
effort was made to separate these reducing products, and only TLC was used to evaluate its reactivity
toward various substrates.
In summary, we have developed two efficient six-membered heterocyclic organic reductants,
1-acetyl-2,3-dimethylpyrimidine (ADMP) and 1-Ts-2,3-dimethylpyrimidine (TDMP), for the reduction

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HETEROCYCLES, Vol. 78, No. 6, 2009
of aromatic, aliphatic and α,β-unsaturated aldehydes as well as imines in good yields. Investigation to
understand the reducing mechanism and to evaluate the process with a broader scope of substrates are in
progress in our lab.
Table 1 Transfer hydrogenation of ADMP with various aldehydesa
Entry
1
Products
Time (h)
0.5
Yield (%)b
90
O2N
CH2OH
N
CH OH
2
2
3
4
5
0.5
0.5
1
84
87
93
88
Cl
CH OH
2
CH2OH
MeO
CH2OH
OH
1
6
7
8
9
1
1
1
1
90
93
94
95
OH
O2N
OH
OH
MeO
aConditions: ADMP (1.0 mmol), substrate (1.0 mmol), Mg(ClO4)2 (0.1 mmol),
MeCN-MeOH: 1:1 (v/v), 4 mL, 50 oC. b Isolated yields.
Table 2 Transfer hydrogenation of ADMP with various iminesa
Entry
1
Products
Time (h)
2
Yield (%)b
60
NHTs
O2N
NHTs
NHTs
2
3
0.5
2
94
95
MeO
NHPh
4
5
6
5
3
3
32
80
75
O N
2
NHPh
NHPh
MeO
aConditions: ADMP (1.0 mmol), substrate (1.0 mmol), Mg(ClO4)2 (0.1 mmol),
MeCN-MeOH: 1:1 (v/v), 4 mL, 50 oC. b Isolated yields.

HETEROCYCLES, Vol. 78, No. 6, 2009
1545
EXPERIMENTAL
Commercially available compounds were used without further purification. Solvents were dried
according to standard procedures. All reactions were magnetically stirred and monitored by thin-layer
chromatography (TLC) using Huanghai GF254 silica gel coated plates. Flash chromatography (FC) was
carried out using silica gel 60 (230-400 mesh). The 1H NMR and 13C NMR spectra were recorded at 300
and 75MHz, respectively. The following abbreviations were used to explain the multiplicities: s = singlet;
d = doublet; t = triplet; q = quartet; m = multiplet; br = broad. MS spectra were obtained on a JMS-D300
GC/MS spectrometer. IR spectra were obtained on a Shimadzu IR-1700 spectrophotometer. Melting
points were uncorrected.
Synthesis of 1-acetyl-2,3-dimethyltetrahydropyrimidine (ADMP)
o
2-Methyltetrahydropyrimidine (0.98 g, 10 mmol) was dissolved in 15 mL dry CH2Cl2 at 0 C, followed
by the addition of triethylamine (1.01 g, 10 mmol). Then this solution was added dropwise a solution of
acetic anhydride (1.02 g, 10 mmol) in 5 mL CH2Cl2. After the addition, the reaction mixture was allowed
to rt for an additional 3 h. The resulted solution was treated with 10% aqueous NaHCO3 (10 mL). After
stirring 0.5 h, the mixture was extracted with CH2Cl2, and the organic layers were washed with the
saturated brine, and dried over anhydrous sodium sulfate. Evaporation of CH2Cl2 in vacuo gave 0.96 g of
1-acetyl-2-methyltetrahydropyrimidine (2a) as an oil (yield: 69%).
1-Acetyl-2-methyltetrahydropyrimidine (0.96 g, 6.9 mmol) and iodomethane (1.3 mL, 20.7 mmol) were
stirred in a sealed flask for 5 h in rt. Then 2 mL of acetone was added, the mixture was stirred for a few
minutes, and the solid obtained was collected by vacuum filtration to give 1.36 g of
1
1-acetyl-2,3-dimethyltetrahydropyrimidinium iodide (3a) as a white solid (yield: 70%). H NMR (300
MHz, δ ppm, CDCl3): 2.38 (m, 2H), 2.54 (s, 3H), 2.75 (s, 3H), 3.50 (s, 3H), 3.86 (m, 2H), 4.14 (t, J =
5.70, 2H).
1-Acetyl-2,3-dimethyltetrahydropyrimidinium iodide (0.85 g, 3 mmol) was dissolved in 10 mL of MeCN
o
at 0 C, followed by the addition of NaBH4 (0.13 g, 3.3 mmol). After the addition, the reaction mixture
was allowed to rt for an additional 5 h. The resulted solution was treated with 50 mL of water. The
mixture was extracted with CH2Cl2, and the organic layers were washed with the saturated brine, and
dried over anhydrous sodium sulfate. Evaporation of dichloromethane in vacuo gave 0.43 g of
1
1-Acetyl-2,3-dimethyltetrahydropyrimidine (ADMP) as a clear oil (yield: 91%). H NMR (300 MHz, δ
ppm, D2O): 1.29−1.44 (2×m, 5H), 1.82−1.92 (2×s, 3H), 2.36−2.45 (2×s, 3H), 2.65 and 3.58 (2×m, 2H),
3.21 and 4.14 (2×m, 2H), 4.53 and 5.01 (2×m, 1H). IR (film) cm-1: 2960, 2381, 1635, 1427, 1369, 1296,
1072. MS m/z: 157 ([M+1]+). Anal. Calcd for C8H16N2O: C, 61.50; H, 10.32; N, 17.93. Found C, 61.34;
H, 10.21, N, 17.85.
Synthesis of 1-tosyl-2,3-dimethyltetrahydropyrimidine (TDMP)

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HETEROCYCLES, Vol. 78, No. 6, 2009
o
2-Methyltetrahydropyrimidine (0.98 g, 10 mmol) was dissolved in 15 mL dry CH2Cl2 at 0 C, followed
by the addition of triethylamine (1.01 g, 10 mmol). Then this solution was added dropwise a solution of
TsCl (1.905 g, 10 mmol) in 10 mL CH2Cl2. After the addition, the reaction mixture was allowed to rt for
an additional 3 h. The resulted solution was treated with 10% NaHCO3 (10 mL). After stirring 0.5 h, the
mixture was extracted with CH2Cl2, and the organic layers were washed with the saturated brine, and
dried over anhydrous sodium sulfate. Evaporation of CH2Cl2 in vacuo gave 1.27 g of
1-tosyl-2-methyltetrahydropyrimidine (2b) as an oil (yield: 50%).
1-Tosyl-2-methytetrahydropyrimidine (1.27 g, 5 mmol) and iodomethane (0.94 mL, 15 mmol) were
refluxed in Et2O (10 mL) for 8 h. After cooled to rt, 1 mL of acetone was added. The mixture was stirred
for several minutes, and the solid obtained was collected by vacuum filtration to give 1.38 g of
1
1-tosyl-2,3-dimethyltetrahydropyrimidinium iodide (3b) as a white solid (yield: 70%). H NMR (300
MHz, δ ppm, CDCl3): 2.33 (m, 2H), 2.44 (s, 3H), 2.71 (s, 3H), 3.45 (s, 3H), 3.85 (m, 2H), 4.30 (m, 2H),
7.44 (d, J = 7.89, 2H), 7.91 (d, J = 7.92, 2H).
1-Tosyl-2,3-dimethyltetrahydropyrimidinium iodide (1.18 g, 3 mmol) was dissolved in 10 mL of MeCN
o
at 0 C, followed by the addition of NaBH4 (0.13 g, 3.3 mmol). After the addition, the reaction mixture
was allowed to rt for an additional 5 h. The resulted solution was treated with 50 mL of water. The
mixture was extracted with CH2Cl2, and the organic layers were washed with the saturated brine, and
dried over anhydrous sodium sulfate. Evaporation of CH2Cl2 in vacuo gave 0.76 g of
1
1-tosyl-2,3-dimethyltetrahydropyrimidine (TDMP) as a clear oil (yield: 95%). H NMR (300 MHz, δ
ppm, CDCl3): 1.33 (d, J = 6.54, 3H), 1.54 (m, 1H), 2.05 (m, 1H), 2.40 (s, 3H), 2.77 (s, 3H), 2.83 (m, 1H),
2.96 (t, J = 12.96, 1H), 3.24 (t, J = 12.69, 1H), 3.75 (m, 1H), 4.74 (m, 1H), 7.28 (d, J = 7.74, 2H), 7.60 (d,
J = 7.86, 2H). IR (film) cm-1: 2956, 2380, 1596, 1450, 1384, 1338, 1157. MS m/z: 269 ([M+1]+). Anal.
Calcd for C13H20N2O2S: C, 58.18; H, 7.51; N, 10.44. Found C, 58.24; H, 7.25, N, 10.25.
General procedure for the transfer hydrogenation reaction with ADMP and TDMP as reductants
To a solution of substrate (1 mmol) and Mg(ClO4)2 (22.3 mg, 0.1 mmol) in MeOH (2 mL) was added a
o
solution of reductant (1 mmol) in 2 mL of anhydrous MeCN. The reaction mixture was stirred at 50 C
and monitored by TLC. Upon completion, the solvent was removed in vacuo and the residue was
chromatographed on silica gel to give the desired products.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China (No. 20502014 and 20772073) for financial
support.
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