A novel hydride-mediated reductive rearrangement of amide: a facile synthesis of pyrimidyl and triazinyl amines

Article abstract of DOI:10.1016/j.tetlet.2007.11.096

LiAlH₄ and NaBH₄ were found to mediate the conversion of 2-(pyrimidyl-2-ylsulfanyl)-N-arylbenzamides and 2-(triazinyl-2-ylsulfanyl)-N-arylbenzamides into pyrimidyl and triazinyl amines under notably mild conditions via a novel reductive rearrangement mechanism. These reactions invent a new route to prepare amines, which are a kind of important biologically active compounds and provide the first insight into a novel hydride-promoted reductive rearrangement of amides.

Full text of DOI:10.1016/j.tetlet.2007.11.096

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 495–499
A novel hydride-mediated reductive rearrangement of amide:
a facile synthesis of pyrimidyl and triazinyl amines
a
a,
a,
a
a
*
*
Xiang Chen , Jun Wu , Zhicai Shang , Meifeng Chen , Yanping Sun ,
Jing Lv a, Meikang Lei a, Peizhi Zhang b
a Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
b School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310012, PR China
Received 28 July 2007; revised 7 November 2007; accepted 16 November 2007
Available online 22 November 2007
Abstract
LiAlH4 and NaBH4 were found to mediate the conversion of 2-(pyrimidyl-2-ylsulfanyl)-N-arylbenzamides and 2-(triazinyl-2-ylsulf-
anyl)-N-arylbenzamides into pyrimidyl and triazinyl amines under notably mild conditions via a novel reductive rearrangement mech-
anism. These reactions invent a new route to prepare amines, which are a kind of important biologically active compounds and provide
the first insight into a novel hydride-promoted reductive rearrangement of amides.
Ó 2007 Elsevier Ltd. All rights reserved.
The reduction of amides with metallic hydrides is no
doubt a key reaction in organic synthesis.1–4 It has been
suggested that the reduction affords various products via
two typical pathways: path a and path b. The attack of
the amide carbonyl group by metallic hydride (HÀM+,
i.e., LiAlH4, NaBH4 and so on) occurs through a tetrahe-
dral intermediate, which can proceed either by the breaking
of the C–O bond, producing an iminium salt which is
further converted to the corresponding amine with the
same number of carbon atoms (path a),1,2 or by the break-
ing of the C–N bond, leading thus to the amine and the
aldehyde which can eventually be reduced to an alcohol
(path b).1,3
Recently, we used the 2-(pyrimidyl-2-ylsulfanyl)-N-
arylbenzamides and 2-(triazinyl-2-ylsulfanyl)-N-arylbenz-
amides 1 as probes to investigate whether path a or b
would operate in the reduction of heterocyclic amide with
lithium aluminum hydride. However, unexpected cleavage
products pyrimidyl and triazinyl amines 2 (a kind of impor-
tant biologically active compounds which have aroused
considerable interest and attention in drugs and pesticides5)
and alcohol 3 were obtained (Scheme 1). Such a strange
phenomenon has attracted our considerable interest and
R2
N
path a
H
S
R1
4
O
R2
OH
H-M+
N
path b
R2
+
+
R1
H2N
H
S
S
R1
THF
5
6
1
OH
SH
H
path c
N
R1
R2
2
3
N
N
N
N
N
N
R1
=
O
O
O
N
O
,
,
Me
Het3
Me
*
Corresponding authors. Tel.: +86 571 87951352; fax: +86 571
Me
Me
Me
Me
87951895 (J.W.); tel.: +86 571 87952379; fax: +86 571 87951895 (Z.S.).
E-mail addresses: wujunwu@zju.edu.cn (J. Wu), shangzc@zju.edu.cn
(Z. Shang).
Het1
Het2
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.096

496
X. Chen et al. / Tetrahedron Letters 49 (2008) 495–499
Table 1
may imply a novel amide reductive pathway. Obviously 2
are not afforded via path a which should arrive to pyrim-
idyl and triazinyl benzylamine 4 (Scheme 1). Furthermore,
a mechanism involving 1,2-fission of amide via path b,
followed by an intermolecular nucleophilic substitution of
5 with 6 (Scheme 1) to afford 2 does not occur. This has
been confirmed by the crossing experiment. When a solu-
tion of 1, LiAlH4 and p-toluidine (molar ratio 1:6:10) was
refluxed, only amine 2 was obtained, without isolation of
the crossing product amine. Therefore, the reaction may
proceed via an intramolecular rearrangement, namely,
nucleophilic attack on heterocyclic ring by the amide nitro-
gen atom occurs without an earlier breakage of the amide
C–N. Consequently, such pathway is essentially different
from the well-known reductive routes of amide by metallic
hydrides. We disclose herein a new methodology to poten-
tially biologically important pyrimidyl and triazinyl amines
via a novel reductive rearrangement of amides.
LiAlH4-mediated reduction of amides 1a via path ca
H
O
N
H
N
H3CO
N
CH3O
N
S
LiAlH4
THF
OCH3
N
N
OCH3
OCH3
OCH3
1a
2a
Entry Ratio of 1a/LiAlH4 Temp (°C) Time (h) Yield of 2ab (%)
1
2
3
4
5
6
7
8
9
1/1
1/2
1/3
1/4
1/5
1/6
1/7
1/8
1/9
1/6
1/6
1/5
1/4
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
Reflux
Reflux
Reflux
10
10
10
6
6
6
6
6
6
3.5
3
5
8
15
83
85
89
88
89
90
92
95
91
88
10
11
12
13
a
The starting materials for the reductions are 2-(pyr-
imidyl-2-ylsulfanyl)-N-arylbenzamides and 2-(triazinyl-2-
ylsulfanyl)-N-arylbenzamides 1, which were easily prepared
from the corresponding pyrimidyl and triazinyl benzonic
acids and amines in high yields (more than 78%) using a
procedure6 described in Scheme 2.
3
3
The reduction of 1a (1.5 mmol) was carried out in THF (20 mL). A
variety of conditions to generate 2a were investigated including the ratio of
amide 1a/LiAlH4 and temperature.
b
Isolated yield after column chromatography.
Our initial investigation was based on the reduction of
1a [R1 = 4,6-dimethoxypyrimidin-2-yl, R2 = 4-MeOC6H4]
with LiAlH4 (Table 1, entries 1–13). The reduction was
originally carried out by mixing LiAlH4 and 1a in THF
under room temperature. The reaction mainly yielded 2a
and 3. Further studies showed that a higher yield of 2a
could be obtained with 6.0 equiv of LiAlH4 in THF under
refluxing for 3 h (Table 1, entry 11).7 Under the same con-
dition, the reduction of substrates with R2 being other aryl
showed that the formation of pyrimidyl amines 2b–h (Table
2, entries 2–8) is also predominant. Interestingly, the reduc-
tion of 1a–d afforded 2a–d in 95%, 94%, 85%, and 80%
yields, respectively. It seems likely to depend on electronic
factors, that is, the electron-donating substituents of the
anilines at C4 are favored over the LiAlH4-mediated reduc-
tive rearrangement.
To investigate the scope of hydride, sodium borohydride
(NaBH4), a weak reducing agent was then employed.
Reductions of amides 1a–c, 1i, 1k, 1l, and 1o–q were car-
ried out with 12.0 equiv of NaBH4 in THF under refluxing
(Table 3).7 To our surprise, the reaction absolutely afforded
substituted heterocyclic amines 2 in satisfactory yields. The
presence of electron-donating substituents of aniline at C4
also appeared to be effective. Interestingly, the reactions of
1i, 1k, and 1l with NaBH4 provided products in higher
yields compared with the reactions with LiAlH4 (Table 2,
entries 9, 11, 12; Table 3, entries 4–6). These results indi-
cated that NaBH4 was favored over converting 2-(4,6-
dimethoxy-1,3,5-triazin-2-ylsulfanyl)-N-arylbenzamides into
triazinyl amines. As we know, NaBH4 is a mild metallic
hydride, which can not reduce secondary amides even at
high temperatures without any auxiliary or catalyst.8
As summarized in Tables 2 and 3, LiAlH4 and NaBH4
were found to mediate the conversion of a broad variety
of 1 containing the different heterocyclic rings R1 and
amide groups R2 into 2 in moderate to high yields under
mild conditions: 1.0 equiv of 1, 6.0 equiv of LiAlH4 or
12.0 equiv of NaBH4, in THF under reflux for 2–4 h (Table
2, entries 1–17; Table 3, entries 1–9). To the best our
knowledge, this is the first example of a new route to
pyrimidyl and triazinyl amines via a novel hydride-medi-
ated reductive rearrangement of amide. This class of deriv-
atives is generally prepared via the direct displacement
reactions of heterocyclic halides with neutral nitrogen
nucleophiles in the presence of bases as catalysts. However,
this conventional direct displacement process often
result in low isolated yields in the synthesis of pyrimidyl
Under the same conditions, reactions of 1i–n [R1 =
4,6-dimethoxy-1,3,5-triazin-2-yl, R2 = 4-Me2NC6H4, 4-
MeOC6H4, 4-MeC6H4, 4-ClC6H4, phenyl, benzyl] with
6.0 equiv of LiAlH4 gave triazinyl amines 2i–n in yields
from 52% to 67% (Table 2, entries 9–14). Reactions of
1o–q [R1 = 4,6-dimethylpyrimidin-2-yl, R2 = 4-MeOC6H4,
4-MeC6H4, phenyl] with 6.0 equiv of LiAlH4 gave the
desired pyrimidyl amines 2o–q in excellent yields (Table
2, entries 15–17).
O
S
O
O
O
S
R1
R2
R2
H3C
H2N
N
OH
OH
R1
O
H
DCC, CH2Cl2
S
R1
SH
K2CO3, THF
1 ( > 78% )
Scheme 2.

X. Chen et al. / Tetrahedron Letters 49 (2008) 495–499
497
Table 2
A new methodology to pyrimidyl and triazinyl amines 2 via path ca
OCH3
CH3
CH3
O
OCH3
OCH3
R2
N
N
N
N
R1
LiAlH4 (6.0 equiv )
N
N
N
N
R1
:
HN
H
R2
THF, reflux
S
R1
OCH3
Het2
Het1
Het3
1
2
Entry
1
Time (h)
Yield of 2b (%)
R1
R2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
a
Het1
Het1
Het1
Het1
Het1
Het1
Het1
Het1
Het2
Het2
Het2
Het2
Het2
Het2
Het3
Het3
Het3
4-MeOC6H4
4-MeC6H4
Ph
3
3
3.5
4
4
3.5
3
4
2
2
2
2.5
3
3
2
95 (2a)
94 (2b)
85 (2c)
80 (2d)
79 (2e)
84 (2f)
92 (2g)
82 (2h)
67 (2i)
64 (2j)
60 (2k)
56 (2l)
52 (2m)
52 (2n)
95 (2o)
94 (2p)
87 (2q)
4-ClC6H4
2-MeC6H4
3-MeC6H4
3,4-Me2C6H3
1-Naphthyl
4-Me2NC6H4
4-MeOC6H4
4-MeC6H4
Ph
4-ClC6H4
Benzyl
4-MeOC6H4
4-MeC6H4
Ph
2
2
Conditions: 1.0 equiv 1, 6.0 equiv LiAlH4, in THF under refluxing.
Isolated yield after column chromatography.
b
Table 3
The NaBH4-mediated reduction of amides 1 via path ca
OCH3
CH3
CH3
O
OCH3
OCH3
R2
N
N
N
N
R1
R2
NaBH4 (12.0 equiv )
N
N
N
H
N
R1
:
HN
THF, reflux
S
R1
1
OCH3
Het2
Het1
Het3
2
Entry
1
Time (h)
Yield of 2b (%)
R1
R2
1
2
3
4
5
6
7
8
9
a
Het1
Het1
Het1
Het2
Het2
Het2
Het3
Het3
Het3
4-MeOC6H4
4-MeC6H4
Ph
4-Me2NC6H4
4-MeC6H4
Ph
4-MeOC6H4
4-MeC6H4
Ph
3
3
3.5
2
2
2.5
2
2
90 (2a)
88 (2b)
78 (2c)
88 (2i)
80 (2k)
77 (2l)
90 (2o)
87 (2p)
82 (2q)
2
Conditions: 1.0 equiv 1, 12.0 equiv NaBH4, in THF under refluxing.
Isolated yield after column chromatography.
b
amines with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine
and amines.9,10
the deuterated product 7 (Scheme 3), along with 2a. Anal-
ysis of product 7 suggests hydride is transferred from
LiAlD4 to amide carbonyl carbon. Moreover, amine 4a
(Scheme 3) reacted with LiAlH4, and the reaction did not
proceed at all. It is suggested that the reaction does not
occur due to the absence of the initial nucleophilic attack
of hydride from LiAlH4 to amide carbonyl group. Surely
At this juncture, it is necessary to make clear what is the
essential factor of such a novel reaction. To examine which
group of compound 1a metallic hydride attacked, a deute-
rium labeling experiment was performed. Under the equal
condition the reaction of LiAlD4 with amide 1a afforded

498
X. Chen et al. / Tetrahedron Letters 49 (2008) 495–499
H
H
N
H
N
O
N
CD2OH
SH
O
N
O
S
S
S
OMe
OMe
OMe
N
4a
7
8
9
Scheme 3.
R2
≠
R2
N
OM
H
R1
X
N
X
N
N
N
MH
N
R2
R3
N
S
R3
S
S
H
X
H
N
R1
OM
O
N
R1
R3
1 (X= CH, N)
10
R3
X
H3O+
MH
N
H
N
R1
+
-S
HS
OH
N
OM
R2
2
11
Scheme 4.
3
such a hydride-transfer step is very critical in the whole
process, in other words, the total reaction is triggered
and promoted by hydride.
Scheme 4, an increase in the electron density of aromatic
nitrogen atom would be favorable, due to the result of
strengthening the nucleophilic reactivity of the nitrogen
atom of amide.
In summary, the experimental investigation has resulted
in the first insight into a novel hydride-mediated reductive
rearrangement of amide via pyrimidyl and triazinyl partic-
ipation. Furthermore, our finding provides a new route to
prepare the other substituted heterocyclic amines. Further
work will systematically address the effect of other hetero-
cyclic ring, bridge atom, amide moiety, and hydride in our
laboratory.
The further mechanistic implication of the reaction was
involved in heterocyclic rings. A series of analogues 1 have
been proved to be general for the reaction (Tables 2 and 3).
However, the reduction of 2-(methylthio)-N-phenylbenza-
mide 8 led to the normal corresponding amine 9 (Scheme
3) without the formation of any rearrangement product.
The similar reduction of 2-(arylthio)-N-alkylbenzamide
with LiAlH4 to the corresponding amines was well docu-
mented.11 Hereby, it can be suggested that the heterocyclic
ring at the ortho-position of benzamide and the highly elec-
tron-deficient nature of the pyrimidyl and triazinyl rings,
which renders the nucleophilic substitution reaction plays
a pivotal role.
On the basis of the above experimental results, hydride-
promoting effect and pyrimidyl and triazinyl ring participa-
tion impact are suggested to be the essential factor of such
a novel reductive rearrangement reaction. A plausible
mechanism for the hydride-mediated formation of pyr-
imidyl and triazinyl amines reported herein is shown in
Scheme 4. Treatment of the starting material amides 1
initially affords a tetrahedral intermediate 10 via transfer-
ring a hydride from metallic hydride to carbonyl carbon,
followed by an intramolecular nucleophilic attack, an elec-
tronic feedback, and a concerted formation and cleavage
pathway, leading to the occurrence of 1,5-nitrogen shift
and the formation of product amine 2 and intermediate
aldehyde 11, which after reduction and hydrolysis gives
alcohol 3. In the rearrangement process described in
Acknowledgments
We thank the National Natural Science Foundation of
China (Grant No. 20272052) and Zhejiang Natural Science
Foundation (Grant No. M203087) for financial support of
this research.
Supplementary data
General experimental details and characterization data
for compounds 2a–q and 3. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.11.096.
References and notes
1. (a) Micovic, V. M.; Mihailovic, M. L. J. Org. Chem. 1953, 18,
1190–1200; (b) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1961,

X. Chen et al. / Tetrahedron Letters 49 (2008) 495–499
499
83, 4549–4552; (c) Seyden-Penne, J. Reductions by the Alumino- and
Borohydrides in Organic Synthesis, 2nd ed.; Wiley: New York, 1997, p
99–110.
7. A variety of conditions to generate 2a were investigated at first,
including the ratio of amide 1a:LiAlH4 and temperature. It is shown
that high yield (95%) of 2a could be obtained with 6.0 equiv of LiAlH4
in THF under reflux for 3 h. General procedure for the preparation of
2 from the reduction of 1 with LiAlH4 or NaBH4: To a suspension
solution of lithium aluminum hydride (9 mmol, 343 mg) or sodium
borohydride (18 mmol, 702 mg) in tetrahydrofuran (20 mL) was
added dropwise 1 (1.5 mmol) in tetrahydrofuran (15 mL) at room
temperature for about 20 min. The mixture was refluxed for 2–4 h.
Afterwards, the reaction was then cooled and quenched by the careful
addition of ice water (15 mL) and sodium hydroxide (10%, 15 mL) for
1 h. The solid was filtered off under reduced pressure and washed with
ethyl acetate (3 Â 20 mL). The organic layer was washed with brine
(3 Â 20 mL) and dried over anhydrous magnesium sulfate. The
solvent was removed under vacuo and the residue was purified by
column chromatography on silica gel with petroleum ether–ethyl
acetate (10:1) to afford the corresponding products 2 in 52–95% yield.
8. (a) Kanth, J. V. B.; Periasamy, M. J. Org. Chem. 1991, 56, 5964–5965;
(b) McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
3568–3571.
9. The most popular synthetic method of such substituted pyrimidine
amines is nucleophilic substitution of heterocyclic halides with neutral
nitrogen nucleophiles with bases as catalysts. (a) Eur. Patent, 224339,
1987; (b) PCT Int. Patent, 2006068213, 2006; (c) Peng, Z.-H.;
Journet, M.; Humphrey, G. Org. Lett. 2006, 8, 395–398; (d)
Bursavich, M. G.; Lombardi, S.; Gilbert, A. M. Org. Lett. 2005, 7,
4113–4116; (e) Cherng, Y. J. Tetrahedron 2002, 58, 887–890.
10. Corresponding experiments with such conventional direct displace-
ment method adopted were also conducted in the synthesis of amine
2a with 1 equiv of 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine and
1.2 equiv of 4-methoxybenzenamine in the presence of 1.5 equiv of
K2CO3 in refluxing THF or DMSO. However, trace of amine 2a was
obtained in THF under reflux for 10 h, and in refluxing DMSO the
reaction afforded 2a only in 20% yield.
2. (a) Brosius, A. D.; Overman, L.; Schwink, L. J. Am. Chem. Soc. 1999,
121, 700–709; (b) Smith, M. B. Organic Synthesis, 2nd ed.; McGraw-
Hill: New York, 2002, p 314.
3. (a) Ghosh, A. K.; Shin, D.; Downs, B.; Koelsch, G.; Lin, X.;
Ermolieff, J.; Tang, J. J. Am. Chem. Soc. 2000, 122, 3522–3523; (b)
Van Brabandt, W.; Dejaegher, Y.; Van Landeghem, R.; De Kimpe,
N. Org. Lett. 2006, 8, 1101–1104; (c) Soon Cha, J.; Brown, H. C. J.
Org. Chem. 1993, 58, 4727–4731.
4. (a) Pettit, G. R.; Eastham, S. A.; Melody, N.; Orr, B.; Herald, D. L.;
McGregor, J.; Knight, J. C.; Doubek, D. L.; Pettit, G. R. J. Nat.
Prod. 2006, 69, 7–13; (b) Atta, U. R.; Anjum, S.; Farooq, A.; Khan,
M. R.; Parveen, Z.; Choudhary, M. I. J. Nat. Prod. 1998, 61, 202–206;
(c) Nakao, Y.; Yoshida, W. Y.; Takada, Y.; Kimura, J.; Yang, L.;
Mooberry, S. L.; Scheuer, P. J. J. Nat. Prod. 2004, 67, 1332–1340; (d)
Tan, R. X.; Jensen, P. R.; Williams, P. G.; Fenical, W. J. Nat. Prod.
2004, 67, 1374–1382.
5. (a) Ruiz-Caro, J.; Basavapathruni, A.; Kim, J. T.; Bailey, C. M.;
Wang, L.; Anderson, K. S.; Hamilton, A. D.; Jorgensen, W. L.
Bioorg. Med. Chem. Lett. 2006, 16, 668–671; (b) Thakur, V. V.; Kim,
J. T.; Hamilton, A. D.; Bailey, C. M.; Domaoal, R. A.; Wang, L.;
Anderson, K. S.; Jorgensen, W. L. Bioorg. Med. Chem. Lett. 2006, 16,
5664–5667; (c) Nagata, T.; Masuda, K.; Maeno, S.; Miura, I. Pest
Manage. Sci. 2004, 60, 399–407; (d) Brown, D. J. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 3, Chapter 2.13; (e) Pratap, P.; Roy,
A. D.; Kushwaha, S. P.; Geol, A.; Roy, R.; Ram, V. J. Tetrahedron
Lett. 2007, 48, 5845–5849; (f) Herrera, A.; Alvarez, R. M.; Chioua,
R.; Almy, J. Tetrahedron Lett. 2006, 47, 5463–5465.
6. For the first step, see: (a) Wu, J.; Cheng, J.; Lu, L. J. Agric. Food
Chem. 2006, 54, 5954–5957; (b) Bessard, Y.; Crettaz, R. Tetrahedron
2000, 56, 4739–4745; For the second step, see: (c) Horenstein, B. A.;
Nakanishi, K. J. Am. Chem. Soc. 1989, 111, 6242–6246; (d)
Woydowski, K.; Liebscher, J. Tetrahedron 1999, 55, 9205–9220.
11. Jarkas, N.; McConathy, J.; Voll, R. J.; Goodman, M. M. J. Med.
Chem. 2005, 48, 4254–4265.