Gold- and platinum-catalyzed formal Markownikoff's double hydroamination of alkynes: A rapid access to tetrahydroquinazolinones and angularly-fused analogues thereof

Article abstract of DOI:10.1021/jo902293f

(Chemical Equation Presented) A highly efficient gold(I)- and platinum(II)-catalyzed process for formal Markownikoff's double hydroamination of alkynes tethered with hydroxyl group has been developed. The method was shown to be applicable to a broad range of 2-aminobenzamides and alkynols leading to the formation of multiply substituted tetrahydroquinazolinones. Interestingly, when Pt(IV)Cl₄ catalyst was employed, cyclic angularly fused compound was obtained. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902293f

pubs.acs.org/joc
manner.1 Catalysts derived from both early and late transi-
Gold- and Platinum-Catalyzed Formal
Markownikoff’s Double Hydroamination of Alkynes:
A Rapid Access to Tetrahydroquinazolinones and
Angularly-Fused Analogues Thereof
tion metals2 as well as lanthanides3 have shown significant
activity for the addition of N-H bonds across alkynes. In
general, primary or secondary amines can undergo addition
reactions with alkynes to give imines or enamines (Figure 1,
path a). The imines or enamines thus obtained can be
isolated or can be further used for various subsequent
cascade transformations4 without isolating them.5 We
sought to expand the alkyne hydroamination strategy
beyond the example of imines/enamines formation and
further develop a cascade reactions involving formal double
hydroamination of alkynes as shown in Figure 1, path b.
Nitin T. Patil,*,† Rahul D. Kavthe,† Vivek S. Raut,†
Valmik S. Shinde,† and Balasubramanian Sridhar‡
†Organic Chemistry Division II and ‡Laboratory of X-ray
Crystallography, Indian Institute of Chemical Technology,
Hyderabad 500 607, India
nitin@iict.res.in; patilnitint@yahoo.com
Received October 28, 2009
FIGURE 1. Hydroamination of alkynes.
A highly efficient gold(I)- and platinum(II)-catalyzed
process for formal Markownikoff’s double hydroamina-
tion of alkynes tethered with hydroxyl group has been
developed. The method was shown to be applicable to a
broad range of 2-aminobenzamides and alkynols leading
to the formation of multiply substituted tetrahydro-
quinazolinones. Interestingly, when Pt(IV)Cl4 catalyst
was employed, cyclic angularly fused compound was
obtained.
FIGURE 2. Formal double hydroamination of alkynes.
We recently described platinum-catalyzed hydroami-
nation/hydroarylation of terminal alkynes assisted by
tethered hydroxyl groups.6 On the basis of this reactivity
principle, we envisioned that imines could be generated
from diamines 1 and alkynes 2 via a metal-catalyzed
formal hydroamination, which would undergo trapp-
ing by tethered amines to form heterocycles 3 (Figure 2).
(3) Reviews: (a) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673–
686. For recent references, see: (b) Yuen, H. F.; Marks, T. J. Organometallics
Catalytic hydroamination of alkynes is a potentially
powerful synthetic method by which valuable nitrogen-
containing products can be obtained in an atom-economical
ꢀ
2009, 28, 2423–2440. (c) Motta, A.; Fragala, I. L.; Marks, T. J. Organome-
tallics 2006, 25, 5533–5539. (d) Kim, H.; Livinghouse, T.; Shim, J. H.; Lee, S.
G.; Lee, P. H. Adv. Synth. Catal. 2006, 348, 701–704.
(4) General reviews on cascade processes, see: (a) Nicolaou, K. C.; Chen,
J. S. Chem. Soc. Rev. 2009, 38, 2993–3009. (b) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (c) de
(1) Reviews on atom economy: (a) Sheldon, R. A. Pure Appl. Chem. 2000,
72, 1233–1246. (b) Trost, B. M. Science 1991, 254, 1471–1477. (c) Trost, B. M.
Angew. Chem., Int. Ed. 1995, 34, 259–281.
€
Meijere, A.; von Zezschwitz, P.; Brase, S. Acc. Chem. Res. 2005, 38, 413–422.
€
(2) Reviews: (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
(d) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001–1020. (e) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev.
2004, 33, 302–312. (f) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed.
2004, 43, 3754–3760. (g) Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
(5) Metal catalyzed cascade reaction involving imines: (a) Zhou, L.;
Bohle, D. S.; Jiang, H.-F.; Li, C.-J. Synlett 2009, 937–940. (b) Liu, X.-Y.; Che,
C.-M. Angew. Chem., Int. Ed. 2009, 48, 2367–2371. (c) Liu, X.-Y.; Che, C.-M.
Angew. Chem., Int. Ed. 2008, 47, 3805–3810. (d) Alex, K.; Tillack, A.; Schwarz,
N.; Beller, M. Org. Lett. 2008, 10, 2377–2379. (e) Alex, K.; Tillack, A.; Schwarz,
N.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2304–2307. (f) Liu, X.-Y.; Ding,
P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645–2649. (g) Ramanathan, B.;
Keith, A. J.;Armstrong, D.;Odom, A. L.Org.Lett.2004, 6, 2957–3061. (h) Cao,
C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853–2856.
Tada, M. Chem. Rev. 2008, 108, 3795–3892. (b) Severin, R.; Doye, S. Chem.
Soc. Rev. 2007, 36, 1407–1420. (c) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003,
32, 104–114. (d) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
€
3079–3159. (e) Nobis, M.; Driessen-Holscher, B. Angew. Chem., Int. Ed.
2001, 40, 3983–3985. (f) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675–
704. Selected recent examples: (g) Duan, H.; Sengupta, S.; Petersen, J. L.;
Akhmedov, N. G.; Shi, X. J. Am. Chem. Soc. 2009, 131, 12100–12102.
(h) Liu, X.-Y.; Che, C.-M. Org. Lett. 2009, 11, 4204–4207. (i) Zeng, X.; Frey,
G. D.; Kousar, S.; Bertrand, G. Chem.;Eur. J. 2009, 15, 3056–3060.
(j) Beeren, S. R.; Dabb, S. L.; Messerle, B. A. J. Organomet. Chem. 2009,
694, 309–312. (k) Carney, J. M.; Donoghue, P. J.; Wuest, W. M.; Wiest, O.;
Helquist, P. Org. Lett. 2008, 10, 3903–3906.
€
DOI: 10.1021/jo902293f
r
Published on Web 01/21/2010
J. Org. Chem. 2010, 75, 1277–1280 1277
2010 American Chemical Society

Patil et al.
JOCNote
TABLE 1. Scope with 2-Aminobenzamidesa
entry
1
3
time (h)
yieldb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a, R1 = R2 = R3 = R4 = R5 = R6 = H
1b, R3 = Me, R1 = R2 = R4 = R5 = R6 = H
1c, R2 = Me, R1 = R3 = R4 = R5 = R6 = H
1d, R2 = R4 = Me, R1 = R3 = R5 = R6 = H
1e, R2 = OMe, R1 = R3 = R4 = R5 = R6 = H
1f, R2 = R3 = OMe, R1 = R4 = R5 = R6 = H
1g, R3 = Cl, R1 = R2 = R4 = R5 = R6 = H
1h, R1 = Cl, R2 = R3 = R4 = R5 = R6 = H
1i, R2 = Cl, R4 = Me, R1= R3 = R5 = R6 = H
1j, R2 = Br, R1 = R3 = R4 = R5 = R6 = H
1k, R1 = F, R2 = R3 = R4 = R5 = R6 = H
1l, R6 = Bn, R1 = R2 = R3 = R4 = R5 = H
1m, R5 = Me, R1 = R2 = R3 = R4 = R6 = H
1n, R5 = Bn, R1 = R2 = R3 = R4 = R6 = H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
12
12
12
12
12
12
12
12
12
12
12
24
30
30
96 (94)
97
94 (70)
91 (85)
84
62
95
85
89
97
94 (85)
76
69
60
aReaction conditions: 0.59 mmol of 1, 0.59 mmol of 2a, 5 mol % of catalyst, MeOH (0.4 M), 80 °C. bIsolated yields. cTwo catalysts were employed:
(a) 5 mol % of PtBr2, (b) 5 mol % of Au(PPh3)Cl/10 mol % of AgOTf. Yields in parentheses refer to those obtained by Au catalyst.
Overall, the process can be referred to as formal Markow-
nikoff’s double hydroamination of alkynes. Although
formal or direct hydroalkoxylation-hydroarylation,7
double hydroalkoxylation,8 hydroamination-hydroary-
lation,9 double hydroarylation,10 and hydroamination-
hydroalkoxylation11 of alkynes have recently been
reported, to the best of our knowledge, there is no prece-
dence for the analogues’ double-hydroamination process12
as described in Figure 2.
In order to explore the hypothesis, 2-aminobenzamide 1a
and 4-pentyn-1-ol 2a (n = 1, R7 = R8 = H)13 was treated
with 5 mol % of alkynophilic catalysts14 in various solvents
at variable temperature. We were delighted to find15 that
PtBr2 and Au(PPh3)Cl/AgOTf catalysts in methanol gave
product 3a in 96 and 94% yields, respectively (Table 1,
entry 1).16 Treatment of methyl- and methoxy-substituted
2-aminobenzamide 1b-f with 2a under the platinum cata-
lysis (or gold catalysis wherever specified) gave 3b-f in high
yields (entries 2-6). As can be judged from entries 7-11,
halo-substituted amines can also be tolerated without affect-
ing yields in the formal double-hydroamination of alkynes.
Further investigations on the groups on the amines were then
pursued. The substrate 1l containing a benzyl group on amide
nitrogen when reacted with 2a in the presence of 5 mol % of
PtBr2 for 24 h, afforded tetrahydroquinazolinones 3l
in 76% yield (entries 12). However, the use of methyl and
benzyl groups on the aromatic amine seems to hamper
the reaction rate, and therefore, a longer reaction time was
needed to obtain the products in acceptable yields (entries 13
and 14).
(6) (a) Patil, N. T.; Kavthe, R. D.; Raut, V. S.; Reddy, V. V. N. J. Org.
Chem. 2009, 74, 6315–6318. For other reports on alkyne activation from our
laboratory, see: (b) Patil, N. T.; Konala, A.; Singh, V.; Reddy, V. V. N. Eur.
J. Org. Chem. 2009, 5178–5184. (c) Patil, N. T.; Raut, V. S.; Kavthe, R. D.;
Reddy, V. V. N.; Raju, P. V. K. Tetrahedron Lett. 2009, 50, 6576–6579.
ꢁ
~ ꢁ
(7) (a) Barluenga, J.; Fernandez, A.; Rodrıguez, F.; Fananas, F. J.
´
~
ꢁ
ꢁ
J. Organomet. Chem. 2009, 694, 546–550. (b) Fananas, F. J.; Fernandez, A.;
Cevic, D.; Rodrıguez, F. J. Org. Chem. 2009, 74, 932–934. (c) Bhuvaneswari,
S.; Jeganmohan, M.; Cheng, C.-H. Chem.;Eur. J. 2007, 13, 8285–8293.
´
ꢁ
ꢁ
~ ꢁ
(d) Barluenga, J.; Dieguez, A.; Fernandez, A.; Rodrıguez, F.; Fananas, F. J.
´
Angew. Chem., Int. Ed. 2006, 45, 2091–2093. (e) Hashmi, A. S. K.; Schwartz,
L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285–2288.
ꢁ
ꢁ
ꢁ
(8) (a) Barluenga, J.; Fernandez, A.; Satrustegui, A.; Dieguez, A.;
~ ꢁ
Rodrıguez, F.; Fananas, F. J. Chem.;Eur. J. 2008, 14, 4153–4156.
´
ꢁ
ꢁ
(b) Dieguez-Vazquez, A.; Tzschucke, C. C.; Lam, W. Y.; Ley, S. V. Angew.
Chem., Int. Ed. 2008, 47, 209–212. (c) Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li,
Y. Synlett 2008, 940–944. (d) Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem.,
Int. Ed. 2007, 46, 279–282. (e) Dai, L.-Z.; Qi, M.-J.; Shi, Y.-L.; Liu, X.-G.;
Shi, M. Org. Lett. 2007, 9, 3191–3194. (f) Belting, V.; Krause, N. Org. Lett.
2006, 8, 4489–4492. (g) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907–
^
4910. (h) Genin, E.; Antoniotti, S.; Michelet, V.; Genet, J.-P. Angew. Chem.,
Int. Ed. 2005, 44, 4949–4953. (i) Antoniotti, S.; Genin, E.; Michelet, V.;
Genet, J.-P. J. Am. Chem. Soc. 2005, 127, 9976–9977.
(9) (a) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.;
Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796–10797.
(b) Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129, 12070–
12071. (c) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000–17006.
(10) (a) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur. J.
2007, 13, 1358–1373. (b) Hashmi, A. S. K.; Blanco, M. C. Eur. J. Org. Chem.
2006, 4340–4342. (c) ref 7b.
€
(14) Selected recent reviews on pi-activation chemistry: (a) Furstner, A.
Chem. Soc. Rev. 2009, 38, 3208–3221. (b) Patil, N. T.; Yamamoto, Y. Chem.
Rev. 2008, 108, 3395–3442. (c) Kirsch, S. F. Synthesis 2008, 3183–3204.
(d) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351–3378.
(e) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265. (f) Arcadi,
A. Chem. Rev. 2008, 108, 3266–3325. (g) Bongers, N.; Krause, N. Angew.
(11) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 6646–
€
6647.
Chem., Int. Ed. 2008, 47, 2178–2181. (h) Furstner, A.; Davies, P. W. Angew.
(12) For reactions involving double hydroamination but differing con-
ceptually, see: Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett. 2007, 9, 627–
630.
Chem., Int. Ed. 2007, 46, 3410–3449. (i) Hashmi, A. S. K. Chem. Rev. 2007,
107, 3180–3211. (j) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403.
ꢁ
ꢁ~
(k) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun. 2007, 333–346.
(l) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896–
7936. (m) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200–203.
(n) Nevado, C.; Echavarren, A. M. Synthesis 2005, 167–182.
(13) A cascade process triggered by the cyclization of alkynols for entirely
ꢁ
ꢁ
different transformations, see: (a) Barluenga, J.; Fernandez, A.; Dieguez, A.;
~ ꢁ
´
guez, F.; Fananas, F. J. Chem.;Eur. J. 2009, 15, 11660–11667.
Rodrı
(b) Barluenga, J.; Mendoza, A.; Rodrı
Int. Ed. 2009, 48, 1644–1647. (c) Barluenga, J.; Mendoza, A.; Rodrı
~
ꢁ
´
guez, F.; Fananas, F. J. Angew. Chem.,
guez, F.;
Fananas, F. J. Angew. Chem., Int. Ed. 2008, 47, 7044–7047. (d) Barluenga, J.;
(15) See the Supporting Information for details.
´
(16) Several diamines were reacted with 2a with various catalysts; how-
ever, the desired product could not be obtained. Only 2-aminobenzamides
worked well indicating that the special electronic nature of both the amines is
responsible for this formal double-hydroamination reaction to occur.
~
ꢁ
~ ꢁ
´
Mendoza, A.; Rodrıguez, F.; Fananas, F. J. Chem.;Eur. J. 2008, 14, 10892–
10895.
1278 J. Org. Chem. Vol. 75, No. 4, 2010

Patil et al.
JOCNote
TABLE 2. Scope with Alkynolsa
TABLE 3. PtCl4-Catalyzed Double Hydroamination-Dehydrative
Cyclization Cascade
entry
2
conditions
yielda (%)
1
2
3
4
2a
2h
2a
2h
methanol, 48 h
methanol, 48 h
neat, 8 h
91
80
82
85
neat, 8 h
aIsolated yields.
aReaction conditions: 0.59 mmol 1a, 0.59 mmol 2a, 5 mol % catalyst,
MeOH (0.4 M), 80 °C. bIsolated yields. cTwo catalysts were employed;
a) 5 mol % PtBr2 b) 5 mol % Au(PPh3)Cl/10 mol % AgOTf. Yields
in parentheses refer to those obtained by Au catalyst. d1:1 mixture of
diastereomers. e7:3 mixture of diastereomers. f8:2 mixture of regio-
isomers.
FIGURE 3. Plausible mechanism for double hydroamination of
alkynes.
Next, scope of the reaction with various alkynols was
studied. The alkynols bearing sterically demanding sub-
stituents in the tether such as 2b, 2c, and 2d reacted well
giving corresponding products 3o, 3p, and 3q in high yields
(Table 2, entries 1-3). As can be judged from entries 4-6
that 5-hexyn-1-ols and 6-heptyn-1-ols can also be used as
substrates. Even internal alkynes such as 2h, 2i, and 2j were
tolerated giving the corresponding products in 92%, 80%,
and 85% yields (entries 7-9). However, in the case of 2k, a
longer reaction time was required to get a regioisomeric
mixture of products 3w and 3w0 in 52% yield (entry 10). To
further examine the scope of this process with secondary
alcohols, the substrates 2l and 2m have been synthesized and
their reactivity tested. The products 3x and 3y were obtained
in 66% and 74% yields, respectively (entries 11 and 12).
Interestingly, when 1a was allowed to react with 2a and 2h
in the presence of 10 mol % of PtCl4 in MeOH, double
hydroamination-dehydrative cyclization reaction occurred
to give hexahydropyrrolo[1,2-a]quinazolin-5-one 4a in high
yields (Table 3, entries 1 and 2). The use of methanol as a
solvent was not necessary; under neat conditions, 2a and 2h
gave 4a in 82% and 85% yields, respectively. The structure of
4a was unequivocally determined by single-crystal X-ray
structure analysis.17
A proposed mechanism, which is similar to that reported
previously,6a is outlined in Figure 3. An intramolecular
hydroalkoxylation of alkynol 2a by metals likely occurs to
give 2-methylenetetrahydrofuran 7 through intermediates 5
and 618 (cycle A). Next, imine 10 would be generated from 7
and 1a (cf. 8 and 9) with assistance of the catalyst (cycle B).19
(17) X-Ray crystal structure of 4a is given in Supporting Information.
(18) Hashmi, A. S. K.; Schuster, A. M.; Rominger, F. Angew. Chem., Int.
Ed. 2009, 48, 8247–8249.
(19) The product 3a could not be obtained when 1a and 1-octyne reacted
under standard conditions, clearly indicating that tethered hydroxyl groups
in alkyne is essential for the present reaction to occur.
J. Org. Chem. Vol. 75, No. 4, 2010 1279

Patil et al.
JOCNote
Platinum Catalysis. To a methanol (1.5 mL, 0.40 M) solution
of 2a (50 mg, 0.59 mmol) and 1a (77 mg, 0.59 mmol) in a 2.5 mL
screw-cap vial was added PtBr2 (11 mg, 5 mol %) under nitrogen
atmosphere. The mixture was stirred at 80 °C for the specified
time. Then, the reaction mixture was filtered through a pad of
silica gel eluted with ethyl acetate and the solvent was evapo-
rated under reduced pressure. The residue was purified by flash
silica gel column chromatography using CH2Cl2/MeOH (95/5)
as an eluent to obtain 3a (125 mg, 96%) as a pure compound.
Gold Catalysis. To a methanol (1.5 mL, 0.40 M) solution of
2a (50 mg, 0.59 mmol) and 1a (77 mg, 0.59 mmol) in 2.5 mL
screw-cap vial were added Au(PPh3)Cl (14 mg, 5 mol %) and
AgOTf (15 mg, 10 mol %) under nitrogen atmosphere. The
mixture was stirred at 80 °C for the specified time. Then, the
reaction mixture filtered through a pad of silica gel eluted with
ethyl acetate, and the solvent was evaporated under reduced
pressure. The residue was purified by flash silica gel column
chromatography using CH2Cl2/MeOH (95/5) as an eluent to
obtain 3a (122 mg, 94%) as a pure compound.
FIGURE 4. Possible involvement of iminium ions in the case of
substrate 1m and 1n.
The activation of imine 10 by the co-ordination with metal
catalyst would trigger the cyclization to form intermediate 11.
Protonation of the organometal complex 11 affords final
product 3a with the regeneration of metal catalyst. Since the
formation of intermediate imine 10 would not be possible in
the case of substrate 1m and 1n, an involvement of iminium
ions 12 was proposed (Figure 4).20 The iminium ions 12 would
undergo intramolecular trapping by amide nitrogen followed
by protonation to give 3m/3n with regeneration of catalyst.
To understand the reaction mechanism for the formation
of 4a, the product 3a was reacted under PtCl4 and HCl
catalysts independently. In the case of PtCl4, dehydration
proceeded smoothly to give product 4a (MeOH, 95% and
neat, 87%).14,21 The reaction in the presence of catalytic
amounts of HCl in methanol appeared to be sluggish, and
only 20% of 4a was isolated. Therefore, the involvement of
Bronsted acid (HCl) as a catalyst, generated during the
course of reaction, is unlikely.14
In conclusion, platinum and gold-catalyzed formal
Markownikoff’s double hydroamination of alkynes has been
developed. This method employs 2-aminobenzamides and
alkynols to provide efficient access to tetrahydroquinazoli-
nones. We have also described the possibility toward the
development of double hydroamination-dehydrative cycli-
zation for the synthesis of angularly fused compounds.
Owing to the importance of related compounds in medicinal
chemistry,22 the present method may prove applicable for
generation of many compounds for biological evaluation.23
2-(3-Hydroxypropyl)-2-methyl-1,2,3,4-tetrahydro-4-quinazo-
linone (3a): thick liquid; Rf 0.23 (CH2Cl2/MeOH = 95/5);
1H NMR (500 MHz, DMSO-d6) δ 7.70 (brs, 1H, D2O
exchangeable), 7.58 (d, J = 7.8 Hz, 1H), 7.14 (t, J = 7.8 Hz,
1H), 6.62 (d, J = 7.8 Hz, 1H), 6.56 (t, J = 7.8 Hz, 1H), 3.42 (dd,
J = 6.8, 5.8 Hz, 2H), 1.75-1.65 (m, 2H), 1.64-1.51 (m, 2H),
1.39 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 147.2,
133.2, 127.0, 116.1, 114.0, 113.5, 69.0, 60.9, 38.1, 27.9, 27.1; IR
(film) νmax 3412, 3249, 2928, 1642, 1571, 1522, 1435, 1392, 1274,
1160, 1072, 760, 715, 655 cm-1; HRMS calcd for C12H16N2O2-
Na (Mþ þ Na) 243.1109, found 243.1114.
2-(3-Hydroxypropyl)-2,7-dimethyl-1,2,3,4-tetrahydro-4-quina-
zolinone (3b): thick liquid; Rf 0.34 (CH2Cl2/MeOH = 95/5); 1H
NMR (500 MHz, DMSO-d6) δ 7.78 (s, 1H, D2O exchangeable),
7.50 (d, J = 7.7 Hz, 1H), 7.36 (brs, 1H), 6.41 - 6.39 (m, 2H), 5.90
(brs, 1H, D2O exchangeable), 3.46 (t, J = 5.9 Hz, 2H), 2.24 (s,
3H), 1.73 (m, 2H), 1.64 -1.60 (m, 2H), 1.40 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ 163.2, 147.2, 143.1, 127.2, 117.4, 114.0,
111.2, 69.0, 60.9, 38.1, 27.9, 27.2, 21.4; IR (film) νmax 3420, 2924,
1645, 1531, 1457, 1282, 1025, 999, 825, 765, 627 cm-1; HRMS
calcd for C13H18N2O2 Na (Mþ þ Na) 257.1265, found 257.1272.
Experimental Section
Acknowledgment. We gratefully acknowledge financial
support by the Council of Scientific and Industrial Research,
India. N.T.P. is grateful to Dr. J. S. Yadav, Director,
IICT, and Dr. T. K. Chakraborty, Director, CDRI, for their
support and encouragement. We are indebted to Dr. V. V. N.
Reddy, Head, Org II division, IICT, for providing labora-
tory facilities.
Preparation of 3a as a representative example.
(20) We are thankful to one of the reviewers for pointing out this
information.
(21) The fact that reaction of 3a in methanol at 80 °C or under neat
conditions for 24 h did not give 4a clearly indicates that catalyst is essential
for the reaction.
(22) Reviews: (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62,
9787–9826. (b) Orfi, L.; Waczek, F.; Pato, J.; Varga, I.; Hegymegi-Barako-
nyi, B.; Houghten, R. A.; Keri, G. Curr. Med. Chem. 2004, 11, 2549–2553. (c)
Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005,
61, 10153–10202. (d) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223–246. (e)
Michael, J. P. Nat. Prod. Rep. 2005, 22, 627–646. (f) Michael, J. P. Nat. Prod.
Rep. 2004, 21, 650–668.
Supporting Information Available: All experimental proce-
dures, analytical data, and copies of 1H and 13C NMR spectra
of all newly synthesized products; X-ray structural data (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) (a) Schreiber, S. L. Chem. Eng. News 2003, 81, 51–61. (b) Schreiber,
S. L. Science 2000, 287, 1964–1969.
1280 J. Org. Chem. Vol. 75, No. 4, 2010