Microwave-Promoted Transformations: Fast and Chemoselective N-Acylation of Amino Alcohols Using Catalytic Amounts of Dibutyltin Oxide. Influence of the Power Output and the Nature of the Acylating Agent on the Selectivity

Article abstract of DOI:10.1021/jo9605511

The influence of the nature of the acylating agent and the power output on the chemoselectivity of the microwave-mediated acylation of 1,2- and 1,3-amino alcohols catalyzed by dibutyltin oxide has been studied.The method constitutes an efficient procedure for the selective N-acylation of amino alcohols.

Full text of DOI:10.1021/jo9605511

5264
J . Org. Chem. 1996, 61, 5264-5270
Micr ow a ve-P r om oted Tr a n sfor m a tion s: F a st a n d Ch em oselective
N-Acyla tion of Am in o Alcoh ols Usin g Ca ta lytic Am ou n ts of
Dibu tyltin Oxid e. In flu en ce of th e P ow er Ou tp u t a n d th e Na tu r e
of th e Acyla tin g Agen t on th e Selectivity
Anabel Morcuende, Marta Ors, Seraf´ın Valverde, and Bernardo Herrado´n*
Instituto de Quı´mica Orga´nica General, C. S. I. C., c/ J uan de la Cierva 3, 28006 Madrid, Spain
Received March 25, 1996X
The influence of the nature of the acylating agent and the power output on the chemoselectivity of
the microwave-mediated acylation of 1,2- and 1,3-amino alcohols catalyzed by dibutyltin oxide has
been studied. The method constitutes an efficient procedure for the selective N-acylation of amino
alcohols.
Sch em e 1
Microwave irradiation using either commercial or
domestic microwave ovens is becoming a powerful tech-
nology to accelerate synthetically useful thermal organic
reactions.1 Although the reason of the rate acceleration
is still not clear,2 it is known that the higher the polarity,
the more microwave energy is absorbed by the organic
compound.3 Usually, highly polar solvents have been
employed in microwave-mediated transformations, the
solvent being only a vehicle for the transmission of heat.
Although the technique has been used many times, the
issue of the selectivity has not been addressed.4
power output of the microwave oven, and (c) the nature
of the reactants.
A further improvement of the tin-mediated regioselec-
tive acylation of diols was the discovery that the reaction
could be carried out using catalytic amounts of dibutyltin
oxide in the presence of an acylating agent and a base
(Scheme 1).8 Furthermore, in that paper, we showed that
some of our expectations (namely, a and b indicated
above) were realized.
In our first contribution to the field,5 we used an apolar
solvent (toluene) for the rapid synthesis of dibutyl-
stannylene acetals, finding that this reaction was 50-
100 times faster under microwave irradiation than under
standard thermal conditions. Although stannylene ace-
tals are useful intermediates for the regioselective func-
tionalization of diols, an inconvenient aspect is the long
reaction time required for their formation.6,7 In our first
report,5 we anticipated the possibility of modulating the
selectivity of the process upon changing some experi-
mental parameters, namely, (a) the use of either polar
or nonpolar solvent (that is, absorbing or nonabsorbing
microwave irradiation), (b) the proper selection of the
In order to extend our work further as well as to test
the influence of the acylating agent on the selectivity,
we have applied the catalytic method to the acylation of
amino alcohols. The rationale for the success of the
catalytic method is diagramed in Scheme 2.
The first step of the reaction course would be the
reaction of the amino alcohol A with dibutyltin oxide to
give the N,O-dibutylstannylene acetal B and water. The
reaction of B with the acyl chloride would afford the
intermediate C, which, by reaction with the water
molecule generated in the first step, would liberate the
N-monoacylated amino alcohol D and the intermediate
E. If the transformation is carried out in the presence
of 1 equiv of a base, it would react with E to produce
dibutyltin oxide, which could start a catalytic cycle.
According to this simple idea, it is possible to use a
catalytic amount of dibutyltin oxide to perform the
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) (a) For a recent review, see: Caddick, S. Tetrahedron 1995, 51,
10403-10432. For more recent applications, see: (b) D´ıaz-Ort´ız, A.;
D´ıez-Barra, E.; de la Hoz, A.; Prieto, P.; Moreno, A.; Langa, F.; Prange´,
T.; Neuman, A. J . Org. Chem. 1995, 60, 4160-4166. (c) Raner, K. D.;
Strauss, C. R.; Trainor, R. W.; Thorn, J . S. J . Org. Chem. 1995, 60,
2456-2460. (d) Khadilkar, B. M.; Gaikar, V. G.; Chitnavis, A. A.
Tetrahedron Lett. 1995, 36, 8083-6. (e) Acosta, A.; de la Cruz, P.; de
Miguel, P.; D´ıez-Barra, E.; de la Hoz, A.; Langa, F.; Loupy, A.; Majdoub,
M.; Mart´ın, N.; Sa´nchez, C.; Seoane, C. Tetrahedron Lett. 1995, 36,
2165-2168. (f) Bougrin, K.; Soufiaoui, M. Tetrahedron Lett. 1995, 36,
3683-3686. (g) Pe´ra, E. R.; Marrero, A. L.; Pe´rez, R.; Autie´, M. A.
Tetrahedron Lett. 1995, 36, 1779-1782. (h) Srikrishna, A.; Kumar, P.
P. Tetrahedron Lett. 1995, 36, 6313-6316. (i) Rault, S.; Gillard, A.-C.;
Foloppe, M.-P.; Robba, M. Tetrahedron Lett. 1995, 36, 6673-6674. (j)
Dayal, B.; Rapole, K. R.; Salen, G.; Shefer, S.; Tint, G. S.; Wilson, S.
R. Synlett 1995, 861-862. (k) Alajar´ın, R.; J orda´n, P.; Vaquero, J . J .;
Alvarez-Builla, J . Synthesis 1995, 389-391. (l) Laurent, A.; J acquault,
P.; Di Martino, J .-L.; Hamelin, J . J . Chem. Soc., Chem. Commun. 1995,
1101. (m) Majdoub, M.; Loupy, A.; Pettit, A.; Roudesli, S. Tetrahedron
1996, 52, 617-628.
(6) For some reviews, see: (a) Grindley, T. B. In Synthetic Oligo-
saccharides Indispensable Probes for the Life for the Life Sciences;
Kova´cs, P., ed.; ACS Symposium Series 560; American Chemical
Society: Washington, DC, 1994; pp 51-76. (b) Pereyre, M.; Quintard.
J .-P.; Rahm, A. Tin in Organic Synthesis; Butterworths: London, 1987;
pp 261-285. (c) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-
663.
(7) Usually, dibutylstannylene acetals are prepared by heating at
reflux the diol (or polyol) and an equimolecular amount of dibutyltin
oxide with azeotropic removal of water. The synthesis of dibutyl-
stannylene acetals is faster in methanol, but this solvent must be
removed prior to the addition of some electrophiles. Moreover, the use
of methanol is incompatible with the presence of ester functionalities
in the substrate, see: Chwang, T. L.; Ne´mec, J .; Welch, A. D. J .
Carbohydr. Nucleosides Nucleotides 1980, 7, 159-166.
(8) Herrado´n, B.; Morcuende, A.; Valverde, S. Synlett 1995, 455-
458.
(2) Mingos, M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1-47.
(3) Giguere, R. J . Org. Synth.: Theory Applications 1989, 1, 103-
172.
(4) (a) Previous to our disclosure,5 only one paper, discussing the
effect of power output of the microwave oven on the selectivity of the
sulfonation of naphthalene, had been reported; see: Stuerga, D.;
Gonon, K.; Lallemant, M. Tetrahedron 1993, 49, 6229-6234. (b) For a
recent paper dealing with the effect of the power output on the
stereoselectivity of the Staudinger reaction, see: Bose, A. K.; Banik,
B. K.; Manhas, M. S. Tetrahedron Lett. 1995, 36, 213-216.
(5) Morcuende, A.; Valverde, S.; Herrado´n, B. Synlett 1994, 89-91.
S0022-3263(96)00551-8 CCC: $12.00 © 1996 American Chemical Society

Microwave-Promoted Transformations
J . Org. Chem., Vol. 61, No. 16, 1996 5265
Sch em e 2
Sch em e 3
7, Schemes 3-5),11 we have required N-acyl derivatives
of these amino alcohols (e.g., 3, 6, and 9, Schemes 3-5).12
Since the preparation of these targets using 1 molar equiv
of an acylating agent and different basic catalyst under
standard conditions failed in our hands,13 we have tried
our recently developed method of microwave-mediated
acylation catalyzed by dibutyltin oxide.8 In this paper
we report that the desired transformations of acyclic and
heterocyclic 1,2- and 1,3-amino alcohols are achieved in
just a few minutes with moderate to excellent selectivi-
ties.14
desired transformation, provided that a base is present.
Under the standard thermal conditions for the formation
of the stannylene acetal,6 the non-tin-mediated acylation
catalyzed by the base (to give F ) is faster than the
formation of the N,O-dibutylstannylene acetal; thus no
advantage (that is, nonselective transformation) is at-
tained from the presence of the tin-containing species.
The formation of the N,O-dibutylstannylene acetal under
microwave heating could be so fast that it would favor-
ably compete with the non-tin-mediated acylation; thus,
in principle, it may be possible to carry out selective
acylations using catalytic amounts of dibutyltin oxide.
The advantages of catalytic processes are evident: easier
workup of the reaction and purification of the product
as well as a more convenient method from an environ-
mental point of view.9
In this paper, we report the successful implementation
of this methodology to the chemoselective functionaliza-
tion of 1,2- and 1,3-amino alcohols. Furthermore, the
selectivity of the microwave-mediated acylation of amino
alcohols using dibutyltin oxide as catalyst is dependent
on both the power output of the microwave oven (re-
inforcing our previous finding8) and the nature of the
acylating agent [i.e., our third expectation (c, see above)
has been accomplished]. To the best of our knowledge,
this is the first time that a chemoselective acylation of
amino alcohols through N,O-stannylene acetals is re-
ported.10
The microwave-promoted acylation of 2-(hydroxy-
methyl)piperidine (1) catalyzed by dibutyltin oxide
(Scheme 3) has been carried out at various power outputs
of the microwave oven and using differently substituted
(11) Ors, M.; Morcuende, A.; J ime´nez-Vacas, M.-I.; Valverde, S.;
Herrado´n, B. Synlett 1996, 449-451.
(12) For some recent synthetic applications of derivatives of 2-(hy-
droxymethyl)piperidine, see: (a) Kozikowski, A. P.; Fauq, A. H.; Miller,
J . H.; McKinney, M. Bioorg. Med. Chem. Lett. 1992, 2, 797-802. (b)
Romo, D.; Meyer, S. D.; J ohnson, D. D.; Schreiber, S. L. J . Am. Chem.
Soc. 1993, 115, 7906-7. (c) Gurjar, M. K.; Ghosh, L.; Syamala, M.;
J ayasree, V. Tetrahedron Lett. 1994, 35, 8871-8872. (d) Hart, D. J .;
Wu, W.-L.; Kozikowski, A. P. J . Am. Chem. Soc. 1995, 117, 9369-
9370. (e) For a recent application of derivatives of 3-(hydroxymethyl)-
piperidine, see: Wirz, B.; Walther, W. Tetrahedron: Asymmetry 1992,
3, 1049-1054. For recent applications of derivatives of 2-(2-hydroxy-
ethyl)piperidine, see: (f) Ito, M.; Maeda, M.; Kibayashi, C. Tetrahedron
Lett. 1992, 33, 3765-3768. (g) Ina, H.; Ito, M.; Kibayashi, C. J . Org.
Chem. 1996, 61, 1023-1029. (h) Amino alcohol derivatives are useful
auxiliaries for organic synthesis, see: Tillyer, R. D.; Boudreau, C.;
Tschaen, D.; Dolling, U.-H.; Reider, P. J . Tetrahedron Lett. 1995, 36,
4337-4340 and references cited therein.
(13) (a) Several bases (Et3N, pyridine, NaHCO3) and solvents
(CH2Cl2, pyridine, dioxane/water) have been used to try to prepare 3
and 6. Beside the desired N-acyl derivatives (compounds 3 and 6),
substantial amounts of N,O-diacylated products (2 and 5, respectively)
and starting amino alcohols (1 and 4, respectively) have been isolated.
One of the experimental difficulties we have observed with the isolation
of the relatively polar N-acylderivatives of 2- and 3-(hydroxymethyl)-
piperidine is that they are quite water soluble. The tin-mediated
procedure avoids any water treatment. (b) We have also prepared the
N,O-diacyl derivatives (2 and 5) using excess reagents. The selective
ester hydrolyses (LiOH/H2O/MeOH/THF and K2CO3/MeOH) of 2 and
5 have been tried; but we have always obtained mixtures of amino
alcohols (1 and 4), monoacyl derivatives (3 and 6), and diacyl deriva-
tives (2 and 5). It seems that N- to O-acyl migration is very easy in
these systems, which would explain the lack of selectivity in these
transformations. (c) For a recent report on easy N- to O-acyl migration
in amino alcohol derivatives, see: Myers, A. G.; Gleason, J . L.; Yoon,
T. J . Am. Chem. Soc. 1995, 117, 8488-8489. (d) For a recent two-step
synthesis (N,O-diacylation and ester hydrolysis) of amino alcohols (with
moderate overall yield), see: Chiacchio, U.; Casuscelli, F.; Corsaro, A.;
Librrando, V.; Rescifina, A.; Romeo, R.; Romeo, G. Tetrahedron 1995,
51, 5689-5700.
Resu lts a n d Discu ssion
In the course of our work on the chemoenzymatic
synthesis of chiral derivatives of piperidine (e.g., 1, 4, and
(9) The advantages of catalytic processes have been discussed
elsewhere, see: Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29,
1320-1367.
(10) N,O-Stannylene acetals have been used for the synthesis of
diester diamides macrocycles through the N,O-diacylation, see: Mac-
cioni, E.; Sinico, C. J . Heterocycl. Chem. 1994, 31, 1673-1679.

5266 J . Org. Chem., Vol. 61, No. 16, 1996
Morcuende et al.
Ta ble 1. Resu lts of th e Micr ow a ve-Med ia ted Acyla tion of th e Am in o Alcoh ols 1, 4, 7, 10, 13, a n d 16 Ca ta lyzed by
Dibu tyltin Oxid e (Sch em es 3-6)a
starting
material
power
output (W)
diacyl derivative
(% yield)
monoacyl derivative
(% yield)
entry
acyl chloride
PhCOCl
PhCOCl
PhCOCl
PhCOCl
selectivityb
1
2
3
4
1
1
1
1
100
445
645
815
2a (5)
2a (5)
2a (11)
2a (14)
3a (81)
3a (93)
3a (83)
3a (78)
16
19
8
6
5
6
7
8
1
1
1
1
2-MeC6H4COCl
2-MeC6H4COCl
2-MeC6H4COCl
2-MeC6H4COCl
100
445
645
815
2b (<2)
2b (<2)
2b (<2)
2b (<2)
3b (79)
3b (69)
3b (93)
3b (85)
>40
>35
>47
>43
9
10
11
12
13
1
1
1
1
1
4-MeC6H4COCl
4-MeC6H4COCl
4-MeC6H4COCl
4-MeC6H4COCl
4-MeC6H4COCl
100
250
445
645
815
2c (<2)
2c (4)
2c (6)
2c (8)
2c (8)
3c (91)
3c (75)
3c (82)
3c (69)
3c (56)
>46
19
14
9
7
14
15
16
1
1
1
4-tBuC6H4COCl
4-tBuC6H4COCl
4-tBuC6H4COCl
100
445
815
2d (4)
2d (<2)
2d (8)
3d (61)
3d (86)
3d (66)
15
>43
8
17
18
19
20
1
1
1
1
4-MeOC6H4COCl
4-MeOC6H4COCl
4-MeOC6H4COCl
4-MeOC6H4COCl
100
250
645
815
2e (<2)
2e (6)
2e (7)
2e (8)
3e (79)
3e (80)
3e (65)
3e (60)
>40
13
9
7
21
22
23
24
1
1
1
1
4-NO2C6H4COCl
4-NO2C6H4COCl
4-NO2C6H4COCl
4-NO2C6H4COCl
100
250
445
645
2f (18)
2f (24)
2f (18)
2f (22)
3f (52)
3f (43)
3f (37)
3f (51)
3
2
2
2
25
26
27
1
1
1
3-NO2C6H4COCl
3-NO2C6H4COCl
3-NO2C6H4COCl
250
445
815
2g (21)
2g (13)
2g (11)
3f (47)
3f (65)
3f (51)
2
5
5
28
29
30
31
4
4
4
4
PhCOCl
PhCOCl
PhCOCl
PhCOCl
100
250
445
815
5 (17)
5 (9)
5 (7)
6 (58)
6 (46)
6 (73)
6 (83)
3
5
10
8
5 (11)
32
33
34
35
36
7
7
7
7
7
PhCOCl
PhCOCl
PhCOCl
PhCOCl
PhCOCl
100
250
445
645
815
8 (12)
8 (8)
8 (7)
8 (11)
8 (19)
9 (68)
9 (80)
9 (74)
9 (82)
9 (76)
6
10
11
7
8
37
38
39
40
10
10
10
10
PhCOCl
PhCOCl
PhCOCl
PhCOCl
100
250
445
815
11(29)
11 (22)
11 (13)
11 (23)
12 (15)
12 (38)
12 (46)
12 (36)
<1
2
3
2
41
42
43
13
13
13
PhCOCl
PhCOCl
PhCOCl
100
645
815
14 (4)
14 (6)
14 (6)
15 (68)
15 (87)
15 (91)
17
14
15
44
45
46
16
16
16
PhCOCl
PhCOCl
PhCOCl
100
645
815
17 (14)
17 (10)
17 (15)
18 (18)
18 (65)
18 (41)
1
6
3
a
All the reactions have been carried out for an overall heating time of 9 mins, as indicated in the Experimental Section. All the yields
b
refer to isolated, chromatographically homogeneous compounds. See ref 14.
benzoyl chlorides as acylating agents. For the sake of
comparison, all the reactions have been performed under
identical conditions using toluene as solvent, and the
procedure has not been optimized. The results of the
acylations of 1 are indicated in entries 1-27 of Table 1.
The ratio of monoacyl derivative 3 to diacyl derivative
2 (indicated as selectivity14 in Table 1) probably reflects
the competition between the two possible acylation
routes: through the intermediary of the N,O-stannylene
acetals B, resulting in chemoselective acylation to D (e.g.,
3), and the direct, nonselective, acylation to give the
diacyl derivative F (e.g., 2) (see Scheme 2).15
Thus, it is expected that the reactivity of the acylating
agent influences the selectivity of the transformation. It
is observed that the chemoselectivities of the acylations
with the less reactive and sterically undemanding acyl
chlorides, namely, 4-methylbenzoyl chloride (entries
9-13, Table 1) and 4-methoxybenzoyl chloride (entries
17-20), decrease on augmenting the power output. The
amides 3c and 3e are obtained in excellent selectivities
and yields when operating at low power output (entries
9 and 17, respectively). On the other hand, the reaction
(14) The term selectivity indicated in Table 1 refers to the ratio of
isolated yields of monoacyl to diacyl compounds. Because the 1H and
13C NMR spectra of these compounds are complex (due to conforma-
tional equilibria), it is difficult to determine accurately the proportion
of the products of the transformation. Thus, the values of selectivity
indicated in Table 1 are only approximate, although careful analysis
of 1H- and 13C-NMR spectra of crude reaction products corroborate (in
a semiquantitative manner) the values of selectivity indicated in Table
1.
(15) The product of the O-chemoselective monoacylation has not
been detected in any case examined. The only reaction products have
been the N-monoacyl derivatives and the N,O-diacyl derivatives and,
in some experiments, starting amino alcohol. The latter has not been
isolated and only detected by TLC and 1H- and 13C-NMR spec-
troscopies.

Microwave-Promoted Transformations
J . Org. Chem., Vol. 61, No. 16, 1996 5267
Sch em e 4
Sch em e 6
Sch em e 5
benzoylation of 1. This fact probably reflects the higher
difficulty of formation of the six-membered N,O-stan-
nylene acetal as compared with the analogous five-
membered ring.17 In both cases, the selectivity is de-
pendent on the power output of the microwave oven; it
is observed that the selectivity increases with the power
output up to a maximum (entries 30, 33 and 34) and then
it decreases. Although the higher selectivity14 in the
benzoylation of 4 is achieved at 445 W (entry 30), the
higher isolated yield of monoacylated product 6 is ob-
tained at 815 W (entry 31), which indicates a higher
conversion degree under this experimental condition.
Similar behavior is observed in the benzoylation of the
1,3-amino alcohol 7, the higher selectivity is achieved at
250 and 445 W (entries 33 and 34), but the higher
isolated yield of the amide 9 is achieved at 645 W (entry
35). Although the selectivity is not excellent, it allows
for preparation of the N-acyl derivatives 6 and 9 in
synthetically useful yields (entries 30, 31, 33, and 35).
The selectivities and conversions of the acylations of
the acyclic amino alcohols 10, 13, and 16 (Scheme 6) are,
in general, less dependent on the power output than those
of the cyclic amino alcohols. It seems that both the
selectivities and the conversions are mainly dependent
on the solubility of the starting amino alcohol in toluene.
Thus, the benzoylation of 2-aminoethanol at any power
output (entries 37-40, Table 1) shows poor selectivity
and overall yield; and even at 100 W, the main product
is the dibenzoyl derivative 11. Better selectivities are
achieved when the alkyl substitution of the substrate
increases. Hence, the acylation of the 1,2-amino alcohol
13 (entries 41-43) is good at any power output tested; a
higher conversion is obtained at maximum power output,
which allows one to obtain a synthetically useful yield of
the monoacyl derivative 15 (entry 43). An intermediate
situation is achieved using 3-aminopropanol (16) as
substrate (entries 44-46): the selectivity is from low to
moderate, depending on the power output.
of 1 with 4-nitrobenzoyl chloride (entries 21-24, Table
1) shows poor selectivity at any power output tested. The
same behavior, although with a slightly better selectivity,
is observed when 3-nitrobenzoyl chloride is the acylating
agent (entries 25-27), as expected from their respective
reactivities versus nucleophiles. The selectivity of the
acylation of the amino alcohol 1 using 4-tert-butylbenzoyl
chloride is also dependent on the power output (entries
14-16), ranging from moderate to excellent (entry 15).
The reactions with the sterically demanding, relatively
unreactive, 2-methylbenzoyl chloride (entries 5-8) show
good selectivity at all the power outputs examined, and
the only difference between these experiments is the
isolated yield of the monoacyl derivative 3b. When
benzoyl chloride is the acylating agent (entries 1-4), an
intermediate situation is achieved: the selectivity is not
so high as that of the acylation with electron-rich aroyl
chlorides (entries 5-20) and it is higher than that of the
acylation with nitrosubstituted aroyl chlorides (entries
21-27); the best selectivity and yield of 3a is achieved
at 445 W (entry 2).16
The method has also been applied to the benzoylation
of the cyclic 1,3-amino alcohols 4 (Scheme 4) and 7
(Scheme 5), the acyclic 1,2-amino alcohols 10 and 13, and
the acyclic 1,3-amino alcohol 16 (Scheme 6). The results
are indicated in Table 1 (entries 28-31, 32-36, 37-40,
41-43, and 44-46, respectively).
It is found that the selectivities of the acylations of the
1,3-amino alcohols 4 (entries 28-31, Table 1) and 7
(entries 32-36) are lower than the selectivity of the
Con clu sion s
Summarizing, it is demonstrated that the selectivity
of microwave-mediated acylations depends on both the
power output and the nature of the acylating agent. This
result complements our earlier findings.8 We now have
several experimental parameters to modify in order to
achieve high selectivity (experimental modulation of the
selectivity) in microwave-mediated transformations.
(16) Previously, we reported8 some preliminary results on the
benzoylation of 1 using a different microwave oven operating at
different power outputs (720, 465, and 305). Although the selectivities
of our preliminary results were quite similar to that reported in the
present paper, we observed some decomposition in some of the
experiments reported previously. Now we have worked in a more
concentrated solution (see Experimental Section), which seems fun-
damental to avoid decomposition of very polar substrates under
microwave heating.
(17) Munavu, R. M.; Szmant, H. H. J . Org. Chem. 1976, 41, 1832-
1836.

5268 J . Org. Chem., Vol. 61, No. 16, 1996
Morcuende et al.
cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.96 (broad d, J ) 7.3,
It is also noteworthy that, although the transforma-
tions reported in the present paper have not been
optimized, excellent selectivities and conversions have
been achieved in the chemoselective transformations of
these amino alcohols (see entries 7, 9, 15, 17, 30, 33, and
43. Table 1), which has been difficult to achieve by
conventional methods.13a,d Also the short reaction time
is remarkable, which is important in some synthetic
problems, for instance, for the preparation of isotopically
labeled molecules,18 as well as the fact that the reactions
are carried out using catalytic amounts of dibutytin
oxide,19 avoiding any water treatment, which supposes
an additional advantage when working with water-
sensitive and/or water-soluble compounds.
2H), 7.48 (distorted dt, J ) 1.3, 7.3, 1H), 7.36 (m, 2H), 7.29-
7.19 (m, 5H), 4.85 (very broad s, 1H), 4.69 (distorted t, J )
10.1, 1H), 4.28 (dd, J ) 5.8, 11.1, 1H), 3.90 (very broad s, 1H),
3.06 (distorted t, J ) 12.9, 1H), 1.73-1.40 (m, 6H); 13C NMR
(50.3 MHz, CDCl3) δ 171.0 (s), 166.0 (s), 136.3 (s), 132.8 (d),
129.7 (s), 129.5 (d), 129.1 (d, 2C), 128.1 (d, 2C), 127.7 (d, 2C),
126.4 (d, 2C), 62.0 (t), 49.6 (d), 41.2 (t), 25.7 (t), 25.5 (t), 19.5
(t); MS (EI) m/z 323 (M+, 0.4), 218 (0.9), 201 (2.8), 188 (37.7),
173 (3.9), 172 (2.3), 122 (3.9), 105 (100), 77 (29.9). Anal. Calcd
for C20H21NO3: C, 74.27; H, 6.55; N, 4.33. Found: C, 73.89;
H, 6.57; N, 4.21.
N-Ben zoyl-2-(h yd r oxym eth yl)p ip er id in e (3a ): mp 93-5
°C; IR (KBr) 3430, 2920, 1610, 1435, 1380, 1290, 1080, 1070,
1050, 790, 745, 710 cm-1; H NMR (200 MHz, CDCl3) δ 7.33
1
(m, 5H), 4.45 (very broad s, 1H), 3.88 (dd, J ) 9.4, 11.1, 1H),
3.58 (dd, J ) 5.8, 11.1, 1H), 3.01-2.83 (m, 2H), 1.61-1.34 (m,
6H); 13C NMR (50.3 MHz, CDCl3) δ 171.9 (s), 136.4 (s), 129.0
(d), 128.0 (d, 2C), 126.6 (d, 2C), 60.5 (t), 52.8 (very broad d),
41.8 (very broad t), 25.4 (t), 25.2 (t), 19.3 (t); MS (EI) m/z 219
(M+, 0.4), 189 (8.4), 188 (52.5), 149 (3.0), 106 (11.6), 105 (100),
85 (13.8), 84 (18.2), 83 (22.7), 77 (49.7), 51 (10.5). Anal. Calcd
for C13H17NO2: C, 71.19; H, 7.82; N, 6.39. Found: C, 70.89;
H, 7.81; N, 6.30.
Work is in progress in order to understand the origin
of the selectivity in microwave-mediated transformations,
to find new sources of selectivity of the dibutyltin oxide-
catalyzed process, and to apply this methodology to
further synthetic issues.
Exp er im en ta l Section 20
N-(2-Meth ylben zoyl)-2-[[(2-m eth ylben zoyl)oxy]m eth -
yl]p ip er id in e (2b): mp 93-6 °C; IR (KBr) 2935, 1720, 1630,
Gen er a l P r oced u r e for th e Acyla tion of Am in o Alco-
h ols Ca ta lyzed by Dibu tyltin Oxid e u n d er Micr ow a ve
Ir r a d ia tion . A hetereogeneous mixture of the starting amino
alcohol (either 1, 4, 7, 10, 13, or 16),21 dibutyltin oxide (0.2
molar equiv), an acyl chloride chloride (1.05 molar equiv) (as
indicated in Table 1), and triethylamine (1.0 mol equiv) in dry
toluene (10-15 mL/mmol of starting amino alcohol) is heated
in a microwave oven22 at the power output indicated in Table
1 for 1 min.23 After this heating, an interval of 30 s is allowed
in order to avoid excessive evaporation of the solvent. This
protocol is repeated until reaching an overall heating time of
9 min. The solid residue (if any)24 is filtered off and washed
with a small amount of CH2Cl2. The solvents are removed at
room temperature under vacuum to give a crude material
which is carefully analyzed by 1H- and 13C-NMR spectroscopies
in order to determine the approximate ratio of acylated
products.14 The products are purified by flash chromatogra-
phy25 using hexane/ethyl acetate mixtures as eluent, to give
the pure compounds in the isolated yields indicated in Table
1. The spectroscopic (J values in hertz) and analytical data
of all the products are indicated below.
1
1428, 1310, 1265, 1140, 1085, 750 cm-1; H NMR (300 MHz,
CDCl3) (mixture of rotamers) δ 7.98 (d, J ) 7.6, 1H), 7.39 (t,
J ) 7.4, 2H), 7.20-6.85 (m, 13H), 5.41 (broad, s, 1H), 4.92-
4.28 (m, 6H), 4.15-3.80 (m, 1H), 3.35 (broad d, J ) 12.9, 1H),
3.16 (broad t, J ) 12.9, 1H), 2.63 (s, 6H), 2.55 (m, 1H), 2.35 (s,
3H), 2.07 (s, 3H), 2.00-1.35 (m, 11H); 13C NMR (50.3 MHz,
CDCl3, at 298 K) (mixture of rotamers) δ 170.1, 170.0, 166.5,
139.8, 136.2, 133.3, 131.5, 131.0, 130.3, 129.9, 129.6, 128.6,
127.9, 127.8, 125.8, 125.1, 124.8, 61.2, 46.1, 45.9, 42.8, 41.8,
36.5, 26.6, 26.3, 25.8, 25.4, 25.1, 24.9, 21.2, 19.1, 18.5, 18.1;
MS (EI) m/z 351 (M+, 0.2), 202 (21.7), 188 (3.9), 120 (11.3),
119 (100), 105 (13.7), 91 (35.8), 77 (6.0), 65 (11.7), 55 (6.0).
Anal. Calcd for C22H25NO3: C, 75.18; H, 7.17; N, 3.99.
Found: C, 74.82; H, 7.27; N, 4.06.
2-(Hydr oxym eth yl)-N-(2-m eth ylben zoyl)piper idin e (3b):
mp 108-111 °C; IR (KBr) 3385, 2940, 1615, 1600, 1452, 1280,
1
1075, 785 cm-1; H NMR (300 MHz, CDCl3) (as a mixture of
rotamers) δ 7.28-7.14 (m, 5H), 4.95 (broad s, 1H), 4.70 (broad,
minor rotamer), 3.96-3.75 (m, 2H), 3.70-3.35 (broad m, minor
rotamer), 3.31 (broad m, 1H), 3.07 (distorted t, J ) 11.7, 1H),
2.83-2.68 (m, 1H), 2.36 (s, minor rotamer), 2.32 (s, 3H), 1.90-
1.37 (m, 6H); 13C NMR (50.3 MHz, CDCl3) (as a mixture of
rotamers) δ 171.8, 171.2, 170.8, 136.5, 136.4, 134.1, 133.4,
130.7, 130.1, 129.7, 128.4, 128.1, 126.5, 125.6, 125.0, 60.8, 59.5,
55.9, 55.2, 50.2, 43.6, 42.6, 36.9, 29.4, 26.0, 25.3, 24.7, 19.3,
18.7; MS (EI) m/z 233 (M+, 0.15), 202 (14.7), 120 (10.1), 119
N-Ben zoyl-2-[(ben zoyloxy)m eth yl]piper idin e (2a): thick
oil; IR (neat) 2940, 1720, 1630, 1445, 1425, 1270, 1115, 710
(18) Zijlstra, S.; de Groop, T. J .; Kok, L. P.; Visser, G. M.; Vaalburg,
W. J . Org. Chem. 1993, 58, 1643-1645.
(19) Blank experiments, in the absence of dibutyltin oxide, showed
that the procedure is catalytic. Thus, for example, the reaction of 1
with 4-methylbenzoyl chloride (1.05 molar equiv) and triethylamine
(1.0 molar equiv) under microwave irradiation at 100 W, in the
conditions reported in the Experimental Section, gave 11% of 2c and
21% of 3c in isolated yield (compare with entry 9, Table 1). On the
other hand, the same reaction with 4-nitrobenzoyl chloride (1.05 molar
equiv) at 250 W afforded 21% of 2f and 34% of 3f in isolated yield,
which it is quite close to the result obtained in the presence of Bu2SnO
(compare with entry 22), which reinforces our hypothesis, indicated
above, that the non-tin-mediated reaction with electron-poor acyl
chloride competes with the formation of the N,O-stannylene acetals
(see Scheme 2).
(100), 91 (27.7), 65 (12.9), 55 (10.7). Anal. Calcd for C14H19
-
NO2: C, 72.06; H, 8.21; N, 6.01. Found: C, 72.17; H, 8.33; N,
5.91.
N-(4-Meth ylben zoyl)-2-[[(4-Meth ylben zoyl)oxy]m eth -
yl]p ip er id in e (2c): mp 123-6 °C; IR (KBr) 1725, 1625, 1430,
1
1285, 1275, 1125, 758, 752 cm-1; H NMR (300 MHz, CDCl3)
δ 7.90 (d, J ) 8.0, 2H), 7.24 (d, J ) 8.0, 2H), 7.19 (d, J ) 7.8,
2H), 7.11 (d, J ) 7.8, 2H), 4.95 (very broad s, 1H), 4.71
(distorted t, J ) 10.0, 1H), 4.32 (dd, J ) 5.8, 11.2, 1H), 4.05
(very broad s, 1H), 3.10 (distorted t, J ) 12.5, 1H), 2.39 (s,
3H), 2.33 (s, 3H), 1.90-1.60 (m, 5H), 1.50 (m, 1H); 13C NMR
(50.3 MHz, CDCl3) δ 171.2 (s), 166.1 (s), 143.5 (s), 139.1(s),
133.3 (s), 129.5 (d, 2C), 128.9 (d, 2C), 128.7 (d, 2C), 126.9 (s),
126.5 (d, 2C), 61.8 (t), 49.7 (broad d), 41.5 (broad t), 25.5 (broad
t, 2C), 21.4 (q), 21.1 (q), 19.5 (t); MS (EI) m/z 351 (M+, 0.2),
215 (1.7), 202 (20.5), 129 (100), 91 (22.2), 65 (9.5), 55 (4.8).
Anal. Calcd for C22H25NO3: C, 75.18; H, 7.17; N, 3.99.
Found: C, 74.91; H, 7.43; N, 3.92.
(20) For
a general experimental procedure, see: Herrado´n, B.;
Valverde, S. Tetrahedron: Asymmetry 1994, 5, 1479-1500. Unless
otherwise indicated, all the NMR spectra were taken at 313 K.
(21) All the reactions were carried out at 1-5 mmol scale. The
results are reproducible. Our limitation on scaling up further the
reactions is the size of the microwave oven, which is compensated by
the short reaction time.
(22) A Balay Model W-2235 microwave oven, operating at five
different power outputs, as indicated in Table 1 [calibrated according
to Watkins, K. W. J . Chem. Ed. 1983, 60, 1043-1044], was used.
(23) Previously5 we carried out the reactions in an open Erlenmeyer
flask. We have improved the glassware equipment by using an
Erlenmeyer flask capped with an open spiralic stopper. Using this
device, less evaporation of the solvent is observed.
2-(Hydr oxym eth yl)-N-(4-m eth ylben zoyl)piper idin e (3c):
mp 105-8 °C; IR (KBr) 3390, 2945, 1610, 1435, 1375, 1270,
1
1050, 840, 835, 760 cm-1; H NMR (300 MHz, CDCl3) δ 7.32
(24) This solid residue consists mainly of unreacted starting mate-
rial.
(25) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
(dd, J ) 1.7, 8.1, 2H), 7.20 (broad d, J ) 8.1, 2H), 4.63 (broad
s, 1H), 4.00-3.80 (very broad m, 1H), 3.96 (distorted t, J )
11.0, 1H), 3.70 (dd, J ) 5.1, 11.0, 1H), 3.06 (broad m, 1H),

Microwave-Promoted Transformations
J . Org. Chem., Vol. 61, No. 16, 1996 5269
2.38 (s, 3H), 1.72-1.54 (m, 6H); 13C NMR (50.3 MHz, CDCl3)
δ 172.4 (s), 139.2 (s), 133.5 (s), 128.8 (d, 2C), 126.6 (d, 2C),
60.8 (t), 53.1 (broad d), 41.9 (broad t), 25.5 (t), 25.3 (t), 21.1
(q), 19.5 (t); MS (EI) m/z 233 (M+, 0.1), 202 (18.6), 120 (11.1),
43.7 (broad t), 25.5 (broad t, 2C), 19.5 (t); MS (EI) m/z 413
(M+, 0.2), 263 (1.2), 246 (2.7), 234 (15.1), 233 (100), 218 (6.9),
217 (4.5), 150 (88.1), 104 (16.6). Anal. Calcd for C20H19N3O7:
C, 58.09; H, 4.64; N, 10.17. Found: C, 58.32; H, 4.75; N, 10.21.
2-(Hyd r oxym eth yl)-N-(4-n itr oben zoyl)p ip er id in e (3f):
mp 153-4 °C; IR (KBr) 3410, 1620, 1600, 1525, 1445, 1350,
1060, 860, 715 cm-1; 1H NMR (300 MHz, DMSO-d6, at 318 K)
δ 8.27 (dt, J ) 8.8, 2.1, 2H), 7.64 (dt, J ) 8.8, 2.1, 2H), 4.74 (t,
J ) 5.5, 1H), 4.35 (very broad s, 1H), 3.67 (m, 1H), 3.45 (broad
s, 1H), 2.95 (broad s, 1H), 1.80-1.30 (m, 6H); 13C NMR (50.3
MHz, DMSO-d6 at 353 K) δ 167.8 (s), 147.3 (s), 143.3 (s), 127.6
(d, 2C), 123.1 (d, 2C), 58.7 (t), 53.4 (broad d), 39.0 (broad t),
24.8 (t), 24.7 (t), 18.7 (t); MS (EI) m/z 264 (M+, 0.2), 234 (13.5),
233 (74.7), 159 (3.2), 151 (14.4), 150 (100), 134 (5.6), 120 (15.7),
104 (43.0), 92 (15.6), 84 (8.3), 76 (31.5), 55 (13.0). Anal. Calcd
for C13H16N2O4: C, 59.09; H, 6.11; N, 10.60. Found: C, 59.26;
H, 5.98; N, 10.32.
119 (100), 91 (25.0), 65 (10.7), 55 (5.0). Anal. Calcd for C14H19
-
NO2: C, 72.06; H, 8.21; N, 6.01. Found: C, 72.30; H, 8.05; N,
5.90.
N-(4-ter t-Bu tylben zoyl)-2-[[(4-ter t-bu tylben zoyl)oxy]-
m eth yl]p ip er id in e (2d ): mp 133-4 °C; IR (KBr) 2970, 1725,
1630, 1610, 1435, 1288, 1278, 1125, 855, 780, 710 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 7.95 (broad d, J ) 8.6, 2H), 7.46 (t,
J ) 2.0, 1H), 7.43 (t, J ) 1.8, 1H), 7.34-7.31 (m, 2H), 7.25-
7.22 (m, 2H), 5.00 (very broad s, 1H), 4.71 (distorted t, J )
10.0, 1H), 4.36 (dd, J ) 6.0, 11.3, 1H), 4.09 (very broad s, 1H),
3.12 (broad t, J ) 14.1, 1H), 1.80-1.60 (m, 6H), 1.34 (s, 9H),
1.30 (s, 9H); 13C NMR (50.3 MHz, CDCl3, at 298 K) δ 171.5
(s), 166.5 (s), 156.8 (s), 152.5 (s), 133.5 (s), 129.7 (d, 2C), 127.0
(s), 126.5 (d, 2C), 125.4 (d, 2C), 125.3 (d, 2C), 62.1 (t), 35.1 (s),
34.7 (s), 31.2 (q, 3C), 31.1 (q, 3C), 26.0 (t), 25.8 (t), 19.8 (t);26
MS (EI) m/z 435 (M+, 0.02), 202 (4.5), 201 (4.7), 189 (10.1),
188 (66.5), 161 (3.3), 105 (100), 77 (34.7). Anal. Calcd for
C28H37NO3: C, 77.19; H, 8.57; N, 3.22. Found: C, 77.01; H,
8.82; N, 3.29.
N-(3-Nit r ob en zoyl)-2-[[(3-n it r ob en zoyl)oxy]m et h yl]-
p ip er id in e (2g): mp 113-7 °C; IR (KBr) 1730, 1640, 1615,
1
1535, 1350, 1240, 1210, 1125, 720 cm-1; H NMR (300 MHz,
CDCl3) δ 8.82 (broad s, 1H), 8.42 (ddd, J ) 1.1, 2.3, 8.2, 1H),
8.36 (broad d, J ) 7.8, 1H), 8.24 (ddd, J ) 1.3, 2.3, 8.1, 1H),
8.12 (t, J ) 1.9, 1H), 7.64 (m, 2H), 7.57 (t, J ) 7.9, 1H), 5.10
(very broad m, 1H), 4.91 (dd, J ) 9.5, 11.4, 1H), 4.42 (m, 1H),
N -(4-t er t -Bu t ylb e n zoyl)-2-(h yd r oxym e t h yl)p ip e r i-
d in e (3d ): mp 114-6 °C; IR (KBr) 3390, 2950, 2860, 1610,
3.85 (very broad m, 1H), 3.26 (m, 1H), 2.00-1.50 (m, 6H); 13
C
1
1440, 1280, 1120, 1065, 1050, 1015, 845 cm-1; H NMR (300
NMR (50.3 MHz, CDCl3) δ 166.7 (s), 164.3 (s), 148.4 (s), 148.1
(s), 137.8 (s), 135.2 (d), 132.6 (d), 131.4 (s), 129.9 (d), 129.8
(d), 127.6 (d), 124.6 (d), 124.3 (d), 121.9 (d), 63.0 (t), 49.5 (broad
d), 42.5 (broad t), 25.8 (t), 25.6 (t), 19.6 (t); MS (EI) m/z 414
(M + 1, 10.2), 413 (M+, 0.4), 247 (5.1), 246 (6.3), 243 (8.7), 234
(15.6), 233 (100), 151 (7.8), 150 (84.0), 104 (10.8). Anal. Calcd
for C20H19N3O7: C, 58.09; H, 4.64; N, 10.17. Found: C, 58.15;
H, 4.74; N, 10.22.
MHz, CDCl3) δ 7.36 (m, 4H), 4.60 (very broad s, 1H), 3.91
(broad t, J ) 9.9, 1H), 3.66 (broad s, 1H), 3.20-2.60 (very broad
s, 2H), 1.70-1.43 (m, 6H), 1.31 (s, 9H); 13C NMR (50.3 MHz,
CDCl3) δ 172.1 (s), 152.2 (s), 133.4 (s), 126.6 (d, 2C), 124.9 (d,
2C), 60.6 (t), 50.3 (broad d), 40.2 (broad t), 34.4 (s), 30.9 (q,
3C), 25.4 (t), 25.2 (t), 19.4 (t); MS (EI) m/z 275 (M+, 0.2), 245
(4.6), 244 (21.7), 202 (3.2), 162 (14.7), 161 (100), 146 (7.5), 145
(3.1), 119 (14.9), 118 (9.3), 115 (6.2), 91 (8.0), 55 (5.1). Anal.
Calcd for C17H25NO2: C, 74.13; H, 9.16; N, 5.09. Found: C,
73.89; H, 8.99; N, 4.82.
2-(Hyd r oxym eth yl)-N-(3-n itr oben zoyl)p ip er id in e (3g):
mp 116-8 °C; IR (KBr) 3390, 2950, 1625, 1530, 1480, 1445,
1350, 1290, 1280, 1055, 815, 735, 725 cm-1; 1H NMR (200 MHz,
CDCl3, at 298 K) δ 8.30-8.11 (m, 2H), 7.71 (broad d, J ) 6.9,
1.3, 1H), 7.52 (broad t, J ) 7.7, 1H), 4.79 (broad s, 1H), 4.44
(broad s, 1H), 4.20-2.60 (m, 4H), 1.59 (m, 6H); 13C NMR (50.3
MHz, CDCl3, at 298 K) (mixture of conformers) δ 169.4 (s),
147.8 (s), 138.0 (s), 132.8 (d), 129.4 (d), 123.9 (d), 122.1 (d),
60.3 (broad t), 55.2 (broad d, C-2 of one conformer), 51.4 (broad
d, C-2 of one conformer), 44.0 (t, C-6 of one conformer), 37.4
(t, C-6 of one conformer), 25.3 (broad t, 2C), 19.3 (t); MS (EI)
m/z 264 (M+, 0.2), 234 (4.1), 233 (27.7), 150 (37.1), 104 (11.7),
84 (100), 76 (12.4), 56 (6.6), 55 (4.6). Anal. Calcd for
C13H16N2O4: C, 59.09; H, 6.11; N, 10.60. Found: C, 59.36; H,
5.88; N, 10.22.
N -(4-Me t h oxyb e n zoyl)-2-[[(4-m e t h oxyb e n zoyl)oxy]-
m eth yl]p ip er id in e (2e): mp 88-92 °C; IR (KBr) 2940, 1715,
1
1608, 1510, 1420, 1260, 1170, 1105, 1030, 845, 770 cm-1; H
NMR (300 MHz, CDCl3) δ 7.97 (d, J ) 8.8, 2H), 7.28 (dt, J )
1.9, 8.4, 2H), 6.91 (dt, J ) 2.0, 9.0, 2H), 6.83 (dt, J ) 2.1, 8.8,
2H), 4.93 (broad s, 1H), 4.72 (dt, J ) 9.1, 11.2, 1H), 4.32 (dd,
J ) 5.8, 11.2, 1H), 4.06 (broad s, 1H), 3.86 (s, 3H), 3.80 (s,
3H), 3.13 (distorted t, J ) 12.8, 1H), 1.85-1.40 (m, 6H); 13C
NMR (50.3 MHz, CDCl3) δ 171.2 (s), 166.0 (s), 163.5 (s), 160.5
(s), 131.9 (s), 131.7 (d, 2C), 128.2 (d, 2C), 122.2 (s), 113.6 (d,
2C), 113.4 (d, 2C), 61.9 (t), 55.3 (q), 55.2 (q), 49.8 (broad d),
41.4 (broad t), 25.8 (t), 25.7 (t), 19.6 (t); MS (EI) m/z 383 (M+,
0.06), 218 (8.8), 203 (2.5), 152 (9.7), 135 (100), 107 (6.4), 92
(10.2), 77 (18.0). Anal. Calcd for C22H25NO5: C, 68.90; H, 6.58;
N, 3.65. Found: C, 69.06; H, 6.38; N, 3.45.
N-Ben zoyl-3-[(ben zoyloxy)m eth yl]p ip er id in e (5): mp
109-113 °C; IR (KBr) 2860, 1715, 1625, 1450, 1440, 1305,
1
1270, 715, 705 cm-1; H NMR (300 MHz, CDCl3) δ 7.82 (very
2-(H yd r oxym et h yl)-N-(4-m et h oxyb en zoyl)p ip er id in e
(3e): mp 127-8 °C; IR (KBr) 3335, 2940, 1605, 1585, 1450,
broad m, 2H), 7.53 (broad t, J ) 7.7, 1H), 7.36 (m, 7H), 4.9-
3.4 (very broad m, 4H), 3.00 (broad t, J ) 11.8, 1H), 2.86 (broad
t, J ) 11.8, 1H), 2.07 (broad m, 1H), 1.95 (m, 1H), 1,74 (broad
m, 1H), 1.60 (broad m, 1H), 1.41 (m, 1H); 13C NMR (50.3 MHz,
CDCl3) (mixture of conformers) δ 170.4, 166.1, 136.24, 136.17,
132.93, 132.87, 129.9, 129.4, 129.3, 129.0, 128.7, 128.6, 128.34,
128.30, 128.26, 128.23, 126.7, 66.2, 51.0, 48.2, 45.3, 43.0, 36.4,
36.1, 29.5, 27.3, 24.6; MS (EI) m/z 219 (6.3), 201 (2.5), 189 (6.6),
188 (11.7), 173 (4.0), 141 (4.5), 127 (5.7), 123 (5.3), 119 (8.5),
109 (7.7), 106 (11.1), 105 (100), 96 (9.2), 85 (11.2), 83 (10.7),
81 (14.3), 77 (67.3), 75 (11.9), 71 (27.2), 70 (15.3), 69 (24.0), 57
(41.8), 56 (17.8), 55 (21.5), 43 (57.4), 41 (55.5). Anal. Calcd
for C20H21NO3: C, 74.27; H, 6.55; N, 4.33. Found: C, 74.02;
H, 6.70; N, 4.33.
1
1435, 1280, 1250, 1175, 1065, 1025, 845; H NMR (300 MHz,
CDCl3) δ 7.40 (dd, J ) 2.1, 6.7, 2H), 6.90 (dd, J ) 2.1, 6.7,
2H), 4.60 (broad s, 1H), 3.94 (m, 1H), 3.82 (s, 3H), 3.70 (m,
1H), 3.06 (m, 1H), 2.83 (m, 1H), 1.78-1.48 (m, 6H); 13C NMR
(50.3 MHz, CDCl3) δ 172.5 (s), 160.6 (s), 128.9 (d, 2C), 128.6
(s), 113.6 (d, 2C), 61,3 (t), 55.2 (q), 53.4 (broad d), 42.0 (broad
t), 25.6 (t), 25.5 (t), 19.7 (t); MS (EI) m/z 249 (M+, 0.1), 218
(3.3), 202 (15.6), 135 (24.3), 120 (9.7), 119 (100), 91 (25.0), 77
(3.3), 65 (7.2), 43 (10.5). Anal. Calcd for C14H19NO3: C, 67.43;
H, 7.69; N, 5.62. Found: C, 67.25; H, 7.93; N, 5.59.
N-(4-Nit r ob en zoyl)-2-[[(4-n it r ob en zoyl)oxy]m et h yl]-
p ip er id in e (2f): mp 144-7 °C; IR (KBr) 2950, 2880, 1728,
1635, 1525, 1440, 1355, 1280, 1128, 1110, 1015, 870, 728 cm-1
;
N-Ben zoyl-3-(h yd r oxym eth yl)p ip er id in e (6): mp 90-93
°C; IR (KBr) 3430, 2940, 2850, 1610, 1600, 1445, 1275, 690;
1H NMR (300 MHz, CDCl3) δ 7.38 (m, 5H), 4.05 (broad m, 1H),
3.50 (very broad s, 2H), 3.40-2.55 (m, 3H), 1.85 (m, 2H), 1.85-
1.30 (m, 3H); 13C NMR (50.3 MHz, CDCl3) δ 170.5 (s), 135.9
(s), 129.3 (d), 128.1 (d, 2C), 126.6 (d, 2C), 63.9 (t), 48.3 (very
broad t), 45.0 (very broad t), 38.4 (d), 26.8 (t), 24.4 (t); MS (EI)
m/z 219 (M+, 2.7), 218 (6.1), 215 (5.6), 203 (6.7), 203 (6.7), 202
(7.4), 189 (5.2), 188 (6.0), 184 (15.7), 168 (40.8), 155 (13.1), 141
(42.1), 140 (21.4), 139 (28.6), 128 (23.9), 127 (11.9), 115 (61.9),
105 (47.5), 92 (12.6), 77 (100), 64 (32.0), 51 (33.8). Anal. Calcd
1H NMR (300 MHz, CDCl3) δ 8.28 (broad d, J ) 9.0, 2H), 8.23-
8.15 (m, 4H), 7.42 (boad d, J ) 8.8, 2H), 5.30 (very broad s,
1H), 4.88 (distorted t, J ) 10.5, 1H), 4.39 (dd, J ) 5.4, 11.3,
1H), 3.55 (very broad s, 1H), 3.22 (broad s, 1H), 1.93-1.41 (m,
6H); 13C NMR (50.3 MHz, CDCl3, at 298 K) δ 168.9 (s), 164.5
(s), 150.6 (s), 148.1 (s), 142.2 (s), 134.9 (s), 130.7 (d, 2C), 127.5
(d, 2C), 123.8 (d, 2C), 123.6 (d, 2C), 63.0 (t), 47.4 (broad d),
(26) The signals of C-2 and C-6 are barely detected in the 45-40
ppm region, as very broad peaks.

5270 J . Org. Chem., Vol. 61, No. 16, 1996
Morcuende et al.
for C13H17NO2: C, 71.19; H, 7.82; N, 6.39. Found: C, 70.89;
H, 8.07; N, 6.45.
N,O-Diben zoyl-2-a m in o-2-m eth yl-1-p r op a n ol (14): mp
99-102 °C; IR (KBr) 3260, 1708, 1635, 1535, 1365, 1275, 1110,
1
705, 685 cm-1; H NMR (300 MHz, CDCl3, at 298 K) δ 8.06
N-Ben zoyl-2-[(2-ben zoyloxy)eth yl]p ip er id in e (8): thick
oil; IR (neat) 2930, 1715, 1625, 1445, 1425, 1315, 1270, 1115,
1070, 710 cm-1; 1H NMR (300 MHz, CDCl3, at 298 K) δ 8.01-
7.83 (m, 2H), 7.54 (m, 1H), 7.35 (m, 7H), 5.20-4.70 (m, 1H),
4.33 (m, 2H), 3.90-3.40 (m, 1H), 3.04 (m, 1H), 2.28 (m, 1H),
2.02 (m, 1H), 1.90-1.45 (m, 6H); 13C NMR (50.3 MHz, CDCl3)
δ 170.9 (s), 166.4 (s), 136.8 (s), 132.8 (d), 129.6 (d, 2C), 129.2
(s, d, 2C), 128.4 (d, 2C), 128.3 (d, 2C), 126.5 (d, 2C), 62.1 (t),
29.1 (t), 28.6 (t), 26.0 (t), 19.2 (t);27 MS (EI) m/z 337 (M+, 0.6),
232 (2.5), 215 (1.8), 189 (4.6), 188 (12.6), 122 (11.4), 110 (12.3),
105 (100), 77 (55.5), 51 (9.2).
(distorted td, J ) 7.1, 1.5, 2H), 7.75 (distorted td, J ) 6.6, 1.7,
2H), 7.58 (distorted tt, J ) 1.6, 7.4, 1H), 7.51-7.39 (m, 5H),
6.50 (broad s, 1H), 4.55 (s, 2H), 1.59 (s, 6H); 13C NMR (50.3
MHz, CDCl3, at 298 K) δ 167.2 (s), 166.8 (s), 135.2 (s), 133.2
(d, 2C), 131.2 (d), 129.7 (s), 129.5 (d, 2C), 128.4 (d, 2C), 128.2
(d), 126.7 (d, 2C), 70.1 (t), 54.2 (s), 23.9 (q, 2C); MS (EI) m/z
298 (M + 1, 0.4), 176 (4.0), 162 (23.0), 105 (100), 77 (21.1).
Anal. Calcd for C18H19NO3: C, 72.69; H, 6.44; N, 4.71.
Found: C, 72.42; H, 6.65; N, 4.55.
N-Ben zoyl-2-(2-h yd r oxyeth yl)p ip er id in e (9): thick oil;
IR (neat) 3400, 2950, 2870, 1605, 1445, 1275, 1065, 1055, 705
N-Ben zoyl-2-a m in o-2-m eth yl-1-p r op a n ol (15): mp 88-
90 °C; IR (KBr) 3305, 3195, 2980, 2900, 2860, 1630, 1580, 1545,
1490, 1315, 1070, 690 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.72
(m, 2H), 7.43 (m, 3H), 6.15 (broad s, 1H), 4.44 (t, J ) 6.1, 1H),
3.72 (d, J ) 6.1, 2H), 1.43 (s, 6H); 13C NMR (50.3 MHz, CDCl3,
at 298 K) δ 168.3 (s), 134.5 (s), 130.9 (d), 127.9 (d, 2C), 126.6
(d, 2C), 69.8 (t), 55.5 (s), 23.5 (q, 2C); MS (EI) m/z 194 (M + 1,
0.4), 162 (14.4), 122 (9.6), 106 (7.9), 105 (100), 77 (34.9). Anal.
Calcd for C11H15NO2: C, 68.35; H, 7.83; N, 7.25. Found: C,
68.06; H, 8.21; N, 7.36.
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.39 (m, 5H), 4.95 (broad
s, 1H), 3.95 (broad s, exchange with D2O, 1H), 3.64 (m, 2H),
3.50 (dq, J ) 11.0, 3.0, 1H), 2.92 (distorted td, J ) 11.0, 2.8,
1H), 2.04 (m, 1H), 1.99 (m, 1H), 1.75-1.44 (m, 6H); 13C NMR
(50.3 MHz, CDCl3) δ 171.5 (s), 135.8 (s), 129.4 (d), 128.1 (d,
2C), 126.3 (d, 2C), 58.3 (t), 45.5 (d), 42.9 (t), 32.1 (t), 28.8 (t),
25.6 (t), 18.9 (t); MS (EI) m/z 233 (M+, 0.6), 188 (6.6), 122 (22.6),
105 (100), 84 (12.2), 77 (43.2), 51 (14.4).
N,O-Diben zoyl-2-a m in oeth a n ol (11): mp 87-90 °C; IR
(KBr) 3390, 1705, 1645, 1520, 1485, 1340, 1290, 1265, 710
cm-1; 1H-NMR (300 MHz, CDCl3) δ 8.06 (m, 2H), 7.78 (m, 2H),
7.61-7.40 (m, 6H), 6.59 (broad s, 1H), 4.57 (t, J ) 5.3, 2H),
3.88 (q, J ) 5.3, 2H); 13C NMR (50.3 MHz, CDCl3, at 298 K) δ
167.9 (s), 166.5 (s), 134.0 (s), 132.9 (d), 131.2 (d), 129.5 (s),
129.3 (d, 2C), 128.14 (d, 2C), 128.08 (d, 2C), 126.8 (d, 2C), 63.3
(t), 39.2 (t); MS (EI) m/z 269 (0.04), 226 (2.1), 164 (3.0), 147
(18.6), 134 (6.5), 122 (9.8), 105 (100), 77 (52.1), 51 (14.9). Anal.
Calcd for C16H15NO3: C, 71.35; H, 5.62; N, 5.20. Found: C,
71.15; H, 5.55; N, 5.08.
N-Ben zoyl-2-a m in oeth a n ol (12): mp 56-7 °C; IR (KBr)
3190, 2940, 1640, 1545, 1305, 1210, 1060, 1040, 695 cm-1; 1H
NMR (300 MHz, CDCl3, at 298 K) δ 7.72 (m, 2H), 7.49 (m,
1H), 7.41 (m, 2H), 6.85 (broad s, 1H), 3.81 (distorted t, J )
5.1, 2H), 3.61 (distorted t, J ) 5.1, 2H), 3.35 (very broad s,
1H); 13C NMR (50.3 MHz, CDCl3, at 298 K) δ 168.7 (s), 133.7
(s), 131.3 (d), 128.2 (d, 2C), 126.8 (d, 2C), 61.1 (t), 42.5 (t); MS
(EI) m/e 165 (M+, 1.0), 147 (14.8), 134 (11.4), 122 (25.3), 105
N,O-Diben zoyl-3-a m in o-1-p r op a n ol (17): mp 46-50 °C;
IR (KBr) 3320, 1720, 1645, 1540, 1275, 1115, 710 cm-1 1H
;
NMR (300 MHz, CDCl3, at 298 K) δ 8.12-8.02 (m, 2H), 7.70
(dd, J ) 1.6, 6.9, 2H), 7.60-7.37 (m, 6H), 6.70 (broad s, 1H),
4.49 (t, J ) 6.0, 2H), 3.61 (q, J ) 6.3, 2H), 2.09 (m, 2H); 13C
NMR (50.3 MHz, CDCl3, at 298 K) δ 167.5 (s), 166.7 (s), 134.3
(s), 132.9 (d), 131.2 (d), 129.8 (s), 129.4 (d, 2C), 128.3 (d, 2C),
128.2 (d, 2C), 126.8 (d, 2C), 62.5 (t), 36.8 (t), 28.6 (t); MS (EI)
m/z 283 (M+, 0.6), 178 (2.8), 161 (9.2), 105 (100), 77 (35.1), 56
(10.4). Anal. Calcd for C17H17NO3: C, 72.05; H, 6.05; N, 4.95.
Found: C, 71.89; H, 5.81; N, 4.87.
N-Ben zoyl-3-a m in o-1-p r op a n ol (18): mp 54-7 °C; IR
1
(KBr) 3320, 2950, 1640, 1545, 1310, 1075, 710, 695 cm-1; H
NMR (300 MHz, CDCl3, at 298 K) δ 7.78 (m, 2H), 7.54-7.40
(m, 3H), 6.58 (broad s, 1H), 3.74 (broad m, 2H), 3.65 (q, J )
6.1, 2H), 2.86 (broad s, 1H), 1.86-1.78 (m, 2H); 13C NMR (50.3
MHz, CDCl3, at 298 K) δ 168.4 (s), 133.8 (s), 131.2 (d), 128.1
(d, 2C), 126.7 (d, 2C), 59.5 (t), 37.0 (t), 31.4 (t); MS (EI) m/z
179 (M+, 0.9), 161 (7.8), 148 (3.0), 135 (17.7), 134 (11.4), 105
(100), 77 (54.2), 51 (12.3). Anal. Calcd for C10H13NO2: C,
67.00; H, 7.32; N, 7.82. Found: C, 67.32; H, 7.29; N, 7.38.
(100), 77 (75.6), 51 (32.3), 50 (12.7). Anal. Calcd for C9H11
-
NO2: C, 65.42; H, 6.72; N, 8.48. Found: C, 65.21; H, 7.00; N,
8.54.
(27) The signals of C-2 and C-6 are barely detected in the 45-40
ppm region, as very broad peaks; the signals of these carbons appear
at 45.6 and 43.0, respectively, when the spectrum is run at room
temperature.
J O9605511