Direct, facile aldehyde and ketone α-selenenylation reactions promoted by L-prolinamide and pyrrolidine sulfonamide organocatalysts

Article abstract of DOI:10.1021/jo0506940

A new catalytic method for direct α-selenenylation reactions of aldehydes and ketones has been developed. The results of exploratory studies have demonstrated that L-prolinamide is an effective catalyst for α-selenenylation reactions of aldehydes, whereas

Full text of DOI:10.1021/jo0506940

Direct, Facile Aldehyde and Ketone r-Selenenylation Reactions
Promoted by L-Prolinamide and Pyrrolidine Sulfonamide
Organocatalysts
Jian Wang,† Hao Li,† Yujiang Mei,† Bihshow Lou,†,‡ Dingguo Xu,† Daiqian Xie,§
Hua Guo,*,† and Wei Wang*,†,
Department of Chemistry, University of New Mexico, Albuquerque, New Mexico 87131, Department of
Chemistry, Laboratory of Mesoscopic Chemistry, Institute of Theoretical and Computational Chemistry,
Nanjing University, Nanjing 210093, People’s Republic of China, and School of Pharmacy, East China
University of Science & Technology, P.O. Box 268, Shanghai 200237, People’s Republic of China
hguo@unm.edu; wwang@unm.edu
Received April 7, 2005
A new catalytic method for direct R-selenenylation reactions of aldehydes and ketones has been
developed. The results of exploratory studies have demonstrated that L-prolinamide is an effective
catalyst for R-selenenylation reactions of aldehydes, whereas pyrrolidine trifluoromethanesulfona-
mide efficiently promotes reactions of ketones. Under optimized reaction conditions, using
N-(phenylseleno)phthalimide as the selenenylation reagent in CH2Cl2 in the presence of L-
prolinamide (2 mol %) or pyrrolidine trifluoromethanesulfonamide (10 mol %), a variety of aldehydes
and ketones undergo this process to generate R-selenenylation products in high yields. Mechanistic
insight into the L-proline and L-prolinamide catalyzed R-selenenylation reactions of aldehydes with
N-(phenylseleno)phthalimide has come from theoretical studies employing ab initio methods and
density functional theory. The results reveal that (1) the rate-limiting step of the process involves
attack of the enamine intermediate at selenium in N-(phenylseleno)phthalimide and (2) the energy
of the transition state for the reaction catalyzed by prolinamide is lower than that promoted by
proline. This result is consistent with experimental observations. The role of hydrogen bond
interactions in stabilizing the transition states for this process is also discussed.
Introduction
urated carbonyl compounds.2 Several methods have been
developed for the preparation of R-phenylseleno alde-
hydes and ketones. The most widely used procedure
involves reaction of the aldehyde or ketone enolate with
an electrophilic selenium reagent.2 Direct methods for
R-selenenylation of aldehydes and ketones have been
developed, but these reactions often proceed in low yields
and lack generality.3 Indirect approaches employing
reactions of silyl enol ether with PhSeBr4 and nucleo-
philic displacement of R-bromo aldehydes and ketones
with PhSeLi/Na2b also have been described. An acid
Synthesis of R-phenylseleno derivatives of carbonyl
compounds is of considerable importance since these
substances serve as versatile intermediates in organic
synthesis.1 For example, oxidation of the R-phenylseleno
derivatives by H2O2 or NaIO4 followed by spontaneous
syn elimination produces synthetically useful R,â-unsat-
* Address correspondence to these authors. H.G.: phone (505) 277-
1716, fax (505) 277-2609. W.W.: phone (505) 277-0756, fax (505) 277-
2609.
† University of New Mexico.
‡ On leave from the Chemistry Division, Center of Education, Chang
Gung University, Tao-Yuan, Taiwan, Republic of China.
§ Nanjing University.
(2) For leading references of syn elimination of selenoxides, see: (a)
Reich, H. J.; Lenga, I. L.; Reich, I. L. J. Am. Chem. Soc. 1973, 95,
5813. (b) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc.
1975, 97, 5434. (c) Clive, D. L. J. J. Chem. Soc., Chem. Commun. 1973,
695.
(3) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem.
Soc. 1973, 95, 6137.
(4) Ryu, I.; Murai, S.; Niwa, I.; Sonoda, N. Synthesis 1977, 874.
East China University of Science & Technology.
(1) (a) Back, T. G. Organoselenium Chemistry: A Practical Ap-
proach; Oxford University Press: New York, 1999. (b) Paulmier, C.
Selenium Reagents and Intermediates in Organic Synthesis; Pergamon
Press: Oxford, UK, 1986. (c) Reich, H. J. Acc. Chem. Res. 1979, 12,
22.
10.1021/jo0506940 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/03/2005
5678
J. Org. Chem. 2005, 70, 5678-5687

Direct R-Selenenylation Reactions of Aldehydes and Ketones
SCHEME 1. r-Selenenylation of Carbonyl
Compounds by Preformation of Pyrrolidine-Based
Enamines
SCHEME 2. l-Prolinamide 1/Pyrrolidine
Sulfonamide 2 Catalyzed r-Selenenylation
Reactions of Aldehydes and Ketones
(TsOH)5 or base (piperidine, Scheme 1)6 promoted process
has been used to prepare R-phenylselenocarbonyl com-
pounds, but in both cases stoichiometric amounts of acid
or base are employed. Furthermore, in the latter case
preformation of an enamine from piperidine and the
aldehyde or ketone is required (Scheme 1).
In recent years, the use of secondary amines, such as
proline and its derivatives, as organocatalysts for reac-
tions of carbonyl compounds has become increasingly
popular as a result of the operational simplicity of these
processes and the fact that toxic transition metal cata-
lysts and byproducts are not involved.7-14 The organo-
catalytic processes share a common mechanistic pathway
in which electron-rich enamine intermediates are formed
initially in situ. These intermediates then react with
electrophiles to generate products. The working hypoth-
esis for the development of the catalytic R-selenenylation
reaction derives from the results of a previous study,
which has shown that preformed piperidine enamines of
enolizable aldehydes or ketones react with electrophilic
selenium agents to generate corresponding R-selenenyl-
ation products (Scheme 2).6 Accordingly, we anticipated
that reaction of an in situ formed aldehyde or ketone
enamine with an electrophilic selenium reagent would
serve as the basis for a catalytic method for the prepara-
tion of R-seleno carbonyl compounds (Scheme 2). An
investigation of this methodology has given rise to a new,
direct route for the preparation of R-phenylseleno alde-
hydes and ketones that relies on the use of the proline
derivatives, L-prolinamide (1; Scheme 2)15 and organo-
catalyst pyrrolidine trifluoromethanesulfonamide (2)16 as
organocatalysts.
(5) Cossy, J.; Furet, N. Tetrahedron Lett. 1993, 34, 7755.
(6) Williams, D. R.; Nishitani, K. Tetrahedron Lett. 1980, 21, 4417.
(7) For an excellent book regarding organocatalysis, see: Berkessel,
A.; Groger, H. Asymmetric Organocatalysis-From Biomimetic Concepts
to Applications in Asymmetric Synthesis; Wiley-VCH Verlag GmbH &
Co. KGaA: Weinheim, Germany, 2005.
(8) For selected reviews on organocatalysis, see: (a) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) List, B. Synlett
2001, 1675. (d) List, B. Tetrahedron 2002, 58, 5573. (e) Jarvo, E. R.;
Miller, S. J. Tetrahedron 2002, 58, 2481. (f) Special issue: Asymmetric
organocatalysis. Acc. Chem. Res. 2004, 37, 487. (g) Notz, W.; Tanaka,
F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. (h) Seayad, J.;
List, B. Org. Biomol. Chem. 2005, 3, 719.
(9) For proline-catalyzed aldol reactions, see: (a) List, B.; Lerner,
R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395. (b) List,
B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (c) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260.
(d) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
6798. (e) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D.
W. C. Angew. Chem., Int. Ed. 2004, 43, 2152.
(10) For proline-catalyzed Mannich reactions, see: (a) List, B. J.
Am. Chem. Soc. 2000, 122, 9336. (b) List, B.; Pojarliev, P.; Biller, W.
T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (c) Co´rdova, A.;
Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem.
Soc. 2002, 124, 1842. (d) Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz,
W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866. (e) Co´rdova,
A.; Barbas, C. F., III Tetrahedron Lett. 2003, 44, 1923. (f) Notz, W.;
Tanaka, F.; Watanabe, S.-I.; Chowdari, N. S.; Turner, J. M.;
Thayumanavan, R.; Barbas, C. F., III J. Org. Chem. 2003, 68, 9624.
(g) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.;
Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677. (h) Hayashi, Y.;
Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208.
(11) For proline-catalyzed R-amination reactions, see: (a) List, B.
J. Am. Chem. Soc. 2002, 124, 5656. (b) Kumaragurubaran, N.; Juhl,
K.; Zhuang, W.; Bogevig, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002,
124, 6254.
Results and Discussion
L-Prolinamide-Catalyzed r-Selenenylation Reac-
tions of Aldehydes:15 Catalyst Screening. As dis-
cussed above, a critical issue, which needed to be
addressed in developing a catalytic method for the
R-selenenylation reactions, is the identification of proper
organocatalysts. Consequently, our initial studies focused
on screening different amines which could be used for
this purpose. First on the list was L-proline since it has
been widely used for catalyzing a variety of organic
transformations which take place via enamine interme-
diates.9-12 We observed that reaction of isovaleraldehyde
with N-(phenylseleno)phthalimide as the electrophilic
selenium reagent occurred in the presence of 30 mol %
of L-proline in CH2Cl2 at room temperature to afford the
(14) Other organocatalysts have also been developed for catalysis
via enamine chemistry; for selected examples, see: (a) Chiral di-
amine: Mase, N.; Tanaka, F.; Barbas, C. F., III Angew. Chem., Int.
Ed. 2004, 43, 2420. (b) MacMillan’s imidazolidinone catalyzed aldol
and R-chlorination reactions: Mangion, I. K.; Northrup, A. B.; Mac-
Millan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 6722. Brochu, M.
P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126,
4108. (c) Chiral amine alcohol: Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.;
Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003,
125, 5262. (d) Pyrrolidine tetrazole: Torii, H.; Nakadai, M.; Ishihara,
K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983.
(e) Pyrrolidine imide: Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
(12) For proline-catalyzed R-aminoxylation reactions, see: (a) Brown,
F. J.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 10808. (b) Zhong, G. Angew. Chem., Int. Ed. 2003, 42,
4247. (c) Bogevig, A.; Sunden, H.; Cordova, A. Angew. Chem., Int. Ed.
2004, 43, 1109. (d) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M.
Angew. Chem., Int. Ed. 2004, 43, 1112.
(13) Recently, Jørgensen and co-workers reported L-prolinamide
catalyzed R-chlorination of ketones: Halland, N.; Braunton, A.; Bach-
mann, S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126,
4790.
(15) The preliminary study of aldehyde R-selenenylations has been
communicated in: Wang, W.; Wang, J.; Li, H. Org. Lett. 2004, 6, 2817.
J. Org. Chem, Vol. 70, No. 14, 2005 5679

Wang et al.
TABLE 1. Catalyst Screening for the r-Selenenylation
dinone (Table 1, entries 3, 5, and 7) took place with 30%,
60%, and 40% ee, respectively.18 The results indicate that
the size of amide or sulfonamide moieties in the sulfon-
amide catalysts could be critical in affecting the enanti-
oselectivity of the process.19
Reaction of Isovaleraldehydea
We also observed that pyrrolidine and piperidine,
which have been used in the procedure that requires
preformation of an enamine,6 were not good catalysts for
this process when 30 mol % loading was employed (Table
1, entries 8 and 9). The results suggest that the amide
group in L-prolinamide or the carboxylic acid group in
L-proline is essential for catalyst activity.9c,20 The amide
or carboxylic group is thought to play two roles in this
process. First, they can efficiently activate amine addition
to the carbonyl compound in the pathway for enamine
formation. Second, hydrogen bonding between the amide
or carboxylic acid groups and N-(phenylseleno)phthal-
imide can stabilize the transition state for the seleneny-
lation step (see below).
Optimization of Reaction Conditions. On the basis
of the observation described above, we chose L-prolina-
mide (1) as the catalyst used in further studies of the
R-selenenylation reaction aimed at optimizing reaction
conditions by varying the nature of the selenium re-
agents, the reaction medium, and catalyst loading.
An exploration of four commonly used selenium re-
agents (N-(phenylseleno)phthalimide, phenylselenyl chlo-
ride, phenylselenyl bromide, and diphenyl diselenide)
showed that N-(phenylseleno)phthalimide was superior
in promoting selenenylation reactions with 30 mol % of
L-prolinamide (1) in CH2Cl2 (Table 2, entries 1-4). Under
the identical reaction conditions, much longer times were
required for reactions with phenylselenyl chloride, phe-
nylselenyl bromide, and diphenyl diselenide and lower
yields were obtained (15 h, 75%; 1 d, 24%; and 1 d, <10%
yield, respectively, Table 2). The low rates of these
processes resulted in recovery starting materials when
bromide and diphenyl diselenide were employed. We
believe that the reason N-(phenylseleno)phthalimide
serves as the most effective selenenylation agent is that
effective CdO- - -H2N hydrogen bonding interactions take
place between the carbonyl oxygen atom in N-(phenylse-
leno)phthalimide with the amide NH2 in L-prolinamide
(1; Scheme 3). This interaction stabilizes the transition
state for enamine attack on the Se atom in the rate
a Unless otherwise specified, the R-selenenylation reaction was
performed at room temperature with isovaleraldehyde (0.25
mmol), N-(phenylseleno)phthalimide (0.30 mmol), and catalyst
(0.075 mmol) in 0.5 mL of anhydrous CH2Cl2. b Isolated yields.
c 5% ee observed. d 40% ee observed.
desired selenenylation product in 82% yield (Table 1,
entry 1). Encouraged by this result, we explored reactions
promoted by eight additional amine catalysts under the
same conditions (Table 1, entries 2-9). The results
showed that L-prolinamide (1) was the best catalyst out
of the nine tested. The L-prolinamide (1) promoted
reaction took place within less than 5 min in nearly
quantitative yield (96%) (Table 1, entry 2). Interestingly,
blocking one NH in L-prolinamide by a methyl group
resulted in a considerable reduction of catalytic activity
(Table 1, entry 4).
L-Proline and L-prolinamide exhibit no enantioselec-
tivity in the R-selenenylation reaction of isovaleralde-
hyde.17 However, the processes catalyzed by (S)-pyrroli-
dine trifluoromethanesulfonamide (2) and the analogous
tosyl sulfonamide and the MacMillan’s chiral imidazoli-
(17) Recently, Jørgensen and co-workers reported an organocatalytic
asymmetric R-sulfenylation, see: Marigo, M.; Wabnitz, T. C.; Fielen-
bach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. They
tested L-proline and L-prolinamide catalyzed R-sulfenylation of iso-
valeraldehyde with very poor enantioselectivity (0 and 25% ee in
toluene, respectively).
(18) As cited in ref 16d, we have reported using (S) pyrrolidine
trifluoromethanesulfonamide 2 as catalyst for R-sulfenylation reactions
of aldehydes and ketones, unfortunately no enantioselectivities were
observed for the processes.
(19) As reported in ref 17, Jørgensen and co-workers found that the
bulk silylated L-prolinol derivatives as catalysts afforded R-sulfenyla-
tion products with high ee.
(20) Extensive mechanistic studies of L-proline catalyzed aldol
reactions have been reported, see: (a) Allemann, C.; Gordillo, R.;
Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004,
37, 558. (b) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
11273. (c) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. 2002,
A106, 5515. (d) Arno´, M.; Domingo, L. R. Thero. Chem. Acc. 2002, 108,
232. (e) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem.
Soc. 2003, 125, 16. (f) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List,
B. J. Am. Chem. Soc. 2003, 125, 2475. (g) Tang, Z.; Jiang, F.; Yu, L.-
T.; Gong, L.-Z.; Mi, A.-Q.; Jian, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc.
2003, 125, 5262.
(16) The (S) pyrrolidine trifluoromethanesulfonamide 2 has been
demonstrated for the following reactions: (a) Michael addition: Wang,
W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (b)
R-Aminoxylation: Wang, W.; Wang, J.; Li, H.; Liao, L.-X. Tetrahedron
Lett. 2004, 45, 7235. (c) Mannich reaction: Wang, W.; Wang, J.; Li,
H. Tetrahedron Lett. 2004, 45, 7243. (d) R-Sulfenylation: Wang, W.;
Li, H.; Wang, J.; Liao, L.-X. Tetrahedron Lett. 2004, 45, 8229. (e)
Dehydration: Wang, W.; Mei, J.; Li, H.; Wang, J. Org. Lett. 2005, 7,
601.
5680 J. Org. Chem., Vol. 70, No. 14, 2005

Direct R-Selenenylation Reactions of Aldehydes and Ketones
TABLE 2. Optimization of r-Selenenylation Reactions of Isovaleraldehyde Catalyzed by L-Prolinamidea
catalyst loading
yieldb
(%)
entry
PhSeX
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
toluene
1,4-dioxane
CH3CN
DMSO
CH3NO2
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(% mol)
t
1
2
N-(phenylseleno)phthalimide
PhSeCl
30
30
30
30
30
30
30
30
30
30
30
20
10
5
<5 min
15 h
96
75
24
<10
88
38
93
74
83
66
46
94
94
86
88
62
31
3
PhSeBr
PhSeSePh
1 d
4
1 d
5
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
10 min
2 h
15 min
30 min
1 h
6
7
8
9
10
11
12
13
14
15
16
17
2 h
2 h
<5 min
<5 min
10 min
10 min
1 h
2
1
0.5
2 d
a Unless otherwise specified, for reaction conditions: see footnote a in Table 1. b Isolated yield.
determining step of the process. Indeed, the theoretical
studies have shown that the hydrogen bonding interac-
tions play a key role in involving the formation of
transition states (see below). In contrast, the other
selenenylation reagents provide only weak or no hydro-
gen bonding interactions. Furthermore, it is observed
that the R-selenenylation rates are parallel to the degree
of polarization of the Se-X bond in the selenium re-
agents: the higher the polarization (a decreasing order
of polarization: Se-N, Se-Cl, Se-Br, and Se-Se), the
faster the reaction.
Solvents play an important role in governing the rates
of organic reactions. Therefore, we evaluated the effects
of the medium on the L-prolinamide-catalyzed R-selene-
nylation process. We observed that solvents significantly
controlled the efficiencies of these reactions (Table 2,
entries 1, and 5-11). Reactions in less polar solvents,
such as CH2Cl2, EtOAc, and 1,4-dioxane (Table 2, entries
1, 5, and 7), generally proceeded with higher yields,
whereas in polar solvents (CH3CN, DMSO, CH3NO2, and
DMF; entries 8-11) low yields were obtained. The results
show that the best yields and lowest reaction times are
seen when CH2Cl2 was used as solvent.
Having identified the best selenium reagent and reac-
tion medium, we next probed the effect of catalyst loading
on the reaction (Table 2, entries 12-17). Catalyst load-
ings, ranging from 30 to 0.5 mol %, were evaluated. The
results showed that a catalyst loading as low as 1 mol %
still brought about a significant reaction (Table 2, entry
16). From an operational perspective, the use of 2 mol %
of L-prolinamide (1) was found to provide high reaction
efficiency (88% yield) and maintained a reasonable reac-
tion time (10 min, Table 2, entry 15).
Scope of the r-Selenenylation Reactions of Alde-
hydes. Having uncovered the optimal reaction conditions
for the R-selenenylation process, we evaluated the scope
of the reactions with a variety of aldehydes. The results,
summarized in Table 3, show that a variety of different
aldehydes undergo this selenenylation reaction with
N-(phenylseleno)phthalimide in the presence of L-proli-
namide (1). Regardless of the length of the side chain
(C1-C8) (entries 1-9, Table 3), the reactions were
completed within 10 min in high yields (78-95%). Reac-
tions of highly sterically hindered R,R-disubstituted al-
dehydes occurred in very poor yields (entries 11 and 12).
However, addition of 4 Å molecular sieves resulted in
significant enhancements of the reaction rates. Under
these conditions, R,R-dialkyl R-selenenylation products
were formed within 1 h in high yields (76-81%). The
enhanced reaction rates caused by 4 Å molecular sieves
could be due to facilitated formation of the enamine
intermediate.21
Pyrrolidine Trifluoromethanesulfonamide-Cata-
lyzed r-Selenenylation Reactions of Ketones: Op-
timization of Reaction Conditions. Encouraged by
the results of the studies carried out with aldehydes, we
attempted to extend the methodology to ketone systems.
In an exploratory investigation using cyclohexanone as
a model, we found that only a moderate yield (61%) of
the selenenylation product was obtained when L-proli-
namide (1) (30 mol %) was used as the catalyst and a
much longer reaction time (12 h) was required (Table 4,
entry 1). Interestingly, in addition to forming the mono
R-selenenylation adduct (a), bis R,R- (b) and R,R′- (c)
selenenylation products were also produced (17:3:1 a:b:c
ratio). Several different reaction conditions were tested
in an attempt to minimize formation of bis-addition
products. Slow addition of N-(phenylseleno)phthalimide
to the reaction mixture over a 2 h period did not
substantially affect the product ratio (15:1.4:1 of a:b:c)
(Table 4, entry 2). Earlier studies have shown that the
formation of bis-addition products can be suppressed by
using polar reaction media.14c,d Indeed, when DMSO was
employed as solvent and slow addition of the selenium
(21) Molecular sieves could retard the hydrolysis of iminium to
release catalyst. However, this step is not the rate-determining step
in the reaction.
J. Org. Chem, Vol. 70, No. 14, 2005 5681

Wang et al.
TABLE 3. L-Prolinamide Catalyzed r-Selenenylation
TABLE 4. Catalyst Screening for r-Selenenylation
Reactions of Aldehydesa
Reaction of Cyclohexanonea
a Unless otherwise specified, for reaction conditions: see foot-
note a in Table 1. b Isolated yields. c Molar ratio determined by
1H NMR. d N-(Phenylseleno)phthalimide was added once into a
mixture of cyclohexanone and 30 mol %of L-prolinamide in CH2Cl2.
e N-(Phenylseleno)phthalimide in CH2Cl2 was added dropwise over
30 min into a mixture of cyclohexanone and 30 mol % of
f
L-prolinamide in CH2Cl2. N-(Phenylseleno)phthalimide in DMSO
was added dropwise over 30 min into a mixture of cyclohexanone
and 30 mol % of L-prolinamide in DMSO. g -: Products b and c
not observed by 1H NMR. h 18% ee observed. i Not determined.
5). In this case, a much shorter time (3.5 h) was required
to reach complete reaction and a significantly higher yield
of 88% was obtained. More importantly, the mono-adduct
was formed exclusively in this process even when slow
addition of the selenium reagent was not used. Not
surprisingly, low enantioselectivity (18% ee) was observed
for this reaction. More sterically demanding pyrrolidine
p-bromophenylsulfonamide (Table 4, entry 6) showed a
poor catalytic activity. Again, pyrrolidine and piperidine
are not effective catalysts for the R-selenenylation reac-
tion of ketones (Table 4, entries 7 and 8).
A possible reason for why the reaction catalyzed by
pyrrolidine trifluoromethanesulfonamide (2) affords only
a mono-addition product is that the steric hindrance
imposed by the bigger trifluoromethanesulfonamide group
in 2 (vs OH in L-proline and NH2 in L-prolinamide) could
make enamine formation from the mono-selenenylated
product more difficult.
a Unless otherwise specified, all R-selenenylation reactions of
aldehydes were performed at room temperature with an aldehyde
(0.25 mmol), N-(phenylseleno)phthalimide (0.30 mmol), and 1
(0.005 mmol) in 0.5 mL of anhydrous CH2Cl2. b Isolated yield. c 4
Å molecular sieves added. In the absence of molecular sieves, the
conversion was very slow and the TLC analysis showed only a
small amount of product (ca. <10% yield) was formed after 3 h.
reagent was used, the a:b:c ratio was improved to 26:
1.2:1 (Table 4, entry 3).
Our focus shifted to other organocatalysts for the
selenenylation reaction of cyclohexanone (Table 4). Of the
five catalysts screened (Table 4, entries 4-8), L-proline
displayed a similar catalytic activity as L-prolinamide (1)
in CH2Cl2, but the bis-adducts were also formed in an
a:b:c ratio of 18:2.4:1 (Table 4, entry 4). Interestingly,
the pyrrolidine trifluoromethanesulfonamide (2)16 exhib-
ited the most promising catalytic activity (Table 4, entry
The results of the preliminary studies prompted us to
carry out a more thorough investigation of pyrrolidine
5682 J. Org. Chem., Vol. 70, No. 14, 2005

Direct R-Selenenylation Reactions of Aldehydes and Ketones
TABLE 5. Optimization of Reaction Conditions for r-Selenenylation Reactions of Cyclohexanonea
catalyst loading
t
yieldb
(%)
entry
selenium reagent
solvent
CH2Cl2
CH2Cl2
CH2Cl2
THF
1,4-dioxane
DMSO
DMF
CH2Cl2
CH2Cl2
CH2Cl2
(% mol)
(h)
1
2
N-(phenylseleno)phthalimide
PhSeCl
PhSeBr
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
N-(phenylseleno)phthalimide
30
30
30
30
30
30
30
20
10
5
3.5
24
24
10
6
6
12
8
16
48
88
57
3
<10
73
4
5
82
6
47
7
41
8
86
9
80
10
62
a Unless otherwise specified, for reaction conditions: see footnote a in Table 1. b Isolated yield.
trifluoromethanesulfonamide (2) catalyzed ketone R-se-
lenenylation reactions. A similar strategy was used to
uncover optimal reaction conditions for the process. First,
we evaluated other selenium reagents, phenylselenyl
chloride and bromide, to determine selenenylation ef-
ficiencies. Again it was found that the rates of reactions
with phenylselenyl chloride and bromide were much
smaller than that when N-(phenylseleno)phthalimide
was employed and 57% and <10% product yields, respec-
tively, were observed (Table 5, entries 2 and 3). As a
result, N-(phenylseleno)phthalimide is the choice, used
as the selenium reagent for subsequent studies.
As the data in Table 5 demonstrate, in a manner
similar to R-selenenylation reactions of aldehydes, the
reaction medium has a significant impact on ketone
R-selenenylation processes. Reactions in less polar sol-
vents, such as CH2Cl2, THF, and 1,4-dioxane (Table 5,
entries 1, 4, and 5) generally took place with higher
yields, whereas low yields were obtained when more polar
solvents (DMSO and DMF) were employed (entries 6 and
7). Finally, an evaluation of the effect of catalyst loading
on the reaction (Table 5, entries 8-10) showed that the
use of 10 mol % of pyrrolidine sulfonamide 2 was
sufficient to maintain a high reaction rate without
sacrificing the reaction yield (80% yield, Table 5, entry
9).
Scope of the r-Selenenylation Reactions of Ke-
tones. Under the optimized reaction conditions, a series
of ketones smoothly undergo the pyrrolidine trifluo-
romethanesulfonamide (2) catalyzed R-selenenylation
reactions (Table 6). Generally, mono-addition products
were formed in moderate to high yields. A wide range of
acyclic (entries 1-6) and cyclic ketones (entries 7-14)
participate in this process. The mild reaction conditions
tolerate a variety of other functional groups (Table 6,
entries 5, 12, and 13). We also observed that 2 catalyzed
reactions of various ring-sized cyclic ketones (Table 6,
entries 7-14). Importantly, we found that R-selenenyla-
tion reactions of unsymmetric ketones proceeded prefer-
entially at the less substituted R-sites presumably be-
cause of sterically guided preferences in enamine forming
steps of the process (Table 6, entries 4 and 5). This trend
parallels those seen in LDA promoted R-selenenylations,
which are governed by kinetically controlled R-deproton-
ation2a and contrast with acid promoted R-selenenyla-
tions, which are controlled by thermodynamically con-
trolled enolization.5
Theoretical Analysis of L-Proline and L-Polina-
mide Catalyzed r-Selenenylation Reactions of Al-
dehydes. The significant difference observed in the
activities of L-proline and L-prolinamide in catalyzing
R-selenenylation reactions of aldehydes promoted us to
explore these processes by using ab initio and density
functional theoretical (DFT) methods. A reaction mech-
anism similar to that proposed for the L-proline promoted
aldol reaction (Scheme 3) was presumed to be operating
in the selenenylation reactions.20 The initial step of the
sequence involves formation of an enamine intermediate
which then undergoes rate-limiting attack at the elec-
trophilic selenium (Se) atom of N-(phenylseleno)phthal-
imide. Formation of the Se-C bond takes place in concert
with departure of phthalimide anion to produce the
R-selenoiminium ion intermediate A. Hydroxide ion,
formed by water protonation of the phthalimide nitrogen,
then adds to the iminium carbon to produce a carbino-
lamine B, the precursor of the R-selenoaldehyde product.
On the basis of this mechanistic scenario, the compu-
tational studies were designed to gain an insight into the
factors that govern the energies of stationary points along
the reaction coordinates involved in rate determining
reactions of L-prolinamide and L-proline enamine with
N-(phenylseleno)phthalimide. Energies of stationary points
obtained by using different levels of theory and some
important atom-atom distances and angles and energies
of reaction intermediates and TSs are listed in the Table
7.
The reactant complex (RC), containing the enamine,
N-(phenylseleno)phthalimide, and a water molecule (Fig-
ure 1), is held together largely by hydrogen bonds. For
the complex with prolinamide catalyst 1 (RC), two
presumably cooperative hydrogen bonds (rO‚‚‚HN ) 2.74
and 2.83 Å) exist between the amide NH and a carbonyl
oxygen of N-(phenylseleno)phthalimide. For the proline
catalyst derived complex (RC′), a hydrogen bond exists
(rO‚‚‚HO ) 1.89 Å) between the carboxylate OH and a
carbonyl oxygen of the phthalimide.
As the data in Table 7 suggest, the barrier for the rate-
limiting prolinamide-enamine attack on the electrophilic
J. Org. Chem, Vol. 70, No. 14, 2005 5683

Wang et al.
TABLE 6. Pyrrolidine Trifluoromethanesulfonamide 2
kcal/mol is close to that obtained from a B3LYP calcula-
tion (8.82 kcal/mol). The corresponding barrier heights
for reaction of the proline-enamine are consistently
higher (27.63, 9.44, and 9.80 kcal at the HF, MP2, and
B3LYP levels of theory, respectively).
Catalyzed r-Selenenylation Reactions of Ketonesa
TS1 is characterized by an elongated Se-N bond and
a shorter distance between Se and the CdC bond. This
concerted, electrophilic substitution reaction is accom-
panied by an increase in the hydrogen bond strength
between the phthalimide carbonyl oxygen and both the
OH and NH2 groups in the respective proline- and
prolinamide-enamines. For the proline-enamine de-
rived TS1′, rO‚‚‚HO is reduced to 1.75 Å, whereas for the
prolinamide-enamine TS1, the rO‚‚‚HN distances are 2.45
and 2.67 Å. The strengthening of the hydrogen bonds,
as evidenced by reduced hydrogen bond lengths, can be
attributed to the increase of the negative charge on
carbonyl oxygen as selenium departs from the phthal-
imide nitrogen. It is clear that these hydrogen bonds are
essential for the catalytic activity in the selenenylation
reaction. The role of hydrogen bond interactions in
stabilizing proline-catalyzed aldol reactions has been
extensively discussed in the literature.20 It is also obvious
by comparing barrier heights that the two hydrogen
bonds in the TS1 of the prolinamide-enamine reaction
have a larger stabilizing effect on the transition state
than the lone hydrogen bond in the proline-enamine
process.
The inclusion of solvent (CH2Cl2) does not qualitatively
change the theoretically derived conclusion that the rate-
limiting TS1 is lower for reaction of the prolinamide-
enamine (23.27 kcal/mol at the HF/6-31G(d) level) than
that for the proline analogue (24.20 kcal/mol). The ca. 3
kcal/mol lower TS1 energy relative to RC can be at-
tributed to the charge separation that develops between
Se and the phthalimide nitrogen. Importantly, the results
from the theoretical calculations are consistent with the
experimental observations,
The calculations indicate that reaction of the prolina-
mide-enamine with N-(phenylseleno)phthalimide to pro-
duce the intermediate (INT) has energies of 3.25, -5.27,
and -6.33 kcal/mol relative to RC at the HF, MP2, and
B3LYP levels, respectively. Similar results, 12.90, 4.48,
and 6.25 kcal/mol, were found for proline-enamine
reaction. Interestingly, only one, shorter (rO‚‚‚HN ) 1.85
Å) hydrogen bond is preserved between the phthalimide
anion and the NH2 group of the prolinamide catalyst. In
contrast, the hydrogen bond between the phthalimide
anion and the proline OH is also shorter (rO‚‚‚HO ) 1.61
Å). These phenomena are almost certainly due to nega-
tive charges developed in the carbonyl oxygen atoms in
the phthalimide anion. In both cases, water is hydrogen
bonded with the nitrogen in the phthalimide anion with
the oxygen pointing toward the R-carbon of the iminium
ion A. Like TS1, there is a significant solvent effect on
complex INT because of its zwitterionic nature.
Deprotonation of water by the phthalimide anion
seems to take place in concert with nucleophilic addition
of hydroxide to the iminium carbon. The transition state
for this general base-catalyzed process is labeled TS2.
In this process, the hydrogen bonds between the phthal-
imide anion and proline OH or prolinamide NH2 groups
are weaken, as evidenced by larger OH‚‚‚O and NH2‚‚‚O
distances in TS2 and TS2′, respectively. TS2 is much
a Unless otherwise specified, all R-selenenylation reactions of
ketones were performed at room temperature with a ketone (0.25
mmol), N-(phenylseleno)phthalimide (0.30 mmol), and 2 (0.025
mmol) in 0.5 mL of anhydrous CH2Cl2. b Isolated yield. c Two
regioisomers at less substituted (structure shown) and more
substituted site with a 10:1 ratio (observed by 1H NMR).
Se atom (TS1) is 26.00 kcal/mol at the HF level. As
expected, the inclusion of electron correlation signifi-
cantly lowers this barrier. The MP2 barrier height of 6.74
5684 J. Org. Chem., Vol. 70, No. 14, 2005

Direct R-Selenenylation Reactions of Aldehydes and Ketones
SCHEME 3. Proposed Enamine Mechanism of the Prolinamide-Catalyzed r-Selenenylation Reaction of
N-(Phenylseleno)phthalimide with Propionaldehyde
TABLE 7. Ab Initio and DFT Results for the Selenenylation Reaction between Enamine and
N-(Phenylseleno)phthalimide with Two Different Organocatalysts: L-Prolinamide (NH2) and L-Proline (OH)
reactant complex
NH2 OH
transition state 1
NH2 OH
intermediate
NH2
3.25
-5.27
-6.33
0.74
OH
energy (kcal/mol)
HF/6-31G* Opt
B3LYP/6-31G* SP
MP2 SP
0
0
0
0
0
0
0
0
26.00
8.82
27.63
9.80
9.44
12.90
4.48
6.25
7.63
6.74
23.27
HF/6-31G* PCM/SP
distances (Å)
NH2‚‚‚OdC
OH‚‚‚OdC
24.20
2.74/2.83
-
4.12
1.87
2.45/2.67
1.85/3.24
1.89
1.75
1.61
Se‚‚‚CdC
5.08
2.24
2.42
2.30
2.02
6.09
2.02
Se‚‚‚N
1.88
2.40
5.76
CdCdN
1.33/1.39
4.30/4.09
4.80
1.33/1.38
3.75/4.12
3.55
1.42/1.30
2.21/3.37
4.83
1.41/1.31
2.31/3.23
4.83
1.49/1.27
1.94/3.09
4.52
1.49/1.27
1.89/2.99
3.64
OH2‚‚‚N
H2O‚‚‚CdC
H-O-H
0.95/0.95
0.95/0.95
0.95/0.95
0.95/0.95
0.96/0.95
0.97/0.95
dihedral angles (deg)
N-C-C-Se
C-C-Se-N
-88.41
3.86
-127.14
-54.81
-80.34
-101.24
-84.21
-99.83
-124.17
-74.70
-123.15
-72.43
transition state 2
product complex
NH2
10.45
-2.37
-2.18
9.32
OH
NH2
OH
energy (kcal/mol)
HF/6-31G* Opt
B3LYP/6-31G* SP
MP2 SP
19.30
6.30
8.34
16.29
-26.45
-26.70
-27.56
-25.52
-18.36
-18.04
-17.02
-20.32
HF/6-31G* PCM/SP
distances (Å)
NH2‚‚‚OdC
OH‚‚‚OdC
2.29/3.59
-
2.01
5.26
-
2.19/3.61
-
2.02
6.22
-
1.73
1.95
Se‚‚‚CdC
2.01
2.02
Se‚‚‚N
5.46
6.23
CdCdN
1.51/1.32
1.63/3.08
1.86
1.52/1.34
1.69/3.19
1.77
1.53/1.44
1.00/3.70
1.40
1.53/1.44
1.01/3.70
1.40
OH2‚‚‚N
H2O‚‚‚CdC
H-O-H
1.01/0.96
1.00/0.96
1.98/0.95
2.00/0.95
dihedral angles (deg)
N-C-C-Se
C-C-Se-N
-77.21
148.11
-78.62
146.32
-53.16
-166.36
-53.76
-162.22
lower in energy than TS1 and, as a result, it is kinetically
insignificant. However, the HF, MP2, and B3LYP results
show that here again the energy barrier is lower for the
prolinamide-iminum hydrolysis reaction. This provides
further support for the hypothesis that hydrogen bond
interactions are responsible for the stabilization of the
transition state.
Finally, the product complex (PC), comprised of ph-
thalimide and carbinolamine B, is of much lower energy
than the reactants, roughly 26 and 18 kcal/mol for the
two reactions. The hydrogen bonds between the carbonyl
of phthalimide and the OH of proline or the NH2 of
prolinamide still exist, but they are weak (rO‚‚‚HO ) 1.95
Å and rO‚‚‚HN ) 2.19 Å). In addition, hydrogen bonds
between the NH of phthalimide and the OH group of the
carbinolamine ion B exist with a NH‚‚‚O distance of 2.00
and 1.98 Å for the proline and prolinamide catalysts,
respectively. Since the two products are neutral, solvation
has a relatively small effect.
To investigate the effect of water on the rate-limiting
step of the R-selenenylation reaction, we calculated the
optimized gas phase structures of the reactant complex
and first transition state. The energy barriers are cal-
culated to be 34.24, 18.38, and 18.26 kcal/mol for the
J. Org. Chem, Vol. 70, No. 14, 2005 5685

Wang et al.
FIGURE 1. Geometries of stationary points along the reaction pathways. (Hydrogen bonds are represented by thin
dashed lines, while the partial bonds at transition states are represented by thick dashed lines.)
prolinamide-enamine reaction at the HF, B3LYP, and
MP2 levels of theory, respectively. The corresponding
values for the proline-enamine reaction are 37.13, 19.72,
and 20.79 kcal/mol. The higher barriers found for the
latter process, as compared with those calculated for the
transition state incorporating a water molecule, indicate
that the water plays an important role in the first
reaction step, via hydrogen bond interaction with the
phthalimide nitrogen. Although the barriers are larger
in the absence of water, the trend is the same, namely
the two hydrogen bonds between the carbonyl oxygen in
phthalimide and the prolinamide NH2 group provide
more stabilization of the rate-limiting transition state
than the single hydrogen bond existing between the
carbonyl oxygen in phthalimide and the proline OH
group.
active catalyst for selenenylation of ketones. Moreover,
the investigation reveals that the reactions of unsym-
metric ketones take place preferentially at the least
substituted R-sites. Theoretical studies with ab initio and
DFT methods have been carried out to understand why
L-prolinamide is the most effective oragnocatalyst for
R-selenenylation reactions of aldehydes. Energy barriers
for rate limiting formation of Se-C bond, through enam-
ine attack of the Se atom in N-(phenylseleno)phthalimide,
are calculated for the L-prolinamide and L-proline cata-
lyzed processes. The results show that the transition
state energy is lower for the prolinamide-enamine
reaction than for the proline-enamine process. Moreover,
the calculations demonstrate that hydrogen bonding
plays an important role in stabilizing the transition states
for the rate-limiting step of the selenenylation reaction.
Conclusions
Experimental Sections
We have uncovered direct, mild methods for the
preparation of R-phenylseleno aldehydes and ketones,
important intermediates in the synthesis of R,â-unsatur-
ated aldehydes and ketones. These processes are ef-
ficiently promoted by the organocatalysts, L-prolinamide
(1) and pyrrolidine trifluoromethanesulfonamide (2).
Unlike other existing methods, the operational procedure
for these processes is simple and economic. The studies
have demonstrated that the methodology is applicable
to a wide range of aldehydes and ketones, having a broad
spectrum of structural features. In addition, we have
found that L-prolinamide (1) efficiently catalyzes alde-
hyde R-selenenylation reactions, whereas pyrrolidine
trifluoromethanesulfonamide (2) serves as the most
General Procedure A for r-Selenenylation of Alde-
hydes (Table 3, Entries 1-10). To a vial containing aldehyde
(0.25 mmol), 0.5 mL of anhydrous CH2Cl2, and catalyst
l-prolinamide (1) (0.005 mmol) was added N-(phenylseleno)-
phthalimide (0.3 mmol) at room temperature. After 10 min,
the reaction mixture was treated with water (5 mL), then the
solution was extracted with ethyl acetate (3 × 5 mL). The
combined extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The resulting residue was then purified
by silica gel chromatography, eluting with EtOAC/hexane to
afford a clear oil.
2-(Phenylseleno)propanal (Table 3, entry 1). The reac-
tion was carried out following the general procedure A to
provide a clear oil (45 mg, 81%). 1H NMR (500 MHz, CDCl3) δ
9.45 (d, 1H, J ) 3.0 Hz), 7.51 (d, 2H, J ) 7.0 Hz), 7.35 (t, 1H,
5686 J. Org. Chem., Vol. 70, No. 14, 2005

Direct R-Selenenylation Reactions of Aldehydes and Ketones
J ) 7.5 Hz), 7.29 (t, 2H, J ) 7.5 Hz), 3.71 (dq, 1H, J ) 7.0, 3.0
Hz), 1.46 (d, 3H, J ) 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ
193.7, 136.3, 129.5, 129.1, 125.9, 46.8, 13.6; HRMS (EI) calcd
for C9H10OSe (M+) 213.9891, obsd 213.9909.
state (TS2), and product complex (PC), were optimized in
vacuo at the HF/6-31G(d) level of theory. The standard
effective core potentials (ECP) were used for the selenium atom
with the LANL2DZ basis set.23 The stationary points were
confirmed by frequency calculations. To include the electron
correlations, single-point energy calculations were performed
at these geometries at the MP224 and B3LYP25 levels of theory
with the same basis set.
The solvent effect on the reaction pathway was estimated
by using the polarizable continuum model (PCM),26 as imple-
mented in Guassian 03. PCM calculations were performed at
both the HF and DFT levels with the 6-31G(d) basis set.
Calculations were performed with the dielectric constant
corresponding to CH2Cl2 at 25 °C: ꢀ ) 8, as in the experiment.
General Procedure B for r-Selenenylation of Alde-
hydes (Table 3, Entries 11 and 12). To a vial containing an
aldehyde (0.25 mmol) and 0.5 mL of anhydrous CH2Cl2 was
added catalyst L-prolinamide (1) (0.005 mmol) at room tem-
perature. The mixture was vigorously stirred for 0.5 h in the
presence of 4 Å molecule sieves (40 mg). Then N-(phenylsele-
no)phthalimide (0.3 mmol) was added. After 0.5 h, the molecule
sieves were removed by filtrating paper and then the filtrate
was treated with water (5 mL), the solution was extracted with
ethyl acetate (3 × 5 mL). The combined extracts were dried
over MgSO4, filtered, and concentrated in vacuo. The resulting
residue was then purified by silica gel chromatography, eluting
with EtOAc/hexane (1/40) to provide a clear oil.
2-Methyl-2-(Phenylseleno)propionaldehyde (Table 3,
Entry 11). The reaction was carried out following the general
procedure B to provide a clear oil (45 mg, 76%). 1H NMR (500
MHz, CDCl3) δ 9.26 (s, 1H), 7.49 (d, 2H, J ) 7.0 Hz), 7.39 (t,
1H, J ) 7.5 Hz), 7.30 (t, 2H, J ) 8.0 Hz), 1.44 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 193.7, 138.0, 129.7, 129.3, 126.3,
53.6, 21.7; HRMS (EI) calcd for C10H12OSe (M+) 228.0048, obsd
228.0065.
General Procedure for r-Selenenylation of Ketones
(Table 6, Entries 1-14). To a vial containing ketone (0.3
mmol) and 1.0 mL of anhydrous CH2Cl2 was added catalyst
pyrrolidine trifluoromethanesulfonamide (2) (0.03 mmol) at
room temperature. The mixture was vigorously stirred for 0.5
h before N-(phenylseleno)phthalimide (0.3 mmol) was added.
After 16-48 h, the reaction mixture was treated with water
(10 mL), and then the solution was extracted with ethyl acetate
(3 × 10 mL). The combined extracts were dried over MgSO4,
filtered, and concentrated in vacuo. The resulting residue was
then purified by silica gel chromatography (EtOAc/hexanes)
and fractions were collected and concentrated in vacuo to
provide a clear oil.
1-(Phenylselanyl)propan-2-one (Table 6, Entry 1). The
title compound was prepared according to the general proce-
dure in 69% yield. 1H NMR (500 MHz, CDCl3) δ 7.55-7.50
(m, 2H), 7.26-7.31 (m, 3H), 3.59 (s, 2H), 2.27 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 203.7, 33.5, 129.6, 128.9, 128.2, 37.0, 28.2;
HRMS (EI) calcd for C9H10OSe (M+) 213.9891, obsd 213.9909.
Computational Methods. All the calculations, including
Hartree-Fock (HF), Møller-Plesset (MP2), and density func-
tional theory (DFT), were carried out with the Gaussian 03
package.22 Molecular geometries of all the stationary points,
including the enamine reactant complex (RC), the first transi-
tion state (TS1), the intermediate (INT), the second transition
Acknowledgment. Support for this research was
provided by the Department of Chemistry and the
Research Allocations Committee, the University of New
Mexico. We thank Professor Patrick S. Mariano for
making critical editorial comments about the manu-
script.
Supporting Information Available: The 1H and 13C
NMR and HRMS spectral characterization data for all R-se-
lenenylation products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0506940
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; T. V.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone,
V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma,
K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. Gaussian 03, Revision A.1; Gaussian, Inc.:
Pittsburgh, PA, 2003.
(23) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.
(24) Moller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618.
(25) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(26) (a) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55,
117. (b) Miertus, E.; Tomasi, J. Chem. Phys. 1982, 65, 239.
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