Dual mechanisms of an organocatalytic homodimerization reaction

Article abstract of DOI:10.1016/j.tetlet.2010.07.114

The L-proline organocatalytic homodimerization of 2-cyclohexenone has been studied and it is concluded that the mechanism of the reaction follows competing pathways involving either a two-step imine/ enamine addition or a concerted Diels-Alder cycloaddition where the ultimate product distribution is dependent upon the ratio of the organocatalyst to 2-cyclohexenone and a base present.

Full text of DOI:10.1016/j.tetlet.2010.07.114

Tetrahedron Letters 51 (2010) 5086–5090
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Tetrahedron Letters
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Dual mechanisms of an organocatalytic homodimerization reaction
*
Vanina Guidi, Sergio Sandoval, Michael A. McGregor, William Rosen
Department of Chemistry, University of Rhode Island, Kingston, RI 02881, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The L-proline organocatalytic homodimerization of 2-cyclohexenone has been studied and it is concluded
Received 22 June 2010
Revised 19 July 2010
Accepted 20 July 2010
Available online 25 July 2010
that the mechanism of the reaction follows competing pathways involving either a two-step imine/
enamine addition or a concerted Diels–Alder cycloaddition where the ultimate product distribution is
dependent upon the ratio of the organocatalyst to 2-cyclohexenone and a base present.
Ó 2010 Elsevier Ltd. All rights reserved.
The self-condensation reaction of
a
,b-unsaturated enals1 and
,b-unsaturated enones2 have
well to the side of the adduct (99:1 by NMR). When L-proline
the homodimerization reaction of
a
was added to this resultant equilibrium mixture, and stirring was
continued for 24 h, the homodimer was found to be the major
product in ꢀ40% yield, based upon I, after aqueous work-up and
column chromatography.7 This result implied that an organocata-
lyst like L-proline could catalyze the conversion of the conjugate
addition adduct to the homodimer 1. The question that thus
been known for many years. Usually these reaction processes use
strong bases as catalysts but recently it has been shown that
organocatalysts, such as
yield the dimeric products. While the mechanism of the
L
-proline, can be usefully employed to
-proline
,b-unsaturated
L
organocatalytic self-condensation reaction of the
a
enals3 appears to proceed via an imine/enamine addition mecha-
nism the analogous reaction pathway for homodimerization of
needed to be answered was how? Consequently we explored the
mechanism of how an organocatalyst like
L-proline could promote
a
,b-unsaturated enones has been postulated to proceed through
the homodimerization of I in the presence of either pyrrolidine or
a concerted Diels–Alder reaction.4
L-methyl prolinate as the Bronsted base.
Homodimerization of 2-cyclohexenone (I) with pyrrolidinium
perchlorate in the presence of a catalytic amount of pyrrolidine fol-
lowed by aqueous hydrolysis of the initial dicationic dipyrrolidini-
um product yielded a tricyclo[6.2.2.02,7]dodeca-3,9-dione, 1, as the
major product.5 The major homodimer having structure 1 was later
shown by others to have the configuration of the endo-isomer as
derived from the dimerization of the ethylene ketal of I by a pro-
posed acid catalyzed Diels–Alder route.6 We were interested to
A model reaction [1–5 mmol scale] of L-methyl-prolinate and I
neat was studied to evaluate the feasibility and the applicable con-
ditions. Initially we utilized a 1:1 equiv mmol ratio of the reactants
(rt) and found that the conjugate or 1,4-addition process was
nearly complete after stirring for 5 h to yield an equilibrium mix-
ture that was well to the side of the adduct (95:5 by NMR). If the
formed adduct was allowed to stir for an additional 10 h it was
found that there was no apparent continuation beyond this equi-
librium process. However after this 10 h induction period/lag time
the major homodimerization reaction was initiated and completed
within a 3 h period along with a minor intramolecular cyclization
process derived from the conjugate addition adduct. Aqueous acid
work-up and subsequent chromatographic separation of the reac-
tion mixture produced the major endo-homodimer product 1 in
reasonable isolated yield (ꢀ30%). Minor amounts8 of four other
determine whether a
L-proline organocatalytic homodimerization
of I with either pyrrolidine or
L
-methyl-prolinate as the base would
proceed by a stepwise enamine/iminium ionaddition mechanism
or a concerted Diels–Alder pathway. While we now show that
the endo-homodimer is the major product of this organocatalytic
reaction we have also isolated interesting side products that impli-
cate a dominant reaction mechanism that involves a stepwise en-
amine/iminium ion addition process when an amine is present
products could also be isolated: One being 2, two others being L-
along with the organocatalyst
details our research using neat conditions to explore this interest-
ing homodimerization reaction.
The reaction of a 1:1 mixture of pyrrolidine with I (3 mmol) was
conducted under neat conditions at room temperature (rt). Upon
stirring a fast reaction was initiated producing the expected conju-
gate addition process leading to an equilibrium mixture that was
L
-proline. Consequently this report
proline and its dimer and the fourth being the exo-homodimer of 1.
When the mmol ratio of the same two reactants as above was
set at 1.15:1 a similar sequence was found. The conjugate addition
reaction required 4 h to complete and then the homodimerization
process was initiated, after another 8 h induction period/lag time,
with overall completion taking 15 h. If this reaction mixture was
allowed to sit for an additional 24 h, without aqueous work-up, a
precipitate was noted within the resultant thick liquid. Removal
by filtration of the precipitate led to its identification as
L-proline.
* Corresponding author. Tel.: +1 401 874 2361; fax: +1 401 874 5072.
E-mail address: wrosen@chm.uri.edu (W. Rosen).
After removal of the -proline the thick liquid was subjected to an
L
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.114

V. Guidi et al. / Tetrahedron Letters 51 (2010) 5086–5090
5087
aqueous acid work-up and chromatographic separation resulted in
the same major (endo-1) and minor products consisting of the exo-
isomer of 1, the intramolecular cyclization product 2 along with
Increasing the L-proline catalyst load from 10 to 50 mol % indeed
showed that the rate of gain of the homodimerization products in-
creased at the expense of the conjugate addition adduct. The anal-
ysis of the derived GC/MS data, with respect to homodimer
formation, can be summarized as follows: (1) an intermediate hav-
ing a molecular ion with M+ꢁ = 149 amu was observable in early GC
traces and corresponded to the diene amine 3; (2) the initial rate of
formation of exo-1 was always greater than that of its endo-isomer
regardless of catalyst load; (3) the final (24 h) endo-1 to exo-1 ratio
the dimer of
nate.8 Interestingly the amount of
to be ꢀ0.12 equiv mmol or essentially equal to the mmol excess of
-methyl-prolinate that was initially utilized. We surmised that L-
L-proline presumably derived from
L-methyl proli-
L-proline precipitate was shown
L
proline was produced during the induction period/lag time by
hydrolysis and was an autocatalyst for the homodimerization lead-
ing to 1. Consequently when this same reaction was initiated using
an equiv mmol ratio (1:1) of reactants, to which was added
changed from 9:1 to 1:1 as the load of the organocatalyst, L-proline,
increased from 10 to 50 mol %; (4) in late GC traces the major prod-
ucts, prior to aqueous acid work-up, proved to have MS molecular
ions of M+ꢁ = 245 amu; (5) GC bands exhibiting M+ꢁ = 245 amu were
10 mol % of L-proline, dissolved in a minimal amount (<30 ll) of
methanol for homogeneity, the conjugate addition/homodimeriza-
tion process was shown to go to completion without an induction
period/lag time in <6 h. The above results implied that the conju-
gate addition adduct is the initial intermediate in this organocata-
lytic reaction sequence leading to homodimerization (see
Scheme 19). However the mechanism of production of 1, either
the endo-homodimer or even its exo-homodimer isomer, was not
only noted when L-proline was present as the organocatalyst; (6)
partial conversion of GC fractions having a 245 amu M+ꢁ could be
induced to provide an increased amount of homodimer, with
endo-1 being the major isomer, by treating the crude reaction mix-
ture with acetic acid; (7) isolation of a small amount of the side
product having M+ꢁ = 246ꢁ1852 amu (high resolution) could be
achieved by dissolution of the crude reaction mixture in CH2Cl2,
followed by a HCl wash, and subsequent isolation from the organic
layer of compound 4ꢁHCl; (8) prolonged stirring (rt) of any of these
crude reaction mixtures for more than 24 h eventually lead to ꢀ1:1
endo/exo-1 ratio regardless of the starting conditions; (9) reaction
apparent. Thus we decided to examine the L-proline organocatalyt-
ic homodimerization of I in the presence of the Bronsted base pyr-
rolidine in detail in an attempt to determine whether the
intermediates could be observed without interference from side-
reactions involving
L-methyl prolinate which had produced the L-
proline dimer and the intramolecular cyclization product 2.
of I and
1 but when the ratio of I to
L
-proline (1:0.15 mmol) without any pyrrolidine gave no
-proline was increased (1:1.15 mmol)
The rt neat reaction of I and pyrrolidine (1:1 equiv mmol), with
L
L
-proline as the organocatalyst dissolved in a minimal amount of
a small homodimer fraction having an exo/endo-1 ratio of 3:1 was
produced initially (5 h) which eventually converted to a ratio of
1:2.5 (3 days) albeit in low yield and with several other higher
methanol for homogeneity, was followed over a 24 h period or
more utilizing GC/ESI-MS as the primary method of analysis.7
CO2Me
CO2H
CO2H
N
O
O
HN
NH
CO2Me
CO2Me
N
N
M
+. = 225 amu
+L-Pro-OMe
-L-Pro-OMe
CO2
-MeOH
MeO2C
N
N
CO2
OH
N
+
N
1) Neat
RT
M+. = 207 amu
H3O
2) H3O
O
O
N
O
H
O
+
H
O
H
O
H
H
exo-1
endo-1
2
Scheme 1.

5088
V. Guidi et al. / Tetrahedron Letters 51 (2010) 5086–5090
molecular mass materials in the crude mixture; and (10) the reac-
tion of I and -proline (1:1) with triethylamine (15 mol %) replacing
the endo-1 hydrolysis precursor 60 via a slower concerted reaction
of 3 + 5 (R = H) via path b.10b As the load of
-proline is increased
L
L
pyrrolidine initially (5 h) lead to a mixture of homodimers (exo/
endo = 2.4:1) which upon prolonged stirring (1 week) resulted in
isomerization (exo/endo = 1:1) in very low yield. The interpretation
of all these data is displayed in Schemes 2 and 39 and summarized
below with respect to the two mechanisms being proposed.
Our overall conclusion from the above evidence is that this
homodimerization reaction (see Scheme 2) can follow both the
proposed mechanistic pathways but the actual outcome of the
the exo/endo ratio decreases in accord with these mechanisms pre-
sumably because of the introduction of the increased H-bond capa-
bilities.11 Amines play an important role here as is evidenced by
the inability of L-proline to produce significant 1 in their absence.
The crucial role played by pyrrolidine, besides for enamine/imini-
um cation formation from the conjugate addition product, is as a
Bronsted base for salt bridge formation between 3 (R = H) and 5
(R = CO2ꢂ) but it can also act as a catalyst for the isomerization
of endo-1 to exo-1 which was always observed with the prolonga-
reaction is dependent upon the ratio of L-proline to I that is used
to initiate the process and whether an amine base is present or
not. The mechanistic pathways leading to the homodimerization
of I appear to be initiated by the rapid establishment of a conjugate
addition equilibrium whereby a 3-N-pyrrolidino-cyclohexanone
adduct is formed initially. This intermediate adduct can then un-
dergo 1,2-addition with either pyrrolidine to form the diene amine
tion of the process. As the load of L-proline increases the role of
pyrrolidine changes from being a Bronsted base to a Bronsted acid
thus coaxing the homodimerization mechanism to convert from
the salt bridge-assisted pathway to a H-bond-assisted one.11
The most revealing result, however, was the observation of the
minor product 4ꢁHCl. The isolation of the 4ꢁHCl salt can only result
from a three-step mechanism12 where the tandem two-step enam-
ine/imine addition of 30 + 5 (R = H) cascades into a Mannich reac-
tion, step three, (see Scheme 3) yielding after acid hydrolysis the
salt of the b-pyrrolidino-carbonyl-adduct 4ꢁHCl. This racemic13
HCl salt was isolable (mp = 187–190 °C) in ꢀ5% yield and its struc-
ture was proven using HRMS in conjunction with 1D and 2D PMR
and CMR analyses as well as the observation that an AgCl precipi-
tate formed when ethanolic solutions of AgNO3 and 4ꢁHCl were
mixed. Particularly noteworthy is an intramolecular hydrogen
bond (D2O exchangeable) in the PMR spectrum at 12.6 ppm which
presents COSY cross peaks with methylene protons from a pyrro-
lidinium ion. The COSY also indicates that 4ꢁHCl adopts a cis-con-
figuration for the bridgehead protons. The 1D-CMR exhibits 16
carbon resonances in which DEPT spectra account for five CH’s,
nine CH2’s as well as one C@O and one quaternary C–N+. The 2D
HETCOR spectrum allows for the completion of the assignment of
the structure by displaying a correlation between the C@O and
1-CH and 1-CH2 while the quaternary C–N+ correlates with the
same CH, a different CH, and a different CH2. Modeling predicts
two possible structures that are very similar but differ in the rela-
3 (R = H) and the iminium cation 5 (R = H) or with L-proline to form
the comparable 30 (R = CO2ꢂ) and 5 (R = CO2ꢂ). The intermediates 3
(R = H) + 5 (R = CO2ꢂ) can undergo a stepwise imine/enamine addi-
tion process (Scheme 2, path a) leading to exo-1 initially. Subse-
quently 3 + 5 (R = H) can undergo the concerted Diels–Alder
reaction process (Scheme 2, path b) leading to endo-1 once L-pro-
line has been sequestered as the exo-1 hydrolysis precursor 6 prior
to hydrolysis. A stepwise mechanism where a prochiral enamine
nucleophilic face, as in 3, attacks a prochiral electrophilic face, as
in 5 (R = CO2ꢂ) leads to a first intermediate. Consequently the first
step in path a of Scheme 2 proceeds via a Re to Si nucleophilic face
to an electrophilic face bond formation.10a The second step bond
formation then rapidly results in the production of the exo-config-
uration by rotation of the covalently bonded rings of the first inter-
mediate with respect to one another. This lowest energy route via
path a is controlled by the transient formation of a salt bridge di-
mer between the carboxylate of the
(R = CO2ꢂ)}and the pyrrolidinium cation of I {3 (R = H)}. Once the
-proline catalyst has been sequestered as the exo-1 hydrolysis pre-
cursor 6 then the higher energy Diels–Alder pathway can lead to
L-prolino-enamine of I {5
L
O2C
N
N
Path a
Step one
H
R
N
N
Re
H
+
Si
5
3
-
M+. = 149 amu
R = H or CO 2
Path a
Step two
Path b
Diels/Alder
H3O
N
endo-1
exo-1
N
H3O
H
CO2
H
H
6'
N
6
N
H
H
Scheme 2.

V. Guidi et al. / Tetrahedron Letters 51 (2010) 5086–5090
5089
N
O2C
N
N
Step one
+
CO2
3'
N
5 R = H
Step two
HO2C
N
N
N
CO2
Step three
Mannich
N
H
H
HCl/H2O
endo-7
N
H
Cl
N
H
O
Cl
O
H
H
H
H
4.HCl
4'.HCl
Scheme 3.
tive positioning of the C@O (see Scheme 3 comparing structure
4ꢁHCl to 40ꢁHCl). The structure represented by 4ꢁHCl has a similar
strength intramolecular hydrogen bond (C–N+–Hꢁ ꢁ ꢁO@C) to that
of 40ꢁHCl but the most compelling reason to favor the structure
4ꢁHCl as the minor product over that of 40ꢁHCl is a mechanistic
one. A Mannich reaction in the third and last step of this cascade
can only occur if the two-step enamine/imine process leads to
the salt bridge-stabilized intermediate endo-7 which can exclu-
sively collapse via a Mannich process to produce 4ꢁHCl after hydro-
lysis. A comparable exo-intermediate to endo-7 cannot lead to a
Mannich process following either a two-step addition mechanism
or a concerted Diels–Alder pathway and thus the hydrolysis prod-
uct 40ꢁHCl can be eliminated from consideration.
for the HRMS results and Gregory Naumiec for the help with Pre-
parative LC separations.
References and notes
1. Tiemann, F. Ber. Dtsch. Chem. Ges. 1898, 31, 3278; Fischer, F. G.; Lowenberg, K.
Liebigs Ann. Chem. 1932, 494, 263; Thomas, A. F.; Guntz-Dubin, R. Helv. Chim.
Acta 1976, 59, 2261.
2. Knovenagel, E.; Black, L. Chem. Ber. 1906, 39, 3441; Roger, A.; Godfroid, J. J.;
Wiemar, J. Bull. Soc. Chim. Fr. 1967, 8, 3030.
3. Bench, B. J.; Liu, C.; Evett, C. R.; Watanabe, C. M. H. J. Org. Chem. 2006, 71, 9458.
4. Ramachary, D. B.; Choudari, N. S.; Barbas, C. F., III Tetrahedron Lett. 2003, 43,
6743.
5. Leonard, N. J.; Musliner, W. J. J. Org. Chem. 1966, 31, 639.
6. (a) Chou, Y. L.; Cheng, X. E.; Zhang, Y. H. Chin. J. Chem. 1999, 11, 350; (b) Ohkite,
M.; Tsuji, T.; Nishida, S. Chem. Commun. 1991, 37.
In conclusion we have shown that the homodimerization of 2-
cyclohexenone(I) in the presence of the Bronsted base pyrrolidine
7. General procedure for preparation of 1: Freshly distilled amine (1–10 mmol) and
L
-proline (0.1–0.5 equiv mmol) were stirred while 2-cyclohexenone (1–
and the organocatalyst L-proline proceeds predominantly through
10 mmol) was added. This mixture was stirred for the designated period of
time and then an aliquot was withdraw, dissolved in diethyl-ether and
analyzed by GC/ESI-MS to determine the intermediates. For the analysis of the
ratio of homodimer isomers aq acid was added to the ether solution followed
by the same analysis after drying the ether layer.
a two-step mechanism12 after an initial conjugate adduct is
formed. We have characterized several reaction intermediates
and isolated an interesting side-product that supports the two-step
enamine/imine process as the preferred organocatalytic mecha-
nism over a concerted Diels–Alder reaction pathway.
8. Preparation and isolation of 2: The reaction was run as described7 except
L-
methyl-prolinate (3.0 mmol) was the freshly prepared amine. After 6 h the
thick red liquid was diluted with 30 ml of CH2Cl2 and washed with 15 ml of
10% aq citric acid soln, followed by 15 ml of satd NaHCO3 soln. The organic
layer was dried over anhyd MgSO4, filtered and concentrated to deliver a red oil
in 85% yield. Column chromatography over silica gel eluted the homodimers
Acknowledgments
(hexane/CHCl3), followed by the L-proline dimer (CHCl3) and then a fraction
containing 2 (EtOAc/CH3OH). Preparative RPLC of this mixture containing 2,
using a CH3CN/H2O gradient, produced two fractions with the early fraction
We thank the Department of Chemistry at the University of
Rhode Island and the URI Foundation each for the partial financial
support of this research. We would also like to thank Joseph Brady
delivering
a
yellow solid (2) mp = 159–163 °C;
C11H15NO2; MS/ESI:

5090
M+H+ = 194 amu; FT-IR (KBr):
V. Guidi et al. / Tetrahedron Letters 51 (2010) 5086–5090
= 3179 (w), 2953 (m), 2876 (w), 1642 (s) cmꢂ1
11. The -proline organocatalyst must be present to derive either of the
m
;
L
PMR (CDCl3): 1.7–2.2 (m, 7H), 3.2 (td, 1H), 3.3 (td, 1H), 3.5 (dt, 2H), 3.7 (exch.,
1H), 4.0 (dt, 2H), 4.2 (t, 1H) ppm; CMR (CDCl3): d = 22, 23, 28, 30, 44, 45, 60, 61,
110, 164, 166 ppm.
homodimeric isomers and thus it dictates the two-step mechanistic pathway
that produces exo-1 initially in preference to endo-1. This two-step mechanism
can in theory also deliver the endo-1 isomer [3 (Re) + E,S-5 (Re) first step9a] but
this latter two-step pathway must surmount a higher barrier than the former
mechanism. The one-step and energetically similar H-bond assisted Diels–
Alder reaction to this latter pathway can derive endo-1 with pyrrolidine but an
acid catalyst5,6a is required.
9. At the suggestion of a referee we have included the mass of intermediate
molecular ions determined by GC/ESI-MS. These M+ꢁ mass values (amu) were
characterized by their associated cracking patterns. [Note for example: Schmid,
M.B.; Zeitler, K.; Gschwind, R.M. Angew. Chem., Int. Ed, 2010 49, 4997.]
10. (a) There are two possible structures for intermediate 5 (CO2ꢂ). In theory these
two structures are interconvertible diastereomeric zwitterions with either a Z
or E iminium cation bonded to the S-prolinate anion. The nucleophilic face of 3
that attacks the electrophilic face of Z,S-5 (R = CO2ꢂ) in the first step thus
determines the ultimate stereochemical result of homodimerization. (b)
Homodimers produced by hydrolysis of 6 and 60 may be one of several rate-
limiting steps in the crude reaction mixture where the concentration of H2O is
very low. [For example: Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J.
Am. Chem. Soc. 2010, 132, 6.]
12. (a) Westermann, B.; Ayaz, M.; van Berkel, S. S. Angew. Chem., Int. Ed. 2010, 49,
846; (b) Grondel, C.; Jeanty, M.; Enders, E. Nat. Chem. 2010, 2, 167.
13. The racemic nature of isolated 4.HCl is due to the excess base that was utilized
in the organocatalytic reaction. Pyrrolidine, a fairly strong base (pKa ꢀ 11.3), is
able to initiate either an isomerization or racemization process during the
course of the reaction. [For example: Blackmond, D.G.; Moran, A.; Hughes, M.;
Armstrong, A. J. Am. Chem. Soc. 2010, 132, 7598.]