Electrophilicities of α-chlorinating agents used in organocatalysis

Article abstract of DOI:10.1021/ol100592j

Kinetics of the reactions of the chlorinating agents 1a-c with π-nucleophiles have been studied to include these compounds in our comprehensive electrophilicity scale.

Full text of DOI:10.1021/ol100592j

ORGANIC
LETTERS
2
010
Vol. 12, No. 10
238-2241
Electrophilicities of r-Chlorinating
Agents Used in Organocatalysis
2
Xin-Hua Duan and Herbert Mayr*
Department Chemie, Ludwig-Maximilians-UniVersit a¨ t M u¨ nchen, Butenandtstrasse 5-13
(
Haus F), 81377 M u¨ nchen, Germany
herbert.mayr@cup.uni-muenchen.de
Received March 11, 2010
ABSTRACT
Kinetics of the reactions of the chlorinating agents 1a-c with π-nucleophiles have been studied to include these compounds in our
comprehensive electrophilicity scale.
3
Nucleophilic substitutions of C-Cl bonds are an important
method for the stereocontrolled generation of C-C, C-N,
and C-O bonds. For that reason, enantioselective construc-
organocatalysts such as amines and phosphanes. Using the
linear free energy relationship (eq 1), where E is an
electrophile-specific parameter, and N and s are nucleophile-
1
4
tions of stereogenic centers carrying a chlorine substituent
are of eminent importance for organic synthesis. Among
various methods developed for this purpose, organocatalytic
R-halogenations of carbonyl compounds have been found
to be particularly efficient, and the polychloroquinone derived
reagents 1a-c belong to the most frequently used chlorinat-
specific parameters, we have furthermore characterized
nucleophilicities of substrates for iminium-catalyzed reac-
tions, e.g., pyrroles, indoles, and sulfur ylides, as well
as the nucleophilicities of enamines and the electrophilici-
ties of iminium ions, key intermediates of organocatalytic
reactions.
5
c
5b
5e
5a
5
d
2
ing agents.
log k(20°C) ) s(N + E)
(1)
In previous reviews on scope and limitations of eq 1 we
have stated that this correlation, which was initially derived
4
a-c
for reactions of carbocations with olefins,
cannot be
expected to hold for halogenation reactions, because bridging
(
2) Reviews: (a) France, S.; Weatherwax, A.; Lectka, T. Eur. J. Org.
During our efforts to rationalize scope and limitations of
organocatalytic processes, we have previously characterized
nucleophilicities and carbon basicities of frequently used
Chem. 2005, 475–479. (b) Marigo, M.; Jørgensen, K. A. Chem. Commun.
2006, 2001–2011. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. ReV. 2007, 107, 5471–5569. (d) Czekelius, C.; Tzschucke, C. C.
Synthesis 2010, 543–566, and references cited therein.
(
3) (a) Kempf, B.; Mayr, H. Chem.sEur. J. 2005, 11, 917–927. (b)
(
1) (a) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Baidya, M.; Kobayashi, S.; Brotzel, F.; Schmidhammer, U.; Riedle, E.;
Mayr, H. Angew. Chem., Int. Ed. 2007, 46, 6176–6179. (c) Baidya, M.;
Mayr, H. Chem. Commun. 2008, 1792–1794. (d) Baidya, M.; Horn, M.;
Zipse, H.; Mayr, H. J. Org. Chem. 2009, 74, 7157–7164. (e) Kanzian, T.;
Nigst, T. A.; Maier, A.; Pichl, S.; Mayr, H. Eur. J. Org. Chem. 2009, 6379–
6385.
Reactions, Mechanisms, and Structure, 6th ed.; John Wiley & Sons: New
York, 2007. (b) House, H. Modern Synthetic Reactions, 2nd ed.; W. A.
Benjamin: New York, 1972. (c) De Kimpe, N.; Verh e´ , R. The Chemistry
of R-Haloketones, R-Haloaldehydes, and R-Haloimines; John Wiley & Sons:
New York, 1988.
10.1021/ol100592j  2010 American Chemical Society
Published on Web 04/22/2010

+
2 2
electrophiles (Br , Cl , RS ) are known to follow a different
selectivity pattern as nonbridging electrophiles (Scheme 1).
As shown in Scheme 1, the reactivities of CC double bonds
Table 1. N and s Parameters of the Employed Nucleophiles
Scheme 1
.
Relative Reactivities of Alkenes toward Various
Electrophiles (from ref 6)
toward nonbridging electrophiles are hardly affected by alkyl
groups at the position of electrophilic attack but are strongly
6
increased by alkyl groups at the new carbenium center. In
contrast, reactivities toward bridging electrophiles are in-
creased almost equally by alkyl groups at both termini of
the double bond.
Scheme 2
.
R-Chlorinations of Carbonyl Compounds Catalyzed
by Secondary Amines
that of the pentachlorophenolate ion, which absorbs at shorter
wavelength (λmax ) 351 nm). For that reason, the kinetics
of the reactions of 1a, as well as of 5,7,7-trichloro-8(7H)-
quinolinone (1b) and 2,2,4-trichloro-1(2H)-naphthalenone
(1c), with the nucleophiles 2 could be determined photo-
metrically by monitoring the disappearance of the absor-
bances of 1a-c at 366-378 nm.
When equimolar amounts of the chlorinated quinones 1a
and the N-methylindole (2a) were combined in CH CN at
3
room temperature, the corresponding 3-chloro-N-methylin-
dole was isolated in 81% yield after aqueous workup
(Scheme 3). Silyl enol ethers usually gave moderate yields
of R-chlorocarbonyl compounds. For instance, when 1a was
slowly added to a solution of 1-(trimethylsiloxy)cyclopentene
(
2c) or 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (2f)
in CH CN at room temperature, 2-chlorocyclopentanone and
methyl 2-chloroisobutyrate were obtained in low yields. The
yields increased to 55% and 51%, respectively, when CH Cl
2
As illustrated in Scheme 2, enamines have been suggested
to be the key intermediates in organocatalytic chlorinations
of carbonyl compounds. Because chloro-bridging does not
3
2
2
occur in ꢀ-chloro-substituted iminium ions, we had specu-
was used as the solvent. Treatment of 1a with 1 equiv of
lated that the relative reactivities of enamines and other
electron-rich π-systems toward “Cl ” may follow the same
reactivity order as toward carbenium ions, with the conse-
quence that the N and s parameters of the π-nucleophiles
+
(4) Reviews: (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994,
3
3, 938–957. (b) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.;
Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel,
H. J. Am. Chem. Soc. 2001, 123, 9500–9512. (c) Mayr, H.; Kempf, B.;
Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77. (d) Mayr, H.; Ofial, A. R.
Pure Appl. Chem. 2005, 77, 1807–1821. (e) Mayr, H.; Ofial, A. R. J. Phys.
Org. Chem. 2008, 21, 584–595.
2
a-m (Table 1) which have been derived from the rates of
their reactions with benzhydrylium ions can also be used to
describe the rates of their reactions with the electrophiles
(
5) (a) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.sEur. J.
2
003, 9, 2209–2218. (b) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont,
R.; Boubaker, T.; Ofial, A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088–
095. (c) Nigst, T. A.; Westermaier, M.; Ofial, A. R.; Mayr, H. Eur. J.
1
a-c.
9
As shown in Scheme 3 for the reaction of 2,3,4,5,6,6-
Org. Chem. 2008, 2369–2374. (d) Lakhdar, S.; Tokuyasu, T.; Mayr, H.
Angew. Chem., Int. Ed. 2008, 47, 8723–8726. (e) Lakhdar, S.; Appel, R.;
Mayr, H. Angew. Chem., Int. Ed. 2009, 48, 5034–5037.
hexachlorocyclohexa-2,4-dien-1-one (1a) with the indole 2a,
the silyl enol ether 2c, and the enamine 2g, the chlorine
transfer step is associated with the conversion of the
cyclohexadienone chromophor of 1a (λmax ) 378 nm) into
(
6) Mayr, H. In Cationic Polymerization: Mechanisms, Synthesis and
Applications; Matyjaszewski, K., Ed.; Marcel Dekker: New York, 1996;
pp 51-136.
Org. Lett., Vol. 12, No. 10, 2010
2239

2 2
N-(1-phenylvinyl)morpholine (2g) in CH Cl gave R-chlo-
roacetophenone in 78% yield. Under the same conditions,
the reactions of the polychlorinated quinones 1b and 1c also
produced 60% and 65% yields of R-chloroacetophenone,
respectively. Because analogous reaction products can be
expected for the combination of 1a-c with other substrates,
product studies have not been performed for all reactions
that have been studied kinetically.
Scheme 3. Reactions of 1a with π-Nucleophiles
Figure 1. Exponential decay of the absorbance at 378 nm during
-4
-3
the reaction of 1a (4.19 × 10 M) with 2g (4.43 × 10 M) and
correlation of kobs with the concentrations of 2g (in the insert).
2
Lindo systems. In this way a unity slope for the (log k )/s
vs N plots was enforced. Table S1 in the Supporting
Information shows that experimental and calculated rate
constants determined in this way agree within a factor of
12. The correlations are of lower quality for the correspond-
ing reactions of 1b and 1c, but also in these cases, the
deviations between calculated and experimental rate constants
are less than a factor of 22, which is quite satisfactory for a
three-parameter equation covering a reactivity range of 40
orders of magnitude.
As mentioned above, the kinetics of the reactions of 1a-c
with π-nucleophiles were determined photometrically by
following the disappearance of the absorbances of the
R-chlorinating agents at 366-378 nm, using conventional
and stopped-flow UV/vis spectrometers. All kinetic experi-
ments were performed at 20 °C in CH CN with a high excess
3
of the nucleophiles 2a-m in order to achieve first-order
As an alternative to the direct chlorine attack at the π-bond
of the enamine (Scheme 2 and upper reaction path in Scheme
4), initial N-chlorination and subsequent 1,3-sigmatropic shift
of chlorine to the carbon atom (lower pathway in Scheme
8
4
) has been suggested. Figure 2 shows that the relative
conditions (eq 2).
-
d[1]/dt ) kobs[1]
(2)
Table 2. Second-Order Rate Constants k
the Polychlorinated Quinones 1a-c with the π-Nucleophiles
a-m in CH CN at 20 °C
2
for the Reactions of
As a consequence, exponential decays of the concentra-
tions of the UV-active electrophiles were observed. The first-
order rate constants kobs were obtained by least-squares fitting
2
3
2
k ]
[M- s-1
1
electrophile
λ
max [nm]
378
nucleophile
of the time-dependent absorbances of the electrophiles to A
t
-2
-2
1
a
2a
2b
2c
4.01 × 10
1.89 × 10
1.26
-
k
t
obs
)
A
0
e
+ C. Plots of kobs versus the concentrations of
the nucleophiles [2] gave straight lines with the slopes k
2
as
2
d
6.52
shown for one example in Figure 1. The slopes of these plots
1
-1
-1
2e
1.60 × 10
1.36 × 10
3.24 × 10
1.04 × 10
8.76 × 10
4.59 × 10
1.38 × 10
1.93 × 10
6.97 × 10
2.91
2.82 × 10
6.21 × 10
4.84 × 10
2.40 × 10
1.20 × 10
3.81 × 10
4.85 × 10
1.18 × 10
2
gave the second-order rate constants k [M s ], which are
2
2
2
2
2
f
g
i
summarized in Table 2.
3
If eq 1 were followed, plots of (log k)/s versus N should
be linear with a slope of 1. Figure 2 shows that the reactivities
of different classes of compounds, i.e., pyrroles, indoles, enol
ethers, and ketene acetals, with the chlorinating agent 1a are,
indeed, linearly correlated with the nucleophilicity parameters
N, but the slope (s ) 1.25) is slightly larger than 1. Though
the nonunity slope might be taken care of by introducing a
4
4
j
-2
1
1
b
c
366
375
2f
2g
2h
-
-
1
1
1
2
2
2
2
j
k
l
2
second, electrophile-specific slope parameter, as previously
2
m
7
suggested for the treatment of S
N
2 reactions, we have
-1
-2
1
2g
abstained from introducing an electrophile-specific slope
2
h
2
parameter and determined E by minimizing ∆ ) ∑(log k
2j
2k
2
-1
1
-
s(N + E)) with the nonlinear solver “What’s Best!” by
2
l
2
(
7) Phan, T. B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2006,
2m
4
5, 3869–3874.
2240
Org. Lett., Vol. 12, No. 10, 2010

Figure 2
N for the reactions of the chlorinated quinones 1a and 1b with the
nucleophiles 2 (CH CN, 20 °C).
2
. Correlation of (log k )/s with the nucleophilicity parameter
3
reactivities of enamines, silylated enols, and ketene acetals,
as well as of pyrroles and indoles toward the chlorinating
agents 1a and 1b, are the same as toward donor-substituted
diarylcarbenium ions, from which the N-scale has been
derived. Though highly reversible N-attack by diarylcarbe-
nium ions at enamines could not be excluded, it has been
demonstrated that the observed second-order rate constants
for these reactions reflect the rates of the CC bond-forming
Figure 3
. Comparison of the electrophilicities of chlorinated
quinones 1a-c with those of carbon electrophiles.
4
5
3
), which shows that 1a is a 10 - to 10 -fold stronger
electrophile than 1b and 1c, comparable to amino-substituted
benzhydrylium ions and R,ꢀ-unsaturated iminium ions. This
reactivity order is in line with the observation that 1a is a
particularly suitable reagent for the imidazolidinone catalyzed
5
a
step. As a consequence, the N and s parameters in Table
, including those of enamines, reflect π-nucleophilicities,
and the correlations shown in Figure 2 indicate analogous
1
9
R-chlorination reactions of aldehydes, or R-chlorinations of
10
acyl chlorides via intermediate ketenes. On the other hand,
the more reactive carbanions derived from 1,3-dicarbonyl
compounds have been found to react with much better
enantioselectivities with the mild chlorinating agent 1b than
Scheme 4. Ambident Reactivity of Enamines
1
1
with the more reactive electrophile 1a.
The linear free-energy relationship log k(20°C) ) s(N +
E) (eq 1) has thus been found to be suitable for predicting
the rate constants for the reactions of the chlorinated quinones
1
a-c with π-nucleophiles from the E parameters of 1a-c
determined in this work and the nucleophile specific param-
4
,5
eters N and s for 2a-m reported earlier. With these
parameters at hand, one can compare the electrophilicities
of chlorinated quinones with those of carbon electrophiles,
and even more important, use them as a guide for selecting
suitable electrophiles for organocatalytic halogenations.
transition states for electrophilic chlorinations and alkylations
of the nucleophiles 2. In view of these findings, the generality
8
of the suggested N-attack of electrophilic chlorinating agents
at enamines in amine-catalyzed R-chlorinations of aldehydes
should be examined.
The kinetic data now allow us to include the chlorinating
agents into our comprehensive electrophilicity scale (Figure
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (Ma 673/21-3) and the Fonds der Chemischen
Industrie for financial support. Valuable suggestions by Dr.
Armin R. Ofial and Dr. Mahiuddin Baidya are gratefully
acknowledged.
(8) (a) Halland, N.; Alstrup Lie, M.; Kjærsgaard, A.; Marigo, M.; Schiøtt,
B.; Jørgensen, K. A. Chem.sEur. J. 2005, 11, 7083–7090. (b) Marquez,
C. A.; Fabbretti, F.; Metzger, J. O. Angew. Chem., Int. Ed. 2007, 46, 6915–
6
917.
9) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2004, 126, 4108–4109.
10) (a) Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Lectka, T.
(
Supporting Information Available: Details of the prod-
uct characterization and the kinetic experiments. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
(
J. Am. Chem. Soc. 2001, 123, 1531–1532. (b) France, S.; Wack, H.; Taggi,
A. E.; Hafez, A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C. L.; Lectka,
T. J. Am. Chem. Soc. 2004, 126, 4245–4255.
(
11) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Angew. Chem., Int. Ed. 2005, 44, 6219–6222.
OL100592J
Org. Lett., Vol. 12, No. 10, 2010
2241