Development of a catalytic platform for nucleophilic substitution: Cyclopropenone-catalyzed chlorodehydration of alcohols

Article abstract of DOI:10.1002/anie.201104638

Cyclopropenone makes the switch: 2,3-Bis-(p-methoxyphenyl)cyclopropenone is a highly efficient catalyst for the chlorodehydration of 20 diverse alcohol substrates (see scheme; X=Cl). With oxalyl chloride as catalytic activator, this nucleophilic substitution proceeded through cyclopropenium-activated intermediates and resulted in complete stereochemical inversion in substrates with chiral centers.

Full text of DOI:10.1002/anie.201104638

Communications
DOI: 10.1002/anie.201104638
Synthetic Methods
Development of a Catalytic Platform for Nucleophilic Substitution:
Cyclopropenone-Catalyzed Chlorodehydration of Alcohols**
Christine M. Vanos and Tristan H. Lambert*
The nucleophilic substitution of alcohols is one of the most
commonly executed and strategically important transforma-
tions in organic chemistry.[1] These reactions have long been
used to transfer the structural and stereochemical complexity
of alcohols to a myriad of other products.[2] Despite this
importance, the traditional reagents for alcohol substitution
leave much to be desired. Such reagents often produce
problematic by-products or suffer from a narrow scope or
poor reactivity. Most importantly, many of these processes are
not amenable to catalysis or enantioselection (for example,
Figure 1. Cyclopropenones.
kinetic resolution or desymmetrization), with two recent
exceptions.[3,4]
As a powerful alternative to the established methods, we
recently reported a new strategy for promoting nucleophilic
substitution and other dehydration reactions, based on the
facile formation of aromatic cyclopropenium ions.[5] We have
demonstrated the effectiveness of this “cyclopropenium
activation” approach in a number of dehydration reactions,
including alcohol[5a] and carboxylic acid[5b] chlorodehydration,
diol cyclodehydration,[5c] and the Beckmann rearrange-
ment.[5d] This strategy offers potent reactivity, adaptable
reagents, and significant operational convenience. Herein,
we report the development of a catalytic platform for the
nucleophilic substitution of alcohols through simple cyclo-
propenone catalysts. This work provides a new means to
prepare alkyl chlorides from alcohols and sets the conceptual
framework for developing cyclopropenones into a new class
of organocatalysts.
polarization is also responsible for the unusual nucleophilicity
of the cyclopropenone carbonyl,[10] which is the reactivity we
have exploited in previous studies on the activation of
cyclopropenium ions. In those studies, cyclopropenones
served as the precursors to activated cyclopropenium ions,
and were the eventual by-products of dehydration. Therefore,
we hypothesized that a catalytic process that involves the
concurrent activation of cyclopropenone and substitution of
an alcohol could be realized.
Under our proposed design, cyclopropenone catalyst 1
would react rapidly with an activating agent, to produce
cyclopropenium salt 2 (Scheme 1). This cyclopropenium ion
Cyclopropenones were first prepared by Breslow et al.[6]
and Volpin and co-workers[7] more than 50 years ago. These
compounds have a number of useful qualities for applications
in catalysis, which include straightforward preparation[8] in
one or two steps from commercially available materials, and
the ability to tune their physical and electronic properties
(Figure 1).[9] In terms of reactivity, the pseudo-aromatic
character of the cyclopropenone ring (c.f. resonance form
1a) manifests itself in a remarkably large dipole moment,[6d]
and a relatively high carbonyl basicity.[6d,9b] This substantial
Scheme 1. General design of cyclopropenone-catalyzed nucleophilic
substitution.
would then react with an alcohol substrate 3, to generate the
key cyclopropenium-activated intermediate 4. Nucleophilic
displacement by the cyclopropenium counterion, or other
exogenous nucleophile, would then furnish the substitution
product 5, and return cyclopropenone 1 to the catalytic cycle.
The viability of this process depends on favorable competition
between the catalyst and the substrate in the reaction with the
activating agent. As a factor in this competition, the turnover
of the catalyst must also be facile. We were optimistic that
such selectivity could be achieved through tuning the
electronic profile of the cyclopropenone.
[*] C. M. Vanos, Prof. T. H. Lambert
Department of Chemistry, Columbia University
3000 Broadway, New York, NY 10027 (USA)
E-mail: tl2240@columbia.edu
[**] T.H.L. is grateful for an Alfred P. Sloan Research Fellowship and
Young Investigator Awards from Abbott and Amgen. We thank Prof.
Ronald Breslow for a helpful discussion and the Turro group
(especially Arun Sundaresan) and the Sames group, both of
Columbia University, for use of their instruments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104638.
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Table 2: Substrate scope of the cyclopropenone-catalyzed chlorodehy-
dration.
Initially, we chose to examine the chlorodehydration of 1-
phenylethanol (6) with oxalyl chloride and catalytic amounts
of various cyclopropenones 1 (Table 1). In the absence of any
Table 1: Optimization of the cyclopropenone-catalyzed alcohol chloro-
dehydration.[a]
Entry, Alcohol
Cond.
1, A
Product
Yield
[%][b]
84
2, A
90
Entry
R
Catalyst
conc. [m]
(COCl)2
Addition
time [h][b]
7 [%][c]
8 [%][c]
3, A
4, A
5, B
6, B
99
86
75
82
1
2
3
4
5
6
7
8
no catalyst
Ph
Ph
2,4-xylyl
Mes
m-NO2Ph
p-tBu-Ph
p-MeO-Ph
2,4-(MeO)2-Ph
Ph, iPr2N
iPr
adamantyl
p-MeO-Ph
p-MeO-Ph
p-MeO-Ph
p-MeO-Ph
–
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
0.25
0
100
32
25
25
33
86
13
9
62
83
11
8
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.05
0.03
0.03
68
75
75
67
14
87
91
38
17
89
92
33
96
>98
94
7, B
8, A
72[c]
94
9
10
11
12
13
14
15
16
9, A
90
99
67
4
<2
6
10, A
11, A
81
[a] The reactions were performed by combining 1-phenylethanol (6) with
the cyclopropenone catalyst 9 (10 mol%) in CH2Cl2, then adding a
solution of oxalyl chloride (1 equiv) in CH2Cl2 (0.5 mL) through a syringe
pump, over the time indicated. [b] 0 Indicates (COCl)2 was added as one
aliquot at the beginning of the reaction. [c] Percent conversion was
12, A
13, B
96
67[c]
1
determined by H NMR spectroscopy. The text in bold highlights the
conditions giving the highest yield of 7.
14, B
15, C
16, A
67
77
91
cyclopropenone, no alkyl chloride 7 was obtained, and
chloroxalate 8 was the only product (Table 1, entry 1). In
contrast, adding 10 mol% of 2,3-diphenylcyclopropenone
and a single aliquot of neat oxalyl chloride to the reaction
at room temperature increased the percentage of 7 obtained
to 68% (Table 1, entry 2). Adding the oxalyl chloride over
one hour by syringe pump increased the amount of 7 obtained
to 75% (Table 1, entry 3).
62
>98:2
d.r.
17, A
[a] Reaction conditions A: The alcohol substrate was combined with
cyclopropenone 9 (10 mol%, 0.03m in CH2Cl2) and a solution of oxalyl
chloride (1 equiv) in CH2Cl2 (0.5 mL) was added through a syringe
pump, over 1 h. Reaction conditions B: The same as reaction con-
ditions A, except PhCF3 was used as the solvent and the reaction was
performed at 808C. Reaction conditions C: The same as reaction
conditions A, except the oxalyl chloride solution was added over 8 h and
20 mol% of 9 was used. [b] Percent yield was determined after the
products were isolated and purified, except for entries 1 and 11, which
were determined by 1H NMR spectroscopy versus Bn2O as an internal
standard. [c] The oxalyl chloride solution was added over 4 h. PMP=p-
methoxyphenyl.
We expected that changing the substituents of the cyclo-
propenone ring would have a significant impact on the
efficiency of the reaction. Therefore, we screened a range of
cyclopropenones bearing different R groups. Increasing the
size of the aryl substituents made little impact on the ratio of
7:8 produced (Table 1, entries 4 and 5). On the other hand,
changing the electronic properties of the aryl substituents
significantly affected the outcome of the reaction. The
presence of an electron-withdrawing substituent (m-NO2)
was detrimental to the formation of 7 (Table 1, entry 6). In
contrast, the electron-donating substituents p-tert-butyl
(Table 1, entry 7) and p-methoxy (Table 1, entry 8) increased
the ratio of 7:8 to approximately 9:1. A further increase in the
electron-donating character of the cyclopropenone substitu-
ents was counterproductive (Table 1, entries 9 and 10),
although good selectivity was achieved with alkyl substituents
(Table 1, entries 11 and 12).
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Communications
Since it is readily available, we chose 2,3-bis-(p-methoxy-
To demonstrate the practical benefits of the cycloprope-
none-catalyzed strategy, catalyst 9 was compared with the
common chlorodehydration reagent, thionyl chloride
(Table 3). In the presence of 9, the anti-b-hydroxy ester 10
was converted into the chloride adduct 11 as a single
diastereomer, with a 90% yield of isolated product (Table 3,
entry 1). The same reaction with thionyl chloride in place of 9
afforded quantitative conversion of 10; however, the diaste-
reomeric chlorides 11 and 12 were obtained in a 93:7 ratio
(Table 3, entry 2). The use of thionyl chloride with pyridine
resulted in an approximately 1:1 mixture of the two diaste-
reomers (Table 3 , entry 3).
The same comparison was conducted with the syn alcohol
substrate 13 (Table 3, entries 4–6). The cyclopropenone-
catalyzed method generated the chloride adduct 14 in 79%
yield, with complete stereoselectivity (Table 3, entry 4).
Interestingly, the reaction with thionyl chloride did not
produce any chloride product under the same conditions
(Table 3, entry 5). The use of pyridine in addition to thionyl
chloride resulted in a modest conversion of the starting
material, but almost no stereoselectivity (Table 3, entry 6).
Our proposed mechanism for the cyclopropenone-cata-
lyzed chlorodehydration reaction is shown in Scheme 2. The
cyclopropenone catalyst 1 undergoes a rapid reaction with
phenyl)cyclopropenone for further optimization studies.
Interestingly, a twofold increase in the concentration of the
catalyst favored the production of 8 by a 2:1 ratio (Table 1,
entry 13), whereas a twofold dilution increased the selectivity
for chlorination to 96% (Table 1, entry 14). Diluting the
catalyst further almost completely suppressed the production
of 8 (Table 1, entry 15). The oxalyl chloride addition time
could also be reduced to 15 min, which did not significantly
affect the selectivity of the reaction (Table 1, entry 16).
A range of benzylic (Table 2, entries 1–8), allylic (Table 2,
entries 9–11), and propargylic alcohols (Table 2, entry 12)
were efficiently chlorodehydrated using cyclopropenone
catalysis. Notably, with some modifications to the reaction
conditions, a- and b-hydroxynitriles (Table 2, entries 5 and 6),
as well as an a-hydroxyester (Table 2, entry 7), were also
viable substrates. The modified reaction conditions, which
also included a higher temperature, were also effective for
converting aliphatic alcohols to the corresponding alkyl
chlorides (Table 2, entries 13 and 14). Moreover, this catalytic
method was rendered compatible with basic functional
groups, such as a pyridine ring (Table 2, entry 15). To
demonstrate the cyclopropenone-catalyzed procedure on a
preparative scale, we conducted the reaction with one gram of
1,3-diphenyl-1-propanol. This reaction produced the corre-
sponding chloride product in 91% yield (Table 2, entry 16).
Importantly, we determined that the chlorination occurs with
inversion of stereochemistry at chiral centers (entries 3, 7, and
17; see also Table 3).
Table 3: Comparison of the cyclopropenone-catalyzed and thionyl chlo-
ride mediated chlorodehydrations.
Entry
Conditions[a]
Yield [%][b]
syn/anti[c]
1
2
3
9 (10 mol%), (COCl)2
SOCl2
SOCl2, pyridine
90
100
90
>98:2
93:7
57:43
Scheme 2. Proposed mechanism for the cyclopropenone-catalyzed
chlorodehydration.
Entry
Conditions[a]
Yield [%][b]
syn/anti[c]
4
5
6
9 (10 mol%), (COCl)2
SOCl2
SOCl2, pyridine
79
0
55
>98:2
–
58:42
oxalyl chloride to generate the 1,1-dichlorocyclopropene
16.[11] Ionization of 16 affords the cyclopropenium chloride
salt 17. The salt then reacts with the alcohol substrate 18 to
produce the protonated cyclopropenyl ether 19. After depro-
tonation of 19, the neutral cyclopropene 20 re-ionizes to give
the key alkoxy cyclopropenium salt 21. Compound 21 is a
species we have detected by 1H NMR spectroscopy.[5a]
Nucleophilic displacement of the cyclopropenium oxide by
a chloride ion then produces the chloride adduct 22, and
regenerates the catalyst 1.
[a] The reactions in entries 1 and 4 were performed by combining the
alcohol substrate with cyclopropenone 9 (10 mol%) in PhCF3 at 808C, then
adding a solution of oxalyl chloride (1 equiv) through a syringe pump, over
1 h. The reactions in entries 2 and 5 were performed by combining the
alcohol substrate with thionyl chloride (1.5 equiv) in PhMe at 558C for
90 min. The reactions in entries 3 and 6 were performed by combining the
alcohol substrate with thionyl chloride (1.1 equiv) and pyridine (1.1 equiv)
in CHCl3 at 558C for 90 min. [b] For entries 1 and 4, percent yield was
determined after the products were isolated and purified. For entries 2, 3,
5, and 6, percent yield was calculated by 1H NMR spectroscopy versus
Bn2O as an internal standard. [c] Ratios were determined on the crude
reaction product by 1H NMR spectroscopy.
The mechanism proposed in Scheme 2 is in accordance
with our previous studies on the potent reactivity of
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Angew. Chem. Int. Ed. 2011, 50, 12222 –12226

dichlorocyclopropenes 16.[5] However, another plausible
pathway by which the reaction might occur must be consid-
ered (Scheme 3).[12] Thus, reaction of 18 with oxalyl chloride
produces the chloroxalate 23, which was a by-product
detected in our reactions. Theoretically, nucleophilic attack
productive intermediate for cyclopropenone-catalyzed chlor-
odehydration with suitably reactive substrates. However,
because our catalytic procedure has a vastly superior rate
(99% conv. in 1 h after 1 h addition of oxalyl chloride) to that
shown in Table 4, entry 3, we favor the mechanism shown in
Scheme 2.
In summary, we have developed a cyclopropenone-based
catalyst for nucleophilic substitution in the context of alcohol
chlorodehydration. The ability to generate alkyl chlorides
from alcohols by using a catalytic amount of a ketone is a
major improvement over traditional methods. Broadly speak-
ing, we expect that the concept of cyclopropenone catalysis
will be applicable to a wide range of dehydration reactions.
Importantly, this work raises the intriguing possibility of
applying enantioselective catalysts to kinetic resolutions or
desymmetrizations. Efforts in this regard are currently under-
way in our laboratory.
Scheme 3. Alternative mechanism for the cyclopropenone-catalyzed
chlorodehydration.
Received: July 5, 2011
Revised: September 14, 2011
Published online: October 26, 2011
of 1 on 23 could result in the intermediate 24, which would
then decompose into the chloride product 22, carbon dioxide,
and carbon monoxide, while regenerating 1. This alternative
mechanism is analogous to that proposed, and subsequently
disproved, by Denton et al. for their triphenylphosphine
oxide catalyzed chlorodehydration procedure.[3b]
Keywords: alcohols · chlorodehydration · cyclopropenones ·
.
nucleophilic substitution
[1] For Reviews, see a) Comprehensive Organic Synthesis, Vol. 6
(Eds.: B. Trost, I. Flemming), Pergamon, Oxford, 1991,
chap. 1.1 – 1.9, p. 1 – 284; b) E. Emer, R. Sinisi, M. G. Capdevila,
D. Petruzziello, F. D. Vincentiis, P. G. Cozzi, Eur. J. Org. Chem.
2011, 647 – 666.
[2] a) R. C. Larock in Comprehensive Organic Transformations, 2nd
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S. R. James in Comprehensive Organic Chemistry, Vol. 1 (Eds.:
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c) M. Hudlicky, T. Hudlicky in Chemistry of Functional Groups,
Supplement D (Eds.: S. Patai, Z. Rappoport), Wiley, New York,
1983, p. 1021.
[3] Denton et al. have recently described a method for triphenyl-
phosphine oxide catalyzed chlorodehydration, which may allow
the development of enantioselective variants; a) R. M. Denton,
A. Jie, B. Adeniran, Chem. Commun. 2010, 46, 3025 – 3027;
b) R. M. Denton, J. An, B. Adeniran, A. J. Blake, W. Lewis,
A. M. Poulton, J. Org. Chem. 2011, 76, 6749 – 6767.
To determine if the mechanism shown in Scheme 3 was
operating in the cyclopropenone-catalyzed process, three
different alcohol substrates were treated with one equivalent
of oxalyl chloride, to generate a series of chloroxalate esters
(23), and then with 10 mol% of 9 (Table 4). In the case of a
non-activated alcohol (Table 4, entry 1) or an a-hydroxy ester
(Table 4, entry 2), no chloride products 22 were observed
after 4 h. These results demonstrate that the reaction did not
proceed through the mechanism shown in Scheme 3 with
these two substrates. On the other hand, the reaction with 1-
phenylethanol proceeded to 50% conversion after 1 h
(Table 4, entry 3). Therefore, side product 23 may still be a
Table 4: Investigation of alternative chlorodehydration mechanism.
[4] An intriguing approach to alcohol halodehydration using photo-
redox catalysis has recently been reported. C. Dai, J. M. R.
Narayanam, C. R. J. Stephenson, Nat. Chem. 2011, 3, 140 – 145.
[5] a) B. D. Kelly, T. H. Lambert, J. Am. Chem. Soc. 2009, 131,
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Lambert, Org. Lett. 2011, 13, 740 – 743.
[6] a) R. Breslow, R. R. Haynie, J. Mirra, J. Am. Chem. Soc. 1959,
81, 247 – 248. See also: b) R. Breslow, R. Peterson, J. Am. Chem.
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1326 – 1331.
Entry
Alcohol
Conditions[a]
PhCF3, 808C
PhCF3, 808C
CH2Cl2, 238C
Time [h]
Conv [%][b]
0 (67)
1
2
3
4
4
1
0 (88)
50 (99)
[a] The reactions were performed by combining the alcohol substrate
with oxalyl chloride (1 equiv) in the solvent indicated. After 30 min
cyclopropenone 9 (10 mol%) was added, and the reaction stirred at the
temperature indicated for 1 or 4 h. [b] Conversion rates were determined
by 1H NMR spectroscopy versus Bn2O as an internal standard. The
numbers in parentheses indicate the yield of isolated chloride product
obtained by using the corresponding cyclopropenone-catalyzed reaction.
[7] D. N. Kursanov, M. E. Volpin, Y. D. Koreshkov, Izv. Akad. Nauk
SSSR, Otd. Khim. Nauk 1959, 560.
[8] We find that the most useful method for synthesizing diaryl-
cyclopropenones is that described by West et al., starting from
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Communications
tetrachlorocyclopropene. R. West, D. C. Zecher, W. Goyert, J.
Am. Chem. Soc. 1970, 92, 149 – 154.
[10] For example, see a) B. Fçhlisch, P. Bꢀrgle, Justus Liebigs Ann.
Chem. 1967, 701, 67 – 87; b) M. Oda, R. Breslow, J. Pecoraro,
Tetrahedron Lett. 1972, 13, 4415 – 4417.
[11] 1,1,-dichlorocyclopropenes are readily prepared from the corre-
sponding 2,3-disubstituted cyclopropenones by treatment with
sulfonyl chloride or oxalyl chloride. a) B. Fçhlisch, P. Bꢀrgle,
Justus Liebigs Ann. Chem. 1967, 701, 67 – 87; b) R. Breslow, J.
Posner, Org. Synth. 1967, 47, 62.
[9] For Reviews on cyclopropenium ions and cyclopropenones, see
a) K. Komatsu, T. Kitagawa, Chem. Rev. 2003, 103, 1371 – 1428;
b) A. W. Krebs, Angew. Chem. 1965, 77, 10 – 22; Angew. Chem.
Int. Ed. Engl. 1965, 4, 10 – 22; c) A. W. Krebs, Angew. Chem.
1965, 77, 10 – 22.
[12] We are grateful to a referee for pointing out this possibility.
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