1-(Arylsulfonyl)cyclopropanol, a new cyclopropanone equivalent and its application to prepare 1-alkynyl cyclopropylamine

Article abstract of DOI:10.1016/j.tetlet.2007.11.093

Cyclopropanone derivative 1-(arylsulfonyl)cyclopropanol 4 simply prepared from the reaction of cyclopropanone ethyl hemiacetal 3 with sodium arylsufinate in the presence of formic acid is a new cyclopropanone equivalent to react with terminal acetylenes,

Full text of DOI:10.1016/j.tetlet.2007.11.093

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 490–494
1-(Arylsulfonyl)cyclopropanol, a new cyclopropanone equivalent
and its application to prepare 1-alkynyl cyclopropylamine
*
Jie Liu, Yan An, Hai-Ying Jiang, Zili Chen
Department of Chemistry, Renmin University of China, Beijing 100872, China
Received 14 September 2007; revised 14 November 2007; accepted 16 November 2007
Available online 22 November 2007
Abstract
Cyclopropanone derivative 1-(arylsulfonyl)cyclopropanol 4 simply prepared from the reaction of cyclopropanone ethyl hemiacetal 3
with sodium arylsufinate in the presence of formic acid is a new cyclopropanone equivalent to react with terminal acetylenes, and disub-
stituted amines in water catalyzed by AuCl3, to provide an unprecedented synthesis of 1-alkynyl cyclopropylamines in moderate yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Cyclopropanone; 1-Alkynyl cyclopropylamine; AuCl3; Terminal alkyne
1. Introduction
Cyclopropanone, which is formed from ketene and
diazomethane in inert solvent at À78 ꢁC,6 seems to be a fea-
sible precursor to incorporate a cyclopropyl group in
organic compounds, but is not sufficiently stable to permit
useful synthetic applications. Two cyclopropanone deriva-
tives, hydrated cyclopropanone 27 and cyclopropanone
hemiacetal 3,8 (Fig. 1) have been developed to provide a
convenient source of the parent ketone. However, their util-
ity was dwarfed either by their volatility and low stability,
or by their decreased reactivity, (EtOÀ is not a good leaving
group9). In this Letter, a new cyclopropanone surrogate and
its application in the synthesis of 1-alkynyl cyclopropyl-
amines are reported. Although some methods have been
reported to incorporate a cyclopropyl group into an amine
group either directly10 or indirectly,11 to the best of our
knowledge, there is no procedure allowing the simple con-
struction of alkynyl-substituted cyclopropylamines.12
The cyclopropyl group is found as a basic structural ele-
ment in a wide range of naturally occurring compounds in
plants and in microorganisms, and as a privileged unit in
medicinal chemistry since it possesses unique spatial and
electronic properties in conjunction with high metabolic
stability.1 The cyclopropane chemical reactivity not only
closely resembles that of an olefinic double bond but more-
over also involves rearrangements of particular synthetic
importance: that is, ring-opening and expansion reactions,
and it has established its potential as useful building blocks
in organic synthesis.2
Most synthetic strategies for constructing cyclopropyl
group in organic compounds resorted to carbene addition
to an alkene, for example, Simmons–Smith cyclopropana-
tion,3 sulfur ylide chemistry4 or the transition metal cata-
lyzed cyclopropanation of an alkene with a-diazocarbonyl
compounds.5 Developing new approach of cyclopropana-
tion therefore can enhance the flexibility to construct these
important structural entities.
R
O
O
ΗΟ
ΟΗ
ΗΟ
ΟΕτ
ΗΟ
S
O
4a, R=H
4b, R=Me
1
2
3
*
Corresponding author. Tel./fax: +86 10 62516660.
Fig. 1. Cyclopropanone and its derivatives.
E-mail address: zilichen@ruc.edu.cn (Z. Chen).
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.093

J. Liu et al. / Tetrahedron Letters 49 (2008) 490–494
491
Table 1
R
Three components coupling of 4a, phenyl-acetylene, and piperidine
O
ΗΟ
ΟΕτ
HCOOH
ΗΟ
S
Catalyst
(mol %)
Solvent/
additive
5/6/4a
(equiv)
Time (h)/
temp
Yielda
+
R
SO2Na
O
CH3OH
H2O
1
2
3
4
5
6
7
8
9
AuCl3 (1)
AuCl3 (1)
AuCl3 (1)
AuCl3 (1)
HAuCl4 (1)
NaAuCl4 (1)
AuCl3 (1)
AuCl3 (1)
AuCl3 (1)
H2O
H2O
H2O
H2O
H2O
H2O
C2H5OH
CH3CN
CH2Cl2
H2O
1.5/1/1
1.5/0.9/1
2/1.5/1
2/2/1
2/1.5/1
2/1.5/1
2/1.5/1
2/1.5/1
2/1.5/1
2/1.5/1
2/1.5/1
2/1.5/1
2/1.5/1
12/rt
12/rt
12/rt
12/rt
12/rt
12/rt
12/rt
12/rt
12/rt
12/rt
12/rt
12/35 ꢁC
12/rt
12/rt
12/rt
30
13
42
36
3
4a, R=H
4b, R=Me
Scheme 1. Synthesis of 1-(arylsulfonyl)cyclopropanol.
<10
13
27
11
5
56
62b
55
34
31
34
10 AuCl3 (2)
11 AuCl3 (2)
12 AuCl3 (2)
13 AuCl3 (5)
14 AuCl3 (2)
15 AuCl3 (2)
a
H2O
H2O
H2O
H2O/Na2CO3 2/1.5/1
H2O/Et3N 2/1.5/1
Isolated yields based on compound 4a.
Compound 4a was added in three batches.
b
structure of 4a was also confirmed by X-ray crystallogra-
phy (Fig. 2).15
Fig. 2. The X-ray crystal structure of compound 4a.
When we explored the reaction of 4a with phenylacety-
lene and piperidine in water with 1 mol % AuCl3 as cata-
lyst,16 the compound N-piperidinyl-1-(phenylethynyl)
cyclopropane 7a was obtained in 30% yield (Table 1, entry
1). In contrast, cyclopropanone hemiacetal 3a afforded no
product under the same condition (Scheme 2, Eq. 1). The
effect of the amount of amine on the yield was then tested.
When 1.5 equiv piperidine was employed with 2 equiv
phenylacetylene, 7a was obtained in 42% yield (Table 1,
entry 3). Further increasing the amount of the amine was
proved fruitless.
Subsequently, other gold salts such as HAuCl4 and
NaAuCl4 were investigated and showed much lower cata-
lytic activity than AuCl3 (Table 1, entries 5 and 6); whereas
the copper and silver salts, such as CuI,17 CuCl, and AgI,18
were totally inactive. In solvent screening experiments,
water was found to be superior to other protic or nonprotic
solvent, such as C2H5OH, CH3CN, and CH2Cl2 (Table 1,
entries 7–9). A number of additives such as Et3N and
Na2CO3 were evaluated (Table 1, entries 14 and 15), but
all of them lowered the yield. Optimization of reaction
temperature and the amount of AuCl3 identified a set of
2. Results
Cyclopropanone derivative 1-(benzenesulfonyl) cyclo-
propanol 4a can be simply prepared by the reaction of
cyclopropanone ethyl hemiacetal 3 with sodium benzene-
sulfinate in a mixture of solvents, CH3OH:H2O (1:2) in
the presence of 10 equiv HCOOH as a catalyst (Scheme
1). Extraction of the water diluted reaction mixture with
dichloromethane followed by recrystallization gave com-
pound 4a as a colorless crystal in 63% yield. Increasing
the equivalents of HCOOH significantly reduced the reac-
tion time. Compound 4b can be prepared by the same
method. The effort to synthesize 1-(benzenesulfonyl) cyclo-
butanol failed,13 perhaps because of less I strain in
cyclobutanone.
The new compounds were quite stable and could be kept
at 0 ꢁC for several months without explicit decomposi-
1
tion.14 Their structures were characterized by H and 13C
1
NMR spectral data including the H H-2/H-3 signals (t,
1.2–1.6 ppm) and 13C C-2/C-3 signals (13.5 ppm). The
AuCl3
ΗΟ
OEt
+
+
Ph
5a
NR
(1)
N
H
H2O
3
6a
Ph
catalyst
solvent
O
S
+
+
N
Ph
ΗΟ
(2)
N
O
H
4a
5a
6a
7a
Scheme 2. The coupling reaction of 3 or 4a, phenylacetylene and piperidine.

492
J. Liu et al. / Tetrahedron Letters 49 (2008) 490–494
Table 2
Coupling reactiona of compound 4 with a series of terminal alkynes and disubstituted aminesb
Entry
Alkyne 5
Amine 6
Product (yield %)
1
N
NH
7a 62% (34%C)
2
3
N
NH
7b 55%
N
NH
7c 65%
4
5
N
NH
NH
7d 54%d
N
7e 57%d
6
N
NH
7f 64%d
O
O
O
7
8
N
NH
7g 70%
O
N
NH
7h 64%
O
9
N
O
NH
7i 30%

J. Liu et al. / Tetrahedron Letters 49 (2008) 490–494
493
Table 2 (continued)
Entry
Alkyne 5
Amine 6
Product (yield %)
O
10
N
O
NH
7j 32%
11
12
13
N
NH
7k 41%
N
NH
7l 48%
Cl
Cl
N
NH
7m 42%
14
N
NH
7n 55%
a
All reactions were carried out at 0.5 mmol scale with alkyne/amine/4a = 2/1.5/1 (4a was added in three batches), using 2 mol % of AuCl3 as catalyst in
1 mL water at rt for 12 h.
b
Unless noted, isolated yields were based on 4a.
Compound 4b was used as substrate.
Reaction temperature was improved to 35 ꢁC to enhance the solubility of p-methyl phenylacetylene in water.
c
d
conditions (2 mol % of AuCl3, water, rt Table 1, entry 10)
to give the desired product in 55% yield. To prevent the
possible decomposition during the course of the reaction,
4a was added in three batches. This way, the reaction yield
was slightly improved (Table 1, entry 11).
mized reaction conditions with Au(III) catalyst (2 mol %
of AuCl3, alkyne/amine/4a = 2/1.5/1, 0.5 M in water, addi-
tion of 4a in three batches, rt, 12 h). Both aromatic and
hetero-aromatic terminal alkynes including those bearing
functional groups such as alkoxy, chloro, and methyl, were
able to undergo the corresponding three-component-cou-
pling reaction. Aryl alkynes with electron-donating groups
(Table 2, entries 4–8) displayed relatively high reactivity
and gave higher conversion. However, other aryl alkynes
such as 4-chlorophenylacetylene (Table 2, entry 13) with
electron-withdrawing substituent and hetero-aromatic
2-furyl ethyne (Table 2, entries 9 and 10) exhibited rela-
tively low reactivity. Alkene substituted alkynes also
worked effectively in this reaction (Table 2, entries 11 and
12). But aliphatic alkynes such as 3-phenyl-1-propyne only
gave trace amount of the desired product. The correspond-
ing amine also plays a crucial role in the reaction: whereas
dialkylamines reacted smoothly in these conditions, the
dibenzyl amine afforded the corresponding product in very
low yield (7%), possibly due to the steric hindrance. Amide
As shown in Table 2, a range of 1-alkyne cyclopropyl
amine products19 were easily obtained utilizing the opti-
R2
R3
R3
N
N
O
S
O
H
OH
ΗΟ
R2
O
4a
-H2O
R1
R3
N
R1
R2
R3
N
Au(III)
R2
7
8
Scheme 3. Proposed mechanism.

494
J. Liu et al. / Tetrahedron Letters 49 (2008) 490–494
3. (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323;
(b) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307; (c) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1–
415.
4. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353;
(b) Aggarwal, V.; Richardson, J.. In Science of Synthesis; Padwa, A.,
Bellus, D., Eds.; Thieme: Stuttgart, 2004; 27, p 21.
5. Brookhart, M.; Studabaker, W. B. Chem. Rev. 1907, 87, 411.
6. (a) Semenow, A.; Cox, E. F.; Roberts, J. D. J. Am. Chem. Soc. 1956,
78, 3221; (b) Turro, N. J.; Hammond, W. B. J. Am. Chem. Soc. 1966,
88, 3672; (c) Turro, N. J. Acc. Chem. Res. 1969, 2, 25.
7. Few studies on compound 2’s reactivity have been reported till now,
which might be because of its volatility or instability.
compounds and 1ꢁ amine such as aniline were inert to these
reactions. When 1-toluene sulfonyl cyclopropanol 4b was
employed as a reactant, the reaction yield (Table 2, entry
1, yield in parentheses) was lower than that of 4a.
Presumably, the mechanism in this reaction could be
similar to the coupling reaction of AuCl3 activated terminal
alkyne with aldehydes.16 Cyclopropanone, in situ gener-
ated from compound 4a (Scheme 3), would react with
disubstituted amine to provide imine cation 8, which then
could couple with terminal alkynes to yield product 7.
8. (a) Salaun, J. Chem. Rev. 1983, 83, 619; (b) Wasserman, H. H.;
Clagett, D. C. J. Am. Chem. Soc. 1966, 88, 5368; (c) Wasserman, H.
H.; Cochoy, E.; Baird, M. S. J. Am. Chem. Soc. 1969, 91, 2375.
9. Upon treatment with an equimolar amount of methylmagnesium
iodide, the cyclopropanone ethyl hemiacetal 3 was converted into
iodomagnesium 1-ethoxycyclopropylate, which could react with
hydrides, organometallic reagents, cyanide carbanion, and phospho-
rus ylides. Org. Synth. 1985, 63, 147.
10. Gagnon, A.; St-Onge, M.; Little, K.; Duplessis, M.; Barabe, F. J. Am.
Chem. Soc. 2007, 129, 44.
11. Kang, J.; Kim, K. S. J. Chem. Soc., Chem. Commun. 1987, 897.
12. Some of recent progress on the synthesis of cyclopropyl amines
Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N. Org.
Lett. 2007, 9, 187.
3. Conclusion
In summary, a new cyclopropanone derivative 1-aryl-
sulfonyl cyclopropanol was developed in a simple and
expedient method. Unlike previous cyclopropanone
derivatives, this new surrogate exhibited relatively higher
reactivity. It can be used to construct 1-alkynyl cyclopro-
pylamines in moderate yields, from terminal alkynes, and
disubstituted amines in water with AuCl3 as the catalyst.
Further work directed to study the reactivity of the new
compound 4a, particularly its applications either as a
cyclopropanone equivalent or as a new synthetic subunit
is in progress.
13. A new product, which had similar polarity with 1-(benzenesulfonyl)
cyclopropanol, could be detected in TLC. It was not stable enough for
separation or further purification.
14. It was found that compound 4a could be kept in bottle at rt for three
weeks without explicit decomposition.
15. The spectral data of 1-(benzenesulfonyl) cyclopropanol 4a: H NMR
Acknowledgements
1
Support of this work by a starter grant from Renmin
University of China and the grant from National Sciences
Foundation of China (No. 20502033) is gratefully
acknowledged.
(300 MHz, CDCl3) d 1.22 (t, J = 6.9 Hz, 2H), 1.66 (t, J = 6.9 Hz, 2H),
3.95 (s, 1H), 7.58 (m, 2H), 7.68 (m, 1H), 7.95 (m, 2H). 13C NMR
(CDCl3) d 13.6, 71.3, 129.0, 129.1, 133.9, 137.0. Supplementary data
have been deposited with the CCDC in the CIF format with the
deposition number CCDC 667597.
16. Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584.
Supplementary data
17. Zhang, J. H.; Wei, C. M.; Li, C. J. Tetrahedron Lett. 2002, 43, 5731.
18. Ji, J.-X.; Au-Yeung, T. T.-L.; Wu, J.; Yip, C. W.; Chan, A. S. C. Adv.
Synth. Catal. 2004, 346, 42.
Supplementary data associated with this article include
brief experimental details, X-ray structure, and other spec-
tra data. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
2007.11.093.
19. General procedure for the coupling reaction of 1-benzenesulfonyl
cyclopropanol 4a with the terminal alkynes, and disubstituted amines
catalyzed by AuCl3. To a solution of a terminal alkyne (1 mmol), and
a disubstituted amine (0.75 mmol) in water (1 mL), was added 1-
benzenesulfonyl cyclopropanol 4a (33 mg, 0.17 mmol) followed by
AuCl3 (3 mg, 0.01 mmol, 2% equiv). After 4 h, another batch of 4a
(33 mg, 0.17 mmol) was added. And the third batch of 4a (33 mg,
0.17 mmol) was added 8 h later. The reaction mixture was stirred at rt
for 12 h under N2, and extracted with EtOAc (3 · 10 mL). The
combined organic phase was dried over MgSO4 and evaporated in
vacuo. The crude product was then purified by flash chromatograph
on silica gel to give the desired 1-alkynyl cyclopropyl amine (PE/
EA = 50/1). The spectral data of N-piperidinyl-1-(phenylethynyl)
cyclopropane 7a: 1H NMR (CDCl3, Me4Si) d 0.89 (t, J = 4.3 Hz, 2H),
0.99 (t, J = 4.3 Hz, 2H), 1.45 (t, J = 4.4 Hz, 2H), 1.56 (m, 4H), 2.70 (t,
J = 4.7 Hz, 4H), 7.24–7.30 (m, 3H), 7.41 (t, J = 3.8 Hz, 2H). 13C
NMR (CDCl3) d 17.8, 24.6, 26.3, 38.0, 51.8, 82.6, 89.7, 123.8, 127.9,
128.4, 131.9.
References and notes
1. (a) The Chemistry of the Cyclopropyl Group; Patai, S., Rappoport, Z.,
Eds.; Wiley: Chichester, New York, Brisbane, Toronto, Singapore,
1987; (b) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. Rev.
2003, 103, 1625; (c) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006,
39, 433.
2. (a) Small Ring Compounds in Organic Synthesis I–IV; de Meijere, A.,
Ed.; Topics in Current Chemistry; Springer: Berlin, 1986; Vol. 133,
1987; Vol. 135, 1988; Vol. 144, 1990; Vol. 155; (b) Wong, H. N. C.;
Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. Rev. 1989, 89, 165; (c)
Salaun, J. Chem. Rev. 1989, 89, 1247.