Convenient access to cycloalk-2-enone-derived N -sulfonyl imines

Article abstract of DOI:10.1055/s-0034-1378203

The first synthesis of N-tosyl imines from various cyclopent-2-enones and cyclohex-2-enones was achieved by direct condensation with tosyl amide in the presence of TiCl(OEt)₃ and Et₃N. In addition, N-tert-butylsulfonyl imines from five- to seven-membered cycloalk-2-enones were obtained through formation of the respective oximes and subsequent Hudson reaction. These compounds are easy to handle solids and they are interesting starting materials for a variety of transformations. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378203

LETTER
▌1697
lCettoernvenient Access to Cycloalk-2-enone-Derived N-Sulfonyl Imines
Cycloalk-2-enone-Derived N-Sulfonyl Imines
Sebastian Hirner, Johannes Westmeier, Sandra Gebhardt, Christian H. Müller, Paultheo von Zezschwitz*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35032 Marburg, Germany
Fax +49(6421)2825362; E-mail: zezschwitz@chemie.uni-marburg.de
Received: 24.02.2014; Accepted after revision: 02.05.2014
the most prominent building blocks in organic synthesis.
In connection with our research on asymmetric 1,2- and
1,4-additions of organometallic reagents to cycloalk-2-
enones,11 we became interested in the analogous N-tosyl
Abstract: The first synthesis of N-tosyl imines from various cyclo-
pent-2-enones and cyclohex-2-enones was achieved by direct con-
densation with tosyl amide in the presence of TiCl(OEt)3 and Et3N.
In addition, N-tert-butylsulfonyl imines from five- to seven-mem-
bered cycloalk-2-enones were obtained through formation of the imines and now report the first successful preparation of
respective oximes and subsequent Hudson reaction. These com-
pounds are easy to handle solids and they are interesting starting
materials for a variety of transformations.
such compounds.
In contrast to N-sulfonyl imines, N-sulfinyl imines have
already been prepared by condensing cycloalk-2-enones
Key words: condensation, enones, imines, titanium, sulfonamides
with tert-butanesulfinamide in the presence of Ti(OEt)4 as
a mild Lewis acid.12 When adopting this method for the
condensation of cyclohex-2-enone (1a) with the less reac-
N-Sulfonyl imines form a synthetically very useful class
tive tosyl amide, the desired imine 2a was obtained in
of compounds that are commonly employed in a range of
poor yield due to incomplete conversion (Table 1, entry
transformations including addition of nucleophiles and
1). The strong Lewis acid TiCl4 was also not suitable,
pericyclic reactions as well as in the preparation of ox-
leading mainly to decomposition of the starting material
(entry 2). By employing a 5:1 mixture of Ti(OiPr)4 and
TiCl4, decomposition was less pronounced, and a moder-
aziridines and aziridines.1 On the one hand, this is a con-
sequence of the central role played by nitrogen in the
bioactivity of organic compounds, making imines valu-
ate yield was achieved (entry 3). Better results were ob-
able starting materials. On the other hand, the electron-
tained with a 3:1 mixture of Ti(OEt)4 and TiCl4 when
withdrawing effect of the sulfonyl moiety strongly acti-
Et3N was present in a 1:1 ratio calculated based on the
vates the C=N double bond so that its reactivity becomes
amount of chloride (entries 4 and 5).
comparable to that of a C=O double bond.2 Therefore, N-
sulfonyl imines are typically the first choice when intend-
ing to transfer a reaction that is known for carbonyls to the
respective aza analogues.
Table 1 Optimization of the Formation of N-Tosyl Imine 2a
O
NTs
'Ti', Et3N, toluene
TsNH2
+
In the case of aldehydes or ketones with stabilizing aryl or
2-arylethenyl groups, N-sulfonyl imines are readily pre-
pared by condensation with primary sulfonamides in the
presence of strong Brønsted or Lewis acids such as TiCl4
or AlCl3.3,4 N-Sulfonyl imines of aliphatic ketones, how-
ever, are rather labile, making them much more difficult
to synthesize. They have been formed from the respective
oximes through reaction with sulfinyl chlorides5 or sulfo-
nyl cyanides6 with subsequent radical rearrangement
(Hudson reaction), by palladium-catalyzed isomerization
of terminal alkene-derived N-tosyl aziridines,7 by reaction
of arenesulfonyl azides with alkenes,8 or by oxidation of
secondary alcohols with chloramine-T in the presence of
saccharin-lithium bromide.9 Another approach is to pro-
ceed through oxidation of the respective N-sulfinyl im-
ines, which are more readily prepared from carbonyls due
to the higher nucleophilicity of sulfinamides compared
with sulfonamides.10 N-Sulfonyl imines derived from
plain cycloalk-2-enones have not been described in the lit-
erature, even though the corresponding ketones belong to
(1–2 equiv)
1a
2a
Entry Titanium reagent
(equiv)
Et3N
T
t
Yield
(equiv) (°C) (h) (%)a
1
Ti(OEt)4 (4.0)
–
80
r.t.
Δ
2
3
15
26
2b
3
TiCl4 (1.0)
2.0
–
Ti(OiPr)4 (1.7) + TiCl4 (0.3)
Ti(OEt)4 (3.0) + TiCl4 (1.0)
24 40
4
–
Δ
4
4
1
1
0
5
Ti(OEt)4 (3.0) + TiCl4 (1.0) 4.0
Δ
68
78
24d
6
TiCl(OEt)3 (2.0)
TiCl(OEt)3 (1.2)
2.0
1.5
Δ
7c
Δ
a Determined by 1H NMR analysis of the crude product.
b Performed in CH2Cl2.
c Performed in benzene.
d Conversion of starting material 1a.
Finally, use of the preformed mixed reagent TiCl(OEt)3
turned out to be advantageous, and the conversion was
complete after 1 h heating to reflux in toluene, whereas
SYNLETT 2014, 25, 1697–1700
Advanced online publication: 28.05.2014
DOI: 10.1055/s-0034-1378203; Art ID: st-2014-b0158-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1698
S. Hirner et al.
LETTER
Table 2 Synthesis of α,β-Unsaturated N-Tosyl Ketimines
only 24% conversion was observed after the same time in
benzene heated to reflux (entries 6 and 7).
NTs
O
Under the optimized conditions, ketimine 2a was isolated
in a 66% yield as a 62:38 mixture of E- and Z-isomers (Ta-
ble 2, entry 1).13 No evidence for competing 1,4-addition
of tosyl amide to the enone moiety was detected,14 and in-
ferior yields were observed when trying to prepare imine
2a by Hudson reaction6 or by oxidation of the respective
p-toluenesulfinyl imine.10 To evaluate substituent effects,
this protocol was then applied to a set of methyl-substitut-
ed cyclohex-2-enones 1b–g, and the imines were obtained
in yields ranging from 61 to 74% (entries 2–7). In the case
of five-membered rings, cyclopent-2-enone 1h furnished
a negligible yield of imine 2h due to rapid decomposition
(entry 8), whereas the substituted derivatives 1i–k were
more stable and furnished the imines in yields ranging
from 49 to 77% (entries 9–11). With cyclohept-2-enone as
starting material, complete conversion occurred but the
crude product consisted of an inseparable 2:1 mixture of
the desired imine and the tautomeric cyclohept-1,3-dienyl
tosyl amide. Moreover, enone 1l, with an exocyclic car-
bonyl moiety, also underwent imine formation to deliver
2l in a 63% yield (entry 12).15 As examples of functional-
ized cycloalkenones, 2-chloro-, 2-bromo-, and 3-(phenyl-
sulfonyl)cyclohex-2-enone were subjected to this
reaction; however, imine formation was accompanied by
elimination to yield N-phenyltosyl amide in high purity.
This smooth aromatization was suppressed in the case of
enone 1m with two geminal methyl groups, and imine 2m
was obtained in good yield (entry 13). In addition, this
method tolerates electron-donating groups: an excellent
yield was achieved in the case of substrate 1n, with a
phenylthio group at C-3 (entry 14). All imines 2 are color-
less to off-white solids, stable against chromatography on
silica gel and handling under air, can be stored at –28 °C,
and only slowly hydrolyze in the presence of water.
TiCl(OEt)3, Et3N
+ TsNH2
toluene, Δ, 1–5 h
2a–n
1a–n
Entry Imine 2
Yield (%)a Entry Imine 2
Yield (%)a
9 (69:31)
NTs
NTs
1
66 (62:38)
61 (100:0)
8
9
h
a
NTs
NTs
2
75 (74:26)
49 (100:0)
b
i
NTs
NTs
3
64 (55:45) 10
74 (65:35) 11
j
c
NTs
NTs
4
77 (60:40)
63 (0:100)
72 (100:0)
91 (62:38)
k
d
NTs
NTs
5
6
7
62 (57:43) 12
68 (61:39) 13
70 (100:0) 14
l
e
f
NTs
NTs
Tosyl amides are readily deprotected under reductive con-
ditions.16 In contrast, tert-butylsulfonyl (busyl) groups
can be cleaved under acidic conditions and thus represent
an orthogonal protecting group.17 For this reason, and due
to problems with the preparation of N-tosyl imines from
cyclopent-2-enone and cyclohept-2-enone, synthesis of
the corresponding N-busyl imines was pursued by adopt-
ing a two-step sequence that was developed by Weinreb et
al. for the transformation of several aromatic and saturat-
ed aliphatic aldehydes and ketones.5c First, the cycloalk-
enones were converted into the corresponding oximes, in
a reaction that proceeded rather slowly with conventional
heating but could be accelerated tremendously with mi-
crowave irradiation (Scheme 1).18 The crude products
thus obtained were immediately converted by using a
Hudson reaction to deliver the N-busyl imines 3. Again,
the six-membered ring furnished a better yield than the
Br
m
n
NTs
NTs
SPh
g
a Isolated yield; values in parentheses indicate the E/Z ratio as deter-
mined by NOESY analysis after purification.
five- or seven-membered rings, which were clearly less
stable under these conditions.
Synlett 2014, 25, 1697–1700
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cycloalk-2-enone-Derived N-Sulfonyl Imines
1699
2626. (d) Monbaliu, J.-C. M.; Masschelein, K. G. R.;
Stevens, C. V. Chem. Soc. Rev. 2011, 40, 4708.
NSO2t-Bu
n
Yield
1) NH2OH⋅HCl, NaOAc
MeOH–H2O, MW, 5 min
1
2
3
20%
48%
25%
3h
3a
3o
(2) For a calculation of the LUMO energies of benzaldehyde
and various derived imines, see: Charette, A. In Chiral
Amine Synthesis; Nugent, T. C., Ed.; Wiley-VCH:
Weinheim, 2010, 1–49.
2) t-BuSOCl, Et3N, Et2O
–35 °C to r.t.,18 h
n
O
3
(3) (a) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org.
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(5) (a) Brown, C.; Hudson, R. F.; Record, K. A. F. J. Chem.
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W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991,
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(6) Boger, D. L.; Corbett, W. L. J. Org. Chem. 1992, 57, 4777.
(7) Wolfe, J. P.; Ney, J. E. Org. Lett. 2003, 5, 4607.
(8) (a) Wohl, R. A. J. Org. Chem. 1973, 38, 3862.
(b) Abramovitch, R. A.; Knaus, G. N.; Pavlin, M.; Holcomb,
W. D. J. Chem. Soc., Perkin Trans. 1 1974, 2169.
(9) Patel, R.; Srivastava, V. P.; Yadav, L. D. S. Adv. Synth.
Catal. 2010, 352, 1610.
(10) (a) Ruano, J. L. G.; Alemán, J.; Cid, M. B.; Parra, A. Org.
Lett. 2005, 7, 179. (b) Yang, Q.; Shang, G.; Gao, W.; Deng,
J.; Zhang, X. Angew. Chem. Int. Ed. 2006, 45, 3832.
(c) Chen, S.; Zhao, Y.; Wang, J. Synthesis 2006, 1705.
(11) (a) Siewert, J.; Sandmann, R.; von Zezschwitz, P. Angew.
Chem. Int. Ed. 2007, 46, 7122. (b) Kolb, A.; Hirner, S.;
Harms, K.; von Zezschwitz, P. Org. Lett. 2012, 14, 1978.
(c) Kolb, A.; Zuo, W.; Siewert, J.; Harms, K.; von
Zezschwitz, P. Chem. Eur. J. 2013, 19, 16366.
NP(O)Ph2
1
1) NH2OH⋅HCl, NaOAc
R
H
Yield
39%
MeOH–H2O, MW, 5 min
4a
4d
2) Ph2PCl, Et3N
hexane–CH2Cl2
–40 °C, 2 h
Me 63%
R
R
4
Scheme 1 Synthesis of N-busyl and N-phosphinoyl imines
Besides sulfonyl groups, the diphenylphosphinoyl (dpp)
group also effectively activates C=N double bonds to-
wards nucleophilic attack.2 Moreover, this group can be
cleaved under rather mild acidic conditions.16 The prepa-
ration of such imines from various substituted cyclohex-
2-enones has already been reported by Hutchins et al.19
However, the products were immediately subjected to
subsequent reductions and, thus, neither purified nor ana-
lytically characterized because rapid hydrolysis was an-
ticipated. We have prepared the cyclohex-2-enone-
derived dpp-imine for the first time as well as the 4,4-di-
methyl-substituted homologue already prepared by
Hutchins et al. (Scheme 1).19b Both compounds are stable
against chromatography on silica gel, can be handled un-
der air, and can be stored for extended time at –28 °C.
In conclusion, we have achieved the first preparation of
cycloalk-2-enone-derived N-tosyl imines.20 The choice of
an appropriate titanium reagent turned out to be critical
for this success, and several five- and six-membered com-
pounds were obtained in good yields. In addition, the first
preparation of five- to seven-membered cycloalkenone-
derived N-busyl imines is reported. All these compounds
are promising building blocks for subsequent reactions
with nucleophiles, and we are working on employing
them in asymmetric 1,2- and 1,4-additions.
(d) Westmeier, J.; Pfaff, C.; Siewert, J.; von Zezschwitz, P.
Adv. Synth. Catal. 2013, 355, 2651.
(12) (a) McMahon, J. P.; Ellman, J. A. Org. Lett. 2005, 7, 5393.
(b) Sirvent, J. A.; Foubelo, F.; Yus, M. Chem. Commun.
2012, 48, 2543.
(13) The E/Z configuration of imines 2 was assigned based
on NOE signals between the aromatic protons and either
the proton(s) at C-6 or C-2, respectively. Moreover, the
proton(s) at either C-6 or C-2 are deshielded in the case of
(E)-2a or (Z)-2a, respectively.
(14) Lin, Y.-D.; Kao, J.-Q.; Chen, C.-T. Org. Lett. 2007, 9, 5195.
(15) Acyclic aliphatic enones such as butenone or (E)-5-
methylhex-3-en-2-one decomposed under these conditions.
For a synthesis of the N-phenylsulfonyl imine of butenone
by Hudson reaction in a 15% yield, see reference 5b.
(16) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups
in Organic Synthesis; John Wiley & Sons, Inc: Hoboken,
2007, 4th ed.
Acknowledgment
The authors thank the Bengt Lundqvist foundation and the Konrad-
Adenauer-Stiftung for providing scholarships for S.H. and J.W.,
respectively, and BASF SE, Ludwigshafen, and Symrise AG,
Holzminden, for the generous donation of chemicals.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
(17) Sun, P.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1997, 62,
8604.
(18) Bergström, M. A.; Andersson, S. I.; Broo, K.; Luthman, K.;
Karlberg, A.-T. J. Med. Chem. 2008, 51, 2541.
References and Notes
(1) (a) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131.
(b) Shukla, D. K. Synlett 2009, 1859. (c) Kobayashi, S.;
Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1697–1700

1700
S. Hirner et al.
LETTER
5.20 mmol) in MeOH–H2O (9:1, 5.0 mL) in a 10 mL
(19) (a) Hutchins, R. O.; Adams, J.; Rutledge, M. C. J. Org.
Chem. 1995, 60, 7396. (b) Hutchins, R. O.; Rao, S. J.;
Adams, J.; Hutchins, M. K. J. Org. Chem. 1998, 63, 8077.
(20) N-(Cyclohex-2-en-1-ylidene)-4-methylbenzene-
sulfonamide (2a); Typical Procedure: To a solution of
TiCl(OEt)3 (4.37 g, 20.0 mmol) in toluene (10 mL) was
added Et3N (2.79 mL, 20.0 mmol). The resulting mixture
was stirred for 5 min at r.t. before TsNH2 (3.42 g,
microwave reaction vessel were added hydroxylamine
hydrochloride (398 mg, 5.72 mmol) and sodium acetate
(512 mg, 6.24 mmol). The vessel was sealed, and the
mixture was heated in a microwave reactor at 135 °C for
5 min and then cooled to r.t. The reaction mixtures of three
such batches were combined, poured into H2O (30 mL) and
extracted with CHCl3 (3 × 30 mL). The combined organic
phases were washed with sat. NaHCO3 (3 × 30 mL), dried
over MgSO4, and concentrated under reduced pressure to
give the crude oxime (1.70 g).
The crude oxime was dissolved in Et2O (30 mL), Et3N (3.18
mL, 23.0 mmol) was added, and the solution was cooled to
–35 °C. Then, tert-butylsulfinyl chloride (4.28 g, 30.6 mmol)
was added dropwise, and the resulting suspension was
stirred at –35 °C for 1.5 h before the cooling bath was
removed. Stirring was continued for 16 h, and the reaction
mixture was then filtered over Celite and concentrated under
vacuum. Purification by flash chromatography (pentane–
EtOAc, 5:1; Rf = 0.38) on silica gel furnished ketimine 3a
(1.62 g, 48%) as a pale-yellow oil that crystallized in the
freezer.
20.0 mmol) was added, and the reaction mixture was heated
to reflux for 15 min. A solution of 1a (961 mg, 10.0 mmol)
in toluene (20 mL) was added dropwise over 15 min to the
refluxing solution, and stirring was continued for 1 h. The
reaction mixture was poured into a stirred and precooled
(0 °C) suspension of NaHCO3 (5.0 g) in acetone–H2O (200
mL, 100:1), diluted with pentane (100 mL), dried over
MgSO4, and filtered. The filtrate was concentrated under
reduced pressure, and the crude product was purified by
flash chromatography (CH2Cl2; Rf = 0.26) on silica gel to
furnish ketimine 2a (1.65 g, 66%) as a pale-yellow oil that
crystallized in the freezer.
1H NMR (300 MHz, CDCl3): δ (62:38 E/Z-ratio, asterisk
denotes minor isomer peaks) = 7.86 (mc, 2 H), 7.32 (mc,
2 H), 7.32* (mc, 1 H), 6.94 (mc, 1 H), 6.14 (dt, J = 10.0,
1.9 Hz, 1 H), 3.18 (mc, 2 H), 2.54* (mc, 2 H), 2.43 (s, 3 H),
2.40–2.30 (m, 2 H), 2.01–1.90 (m, 2 H). 13C NMR
(75.5 MHz, CDCl3): δ = 180.1, 178.0*, 151.6*, 150.6, 143.4,
138.6, 130.1, 129.4, 127.1*, 127.0, 124.1*, 35.5*, 31.4,
26.0*, 25.2, 22.1*, 21.53, 21.49. HRMS (ESI+): m/z [M +
Na]+ calcd. for C13H15NO2SNa: 272.0716; found: 272.0711.
N-(Cyclohex-2-en-1-ylidene)-tert-butanesulfonamide
(3a); Typical Procedure: To a solution of 1a (500 mg,
1H NMR (300 MHz, CDCl3): δ (62:38 E/Z-ratio, asterisk
denotes minor isomer peaks) = 7.12* (dt, J = 10.2, 2.0 Hz,
1 H), 6.90–6.80 (m, 1 H), 6.12 (dt, J = 10.0, 2.0 Hz, 1 H),
3.04 (t, J = 6.7 Hz, 2 H), 2.51* (t, J = 6.7 Hz, 2 H), 2.35–
2.25 (m, 2 H), 1.97–1.83 (m, 2 H), 1.42 (s, 9 H). 13C NMR
(75.5 MHz, CDCl3): δ = 180.7, 178.7*, 150.4*, 149.8, 130.2,
124.5*, 58.7, 35.5*, 31.5, 26.0*, 25.2, 23.9, 22.2*, 21.5.
HRMS (ESI+): m/z [M + H]+ calcd. for C10H18NO2S:
216.1053; found: 216.1054.
Synlett 2014, 25, 1697–1700
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