Copper-catalyzed four-component reaction of Baylis-Hillman adducts with alkynes, sulfonyl azides and alcohols

Article abstract of DOI:10.1002/adsc.201000400

4-(Alkoxycarbonyl)-pent-4-enimidates were regioselectively synthesized via a copper-catalyzed four-component reaction of Baylis-Hillman adducts with terminal alkynes, sulfonyl azides and alcohols. The procedure is concise, general and efficient. The resul

Full text of DOI:10.1002/adsc.201000400

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DOI: 10.1002/adsc.201000400
Copper-Catalyzed Four-Component Reaction of Baylis–Hillman
Adducts with Alkynes, Sulfonyl Azides and Alcohols
Wangze Song,a Ming Lei,a Yang Shen,a Shuying Cai,a Wei Lu,a Ping Lu,a,*
and Yanguang Wanga,b,*
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, Peopleꢀs Republic of China
Fax : (+86) 571-8795-1512; e-mail: pinglu@zju.edu.cn or orgwyg@zju.edu.cn
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
b
Received: May 20, 2010; Published online: October 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000400.
Abstract:
4-(Alkoxycarbonyl)-pent-4-enimidates
Baylis–Hillman adducts, containing a minimum of
three chemospecific functional groups, which are hy-
droxy/amino, alkene, and electron-withdrawing
groups, are important precursors for the synthesis of
various complicated molecules and biologically active
products.[8] Upon the conversion of the hydroxy to a
better leaving group, such as their tert-butyl carbo-
nates (1a), Baylis–Hillman adducts become more
pratical and easily to undergo allylic substitution with
different nucleophiles,[9] which makes Baylis–Hillman
chemistry more valuable.
Attracted by the versatile ketenimine intermediate
and Baylis–Hillman chemistry, we designed a new re-
action, using Baylis–Hillman adducts 1, terminal al-
kynes 2, sulfonyl azides 3, and alcohols 4 as substrates
for a cascade, four-component process. The reaction
were regioselectively synthesized via a copper-cata-
lyzed four-component reaction of Baylis–Hillman
adducts with terminal alkynes, sulfonyl azides and
alcohols. The procedure is concise, general and effi-
cient. The resulting pentenimidates could be further
transformed to 3-methylene-2,3-dihydroindene-1-
imidates.
Keywords: Baylis–Hillman adducts; cascade reac-
tions; copper; imidates; ketenimines; multicompo-
nent reactions
Ketenimine, as an active intermediate, has attracted was promoted by copper (I) and occurred smoothly.
much attention in organic synthesis due to its reactivi- It regioselectively afforded 4-(alkoxycarbonyl)-pent-
ty and diverse chemistry.[1] Based on the in situ forma- 4-enimidates 5 in a single step.
tion of ketenimine via copper-catalyzed azide-alkyne
In our initial investigation, the tert-butyl carbonate
cycloaddition (CuAAC),[2] Chang,[3] our group[4] and of Baylis–Hillman adduct (1a), phenylacetylene (2a),
others[5] developed a series of three-component reac- p-toluenesulfonyl azide (3a), and methanol (4a) were
tions (3-CRs) based on sulfonyl or phosphoryl azides, selected as starting materials for optimizing the reac-
terminal alkynes and various nucleophiles. The reac- tion condition (Table 1). The reaction occurred
tions were conducted in a single step with both eco- smoothly in dichloroethane (DCE), chloroform and
nomic and ecological values and were proved to pro- acetonitrile, respectively (Table 1, entries 1–3). The
cess through a ketenimine intermediate. Using this reaction in THF or toluene only afforded the three-
strategy, a number of interesting products, such as component product, which was not associated with 1a
functionalized amidines, imidates, iminocoumarins, (Table 1, entries 4 and 5). Starting materials 1a, 2a
iminodihydrocoumarins, iminodihydroquinolines, ben- and 3a remained unreacted when dimethyl sulfoxide
zimidazoles, tetrahydropyrimidines and pyrroles were (DMSO) or N,N-dimethylformamide (DMF) was
efficiently constructed. However, to the best of our used as solvent (Table 1, entries 6 and 7). Besides the
knowledge, there were only two published examples solvent effect on this 4-CR reaction, the base also
of four-component reactions (4-CRs) on the basis of functioned as a major factor. In the case of pyridine,
formation of ketenimine via CuAAC, which furnished only a trace amount of four-components adduct 5a
a-aryl-b-hydroxyimidates[6] and g-nitroimidates[7] in was detected on TLC (Table 1, entry 8). Potassium
one pot, respectively.
carbonate did not trigger the reaction at all (Table 1,
entry 9). DBU worked for the reaction, but its effi-
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Copper-Catalyzed Four-Component Reaction of Baylis–Hillman Adducts
Table 1. Optimization of conditions for four-component reactions.[a]
Entry
Cu(I)
Solvent
MeOH (equiv.)
Base/equiv.
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCN
CuCl
DCE
CH3CN
CHCl3
THF
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
5
5
5
1.2
1.2
1.2
TEA/1.2
TEA/1.2
TEA/1.2
TEA/1.2
TEA/1.2
TEA/1.2
TEA/1.2
Py/1.2
K2CO3/1.2
DBU/1.2
TEA/3
TEA/3
TEA/5
81
71
51
trace[c]
trace[c]
none[d]
none[d]
trace[c]
none[d]
31
toluene
DMSO
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
9
10
11
12
13
14
15
16
17
52
43
42
68
74
32
78
TEA/1.2
TEA/1.2
TEA/1.2
TEA/1.2
[a]
Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), 3a (1.2 mmol), Cu(I) (0.1 mmol), solvent, room temperature, under N2,
24 h.
Isolated yield.
Major 3-CR product and reactant 1a.
All of the reactants remained unchanged.
[b]
[c]
[d]
ciency was not comparable to that of triethylamine table diastereoselectivity (Table 2, entries 4–6). Vari-
(TEA) (Table 1, entry 1 and 10). An equivalent ous terminal alkynes 2a–f worked well for this reac-
amount of TEA to methanol was important for tion (Table 2, entries 8–13). Along with the formation
achieving high efficiency (Table 1, entries 1 and 11– of the normal 4-CR adduct 5l, 6a (Scheme 1) was also
14). Among the different sources of copper (I), CuI isolated in 11% yield when 2-pyridinylacetylene (2f)
presented the most efficiency for this transformation was employed (Table 2, entry 13). 4-Nitrophenylsul-
(Table 1, entries 1 and 15–17). Thus, the optimized re- fonyl azide (3c) also worked for this transformation
action conditions were established. We selected DCE and generated 5n and 6b in yields of 42% and 14%,
as solvent, TEA as base, and CuI as catalyst, and per- respectively (Table 2, entry 15).
formed the reaction under a nitrogen atmosphere at
room temperature for 24 h.
It is noteworthy that a 3-CR product 7a was isolat-
ed in 64% yield instead of the formation of the pre-
With the optimized reaction conditions in hand, the dicted 4-CR product when a secondary alcohol (for
scope of this transformation was further investigated example, 4c) was used as nucleophile (Scheme 2).
with a variety of Baylis–Hillman adducts 1, terminal Two similar cases occurred when aliphatic alkyne 2g
alkynes 2, sulfonyl azides 3 and alcohols 4 (Table 2). or aliphatic sulfonyl azide 3d was used as the sub-
In all cases, the reactions proceeded smoothly and af- strate (Scheme 2). In these cases, the Baylis–Hillman
forded the desired 4-CR products in moderate to high adduct 1a failed to participate in the cascade process.
yields (35–81%). For Baylis–Hillman adducts 1, the
Based on the reaction condition survey and the
tert-butyl carbonate (BocO), as a better leaving group substrate investigation, a plausible mechanistic path-
(Table 2, entry 1) and gave a much higher yield than way is presented in Scheme 3. A Michael donor B is
the acetate group (AcO) (Table 2, entry 2). When assumed to be generated by the nucleophilic addition
methyl ester 1c was used instead of ethyl ester 1a, the of alcohol 4a to the reactive N-sulfonyl ketenimine in-
isolated yields decreased significantly when methanol termediate A, which is formed via the copper-cata-
or ethanol was used as nucleophile (Table 2, entries 1 lyzed reaction of alkyne 2 and sulfonyl azide 3
and 3, 7 and 8) , respectively. Steric hindrance in the (CuAAC).[2–5] Simultaneously, the Baylis–Hillman
allylic position of the Baylis–Hillman adducts 1d–f adduct 1 undergoes an allylic nucleophilic substitution
slightly influenced the isolated yields, but without no- with TEA to form the Michael acceptor D by releas-
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Table 2. Substrate scope for the four-component reaction.[a]
Entry
1 (R1/R2/R3)
2 (R4)
3 (R5)
4 (R6)
Product/Yield [%][b]
1
2
1a (t-BuO/H/Et)
1b (Me/H/Et)
2a (Ph)
2a
3a (4-MeC6H4)
3a
4a (Me)
4a
5a/81
5a/35
3
4
5
6
7
8
9
10
11
12
13
14
15
1c (t-BuO/H/Me)
1d (t-BuO/Ph/Et)
1e (t-BuO/4-NO2C6H4/Et)
1f (t-BuO/Ph/Me)
1a
1c
1c
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b (Ph)
4a
4a
4a
4a
4b (Et)
4b
4a
4a
4a
4a
4a
4a
4a
5b/52
5c/61[c,d]
5d/68[c,e]
5e/51[c,f]
5f/58
5g/38
5h/57
5i/73
5j/64
2b (4-EtC6H4)
2c (3-MeC6H4)
2d (3-ClC6H4)
2e (2-BrC6H4)
2f (2-Py)
2a
5k/61
5l/56[g]
5m/72
5n/42[h]
2a
3c (4-NO2C6H4)
[a]
Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), 3 (1.2 mmol), 4 (1.2 mmol), CuI (0.1 mmol), TEA (1.2 mmol), DCE
(2 mL), N2, room temperature, 24 h.
Isolated yield.
Diastereomeric ratio (syn/anti) was determined by HPLC of the crude product.
(syn/anti) 72:28.
(syn/anti) 74:26.
(syn/anti) 68:32.
6a (Scheme 1) was also isolated in 11% yield.
6b (Scheme 1) was also isolated in 14% yield.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
ing the tertiary butyl alcohol and carbon dioxide.[9] and formaldehyde.[10] Nucleophilic substitution of Mi-
Allylic nucleophilic substitution of Michael acceptor chael acceptor D with deprotonated sulfonamide
D with Michael donor B gives the desired 4-CR anion E generates allyl sulfonamide F. In the case of
adduct 5 by giving off triethylamine via Pathway (a). 2-pyridinylacetylene (2f), the further deprotonated
When aliphatic alkyne 2g or aliphatic azide 3d is used
as the substrate, the anion B is quickly protonated to
afford the 3-CR product 7 via Pathway (b) due to the
increased basicity of anion B. Tuning the electrophilic-
ity of the Michael acceptor 1 to D is very important
for this 4-CR reaction. As we can conclude from the
isolated product, 8 was not observed in any cases be-
cause the Michael acceptor 1 was unable to be nucle-
ophilically replaced by B via Pathway (c).
The formation of the side-products 6a and 6b is il-
lustrated in the Supporting Information. Copper-cata-
lyzed decomposition of azide 3 in the presence of
methanol (4a) results in the formation of sulfoamide
Scheme 1. Structures of the side-products 6a and 6b.
Scheme 2. Formation of three-component products 7.
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Adv. Synth. Catal. 2010, 352, 2432 – 2436

Copper-Catalyzed Four-Component Reaction of Baylis–Hillman Adducts
Scheme 3. Possible mechanism for the four-component reaction.
anion H nucleophilically attacks D to afford the side- The scope, enantioselectivity and synthetic applica-
product 6a. When 4-nitrobenenesulfonyl azide (3c) is tions for this reaction are under investigation.
used, the increasing acidity of the sulfoamide F, due
to the electron-withdrawing nature of the nitro group,
makes the Mannich-type condensation possible and Experimental Section
forms 6b in a certain amount.
As an extension of this transformation, we tested General Procedure for the Synthesis of Imidates 5
the application of this cascade reaction in the synthe-
sis of a complicated compound. Based on this consid-
To a mixture of CuI (0.1 mmol), Baylis–Hillman adducts 1
(1 mmol), alkyne 2 (1.2 mmol) and azide 3 (1.2 mmol) in
eration, 5k was synthesized and tested for the palladi-
um-catalyzed intramolecular coupling.[11] Instead of
obtaining the normal Heck reaction product with a di-
hydronaphthlene substructure, a decarboxylative cou-
pling process occurred and 3-methylene-2,3-dihy-
droindene-1-imidate 9 was obtained (Scheme 4).
DCE (1 mL) were added TEA (1.2 mmol), alcohol
4
(1.2 mmol) in DCE (1 mL) under an N2 atmosphere. The
mixture was then stirred at ambient temperature for 24 h
and then evaporated under vacuum. The residue was sub-
jected to silica gel column chromatography with petroleum
ether/ethyl acetate as eluent.
In conclusion, we have developed a highly regiose-
lective four-component reaction of Baylis–Hillman
adducts with alkynes, sulfonyl azides and alcohols,
which afforded 4-(alkoxycarbonyl)-pent-4-enimidates
in a single step by nicely tuning the electrophilicity of
Baylis–Hillman adducts. The products could be fur-
ther transformed to potentially useful compounds,
Procedure for the Synthesis of Indene 9
To
a mixture of PdACHTUNTGENRU(NG OAc)2 (0.015 mmol) and PPh3
(0.06 mmol) in toluene (1 mL) was added TEA
(0.188 mmol) and 5k (0.15 mmol) in toluene (1 mL) under
an N2 atmosphere. The mixture was then stirred at 1008C
for 20 h and then evaporated under vacuum. The residue
such as 3-methylene-2,3-dihydroindene-1-imidates. was subjected to silica gel column chromatography with pe-
troleum ether/ethyl acetate as eluent to afford pure 9.
1
Data for compound 5a: Yellow oil; H NMR (400 MHz,
CDCl3): d=7.75 (d, J=8.4 Hz, 2H), 7.44 (d, J=7.2 Hz, 2H),
7.32–7.21 (m, 5H), 6.21ACTHUNRGTNE(NUG s, 1H), 5.57 (s, 1H), 5.30–5.26 (m,
1H), 4.24 (q, J=14.4, 7.2 Hz, 2H), 3.72 (s, 3H), 3.12–3.06
(m, 1H), 2.94–2.89 (m, 1H), 2.38 (s, 3H), 1.33 (t, J=7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=174.1, 166.3, 143.0,
139.0, 137.3, 137.2, 129.1, 128.5, 127.5, 126.9, 126.5, 60.8,
55.5, 47.8, 35.4, 21.3, 14.0; IR: n=2983, 1716, 1595, 1153,
1092, 814 cmÀ1; MS (ESI): m/z=416.2 ([M+H]+); HR-MS
(EI): m/z=415.1454, calcd. for C22H25NO5S: 415.1453.
Scheme 4. Transformation of product 5k.
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Wangze Song et al.
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Data for compound 9: White solid; mp: 122–1238C;
1H NMR (400 MHz, CDCl3): d=7.91 (d, J=8.4 Hz, 2H),
7.53 (d, J=8.0 Hz, 1H), 7.35–7.26 (m, 4H), 7.26–7.23 (m,
1H), 5.52 (s, 1H), 5.36–5.33 (m, 1H), 5.09 (s, 1H), 3.65 (s,
3H), 3.24–3.18 (m, 1H), 3.03–2.97 (m, 1H), 2.45 (s, 3H);
13C NMR (125 MHz, CDCl3): d=176.5, 147.6, 143.3, 141.2,
139.1, 129.4, 128.8, 128.0, 126.7, 125.5, 120.8, 103.8, 55.7,
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46.4, 36.7, 21.5; IR (KBr): n=2923, 1170, 913, 744, 666 cmÀ1
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Acknowledgements
The authors thank the financial support from the National
Natural Science Foundation of China (No. 20872128;
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Adv. Synth. Catal. 2010, 352, 2432 – 2436