Titanium(IV) chloride-mediated carbocyclization of 1,6-Enynes: Selective synthesis of 3-Azabicyclo[3.1.0]hexanes and functionalized allenes by controlling the reaction temperature

Article abstract of DOI:10.1002/ejoc.201100129

1,6-Enynes can be transformed into 3-azabicyclo[3.1.0]hexanes and functionalized allenes in moderate to good yields along with moderate to high diastereoselectivities by controlling the reaction temperature in the presence of titanium(IV) chloride. A plausible mechanism is proposed. 1,6-Enynes can be transformed into 3-azabicyclo[3.1.0]hexanes and functionalized allenes respectively in moderate to goodyields along with moderate to high diastereoselectivities by controlling the reaction temperature in the presence of titanium(IV) chloride. A plausible mechanism is proposed.

Full text of DOI:10.1002/ejoc.201100129

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100129
Titanium(IV) Chloride-Mediated Carbocyclization of 1,6-Enynes: Selective
Synthesis of 3-Azabicyclo[3.1.0]hexanes and Functionalized Allenes by
Controlling the Reaction Temperature
Zhen Zhang[a] and Min Shi*[a,b]
Keywords: Cyclization / Carbocycles / Carbocyclization / Enynes / Allenes / Titanium
1,6-Enynes can be transformed into 3-azabicyclo[3.1.0]hex-
anes and functionalized allenes in moderate to good yields
along with moderate to high diastereoselectivities by con-
trolling the reaction temperature in the presence of titani-
um(IV) chloride. A plausible mechanism is proposed.
allenes by controlling the reaction temperature. These 3-
azabicyclo[3.1.0]hexanes are core structures of a variety of
biologically active natural products[11] and the examples of
direct transformation of enynes into allenes accompanied
with ring formation are rare.[12]
Introduction
Carbocyclization of 1,6-enynes is a powerful method in
organic synthesis to access five or six-membered rings and
has drawn increasing attention. One of the most interesting
aspects in this field is the construction of nitrogen-contain-
ing heterocyclic compounds which are important structural
motifs found in many natural and pharmaceutical materi-
als. Although a variety of transition metals, such as gold,[1]
platinum,[2] palladium,[3] ruthenium,[4] rhodium,[5] irid-
ium,[6] and mercury,[7] have been examined for their cata-
lytic abilities in this reaction, finding new types of cycliza-
tion of enyne derivatives is still highly desirable due to the
synthetic diversity of these reactions.[6a]
Results and Discussion
Initially, we tested the carbocyclization of enyne 1a using
various Lewis acids such as BiCl3, TiCl4, BCl3 and TiBr4
(see the Supporting Information for the details). We found
that only TiCl4 gave good results, affording 2a in 73% yield
within 20 min at room temperature (25 °C) (Table 1, en-
try 4). Further optimization of the reaction conditions re-
TiCl4 has been widely used in many carbon–carbon
bond-forming reactions,[8] to the best of our knowledge, no
investigation of cyclization of enynes has been carried out
using TiCl4 as a promoter. Thus far, TiCl4-catalyzed or me-
diated carbon–carbon bond forming reactions with alkynes
include the additions of propargylsilanes or silylacetylenes
to carbonyl compounds;[9] unactivated alkynes to alde-
hydes,[8a,8b] expoxides,[8f,8g] and α-aryl-substituted carbonyl
compounds.[8h] Only one notable example is the TiCl4–
Et3N-mediated intramolecular carbocyclization of active
methine compounds with unactivated alkyne groups.[10]
Herein, we wish to report a novel carbocyclization of 1,6-
enynes in which easily available and inexpensive metal ha-
lides can serve as effective mediates to achieve the selective
synthesis of 3-azabicyclo[3.1.0]hexanes and functionalized
Table 1. Optimization of the reaction conditions.[a]
Entry Lewis acid
[equiv.]
Solvent
T [°C] t [min] Yield [%][b]
2a
3a
1
2
3
4
5
6
7
8
TiCl4 (1.40) toluene
TiCl4 (1.40) CH2Cl2
r.t.
r.t.
r.t.
r.t.
20
20
20
20
20
30
120
30
39
42
69
73
67
13
–
–
–
–
–
[a] Laboratory for Advanced Materials & Institute of Fine Chemi-
cals, East China University of Science and Technology,
130 Mei Long Road, Shanghai 200237, China
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
TiCl4 (1.40) ClCH2CH2Cl
TiCl4 (1.70) ClCH2CH2Cl
TiCl4 (2.00) ClCH2CH2Cl
TiCl4 (1.70) ClCH2CH2Cl
TiCl4 (1.05) ClCH2CH2Cl
TiCl4 (1.70) ClCH2CH2Cl
r.t.
–
–15
–20
–20
52
67
69
Fax: +86-21-64166128
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100129.
–
[a] [substrate] = 0.10 m. [b] Isolated yield.
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Titanium(IV) Chloride-Mediated Carbocyclization of 1,6-Enynes
Table 2. TiCl4-mediated synthesis of 3-azabicyclo[3.1.0]hexanes 2 from 1,6-enynes 1.[a]
Entry
1
X
Ar
R1
R2/R3
T [°C]
Yield [%][b]
dr[c] (anti/syn)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1g
1h
1h
1i
1j
1k
1l
1q
1r
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Bs
Bs
Ts
Ts
Ts
Bs
Ts
Ts
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
pMeC6H4
pClC6H4
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Piv
Ac
Ac
Piv
Ac
Ac
Me/Me
Et/Et
iPr/iPr
nBu/nBu
–CH2(CH2)2CH2– room temp.
–CH2(CH2)3CH2– room temp.
–CH2(CH2)3CH2– –20
–CH2(CH2)3CH2– –20
–CH2(CH2)3CH2– –30
Me/Me
nPr/H
Me/nPr
room temp.
room temp.
reflux
2b, 65
2c, 72
2d, –
8:1
6:1
–
room temp.
2e, 58
2f, 70
2g, 77
2g, 54
2h, 61
2h, 55
2b, 58
2j, –
2k, 58
2h, 76
2q, –[d]
2r, 61
9:1
47:1
22:1
36:1
11:1
15:1
8:1
–
9
10
11
12
13
14
15
room temp.
room temp.
room temp.
7:1
22:1
–
–CH2(CH2)3CH2– –30
Et/Et
Me/Me
room temp.
room temp.
4:1
1
[a] [substrate] = 0.10 m. [b] Isolated yield. [c] Determined by H NMR spectroscopic data. [d] 2q could not be isolated in pure form.
vealed that decreasing the reaction temperature to –5 °C, form (Table 2, entry 14). In contrast, substrate 1r with a
allene 3a was formed along with 2a although it could not chlorine atom on the benzene ring gave the desired product
be separated from 2a by silica gel column chromatography 2r in 61% yield (Table 2, entry 15).
(Table 1, entry 6). However, it was found that 3a could be
To obtain allene derivatives 3, the reaction should be
obtained as the sole product in 69% yield at –20 °C after conducted at lower temperature (–20 or –30 °C) and the
30 min in the presence of 1.70 equiv. TiCl4 (Table 1, en- results are shown in Table 3. For various alkyl groups sub-
try 8). The configuration of anti-2a has been unequivocally stituted 1b–1e as well as 1m and 1n, the corresponding al-
assigned by X-ray diffraction and its X-ray crystal data are lene derivatives 3b–3e, 3m and 3n could be obtained in 60–
presented in the Supporting Information.[13]
85% yields along with excellent diastereoselectivities (8:1 to
With these optimized conditions in hand, we next investi- 26:1) at –20 °C (Table 3, entries 1–5, 11 and 12). In the case
gated the tolerance of TiCl4-mediated carbocyclization with of substrate 1d, product 3d was obtained in 60% yield with
various enynes 1b–1r to construct the corresponding 3-aza- moderate diastereoselectivity (4:1) even at room tempera-
bicyclo[3.1.0]hexanes and the results are outlined in Table 2. ture without the formation of 2d, perhaps due to the steric
As depicted in Table 2, all of the reactions proceeded bulkiness of two isopropyl groups (Table 3, entry 4). As for
smoothly to give the desired products 2b, 2c and 2e in mod- substrate 1f with a cyclopentyl group, 2f was formed rather
erate yields at room temperature (25 °C) when R2 and R3 than the allene derivative 3f (Table 3, entry 6). In the case
were methyl, ethyl or n-butyl group (Table 2, entries 1, 2 of substrate 1g with a cyclohexyl group, the product (E)-3-
and 4). However, no formation of 2d was observed even
[chloro(phenyl)methyl]-4-(cyclohexenylmethylene)-1-tosyl-
under reflux presumably due to the isopropyl group’s steric pyrrolidine (3g) was obtained in 68% yield without the for-
hindrance (Table 2, entry 3). As for the cycloalkyl-substi- mation of the corresponding allene derivative (Table 3, en-
tuted enynes 1f–1h, products 2f–2h were obtained in 54– try 7). For pivalate ester 1i, the reaction also proceeded
77% yields along with excellent diastereoselectivities and it smoothly to give the corresponding allene derivative 3b in
was found that these products could be given in better dia- 53% yield (Table 3, entry 8). Substrate 1j in which R3 was
stereoselectivities at lower temperature (Table 2, entries 6– a hydrogen atom gave no reaction under the standard con-
9). For various propargylic esters 1i and 1l in which R1 is a ditions (Table 3, entry 9). Substrate 1k bearing different
pivalyl group, the corresponding products 2b and 2h were substitutions of R2 and R3 can be transformed to the corre-
obtained in 55% yield and 76% yield, respectively (Table 2, sponding product 3k as isomeric mixtures (Table 3, en-
entries 10 and 13). Moreover, substrate 1j in which R3 was try 10). Notably, substrate 1o having two cyclohexyl groups
a hydrogen atom gave no reaction (Table 2, entry 11). Sub- reacted efficiently in the presence of TiCl4, giving the de-
strate 1k with the different substitutions of R2 and R3 also sired product 3o in 91% yield (Table 3, entry 13). Substrates
gave the corresponding product 2k in reasonable yield with 1p and 1q having a methyl group and a chlorine atom on
moderate diastereoselectivity (7:1 mixture of major and the benzene rings gave the corresponding products 3p and
minor diastereomers) (Table 2, entry 12). In the case of sub- 3q in 88% yield and 50% yield along with moderate to ex-
strate 1q having a methyl group on the benzene ring, the cellent diastereoselectivities (4:1 and 12:1) (Table 3, en-
corresponding product 2q could not be obtained as pure tries 14 and 15). The anti-configuration of the major isomer
Eur. J. Org. Chem. 2011, 2610–2614
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2611

Z. Zhang, M. Shi
SHORT COMMUNICATION
Table 3. TiCl4-mediated synthesis of allenes 3 from 1,6-enynes 1.[a]
Entry
1
X
Ar
R1
R2/R3
T [°C]
Yield [%][b]
dr[c] (anti/syn)
1
2
3
4
5
6
7
8
1b
1c
1d
1d
1e
1f
1g
1i
1j
1k
1m
1n
1o
1p
1q
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Bs
Ts
Ts
Ts
Ts
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
pClC6H4
pMeC6H4
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Piv
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Me/Me
Et/Et
iPr/iPr
iPr/iPr
nBu/nBu
–CH2(CH2)2CH2–
–CH2(CH2)3CH2–
Me/Me
nPr/H
Me/nPr
Et/Et
–20
–20
–20
room temp.
–20
–30
–30
–20
–20
–20
–20
–20
–20
–20
–25
3b, 62
3c, 80
3d, 69
3d, 60
3e, 75
3f,–[d]
12:1
8:1
11:1
4:1
26:1
–
Ͼ99:1
6:1
–
–
18:1
13:1
14:1
12:1
4:1
3g, 68[e]
3b, 53
3j, –
9
10
11
12
13
14
15
3k, 61[f]
3m, 85
3n, 64
3o, 91
3p, 88
3q, 50[g]
iBu/iBu
Cy/Cy
Et/Et
Et/Et
1
[a] [substrate] = 0.10 m. [b] Isolated yield. [c] Determined by H NMR spectroscopic data. [d] See Table 2, entry 5. [e] The product is (E)-
1
3-[chloro(phenyl)methyl]-4-(cyclohexenylmethylene)-1-tosylpyrrolidine. [f] The product’s H NMR spectrum is complex. [g] The reaction
was carried out in CH2Cl2.
of 3p has been unequivocally assigned by X-ray diffraction
To gain more mechanistic insight into the carbocycli-
and its X-ray crystal data are presented in the Supporting zation of 1 into 2 and 3, the control experiments have been
Information.[13]
performed using catalytic amount of TiCl4 (20 mol-%) as
the promoter and it was found that 2a could be obtained
in 19% yield along with recovery of 1a in 57% yield [Equa-
(1)
(3)
(4)
(2)
Scheme 1. Plausible TiCl4-mediated carbocyclization mechanism.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2610–2614

Titanium(IV) Chloride-Mediated Carbocyclization of 1,6-Enynes
China (973)-2009CB825300, the Fundamental Research Funds for
the Central Universities and the National Natural Science Founda-
tion of China for financial support (grant numbers 21072206,
20472096, 20872162, 20672127, 20821002, and 20732008) and Mr.
Jie Sun for performing X-ray diffraction.
tion (1)]. Compound 4a which is derived from 1,5-acyloxy
migration remained unchanged in the presence of TiCl4
[Equation (2)].[12a] Moreover, compound 3a could not be
isomerized to 2a upon treatment with 1.05 equiv. TiCl4 at
room temperature [Equation (3)].[14] Treatment of com-
pound 2a with TiCl4 (1.05 equiv.) could also not afford al-
lene 3a under the standard conditions [Equation (4)].
Based on above studies, we proposed a mechanism for
the TiCl4-mediated carbocyclization in Scheme 1.[15] Coor-
dination of the ester group to TiCl4 gives intermediate A.
The nucleophilic intramolecular addition of the pendant
olefin to the alkyne along with acyloxy group leaving af-
fords carbocation B, which contains a vinylidene moiety.[12a]
At low temperature, the chloride ion from the metal is
transferred to incipient benzylic carbocation to produce
chlorinated allene 3 (path a).[16] Due to the stability of the
benzylic cation, the intermediate B could be isomerized to
vinyl cation C at elevated temperature, which then un-
dergoes chloride ion transfer from the metal to generate
the chlorinated 3-azabicyclo[3.1.0]hexane 2 (path b). Steric
hindrance effect occurs at intermediate C when R2/R3 are
sterically bulky substituents.
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Conclusions
In conclusion, we have reported a novel TiCl4-mediated
carbocyclization of 1,6-enynes containing propargylic ester
moiety. By controlling the reaction temperature, 3-azabicy-
clo[3.1.0]hexanes and functionalized allenes could be syn-
thesized respectively in moderate to good yields along with
moderate to high diastereoselectivities. Further investiga-
tion on the mechanism of TiCl4-mediated carbocyclization
and the extension of this procedure to other carbon-carbon
bond forming reactions are in progress.
Experimental Section
General Procedure for the Preparation of 2 or 3: A solution of TiCl4
(1.0 m in 1,2-dichloroethane, 1.70 equiv.) was added dropwise to a
solution of 1 (0.20 mmol, 1.00 equiv.) in anhydrous 1,2-dichloroe-
thane (1.6 mL) under Ar at room temperature (25 °C) or at –20 °C.
The resulting reaction mixture was stirred for over 2 min and the
reaction was monitored by TLC. When all the starting material
consumed, the mixture was quenched by addition of saturated
aqueous NaHCO3 solution (5.0 mL). After filtration, the filtrate
was extracted with dichloromethane (5.0 mLϫ2) and dried with
anhydrous Na2SO4. The solvent was removed under reduced pres-
sure and the residue was purified by flash silica gel chromatography
to give compound 2 or 3 (eluent: ethyl acetate/petroleum ether,
1:10, products 2 and 3 have the same Rf value, some unidentified
byproducts could not be separated in pure form by silica gel col-
umn chromatography).
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, compound characterization data
and X-ray crystal data of anti-2a and anti-3p.
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Eur. J. Org. Chem. 2011, 2610–2614
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2613

Z. Zhang, M. Shi
SHORT COMMUNICATION
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[13] CCDC-779201 (for anti-2a) and -201478 (for anti-3p) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[14] For the control experiments related to BiCl3 and the plausible
mechanism of BiCl3-mediated carbocyclization of 1, see the
Supporting Information.
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Received: January 28, 2011
Published Online: March 25, 2011
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Eur. J. Org. Chem. 2011, 2610–2614