Facile synthesis of spiropyrans from chromene hemiacetal esters and bifunctional nucleophiles

Article abstract of DOI:10.1055/s-0030-1260766

Facile synthesis of several new kinds of spiropyrans has been accomplished through the condensation of chromene hemi-acetal esters with bifunctional nuclephiles, in which previously nonpractical amination and amidation processes help each other and all become practical processes of the corresponding tandem reactions. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260766

LETTER
1573
Facile Synthesis of Spiropyrans from Chromene Hemiacetal Esters and
Bifunctional Nucleophiles
S
ynthesis of Spiro
a
pyrans n-Chao Wu,*a,b Hui-Jing Li,a Li Liu,a Nicolas Demoulin,b Zhe Liu,a Dong Wang,a Yong-Jun Chen*a
a
Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory for Molecular Recognition and Function, Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax +86(10)62554449; E-mail: ycwu@iccas.ac.cn; E-mail: yjchen@iccas.ac.cn
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
b
Received 13 February 2011
During our ongoing interest aiming at the synthesis of
functional heterocycles,4 we observed that treatment of
simple amines 1a–c with hemiacetal ester 2a in refluxing
dichloromethane afforded the corresponding amides 4a–c
in good yields (Scheme 1).5 However, when modestly
sterically hindered amines such as cyclohexylamine (1d)
and a-methylbenzylamine (1e) were used, no reaction
products were detected, and the starting materials were re-
covered, even with an excess of amines 1d,e as nucleo-
philes, indicating that the steric factor affects the amide
formation.5 It is reasonable to suggest that the potential
adducts 5, which was supposed to be formed from the am-
ination of hemiacetals 2 with amines 1d,e, are probably
unstable in refluxing dichloromethane. The nitrogen’s
lone pair of electrons, in aliphatic amines 5, is likely to
cause the transformation of 5 into a-ketoesters 7, which
underwent intramolecular cyclization to convert back to
the hemiacetals 2 (Scheme 1). In contrast to the nitrogen’s
lone pair of electrons in N,O-acetals 5, the oxygen’s lone
pair of electrons in acetal 8 (Figure 1) display relatively
Abstract: Facile synthesis of several new kinds of spiropyrans has
been accomplished through the condensation of chromene hemi-
acetal esters with bifunctional nuclephiles, in which previously non-
practical amination and amidation processes help each other and all
become practical processes of the corresponding tandem reactions.
Key words: spiropyran, tandem reaction, hemiacetal ester,
chromene, bifunctional nucleophile
Spiropyrans have attracted increasing attention in the area
of molecular sensors, switches, and information proces-
sors due to the reversible structural transformations be-
tween neutral spiropyran (SP) forms and zwitterionic
merocyanine (MR) forms that accompanied significant
changes of characteristic photochemical and photophysi-
cal properties in response to external chemical,1 thermal,2
and optical3 stimulation. Herein, we would like to report
that the condensation of chromene hemiacetal esters with
bifunctional nuclephiles could afford several new kinds of
spiropyrans.
Ph
Ph
O
CH2Cl2
R1CH2NH2
CO2Me
+
NHCH2R1
reflux, 1–2 d
O
1a–c
O
OH
OH
R1 = n-hexyl (1a), Ph (1b),
cyclohexenylmethyl (1c)
2a
4a–c 77–83%
Ar
Ar
H
CH2Cl2
N
R
R2R3CHNH2
CO2Me
+
x
reflux, 3 d
1d–e
O
O
OH
1d R2 = Ph, R3 = Me
5
CO2Me
2
1e R2, R3 = CH2(CH2)3CH2
R = R2R3CH
Ar
O
Ar
H2O
H
N
R
O
– NH2R
OH
CO2Me
CO2Me
7
6
Scheme 1 Reactions of hemiacetal esters 2 with amines 1a–e
SYNLETT 2011, No. 11, pp 1573–1578
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260766; Art ID: W05211ST
© Georg Thieme Verlag Stuttgart · New York

1574
Y.-C. Wu et al.
LETTER
weak electron-transfer ability, and thus avoid the similar one spiropyran 3b in 84% yield (Scheme 2, entry 2 in
decomposition (Scheme 1). Indeed, compound 8 is a Table 1).
stable molecule whose structure has been determined by
As indicated above, modestly sterically hindered amines
1d,e are not appropriate nucleophiles for the intermolecu-
single-crystal X-ray analysis.6
lar amidations of ester 2a (Scheme 1), the amidation of
sterically hindered b-hydroxy amine 1g with 2a did not
Cl
take place directly. Presumably, the hindered b-hydroxy
amine 1g can react with 2a via its unhindered hydroxyl to
form intermediate 9, and the subsequent amidation is ac-
tually an intramolecular process and hence easier than the
corresponding intermolecular amidation. With 1,2-di-
amines as nucleophiles, a small concentration of the ad-
Ph
O
OEt
8
ducts 10 would also potentially allow an otherwise
unfavorable amidation to occur by an intramolecular path-
way to afford spiropyrans 3c–h (Scheme 3). Instead, with
the original modestly hindered amines 1d,e there is no op-
portunity for an intramolecular amidation and species re-
lated to 10 simply to hydrolyze back to 2a. Similarly,
spiropyrans 3c–h are potentially hydrolyzed to com-
pounds 11. However, the irreversible amide formation
would enable the intramolecular amination processes eas-
ier than the corresponding intermolecular ones, and thus
facilitates the conversion of compounds 11 into spiropyr-
ans 3c–h (Scheme 3). This analysis suggests that these
two previously nonpractical amination and amidation pro-
Figure 1 Structure of compound 8
Based on the above results and analysis, simple b-hydroxy
amine 1f was selected for the exploration of the potential
double nucleophilic substitutions of hemiacetal ester 2a
(Scheme 2). As expected, condensation of 1f with 2a in
dichloromethane under reflux for 1 day in the absence of
any catalyst and additives afforded 2H-chromene-mor-
pholin-3-one spiropyran 3a in 98% yield (Scheme 2, entry
1 in Table 1). The commercially available sterically hin-
dered b-hydroxy amine 1g was also used, which reacted
smoothly with 2a to afford 2H-chromene-morpholin-3-
Ph
Ph
NH2
O
CH2Cl2
HO
+
R
CO2Me
OH
reflux, 1–3 d
NH
R
R
O
O
O
1f R = H
1g R = Me
R
2a
3a,b
Ph
CO2Me
NH2
O
O
9
R
R
Scheme 2 Synthesis of spiropyrans 3a,b
Ar
O
Ar
NH2
O
R
CH2Cl2
reflux, 1–3 d
H2N
CO2Me
H2O
+
R
NH
O
OH
2
R
HN
R
1h–i
3c–h
– H2O
Ar
– H2O
Ar
CO2Me
NH2
– MeOH
H2O
NH
O
HN
O
R
10
R
O
R
OH
H2N
R
11
Scheme 3 Synthesis of spiropyrans 3c–h
Synlett 2011, No. 11, 1573–1578 © Thieme Stuttgart · New York

LETTER
Synthesis of Spiropyrans
1575
cesses might help each other and all become practical pro- with hemiacetal esters 2a–c uneventfully under the same
cesses of these tandem reactions.
reaction conditions to afford spiropyrans 3f–h in 83–86%
yields (Table 1, entries 6–8). The significance of spiro-
pyrans inspired and encouraged us to further explore their
preparations from hemiacetal esters 2. Accordingly, treat-
ment of hemiacetal esters 2a,b and 2d with naphthalen-1-
amine (1j) in dichloromethane under reflux for 2 days af-
forded another new kind of spiropyrans 3i–k in high
yields (Scheme 4, Table 1, entries 9–11).
As expected, the treatment of hemiacetal ester 2a with
1,2-diamine 1h in dichloromethane under reflux for 3
days afforded spiropyran 3c in 85% yield (Table 1, entry
3). The reactions of hemiacetal esters 2b,c with 1h under
the same reaction conditions proceeded equally well to af-
ford spiropyrans 3d,e in 81–84% yields (Table 1, entries
4 and 5). 1,2-Diamine 1i was also used, which reacted
Table 1 Highly Selective Synthesis of Spiropyrans 3a–k from Hemiacetal Esters 2a–d and Amines 1f–ja
Ar
Ar
R
R
O
NH2
CH2Cl2
+
CO2Me
HX
reflux, 12–72 h
NH
O
O
OH
X
2a–d
1f–j
3a–k
Entry
1
Hemiacetal esters 2
Amines 1
Time (h)
Spiropyrans 38
Yield (%)
98
Ph
Ph
O
O
NH2
24
HO
NH
NH
CO2Me
OH
O
O
1f
O
O
2a
3a
3b
Ph
NH2
2
3
2a
HO
48
72
84
85
O
1g
Ph
O
NH2
H
Ph
2a
Ph
Ph
Ph
N
N
NH2
H
O
1h
3c
4
1h
72
84
H
Ph
N
CO2Me
OH
O
N
Ph
O
O
H
2b
3d
OMe
OMe
5
1h
72
81
H
Ph
N
CO2Me
OH
O
N
Ph
O
O
H
2c
3e
Synlett 2011, No. 11, 1573–1578 © Thieme Stuttgart · New York

1576
Y.-C. Wu et al.
LETTER
Table 1 Highly Selective Synthesis of Spiropyrans 3a–k from Hemiacetal Esters 2a–d and Amines 1f–ja (continued)
Ar
O
Ar
O
R
R
O
NH2
CH2Cl2
+
CO2Me
HX
reflux, 12–72 h
NH
OH
X
2a–d
1f–j
3a–k
Entry
6
Hemiacetal esters 2
Amines 1
Time (h)
Spiropyrans 38
Yield (%)
Ph
H2N
O
2a
72
86
NH
O
H2N
HN
1i
3f
7
2b
1i
72
85
O
HN
NH
O
3g
OMe
8
2c
1i
72
83
O
HN
NH
O
3h
Ph
O
O
NH2
NH
9
2a
48
91
1j
1j
3i
Ph
Ph
O
Ph
Ph
O
NH
10
48
83
CO2Me
OH
O
2d
3j
Synlett 2011, No. 11, 1573–1578 © Thieme Stuttgart · New York

LETTER
Synthesis of Spiropyrans
1577
Table 1 Highly Selective Synthesis of Spiropyrans 3a–k from Hemiacetal Esters 2a–d and Amines 1f–ja (continued)
Ar
O
Ar
O
R
R
O
NH2
CH2Cl2
+
CO2Me
HX
reflux, 12–72 h
NH
OH
X
2a–d
1f–j
3a–k
Entry
Hemiacetal esters 2
Amines 1
Time (h)
Spiropyrans 38
Yield (%)
O
11
2b
1j
48
89
O
NH
3k
a Conditions: 1 (1.1 equiv) and 2 (1.0 equiv.) in CH2Cl2 (c 0.1 M) under reflux for 24–72 h.
Ar
in which previously nonpractical amination and amida-
tion processes help each other and all become practical
processes of the corresponding tandem reactions. We en-
vision that the above consideration would be explored for
the development of various tandem reactions that might
be difficult to obtain by usual methods.
R
O
NH2
Ar
O
NH
CH2Cl2
R
+
reflux, 2 d
CO2Me
O
OH
1j
2a,b,d
3i–k
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Scheme 4 Synthesis of spiropyrans 3i–k
The products were confirmed from their spectra and
supported by the single-crystal X-ray analysis of 3i
(Figure 2).7
Acknowledgment
We thank the National Natural Science Foundation of China, Mini-
stry of Science and Technology (No. 2009ZX09501-006) and the
Chinese Academy of Sciences for the financial support.
References and Notes
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Figure 2 ORTEP plot of spiropyran 3i
In conclusion, several new kinds of spiropyrans have been
efficiently synthesized through the condensation of
chromene hemiacetal esters with bifunctional nuclephiles,
(3) For selected recent examples, see: (a) Walsh, Z.;
Scarmagnani, S.; Benito-Lopez, F.; Abele, S.; Nie, F. Q.;
Synlett 2011, No. 11, 1573–1578 © Thieme Stuttgart · New York

1578
Y.-C. Wu et al.
LETTER
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obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(8) Synthetic Procedure for Spiropyrans 3
A solution of (1R,2R)-1,2-diphenylethane-1,2-diamine (1h,
42.5mg, 0.2 mmol) and hemiacetal esters 2a (67.7mg, 0.2
mmol) in CH2Cl2 (2 mL) was stirred at reflux for 3 d. The
mixture was concentrated, and the residue was purified
by column chromatography over silica gel to afford 2H-
chromene-piperazin-2-one spiropyran 3c (85.1 mg) in 85%
yield as a single diastereomer. White solid; mp 136–137 °C.
[a]D24 +101.27 (c 2.0, MeCO2Et). 1H NMR (300 MHz,
CDCl3): d = 7.43–7.05 (m, 18 H), 5.95 (s, 2 H), 4.67 (s, 2 H),
2.98 (br s, 1 H), 1.18 (s, 9 H). 13C NMR (75 MHz, CDCl3):
d = 167.2, 148.1, 144.1, 138.0, 137.9, 137.8, 137.6, 129.0,
128.6, 128.5, 128.4, 128.4, 128.3, 128.2, 128.1, 127.7,
126.6, 123.3, 120.4, 120.2, 117.0, 86.9, 65.8, 58.6, 34.3,
31.4. FT-IR (KBr): 3350, 3033, 2361, 1693, 1489, 1245,
921, 700 cm–1. Anal. Calcd for C34H32N2O2: C, 81.57; H,
6.44; N, 5.60. Found: C, 81.43; H, 6.67; N, 5.82.
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Synlett 2011, No. 11, 1573–1578 © Thieme Stuttgart · New York