Organocatalytic asymmetric nitrocyclopropanation of α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.04.162

A novel organocatalytic highly enantioselective nitrocyclopropanation reaction of α,β-unsaturated aldehydes is presented. The 1-nitro-2-formylcyclopropane derivatives synthesized from this catalytic transformation were converted to the corresponding β-nitromethyl-acid esters, which are excellent precursors of GABA analogues such as Baclofen, by subsequent organocatalytic chemoselective ring-opening.

Full text of DOI:10.1016/j.tetlet.2008.04.162

Tetrahedron Letters 49 (2008) 4209–4212
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic asymmetric nitrocyclopropanation
of a,b-unsaturated aldehydes
*
Jan Vesely, Gui-Ling Zhao, Agnieszka Bartoszewicz, Armando Córdova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel organocatalytic highly enantioselective nitrocyclopropanation reaction of a,b-unsaturated alde-
hydes is presented. The 1-nitro-2-formylcyclopropane derivatives synthesized from this catalytic trans-
formation were converted to the corresponding b-nitromethyl-acid esters, which are excellent precursors
of GABA analogues such as Baclofen, by subsequent organocatalytic chemoselective ring-opening.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 25 March 2008
Revised 22 April 2008
Accepted 30 April 2008
Available online 4 May 2008
The cyclopropane motif is an important target for organic
chemists and is also a constituent of several natural products and
biologically active agents.1 Moreover, cyclopropyl derivatives are
attractive synthetic intermediates2 and are employed as building
blocks in complex molecule3 and peptide synthesis.4 Consequently,
the importance of cyclopropyl derivatives has encouraged organic
chemists to develop asymmetric methods for their synthesis.5 High
levels of asymmetric induction have been achieved involving metal
catalyzed intermolecular cyclopropanations of electron rich ole-
fins.6 In pioneering work, Aggarwal,7 Gaunt8 and MacMillan9 have
employed either preformed or in situ generated ylides for the
catalytic cyclopropanation of a,b-unsaturated ketones, amides,
esters, nitriles, sulfones and aldehydes. Connon utilised cinchona
alkaloids as catalysts for the cyclopropanation of nitroalkanes.10
We recently developed an organocatalytic, highly enantioselective
cyclopropanation of enals using chiral pyrrolidine derivatives as
catalysts (Eq. 1).11
ponding 1-nitrocyclopropanes (Eq. 2). Herein, we disclose the
novel organocatalytic, highly enantioselective nitrocyclopropana-
tion of a,b-unsaturated aldehydes and the formal asymmetric
synthesis of important GABA (c-amino butyric acid) analogues
such as Baclofen.
X*
NO2
N
H
O
O2N
ð2Þ
O
Br
+
R
H
R
-HBr
H
In initial catalyst, organic base and solvent screens, we found
that chiral amines 4–8 catalyzed the reaction between cinnamic
aldehyde 1a and 2-bromonitromethane 2a, to give the correspond-
ing 2-formyl-cyclopropanes 3a and 3a0 (Table 1).17
The reactions catalyzed by (S)-proline 4 and diamine 5 fur-
nished 3a and 3a0 in good combined yields (1:1 and 3:1 ratio,
respectively) but with modest ees. The reaction with 2-carboxylic
acid dihydroindole 6 as the catalyst led to the formation of ent-
3a and ent-3a0 in 52% combined yield (1:1 ratio) with 91% and
86% ee, respectively, after 48 h reaction time (entry 3). Notably,
after 3 h, using protected diphenylprolinol 8 as the catalyst, we
were able to isolate 1-nitrocyclopropanes 3a and 3a0 containing
three contiguous stereocentres in 63% combined yield with 95%
and 97% ee, respectively (entry 5). Thus, we decided to further
optimize the organocatalytic nitrocyclopropanation of enals using
chiral amine 818 as the catalyst. The reaction was highly enantio-
selective in CHCl3, CH2Cl2, toluene, Et2O and CH3CN. However,
the diastereoselectivity decreased in CH2Cl2, Et2O and CH3CN
where an additional minor diastereoisomer 3a00 was formed. The
diastereo- and enantioselectivity of the reaction was also sensitive
to the choice of organic base (entries 10–12). For example, the dia-
stereoselectivity increased when morpholine was used instead of
TEA as an additive but the enantioselectivity decreased. With these
results in hand, we decided to use CHCl3 as the solvent, TEA as a
X*
EtO2C CO2Et
N
H
O
EtO2C
EtO2C
ð1Þ
O
Br
+
R
H
R
-HBr
H
Nitro-substituted cyclopropanes are valuable synthons which
can be converted to a variety of functionalities.12,13 For example,
a
diastereoselective nitrocyclopropanation has been reported
by Ballini et al.14 Notably, Ley and co-workers reported the
first organocatalytic nitrocyclopropanation of cyclohexanone using
their proline tetrazole catalyst.15 Inspired by this work and
our own research on catalytic domino Michael/a-alkylation reac-
tions,11a,b,16 we envisioned that reaction between 2-bromonitro-
methane and a,b-unsaturated aldehydes would give the corres-
* Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908.
E-mail addresses: acordova@organ.su.se, acordova1a@netscape.net (A. Córdova).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.162

4210
J. Vesely et al. / Tetrahedron Letters 49 (2008) 4209–4212
Table 1
Screening of the enantioselective reaction between 1a and 2aa
NO2
NO2
NO2
NO2
Catalyst (20%)
Base (1 equiv.)
+
+
+
Br
Ph
O
O
O
O
Ph
Ph
Solvent, rt
Ph
1a
2a
3a
3a'
3a''
Ph
Ph
OTMS
Ph
Ph
OH
CO2H
COOH
N
N
N
N
N
H
N
H
H
H
H
4
5
6
7
8
Entry
Catalyst
Base
Solvent
Time (h)
Yieldb (%)
Drc (3a:3a0:3a00)
eed (%) (3a:3a0)
1
2
3
4
5
6
7
8
9
4
5
6
7
8
8
8
8
8
8
8
8
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
Toluene
CH3CN
Et2O
1
2
48
24
3
6
3
8
8
59
69
52
Trace
63
61
59
58
35
69
46
59
1:1:0
3:1:0
1:1:0
n.d.
1:1:0
4:2:1
1:1:0
3:2:1
1:1:1
3:1:0
1:1:0
1:1:0
25:25
25:25
ꢁ91:ꢁ86
n.d.
95:97
91:93
95:95
92:96
78:87
51:54
21:22
95:95
10
11
12
Morpholine
Piperazine
Lutidine
CHCl3
CHCl3
CHCl3
2
3
6
a
Experimental conditions: To a mixture of 1a (0.30 mmol), chiral pyrrolidine (20 mol %) and base (0.25 mmol) in 1.0 mL of solvent was added 2-bromonitromethane 2a
(0.25 mmol) and the reaction mixture was stirred under the conditions shown in the Table.
b
Isolated combined yield of pure compounds 3.
c
Diastereoisomeric ratio as determined by 1H NMR.
d
Enantiomeric excess determined by chiral-phase HPLC analysis. n.d. = not determined.
proton sponge and chiral amine 8 as the catalyst for the reactions
between various enals 1 and 2-bromonitromethane 2a (Table 2).17
The chiral amine 8 catalyzed reactions were highly chemo- and
enantioselective (91–99% ee) and gave the corresponding 1-nitro-
2-formyl-cyclopropanes 3 in moderate to high yields. Of the four
possible diastereoisomers only two were formed in ratios ranging
from 1:1 to 3:1. Based on the importance of GABA (c-amino butyric
acid) analogues such as Baclofen,19 we decided to investigate the
possibility of chemoselective ring-opening of the 1-nitro-2-for-
myl-cyclopropane derivatives 3 using heterocyclic carbene cataly-
sis (Scheme 1).11a,b,20
the literature revealed that the absolute configuration at C-3 of
25
25
9e was (S) (½aꢀD ꢁ4.4 (c 0.5, CHCl3)), lit. (R-9e, ½aꢀD 4.0 (c 1.0,
CHCl3)19a). Moreover, by employing our newly developed one-pot
combination of amine and heterocyclic carbene catalysis (AHCC),
it was possible to prepare directly 3-nitromethyl acid esters 9
starting from the enals 1 and nitromethane 2a.11b
The relative stereochemistry of the different diastereoisomers 3
was confirmed by NOE experiments on diastereoisomers 3a, 3a0
and 3a00, respectively, and from the coupling constants of the
ring-protons.The experiments revealed that the phenyl- and 2-
formyl-groups of 3a have a cis-relationship and the nitro group
was trans to these two groups. In the case of 1-nitrocyclopropane
3a0, the relative configuration between the phenyl group and the
2-formyl group was trans and the nitro group was cis to the 2-
formyl group.
To our delight, the ring-opening worked well for nitrocyclopro-
panes 3a and 3e giving the corresponding 3-nitromethyl acid
esters 9 in high yields and ees. For example, 3-nitromethyl acid
ester 9e was isolated in 85% yield and 92% ee.21 Comparison with
Table 2
Direct organocatalytic asymmetric nitrocyclopropanation of a,b-unsaturated aldehydes 1a
NO2
NO2
NO2
8 (20%)
TEA (1 equiv.)
+
+
Br
R
O
O
O
R
R
CHCl3, r.t.
1
2a
3
3'
Entry
R
Time (h)
Products
Yieldb (%)
Drc (3:30)
eed (%) (3:30)
1
2
3
Ph
4-BrC6H4
n-Pr
3
2
1
3a:3a0
3b:3b0
3c:3c0
63
1:1
3:1
1:1
95:95
95:n.d.
91:92
35 (95)e
42
4
1
2
3d:3d0
3e:3e0
56
3:2
3:1
98:99
5
4-ClC6H4
29 (94)e
92:n.d.
a
Experimental conditions: To a mixture of enal 1 (0.30 mmol), catalyst 8 (20 mol %) and TEA (0.25 mmol) in CHCl3 (1.0 mL) was added 2-bromonitromethane 2a
(0.25 mmol) and the reaction mixture was stirred under the conditions shown in the Table.
b
Isolated combined yield of pure compounds 3.
c
Diastereoisomeric ratio as determined by 1H NMR.
d
Enantiomeric excess determined by chiral-phase HPLC analysis.
Yield based on recovered starting material 1. n.d. = not determined.
e

J. Vesely et al. / Tetrahedron Letters 49 (2008) 4209–4212
4211
Bn
+
-
N
Cl
NO2
(20 mol%)
S
O2N
R
H2N
R
O
O
DIPEA (40 mol%)
MeOH (3 equiv.)
CH2Cl2, rt, 15 h
R
CHO
OMe
OH
(S)
9a: 86% yield, 95% ee
9e: 85% yield, 92% ee
3a: R = Ph; dr = 1:1
3e: R = 4-ClC6H4; dr = 3:1
R = 4-ClC6H4; Baclofen
Scheme 1. Organocatalytic ring-opening of 1-nitrocyclopropanes 3a and 3e.
3.1%
<1.0%
<1.0%
<1.0%
<1.0%
4.4%
NO
H
H
H
O2N
H
O2N
H
2
H
CHO
H
H
H
CHO
CHO
Ph
Ph
Ph
3a
3a'
3a''
4.3%
6.1%
1H NMR 9.3 ppm (C
<1.0%
<1.0%
1H NMR 9.90 ppm (CHO)
H
O)
1H NMR 9.66 ppm (C
HO)
Based on the absolute and relative configuration of nitrocyclo-
propane derivatives 3, we propose the following mechanism to
account for the organocatalytic nitrocyclopropanation reaction of
enals 1. Accordingly, efficient shielding of the Si-face (Re when
R = Aryl) of the chiral iminium intermediate I by the bulky aryl
groups of chiral pyrrolidine 8 leads to stereoselective Re-facial
nucleophilic conjugate addition by the 2-bromonitromethane 2a
(Scheme 2). Next, the generated chiral enamine intermediate
undergoes intramolecular 3-exo-tert nucleophilic attack to form
the cyclopropane ring. The intramolecular ring-closure pushes
the equilibrium forward and makes this step irreversible. This
is the same type of mechanism that occurs during the organocata-
lytic asymmetric epoxidation,22a,b aziridination23 and cyclopropa-
nation of enals.11 Hydrolysis of iminium intermediate II releases
the catalyst and gives the corresponding 2-formyl cyclopropane
30. Due to steric repulsion between the nitro-group and the catalyst
of iminium complex II or the nitro- and 2-formyl-groups of 30,
epimerization occurs via intermediate III and diastereoisomer 3
is formed. Moreover, we also observed that enal 10 could be
formed via intermediate III and subsequent ring-opening under
certain reaction conditions.11 In the case of (S)-2-carboxylic acid
dihydroindole 6 catalysis, the bromomalonate 2 approached the
opposite face of the iminium intermediate to give cyclopropanes
ent-3.
X*
X*
-H+
+
N
N
In summary, we have reported a simple, highly enantioselective
catalytic nitrocyclopropanation reaction of unmodified enals,
which gives the corresponding 1-nitro-2-formylcyclopropanes in
91–99% ee. This is the first example of a highly enantioselective
organocatalytic nitrocyclopropanation of a,b-unsaturated alde-
hydes. Examples of the 1-nitro-2-formylcyclopropane products
were converted to the corresponding b-nitromethyl-esters (>92%
ee), which are excellent precursors of GABA analogues such as
Baclofen, by organocatalytic chemoselective ring-opening.
R
R
I
O2N
Br
Br
NO2
2a
O
-
Br
1
R
H2O
Acknowledgements
X*
II
We gratefully acknowledge the Swedish National Research
Council, Carl-Trygger Foundation and the Swedish Governmental
Agency for Innovation Systems (VINNOVA) for financial support.
N
+
X*
R
N
H
H
NO2
NO2
NO2
Base
O
O
References and notes
R
R
3
3'
H2O
1. (a) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. Rev. 2003, 103, 1625; (b)
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X*
N
X*
H+
N
+
R
R
III
NO2
NO2
3. Donaldson, W. A. Tetrahedron 2001, 57, 8589.
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NO2
R
O
10
Scheme 2. Proposed reaction mechanism.

4212
J. Vesely et al. / Tetrahedron Letters 49 (2008) 4209–4212
6. Selected examples of metal catalyzed cyclopropanations: (a) Charette, A. B.;
Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001, 123, 12168; (b) Davis, H. M. L.;
Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. Am. Chem. Soc. 1996, 118, 6897;
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1994, 116, 2223; (d) Rios, R.; Liang, J.; Lo, M.-C.; Fu, G. C. Chem. Commun. 2000,
377; (e) Denmark, S. E.; O’Connor, S. P.; Wilson, S. R. Angew. Chem., Int. Ed. 1998,
37, 1149; (f) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am.
Chem. Soc. 1991, 113, 726; (g) Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 13410.
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Chem., Int. Ed. 2001, 40, 1433.
8. (a) Papageorgiou, C. D.; Cubillo de Dios, M. A.; Ley, S. V.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2004, 43, 4641; (b) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.;
Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45,
6024.
11.2 Hz, 1H), 3.42 (dt, J = 3.6 Hz, 11.2 Hz, 1H ); 13C NMR (100 MHz, CDCl3):
193.1, 129.4, 129.2, 129.0, 128.7, 62.6, 38.7, 36.4. HRMS (ESI): calcd for
[M+Na]+ (C10H9NO3) requires m/z 214.0475, found, 214.0482. The
enantiomeric excess was determined by HPLC using an OD-H column (n-
hexane/i-PrOH = 90:10, k = 230 nm), 1.0 mL/min; tR = major enantiomer
23
23.5 min, minor enantiomer 26.9 min. ½aꢀD ꢁ51.9 (c = 1.0, CHCl3) (for
a
diastereomeric mixture 3a/3a0 of 3:1).
Compound 3a0: Colourless oil. 1H NMR (400 MHz, CDCl3): d = 9.69 (d, J = 5.2 Hz,
1H), 7.37–7.24 (m, 5H), 4.81 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 4.00 (dd, J = 4.8 Hz,
7.6 Hz, 1H), 2.70 (dt, J = 4.8 Hz, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): 193.4,
130.4, 129.2, 129.0, 128.8, 39.4, 32.7, 29.8. HRMS (ESI): calcd for [M+Na]+
(C10H9NO3) requires m/z 214.0475, found 214.0482. The enantiomeric excess
was determined by HPLC using an OD-H column (n-hexane/i-PrOH = 90:10,
k = 230 nm), 1.0 mL/min; tR = major enantiomer 37.1 min, minor enantiomer
39.5 min.
9. Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 127, 3240; For similar
work see: Hartikka, A.; Arvidsson, P. I. J. Org. Chem. 2007, 72, 5874; Hartikka, A.;
Slosarczyka, A. T.; Arvidsson, P. I. Tetrahedron: Asymmetry 2007, 18, 1403.
10. (a) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494; See
also: (b) Kojima, S.; Suzuki, M.; Watanabe, A.; Ohkata, K. Tetrahedron Lett. 2006,
47, 9061.
11. (a) Rios, R.; Sundén, H.; Vesely, J.; Zhao, G.-L.; Dziedzic, P.; Córdova, A. Adv.
Synth. Catal. 2007, 349, 1028; (b) Zhao, G.-L.; Córdova, A. Tetrahedron Lett. 2007,
48, 5976; For a later report see: (c) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J.
Am. Chem. Soc. 2007, 129, 10886.
12. Rosini, G.; Ballini, R. Synthesis 1988, 833; Ballini, R.; Bosica, G.; Fiorini, A.;
Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933.
13. (a) Hubner, J.; Liebscher, J.; Patzel, M. Tetrahedron 2002, 58, 10485; (b) Wurz, R.
P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262; (c) Kumaran, G.; Kulkarni, G. H.
Synthesis 1995, 1545; (d) Yu, J. R.; Falck, J. R.; Mioskowski, C. J. Org. Chem. 1992,
57, 3757; (e) Kocor, M.; Kroszczynski, W. Synthesis 1976, 813.
18. (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 794; (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212.
19. For selected examples of the synthesis of Baclofen see: (a) Fellunga, F.;
Gombac, V.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2005, 16, 1341; (b)
Camps, P.; Munoz-Torrero, D.; Sanchez, L. Tetrahedron: Asymmetry 2004, 15,
2039; (c) Armstrong, A.; Convine, N. J.; Popkin, M. E. Synlett 2006, 1589; For
alternative organocatalytic routes to GABA analogues such as Baclofen see: (d)
Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Angew.
Chem., Int. Ed. 2007, 46, 8431; (e) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Adv.
Synth. Catal. 2007, 349, 2660; (f) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2007, 9, 5307; For examples of literature on the biological importance of
GABAB receptor agonists see: (g) Olpe, H. R.; Demieville, H.; Baltzer, V.; Bencze,
W. L.; Koella, W. B.; Wolf, P.; Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133; (h)
Silverman, R. B. Angew. Chem., Int. Ed. 2008, 47, 3500.
20. Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021.
25
14. Ballini, R.; Fiorini, D.; Palmieri, A. Synlett 2003, 1704.
21. Methyl (S)-3-(4-chlorophenyl)-4-nitrobutanoate 9e: ½aꢀD ꢁ4.4 (c 0.5, CHCl3);
25
15. Hansen, H. M.; Longbottom, D. A.; Ley, S. A. Chem. Commun. 2006, 4838.
16. (a) Rios, R.; Vesely, J.; Sundén, H.; Ibrahem, I.; Zhao, G.-L.; Córdova, A.
Tetrahedron Lett. 2007, 48, 5835; (b) Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.;
Sundén, H.; Dziedzic, P.; Córdova, A. Chem. Eur. J., in press.
(lit. for the (R) enantiomer: ½aꢀD +4.0 (c 1.0, CHCl3)19a); 1H NMR (400 MHz,
CDCl3): d 7.33–7.28 (m, 2H), 7.19–7.16 (m, 2H), 4.72 (dd, J = 5.1, 12.8 Hz, 1H),
4.61 (dd, J = 8.0, 12.8 Hz, 1H), 3.99–3.95 (m, 1H), 3.64 (s, 3H), 2.75 (dd, J = 4.0,
7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 170.9. 136.9, 134.1, 129.5, 128.9,
79.3, 52.2, 39.7, 37.5; The enantiomeric excess was determined by HPLC with
an ODH column (n-hexane/i-PrOH = 85:15, k = 205 nm), 0.5 mL/min; tR = minor
enantiomer 25.8 min, major enantiomer 39.8 min. HRMS(ESI) the exact mass
calculated for [M+Na]+ (C11H12ClO4NNa) requires m/z 280.0347, found m/z
280.0341.
17. Typical experimental procedure for the organocatalytic nitrocyclopropanation:
To
a stirred solution of catalyst 8 (0.05 mmol, 20 mol %), a,b-unsaturated
aldehyde 1 (0.30 mmol, 1.2 equiv) and Et3N (0.25 mmol, 1.0 equiv) in CHCl3
(1.0 mL) was added bromonitromethane 2a (0.25 mmol, 1.0 equiv). The
reaction mixture was stirred vigorously at room temperature for the
reported time. Next, the crude product was purified by silica gel
chromatography (pentane/EtOAc-mixtures) to give the corresponding
nitrocyclopropane derivatives 3.
22. (a) Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 6964; (b) Sundén, H.; Ibrahem, I.; Córdova, A. Tetrahedron
Lett. 2006, 47, 99.
23. Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova, A. Angew. Chem., Int. Ed.
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Compound 3a: Colourless oil. 1H NMR (400 MHz, CDCl3): d = 9.29 (d, J = 3.2 Hz,
1H), 7.32–7.24 (m, 5H), 5.31 (dd, J = 3.6 Hz, 4.8Hz, 1H), 3.85 (dd, J = 4.8 Hz,