C. Pathirana et al. / Tetrahedron Letters 50 (2009) 1586–1587
1587
O
a
b
N
N
7.72
H
6.41
H
H
H
R
OH
OH
OH
OH
N
N
R
R
R
NHBoc
134
R
NHBoc
107
H2O
CHO
N
R
OH
OH
N
OH
OH
126
N
137
O
OH
CHO
9.66
NH
167
OH
OH
N
R
N
R
N
NHBoc
R
NHBoc
Figure 1. Heteronuclear multiple bond correlations (HMBC), (a) 1H–13C correla-
tions, (b) 1H–15N correlations. The numbers beside the atoms denote chemical shifts
d in ppm relative to DMSO-d6 at d 2.49 for 1H, d 39.5 for 13C and NH3 (external) at d
0.0 for 15N.
R
NHBoc
BocHN
R =
Bn
Scheme 2.
product 5 indicates that 5 arises from an extended reaction
where addition of two molecules of epoxide to one molecule
of the hydrazine has taken place. The product ions generated
from the protonated molecule [M+H]+ of the 841 Da side product
provided useful information.4 The fragment ion at m/z 542
([M+H]+ À3 Boc) indicated that 5 contained 3 Boc groups. 4 pro-
duced a fragment ion at m/z 168 corresponding to a 1-methyl-4-
pyridylphenyl fragment. The absence of this ion in the fragmen-
tation of 5 indicates that 5 contains, if present, a modified 2-
phenylpyridine moiety. Supporting this observation, 1H NMR
spectrum of 5 lacked the characteristic four multiplets assigned
to the four protons on the pyridine ring of 4. Instead, there were
three singlets at d 6.41, 7.72, and 9.66, of which the last indi-
cated the presence of an aldehyde.
product (5) was observed at a level as high as 1.6%. Compound 5
was undetectable when the coupling reaction was carried out un-
der inert conditions.
Conclusion
A minor side product isolated from a coupling reaction between
an epoxide and a hydrazine containing a pyridine ring was identi-
fied as a pyrrole that arises from an addition of a second molecule
of the epoxide to the pyridine moiety in the starting material. The
complete identification of the pyrrole containing side product was
achieved using NMR and MS. The structure of the side product
indicates a rearrangement of the pyridine moiety to produce a
pyrrole.
Long-range correlations observed in a 1H–13C HMBC experi-
ment clearly showed that these protons and 5-carbons form an iso-
lated fragment in the molecule. This 5-carbon structural fragment
is shown in Figure 1a. The two protons in the above structural frag-
ment showed correlations to a nitrogen at d 167 in a 1H–15N HMBC
experiment. These correlations supported the insertion of a nitro-
gen into the above structural fragment to form a pyrrole ring as
shown in Figure 1b. All the NMR data are in agreement with the
structure 5 assigned to the minor side product.5
Acknowledgments
We thank Drs. Shawn Pack, Rich Mueller and Percy Manchand
for helpful discussions on the reaction mechanism.
References and notes
1. Xu, Z.; Singh, J.; Schwinden, M. D.; Zheng, B.; Kissick, T. P.; Patel, B.; Humora, M.
J.; Quiroz, F.; Dong, L.; Hsieh, D.; Heikes, J. E.; Pudipeddi, M.; Lindrud, M. D.;
Srivastava, S. K.; Kronenthal, D. R.; Mueller, R. H. Org. Process Res. Dev. 2002, 6,
323.
CHO
N
2. Fassler, A.; Bold, G.; Steiner, H. Tetrahedron Lett. 1998, 39, 4925.
3. This work was first presented at SMASH, Small Molecule NMR Conference,
Verona, Italy, September, 2005.
OH
OH
BocHN
N
NH
Boc
HN
Boc
Bn
4. HRMS/MS (+ve ESI): m/z 842.4694 ([M+H]+, À1.2 ppm, C47H64N5O9); 786.4105
(+3.4 ppm, C43H56N5O9); 742.4180 (0.0 ppm, C42H56N5O7); 686.3575
(+3.1 ppm, C38H48N5O7); 642.3685 (+4.6 ppm, C37H48N5O5); 586.3068
(+6.6 ppm, C33H40N5O5); 542.3160 (+5.3 ppm, C32H40N5O3).
Bn
5
The formation of 5 indicates a rare conversion of a pyridine to a
pyrrole.6,7 This conversion proceeds via opening of a second epox-
ide ring by the attack of pyridine nitrogen resulting in the first
intermediate, a pyridinium salt (Scheme 2). This may then undergo
opening of the pyridine ring to yield an aldehyde. Ring opening of
pyridinium salts is described in the well-known Zincke reaction
and the resulting aldehyde is known as Zincke aldehyde.8–10 The
hydroxy group (b to N+) on the side chain of the salt may facilitate
this transformation by the formation of an aminal that may be
hydrolyzed to yield the aldehyde. It is likely that this intermediate
aldehyde proceeds through a 1,2-dihydroazete which may rear-
range under thermal conditions to produce a pyrrole.11 The side
5. 1H NMR (600.13 MHz, DMSO-d6): d 9.66 (s, 1H), 7.72 (br s, 1H), 7.1–7.4 (m,
14H), 6.41 (br s, 1H), 4.01 (br d, J = 13 Hz, 1H), 3.90 (br s, 2H), 3.83 (br dd,
J = 9.6, 13.0 Hz, 1H), 3.75 (m, 1H), 3.69 (br s, 1H), 3.61 (m, 1H), 3.54 (m, 1H),
2.77 (m, 1H), 2.81 (m, 1H), 2.67 (m, 3H), 2.60 (m, 1H), 1.26 (br s, 27H); 13C NMR
(100.6 MHz, DMSO-d6): d 185.6, 156.2, 155.7, 139.5, 139.2, 137.0, 133.3, 130.2,
129.4, 129.3, 129.1, 128.8, 128.4, 126.3, 126.2, 125.3, 106.6, 78.2, 78.0, 71.1,
68.4, 61.4, 60.6, 54.7, 53.8, 50.7, 37.3, 36.5, 28.4.
6. Joshi, U.; Pipelier, M.; Naud, S.; Dubreuil, D. Curr. Org. Chem. 2005, 9, 261.
7. Streith, J.; Sigwalt, C. Tetrahedron Lett. 1966, 1347.
8. Cheng, Wei-Chieh; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585–608.
9. Kearney, A. M.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2006, 45, 7803. and
references cited therein.
10. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423.
11. Bach, P.; Bergsträber, U.; Leininger, S.; Regitz, M. Bull. Soc. Chim. Fr. 1997, 134,
927–936.