A [2 + 3] Reductive Cyclodimerization of Quinoline by SmI2

Article abstract of DOI:10.1021/acs.joc.5b01572

Pyridine and its derivatives are rather difficult to reduce, and the products often undergo a very fast reoxidation to regain aromaticity. The reduction of quinoline by SmI₂ results in an instantaneous [2 + 3] cyclization reaction, forming a bridged seven-membered ring within a polycyclic system.

Full text of DOI:10.1021/acs.joc.5b01572

Note
pubs.acs.org/joc
A [2 + 3] Reductive Cyclodimerization of Quinoline by SmI2
Ramesh Yella, Hugo E. Gottlieb,* and Shmaryahu Hoz*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 5290002, Israel
*
S Supporting Information
ABSTRACT: Pyridine and its derivatives are rather difficult to reduce, and
the products often undergo a very fast reoxidation to regain aromaticity. The
reduction of quinoline by SmI results in an instantaneous [2 + 3] cyclization
2
reaction, forming a bridged seven-membered ring within a polycyclic system.
n the last five years, we have explored the reduction of
I
nitrogen-containing substrates by SmI . It turned out that
2
these substrates exhibit a rich and novel behavior not
observed before in any other group of substrates in the
1
field of SmI chemistry. For example, the three compounds
2
1
, 2, and 3 displayed surface catalysis and autocatalysis for the
2
reduction of the central CN bond.
The present study shows that nitrogen compounds contain
even more surprises.
In this study, we simplified the system by considering an
isolated aromatic nuclei containing nitrogen (pyridine
derivative) with no double bond attached to it. It is well-
known that partial reduction of pyridine and its derivatives is
rather difficult and apparently the reduced product undergoes
a very fast reoxidation to regain aromaticity. Therefore, we
The reactivity order for these three substrates was 3 > 2 >
. This reactivity order is not in accord with the electron
affinity of these substrates but rather with the accessibility of
the lone pair on the nitrogen. Namely, it correlates with the
6
1
have moved to the next simple pyridine derivativequinoline
(
Q). The surprising result is depicted in eq 3.
ability of SmI to coordinate to the substrate via the nitrogen
2
lone pair. In the next step, we moved the nitrogen from the
3
reaction center to the periphery. Namely, we moved the
nitrogen of 1 to the para position of the ring, generating a
stilbene-like substrate4 (eq 1). Thus, this substrate retained
the ability to coordinate to SmI , but in this case, the
The formation of 5 was accompanied under all conditions
by polymeric material. Attempts to optimize its yield led to
2
coordination site was displaced away from the reaction center.
the following conditions: [Q] = 40 mM, [SmI ] = 80 mM in
2
THF in the presence of 0.1 M TFE. The reaction was
instantaneous, and the isolated yield of 5 was 45%. This was
accompanied by 5% of the 2,2′ dimer 6 and polymeric
material.
The major product 5 was obtained as a mixture of two
diastereoisomers 7 and 8.
This substrate manifested another unexpected phenomen-
on: An unusual rate dependence on the concentration of the
additives MeOH, trifluoroethanol (TFE), hexamethylphos-
phoramide (HMPA), and SmI . The advantage of anchoring
3
the SmI in the vicinity of the reaction center was recently
The structures for 7 and 8 were established by a careful
analysis of their NMR spectra, which included several two-
dimensional NMR techniques. The NMR data are summar-
ized in Table 1 (for atom numbering, see 9 below). The usual
2
explored also by Procter, Flowers, and co-workers in
4
enhancing reduction of esters.
The surprises displayed by the nitrogen-containing
substrates culminated in the discovery of a system where
the radical produced after a proton coupled electron transfer
Received: July 9, 2015
5
step showed resistance to further reduction by SmI (eq 2).
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01572
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. NMR Data for 6, 7, and 8
a
6
7
(exo)
8 (endo)
1H
3.83
2.48
1H
13C
1H
3.74
2.64
13C
13C
2
3
4
5
6
7
8
9
0
156.25
119.43
136.74
127.65
126.70
129.55
129.94
147.95
128.48
65.72
51.39
30.26
62.79
46.31
8.85
8.33
7.89
7.58
7.76
8.23
2.28, 2.87
7.04
2.57, 2.70
7.00
27.62
b
127.52
119.37
127.65
114.55
146.11
126.29
59.88
127.35
119.44
126.40
115.57
145.10
128.00
55.73
6.77
6.68
b
c
7.06
6.90
In order to get unambiguous structural information
regarding the structure of 5, we carried out an X-ray analysis,
which supported the structure of the two enantiomers of 5
6.67
6.52
1
(
see ORTEP view of the endo isomer, Figure S1). It is
2
′
′
′
′
′
′
′
′
3.52
3.71
interesting to note that the Zn/AcOH method also provides
the structure of 5, but only when C4 was methylated.
We have recently delineated the advantage of reduction by
3
1.80, 2.35
2.92
27.76
2.01, 2.10
3.12
30.68
4
5
6
7
8
9
48.98
45.21
b
6.98
126.95
117.47
127.36
114.36
142.45
126.65
6.87
129.10
116.89
127.86
113.35
142.80
125.71
SmI over other reducing agents, which is manifested in its
2
6.64
6.54
versatility and enhanced chemoselectivity. Despite the differ-
ence in the products, it is instructive to compare the reaction
conditions and the reaction times of the two reactions. While
the Zn/AcOH method demands 15 h and reflux in THF, the
SmI2 reaction is instantaneous and at room temperature.
b
c
7.01
6.85
6.51
6.26
1
15
0′
a
N chemical shifts (from HMBC spectrum) −303.4 (N-1) and
Thus, another facet of the SmI advantage is in its enhanced
b
2
−
300.9 (N-1′). Chemical shifts with the same superscript may be
reactivity.
c
interchanged. Chemical shifts with the same superscript may be
interchanged.
We will turn now to the mechanistic aspects of the
reaction. Using ab initio calculations at the B3LYP/6-31+G*
8
level on both the radical and the radical anion of quinoline,
we determined the spin densities at the 2-, 3-, and 4-positions
(
Figure 1).
strategy for structure determination by NMR involves
1
establishing sequences of hydrogens (and, by one-bond H
13
×
C correlation, HMQC, the carbons connected to them)
and then connecting partial structures thus obtained by
1
13
HMBC (long-range H × C correlation). In the case of 7,
3
3
we had the problem that the values of J
and of J
H‑3,H‑2′
H‑2,H‑4′
were very small, reflecting a dihedral angle close to 90°, and,
therefore, causing a break in the proton sequence. This is a
consequence of the exo stereochemistry of this diaster-
eoisomer; for 8, the coupling constants were 4 and 6 Hz,
respectively. In the latter, NOE correlations (from a NOESY
spectrum) were seen between the one of the protons on C-3′
Figure 1. Spin densities on the relevant carbon atoms of the pyridine
ring calculated at the B3LYP/6-31+G* level for the radical and the
radical anion.
(
δ 2.01) and the bridgehead protons (H-2 and H-3),
The spin data do not support a concerted cyclization
reaction as in both, the radical and the radical anion, the spin
density on C3 is miniscule. A reasonable stepwise mechanism
is shown in Scheme 1. The first C2−C4′ bond could be a
radical combination reaction since the spin density at both
positions is high in the neutral as well as in the charged
intermediate. The second C−C bond formation is somewhat
more problematic since a nucleophilic attack by one ring on
the other will place a negative charge on the bridge carbon. A
reasonable alternative is that the allylic aza anion will undergo
protonation on the carbon to become the bridge (protonation
indicating that this was the endo isomer. No equivalent
interactions were seen for the exo isomer (7). Instead, a weak,
but diagnostically important, interaction was seen between H-
2
and H-5′ for the latter.
9
on the nitrogen is of course much faster but reversible) and
the nucleophilic attack by the neighboring group will take
place on the carbon atom of the imine moiety, delocalizing
the negative charge onto the nitrogen in a typical Michael
addition reaction. This is followed by protonation on the
A literature search for a similar structure revealed only one
case where the reduction of quinoline by the Zn/AcOH
7
method gave a [2 + 3] cyclization product. However, the
structure assigned to it was somewhat different from the one
we obtained. Instead of the participation of carbons 2 and 3
in the cyclization, carbon atoms 3 and 4 (see structure 10)
took part in the cyclization.
nitrogen and a two-electron two-proton reduction by SmI to
2
provide the final two diastereoisomers.
A plausible mechanism for the formation of the dimer is
10
given in eq 4.
B
DOI: 10.1021/acs.joc.5b01572
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1
eluent in 118 mg (45%) yield along with trace amounts of the dimer
6
contaminated with some polymeric material. The two diaster-
eoisomers were separated using thick layer chromatography with
hexane and ethyl acetate (98:2) as eluent. The two were crystallized
from ether.
exo-(6R,12R)-5a,6,11,12,12a,13-Hexahydro-5H-6,12-methano-
1
benzo[6,7]azepino[4,3-b]quinoline (7). Mp: 128−130 °C. H NMR
(
1
2
700 MHz, CDCl ): δ 1.80 (d, 1H, J = 11.5 Hz), 2.28 (dd, 1H, J =
4, 10.5 Hz), 2.35 (dt, 1H, J = 11.5, 4 Hz), 2.64 (q, 1H, J = 8.5 Hz),
.87 (dd, 1H, J = 14, 7 Hz), 2.92 (d, 1H, J = 3.5 Hz), 3.52 (d, 1H, J
3
In light of the reasonable yield of 5 and the mild conditions
short reaction times and room temperature) as opposed to
5 h reflux in the traditional methods, it is highly
(
1
=
1
3.5 Hz), 3.74 (d, 1H, J = 8 Hz), 6.51 (d, 1H, J = 8 Hz), 6.64 (td,
H, J = 7.5, 1 Hz), 6.67 (t, 1H, J = 7.5 Hz), 6.77 (td, 1H, J = 7.5, 1
Hz), 6.98 (dd, 1H, J = 7.5, 1 Hz), 7.01 (td, 1H, J = 7.5, 1.5 Hz),
recommended that the scope and limitation of this reaction
be explored and developed by the synthetic community.
1
3
7.04 (d, 1H, J = 8 Hz), 7.06 (t, 1H, J = 7.5 Hz); C NMR (175
MHz, CDCl ): δ 27.8, 30.3, 49.0, 51.4, 59.9, 65.7, 114.4, 114.6,
3
1
17.5, 119.4, 126.3, 126.7, 127.0, 127.4, 127.5, 127.7, 142.5, 146.1;
EXPERMENTAL SECTION
■
+
HRMS (ESI): m/z: [M + H] Calcd for C H N : 263.1548; found:
2
18
19
2
General Information. Reactions were performed inside the
glovebox and repeated under various concentrations by changing
proton donor (MeOH and TFE) concentrations to diminish the
polymer formation. THF was dried over sodium/benzophenone and
distilled under an argon atmosphere. MeOH and TFE were dried
63.1582.
endo-(6R,12R)-5a,6,11,12,12a,13-Hexahydro-5H-6,12-methano-
1
benzo[6,7]azepino[4,3-b]quinoline (8). Mp: 228−230 °C. H NMR
700 MHz, CDCl ): δ 2.01 (dd, 1H, J = 11.5, 4 Hz), 2.10 (d, 1H, J
(
3
=
11.5 Hz), 2.48 (dd, 1H, J = 10, 5.5 Hz), 2.57 (dd, 1H, J = 14, 10
Hz), 2.70 (dd, 1H, J = 14, 7 Hz), 3.12 (t, 1H, J = 4 Hz), 3.71 (t,
H, J = 4 Hz), 3.83 (dd, 1H, J = 11, 6 Hz), 6.26 (d, 1H, J = 7.5
11
according to a known procedure. Water content was determined
and found to be lower than 20 ppm. SmI was diluted as needed
from a 0.1 M freshly prepared THF solution. The concentration of
2
1
12
Hz), 6.52 (d, 1H, J = 7.5 Hz), 6.54 (t, 1H, J = 7.5 Hz), 6.68 (t, 1H,
J = 7.5 Hz), 6.85 (t, 1H, J = 7.5 Hz), 6.87 (d, 1H, J = 7.5 Hz), 6.90
the SmI solution was spectroscopically determined (λ = 615 nm; ε
2
=
635). Quinoline (Q) was used after distillation. Silica gel (60−120
13
(
t, 1H, J = 7.5 Hz), 7.00 (d, 1H, J = 7 Hz); C NMR (175 MHz,
mesh size) was used for column chromatography. Thick layer
chromatography (silica gel 60 F254, 0.5 mm, 20 × 20 cm) was used
for separation of two diastereomers. NMR spectra were recorded on
CDCl ): δ 27.6, 30.7, 45.2, 46.3, 55.7, 62.8, 113.4, 115.6, 116.9,
3
1
19.4, 125.7, 126.4, 127.4, 127.9, 128.0, 129.1, 142.8, 145.1; HRMS
+
(ESI): m/z: [M + H] Calcd for C H N : 263.1548; found:
18 19 2
a 700 mHz instrument using CDCl with tetramethylsilane as the
3
2
63.1582.
1
internal standard for H NMR (700 MHz) and CDCl solvent as the
3
internal standard for 13C NMR (176 MHz).
ASSOCIATED CONTENT
Supporting Information
Experimental Procedure for Reduction of Quinoline. To the
homogeneous solution of quinoline (0.236 mL, 40 mM) and TFE
0.377 mL, 0.1 M) in dry THF (10 mL) was added a freshly
prepared solution of SmI2 in THF (80 mM, 40 mL) at room
temperature. The final concentrations were [Q] = 40 mM, [SmI ] =
0 mM, and [TFE] = 0.1 M. The reaction is instantaneous, and
■
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01572.
2
Figure S1; H NMR, 13C NMR, DEPT of 6; 1D and
1
8
2
D NMR spectra of new compounds 7 and 8; and
following the addition, the reaction was treated with iodine dissolved
in THF and the solvent was evaporated under reduced pressure. The
crude reaction mixture was redissolved in CHCl3 (30 mL) and
washed with saturated NaHCO (10 mL), saturated Na S O (10
coordinates for the Gaussian calculations (PDF)
Crystallographic data of 8 (CIF)
3
2
2
3
mL), and potassium dihydrogen phosphate buffer (10 mL), followed
by brine (10 mL). The organic layer was dried over anhydrous
AUTHOR INFORMATION
Corresponding Authors
*E-mail: Hugo.Gottlieb@biu.ac.il (H.E.G.).
*E-mail: shoz@biu.ac.il (S.H.).
■
Na SO4 and evaporated under reduced pressure. The pure
2
diastereomers 5 (endo/exo, 1:1 ratio) were obtained after column
chromatography (silica gel) using hexane and ethyl acetate (98:2) as
C
DOI: 10.1021/acs.joc.5b01572
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Notes
The authors declare no competing financial interest.
REFERENCES
■
(
1) For some recent reviews on SmI , see: (a) Just-Baringo, X.;
2
Procter, D. J. Acc. Chem. Res. 2015, 48, 1263−1275. (b) Szostak, M.;
Spain, M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155−9183.
(
c) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004,
104, 3371−3403. (d) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001,
2727−2751. (e) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745−
777. (f) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321−
3354. (g) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307−
338.
(
2) Rao, C. N.; Hoz, S. J. Am. Chem. Soc. 2011, 133, 14795−14803.
(
(
3) Yella, R.; Hoz, S. Org. Lett. 2013, 15, 5262−5265.
4) Szostak, M.; Spain, M.; Choquette, M. A.; Flowers, R. A.;
Procter, D. J. J. Am. Chem. Soc. 2013, 135, 15702−15705.
(5) Yella, R.; Hoz, S. Org. Lett. 2014, 16, 3876−3879.
(6) (a) Kamochi, Y.; Kudo, T. Heterocycles 1993, 36, 2383.
(
b) Konigs, C. D. F.; Klare, H. F. T.; Oestreich, M. Angew. Chem.,
Int. Ed. 2013, 52, 10076−10079.
7) Gauffre, J. C.; Grignon-Dubois, M.; Rezzonico, B.; Leger, J. M.
J. Org. Chem. 2002, 67, 4696−4701.
8) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
(
(
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross,
J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann,
R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J.
W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Iiskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 09,
Revision A.01; Gaussian, Inc.: Wallingford, CT, 2009.
(
9) Bell, R. P. The Proton in Chemistry, 2nd ed.; Chapman and Hall:
London, 1973.
10) A referee has suggested an alternative mechanism based on
(
radical−radical coupling between two radical anions or neutral radical
species. On the basis of spin densities (Figure 1), the C4−C4′ dimer
should have been obtained rather than the C2−C2′ dimer. A second
referee suggested a H-atom abstraction from Q by some other side
product, and coupling of the resulting radicals was suggested by
another referee.
(
11) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: New York, 1989.
12) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
02, 2693−2698.
(
1
D
DOI: 10.1021/acs.joc.5b01572
J. Org. Chem. XXXX, XXX, XXX−XXX