A one-pot organometallic route from a 4-alkenylpyridine to a 4,4-spiro-linked ethyl 1,4-dihydropyridine-1-carboxylate

Article abstract of DOI:10.1002/hlca.201200373

In a one-pot process without isolation of intermediates, (but-3-en-1-yl)pyridine (13) is treated sequentially with dicyclohexylborane, trimethylaluminium, and ethyl carbonochloridate yielding ethyl 1,4-dihydro-4,4-(tetramethylene)pyridine-1-carboxylate (=ethyl 8-azaspiro[4.5]deca-6,9-diene-8-carboxylate; 2) in 46% yield based on starting alkenylpyridine 13 (Scheme 5). Copyright

Full text of DOI:10.1002/hlca.201200373

Helvetica Chimica Acta – Vol. 95 (2012)
2063
A One-Pot Organometallic Route from a 4-Alkenylpyridine to a 4,4-Spiro-
Linked Ethyl 1,4-Dihydropyridine-1-carboxylate
by Gideon Fraenkel*, Albert Chow, Yulan Liang, Jinhua Song, and Judith Gallucci
Department of Chemistry, Ohio State University, 100 W. 18th Avenue, Columbus, Ohio 43210, USA
(
phone: þ 1-614-292-4210; fax: þ 1-614-292-1685; e-mail: fraenkel@mps.ohio-state.edu)
Dedicated to Prof. Dieter Seebach on the occasion of his 75th birthday
In a one-pot process without isolation of intermediates, (but-3-en-1-yl)pyridine (13) is treated
sequentially with dicyclohexylborane, trimethylaluminium, and ethyl carbonochloridate yielding ethyl
1
,4-dihydro-4,4-(tetramethylene)pyridine-1-carboxylate (¼ethyl 8-azaspiro[4.5]deca-6,9-diene-8-car-
boxylate; 2) in 46% yield based on starting alkenylpyridine 13 (Scheme 5).
Introduction. – Previous studies of potential spiro conjugation in 4,4-disubstituted
dihydropyridine anions such as 1 [1a] required the intermediacy of ethyl 1,4-
dihydropyridine-1-carboxylates such as 2 [1b] (Scheme 1). Compound 2 was originally
prepared via a ten step sequence starting with malonic acid esters [1].
Scheme 1
While conversion of alkenes to main group organometallics, via the hydroboration/
organometallic exchange, has been widely used for over 60 years [2], the procedure has
never been applied to the annulation of aromatic heterocycles. The purpose of this
article is to report the first example of such a sequence, the highly efficient one-pot
conversion of an alkenylpyridine to a spiro-linked dihydropyridine, and to recommend
such reactions as an attractive addition to the armamentarium of heterocyclic synthesis,
specifically annulation of aromatic N-heterocycles.
For background, we have shown that Grignard reagent 3 [3], easily prepared from
4
, reacts exclusively with ClCO Et to produce spiro urethane 5 [3], presumably due to
2
the reactive intermediate pyridinium salt 6 (Scheme 2). We also showed that whereas
mixtures of pyridine with Grignard reagents 7 remained unchanged for several days at
room temperature, addition of ClCO Et to the mixtures immediately produced the
2
ethyl 1,2-dihydropyridine-1-carboxylate 8 [4] (Scheme 3). Thus, apparently, formation
ꢀ
2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2
Scheme 3
of the 1-(ethoxycarbonyl)pyridinium salt 9 is competitive with acylation at magnesium
bonded C-atom.
Results and Discussion. – In principle, acylation of a (pyridin-4-ylalkyl)magnesium
halide such as 10 should easily produce a 4,4-spiro-linked dihydropyridine 11, by
analogy to the above transformation 3 ! 6 ! 5. Unfortunately precursor halides to
such a required Grignard reagent, e.g., 12, may be unstable, and according to the
literature, they convert only inefficiently to Grignard reagents [5] (Scheme 4). To avoid
such problems, we elected to try out a possible one-pot synthesis of 2 starting with
hydroboration of 4-alkenylpyridine 13 with dicyclohexylborane. This new process
exploits the well-known aluminium-boron exchange [2]. Thus hydroboration of 4-
alkenylpyridine 13 [6] followed by treatment of the reaction mixture with trimethyl-
aluminium and then ClCO Et, in fact, gave the known spiro carbamate 2 [1] after
2
isolation in 48% yield based on starting alkenylpyridine 13 [6] (Scheme 5), presumably
via the proposed intermediates 14 and 15, neither of which were isolated.
Scheme 4
1H- and 13C-NMR Spectra of 2 are consistent with the given structure. Since all
olefinic C- and H-atoms of 2 are magnetically nonequivalent at 258, rotation around
the NꢀCO bond must be slow relative to the NMR time scale at this temperature.
Chemical-shift data are summarized in Fig. 1.

Helvetica Chimica Acta – Vol. 95 (2012)
2065
Scheme 5
Fig. 1. 1H- and 13C-NMR Data of 2. d in ppm, J in Hz.
We also prepared the methyl carboxylate analog of 2, compound 16 (see Scheme 1),
in 37% yield after isolation in a similar fashion to Scheme 5, substituting diethylborane,
diethylzinc [7], and ClCO Me for dicyclohexylborane, trimethylaluminium, and
2
ClCO Et, respectively.
2
Finally in a third and less efficient process, reaction of 4-(4-chlorobutyl)pyridine
(
17) [8] with Mg in THF gave a mixture of Grignard reagent 18 and 4-butylpyridine
1
(19) in a ratio of 55 :45, determined by analysis of the H-NMR spectrum of the reation
mixture (Scheme 6). Treatment of this mixture with ClCO Et gave a 25.5% yield of 2
2
based on the content of Grignard reagent 18 in the reaction mixture.
The X-ray crystallographic data of 16 are summarized by the ORTEP diagram in
Fig. 2. The angles and bond lengths are listed around the structure in Fig. 3, and
selected torsional angles are collected in Table 1. Bond lengths and torsional angles
reveal coplanarity of the azadiene and methoxycarbonyl group and thus extended
conjugation throughout, see Fig. 3. Interestingly, these results are quite similar to
published crystallographic data for several N-acetyl-1,4-dihydropyridines [9]. Note that
while C(3) of 16 lies in the plane of the dihydropyridine moiety, the four CH C-atoms
2
of the spiro ring C(3) to C(7) are out of the plane of the rest of the molecule. This five-
membered ring contains a C-atom which is disordered over two sites, C(6a) and C(6b).
The ORTEP diagram of 16, (Fig. 2) includes C(6a). Interestingly, the four CH C-
2
atoms are near coplanar with a torsional angle C(4)ꢀC(5)ꢀC(6a)ꢀC(7) ¼ ꢀ5.7(4)8.

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 6
Fig. 2. ORTEP Diagram of compound 16. Drawn with 50% probability displacement ellipsoids for the
non-H-atoms; the H-atoms are drawn with an artificial radius. Arbitrary atom numbering. Atom C(6) is
disordered over two sites, and only one of these is shown as C(6a).
Table 1. Selected Torsional Angles [8] of Compound 16
C(1)ꢀNꢀC(9)ꢀC(8)
NꢀC(1)ꢀC(2)ꢀC(3)
C(9)ꢀNꢀC(10)ꢀO(1)
C(9)ꢀNꢀC(10)ꢀO(2)
NꢀC(9)ꢀC(8)ꢀC(3)
2.3 (2)
0.5 (2)
179.69 (12)
0.5 (2)
C(1)ꢀNꢀC(10)ꢀO(1)
C(1)ꢀNꢀC(10)ꢀO(2)
C(4)ꢀC(5)ꢀC(6a)ꢀC(7)
C(3)ꢀC(4)ꢀC(5)ꢀC(6a)
4.9 (2)
174.91 (10)
5.7 (4)
25.4 (3)
1.2 (2)
However the torsional angle for the four CH C-atoms with the other disordered C-
2
atom, C(6b), i.e., C(4)ꢀC(5)ꢀC(6b)ꢀC(7)8, is ꢀ 33.6(14)8.
Thus it appears that in the solid state, 16 assumes two very similar structures, 16a
and 16b, which differ in the arrangement around the five-membered rings as illustrated

Helvetica Chimica Acta – Vol. 95 (2012)
2067
Fig. 3. Selected X-ray crystallographic bond distances [ꢂ] and angles [8] of compound 16. Arbitrary atom
numbering.
by the ORTEP diagrams in Fig. 4. Fig. 5 shows the five-membered rings of 16a and 16b,
respectively, viewed from the direction C(3) to N. Further, it is also interesting that in
the solid state, the five-membered ring is bent in the direction of the C¼O O-atom.
Fig. 4. ORTEP Diagrams of 16a (top) and 16b (bottom). Arbitrary atom numbering.
The NMR data of 16 are very similar to that of 2. In both, all olefinic C- and H-
atoms are magnetically nonequivalent, most likely due to slow rotation around the
NꢀC(carbonyl) bond, as noted above. The NMR spectra provide no information on the
orientation or orientations of the five-membered ring. However, should different
conformers be present in solution, interconversion between them would be fast enough
to average out shifts among them, even at low temperature.

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Helvetica Chimica Acta – Vol. 95 (2012)
Fig. 5. ORTEP Diagram of the five-membered rings of 16a (left) and 16b (right). Viewed from the
direction C(3) to N. Arbitrary atom numbering.
On warming a (D )benzene solution of 16 above 280 K, there is progressive
6
averaging of the d(H) and d(C) of HꢀC(1) with HꢀC(9) and of HꢀC(2) with HꢀC(8)
(
see Fig. 2 for atom numbering). Careful NMR line shape analysis of these changes
‡
‡
yields DH ¼ 19 kcal/mol and DS ¼ þ12 eu for rotation around the NꢀC(carbonyl)
bond. Note that while entropies of activation for conformational changes are largely
expected to be near neutral, positive deviations have been reported, e.g., for amide
rotation in aromatic solvents [10]. In those cases, it has been proposed that there is a
substantial decrease in polarity in the transition state for rotation compared to the
ground state. The difference in interaction of the two states with aromatic solvent has
‡
been ascribed responsible for the large positive change in DS for rotation. Interest-
ingly, most barriers to rotation in urethanes have been reported as DG values of
z
3
00
1
5 kcal/mol to 18 kcal/mol, determined from coalescence measurements [11]. The
z
DG coalescence measurement for 16 is 15 kcal/mol, obtained also from the line-
300
shape calculation.
In sum, we showed how organometallic spirocyclization of the pyridinium system is
an unusually rapid and efficient route to potentially important spiro-connected
dihydropyridines especially when use is made of the organoboron/organoaluminium or
1
organozinc exchange ).
This research was generously supported by the National Science Foundation. We also thank the late
Dr. Charles Cottrell (deceased), Central Campus Instrumentation Center for untiring technical assistance.
Experimental Part
General. Commercially available materials were used without purification. 1H- and 13C-NMR
1
13
Spectra: Bruker Avance 300; at 300 ( H) and 75.47 MHz ( C); d in ppm rel. to Me Si as internal standard,
4
J in Hz.
Ethyl 1,4-Dihydro-4,4-(tetramethylene)pyridine-1-carboxylate (¼ Ethyl 8-Azaspiro[4.5]deca-6,9-di-
ene-8-carboxylate; 2). Cyclohexene (20.5 g, 0.25 mol) was added to 1m diborane in THF (125 ml) at 08.
1)
The H- and 13C-NMR spectra of new compounds are available as Supplementary Material from the
1
corresponding authors.

Helvetica Chimica Acta – Vol. 95 (2012)
2069
The mixture was stirred at 08 for 1 h. Dicyclohexylborane precipitated from this soln. A soln. of 4-(but-3-
en-1-yl)pyridine (13; 18.32 g, 0.025 mol) was slowly added to the dicyclohexylborane soln. at ꢀ 10 to
ꢀ
208. The mixture was then brought to 08 and stirred at 08 for 8 h. At the conclusion of stirring, the
alkenylpyridine could not be detected by H-NMR. Then, a soln. of trimethylaluminium (9.0 g,
1
0
.125 mol) in THF (12 ml) was slowly added to the mixture at 20 – 258. After stirring for 0.5 h, ClCO Et
2
(
41 g, 0.375 mol) was added dropwise to the mixture, which was then stirred for 0.5 h at r.t. Then, the
mixture was dropped into sat. aq. NaCl soln. (200 ml) cooled with an ice-water bath. The aq. layer was
extracted with Et O, the combined Et O phase washed with H O, dried, and concentrated, and the
2
2
2
1
residue distilled at 102 – 1138/0.25 Torr: 2 (6.1 g, 47.2% rel. to 13). H-NMR (300 MHz, CDCl ): 1.226 (t,
3
J ¼ 7.2, 3.04 H); 1.44 (m, 4.09 H); 1.557 (m, 4.11 H); 4.170 (q, J ¼ 7.2, 2.04 H); 4.703 (d, J ¼ 8, 1.01 H);
1
3
4
(
.792 (d, J ¼ 8, 1.01 H); 6.593 (d, J ¼ 8, 1 H); 6.707 (d, J ¼ 8, 1 H). C-NMR (75.47 MHz, CDCl ): 14.33
3
Me); 24.40 (CH ); 43.87 (CH ); 114.48 (CH); 114.91 (CH); 119.7 (CH); 119.90 (CH); 151.25 (C). MS:
2
2
2
07.12621 (C H NO ; calc 207.12590).
12 17 2
Ethyl 1,4-Dihydro-4,4-(tetramethylene)pyridine-1-carboxylate (¼ Methyl 8-Azaspiro[4.5]deca-6,9-
diene-8-carboxylate; 16). Diethyl borane (31.5 mmol), was freshly prepared [7b] by mixing triethylbor-
ane (2.6 g, 21 mmol) and boraneꢀdimethyl sulfide (1.05 ml, 10.5 mmol) under Ar at 08 for 10 – 30 min.
Over 10 min under Ar, 13 (2.1 g, 15.8 mmol) was added slowly to the diethylborane. Stirring was
continued for 0.5 h at 08 and another 0.5 h at r.t. Then dimethyl sulfide and excess diethylborane were
removed under vacuum (1 Torr, 0.5 – 1 h). The remaining mixture was dissolved in dry THF (20 ml) and
cooled to 08. Then 1.5m diethyl zinc in toluene (11 ml) (17 ml, 16.5 mmol, 1.04 equiv.) was added
dropwise over 10 min. Stirring was continued for 0.5 h at 08 and another 0.5 h at r.t. ClCO Me (2.53 ml,
2
3
.1 g, 32.7 mmol, 2.07 equiv.) then was added to the mixture, and stirring was continued overnight.
Finally, the reaction soln. was slowly added to degassed cooled sat. NaCl soln. The aq. phase containing a
white precipitate was extracted with Et O (3 ꢁ 30 ml). The combined org. phase was dried (MgSO ) and
2
4
concentrated and the residue purified by CC (SiO , AcOEt/hexane 1:19): 16 (1.15 g, 37%). During
2
removal of the solvents, just described, crystals suitable for X-ray diffraction studies were obtained.
1
H-NMR (300 MHz CDCl ): 1.484 (m, 4.2 H); 1.590 (m, 4.2 H); 3.668 (s, 3.02 H); 4.654 (d, J ¼ 8.1,
3
13
1
.0 H); 4.742 (d, J ¼ 8.1, 1.0 H); 6.511 (d, J ¼ 8.1, 1.0 H); 6.652 (d, J ¼ 8.1, 1.0 H). C-NMR (75.47 MHz,
3
CDCl ): 22.92; 43.95; 52.67; 114.43; 114.86; 119.48; 119.82; 151.51.
Spiro Compound 2 from 4-(Pyridin-4-yl)butylmagnesium Chloride (18). Mg (0.19 g, 0.079 mol) was
treated with 4-(4-chlorobutyl)pyridine (17; 1.35 g, 8 mmol) in dry THF (20 ml) under Ar and stirred
overnight at r.t. (!orange mixture). The NMR spectra of a sample of this mixture, with the solvent
replaced by (D )THF, included a t d(H) at ꢀ 0.55 and a signal at d(H) 7.82 ascribed to the CH MgCl of
8
2
Grignard reagent 18, and a t at d(H) 0.86 and a signal at d(C) 14.25 most likely due to Me of 4-
butylpyridine (19). These results establish the formation of 18 and its hydrolysis product 19 in a ratio of
6
5 :35.
The remainder of the mixture was transferred to a flask and divided into two equal parts. One part
was hydrolyzed with degassed H O and extracted into Et O (3 ꢁ 10 ml). The combined org. phase was
2
2
dried (MgSO ) and concentrated. CC (SiO , AcOEt) of this material yielded 19 (0.47 g, 44% rel. to 17),
4
2
1
contaminated with a small amount of 17. H-NMR (CDCl ): 0.800 (t, J ¼ 7.3, 3.08 H); 1.23 (m, 2.1 H);
3
13
1
.434 (m, 2.0 H); 2.425 (t, J ¼ 7.7, 2.0 H); 6.805 (d, J ¼ 5.7, 2.16 H); 8.288 (d, J ¼ 5.7, 2.10 H). C-NMR
(
CDCl ): 13.44; 21.85; 32.02; 34.50; 121.26; 123.48; 149.21; 151.23.
3
The second portion of the mixture obtained from Mg and 17 was cooled to 08. Then ClCO Et (0.19 g,
2
0
.08 ml, 8.4 mmol) was added dropwise, and stirring was continued for 3 h while the mixture was allowed
to warm to r.t. Degassed H O was added to the mixture which was extracted with Et O (3 ꢁ 10 ml). The
2
2
combined org. phase was dried (MgSO ) and concentrated and the residue subjected to CC (SiO ,
4
2
AcOEt/hexanes 1:19): 2 (0.23 g, 14% rel. to 17). NMR Data: identical to those described above for 2.
2
Crystallography ). The data-collection crystal of 16 was a clear, colorless rectangular rod. Data was
collected with a Nonius-Kappa-CCD diffractometer at 150 K and an Oxford-Cryosystems-Cryostream
cooler (Table 2). The data-collection strategy was set up to measure a quadrant of reciprocal space with a
2)
CCDC-890670 contains the supplementary crystallographic data for this article. These data can be
obtained free of charge via http://www.dc.ac.uk/data_request/cif.

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 2. Crystallographic Data of 16 and Structure-Refinement Details
Chemical formula
C H N O
2
Absorption coefficient, m [mmꢀ1] 0.085
1
1
15
1
Mr
193.24
q range for data collection [8]
No. of reflections measured
No. of independent reflections
Rint
2.28 to 27.48
19896
2367
Crystal system
a [ꢂ]
b [ꢂ]
c [ꢂ]
b [8]
Unit cell volume [ꢂ ]
Temperature [K]
Space group
No. of formula units per unit cell, Z 4
Radiation type
Crystal size
monoclinic
5.8949(1)
10.6130(2)
16.5751(4)
95.893(1)
1031.50(4)
150(2)
0.034
Completeness to q ¼ 27.488
100.0%
2367, 2, 138
0.0445
0.1129
0.0607
Data, restraints, parameters
3
Final R values (I > 2s(I))
1
2
Final wR(F ) values (I > 2s(I))
P2 /n
1
Final R values (all data)
1
2
Final wR(F ) values (all data)
0.1214
ꢀ3
MoK (0.71073 ꢂ)
Largest diff. peak and hole [e ꢂ ] 0.171; ꢀ 0.223
a
2
0.16 ꢁ 0.16 ꢁ 0.40 mm Goodness of fit on F
1.057
890670
3
Density (calc.) [Mg/m ]
1.244
CCDC number
redundancy factor of 3.9, which means that 90% of these reflections were measured at least 3.9 times; f
and w scans with a frame width of 2.08 were used. Data integration was done with Denzo [12], and scaling
and merging of the data was done with Scalepack [12].
The structure was solved by the direct methods program in SHELXS-97 [13]. Full-matrix WinGX
package [14]. The five-membered ring contains a C-atom which is disordered over two sites; least-
2
squares refinements based on F were performed in SHELXL-97 [13], as incorporated in the two sites:
C(6a) and C(6b). Restraints were used in the least-squares refinement of the bond lengths involving
these two atoms.
For the Me group, the H-atoms were added at calculated positions by using a riding model with
U(H) ¼ 1.5 · U (bonded C-atom). The torsion angle which defines the orientation of the Me group
eq
about the OꢀC bond was refined. The rest of the H-atoms were included in the model at calculated
positions by using a riding model with U(H) ¼ 1.2 · U (bonded atom). Neutral atom scattering factors
eq
were used and include terms for anomalous dispersion [15].
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Received July 17, 2012