The expedient access to bromo-pyridine carbaldehyde scaffolds using gem-dibromomethyl intermediates

Article abstract of DOI:10.1016/j.tetlet.2005.07.016

A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds is described. This direct route involves sequential reactions employing the dibromination of bromo-picolines followed by hydrolysis using an aqueous solution of calcium carbonate. Bromo-pyridine carbaldehyde scaffolds 1-7 were obtained in good overall yield. Bromo-dibromomethyl-pyridine intermediates have been isolated and characterized.

Full text of DOI:10.1016/j.tetlet.2005.07.016

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6033–6036
The expedient access to bromo-pyridine carbaldehyde
scaffolds using gem-dibromomethyl intermediates
Ashis Baran Mandal,a John Kallikat Augustine,a
Anna Quattropanib and Agnes Bombrunb,*
aSyngene International Private Limited, 20th KM Hosur Road, Electronic City PO, Bangalore 560 100, India
bSerono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland
Received 21 April 2005; revised 4 July 2005; accepted 5 July 2005
Abstract—A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds is described. This direct route
involves sequential reactions employing the dibromination of bromo-picolines followed by hydrolysis using an aqueous solution of
calcium carbonate. Bromo-pyridine carbaldehyde scaffolds 1–7 were obtained in good overall yield. Bromo-dibromomethyl-pyridine
intermediates have been isolated and characterized.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Pyridine derivatives are one of the most used frame-
works for medicines, food flavorings, dyes, agrochemi-
cals, rubber chemicals, and adhesives.1 In drug
discovery, it was well demonstrated that to avoid screen-
ing millions of compounds, one might attempt to bias
combinatorial chemistry efforts to produce a set of
molecules, which contain drug like patterns such as
the pyridine heterocyclic ring.2 From the perspective of
structural diversification, we were interested in pyridine
scaffolds bearing reactive orthogonal functional groups,
with minimal protecting group transformation and syn-
thetic manipulations. For the ease of subsequent deriva-
tization, preferred orthogonal functional groups include
halides and aldehydes. Aromatic halides and aldehydes
represent very versatile reagents. However, to our
knowledge, there is no methodology using the same
chemical transformation of appropriate starting materi-
als giving access to diverse regioisomers of bromo-pyri-
dine carbaldehydes. Indeed, it is well described that
substitution of the pyridine directs further derivatiza-
tion, resulting in different specific routes for each regio-
isomer. Herein, we describe preliminary results
concerning the expedient transformation of bromopico-
lines into gem-dibromomethyl derivatives to access
seven bromopyridine carbaldehydes as useful building
blocks.
The review of the most frequently used syntheses of
bromopyridine carbaldehydes 1–7 shows that a common
preparation from precursors bearing the same substitu-
ents is missing. Access to several regioisomers of bromo-
pyridine carbaldehyde scaffolds has been reported and
can be divided into three main methods. A first method
consists in a conversion of halopyridines via a halogen–
metal exchange reaction. Organolithium,3 Grignard,4
and palladium5 reagents were reported as the most com-
monly used in the halogen–metal exchange. Such strat-
egy allowed preparing regioisomers 1–4 and 5-bromo-
pyridine-3-carbaldehyde. However, modifications such
as nature of base, solvent, metal are required for each
of the five regioisomers. A second method is the treat-
ment of ortho-lithio bromopyridine with dimethylform-
amide following the procedure of Corey et al.6 The
four regioisomers 2, 5, 6, and 4-bromo- pyridine-3-carb-
aldehyde, bearing both substituents in ortho position,
were thus obtained.7 A third approach consists of an
oxidation of bromopicolines into the corresponding
acid, ester, hydroxymethyl, or oxime bromo-pyridine
derivatives.8 Then a further specific transformation for
each intermediate leads to bromo-pyridine carbaldehy-
des. An additional example of the third approach,
known for benzaldehydes synthesis, is the preparation
of dibromo derivatives, which are subsequently trans-
formed into aldehydes. Interestingly, this method has
Keywords: Picoline; Pyridine carbaldehydes; Dibromomethyl; Hydro-
lysis; Scaffolds.
*
Corresponding author. Tel.: +41 22 706 9823; fax: +41 22 706
9566; e-mail: agnes.bombrun@serono.com
0040-4039/$ - see front matter ꢀ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.016

6034
A. B. Mandal et al. / Tetrahedron Letters 46 (2005) 6033–6036
not been exploited for the preparation of bromo-pyri-
dine carbaldehydes.
line 11 or 3-bromo-4-picoline 12, or readily prepared
from the corresponding amino-picoline using a reported
protocol analogous to Sandmeyer reaction,10 as for
compounds 2-bromo-5-picoline 8, 2-bromo-3-picoline
9, 2-bromo-6-picoline 10, and 2-bromo-4-picoline 14,
or by bromination of 2-methylpyridine to give 3-bromo-
2-picoline 13.11 Then the bromopicolines were converted
into the corresponding bromo-dibromomethyl-pyridine
intermediates using a radical bromination at reflux.7
Use of 2.0 equiv of N-bromosuccinimide was found
optimal to complete dibromination. The bromo-dibro-
momethyl-pyridine compounds 15–21 were purified by
flash chromatography and stored at room temperature.
Intermediates 15, 17, and 18 were described earlier.12
Intermediates 16, 19, 20, and 21 were isolated and char-
acterized for the first time. Exposure of 15–20 to a solu-
tion of CaCO3 (2.2 equiv) in water (10 vol) at reflux gave
the corresponding aldehydes 1–6. Reaction of 21 to a
We wish to report here a concise and practical prepara-
tion of seven bromo-pyridine carbaldehydes from the
same
appropriate
bromo-dibromomethyl-pyridine
precursors (Scheme in Table 1). We account the
straightforward methyl oxidation of bromopicolines
into gem-dibromomethyl intermediates. Such pyridine
precursors showed limited interest so far,9 so we decided
to explore the subsequent hydrolysis into the corre-
sponding aldehydes for the different regioisomers of bro-
mo-pyridines. The scope and generality of this process is
illustrated with respect to various bromopicolines and
the results are presented in Table 1.
The required starting materials, bromopicolines, were
either commercially available, such as 3-bromo-6-pico-
Table 1. Synthesis of bromo-pyridine carbaldehyde scaffolds 1–7
i) NBS (2.2 eq.), (PhCO)2O2 (0.12 eq.)
in CCl4, 80-90 °C, 8-10 h
Br
CHO
Br
ii) CaCO3 / H2O at reflux, 6-8 h
Br
Me
Br
N
Br
N
N
1-7
15-21
8-14
Entry
1
Reagent
Bromo-dibromomethyl-pyridine15
Product16
Yielda (%)
(i) Bromination (ii) Hydrolysis
Br
OHC
1
15
Br
16
2-Bromo-5-picoline 814
82
79
Br
N
Br
N
Br
CHO
Br
2
2
2-Bromo-3-picoline 914
83
83
Br
N
N
Br
17
3
3
4
2-Bromo-6-picoline 1014
3-Bromo-6-picoline 11
88
88
86
73
Br
N
Br
OHC
Br
N
Br
Br
Br
Br
18
4
Br
N
N
CHO
Br
19
Br
5
CHO
Br
Br
53-Bromo-4-picoline
12
78
77
N
N
Br
20
Br
6
6
7
3-Bromo-2-picoline 1311
2-Bromo-4-picoline 1414
76
84
Br
N
N
CHO
7
Br
Br
Br
CHO
21
72b
60c
N
Br
N
Br
a Yields of bromination (i), hydrolysis (ii) steps were calculated after purification by flash chromatography or crystallization.
b The bromination was carried out for 24 h.
c Hydrolysis was carried out in dry DMSO instead of water.

A. B. Mandal et al. / Tetrahedron Letters 46 (2005) 6033–6036
6035
solution of CaCO3 (5.0 equiv) in DMSO (5 vol) at
References and notes
145 ꢁC yielded the aldehyde 7. Pyridine carbaldehydes
1–7 were isolated in moderate to good yield. This hydro-
lysis condition was reported earlier for the synthesis
of 4-bromobenzaldehyde from the corresponding
gem-dibromomethyl intermediate but such simple
hydrolysis conditions have not been applied to pyridine
derivatives.13
1. Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R.
Heterocycles in Life and Society; John Wiley and Sons:
UK, 1997.
2. (a) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39,
2887–2893; (b) Xu, J.; Stevenson, J. J. Chem. Inf. Comput.
Sci. 2000, 40, 1177–1187.
3. (a) Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.;
Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.;
Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.;
Lynch, J.; Maligres, P.; Molina, A.; Nemoto, T.; Okada,
S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada, T.;
Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. J.
Org. Chem. 2001, 66, 6775–6786; (b) Romero-Salguero, F.
J.; Lehn, J.-M. Tetrahedron Lett. 1999, 40, 859–862; (c)
Mallet, M.; Branger, G.; Marsais, F.; Queguiner, G. J.
Organomet. Chem. 1990, 382, 319–332.
4. (a) Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetra-
hedron Lett. 2001, 42, 4841–4844; (b) Trecourt, F.; Breton,
G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner, G.
Tetrahedron 2000, 56, 1349–1360.
5. Song, J. J.; Yee, N. K.; Kapadia, S. R. Int. Appl. WO 01/
90072, 2001.
6. Corey, E. J.; Pyne, S. G.; Schafer, A. I. Tetrahedron Lett.
1983, 24, 3291–3294.
7. Numata, A.; Kondo, Y.; Sakamoto, T. Synthesis 1999,
306–311.
8. (a) Frey, L. F.; Marcantonio, K.; Frantz, D. E.; Murry, J.
A.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J.
Tetrahedron Lett. 2001, 42, 6815–6818; (b) Ashimori, A.;
Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.; Watanabe,
M.; Yokoyama, K. Chem. Pharm. Bull. 1990, 38, 2446–
2548; (c) Shi, D.-F.; Wheelhouse, R. T.; Sun, D.; Hurley,
L. H. J. Med. Chem. 2001, 44, 4509–4523; (d) Felpin,
F.-X.; Bertrand, M.-J.; Lebreton, J. Tetrahedron 2002, 58,
7381–7389.
9. (a) Windscheif, P.-M.; Voegtle, F. Synthesis 1994, 87–92;
(b) Green, J. O.; Baird, J.-H.; Gibb, B. C. Org. Lett. 2000,
2, 3845–3848.
10. (a) Case, F. H. J. Am. Chem. Soc. 1946, 68, 2574–2577; (b)
Voegtle, F.; Hochberg, R.; Kochendoerfer, F.; Winds-
cheif, P.-M.; Volkmann, M.; Jansen, M. Chem. Ber. 1990,
123, 2181–2185.
Optimization of experimental conditions (temperature,
solvent) allowed us to obtain regioiomers 1–7 in parallel
from the corresponding intermediates 15–21. An amount
of 2.2 equiv of CaCO3 was found optimal for complete
hydrolysis to give the desired carbaldehydes 1–6. A plau-
sible route could involve the formation of bromohydrin
intermediate followed by HBr elimination to give the
product. Analysis of Table 1 showed that every regio-
isomer could be synthesized efficiently. Surprisingly,
2-bromo-4-dibromomethylpyridine 21 was the only reg-
ioisomer, which exhibited different reactivity in an aque-
ous solution of CaCO3. In contrast to the close analogue
19, intermediate 21 exhibited lower solubility. Replace-
ment of CaCO3 by CsCO3 or K2CO3 in water did not im-
prove the reaction. The use of DMSO, a well solubilizing
polar solvent circumvented this issue and 2-bromopyri-
dine-4-carbaldehyde 7 could be obtained in 60% yield
in the presence of 5equiv of CaCO 3. A mixture of sol-
vents, such as a water/dioxane (3/7), led to a better but
not total solubility of the reactants and the formation
of a complex combination of starting material, com-
pound 7 and 2-bromo-pyridine-4-carboxylic acid deriva-
tive were obtained. We presume that the solubility of
reagents could be the limiting factor for this transforma-
tion and was observed only for regioisomer 21.
As an example of scale-up production, a 150 g batch of
2-bromo-5-picoline 8 was transformed into 2-bromo-5-
dibromomethyl-pyridine in an isolated 70% yield. The
further exposure of 201 g of compound 15 to an aqueous
solution of CaCO3 gave 6-bromo-pyridine-3-carbalde-
hyde 1 in 80% yield. This example illustrates the possi-
bility of efficient scale up of bromo-pyridine
carbaldehydes synthesis.
11. Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods,
M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem.
1987, 30, 871–880.
12. For 15 and 17: see Ref. 9b and for 18: Boschelli, D. H.;
Wang, Y.; Boschelli, F. C.; Berger, D. M.; Zhang, N.;
Powell, D. W.; Ye, F.; Yamashita, A.; Demorin, F. F.,
Wu, B.; Tsou, H.; Overbeek-Klumpers, E. G.; Wissner, A.
Int. Appl. WO 01/72711, 2001.
13. (a) Coleman, G. H.; Honeywell, G. E. In Organic
Synthesis Collective; John Wiley and Son, 1943; Vol. II,
pp 89–91; (b) Adams, R.; Vollweiler, E. H. J. Am. Chem.
Soc. 1918, 40, 1732–1746. Transformation of gem-di-
bromo-pyridine derivatives into pyridine carbaldehydes
was only perfomed for the preparation of 5-bromo-
3-pyridine carbaldehyde via hydrolysis of bis(morpho-
lino)methylpyridine.9a
14. General procedure for bromo-picolines 8, 9, 10, and 14: at
À20 ꢁC, to a mixture of amino-methyl-pyridine (60.0 g,
0.55 mol) in 48% HBr (1 L) was added Br2 (80 mL,
1.55 mol) dropwise over a period of 20 min. The reaction
mixture was stirred for 30 min at À20 ꢁC. Then a solution
of NaNO2 (101.0 g, 1.47 mol) in water (200 mL) was
added over a period of 30 min. The resulting reaction
mixture was stirred for 2 h at the same temperature, then
quenched with aqueous NaOH (20%) until pH = 10. The
In summary, a general and expedient synthesis of bromo-
pyridine carbaldehydes 1–7 from the corresponding
bromo-gem-dibromomethyl intermediates has been
developed. No drastic difference in reactivity was
observed among the pyridine regioisomers. The simple
and ready availability of starting materials distinguishes
this preparation from other regioisomer-dependent
routes to bromo-pyridine carbaldehydes. Furthermore,
we believe that this protocol will improve the access to
every regioisomer of bromo-pyridine carbaldehyde scaf-
folds and analogues, and increase their use especially in
combinatorial chemistry for structure–activity relation-
ship studies.
Acknowledgments
We would like to thank Stefano Crosignani for his use-
ful comments on the manuscript.

6036
A. B. Mandal et al. / Tetrahedron Letters 46 (2005) 6033–6036
mixture was extracted with diethyl ether, dried over
Na2SO4, concentrated, and distilled under reduced pres-
sure to give the desired compounds in 86–91%.
for 8 h. The reaction mixture was cooled to rt and
extracted with EtOAc (2 · 250 mL). The organic layer was
washed with water, brine and dried over Na2SO4. The
solvent was removed under reduced pressure and the crude
compound was purified by crystallization from Petroleum
ether/EtOAc (95/5).
15. General procedure for bromo-dibromomethyl-pyridines
15–21: To a solution of bromo-picoline (25.0 g, 0.145 mol)
in CCl4 (250 mL) was added NBS (51.66 g, 0.29 mol),
benzoylperoxide (2.5g, 0.018 mol) and gradually heated
to reflux for 4 h. The reaction mixture was cooled to rt.
The succinimide was filtered off and the filtrate was
concentrated under reduced pressure. The crude was
purified by flash chromatography using petroleum ether/
EtOAc (9/1).
6-Bromo-pyridine-3-carbaldehyde 1:9a white solid; yield:
7.2 g (79%); mp 101–103 ꢁC; Rf = 0.5(petroleum ether/
EtOAc, 4/1); IR (neat) mmax 3055, 1695 cmÀ1 1H NMR
;
(DMSO-d6): d 7.88 (d, 1H, J = 8.1 Hz), 8.15(dd, 1H,
J = 8.1, 2.4 Hz), 8.88 (d, 1H, J = 1.8 Hz), 10.08 (s, 1H,
CHO). 13C NMR (DMSO-d6): d 128.8, 130.7, 138.6, 146.8,
152.3, and 191.5.
2-Bromo-5-dibromomethyl-pyridine 15:9b white solid;
yield: 38.0 g (82%); Rf = 0.8 (petroleum ether/EtOAc, 9/
1), mp 91–92 ꢁC; 1H NMR (DMSO-d6): d 7.44 (s, 1H),
7.76 (d, 1H, J = 9.0 Hz), 8.03 (d, 1H, J = 9.0 Hz), 8.59 (s,
1H).
2-Bromo-pyridine-3-carbaldehyde 2:3c white solid; yield:
9.6 g (83%); mp 73–75 ꢁC; Rf = 0.5(petroleum ether/
EtOAc, 4/1); IR (KBr pellet) mmax 3025, 1695 cmÀ1 1H
;
NMR (DMSO-d6): d 7.64 (dd, 1H, J = 6.4 and 2.8 Hz),
8.18 (m, 1H), 8.63 (m, 1H), 10.17 (s, 1H); 13C NMR
(DMSO-d6): d 124.2, 130.2, 138.4, 143.9, 154.7, 191.2.
6-Bromo-pyridine-2-carbaldehyde 3:8b white solid; yield:
9.9 g (86%); mp 76–78 ꢁC; Rf = 0.5(petroleum ether/
2-Bromo-3-dibromomethyl-pyridine 16: colorless oil;
yield: 39.0 g (83%); Rf = 0.8 (petroleum ether/EtOAc, 9/
1
1); H NMR (300 MHz, DMSO-d6): d 7.28 (s, 1H), 7.62
(m, 1H), 8.36–8.4 (m, 2H). Anal. Calcd for C6H4Br3N: C,
21.85; H, 1.22; N, 4.25. Found: C, 22.06; H, 1.39; N, 4.13.
2-Bromo-6-dibromomethyl-pyridine 17:9b a white solid;
yield: 40.0 g (88%); Rf = 0.78 (petroleum ether/EtOAc, 9/
1), mp 130–131 ꢁC; 1H NMR (300 MHz, DMSO-d6) d 7.32
(s, 1H), 7.65–7.71 (m, 2H), 7.82–7.86 (m, 1H).
EtOAc, 4/1); IR (neat) mmax 3040, 1700 cmÀ1 1H NMR
;
(DMSO-d6) d 7.94–8.06 (m, 3H) and 9.88 (s, 1H); 13C
NMR (DMSO-d6) d 121.4, 132.8, 140.9, 141.8, 153.1,
191.8.
5-Bromo-pyridine-2-carbaldehyde 4 (Jones, G.; Pitman,
M. A.; Lunt, E.; Lythgoe, D. J.; Abarca, B.; Ballesteros,
R.; Elmasnaouy, M. Tetrahedron 1997, 53, 8257–8268):
white solid; yield: 8.4 g (73%); mp 95–97 ꢁC; Rf = 0.5
(petroleum ether/EtOAc, 4/1); IR (neat) mmax 3055,
5-Bromo-2-dibromomethyl-pyridine 18 (Int. Appl. 01/
72711, 2001): white solid; yield: 40.0 g (88%); mp 56–
1
59 ꢁC; Rf = 0.78 (petroleum ether/EtOAc, 9/1); H NMR
(DMSO-d6): d 6.6 (s, 1H), 7.56 (d, 1H, J = 6.4 Hz), 7.88
(dd, 1H, J = 6.4, 2.4 Hz), 8.46 (d, 1H, 2.4 Hz). Anal.
Calcd for C6H4Br3N: C, 21.85; H, 1.22; N, 4.25. Found: C,
22.22; H, 1.46; N, 4.15.
1700 cmÀ1
;
1H NMR (CDCl3):
d
7.85(d, 1H,
J = 6.4 Hz), 8.00–8.04 (m, 1H), 8.85(s, 1H), 10.03 (s,
1H); 13C NMR(CDCl3): d 122.6, 126.1, 138.3, 139.8,
151.4, 192.2.
3-Bromo-4-dibromomethyl-pyridine 19: colorless oil;
yield: 36.0 g (78%); Rf = 0.7 (petroleum ether/EtOAc,
9/1); 1H NMR (DMSO-d6) d 7.1 (s, 1H), 7.62 (d, 1H,
J = 6.4 Hz), 7.72 (s, 1H), 8.42 (d, 1H, J = 6.4 Hz). Anal.
Calcd for C6H4Br3N: C, 21.85; H, 1.22; N, 4.25. Found: C,
21.92; H, 1.44; N, 4.20.
3-Bromo-pyridine-4-carbaldehyde 5:7 white solid; yield:
8.9 g (77%); mp 84–86 ꢁC; IR (neat) mmax 3045, 1690 cmÀ1
;
1H NMR (DMSO-d6): d 7.82 (d, 1H, J = 6.4 Hz), 8.10 (d,
1H, J = 6.4 Hz) 8.62 (s, 1H), 10.12 (s, 1H); 13C NMR
(DMSO-d6): 124.2, 129.5, 136.3, 144.4, 151.2, 191.9.
3-Bromo-pyridine-2-carbaldehyde 6 (Int. Appl. 02/22600,
2002): white solid; yield: 0.98 g (84%); mp 87–89 ꢁC;
Rf = 0.55 (petroleum ether/EtOAc, 4/1); IR (KBr pellet)
3-Bromo-2-dibromomethyl-pyridine 20: white solid; yield:
2.3 g (76%); mp 48–50 ꢁC; Rf = 0.75(petroleum ether/
1
EtOAc, 9/1); H NMR (CDCl3) d 6.99 (s, 1H), 7.30–7.42
1
(m, 1H), 8.28–8.32 (m, 2H). Anal. Calcd for C6H4Br3N: C,
21.85; H, 1.22; N, 4.25. Found: C, 22.07; H, 1.42; N, 4.23.
2-Bromo-4-dibromomethyl-pyridine 21: white solid; yield:
33.0 g (72%); Rf = 0.75(petroleum ether/EtOAc, 9/1), mp
65–67 ꢁC; 1H NMR (DMSO-d6) d 7.3 (s, 1H), 7.66 (d, 1H,
J = 6.4 Hz), 7.78 (s, 1H), 8.48 (d, 1H, J = 6.4 Hz). Anal.
Calcd for C6H4Br3N: C, 21.85; H, 1.22; N, 4.25. Found: C,
21.82; H, 1.33; N, 4.19.
mmax 3025, 1695 cmÀ1; H NMR (CDCl3): d 7.41–7.46 (m,
1H), 8.16–8.17 (m, 1H), 8.56–8.57 (m, 1H), 10.33 (s, 1H);
13C NMR (CDCl3): d 123.3, 130.3, 137.8, 145.2, 154.3, and
190.9.
2-Bromo-pyridine-4-carbaldehyde 7:8b white solid; yield:
1.44 g (60%); mp 56–57 ꢁC; Rf = 0.6 (petroleum ether/
EtOAc, 7/3); IR (KBr pellet) mmax 3015, 1700 cmÀ1 1H
;
NMR (DMSO-d6): d 7.84 (dd, 1H, J = 5.1, 1.0 Hz),
8.07 (s, 1H), 8.67 (d, 1H, J = 5.1 Hz), 10.02 (s, 1H); 13C
NMR (DMSO-d6): d 121.3, 127.3, 142.3, 144.3, 152.0, and
191.7.
16. General procedure for scaffolds 1–7: A mixture of bromo-
dibromomethyl-pyridine (20.0 g, 0.062 mol), CaCO3
(13.6 g, 0.136 mol) in water (500 mL) was heated at reflux