Synthesis of substituted 1-methyl-2-cyanopyrroles via unprecedented addition of N,N-dimethylformamide to electron-deficient alkenes in the presence of copper(I) cyanide

Full text of DOI:10.1021/jo991440f

2222
J . Org. Chem. 2000, 65, 2222-2224
Sch em e 1
Syn th esis of Su bstitu ted
1-Meth yl-2-cya n op yr r oles via
Un p r eced en ted Ad d ition of
N,N-Dim eth ylfor m a m id e to
Electr on -Deficien t Alk en es in th e P r esen ce
of Cop p er (I) Cya n id e
J effrey P. Fitzgerald,* Hirsh Nanda,
Patrick Fitzgerald, and Gordon T. Yee
Department of Chemistry, United States Naval Academy,
Annapolis, Maryland 21402, and the Department of
Chemistry and Biochemistry, University of Colorado,
Boulder, Colorado 80309
Received September 13, 1999
Our initial hypothesis was that the observed products
were the result of isomerization of the expected trans-
dinitrile to its cis stereoisomer, which then cyclized to
the pyrrole via a Paal-Knorr-like reaction.5 Accordingly,
the reaction temperature and time were reduced in an
effort to produce the putative fumaronitrile or maleoni-
trile under conditions at which it would be stable, all to
no avail. In an effort to better understand the formation
of these products, 3a was allowed to react with 13C-
labeled CuCN6 under identical conditions. Suprisingly,
the 13C label appeared only in the cyano groups of 4a and
5a ; neither R carbon atom of 4a or 5a was isotopically
labeled. Thus, the pyrrole ring is not formed by cycliza-
tion of a dicyanoethylene intermediate but instead results
from reaction of the alkene, 3a , with the solvent, DMF
(or intermediates derived therefrom). This conclusion has
been confirmed by reaction of 3a with CuCN in 13C-
labeled DMF (isotopically labeled at the carbonyl carbon
atom). In this reaction, product 4a is shown by mass
spectrometry and NMR to be labeled only at C2; the other
R carbon, C5, was unlabeled. Also 5a is formed exclu-
sively with only one of its R-carbon atoms isotopically
labeled. Thus the two pyrrolic R-carbon atoms are derived
from the formyl group and one of the N-methyl groups
of DMF. Activation of the alkyl group on a substituted
amide under these conditions is unprecedented.
The generality of this reaction was explored by varying
the reactants, the stoichiometry, and the solvent. Sub-
stitution of DMF with N,N-diethylformamide or N,N-
dimethylacetamide resulted in formation of intractable
products. Similarly, no identifiable products were ob-
tained when copper(I) cyanide was replaced by either
copper(I) bromide or potassium cyanide. The ratio of
products 4a to 5a were found to depend on the reactant
stoichiometry. Reducing the amount of copper(I) cyanide
to 1 equiv based on dibromide, 3a , resulted in almost
exclusive production of 4a , still in approximately 70%
In tr od u ction
Unsaturated molecules bearing strongly electron-
withdrawing groups, such as tetracyanoethylene (TCNE),
dichlorodicyanoquinone (DDQ), etc., have been used
recently as electron acceptors in charge-transfer salts
that show unusual magnetic properties.1 Our interest in
these materials led us to consider 1,2-bis(trifluorometh-
yl)-1,2-dicyanoethylene, 1, as a potential electron accep-
tor. While trying to develop a convenient synthesis of 1,
we discovered, and are reporting here, an unprecedented
reaction in which electron-deficient alkenes react with
DMF in the presence of CuCN to form substituted
1-methyl-2-cyanopyrroles.
The published three-step synthesis of 1, which includes
steps involving liquid HCN and a pyrolysis in molten
sulfur, produces an equimolar mixture of cis and trans
stereoisomers.2 While we were able to produce 1 by this
method, its difficulty and scale limitations prompted us
to seek an alternate synthesis. One possibility was
bromination of commercially available hexafluoro-2-
butyne, 2a , followed by copper-mediated substitution of
bromide by cyanide.3
Resu lts a n d Discu ssion
As shown in Scheme 1, the addition of 1 equiv of
bromine to 2a gave the expected product, 1,2-bis(trifluo-
romethyl)-1,2-dibromoethylene, 3a , (approximately equal
amounts cis and trans isomers) in 95% yield. Treatment
of this vinylic dibromide with 2 equiv of copper(I) cyanide
in DMF did not produce 1 but instead provided a 6:1
mixture of 1-methyl-2-cyano-3,4-bis(trifluoromethyl)pyr-
role, 4a , and 1-methyl-2,5-dicyano-3,4-bis(trifluorometh-
yl)pyrrole, 5a , in a combined yield of 74%.4
(4) In addition to the spectroscopic characterization of 4 and 5 given
in the Experimental Section, the atom connectivity for 4a has also been
unambiguously characterized by a single-crystal diffraction study that
was of low quality due to extensive decomposition in the X-ray beam.
Yap, G. P. A.; Rheingold, A. L., The University of Delaware, unpub-
lished results, 1994.
(1) Miller, J . S.; Epstein, A. J . J . Chem. Soc., Chem. Commun. 1998,
1319-1325 and references therein.
(5) Davies, D. T. Aromatic Heterocyclic Chemistry; Oxford Univer-
sity: Oxford, 1992; pp 11-12.
(2) Proskow, S.; Simmons, H. E.; Cairns, T. L. J . Am. Chem. Soc.
1963, 85, 2341. Proskow, S.; Simmons, H. E.; Cairns, T. L. J . Am.
Chem. Soc. 1966, 88, 5254-5266.
(6) 13C-labeled copper(I) cyanide was prepared from 13C-labeled
potassium cyanide by the procedure of Barber, H. J . Chem. Soc. 1943,
79.
(3) Fitzgerald, J .; Taylor, W.; Owens, H. Synthesis 1991, 686-688.
10.1021/jo991440f CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/14/2000

Notes
J . Org. Chem., Vol. 65, No. 7, 2000 2223
Sch em e 2
the dibromoalkene. Loss of another proton from 11
followed by displacement of the second bromide, by an
addition-elimination process, completes the ring, which
is then oxidized to 5 on workup.
The above mechanism is consistent with the facts that
(1) the observed ratio of 4 to 5 depends on the relative
amount of CuCN to 3 and (2) that 4 is not an intermedi-
ate in the formation of 5. One can rationalize the lack of
similar products when N,N-dimethylacetamide or N,N-
diethylformamide were used as solvents on steric grounds.
The role of the copper(I) ion is not obvious; it may activate
the carbonyl group of DMF for addition of cyanide and/
or it may act as a Lewis acid, facilitating the loss of the
oxide or bromide ions.
Preliminary attempts to trap the proposed azomethine
ylide, 8, with reactive dipolarophiles have been unsuc-
cessful. Substitution of 3 with either fumaronitrile or
maleic anhydride under the usual reaction conditions
gave no evidence for a 3 + 2 cycloaddition product. While
the maleic anhydride was likely hydrolyzed in the reac-
tion, all of the fumaronitrile was recovered unreacted.
Con clu sion
Two reaction manifolds are possible for mixtures of
vinylic dihalides, CuCN and DMF. A copper-mediated
substitution reaction to give dinitriles occurs for vinylic
dihalides bearing alkyl and aryl groups3 while those
bearing electron-withdrawing groups give 3,4-disubsti-
tuted 1-methyl-2-cyanopyrroles possibly via cycloaddi-
tions with an azomethine ylide generated in situ from
DMF. It is reasonable to expect that electron-withdraw-
ing groups on the alkene raise the activation energy for
the former reaction10 while reducing it for the latter.11
3,4-Bis(trifluoromethyl)pyrroles have been prepared by
Diels-Alder addition of hexafluoro-2-butyne to pyrroles
followed by a retro Diels-Alder elimination of acetyl-
ene.12 However, the initial Diels-Alder reaction fails for
pyrroles bearing electron-withdrawing groups at the
R-positions. Thus, the reaction reported here is the only
method, of which we are aware, for preparing 2-cyano-
pyrroles bearing additional electron-withdrawing groups
in the 3 and 4 positions.
yield. When the reaction was conducted with a 4:1 initial
ratio of CuCN to 3a , products 4a and 5a were obtained
in essentially equal amounts. Interestingly, replacement
of the vinylic dibromide starting material, 3a , with 4a ,
under the usual reaction conditions, did not produce any
dicyanopyrrole, 5a , indicating that 4a is not an interme-
diate in the production of 5a .
Substitution of 3a with dimethyl 2,3-dibromo-2-butene-
dioate,7 3b (approximately equal amounts of cis and trans
isomers) gave an analogous mixture of N-methylpyrroles;
dimethyl 1-methyl-2-cyano-3,4-pyrroledicarboxylate, 4b,
and dimethyl 1-methyl-2,5-dicyano-3,4-pyrroledicarbox-
ylate, 5b, were produced in a 10:1 ratio in an overall yield
of 35%. Thus, this pyrrole-forming reaction appears to
be general for vinylic dihalides bearing electron-with-
drawing groups.
These results are most consistent with a 3 + 2
cycloaddition between the alkene and an azomethine
ylide8 generated by reaction of DMF and CuCN as
outlined in Scheme 2. Formation of a cyanohydrin-like
intermediate, 6, is followed by nitrogen-assisted loss of
oxygen to give an iminium ion, 7. Loss of a proton from
the activated N-alkyl group forms a resonance-stabilized
azomethine ylide, 8. Grigg has reported N-alkyl group
activation in similar iminium ions prepared by condensa-
tions of secondary amines and carbonyl groups bearing
a conjugated moiety.9 Addition of 8 to the alkene followed
by elimination of 2 equiv of HBr from intermediate 9
would give products 4. Products 5 could arise from
cyanide attack on 8, followed by nucleophilic attack on
Exp er im en ta l Section
All reagents were purchased from Aldrich Chemical Co. except
for hexafluoro-2-butyne, which was purchased from PCR, Inc.,
Gainesville, FL, and 13C-potassium cyanide and 13C-DMF, both
of which were purchased from Cambridge Isotope Laboratories.
13C-CuCN6 and dimethyl 2,3-dibromo-2-butenedioate7 were pre-
pared by modifications of literature procedures. All reagents
were of commercial quality. Samples were submitted to Gal-
braith Laboratories or Desert Analytics Laboratory for elemental
analyses.
1,2-Dibr om o-1,2-bis(tr iflu or om eth yl)eth ylen e (3a ). A 2
L three-neck round-bottom flask was used as a gas-phase
reactor. To one neck of the reactor was connected a small round-
bottom flask containing a few milliliters of liquid bromine. To
another neck was connected a cylinder of hexafluoro-2-butyne,
and the third neck was connected to the sidearm of a T-shaped
stopcock. The central arm of the stopcock was connected to a
manometer while the other sidearm was connected to a liquid
nitrogen-cooled trap and then a mechanical vacuum pump. The
(7) Produced from dimethylacetylenedicarboxylate by the method
of Kloster-J ensen, E. Acta Chem. Scand. 1963, 17, 1866-1874.
Identical to dimethyl 2,3-dibromo-2-butenedioate reported by Lutz, R.
J . Am. Chem. Soc. 1930, 52, 3405-3422.
(8) Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231-
349.
(9) Ardill, H.; Grigg, R.; Sridharan, V.; Surendrakumar, S.; Thian-
patanagul, S.; Kanajun, S. J . Chem. Soc., Chem. Commun. 1986, 602-
604.
(10) Carey, F.; Sundberg, R. Advanced Organic Chemistry; Ple-
num: New York, 1977; pp 601-603.
(11) Carey, F.; Sundberg, R. Advanced Organic Chemistry; Ple-
num: New York, 1977; pp 300-307.
(12) Kaesler, R. W.; LeGoff, E. J . Org. Chem. 1982, 47, 4779-4780.

2224 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
entire system was evacuated, and the T-shaped stopcock was
used to isolate the reactor and manometer from the vacuum.
The stopcock to the bromine solution was opened, and bromine
vapor was allowed into the reactor until the pressure had
increased by 50 Torr. When the pressure had stabilized an
equimolar amount of hexafluoro-2-butyne, as measured by the
pressure changes on the manometer, was allowed into the flask.
The gas mixture was irradiated with a heat lamp. Within 1 min
of irradiation the reddish color of the bromine vapor had
disappeared and the pressure had dropped to one-half the
pressure of the gas mixture. The entire system was evacuated
and the product collected in the trap. This process was repeated
10 times within 1 h. The trap containing the frozen product, as
well as some unreacted starting materials, was allowed to warm
to room temperature where unreacted hexafluoro-2-butyne
evaporated. The crude product was purified by vacuum distil-
lation using a water aspirator (bp ) 38 °C). Yield ) 16.65 g
(95%). GC and 19F NMR confirmed the presence of two isomers
in a 3:4 ratio: 19F NMR (CDCl3) δ ) 56.3 (s, 3F), 52.8 (s, 4F) vs
C6 H5 F; 13C NMR (1H decoupled, CDCl3) δ ) 127.0-125.3 (m),
119.7 (q, J CF ) 276 Hz) 119.4 (q, J CF ) 276 Hz), 116.9 (q of q,
J CF ) 39 Hz, J CF′′ ) 1.5 Hz); IR (neat): 1/λ ) 1596, 1245, 1190,
1162 cm-1; MS (EI) m/z ) 320, 322, 324 (M+.).
1-Meth yl-2-cya n op yr r oles (4a -5b). A 25 mL round-bottom
flask, charged with 1.00 g (11.2 mmol) of CuCN and 10 mL of
DMF, was fitted with a magnetic stir bar and a condenser. This
mixture was heated with stirring at 95 °C under an inert
atmosphere for 1 h after which 5 mmol of either 1,2-dibromo-
1,2-bis(trifluoromethyl)ethylene or dimethyl 2,3-dibromo-2-
butenedioate (approximately equal amounts of cis and trans
isomers) were added. The mixture quickly turned a deep brick-
red color. After stirring for 4 h at 95 °C under an inert
atmosphere, the solution was cooled to room temperature and
poured into 100 mL of water. This mixture was extracted three
times with 50 mL of ether, and the combined ether layers were
washed once with 50 mL of water and once with 50 mL of
saturated aqueous NaCl, dried over sodium sulfate, filtered, and
reduced to a viscous red oil on a rotary evaporator. The crude
product was analyzed on capillary GC (100 °C, 1 min, 4 °C/min,
140 °C, 5 min) and by TLC (SiO2, 2/1 hexanes/CH2Cl2 eluent).
The major products were isolated by flash chromatography on
silica gel (solvent gradient of hexanes f 1/1 hexanes/CH2Cl2 for
4a and 5a while a solvent gradient of hexanes f 1/1 hexanes/
ether for 4b and 5b). Removal of solvent gave either white solids
or clear oils which solidified on standing.
1-Met h yl-2-cya n o-3,4-b is(t r iflu or om et h yl)p yr r ole (4a ).
Yield ) 0.77 g (64%); mp 37 °C; H NMR (CDCl3): δ ) 7.22 (s,
1
1H), 3.89 (s, 3H); 19F NMR (CDCl3): δ ) 55.5 (s, 1F), 56.0 (s,
1F) vs C6H5F; 13C NMR (1H decoupled, CDCl3): δ ) 127.7 (s),
121.0 (q, J CF′ ) 267.3 Hz), 120.4 (q, J CF′ ) 269.8 Hz) 120.1 (q of
q, J CF′ ) 39.1 Hz, J CF′′ ) 2.5 Hz), 113.7 (q of q, J CF′ ) 38.3 Hz,
J CF′′ ) 2.5 Hz) 109.3 (s), 106.9 (q, J CF′′ ) 3.0 Hz), 36.1 (s); IR
(neat): 1/λ ) 2240, 1315, 1245, 1150 cm-1; MS (EI) m/z ) 242
(M+.). Anal. Calcd for C8H4N2F6: C, 39.69; H, 1.67; N, 11.56.
Found: C, 39.95; H, 1.87; N, 11.60.
1-Meth yl-2,5-dicyan o-3,4-bis(tr iflu or om eth yl)pyr r ole (5a).
Yield ) 0.14 g (10%); mp 135 °C; 1H NMR (CDCl3): δ ) 4.06 (s);
19F NMR (CDCl3): δ ) 56.0 (s) vs C6H5F; 13C NMR (1H
decoupled, CDCl3): δ ) 120.6 (q of q, J CF′ ) 41 Hz, J CF′′ ) 2.2
Hz), 119.4 (q, J CF′ ) 271 Hz), 110.4 (br s), 107.9 (s), 36.0 (s); IR
(KBr): 1/λ ) 2234, 1322, 1251, 1157 cm-1; MS (EI) m/z ) 267
(M+.). Anal. Calcd for C9H3N3F6: C, 40.47; H, 1.13; N, 15.72.
Found: C, 40.81; H, 1.32; N, 15.81.
Dim eth yl 1-Meth yl-2-cyan o-3,4-pyr r oledicar boxylate (4b).
Yield ) 0.35 g (31.5%); mp 84 °C; 1H NMR (CDCl3): δ ) 7.34 (s,
1H), 3.92 (s, 3H), 3.83 (s, 6H); 13C NMR (1H decoupled, CDCl3):
δ ) 162.2, 161.5, 131.6, 116.7, 111.0, 52.5, 52.0, 36.2; IR (KBr):
1/λ ) 3120, 2240, 1725, 1300 cm-1; MS (EI) m/z ) 222 (M+.).
Anal. Calcd for C10H10N2O4: C, 54.06; H, 4.54; N, 12.60. Found:
C, 53.87; H, 3.80; N, 12.93.
Dim et h yl 1-Met h yl-2,5-d icya n o-3,4-p yr r oled ica r b oxyl-
a te (5b). Yield ) 0.039 g (3.2%); mp 199 °C: 1H NMR (CDCl3):
δ ) 3.99 (s, 3H), 3.94 (s, 6H); 13C NMR (1H decoupled, CDCl3):
δ ) 176.2, 159.5, 123.7, 108.9, 52.6, 35.2; IR (KBr): 1/λ ) 2220,
1735, 1300 cm-1; MS (EI) m/z ) 247 (M+.). Anal. Calcd for
C11H9N3O4‚1/2C2H6O: C, 53.33; H, 4.44; N, 15.55. Found: C,
53.88; H, 3.96; N, 15.89.
Ack n ow led gm en t. Financial support was provided
to J .P.F. by the Kinnear Research Foundation and to
G.T.Y. by the donors of the Petroleum Research Fund,
administered by the American Chemical Society.
Su p p or tin g In for m a tion Ava ila ble: Mass, NMR, and IR
spectra available for 3a , 4a , 5a , 4b, and 5b. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O991440F