The reaction of 4-substituted aryl isocyanates with NaBH4/trifluoroacetic acid (TFA)

Article abstract of DOI:10.1055/s-1999-3400

Treatment of 4-substituted aryl isocyanates (cf. 2a-f) with NaBH₄/TFA leads to the corresponding 4-substituted N,N-bis(2,2,2-trifluoroethyl)aniline derivatives (3a-d) in excellent yield except where an electron-withdrawing group is present (cf.

Full text of DOI:10.1055/s-1999-3400

SHORT PAPER
391
The Reaction of 4-Substituted Aryl Isocyanates with NaBH4/Trifluoroacetic
Acid (TFA)
Kenneth Turnbull,* Douglas M. Krein
Chemistry Department, Wright State University, Dayton, Ohio 45435, USA
Fax +1(937)7752717
Received 18 May 1998; revised 18 September 1998
time for hydrolysis to 4-nitroaniline to occur both from
Abstract: Treatment of 4-substituted aryl isocyanates (cf. 2aÐf)
the isocyanate and the trifluoroacetylaniline derivative 4.
with NaBH4/TFA leads to the corresponding 4-substituted N,N-
Hydrolysis of the latter also would be slow and might oc-
bis(2,2,2-trifluoroethyl)aniline derivatives (3aÐd) in excellent yield
cur to only a minor extent in the 4 day timescale of the
present reaction. Like the corresponding aroyl azide, fur-
ther reductive acylation occurred when the para position
of the aryl isocyanate was open and phenyl isocyanate (2f)
gave 2,2-bis({4-[N,N-bis(2,2,2-trifluoroethyl)anilino]})-
1,1,1-trifluoroethane (5) in 73% yield.
except where an electron-withdrawing group is present (cf. 2e) or
the para-position is open (cf. 2f).
Key words: isocyanates, rearrangement, reductive alkylation, tri-
fluoroethylanilines, sodium borohydride
Acyloxyborohydrides, prepared by reaction of alkali
borohydrides with carboxylic acids, have been of consid-
erable utility in organic synthesis.1 The combination of
sodium borohydride and TFA in particular, inter alia, has
been effective for the reduction of nitriles,2 amides,3Ð5 di-
and triaryl methanols,6 diaryl ketones7 and activated
monoaryl ketones.8 Additionally, valuable N-trifluoroeth-
ylations of amines5 and novel formation of 1,1,1-trifluoro-
2,2-diarylethanes from the corresponding arenes9 have
been reported with this reagent. In line with the latter two
findings, recently, we found that 4-substituted aroyl
azides 1 react with NaBH4 in TFA to form the correspond-
ing 4-substituted N,N-bis(2,2,2-trifluoroethyl)aniline de-
rivatives 3 or other products 4 or 5 depending on the
nature of the substituent in the para-position.10 While the
mechanisms of these novel transformations are unclear, it
seems likely that the initial step in all cases is an acid-in-
duced Curtius rearrangement to an isocyanate.11 Accord-
ingly, to test the likelihood of an isocyanate intermediate,
and to provide another potentially useful synthetic proce-
dure, we subjected a series of aryl isocyanates (viz. 2aÐf)
to reduction with NaBH4 in TFA at room temperature
(Scheme). The results mirrored those with the correspond-
ing aroyl azides, lending support to the premise that iso-
cyanates are intermediates therein, except that in most
cases a 10Ð15% yield of the appropriate trifluoroacetyl-
aniline derivative 4 also was isolated.12 Thus, where the
para substituent was electron donating (viz. 2cÐd) or
weakly electron withdrawing (viz. 2aÐb) efficient trans-
formation (71Ð82%) to the corresponding N,N-bis(2,2,2-
trifluoroethyl)aniline derivatives 3aÐd was observed (Ta-
ble). With a resonance withdrawing group on the aryl ring
(viz. 2e, R = NO2) the major product (78%) was 4-nitro-N-
trifluoroacetylaniline (4, R = NO2). This result differed
from that with 4-nitrobenzoyl azide (1, R = NO2) where 4-
nitroaniline was the major product (in addition to 4) and,
additionally, the reaction time (4 days) was considerably
shorter than that for the aroyl azide (14 days). It is possible
that, for the latter, the initial rearrangement to the isocyan-
ate is very slow and, thus, over 14 days there is sufficient
Scheme
The identities of the products 3aÐd, 4, 5 were ascertained
from their satisfactory spectral (IR, 1H and 13C NMR) and
microanalytical data and by comparison with an authentic
sample (for 4). The main feature of their IR spectra was
the CÐF stretch at ca. 1150 cmÐ1 and the presence of CF3
1
groups was also apparent in their H NMR spectra from
the splitting of the adjacent methylene (in 3aÐd, 5) or
methine protons (in 5) into quartets (J = 8Ð10 Hz). Further
evidence for CF3 incorporation was garnered from the 13C
NMR spectra wherein the methylene or methine carbon
atoms adjacent to the CF3 appeared as quartets (J = 33 and
27 Hz, respectively), as did the corresponding CF3 car-
bons (J = 281 and 278 Hz, respectively).
From the results of this study it is very likely that, in the
reaction of aroyl azides with NaBH4/TFA, initial rear-
rangement to the isocyanate does take place and, overall,
with the limitations described, we have developed a useful
Table Reactions of 4-Substituted Aryl Isocyanates 2 with NaBH4/
TFA
2
R
Product Yield (%)a mp (¡C)
lit. mp (¡C)
a
b
c
d
e
f
Br
Cl
Me
MeO
NO2
H
3a
3b
3c
3d
4
82
78
71
80
78
73
84Ð5
73Ð4
72Ð3
oil
149Ð50
82Ð3
83.5Ð4.510
73Ð410
72Ð310
oil10
147Ð914
82Ð310
5
a Yield of isolated pure product.
Synthesis 1999, No. 3, 391Ð392 ISSN 0039-7881 © Thieme Stuttgart á New York

392
K. Turnbull, D. M. Krein
SHORT PAPER
4-Methoxy-N,N-bis(2,2,2-trifluoroethyl)aniline (3d)
colorless oil, yield; 0.23g (80%).
preparation of N,N-bis(trifluoroethyl)anilines 3 and relat-
ed species. It should be noted that the current approach is
favoured over that from aroyl azides in that the isocyan- IR (NaCl): n = 2959, 2841 (alkyl CH), 1516, 1466, 1392, 1262,
1151, 1039, 822 cmÐ1.
ates are commercially available (the aroyl azides are not)
and are safer to work with.13
1H NMR (CDCl3): d = 3.76 (s, 3H, CH3), 3.91 (q, 4H, J = 8.7 Hz,
CH2CF3), 6.83 (d, 2H, J = 9.3 Hz, Harom), 6.93 (d, 2H, J = 9.3 Hz,
Harom).
13C NMR (CDCl3): d = 53.76 (q, J = 32 Hz, CH2CF3), 55.52,
114.72, 119.07, 125.25 (q, J = 281 Hz, CH2CF3), 141.16, 154.80.
Reactions of 4-Substituted Aryl Isocyanates 2 with NaBH4 /
TFA; General Procedure
To TFA (25 mL) was added NaBH4 (3 pellets, each ~0.4g) with stir-
ring. After complete dissolution, the aryl isocyanate (0.001 mol)
was introduced and, after 24 h, an additional pellet (broken into 4
pieces) was added and the mixture was stirred for a further 72 h. Af-
ter cooling to 0¡C the mixture was made basic (to pH 8Ð9) with aq
NaOH (15%, w/v) and extracted with CH2Cl2 (4 × 100 mL). The
combined organic layers were dried (MgSO4) and evaporated in
vacuo to yield a slightly impure product which was purified by col-
umn chromatography (silica gel, hexane/CH2Cl2(usually 80:20) as
eluant).
C11H11F6NO: Calc. C 46.00, H 3.86, N 4.88; Found: C 46.13, H
4.02, N 4.93.
2,2-(Bis(4-[N,N-bis(2,2,2-trifluoroethyl)anilino])-1,1,1-trifluo-
roethane (5)
Colorless solid, yield; 0.23g (73%), mp 82Ð83¡C (CH2Cl2/hexane).
IR (KBr): n = 2968 (alkyl CH), 1617, 1524, 1399, 1265, 1152,
1116, 1020, 820 cmÐ1.
1H NMR (CDCl3): d = 4.01 (q, 8H, J = 8.0 Hz, CH2CF3), 4.54 (q,
1H, J = 10.0 Hz, CHCF3), 6.86 (d, 4H, J = 8.0 Hz, Harom), 7.26 (d,
4H, J = 8.0 Hz, Harom).
13C NMR (CDCl3): d = 51.86 (q, J = 33 Hz, CH2CF3), 53.69 (q, J =
27 Hz, CHCF3) 114.22, 125.17 (q, J = 281 Hz, CH2CF3), 126.33 (q,
J = 278 Hz, CHCF3), 127.24, 130.04, 146.11.
4-Bromo-N,N-bis(2,2,2-trifluoroethyl)aniline (3a)
Colorless solid, yield; 0.276g (82%), mp 84Ð85¡C (CH2Cl2/hex-
ane).
IR (KBr): n = 2973, 2925 (alkyl CH), 1595, 1390, 1244, 1167,
1015, 805 cmÐ1.
1H NMR (CDCl3): d = 3.99 (q, 4H, J = 8.5 Hz, CH2CF3), 6.78 (d,
2H, J = 9.0 Hz, Harom), 7.36 (d, 2H, J = 9.0 Hz, Harom).
13C NMR (CDCl3): d = 52.09 (q, J = 33 Hz, CH2CF3), 112.86,
116.29, 125.01 (q, J = 281 Hz, CH2CF3), 132.20, 145.61.
C22H17F15N2: Calc. C 44.46, H 2.88, N 4.71; Found: C 44.43, H
2.82, N 4.68.
Acknowledgement
C10H8BrF6N: Calc. C 35.74, H 2.40, N 4.17; Found: C 35.74, H
2.49, N 3.91.
The authors would like to thank Pamela J. Sullivan for conducting
some initial experiments.
4-Chloro-N,N-bis(2,2,2-trifluoroethyl)aniline (3b)
Colorless solid, yield; 0.228g (78%), mp 73Ð74¡C (CH2Cl2/hex-
ane).
References
IR (KBr): n = 2925 (alkyl CH), 1601, 1387, 1264, 1167, 1109, 1015,
(1) Gribble, G.W.; Nutaitis, C.F. Org. Prep. Proced. Int. 1985,
17, 317.
(2) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976,
2875.
(3) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976,
763.
(4) Bailey, A.S.; Scott, P.W.; Vandrevala, M.H. J. Chem. Soc.,
812 cm–1.
1H NMR (CDCl3): d = 3.99 (q, 4H, J = 8.5 Hz, CH2CF3), 6.83 (d,
2H, J = 9.0 Hz, Harom), 7.23 (d, 2H, J = 9.0 Hz, Harom).
13C NMR (CDCl3): d = 52.23 (q, J = 33 Hz, CH2CF3), 116.04,
124.98 (q, J = 281 Hz, CH2CF3), 125.72, 129.30, 145.21.
C10H8ClF6N: Calc. C 41.19, H 2.77, N 4.80; Found: C 41.50, H
2.63, N 4.79.
Perkin Trans. 1 1980, 97.
(5) Gribble, G.W.; Nutaitis, C.F.; Leese, R.M. Heterocycles
1984, 22, 379.
4-Methyl-N,N-bis(2,2,2-trifluoroethyl)aniline (3c)
Colorless solid, yield; 0.193g (71%), mp 72Ð73¡C (CH2Cl2/hex-
ane).
(6) Gribble, G.W.; Leese, R.M.; Evans, B.E. Synthesis 1977, 172.
(7) Gribble, G.W.; Kelly, W.J.; Emery, S.E. Synthesis 1978, 763.
(8) Ketcha, D.M.; Gribble, G.W. J. Org. Chem. 1985, 50, 5451.
(9) Nutaitis, C.F.; Gribble, G.W. Synthesis 1985, 756.
(10) Krein, D.M.; Sullivan, P.J.; Turnbull, K. Tetrahedron Lett.
1996, 37, 7213.
(11) Scriven, E.F.V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(12) TFA induced conversion of aroyl azides to the corresponding
trifluoroacetylanilines cf. 4 has been reported: Pfister, J.R.;
Wymann, W.E. Synthesis 1983, 38.
IR (KBr): n = 2926 (alkyl CH), 1621, 1523, 1266, 1156, 1111,
1018, 808 cmÐ1.
1H NMR (CDCl3): d = 2.70 (s, 3H, CH3), 3.97 (q, 4H, J = 8.6 Hz,
CH2CF3), 6.85 (d, 2H, J = 8.5 Hz, Harom), 7.09 (d, 2H, J = 8.5 Hz,
Harom).
13C NMR (CDCl3): d = 20.20, 52.45 (q, J = 33 Hz, CH2CF3),
115.32, 125.28 (q, J = 281 Hz, CH2CF3), 129.92, 130.16, 144.51.
(13) All azides should be considered as a potential explosion ha-
zard.
C11H11F6N: Calc. C 48.72, H 4.01, N 5.17; Found: C 48.67, H 4.09,
N 5.23.
(14) Staab, H.A.; Walther, G. Chem. Ber. 1962, 95, 2070.
Synthesis 1999, No. 3, 391–392 ISSN 0039-7881 © Thieme Stuttgart · New York