A new route to hindered tertiary amines

Article abstract of DOI:10.1021/jo010583a

The Rh₂(OAc)₄-stabilized carbenoid derived from dimethyl diazomalonate has been found to insert into the N-H bond of sterically hindered secondary aliphatic amines to afford hindered tertiary aliphatic amines in quite satisfactory yields. For example dimethyl 2-(dicyclohexylamino)-propanedioate was formed in 85% yield from dicyclohexylamine, and the severely hindered dimethyl 2-(2,2,6,6-tetramethyl-1-piperidinyl)propanedioate was formed in 38% yield from 2,2,6,6-tetramethylpiperidine. The Rh₂(OAc)₄ - dimethyl diazomalonate reaction was found to work also for arylalkylamines and diarylamines. In these cases, small amounts of products resulting from formal insertion of the carbenoid into an aromatic C-H bond were detected. Substitution at ortho positions caused the yield of C-H insertion products to increase. Other diazo compounds, viz. ethyl diazoacetoacetate, 2-diazocyclohexane-1,3-dione, and 2-diazo-5,5-dimethylcyclohexane-1,3-dione, performed satisfactorily in Rh₂(OAc)₄-catalyzed reactions with arylalkylamines and diarylamines, but led to complicated reaction mixtures with dialkylamines.

Full text of DOI:10.1021/jo010583a

J . Org. Chem. 2001, 66, 6729-6733
6729
A New Rou te To Hin d er ed Ter tia r y Am in es
Minmin Yang, Xing Wang, Hui Li, and Peter Livant*
Department of Chemistry, Auburn University, Auburn, Alabama 36849-5312
livanpd@auburn.edu
Received J une 11, 2001
The Rh2(OAc)4-stabilized carbenoid derived from dimethyl diazomalonate has been found to insert
into the N-H bond of sterically hindered secondary aliphatic amines to afford hindered tertiary
aliphatic amines in quite satisfactory yields. For example dimethyl 2-(dicyclohexylamino)-
propanedioate was formed in 85% yield from dicyclohexylamine, and the severely hindered dimethyl
2-(2,2,6,6-tetramethyl-1-piperidinyl)propanedioate was formed in 38% yield from 2,2,6,6-tetra-
methylpiperidine. The Rh2(OAc)4 - dimethyl diazomalonate reaction was found to work also for
arylalkylamines and diarylamines. In these cases, small amounts of products resulting from formal
insertion of the carbenoid into an aromatic C-H bond were detected. Substitution at ortho positions
caused the yield of C-H insertion products to increase. Other diazo compounds, viz. ethyl
diazoacetoacetate, 2-diazocyclohexane-1,3-dione, and 2-diazo-5,5-dimethylcyclohexane-1,3-dione,
performed satisfactorily in Rh2(OAc)4-catalyzed reactions with arylalkylamines and diarylamines,
but led to complicated reaction mixtures with dialkylamines.
Sch em e 1
In tr od u ction
In the course of studies in our laboratory, the need
arose for hindered tertiary amines similar to triisopro-
pylamine. The desired amines were tertiary aliphatic
amines in which all R-positions were branched, and which
carried other functionality in addition. A search of the
literature for possible synthetic methods was dishearten-
ing. Collected in Scheme 1 are all reported routes to such
compounds, to the best of our knowledge.
Most of these methods give the hindered amine product
in low or, at best, modest yields. The method of eq 6 is
an exception, but the necessity of using phosgene makes
this route less attractive. The use of Grignard reagents,
organolithiums, or high temperatures limits the general-
ity of these methods since the presence of a large variety
of functional groups is thereby precluded.
The insertion of a carbene or carbenoid into an N-H
bond is a known process which leads to C-N bond
formation (eq 7).7,8 The case in which the substrate is an
amide and the carbenoid is generated from a diazo
(1) (a) Kuffner, F.; Koechlin, W. Monatsh. Chem. 1962, 93, 476. For
other processes that may have led to triisopropylamine, see: (b)
Whitehead, W.; Imperial Chemical Industries, Ltd. Brit. Pat. 659,980;
Chem. Abstr. 1951, 45, 8547. (c) Popov, M. A.; Shuikin, N. I. Chem.
Abstr. 1956, 50, 4769.
(2) Bock, H.; Go¨bel, I.; Havlas, Z.; Liedle, S.; Oberhammer, H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 187-190.
(3) Eisele, G.; Simchen, G. Synthesis 1978, 757-758.
(4) Guziec, F. S., J r.; Torres, F. F. J . Org. Chem. 1993, 58, 1604-
1606.
(5) Stachel, S. J .; Ziller, J . W.; Van Vranken, D. L. Tetrahedron Lett.
1999, 40, 5811-5812.
compound and Rh2(OAc)4 has been used widely with
great success. For example, this approach has been
particularly fruitful in the synthesis of penicillins and
related â-lactams.7a On the other hand, Rh2(OAc)4-
catalyzed carbenoid insertion into an amine N-H bond
(6) Wieland, G.; Simchen, G. Liebigs Ann. Chem. 1985, 2178-2193.
(7) For reviews of this area, see: (a) Doyle, M. P.; McKervey, M. A.;
Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley: New York, 1998; Chapter 8. (b) Maas, G. Top.
Curr. Chem. 1987, 137, 75-253 (c) Davies, H. M. L. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 4,
Chapter 4.8. (d) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48,
5385-5453 (e) Kirmse, G. Carbene Chemistry, 2nd ed.; Academic: New
York, 1971; pp 409-412. (f) Aller, E.; Buck, R. T.; Drysdale, M. J .;
Ferris, L.; Haigh, D.; Moody, C. J .; Pearson, N. D.; Sanghera, J . B. J .
Chem. Soc., Perkin Trans. 1 1996, 2879-2884.
10.1021/jo010583a CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

6730 J . Org. Chem., Vol. 66, No. 20, 2001
Yang et al.
has been reported much less.9 Dirhodium tetraacetate
and related compounds are known to form strong com-
plexes with Lewis bases.10 Therefore it is reasonable to
suggest that attempted Rh2(OAc)4-catalyzed amine N-H
insertion reactions may have failed, and have gone
unreported, because the rhodium catalyst was rendered
inactive by complexation with the amine substrate.
Nevertheless, we reasoned that amine N-H insertion (eq
7) might succeed for the particular class of amines which
was of interest to us, namely those amines in which R
and R′ are bulky groups, because complexation with the
catalyst would be sterically inhibited. We have indeed
found that secondary amines bearing bulky groups
perform successfully in the reaction of eq 7 and we report
our results herein.
Ta ble 1. Rh 2(OAc)4-Ca ta lyzed Rea ction s of Dim eth yl
Dia zom a lon a te (DDM) w ith Dia lk yla m in es
Resu lts a n d Discu ssion
In refluxing benzene, dimethyl diazomalonate (“DDM”),
catalyzed by Rh2(OAc)4, reacts with a variety of hindered
secondary amines to afford hindered tertiary amine
diesters in good yield (eq 8). Results are organized,
mainly, according to the secondary amine used: Table 1
pertains to dialkylamines, Table 2 to arylalkylamines,
and Table 3 to diarylamines. Table 4 reports results
obtained with diazo compounds other than DDM.
Dia lk yla m in es. Table 1 shows generally good yields
(isolated) of hindered tertiary trialkylamines by the
present method. However, in the cases of diallylamine
and 2,6-dimethylpiperidine no reaction took place under
our standard conditions (refluxing benzene, 3 h). We
presume that these amines bound to the catalyst to the
exclusion of DDM and thereby prevented catalysis of
diazo decomposition. In studies of binding of Lewis bases
by dirhodium tetracarboxylates, piperidine was found to
be among the most strongly bound amines examined.10c
a
All yields are isolated yields.
Ta ble 2. Rh 2(OAc)4-Ca ta lyzed Rea ction s of Dim eth yl
Dia zom a lon a te (DDM) w ith Ar yla lk yla m in es, 8a
(8) Recent work: (a) Ferris, L.; Haigh, D.; Moody, C. J . J . Chem.
Soc., Perkin Trans. 1 1996, 2885-2888. (b) Bolm, C.; Kasyan, A.;
Drauz, K.; Gu¨nther, K.; Raabe, G. Angew. Chem., Int. Ed. 2000, 39,
2288-2290. (c) Galardon, E.; LeMaux, P.; Simonneaux, G. J . Chem.
Soc., Perkin Trans. 1 1997, 2455-2456. (d) Moody, C. J .; Bagley, M.
C. J . Chem. Soc., Perkin Trans. 1 1998, 601-607. (e) Bagley, M. C.;
Buck, R. T.; Hind, S. L.; Moody, C. J . J . Chem. Soc., Perkin Trans. 1
1998, 591-600. (f) Wang, J .; Hou, Y.; Wu, P. J . Chem. Soc., Perkin
Trans. 1 1999, 2277-2280. (g) DelZotto, A.; Baratta, W.; Rigo, P. J .
Chem. Soc., Perkin Trans. 1 1999, 3079-3081. (h) Simonneaux, G.;
Galardon, E.; Paul-Roth, C.; Gulea, M.; Masson, S. J . Organomet.
Chem. 2001, 617-618, 360-363. (i) Fehn, S.; Burger, K. Tetrahedron:
Asymmetry 1997, 8, 2001-2005. (j) Moody, C. J .; Ferris, L.; Haigh,
D.; Swann, E. Chem. Commun. 1997, 2391-2392. (k) Moody, C. J .;
Swann, E. Synlett 1998, 135-136.
(9) (a) Paulissen, R.; Hayez, E.; Hubert, A. J .; Teyssie, P. Tetra-
hedron Lett. 1974, 607-608. (b) Liu, J .-M.; Young, J .-J .; Li, Y.-J .; Sha,
C.-K. J . Org. Chem. 1986, 51, 1120-1123. (c) Lawton, G.; Moody, C.
J .; Pearson, C. J . J . Chem. Soc., Perkin Trans. 1 1987, 899-902. (d)
Chorvat, R. J .; Rorig, K. J . J . Org. Chem. 1988, 53, 5779-5781. (e)
Haigh, D. Tetrahedron 1994, 50, 3177-3194. (f) Osipov, S. N.; Sewald,
N.; Kolomiets, A. F.; Fokin, A. V.; Burger, K. Tetrahedron Lett. 1996,
37, 615-618. (g) Moody, C. J .; Swann, E. Synlett 1998, 135-136
(10) (a) Doyle, M. P.; Colsman, M. R.; Chinn, M. S. Inorg. Chem.
1984, 23, 3684-3685. (b) Cotton, F. A.; Dikarev, E. V.; Petrukhina,
M. A.; Stiriba, S.-E. Polyhedron 2000, 19, 1829-1835. (c) Drago, R.
S.; Tanner, S. P.; Richman, R. M.; Long, J . R. J . Am. Chem. Soc. 1979,
101, 2897-2903. (d) Pruchnik, F. P.; Starosta, R.; Kowalska, M. W.;
Galdecka, E.; Galdecki, Z.; Kowalski, A. J . Organomet. Chem. 2000,
597, 20-28.
a
All yields are isolated yields.
Di-tert-butylamine was tried as a substrate under a
variety of conditions. In all cases, a very complex product
mixture was obtained. The 1H NMR “marker” for a
successful reaction, a singlet at ca. 4.4 ppm corresponding

New Route To Hindered Tertiary Amines
J . Org. Chem., Vol. 66, No. 20, 2001 6731
Ta ble 3. Rh 2(OAc)4-Ca ta lyzed Rea ction s of Dim eth yl
Dia zom a lon a te (DDM) w ith Dia r yla m in es
Ta ble 4. Rh 2(OAc)4-Ca ta lyzed Rea ction s of Va r iou s
Dia zo Com p ou n d s w ith Ar yla lk yla m in es a n d
Dia r yla m in esa
a
b
Solvent ) CH2Cl2, reflux 1.5 h. All yields are isolated yields.
of N-H insertion, 9, the product of C-H insertion, 10,
and the product of both types of insertion, 11, were
observed. When the ratio of arylalkylamine 8 to DDM
was close to 1.0, the N-H insertion product was formed
in g70% yield, except in the case of N-isopropyl-o-
anisidine, 8c. Increasing the 8/DDM ratio to 2.0 caused
the N-H plus C-H insertion product, 11, to become the
major product. Proof of structure of 10c was not trivial,
since two chemically reasonable isomers, 10c and 10c′,
could be drawn. A 13C-13C INADEQUATE experiment
finally confirmed 10c as the correct structure.
a
All yields are isolated yields.
to the methine proton neighboring nitrogen and two
carbomethoxy groups, was absent from the spectra of the
di-tert-butylamine product mixtures. Therefore, we con-
clude that the desired N-H insertion, leading to 18, did
not occur. However, 5, an amine bearing two tertiary
carbons and a secondary carbon, like 18, was formed in
10% yield under standard conditions and in 38% yield
when 2,2,6,6-tetramethylpiperidine was used in excess
as solvent.
With diisopropylamine (Table 1, entry 2), a 12% yield
of amide 19 was obtained in addition to 2. The analogous
amide was not observed in any other case.
Dia r yla m in es. Only a few examples of this type were
examined (Table 3), since the tertiary amine produced
was not judged to be particularly hindered per se. The
carbenoid derived from DDM inserted into the N-H bond
of diphenylamine in good yield and gave no sign of
aromatic C-H insertion.
The relatively high yield of 10c vs 9c as compared to
10 vs 9 for other arylalkylamines in Table 2 (when
8/DDM was 1:1) caused us to wonder whether the
2-methoxy group of 8c was exerting a steric or an
electronic effect. The presence of the 3-methoxy group of
13 gave rise to no detectable C-H insertion product.
Ar yla lk yla m in es. The carbenoid derived from DDM
reacted more rapidly with arylalkylamines than with
dialkylamines. Thus, 1.5 h reflux in CH2Cl2, versus 3 h
reflux in benzene for the dialkylamines, was sufficient
to complete the reaction. The occurrence of aromatic C-H
insertion in competition with N-H insertion led to
slightly more complex reaction mixtures (see Table 2).
(We use the phrase “C-H insertion” to describe the net
change in the reaction. We do not intend the phrase to
imply a particular mechanism). In all cases, the product

6732 J . Org. Chem., Vol. 66, No. 20, 2001
Yang et al.
Therefore a steric explanation of the anomalous behavior
of 8c is probably correct. The steric effect of an ortho
methoxy is carried to the limit in 15, which gives only
C-H insertion products 16 and 17, and no N-H insertion
product.
Further transformations of some of the amines re-
ported in Table 1 have resulted in amines that are even
more planar about nitrogen than triisopropylamine,
which had been thought to be the most nearly planar
trialkylamine known.13 These results will be reported in
due course.
Oth er Dia zo Com p ou n d s. The Rh2(OAc)4-catalyzed
reaction of 2-diazo-5,5-dimethylcyclohexane-1,3-dione, 20,
with diisopropylamine (as solvent) gave only orange
crystalline 21, the structure of which was established by
X-ray crystallography (eq 9). N-H insertion was not
observed. The structural features of 21 are interesting
and are only adumbrated in eq 9. A crystallographic C2
axis passes through the N of the diisopropylammonium
cation and the H bonded to the -NdN- linkage. All four
C-O bond lengths are equal. The -NdN- linkage is
disordered between two orientations, one of which is
Exp er im en ta l Section
Diazo compounds DDM, 20, 22, and 26 were prepared by a
literature method.14
Gen er a l P r oced u r es for th e Rea ction of Dim eth yl
Dia zom a lon a t e (“DDM”) w it h H in d er ed Secon d a r y
Am in es. Procedure A. A mixture of DDM, hindered secondary
dialkylamine, rhodium acetate, and dry benzene (10-20 mL)
was heated at reflux under nitrogen for 3 h. Procedure B for
arylalkylamine and diarylamine substrates: the solvent was
CH2Cl2, and the time of reflux was 1.5 h. In both procedures,
following removal of solvent at reduced pressure, the residue
was purified by column chromatography on silica gel (60-200
mesh). Elution systems are described in each case below.
Yields are given in Tables 1-4. Characterization data are
given in the Supporting Information.
1
shown in lighter lines for clarity. The H NMR chemical
shift of the proton bonded to -NdN- and H-bonded to
two oxygens was 17.1 ppm (CDCl3 solvent).
Dim eth yl 2-(Dicycloh exyla m in o)pr opa n edioa te, 1. Pro-
cedure A. Dicyclohexylamine (226 mg, 1.25 mmol), DDM (161
mg, 1.02 mmol), rhodium acetate (5 mg, 0.01 mmol). Column
eluted with benzene. Obtained 269 mg of 1 as a colorless solid,
mp 51-52 °C.
Dim eth yl 2-(Diisop r op yla m in o)p r op a n ed ioa te, 2. Pro-
cedure A. Diisopropylamine (253 mg, 2.50 mmol), DDM (316
mg, 2.00 mmol), rhodium acetate (8 mg, 0.02 mmol). Elution
with EtOAc/hexanes 1:4 (v/v). Obtained 337 mg 2 as a colorless
oil, and 73 mg 19 as a colorless crystalline solid, mp 96-7 °C.
Dim eth yl 2-(N-ter t-Bu tyl-N-isop r op yla m in o)p r op a n e-
d ioa te, 3. Procedure A. tert-Butylisopropylamine (131 mg, 1.14
mmol), DDM (165 mg, 1.04 mmol), rhodium acetate (4 mg,
0.009 mmol). Eluted with benzene. Obtained 137 mg of 3 as a
colorless oil.
Dim eth yl 2-(2,2,6,6-Tetr am eth yl-1-piper idin yl)pr opan e-
d ioa te, 5. When procedure A was followed, 5 was obtained in
only 10% yield. Therefore, we used excess amine as solvent:
2,2,6,6-tetramethylpiperidine (2.201 g, 15.61 mmol), DDM (501
mg, 3.17 mmol), rhodium acetate (13 mg, 0.030 mmol). Eluted
with EtOAc/hexanes 1:6 (v/v). Afforded 332 mg 5 as a colorless
oil.
By contrast, the carbenoid derived from 22 inserted
into the N-H bond of N-isopropylaniline (eq 10), afford-
ing 23 in 35% yield. The solvent here was fluorobenzene.
Other experience in our laboratory with a similar car-
benoid in this solvent led us to believe that fluorobenzene
had suffered attack by the 22-derived carbenoid. Accord-
ingly, we dispensed with fluorobenzene and used excess
N-isopropylaniline as solvent, which afforded 23 in 65%
yield. Similarly, the low mp of diphenylamine allowed it
to function as solvent, giving 24 in 75% yield. In this case
C-H insertion product 25 was obtained in 17% yield. In
contrast to the results of Rh2(OAc)4-catalyzed reactions
presented here, the photochemical reaction of 20 or 22
with primary and secondary amines has been reported
to proceed by a Wolff rearrangement to give ring-
contracted N-substituted or N,N-disubstituted 2-oxo-
cyclopentane-1-carboxamides.11,12
Dim eth yl 2-(Di(4,4-d im eth yl-3,5-d ioxa n yl)a m in o)p r o-
p a n ed ioa te, 7. Procedure A. Compound 6 (220 mg, 0.898
mmol),15 DDM (169 mg, 1.07 mmol), rhodium acetate (16 mg,
0.036 mmol). Eluted with EtOAc/hexanes 1:3 (v/v). Afforded
240 mg 7 as a white solid, mp 63-64.5 °C
Ar yla lk yla m in es, 8a -d . These were prepared by reductive
amination of aniline or o-anisidine according to literature
procedure,16 in yields of 99% (8a ), 81% (8b), 95% (8c), and 81%
(8d ). Amine 8a was isolated chromatographically (silica gel,
EtOAc/hexanes 1:6 (v/v)) instead of by vacuum distillation.
Spectroscopic characteristics agreed with those previously
reported for 8a ,16 8b,16 8c,17 and 8d .18
Dim et h yl 2-(N-Cycloh exyl-N-p h en yla m in o)p r op a n e-
d ioa te, 9a . Procedure B. Aniline 8a (0.210 g, 1.20 mmol), DDM
Ethyl diazoacetoacetate, CH3C(dO)C(dN2)COOEt, 26,
reacts smoothly with 8b and diphenylamine in CH2Cl2
solvent to afford, respectively, 27 (59% yield) and 28 (70%
yield).
In contrast to the satisfactory results obtained with
arylalkylamines and diarylamines, the Rh2(OAc)4-cata-
lyzed reactions of diazo compounds 20, 22, and 26 with
hindered dialkylamines generally produced complex mix-
tures of little value to the synthetic chemist.
(13) Boese, R.; Bla¨ser, D.; Antipin, M. Y.; Chaplinski, V.; deMeijere,
A. Chem. Commun. 1998, 781-782.
(14) Baum, J . S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709-1716.
(15) Scott, D. A.; Kru¨lle, T. M.; Finn, M.; Nash, R. J .; Winters, A.
L.; Asano, N.; Butters, T. D.; Fleet, G. W. J . Tetrahedron Lett. 1999,
40, 7581.
(16) Mi’covi′c, I. V.; Ivanovi′c, M. D.; Piatak, D. M.; Boji′c, V. Dj.
Synthesis 1991, 1043-1045.
(17) Henke, B. R.; Aquino, C. J .; Birkemo, L. S.; Croom, D. K.;
Dougherty, R. W., J r.; Ervin, G. N.; Grizzle, M. K.; Hirst, G. C.; J ames,
M. K.; J ohnson, M. F.; Queen, K. L.; Sherrill, R. G.; Sugg, E. E.; Suh,
E. M.; Szewczyk, J . W.; Unwalla, R. J .; Yingling, J .; Willson, T. M. J .
Med. Chem. 1997, 40, 2706-2725.
(11) Cossy, J .; Belotti, D.; Thelland, A.; Pete, J . P. Synthesis 1988,
720-721.
(12) Cossy, J .; Belotti, D.; Bouzide, A.; Thelland, A. Bull. Soc. Chim.
Fr. 1994, 131, 723-729.
(18) For 8d , ref 16 reports the dimethyl ester rather than the diethyl
ester.

New Route To Hindered Tertiary Amines
J . Org. Chem., Vol. 66, No. 20, 2001 6733
(0.182 g, 1.15 mmol), rhodium acetate (5 mg, 0.01 mmol).
Elution solvent EtOAc/hexanes 1:5 (v/v). Three products were
isolated: 9a , 10a , and 11a , in order of elution. Compound 9a
260 mg (71%), colorless oil. Compound 10a 30 mg (8%),
colorless oil. Compound 11a 60 mg (11%), colorless oil.
Dim et h yl 2-(N-Isop r op yl-N-p h en yla m in o)p r op a n e-
d ioa te, 9b. Procedure B. Aniline 8b (0.221 g, 1.66 mmol),
DDM (0.215 g, 1.36 mmol), rhodium acetate (7 mg, 0.02 mmol).
Elution solvent EtOAc/hexanes 1:5 (v/v). Three products were
isolated; 9b, 10b, and 11b, in order of elution. Compound 9b
288 mg (73%), colorless oil. Compound 10b 35 mg (8%),
colorless oil. Compound 11b 46 mg (7%), colorless oil.
Dim eth yl 2-(N-Isop r op yl-N-(2-m eth oxyp h en yl)a m in o)-
p r op a n ed ioa te, 9c. Procedure B. N-Isopropyl-o-anisidine 8c
(0.350 g, 2.12 mmol), DDM (0.310 g, 1.96 mmol), rhodium
acetate (8 mg, 0.02 mmol). Elution solvent EtOAc/hexanes 1:5
(v/v). Three products were isolated: 9c, 10c, and 11c, in order
of elution. Compound 9c 171 mg (29%), colorless solid mp 67-
68 °C. Compound 10c 305 mg (53%), colorless solid mp 69-
69.5 °C. Compound 11c 17 mg (4%), colorless oil.
Diet h yl 3-(N-P h en yl-N-(b is(ca r b om et h oxy)m et h yl)-
a m in o)p en ta n ed ioa te, 9d . Procedure B. Diester 8d (0.501
g, 1.81 mmol), DDM (0.289 g, 1.83 mmol), rhodium acetate (7
mg, 0.02 mmol). Elution solvent EtOAc/hexanes 1:4 (v/v).
Three products were isolated: 9d , 10d , and 11d , in order of
elution. Compound 9d 513 mg (70%), colorless solid, mp 53-
54 °C. Compound 10d 59 mg (8%), colorless oil. Compound
11d 102 mg (12%), colorless oil.
Dim eth yl 2-(Dip h en yla m in o)p r op a n d ioa te, 12. Proce-
dure B. Diphenylamine (341 mg, 2.01 mmol), DDM (312 mg,
1.97 mmol), rhodium acetate (9 mg, 0.02 mmol). Eluted with
EtOAc/hexanes 1:1 (v/v). Compound 12 (498 mg) was obtained
as a colorless oil.
R indices of R1 ) 0.0731, wR2 ) 0.2039 (I > 2σ(I)), R1 )
0.2211, wR2 ) 0.2663 (all data) and a goodness of fit on F2 of
1.079.
2-(N -I s o p r o p y l-N -p h e n y la m in o )c y c lo h e x a n e -1,3-
d ion e, 23. Under a nitrogen atmosphere, a mixture of 138 mg
(0.999 mmol) of 2-diazocyclohexane-1,3-dione and 1.35 g (9.98
mmol) of N-isopropylaniline, 8b, was stirred until homoge-
neous. To this was added 2.2 mg (0.0050 mmol) rhodium
acetate and the stirring continued at room temperature for 4
h. Silica gel chromatography using EtOAc/hexanes 1:30 (v/v)
removed excess 8b. Subsequent elution with EtOAc/hexanes
1:4 (v/v) afforded 0.16 g 23 as a colorless solid: 65%, mp 166-8
°C; 1H NMR (250 MHz, CDCl3) 7.90 (br s, 1H), 7.18 (t, J ) 7.8
Hz, 2H), 6.75-6.81 (m, 3H), 4.07 (septet, J ) 6.4 Hz, 1H), 2.48
(br s, 4H), 1.98 (s, 2H), 1.10 (d, J ) 6.3 Hz, 6H); 13C NMR (63
MHz, CDCl3) 194.9, 175.1, 147.3, 129.3, 119.1, 115.9, 49.1, 37.7,
27.8, 21.9, 21.1, 20.5. Anal. Calcd for C15H19NO2: C, 73.44; H,
7.81; N, 5.71. Found: C, 73.34; H, 7.84; N, 5.69.
2-(Dip h en yla m in o)cycloh exa n e-1,3-d ion e, 24. Diphen-
ylamine, 0.85 g (5.0 mmol), was heated to approximately 57
°C to melt it. 2-Diazocyclohexane-1,3-dione, 138 mg (0.999
mmol), was added with stirring. After dissolution of the diazo
compound, 2.2 mg of rhodium acetate (0.0050 mmol) was added
and the reaction stirred 3 h at 57 °C under nitrogen. Chloro-
form, 1.0 mL, was added, and silica gel chromatography with
the same step gradient as for 23 was performed, affording 0.21
g 24 (75%) as a colorless solid, mp 202-4 °C. When the
reaction was run on a larger scale, C-H insertion product 25,
mp 194-6 °C, could be isolated in addition to 24. For 24: 1H
NMR (250 MHz, CDCl3) 7.23 (t, J ) 8.0 Hz, 2H), 6.95-7.05
(m, 3H), 2.68 (t, J ) 6.2 Hz, 2H), 2.48 (t, J ) 6.5 Hz, 2H), 2.07
(quintet, J ) 6.4 Hz, 2H); 13C NMR (63 MHz, CDCl3) 194.7,
173.0, 146.4, 129.5, 122.9, 122.0, 120.9, 37.8, 27.8, 20.4. Anal.
Calcd for C18H17NO2: C, 77.40; H, 6.13; N, 5.01. Found: C,
77.18; H, 6.26; N, 4.92. For 25: 1H NMR (250 MHz, DMSO-
d6) 10.46 (br s, approximately 1H), 8.08 (s, 1H), 7.18-7.24 (m,
2H), 7.00-7.08 (m, 6H), 6.80-6.75 (m, 1H), 2.45 (br m, 4H),
1.91 (br m, 2H); 13C NMR (63 MHz, DMSO-d6) ca. 185 (very
br), 143.8, 141.0, 131.5, 129.0, 125.5, 119.1, 116.2, 115.9, 33.1
(br), 20.3. EIMS (m/z (rel int)) 280 (15, M + 1), 279 (65, M),
196 (23), 195 (23), 167 (19), 149 (29), 129 (46), 112 (23), 97
(16), 89 (28), 87 (28), 83 (30), 81 (18), 77 (27), 73 (59), 58 (100).
Eth yl 3-Oxo-2-(N-isopr opyl-N-ph en ylam in o)bu tan oate,
27. Procedure B. N-isopropylaniline (0.28 g, 2.1 mmol), ethyl
diazoacetoacetate (0.48 g, 3.1 mmol), rhodium acetate (4 mg,
0.009 mmol). Eluted with 1:9 (v/v) EtOAc/hexanes, affording
0.32 g (59%) 27 as a colorless oil.
Dim et h yl 2-(N-(3-Met h oxyp h en yl)-N-p h en yla m in o)-
p r op a n d ioa t e, 14. Procedure B. 3-Methoxyphenylphenyl-
amine (401 mg, 2.01 mmol), DDM (312 mg, 1.97 mmol),
rhodium acetate (6 mg, 0.01 mmol). Eluted with EtOAc/
hexanes 1:4 (v/v). Compound 14 (510 mg) was obtained as a
colorless oil.
R ea ct ion of DDM w it h Bis(2,6-d im et h oxyp h en yl)-
a m in e, 15. Procedure B followed, except heating for 4 h: 1519
(398 mg, 1.38 mmol), DDM (426 mg, 2.70 mmol), rhodium
acetate (9 mg, 0.02 mmol). Eluted with EtOAc/hexanes 1:2 (v/
v). Obtained 169 mg of 16 as a colorless solid, mp 158-9 °C,
and 235 mg of 17 as a colorless solid that darkens in air, mp
131-2 °C.
Azo Sa lt 21. A solution of 226 mg (1.36 mmol) of 2-diazo-
5,5-dimethylcyclohexane-1,3-dione and 7 mg (0.02 mmol) of
rhodium acetate in 3.150 g (30.88 mmol) of diisopropylamine
was brought to reflux in a nitrogen atmosphere. Within 5 min,
an orange precipitate was observed to form. The reaction was
refluxed for 5 h. Even though TLC showed diazo compound
remaining, the reaction was halted and the orange solid 21
collected by filtration, affording 213 mg after recrystallization
Eth yl 3-Oxo-2-(d ip h en yla m in o)bu ta n oa te, 28. Proce-
dure B. Diphenylamine (0.24 g, 1.4 mmol), ethyl diazoaceto-
acetate (0.32 g, 2.0 mmol), rhodium acetate (5 mg, 0.01 mmol).
Eluted with 1:8 (v/v) EtOAc/hexanes, affording 0.30 g (70%)
28 as a colorless oil.
Ack n ow led gm en t. The authors gratefully acknowl-
edge the financial support of the Auburn University
Department of Chemistry. We thank Professor Thomas
Albrecht-Schmitt for solving the structure of 21, Dr. Eric
Hughes for expert NMR assistance, and Professor H.
M. L. Davies for a suggestion which led to this work.
1
from EtOAc: mp 155-6 °C dec; H NMR (250 MHz, CDCl3)
17.09 (br s, ca. 1H), 10.14 (br s, ca. 2H), 3.33 (br septet, 2H),
2.43 (br m, 8H), 1.26 (d, J ) 6.4 Hz, 12H), 1.07 (s, 12H) 13C
NMR (63 MHz, CDCl3): 194.7, 193.0, 186.4 (br), 127.0, 117.5,
52.2 (br), 51.3 (br), 46.3, 31.4, 28.7, 19.4. A prism 0.20 × 0.20
× 0.20 mm suitable for X-ray crystallography was chosen,
orthorhombic, Pbcn, Z ) 4, a ) 18.631(2) Å, b ) 10.067(5) Å,
c ) 12.5880(8) Å. The diffractometer used was a Rigaku AFC8
with a CCD detector, Mo KR radiation, ambient temperature,
20 723 reflections (6353 unique) collected to a maximum 2θ
of 61.6°. The structure was solved by direct methods with
refinement by full-matrix least-squares on F2, resulting in final
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for 21, characterization data for 1-3, 5, 7, 9a -11a , 9b-
11b, 9c-11c, 9d -11d , 12, 14, 16, 17, 19, 27, 28. This material
is available free of charge via the Internet at http://pubs.ac-
s.org. This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(19) This substance was obtained by a modification of the synthesis
of tris(2,6-dimethoxyphenyl)amine: Northcott, D. J . D., Ph.D. Dis-
sertation, Auburn University, 2000.
J O010583A