Organometallics 2007, 26, 3995-4002 3995

Iron Porphyrin Catalyzed N-H Insertion Reactions with Ethyl

Diazoacetate
Lynnette K. Baumann, Harun M. Mbuvi, Guodong Du, and L. Keith Woo*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011-3111

ReceiVed December 1, 2006

A series of metalloporphyrin complexes were surveyed as catalysts for carbene insertion from ethyl
diazoacetate into the N-H bonds of amines. Iron(III) tetraphenylporphyrin chloride, Fe(TPP)Cl, was
found to be an efficient catalyst for N-H insertion reactions with a variety of aliphatic and aromatic
amines, with yields ranging from 68 to 97%. Primary amines were able to undergo a second insertion
when another equiv of EDA was added by slow addition. N-Heterocyclic compounds were poor substrates,
giving low yields or no N-H insertion products. Competition reactions and linear free energy relationships
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provided mechanistic insights for the insertion reaction. The relative rates for N-H insertion into para-
substituted aniline derivatives correlated with Hammett σ+ parameters. Electron-donating groups enhanced
the reaction, as indicated by the negative value of F (F ) -0.66 ( 0.05, R2 ) 0.93). These results are
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consistent with a rate-determining nucleophilic attack of the amine on an iron carbene complex. In addition,
the decomposition of EDA catalyzed by FeII(TPP) or FeIII(TPP)Cl was examined with various amounts
of added pyridine. The Fe(II) catalyst is strongly inhibited by the presence of pyridine. In contrast, catalysis
by the Fe(III) porphyrin is accelerated by amines. These experiments suggested that an iron(III) porphyrin
carbene complex is the active catalyst.

Introduction in N-heterocyclic compounds, such as indoles10 and imidazo-

lones, are also of great synthetic interest. We now report
Iron porphyrins are useful catalysts for a variety of organic insertion reactions into aliphatic and aromatic N-H bonds using
reactions. These include cyclopropanation,1 epoxidation,2 and ethyl diazoacetate (EDA) as the carbene source and iron(III)
aziridination3 of olefins. Recently, iron porphyrins were shown tetraphenylporphyrin chloride, Fe(TPP)Cl,11 as the catalyst.12
to catalyze the olefination of aldehydes and ketones in the Similar work appeared recently that also illustrated the utility
presence of triphenylphosphine by our group4 and others.5 This of Fe(III/IV) corrole and Fe(III) porphyrin complexes for
suggested to us that iron porphyrins may have the potential to catalytic reactions between EDA and amines.13
mediate a variety of other processes.
Using diazo compounds as carbene sources, transition-metal
Results and Discussion
complexes that catalyze N-H insertion reactions include
methyltrioxorhenium,6 rhodium,7 and copper8 complexes and The activity of a series of metalloporphyrin complexes as
ruthenium porphyrins.9 Reactions that use diazoacetate reagents catalysts for N-H insertion reactions was surveyed, using
for insertion into N-H bonds may provide useful precursors piperidine and EDA (eq 1). Among the catalysts examined, iron
for amino acids. In addition, intramolecular insertions resulting

(1) (a) Du, G.; Andrioletti, B.; Rose, E.; Woo, L. K. Organometallics
2002, 21, 4490. (b) Hamaker, C. G.; Mirafzal, G. A.; Woo, L. K.
Organometallics 2001, 20, 5171. (c) Wolf, J. R.; Hamaker, C. G.; Djukic,
J.-P.; Kodadek, T.; Woo, L. K. J. Am. Chem. Soc. 1995, 117, 9194.
(2) (a) Rose, E.; Ren, P.-Z.; Andrioletti, B. Chem. Eur. J. 2004, 10, 224.
(b) Lindsay Smith, J. R.; Reginato, G. Org. Biomol. Chem. 2003, 1, 2543. porphyrins proved to be the most active, giving high yields in
(c) Yang, S. J.; Nam, W. Inorg. Chem. 1998, 37, 606. (d) Groves, J. T.; relatively short periods of time (Table 1). Fe(TPP)Cl was found
Myers, R. S. J. Am. Chem. Soc. 1983, 105, 5791. to be one of the most efficient in catalyzing the insertion of
(3) (a) Vyas, R.; Gao, G.-Y.; Harden, J. D.; Zhang, X. P. Org. Lett.
2004, 6, 1907. (b) Mahy, J. P.; Bedi, G.; Battioni, P.; Mansuy, D. J. Chem. EDA into the piperidine N-H bond, resulting in a quantitative
Soc., Perkin Trans. 2 1988, 8, 1517. (c) Mansuy, D.; Mahy, J. P.; Dureault, yield in under 10 min. The reactions were run in CH2Cl2 under
A.; Bedi, G.; Battioni, P. J. Chem. Soc., Chem. Commun. 1984, 17, 1161. mild conditions at ambient temperature in a one-pot fashion,
(4) (a) Mirafzal, B. A.; Cheng, G.; Woo, L. K. J. Am. Chem. Soc. 2002,
124, 176. (b) Cheng, G.; Mirafzal, G. A.; Woo, L. K. Organometallics without the need for slow addition of EDA. The insertion
2003, 22, 1468.
(5) (a) Chen, Y.; Huang, L.; Ranade, M. A.; Zhang, X. P. J. Org. Chem. (10) (a)Lee, S.-H.; Clapham, B.; Koch, G.; Zimmerman, J.; Janda, K.
2003, 68, 3714. (b) Chen, Y.; Huang, L.; Zhang, X. P. J. Org. Chem. 2003, D. J. Comb. Chem. 2003, 5, 188. (b) Yamazake, K.; Kondo, Y. Chem.
68, 5925. (c) Chen, Y.; Huang, L.; Zhang, X. P. Org. Lett. 2003, 5, 2493. Commun. 2002, 210. (c) Bashford, K. E.; Cooper, A. L.; Kane, P. D.;
(6) Zhu, Z.; Espenson, J. H. J. Am. Chem. Soc. 1996, 118, 9901. Moody, C. J.; Muthusamy, S.; Swann, E. J. Chem. Soc., Perkin Trans. 1
(7) Yang, M.; Wang, X.; Li, H.; Livant, P. J. Org. Chem. 2001, 66, 2002, 1672.
6729. (11) Abbreviations: TPP, meso-tetraphenylporphyrin; TMeO-PP, meso-
(8) Morilla, M. E.; Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. tetrakis(p-methoxyphenyl)porphyrin; TPFPP, meso-tetrakis(pentafluorophe-
C.; Trofimenko, S.; Perez, P. J. Chem. Commun. 2002, 2998. nyl)porphyrin; TMP, meso-tetramesitylporphyrin, Saldach, N,N′-bis-
(9) (a) Galardon, E.; Le Maux, P.; Simonneaux, G. J. Chem. Soc., Perkin (salicylidene)-1,2-cyclohexyldiamine.
Trans. 1 1997, 2455. (b) Galardon, E.; Le Maux, P.; Simonneaux, G. (12) Baumann, L. M.S. Thesis, Iowa State University, Ames, IA, 2005.
Tetrahedron 2000, 56, 615. (13) Aviv, I.; Gross, Z. Synlett 2006, 951.

10.1021/om0610997 CCC: $37.00 © 2007 American Chemical Society

Publication on Web 07/04/2007
3996 Organometallics, Vol. 26, No. 16, 2007 Baumann et al.

Table 1. Piperidine N-H Insertion with EDA Catalyzed by Table 3. Results for Single EDA Insertion into Amines with
Metalloporphyrins11 in CH2Cl2a 1 mol % Fe(TPP)Cla
entry cat. time yield (%) amine-EDA yield
entry amine ratio time (%)b
1 Fe(TPP)Cl <5 min >97
2 Mn(TPP)Cl 24 h ndb 1 Et2NH 1:1.1 10 min 86
3 Zn(TPP) 24 h nd 2 t-Bu-NH2 1:1 10 min 68
4 Co(TTP) 24 h nd 3 C5H10NH 1:1.2 10 min 85
5 Os(TTP)(CO) 28 h 4 4 PhCH2NH2 1:1 10 min 76
6 Os(TTP)(CO)c 20 min 90 5 Ph2NH 1:1.1 1 h (60 °C) <5
7 no catalyst 24 h nd 6 tetramethylpiperidinec 1:1.1 48 h NR
8 Fe(TMeO-PP)Cl <5 min >97 7 benzamide 1:1.1 48 h NR
9 Fe(TPFPP)Cl 40 min >97 8 p-CH3O-C6H4-NH2 1:1.2 10 min 82
10 Fe(TMP)Cl 1h 80 9 p-CH3-C6H4-NH2 1:1.2 10 min 95
11 Fe(Saldach)Cl 22 h nd 10 C6H5-NH2 1:1.2 10 min 91
a A molar ratio of 1:100:120 for catalyst-EDA-piperidine was employed
11 p-Cl-C6H4-NH2 1:1 20 min 58 (13)d
12 p-Br-C6H4-NH2 1:1.1 10 min 92
at ambient temperature with 0.0025-0.01 mmol of catalyst. Yields were 13 p-CN-C6H4-NH2 1:1.2 20 min 87
determined by GC. b nd ) not detected. c This reaction was carried out 14 p-NO2-C6H4-NH2 1:1.1 1h 91
under reflux conditions. 15 imidazole 1:1.4 48 h 51
16 pyrrole 1:1.3 48 h 0 (37)e
Table 2. N-H Insertion Using EDA with Various Loadings 17 indole 1:1.4 48 h NR
of Fe(TPP)Cl in CH2Cl2a
a Reactions were run with 1.0 mmol of amine in 7.0 mL of CH Cl at
2 2
entry amine amt of cat. (%) time yield (%)b
ambient temperature. b NMR yields using Ph3CH as an internal standard.
c 2,2,6,6-Tetramethylpiperidine. d Yield of double-insertion product given
1 aniline 1.0 1 min 91
2 aniline 0.50 5 min 87 in parentheses. e R-C-H insertion product.
3 aniline 0.25 10 min 90
4 aniline 0.14 25 min 88 loadings can be lowered to 0.1 mol %, albeit requiring longer
5 aniline 0.10 1h 89 reaction times at ambient temperature (Table 2). A variety of
6 piperidine 1.0 10 min >95
7 piperidine 0.5 10 min >95 amine substrates were used to study the scope of Fe(TPP)Cl as
8 piperidine 0.1 5h 82 a catalyst for insertion into N-H bonds with EDA. Originally,
a Amounts used were 1.0 mmol of EDA and 1.2 mmol of amine at amines were used in slight excess to EDA on the basis of
ambient temperature. b Yields determined by GC. previous methods used to suppress maleate and fumarate
formation.9a However, 1:1 ratios of EDA to amine could be
reactions proceeded rapidly, and the reaction mixtures warmed used with Fe(TPP)Cl without significant formation of side
up upon addition of EDA, accompanied by observable gaseous products. N-H insertions were successfully achieved using
N2 release. Evidence of the desired piperidine insertion product primary and secondary alkyl amines (eq 2) in good to high yields
was obtained by 1H NMR spectroscopy with the appearance of
a new two-proton singlet at 3.17 ppm for the N-acetate
methylene hydrogens and the disappearance of the one-proton
singlet at 4.72 ppm for the methine proton of EDA. No
formation of diethyl fumarate or maleate was observed by GC
analysis. These results illustrate that Fe(TPP)Cl is among the of 68-97% (Table 1, entry 1; Table 3, entries 1-4). Evidence
best porphyrin catalysts for amine N-H insertion reactions. For of the desired insertion product with diethylamine was observed
example, a ruthenium porphyrin catalyzed N-H insertion in the 1H NMR spectrum, with the appearance of a new two-
required longer reaction times (2-18 h) and afforded lower proton N-acetate methylene singlet at 3.27 ppm and the
yields (63-81%).9a The only results comparable with those of disappearance of the one-proton singlet at 4.72 ppm for the
Fe(TPP)Cl were obtained with copper complexes bearing methine proton of EDA. Arylamine substrates also gave
homoscorpionate (tris(pyrazolyl)borate) ligands.8 An osmium successful insertion reactions (eq 3) with yields of 58-95%
porphyrin complex, Os(TTP)(CO), was also able to catalyze
the insertion of EDA into an N-H bond. While the reaction
yield was low at ambient temperature, the complex afforded a
90% yield of insertion product after heating at reflux for
20 min.
A number of iron porphyrins with different steric and
electronic properties were examined in catalytic N-H insertions
(Table 1, entries 8-11). The varying completion times and
yields indicated that the catalytic activity of these complexes (Table 3, entries 8-14), comparable to reported yields for
depended on their steric and electronic properties. Electron- reactionscatalyzedbycopper,ruthenium,andrheniumcomplexes.6-9
donating groups on the porphyrin periphery enhanced the The 1H NMR spectrum of the product from EDA and aniline
activity. Fe(TMeO-PP)Cl appeared to be the best catalyst among showed a new two-proton methylene singlet at 3.91 ppm.
those investigated, with the reaction reaching completion in Almost all of the single N-H insertion reactions reached
under 5 min. In contrast, the electron-deficient complex Fe- completion in 20 min or less. The exception was the p-
(TPFPP)Cl required 40 min to complete the N-H insertion into nitroaniline reaction, which took 1 h for complete consumption
piperidine with EDA. Fe(TMP)Cl catalyzed the same reaction, of the reagents. Also, insertion of EDA into the N-H bond of
affording an 80% yield after 1 h, suggesting that steric hindrance benzamide was not successful (Table 3, entry 7).
also plays a role. Side products from the dimerization of EDA, diethyl maleate
The subsequent studies focused on Fe(TPP)Cl because it is and diethyl fumarate, were generally observed in only trace
commercially available and relatively inexpensive. The catalyst amounts, and reactions could be run in a practical one-pot
Iron Porphryin Catalyzed N-H Insertion Reactions Organometallics, Vol. 26, No. 16, 2007 3997

Table 4. Results for Double Insertion of EDA into Amines Table 5. Single Insertion of EDA into Ortho-Substituted
with 1 mol % Fe(TPP)Cla Anilines with 1 mol % Fe(TPP)Cla
amine-EDA amine-EDA
entry amine ratio time yield (%)b entry amine ratio time yield (%)b
1 PhCH2NH2 1:3 15 min 97 1a 2-chloroaniline 1:1.2 10 min 70
2 p-CH3O-C6H4-NH2 1:2.8 1h 81 1b 2-chloroaniline 1:2.5 48 h 70
3 p-CH3-C6H4-NH2 1:2.4 1h 76 2 2-aminoacetophenone 1:1.2 20 min 57
4 C6H5-NH2 1:2.9 2h 92 3 2,6-dimethylaniline 1:1.5 24 h NR
5 p-Cl-C6H4-NH2 1:2.4 1.5 h 72 (16)c a Reactions were run with 1.0 mmol of amine in 7.0 mL of CH Cl at
6 p-Br-C6H4-NH2 1:4.1 2h 78 (14)c 2 2

7 p-CN-C6H4-NH2 1:4 4h <20 (81)c ambient temperature. b NMR yield.

8 p-NO2-C6H4-NH2 1:4 48 h 0 (91)c
Scheme 1
a Reactions were run with 1.0 mmol of amine in 7.0 mL of CH2Cl2 at
ambient temperature. b NMR yields using Ph3CH as an internal standard.
c Single-insertion product yield given in parentheses.

fashion. Therefore, it was not necessary to add EDA and/or

amine slowly to the catalyst solution. This also indicated that
equivalents of EDA did not result in any double-insertion
Fe(TPP)Cl is not poisoned by coordination of amine. In contrast,
product of either substrate, indicating the reaction site may be
an amine poisoning effect was reported for a ruthenium
too sterically hindered after the initial insertion reaction. Single
porphyrin10a and a rhodium catalyst.14
insertion into 2,6-dimethylaniline was unsuccessful, also indicat-
Primary amines were able to undergo a double N-H insertion
ing that steric hindrance affects the reaction. Steric hindrance
reaction (Table 4) with excess EDA. The double-insertion
was also observed with 2,2,6,6-tetramethylpiperidine (Table 3,
product of aniline gives a four-proton NMR singlet at 4.14 ppm
entry 6).
for the methylene hydrogens of the two N-acetate groups,
exhibiting an upfield shift smaller than that observed for the Dimethyl diazomalonate (DMM) and methyl phenyldiazoac-
methylene fragment of the single-insertion product. This dual etate (MPDA) (Scheme 1) were also investigated as carbene
reaction could be done stepwise: first forming the single sources for insertion into aniline. Catalytic reactions with MPDA
insertion product and then introducing a second equivalent of and aniline gave a 92% yield of the N-H insertion product.
EDA by slow addition. Addition of 2 equiv of EDA to the This reaction required refluxing in methylene chloride for
substrate in one aliquot resulted mainly in the single-insertion 40 h, harsher conditions in comparison to the ambient temper-
product, low yields of double-insertion product, and more ature used for insertions with EDA. The 1H NMR spectrum of
dimeric side products. The second insertion is a slower reaction, the product showed a new one-proton singlet at 5.09 ppm for
allowing more dimer to form in these reactions in comparison the new malonyl methine hydrogen. Insertion reactions with
to the single-insertion reaction. Increasing the electron- DMM and aniline in refluxing benzene for 72 h yielded only a
withdrawing ability of the substituents on the aniline made the trace of the single-insertion product, as detected by GC-MS
second insertion more difficult and prolonged the reaction times. analysis: m/z 224 (M + 1), 104 (base peak).
When aminobenzonitrile was the substrate, the double-insertion Our group previously used Fe(TPP)Cl as a precatalyst for
product was observed in low yield, as monitored by GC and the cyclopropanation of olefins using EDA as both a reductant
GC-MS, but could not be isolated from the single-insertion and a carbene source.1c In the present study, a competition
product. No double-insertion product was formed when p- experiment between cyclopropanation of styrene and N-H
nitroaniline was the substrate (Table 4, entry 8), indicating that insertion of aniline was conducted. Equimolar amounts of
the strong electron-withdrawing effect of the nitro substituent aniline, styrene, and EDA were used with 1.0 mol % Fe(TPP)-
was reinforced by the first N-acetate fragment. Cl in methylene chloride. The reaction was run both at room
Reactions with N-heterocyclic compounds gave results sig- temperature and in refluxing methylene chloride. Under both
nificantly different from those of the aniline derivatives. With conditions, only the N-H insertion product was observed by
imidazole as the substrate, the N-H insertion product was GC-MS and 1H NMR. The preference for X-H insertion over
formed in 51% yield (eq 4). Under the same conditions, carbene cyclopropanation has been previously reported for ruthenium-
catalyzed N-H and S-H insertions,9b a rhodium-catalyzed
O-H insertion,16 and iron porphyrin and iron corrole catalyzed
N-H insertions.13
Mechanistic Considerations. Competition reactions were
undertaken to gain insight into the mechanism of the insertion
insertion from EDA occurred at the R-C-H bond of pyrrole in reaction. Para-substituted anilines were paired with aniline in
low yields, and no reaction was observed with indole. Carbene equimolar amounts and treated with EDA in the presence of
insertion from EDA into the C-H bond of pyrrole was Fe(TPP)Cl. Relative rate data are summarized in a Hammett
previously reported.15 Imidazole is more basic than pyrrole and plot (Figure 1). A better correlation was found with σ+ (R2 )
indole and is a better nucleophile for attack at the carbene 0.93) than with σ (R2 ) 0.88) or σ- (R2 ) 0.70), indicating
intermediate (vide infra). Several ortho-substituted anilines were that a partial positive charge develops in the transition state that
also evaluated (Table 5). A single insertion of carbene from is stabilized by resonance effects.17 Electron-donating groups
EDA into 2-chloroaniline gave a yield of 70%, and insertion on the aniline derivatives increased the reaction rate, as indicated
into 2-aminoacetophenone resulted in a 57% yield. Additional by a negative value of F (F ) -0.66 ( 0.05). This is consistent

(14) Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody, (16) Noels, A. F.; Demonceau, A.; Petiniot, N.; Hubert, A. J.; Theyssie,
C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem. Soc., Perkin Trans. 1 1996, P. Tetrahedron 1982, 2733.
2879. (17) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry: Part
(15) Marynoff, B. E. J. Org. Chem. 1979, 44, 4410. A, Structure and Mechanisms; Plenum: New York, 1990.
3998 Organometallics, Vol. 26, No. 16, 2007 Baumann et al.

Table 6. Dimerization of EDA by 1 mol % Iron Porphyrin

Complexes at 20 °C under N2a
DEM-
amine yield time to DEF
run cat. (amt (mol %)) (%)b completion ratio
1 FeIII(TPP)Cl 82 6h 33:1
2 FeIII(TPP)Cl pyridine (1) 94 20 min 6:1
3 FeIII(TPP)Cl pyridine (2) 95 20 min 6:1
4 FeIII(TPP)Cl pyridine (3) 93 20 min 6:1
5 [FeIII(TPP)py2]BF4 96 20 min 6:1
6 FeII(TPP) 94 50 min 32:1
7 FeII(TPP) pyridine (1) 56 16 h 11:1
8 FeII(TPP) pyridine (2) <2 16 h NA
9 FeIII(TPP)Cl 2,6-lutidine (1) 86 8h 31:1
10 FeIII(TPP)Cl 2,6-lutidine (2) 86 8h 30:1
11 FeIII(TPP)Cl 2,6-lutidine (3) 88 8h 32:1
12 FeII(TPP) 2,6-lutidine (1) 92 50 min 32:1
13 FeII(TPP) 2,6-lutidine (2) 93 50 min 36:1
a Reactions were run with 0.08 mmol of EDA in 5 mL of CH Cl . b NMR
2 2
yields using CHPh3 as an internal standard.

Figure 1. Hammett plot from competition reactions. silyl)diazomethane produced carbene complexes that have been
spectroscopically detected.1b,c An osmium analogue prepared
Scheme 2 from EDA, (TTP)OsdCHCO2Et, has been isolated and fully
characterized.19
A series of experiments indicate that reduction of the Fe(III)
does not appear to be necessary in the N-H insertion process
with EDA. For example, the insertion reactions could be done
in air with only a slight decrease in yield. In assessing a possible
prereduction step at ambient temperature, the Fe(TPP)Cl-
catalyzed decomposition of EDA was examined in the presence
and absence of tertiary amines that could coordinate to the
porphyrin complex but not undergo an N-H insertion. These
reactions were followed by 1H NMR with CHPh3 as an internal
standard. GC analysis was unreliable, as the temperature in the
with a nucleophilic attack of the amine on the electron-deficient injection port was sufficient to convert EDA to butenediolates
carbon of a putative carbene intermediate as the rate-determining in the absence of a catalyst. When no amine was added, EDA
effect. dimerized slowly (eq 5) in 6 h to form diethyl fumarate (DEF)
Competitive N-H/N-D experiments were undertaken to
measure the kinetic isotope effects on the insertion reaction.
The reaction of Et2NH and Et2ND (88.5% D) in a 1:1 molar
ratio was treated with a limiting amount of EDA with 1 mol %
Fe(TPP)Cl in C6D6 at ambient temperature. The resulting kinetic
product ratio was determined on a 700 MHz Bruker NMR
and diethyl maleate (DEM). When small amounts (1-3%) of
spectrometer by integrating the baseline-resolved methylene
amine were present, the reaction times were significantly
proton peaks of the products: Et2NCH2CO2Et (s) and Et2-
reduced to 20 min (Table 6). This indicated that the amine is
NCHDCO2Et (t). After correction for the percent H content in
important to the active Fe(III) catalytic species.
Et2ND, the measured kH/kD value was 1.41 ( 0.05. A similar
To probe further the nature of the catalytic species, a
competition experiment with aniline and aniline-d7 (98% D)
comparison of FeIII(TPP)Cl and FeII(TPP) was undertaken for
produced a comparable ratio: kH/kD ) 1.40 ( 0.04.
the dimerization of EDA. As shown in Table 6, FeII(TPP) is a
Initially, the catalytic cycle for N-H insertion was thought
more efficient catalyst (entry 6) than FeIII(TPP)Cl (entry 1),
to parallel the proposed mechanism for the cyclopropanation
promoting the formation of DEF and DEM in a shorter time in
of olefins by Fe(TPP)Cl, involving the reduction of Fe(III) to
the absence of amine with slightly higher yields, albeit with
Fe(II), as shown in Scheme 2.1c These cyclopropanation
similar product ratios. However, addition of 1% pyridine to FeIII-
reactions were done under an inert atmosphere to prevent
(TPP)Cl (py:Fe ) 1:1, entry 2) substantially enhanced the
oxidation of the iron(II) species. EDA is a mild reducing agent,18
catalytic rate of dimerization of EDA and improved the product
and we have proposed previously that EDA reduces FeIII
yields. In contrast, the addition of 1% pyridine to FeII(TPP) had
porphyrins to FeII porphyrins in refluxing methylene chloride.1c
the opposite effect (entry 7), degrading the reaction time by
After the reduction, the resulting FeII(TPP) is sufficiently
more than 16-fold and decreasing the yield by approximately
nucleophilic to displace N2 from the R-carbon of EDA to
half. In both cases, the DEM:DEF ratio also dropped signifi-
produce a reactive iron(II) carbene complex. The carbene ligand
cantly with the addition of 1% pyridine. Increasing the amount
is subsequently attacked by the amine, and proton migration
of pyridine above 1% in the Fe(III) system did not produce
from nitrogen to carbon produces the amino acid ester. While
any further changes (entries 3 and 4). Moreover, the previously
(TPP)FedCHCO2Et is very reactive and has not been detected,
the reaction of FeII(TTP) and mesityldiazomethane or (trimethyl- (19) (a) Woo, L. K.; Smith, D. A. Organometallics 1992, 11, 2344. (b)
Smith, D. A.; Reynolds, D. N.; Woo, L. K. J. Am. Chem. Soc. 1993, 115,
(18) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95, 3300. 2511.
Iron Porphryin Catalyzed N-H Insertion Reactions Organometallics, Vol. 26, No. 16, 2007 3999

Scheme 3 the rate-determining step is the addition of amine to the carbene

carbon. In addition, the hydrogen transfer step exhibits N-H/
N-D isotope effects, kH/kD ) 1.41 ( 0.05 (diethyl amine) and
1.40 ( 0.04 (aniline).
The N-glycine ester formed from the first insertion is less
nucleophilic than the original amine, resulting in a slower second
N-H insertion step. Since the second insertion process is less
competitive with carbene dimerization, stepwise addition of
EDA is necessary to optimize the formation of the double-
insertion product. Although it is possible that the N-H insertion
reactions catalyzed by the related Fe(III) corrole complexes13
may involve a similar mechanism, it is unclear what pathway
the corresponding Fe(IV) corrole compounds employ. Although
no induction period was reported for the Fe(IV) case, a
possibility involves reduction of the iron center from IV to III.

Conclusions
characterized Fe(III) bis(pyridine) complex [Fe(TPP)py2]BF420
catalyzed the decomposition of EDA (entry 5) in a manner Catalytic carbene insertion from EDA into N-H bonds
similar to that for the FeIII(TPP)Cl-pyridine system. However, mediated by Fe(TPP)Cl is a very efficient process. Fe(TPP)Cl
addition of 2% pyridine to FeII(TPP) (py:Fe ) 2:1, entry 8) appears to be among the best catalysts for insertion of EDA
drastically inhibited the dimerization of EDA. These results into amine N-H bonds, and insertion reactions could also be
indicate that if Fe(III) were reduced to Fe(II), the presence of performed at ambient temperatures and under atmospheric
pyridine would strongly inhibit its catalytic behavior. Thus, it conditions in relatively short reaction times. Aliphatic and
is highly likely that prereduction of Fe(III) is not necessary for aromatic amines were both shown to be good substrates, giving
catalytic carbene insertion from EDA into N-H bonds of high yields (>85%). Single- and double-insertion products were
amines. successfully obtained when primary amines were used as the
Additional support for ligand binding effects on the catalytic substrate. Unlike other reported N-H insertion catalysts, the
dimerization of EDA by FeIII(TPP)Cl was illustrated with 2,6- insertion reaction was faster than EDA dimerization and slow
lutidine (Table 6, entries 9-11). Since 2,6-lutidine is sterically addition of EDA is not necessary with Fe(TPP)Cl. Mechanistic
hindered and is a poor ligand for metalloporphyrins,21 no studies and comparisons with FeII(TPP) suggest that an Fe(III)
enhancement was expected as was observed when pyridine was form of the porphyrin complex is the active catalyst. Moreover,
added to a catalytic FeIII(TPP)Cl system. Indeed, the rate of FeIII(TPP)Cl has the advantages of not being poisoned by the
EDA dimerization by FeIII(TPP)Cl with 1-3 equiv of 2,6- amine, producing little of the dimerization side products from
lutidine was qualitatively the same as that by FeIII(TPP)Cl alone. EDA, and being commercially available and relatively inex-
In complementary experiments, addition of 1-2 equiv of 2,6- pensive.
lutidine to FeII(TPP) also had no effect on the catalytic
dimerization of EDA. Thus, the rate acceleration of EDA Experimental Section
dimerization on addition of pyridine must involve binding of
the amine to the metal center of FeIII(TPP)Cl. General Methods. EDA, solvents, and amines were used as
received, except as noted. Fe(TPP)Cl, Mn(TPP)Cl, Fe(TMeO-PP)-
The proposed mechanism for N-H insertion into aniline is Cl, and Fe(TPFPP)Cl were all used as received. Os(TTP)(CO),23
shown in Scheme 3. In the presence of unhindered bases, Fe- Fe(saldach)Cl,24 and Zn(TPP)25 were prepared according to literature
(TPP)Cl typically forms bis(amine) complexes, [(TPP)FeL2]+.22 procedures. Co(TTP) was prepared using a modified literature
Dissociation of a ligand produces a five-coordinate mono(amine) procedure.26 DMM27 and MPDA28 were synthesized by following
species that has sufficient electron density and an open literature procedures. Aniline was distilled from CaH2 under reduced
coordination site at the metal center so that a six-coordinate pressure. Diethylamine was distilled from KOH pellets. The reaction
Fe(III) porphyrin carbene complex can be produced readily. progress and competition reactions were monitored by gas chro-
Formation of the carbene complex is extremely rapid, as is matography on a HP5890 Series II Plus gas chromatograph using
evident by the notable evolution of gas on addition of EDA to a HP-5 cross-linked 5% PH ME silicone column, with 30 m ×
the reaction flask. In the absence of amine, formation of a 0.32 mm × 0.25 µm film thickness. 1H and 13C spectra were
carbene complex directly from Fe(TPP)Cl is unfavorable. The obtained in CDCl3 on a Varian VXR-300 spectrometer. MS analysis
carbene carbon then undergoes nucleophilic attack by an was done on a Finnigan Magnum GC-MS. Elemental analyses for
additional amine to form the insertion product. The amine new compounds were performed on a Perkin-Elmer Model 2400
nitrogen is more nucleophilic than EDA, and single N-H Series II CHN/S elemental analyzer. Fe(TMP)Cl was prepared
insertion occurs faster than dimerization. Moreover, the qualita-
tive variation of rates as a function of the amine indicated that (23) Buchler, J. W.; Kuenzel, B. M. Z. Anorg. Allg. Chem. 1994, 620,
888.
(24) Bottcher, A.; Grinstaff, M. W.; Labinger, J. A.; Gray, H. B. J. Mol.
(20) Reed, C. A.; Mashiko, T.; Bentley, S. P.; Kastner, M. E.; Scheidt, Catal. A: Chem. 1996, 113, 191.
W. R.; Spartalian, K.; Lang, G. J. Am. Chem. Soc. 1979, 101, 2948. (25) Fuhrhop, J.-H.; Smith, K. M. In Porphyrins and Metalloporphy-
(21) (a) Retsek, J. L.; Drain, C. M.; C. K.; Nurco, D. J.; Medforth, C. J.; rins: A New Edition Based on the Original Volume by J. E. Falk; Smith,
Smith, K. M.; Sazanovich, I. V.; Chirvony, V. S.; Fajer, J.; Holten, D. J. K. M., Ed.; Elsevier: Amsterdam, 1975; p 798.
Am. Chem. Soc. 2004, 125, 9787. (b) Mohajer, D.; Karimipoura, G.; (26) Dorough, G. D.; Miller, J. R.; Huennekens, F. M. J. Am. Chem.
Bagherzadeh, M. New J. Chem. 2004, 28, 740. Soc. 1951, 73, 4315.
(22) (a) Walker, F. A.; Lo, M.-W.; Ree, M. T. J. Am. Chem. Soc. 1976, (27) Peace, B. W.; Carman, F.; Wulfman, D. S. Synthesis 1971, 12, 658.
98, 5552. (b) Satterlee, J. D.; La Mar, G. N.; Frye, J. S. J. Am. Chem. Soc. (28) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc.
1976, 98, 7275. 2000, 122, 3063.
4000 Organometallics, Vol. 26, No. 16, 2007 Baumann et al.

according to a literature procedure29 and then reduced with Zn/Hg 14.5, 50.3, 53.5, 60.9, 127.4, 128.5, 128.7, 139.7, 172.6. MS
in toluene. [Fe(TPP)py2]BF4 was synthesized as reported previ- (m/z): 194 (M + 1), 91 (base peak). Spectral results match reported
ously.20 values.6
General Procedure for Single-Insertion Reactions (Method Synthesis of PhCH2N(CH2CO2CH2CH3)2. Procedure B was
A). In a typical experiment, an amine (0.250-1.0 mmol) was followed using an overall amine to EDA ratio of 1:3 and a total
dissolved in 5 mL of methylene chloride in a 25 mL round-bottom reaction time of 15 min: benzylamine (60.9 mg, 0.568 mmol), EDA
flask. Fe(TPP)Cl (0.0025-0.010 mmol, 1 mol %) was added, and (218.4 mg, 1.92 mmol), and Fe(TPP)Cl (3.8 mg, 0.0054 mmol). A
nitrogen was bubbled through the solution for 20 min. Ethyl yellow-green oil was obtained (153.5 mg). 1H NMR (δ, ppm): 1.29
diazoacetate (EDA; 1.20 equiv, 0.275-1.20 mmol) in 2 mL of CH2- (t, 6H, OCH2CH3), 3.59 (s, 4H, NCH2CO), 3.96 (s, 2H, PhCH2N),
Cl2 was added in one aliquot, and the reaction mixture was stirred 4.20 (q, 4H, OCH2CH3), 7.21-7.37 (m, 5H, C6H5). 13C NMR (δ,
for 10 min. Almost immediate release of N2 was evident in most ppm): 14.2, 54.2, 57.8, 60.4, 127.3, 128.3, 129.0, 138.1, 171.1.
reactions. Upon completion of the reaction, as indicated by GC
MS (m/z): 280 (M + 1), 206 (base peak). Spectral results match
analysis, the solvent was removed in vacuo and the reaction yield
those of the commercially available compound from Aldrich.
was determined by 1H NMR with triphenylmethane as an internal
standard. Products were purified by column chromatography on Synthesis of p-CH3O-C6H4-NH(CH2CO2CH2CH3). Anisidine
silica gel (2.5 cm × 11 cm) and eluted with hexane-ethyl acetate (123.3 mg, 1.001 mmol) was treated with EDA (128.7 mg, 1.128
(10:1) unless specified otherwise. mmol) and Fe(TPP)Cl (6.5 mg, 0.0092 mmol) using method A. A
General Procedure for Double-Insertion Reactions (Method white solid (125.0 mg) was isolated. 1H NMR (δ, ppm): 1.29 (t,
B). The single-insertion product was formed using the reaction 3H, OCH2CH3), 3.74 (s, 3H, CH3O), 3.86 (s, 2H, NCH2CO), 4.23
conditions described above. An additional 1.20 equiv of EDA in 2 (q, 2H, OCH2CH3), 6.59 (d, 2H, C6H4), 6.79 (d, 2H, C6H4), NH
mL of CH2Cl2 was added by syringe over 1 min, and the reaction not observed. 13C NMR (δ, ppm): 14.2, 46.8, 55.7, 61.2, 114.4,
mixture was stirred for an additional 1 h and monitored by GC. 114.9, 141.2, 152.6, 171.4. MS (m/z): 209 (M). Anal. Calcd: C,
Upon completion of the reaction, the solvent was removed in vacuo 63.14; H, 7.23; N, 6.70. Found: C, 63.16; H, 7.25; N, 6.99.
and the reaction mixture was analyzed by 1H NMR with triphenyl- Synthesis of p-CH3O-C6H4-N(CH2CO2CH2CH3)2. A yellow-
methane as an internal standard. Products were purified by column orange oil (245.7 mg) was obtained using method B: p-anisidine
chromatography (2.5 cm × 11 cm) on silica gel and eluted with (126.7 mg, 1.029 mmol), EDA (235.7 mg, 2.854 mmol), and Fe-
hexane-ethyl acetate (10:1) unless specified otherwise. (TPP)Cl (7.5 mg, 0.011 mmol). 1H NMR (δ, ppm): 1.26 (t, 6H,
General Procedure for Competition Reactions. Equimolar OCH2CH3), 3.73 (s, 3H, OCH3), 4.10 (s, 4H, NCH2CO), 4.20 (q,
quantities (0.300 mmol) of aniline and an aniline derivative and 4H, OCH2CH3), 6.61 (m, 2H, C6H4), 6.80 (m, 2H, C6H4). 13C NMR
Fe(TPP)Cl (0.0030 mmol) in 4 mL of methylene chloride were (δ, ppm): 14.2, 54.0, 55.6, 60.9, 114.4, 114.7, 142.3, 152.6, 171.1.
stirred under nitrogen. EDA (0.300 mmol) in 2 mL of methylene MS (m/z): 295 (M). Anal. Calcd: C, 61.00; H, 7.17; N, 4.74.
chloride was added by syringe in one aliquot. After 5 min, a sample Found: C, 60.32; H, 7.70; N, 5.27.
was removed and the ratio of product yields was determined by
Synthesis of p-CH3-C6H4-NH(CH2CO2CH2CH3). A white solid
gas chromatography using dodecane as an internal standard.
(86.8 mg) was obtained using method A: toluidine (53.5 mg, 0.499
Synthesis of Et2NCH2CO2CH2CH3. Method A was followed
mmol), EDA (65.6 mg, 0.575 mmol), and Fe(TPP)Cl (3.7 mg,
using diethylamine (43.7 mg, 0.597 mmol), EDA (83.5 mg, 0.732
0.0053 mmol). 1H NMR (δ, ppm): 1.29 (t, 3H, OCH2CH3), 2.24
mmol), and Fe(TPP)Cl (4.2 mg, 0.0060 mmol). A yellow oil was
(s, 3H, CH3C6H4), 3.88 (s, 2H, NCH2CO), 4.24 (q, 2H, OCH2-
isolated (74.0 mg). 1H NMR (δ, ppm): 1.02 (t, 6H, NCH2CH3),
CH3), 6.53 (m, 2H, C6H4), 7.00 (d, 2H, C6H4), NH not observed.
1.27 (t, 3H, OCH2CH3), 2.61 (q, 4H, CH2CH3), 3.27 (s, 2H, NCH2- 13C NMR (δ, ppm): 14.2, 20.4, 46.2, 61.2, 113.1, 127.4, 129.8,
CO), 4.14 (q, 2H, OCH2CH3). 13C NMR (δ, ppm): 12.4 (NCH2CH3),
14.5 (OCH2CH3), 48.0 (NCH2CH3), 54.5 (NCH2CO), 60.6 (OCH2- 144.8, 171.3. MS (m/z): 193 (M + 1). Spectral results match
CH3), 171.8 (CO). MS (m/z): 160 (M + 1). Anal. Calcd: C, 60.34; reported values.6
H, 10.76; N, 8.80. Found: C, 60.26; H, 10.83; N, 8.42. Synthesis of p-CH3-C6H4-N(CH2CO2CH2CH3)2. A yellow oil
Synthesis of t-BuNH(CH2CO2CH2CH3). A yellow oil (87.9 mg) (405.3 mg) was isolated using method B; toluidine (206.7 mg, 1.929
was obtained using method A with tert-butylamine (75.8 mg, 1.04 mmol), EDA (500.1 mg, 4.383 mmol), and Fe(TPP)Cl (12.8 mg,
mmol), EDA (126.6 mg, 1.11 mmol), and Fe(TPP)Cl (7.4 mg, 0.011 0.0182 mmol). 1H NMR (δ, ppm): 1.30 (t, 6H, OCH2CH3), 2.27
mmol). 1H NMR (δ, ppm): 1.11 (s, 9H, CCH3), 1.28 (t, 3H, (s, 3H, CH3C6H5), 4.15 (s, 4H, NCH2CH3), 4.24 (q, 4H, OCH2-
OCH2CH3), 1.7 (broad, NH), 3.40 (s, 2H, NCH2CO), 4.19 (q, 2H, CH3), 6.59 (d, 2H, C6H4), 7.07 (d, 2H, C6H4). 13C NMR (δ, ppm):
OCH2CH3). 13C NMR (δ, ppm): 14.3 (CCH3), 28.9, 45.0, 50.3, 14.2, 54.0, 55.6, 60.9, 114.4, 114.7, 142.3, 152.6, 171.1. MS (m/
60.9, 173.1 (CO). MS (m/z): 160 (M + 1). Spectral results match z): 279 (M), 206 (base peak). Anal. Calcd: C, 64.49; H, 7.58; N,
reported values.6 5.02. Found: C, 63.93; H, 7.70; N, 5.41.
Synthesis of C5H10NCH2CO2CH2CH3. A yellow oil (83.0 mg) Synthesis of C6H5-NH(CH2CO2CH2CH3). A yellow oil (115.0
was obtained using method A with piperidine (48.7 mg, 0.572 mg) was obtained using method A: aniline (68.7 mg, 0.738 mmol),
mmol), EDA (78.3 mg, 0.687 mmol), and Fe(TPP)Cl (3.5 mg, EDA (99.7 mg, 0.874 mmol), and Fe(TPP)Cl (4.0 mg, 0.0057
0.0050 mmol). 1H NMR (δ, ppm): 1.27 (t, 3H, OCH2CH3), 1.43 mmol). 1H NMR (δ, ppm): 1.30 (t, 3H), 3.91 (s, 2H), 4.25 (q,
(m, 2H, C5H10), 1.62 (m, 4H, C5H10), 2.50 (m, 4H, C5H10), 3.17 (s, 2H), 6.65 (d, 2H), 6.77 (t, 1H), 7.21 (t, 2H), NH not observed. 13C
2H, NCH2CO), 4.18 (q, 2H, OCH2CH3). 13C NMR (δ, ppm): 14.3, NMR (δ, ppm): 14.1, 45.8, 61.2, 112.9, 118.1, 129.2, 146.9, 171.0.
23.9, 25.8, 54.4, 60.4, 60.5, 170.7. MS (m/z): 172 (M + 1), 98 MS (m/z): 180 (M + 1, base peak). Spectral results match reported
(base peak). Spectral results match reported values.6 values.6
Synthesis of PhCH2NH(CH2CO2CH2CH3). A yellow oil (164.2
mg) was obtained using method A with benzylamine (124.8 mg, Synthesis of C6H5-N(CH2CO2CH2CH3)2. A yellow oil (106.4
1.16 mmol), EDA (148.0 mg, 1.30 mmol), and Fe(TPP)Cl (7.5 mg, mg) was isolated using method B with an overall amine to EDA
0.011 mmol). 1H NMR (δ, ppm): 1.27 (t, 3H, OCH2CH3), 1.85 (s, ratio of 1:2.9 and a reaction time of 2 h after the second addition
1H, NH), 3.41 (s, 2H, NCH2CO), 3.81 (s, 2H, PhCH2N), 4.19 (q, of EDA: aniline (47.1 mg, 0.506 mmol), EDA (169.5 mg, 1.485
2H, OCH2CH3), 7.27-7.34 (m, 5H, C6H5). 13C NMR (δ, ppm): mmol), and Fe(TPP)Cl (3.5 mg, 0.0050 mmol). 1H NMR (δ,
ppm): 1.28 (t, 6H, OCH2CH3), 4.14 (s, 4H, NCH2CO), 4.22 (q,
(29) Kobayashi, H.; Higuchi, T.; Kaizu, Y.; Osada, J.; Aoki, M. Bull. 4H, OCH2CH3), 6.60-6.65 (m, 2H, C6H5), 6.75-6.80 (m, 1H,
Chem. Soc. Jpn. 1975, 48, 3137. C6H5), 7.19-7.25 (m, 2H, C6H5). 13C NMR (δ, ppm): 14.0, 53.3,
Iron Porphryin Catalyzed N-H Insertion Reactions Organometallics, Vol. 26, No. 16, 2007 4001

60.9, 112.3, 118.0, 129.1, 147.7, 170.7. MS (m/z): 265 (M). Anal. z): 224 (M), 151 (base peak). Anal. Calcd: C, 53.56; H, 5.39; N,
Calcd: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.17; H, 7.68; N, 12.50. Found: C, 53.20; H, 5.58; N, 12.35.
5.57. Insertion into Imidazole. A yellow oil (157.4 mg) was obtained
Synthesis of p-Cl-C6H4-NH(CH2CO2CH2CH3). A pale yellow using method A, with the reaction being complete in 48 h:
solid (42.4 mg) was isolated using method A: p-chloroaniline (63.3 imidazole (135.4 mg, 1.989 mmol), EDA (321.7 mg, 2.819 mmol),
mg, 0.496 mmol), EDA (57.3 mg, 0.502 mmol), and Fe(TPP)Cl and Fe(TPP)Cl (13.3 mg, 0.019 mmol). The chromatography eluent
(3.7 mg, 0.0053 mmol). 1H NMR (δ, ppm): 1.30 (t, 3H, OCH2CH3), was 10:1 ethyl acetate-methanol. 1H NMR (δ, ppm): 1.26 (t, 3H,
3.88 (s, 2H, NCH2CO), 4.25 (q, 2H, OCH2CH3), 6.52-6.56 (m, OCH2CH3), 4.21 (q, 2H, OCH2CH3), 4.66 (s, 2H, NCH2CO), 6.93
2H, C6H4), 7.12-7.16 (m, 2H, C6H4), NH not observed. 13C NMR (s, 1H, CdCH), 7.06 (s, 1H, CdCH), 7.47 (s, 1H, NCHN). 13C
(δ, ppm): 14.2, 45.9, 61.5, 114.1, 122.9, 129.1, 145.5, 170.8. MS NMR (δ, ppm): 14.3, 48.3, 62.3, 120.2, 129.9, 138.1, 167.6. MS
(m/z): 213 (M), 140 (base peak). Spectral results match reported (m/z): 154 (M), 81 (base peak). Anal. Calcd: C, 54.53; H, 6.54;
values.6 N, 18.17. Found: C, 54.12; H, 6.58; N, 18.17.
Insertion of MPDA into Aniline. A yellow-white solid (69.6
Synthesis of p-Cl-C6H4-N(CH2CO2CH2CH3)2. A yellow oil
mg, 92% yield) was prepared using method A, except that the
(91.8 mg) was isolated using method B: p-chloroaniline (64.4 mg,
reaction solution was refluxed: aniline (29.2 mg, 0.314 mmol),
0.505 mmol), EDA (140.0 mg, 1.227 mmol), and Fe(TPP)Cl (3.5
MPDA (63.9 mg, 0.363 mmol). The reaction was complete in
mg, 0.0050 mmol). 1H NMR (δ, ppm): 1.28 (t, 6H, OCH2CH3),
40 h. The chromatography eluent was 10:1 hexane-ethyl acetate.
4.10 (s, 4H, NCH2CO), 4.21 (q, 4H, OCH2CH3), 6.54 (d, 2H, C6H4), 1H NMR (δ, ppm): 3.74 (s, 3H, CH ), 4.97 (s, 1H, NH), 5.09 (s,
3
7.16 (d, 2H, C6H4). 13C NMR (δ, ppm): 14.4, 53.8, 61.4, 114.0,
1H, NCHCO), 6.57 (d, 2H, C6H5), 6.71 (t, 1H, C6H5), 7.13 (t, 2H,
123.4, 129.3, 146.8, 170.7. MS (m/z): 299 (M), 154 (base peak).
C6H5), 7.35 (m, 3H, C6H5), 7.51 (dd, 2H, C6H5). 13C NMR (δ,
Anal. Calcd: C, 56.09; H, 6.05; N, 4.67. Found: C, 55.69; H, 6.49;
ppm): 52.8, 60.7, 113.4, 118.1, 127.2, 128.3, 128.8, 129.2, 137.6,
N, 4.92.
145.9, 172.3. MS (m/z): 242 (M + 1), 121 (base peak).
Synthesis of p-Br-C6H4-NH(CH2CO2CH2CH3). A pale yellow General Procedure for Dimerization of EDA using Fe(TPP)-
solid (183.6 mg) was obtained using method A: p-bromoaniline Cl. In a typical experiment, Fe(TPP)Cl (1.1 mg, 0.0015 mmol) was
(153.9 mg, 0.8947 mmol), EDA (108.1 mg, 0.9473 mmol), and dissolved in 2 mL of deuterated methylene chloride and the mixture
Fe(TPP)Cl (6.5 mg, 0.0092 mmol). 1H NMR (δ, ppm): 1.30 (t, stirred under nitrogen. From a pyridine or a 2,6-lutidine stock
3H, OCH2CH3), 3.86 (s, 2H, NCH2CO), 4.25 (q, 2H, OCH2CH3), solution (0.018 mmol/mL of CD2Cl2), an appropriate volume was
6.49 (d, 2H, C6H4), 7.27 (d, 2H, C6H4), NH not observed. 13C NMR added to the Fe(TPP)Cl mixture to produce the required catalyst
(δ, ppm): 14.2, 45.7, 61.5, 109.9, 114.5, 132.0, 146.0, 170.6. MS to amine ratio. EDA (18 mg, 0.15 mmol) in 1 mL of deuterated
(m/z): 258 (M + 1). Anal. Calcd: C, 46.53; H, 4.69; N, 5.43. methylene chloride was added by syringe in one aliquot. The
Found: C, 46.65; H, 4.79; N, 5.57. progress of the reactions was monitored by 1H NMR spectroscopy.
Synthesis of p-Br-C6H4-N(CH2CO2CH2CH3)2. A yellow oil Triphenylmethane (24 mg, 0.1 mmol) was used as an internal
(208.8 mg) was isolated using method B with an overall amine to standard to determine the yields.
EDA ratio of 1:4.1 and a reaction time of 24 h after the second General Procedure for Dimerization of EDA using FeII(TPP).
addition of EDA: p-bromoaniline (143.3 mg, 0.8330 mmol), EDA In a typical experiment, Fe(TPP)Cl (2.1 mg, 0.0030 mmol) was
(389.3 mg, 3.412 mmol), and Fe(TPP)Cl (5.4 mg, 0.0077 mmol). dissolved in 2 mL of THF and excess Zn/Hg amalgam (6-8 mg)
1H NMR (δ, ppm): 1.27 (t, 6H, OCH CH ), 4.09 (s, 4H, NCH - added in a glovebox. This mixture was stirred overnight (about
2 3 2
CO), 4.21 (q, 4H, OCH2CH3), 6.49 (d, 2H, C6H4), 7.29 (d, 2H, 16 h). The resulting solution was then filtered through a fine frit to
C6H4). 13C NMR (δ, ppm): 14.2, 53.6, 61.2, 110.4, 114.2, 131.9, remove the Zn/Hg amalgam. The solvent was removed under
146.9, 170.5. MS (m/z): 343 (M - 1), 59 (base peak). Anal. reduced pressure. The resulting Fe(TPP) was then redissolved in 2
Calcd: C, 48.85; H, 5.27; N, 4.07. Found: C, 48.38; H, 5.84; N, mL of deuterated methylene chloride. From this solution, an
3.90. appropriate volume of Fe(TPP) (0.0008 mmol) was measured and
Synthesis of p-CN-C6H4-NH(CH2CO2CH2CH3). A pale yellow placed in a 5 mL round-bottom flask. From a pyridine or a 2,6-
solid (166.2 mg) was obtained using method A and a reaction time lutidine stock solution (0.018 mmol/mL of CD2Cl2), an appropriate
of 20 min with p-cyanoaniline (110.5 mg, 0.9353 mmol), EDA volume was added to the Fe(TPP)Cl mixture to produce the required
(123.4 mg, 1.081 mmol), and Fe(TPP)Cl (7.0 mg, 0.0099 mmol). catalyst to amine ratio. EDA (9.0 mg, 0.08 mmol) in 1 mL of
The chromatography eluent was 5:1 hexane-ethyl acetate. 1H NMR deuterated methylene chloride was added by syringe in one aliquot.
(δ, ppm): 1.29 (t, 3H, OCH2CH3), 3.90 (s, 2H, NCH2CO), 4.25 The progress of the reactions was monitored by 1H NMR
(q, 2H, OCH2CH3), 6.55 (d, 2H, C6H4), 7.42 (d, 2H, C6H4), NH spectroscopy. Triphenylmethane (12 mg, 0.05 mmol) was used as
not observed. 13C NMR (δ, ppm): 14.1, 44.7, 61.7, 99.6, 112.4, an internal standard to determine the yields.
120.1, 133.6, 150.0, 169.9. MS (m/z): 204(M), 131 (base peak). Et2N-D. N-deuterated diethylamine was prepared by three
Anal. Calcd: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.64; H, fractional distillations of a mixture of the amine and a 10-fold molar
6.12; N, 13.89. excess of D2O using a 20 cm Vigreux column.30 The product was
dried and distilled from calcium hydride. The percent deuteration
Synthesis of p-CN-C6H4-N(CH2CO2CH2CH3)2. Procedure B
was determined by reaction with excess EDA to form monodeu-
was followed using an overall amine to EDA ratio of 1:4 and a
terated Et2NCHDCO2Et catalyzed by Fe(TPP)Cl in CD2Cl2. Re-
reaction time of 4 h after the second addition of EDA. This reaction
sidual H-N protons resulted in the production of Et2NCH2CO2Et,
had a low double-insertion yield (<20%), and the desired product
and amounts of the d0/d1 products could be quantitatively measured
could not be isolated from the single-insertion product. MS (m/z):
by 1H NMR at 700 MHz by integration of the baseline-separated
290 (M+), 217 (base peak).
N-methylene signals. A d1/d0 product ratio of 7.72:1 was obtained
Synthesis of p-NO2-C6H4-NH(CH2CO2CH2CH3). A yellow (88.5 atom % d). Aniline-d7 was obtained from Aldrich and used
solid (200.6 mg) was obtained using method A, requiring 18 h: as received.
p-nitroaniline (141.0 mg, 1.02 mmol), EDA (128 mg, 1.12 mmol), Kinetic Isotope Effect. C6D6 was dried by stirring with
and Fe(TPP)Cl (7.2 mg, 0.010 mmol). The chromatography eluent phosphorus pentoxide for 18 h in a sealed Schlenk tube under
was 5:1 hexane-ethyl acetate. 1H NMR (δ, ppm): 1.33 (t, 3H, reduced pressure. Using vacuum line techniques, ca. 0.6 mL of
OCH2CH3), 3.98 (s, 2H, NCH2CO), 4.29 (q, 2H, OCH2CH3), 6.56
(d, 2H, C6H4), 8.12 (d, 2H, C6H4), NH not observed. 13C NMR (δ, (30) Garcia-Rio, L.; Leis, J. R.; Moreira, J. A.; Serantes, D. Eur. J. Org.
ppm): 14.4, 45.1, 62.2, 111.7, 126.6, 139.1, 152.1, 169.9. MS (m/ Chem. 2004, 3, 614.
4002 Organometallics, Vol. 26, No. 16, 2007 Baumann et al.

dry C6D6 was added by trap-to-trap distillation to a dry 20 mL Bruker NMR spectrometer by integrating the baseline-resolved
round-bottom flask containing Fe(TPP)Cl (0.5 mg, 0.07 µmol) and methylene proton peaks of the products, Et2NCH2CO2Et (s) and
a magnetic bar. The flask was warmed to ambient temperature, Et2NCHDCO2Et (t). A similar procedure was used for deuterated
back-filled with dry nitrogen, and immediately capped using a aniline. The kinetic isotope effect was determined from averaging
rubber septum under a positive flow of N2. Diethylamine (10.0 µL, the results of three separate reactions.
7.07 mg, 96.7 µmol) and diethylamine-N-d (10.0 µL, 7.07 mg,
96.6 µmol, 88.5 atom % D) were added to the stirred solution using
Acknowledgment. We gratefully acknowledge funding from
a gastight syringe. To initiate the reaction, a limiting amount of
the Petroleum Research Fund and the National Science
ethyl diazoacetate (10.0 µL, 8.50 mg, 74.6 µmol) was added by
Foundation.
syringe. The resulting contents were transferred to an NMR tube,
and the kinetic ratio of products was determined on a 700 MHz OM0610997